# AMR release; corpus: bio; section: training; number of AMRs: 5452 (generated on Mon Mar 14, 2016 at 21:45:05)

# ::id a_pmid_2094_2929.7 ::date 2015-05-20T09:19:50 ::annotator SDL-AMR-09 ::preferred
# ::snt 1- RT-PCR and western blot analyses confirmed the strong up-regulation of serpinE2 expression and secretion by IECs expressing oncogenic MEK, Ras or BRAF.
# ::save-date Sun Jan 17, 2016 ::file a_pmid_2094_2929_7.txt
(c / confirm-01 :li 1
      :ARG0 (a / and
            :op1 (a2 / analyze-01
                  :instrument (t / thing :name (n4 / name :op1 "RT-PCR")))
            :op2 (i / immunoblot-01))
      :ARG1 (a4 / and
            :op1 (u / upregulate-01
                  :ARG1 (e3 / express-03
                        :ARG2 (p / protein :name (n6 / name :op1 "serpinE2")))
                  :ARG1-of (s / strong-02))
            :op2 (s2 / secrete-01
                  :ARG0 (c2 / cell :name (n7 / name :op1 "IEC")
                        :ARG3-of (e4 / express-03
                              :ARG2 (o2 / or
                                    :op1 (e / enzyme :name (n2 / name :op1 "MEK"))
                                    :op2 (e2 / enzyme :name (n3 / name :op1 "Ras"))
                                    :op3 (e5 / enzyme :name (n8 / name :op1 "BRAF"))
                                    :ARG0-of (c3 / cause-01
                                          :ARG1 (d / disease :wiki "Cancer" :name (n / name :op1 "cancer"))))))
                  :ARG1 p)))

# ::id a_pmid_2094_2929.8 ::date 2015-05-20T10:16:34 ::annotator SDL-AMR-09 ::preferred
# ::snt 2- Interestingly, serpinE2 mRNA and protein were also markedly enhanced in human CRC cells exhibiting mutation in <i>KRAS </i>and <i>BRAF</i>.
# ::save-date Sun Jan 17, 2016 ::file a_pmid_2094_2929_8.txt
(e / enhance-01 :li 2
      :ARG1 (a3 / and
            :op1 (n6 / nucleic-acid :name (n / name :op1 "mRNA")
                  :ARG0-of (e2 / encode-01
                        :ARG1 p))
            :op2 (p / protein :name (n2 / name :op1 "serpinE2")))
      :manner (m / marked)
      :mod (a2 / also)
      :location (c / cell
            :ARG0-of (e3 / exhibit-01
                  :ARG1 (m2 / mutate-01
                        :ARG1 (a4 / and
                              :op1 (g / gene :name (n4 / name :op1 "KRAS"))
                              :op2 (g2 / gene :name (n5 / name :op1 "BRAF")))))
            :mod (h / human)
            :mod (d / disease :name (n3 / name :op1 "CRC")))
      :manner (i / interesting))

# ::id a_pmid_2094_2929.9 ::date 2015-05-20T10:25:33 ::annotator SDL-AMR-09 ::preferred
# ::snt 3- RNAi directed against serpinE2 in caMEK-transformed rat IECs or in human CRC cell lines HCT116 and LoVo markedly decreased foci formation, anchorage-independent growth in soft agarose, cell migration and tumor formation in nude mice.
# ::save-date Fri Feb 12, 2016 ::file a_pmid_2094_2929_9.txt
(d / decrease-01 :li 3
      :ARG0 (i2 / interfere-01
            :ARG1 (n / nucleic-acid :name (n11 / name :op1 "RNA"))
            :ARG1-of (d2 / direct-01
                  :ARG2 (o2 / oppose-01
                        :ARG1 (o / or
                              :op1 (p / protein :name (n2 / name :op1 "serpinE2")
                                    :location (c / cell :name (n3 / name :op1 "IEC")
                                          :mod (r / rat)
                                          :ARG1-of (t / transform-01
                                                :ARG0 (e / enzyme :name (n4 / name :op1 "MEK")
                                                      :ARG2-of (m5 / mutate-01)
                                                      :mod (c3 / constitutive)
                                                      :ARG1-of (a4 / activate-01)))))
                              :op2 (p2 / protein :name (n5 / name :op1 "serpinE2")
                                    :location (c6 / cell
                                          :ARG2-of (i / include-91
                                                :ARG1 (a3 / and
                                                      :op1 (c2 / cell-line :name (n6 / name :op1 "HCT116"))
                                                      :op2 (c4 / cell-line :name (n8 / name :op1 "LoVo"))))
                                          :mod (h / human)
                                          :mod (d4 / disease :name (n10 / name :op1 "CRC"))))))))
      :ARG1 (a / and
            :op1 (f / form-01
                  :ARG1 (f2 / focus))
            :op2 (g / grow-01
                  :ARG1-of (d3 / depend-01 :polarity -
                        :ARG0 (a2 / anchorage))
                  :location (a5 / agarose
                        :ARG1-of (s / soft-02)))
            :op3 (m3 / migrate-01
                  :ARG0 (c5 / cell))
            :op4 (f3 / form-01
                  :ARG1 (t2 / tumor)
                  :location (m4 / mouse
                        :mod (n9 / nude))))
      :manner (m2 / marked))

# ::id a_pmid_2094_2929.10 ::date 2015-05-20T10:50:46 ::annotator SDL-AMR-09 ::preferred
# ::snt 4- Treatment of CRC cell lines with U0126 markedly reduced <i>serpinE2 </i>mRNA levels, indicating that expression of <i>serpinE2 </i>is likely dependent of ERK activity.
# ::save-date Sun Jan 17, 2016 ::file a_pmid_2094_2929_10.txt
(r / reduce-01 :li 4
      :ARG0 (t / treat-04
            :ARG1 (c / cell-line
                  :mod (d2 / disease :name (n3 / name :op1 "CRC")))
            :ARG2 (s / small-molecule :name (n / name :op1 "U0126")))
      :ARG1 (l / level
            :quant-of (n6 / nucleic-acid :name (n4 / name :op1 "mRNA")
                  :ARG0-of (e2 / encode-01
                        :ARG1 (p / protein :name (n5 / name :op1 "serpinE2")))))
      :manner (m / marked)
      :ARG0-of (i / indicate-01
            :ARG1 (l2 / likely-01
                  :ARG1 (d / depend-01
                        :ARG0 (e3 / express-03
                              :ARG2 p)
                        :ARG1 (a / activity-06
                              :ARG0 (e / enzyme :name (n2 / name :op1 "ERK")))))))

# ::id a_pmid_2094_2929.11 ::date 2015-05-20T11:37:23 ::annotator SDL-AMR-09 ::preferred
# ::snt 5- Finally, Q-PCR analyses demonstrated that mRNA levels of serpinE2 were markedly increased in human adenomas in comparison to healthy adjacent tissues and in colorectal tumors, regardless of tumor stage and grade.
# ::save-date Thu Jan 7, 2016 ::file a_pmid_2094_2929_11.txt
(d / demonstrate-01 :li 5 :li "-1"
      :ARG0 (a / analyze-01
            :mod (t / thing :name (n / name :op1 "Q-PCR")))
      :ARG1 (i / increase-01
            :ARG1 (l / level
                  :quant-of (n4 / nucleic-acid :name (n2 / name :op1 "mRNA")
                        :ARG0-of (e / encode-01
                              :ARG1 (p / protein :name (n3 / name :op1 "serpinE2")))))
            :location (a2 / and
                  :op1 (a3 / adenomas
                        :mod (h / human))
                  :op2 (t3 / tumor
                        :mod (c / colon)))
            :ARG1-of (r / regardless-91
                  :ARG2 (a5 / and
                        :op1 (t5 / thing
                              :ARG2-of (s / stage-02
                                    :ARG1 (t4 / tumor)))
                        :op2 (g / grade
                              :mod t4)))
            :manner (m / marked)
            :compared-to (t2 / tissue
                  :mod (a4 / adjacent)
                  :mod (h2 / healthy))))

# ::id a_pmid_2094_2929.39 ::date 2015-05-20T11:47:11 ::annotator SDL-AMR-09 ::preferred
# ::snt SerpinE2 is overexpressed in intestinal epithelial cells transformed by activated MEK1 and oncogenic RAS and BRAF
# ::save-date Thu Dec 17, 2015 ::file a_pmid_2094_2929_39.txt
(o / overexpress-01
      :ARG1 (p / protein :name (n2 / name :op1 "serpinE2"))
      :location (c / cell
            :mod (e2 / epithelium)
            :part-of (i / intestine)
            :ARG1-of (t / transform-01
                  :ARG0 (a / and
                        :op1 (e3 / enzyme :name (n3 / name :op1 "MEK1")
                              :ARG1-of (a2 / activate-01))
                        :op2 (e4 / enzyme :name (n4 / name :op1 "RAS")
                              :ARG0-of (c2 / cause-01
                                    :ARG1 (d / disease :wiki "Cancer" :name (n / name :op1 "cancer"))))
                        :op3 (e / enzyme :name (n5 / name :op1 "BRAF")
                              :ARG0-of c2)))))

# ::id a_pmid_2094_2929.40 ::date 2015-05-20T12:22:30 ::annotator SDL-AMR-09 ::preferred
# ::snt Among the most harmful of all genetic abnormalities that appear in CRC development are mutations of KRAS and its downstream effector BRAF as they result in abnormal ERK signaling.
# ::save-date Sun Jan 17, 2016 ::file a_pmid_2094_2929_40.txt
(i / include-91
      :ARG1 (a4 / and
            :op1 (m2 / mutate-01
                  :ARG1 (e4 / enzyme :name (n3 / name :op1 "KRAS")))
            :op2 (e2 / effector
                  :mod (d2 / downstream)
                  :mod (e3 / enzyme :name (n4 / name :op1 "BRAF"))
                  :poss e4)
            :ARG1-of (r / result-01
                  :ARG2 (s / signal-07
                        :ARG0 (e / enzyme :name (n / name :op1 "ERK"))
                        :ARG1-of (n6 / normal-02 :polarity -))))
      :ARG2 (n5 / normal-02 :polarity -
            :ARG2 (g / genetics)
            :mod (a2 / all)
            :ARG0-of (h / harmful-02
                  :degree (m / most))
            :ARG1-of (a3 / appear-01
                  :time (d / develop-02
                        :ARG1 (c / cell
                              :mod (d3 / disease :name (n2 / name :op1 "CRC")))))))

# ::id a_pmid_2094_2929.41 ::date 2015-05-20T12:49:26 ::annotator SDL-AMR-09 ::preferred
# ::snt In a previous report, we had shown that expression of a constitutive active mutant of MEK1 (caMEK) in the intestinal epithelial cell line IEC-6 induced morphological transformation and growth in soft agar; in marked contrast, wtMEK overexpression had no effect on IEC-6 phenotype [<xref ref-type="bibr" rid="B3">3</xref>].
# ::save-date Sun Dec 20, 2015 ::file a_pmid_2094_2929_41.txt
(a / and
      :op1 (s / show-01
            :ARG0 (w / we)
            :ARG1 (i / induce-01
                  :ARG0 (e / express-03
                        :ARG2 (m / mutate-01
                              :ARG2 (e2 / enzyme :name (n / name :op1 "MEK1"))
                              :mod (c / constitutive)
                              :ARG0-of (a2 / activity-06))
                        :ARG3 (c2 / cell-line :name (n3 / name :op1 "IEC-6")
                              :mod (e4 / epithelium
                                    :part-of (i2 / intestine))))
                  :ARG2 (a3 / and
                        :op1 (t / transform-01
                              :mod (m3 / morphological))
                        :op2 (g / grow-01
                              :location (a4 / agar
                                    :ARG1-of (s2 / soft-02)))))
            :medium (r / report
                  :time (p / previous)))
      :op2 (a5 / affect-01 :polarity -
            :ARG0 (o / overexpress-01
                  :ARG1 (e5 / enzyme :name (n4 / name :op1 "MEK")
                        :mod (w2 / wild-type)))
            :ARG1 (p2 / phenotype
                  :mod (c3 / cell-line :name (n5 / name :op1 "IEC-6")))
            :ARG1-of (d / describe-01
                  :ARG0 (p3 / publication
                        :ARG1-of (c4 / cite-01
                              :ARG2 3)))
            :ARG2-of (c5 / contrast-01
                  :ARG1-of (m4 / mark-01))))

# ::id a_pmid_2094_2929.42 ::date 2015-05-20T13:09:11 ::annotator SDL-AMR-09 ::preferred
# ::snt In order to understand the mechanisms by which activated MEK1 induces intestinal cell tumorigenesis, the pattern of gene expression was analyzed by microarray in IEC-6 cells overexpressing activated MEK1.
# ::save-date Sun Dec 20, 2015 ::file a_pmid_2094_2929_42.txt
(a3 / analyze-01
      :ARG0 (m2 / microarray)
      :ARG1 (p / pattern-01
            :ARG1 (e2 / express-03
                  :ARG2 (g / gene)))
      :location (c2 / cell-line :name (n2 / name :op1 "IEC-6")
            :ARG0-of (o / overexpress-01
                  :ARG1 e))
      :purpose (u / understand-01
            :ARG1 (m / mechanism
                  :instrument-of (i / induce-01
                        :ARG0 (e / enzyme :name (n / name :op1 "MEK1")
                              :ARG1-of (a / activate-01))
                        :ARG2 (c3 / create-01
                              :ARG1 (t / tumor
                                    :mod (c / cell
                                          :part-of (i2 / intestine))))))))

# ::id a_pmid_2094_2929.43 ::date 2015-05-20T13:24:51 ::annotator SDL-AMR-09 ::preferred
# ::snt Results from microarrays comparing control (wtMEK) to caMEK-expressing IEC-6 cells identified the <i>Serpin clade E member 2 </i>(<i>serpinE2 </i>or <i>PN-1</i>) gene as a potential target of activated MEK1.
# ::save-date Sat May 30, 2015 ::file a_pmid_2094_2929_43.txt
(i / identify-01
      :ARG0 (t / thing
            :ARG2-of (r / result-01)
            :source (m / microarray
                  :ARG0-of (c / compare-01
                        :ARG1 (c2 / control
                              :ARG1-of (m2 / mean-01
                                    :ARG2 (e / enzyme :name (n / name :op1 "MEK")
                                          :mod (w / wild-type))))
                        :ARG2 (c3 / cell-line :name (n2 / name :op1 "IEC-6")
                              :ARG3-of (e2 / express-03
                                    :ARG2 (e3 / enzyme :name (n3 / name :op1 "MEK")
                                          :ARG2-of (m4 / mutate-01)
                                          :mod (c4 / constitutive)
                                          :ARG1-of (a4 / activate-01)))))))
      :ARG1 (g / gene :name (n4 / name :op1 "Serpin" :op2 "clade" :op3 "E" :op4 "member" :op5 "2")
            :ARG1-of (m3 / mean-01
                  :ARG2 (a / and
                        :op1 (g2 / gene :name (n5 / name :op1 "serpinE2"))
                        :op2 (g3 / gene :name (n6 / name :op1 "PN-1")))))
      :ARG2 (t2 / target-01
            :ARG0 (e4 / enzyme :name (n7 / name :op1 "MEK1")
                  :ARG1-of (a2 / activate-01))
            :ARG1 g
            :mod (p / potential)))

# ::id a_pmid_2094_2929.44 ::date 2015-05-20T13:31:22 ::annotator SDL-AMR-09 ::preferred
# ::snt Indeed, <i>serpinE2 </i>expression was significantly induced by more that 28-fold (p < 0.05) in cells overexpressing activated MEK1 in comparison to cells expressing wtMEK (data not shown).
# ::save-date Sun Dec 20, 2015 ::file a_pmid_2094_2929_44.txt
(i / induce-01
      :ARG2 (e / express-03
            :ARG1 (g / gene :name (n / name :op1 "serpinE2")))
      :mod (i2 / indeed)
      :ARG1-of (s / significant-02)
      :location (c / cell
            :location-of (o / overexpress-01
                  :ARG1 (e2 / enzyme :name (n2 / name :op1 "MEK1")
                        :ARG1-of (a / activate-01))))
      :compared-to (c2 / cell
            :ARG3-of (e3 / express-03
                  :ARG2 (e4 / enzyme :name (n3 / name :op1 "MEK")
                        :mod (w / wild-type))))
      :ARG1-of (d / describe-01
            :ARG0 (d2 / data
                  :ARG1-of (s2 / show-01 :polarity -)))
      :quant (m2 / more-than
            :op1 (p / product-of :op1 28))
      :ARG1-of (s3 / statistical-test-91
            :ARG2 (l / less-than :op1 0.05)))

# ::id a_pmid_2094_2929.45 ::date 2015-05-20T13:46:38 ::annotator SDL-AMR-09 ::preferred
# ::snt Overexpression of <i>serpinE2 </i>in caMEK-expressing IECs was furthermore confirmed following RT-PCR analysis as shown in Figure <xref ref-type="fig" rid="F1">1A</xref>.
# ::save-date Mon Dec 21, 2015 ::file a_pmid_2094_2929_45.txt
(a / and
      :op2 (c / confirm-01
            :ARG1 (o / overexpress-01
                  :ARG1 (g / gene :name (n / name :op1 "serpinE2"))
                  :location (c2 / cell :name (n2 / name :op1 "IEC")
                        :ARG3-of (e / express-03
                              :ARG2 (e2 / enzyme :name (n3 / name :op1 "MEK")
                                    :mod (c3 / constitutive)
                                    :ARG2-of (m / mutate-01)
                                    :ARG1-of (a4 / activate-01)))))
            :time (f / follow-01
                  :ARG2 (a2 / analyze-01
                        :mod (t / thing :name (n4 / name :op1 "RT-PCR")))))
      :ARG1-of (s / show-01
            :ARG0 (f2 / figure :mod "1A")))

# ::id a_pmid_2094_2929.46 ::date 2015-05-20T13:59:27 ::annotator SDL-AMR-09 ::preferred
# ::snt SerpinE2 expression was also markedly enhanced in IEC-6 cells transformed by oncogenic RAS (26-fold) or BRAF (12-fold after 12 h of 4-hydroxytamoxifen (4-OHT) (Figure <xref ref-type="fig" rid="F1">1B</xref> and <xref ref-type="fig" rid="F1">1C</xref>).
# ::save-date Fri Jan 15, 2016 ::file a_pmid_2094_2929_46.txt
(o / or
      :op1 (e2 / enhance-01
            :ARG1 (e3 / express-03
                  :ARG2 (p / protein :name (n2 / name :op1 "SerpinE2")))
            :ARG3 (p2 / product-of :op1 26)
            :manner (m / marked)
            :mod (a / also)
            :location (c / cell-line :name (n3 / name :op1 "IEC-6")
                  :ARG1-of (t / transform-01
                        :ARG0 (e / enzyme :name (n / name :op1 "Ras")
                              :ARG0-of (c2 / cause-01
                                    :ARG1 (d2 / disease :wiki "Cancer" :name (n6 / name :op1 "cancer")))))))
      :op2 (e4 / enhance-01
            :ARG1 e3
            :ARG3 (p4 / product-of :op1 12)
            :time (a2 / after
                  :op1 (s / stimulate-01
                        :ARG2 (s2 / small-molecule :name (n5 / name :op1 "4-hydroxytamoxifen")))
                  :quant (t2 / temporal-quantity :quant 12
                        :unit (h / hour)))
            :location (c4 / cell-line :name (n7 / name :op1 "IEC-6")
                  :ARG1-of (t3 / transform-01
                        :ARG0 (e5 / enzyme :name (n4 / name :op1 "BRAF")
                              :ARG0-of c2))))
      :ARG1-of (d / describe-01
            :ARG0 (a3 / and
                  :op1 (f / figure :mod "1B")
                  :op2 (f2 / figure :mod "1C"))))

# ::id a_pmid_2094_2929.47 ::date 2015-05-20T14:21:28 ::annotator SDL-AMR-09 ::preferred
# ::snt Of note, the induction of serpinE2 was induced within 1 h following ERK activation as observed in cells expressing the inducible BRAF:ER fusion protein stimulated with 4-OHT (Figure <xref ref-type="fig" rid="F1">1C</xref>).
# ::save-date Fri Feb 12, 2016 ::file a_pmid_2094_2929_47.txt
(n2 / note-02
      :ARG1 (i / induce-01
            :ARG2 (i2 / induce-01
                  :ARG2 (p / protein :name (n3 / name :op1 "serpinE2")))
            :time (a / after
                  :op1 (a2 / activate-01
                        :ARG1 (e / enzyme :name (n / name :op1 "ERK")))
                  :quant (u / up-to
                        :op1 (t / temporal-quantity :quant 1
                              :unit (h / hour))))
            :ARG1-of (f / follow-01)
            :ARG1-of (o / observe-01
                  :location (c / cell
                        :ARG3-of (e2 / express-03
                              :ARG2 (p3 / protein :name (n5 / name :op1 "BRAF:ER" :op2 "fusion")
                                    :ARG1-of (i3 / induce-01
                                          :ARG1-of (p2 / possible-01))
                                    :ARG1-of (s / stimulate-01
                                          :ARG2 (s2 / small-molecule :name (n4 / name :op1 "4-OHT"))))))))
      :ARG1-of (d / describe-01
            :ARG0 (f2 / figure :mod "1C")))

# ::id a_pmid_2094_2929.48 ::date 2015-05-21T09:43:34 ::annotator SDL-AMR-09 ::preferred
# ::snt Treatment with the MEK-inhibitor U0126 completely abrogated serpinE2 gene expression induced by oncogenic MEK1 (Figure <xref ref-type="fig" rid="F1">1A</xref>) and BRAF (Figure <xref ref-type="fig" rid="F1">1C</xref>), indicating that induction of serpinE2 is an early and direct event occurring following the activation of ERK signaling.
# ::save-date Sat Jan 16, 2016 ::file a_pmid_2094_2929_48.txt
(a / abrogate-01
      :ARG1 (e3 / express-03
            :ARG2 (g / gene :name (n5 / name :op1 "serpinE2"))
            :ARG2-of (i2 / induce-01
                  :ARG0 (e4 / enzyme :name (n6 / name :op1 "MEK1")
                        :ARG0-of (c2 / cause-01
                              :ARG1 (d4 / disease :wiki "Cancer" :name (n / name :op1 "cancer"))))
                  :ARG1-of (d / describe-01
                        :ARG0 (f / figure :mod "1A")))
            :ARG2-of (i3 / induce-01
                  :ARG0 (e7 / enzyme :name (n7 / name :op1 "BRAF")
                        :ARG0-of c2)
                  :ARG1-of (d2 / describe-01
                        :ARG0 (f2 / figure :mod "1C"))))
      :ARG2 (t / treat-04
            :ARG2 (s2 / small-molecule :name (n3 / name :op1 "U0126")
                  :ARG0-of (i / inhibit-01
                        :ARG1 (p2 / protein-family :name (n4 / name :op1 "MEK")))))
      :ARG1-of (c / complete-02)
      :ARG0-of (i4 / indicate-01
            :ARG1 (e5 / event
                  :mod (e6 / early)
                  :ARG1-of (d3 / direct-02)
                  :domain (i5 / induce-01
                        :ARG1 g)
                  :ARG1-of (f3 / follow-01
                        :ARG2 (a2 / activate-01
                              :ARG1 (s3 / signal-07
                                    :ARG0 (p / protein-family :name (n2 / name :op1 "ERK"))))))))

# ::id a_pmid_2094_2929.49 ::date 2015-05-21T10:05:41 ::annotator SDL-AMR-09 ::preferred
# ::snt Since serpinE2 protein is known to be secreted [<xref ref-type="bibr" rid="B22">22</xref>,<xref ref-type="bibr" rid="B33">33</xref>], we easily confirmed its presence in conditioned culture medium of caMEK-expressing IECs whereas no serpinE2 protein was detected in the culture medium of wtMEK-expressing or parental IECs (Figure <xref ref-type="fig" rid="F1">1D</xref>).
# ::save-date Mon Nov 2, 2015 ::file a_pmid_2094_2929_49.txt
(c / confirm-01
      :ARG0 (w2 / we)
      :ARG1 (p / present-02
            :ARG1 (p2 / protein :name (n / name :op1 "serpinE2"))
            :ARG2 (m / medium
                  :mod (c3 / culture)
                  :ARG1-of (c4 / condition-01)
                  :poss (c7 / cell :name (n4 / name :op1 "IEC")
                        :ARG3-of (e2 / express-03
                              :ARG2 (e / enzyme :name (n3 / name :op1 "MEK")
                                    :ARG2-of (m2 / mutate-01)
                                    :mod (c6 / constitutive)
                                    :ARG1-of (a3 / activate-01))))))
      :ARG1-of (d2 / describe-01
            :ARG0 (f / figure :mod "1D"))
      :ARG1-of (e5 / easy-05)
      :ARG0-of (c10 / cause-01
            :ARG1 (k / know-01
                  :ARG1 (s2 / secrete-01
                        :ARG1 p2))
            :ARG1-of (d3 / describe-01
                  :ARG0 (p5 / publication
                        :ARG1-of (c9 / cite-01
                              :ARG2 (a2 / and :op1 22 :op2 33)))))
      :ARG1-of (c2 / contrast-01
            :ARG2 (d / detect-01 :polarity -
                  :ARG1 p2
                  :location (o / or
                        :op1 (m3 / medium
                              :mod (c5 / culture-01)
                              :poss (c12 / cell :name (n2 / name :op1 "IEC")
                                    :ARG3-of (e4 / express-03
                                          :ARG2 (e3 / enzyme :name (n5 / name :op1 "MEK")
                                                :mod (w / wild-type)))))
                        :op2 (m4 / medium
                              :mod (c11 / culture-01)
                              :poss (c8 / cell :name (n6 / name :op1 "IEC")
                                    :mod (p4 / parent)))))))

# ::id a_pmid_2094_2929.50 ::date 2015-05-21T10:23:01 ::annotator SDL-AMR-09 ::preferred
# ::snt Again, treatment with the MEK-inhibitor U0126 completely abrogated serpinE2 secretion (Figure <xref ref-type="fig" rid="F1">1D</xref>).
# ::save-date Sat Jan 16, 2016 ::file a_pmid_2094_2929_50.txt
(a / abrogate-01
      :ARG1 (s2 / secrete-01
            :ARG1 (p / protein :name (n3 / name :op1 "serpinE2")))
      :ARG2 (t / treat-04
            :ARG2 (s / small-molecule :name (n / name :op1 "U0126")
                  :ARG0-of (i / inhibit-01
                        :ARG1 (p2 / protein-family :name (n2 / name :op1 "MEK")))))
      :mod (a2 / again)
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod "1D"))
      :ARG1-of (c / complete-02))

# ::id a_pmid_2094_2929.51 ::date 2015-05-21T10:26:14 ::annotator SDL-AMR-09 ::preferred
# ::snt Interestingly, serpinE2 protein was difficult to detect in total cell lysates (Figure <xref ref-type="fig" rid="F1">1E</xref>, lane 2).
# ::save-date Sun May 31, 2015 ::file a_pmid_2094_2929_51.txt
(d / difficult
      :ARG1-of (d3 / describe-01
            :ARG0 (a / and
                  :op1 (f / figure :mod "1E"
                        :part (l2 / lane :mod 2))))
      :mod (i / interesting)
      :domain (d2 / detect-01
            :ARG1 (p / protein :name (n / name :op1 "serpinE2"))
            :location (l / lysate
                  :mod (c / cell)
                  :mod (t / total))))

# ::id a_pmid_2094_2929.52 ::date 2015-05-21T10:42:36 ::annotator SDL-AMR-09 ::preferred
# ::snt However, serpinE2 was easily observed in lysates prepared from foci of post-confluent caMEK-expressing cells (Figure <xref ref-type="fig" rid="F1">1E</xref>, lane 4), while it was not detectable in the surrounding monolayer (Figure <xref ref-type="fig" rid="F1">1E</xref>, lane 3).
# ::save-date Wed Mar 9, 2016 ::file a_pmid_2094_2929_52.txt
(h / have-concession-91
      :ARG1 (c / contrast-01
            :ARG1 (o / observe-01
                  :ARG1 (p / protein :name (n / name :op1 "serpinE2"))
                  :ARG1-of (e / easy-05)
                  :location (l / lysate
                        :ARG1-of (p2 / prepare-01
                              :ARG2 (f / focus
                                    :part-of (c2 / cell
                                          :time (a / after
                                                :op1 (c4 / confluent
                                                      :domain c2))
                                          :ARG3-of (e3 / express-03
                                                :ARG2 (e2 / enzyme :name (n2 / name :op1 "MEK")
                                                      :mod (c3 / constitutive)
                                                      :ARG2-of (m / mutate-01)
                                                      :ARG1-of (a4 / activate-01)))))))
                  :ARG1-of (d / describe-01
                        :ARG0 (a2 / and
                              :op1 (f2 / figure :mod "1E"
                                    :part (l2 / lane :mod 4)))))
            :ARG2 (p4 / possible-01
                  :ARG1 (d2 / detect-01 :polarity -
                        :ARG1 p
                        :location (m2 / monolayer
                              :ARG1-of (s / surround-01))
                        :ARG1-of (d3 / describe-01
                              :ARG0 (a3 / and
                                    :op1 (f3 / figure :mod "1E"
                                          :part (l3 / lane :mod 3))))))))

# ::id a_pmid_2094_2929.53 ::date 2015-05-21T10:57:06 ::annotator SDL-AMR-09 ::preferred
# ::snt This indicates a stronger expression of serpinE2 protein by the transformed IECs forming the foci.
# ::save-date Fri Jul 10, 2015 ::file a_pmid_2094_2929_53.txt
(i / indicate-01
      :ARG0 (t / this)
      :ARG1 (e / express-03
            :ARG2 (p / protein :name (n / name :op1 "serpinE2"))
            :ARG3 (c / cell :name (n2 / name :op1 "IEC")
                  :ARG1-of (t2 / transform-01)
                  :ARG0-of (f / form-01
                        :ARG1 (f2 / focus)))
            :ARG1-of (s / strong-02
                  :degree (m / more))))

# ::id a_pmid_2094_2929.54 ::date 2015-05-21T11:03:14 ::annotator SDL-AMR-09 ::preferred
# ::snt Gene silencing of serpinE2 decreases foci formation, growth in soft agarose and migration induced by activated MEK
# ::save-date Fri Feb 12, 2016 ::file a_pmid_2094_2929_54.txt
(d / decrease-01
      :ARG0 (s / silence-01
            :ARG1 (p / protein :name (n2 / name :op1 "serpinE2"))
            :mod (g / gene))
      :ARG1 (a / and
            :op1 (f / form-01
                  :ARG1 (f2 / focus))
            :op2 (g2 / grow-01
                  :location (a3 / agarose
                        :ARG1-of (s2 / soft-02)))
            :op3 (m2 / migrate-01
                  :ARG2-of (i / induce-01
                        :ARG0 (e2 / enzyme :name (n4 / name :op1 "MEK")
                              :ARG1-of (a2 / activate-01))))))

# ::id a_pmid_2094_2929.55 ::date 2015-05-21T11:19:25 ::annotator SDL-AMR-09 ::preferred
# ::snt In order to determine the contribution of serpinE2 in intestinal transformation induced by activated MEK, foci from post-confluent caMEK-expressing IECs were retrieved by aspiration with a pipette and pooled as one caMEK-expressing cell population.
# ::save-date Wed Mar 9, 2016 ::file a_pmid_2094_2929_55.txt
(a5 / and
      :op1 (r / retrieve-01
            :ARG1 (f / focus)
            :ARG2 (c2 / cell :name (n3 / name :op1 "IEC")
                  :ARG3-of (e2 / express-03
                        :ARG2 (e3 / enzyme :name (n4 / name :op1 "MEK")
                              :mod (c3 / constitutive)
                              :ARG2-of (m / mutate-01)
                              :ARG1-of (a4 / activate-01)))
                  :time (a2 / after
                        :op1 (c5 / confluent
                              :domain c2)))
            :manner (a3 / aspirate-101
                  :ARG1 f
                  :ARG2 c2
                  :instrument (p3 / pipette)))
      :op2 (p4 / pool-01
            :ARG1 f
            :ARG2 (p5 / population
                  :mod (c4 / cell
                        :ARG3-of (e4 / express-03
                              :ARG2 e3))))
      :purpose (d / determine-01
            :ARG1 (c / contribute-01
                  :ARG0 (p / protein :name (n2 / name :op1 "serpinE2"))
                  :ARG2 (t / transform-01
                        :mod (i / intestine)
                        :ARG2-of (i2 / induce-01
                              :ARG0 (e / enzyme :name (n / name :op1 "MEK")
                                    :ARG1-of (a / activate-01)))))))

# ::id a_pmid_2094_2929.56 ::date 2015-05-21T11:35:30 ::annotator SDL-AMR-09 ::preferred
# ::snt All further experiments were performed with this previously characterized caMEK-expressing IEC population [<xref ref-type="bibr" rid="B14">14</xref>] and compared with wtMEK-expressing cell populations.
# ::save-date Tue Jul 28, 2015 ::file a_pmid_2094_2929_56.txt
(a3 / and
      :op1 (p / perform-02
            :ARG1 (e / experiment-01
                  :ARG1 (p2 / population
                        :ARG1-of (c / characterize-01
                              :time (p3 / previous))
                        :mod (c2 / cell :name (n / name :op1 "IEC")
                              :ARG3-of (e2 / express-03
                                    :ARG2 (e3 / enzyme :name (n2 / name :op1 "MEK")
                                          :mod (c3 / constitutive)
                                          :ARG2-of (m / mutate-01)
                                          :ARG1-of (a4 / activate-01))))
                        :mod (t / this))
                  :degree (f / further)
                  :mod (a / all))
            :ARG1-of (d / describe-01
                  :ARG0 (p4 / publication
                        :ARG1-of (c4 / cite-01
                              :ARG2 14))))
      :op2 (c5 / compare-01
            :ARG1 e
            :ARG2 (p5 / population
                  :mod (c6 / cell
                        :ARG3-of (e4 / express-03
                              :ARG2 (e5 / enzyme :name (n3 / name :op1 "MEK")
                                    :mod (w / wild-type)))))))

# ::id a_pmid_2094_2929.57 ::date 2015-05-21T11:50:42 ::annotator SDL-AMR-09 ::preferred
# ::snt Recombinant lentiviruses encoding anti-<i>serpinE2 </i>short hairpin RNA (shRNA) were therefore developed to stably suppress serpinE2 levels in these cells.
# ::save-date Sun Dec 20, 2015 ::file a_pmid_2094_2929_57.txt
(c / cause-01
      :ARG1 (d / develop-02
            :ARG1 (l / lentivirus
                  :ARG3-of (r / recombine-01)
                  :ARG0-of (e / encode-01
                        :ARG1 (n4 / nucleic-acid :name (n / name :op1 "short" :op2 "hairpin")
                              :ARG0-of (e2 / encode-01
                                    :ARG1 (a / antibody
                                          :ARG0-of (o / oppose-01
                                                :ARG1 (p / protein :name (n2 / name :op1 "serpinE2")))))
                              :ARG1-of (m / mean-01
                                    :ARG2 (n5 / nucleic-acid :name (n3 / name :op1 "shRNA"))))))
            :ARG4 (s / suppress-01
                  :ARG1 (l2 / level
                        :quant-of p)
                  :ARG1-of (s2 / stable-03)
                  :location (c2 / cell
                        :mod (t / this)))))

# ::id a_pmid_2094_2929.58 ::date 2015-05-21T12:13:53 ::annotator SDL-AMR-09 ::preferred
# ::snt Several lentiviral constructs were generated and tested for their ability to knock down serpinE2 protein.
# ::save-date Thu Jun 25, 2015 ::file a_pmid_2094_2929_58.txt
(a / and
      :op1 (g / generate-01
            :ARG1 (c / construct-01
                  :ARG1 (l / lentiviral)
                  :quant (s / several)))
      :op2 (t / test-01
            :ARG1 c
            :ARG2 (c2 / capable-01
                  :ARG1 c
                  :ARG2 (k / knock-down-02
                        :ARG0 c
                        :ARG1 (p / protein :name (n / name :op1 "serpinE2"))))))

# ::id a_pmid_2094_2929.59 ::date 2015-05-21T12:19:50 ::annotator SDL-AMR-09 ::preferred
# ::snt One of these viral shRNAs was selected and designated as shSerpinE2.
# ::save-date Fri Feb 12, 2016 ::file a_pmid_2094_2929_59.txt
(a / and
      :op1 (s / select-01
            :ARG1 (n6 / nucleic-acid
                  :ARG1-of (i / include-91
                        :ARG2 (n4 / nucleic-acid :name (n / name :op1 "shRNA")
                              :mod (v / virus)
                              :mod (t / this)))))
      :op2 (d / designate-01
            :ARG1 n6
            :ARG2 (n5 / nucleic-acid :name (n2 / name :op1 "shRNA")
                  :ARG0-of (e / encode-01
                        :ARG1 (p / protein :name (n3 / name :op1 "serpinE2"))))))

# ::id a_pmid_2094_2929.60 ::date 2015-05-21T12:27:20 ::annotator SDL-AMR-09 ::preferred
# ::snt caMEK-expressing cells were henceforth infected with shSerpinE2 lentiviruses or with lentiviruses expressing a control shRNA (shScrambled).
# ::save-date Sun May 31, 2015 ::file a_pmid_2094_2929_60.txt
(i / infect-01
      :ARG1 (c / cell
            :ARG3-of (e / express-03
                  :ARG2 (e2 / enzyme :name (n / name :op1 "MEK")
                        :mod (c2 / constitutive)
                        :ARG2-of (m / mutate-01)
                        :ARG1-of (a2 / activate-01))))
      :ARG2 (o / or
            :op1 (l / lentivirus
                  :mod (n6 / nucleic-acid :name (n2 / name :op1 "shRNA")
                        :ARG0-of (e3 / encode-01
                              :ARG1 (p / protein :name (n3 / name :op1 "serpinE2")))))
            :op2 (l2 / lentivirus
                  :ARG1-of (e4 / express-03
                        :ARG2 (n7 / nucleic-acid :name (n4 / name :op1 "shRNA")
                              :ARG0-of (c3 / control-01)
                              :ARG1-of (m2 / mean-01
                                    :ARG2 (n8 / nucleic-acid :name (n5 / name :op1 "shScrambled")))))))
      :time (h / henceforth))

# ::id a_pmid_2094_2929.61 ::date 2015-05-21T12:35:49 ::annotator SDL-AMR-09 ::preferred
# ::snt Secretion of serpinE2 protein was analyzed 14 days after selection with blasticidin S in these populations.
# ::save-date Fri Feb 12, 2016 ::file a_pmid_2094_2929_61.txt
(a / analyze-01
      :ARG1 (s / secrete-01
            :ARG1 (p / protein :name (n / name :op1 "serpinE2")))
      :time (a2 / after
            :op1 (s2 / select-01
                  :ARG2 (p2 / population
                        :mod (t2 / this))
                  :instrument (s3 / small-molecule :name (n2 / name :op1 "blasticidin" :op2 "S")))
            :quant (t / temporal-quantity :quant 14
                  :unit (d2 / day))))

# ::id a_pmid_2094_2929.62 ::date 2015-05-21T12:49:09 ::annotator SDL-AMR-09 ::preferred
# ::snt As shown in Figure <xref ref-type="fig" rid="F2">2A</xref>, secreted serpinE2 levels were markedly reduced (> 60%) in cells-expressing shSerpinE2; in contrast, shScrambled had no effect on the secretion of serpinE2 (data not shown).
# ::save-date Thu May 21, 2015 ::file a_pmid_2094_2929_62.txt
(a / and
      :op1 (r / reduce-01
            :ARG1 (l / level
                  :quant-of (p2 / protein :name (n / name :op1 "serpinE2"))
                  :ARG1-of (s / secrete-01))
            :ARG2 (m2 / more-than
                  :op1 (p / percentage-entity :value 60))
            :manner (m / marked)
            :location (c / cell
                  :ARG3-of (e2 / express-03
                        :ARG2 (n4 / nucleic-acid :name (n2 / name :op1 "shRNA")
                              :ARG0-of (e / encode-01
                                    :ARG1 p2))))
            :ARG1-of (s3 / show-01
                  :ARG0 (f / figure :mod "2A")))
      :op2 (c2 / contrast-01
            :ARG2 (a2 / affect-01 :polarity -
                  :ARG0 (n5 / nucleic-acid :name (n3 / name :op1 "shScrambled"))
                  :ARG1 (s2 / secrete-01
                        :ARG1 p2))
            :ARG1-of (d / describe-01
                  :ARG0 (d2 / data
                        :ARG1-of (s4 / show-01 :polarity -)))))

# ::id a_pmid_2094_2929.63 ::date 2015-05-21T13:19:55 ::annotator SDL-AMR-09 ::preferred
# ::snt To determine the functional role of serpinE2 in caMEK-expressing cells, the proliferation rate of these cell populations was assessed when cultured on plastic.
# ::save-date Sun May 31, 2015 ::file a_pmid_2094_2929_63.txt
(a3 / assess-01
      :ARG1 (r2 / rate
            :degree-of (p2 / proliferate-01
                  :ARG0 (p3 / population
                        :mod (c3 / cell)
                        :mod (t / this))))
      :time (c4 / culture-01
            :ARG1 p3
            :manner (p4 / plastic))
      :purpose (d / determine-01
            :ARG1 (r / role
                  :topic (p / protein :name (n / name :op1 "serpinE2"))
                  :ARG1-of (f / function-01)
                  :location (c / cell
                        :ARG3-of (e / express-03
                              :ARG2 (e2 / enzyme :name (n2 / name :op1 "MEK")
                                    :mod (c2 / constitutive)
                                    :ARG2-of (m / mutate-01)
                                    :ARG1-of (a2 / activate-01)))))))

# ::id a_pmid_2094_2929.64 ::date 2015-05-20T05:45:12 ::annotator SDL-AMR-09 ::preferred
# ::snt No difference was observed in the proliferation rate of subconfluent caMEK-expressing cells when serpinE2 expression was downregulated (Figure <xref ref-type="fig" rid="F2">2B</xref>).
# ::save-date Wed May 20, 2015 ::file a_pmid_2094_2929_64.txt
(o / observe-01
      :ARG1 (d / differ-02 :polarity -
            :ARG1 (r / rate
                  :degree-of (p / proliferate-01
                        :ARG0 (c / cell
                              :ARG3-of (e / express-03
                                    :ARG2 (e2 / enzyme :name (n / name :op1 "caMEK")))
                              :mod (s / subconfluent)))))
      :time (d2 / downregulate-01
            :ARG1 (e3 / express-03
                  :ARG2 (p2 / protein :name (n2 / name :op1 "serpinE2"))))
      :ARG1-of (d3 / describe-01
            :ARG0 (f / figure :mod "2B")))

# ::id a_pmid_2094_2929.65 ::date 2015-05-20T05:53:44 ::annotator SDL-AMR-09 ::preferred
# ::snt In a previous study, we had shown that expression of activated MEK in intestinal epithelial cells resulted in loss of cell-cell contact growth inhibition and produced colonies or multilayered domes which grew to increased saturation density and formed tumors when transplanted into nude mice [<xref ref-type="bibr" rid="B14">14</xref>].
# ::save-date Sun Dec 20, 2015 ::file a_pmid_2094_2929_65.txt
(s / show-01
      :ARG0 (w / we)
      :ARG1 (a2 / and
            :op1 (r / result-01
                  :ARG1 (e / express-03
                        :ARG2 (e2 / enzyme :name (n / name :op1 "MEK")
                              :ARG1-of (a / activate-01))
                        :ARG3 (c / cell
                              :source (e3 / epithelium
                                    :part-of (i / intestine))))
                  :ARG2 (l / lose-02
                        :ARG1 (i2 / inhibit-01
                              :ARG0 (c2 / contact-01
                                    :ARG0 (c4 / cell)
                                    :ARG1 (c3 / cell))
                              :ARG1 (g / grow-01))))
            :op2 (p / produce-01
                  :ARG0 e
                  :ARG1 (o / or
                        :op1 (c5 / colony)
                        :op2 (d / dome
                              :mod (m / multilayered))
                        :ARG1-of (g2 / grow-01
                              :ARG4 (d2 / density
                                    :mod (s2 / saturate-01)
                                    :ARG1-of (i3 / increase-01)))
                        :ARG0-of (f / form-01
                              :ARG1 (t / tumor)
                              :time (t2 / transplant-01
                                    :ARG1 o
                                    :ARG2 (m2 / mouse
                                          :mod (n2 / nude)))))))
      :medium (s3 / study-01
            :time (p2 / previous))
      :ARG1-of (d3 / describe-01
            :ARG0 (p3 / publication
                  :ARG1-of (c6 / cite-01
                        :ARG2 14))))

# ::id a_pmid_2094_2929.66 ::date 2015-05-20T06:09:22 ::annotator SDL-AMR-09 ::preferred
# ::snt Of note, focus formation assays performed herein revealed that initially, there was little difference in the number of foci obtained between control cells and serpinE2-depleted cells (data not shown).
# ::save-date Sun Dec 20, 2015 ::file a_pmid_2094_2929_66.txt
(r / reveal-01
      :ARG0 (a / assay-01
            :ARG1 (f2 / form-01
                  :ARG1 (f3 / focus))
            :ARG1-of (p / perform-02
                  :medium (h / herein)))
      :ARG1 (d / differ-02
            :ARG1 (c / cell
                  :mod (c2 / control))
            :ARG2 (c3 / cell
                  :ARG1-of (d2 / deplete-01
                        :ARG2 (p2 / protein :name (n3 / name :op1 "serpinE2"))))
            :ARG3 (n2 / number
                  :quant-of (f / focus)
                  :ARG1-of (o / obtain-01))
            :degree (l / little)
            :time (i / initial))
      :ARG1-of (n4 / note-02)
      :ARG1-of (d3 / describe-01
            :ARG0 (d4 / data
                  :ARG1-of (s / show-01 :polarity -))))

# ::id a_pmid_2094_2929.67 ::date 2015-05-20T06:21:04 ::annotator SDL-AMR-09 ::preferred
# ::snt However, <i>serpinE2 </i>silencing markedly reduced the size of foci (Figure <xref ref-type="fig" rid="F2">2C</xref>) suggesting a reduced capacity of these foci to grow.
# ::save-date Fri Jun 5, 2015 ::file a_pmid_2094_2929_67.txt
(c2 / contrast-01
      :ARG2 (r / reduce-01
            :ARG0 (s / silence-01
                  :ARG1 (g2 / gene :name (n / name :op1 "serpinE2")))
            :ARG1 (s2 / size
                  :poss (f / focus))
            :manner (m / marked)
            :ARG1-of (d / describe-01
                  :ARG0 (f2 / figure :mod "2C"))
            :ARG0-of (s3 / suggest-01
                  :ARG1 (c / capable-01
                        :ARG1 f
                        :ARG2 (g / grow-01
                              :ARG1 f)
                        :ARG1-of (r2 / reduce-01)))))

# ::id a_pmid_2094_2929.68 ::date 2015-05-20T06:29:21 ::annotator SDL-AMR-09 ::preferred
# ::snt Indeed, phase-contrast microscopy revealed that the colonies were smaller when serpinE2 was downregulated (Figure <xref ref-type="fig" rid="F2">2D</xref>).
# ::save-date Wed May 20, 2015 ::file a_pmid_2094_2929_68.txt
(r / reveal-01
      :ARG0 (t / thing :name (n / name :op1 "phase-contrast" :op2 "microscopy"))
      :ARG1 (s / small
            :degree (m / more)
            :domain (c / colony)
            :time (d / downregulate-01
                  :ARG1 (p / protein :name (n2 / name :op1 "serpinE2"))))
      :ARG1-of (d2 / describe-01
            :ARG0 (f / figure :mod "2D"))
      :mod (i / indeed))

# ::id a_pmid_2094_2929.69 ::date 2015-05-20T06:32:08 ::annotator SDL-AMR-09 ::preferred
# ::snt Finally, expression of shSerpinE2 led to a significant decrease in the ability of caMEK-expressing cells to grow under anchorage-independent conditions in soft agarose (Figure <xref ref-type="fig" rid="F2">2E</xref>).
# ::save-date Fri Oct 23, 2015 ::file a_pmid_2094_2929_69.txt
(l / lead-03 :li "-1"
      :ARG0 (e / express-03
            :ARG2 (p / protein :name (n / name :op1 "shSerpinE2")))
      :ARG1 (d / decrease-01
            :ARG1 (c / capable-01
                  :ARG1 (c2 / cell
                        :ARG3-of (e2 / express-03
                              :ARG2 (e3 / enzyme :name (n2 / name :op1 "caMEK"))))
                  :ARG2 (g / grow-01
                        :ARG1 c2
                        :location (a2 / agarose
                              :ARG1-of (s2 / soft-02))
                        :condition (d2 / depend-01 :polarity -
                              :ARG0 g
                              :ARG1 (a / anchorage))))
            :ARG2 (s / significant-02))
      :ARG1-of (d3 / describe-01
            :ARG0 (f / figure :mod "2E")))

# ::id a_pmid_2094_2929.70 ::date 2015-05-20T06:46:14 ::annotator SDL-AMR-09 ::preferred
# ::snt Cell migration is an important process of tumorigenesis and metastasis.
# ::save-date Mon Jul 13, 2015 ::file a_pmid_2094_2929_70.txt
(p / process-02
      :ARG1 (m / migrate-01
            :ARG0 (c / cell))
      :mod (i / important)
      :subevent-of (a / and
            :op1 (c2 / create-01
                  :ARG1 (t / tumor))
            :op2 (m2 / metastasis)))

# ::id a_pmid_2094_2929.71 ::date 2015-05-20T06:48:09 ::annotator SDL-AMR-09 ::preferred
# ::snt Moreover, we recently reported that intestinal epithelial cells expressing activated MEK1 clearly acquire an increased capacity to migrate as compared to wtMEK-expressing cells [<xref ref-type="bibr" rid="B14">14</xref>].
# ::save-date Sun Dec 20, 2015 ::file a_pmid_2094_2929_71.txt
(a / and
      :op2 (r / report-01
            :ARG0 (w / we)
            :ARG1 (a2 / acquire-01
                  :ARG0 (c2 / cell
                        :source (e / epithelium
                              :part-of (i / intestine))
                        :ARG3-of (e2 / express-03
                              :ARG2 (e3 / enzyme :name (n / name :op1 "MEK1")
                                    :ARG1-of (a3 / activate-01))))
                  :ARG1 (c3 / capable-01
                        :ARG1 c2
                        :ARG2 (m / migrate-01
                              :ARG0 c2)
                        :ARG1-of (i2 / increase-01)
                        :compared-to (c4 / capable-01
                              :ARG1 (c5 / cell
                                    :ARG3-of (e4 / express-03
                                          :ARG2 (e5 / enzyme :name (n2 / name :op1 "MEK")
                                                :mod (w2 / wild-type))))
                              :ARG2 m))
                  :ARG1-of (c / clear-06))
            :time (r2 / recent))
      :ARG1-of (d / describe-01
            :ARG0 (p / publication
                  :ARG1-of (c6 / cite-01
                        :ARG2 14))))

# ::id a_pmid_2094_2929.72 ::date 2015-05-20T06:54:31 ::annotator SDL-AMR-09 ::preferred
# ::snt Herein, in an <i>in vitro </i>transwell migration assay, serpinE2 deficiency significantly reduced caMEK-expressing IEC migration to the undersurface of the polycarbonate membrane of Boyden chambers coated with fibronectin or vitronectin (Figure <xref ref-type="fig" rid="F2">2F</xref>), two extracellular matrix proteins which can interact with serpinE2 [<xref ref-type="bibr" rid="B34">34</xref>,<xref ref-type="bibr" rid="B35">35</xref>].
# ::save-date Sun Dec 20, 2015 ::file a_pmid_2094_2929_72.txt
(r / reduce-01
      :ARG0 (l / lack-01
            :ARG1 (p / protein :name (n / name :op1 "serpinE2")))
      :ARG1 (m / migrate-01
            :ARG0 (c / cell :name (n2 / name :op1 "IEC")
                  :ARG3-of (e / express-03
                        :ARG2 (e2 / enzyme :name (n3 / name :op1 "caMEK"))))
            :ARG1 (u / undersurface
                  :part-of (m2 / membrane
                        :consist-of (p2 / polycarbonate)
                        :poss (t / thing :name (n4 / name :op1 "Boyden" :op2 "chamber")))
                  :ARG1-of (c2 / coat-01
                        :ARG2 (o / or
                              :op1 (p3 / protein :name (n5 / name :op1 "fibronectin"))
                              :op2 (p4 / protein :name (n6 / name :op1 "vitronectin"))
                              :ARG1-of (m3 / mean-01
                                    :ARG2 (p5 / protein :quant 2
                                          :ARG1-of (d / describe-01
                                                :ARG0 (p7 / publication
                                                      :ARG1-of (c3 / cite-01
                                                            :ARG2 (a / and :op1 34 :op2 35))))
                                          :ARG0-of (i / interact-01
                                                :ARG1 p
                                                :ARG1-of (p6 / possible-01))
                                          :mod (m4 / matrix
                                                :mod (e3 / extracellular))))))))
      :ARG2 (s / significant-02)
      :medium (h / herein)
      :ARG1-of (d2 / describe-01
            :ARG0 (f / figure :mod "2F"))
      :condition (a2 / assay-01
            :ARG1 (m5 / migrate-01
                  :mod (t3 / transwell))
            :manner (i2 / in-vitro)))

# ::id a_pmid_2094_2929.73 ::date 2015-05-20T07:10:51 ::annotator SDL-AMR-09 ::preferred
# ::snt Taken together, these results support a role of serpinE2 in MEK1-induced transformation whereby serpinE2 activates anchorage-independent growth and cell migration.
# ::save-date Sun Dec 20, 2015 ::file a_pmid_2094_2929_73.txt
(h / have-condition-91
      :ARG1 (s / support-01
            :ARG0 (t / thing
                  :mod (t2 / this)
                  :ARG2-of (r / result-01))
            :ARG1 (r2 / role
                  :poss (p / protein :name (n / name :op1 "serpinE2"))
                  :purpose (t3 / transform-01
                        :ARG2-of (i / induce-01
                              :ARG0 (e / enzyme :name (n2 / name :op1 "MEK1")))
                        :subevent (a / activate-01
                              :ARG0 p
                              :ARG1 (a2 / and
                                    :op1 (g / grow-01
                                          :ARG1 (c2 / cell)
                                          :ARG0-of (d / depend-01 :polarity -
                                                :ARG1 (a3 / anchorage)))
                                    :op2 (m / migrate-01
                                          :ARG0 c2))))))
      :ARG2 (t4 / take-01
            :ARG1 t
            :mod (t5 / together)))

# ::id a_pmid_2094_2929.74 ::date 2015-05-20T07:17:12 ::annotator SDL-AMR-09 ::preferred
# ::snt Expression of serpinE2 in colorectal cancer cells is dependent on MEK/ERK activity
# ::save-date Wed Dec 9, 2015 ::file a_pmid_2094_2929_74.txt
(d / depend-01
      :ARG0 (e / express-03
            :ARG2 (p / protein :name (n / name :op1 "serpinE2"))
            :ARG3 (c / cell
                  :source (d2 / disease :name (n3 / name :op1 "colorectal" :op2 "cancer"))))
      :ARG1 (a / activity-06
            :ARG0 (p2 / pathway :name (n2 / name :op1 "MEK/ERK"))))

# ::id a_pmid_2094_2929.75 ::date 2015-05-20T07:19:36 ::annotator SDL-AMR-09 ::preferred
# ::snt To assess the contribution of serpinE2 in human colorectal cancer, serpinE2 expression was first examined in various CRC cell lines including Caco-2/15 as well as others exhibiting mutation in <i>KRAS </i>(HCT-116, DLD-1, LoVo, SW480, T84) or <i>BRAF </i>(Colo-205, HT-29) [<xref ref-type="bibr" rid="B36">36</xref>].
# ::save-date Sun Jan 17, 2016 ::file a_pmid_2094_2929_75.txt
(e / examine-01
      :ARG1 (e2 / express-03
            :ARG2 (p / protein :name (n / name :op1 "serpinE2")))
      :time (f / first)
      :location (c / cell-line
            :mod (v / various)
            :ARG2-of (i / include-01
                  :ARG1 (a / and
                        :op1 (c2 / cell-line :name (n3 / name :op1 "Caco-2/15"))
                        :op2 (c3 / cell-line
                              :mod (o / other)
                              :ARG0-of (e3 / exhibit-01
                                    :ARG1 (m / mutate-01
                                          :ARG1 (g / gene :name (n4 / name :op1 "KRAS"))))
                              :ARG1-of (m3 / mean-01
                                    :ARG2 (a2 / and
                                          :op1 (c5 / cell-line :name (n6 / name :op1 "HCT-116"))
                                          :op2 (c6 / cell-line :name (n7 / name :op1 "DLD-1"))
                                          :op3 (c7 / cell-line :name (n8 / name :op1 "LoVo"))
                                          :op4 (c8 / cell-line :name (n9 / name :op1 "SW480"))
                                          :op5 (c9 / cell-line :name (n10 / name :op1 "T84")))))
                        :op3 (c4 / cell-line
                              :ARG0-of (e4 / exhibit-01
                                    :ARG1 (m2 / mutate-01
                                          :ARG1 (g2 / gene :name (n5 / name :op1 "BRAF"))))
                              :mod o
                              :ARG1-of (m4 / mean-01
                                    :ARG2 (a3 / and
                                          :op1 (c10 / cell-line :name (n11 / name :op1 "Colo-205"))
                                          :op2 (c11 / cell-line :name (n12 / name :op1 "HT-29")))))))
            :mod (d3 / disease :name (n2 / name :op1 "CRC")))
      :ARG1-of (d / describe-01
            :ARG0 (p2 / publication
                  :ARG1-of (c12 / cite-01
                        :ARG2 36)))
      :purpose (a4 / assess-01
            :ARG1 (c13 / contribute-01
                  :ARG0 p
                  :ARG2 (d2 / disease :name (n13 / name :op1 "colorectal" :op2 "cancer")
                        :mod (h / human)))))

# ::id a_pmid_2094_2929.76 ::date 2015-05-20T07:31:52 ::annotator SDL-AMR-09 ::preferred
# ::snt As shown in Figure <xref ref-type="fig" rid="F3">3A</xref>, <i>serpinE2 </i>mRNA levels were barely detectable in the Caco-2/15 cell line while being markedly expressed in all other CRC cell lines tested.
# ::save-date Sun Jan 17, 2016 ::file a_pmid_2094_2929_76.txt
(c / contrast-01
      :ARG1 (p / possible-01
            :ARG1 (d / detect-01
                  :ARG1 (l / level
                        :quant-of (n5 / nucleic-acid :name (n / name :op1 "mRNA")
                              :ARG0-of (e / encode-01
                                    :ARG1 (g / gene :name (n2 / name :op1 "serpinE2")))))
                  :degree (b / bare)
                  :location (c2 / cell-line :name (n3 / name :op1 "Caco-2/15"))))
      :ARG2 (e2 / express-03
            :ARG1 n5
            :ARG3 (c3 / cell-line
                  :mod (a / all)
                  :mod (o / other)
                  :ARG1-of (t / test-01)
                  :mod (d2 / disease :name (n4 / name :op1 "CRC")))
            :manner (m / marked))
      :ARG1-of (s / show-01
            :medium (f / figure :mod "3A")))

# ::id a_pmid_2094_2929.77 ::date 2015-05-20T07:45:39 ::annotator SDL-AMR-09 ::preferred
# ::snt Two human CRC cell lines, namely HCT116 and LoVo, which have an activating mutation in the <i>KRAS </i>gene resulting in elevated MEK/ERK activities [<xref ref-type="bibr" rid="B37">37</xref>], were thereby chosen to further analyze the regulation and role of serpinE2 expression in human colorectal cancer cells.
# ::save-date Sun Jan 17, 2016 ::file a_pmid_2094_2929_77.txt
(c9 / cause-01
      :ARG1 (c / choose-01
            :ARG1 (c2 / cell-line :quant 2
                  :mod (h / human)
                  :location-of (m2 / mutate-01
                        :ARG1 (g / gene :name (n4 / name :op1 "KRAS"))
                        :ARG1-of (r / result-01
                              :ARG2 (a3 / act-02
                                    :ARG0 (p3 / pathway :name (n8 / name :op1 "MEK/ERK"))
                                    :ARG1-of (e / elevate-01)))
                        :ARG0-of (a2 / activate-01)
                        :ARG1-of (d / describe-01
                              :ARG0 (p / publication
                                    :ARG1-of (c5 / cite-01
                                          :ARG2 37))))
                  :ARG1-of (m / mean-01
                        :ARG2 (a / and
                              :op1 (c3 / cell-line :name (n2 / name :op1 "HCT116"))
                              :op2 (c4 / cell-line :name (n3 / name :op1 "LoVo"))))
                  :mod (d3 / disease :name (n / name :op1 "CRC")))
            :purpose (a4 / analyze-01
                  :ARG1 (a5 / and
                        :op1 (r2 / regulate-01
                              :ARG1 (e4 / express-03
                                    :ARG2 (p2 / protein :name (n7 / name :op1 "serpinE2"))
                                    :ARG3 (c6 / cell
                                          :source (d2 / disease :name (n5 / name :op1 "colorectal" :op2 "cancer")
                                                :mod (h2 / human)))))
                        :op2 (r3 / role
                              :poss e4))
                  :degree (f / further))))

# ::id a_pmid_2094_2929.78 ::date 2015-05-20T10:43:47 ::annotator SDL-AMR-09 ::preferred
# ::snt In addition, the impact of U0126 treatment was also investigated to evaluate the contribution of endogenous MEK/ERK activities in serpinE2 expression in human cell models.
# ::save-date Thu Jun 4, 2015 ::file a_pmid_2094_2929_78.txt
(a / and
      :op2 (i2 / investigate-01
            :ARG1 (i / impact-01
                  :ARG0 (t / treat-04
                        :ARG2 (s / small-molecule :name (n / name :op1 "U0126"))))
            :ARG2 (e / evaluate-01
                  :ARG1 (c / contribute-01
                        :ARG0 (a3 / act-02
                              :ARG0 (p / pathway :name (n2 / name :op1 "MEK/ERK")
                                    :mod (e2 / endogenous)))
                        :ARG2 (e3 / express-03
                              :ARG2 (p2 / protein :name (n4 / name :op1 "serpinE2"))
                              :ARG3 (m / model
                                    :mod (c2 / cell
                                          :mod (h / human))))))
            :mod (a2 / also)))

# ::id a_pmid_2094_2929.79 ::date 2015-05-20T10:49:34 ::annotator SDL-AMR-09 ::preferred
# ::snt Forty-eight-hour treatment of HCT116 and LoVo cell lines with U0126 efficiently blocked endogenous MEK activity as confirmed by the marked inhibition of ERK1/2 phosphorylation (data not shown) [<xref ref-type="bibr" rid="B14">14</xref>].
# ::save-date Mon Jul 6, 2015 ::file a_pmid_2094_2929_79.txt
(b2 / block-01
      :ARG0 (t2 / treat-04
            :ARG1 (a / and
                  :op1 (c / cell-line :name (n3 / name :op1 "HCT116"))
                  :op2 (c2 / cell-line :name (n4 / name :op1 "LoVo")))
            :ARG2 (s / small-molecule :name (n / name :op1 "U0126"))
            :duration (t / temporal-quantity :quant 48
                  :unit (h / hour)))
      :ARG1 (a2 / activity-06
            :ARG0 (e / enzyme :name (n2 / name :op1 "MEK")
                  :mod (e3 / endogenous)))
      :ARG2-of (e2 / efficient-01)
      :ARG1-of (c3 / confirm-01
            :ARG0 (i / inhibit-01
                  :ARG1 (p / phosphorylate-01
                        :ARG1 (s2 / slash
                              :op1 (e4 / enzyme :name (n5 / name :op1 "ERK1"))
                              :op2 (e5 / enzyme :name (n6 / name :op1 "ERK2"))))
                  :mod (m / marked)))
      :ARG1-of (d / describe-01
            :ARG0 (a3 / and
                  :op1 (d2 / data
                        :ARG1-of (s3 / show-01 :polarity -))
                  :op2 (p2 / publication
                        :ARG1-of (c4 / cite-01
                              :ARG2 14)))))

# ::id a_pmid_2094_2929.80 ::date 2015-05-20T10:59:16 ::annotator SDL-AMR-09 ::preferred
# ::snt As shown in Figure <xref ref-type="fig" rid="F3">3B</xref>, treatment of these CRC cell lines with U0126 markedly and significantly reduced <i>serpinE2 </i>mRNA levels, indicating that expression of <i>serpinE2 </i>is likely dependent of ERK activity in these cell lines.
# ::save-date Sun Jan 17, 2016 ::file a_pmid_2094_2929_80.txt
(r / reduce-01
      :ARG0 (t / treat-04
            :ARG1 (c / cell-line
                  :mod (t2 / this)
                  :mod (d2 / disease :name (n3 / name :op1 "CRC")))
            :ARG2 (s / small-molecule :name (n / name :op1 "U0126")))
      :ARG1 (l / level
            :quant-of (n6 / nucleic-acid :name (n4 / name :op1 "mRNA")
                  :ARG0-of (e2 / encode-01
                        :ARG1 (g / gene :name (n5 / name :op1 "serpinE2")))))
      :ARG2 (a / and
            :op1 (m / marked)
            :op2 (s2 / significant-02))
      :ARG0-of (i / indicate-01
            :ARG1 (l2 / likely-01
                  :ARG1 (d / depend-01
                        :ARG0 (e3 / express-03
                              :ARG1 g
                              :ARG3 c)
                        :ARG1 (a2 / activity-06
                              :ARG0 (p / protein-family :name (n2 / name :op1 "ERK"))))))
      :ARG1-of (s3 / show-01
            :medium (f / figure :mod "3B")))

# ::id a_pmid_2094_2929.81 ::date 2015-05-20T11:05:19 ::annotator SDL-AMR-09 ::preferred
# ::snt Down-regulation of serpinE2 expression in human colorectal cancer cells inhibits soft agarose colony formation, migration and tumor growth in nude mice
# ::save-date Wed Dec 9, 2015 ::file a_pmid_2094_2929_81.txt
(i / inhibit-01
      :ARG0 (d / downregulate-01
            :ARG1 (e / express-03
                  :ARG2 (p / protein :name (n / name :op1 "serpinE2"))
                  :ARG3 (c / cell
                        :source (d2 / disease :name (n3 / name :op1 "colorectal" :op2 "cancer")
                              :mod (h / human)))))
      :ARG1 (a / and
            :op1 (f / form-01
                  :ARG1 (c4 / colony)
                  :location (a2 / agarose
                        :ARG1-of (s / soft-02)))
            :op2 (m / migrate-01)
            :op3 (g / grow-01
                  :ARG1 (t / tumor)))
      :location (m2 / mouse
            :mod (n2 / nude)))

# ::id a_pmid_2094_2929.82 ::date 2015-05-20T11:08:56 ::annotator SDL-AMR-09 ::preferred
# ::snt We next investigated the effect of serpinE2 knockdown on anchorage independent growth and cell migration after downregulation of <i>serpinE2 </i>gene expression by RNA interference in HCT116 and LoVo cells.
# ::save-date Thu Jun 25, 2015 ::file a_pmid_2094_2929_82.txt
(i / investigate-01
      :ARG0 (w / we)
      :ARG1 (a / affect-01
            :ARG0 (k / knock-down-02
                  :ARG1 (p / protein :name (n2 / name :op1 "serpinE2")))
            :ARG1 (a2 / and
                  :op1 (g / grow-01
                        :ARG0-of (d / depend-01 :polarity -
                              :ARG1 (a3 / anchorage)))
                  :op2 (m / migrate-01
                        :ARG0 (c / cell))))
      :time (n / next)
      :time (a4 / after
            :op1 (d2 / downregulate-01
                  :ARG1 (e / express-03
                        :ARG1 (g2 / gene :name (n3 / name :op1 "serpinE2"))
                        :ARG3 (a5 / and
                              :op1 (c2 / cell-line :name (n4 / name :op1 "HCT116"))
                              :op2 (c3 / cell-line :name (n5 / name :op1 "LoVo"))))
                  :ARG2 (i2 / interfere-01
                        :ARG0 (n6 / nucleic-acid :name (n7 / name :op1 "RNA"))))))

# ::id a_pmid_2094_2929.83 ::date 2015-05-20T11:17:25 ::annotator SDL-AMR-09 ::preferred
# ::snt As shown in Figure <xref ref-type="fig" rid="F4">4A</xref>, <i>serpinE2 </i>mRNA were significantly reduced by respectively 37% and 88% in LoVo cells expressing shSerpinE2(#15) or shSerpinE2(#16) and by 77% and 92% in HCT116 expressing shSerpinE2(#15) or shSerpinE2(#16); conversely, expression of the control shRNA (shTGFP) had no effect on endogenous <i>serpinE2 </i>expression (data not shown).
# ::save-date Wed Dec 30, 2015 ::file a_pmid_2094_2929_83.txt
(c5 / contrast-01
      :ARG1 (a5 / and
            :op1 (r / reduce-01
                  :ARG1 (n12 / nucleic-acid :name (n / name :op1 "mRNA")
                        :ARG0-of (e / encode-01
                              :ARG1 (g / gene :name (n2 / name :op1 "serpinE2"))))
                  :ARG2 (p / percentage-entity :value 37)
                  :ARG1-of (s / significant-02)
                  :location (c / cell-line :name (n3 / name :op1 "LoVo")
                        :ARG3-of (e2 / express-03
                              :ARG2 (p5 / protein :name (n5 / name :op1 "shSerpinE2")
                                    :ARG1-of (l / label-01
                                          :ARG2 15)))))
            :op2 (r8 / reduce-01
                  :ARG1 n12
                  :ARG2 (p2 / percentage-entity :value 88)
                  :location (c6 / cell-line :name (n10 / name :op1 "LoVo")
                        :ARG3-of (e6 / express-03
                              :ARG2 (p6 / protein :name (n4 / name :op1 "shSerpinE2")
                                    :ARG1-of (l2 / label-01
                                          :ARG2 16))))
                  :ARG1-of s)
            :op3 (r9 / reduce-01
                  :ARG1 n12
                  :ARG2 (p3 / percentage-entity :value 77)
                  :location (c2 / cell-line :name (n6 / name :op1 "HCT116")
                        :ARG3-of e2)
                  :ARG1-of s)
            :op4 (r10 / reduce-01
                  :ARG1 n12
                  :ARG2 (p4 / percentage-entity :value 92)
                  :ARG1-of s
                  :location (c7 / cell-line :name (n11 / name :op1 "HCT116")
                        :ARG3-of e6))
            :ARG1-of (s3 / show-01
                  :medium (f / figure :mod "4A")))
      :ARG2 (c3 / contrast-01
            :ARG1 (a4 / affect-01 :polarity -
                  :ARG0 (e3 / express-03
                        :ARG2 (n15 / nucleic-acid :name (n7 / name :op1 "shRNA")
                              :mod (c4 / control)
                              :ARG1-of (d / describe-01
                                    :ARG2 (p7 / protein :name (n8 / name :op1 "shTGFP")))))
                  :ARG1 (e4 / express-03
                        :ARG1 (g2 / gene :name (n9 / name :op1 "serpinE2")
                              :mod (e5 / endogenous))))
            :ARG1-of (d2 / describe-01
                  :ARG0 (d3 / data
                        :ARG1-of (s2 / show-01 :polarity -)))))

# ::id a_pmid_2094_2929.84 ::date 2015-05-20T11:40:23 ::annotator SDL-AMR-09 ::preferred
# ::snt Again, the proliferation rate of these cell populations was assessed when cultured on plastic.
# ::save-date Thu May 21, 2015 ::file a_pmid_2094_2929_84.txt
(a / assess-01
      :ARG1 (r / rate
            :degree-of (p / proliferate-01
                  :ARG0 (p2 / population
                        :mod (t / this)
                        :mod (c / cell))))
      :time (c2 / culture-01
            :ARG1 p2
            :location (p3 / plastic))
      :mod (a2 / again))

# ::id a_pmid_2094_2929.85 ::date 2015-05-20T11:43:30 ::annotator SDL-AMR-09 ::preferred
# ::snt No difference was observed in the proliferation rate of subconfluent cells when serpinE2 expression was downregulated (Figure <xref ref-type="fig" rid="F4">4B</xref>).
# ::save-date Thu May 21, 2015 ::file a_pmid_2094_2929_85.txt
(o / observe-01
      :ARG1 (d / differ-02 :polarity -
            :ARG1 (r / rate
                  :degree-of (p / proliferate-01
                        :ARG0 (c / cell
                              :mod (s / subconfluent)))))
      :time (d2 / downregulate-01
            :ARG1 (e / express-03
                  :ARG2 (p2 / protein :name (n / name :op1 "serpinE2"))))
      :ARG1-of (d3 / describe-01
            :ARG0 (f / figure :mod "4B")))

# ::id a_pmid_2094_2929.86 ::date 2015-05-20T11:46:44 ::annotator SDL-AMR-09 ::preferred
# ::snt We then verified whether the reduction in <i>serpinE2 </i>expression alters the ability of colon cancer cells to form colonies in soft agarose.
# ::save-date Wed Dec 9, 2015 ::file a_pmid_2094_2929_86.txt
(v / verify-01
      :ARG0 (w / we)
      :ARG1 (a / alter-01 :mode interrogative
            :ARG0 (r / reduce-01
                  :ARG1 (e / express-03
                        :ARG1 (g / gene :name (n / name :op1 "serpinE2"))))
            :ARG1 (c / capable-01
                  :ARG1 (c2 / cell
                        :source (d / disease :name (n2 / name :op1 "colon" :op2 "cancer")))
                  :ARG2 (f / form-01
                        :ARG0 c2
                        :ARG1 (c5 / colony)
                        :location (a2 / agarose
                              :ARG1-of (s / soft-02)))))
      :time (t / then))

# ::id a_pmid_2094_2929.87 ::date 2015-05-20T11:50:05 ::annotator SDL-AMR-09 ::preferred
# ::snt As shown in Figure <xref ref-type="fig" rid="F4">4C</xref>, expression of both shRNA against SerpinE2 (#15 and #16) decreased the ability of HCT116 and LoVo cells to form colonies in soft agarose.
# ::save-date Mon Jul 27, 2015 ::file a_pmid_2094_2929_87.txt
(d / decrease-01
      :ARG0 (e / express-03
            :ARG2 (n7 / nucleic-acid :name (n / name :op1 "shRNA")
                  :mod (b / both)
                  :ARG0-of (c / counter-01
                        :ARG1 (p / protein :name (n2 / name :op1 "SerpinE2")
                              :ARG1-of (m / mean-01
                                    :ARG2 (a / and
                                          :op1 (p2 / protein :name (n3 / name :op1 "SerpinE2")
                                                :ARG1-of (l / label-01
                                                      :ARG2 15))
                                          :op2 (p3 / protein :name (n4 / name :op1 "SerpinE2")
                                                :ARG1-of (l2 / label-01
                                                      :ARG2 16))))))))
      :ARG1 (c2 / capable-01
            :ARG1 (a2 / and
                  :op1 (c3 / cell-line :name (n5 / name :op1 "HCT116"))
                  :op2 (c4 / cell-line :name (n6 / name :op1 "LoVo")))
            :ARG2 (f / form-01
                  :ARG0 a2
                  :ARG1 (c5 / colony)
                  :location (a3 / agarose
                        :ARG1-of (s / soft-02))))
      :ARG1-of (s2 / show-01
            :ARG0 (f2 / figure :mod "4C")))

# ::id a_pmid_2094_2929.88 ::date 2015-05-21T00:44:50 ::annotator SDL-AMR-09 ::preferred
# ::snt Of note, shSerpinE2(#15) which was less efficient than the shRNA (#16) to reduce <i>serpinE2 </i>gene expression (Figure <xref ref-type="fig" rid="F4">4A</xref>) was also less efficient to reduce colony formation.
# ::save-date Wed Dec 30, 2015 ::file a_pmid_2094_2929_88.txt
(e / efficient-01
      :ARG1 (p / protein :name (n / name :op1 "shSerpinE2")
            :ARG1-of (e2 / efficient-01
                  :ARG2 (r4 / reduce-01
                        :ARG0 p
                        :ARG1 (e3 / express-03
                              :ARG1 (g / gene :name (n3 / name :op1 "serpinE2"))))
                  :degree (l / less)
                  :ARG1-of (d / describe-01
                        :ARG0 (f2 / figure :mod "4A"))
                  :compared-to (n6 / nucleic-acid :name (n2 / name :op1 "shRNA")
                        :ARG1-of (l3 / label-01
                              :ARG2 16)))
            :ARG1-of (l2 / label-01
                  :ARG2 15)
            :ARG1-of (n4 / note-02))
      :ARG2 (r / reduce-01
            :ARG0 p
            :ARG1 (f / form-01
                  :ARG1 (c / colony)))
      :mod (a / also)
      :degree l)

# ::id a_pmid_2094_2929.89 ::date 2015-05-21T00:50:43 ::annotator SDL-AMR-09 ::preferred
# ::snt This indicates that serpinE2 controls anchorage-independent growth of human colon carcinoma cells.
# ::save-date Thu May 21, 2015 ::file a_pmid_2094_2929_89.txt
(i / indicate-01
      :ARG0 (t / this)
      :ARG1 (c / control-01
            :ARG0 (p / protein :name (n / name :op1 "serpinE2"))
            :ARG1 (g / grow-01
                  :ARG1 (c2 / cell
                        :source (c3 / carcinoma
                              :mod (h / human)
                              :mod (c4 / colon)))
                  :ARG0-of (d / depend-01 :polarity -
                        :ARG1 (a / anchorage)))))

# ::id a_pmid_2094_2929.90 ::date 2015-05-21T00:52:39 ::annotator SDL-AMR-09 ::preferred
# ::snt Additionally, as observed in caMEK-expressing IECs, the size of foci formed at post-confluency was significantly decreased in serpinE2-depleted LoVo cells (Figure <xref ref-type="fig" rid="F4">4D</xref>).
# ::save-date Sat Jun 6, 2015 ::file a_pmid_2094_2929_90.txt
(a / and
      :op2 (d / decrease-01
            :ARG1 (s2 / size
                  :poss (f / focus
                        :ARG1-of (f2 / form-01
                              :time (a2 / after
                                    :op1 (c3 / confluency)))))
            :ARG2 (s / significant-02)
            :location (c / cell-line :name (n / name :op1 "LoVo")
                  :ARG1-of (d2 / deplete-01
                        :ARG2 (p2 / protein :name (n2 / name :op1 "serpinE2"))))
            :ARG1-of (o / observe-01
                  :location (c2 / cell :name (n3 / name :op1 "IEC")
                        :ARG3-of (e / express-03
                              :ARG2 (e2 / enzyme :name (n4 / name :op1 "caMEK"))))))
      :ARG1-of (d3 / describe-01
            :ARG0 (f3 / figure :mod "4D")))

# ::id a_pmid_2094_2929.91 ::date 2015-05-21T00:57:22 ::annotator SDL-AMR-09 ::preferred
# ::snt The tumorigenicity of colorectal cell lines was next assessed after subcutaneous (s.c.) injection into the flank of nude mice.
# ::save-date Thu Sep 24, 2015 ::file a_pmid_2094_2929_91.txt
(a / assess-01
      :ARG1 (p / possible-01
            :ARG1 (c3 / create-01
                  :ARG0 (c / cell-line
                        :source (c2 / colorectal))
                  :ARG1 (t / tumor)))
      :time (n / next)
      :time (a2 / after
            :op1 (i / inject-01
                  :ARG2 (f / flank
                        :poss (m / mouse
                              :mod (n2 / nude)))
                  :mod (s / subcutaneous))))

# ::id a_pmid_2094_2929.92 ::date 2015-05-21T01:00:22 ::annotator SDL-AMR-09 ::preferred
# ::snt As shown in Figure <xref ref-type="fig" rid="F5">5A</xref> and <xref ref-type="fig" rid="F5">5B</xref>, HCT116 and LoVo cell lines induced palpable tumors with a short latency period of respectively 15 and 10 days after their injection.
# ::save-date Mon Dec 21, 2015 ::file a_pmid_2094_2929_92.txt
(i / induce-01
      :ARG0 (a / and
            :op1 (c / cell-line :name (n / name :op1 "HCT116"))
            :op2 (c2 / cell-line :name (n2 / name :op1 "LoVo")))
      :ARG2 (t2 / tumor
            :mod (p / palpable)
            :mod (p2 / period
                  :mod (l / latency)
                  :ARG1-of (s / short-07)
                  :time (a3 / after
                        :op1 (i2 / inject-01
                              :ARG1 a)
                        :quant (a2 / and
                              :op1 (t3 / temporal-quantity :quant 15
                                    :unit (d2 / day))
                              :op2 (t4 / temporal-quantity :quant 10
                                    :unit (d / day))
                              :mod (r / respective)))))
      :ARG1-of (s2 / show-01
            :medium (a4 / and
                  :op1 (f / figure :mod "5A")
                  :op2 (f2 / figure :mod "5B"))))

# ::id a_pmid_2094_2929.93 ::date 2015-05-21T01:06:14 ::annotator SDL-AMR-09 ::preferred
# ::snt More importantly, downregulation of serpinE2 expression with shSerpinE2(#16) in these cell lines severely impaired their capacity to grow as tumors in nude mice.
# ::save-date Wed Dec 30, 2015 ::file a_pmid_2094_2929_93.txt
(i / impair-01
      :ARG0 (d / downregulate-01
            :ARG1 (e / express-03
                  :ARG2 (p / protein :name (n / name :op1 "serpinE2"))
                  :ARG3 (c / cell-line
                        :mod (t / this)))
            :ARG2 (p2 / protein :name (n2 / name :op1 "shSerpinE2")
                  :ARG1-of (l / label-01
                        :ARG2 16)))
      :ARG1 (c2 / capable-01
            :ARG1 c
            :ARG2 (g / grow-02
                  :ARG1 c
                  :ARG2 (t2 / tumor)
                  :location (m / mouse
                        :mod (n3 / nude))))
      :manner (s / severe)
      :mod (i2 / important
            :degree (m2 / more)))

# ::id a_pmid_2094_2929.94 ::date 2015-05-21T01:10:20 ::annotator SDL-AMR-09 ::preferred
# ::snt Finally, <i>in vitro </i>transwell migration assays were performed to verify the importance of serpinE2 in colon carcinoma cell migration.
# ::save-date Wed Dec 30, 2015 ::file a_pmid_2094_2929_94.txt
(p / perform-02 :li "-1"
      :ARG1 (a / assay-01
            :ARG1 (m2 / migrate-01
                  :mod (t2 / transwell))
            :manner (i / in-vitro))
      :purpose (v / verify-01
            :ARG1 (i2 / important
                  :domain (p2 / protein :name (n2 / name :op1 "serpinE2"))
                  :purpose (m / migrate-01
                        :ARG0 (c / cell
                              :source (c2 / carcinoma
                                    :mod (c3 / colon)))))))

# ::id a_pmid_2094_2929.95 ::date 2015-05-21T01:17:17 ::annotator SDL-AMR-09 ::preferred
# ::snt As illustrated in Figure <xref ref-type="fig" rid="F6">6A</xref>, serpinE2 deficiency significantly reduced HCT116 (not shown) and LoVo cell migration to the undersurface of the membrane coated or not with fibronectin or vitronectin (data not shown).
# ::save-date Sun Jul 5, 2015 ::file a_pmid_2094_2929_95.txt
(r / reduce-01
      :ARG0 (l / lack-01
            :ARG1 (p / protein :name (n / name :op1 "serpinE2")))
      :ARG1 (m / migrate-01
            :ARG0 (a / and
                  :op1 (c2 / cell-line :name (n2 / name :op1 "HCT116")
                        :ARG1-of (s2 / show-01 :polarity -))
                  :op2 (c4 / cell-line :name (n3 / name :op1 "LoVo")))
            :ARG2 (u / undersurface
                  :part-of (m2 / membrane)
                  :ARG1-of (c5 / coat-01
                        :ARG2 (o / or
                              :op1 (p2 / protein :name (n4 / name :op1 "fibronectin"))
                              :op2 (p3 / protein :name (n5 / name :op1 "vitronectin")))
                        :op1-of (o2 / or
                              :op2 (c6 / coat-01 :polarity -
                                    :ARG1 u
                                    :ARG2 o)))))
      :ARG2 (s / significant-02)
      :ARG1-of (i / illustrate-01
            :medium (f / figure :mod "6A"))
      :ARG1-of (d / describe-01
            :ARG0 (d2 / data
                  :ARG1-of s2)))

# ::id a_pmid_2094_2929.96 ::date 2015-05-21T01:28:49 ::annotator SDL-AMR-09 ::preferred
# ::snt The net effect of serpinE2 knockdown was also determined on invasion by using BD Biocoat Matrigel invasion chambers, in presence of hydroxyurea.
# ::save-date Tue Jul 14, 2015 ::file a_pmid_2094_2929_96.txt
(d / determine-01
      :ARG1 (a / affect-01
            :ARG0 (k / knock-down-02
                  :ARG1 (p / protein :name (n2 / name :op1 "serpinE2")))
            :mod (n / net))
      :mod (a2 / also)
      :time (i / invade-01)
      :manner (u / use-01
            :ARG1 (t / thing :name (n3 / name :op1 "BD" :op2 "Biocoat" :op3 "Matrigel" :op4 "invasion" :op5 "chamber")))
      :condition (p2 / present-02
            :ARG1 (s / small-molecule :name (n4 / name :op1 "hydroxyurea"))))

# ::id a_pmid_2094_2929.97 ::date 2015-05-21T01:35:43 ::annotator SDL-AMR-09 ::preferred
# ::snt As shown in Figure <xref ref-type="fig" rid="F6">6B</xref>, the capacity of LoVo cells to invade Matrigel was also altered by serpinE2 silencing
# ::save-date Sun Jan 17, 2016 ::file a_pmid_2094_2929_97.txt
(a / alter-01
      :ARG0 (s / silence-01
            :ARG1 (p2 / protein :name (n3 / name :op1 "serpinE2")))
      :ARG1 (c / capable-01
            :ARG1 (c2 / cell-line :name (n / name :op1 "LoVo"))
            :ARG2 (i / invade-01
                  :ARG0 c2
                  :ARG1 (p / protein :name (n2 / name :op1 "Matrigel"))))
      :mod (a2 / also)
      :ARG1-of (s2 / show-01
            :medium (f / figure :mod "6B")))

# ::id a_pmid_2094_2929.98 ::date 2015-05-21T01:41:10 ::annotator SDL-AMR-09 ::preferred
# ::snt To test the hypothesis that this altered migration and invasion capacity could result from a defect in cell adhesion, adhesion strength to the substrate was examined for control and shSerpinE2(#16)-expressing LoVo cells.
# ::save-date Wed Dec 30, 2015 ::file a_pmid_2094_2929_98.txt
(e / examine-01
      :ARG1 (s / strong-02
            :degree-of (a / adhere-01
                  :ARG1 (a2 / and
                        :op1 (c / cell-line :name (n / name :op1 "LoVo")
                              :mod (c2 / control))
                        :op2 (c3 / cell-line :name (n2 / name :op1 "LoVo")
                              :ARG3-of (e2 / express-03
                                    :ARG2 (p2 / protein :name (n3 / name :op1 "shSerpinE2")
                                          :ARG1-of (l / label-01
                                                :ARG2 16)))))
                  :ARG2 (s2 / substrate)))
      :ARG2 (t2 / test-01
            :ARG1 (h / hypothesize-01
                  :ARG1 (p / possible-01
                        :ARG1 (r2 / result-01
                              :ARG1 (d / defect
                                    :topic (a5 / adhere-01
                                          :ARG1 (c5 / cell)))
                              :ARG2 (c4 / capable-01
                                    :ARG2 (a3 / and
                                          :op1 (m / migrate-01)
                                          :op2 (i / invade-01))
                                    :ARG1-of (a4 / alter-01)
                                    :mod (t3 / this)))))))

# ::id a_pmid_2094_2929.99 ::date 2015-05-21T01:49:37 ::annotator SDL-AMR-09 ::preferred
# ::snt Using a trypsin-mediated de-adhesion assay, downregulation of serpinE2 significantly delayed LoVo cell detachment after trypsinization (Figure <xref ref-type="fig" rid="F6">6C</xref>), suggesting that serpinE2 expression decreases adhesion of colorectal carcinoma cells to the substrate.
# ::save-date Thu Dec 17, 2015 ::file a_pmid_2094_2929_99.txt
(d / delay-01
      :ARG0 (d2 / downregulate-01
            :ARG1 (p / protein :name (n / name :op1 "serpinE2")))
      :ARG1 (d3 / detach-01
            :ARG1 (c / cell-line :name (n2 / name :op1 "LoVo")))
      :ARG2 (s / significant-02)
      :time (a / after
            :op1 (t / trypsinize-00))
      :manner (u / use-01
            :ARG1 (a2 / assay-01
                  :ARG1 (a3 / adhere-01 :polarity -)
                  :ARG1-of (m / mediate-01
                        :ARG0 (e / enzyme :name (n4 / name :op1 "trypsin")))))
      :ARG1-of (d4 / describe-01
            :ARG0 (f / figure :mod "6C"))
      :ARG0-of (s2 / suggest-01
            :ARG1 (d5 / decrease-01
                  :ARG0 (e2 / express-03
                        :ARG2 p)
                  :ARG1 (a4 / adhere-01
                        :ARG1 (c2 / cell
                              :source (c3 / carcinoma
                                    :mod (c4 / colorectal)))
                        :ARG2 (s3 / substrate)))))

# ::id a_pmid_2094_2929.100 ::date 2015-05-21T01:59:48 ::annotator SDL-AMR-09 ::preferred
# ::snt <i>SerpinE2 </i>gene expression is up-regulated in human colorectal cancers
# ::save-date Wed Dec 9, 2015 ::file a_pmid_2094_2929_100.txt
(u / upregulate-01
      :ARG1 (e / express-03
            :ARG1 (g / gene
                  :name (n / name :op1 "serpinE2"))
            :ARG3 (d / disease :wiki "Cancer"
                  :name (n2 / name :op1 "cancer")
                  :mod (h / human)
                  :mod (c2 / colorectal))))

# ::id a_pmid_2094_2929.101 ::date 2015-05-21T02:00:52 ::annotator SDL-AMR-09 ::preferred
# ::snt We next analyzed <i>serpinE2 </i>gene expression in a series of human paired specimens (resection margins and primary tumors) by Q-PCR analysis.
# ::save-date Thu May 21, 2015 ::file a_pmid_2094_2929_101.txt
(a / analyze-01
      :ARG0 (w / we)
      :ARG1 (e / express-03
            :ARG1 (g / gene :name (n2 / name :op1 "serpinE2"))
            :ARG3 (s / series
                  :consist-of (s2 / specimen
                        :mod (h / human)
                        :ARG1-of (p / pair-01)
                        :ARG1-of (m / mean-01
                              :ARG2 (a2 / and
                                    :op1 (m2 / margin
                                          :mod (r / resection))
                                    :op2 (t / tumor
                                          :mod (p2 / primary)))))))
      :time (n / next)
      :manner (t2 / thing :name (n3 / name :op1 "Q-PCR" :op2 "analysis")))

# ::id a_pmid_2094_2929.102 ::date 2015-05-21T02:08:57 ::annotator SDL-AMR-09 ::preferred
# ::snt As shown in Figure <xref ref-type="fig" rid="F7">7</xref>, mRNA levels of serpinE2 were markedly increased in human adenomas in comparison to healthy adjacent tissues.
# ::save-date Mon Dec 14, 2015 ::file a_pmid_2094_2929_102.txt
(i / increase-01
      :ARG1 (l / level
            :quant-of (n4 / nucleic-acid :name (n / name :op1 "mRNA")
                  :ARG0-of (e / encode-01
                        :ARG1 (p / protein :name (n2 / name :op1 "serpinE2")))))
      :manner (m / marked)
      :ARG1-of (s / show-01
            :medium (f / figure :mod 7))
      :compared-to (l2 / level
            :location (t / tissue
                  :mod (h2 / healthy)
                  :mod (a2 / adjacent))
            :quant-of n4)
      :location (m2 / medical-condition :name (n3 / name :op1 "adenoma")
            :mod (h / human)))

# ::id a_pmid_2094_2929.103 ::date 2015-05-21T02:14:26 ::annotator SDL-AMR-09 ::preferred
# ::snt Furthermore, serpinE2 expression was also significantly enhanced in colorectal tumors, regardless of tumor stage and grade.
# ::save-date Thu Jan 7, 2016 ::file a_pmid_2094_2929_103.txt
(a / and
      :op2 (e / enhance-01
            :ARG1 (e2 / express-03
                  :ARG2 (p / protein :name (n / name :op1 "serpinE2"))
                  :ARG3 (t / tumor
                        :mod (c / colorectal)))
            :ARG3 (s / significant-02)
            :mod (a2 / also)
            :ARG1-of (r / regardless-91
                  :ARG2 (a3 / and
                        :op1 (t2 / thing
                              :ARG2-of (s2 / stage-02
                                    :ARG1 t))
                        :op2 (g / grade
                              :mod t)))))

# ::id a_pmid_2139_2397.12 ::date 2015-05-26T08:45:19 ::annotator SDL-AMR-09 ::preferred
# ::snt The average level of phosphorylation of YB-1 in the breast cancer cell lines SKBr3, MCF-7, HBL100 and MDA-MB-231 was significantly higher than that in normal cells.
# ::save-date Mon Dec 21, 2015 ::file a_pmid_2139_2397_12.txt
(h / high-02
      :ARG1 (l / level
            :ARG1-of (a / average-04)
            :degree-of (p / phosphorylate-01
                  :ARG1 (p2 / protein :name (n / name :op1 "YB-1")))
            :location (a2 / and
                  :op1 (c3 / cell-line :name (n3 / name :op1 "SKBr3"))
                  :op2 (c4 / cell-line :name (n4 / name :op1 "MCF-7"))
                  :op3 (c5 / cell-line :name (n5 / name :op1 "HBL100"))
                  :op4 (c6 / cell-line :name (n6 / name :op1 "MDA-MB-231"))
                  :mod (d / disease :wiki "Breast_cancer" :name (n2 / name :op1 "breast" :op2 "cancer"))))
      :degree (m / more)
      :ARG1-of (s / significant-02)
      :compared-to (c7 / cell
            :ARG1-of (n7 / normal-02)))

# ::id a_pmid_2139_2397.13 ::date 2015-05-26T09:06:52 ::annotator SDL-AMR-09 ::preferred
# ::snt Exposure to IR and stimulation with erbB1 ligands resulted in phosphorylation of YB-1 in <i>K-RAS</i><sub>wt </sub>SKBr3, MCF-7 and HBL100 cells, which was shown to be K-Ras-independent.
# ::save-date Thu Jan 14, 2016 ::file a_pmid_2139_2397_13.txt
(r / result-01
      :ARG1 (a / and
            :op1 (e / expose-01
                  :ARG2 (r2 / radiate-01
                        :ARG0-of (i / ionize-01)))
            :op2 (s / stimulate-01
                  :ARG2 (l / ligand :name (n2 / name :op1 "erbB1"))))
      :ARG2 (p / phosphorylate-01
            :ARG1 (p2 / protein :name (n3 / name :op1 "YB-1"))
            :location (a2 / and
                  :op1 (c / cell-line :name (n4 / name :op1 "SKBr3"))
                  :op2 (c2 / cell-line :name (n5 / name :op1 "MCF-7"))
                  :op3 (c3 / cell-line :name (n6 / name :op1 "HBL100"))
                  :mod (g / gene :name (n7 / name :op1 "K-Ras")
                        :mod (w / wild-type)))
            :ARG1-of (d / depend-01 :polarity -
                  :ARG0 g
                  :ARG1-of (s2 / show-01))))

# ::id a_pmid_2139_2397.14 ::date 2015-05-26T09:24:42 ::annotator SDL-AMR-09 ::preferred
# ::snt In contrast, lack of YB-1 phosphorylation after stimulation with either IR or erbB1 ligands was observed in <i>K-RAS</i><sub>mt </sub>MDA-MB-231 cells.
# ::save-date Thu Jan 14, 2016 ::file a_pmid_2139_2397_14.txt
(c / contrast-01
      :ARG2 (o / observe-01
            :ARG1 (l / lack-01
                  :ARG1 (p / phosphorylate-01
                        :ARG1 (p2 / protein :name (n / name :op1 "YB-1")))
                  :time (a / after
                        :op1 (s / stimulate-01
                              :ARG2 (o2 / or
                                    :op1 (r / radiate-01
                                          :ARG0-of (i / ionize-01))
                                    :op2 (l3 / ligand :name (n3 / name :op1 "erbB1"))))))
            :location (c2 / cell-line :name (n4 / name :op1 "MDA-MB-231")
                  :mod (g / gene :name (n5 / name :op1 "K-RAS")
                        :ARG2-of (m / mutate-01)))))

# ::id a_pmid_2139_2397.15 ::date 2015-05-26T09:29:24 ::annotator SDL-AMR-09 ::preferred
# ::snt Similarly to MDA-MB-231 cells, YB-1 became constitutively phosphorylated in <i>K-RAS</i><sub>wt </sub>cells following the overexpression of mutated <i>K-RAS</i>, and its phosphorylation was not further enhanced by IR.
# ::save-date Thu Jan 14, 2016 ::file a_pmid_2139_2397_15.txt
(a / and
      :op1 (b / become-01
            :ARG1 (p / protein :name (n / name :op1 "YB-1"))
            :ARG2 (p2 / phosphorylate-01
                  :ARG1 p
                  :mod (c / constitutive)
                  :location (c2 / cell
                        :mod (g2 / gene :name (n2 / name :op1 "K-RAS")
                              :mod (w / wild-type))))
            :ARG2-of (f / follow-01
                  :ARG1 (o / overexpress-01
                        :ARG1 (g / gene :name (n3 / name :op1 "K-RAS")
                              :ARG2-of (m / mutate-01)))))
      :op2 (e3 / enhance-01 :polarity -
            :ARG1 p2
            :ARG2 (r2 / radiate-01
                  :ARG0-of (i / ionize-01))
            :degree (f2 / further))
      :ARG1-of (r / resemble-01
            :ARG2 (c3 / cell-line :name (n5 / name :op1 "MDA-MB-231"))))

# ::id a_pmid_2139_2397.16 ::date 2015-05-26T09:43:38 ::annotator SDL-AMR-09 ::preferred
# ::snt Phosphorylation of YB-1 as a result of irradiation or <i>K-RAS </i>mutation was dependent on erbB1 and its downstream pathways, PI3K and MAPK/ERK.
# ::save-date Thu Jan 14, 2016 ::file a_pmid_2139_2397_16.txt
(d / depend-01
      :ARG0 (p2 / phosphorylate-01
            :ARG1 (p3 / protein :name (n2 / name :op1 "YB-1"))
            :ARG2-of (r / result-01
                  :ARG1 (a / and
                        :op1 (i / irradiate-01)
                        :op2 (m / mutate-01
                              :ARG1 (g / gene :name (n3 / name :op1 "K-RAS"))))))
      :ARG1 (a3 / and
            :op1 (p / protein :name (n6 / name :op1 "erbB1"))
            :op2 (p4 / pathway
                  :mod (d2 / downstream)
                  :ARG2-of (i2 / include-91
                        :ARG1 (a2 / and
                              :op1 (p5 / pathway :name (n4 / name :op1 "PI3K"))
                              :op2 (p6 / pathway :name (n5 / name :op1 "MAPK/ERK"))))
                  :poss p)))

# ::id a_pmid_2139_2397.17 ::date 2015-05-26T09:50:26 ::annotator SDL-AMR-09 ::preferred
# ::snt In <i>K-RAS</i><sub>mt </sub>cells <i>K-RAS </i>siRNA as well as YB-1 siRNA blocked repair of DNA-DSB.
# ::save-date Sat Jan 16, 2016 ::file a_pmid_2139_2397_17.txt
(b / block-01
      :ARG0 (a / and
            :op1 (n7 / nucleic-acid :name (n2 / name :op1 "siRNA")
                  :ARG0-of (e2 / encode-01
                        :ARG1 (g / gene :name (n / name :op1 "K-Ras"))))
            :op2 (n8 / nucleic-acid :name (n3 / name :op1 "siRNA")
                  :ARG0-of (e3 / encode-01
                        :ARG1 (p / protein :name (n4 / name :op1 "YB-1")))))
      :ARG1 (r3 / repair-01
            :ARG1 (t / thing :name (n5 / name :op1 "DNA-DSB")))
      :location (c / cell
            :mod (g2 / gene :name (n6 / name :op1 "K-RAS")
                  :ARG2-of (m / mutate-01))))

# ::id a_pmid_2139_2397.18 ::date 2015-05-26T10:05:55 ::annotator SDL-AMR-09 ::preferred
# ::snt Likewise, YB-1 siRNA increased radiation sensitivity.
# ::save-date Wed Jun 3, 2015 ::file a_pmid_2139_2397_18.txt
(i / increase-01
      :ARG0 (n3 / nucleic-acid :name (n / name :op1 "siRNA")
            :ARG0-of (e / encode-01
                  :ARG1 (p / protein :name (n2 / name :op1 "YB-1"))))
      :ARG1 (s / sensitive-03
            :ARG1 (r2 / radiate-01))
      :manner (l / likewise))

# ::id a_pmid_2139_2397.115 ::date 2015-05-26T13:17:25 ::annotator SDL-AMR-09 ::preferred
# ::snt Stimulation of YB-1 phosphorylation in breast cancer cells by IR and exposure to erbB1 ligands
# ::save-date Sun Jan 3, 2016 ::file a_pmid_2139_2397_115.txt
(a / and
      :op1 (s / stimulate-01
            :ARG0 (r / radiate-01
                  :ARG0-of (i / ionize-01))
            :ARG1 (p2 / phosphorylate-01
                  :ARG1 (p3 / protein :name (n2 / name :op1 "YB-1")))
            :location (c / cell
                  :mod (d / disease :wiki "Breast_cancer" :name (n / name :op1 "breast" :op2 "cancer"))))
      :op2 (e / expose-01
            :ARG1 (l / ligand :name (n4 / name :op1 "erbB1"))))

# ::id a_pmid_2139_2397.116 ::date 2015-05-26T13:20:02 ::annotator SDL-AMR-09 ::preferred
# ::snt The level of basal YB-1 phosphorylation at S102 in a panel of breast cancer cells (MDA-MB-231, MCF-7, HBL100 and SKBr3) was compared to the level of YB-1 phosphorylation in normal cells, that is, human skin and lung fibroblasts (HSF1, HSF7 and HFL) as well as normal mammary epithelial cells (MCF-10A) (Figures <xref ref-type="fig" rid="F1">1A</xref> and <xref ref-type="fig" rid="F1">1B</xref>).
# ::save-date Sun Jan 3, 2016 ::file a_pmid_2139_2397_116.txt
(c / compare-01
      :ARG1 (l / level
            :degree-of (p / phosphorylate-01
                  :ARG1 (a / amino-acid :mod 102 :name (n2 / name :op1 "serine")
                        :part-of (p2 / protein :name (n3 / name :op1 "YB-1")))
                  :location (p3 / panel
                        :consist-of (c2 / cell-line
                              :ARG2-of (i / include-91
                                    :ARG1 (a2 / and
                                          :op1 (c4 / cell-line :name (n4 / name :op1 "MDA-MB-231"))
                                          :op2 (c5 / cell-line :name (n5 / name :op1 "MCF-7"))
                                          :op3 (c6 / cell-line :name (n6 / name :op1 "HBL100"))
                                          :op4 (c7 / cell-line :name (n7 / name :op1 "SKBr3"))))
                              :mod (d / disease :wiki "Breast_cancer" :name (n / name :op1 "breast" :op2 "cancer"))))
                  :mod (b2 / basal)))
      :ARG2 (l2 / level
            :degree-of (p4 / phosphorylate-01
                  :ARG1 p2
                  :location (c8 / cell-line
                        :ARG1-of (n8 / normal-02)
                        :ARG2-of (m3 / mean-01
                              :ARG1 (a4 / and
                                    :op1 (s / skin
                                          :mod (h / human))
                                    :op2 (f / fibroblast
                                          :mod (l3 / lung))
                                    :op3 (c12 / cell
                                          :mod (e / epithelium)
                                          :mod (m / mammary)
                                          :ARG1-of (m2 / mean-01
                                                :ARG2 (c13 / cell-line :name (n14 / name :op1 "MCF-10A")))
                                          :ARG1-of n8)
                                    :ARG2-of (i3 / include-91
                                          :ARG1 (a3 / and
                                                :op1 (c10 / cell-line :name (n10 / name :op1 "HSF1"))
                                                :op2 (c9 / cell-line :name (n11 / name :op1 "HSF7"))
                                                :op3 (c11 / cell-line :name (n12 / name :op1 "HFL")))))))))
      :ARG1-of (d2 / describe-01
            :ARG0 (a5 / and
                  :op1 (f2 / figure :mod "1A")
                  :op2 (f3 / figure :mod "1B"))))

# ::id a_pmid_2139_2397.117 ::date 2015-05-26T13:40:47 ::annotator SDL-AMR-09 ::preferred
# ::snt As shown in Figure <xref ref-type="fig" rid="F1">1C</xref>, the ratio of P-YB-1/YB-1 is significantly higher in tumor cells than in fibroblasts.
# ::save-date Fri Dec 18, 2015 ::file a_pmid_2139_2397_117.txt
(h2 / high
      :domain (r / ratio-of
            :op1 (p2 / protein :name (n / name :op1 "YB-1")
                  :ARG3-of (p / phosphorylate-01))
            :op2 (p3 / protein :name (n2 / name :op1 "YB-1"))
            :ARG1-of (h / high-02
                  :degree (m / more)
                  :ARG1-of (s2 / significant-02))
            :location (c / cell
                  :mod (t / tumor))
            :compared-to (f2 / fibroblast))
      :ARG1-of (s / show-01
            :ARG0 (f / figure :mod "1C")))

# ::id a_pmid_2139_2397.118 ::date 2015-05-26T13:49:13 ::annotator SDL-AMR-09 ::preferred
# ::snt The comparisons of the ratio of P-YB-1/YB-1 in tumor cells and normal mammary epithelial cells indicated an even stronger significant difference as tested for MDA-MB-231 and MCF-10A cells (Figures <xref ref-type="fig" rid="F1">1B</xref> and <xref ref-type="fig" rid="F1">1C</xref>).
# ::save-date Mon Dec 21, 2015 ::file a_pmid_2139_2397_118.txt
(i / indicate-01
      :ARG0 (c / compare-01
            :ARG2 (r / ratio-of
                  :op1 (p2 / protein :name (n / name :op1 "YB-1")
                        :ARG3-of (p / phosphorylate-01))
                  :op2 (p3 / protein :name (n2 / name :op1 "YB-1")))
            :location (a3 / and
                  :op1 (c2 / cell
                        :mod (t / tumor))
                  :op2 (c3 / cell
                        :mod (e / epithelium)
                        :mod (m / mammary)
                        :ARG1-of (n5 / normal-02))))
      :ARG1 (d / differ-02
            :mod (s / strong
                  :degree (m2 / more)
                  :mod (e2 / even))
            :ARG1-of (s2 / significant-02)
            :ARG1-of (t2 / test-01
                  :ARG2 (a / and
                        :op1 (c4 / cell-line :name (n3 / name :op1 "MDA-MB-231"))
                        :op2 (c5 / cell-line :name (n4 / name :op1 "MCF-10A")))))
      :ARG1-of (d2 / describe-01
            :ARG0 (a2 / and
                  :op1 (f / figure :mod "1B")
                  :op2 (f2 / figure :mod "1C"))))

# ::id a_pmid_2139_2397.119 ::date 2015-05-26T13:56:53 ::annotator SDL-AMR-09 ::preferred
# ::snt YB-1 has been identified as a direct substrate of Akt [<xref ref-type="bibr" rid="B12">12</xref>,<xref ref-type="bibr" rid="B35">35</xref>].
# ::save-date Mon Dec 21, 2015 ::file a_pmid_2139_2397_119.txt
(i / identify-01
      :ARG1 (p / protein :name (n / name :op1 "YB-1"))
      :ARG2 (s / substrate
            :mod (e / enzyme :name (n2 / name :op1 "Akt"))
            :ARG1-of (d / direct-02))
      :ARG1-of (d2 / describe-01
            :ARG0 (p2 / publication
                  :ARG1-of (c / cite-01
                        :ARG2 (a / and :op1 12 :op2 35)))))

# ::id a_pmid_2139_2397.120 ::date 2015-05-26T14:01:38 ::annotator SDL-AMR-09 ::preferred
# ::snt As previously reported, IR can activate the Akt ligand independently [<xref ref-type="bibr" rid="B30">30</xref>,<xref ref-type="bibr" rid="B36">36</xref>].
# ::save-date Sun Jan 3, 2016 ::file a_pmid_2139_2397_120.txt
(p / possible-01
      :ARG1 (a / activate-01
            :ARG0 (r2 / radiate-01
                  :ARG0-of (i / ionize-01))
            :ARG1 (l / ligand
                  :mod (e / enzyme :name (n3 / name :op1 "Akt")))
            :manner (d2 / depend-01 :polarity -))
      :ARG1-of (d / describe-01
            :ARG0 (p3 / publication
                  :ARG1-of (c / cite-01
                        :ARG2 (a2 / and :op1 30 :op2 36))))
      :ARG1-of (r / report-01
            :time (p2 / previous)))

# ::id a_pmid_2139_2397.121 ::date 2015-05-26T14:08:00 ::annotator SDL-AMR-09 ::preferred
# ::snt Therefore, we asked whether IR could induce YB-1 phosphorylation as well.
# ::save-date Sun Jan 3, 2016 ::file a_pmid_2139_2397_121.txt
(c / cause-01
      :ARG1 (a / ask-01 :mode interrogative
            :ARG0 (w / we)
            :ARG1 (p3 / possible-01
                  :ARG1 (i / induce-01
                        :ARG0 (r / radiate-01
                              :ARG0-of (i2 / ionize-01))
                        :ARG2 (p2 / phosphorylate-01
                              :ARG1 (p4 / protein :name (n2 / name :op1 "YB-1")))
                        :mod (a2 / as-well)))))

# ::id a_pmid_2139_2397.122 ::date 2015-05-26T14:12:54 ::annotator SDL-AMR-09 ::preferred
# ::snt As shown in Figure <xref ref-type="fig" rid="F1">1D</xref>, IR induces YB-1 phosphorylation differentially.
# ::save-date Sun Jan 3, 2016 ::file a_pmid_2139_2397_122.txt
(i / induce-01
      :ARG0 (r / radiate-01
            :ARG0-of (i2 / ionize-01))
      :ARG2 (p / phosphorylate-01
            :ARG1 (p2 / protein :name (n2 / name :op1 "YB-1")))
      :ARG1-of (s / show-01
            :ARG0 (f / figure :mod "1D"))
      :manner (d / differential))

# ::id a_pmid_2139_2397.123 ::date 2015-05-26T14:17:15 ::annotator SDL-AMR-09 ::preferred
# ::snt A strong phosphorylation signal was observed in SKBr3, whereas HBL100 showed moderate phosphorylation of YB-1 and phosphorylation in MCF-7 was weak.
# ::save-date Sun Dec 20, 2015 ::file a_pmid_2139_2397_123.txt
(c / contrast-01
      :ARG1 (o / observe-01
            :ARG1 (s / signal-07
                  :ARG1 (p / phosphorylate-01)
                  :mod (s2 / strong)
                  :location (c2 / cell-line :name (n / name :op1 "SKBr3"))))
      :ARG2 (a / and
            :op1 (s3 / show-01
                  :ARG0 (c3 / cell-line :name (n2 / name :op1 "HBL100"))
                  :ARG1 (p2 / phosphorylate-01
                        :ARG1 (p3 / protein :name (n3 / name :op1 "YB-1"))
                        :ARG1-of (m / moderate-03)))
            :op2 (p4 / phosphorylate-01
                  :location (c4 / cell-line :name (n4 / name :op1 "MCF-7"))
                  :ARG1-of (w / weak-02))))

# ::id a_pmid_2139_2397.124 ::date 2015-05-26T14:26:27 ::annotator SDL-AMR-09 ::preferred
# ::snt However, in MDA-MB-231 cells, a lack of IR-induced YB-1 phosphorylation was observed.
# ::save-date Sun Jan 3, 2016 ::file a_pmid_2139_2397_124.txt
(h / have-concession-91
      :ARG1 (o / observe-01
            :ARG1 (l / lack-01
                  :ARG1 (p / phosphorylate-01
                        :ARG1 (p2 / protein :name (n / name :op1 "YB-1"))
                        :ARG2-of (i / induce-01
                              :ARG0 (r / radiate-01
                                    :ARG0-of (i2 / ionize-01))))
                  :location (c / cell-line :name (n3 / name :op1 "MDA-MB-231")))))

# ::id a_pmid_2139_2397.125 ::date 2015-05-26T14:34:37 ::annotator SDL-AMR-09 ::preferred
# ::snt In this cell line, stimulation with the erbB1 ligand EGF, AREG or TGFα did not induce YB-1 phosphorylation, whereas strong phosphorylation at the indicated times after stimulation was observed in the cell lines SKBr3, HBL100 and MCF-7 (Figure <xref ref-type="fig" rid="F1">1D</xref>).
# ::save-date Wed Mar 9, 2016 ::file a_pmid_2139_2397_125.txt
(c / contrast-01
      :ARG1 (i / induce-01 :polarity -
            :ARG0 (s / stimulate-01
                  :ARG2 (l / ligand :name (n / name :op1 "erbB1")
                        :ARG2-of (i2 / include-91
                              :ARG1 (a / and
                                    :op1 (p6 / protein :name (n2 / name :op1 "EGF"))
                                    :op2 (p2 / protein :name (n3 / name :op1 "AREG"))
                                    :op3 (p3 / protein :name (n4 / name :op1 "TGFα"))))))
            :ARG2 (p / phosphorylate-01
                  :ARG1 (p4 / protein :name (n5 / name :op1 "YB-1")))
            :location (c5 / cell-line
                  :mod (t2 / this)))
      :ARG2 (o / observe-01
            :ARG1 (p5 / phosphorylate-01
                  :mod (s3 / strong)
                  :time (t / time
                        :ARG1-of (i3 / indicate-01))
                  :time (a2 / after
                        :op1 s))
            :location (a3 / and
                  :op1 (c2 / cell-line :name (n6 / name :op1 "SKBr3"))
                  :op2 (c3 / cell-line :name (n7 / name :op1 "HBL100"))
                  :op3 (c4 / cell-line :name (n8 / name :op1 "MCF-7"))))
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod "1D")))

# ::id a_pmid_2139_2397.126 ::date 2015-05-26T14:54:13 ::annotator SDL-AMR-09 ::preferred
# ::snt Although the MCF-7 and HBL100 cell lines have <i>K-RAS</i><sub>wt </sub>status, these cells presented high basal YB-1 phosphorylation.
# ::save-date Thu Jan 14, 2016 ::file a_pmid_2139_2397_126.txt
(h / have-concession-91
      :ARG1 (p2 / present-01
            :ARG0 a
            :ARG1 (p / phosphorylate-01
                  :ARG1 (p3 / protein :name (n4 / name :op1 "YB-1"))
                  :ARG1-of (h3 / high-02)
                  :mod (b / basal)))
      :ARG2 (h2 / have-03
            :ARG0 (a / and
                  :op1 (c / cell-line :name (n2 / name :op1 "MCF-7"))
                  :op2 (c2 / cell-line :name (n3 / name :op1 "HBL100")))
            :ARG1 (s / status
                  :mod (g / gene :name (n / name :op1 "K-RAS")
                        :mod (w / wild-type)))))

# ::id a_pmid_2139_2397.127 ::date 2015-05-27T08:54:46 ::annotator SDL-AMR-09 ::preferred
# ::snt To prove whether the high basal phosphorylation status of YB-1 was due to stimulation by growth factors in the culture medium, P-YB-1 was compared under serum supplementation and serum depletion in MCF-7 cells.
# ::save-date Wed Feb 24, 2016 ::file a_pmid_2139_2397_127.txt
(c5 / compare-01
      :ARG0 (a / and
            :op1 (s4 / supplement-01
                  :ARG1 (s5 / serum))
            :op2 (d / deplete-01
                  :ARG1 s5)
            :location (c4 / cell-line :name (n3 / name :op1 "MCF-7")))
      :ARG1 (p4 / protein :name (n4 / name :op1 "YB-1")
            :ARG3-of (p5 / phosphorylate-01))
      :purpose (p2 / prove-01
            :ARG1 (c / cause-01 :mode interrogative
                  :ARG0 (s2 / stimulate-01
                        :ARG0 (g / growth-factor)
                        :location (m / medium
                              :mod (c2 / culture)))
                  :ARG1 (s / status
                        :mod (p / phosphorylate-01
                              :ARG1 (p3 / protein :name (n / name :op1 "YB-1"))
                              :degree (h / high-02)
                              :mod (b / basal))))))

# ::id a_pmid_2139_2397.128 ::date 2015-05-27T09:07:45 ::annotator SDL-AMR-09 ::preferred
# ::snt As shown in Figure <xref ref-type="fig" rid="F1">1F</xref>, P-YB-1 was markedly reduced when cells were incubated in serum-free medium for 24 hours.
# ::save-date Wed Jun 3, 2015 ::file a_pmid_2139_2397_128.txt
(r / reduce-01
      :ARG1 (p / protein :name (n / name :op1 "YB-1")
            :ARG3-of (p2 / phosphorylate-01))
      :manner (m / marked)
      :time (i / incubate-01
            :ARG1 (c / cell)
            :ARG2 (m2 / medium
                  :ARG1-of (f / free-04
                        :ARG2 (s / serum)))
            :duration (t2 / temporal-quantity :quant 24
                  :unit (h2 / hour)))
      :ARG1-of (s2 / show-01
            :ARG0 (f2 / figure :mod "1F")))

# ::id a_pmid_2139_2397.129 ::date 2015-05-27T09:12:09 ::annotator SDL-AMR-09 ::preferred
# ::snt In contrast, serum depletion did not reduce basal YB-1 phosphorylation in <i>K-RAS</i><sub>mt </sub>MDA-MB-231 cells (Figure <xref ref-type="fig" rid="F1">1F</xref>).
# ::save-date Thu Jan 14, 2016 ::file a_pmid_2139_2397_129.txt
(c / contrast-01
      :ARG2 (r / reduce-01 :polarity -
            :ARG0 (d / deplete-01
                  :ARG1 (s / serum))
            :ARG1 (p / phosphorylate-01
                  :ARG1 (p2 / protein :name (n2 / name :op1 "YB-1"))
                  :mod (b / basal))
            :location (c2 / cell-line :name (n3 / name :op1 "MDA-MB-231")
                  :mod (g / gene :name (n / name :op1 "K-RAS")
                        :ARG2-of (m / mutate-01))))
      :ARG1-of (d2 / describe-01
            :ARG0 (f / figure :mod "1F")))

# ::id a_pmid_2139_2397.130 ::date 2015-05-27T09:15:59 ::annotator SDL-AMR-09 ::preferred
# ::snt Constitutive phosphorylation of YB-1 in MDA-MB-231 cells is K-Ras-dependent
# ::save-date Fri Jun 5, 2015 ::file a_pmid_2139_2397_130.txt
(d / depend-01
      :ARG0 (p / phosphorylate-01
            :ARG1 (p2 / protein :name (n / name :op1 "YB-1"))
            :mod (c / constitutive)
            :location (c2 / cell-line :name (n2 / name :op1 "MDA-MB-231")))
      :ARG1 (e / enzyme :name (n3 / name :op1 "K-Ras")))

# ::id a_pmid_2139_2397.131 ::date 2015-05-27T09:18:22 ::annotator SDL-AMR-09 ::preferred
# ::snt MDA-MB-231 cells are characterized by a point mutation at codon 13 in the <i>K-RAS </i>gene [<xref ref-type="bibr" rid="B37">37</xref>].
# ::save-date Wed May 27, 2015 ::file a_pmid_2139_2397_131.txt
(c / characterize-01
      :ARG0 (m / mutate-01
            :ARG1 (c3 / codon :mod 13
                  :part-of (g / gene :name (n3 / name :op1 "K-RAS")))
            :mod (p / point))
      :ARG1 (c2 / cell-line :name (n2 / name :op1 "MDA-MB-231"))
      :ARG1-of (d / describe-01
            :ARG0 (p2 / publication
                  :ARG1-of (c4 / cite-01
                        :ARG2 37))))

# ::id a_pmid_2139_2397.132 ::date 2015-05-27T09:24:03 ::annotator SDL-AMR-09 ::preferred
# ::snt This mutation is responsible for the constitutive phosphorylation of ERK1/2 [<xref ref-type="bibr" rid="B30">30</xref>].
# ::save-date Wed May 27, 2015 ::file a_pmid_2139_2397_132.txt
(r / responsible-01
      :ARG0 (m / mutate-01
            :mod (t / this))
      :ARG1 (p / phosphorylate-01
            :ARG1 (e / enzyme :name (n / name :op1 "ERK1/2"))
            :mod (c / constitutive))
      :ARG1-of (d / describe-01
            :ARG0 (p2 / publication
                  :ARG1-of (c2 / cite-01
                        :ARG2 30))))

# ::id a_pmid_2139_2397.133 ::date 2015-05-27T09:28:03 ::annotator SDL-AMR-09 ::preferred
# ::snt In addition to ERK1/2 phosphorylation, these cells also present a constitutive phosphorylation of YB-1, which is not further modified after exposure to IR or stimulation with erbB1 ligands (Figures <xref ref-type="fig" rid="F1">1D</xref> and <xref ref-type="fig" rid="F1">1E</xref>).
# ::save-date Sun Jan 3, 2016 ::file a_pmid_2139_2397_133.txt
(p5 / present-01
      :ARG0 (c / cell
            :mod (t / this))
      :ARG1 (p3 / phosphorylate-01
            :ARG1 (p4 / protein :name (n2 / name :op1 "YB-1"))
            :mod (c2 / constitutive)
            :ARG1-of (m / modify-01 :polarity -
                  :ARG0 (o / or
                        :op1 (e2 / expose-01
                              :ARG1 c
                              :ARG2 (r / radiate-01
                                    :ARG0-of (i / ionize-01)))
                        :op2 (s / stimulate-01
                              :ARG1 c
                              :ARG2 (l / ligand :name (n4 / name :op1 "erbB1"))))
                  :degree (f3 / further)))
      :mod (a2 / also)
      :ARG1-of (a4 / add-02
            :ARG2 (p / phosphorylate-01
                  :ARG1 (e / enzyme :name (n / name :op1 "ERK1/2"))))
      :ARG1-of (d / describe-01
            :ARG0 (a3 / and
                  :op1 (f / figure :mod "1D")
                  :op2 (f2 / figure :mod "1E"))))

# ::id a_pmid_2139_2397.134 ::date 2015-05-27T09:36:55 ::annotator SDL-AMR-09 ::preferred
# ::snt Thus, we investigated whether the constitutive phosphorylation of YB-1 in MDA-MB-231 cells is due to the described endogenous expression of mutated <i>K-RAS </i>[<xref ref-type="bibr" rid="B37">37</xref>].
# ::save-date Thu Jan 14, 2016 ::file a_pmid_2139_2397_134.txt
(c / cause-01
      :ARG1 (i / investigate-01
            :ARG0 (w / we)
            :ARG1 (c2 / cause-01 :mode interrogative
                  :ARG0 (e2 / express-03
                        :ARG2 (g / gene :name (n / name :op1 "K-RAS")
                              :ARG2-of (m2 / mutate-01))
                        :ARG1-of (d / describe-01)
                        :mod (m / monocot))
                  :ARG1 (p / phosphorylate-01
                        :ARG1 (p2 / protein :name (n2 / name :op1 "YB-1"))
                        :location (c3 / cell-line :name (n3 / name :op1 "MDA-MB-231"))
                        :mod (c4 / constitutive))))
      :ARG1-of (d2 / describe-01
            :ARG0 (p3 / publication
                  :ARG1-of (c5 / cite-01
                        :ARG2 37))))

# ::id a_pmid_2139_2397.135 ::date 2015-05-27T09:43:01 ::annotator SDL-AMR-09 ::preferred
# ::snt Therefore, K-Ras expression was downregulated by siRNA, and the level of P-YB-1 was investigated.
# ::save-date Wed Jun 3, 2015 ::file a_pmid_2139_2397_135.txt
(c / cause-01
      :ARG1 (a / and
            :op1 (d / downregulate-01
                  :ARG1 (e2 / express-03
                        :ARG2 (e / enzyme :name (n / name :op1 "K-Ras")))
                  :ARG2 (n4 / nucleic-acid :name (n2 / name :op1 "siRNA")))
            :op2 (i / investigate-01
                  :ARG1 (l / level
                        :quant-of (p / protein :name (n3 / name :op1 "YB-1")
                              :ARG3-of (p2 / phosphorylate-01))))))

# ::id a_pmid_2139_2397.136 ::date 2015-05-27T09:47:42 ::annotator SDL-AMR-09 ::preferred
# ::snt Using a similar approach, we analyzed the effect of ERK1 on YB-1 phosphorylation downstream of mutated K-Ras.
# ::save-date Wed Jun 3, 2015 ::file a_pmid_2139_2397_136.txt
(a4 / analyze-01
      :ARG0 (w / we)
      :ARG1 (a3 / affect-01
            :ARG0 (e2 / enzyme :name (n2 / name :op1 "ERK1"))
            :ARG1 (p / phosphorylate-01
                  :ARG1 (p2 / protein :name (n3 / name :op1 "YB-1"))
                  :location (r2 / relative-position
                        :op1 (e / enzyme :name (n / name :op1 "K-Ras")
                              :ARG2-of (m / mutate-01))
                        :direction (d / downstream))))
      :manner (u / use-01
            :ARG1 (a / approach-02
                  :ARG1-of (r / resemble-01))))

# ::id a_pmid_2139_2397.137 ::date 2015-05-27T09:53:55 ::annotator SDL-AMR-09 ::preferred
# ::snt As shown in Figure <xref ref-type="fig" rid="F2">2A</xref>, <i>K-RAS </i>siRNA led to a strong reduction in P-ERK1/2 and P-YB-1 (Figure <xref ref-type="fig" rid="F2">2A</xref>).
# ::save-date Thu Jan 14, 2016 ::file a_pmid_2139_2397_137.txt
(l / lead-03
      :ARG0 (n5 / nucleic-acid :name (n2 / name :op1 "siRNA")
            :ARG0-of (e2 / encode-01
                  :ARG1 (g / gene :name (n / name :op1 "K-Ras"))))
      :ARG2 (r2 / reduce-01
            :ARG1 (a / and
                  :op1 (e3 / enzyme :name (n3 / name :op1 "ERK1/2")
                        :ARG1-of (p / phosphorylate-01))
                  :op2 (p2 / protein :name (n4 / name :op1 "YB-1")
                        :ARG3-of (p3 / phosphorylate-01)))
            :mod (s / strong))
      :ARG1-of (s2 / show-01
            :ARG0 (f / figure :mod "2A")))

# ::id a_pmid_2139_2397.138 ::date 2015-05-27T09:59:01 ::annotator SDL-AMR-09 ::preferred
# ::snt Yet, ERK1/2 and YB-1 protein levels were not affected.
# ::save-date Wed Jun 3, 2015 ::file a_pmid_2139_2397_138.txt
(h / have-concession-91
      :ARG1 (a / affect-01 :polarity -
            :ARG1 (a2 / and
                  :op1 (l / level
                        :quant-of (e / enzyme :name (n / name :op1 "ERK1/2")))
                  :op2 (l2 / level
                        :quant-of (p / protein :name (n2 / name :op1 "YB-1"))))))

# ::id a_pmid_2139_2397.139 ::date 2015-05-27T11:48:06 ::annotator SDL-AMR-09 ::preferred
# ::snt Likewise, a marked reduction of P-YB-1 was observed when ERK1 was targeted with siRNA.
# ::save-date Fri Jun 5, 2015 ::file a_pmid_2139_2397_139.txt
(o / observe-01
      :ARG1 (r / reduce-01
            :ARG1 (p / protein :name (n / name :op1 "YB-1")
                  :ARG3-of (p2 / phosphorylate-01))
            :time (t / target-01
                  :ARG1 (e / enzyme :name (n2 / name :op1 "ERK1"))
                  :ARG2 (n4 / nucleic-acid :name (n3 / name :op1 "siRNA")))
            :degree (m / marked))
      :manner (l / likewise))

# ::id a_pmid_2139_2397.140 ::date 2015-05-27T12:44:40 ::annotator SDL-AMR-09 ::preferred
# ::snt The role of stimulated ERK1/2 phosphorylation on YB-1 phosphorylation was further supported by the results when a MEK inhibitor was used.
# ::save-date Sat Jan 16, 2016 ::file a_pmid_2139_2397_140.txt
(s / support-01
      :ARG0 (t2 / thing
            :ARG2-of (r2 / result-01))
      :ARG1 (r / role
            :poss (p / phosphorylate-01
                  :ARG1 (e2 / enzyme :name (n2 / name :op1 "ERK1/2"))
                  :ARG1-of (s2 / stimulate-01))
            :topic (p2 / phosphorylate-01
                  :ARG1 (p3 / protein :name (n3 / name :op1 "YB-1"))))
      :degree (f / further)
      :time (u / use-01
            :ARG1 (m / molecular-physical-entity
                  :ARG0-of (i / inhibit-01
                        :ARG1 (p4 / protein-family :name (n / name :op1 "MEK"))))))

# ::id a_pmid_2139_2397.141 ::date 2015-05-27T13:10:48 ::annotator SDL-AMR-09 ::preferred
# ::snt As shown in Figure <xref ref-type="fig" rid="F2">2B</xref>, pretreatment of MDA-MB-231 cells with the MEK inhibitor PD98059 markedly blocked YB-1 phosphorylation.
# ::save-date Tue Jan 19, 2016 ::file a_pmid_2139_2397_141.txt
(b / block-01
      :ARG0 (p2 / pretreat-01
            :ARG1 (c / cell-line :name (n2 / name :op1 "MDA-MB-231"))
            :ARG3 (s2 / small-molecule :name (n3 / name :op1 "PD98059")
                  :ARG0-of (i2 / inhibit-01
                        :ARG1 (p4 / protein-family :name (n / name :op1 "MEK")))))
      :ARG1 (p / phosphorylate-01
            :ARG1 (p3 / protein :name (n4 / name :op1 "YB-1")))
      :degree (m2 / marked)
      :ARG1-of (s / show-01
            :ARG0 (f / figure :mod "2B")))

# ::id a_pmid_2139_2397.142 ::date 2015-05-27T13:16:54 ::annotator SDL-AMR-09 ::preferred
# ::snt Similar to the data shown in Figure <xref ref-type="fig" rid="F1">1D</xref>, exposure to IR did not induce YB-1 phosphorylation.
# ::save-date Sun Jan 3, 2016 ::file a_pmid_2139_2397_142.txt
(i2 / induce-01 :polarity -
      :ARG0 (e / expose-01
            :ARG2 (r2 / radiate-01
                  :ARG0-of (i / ionize-01)))
      :ARG2 (p / phosphorylate-01
            :ARG1 (p2 / protein :name (n2 / name :op1 "YB-1")))
      :ARG1-of (r / resemble-01
            :ARG2 (d / data))
      :ARG1-of (s / show-01
            :ARG0 (f / figure :mod "1D")))

# ::id a_pmid_2139_2397.143 ::date 2015-05-27T13:20:06 ::annotator SDL-AMR-09 ::preferred
# ::snt These results indicates that the constitutive YB-1 phosphorylation in MDA-MB-231 cells is a consequence of mutated K-Ras-mediated ERK1/2 phosphorylation.
# ::save-date Wed Jun 3, 2015 ::file a_pmid_2139_2397_143.txt
(i / indicate-01
      :ARG0 (t / thing
            :ARG2-of (r / result-01)
            :mod (t2 / this))
      :ARG1 (c / consequence
            :domain (p / phosphorylate-01
                  :ARG1 (p2 / protein :wiki "Y_box_binding_protein_1"
                        :name (n / name :op1 "YB-1"))
                  :mod (c2 / constitutive)
                  :location (c3 / cell-line :wiki -
                        :name (n2 / name :op1 "MDA-MB-231")))
            :ARG1-of (c4 / cause-01
                  :ARG0 (p3 / phosphorylate-01
                        :ARG1 (e / enzyme :wiki "Extracellular_signal-regulated_kinases"
                              :name (n3 / name :op1 "ERK1/2"))
                        :ARG1-of (m / mediate-01
                              :ARG0 (e2 / enzyme :wiki "KRAS"
                                    :name (n4 / name :op1 "K-Ras")
                                    :ARG2-of (m2 / mutate-01)))))))

# ::id a_pmid_2139_2397.144 ::date 2015-05-27T13:33:31 ::annotator SDL-AMR-09 ::preferred
# ::snt Overexpression of mutated <i>K-RAS</i><sup>V12 </sup>enhances basal YB-1 phosphorylation
# ::save-date Thu Jan 14, 2016 ::file a_pmid_2139_2397_144.txt
(e2 / enhance-01
      :ARG0 (o / overexpress-01
            :ARG1 (g / gene :name (n / name :op1 "K-RAS")
                  :ARG2-of (m / mutate-01 :value "V12")))
      :ARG1 (p / phosphorylate-01
            :ARG1 (p2 / protein :name (n2 / name :op1 "YB-1"))
            :mod (b / basal)))

# ::id a_pmid_2139_2397.145 ::date 2015-05-27T13:36:13 ::annotator SDL-AMR-09 ::preferred
# ::snt To investigate the role of K-Ras in the constitutive phosphorylation of YB-1, we further analyzed the status of <i>K-RAS </i>in SKBr3, MCF-7 and HBL100 cells.
# ::save-date Sat Jan 16, 2016 ::file a_pmid_2139_2397_145.txt
(a / analyze-01
      :ARG0 (w / we)
      :ARG1 (s / status
            :location (a2 / and
                  :op1 (c / cell-line :name (n2 / name :op1 "SKBr3"))
                  :op2 (c2 / cell-line :name (n3 / name :op1 "MCF-7"))
                  :op3 (c3 / cell-line :name (n4 / name :op1 "HBL100")))
            :poss (g / gene :name (n6 / name :op1 "K-RAS")))
      :degree (f / further)
      :purpose (i / investigate-01
            :ARG0 w
            :ARG1 (r / role
                  :topic (p / phosphorylate-01
                        :ARG1 (p2 / protein :name (n5 / name :op1 "YB-1"))
                        :mod (c4 / constitutive))
                  :poss (e / enzyme :name (n / name :op1 "K-Ras")))))

# ::id a_pmid_2139_2397.146 ::date 2015-05-27T13:52:03 ::annotator SDL-AMR-09 ::preferred
# ::snt Sequencing of the <i>K-RAS </i>gene revealed that none of these cell lines presents a <i>K-RAS </i>point mutation in codon 12, codon 13 or 61.
# ::save-date Tue Jan 19, 2016 ::file a_pmid_2139_2397_146.txt
(r / reveal-01
      :ARG0 (s / sequence-01
            :ARG1 (g / gene :name (n2 / name :op1 "K-RAS")))
      :ARG1 (p / present-01
            :ARG0 (c / cell-line
                  :quant (n3 / none)
                  :mod (t / this))
            :ARG1 (m / mutate-01
                  :ARG1 g
                  :mod (p2 / point)
                  :location (o / or
                        :op1 (c2 / codon :mod 12)
                        :op2 (c3 / codon :mod 13)
                        :op3 (c4 / codon :mod 61)))))

# ::id a_pmid_2139_2397.147 ::date 2015-05-29T03:10:45 ::annotator SDL-AMR-09 ::preferred
# ::snt To investigate whether mutated <i>K-RAS</i><sup>V12 </sup>could upregulate YB-1 phosphorylation, we introduced mutated <i>K-RAS </i>into <i>K-RAS</i><sub>wt</sub>, SKBr3 and MCF-7 cells.
# ::save-date Fri Jul 24, 2015 ::file a_pmid_2139_2397_147.txt
(i / introduce-02
      :ARG0 (w / we)
      :ARG1 g
      :ARG2 (a / and
            :op1 (c / cell-line :name (n4 / name :op1 "SKBr3"))
            :op2 (c2 / cell-line :name (n5 / name :op1 "MCF-7"))
            :mod (g2 / gene :name (n3 / name :op1 "K-RAS")
                  :mod (w2 / wild-type)))
      :purpose (i2 / investigate-01
            :ARG0 w
            :ARG1 (p3 / possible-01 :mode interrogative
                  :ARG1 (u / upregulate-01
                        :ARG1 (p2 / phosphorylate-01
                              :ARG1 (p / protein :name (n2 / name :op1 "YB-1")))
                        :ARG2 (g / gene :name (n / name :op1 "K-RAS")
                              :ARG2-of (m / mutate-01 :value "V12"))))))

# ::id a_pmid_2139_2397.148 ::date 2015-05-29T03:19:16 ::annotator SDL-AMR-09 ::preferred
# ::snt Cells were transiently transfected with either a control pEGFP-C1 vector (indicated as con.-vector) or a vector expressing mutated <i>K-RAS</i>, pEGFP-C1/<i>K-RAS</i><sup>V12 </sup>(indicated as <i>K-RAS</i><sup>V12</sup>).
# ::save-date Thu Dec 17, 2015 ::file a_pmid_2139_2397_148.txt
(t / transfect-01
      :ARG1 (c / cell)
      :ARG2 (o / or
            :op1 (v / vector :name (n2 / name :op1 "pEGFP-C1")
                  :mod (c2 / control)
                  :ARG1-of (i / indicate-01
                        :ARG0 (v4 / vector :name (n5 / name :op1 "con.-vector"))))
            :op2 (v2 / vector :name (n4 / name :op1 "pEGFP-C1/K-RASV12")
                  :ARG3-of (e2 / express-03
                        :ARG1 (g / gene :name (n / name :op1 "K-RAS")
                              :ARG2-of (m / mutate-01)))
                  :ARG1-of (i2 / indicate-01
                        :ARG0 (v3 / vector :name (n3 / name :op1 "K-RASV12")))))
      :ARG1-of (t2 / transient-02))

# ::id a_pmid_2139_2397.149 ::date 2015-05-29T03:32:44 ::annotator SDL-AMR-09 ::preferred
# ::snt Fluorescence images of living cells transfected with con.-vector and <i>K-RAS</i><sup>V12 </sup>revealed that GFP in <i>K-RAS</i><sup>V12 </sup>vector-transfected cells was localized to the plasma membrane, but that in con.-vector-transfected cells it was not (Figure <xref ref-type="fig" rid="F3">3A</xref>).
# ::save-date Thu Dec 17, 2015 ::file a_pmid_2139_2397_149.txt
(r / reveal-01
      :ARG0 (i / image-101
            :ARG1 (a / and
                  :op1 (c / cell
                        :ARG0-of (l / live-01)
                        :ARG1-of (t / transfect-01
                              :ARG2 (v / vector :name (n2 / name :op1 "con.-vector"))))
                  :op2 (c3 / cell
                        :ARG0-of l
                        :ARG1-of (t2 / transfect-01
                              :ARG2 (v2 / vector :name (n / name :op1 "K-RASV12"))))))
      :ARG1 (c2 / contrast-01
            :ARG1 (l2 / localize-01
                  :ARG1 (p / protein :name (n3 / name :op1 "GFP"))
                  :location (m / membrane
                        :mod (p2 / plasma))
                  :location (c4 / cell
                        :ARG2-of t2))
            :ARG2 (l3 / localize-01 :polarity -
                  :ARG1 p
                  :location (c5 / cell
                        :ARG2-of t)
                  :location m))
      :mod (f / fluorescence)
      :ARG1-of (d / describe-01
            :ARG0 (f2 / figure :mod "3A")))

# ::id a_pmid_2139_2397.150 ::date 2015-05-29T03:43:20 ::annotator SDL-AMR-09 ::preferred
# ::snt This is due to posttranslational modification and membrane association of K-Ras (Figure <xref ref-type="fig" rid="F3">3A</xref>).
# ::save-date Tue Dec 8, 2015 ::file a_pmid_2139_2397_150.txt
(c / cause-01
      :ARG0 (a / and
            :op1 (m / modify-01
                  :ARG1 (e / enzyme :name (n / name :op1 "K-Ras"))
                  :time (a2 / after
                        :op1 (t2 / translate-02
                              :ARG1 e)))
            :op2 (a3 / associate-01
                  :ARG1 e
                  :ARG2 (m2 / membrane)))
      :ARG1 (t / this)
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod "3A")))

# ::id a_pmid_2139_2397.151 ::date 2015-05-29T03:46:30 ::annotator SDL-AMR-09 ::preferred
# ::snt In con.-vector-transfected cells, GFP expression was not accumulated at the cell membrane, but rather it was equally distributed throughout the cytoplasm.
# ::save-date Fri Dec 18, 2015 ::file a_pmid_2139_2397_151.txt
(i / instead-of-91
      :ARG1 (d / distribute-01
            :ARG1 e
            :location (c / cytoplasm)
            :mod (r / rather)
            :ARG1-of (e2 / equal-01))
      :ARG2 (a / accumulate-01 :polarity -
            :ARG0 (m / membrane
                  :part-of c2)
            :ARG1 (e / express-03
                  :ARG2 (p / protein :name (n / name :op1 "GFP"))
                  :ARG3 (c2 / cell
                        :ARG1-of (t / transfect-01
                              :ARG2 (v / vector :name (n2 / name :op1 "con.-vector")))))))

# ::id a_pmid_2139_2397.152 ::date 2015-05-29T03:53:52 ::annotator SDL-AMR-09 ::preferred
# ::snt The efficiency of transfection was verified by immunoblotting as well (Figure <xref ref-type="fig" rid="F3">3B</xref>).
# ::save-date Thu Dec 17, 2015 ::file a_pmid_2139_2397_152.txt
(v / verify-01
      :ARG1 (e / efficient-01
            :ARG1 (t / transfect-01))
      :mod (a / as-well)
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod "3B"))
      :manner (i / immunoblot-01))

# ::id a_pmid_2139_2397.153 ::date 2015-05-29T03:58:18 ::annotator SDL-AMR-09 ::preferred
# ::snt In cells transfected with <i>K-RAS</i><sup>V12 </sup>vector, the expression of K-Ras (21 kDa) resulted in a shift of GFP from 27 kDa to 48 kDa (Figure <xref ref-type="fig" rid="F3">3B</xref>).
# ::save-date Thu Dec 17, 2015 ::file a_pmid_2139_2397_153.txt
(r / result-01
      :ARG1 (e2 / express-03
            :ARG2 (e / enzyme :name (n / name :op1 "K-Ras")
                  :quant (m2 / mass-quantity :quant 21
                        :unit (k / kilodalton)))
            :ARG3 (c / cell
                  :ARG1-of (t / transfect-01
                        :ARG2 (v / vector :name (n2 / name :op1 "K-RASV12")))))
      :ARG2 (s / shift-01
            :ARG1 (p / protein :name (n3 / name :op1 "GFP"))
            :ARG2 (m4 / mass-quantity :quant 48
                  :unit k)
            :ARG3 (m3 / mass-quantity :quant 27
                  :unit k))
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod "3B")))

# ::id a_pmid_2139_2397.154 ::date 2015-05-29T04:06:56 ::annotator SDL-AMR-09 ::preferred
# ::snt The expression of GFP-tagged K-Ras with a molecular weight of 48 kDa was further confirmed by stripping the anti-GFP antibody from the membrane and reincubating the blots with a K-Ras antibody.
# ::save-date Tue Jun 9, 2015 ::file a_pmid_2139_2397_154.txt
(c / confirm-01
      :ARG1 (e2 / express-03
            :ARG2 (e / enzyme :name (n / name :op1 "K-Ras")
                  :ARG1-of (t / tag-01
                        :ARG2 (p / protein :name (n2 / name :op1 "GFP")))
                  :mod (w / weight
                        :mod (m / molecule)
                        :quant (m2 / mass-quantity :quant 48
                              :unit (k / kilodalton)))))
      :degree (f / further)
      :manner (a2 / and
            :op1 (s / strip-01
                  :ARG1 (a3 / antibody
                        :ARG0-of (c2 / counter-01
                              :ARG1 p))
                  :ARG2 (m3 / membrane))
            :op2 (i / incubate-01
                  :ARG1 (b / blot)
                  :ARG2 (a4 / antibody
                        :ARG0-of (c3 / counter-01
                              :ARG1 e))
                  :mod (a5 / again))))

# ::id a_pmid_2139_2397.155 ::date 2015-05-29T04:16:28 ::annotator SDL-AMR-09 ::preferred
# ::snt In line with our observations of MDA-MB-231 cells, exogenous expression of <i>K-RAS</i><sup>V12 </sup>in <i>K-RAS</i><sub>wt</sub>, SKBr3 and MCF-7 cells resulted in markedly enhanced basal phosphorylation of YB-1 at S102 (Figure <xref ref-type="fig" rid="F3">3B</xref>), which prevents further enhancement of phosphorylation by IR (Figure <xref ref-type="fig" rid="F3">3C</xref>).
# ::save-date Sun Jan 3, 2016 ::file a_pmid_2139_2397_155.txt
(r / result-01
      :ARG1 (e2 / express-03
            :ARG1 (g / gene :name (n / name :op1 "K-RAS")
                  :ARG2-of (m / mutate-01 :value "V12"))
            :ARG3 (a / and
                  :op1 (c / cell-line :name (n3 / name :op1 "SKBr3"))
                  :op2 (c2 / cell-line :name (n4 / name :op1 "MCF-7"))
                  :mod (g2 / gene :name (n2 / name :op1 "K-RAS")
                        :mod (w / wild-type)))
            :mod (e3 / exogenous))
      :ARG2 (p / phosphorylate-01
            :ARG1 (a2 / amino-acid :mod 102 :name (n5 / name :op1 "serine")
                  :part-of (p2 / protein :name (n6 / name :op1 "YB-1")))
            :mod (b / basal)
            :ARG1-of (e5 / enhance-01
                  :manner (m2 / marked))
            :ARG0-of (p3 / prevent-01
                  :ARG1 (e6 / enhance-01
                        :ARG1 p
                        :ARG2 (r3 / radiate-01
                              :ARG0-of (i / ionize-01))
                        :degree (f2 / further))
                  :ARG1-of (d2 / describe-01
                        :ARG0 (f3 / figure :mod "3C"))))
      :ARG1-of (r2 / resemble-01
            :ARG2 (o / observe-01
                  :ARG0 (w2 / we)
                  :ARG1 (c3 / cell-line :name (n7 / name :op1 "MDA-MB-231"))))
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod "3B")))

# ::id a_pmid_2139_2397.156 ::date 2015-05-29T04:36:53 ::annotator SDL-AMR-09 ::preferred
# ::snt Thus, these data support the hypothesis that in cells expressing mutated <i>K-RAS</i>, the basal phosphorylation of YB-1 is constitutively enhanced and cannot be further stimulated by IR.
# ::save-date Sun Jan 17, 2016 ::file a_pmid_2139_2397_156.txt
(i / infer-01
      :ARG1 (s / support-01
            :ARG0 (d / data
                  :mod (t2 / this))
            :ARG1 (h2 / hypothesize-01
                  :ARG1 (a / and
                        :op1 (e2 / enhance-01
                              :ARG1 (p / phosphorylate-01
                                    :ARG1 (p3 / protein :name (n2 / name :op1 "YB-1"))
                                    :mod (b / basal))
                              :mod (c / constitutive))
                        :op2 (p2 / possible-01 :polarity -
                              :ARG1 (s2 / stimulate-01
                                    :ARG1 p
                                    :ARG2 (r / radiate-01
                                          :ARG0-of (i2 / ionize-01))
                                    :degree (f / further)))
                        :location (c2 / cell
                              :ARG3-of (e3 / express-03
                                    :ARG1 (g / gene :name (n / name :op1 "K-RAS")
                                          :ARG2-of (m / mutate-01))))))))

# ::id a_pmid_2139_2397.157 ::date 2015-05-29T04:43:20 ::annotator SDL-AMR-09 ::preferred
# ::snt IR-induced YB-1 phosphorylation is mediated by erbB1-dependent PI3K/Akt and MAPK/ERK pathways
# ::save-date Sun Jan 3, 2016 ::file a_pmid_2139_2397_157.txt
(m / mediate-01
      :ARG0 (a / and
            :op1 (p2 / pathway :name (n / name :op1 "PI3K/AKT"))
            :op2 (p4 / pathway :name (n4 / name :op1 "MAPK/ERK"))
            :ARG0-of (d / depend-01
                  :ARG1 (p5 / protein :name (n5 / name :op1 "erbB1"))))
      :ARG1 (p / phosphorylate-01
            :ARG1 (p3 / protein :name (n3 / name :op1 "YB-1"))
            :ARG2-of (i / induce-01
                  :ARG0 (r / radiate-01
                        :ARG0-of (i2 / ionize-01)))))

# ::id a_pmid_2139_2397.158 ::date 2015-05-29T04:46:42 ::annotator SDL-AMR-09 ::preferred
# ::snt The phosphorylation of YB-1 at S102 in response to stimulation with EGF has been described as being dependent on p90 ribosomal S6 kinase [<xref ref-type="bibr" rid="B11">11</xref>].
# ::save-date Sun Jan 17, 2016 ::file a_pmid_2139_2397_158.txt
(d / describe-01
      :ARG1 (p / phosphorylate-01
            :ARG1 (a / amino-acid :mod 102 :name (n2 / name :op1 "serine")
                  :part-of (p2 / protein :name (n / name :op1 "YB-1")))
            :ARG2-of (r / respond-01
                  :ARG1 (s / stimulate-01
                        :ARG1 p2
                        :ARG2 (p4 / protein :name (n3 / name :op1 "EGF")))))
      :ARG2 (d2 / depend-01
            :ARG0 p
            :ARG1 (e / enzyme :name (n5 / name :op1 "p90" :op2 "ribosomal" :op3 "S6" :op4 "kinase")))
      :ARG1-of (d3 / describe-01
            :ARG0 (p3 / publication
                  :ARG1-of (c / cite-01
                        :ARG2 11))))

# ::id a_pmid_2139_2397.159 ::date 2015-05-29T04:55:41 ::annotator SDL-AMR-09 ::preferred
# ::snt In that study [<xref ref-type="bibr" rid="B11">11</xref>], Stratford <i>et al</i>. showed that the stimulation of SUM149 breast cancer cells with serum, EGF and phorbol 12-myristate 13-acetate (PMA) leads to phosphorylation of YB-1 at S102, which is dependent on the MAP kinase pathway [<xref ref-type="bibr" rid="B11">11</xref>].
# ::save-date Sun Jan 17, 2016 ::file a_pmid_2139_2397_159.txt
(s / show-01
      :ARG0 (a / and
            :op1 (p2 / person :name (n2 / name :op1 "Stratford"))
            :op2 (p3 / person
                  :mod (o / other)))
      :ARG1 (l / lead-03
            :ARG0 (s2 / stimulate-01
                  :ARG1 (c / cell-line :name (n3 / name :op1 "SUM149")
                        :source (d4 / disease :wiki "Breast_cancer" :name (n9 / name :op1 "breast" :op2 "cancer")))
                  :ARG2 (a2 / and
                        :op1 (s3 / serum)
                        :op2 (p7 / protein :name (n4 / name :op1 "EGF"))
                        :op3 (s5 / small-molecule :name (n5 / name :op1 "phorbol" :op2 "12-myristate" :op3 "13-acetate")
                              :ARG1-of (d2 / describe-01
                                    :ARG2 (s6 / small-molecule :name (n6 / name :op1 "PMA"))))))
            :ARG2 (p / phosphorylate-01
                  :ARG1 (a3 / amino-acid :mod 102 :name (n7 / name :op1 "serine")
                        :part-of (p4 / protein :name (n / name :op1 "YB-1")))
                  :ARG0-of (d / depend-01
                        :ARG1 (p5 / pathway :name (n8 / name :op1 "MAP" :op2 "kinase")))))
      :medium (s7 / study-01
            :mod (t / that)
            :ARG1-of (d3 / describe-01
                  :ARG0 (p6 / publication
                        :ARG1-of (c3 / cite-01
                              :ARG2 11))))
      :ARG1-of d3)

# ::id a_pmid_2139_2397.161 ::date 2015-05-29T05:03:47 ::annotator SDL-AMR-09 ::preferred
# ::snt Because we and others have shown that IR induces activation of erbB1 in a ligand-independent manner [<xref ref-type="bibr" rid="B24">24</xref>,<xref ref-type="bibr" rid="B25">25</xref>], we tested whether the IR-induced YB-1 phosphorylation shown in Figure <xref ref-type="fig" rid="F1">1D</xref> could be blocked by erbB1 tyrosine kinase inhibitors.
# ::save-date Sun Jan 3, 2016 ::file a_pmid_2139_2397_161.txt
(t2 / test-01
      :ARG0 (w / we)
      :ARG1 (p2 / possible-01 :mode interrogative
            :ARG1 (b / block-01
                  :ARG1 (p / phosphorylate-01
                        :ARG1 (p3 / protein :name (n2 / name :op1 "YB-1"))
                        :ARG2-of (i2 / induce-01
                              :ARG0 (r / radiate-01
                                    :ARG0-of (i4 / ionize-01)))
                        :ARG1-of (s / show-01
                              :medium (f / figure :mod "1D")))
                  :ARG3 (m3 / molecular-physical-entity
                        :ARG0-of (i / inhibit-01
                              :ARG1 (e / enzyme :name (n4 / name :op1 "erB1" :op2 "tyrosine" :op3 "kinase"))))))
      :ARG1-of (c / cause-01
            :ARG0 (s2 / show-01
                  :ARG0 (a / and
                        :op1 (w2 / we)
                        :op2 (p5 / person
                              :mod (o / other)))
                  :ARG1 (i3 / induce-01
                        :ARG0 r
                        :ARG2 (a2 / activate-01
                              :ARG1 e)
                        :manner (d / depend-01 :polarity -
                              :ARG0 a2
                              :ARG1 (l / ligand)))
                  :ARG1-of (d2 / describe-01
                        :ARG0 (a3 / and
                              :op1 (p6 / publication
                                    :ARG1-of (c2 / cite-01
                                          :ARG2 24))
                              :op2 (p7 / publication
                                    :ARG1-of (c3 / cite-01
                                          :ARG2 25)))))))

# ::id a_pmid_2139_2397.162 ::date 2015-05-29T05:20:55 ::annotator SDL-AMR-09 ::preferred
# ::snt To test this hypothesis, the effect of the erbB1-RTK inhibitor erlotinib on YB-1 phosphorylation was analyzed in whole cell extracts as well as in cytoplasmic and nuclear fractions.
# ::save-date Sun May 31, 2015 ::file a_pmid_2139_2397_162.txt
(a / analyze-01
      :ARG1 (a2 / affect-01
            :ARG0 (s / small-molecule :name (n / name :op1 "erlotinib")
                  :ARG0-of (i / inhibit-01
                        :ARG1 (p3 / pathway :name (n4 / name :op1 "erbB1-RTK"))))
            :ARG1 (p / phosphorylate-01
                  :ARG1 (p2 / protein :name (n2 / name :op1 "YB-1"))))
      :location (a3 / and
            :op1 (e / extract-01
                  :ARG1 (c / cell
                        :mod (w / whole)))
            :op2 (f / fraction
                  :part-of (c2 / cytoplasm))
            :op3 (f2 / fraction
                  :part-of (n3 / nucleus)))
      :purpose (t3 / test-01
            :ARG1 (t / thing
                  :ARG1-of (h / hypothesize-01)
                  :mod (t4 / this))))

# ::id a_pmid_2139_2397.163 ::date 2015-05-29T05:28:37 ::annotator SDL-AMR-09 ::preferred
# ::snt Pretreatment of SKBr3 cells with erlotinib resulted in complete inhibition of YB-1 phosphorylation in whole cell extract (Figure <xref ref-type="fig" rid="F4">4A</xref>) as well as in cytoplasmic and nuclear fractions (Figure <xref ref-type="fig" rid="F4">4B</xref>).
# ::save-date Tue Jan 19, 2016 ::file a_pmid_2139_2397_163.txt
(r / result-01
      :ARG1 (p3 / pretreat-01
            :ARG1 (c / cell-line :name (n / name :op1 "SKBr3"))
            :ARG3 (s / small-molecule :name (n2 / name :op1 "erlotinib")))
      :ARG2 (i / inhibit-01
            :ARG1 (p / phosphorylate-01
                  :ARG1 (p2 / protein :name (n3 / name :op1 "YB-1")))
            :ARG1-of (c2 / complete-02)
            :location (a / and
                  :op1 (e / extract-01
                        :ARG1 (c3 / cell
                              :mod (w / whole))
                        :ARG1-of (d / describe-01
                              :ARG0 (f / figure :mod "4A")))
                  :op2 (a2 / and
                        :op1 (f2 / fraction
                              :part-of (c4 / cytoplasm))
                        :op2 (f3 / fraction
                              :part-of (n4 / nucleus))
                        :ARG1-of (d2 / describe-01
                              :ARG0 (f4 / figure :mod "4B"))))))

# ::id a_pmid_2139_2397.164 ::date 2015-05-29T05:33:47 ::annotator SDL-AMR-09 ::preferred
# ::snt As expected, erlotinib also blocked basal- and radiation-induced P-Akt and P-ERK1/2 in these cells (Figure <xref ref-type="fig" rid="F4">4A</xref>).
# ::save-date Sun Dec 20, 2015 ::file a_pmid_2139_2397_164.txt
(b / block-01
      :ARG0 (s / small-molecule :name (n / name :op1 "erlotinib"))
      :ARG1 (a / and
            :op1 (a3 / and
                  :op1 (e / enzyme :name (n2 / name :op1 "Akt"))
                  :op2 (s2 / slash
                        :op1 (e2 / enzyme :name (n3 / name :op1 "ERK1"))
                        :op2 (e3 / enzyme :name (n4 / name :op1 "ERK2")))
                  :mod (b2 / basal)
                  :ARG1-of (p / phosphorylate-01))
            :op2 (a4 / and
                  :op1 e
                  :op2 s2
                  :ARG1-of p
                  :ARG2-of (i / induce-01
                        :ARG0 (r / radiate-01))))
      :location (c / cell
            :mod (t / this))
      :ARG1-of (e4 / expect-01)
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod "4A"))
      :mod (a2 / also))

# ::id a_pmid_2139_2397.165 ::date 2015-05-29T05:39:05 ::annotator SDL-AMR-09 ::preferred
# ::snt To rule out off-target effects of erlotinib, the efficacy of the highly specific erbB1-RTK inhibitor BIBX1382BS [<xref ref-type="bibr" rid="B38">38</xref>] on radiation-induced YB-1 phosphorylation was tested in cytoplasmic and nuclear fractions.
# ::save-date Tue Jan 12, 2016 ::file a_pmid_2139_2397_165.txt
(t2 / test-01
      :ARG1 (e / efficient-01
            :ARG1 (s3 / small-molecule :wiki -
                  :name (n2 / name :op1 "BIBX1382BS")
                  :ARG0-of (i / inhibit-01
                        :ARG1 (e2 / enzyme :wiki -
                              :name (n5 / name :op1 "erbB1-RTK")))
                  :ARG1-of (d / describe-01
                        :ARG0 (p3 / publication
                              :ARG1-of (c / cite-01 :ARG2 38)))
                  :ARG1-of (s / specific-02
                        :ARG1-of (h / high-02)))
            :ARG2 (p / phosphorylate-01
                  :ARG1 (p2 / protein :wiki "Y_box_binding_protein_1"
                        :name (n / name :op1 "YB-1"))
                  :ARG2-of (i2 / induce-01
                        :ARG0 (r / radiate-01))))
      :location (a2 / and
            :op1 (f / fraction
                  :part-of (c2 / cytoplasm))
            :op2 (f2 / fraction
                  :mod (n3 / nucleus)))
      :purpose (r2 / rule-out-02
            :ARG1 (a3 / affect-01
                  :ARG0 (s2 / small-molecule :wiki "Erlotinib"
                        :name (n4 / name :op1 "erlotinib"))
                  :mod (o / off-target))))

# ::id a_pmid_2139_2397.166 ::date 2015-05-29T05:44:26 ::annotator SDL-AMR-09 ::preferred
# ::snt EGF was included as positive control.
# ::save-date Sun Jan 17, 2016 ::file a_pmid_2139_2397_166.txt
(i / include-01
      :ARG1 (p2 / protein :name (n / name :op1 "EGF"))
      :condition (c / control
            :mod (p / positive)))

# ::id a_pmid_2139_2397.167 ::date 2015-05-29T05:45:39 ::annotator SDL-AMR-09 ::preferred
# ::snt As shown at the bottom of Figure <xref ref-type="fig" rid="F4">4B</xref>, in both cytoplasmic and nuclear protein fractions treatment with BIBX1382BS resulted in a marked reduction of YB-1 phosphorylation stimulated by IR as well as EGF treatment.
# ::save-date Fri Feb 12, 2016 ::file a_pmid_2139_2397_167.txt
(r / result-01
      :ARG1 (t / treat-04
            :ARG2 (s2 / small-molecule :name (n / name :op1 "BIBX1382BS")))
      :ARG2 (r2 / reduce-01
            :ARG1 (p / phosphorylate-01
                  :ARG1 (p2 / protein :name (n2 / name :op1 "YB-1")))
            :mod (m2 / marked)
            :ARG1-of (s / stimulate-01
                  :ARG0 (a / and
                        :op1 (r3 / radiate-01
                              :ARG0-of (i / ionize-01))
                        :op2 (t2 / treat-04
                              :ARG2 (p5 / protein :name (n4 / name :op1 "EGF"))))))
      :ARG1-of (s4 / show-01
            :medium (b / bottom
                  :mod (f / figure :mod "4B")))
      :location (a2 / and
            :op1 (f2 / fraction
                  :part-of (p3 / protein
                        :mod (c / cytoplasm)))
            :op2 (f3 / fraction
                  :part-of (p4 / protein
                        :mod (n5 / nucleus)))
            :mod (b2 / both)))

# ::id a_pmid_2139_2397.168 ::date 2015-05-29T05:52:02 ::annotator SDL-AMR-09 ::preferred
# ::snt These data indicate that erbB1-RTK activity is necessary for radiation-induced YB-1 phosphorylation, and this is most likely due to activation of the PI3K/Akt and MAPK/ERK pathways.
# ::save-date Sun Dec 20, 2015 ::file a_pmid_2139_2397_168.txt
(a2 / and
      :op1 (i / indicate-01
            :ARG0 (d / data
                  :mod (t / this))
            :ARG1 (n / need-01
                  :ARG0 (p / phosphorylate-01
                        :ARG1 (p3 / protein :name (n3 / name :op1 "YB-1"))
                        :ARG2-of (i2 / induce-01
                              :ARG0 (r / radiate-01)))
                  :ARG1 (a / activate-01
                        :ARG1 (p5 / pathway :name (n5 / name :op1 "erbB1-RTK")))))
      :op2 (l / likely-01
            :ARG1 (c / cause-01
                  :ARG0 (a3 / activate-01
                        :ARG1 (a4 / and
                              :op1 (p2 / pathway :name (n2 / name :op1 "PI3K/AKT"))
                              :op2 (p4 / pathway :name (n4 / name :op1 "MAPK/ERK"))))
                  :ARG1 n)
            :degree (m / most)))

# ::id a_pmid_2139_2397.169 ::date 2015-05-29T05:57:58 ::annotator SDL-AMR-09 ::preferred
# ::snt To test the function of PI3K/Akt and MAPK/ERK pathways in YB-1 phosphorylation, we further investigated whether the inhibitors of PI3K, Akt and MAPK affect YB-1 phosphorylation in irradiated cells.
# ::save-date Sun Jan 17, 2016 ::file a_pmid_2139_2397_169.txt
(i2 / investigate-01
      :ARG0 (w / we)
      :ARG1 (a / affect-01 :mode interrogative
            :ARG0 (a4 / and
                  :op1 (m / molecular-physical-entity
                        :ARG0-of (i / inhibit-01
                              :ARG1 (e / enzyme :name (n3 / name :op1 "PI3K"))))
                  :op2 (m2 / molecular-physical-entity
                        :ARG0-of (i4 / inhibit-01
                              :ARG1 (e2 / enzyme :name (n4 / name :op1 "Akt"))))
                  :op3 (m3 / molecular-physical-entity
                        :ARG0-of (i5 / inhibit-01
                              :ARG1 (p5 / protein-family :name (n5 / name :op1 "MAPK")))))
            :ARG1 (p2 / phosphorylate-01
                  :ARG1 (p4 / protein :name (n6 / name :op1 "YB-1")))
            :location (c / cell
                  :ARG1-of (i3 / irradiate-01)))
      :degree (f / further)
      :purpose (t / test-01
            :ARG0 w
            :ARG1 (f2 / function-01
                  :ARG0 (a3 / and
                        :op1 (p / pathway :name (n / name :op1 "PI3K/Akt"))
                        :op2 (p3 / pathway :name (n2 / name :op1 "MAPK/ERK")))
                  :ARG1 p2)))

# ::id a_pmid_2139_2397.170 ::date 2015-05-29T06:03:30 ::annotator SDL-AMR-09 ::preferred
# ::snt The data shown in Figures <xref ref-type="fig" rid="F4">4C</xref> and <xref ref-type="fig" rid="F4">4D</xref> indicate that treatment with either of the inhibitors markedly reduced the phosphorylation of YB-1 at S102.
# ::save-date Sun May 31, 2015 ::file a_pmid_2139_2397_170.txt
(i2 / indicate-01
      :ARG0 (d / data
            :ARG1-of (s2 / show-01
                  :medium (a / and
                        :op1 (f / figure :mod "4C")
                        :op2 (f2 / figure :mod "4D"))))
      :ARG1 (r / reduce-01
            :ARG0 (t / treat-04
                  :ARG2 (m2 / molecular-physical-entity
                        :mod (e / either)
                        :ARG0-of (i / inhibit-01)))
            :ARG1 (p / phosphorylate-01
                  :ARG1 (a2 / amino-acid :mod 102 :name (n / name :op1 "serine")
                        :part-of (p2 / protein :name (n2 / name :op1 "YB-1"))))
            :manner (m / marked)))

# ::id a_pmid_2139_2397.171 ::date 2015-05-29T06:09:34 ::annotator SDL-AMR-09 ::preferred
# ::snt However, optimal inhibition was observed when cells were treated with a combination of PI3K and MEK inhibitors.
# ::save-date Sat Jan 16, 2016 ::file a_pmid_2139_2397_171.txt
(h / have-concession-91
      :ARG1 (o / observe-01
            :ARG1 (i / inhibit-01
                  :mod (o2 / optimal))
            :time (t2 / treat-04
                  :ARG1 (c / cell)
                  :ARG2 (c2 / combine-01
                        :ARG1 (m / molecular-physical-entity
                              :ARG0-of (i2 / inhibit-01
                                    :ARG1 (p / protein-family :name (n2 / name :op1 "PI3K"))))
                        :ARG2 (m2 / molecular-physical-entity
                              :ARG0-of (i3 / inhibit-01
                                    :ARG1 (p2 / protein-family :name (n / name :op1 "MEK"))))))))

# ::id a_pmid_2139_2397.172 ::date 2015-05-29T06:14:22 ::annotator SDL-AMR-09 ::preferred
# ::snt Constitutive YB-1 phosphorylation due to <i>K-RAS </i>mutation depends on erbB1 and downstream PI3K/Akt and MAPK/ERK pathways
# ::save-date Fri May 29, 2015 ::file a_pmid_2139_2397_172.txt
(d / depend-01
      :ARG0 (p / phosphorylate-01
            :ARG1 (p3 / protein :name (n3 / name :op1 "YB-1"))
            :mod (c / constitutive)
            :ARG1-of (c2 / cause-01
                  :ARG0 (m / mutate-01
                        :ARG1 (g / gene :name (n4 / name :op1 "K-RAS")))))
      :ARG1 (a / and
            :op1 (p4 / protein :name (n5 / name :op1 "erbB1"))
            :op2 (p2 / pathway :name (n2 / name :op1 "PI3K/AKT")
                  :location (d2 / downstream))
            :op3 (p5 / pathway :name (n6 / name :op1 "MAPK/ERK")
                  :location d2)))

# ::id a_pmid_2139_2397.173 ::date 2015-05-29T06:17:55 ::annotator SDL-AMR-09 ::preferred
# ::snt As IR-induced YB-1 phosphorylation was shown to be dependent on erbB1, PI3K/Akt and MAPK/ERK, we further investigated whether <i>K-RAS</i><sub>mt</sub>-dependent constitutive phosphorylation of YB-1 might be sensitive to the inhibition of erbB1, PI3K and MEK.
# ::save-date Sun Jan 3, 2016 ::file a_pmid_2139_2397_173.txt
(i / investigate-01
      :ARG0 (w / we)
      :ARG1 (p3 / possible-01 :mode interrogative
            :ARG1 (s / sensitive-03
                  :ARG0 (p / phosphorylate-01
                        :ARG1 (p4 / protein :name (n4 / name :op1 "YB-1"))
                        :mod (c / constitutive)
                        :ARG0-of (d / depend-01
                              :ARG1 (g / gene :name (n2 / name :op1 "K-RAS")
                                    :ARG1-of (m / mutate-01))))
                  :ARG1 (i2 / inhibit-01
                        :ARG1 (a / and
                              :op1 (p5 / protein :name (n5 / name :op1 "erbB1"))
                              :op2 (e / enzyme :name (n6 / name :op1 "PI3K"))
                              :op3 (e2 / enzyme :name (n3 / name :op1 "MEK"))))))
      :degree (f / further)
      :ARG1-of (c2 / cause-01
            :ARG0 (s2 / show-01
                  :ARG1 (d2 / depend-01
                        :ARG0 (p6 / phosphorylate-01
                              :ARG1 p4
                              :ARG2-of (i3 / induce-01
                                    :ARG0 (r / radiate-01
                                          :ARG0-of (i4 / ionize-01))))
                        :ARG1 (a2 / and
                              :op1 p5
                              :op2 (p2 / pathway :name (n / name :op1 "PI3K/Akt"))
                              :op3 (p7 / pathway :name (n8 / name :op1 "MAPK/ERK")))))))

# ::id a_pmid_2139_2397.174 ::date 2015-05-29T07:05:42 ::annotator SDL-AMR-09 ::preferred
# ::snt To this end, <i>K-RAS</i><sub>wt </sub>MCF-7 cells were transiently transfected with con.-vector or <i>K-RAS</i><sup>V12 </sup>vector, and 48 hours after transfection the cells were treated with the erbB1 inhibitor erlotinib, the PI3K inhibitor LY294002 or the MEK inhibitor PD98059 for 2 hours.
# ::save-date Fri Feb 12, 2016 ::file a_pmid_2139_2397_174.txt
(a / and
      :op1 (t4 / transfect-01
            :ARG1 (c / cell-line :name (n3 / name :op1 "MCF-7")
                  :mod (g / gene :name (n / name :op1 "K-RAS")
                        :mod (w / wild-type)))
            :ARG2 (o / or
                  :op1 (v2 / vector :name (n2 / name :op1 "con.-vector"))
                  :op2 (v / vector :name (n4 / name :op1 "K-RASV12")))
            :ARG1-of (t5 / transient-02))
      :op2 (t / treat-04
            :ARG1 c
            :ARG2 (a2 / and
                  :op1 (s / small-molecule :name (n5 / name :op1 "erlotinib")
                        :ARG0-of (i / inhibit-01
                              :ARG1 (p / protein :name (n6 / name :op1 "erbB1"))))
                  :op2 (s3 / small-molecule :name (n7 / name :op1 "LY294002")
                        :ARG0-of (i2 / inhibit-01
                              :ARG1 (p2 / protein-family :name (n9 / name :op1 "PI3K"))))
                  :op3 (s2 / small-molecule :name (n8 / name :op1 "PD98059")
                        :ARG0-of (i3 / inhibit-01
                              :ARG1 (p3 / protein-family :name (n10 / name :op1 "MEK")))))
            :time (a3 / after
                  :op1 t4
                  :quant (t2 / temporal-quantity :quant 48
                        :unit (h / hour)))
            :duration (t3 / temporal-quantity :quant 2
                  :unit h))
      :purpose (t6 / this))

# ::id a_pmid_2139_2397.175 ::date 2015-05-29T07:16:08 ::annotator SDL-AMR-09 ::preferred
# ::snt Similar to the results shown in Figure <xref ref-type="fig" rid="F3">3</xref>, overexpression of <i>K-RAS</i><sup>V12 </sup>resulted in an about 2.5-fold stimulation of YB-1 phosphorylation.
# ::save-date Thu Dec 17, 2015 ::file a_pmid_2139_2397_175.txt
(r2 / result-01
      :ARG1 (o / overexpress-01
            :ARG1 (g / gene :name (n2 / name :op1 "K-RAS")
                  :ARG2-of (m / mutate-01 :value "V12")))
      :ARG2 (s / stimulate-01
            :ARG1 (p / phosphorylate-01
                  :ARG1 (p2 / protein :name (n / name :op1 "YB-1")))
            :degree (a / about
                  :op1 (p3 / product-of :op1 2.5)))
      :ARG1-of (r / resemble-01
            :ARG2 (t / thing
                  :ARG2-of (r3 / result-01)
                  :ARG1-of (s2 / show-01
                        :medium (f / figure :mod 3)))))

# ::id a_pmid_2139_2397.176 ::date 2015-05-29T07:21:11 ::annotator SDL-AMR-09 ::preferred
# ::snt Erlotinib reduced mutated <i>K-RAS </i><sup>V12</sup>-induced YB-1 phosphorylation by about 50%, while the PI3K inhibitor and the MEK inhibitor reduced <i>K-RAS</i><sup>V12</sup>-induced YB-1 phosphorylation to the control level.
# ::save-date Sat Jan 16, 2016 ::file a_pmid_2139_2397_176.txt
(c / contrast-01
      :ARG1 (r / reduce-01
            :ARG0 (s / small-molecule :name (n3 / name :op1 "erlotinib"))
            :ARG1 (p2 / phosphorylate-01
                  :ARG1 (p3 / protein :name (n4 / name :op1 "YB-1"))
                  :ARG2-of (i2 / induce-01
                        :ARG0 (g / gene :name (n / name :op1 "K-RAS")
                              :ARG2-of (m / mutate-01 :value "V12"))))
            :ARG2 (p4 / percentage-entity :value 50))
      :ARG2 (r2 / reduce-01
            :ARG0 (a / and
                  :op1 (m2 / molecular-physical-entity
                        :ARG0-of (i / inhibit-01
                              :ARG1 (p / protein-family :name (n5 / name :op1 "PI3K"))))
                  :op2 (m3 / molecular-physical-entity
                        :ARG0-of (i3 / inhibit-01
                              :ARG1 (p5 / protein-family :name (n2 / name :op1 "MEK")))))
            :ARG1 p2
            :ARG4 (l / level
                  :mod (c2 / control))))

# ::id a_pmid_2139_2397.177 ::date 2015-05-29T07:29:08 ::annotator SDL-AMR-09 ::preferred
# ::snt However, the combination of PD98059 and LY294002 (PD/LY) blocked basal and <i>K-RAS </i><sup>V12</sup>-induced YB-1 phosphorylation completely (Figure <xref ref-type="fig" rid="F5">5A</xref>).
# ::save-date Fri Feb 12, 2016 ::file a_pmid_2139_2397_177.txt
(h / have-concession-91
      :ARG1 (b / block-01
            :ARG0 (c / combine-01
                  :ARG1 (s / small-molecule :name (n2 / name :op1 "PD98059"))
                  :ARG2 (s2 / small-molecule :name (n3 / name :op1 "LY294002")))
            :ARG1 (a / and
                  :op1 (p / phosphorylate-01
                        :ARG1 (p2 / protein :name (n4 / name :op1 "YB-1"))
                        :mod (b2 / basal))
                  :op2 (p3 / phosphorylate-01
                        :ARG1 p2
                        :ARG2-of (i / induce-01
                              :ARG0 (g / gene :name (n / name :op1 "K-RAS")
                                    :ARG2-of (m3 / mutate-01 :value "V12")))))
            :ARG1-of (c2 / complete-02))
      :ARG1-of (d2 / describe-01
            :ARG0 (f / figure :mod "5A")))

# ::id a_pmid_2139_2397.178 ::date 2015-05-29T07:34:42 ::annotator SDL-AMR-09 ::preferred
# ::snt These data indicate that phosphorylation of YB-1 due to mutation of <i>K-RAS </i>in part depends on activation of erbB1.
# ::save-date Thu Nov 19, 2015 ::file a_pmid_2139_2397_178.txt
(i / indicate-01
      :ARG0 (d / data
            :mod (t / this))
      :ARG1 (d2 / depend-01
            :ARG0 (p / phosphorylate-01
                  :ARG1 (p2 / protein :name (n2 / name :op1 "YB-1"))
                  :ARG1-of (c / cause-01
                        :ARG0 (m / mutate-01
                              :ARG1 (g / gene :name (n / name :op1 "K-RAS")))))
            :ARG1 (a / activate-01
                  :ARG1 (p3 / protein :name (n3 / name :op1 "erbB1")))
            :degree (p4 / part)))

# ::id a_pmid_2139_2397.179 ::date 2015-05-29T07:37:35 ::annotator SDL-AMR-09 ::preferred
# ::snt This is most likely mediated by autocrine production of ligands and is in part independent of erbB1, but it is dependent on activation of the PI3K/Akt and MAPK/ERK pathways.
# ::save-date Thu Nov 19, 2015 ::file a_pmid_2139_2397_179.txt
(c / contrast-01
      :ARG1 (a / and
            :op1 (l / likely-01
                  :ARG1 (m2 / mediate-01
                        :ARG0 (p2 / produce-01
                              :ARG1 (l2 / ligand)
                              :mod (a2 / autocrine))
                        :ARG1 (t / this))
                  :degree (m / most))
            :op2 (d / depend-01 :polarity -
                  :ARG0 t
                  :ARG1 (p3 / protein :name (n2 / name :op1 "erbB1"))
                  :degree (p5 / part)))
      :ARG2 (d2 / depend-01
            :ARG0 t
            :ARG1 (a3 / activate-01
                  :ARG1 (a4 / and
                        :op1 (p / pathway :name (n / name :op1 "PI3K/Akt"))
                        :op2 (p4 / pathway :name (n3 / name :op1 "MAPK/ERK"))))))

# ::id a_pmid_2139_2397.180 ::date 2015-05-29T07:41:26 ::annotator SDL-AMR-09 ::preferred
# ::snt Because K-Ras strongly induces YB-1 phosphorylation when it is mutated (Figures <xref ref-type="fig" rid="F3">3</xref> and <xref ref-type="fig" rid="F5">5A</xref>), we next analyzed whether phosphorylation of YB-1 in <i>K-RAS</i><sub>wt </sub>cells after irradiation or stimulation with EGF depends on K-Ras expression.
# ::save-date Sun Jan 17, 2016 ::file a_pmid_2139_2397_180.txt
(a / analyze-01
      :ARG0 (w / we)
      :ARG1 (d / depend-01 :mode interrogative
            :ARG0 (p / phosphorylate-01
                  :ARG1 (p2 / protein :name (n2 / name :op1 "YB-1"))
                  :location (c / cell
                        :mod (g / gene :name (n3 / name :op1 "K-RAS")
                              :mod (w2 / wild-type))))
            :ARG1 (e2 / express-03
                  :ARG2 (e / enzyme :name (n / name :op1 "K-Ras")))
            :time (a2 / after
                  :op1 (o / or
                        :op1 (i / irradiate-01
                              :ARG1 c)
                        :op2 (s / stimulate-01
                              :ARG1 c
                              :ARG2 (p3 / protein :name (n7 / name :op1 "EGF"))))))
      :time (n5 / next)
      :ARG1-of (c2 / cause-01
            :ARG0 (i2 / induce-01
                  :ARG0 e
                  :ARG2 p
                  :condition (m / mutate-01
                        :ARG2 e)
                  :manner (s3 / strong))
            :ARG1-of (d2 / describe-01
                  :ARG0 (a3 / and
                        :op1 (f / figure :mod 3)
                        :op2 (f2 / figure :mod "5A")))))

# ::id a_pmid_2139_2397.181 ::date 2015-05-29T07:48:43 ::annotator SDL-AMR-09 ::preferred
# ::snt Therefore, following downregulation of K-Ras by siRNA, SKBr3 cells were irradiated or stimulated with EGF.
# ::save-date Sun Jan 17, 2016 ::file a_pmid_2139_2397_181.txt
(i / infer-01
      :ARG1 (o / or
            :op1 (i2 / irradiate-01
                  :ARG1 (c / cell-line :name (n2 / name :op1 "SKBr3")))
            :op2 (s / stimulate-01
                  :ARG1 c
                  :ARG2 (p / protein :name (n3 / name :op1 "EGF")))
            :ARG1-of (f / follow-01
                  :ARG2 (d / downregulate-01
                        :ARG1 (e / enzyme :name (n / name :op1 "K-Ras"))
                        :ARG2 (n5 / nucleic-acid :name (n4 / name :op1 "siRNA"))))))

# ::id a_pmid_2139_2397.182 ::date 2015-05-29T07:52:14 ::annotator SDL-AMR-09 ::preferred
# ::snt As shown in Figure <xref ref-type="fig" rid="F5">5B</xref>, downregulation of K-Ras did not affect either IR- or EGF-induced YB-1 phosphorylation.
# ::save-date Sun Jan 17, 2016 ::file a_pmid_2139_2397_182.txt
(a / affect-01 :polarity -
      :ARG0 (d / downregulate-01
            :ARG1 (e / enzyme :name (n / name :op1 "K-Ras")))
      :ARG1 (o / or
            :op1 (p / phosphorylate-01
                  :ARG1 (p2 / protein :name (n2 / name :op1 "YB-1"))
                  :ARG2-of (i / induce-01
                        :ARG0 (r / radiate-01
                              :ARG0-of (i3 / ionize-01))))
            :op2 (p3 / phosphorylate-01
                  :ARG1 p2
                  :ARG2-of (i2 / induce-01
                        :ARG0 (p4 / protein :name (n4 / name :op1 "EGF")))))
      :ARG1-of (s3 / show-01
            :medium (f / figure :mod "5B")))

# ::id a_pmid_2139_2397.183 ::date 2015-05-29T07:57:28 ::annotator SDL-AMR-09 ::preferred
# ::snt A lack of effect of <i>K-RAS</i>-siRNA on P-ERK1/2 was observed as well (Figure <xref ref-type="fig" rid="F5">5B</xref>).
# ::save-date Sun May 31, 2015 ::file a_pmid_2139_2397_183.txt
(o / observe-01
      :ARG1 (l / lack-01
            :ARG1 (a / affect-01
                  :ARG0 (n / nucleic-acid :name (n2 / name :op1 "siRNA")
                        :mod (g / gene :name (n3 / name :op1 "K-RAS")))
                  :ARG1 (s / slash
                        :op1 (e3 / enzyme :name (n4 / name :op1 "ERK1"))
                        :op2 (e4 / enzyme :name (n5 / name :op1 "ERK2"))
                        :ARG1-of (p / phosphorylate-01))))
      :manner (a2 / as-well)
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod "5B")))

# ::id a_pmid_2139_2397.184 ::date 2015-05-29T08:00:19 ::annotator SDL-AMR-09 ::preferred
# ::snt YB-1 regulates repair of IR-induced DNA-DSB and postirradiation survival
# ::save-date Sun Jan 3, 2016 ::file a_pmid_2139_2397_184.txt
(r / regulate-01
      :ARG0 (p / protein :name (n / name :op1 "YB-1"))
      :ARG1 (a / and
            :op1 (r2 / repair-01
                  :ARG1 (e / event :name (n2 / name :op1 "DSB")
                        :mod (n3 / nucleic-acid :wiki "DNA" :name (n4 / name :op1 "DNA"))
                        :ARG2-of (i / induce-01
                              :ARG0 (r3 / radiate-01
                                    :ARG0-of (i3 / ionize-01)))))
            :op2 (s2 / survive-01
                  :time (a2 / after
                        :op1 (i2 / irradiate-01)))))

# ::id a_pmid_2139_2397.185 ::date 2015-05-29T08:05:03 ::annotator SDL-AMR-09 ::preferred
# ::snt In addition to its function as a transcription factor, YB-1 is also involved in DNA repair, that is, base excision repair and mismatch repair [<xref ref-type="bibr" rid="B39">39</xref>].
# ::save-date Fri May 29, 2015 ::file a_pmid_2139_2397_185.txt
(i / involve-01
      :ARG1 (p / protein :name (n / name :op1 "YB-1"))
      :ARG2 (r / repair-01
            :ARG1 (n4 / nucleic-acid :wiki "DNA" :name (n5 / name :op1 "DNA"))
            :ARG1-of (m / mean-01
                  :ARG2 (a3 / and
                        :op1 (e / event :name (n2 / name :op1 "base" :op2 "excision" :op3 "repair"))
                        :op2 (e2 / event :name (n3 / name :op1 "mismatch" :op2 "repair")))))
      :mod (a / also)
      :ARG1-of (a2 / add-02
            :ARG2 (f / function-01
                  :ARG0 p
                  :ARG1 (f2 / factor
                        :ARG0-of (t / transcribe-01))))
      :ARG1-of (d2 / describe-01
            :ARG0 (p2 / publication
                  :ARG1-of (c / cite-01
                        :ARG2 39))))

# ::id a_pmid_2139_2397.186 ::date 2015-05-29T08:10:16 ::annotator SDL-AMR-09 ::preferred
# ::snt In line with this function, it has been demonstrated that YB-1 binds to double-stranded, single-stranded and DNA-containing abasic sites [<xref ref-type="bibr" rid="B40">40</xref>].
# ::save-date Mon Jan 4, 2016 ::file a_pmid_2139_2397_186.txt
(d / demonstrate-01
      :ARG1 (b / bind-01
            :ARG1 (p / protein :name (n / name :op1 "YB-1"))
            :ARG2 (a / and
                  :op1 (n2 / nucleic-acid :wiki "DNA" :name (n4 / name :op1 "DNA")
                        :mod (s / strand
                              :mod (d3 / double)))
                  :op2 (n5 / nucleic-acid :wiki "DNA" :name (n6 / name :op1 "DNA")
                        :mod (s2 / strand
                              :ARG1-of (s3 / single-02)))
                  :op3 (d2 / dna-sequence :name (n3 / name :op1 "abasic" :op2 "site")
                        :ARG0-of (c / contain-01
                              :ARG1 (n7 / nucleic-acid :wiki "DNA" :name (n8 / name :op1 "DNA"))))))
      :ARG1-of (d7 / describe-01
            :ARG0 (p2 / publication
                  :ARG1-of (c2 / cite-01
                        :ARG2 40)))
      :ARG1-of (r / resemble-01
            :ARG2 (f / function
                  :mod (t / this))))

# ::id a_pmid_2139_2397.187 ::date 2015-05-29T08:16:19 ::annotator SDL-AMR-09 ::preferred
# ::snt So far, however, no data demonstrating the function of YB-1 in repair of IR-induced DNA-DSB and postirradiation survival exist.
# ::save-date Sun Jan 3, 2016 ::file a_pmid_2139_2397_187.txt
(h / have-concession-91
      :ARG1 (e / exist-01
            :ARG1 (d / data :polarity -
                  :ARG0-of (d2 / demonstrate-01
                        :ARG1 (f / function-01
                              :ARG0 (p / protein :name (n / name :op1 "YB-1"))
                              :ARG1 (a / and
                                    :op1 (r / repair-01
                                          :ARG1 (e2 / event :name (n2 / name :op1 "DSB")
                                                :mod (n3 / nucleic-acid :wiki "DNA" :name (n4 / name :op1 "DNA")))
                                          :ARG2-of (i / induce-01
                                                :ARG0 (r2 / radiate-01
                                                      :ARG0-of (i3 / ionize-01))))
                                    :op2 (s3 / survive-01
                                          :time (a2 / after
                                                :op1 (i2 / irradiate-01))))))))
      :time (s / so-far))

# ::id a_pmid_2139_2397.188 ::date 2015-05-29T08:20:53 ::annotator SDL-AMR-09 ::preferred
# ::snt The function of erbB1 and its downstream pathways and the impact of mutated <i>K-RAS </i>on repair of DNA-DSB have been demonstrated previously [<xref ref-type="bibr" rid="B15">15</xref>,<xref ref-type="bibr" rid="B34">34</xref>,<xref ref-type="bibr" rid="B41">41</xref>,<xref ref-type="bibr" rid="B42">42</xref>].
# ::save-date Sun May 31, 2015 ::file a_pmid_2139_2397_188.txt
(d / demonstrate-01
      :ARG1 (a / and
            :op1 (f / function-01
                  :ARG0 (a2 / and
                        :op1 (p2 / protein :name (n2 / name :op1 "erbB1"))
                        :op2 (p3 / pathway
                              :poss p2
                              :location (d2 / downstream))))
            :op2 (i / impact-01
                  :ARG0 (g / gene :name (n / name :op1 "K-RAS")
                        :ARG2-of (m / mutate-01))
                  :ARG1 (r / repair-01
                        :ARG1 (e / event :name (n3 / name :op1 "DSB")
                              :mod (n4 / nucleic-acid :wiki "DNA" :name (n5 / name :op1 "DNA"))))))
      :time (p / previous)
      :ARG1-of (d4 / describe-01
            :ARG0 (a3 / and
                  :op1 (p4 / publication
                        :ARG1-of (c / cite-01
                              :ARG2 15))
                  :op2 (p5 / publication
                        :ARG1-of (c2 / cite-01
                              :ARG2 34))
                  :op3 (p6 / publication
                        :ARG1-of (c3 / cite-01
                              :ARG2 41))
                  :op4 (p7 / publication
                        :ARG1-of (c4 / cite-01
                              :ARG2 42)))))

# ::id a_pmid_2139_2397.189 ::date 2015-05-29T08:27:58 ::annotator SDL-AMR-09 ::preferred
# ::snt Therefore, we next asked whether the cells presenting a differential pattern of basal- and radiation-induced YB-1 phosphorylation additionally exert a differential sensitivity to IR.
# ::save-date Sun Jan 17, 2016 ::file a_pmid_2139_2397_189.txt
(c2 / cause-01
      :ARG1 (a / ask-01
            :ARG0 (w / we)
            :ARG1 (e / exert-01 :mode interrogative
                  :ARG0 (c / cell
                        :ARG0-of (p2 / present-01
                              :ARG1 (p3 / pattern
                                    :mod (d / differential)
                                    :topic (a3 / and
                                          :op1 (p / phosphorylate-01
                                                :ARG1 (p4 / protein :name (n2 / name :op1 "YB-1"))
                                                :mod (b / basal))
                                          :op2 (p5 / phosphorylate-01
                                                :ARG1 p4
                                                :ARG2-of (i2 / induce-01
                                                      :ARG0 (r / radiate-01)))))))
                  :ARG1 (s / sensitive-03
                        :ARG0 c
                        :ARG1 (r2 / radiate-01
                              :ARG0-of (i / ionize-01))
                        :mod d)
                  :manner (a2 / additional))
            :time (n / next)))

# ::id a_pmid_2139_2397.190 ::date 2015-05-29T08:43:16 ::annotator SDL-AMR-09 ::preferred
# ::snt The results obtained by clonogenic assay indicate a differential response in terms of postirradiation survival of the cell lines analyzed.
# ::save-date Fri Jul 24, 2015 ::file a_pmid_2139_2397_190.txt
(i / indicate-01
      :ARG0 (t / thing
            :ARG2-of (r / result-01)
            :ARG1-of (o / obtain-01
                  :manner (a3 / assay-01
                        :mod (c2 / clonogenic))))
      :ARG1 (r2 / respond-01
            :ARG2 (s / survive-01
                  :ARG0 (c / cell-line
                        :ARG1-of (a2 / analyze-01))
                  :time (a / after
                        :op1 (i2 / irradiate-01)))
            :ARG1-of (d / differ-02)))

# ::id a_pmid_2139_2397.191 ::date 2015-05-29T08:49:16 ::annotator SDL-AMR-09 ::preferred
# ::snt The radiation dose, D<sub>37</sub>, which is required to reduce cell survival to 37%, is 1.95 Gy for SKBr3, 1.65 Gy for MDA-MB-23, 1.35 Gy for MCF-7 and 1.10 Gy for HBL100 cells.
# ::save-date Sun Jan 3, 2016 ::file a_pmid_2139_2397_191.txt
(e / equal-01
      :ARG1 (d / dose-01
            :ARG1 (r5 / radiate-01)
            :ARG1-of (r6 / require-01
                  :ARG0 (r7 / reduce-01
                        :ARG1 (s / survive-01
                              :ARG0 c)
                        :ARG4 (p2 / percentage-entity :value 37)))
            :ARG1-of (l / label-01
                  :ARG2 (s2 / string-entity :value "D37")))
      :ARG2 (a / and
            :op1 (r / radiation-quantity :quant 1.95
                  :unit (g / gray)
                  :location (c / cell-line :name (n / name :op1 "SKBr3")))
            :op2 (r2 / radiation-quantity :quant 1.65
                  :unit g
                  :location (c2 / cell-line :name (n2 / name :op1 "MDA-MB-23")))
            :op3 (r3 / radiation-quantity :quant 1.35
                  :unit g
                  :location (c3 / cell-line :name (n3 / name :op1 "MCF-7")))
            :op4 (r4 / radiation-quantity :quant 1.10
                  :unit g
                  :location (c4 / cell-line :name (n4 / name :op1 "HBL100")))))

# ::id a_pmid_2139_2397.192 ::date 2015-05-29T08:57:52 ::annotator SDL-AMR-09 ::preferred
# ::snt We further investigated whether YB-1 activity is involved in the process of DNA-DSB repair and postirradiation survival.
# ::save-date Mon Dec 21, 2015 ::file a_pmid_2139_2397_192.txt
(i / investigate-01
      :ARG0 (w / we)
      :ARG1 (i2 / involve-01 :mode interrogative
            :ARG1 (a / activity-06
                  :ARG0 (p / protein :name (n / name :op1 "YB-1")))
            :ARG2 (a2 / and
                  :op1 (p2 / process-02
                        :ARG1 (r / repair-01
                              :ARG1 (e / event :name (n2 / name :op1 "DSB")
                                    :mod (n3 / nucleic-acid :wiki "DNA" :name (n4 / name :op1 "DNA")))))
                  :op2 (s / survive-01
                        :time (a3 / after
                              :op1 (i3 / irradiate-01)))))
      :degree (f / further))

# ::id a_pmid_2139_2397.193 ::date 2015-05-29T09:02:30 ::annotator SDL-AMR-09 ::preferred
# ::snt For this purpose, a siRNA approach was used.
# ::save-date Fri May 29, 2015 ::file a_pmid_2139_2397_193.txt
(u / use-01
      :ARG1 (a / approach-02
            :mod (n2 / nucleic-acid :name (n / name :op1 "siRNA")))
      :purpose (t / this))

# ::id a_pmid_2139_2397.194 ::date 2015-05-29T09:04:07 ::annotator SDL-AMR-09 ::preferred
# ::snt As shown in Figure <xref ref-type="fig" rid="F6">6</xref>, downregulation of YB-1 by siRNA, either in <i>K-RAS</i><sub>mt </sub>MDA-MB-231 or in <i>K-RAS</i><sub>wt </sub>SKBr3 cells, resulted in impaired repair of DNA-DSB as shown by enhanced residual γ-H2AX foci 24 hours after irradiation.
# ::save-date Sun May 31, 2015 ::file a_pmid_2139_2397_194.txt
(r / result-01
      :ARG1 (d / downregulate-01
            :ARG1 (p / protein :name (n2 / name :op1 "YB-1"))
            :ARG2 (n11 / nucleic-acid :name (n3 / name :op1 "siRNA"))
            :location (o / or
                  :op1 (c / cell-line :name (n4 / name :op1 "MDA-MB-231")
                        :mod (g / gene :name (n6 / name :op1 "K-RAS")
                              :ARG2-of (m / mutate-01)))
                  :op2 (c2 / cell-line :name (n5 / name :op1 "SKBr3")
                        :mod (g2 / gene :name (n7 / name :op1 "K-RAS")
                              :mod (w / wild-type)))))
      :ARG2 (r4 / repair-01
            :ARG1 (e2 / event :name (n8 / name :op1 "DSB")
                  :mod (n / nucleic-acid :wiki "DNA" :name (n10 / name :op1 "DNA")))
            :ARG1-of (i / impair-01))
      :ARG1-of (s2 / show-01
            :medium (f2 / figure :mod 6))
      :ARG1-of (s / show-01
            :ARG0 (f / focus
                  :mod (p2 / protein :name (n9 / name :op1 "γ-H2AX"))
                  :mod (r3 / residual)
                  :ARG1-of (e3 / enhance-01))
            :time (a / after
                  :op1 (i2 / irradiate-01)
                  :quant (t / temporal-quantity :quant 24
                        :unit (h / hour)))))

# ::id a_pmid_2139_2397.195 ::date 2015-05-29T09:13:13 ::annotator SDL-AMR-09 ::preferred
# ::snt Interestingly, downregulating K-Ras resulted in enhanced frequency of residual DSB to the level observed with YB-1 siRNA.
# ::save-date Sun May 31, 2015 ::file a_pmid_2139_2397_195.txt
(r / result-01
      :ARG1 (d / downregulate-01
            :ARG1 (e / enzyme :name (n / name :op1 "K-Ras")))
      :ARG2 (h / have-frequency-91
            :ARG1 (e3 / event :name (n2 / name :op1 "DSB")
                  :mod (r3 / residual))
            :ARG1-of (e2 / enhance-01
                  :ARG3 (l / level
                        :ARG1-of (o / observe-01
                              :location (n5 / nucleic-acid :name (n3 / name :op1 "siRNA")
                                    :mod (p / protein :name (n4 / name :op1 "YB-1")))))))
      :ARG2-of (i / interest-01))

# ::id a_pmid_2139_2397.196 ::date 2015-05-29T09:13:52 ::annotator SDL-AMR-09 ::preferred
# ::snt Likewise, siRNA targeting of YB-1 increased radiation sensitivity tested in MDA-MB-231 cells.
# ::save-date Sun Jan 3, 2016 ::file a_pmid_2139_2397_196.txt
(i / increase-01
      :ARG0 (t / target-01
            :ARG0 (n4 / nucleic-acid :name (n2 / name :op1 "siRNA"))
            :ARG1 (p / protein :name (n / name :op1 "YB-1")))
      :ARG1 (s / sensitive-03
            :ARG1 (r / radiate-01)
            :ARG2-of (t2 / test-01
                  :ARG1 (c / cell-line :name (n3 / name :op1 "MDA-MB-231"))))
      :ARG1-of (r3 / resemble-01))

# ::id a_pmid_2169_9731.11 ::date 2015-05-20T09:32:36 ::annotator SDL-AMR-09 ::preferred
# ::snt Primary macrophages from both naïve and lung-tumor bearing mice stimulated epithelial cell proliferation.
# ::save-date Sun May 31, 2015 ::file a_pmid_2169_9731_11.txt
(s / stimulate-01
      :ARG0 (m / macrophage
            :mod (p2 / primary)
            :source (a / and
                  :op1 (m2 / mouse
                        :mod (n / naive))
                  :op2 (m3 / mouse
                        :ARG0-of (b / bear-01
                              :ARG1 (t / tumor
                                    :mod (l / lung))))))
      :ARG1 (p / proliferate-01
            :ARG0 (c / cell
                  :mod (e / epithelium))))

# ::id a_pmid_2169_9731.12 ::date 2015-05-20T09:37:16 ::annotator SDL-AMR-09 ::preferred
# ::snt The lungs of tumor-bearing mice contained 3.5-times more IGF-1 than naïve littermates, and media conditioned by freshly isolated tumor-educated macrophages contained more IGF-1 than media conditioned by naïve macrophages; IL-4 stimulated IGF-1 production by both macrophage subsets.
# ::save-date Mon Dec 21, 2015 ::file a_pmid_2169_9731_12.txt
(m / multi-sentence
      :snt1 (a / and
            :op1 (c / contain-01
                  :ARG0 (l / lung
                        :part-of (m2 / mouse
                              :ARG0-of (b / bear-01
                                    :ARG1 (t / tumor))))
                  :ARG1 (p2 / protein :name (n / name :op1 "IGF-1"))
                  :compared-to (l2 / littermate
                        :mod (n2 / naive))
                  :quant (m3 / more
                        :degree (p / product-of :op1 3.5)))
            :op2 (c2 / contain-01
                  :ARG0 (m4 / medium
                        :ARG1-of (c3 / condition-01
                              :ARG0 (m5 / macrophage
                                    :ARG1-of (e / educate-01
                                          :ARG0 (t2 / tumor))
                                    :ARG1-of (i / isolate-01
                                          :ARG1-of (f / fresh-04)))))
                  :ARG1 p2
                  :compared-to (m6 / medium
                        :ARG1-of (c4 / condition-01
                              :ARG0 (m7 / macrophage
                                    :mod (n3 / naive))))
                  :quant (m9 / more)))
      :snt2 (s / stimulate-01
            :ARG0 (p3 / protein :name (n4 / name :op1 "IL-4"))
            :ARG1 (p5 / produce-01
                  :ARG0 (s2 / subset
                        :part-of (m8 / macrophage)
                        :mod (b2 / both))
                  :ARG1 (p4 / protein :name (n5 / name :op1 "IGF-1")))))

# ::id a_pmid_2169_9731.13 ::date 2015-05-20T10:11:54 ::annotator SDL-AMR-09 ::preferred
# ::snt The ability of macrophage conditioned media to stimulate neoplastic proliferation correlated with media IGF-1 levels, and recombinant IGF-1 alone was sufficient to induce epithelial proliferation in all cell lines evaluated.
# ::save-date Fri Feb 5, 2016 ::file a_pmid_2169_9731_13.txt
(s / suffice-01
      :ARG0 (c4 / capable-01
            :ARG1 m
            :ARG2 (s2 / stimulate-01
                  :ARG0 (m / medium
                        :ARG1-of (c / condition-01
                              :ARG0 (m2 / macrophage)))
                  :ARG1 (p2 / proliferate-01
                        :ARG0 (t / tumor)
                        :ARG1-of (c2 / correlate-01
                              :ARG2 (a / and
                                    :op1 (l / level
                                          :quant-of (p3 / protein :name (n2 / name :op1 "IGF-1")
                                                :mod (m3 / medium)))
                                    :op2 (p4 / protein :name (n3 / name :op1 "IGF-1")
                                          :mod (a2 / alone)
                                          :ARG3-of (r2 / recombine-01)))))))
      :ARG1 (i / induce-01
            :ARG0 c4
            :ARG2 (p5 / proliferate-01
                  :ARG0 (e / epithelium))
            :location (c5 / cell-line
                  :ARG1-of (e2 / evaluate-01)
                  :mod (a3 / all))))

# ::id a_pmid_2169_9731.14 ::date 2015-05-20T10:54:48 ::annotator SDL-AMR-09 ::preferred
# ::snt Macrophage-conditioned media and IGF-1 stimulated lung tumor cell growth in an additive manner, while EGF had no effect.
# ::save-date Sun May 31, 2015 ::file a_pmid_2169_9731_14.txt
(c3 / contrast-01
      :ARG1 (s / stimulate-01
            :ARG0 (a / and
                  :op1 (m / medium
                        :ARG1-of (c / condition-01
                              :ARG0 (m2 / macrophage)))
                  :op2 (p / protein :name (n / name :op1 "IGF-1")))
            :ARG1 (g / grow-01
                  :ARG1 (c2 / cell
                        :mod (t / tumor
                              :mod (l / lung))))
            :manner (a2 / additive))
      :ARG2 (a3 / affect-01 :polarity -
            :ARG0 (p2 / protein :name (n2 / name :op1 "EGF"))
            :ARG1 g))

# ::id a_pmid_2169_9731.15 ::date 2015-05-20T11:08:13 ::annotator SDL-AMR-09 ::preferred
# ::snt Macrophage-derived factors increased p-Erk1/2, p-Akt and cyclin D1 levels in neoplastic cells, and the combined inhibition of both MEK and PI3K ablated macrophage-mediated increases in epithelial growth.
# ::save-date Thu Dec 17, 2015 ::file a_pmid_2169_9731_15.txt
(a / and
      :op1 (i / increase-01
            :ARG0 (f / factor
                  :ARG1-of (d / derive-01
                        :ARG2 (m3 / macrophage)))
            :ARG1 (a2 / and
                  :op1 (l / level
                        :quant-of (e4 / enzyme :name (n / name :op1 "Erk1/2")
                              :ARG3-of (p / phosphorylate-01)))
                  :op2 (l2 / level
                        :quant-of (e5 / enzyme :name (n2 / name :op1 "Akt")
                              :ARG3-of p))
                  :op3 (l3 / level
                        :quant-of (p3 / protein :name (n3 / name :op1 "cyclin" :op2 "D1"))))
            :location (c / cell
                  :mod (t / tumor)))
      :op2 (a3 / ablate-01
            :ARG1 (i3 / increase-01
                  :ARG1 (g / grow-01
                        :ARG1 (e3 / epithelium))
                  :ARG1-of (m / mediate-01
                        :ARG0 m3))
            :ARG3 (i2 / inhibit-01
                  :ARG1 (a4 / and
                        :op1 (e / enzyme :name (n5 / name :op1 "MEK"))
                        :op2 (e2 / enzyme :name (n6 / name :op1 "PI3K")))
                  :ARG1-of (c2 / combine-01))))

# ::id a_pmid_2169_9731.60 ::date 2015-05-20T11:51:31 ::annotator SDL-AMR-09 ::preferred
# ::snt Macrophage conditioned media profoundly stimulates the anchorage-independent growth of lung tumor cells
# ::save-date Sun May 31, 2015 ::file a_pmid_2169_9731_60.txt
(s / stimulate-01
      :ARG0 (m / medium
            :ARG1-of (c2 / condition-01
                  :ARG0 (m2 / macrophage)))
      :ARG1 (g / grow-01
            :ARG1 (c / cell
                  :mod (t / tumor
                        :mod (l / lung)))
            :ARG0-of (d / depend-01 :polarity -
                  :ARG1 (a / anchorage)))
      :manner (p / profound))

# ::id a_pmid_2169_9731.61 ::date 2015-05-20T11:56:03 ::annotator SDL-AMR-09 ::preferred
# ::snt Despite the correlation between lung macrophage content and lung tumor growth, the direct contribution of alveolar macrophages to lung tumor growth is unclear [<xref ref-type="bibr" rid="B6">6</xref>,<xref ref-type="bibr" rid="B7">7</xref>,<xref ref-type="bibr" rid="B13">13</xref>].
# ::save-date Sun Dec 20, 2015 ::file a_pmid_2169_9731_61.txt
(c / clear-06 :polarity -
      :ARG1 (c2 / contribute-01
            :ARG0 (m / macrophage
                  :mod (a / alveolus))
            :ARG2 (g / grow-01
                  :ARG1 (t / tumor
                        :mod (l / lung)))
            :ARG1-of (d / direct-02))
      :ARG1-of (d2 / describe-01
            :ARG0 (p / publication
                  :ARG1-of (c5 / cite-01
                        :ARG2 (a2 / and :op1 6 :op2 7 :op3 13))))
      :concession (c3 / correlate-01
                  :ARG1 (c4 / content
                        :mod (m2 / macrophage
                              :mod (l2 / lung)))
                  :ARG2 g))

# ::id a_pmid_2169_9731.62 ::date 2015-05-20T12:21:01 ::annotator SDL-AMR-09 ::preferred
# ::snt Media conditioned by an immortalized lung macrophage cell line, MH-S, has been previously reported to stimulate the migration of lung epithelial cells harboring <i>Kras </i>mutations [<xref ref-type="bibr" rid="B18">18</xref>].
# ::save-date Thu Jan 28, 2016 ::file a_pmid_2169_9731_62.txt
(r / report-01
      :ARG1 (s / stimulate-01
            :ARG0 (m3 / medium
                  :ARG1-of (c2 / condition-01
                        :ARG0 (c6 / cell-line
                              :ARG1-of (i / immortalize-03)
                              :ARG1-of (m5 / mean-01
                                    :ARG2 (c4 / cell-line :name (n2 / name :op1 "MH-S")))
                              :mod (m4 / macrophage
                                    :mod (l / lung)))))
            :ARG1 (m / migrate-01
                  :ARG0 (c / cell
                        :mod (e / epithelium)
                        :ARG0-of (h / harbor-01
                              :ARG1 (m2 / mutate-01
                                    :ARG1 (g / gene :name (n / name :op1 "Kras"))))
                        :mod l)))
      :time (p / previous)
      :ARG1-of (d / describe-01
            :ARG0 (p2 / publication
                  :ARG1-of (c5 / cite-01
                        :ARG2 18))))

# ::id a_pmid_2169_9731.63 ::date 2015-05-20T12:42:26 ::annotator SDL-AMR-09 ::preferred
# ::snt To determine if MH-S conditioned media directly stimulates neoplastic growth, we first evaluated neoplastic colony formation and cell number after long-term conditioned media exposure.
# ::save-date Mon Jul 27, 2015 ::file a_pmid_2169_9731_63.txt
(e / evaluate-01
      :ARG0 (w / we)
      :ARG1 (a / and
            :op1 (f / form-01
                  :ARG1 (c / colony
                        :mod (t / tumor)))
            :op2 (n2 / number
                  :quant-of (c2 / cell)))
      :ord (o / ordinal-entity :value 1)
      :time (a2 / after
            :op1 (e2 / expose-01
                  :ARG2 (m / medium
                        :ARG1-of (c3 / condition-01))
                  :duration (l / long-03)))
      :purpose (d / determine-01
            :ARG0 w
            :ARG1 (s / stimulate-01
                  :ARG0 (m2 / medium
                        :ARG1-of (c4 / condition-01)
                        :mod (c5 / cell-line :name (n4 / name :op1 "MH-S")))
                  :ARG1 (g / grow-01
                        :mod t)
                  :ARG1-of (d2 / direct-02))))

# ::id a_pmid_2169_9731.64 ::date 2015-05-20T13:10:21 ::annotator SDL-AMR-09 ::preferred
# ::snt In both the classic model of anchorage-independent neoplastic growth on soft agar (Figure <xref ref-type="fig" rid="F1">1A-C</xref>), and colonization on new ultra-low adherence, neutrally-charged plastic (Figure <xref ref-type="fig" rid="F1">1D-F</xref>), macrophage-conditioned media potently stimulated the proliferation of two <i>Kras </i>mutant lung tumor-derived cell lines (LM2 and JF32).
# ::save-date Fri Feb 5, 2016 ::file a_pmid_2169_9731_64.txt
(s / stimulate-01
      :ARG0 (m / medium
            :ARG1-of (c / condition-01
                  :ARG0 (m2 / macrophage)))
      :ARG1 (p2 / proliferate-01
            :ARG0 (c2 / cell-line :quant 2
                  :ARG1-of (m3 / mutate-01)
                  :ARG2-of (m5 / mean-01
                        :ARG1 (a / and
                              :op1 (c3 / cell-line :name (n2 / name :op1 "LM2"))
                              :op2 (c4 / cell-line :name (n3 / name :op1 "JF32"))))
                  :ARG1-of (d / derive-01
                        :ARG2 (t / tumor
                              :mod (l / lung)))
                  :mod (e / enzyme :name (n / name :op1 "Kras"))))
      :manner (p / potent)
      :location (a2 / and
            :op1 (m4 / model
                  :mod (c5 / classic)
                  :topic (g / grow-01
                        :location (a3 / agar
                              :ARG1-of (s2 / soft-02))
                        :ARG0-of (d2 / depend-01 :polarity -
                              :ARG1 (a4 / anchorage))
                        :mod (t2 / tumor))
                  :ARG1-of (d3 / describe-01
                        :ARG0 (a7 / and
                              :op1 (f / figure :mod "1A")
                              :op2 (f5 / figure :mod "1B")
                              :op3 (f6 / figure :mod "1C"))))
            :op2 (c6 / colonize-01
                  :ARG0 c2
                  :location (p3 / plastic
                        :ARG1-of (c7 / charge-03
                              :ARG0-of (n4 / neutral-02))
                        :ARG1-of (a5 / adhere-01
                              :ARG1-of (n5 / new-01)
                              :ARG1-of (l2 / low-04
                                    :degree (u / ultra))))
                  :ARG1-of (d4 / describe-01
                        :ARG0 (a6 / and
                              :op1 (f2 / figure :mod "1D")
                              :op2 (f3 / figure :mod "1E")
                              :op3 (f4 / figure :mod "1F"))))))

# ::id a_pmid_2169_9731.65 ::date 2015-05-20T13:12:48 ::annotator SDL-AMR-09 ::preferred
# ::snt Thus, macrophages secrete soluble molecules capable of greatly stimulating neoplastic colony formation and proliferation <i>in vitro</i>, which may shed light on the role of macrophage recruitment to lung cancer <i>in vivo</i>.
# ::save-date Wed Dec 30, 2015 ::file a_pmid_2169_9731_65.txt
(c / cause-01
      :ARG1 (s / secrete-01
            :ARG0 (m / macrophage)
            :ARG1 (m2 / molecule
                  :ARG1-of (c2 / capable-01
                        :ARG2 (s2 / stimulate-01
                              :ARG0 m2
                              :ARG1 (a / and
                                    :op1 (f / form-01
                                          :ARG1 (c3 / colony
                                                :mod (t / tumor)))
                                    :op2 (p / proliferate-01
                                          :ARG0 c3))
                              :manner (i / in-vitro)
                              :manner (g / great)))
                  :ARG1-of (d / dissolve-01
                        :ARG1-of (p3 / possible-01)))
            :ARG0-of (s3 / shed-03
                  :ARG1 (l / light)
                  :ARG2 (r / role
                        :topic (r2 / recruit-01
                              :ARG1 m
                              :ARG2 (d2 / disease :wiki "Lung_cancer" :name (n / name :op1 "lung" :op2 "cancer"))
                              :manner (i2 / in-vivo)))
                  :ARG1-of p3)))

# ::id a_pmid_2169_9731.66 ::date 2015-05-20T13:43:56 ::annotator SDL-AMR-09 ::preferred
# ::snt Naïve and tumor-educated primary macrophage co-culture stimulates the proliferation of neoplastic and non-neoplastic pulmonary epithelial cells
# ::save-date Sun May 31, 2015 ::file a_pmid_2169_9731_66.txt
(s / stimulate-01
      :ARG0 (a / and
            :op1 (c / co-culture
                  :mod (n / naive)
                  :mod (p / primary)
                  :mod (m / macrophage))
            :op2 (c2 / co-culture
                  :mod p
                  :mod (m2 / macrophage
                        :ARG1-of (e / educate-01
                              :ARG0 (t / tumor)))))
      :ARG1 (p2 / proliferate-01
            :ARG0 (a2 / and
                  :op1 (c3 / cell
                        :mod (e2 / epithelium)
                        :mod (l / lung)
                        :mod t)
                  :op2 (c4 / cell
                        :mod e2
                        :mod l
                        :mod (t2 / tumor :polarity -)))))

# ::id a_pmid_2169_9731.67 ::date 2015-05-20T13:53:34 ::annotator SDL-AMR-09 ::preferred
# ::snt The relative ability of naïve vs. tumor-educated alveolar macrophages to directly stimulate lung epithelial cell proliferation not been reported.
# ::save-date Wed Nov 4, 2015 ::file a_pmid_2169_9731_67.txt
(r / report-01 :polarity -
      :ARG1 (c2 / capable-01
            :ARG1 (m / macrophage
                  :mod (n / naive)
                  :mod (a / alveolus))
            :ARG2 (s / stimulate-01
                  :ARG0 m
                  :ARG1 (p2 / proliferate-01
                        :ARG0 (c / cell
                              :mod (e2 / epithelium)
                              :mod (l / lung)))
                  :ARG1-of (d / direct-02))
            :ARG2-of (r2 / relative-05)
            :compared-to (m2 / macrophage
                  :ARG1-of (e / educate-01
                        :ARG0 (t / tumor))
                  :mod a)))

# ::id a_pmid_2169_9731.68 ::date 2015-05-20T14:03:02 ::annotator SDL-AMR-09 ::preferred
# ::snt To determine if macrophages from the lungs of tumor-bearing mice could directly stimulate neoplastic cell growth in a co-culture system, neoplastic LM2 cells were co-cultured with bronchoalveolar lavage (BAL) macrophages (MØ) isolated from tumor-bearing mice, and monolayer growth was assessed (Figure <xref ref-type="fig" rid="F2">2A</xref>).
# ::save-date Fri Jul 24, 2015 ::file a_pmid_2169_9731_68.txt
(a2 / and
      :op1 (c / culture-01
            :ARG1 (a / and
                  :op1 (c2 / cell-line :name (n / name :op1 "LM2")
                        :mod (n2 / neoplastic))
                  :op2 (m / macrophage
                        :mod (b / bronchoalveolar
                              :mod (l / lavage))
                        :ARG1-of (i / isolate-01
                              :ARG2 (m2 / mouse
                                    :ARG0-of (b2 / bear-01
                                          :ARG1 (t / tumor)))))))
      :op2 (a3 / assess-01
            :ARG1 (g / grow-01
                  :ARG1 (l2 / layer :quant 1)))
      :purpose (d / determine-01
            :ARG1 (p2 / possible-01
                  :ARG1 (s / stimulate-01
                        :ARG0 (m3 / macrophage
                              :source (l3 / lung
                                    :part-of m2))
                        :ARG1 (g2 / grow-01
                              :mod (c3 / cell
                                    :mod (n3 / neoplastic))
                              :location (s2 / system
                                    :mod (c4 / co-culture)))
                        :ARG1-of (p / possible-01)
                        :ARG1-of (d3 / direct-02))))
      :ARG1-of (d2 / describe-01
            :ARG0 (f / figure :mod "2A")))

# ::id a_pmid_2169_9731.69 ::date 2015-05-21T10:49:28 ::annotator SDL-AMR-09 ::preferred
# ::snt Growth in standard tissue culture conditions measures proliferation <i>per se</i>, and not cell motility or the requirement for solid support, and permits the evaluation of non-neoplastic epithelial cells which do not proliferate in anchorage-independent systems.
# ::save-date Sun Jul 26, 2015 ::file a_pmid_2169_9731_69.txt
(a / and
      :op1 (c2 / contrast-01
            :ARG1 (m / measure-01
                  :ARG0 (g / grow-01
                        :ARG1 (c / culture-01
                              :ARG1 (t / tissue
                                    :ARG1-of (s / standard-02))))
                  :ARG1 (p4 / proliferate-01)
                  :manner (p / per-se))
            :ARG2 (m2 / measure-01 :polarity -
                  :ARG0 g
                  :ARG1 (o / or
                        :op1 (m3 / motility
                              :mod (c3 / cell))
                        :op2 (r / require-01
                              :ARG1 (s2 / support-01
                                    :ARG1-of (s3 / solid-02))))))
      :op2 (p2 / permit-01
            :ARG0 g
            :ARG1 (e / evaluate-01
                  :ARG1 (c4 / cell
                        :mod (e2 / epithelium)
                        :mod (t2 / tumor :polarity -)
                        :ARG0-of (p3 / proliferate-01 :polarity -
                              :location (s4 / system
                                    :ARG0-of (d / depend-01 :polarity -
                                          :ARG1 (a2 / anchorage))))))))

# ::id a_pmid_2169_9731.70 ::date 2015-05-21T11:07:49 ::annotator SDL-AMR-09 ::preferred
# ::snt LM2 cell number significantly increased with BAL macrophage co-culture at 48 (2.3 vs. 4.1-fold) and 72 hrs (3.5 vs. 7.5-fold) (Figure <xref ref-type="fig" rid="F2">2A</xref>).
# ::save-date Fri Feb 12, 2016 ::file a_pmid_2169_9731_70.txt
(a / and
      :op1 (i / increase-01
            :ARG0 (c / co-culture
                  :mod (m / macrophage
                        :mod (l / lavage
                              :mod (a4 / alveolus
                                    :mod (b / bronchus)))))
            :ARG1 (n2 / number
                  :quant-of (c2 / cell-line :name (n3 / name :op1 "LM2")))
            :ARG2 (s / significant-02)
            :ARG3 (p / product-of :op1 2.3)
            :ARG4 (p2 / product-of :op1 4.1)
            :time (a2 / after
                  :op1 (t2 / temporal-quantity :quant 48
                        :unit (h / hour))))
      :op2 (i2 / increase-01
            :ARG0 c
            :ARG1 n2
            :ARG2 s
            :ARG3 (p3 / product-of :op1 3.5)
            :ARG4 (p4 / product-of :op1 7.5)
            :time (a3 / after
                  :op1 (t3 / temporal-quantity :quant 72
                        :unit (h2 / hour))))
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod "2A")))

# ::id a_pmid_2169_9731.71 ::date 2015-05-21T11:52:20 ::annotator SDL-AMR-09 ::preferred
# ::snt As 72 hrs of macrophage co-culture resulted in ≥ 2-times more tumor cells, this time point was used in subsequent experiments.
# ::save-date Fri Dec 18, 2015 ::file a_pmid_2169_9731_71.txt
(u / use-01
      :ARG0 (p / point
            :mod (t / time)
            :mod (t4 / this))
      :ARG1 (e / experiment-01
            :time (s / subsequent))
      :ARG1-of (c / cause-01
            :ARG0 (r / result-01
                  :ARG1 (c2 / co-culture
                        :mod (m / macrophage)
                        :duration (t2 / temporal-quantity :quant 72
                              :unit (h / hour)))
                  :ARG2 (c3 / cell
                        :mod (t3 / tumor)
                        :quant (m2 / more
                              :degree (v / value-interval
                                    :op1 (m3 / more-than
                                          :op1 (p2 / product-of :op1 2))
                                    :op2 (p3 / product-of :op1 2)))))))

# ::id a_pmid_2169_9731.72 ::date 2015-05-21T12:12:40 ::annotator SDL-AMR-09 ::preferred
# ::snt To determine if tumor-educated macrophages stimulated neoplastic growth more effectively than naïve, BAL macrophages from either naïve or tumor-bearing mice were co-cultured with neoplastic LM2 (Figure <xref ref-type="fig" rid="F2">2B</xref>) and JF32 (Figure <xref ref-type="fig" rid="F2">2C</xref>) cells.
# ::save-date Fri Feb 12, 2016 ::file a_pmid_2169_9731_72.txt
(c / culture-01
      :ARG1 (a / and
            :op1 (m / macrophage
                  :source (o / or
                        :op1 (m2 / mouse
                              :mod (n / naive))
                        :op2 (m3 / mouse
                              :ARG0-of (b / bear-01
                                    :ARG1 (t / tumor))))
                  :mod (l / lavage
                        :mod (a2 / alveolus
                              :mod (b2 / bronchus))))
            :op2 (c2 / cell-line :name (n2 / name :op1 "LM2")
                  :ARG1-of (d / describe-01
                        :ARG0 (f / figure :mod "2B"))
                  :mod t)
            :op3 (c3 / cell-line :name (n3 / name :op1 "JF32")
                  :ARG1-of (d2 / describe-01
                        :ARG0 (f2 / figure :mod "2C"))
                  :mod t))
      :purpose (d3 / determine-01
            :ARG1 (s / stimulate-01 :mode interrogative
                  :ARG0 (m4 / macrophage
                        :ARG1-of (e / educate-01
                              :ARG0 t))
                  :ARG1 (g / grow-01
                        :ARG1 t)
                  :ARG1-of (e2 / effective-04
                        :degree (m5 / more)
                        :compared-to (m6 / macrophage
                              :mod (n6 / naive))))))

# ::id a_pmid_2169_9731.73 ::date 2015-05-21T12:25:41 ::annotator SDL-AMR-09 ::preferred
# ::snt LM2 growth was equally stimulated by both naïve and tumor-educated BAL macrophages, while the growth of JF32 cells was enhanced slightly upon co-culture with tumor-educated BAL macrophages (Figure <xref ref-type="fig" rid="F2">2C</xref>).
# ::save-date Fri Feb 12, 2016 ::file a_pmid_2169_9731_73.txt
(c / contrast-01
      :ARG1 (s / stimulate-01
            :ARG0 (g / grow-01
                  :ARG1 (c2 / cell-line :name (n2 / name :op1 "LM2")))
            :ARG1 (a / and
                  :op1 (m / macrophage
                        :mod (n / naive)
                        :mod (l / lavage
                              :mod (a4 / alveolus
                                    :mod (b / bronchus))))
                  :op2 (m2 / macrophage
                        :ARG1-of (e / educate-01
                              :ARG0 (t / tumor))))
            :ARG1-of (e2 / equal-01))
      :ARG2 (e3 / enhance-01
            :ARG1 (g2 / grow-01
                  :ARG1 (c3 / cell-line :name (n3 / name :op1 "JF32")))
            :manner (s2 / slight)
            :time (a3 / after
                  :op1 (c4 / culture-01
                        :ARG1 (a2 / and
                              :op1 c3
                              :op2 m2))))
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod "2C")))

# ::id a_pmid_2169_9731.74 ::date 2015-05-21T12:37:27 ::annotator SDL-AMR-09 ::preferred
# ::snt To determine if primary alveolar macrophages also stimulated the proliferation of non-tumor cells, the non-neoplastic E10 cell line was co-cultured with naïve and tumor-educated BAL macrophages.
# ::save-date Fri Feb 12, 2016 ::file a_pmid_2169_9731_74.txt
(c / culture-01
      :ARG1 (a / and
            :op1 (c2 / cell-line :name (n / name :op1 "E10")
                  :mod (t3 / tumor :polarity -))
            :op2 (m / macrophage
                  :mod (n2 / naive))
            :op3 (m2 / macrophage
                  :ARG1-of (e / educate-01
                        :ARG0 (t / tumor))
                  :mod (l / lavage
                        :mod (a4 / alveolus
                              :mod (b / bronchus)))))
      :purpose (d / determine-01
            :ARG1 (s / stimulate-01 :mode interrogative
                  :ARG0 (m3 / macrophage
                        :mod (p2 / primary)
                        :mod (a2 / alveolus))
                  :ARG1 (p / proliferate-01
                        :ARG0 (c3 / cell
                              :mod t3))
                  :mod (a3 / also))))

# ::id a_pmid_2169_9731.75 ::date 2015-05-21T12:48:37 ::annotator SDL-AMR-09 ::preferred
# ::snt Both macrophage types increased E10 cell number 3.5-fold (Figure <xref ref-type="fig" rid="F2">2D</xref>) when maintained in serum-free conditions; only tumor-educated macrophages stimulated E10 proliferation when cultured in the presence of serum (Figure <xref ref-type="fig" rid="F2">2E</xref>).
# ::save-date Mon Dec 21, 2015 ::file a_pmid_2169_9731_75.txt
(m / multi-sentence
      :snt1 (i / increase-01
            :ARG0 (t / type-03
                  :ARG1 (m2 / macrophage)
                  :mod (b / both))
            :ARG1 (n / number
                  :quant-of (c / cell-line :name (n2 / name :op1 "E10")))
            :ARG2 (p / product-of :op1 3.5)
            :ARG1-of (d / describe-01
                  :ARG0 (f / figure :mod "2D"))
            :time (m3 / maintain-01
                  :ARG1 t
                  :ARG2 (c2 / condition
                        :ARG1-of (f2 / free-04
                              :ARG2 (s / serum)))))
      :snt2 (s2 / stimulate-01
            :ARG0 (m4 / macrophage
                  :ARG1-of (e / educate-01
                        :ARG0 (t2 / tumor))
                  :mod (o / only))
            :ARG1 (p2 / proliferate-01
                  :ARG0 (c3 / cell-line :name (n3 / name :op1 "E10")))
            :time (c4 / culture-01
                  :ARG1 c3)
            :condition (p3 / present-02
                  :ARG1 (s3 / serum))
            :ARG1-of (d2 / describe-01
                  :ARG0 (f3 / figure :mod "2E"))))

# ::id a_pmid_2169_9731.76 ::date 2015-05-21T13:16:10 ::annotator SDL-AMR-09 ::preferred
# ::snt Both types of primary macrophages equally stimulated LM2 proliferation in the presence of serum, though the magnitude was reduced when compared to serum-free co-culture (data not shown).
# ::save-date Mon Dec 21, 2015 ::file a_pmid_2169_9731_76.txt
(s / stimulate-01
      :ARG0 (t / type-03
            :ARG1 (m / macrophage
                  :mod (p3 / primary))
            :mod (b / both))
      :ARG1 (p / proliferate-01
            :ARG0 (c / cell-line :name (n / name :op1 "LM2")))
      :ARG1-of (e / equal-01)
      :condition (p2 / present-02
            :ARG1 (s2 / serum))
      :ARG1-of (d / describe-01
            :ARG0 (d3 / data
                  :ARG1-of (s3 / show-01 :polarity -)))
      :concession (r / reduce-01
                  :ARG1 (m2 / magnitude)
                  :time (c2 / compare-01
                        :ARG1 m2
                        :ARG2 (c3 / co-culture
                              :ARG1-of (f / free-04
                                    :ARG2 s2)))))

# ::id a_pmid_2169_9731.77 ::date 2015-05-21T14:14:27 ::annotator SDL-AMR-09 ::preferred
# ::snt To determine if MH-S macrophages could recapitulate the effects of primary alveolar macrophages in this <i>in vitro </i>model, we co-cultured MH-S macrophages with both neoplastic and non-neoplastic lung epithelial cells.
# ::save-date Sun May 31, 2015 ::file a_pmid_2169_9731_77.txt
(c / culture-01
      :ARG0 (w / we)
      :ARG1 (a / and
            :op1 (m / macrophage
                  :mod (c2 / cell-line :name (n / name :op1 "MH-S")))
            :op2 (c3 / cell
                  :mod (l / lung)
                  :mod (e / epithelium)
                  :mod (t2 / tumor))
            :op3 (c4 / cell
                  :mod l
                  :mod (n3 / neoplastic :polarity -)
                  :mod t2))
      :purpose (d / determine-01
            :ARG0 w
            :ARG1 (p / possible-01
                  :ARG1 (r / recapitulate-01
                        :ARG0 m
                        :ARG1 (a2 / affect-01
                              :ARG0 (m2 / macrophage
                                    :mod (a3 / alveolar)
                                    :mod (p2 / primary)))
                        :location (m3 / model
                              :mod (i / in-vitro)
                              :mod (t / this))))))

# ::id a_pmid_2169_9731.78 ::date 2015-05-21T14:24:54 ::annotator SDL-AMR-09 ::preferred
# ::snt MH-S co-culture increased the growth rate of all pulmonary epithelial cell lines similar to co-culture with tumor-educated BAL macrophages (Figure <xref ref-type="fig" rid="F2">2B-E</xref>).
# ::save-date Fri Feb 12, 2016 ::file a_pmid_2169_9731_78.txt
(i / increase-01
      :ARG0 (c / co-culture
            :mod (c2 / cell-line :name (n / name :op1 "MH-S")))
      :ARG1 (r / rate
            :degree-of (g / grow-01
                  :ARG1 (c3 / cell-line
                        :mod (a / all)
                        :mod (e / epithelium)
                        :mod (l / lung)
                        :ARG1-of (r2 / resemble-01
                              :ARG2 (c4 / culture-01
                                    :ARG1 (m / macrophage
                                          :ARG1-of (e2 / educate-01
                                                :ARG0 (t / tumor))
                                          :mod (l2 / lavage
                                                :mod (a3 / alveolus
                                                      :mod (b / bronchus)))))))))
      :ARG1-of (d / describe-01
            :ARG0 (a2 / and
                  :op1 (f / figure :mod "2B")
                  :op2 (f2 / figure :mod "2C")
                  :op3 (f3 / figure :mod "2D")
                  :op4 (f4 / figure :mod "2E"))))

# ::id a_pmid_2169_9731.79 ::date 2015-05-21T14:34:25 ::annotator SDL-AMR-09 ::preferred
# ::snt These results indicate that primary lung macrophages produce diffusible signals which can augment the proliferation of both non-neoplastic and neoplastic cells <i>in vitro</i>.
# ::save-date Wed Dec 30, 2015 ::file a_pmid_2169_9731_79.txt
(i / indicate-01
      :ARG0 (t / thing
            :ARG2-of (r / result-01)
            :mod (t2 / this))
      :ARG1 (p / produce-01
            :ARG0 (m / macrophage
                  :mod (p4 / primary)
                  :mod (l / lung))
            :ARG1 (s / signal-07
                  :ARG1-of (d / diffuse-01
                        :ARG1-of (p2 / possible-01))
                  :ARG0-of (a / augment-01
                        :ARG1 (p3 / proliferate-01
                              :ARG0 (a2 / and
                                    :op1 (c / cell
                                          :mod (t3 / tumor :polarity -))
                                    :op2 (c2 / cell
                                          :mod (n2 / neoplastic)))
                              :manner (i2 / in-vitro))
                        :ARG1-of p2))))

# ::id a_pmid_2169_9731.80 ::date 2015-05-21T14:40:55 ::annotator SDL-AMR-09 ::preferred
# ::snt Further, we observed that <i>in vivo </i>tumor education of primary lung macrophages slightly enhances this ability to stimulate epithelial proliferation, an effect similar to co-culture with MH-S macrophages.
# ::save-date Sun May 31, 2015 ::file a_pmid_2169_9731_80.txt
(o / observe-01
      :ARG0 (w / we)
      :ARG1 (e / enhance-01
            :ARG0 (e2 / educate-01
                  :ARG0 (t / tumor)
                  :ARG1 (m / macrophage
                        :mod (l / lung)
                        :mod (p / primary))
                  :manner (i / in-vivo))
            :manner (s / slight)
            :ARG1-of (c / capable-01
                  :ARG2 (s2 / stimulate-01
                        :ARG1 (p2 / proliferate-01
                              :ARG0 (e3 / epithelium))))
            :ARG2-of (a / affect-01
                  :ARG1 c
                  :ARG1-of (r / resemble-01
                        :ARG2 (c2 / culture-01
                              :ARG1 (a2 / and
                                    :op1 m
                                    :op2 (m2 / macrophage
                                          :mod (c3 / cell-line :name (n / name :op1 "MH-S"))))))))
      :mod (f / further))

# ::id a_pmid_2169_9731.81 ::date 2015-05-22T11:16:53 ::annotator SDL-AMR-09 ::preferred
# ::snt Macrophage co-culture stimulates epithelial proliferation through kinase activation
# ::save-date Tue Feb 2, 2016 ::file a_pmid_2169_9731_81.txt
(s / stimulate-01
      :ARG0 (c / coculture-01
            :ARG1 (m / macrophage))
      :ARG1 (p / proliferate-01
            :ARG0 (e / epithelium))
      :ARG2 (a / activate-01
            :ARG1 (k / kinase)))

# ::id a_pmid_2169_9731.82 ::date 2015-05-22T23:20:29 ::annotator SDL-AMR-09 ::preferred
# ::snt Since MH-S macrophages and tumor-educated primary macrophages stimulated epithelial proliferation to a similar degree, MH-S macrophages were used to elucidate the mechanisms of increased epithelial proliferation.
# ::save-date Sun Jan 17, 2016 ::file a_pmid_2169_9731_82.txt
(u / use-01
      :ARG1 (m2 / macrophage
            :mod (c2 / cell-line :name (n / name :op1 "MH-S")))
      :ARG2 (e / elucidate-01
            :ARG0 m2
            :ARG1 (m / mechanism
                  :poss (p / proliferate-01
                        :ARG0 (e2 / epithelium)
                        :ARG1-of (i / increase-01))))
      :ARG1-of (c / cause-01
            :ARG0 (s / stimulate-01
                  :ARG0 (a / and
                        :op1 m2
                        :op2 (m3 / macrophage
                              :mod (p2 / primary)
                              :ARG1-of (e3 / educate-01
                                    :ARG0 (t / tumor))))
                  :ARG1 p
                  :degree (r / resemble-01))))

# ::id a_pmid_2169_9731.83 ::date 2015-05-23T12:28:15 ::annotator SDL-AMR-09 ::preferred
# ::snt Because Kras pathways are commonly hyper-activated in lung tumorigenesis [<xref ref-type="bibr" rid="B22">22</xref>,<xref ref-type="bibr" rid="B23">23</xref>], and the tumorigenic lines examined herein contain <i>Kras </i>mutations, activities of downstream mediators Erk and Akt were examined.
# ::save-date Sat Jan 16, 2016 ::file a_pmid_2169_9731_83.txt
(e / examine-01
      :ARG1 (a / act-02
            :ARG0 (a2 / and
                  :op1 (e2 / enzyme :name (n / name :op1 "Erk"))
                  :op2 (e3 / enzyme :name (n2 / name :op1 "Akt"))
                  :ARG0-of (m / mediate-01
                        :direction (d / downstream))))
      :ARG1-of (c / cause-01
            :ARG0 (a3 / and
                  :op1 (a4 / activate-01
                        :ARG1 (p / pathway :name (n3 / name :op1 "K-Ras"))
                        :degree (h / hyper)
                        :time (c2 / create-01
                              :ARG1 (t / tumor
                                    :mod (l / lung)))
                        :ARG1-of (d2 / describe-01
                              :ARG0 (p2 / publication-91
                                    :ARG1-of (c3 / cite-01
                                          :ARG2 (a5 / and :op1 22 :op2 23))))
                        :manner (c4 / common))
                  :op2 (c5 / contain-01
                        :ARG0 (l2 / line
                              :ARG1-of (e5 / examine-01
                                    :medium (h2 / herein))
                              :ARG0-of (c6 / create-01
                                    :ARG1 (t2 / tumor)
                                    :ARG1-of (p3 / possible-01)))
                        :ARG1 (m2 / mutate-01
                              :ARG2 (g / gene :name (n4 / name :op1 "K-Ras")))))))

# ::id a_pmid_2169_9731.84 ::date 2015-05-24T09:44:46 ::annotator SDL-AMR-09 ::preferred
# ::snt Cytosolic Raf functionally links the Erk and Akt pathways; activated Akt can phosphorylate cRaf at S259, placing Erk regulation downstream of Akt activation [<xref ref-type="bibr" rid="B32">32</xref>,<xref ref-type="bibr" rid="B33">33</xref>].
# ::save-date Mon Jun 15, 2015 ::file a_pmid_2169_9731_84.txt
(a / and
      :op1 (l / link-01
            :ARG0 (e / enzyme :name (n / name :op1 "Raf")
                  :location (c / cytosol))
            :ARG1 (a2 / and
                  :op1 (p2 / pathway :name (n2 / name :op1 "Erk"))
                  :op2 (p3 / pathway :name (n3 / name :op1 "Akt")))
            :ARG0-of (f / function-01))
      :op2 (p4 / possible-01
            :ARG1 (p / phosphorylate-01
                  :ARG1 (a4 / amino-acid :mod 259 :name (n6 / name :op1 "serine")
                        :part-of (e2 / enzyme :name (n4 / name :op1 "C-Raf")))
                  :ARG2 (p7 / pathway :name (n5 / name :op1 "Akt")
                        :ARG1-of (a3 / activate-01))
                  :ARG0-of (c2 / cause-01
                        :ARG1 (p5 / place-01
                              :ARG1 (r / regulate-01
                                    :ARG1 p2)
                              :ARG2 (r3 / relative-position
                                    :op1 p7
                                    :direction (d / downstream)))))
            :ARG1-of (d2 / describe-01
                  :ARG0 (p6 / publication-91
                        :ARG1-of (c3 / cite-01
                              :ARG2 (a6 / and :op1 32 :op2 33))))))

# ::id a_pmid_2169_9731.85 ::date 2015-05-25T00:20:41 ::annotator SDL-AMR-09 ::preferred
# ::snt MH-S co-culture stimulated cRaf phosphorylation at S259 in all three cell lines, resulting in significantly higher levels of p-cRaf (Figure <xref ref-type="fig" rid="F3">3A-C</xref>).
# ::save-date Tue Feb 2, 2016 ::file a_pmid_2169_9731_85.txt
(s / stimulate-01
      :ARG0 (c / coculture-01
            :ARG1 (m / macrophage
                  :mod (c3 / cell-line :name (n / name :op1 "MH-S"))))
      :ARG1 (p / phosphorylate-01
            :ARG1 (a / amino-acid :mod 259 :name (n2 / name :op1 "serine")
                  :part-of (e / enzyme :name (n3 / name :op1 "C-Raf"))))
      :ARG3 (l / level
            :ARG1-of (h / high-02
                  :degree (m2 / more)
                  :ARG1-of (s2 / significant-02))
            :quant-of (e2 / enzyme :name (n4 / name :op1 "C-Raf")
                  :ARG3-of (p2 / phosphorylate-01)))
      :location (c2 / cell-line :quant 3
            :mod (a2 / all))
      :ARG1-of (d / describe-01
            :ARG0 (a3 / and
                  :op1 (f / figure :mod "3A")
                  :op2 (f2 / figure :mod "3B")
                  :op3 (f3 / figure :mod "3C"))))

# ::id a_pmid_2169_9731.86 ::date 2015-06-11T03:24:02 ::annotator SDL-AMR-09 ::preferred
# ::snt The smaller (~74 kDa) p-cRaf isoform was most highly abundant and its phosphorylation significantly increased with macrophage co-culture in the LM2 and E10 cells, but a larger (~100 kDa) isoform was heavily phosphorylated at the expense of the 74 kDa isoform in neoplastic JF32 cells (Figure <xref ref-type="fig" rid="F3">3A</xref>).
# ::save-date Tue Feb 2, 2016 ::file a_pmid_2169_9731_86.txt
(c / contrast-01
      :ARG1 (a / and
            :op1 (a2 / abundant
                  :domain (i / isoform
                        :mod (e / enzyme :name (n / name :op1 "C-Raf")
                              :ARG3-of (p2 / phosphorylate-01))
                        :ARG1-of (e2 / equal-01
                              :ARG2 (a4 / approximately
                                    :op1 (m2 / mass-quantity :quant 74
                                          :unit (k / kilodalton))))
                        :mod (s / small
                              :degree (m3 / more)))
                  :ARG1-of (h / high-02
                        :degree (m / most)))
            :op2 (i2 / increase-01
                  :ARG1 (p3 / phosphorylate-01
                        :ARG1 e)
                  :ARG2 (s2 / significant-02)
                  :instrument (c2 / coculture-01
                        :ARG1 (m4 / macrophage)
                        :location (a3 / and
                              :op1 (c3 / cell-line :name (n2 / name :op1 "LM2"))
                              :op2 (c4 / cell-line :name (n3 / name :op1 "E10"))))))
      :ARG2 (p / phosphorylate-01
            :ARG1 (i3 / isoform
                  :mod (l / large
                        :degree (m5 / more))
                  :ARG1-of (e3 / equal-01
                        :ARG2 (a5 / approximately
                              :op1 (m6 / mass-quantity :quant 100
                                    :unit (k2 / kilodalton)))))
            :manner (h2 / heavy)
            :ARG0-of (c5 / compromise-02
                  :ARG1 (i4 / isoform
                        :quant m2))
            :location (c6 / cell-line :name (n5 / name :op1 "JF32")
                  :mod (n6 / neoplastic)))
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod "3A")))

# ::id a_pmid_2169_9731.87 ::date 2015-05-24T09:44:51 ::annotator SDL-AMR-09 ::preferred
# ::snt The 74 kDa isoform was the most abundant in total cRaf immunoblots from all three cell lines.
# ::save-date Mon Dec 21, 2015 ::file a_pmid_2169_9731_87.txt
(a / abundant
      :degree (m / most)
      :location (i2 / immunoblot-01
            :ARG1 (e / enzyme :name (n2 / name :op1 "C-Raf"))
            :ARG2 (c / cell-line :quant 3
                  :mod (a2 / all))
            :mod (t / total))
      :domain (i / isoform
            :quant (m2 / mass-quantity :quant 74
                  :unit (k / kilodalton))))

# ::id a_pmid_2169_9731.88 ::date 2015-05-24T22:39:58 ::annotator SDL-AMR-09 ::preferred
# ::snt MH-S co-culture significantly increased the levels of active Erk1/2 (p-Erk) in LM2 and JF32 cells, as well as non-neoplastic E10 cells, when normalized either to total Erk (panErk) or β-actin levels (Figure <xref ref-type="fig" rid="F3">3A, D</xref> and <xref ref-type="fig" rid="F3">3E</xref>), which correlates with the observed increases in proliferation (Figure <xref ref-type="fig" rid="F2">2</xref>).
# ::save-date Tue Feb 2, 2016 ::file a_pmid_2169_9731_88.txt
(i / increase-01
      :ARG0 (c / coculture-01
            :ARG1 (m / macrophage
                  :mod (c7 / cell-line :name (n / name :op1 "MH-S"))))
      :ARG1 (l / level
            :quant-of (s2 / slash
                  :op1 (e3 / enzyme :name (n10 / name :op1 "Erk1"))
                  :op2 (e4 / enzyme :name (n11 / name :op1 "Erk2"))
                  :ARG0-of (a / activity-06)
                  :ARG1-of (m2 / mean-01
                        :ARG2 (e / enzyme :name (n2 / name :op1 "Erk")
                              :ARG3-of (p3 / phosphorylate-01)))))
      :ARG2 (s / significant-02)
      :location (a2 / and
            :op1 (c2 / cell-line :name (n3 / name :op1 "LM2"))
            :op2 (c3 / cell-line :name (n4 / name :op1 "JF32"))
            :op3 (c4 / cell-line :name (n5 / name :op1 "E10")
                  :mod (n6 / neoplastic :polarity -)))
      :condition (n7 / normalize-01
            :ARG1 s2
            :ARG1-of (c6 / conform-01
                  :ARG2 (o / or
                        :op1 (l3 / level
                              :quant-of (e2 / enzyme :name (n8 / name :op1 "Erk")
                                    :mod (t / total)
                                    :ARG1-of (m3 / mean-01
                                          :ARG2 (e5 / enzyme :name (n12 / name :op1 "Erk")
                                                :mod (p4 / pan)))))
                        :op2 (l2 / level
                              :quant-of (p / protein :name (n9 / name :op1 "β-actin"))))))
      :ARG1-of (d / describe-01
            :ARG0 (a3 / and
                  :op1 (f / figure :mod "3A")
                  :op2 (f2 / figure :mod "3D")
                  :op3 (f3 / figure :mod "3E")))
      :ARG1-of (c5 / correlate-01
            :ARG2 (i2 / increase-01
                  :ARG1 (p2 / proliferate-01)
                  :ARG1-of (o2 / observe-01))
            :ARG1-of (d2 / describe-01
                  :ARG0 (f4 / figure :mod 2))))

# ::id a_pmid_2169_9731.89 ::date 2015-05-29T00:28:05 ::annotator SDL-AMR-09 ::preferred
# ::snt E10 cells expressed lower basal p-Erk/panErk vs. the neoplastic cell lines, consistent with previous observations [<xref ref-type="bibr" rid="B21">21</xref>].
# ::save-date Sun Jan 17, 2016 ::file a_pmid_2169_9731_89.txt
(e / express-03
      :ARG2 (s / slash
            :op1 (e3 / enzyme :name (n4 / name :op1 "Erk")
                  :ARG3-of (p4 / phosphorylate-01))
            :op2 (e4 / enzyme :name (n5 / name :op1 "Erk")
                  :mod (p5 / pan))
            :mod (b / basal)
            :ARG1-of (l / low-04
                  :degree (m / more)))
      :ARG3 (c / cell-line :name (n / name :op1 "E10"))
      :ARG1-of (c2 / contrast-01
            :ARG2 (e2 / express-03
                  :ARG2 s
                  :ARG3 (c3 / cell-line
                        :mod (n3 / neoplastic))))
      :ARG1-of (c4 / consistent-01
            :ARG2 (o / observe-01
                  :time (p2 / previous)))
      :ARG1-of (d / describe-01
            :ARG0 (p3 / publication-91
                  :ARG1-of (c5 / cite-01
                        :ARG2 21))))

# ::id a_pmid_2169_9731.90 ::date 2015-05-29T01:21:42 ::annotator SDL-AMR-09 ::preferred
# ::snt Total Erk remained unchanged in both neoplastic cell lines, while macrophage co-culture caused Erk2 (42 kDa) to nearly disappear in the E10 cells, with little effect on Erk1 (Figure <xref ref-type="fig" rid="F3">3A, D</xref> and <xref ref-type="fig" rid="F3">3E</xref>).
# ::save-date Fri Feb 5, 2016 ::file a_pmid_2169_9731_90.txt
(c / contrast-01
      :ARG1 (r / remain-01
            :ARG1 (e / enzyme :name (n / name :op1 "Erk")
                  :mod (t / total))
            :ARG3 (c2 / change-01 :polarity -
                  :ARG1 e
                  :location (c6 / cell-line
                        :mod (b / both)
                        :mod (n6 / neoplastic))))
      :ARG2 (c3 / cause-01
            :ARG0 (c4 / coculture-01
                  :ARG1 (m / macrophage))
            :ARG1 (d / disappear-01
                  :ARG0 c4
                  :ARG1 (e2 / enzyme :name (n2 / name :op1 "Erk2"))
                  :mod (n3 / near)
                  :location (c5 / cell-line :name (n4 / name :op1 "E10")))
            :ARG0-of (a / affect-01
                  :ARG1 (e3 / enzyme :name (n5 / name :op1 "Erk1"))
                  :degree (l / little)))
      :ARG1-of (d2 / describe-01
            :ARG0 (a2 / and
                  :op1 (f / figure :mod "3A")
                  :op2 (f2 / figure :mod "3D")
                  :op3 (f3 / figure :mod "3E"))))

# ::id a_pmid_2169_9731.91 ::date 2015-05-30T05:16:55 ::annotator SDL-AMR-09 ::preferred
# ::snt Activated Akt (p-Akt) levels rose significantly in both neoplastic cell lines when normalized to either total Akt (panAkt) or β-actin, but macrophage co-culture caused both p-Akt and panAkt levels to rise to similar extents in E10 cells (Figure <xref ref-type="fig" rid="F3">3A</xref> and <xref ref-type="fig" rid="F3">3F</xref>).
# ::save-date Tue Feb 2, 2016 ::file a_pmid_2169_9731_91.txt
(c / contrast-01
      :ARG1 (r / rise-01
            :ARG1 (l / level
                  :quant-of (e / enzyme :name (n / name :op1 "Akt")
                        :ARG1-of (a / activate-01)
                        :ARG1-of (m2 / mean-01
                              :ARG2 (e3 / enzyme :name (n6 / name :op1 "Akt")
                                    :ARG3-of (p2 / phosphorylate-01)))))
            :ARG2 (s / significant-02)
            :location (c3 / cell-line
                  :mod (b / both)
                  :mod (n2 / neoplastic))
            :condition (n3 / normalize-01
                  :ARG1 e
                  :ARG1-of (c5 / conform-01
                        :ARG2 (o / or
                              :op1 (e2 / enzyme :name (n4 / name :op1 "Akt")
                                    :mod (t / total))
                              :op2 (p / protein :name (n5 / name :op1 "β-actin"))))))
      :ARG2 (c2 / cause-01
            :ARG0 (c4 / coculture-01
                  :ARG1 (m / macrophage))
            :ARG1 (r3 / rise-01
                  :ARG0 c4
                  :ARG1 (l2 / level
                        :quant-of (a2 / and
                              :op1 e
                              :op2 e2))
                  :ARG2 (e4 / extent
                        :ARG1-of (r4 / resemble-01
                              :ARG2 l))
                  :location c3))
      :ARG1-of (d / describe-01
            :ARG0 (a3 / and
                  :op1 (f / figure :mod "3A")
                  :op2 (f2 / figure :mod "3F"))))

# ::id a_pmid_2169_9731.92 ::date 2015-05-27T00:33:11 ::annotator SDL-AMR-09 ::preferred
# ::snt When p-Akt was normalized to panAkt expression, there was no change in E10 cells with MH-S co-culture (Figure <xref ref-type="fig" rid="F3">3F</xref>).
# ::save-date Tue Feb 2, 2016 ::file a_pmid_2169_9731_92.txt
(c / change-01 :polarity -
      :ARG1 (c2 / cell-line :name (n / name :op1 "E10")
            :ARG0-of (c3 / contain-01
                  :ARG1 (c4 / coculture-01
                        :ARG1 (m / macrophage
                              :mod (c6 / cell-line :name (n2 / name :op1 "MH-S"))))))
      :time (n3 / normalize-01
            :ARG1 (e2 / enzyme :name (n4 / name :op1 "Akt")
                  :ARG3-of (p / phosphorylate-01))
            :ARG1-of (c5 / conform-01
                  :ARG2 (e3 / enzyme :name (n6 / name :op1 "Akt")
                        :mod (p3 / pan)
                        :ARG2-of (e / express-03))))
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod "3F")))

# ::id a_pmid_2169_9731.93 ::date 2015-05-25T23:39:20 ::annotator SDL-AMR-09 ::preferred
# ::snt Total Akt expression increased slightly in LM2 cells but decreased in JF32 cells (Figure <xref ref-type="fig" rid="F3">3A</xref>).
# ::save-date Sun Jan 17, 2016 ::file a_pmid_2169_9731_93.txt
(c / contrast-01
      :ARG1 (i2 / increase-01
            :ARG1 (e / express-03
                  :ARG2 (e2 / enzyme :name (n / name :op1 "Akt")
                        :mod (t / total)))
            :ARG2 (s / slight)
            :location (c2 / cell-line :name (n2 / name :op1 "LM2")))
      :ARG2 (d / decrease-01
            :ARG1 e
            :location (c3 / cell-line :name (n3 / name :op1 "JF32")))
      :ARG1-of (d2 / describe-01
            :ARG0 (f / figure :mod "3A")))

# ::id a_pmid_2169_9731.94 ::date 2015-05-26T23:50:42 ::annotator SDL-AMR-09 ::preferred
# ::snt When normalized to β-actin, p-Akt levels significantly increased upon MH-S co-culture in all three cell lines (Figure <xref ref-type="fig" rid="F3">3A</xref> and <xref ref-type="fig" rid="F3">3G</xref>).
# ::save-date Tue Feb 2, 2016 ::file a_pmid_2169_9731_94.txt
(i / increase-01
      :ARG0 (c / coculture-01
            :ARG1 (m / macrophage
                  :mod (c4 / cell-line :name (n4 / name :op1 "MH-S"))))
      :ARG1 (l / level
            :quant-of (e / enzyme :name (n3 / name :op1 "Akt")
                  :ARG3-of (p2 / phosphorylate-01)))
      :ARG2 (s / significant-02)
      :condition (n / normalize-01
            :ARG1 e
            :ARG1-of (c3 / conform-01
                  :ARG2 (p / protein :name (n2 / name :op1 "β-actin"))))
      :location (c2 / cell-line :quant 3
            :mod (a / all))
      :ARG1-of (d / describe-01
            :ARG0 (a2 / and
                  :op1 (f / figure :mod "3A")
                  :op2 (f2 / figure :mod "3G"))))

# ::id a_pmid_2169_9731.95 ::date 2015-05-28T22:53:38 ::annotator SDL-AMR-09 ::preferred
# ::snt Increased p-S473 Akt content suggests increased enzymatic activity, which can be confirmed by enhanced phosphorylation of downstream substrates.
# ::save-date Mon Jul 6, 2015 ::file a_pmid_2169_9731_95.txt
(s / suggest-01
      :ARG0 (c / contain-01
            :ARG1 (e / enzyme :name (n / name :op1 "Akt")
                  :part (a / amino-acid :mod 473 :name (n2 / name :op1 "serine")
                        :ARG1-of (p / phosphorylate-01)))
            :ARG1-of (i / increase-01))
      :ARG1 (a2 / activity-06
            :ARG0 (e2 / enzyme)
            :ARG1-of i
            :ARG1-of (c2 / confirm-01
                  :ARG0 (p3 / phosphorylate-01
                        :ARG1 (s2 / substrate
                              :direction (d / downstream))
                        :ARG1-of (e3 / enhance-01))
                  :ARG1-of (p2 / possible-01))))

# ::id a_pmid_2169_9731.96 ::date 2015-05-28T23:24:20 ::annotator SDL-AMR-09 ::preferred
# ::snt To determine if macrophage co-culture increases Akt activity, we measured levels of p-GSK-3β, a known target of Akt [<xref ref-type="bibr" rid="B32">32</xref>].
# ::save-date Tue Feb 2, 2016 ::file a_pmid_2169_9731_96.txt
(m / measure-01
      :ARG0 (w / we)
      :ARG1 (l / level
            :quant-of (e2 / enzyme :name (n2 / name :op1 "GSK-3β")
                  :ARG1-of (t / target-01
                        :ARG0 e
                        :ARG1-of (k / know-01))
                  :ARG3-of (p / phosphorylate-01)))
      :purpose (d / determine-01
            :ARG0 w
            :ARG1 (i / increase-01
                  :ARG0 (c / coculture-01
                        :ARG1 (m2 / macrophage))
                  :ARG1 (a / activity-06
                        :ARG0 (e / enzyme :name (n / name :op1 "Akt")))))
      :ARG1-of (d2 / describe-01
            :ARG0 (p2 / publication-91
                  :ARG1-of (c2 / cite-01
                        :ARG2 32))))

# ::id a_pmid_2169_9731.97 ::date 2015-06-02T00:51:25 ::annotator SDL-AMR-09 ::preferred
# ::snt Consistent with the elevation in p-Akt, MH-S co-culture significantly increased p-GSK-3β in both LM2 and E10 cells and trended towards an increase in JF32 cells (Figure <xref ref-type="fig" rid="F3">3A</xref> and <xref ref-type="fig" rid="F3">3H</xref>); panGSK-3β levels were unchanged (data not shown).
# ::save-date Tue Feb 2, 2016 ::file a_pmid_2169_9731_97.txt
(m / multi-sentence
      :snt2 (c / change-01 :polarity -
            :ARG1 (l / level
                  :quant-of (e2 / enzyme :name (n6 / name :op1 "GSK-3β")
                        :mod (p2 / pan)))
            :ARG1-of (d2 / describe-01
                  :ARG0 (d3 / data
                        :ARG1-of (s2 / show-01 :polarity -))))
      :snt1 (a2 / and
            :op1 (i / increase-01
                  :ARG0 (c2 / coculture-01
                        :ARG1 (m2 / macrophage
                              :mod (c7 / cell-line :name (n / name :op1 "MH-S"))))
                  :ARG1 (e / enzyme :name (n2 / name :op1 "GSK-3β")
                        :ARG3-of (p / phosphorylate-01))
                  :ARG2 (s / significant-02)
                  :location (a / and
                        :op1 (c3 / cell-line :name (n3 / name :op1 "LM2"))
                        :op2 (c4 / cell-line :name (n4 / name :op1 "E10"))))
            :op2 (t / trend-01
                  :ARG1 c2
                  :ARG2 i
                  :location (c5 / cell-line :name (n5 / name :op1 "JF32")))
            :ARG1-of (c6 / consistent-01
                  :ARG2 (e3 / elevate-01
                        :ARG1 (e4 / enzyme :name (n7 / name :op1 "Akt")
                              :ARG3-of p)))
            :ARG1-of (d / describe-01
                  :ARG0 (a3 / and
                        :op1 (f / figure :mod "3A")
                        :op2 (f2 / figure :mod "3H")))))

# ::id a_pmid_2169_9731.98 ::date 2015-05-30T12:17:20 ::annotator SDL-AMR-09 ::preferred
# ::snt Phospho-S259 cRaf is another measure of Akt activity, and p-cRaf levels increased in all three cell lines with macrophage co-culture (Figure <xref ref-type="fig" rid="F3">3A-C</xref>).
# ::save-date Tue Feb 2, 2016 ::file a_pmid_2169_9731_98.txt
(a / and
      :op1 (m / measure-01
            :ARG0 (e / enzyme :name (n / name :op1 "C-Raf")
                  :part (a2 / amino-acid :mod 259 :name (n2 / name :op1 "serine")
                        :ARG3-of (p / phosphorylate-01)))
            :ARG1 (a3 / activity-06
                  :ARG0 (e2 / enzyme :name (n3 / name :op1 "Akt")))
            :mod (a4 / another))
      :op2 (i / increase-01
            :ARG1 (l / level
                  :quant-of e)
            :location (c / cell-line :quant 3
                  :mod (a5 / all)
                  :ARG0-of (c2 / contain-01
                        :ARG1 (c3 / coculture-01
                              :ARG1 (m2 / macrophage)))))
      :ARG1-of (d / describe-01
            :ARG0 (v / value-interval
                  :op1 (f / figure :mod "3A")
                  :op2 (f2 / figure :mod "3C"))))

# ::id a_pmid_2169_9731.99 ::date 2015-06-01T23:52:24 ::annotator SDL-AMR-09 ::preferred
# ::snt Together, the observed increases in epithelial proliferation and the known roles for Erk and Akt in neoplastic lung cell division suggest that macrophage co-culture stimulates lung cell proliferation through increased Erk and Akt activity [<xref ref-type="bibr" rid="B34">34</xref>].
# ::save-date Tue Feb 2, 2016 ::file a_pmid_2169_9731_99.txt
(s / suggest-01
      :ARG0 (a / and
            :op1 (i / increase-01
                  :ARG1 (p / proliferate-01
                        :ARG0 (e / epithelium))
                  :ARG1-of (o / observe-01))
            :op2 (r / role
                  :ARG1-of (k / know-01)
                  :poss (a3 / and
                        :op1 (e2 / enzyme :name (n / name :op1 "Erk"))
                        :op2 (e3 / enzyme :name (n2 / name :op1 "Akt")))
                  :topic (d / divide-02
                        :ARG1 (c / cell
                              :mod (l / lung)
                              :mod (n3 / neoplasm))))
            :mod (t / together))
      :ARG1 (s2 / stimulate-01
            :ARG0 (c2 / coculture-01
                  :ARG1 (m / macrophage))
            :ARG1 (p2 / proliferate-01
                  :ARG0 (c4 / cell
                        :mod l))
            :manner (a2 / activity-06
                  :ARG0 a3
                  :ARG1-of (i2 / increase-01)))
      :ARG1-of (d2 / describe-01
            :ARG0 (p3 / publication-91
                  :ARG1-of (c3 / cite-01
                        :ARG2 34))))

# ::id a_pmid_2169_9731.100 ::date 2015-05-31T04:40:57 ::annotator SDL-AMR-09 ::preferred
# ::snt Combined inhibition of MEK and PI3K abrogates macrophage stimulation of neoplastic growth
# ::save-date Tue Jun 16, 2015 ::file a_pmid_2169_9731_100.txt
(a / abrogate-01
      :ARG0 (i / inhibit-01
            :ARG1 (a2 / and
                  :op1 (e / enzyme :name (n / name :op1 "MEK"))
                  :op2 (e2 / enzyme :name (n2 / name :op1 "PI3K")))
            :ARG3-of (c / combine-01))
      :ARG1 (s / stimulate-01
            :ARG0 (m / macrophage)
            :ARG1 (g / grow-01
                  :ARG1 (n3 / neoplasm))))

# ::id a_pmid_2169_9731.101 ::date 2015-05-31T08:05:23 ::annotator SDL-AMR-09 ::preferred
# ::snt Erk and Akt regulate both proliferation and resistance to apoptotic cell death, are more active in lung tumors than in normal tissue [<xref ref-type="bibr" rid="B21">21</xref>,<xref ref-type="bibr" rid="B35">35</xref>], and were activated with macrophage co-culture.
# ::save-date Tue Feb 2, 2016 ::file a_pmid_2169_9731_101.txt
(a / and
      :op1 (r / regulate-01
            :ARG0 (a4 / and
                  :op1 (e / enzyme :name (n / name :op1 "Erk"))
                  :op2 (e2 / enzyme :name (n2 / name :op1 "Akt")))
            :ARG1 (a5 / and
                  :op1 (p / proliferate-01)
                  :op2 (r2 / resist-01
                        :ARG1 (d / die-01
                              :ARG1 (c / cell)
                              :mod (a6 / apoptosis)))))
      :op2 (a2 / activity-06
            :ARG0 a4
            :degree (m / more)
            :ARG1-of (d2 / describe-01
                  :ARG0 (p2 / publication-91
                        :ARG1-of (c3 / cite-01
                              :ARG2 (a7 / and :op1 21 :op2 35))))
            :location (t / tumor
                  :mod (l / lung)
                  :compared-to (t2 / tissue
                        :ARG1-of (n3 / normal-02))))
      :op3 (a3 / activate-01
            :ARG0 (c2 / coculture-01
                  :ARG1 (m2 / macrophage))
            :ARG1 a4))

# ::id a_pmid_2169_9731.102 ::date 2015-06-01T13:06:36 ::annotator SDL-AMR-09 ::preferred
# ::snt Since combined MEK and PI3K inhibition slowed mutant <i>Kras-</i>driven lung tumor growth <i>in vivo </i>[<xref ref-type="bibr" rid="B25">25</xref>], we determined whether selective inhibition of MEK and PI3K affected macrophage-stimulated proliferation in these <i>Kras </i>mutant lung tumor cell lines.
# ::save-date Thu Jan 14, 2016 ::file a_pmid_2169_9731_102.txt
(d / determine-01
      :ARG0 (w / we)
      :ARG1 (a / affect-01 :mode interrogative
            :ARG0 (i / inhibit-01
                  :ARG1 (a2 / and
                        :op1 (e / enzyme :name (n / name :op1 "MEK"))
                        :op2 (e2 / enzyme :name (n2 / name :op1 "PI3K")))
                  :manner (s / selective))
            :ARG1 (p / proliferate-01
                  :ARG1-of (s2 / stimulate-01
                        :ARG0 (m / macrophage))
                  :location (c / cell-line
                        :mod (g2 / gene :name (n3 / name :op1 "K-Ras")
                              :ARG2-of (m2 / mutate-01))
                        :mod (t / tumor)
                        :mod (l / lung))))
      :ARG1-of (c2 / cause-01
            :ARG0 (s3 / slow-01
                  :ARG0 (i4 / inhibit-01
                        :ARG3-of (c4 / combine-01))
                  :ARG1 (g / grow-01
                        :ARG1 (t2 / tumor
                              :mod (l2 / lung)
                              :ARG1-of (d2 / drive-02
                                    :ARG0 g2))
                        :manner (i2 / in-vivo))
                  :ARG1-of (d3 / describe-01
                        :ARG0 (p2 / publication-91
                              :ARG1-of (c3 / cite-01
                                    :ARG2 25))))))

# ::id a_pmid_2169_9731.103 ::date 2015-06-10T01:46:23 ::annotator SDL-AMR-09 ::preferred
# ::snt Selective inhibition of either MEK (by U0126) or PI3K (by LY294002) significantly decreased basal proliferation, and blocked growth stimulated by macrophage co-culture to different extents in LM2 and JF32 cells (Figure <xref ref-type="fig" rid="F4">4A</xref> and <xref ref-type="fig" rid="F4">4B</xref>, respectively).
# ::save-date Tue Feb 2, 2016 ::file a_pmid_2169_9731_103.txt
(a / and
      :op1 (d / decrease-01
            :ARG0 (o2 / or
                  :op1 (i2 / inhibit-01
                        :ARG0 (s2 / small-molecule :name (n3 / name :op1 "U0126"))
                        :ARG1 (e / enzyme :name (n / name :op1 "MEK")))
                  :op2 (i3 / inhibit-01
                        :ARG0 (s3 / small-molecule :name (n4 / name :op1 "LY294002"))
                        :ARG1 (e2 / enzyme :name (n2 / name :op1 "PI3K")))
                  :manner (s / selective))
            :ARG1 (p / proliferate-01
                  :mod (b2 / basal))
            :ARG2 (s4 / significant-02))
      :op2 (b / block-01
            :ARG0 o2
            :ARG1 (g / grow-01
                  :ARG1-of (s5 / stimulate-01
                        :ARG0 (c / coculture-01
                              :ARG1 (m / macrophage))
                        :degree (e3 / extent
                              :ARG1-of (d2 / differ-02))))
            :location (a2 / and
                  :op1 (c2 / cell-line :name (n5 / name :op1 "LM2"))
                  :op2 (c3 / cell-line :name (n6 / name :op1 "JF32"))))
      :ARG1-of (d3 / describe-01
            :ARG0 (a3 / and
                  :op1 (f / figure :mod "4A")
                  :op2 (f2 / figure :mod "4B"))
            :mod (r / respective)))

# ::id a_pmid_2169_9731.104 ::date 2015-06-10T00:59:40 ::annotator SDL-AMR-09 ::preferred
# ::snt Only the combined inhibition of both kinases ablated the stimulatory effect of macrophage co-culture on neoplastic proliferation (U0 + LY, Figure <xref ref-type="fig" rid="F4">4</xref>).
# ::save-date Tue Feb 2, 2016 ::file a_pmid_2169_9731_104.txt
(a / ablate-01
      :ARG1 (a2 / affect-01
            :ARG0 (c / coculture-01
                  :ARG1 (m / macrophage))
            :ARG1 (p / proliferate-01
                  :ARG0 (n / neoplasm))
            :ARG2 (s / stimulate-01))
      :ARG3 (i / inhibit-01
            :ARG0 a3
            :ARG1 (k / kinase
                  :mod (b / both))
            :ARG3-of (c2 / combine-01
                  :ARG1-of (m2 / mean-01
                        :ARG2 (a3 / and
                              :op1 (s3 / small-molecule :name (n2 / name :op1 "U0"))
                              :op2 (s4 / small-molecule :name (n3 / name :op1 "LY")))
                        :ARG1-of (d / describe-01
                              :ARG0 (f / figure :mod 4))))
            :mod (o / only)))

# ::id a_pmid_2169_9731.105 ::date 2015-06-01T13:07:52 ::annotator SDL-AMR-09 ::preferred
# ::snt Kinase inhibitors were applied at concentrations reported to be cytostatic and not cytotoxic [<xref ref-type="bibr" rid="B34">34</xref>,<xref ref-type="bibr" rid="B36">36</xref>,<xref ref-type="bibr" rid="B37">37</xref>], and none of these treatments significantly increased LM2 or JF32 cell death (data not shown).
# ::save-date Sun Jan 17, 2016 ::file a_pmid_2169_9731_105.txt
(a / and
      :op1 (a2 / apply-02
            :ARG1 (c / concentrate-02
                  :ARG1 (m / molecular-physical-entity
                        :ARG0-of (i2 / inhibit-01
                              :ARG1 (k / kinase)))
                  :ARG1-of (r / report-01)
                  :mod (c2 / cytostatic)
                  :mod (c3 / cytotoxic :polarity -))
            :ARG1-of (d4 / describe-01
                  :ARG0 (p / publication-91
                        :ARG1-of (c6 / cite-01
                              :ARG2 (a3 / and :op1 34 :op2 36 :op3 37)))))
      :op2 (i / increase-01
            :ARG0 (t / treatment
                  :mod (t2 / this)
                  :quant (n / none))
            :ARG1 (d3 / die-01
                  :ARG1 (o / or
                        :op1 (c4 / cell-line :name (n2 / name :op1 "LM2"))
                        :op2 (c5 / cell-line :name (n3 / name :op1 "JF32"))))
            :ARG2 (s2 / significant-02))
      :ARG1-of (d / describe-01
            :ARG0 (d2 / data
                  :ARG1-of (s / show-01 :polarity -))))

# ::id a_pmid_2169_9731.106 ::date 2015-05-31T05:09:30 ::annotator SDL-AMR-09 ::preferred
# ::snt These results suggest that both the MEK and PI3K pathways must be blocked to effectively inhibit macrophage-stimulated neoplastic growth.
# ::save-date Wed Feb 3, 2016 ::file a_pmid_2169_9731_106.txt
(o / obligate-01
      :ARG1 (a / and
            :op1 (p / pathway :name (n / name :op1 "MEK"))
            :op2 (p2 / pathway :name (n2 / name :op1 "PI3K")))
      :ARG2 (b / block-01
            :ARG1 a
            :purpose (i / inhibit-01
                  :ARG0 a
                  :ARG1 (g / grow-01
                        :ARG1 (n3 / neoplasm)
                        :ARG1-of (s2 / stimulate-01
                              :ARG0 (m / macrophage)))
                  :ARG1-of (e / effective-04)))
      :ARG1-of (s / suggest-01
            :ARG0 (t2 / thing
                  :ARG2-of (r / result-01)
                  :mod (t / this))))

# ::id a_pmid_2169_9731.107 ::date 2015-05-30T13:19:48 ::annotator SDL-AMR-09 ::preferred
# ::snt Macrophage conditioned media contains 3-10 kDa factors which stimulate neoplastic proliferation
# ::save-date Wed Jun 17, 2015 ::file a_pmid_2169_9731_107.txt
(c / contain-01
      :ARG0 (m / medium
            :ARG1-of (c2 / condition-01
                  :ARG2 (m2 / macrophage)))
      :ARG1 (f / factor
            :ARG0-of (s / stimulate-01
                  :ARG1 (p / proliferate-01
                        :ARG0 (n / neoplasm)))
            :quant (b / between
                  :op1 (m3 / mass-quantity :quant 3
                        :unit (k3 / kilodalton))
                  :op2 (m4 / mass-quantity :quant 10
                        :unit (k4 / kilodalton)))))

# ::id a_pmid_2169_9731.108 ::date 2015-06-11T02:01:32 ::annotator SDL-AMR-09 ::preferred
# ::snt Macrophages produce numerous cytokines, eicosanoids and other soluble factors depending upon tissue location and environmental stimuli [<xref ref-type="bibr" rid="B4">4</xref>,<xref ref-type="bibr" rid="B18">18</xref>], any number of which could be responsible for the observed neoplastic growth stimulation described above.
# ::save-date Wed Jun 17, 2015 ::file a_pmid_2169_9731_108.txt
(p / produce-01
      :ARG0 (m / macrophage)
      :ARG1 (a / and
            :op1 (c / cytokine
                  :quant (n / numerous))
            :op2 (e / eicosanoid)
            :op3 (f / factor
                  :mod (s / soluble)
                  :mod (o / other))
            :ARG0-of (r / responsible-01
                  :ARG1 (s3 / stimulate-01
                        :ARG1 (g / grow-01
                              :ARG1 (n2 / neoplasm)
                              :ARG1-of (o2 / observe-01))
                        :ARG1-of (d2 / describe-01
                              :location (a4 / above)))
                  :ARG1-of (p2 / possible-01))
            :quant (n3 / number
                  :mod (a3 / any)))
      :ARG0-of (d / depend-01
            :ARG1 (a2 / and
                  :op1 (l / location
                        :mod (t / tissue))
                  :op2 (s2 / stimulus
                        :mod (e2 / environment))))
      :ARG1-of (d3 / describe-01
            :ARG0 (p3 / publication-91
                  :ARG1-of (c2 / cite-01
                        :ARG2 (a5 / and :op1 4 :op2 18)))))

# ::id a_pmid_2169_9731.109 ::date 2015-05-20T06:07:46 ::annotator SDL-AMR-09 ::preferred
# ::snt Media conditioned by primary BAL macrophages (MØCM) stimulated the proliferation of LM2 cells, albeit to a lesser extent than primary macrophage co-culture (Figure <xref ref-type="fig" rid="F5">5</xref> "Total" vs. Figure <xref ref-type="fig" rid="F2">2B</xref>).
# ::save-date Fri Feb 12, 2016 ::file a_pmid_2169_9731_109.txt
(s / stimulate-01
      :ARG0 (m / medium
            :ARG1-of (c / condition-01
                  :ARG0 (m2 / macrophage
                        :source (a / alveolus
                              :mod (b / bronchus))
                        :mod (p / primary))))
      :ARG1 (p2 / proliferate-01
            :ARG0 (c2 / cell-line :name (n2 / name :op1 "LM2")))
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod 5)
            :ARG2 (t / total))
      :concession (s2 / stimulate-01
            :ARG0 m
            :ARG1 p2
            :degree (l / less
                  :degree (m4 / more))
            :ARG1-of (d2 / describe-01
                  :ARG0 (f2 / figure :mod "2B"))
            :compared-to (c3 / coculture-01
                  :ARG1 (m5 / macrophage
                        :mod (p3 / primary)))))

# ::id a_pmid_2169_9731.110 ::date 2015-05-20T06:36:04 ::annotator SDL-AMR-09 ::preferred
# ::snt When size-fractionated MØCM was added to LM2 cells, molecules between 3 and 10 kDa stimulated LM2 growth to the greatest extent (Figure <xref ref-type="fig" rid="F5">5</xref>).
# ::save-date Fri Feb 12, 2016 ::file a_pmid_2169_9731_110.txt
(s / stimulate-01
      :ARG0 (m2 / molecule
            :mod (m3 / mass-quantity
                  :quant (b / between :op1 3 :op2 10)
                  :unit (k / kilodalton)))
      :ARG1 (g2 / grow-01
            :ARG1 (c / cell-line :name (n / name :op1 "LM2")))
      :degree (g / great
            :degree (m / most))
      :condition (a / add-02
            :ARG1 (m4 / medium
                  :ARG1-of (f / fractionate-00
                        :mod (s2 / size))
                  :ARG1-of (c2 / condition-01
                        :ARG0 (m5 / macrophage)))
            :ARG2 c)
      :ARG1-of (d / describe-01
            :ARG0 (f2 / figure :mod 5)))

# ::id a_pmid_2169_9731.111 ::date 2015-05-20T06:44:30 ::annotator SDL-AMR-09 ::preferred
# ::snt Thus, factors of this size mediated the majority of MØCM effects on LM2 growth.
# ::save-date Fri Feb 12, 2016 ::file a_pmid_2169_9731_111.txt
(i / infer-01
      :ARG1 (m / mediate-01
            :ARG0 (f / factor
                  :mod (s / size
                        :mod (t / this)))
            :ARG1 (a / affect-01
                  :ARG0 (m3 / medium
                        :ARG1-of (c2 / condition-01
                              :ARG0 (m4 / macrophage)))
                  :ARG1 (g / grow-01
                        :ARG0 (c / cell-line :name (n2 / name :op1 "LM2")))
                  :quant (m2 / majority))))

# ::id a_pmid_2169_9731.112 ::date 2015-05-20T06:53:29 ::annotator SDL-AMR-09 ::preferred
# ::snt Alveolar macrophages produce numerous growth factors in this size range, including IGF-1, GM-CSF and EGF [<xref ref-type="bibr" rid="B11">11</xref>,<xref ref-type="bibr" rid="B18">18</xref>].
# ::save-date Wed Feb 24, 2016 ::file a_pmid_2169_9731_112.txt
(p / produce-01
      :ARG0 (m / macrophage
            :mod (a / alveolus))
      :ARG1 (g / growth-factor
            :ARG2-of (i / include-01
                  :ARG1 (a2 / and
                        :op1 (p5 / protein :name (n2 / name :op1 "IGF-1"))
                        :op2 (p4 / protein :name (n3 / name :op1 "GM-CSF"))
                        :op3 (p3 / protein :name (n4 / name :op1 "EGF"))))
            :quant (n5 / numerous))
      :prep-in (r / range
            :mod (s2 / size)
            :mod (t / this))
      :ARG1-of (d / describe-01
            :ARG0 (p2 / publication
                  :ARG1-of (c / cite-01
                        :ARG2 (a3 / and :op1 11 :op2 18)))))

# ::id a_pmid_2169_9731.113 ::date 2015-05-20T06:59:27 ::annotator SDL-AMR-09 ::preferred
# ::snt To further narrow down the list of possible candidates, an <i>in silico </i>analysis was performed for each fraction size as described in Materials and Methods.
# ::save-date Tue Dec 29, 2015 ::file a_pmid_2169_9731_113.txt
(p / perform-02
      :ARG1 (a / analyze-01
            :ARG1 (s / size
                  :mod (f / fraction)
                  :mod (e / each))
            :manner (i / in-silico))
      :purpose (n / narrow-down-03
            :ARG1 (l / list
                  :consist-of (c / candidate
                        :ARG1-of (p2 / possible-01)))
            :degree (f2 / further))
      :ARG1-of (d / describe-01
            :ARG0 (s2 / section :name (n2 / name :op1 "Materials" :op2 "and" :op3 "Methods"))))

# ::id a_pmid_2169_9731.114 ::date 2015-05-20T07:11:31 ::annotator SDL-AMR-09 ::preferred
# ::snt The resulting data points were separately fit for each fraction size to the general equation <i>y </i>= <i>y</i><sub>0 </sub>+ <i>a</i>(1-<i>e<sup>-bx</sup></i>) as described, with regression r<sup>2 </sup>= 0.997, 0.842 and 0.918 for the > 3, > 10 and > 30 kDa fractions, respectively.
# ::save-date Tue Dec 29, 2015 ::file a_pmid_2169_9731_114.txt
(f / fit-06
      :ARG1 (p / point
            :mod (d / data)
            :ARG1-of (r / result-01))
      :ARG2 (e2 / equation
            :ARG1-of (g / general-02)
            :mod (s6 / string-entity :value "y=y0+a(1-e-bx)"))
      :manner (s / separate-02)
      :beneficiary (s2 / size
            :mod (f2 / fraction)
            :mod (e / each))
      :condition (a / and
            :op1 (s3 / statistical-test-91
                  :ARG1 (f3 / fraction
                        :mod (m4 / more-than
                              :op1 (m / mass-quantity :quant 3
                                    :unit (k / kilodalton))))
                  :ARG3 0.997)
            :op2 (s4 / statistical-test-91
                  :ARG1 (f4 / fraction
                        :mod (m5 / more-than
                              :op1 (m2 / mass-quantity :quant 10
                                    :unit (k2 / kilodalton))))
                  :ARG3 0.842)
            :op3 (s5 / statistical-test-91
                  :ARG1 (f5 / fraction
                        :mod (m6 / more-than
                              :op1 (m3 / mass-quantity :quant 30
                                    :unit (k3 / kilodalton))))
                  :ARG3 0.918))
      :ARG1-of (d2 / describe-01))

# ::id a_pmid_2169_9731.115 ::date 2015-05-20T07:12:18 ::annotator SDL-AMR-09 ::preferred
# ::snt From regression analysis, the responsible factor(s) appeared to be 7.23-10.8 kDa in size, suggesting that growth factors such as IGF-1 (7.5 kDa) may be responsible for the MØCM-stimulated neoplastic proliferation.
# ::save-date Wed Feb 24, 2016 ::file a_pmid_2169_9731_115.txt
(a / appear-02
      :ARG1 (h / have-03
            :ARG0 (f / factor
                  :ARG0-of (r / responsible-01))
            :ARG1 (s / size
                  :mod (m / mass-quantity
                        :unit (k / kilodalton)
                        :quant (b / between :op1 7.23 :op2 10.8)))
            :ARG0-of (s2 / suggest-01
                  :ARG1 (p / possible-01
                        :ARG1 (r3 / responsible-01
                              :ARG0 (g / growth-factor
                                    :example (p3 / protein :name (n2 / name :op1 "IGF-1")
                                          :mod (m2 / mass-quantity :quant 7.5
                                                :unit (k2 / kilodalton))))
                              :ARG1 (p2 / proliferate-01
                                    :ARG0 (t / tumor)
                                    :ARG1-of (s4 / stimulate-01
                                          :ARG0 (m3 / medium
                                                :ARG1-of (c / condition-01
                                                      :ARG0 (m4 / macrophage)))))))))
      :ARG1-of (d2 / deduce-01
            :ARG2 (a2 / analysis
                  :mod (r2 / regress-01))))

# ::id a_pmid_2169_9731.116 ::date 2015-05-20T07:30:00 ::annotator SDL-AMR-09 ::preferred
# ::snt Macrophage-conditioned media IGF-1 levels correlate to effects on neoplastic proliferation
# ::save-date Thu May 21, 2015 ::file a_pmid_2169_9731_116.txt
(c / correlate-01
      :ARG1 (l / level
            :quant-of (p2 / protein :name (n / name :op1 "IGF-1"))
            :source (m / medium
                  :ARG1-of (c2 / condition-01
                        :ARG0 (m2 / macrophage))))
      :ARG2 (a / affect-01
            :ARG1 (p / proliferate-01
                  :ARG0 (t / tumor))))

# ::id a_pmid_2169_9731.117 ::date 2015-05-20T07:33:14 ::annotator SDL-AMR-09 ::preferred
# ::snt IGF-1 has a well-established role in the metastasis of cancer cells <i>in vivo</i>, as well as stimulating growth <i>in vitro </i>[<xref ref-type="bibr" rid="B27">27</xref>], and alveolar macrophages produce high levels of IGF-1 in response to quartz dust-induced lung injury [<xref ref-type="bibr" rid="B30">30</xref>].
# ::save-date Sun Dec 20, 2015 ::file a_pmid_2169_9731_117.txt
(a / and
      :op1 (h / have-03
            :ARG0 (p4 / protein :name (n2 / name :op1 "IGF-1"))
            :ARG1 (r / role
                  :ARG1-of (e2 / establish-01
                        :mod (w / well))
                  :prep-in (a2 / and
                        :op1 (m / metastasize-101
                              :ARG1 (c / cell
                                    :mod (d / disease :wiki "Cancer" :name (n / name :op1 "cancer")))
                              :manner (i / in-vivo))
                        :op2 (s / stimulate-01
                              :ARG0 p4
                              :ARG1 (g / grow-01)
                              :manner (i2 / in-vitro)))
                  :ARG1-of (d2 / describe-01
                        :ARG0 (p / publication
                              :ARG1-of (c3 / cite-01
                                    :ARG2 27)))))
      :op2 (p2 / produce-01
            :ARG0 (m2 / macrophage
                  :mod (a3 / alveolus))
            :ARG1 (l / level
                  :ARG1-of (h2 / high-02)
                  :quant-of p4)
            :ARG1-of (d3 / describe-01
                  :ARG0 (p3 / publication
                        :ARG1-of (c4 / cite-01
                              :ARG2 30)))
            :ARG2-of (r2 / respond-01
                  :ARG1 (i3 / injure-01
                        :ARG1 (l2 / lung)
                        :ARG2-of (i4 / induce-01
                              :ARG0 (s2 / small-molecule :name (n3 / name :op1 "quartz" :op2 "dust")))))))

# ::id a_pmid_2169_9731.118 ::date 2015-05-20T07:54:18 ::annotator SDL-AMR-09 ::preferred
# ::snt While alveolar macrophages are an important component of the chronic inflammatory milieu responsible for promoting lung tumorigenesis, IGF-1 has not been examined as a possible connection between macrophage recruitment and lung cancer progression.
# ::save-date Sun Dec 20, 2015 ::file a_pmid_2169_9731_118.txt
(c / contrast-01
      :ARG1 (e / examine-01 :polarity -
            :ARG1 (p / protein :name (n2 / name :op1 "IGF-1"))
            :ARG2 (c2 / connect-01
                  :ARG0 p
                  :ARG1 (r / recruit-01
                        :ARG1 (m / macrophage))
                  :ARG1 (p3 / progress-01
                        :ARG1 (d / disease :wiki "Lung_cancer" :name (n / name :op1 "lung" :op2 "cancer")))
                  :ARG1-of (p2 / possible-01)))
      :ARG2 (c4 / component
            :mod (i3 / important)
            :ARG1-of (i / include-91
                  :ARG2 (m3 / milieu
                        :mod (c3 / chronic)
                        :mod (i2 / inflame-01)
                        :ARG0-of (r2 / responsible-01
                              :ARG1 (p4 / promote-01
                                    :ARG1 (c5 / create-01
                                          :ARG1 (t2 / tumor
                                                :mod (l / lung)))))))
            :domain (m2 / macrophage
                  :mod (a / alveolus))))

# ::id a_pmid_2169_9731.119 ::date 2015-05-20T08:11:42 ::annotator SDL-AMR-09 ::preferred
# ::snt BALF from tumor-bearing lungs contained 3.5-times more IGF-1 than BALF from naïve mice, while EGF levels were unchanged (Figure <xref ref-type="fig" rid="F6">6A</xref>).
# ::save-date Fri Feb 12, 2016 ::file a_pmid_2169_9731_119.txt
(c / contrast-01
      :ARG1 (c3 / contain-01
            :ARG0 (f3 / fluid
                  :source (l2 / lung
                        :ARG0-of (b / bear-01
                              :ARG1 (t / tumor)))
                  :mod l3)
            :ARG1 (p2 / protein :name (n3 / name :op1 "IGF-1")
                  :quant (m2 / more
                        :degree (p3 / product-of :op1 3.5)))
            :compared-to (f2 / fluid
                  :part-of (m4 / mouse
                        :mod (n5 / naive))
                  :mod (l3 / lavage
                        :mod (a / alveolus
                              :mod (b2 / bronchus)))))
      :ARG2 (c2 / change-01 :polarity -
            :ARG1 (l / level
                  :quant-of (p / protein :name (n / name :op1 "EGF"))))
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod "6A")))

# ::id a_pmid_2169_9731.120 ::date 2015-05-20T08:30:27 ::annotator SDL-AMR-09 ::preferred
# ::snt Even after normalizing to total BALF protein levels, BALF IGF-1 was significantly higher in tumor-bearing animals than naïve controls (1.81 ± 0.33 vs. 0.95 ± 0.36 pg IGF-1/ug BALF protein, respectively, <i>P </i>< 0.01, mean ± SD), suggesting that more IGF-1 is produced in the lungs of tumor-bearing mice.
# ::save-date Fri Mar 4, 2016 ::file a_pmid_2169_9731_120.txt
(h / high-02
      :ARG1 (l3 / level
            :quant-of (p / protein :name (n / name :op1 "IGF-1")
                  :source (f / fluid
                        :mod (l5 / lavage
                              :mod (a3 / alveolus
                                    :mod (b2 / bronchus)))))
            :ARG1-of (e2 / equal-01
                  :ARG2 (m4 / mass-quantity
                        :unit (r / ratio-of
                              :op1 (p5 / picogram
                                    :mod p)
                              :op2 (m6 / microgram
                                    :mod f))
                        :quant (v / value-interval
                              :op1 (s4 / subtract-01
                                    :ARG1 0.33
                                    :ARG2 1.81)
                              :op2 (a4 / add-02
                                    :ARG1 0.33
                                    :ARG2 1.81)))
                  :condition (a2 / and
                        :op1 (s6 / statistical-test-91
                              :ARG2 (l6 / less-than :op1 0.01))
                        :op2 (d / deviate-01
                              :mod (m8 / mean)
                              :ARG1-of (s3 / standard-02)))))
      :compared-to (l4 / level
            :quant-of (p4 / protein :name (n5 / name :op1 "IGF-1")
                  :source (c / control
                        :mod (n3 / naive)))
            :ARG1-of (e3 / equal-01
                  :ARG2 (m7 / mass-quantity
                        :unit r
                        :quant (v2 / value-interval
                              :op1 (s5 / subtract-01
                                    :ARG1 0.36
                                    :ARG2 0.95)
                              :op2 (a5 / add-02
                                    :ARG1 0.36
                                    :ARG2 0.95)))
                  :condition a2))
      :location (a / animal
            :ARG0-of (b / bear-01
                  :ARG1 (t / tumor)))
      :ARG0-of (s2 / suggest-01
            :ARG1 (p3 / produce-01
                  :ARG1 p
                  :quant (m2 / more)
                  :location (l2 / lung
                        :part-of (m3 / mouse
                              :ARG0-of b))))
      :degree (m5 / more)
      :ARG1-of (s / significant-02)
      :concession (n4 / normalize-01
            :ARG1 p
            :prep-to (l / level
                  :quant-of (p2 / protein
                        :mod f)
                  :mod (t2 / total))))

# ::id a_pmid_2169_9731.121 ::date 2015-05-20T08:58:27 ::annotator SDL-AMR-09 ::preferred
# ::snt Measurement of IGF-1 levels in MØCM from primary naïve and tumor-educated BAL macrophages showed that tumor-educated macrophages produced significantly more IGF-1 than naïve macrophages (Figure <xref ref-type="fig" rid="F6">6B</xref>, grey bars).
# ::save-date Fri Feb 12, 2016 ::file a_pmid_2169_9731_121.txt
(s / show-01
      :ARG0 (m / measure-01
            :ARG1 (l / level
                  :quant-of (p / protein :name (n / name :op1 "IGF-1")))
            :location (m2 / medium
                  :source (a / and
                        :op1 (m3 / macrophage
                              :mod (n4 / naive))
                        :op2 (m5 / macrophage
                              :ARG1-of (e / educate-01
                                    :ARG0 (t / tumor)))
                        :mod (f2 / fluid
                              :mod (a2 / alveolus
                                    :mod (b2 / bronchus)))
                        :mod (p2 / primary))
                  :ARG1-of (c / condition-01
                        :ARG0 (m7 / macrophage))))
      :ARG1 (p3 / produce-01
            :ARG0 m5
            :ARG1 (l2 / level
                  :quant-of p
                  :quant (m6 / more
                        :ARG1-of (s2 / significant-02)))
            :compared-to m3)
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod "6B")
            :ARG2 (b / bar
                  :ARG1-of (g / gray-02))))

# ::id a_pmid_2169_9731.122 ::date 2015-05-20T09:13:12 ::annotator SDL-AMR-09 ::preferred
# ::snt IL-4 potently stimulates alternative macrophage activation, and is more abundant in tumor-bearing lungs than naïve [<xref ref-type="bibr" rid="B38">38</xref>].
# ::save-date Fri May 29, 2015 ::file a_pmid_2169_9731_122.txt
(a / and
      :op1 (s / stimulate-01
            :ARG0 (p2 / protein :name (n / name :op1 "IL-4"))
            :ARG1 (a2 / activate-01
                  :ARG1 (m / macrophage)
                  :mod (a3 / alternative))
            :manner (p / potent))
      :op2 (a4 / abundant
            :domain p2
            :degree (m2 / more)
            :location (l / lung
                  :ARG0-of (b / bear-01
                        :ARG1 (t / tumor)))
            :compared-to (n2 / naive))
      :ARG1-of (d / describe-01
            :ARG0 (p3 / publication
                  :ARG1-of (c / cite-01
                        :ARG2 38))))

# ::id a_pmid_2169_9731.123 ::date 2015-05-20T09:15:59 ::annotator SDL-AMR-09 ::preferred
# ::snt Alternative macrophage polarization is associated with tumorigenesis [<xref ref-type="bibr" rid="B6">6</xref>] and increased macrophage IGF-1 production [<xref ref-type="bibr" rid="B39">39</xref>].
# ::save-date Tue Dec 29, 2015 ::file a_pmid_2169_9731_123.txt
(a / associate-01
      :ARG1 (p / polarize-01
            :ARG1 (m / macrophage)
            :mod (a2 / alternative))
      :ARG2 (a3 / and
            :op1 (c3 / create-01
                  :ARG1 (t / tumor)
                  :ARG1-of (d / describe-01
                        :ARG0 (p2 / publication
                              :ARG1-of (c / cite-01
                                    :ARG2 6))))
            :op2 (p3 / produce-01
                  :ARG0 m
                  :ARG1 (p4 / protein :name (n / name :op1 "IGF-1"))
                  :ARG1-of (i / increase-01)
                  :ARG1-of (d2 / describe-01
                        :ARG0 (p5 / publication
                              :ARG1-of (c2 / cite-01
                                    :ARG2 39))))))

# ::id a_pmid_2169_9731.124 ::date 2015-05-20T09:21:15 ::annotator SDL-AMR-09 ::preferred
# ::snt Therefore, IL-4 was added to wells containing primary naïve and tumor-educated BAL macrophages to determine if alternative activation could increase IGF-1 production in either macrophage group.
# ::save-date Fri Feb 12, 2016 ::file a_pmid_2169_9731_124.txt
(c / cause-01
      :ARG1 (a / add-02
            :ARG1 (p2 / protein :name (n / name :op1 "IL-4"))
            :ARG2 (w / well
                  :ARG0-of (c2 / contain-01
                        :ARG1 (a2 / and
                              :op1 (m2 / macrophage
                                    :mod (n3 / naive))
                              :op2 (m3 / macrophage
                                    :ARG1-of (e / educate-01
                                          :ARG0 (t / tumor)))
                              :mod (p3 / primary)
                              :mod (m / medium
                                    :ARG1-of (c3 / condition-01
                                          :ARG0 (m4 / macrophage))))))
            :purpose (d / determine-01
                  :ARG1 (p4 / possible-01
                        :ARG1 (i / increase-01
                              :ARG0 (a3 / activate-01
                                    :mod (a4 / alternative))
                              :ARG1 (p5 / produce-01
                                    :ARG1 p2)
                              :location a2)))))

# ::id a_pmid_2169_9731.125 ::date 2015-05-20T09:29:17 ::annotator SDL-AMR-09 ::preferred
# ::snt Both naïve and tumor-educated macrophages produced significantly more IGF-1 after IL-4 treatment; tumor-educated macrophages more than doubled IGF-1 output compared to naïve samples (Figure <xref ref-type="fig" rid="F6">6B</xref>, green bars).
# ::save-date Sun Dec 20, 2015 ::file a_pmid_2169_9731_125.txt
(m / multi-sentence
      :snt1 (p / produce-01
            :ARG0 (a / and
                  :op1 (m2 / macrophage
                        :mod (n / naive))
                  :op2 (m3 / macrophage
                        :ARG1-of (e / educate-01
                              :ARG0 (t / tumor))))
            :ARG1 (p2 / protein :name (n2 / name :op1 "IGF-1")
                  :quant (m4 / more
                        :degree (s / significant)))
            :condition (t2 / treat-04
                  :ARG2 (p3 / protein :name (n3 / name :op1 "IL-4"))))
      :snt2 (d / double-01
            :ARG0 (m6 / macrophage
                  :ARG1-of (e2 / educate-01
                        :ARG0 (t3 / tumor)))
            :ARG1 (o / output
                  :mod (p4 / protein :name (n4 / name :op1 "IGF-1")))
            :degree (m5 / more-than)
            :compared-to (t4 / thing
                  :mod (n5 / naive)
                  :ARG1-of (s2 / sample-01)))
      :ARG1-of (d2 / describe-01
            :ARG0 (f / figure :mod "6B")
            :ARG2 (b / bar
                  :ARG1-of (g / green-02))))

# ::id a_pmid_2169_9731.126 ::date 2015-05-20T09:35:19 ::annotator SDL-AMR-09 ::preferred
# ::snt MH-S macrophages produced 20-times more IGF-1 than either non-neoplastic or neoplastic lung cell lines, and all three cell lines produced only trace amounts (< 2 pg/mL) of EGF (Figure <xref ref-type="fig" rid="F6">6E</xref>).
# ::save-date Wed Dec 30, 2015 ::file a_pmid_2169_9731_126.txt
(a / and
      :op1 (p / produce-01
            :ARG0 (m / macrophage
                  :source (c / cell-line :name (n / name :op1 "MH-S")))
            :ARG1 (p2 / protein :name (n2 / name :op1 "IGF-1")
                  :quant (m2 / more
                        :degree (p3 / product-of :op1 20)))
            :compared-to (o / or
                  :op1 (c5 / cell-line
                        :mod (t / tumor :polarity -))
                  :op2 (c6 / cell-line
                        :mod (t2 / tumor))
                  :source (l2 / lung)))
      :op2 (p4 / produce-01
            :ARG0 (a2 / and
                  :op1 m
                  :op2 c5
                  :op3 c6)
            :ARG1 (a3 / amount
                  :mod (t3 / trace)
                  :mod (p5 / protein :name (n3 / name :op1 "EGF"))
                  :ARG1-of (e / equal-01
                        :ARG2 (l5 / less-than
                              :op1 (c4 / concentration-quantity :quant 2
                                    :unit (p6 / picogram-per-milliliter))))
                  :mod (o2 / only)))
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod "6E")))

# ::id a_pmid_2169_9731.127 ::date 2015-05-21T00:09:30 ::annotator SDL-AMR-09 ::preferred
# ::snt In order to determine whether the growth effects of MØCM from samples generated in Figure <xref ref-type="fig" rid="F6">6B</xref> correlated with their IGF-1 content, MØCM was added to neoplastic LM2 cells.
# ::save-date Fri Feb 12, 2016 ::file a_pmid_2169_9731_127.txt
(a / add-02
      :ARG1 (m / medium
            :ARG1-of (c4 / condition-01
                  :ARG0 (m2 / macrophage)))
      :ARG2 (c / cell-line :name (n2 / name :op1 "LM2")
            :mod (t / tumor))
      :purpose (d / determine-01
            :ARG1 (c2 / correlate-01 :mode interrogative
                  :ARG1 (a2 / affect-01
                        :ARG0 m
                        :ARG1 (g / grow-01)
                        :location (t2 / thing
                              :ARG1-of (s / sample-01))
                        :ARG1-of (g2 / generate-01
                              :location (f / figure :mod "6B")))
                  :ARG2 (c3 / contain-01
                        :ARG0 t2
                        :ARG1 (p / protein :name (n3 / name :op1 "IGF-1"))))))

# ::id a_pmid_2169_9731.128 ::date 2015-05-21T00:29:44 ::annotator SDL-AMR-09 ::preferred
# ::snt IL-4 stimulated naïve and tumor-educated MØCM significantly augmented LM2 proliferation (Figure <xref ref-type="fig" rid="F6">6C</xref>, green bars), with IL-4 treated tumor-educated MØCM being the most potent.
# ::save-date Fri Feb 12, 2016 ::file a_pmid_2169_9731_128.txt
(a / and
      :op1 (a2 / augment-01
            :ARG0 (a3 / and
                  :op1 (m / medium
                        :mod (n3 / naive)
                        :ARG1-of (c2 / condition-01
                              :ARG0 (m4 / macrophage)))
                  :op2 (m2 / medium
                        :ARG1-of (e / educate-01
                              :ARG0 (t / tumor))
                        :ARG1-of c2)
                  :ARG1-of (s / stimulate-01
                        :ARG0 (p / protein :name (n4 / name :op1 "IL-4"))))
            :ARG1 (p2 / proliferate-01
                  :ARG0 (c / cell-line :name (n5 / name :op1 "LM2")))
            :ARG1-of (s2 / significant-02)
            :ARG1-of (d / describe-01
                  :ARG0 (f / figure :mod "6C")
                  :ARG2 (b / bar
                        :ARG1-of (g / green-02))))
      :op2 (p3 / potent
            :degree (m3 / most)
            :domain m2))

# ::id a_pmid_2169_9731.129 ::date 2015-05-21T00:38:19 ::annotator SDL-AMR-09 ::preferred
# ::snt MØCM from untreated tumor-educated macrophages did not stimulate LM2 growth significantly more than untreated naïve MØCM (Figure <xref ref-type="fig" rid="F6">6C</xref>, grey bars), corresponding to previous co-culture results (Figure <xref ref-type="fig" rid="F2">2B</xref>).
# ::save-date Fri Feb 12, 2016 ::file a_pmid_2169_9731_129.txt
(s / stimulate-01 :polarity -
      :ARG0 (m / medium
            :source (m2 / macrophage
                  :ARG1-of (t / treat-04 :polarity -)
                  :ARG1-of (e / educate-01
                        :ARG0 (t2 / tumor)))
            :ARG1-of c4)
      :ARG1 (g / grow-01
            :ARG1 (c / cell-line :name (n2 / name :op1 "LM2")))
      :degree (m3 / more
            :degree (s2 / significant))
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod "6C")
            :ARG2 (b / bar
                  :ARG1-of (g2 / gray-02)))
      :ARG1-of (c2 / correspond-02
            :ARG2 (t3 / thing
                  :ARG2-of (r / result-01
                        :ARG1 (c3 / co-culture)
                        :time (p / previous)
                        :ARG1-of (d2 / describe-01
                              :ARG0 (f2 / figure :mod "2B")))))
      :compared-to (m4 / medium
            :ARG1-of t
            :mod (n4 / naive)
            :ARG1-of (c4 / condition-01
                  :ARG0 (m5 / macrophage))))

# ::id a_pmid_2169_9731.130 ::date 2015-05-21T00:46:56 ::annotator SDL-AMR-09 ::preferred
# ::snt As the growth-stimulating ability of MØCM appeared to correlate to media IGF-1 levels, the levels of IGF-1 present were plotted against the fold-change in LM2 cell number after MØCM addition (Figure <xref ref-type="fig" rid="F6">6D</xref>).
# ::save-date Fri Feb 12, 2016 ::file a_pmid_2169_9731_130.txt
(p / plot-01
      :ARG1 (l / level
            :quant-of (p2 / protein :name (n / name :op1 "IGF-1")
                  :location m)
            :ARG1-of (p4 / present-02))
      :ARG2 (c / change-01
            :ARG1 (n2 / number
                  :quant-of (c2 / cell-line :name (n3 / name :op1 "LM2")))
            :condition (a / add-02
                  :ARG1 (m / medium
                        :ARG1-of (c6 / condition-01
                              :ARG0 (m3 / macrophage))))
            :mod (p3 / product-of))
      :ARG1-of (c3 / cause-01
            :ARG0 (a2 / appear-02
                  :ARG1 (c4 / correlate-01
                        :ARG1 (c5 / capable-01
                              :ARG1 m
                              :ARG2 (s / stimulate-01
                                    :ARG0 m
                                    :ARG1 (g / grow-01)))
                        :ARG2 l)))
      :ARG1-of (d / describe-01
            :ARG0 (f2 / figure :mod "6D")))

# ::id a_pmid_2169_9731.131 ::date 2015-05-21T00:56:37 ::annotator SDL-AMR-09 ::preferred
# ::snt The correlation between IGF-1 levels and neoplastic growth stimulation was highly significant (p < 0.001), indicating that MØCM IGF-1 levels were directly related to the ability of MØCM to stimulate neoplastic proliferation.
# ::save-date Fri Feb 12, 2016 ::file a_pmid_2169_9731_131.txt
(s / significant-02
      :ARG1 (c / correlate-01
            :ARG1 (l / level
                  :quant-of (p / protein :name (n / name :op1 "IGF-1")))
            :ARG2 (s2 / stimulate-01
                  :ARG1 (g / grow-01
                        :ARG1 (t / tumor))))
      :ARG1-of (h / high-02)
      :ARG0-of (i / indicate-01
            :ARG1 (r / relate-01
                  :ARG1 (l2 / level
                        :quant-of p
                        :location (m / medium
                              :ARG1-of (c3 / condition-01
                                    :ARG0 (m3 / macrophage))))
                  :ARG2 (c2 / capable-01
                        :ARG1 m
                        :ARG2 (s3 / stimulate-01
                              :ARG0 m
                              :ARG1 (p2 / proliferate-01
                                    :ARG0 t)))
                  :ARG1-of (d / direct-02)))
      :ARG1-of (m2 / mean-01
            :ARG2 (l4 / less-than :op1 0.001)))

# ::id a_pmid_2169_9731.132 ::date 2015-05-21T01:02:29 ::annotator SDL-AMR-09 ::preferred
# ::snt IGF-1 stimulates lung epithelial cell proliferation and is additive with MØCM
# ::save-date Fri Feb 12, 2016 ::file a_pmid_2169_9731_132.txt
(s / stimulate-01
      :ARG0 (a / and
            :op1 (p / protein :name (n / name :op1 "IGF-1"))
            :op2 (m / medium
                  :ARG1-of (c2 / condition-01
                        :ARG0 (m2 / macrophage))))
      :ARG1 (p2 / proliferate-01
            :ARG0 (c / cell
                  :source (l / lung)
                  :mod (e / epithelium))))

# ::id a_pmid_2169_9731.133 ::date 2015-05-21T01:07:18 ::annotator SDL-AMR-09 ::preferred
# ::snt While IGF-1 levels correlated strongly with the ability of MØCM to stimulate neoplastic growth, IGF-1 induced proliferation of these non-neoplastic and neoplastic mouse lung cell lines has not been demonstrated.
# ::save-date Fri Feb 12, 2016 ::file a_pmid_2169_9731_133.txt
(c3 / contrast-01
      :ARG1 (d / demonstrate-01 :polarity -
            :ARG1 (p / proliferate-01
                  :ARG0 (a / and
                        :op1 (c / cell-line
                              :mod (t / tumor :polarity -))
                        :op2 (c2 / cell-line
                              :mod (t2 / tumor))
                        :source (l / lung
                              :part-of (m / mouse))
                        :mod (t3 / this))
                  :ARG2-of (i / induce-01
                        :ARG0 (p2 / protein :name (n / name :op1 "IGF-1")))))
      :ARG2 (c4 / correlate-01
            :ARG1 (l2 / level
                  :quant-of p2)
            :ARG2 (c5 / capable-01
                  :ARG1 (m2 / medium
                        :ARG1-of (c6 / condition-01
                              :ARG0 (m3 / macrophage)))
                  :ARG2 (s2 / stimulate-01
                        :ARG0 m2
                        :ARG1 (g / grow-01
                              :ARG1 t2)))
            :ARG1-of (s / strong-02)))

# ::id a_pmid_2169_9731.134 ::date 2015-05-21T01:11:01 ::annotator SDL-AMR-09 ::preferred
# ::snt Recombinant mouse IGF-1 or MH-S macrophage-conditioned media was sufficient to stimulate the proliferation of neoplastic LM2, JF32 and E9 cells and non-neoplastic E10 cells (Figure <xref ref-type="fig" rid="F7">7A-D</xref>).
# ::save-date Fri Feb 5, 2016 ::file a_pmid_2169_9731_134.txt
(s / suffice-01
      :ARG0 (o / or
            :op1 (m3 / medium
                  :ARG1-of (c3 / condition-01
                        :ARG0 (p / protein :name (n2 / name :op1 "IGF-1")
                              :source (m4 / mouse)
                              :ARG3-of (r / recombine-01))))
            :op2 (m / medium
                  :ARG1-of (c / condition-01
                        :ARG0 (m2 / macrophage
                              :source (c2 / cell-line :name (n / name :op1 "MH-S"))))))
      :ARG1 (s2 / stimulate-01
            :ARG0 o
            :ARG1 (p2 / proliferate-01
                  :ARG0 (a / and
                        :op1 (a2 / and
                              :op1 (c4 / cell-line :name (n3 / name :op1 "LM2"))
                              :op2 (c5 / cell-line :name (n4 / name :op1 "JF32"))
                              :op3 (c6 / cell-line :name (n5 / name :op1 "E9"))
                              :mod (t / tumor))
                        :op2 (c7 / cell-line :name (n6 / name :op1 "E10")
                              :mod (t2 / tumor :polarity -)))))
      :ARG1-of (d / describe-01
            :ARG0 (a3 / and
                  :op1 (f / figure :mod "7A")
                  :op2 (f2 / figure :mod "7B")
                  :op3 (f3 / figure :mod "7C")
                  :op4 (f4 / figure :mod "7D"))))

# ::id a_pmid_2169_9731.135 ::date 2015-05-21T01:39:39 ::annotator SDL-AMR-09 ::preferred
# ::snt The degree of growth stimulated by 50 ng/mL IGF-1 was similar to that of MØCM in each line (Figure <xref ref-type="fig" rid="F7">7A-D</xref>).
# ::save-date Fri Feb 12, 2016 ::file a_pmid_2169_9731_135.txt
(r / resemble-01
      :ARG1 (g / grow-01
            :ARG1-of (s / stimulate-01
                  :ARG0 (p / protein :name (n / name :op1 "IGF-1")
                        :quant (c / concentration-quantity :quant 50
                              :unit (n2 / nanogram-per-milliliter)))))
      :ARG2 (g2 / grow-01
            :ARG1 (m / medium
                  :ARG1-of (c2 / condition-01
                        :ARG0 (m2 / macrophage))))
      :location (l / line
            :mod (e / each))
      :ARG1-of (d / describe-01
            :ARG0 (a / and
                  :op1 (f / figure :mod "7A")
                  :op2 (f2 / figure :mod "7B")
                  :op3 (f3 / figure :mod "7C")
                  :op4 (f4 / figure :mod "7D"))))

# ::id a_pmid_2169_9731.136 ::date 2015-05-21T01:44:37 ::annotator SDL-AMR-09 ::preferred
# ::snt These results confirm that IGF-1 alone can stimulate the growth of long-established neoplastic and non-neoplastic cell lines, as well as cells isolated more recently from primary mouse lung tumors (JF32), consistent with previous reports on human cancer cell lines [<xref ref-type="bibr" rid="B27">27</xref>].
# ::save-date Sun Dec 20, 2015 ::file a_pmid_2169_9731_136.txt
(c / confirm-01
      :ARG0 (t / thing
            :ARG1-of (r / result-01
                  :ARG1-of (c6 / consistent-01
                        :ARG2 (t6 / thing
                              :ARG1-of (r3 / report-01)
                              :time (p4 / previous)
                              :topic (c7 / cell-line
                                    :source (d / disease :wiki "Cancer" :name (n / name :op1 "cancer")
                                          :mod (h / human)))
                              :ARG1-of (d2 / describe-01
                                    :ARG0 (p5 / publication
                                          :ARG1-of (c9 / cite-01
                                                :ARG2 27))))))
            :mod (t2 / this))
      :ARG1 (p / possible-01
            :ARG1 (s / stimulate-01
                  :ARG0 (p2 / protein :name (n2 / name :op1 "IGF-1")
                        :mod (a / alone))
                  :ARG1 (g / grow-01
                        :ARG1 (a2 / and
                              :op1 (a3 / and
                                    :op1 (c2 / cell-line
                                          :mod (t3 / tumor))
                                    :op2 (c3 / cell-line
                                          :mod (t4 / tumor :polarity -))
                                    :ARG1-of (e / establish-01
                                          :ARG1-of (l / long-03)))
                              :op2 (c4 / cell
                                    :ARG1-of (i / isolate-01
                                          :ARG2 (t5 / tumor
                                                :mod (l2 / lung
                                                      :part-of (m2 / mouse))
                                                :mod (p3 / primary)
                                                :ARG1-of (m3 / mean-01
                                                      :ARG2 (c5 / cell-line :name (n3 / name :op1 "JF32"))))
                                          :time (r2 / recent
                                                :degree (m / more)))))))))

# ::id a_pmid_2169_9731.137 ::date 2015-05-21T01:51:28 ::annotator SDL-AMR-09 ::preferred
# ::snt In order to determine any relevant role of EGFR in mediating macrophage-stimulated tumor cell proliferation in these cell lines, recombinant mouse EGF was added at 2 ng/mL.
# ::save-date Sat May 30, 2015 ::file a_pmid_2169_9731_137.txt
(a / add-02
      :ARG1 (p / protein :name (n2 / name :op1 "EGF")
            :quant (c / concentration-quantity :quant 2
                  :unit (n3 / nanogram-per-milliliter))
            :source (m / mouse)
            :ARG3-of (r / recombine-01))
      :purpose (d / determine-01
            :ARG1 (r3 / relevant-01
                  :ARG1 (r4 / role
                        :poss (e / enzyme :name (n / name :op1 "EGFR")))
                  :ARG2 (m2 / mediate-01
                        :ARG0 p
                        :ARG1 (p2 / proliferate-01
                              :ARG0 (c2 / cell
                                    :mod (t / tumor))
                              :ARG1-of (s / stimulate-01
                                    :ARG0 (m3 / macrophage))
                              :location (c3 / cell-line
                                    :mod (t2 / this)))))))

# ::id a_pmid_2169_9731.138 ::date 2015-05-21T01:59:46 ::annotator SDL-AMR-09 ::preferred
# ::snt This is roughly 500-times the reported EC<sub>50 </sub>for growth stimulation and 20-times higher than levels found in the BALF from tumor-bearing animals (Figure <xref ref-type="fig" rid="F6">6A</xref>).
# ::save-date Fri Feb 12, 2016 ::file a_pmid_2169_9731_138.txt
(a / and
      :op1 (e / equal-01
            :ARG1 (t / this)
            :ARG2 (r2 / roughly
                  :op1 (p / product-of :op1 500
                        :op2 (c / concentration-quantity
                              :ARG4-of (h2 / have-percentage-maximal-effective-concentration-01
                                    :ARG2 50
                                    :ARG3 (s / stimulate-01
                                          :ARG1 (g / grow-01)))
                              :ARG1-of (r / report-01)))))
      :op2 (e2 / equal-01
            :ARG1 t
            :ARG2 (r3 / roughly
                  :op1 (h / high-02
                        :ARG1 t
                        :degree (m / more)
                        :degree (p2 / product-of :op1 20)
                        :compared-to (l / level
                              :ARG1-of (f / find-01
                                    :location (f3 / fluid
                                          :mod (l2 / lavage
                                                :mod (a3 / alveolus
                                                      :mod (b2 / bronchus)))
                                          :source (a2 / animal
                                                :ARG0-of (b / bear-01
                                                      :ARG1 (t3 / tumor)))))))))
      :ARG1-of (d / describe-01
            :ARG0 (f2 / figure :mod "6A")))

# ::id a_pmid_2169_9731.139 ::date 2015-05-26T00:07:32 ::annotator SDL-AMR-09 ::preferred
# ::snt EGF had no significant effect on tumor cell proliferation when added alone, and did not significantly affect the ability of either IGF-1 or MØCM to stimulate neoplastic growth (Figure <xref ref-type="fig" rid="F7">7E, F</xref>).
# ::save-date Fri Feb 12, 2016 ::file a_pmid_2169_9731_139.txt
(a4 / and
      :op1 (a / affect-01 :polarity -
            :ARG0 (p / protein :name (n / name :op1 "EGF"))
            :ARG1 (p2 / proliferate-01
                  :ARG0 (c / cell
                        :mod (t / tumor)))
            :ARG1-of (s / significant-02)
            :condition (a2 / add-02
                  :ARG1 p
                  :manner (a3 / alone)))
      :op2 (a5 / affect-01 :polarity -
            :ARG0 p
            :ARG1 (c3 / capable-01
                  :ARG1 o
                  :ARG2 (s3 / stimulate-01
                        :ARG0 (o / or
                              :op1 (p4 / protein :name (n3 / name :op1 "IGF-1"))
                              :op2 (m / medium
                                    :ARG1-of (c2 / condition-01
                                          :ARG0 (m2 / macrophage))))
                        :ARG1 (g / grow-01
                              :ARG1 (n2 / neoplasm))))
            :ARG1-of s)
      :ARG1-of (d / describe-01
            :ARG0 (a6 / and
                  :op1 (f / figure :mod "7E")
                  :op2 (f2 / figure :mod "7F"))))

# ::id a_pmid_2169_9731.140 ::date 2015-05-26T00:37:37 ::annotator SDL-AMR-09 ::preferred
# ::snt This is not surprising in view of recent studies showing that EGFR inhibitors do not inhibit growth of lung cells with <i>KRAS </i>mutations [<xref ref-type="bibr" rid="B40">40</xref>].
# ::save-date Wed Mar 2, 2016 ::file a_pmid_2169_9731_140.txt
(s / surprise-01 :polarity -
      :ARG0 (t2 / this)
      :ARG1-of (d / describe-01
            :ARG0 (p2 / publication
                  :ARG1-of (c3 / cite-01
                        :ARG2 40)))
      :ARG2-of (v / view-02
            :ARG1 (s2 / show-01
                  :ARG0 (s3 / study-01
                        :time (r / recent))
                  :ARG1 (i2 / inhibit-01 :polarity -
                        :ARG0 (m / molecular-physical-entity
                              :ARG0-of (i3 / inhibit-01
                                    :ARG1 (e / enzyme :name (n / name :op1 "EGFR"))))
                        :ARG1 (g / grow-01
                              :ARG1 (c2 / cell
                                    :mod (l / lung)
                                    :mod (g2 / gene :name (n2 / name :op1 "KRAS")
                                          :ARG2-of (m2 / mutate-01))))))))

# ::id a_pmid_2169_9731.141 ::date 2015-05-26T00:59:38 ::annotator SDL-AMR-09 ::preferred
# ::snt As IGF-1 was sufficient to induce neoplastic proliferation, we determined whether the IGF-1 and MØCM growth effects were additive.
# ::save-date Fri Feb 12, 2016 ::file a_pmid_2169_9731_141.txt
(d / determine-01
      :ARG0 (w / we)
      :ARG1 (a / add-02 :mode interrogative
            :ARG1 (a5 / and
                  :op1 (a2 / affect-01
                        :ARG0 (p / protein :name (n / name :op1 "IGF-1"))
                        :ARG2 (g / grow-01))
                  :op2 (a3 / affect-01
                        :ARG0 (m / medium
                              :ARG1-of (c / condition-01
                                    :ARG0 (m2 / macrophage)))
                        :ARG2 g)))
      :ARG1-of (c2 / cause-01
            :ARG0 (s / suffice-01
                  :ARG0 p
                  :ARG1 (i / induce-01
                        :ARG0 p
                        :ARG2 (p2 / proliferate-01
                              :ARG0 (n3 / neoplasm))))))

# ::id a_pmid_2169_9731.142 ::date 2015-05-26T05:53:58 ::annotator SDL-AMR-09 ::preferred
# ::snt A dose of 50 ng/ml IGF-1 stimulated neoplastic growth to a similar extent as MØCM (Figure <xref ref-type="fig" rid="F7">7A-D</xref>); 2 ng/mL IGF is the reported EC<sub>50 </sub>for IGF-1 stimulated proliferation <i>in vitro </i>as well as the concentration detected in the BALF of tumor-bearing mice <i>in vivo </i>(Figure <xref ref-type="fig" rid="F6">6A</xref>).
# ::save-date Fri Feb 12, 2016 ::file a_pmid_2169_9731_142.txt
(a2 / and
      :op1 (s / stimulate-01
            :ARG0 (d / dose-01
                  :ARG2 (p / protein :name (n / name :op1 "IGF-1")
                        :quant (c / concentration-quantity :quant 50
                              :unit (n5 / nanogram-per-milliliter))))
            :ARG1 (g / grow-01
                  :ARG1 (n2 / neoplasm))
            :ARG3 (e / extent
                  :ARG1-of (r2 / resemble-01
                        :ARG2 (s2 / stimulate-01
                              :ARG0 (m / medium
                                    :ARG1-of (c2 / condition-01
                                          :ARG0 (m4 / macrophage)))
                              :ARG1 g)))
            :ARG1-of (d2 / describe-01
                  :ARG0 (a3 / and
                        :op1 (f / figure :mod "7A")
                        :op2 (f3 / figure :mod "7B")
                        :op3 (f4 / figure :mod "7C")
                        :op4 (f5 / figure :mod "7D"))))
      :op2 (p2 / protein :name (n4 / name :op1 "IGF")
            :quant (c3 / concentration-quantity :quant 2
                  :unit n5)
            :ARG1-of (e2 / equal-01
                  :ARG2 (a / and
                        :op1 (h / have-percentage-maximal-effective-concentration-01
                              :ARG2 50
                              :ARG1-of (r3 / report-01))
                        :op2 (c4 / concentrate-02
                              :ARG1 (f6 / fluid
                                    :mod (l / lavage
                                          :mod (a4 / alveolus
                                                :mod (b2 / bronchus)))
                                    :source (m2 / mouse
                                          :ARG0-of (b / bear-01
                                                :ARG1 (t / tumor))))
                              :ARG1-of (d3 / detect-01)
                              :manner (i2 / in-vivo))))
            :condition (p3 / proliferate-01
                  :ARG1-of (s3 / stimulate-01
                        :ARG0 (p5 / protein :name (n6 / name :op1 "IGF-1")))
                  :manner (i / in-vitro)))
      :ARG1-of (d4 / describe-01
            :ARG0 (f2 / figure :mod "6A")))

# ::id a_pmid_2169_9731.143 ::date 2015-05-26T08:10:38 ::annotator SDL-AMR-09 ::preferred
# ::snt IGF-1 dose-dependently stimulated the proliferation of both LM2 and JF32 cells, and augmented the growth-stimulating effects of MØCM when added in combination.
# ::save-date Fri Feb 12, 2016 ::file a_pmid_2169_9731_143.txt
(a / and
      :op1 (s / stimulate-01
            :ARG0 (p / protein :name (n / name :op1 "IGF-1"))
            :ARG1 (p2 / proliferate-01
                  :ARG0 (a3 / and
                        :op1 (c / cell-line :name (n2 / name :op1 "LM2"))
                        :op2 (c2 / cell-line :name (n3 / name :op1 "JF32"))))
            :ARG0-of (d2 / depend-01
                  :ARG1 (d3 / dose)))
      :op2 (a2 / augment-01
            :ARG0 p
            :ARG1 (a5 / affect-01
                  :ARG0 (m / medium
                        :ARG1-of (c3 / condition-01
                              :ARG0 (m2 / macrophage)))
                  :ARG2 (s2 / stimulate-01
                        :ARG1 (g / grow-01)))
            :condition (a4 / add-02
                  :ARG1 p
                  :ARG2 (c4 / combine-01))))

# ::id a_pmid_2169_9731.144 ::date 2015-05-26T08:47:40 ::annotator SDL-AMR-09 ::preferred
# ::snt To determine if IGF-1R signaling mediates both IGF-1 and MØCM stimulation, lung cancer cells were pre-treated with vehicle or 5 μM NVP-AEW541 (- or +, respectively), and cell numbers determined as indicated.
# ::save-date Fri Feb 12, 2016 ::file a_pmid_2169_9731_144.txt
(a / and
      :op1 (p3 / pretreat-01
            :ARG1 (c / cell
                  :source (d / disease :wiki "Lung_cancer" :name (n / name :op1 "lung" :op2 "cancer")))
            :ARG3 (o / or
                  :op1 (v / vehicle)
                  :op2 (s3 / small-molecule :name (n2 / name :op1 "NVP-AEW541")
                        :quant (c3 / concentration-quantity :quant 5
                              :unit (m / micromolar)))))
      :op2 (d2 / determine-01
            :ARG1 (n3 / number
                  :quant-of (c4 / cell))
            :ARG1-of (i / indicate-01))
      :purpose (d3 / determine-01
            :ARG1 (m2 / mediate-01 :mode interrogative
                  :ARG0 (s / signal-07
                        :ARG0 (p / protein :name (n4 / name :op1 "IGF-1R")))
                  :ARG1 (s2 / stimulate-01
                        :ARG1 (a2 / and
                              :op1 (p2 / protein :name (n5 / name :op1 "IGF-1"))
                              :op2 (m3 / medium
                                    :ARG1-of (c2 / condition-01
                                          :ARG0 (m4 / macrophage))))))))

# ::id a_pmid_2169_9731.145 ::date 2015-05-26T08:59:13 ::annotator SDL-AMR-09 ::preferred
# ::snt IGF-1 and MØCM each significantly increased cell numbers after 48 and 72 hrs, while pharmacological inhibition of IGF-1R signaling blocked IGF-1 and MØCM growth effects in both neoplastic lines (Figure <xref ref-type="fig" rid="F7">7G, H</xref>).
# ::save-date Fri Feb 12, 2016 ::file a_pmid_2169_9731_145.txt
(c / contrast-01
      :ARG1 (i / increase-01
            :ARG0 (a / and
                  :op1 (p / protein :name (n / name :op1 "IGF-1"))
                  :op2 (m / medium
                        :ARG1-of (c2 / condition-01
                              :ARG0 (m2 / macrophage))))
            :ARG1 (n3 / number
                  :quant-of (c3 / cell))
            :ARG1-of (s / significant-02)
            :time (a2 / after
                  :quant (a3 / and
                        :op1 (t / temporal-quantity :quant 48
                              :unit (h / hour))
                        :op2 (t2 / temporal-quantity :quant 72
                              :unit h))))
      :ARG2 (b / block-01
            :ARG0 (i2 / inhibit-01
                  :ARG1 (s2 / signal-07
                        :ARG0 (p3 / protein :name (n4 / name :op1 "IGF-1R")))
                  :mod (p2 / pharmacology))
            :ARG1 (a6 / affect-01
                  :ARG2 (g / grow-01
                        :ARG0 (a4 / and
                              :op1 p
                              :op2 m)))
            :location (l / line
                  :mod (n5 / neoplasm)
                  :mod (b2 / both)))
      :ARG1-of (d / describe-01
            :ARG0 (a5 / and
                  :op1 (f / figure :mod "7G")
                  :op2 (f2 / figure :mod "7H"))))

# ::id a_pmid_2169_9731.146 ::date 2015-05-26T23:32:51 ::annotator SDL-AMR-09 ::preferred
# ::snt Parallel comparison of MTS values indicated a highly significant correlation between live cell numbers and relative MTS scores (r<sup>2 </sup>= 0.7912 and 0.8201 for LM2 and JF32, respectively, p < 0.0001, data not shown).
# ::save-date Sun Jan 17, 2016 ::file a_pmid_2169_9731_146.txt
(i / indicate-01
      :ARG0 (c / compare-01
            :ARG1 (v / value
                  :mod (t / thing :name (n / name :op1 "MTS")))
            :ARG2 v
            :manner (p / parallel))
      :ARG1 (c2 / correlate-01
            :ARG1 (n3 / number
                  :quant-of (c3 / cell
                        :ARG0-of (l / live-01)))
            :ARG2 (s / score-01
                  :ARG1 t
                  :ARG1-of (r / relative-05)
                  :ARG1-of (m / mean-01
                        :ARG2 (a / and
                              :op1 (s4 / statistical-test-91
                                    :ARG1 (c4 / cell-line :name (n5 / name :op1 "LM2"))
                                    :ARG3 0.7912)
                              :op2 (s5 / statistical-test-91
                                    :ARG1 (c5 / cell-line :name (n6 / name :op1 "JF32"))
                                    :ARG3 0.8201)
                              :op3 (s6 / statistical-test-91
                                    :ARG2 (l2 / less-than :quant 0.0001)))
                        :ARG1-of (d / describe-01
                              :ARG0 (d2 / data
                                    :ARG1-of (s3 / show-01 :polarity -)))))
            :ARG1-of (s2 / significant-02
                  :ARG1-of (h / high-02))))

# ::id a_pmid_2169_9731.147 ::date 2015-05-27T00:55:54 ::annotator SDL-AMR-09 ::preferred
# ::snt Furthermore, both IGF-1 and MØCM increased the fraction of BrdU<sup>+ </sup>LM2 cells 12-24 hrs after treatment, corresponding with significantly increased cell numbers (data not shown).
# ::save-date Fri Feb 12, 2016 ::file a_pmid_2169_9731_147.txt
(a / and
      :op2 (i / increase-01
            :ARG0 (a2 / and
                  :op1 (p / protein :name (n / name :op1 "IGF-1"))
                  :op2 (m / medium
                        :ARG1-of (c2 / condition-01
                              :ARG0 (m2 / macrophage))))
            :ARG1 (f / fraction
                  :quant-of (c / cell-line :name (n4 / name :op1 "LM2")
                        :mod (s3 / small-molecule :name (n3 / name :op1 "BrdU")
                              :mod (w / wild-type))))
            :time (a3 / after
                  :op1 (t / treat-04)
                  :quant (t2 / temporal-quantity
                        :quant (v / value-interval :op1 12 :op2 24)
                        :unit (h / hour)))
            :ARG1-of (c3 / correspond-02
                  :ARG2 (n5 / number
                        :quant-of (c4 / cell)
                        :ARG1-of (i2 / increase-01
                              :ARG2 (s / significant-02)))))
      :ARG1-of (d / describe-01
            :ARG0 (d2 / data
                  :ARG1-of (s2 / show-01 :polarity -))))

# ::id a_pmid_2169_9731.148 ::date 2015-05-27T01:07:33 ::annotator SDL-AMR-09 ::preferred
# ::snt These observations suggest that IGF-1, but not EGF, plays a major role in macrophage stimulated neoplastic growth <i>in vitro</i>, consistent with the elevated IGF-1 levels observed in lung-tumor bearing animals <i>in vivo</i>.
# ::save-date Thu Jul 30, 2015 ::file a_pmid_2169_9731_148.txt
(s / suggest-01
      :ARG0 (o / observe-01
            :mod (t / this))
      :ARG1 (c / contrast-01
            :ARG1 (p / play-08
                  :ARG0 (p2 / protein :name (n / name :op1 "IGF-1"))
                  :ARG1 (g / grow-01
                        :ARG1 (n2 / neoplasm
                              :ARG1-of (s2 / stimulate-01
                                    :ARG0 (m2 / macrophage))))
                  :manner (i / in-vitro)
                  :ARG1-of (m / major-02))
            :ARG2 (p3 / play-08 :polarity -
                  :ARG0 (p4 / protein :name (n3 / name :op1 "EGF"))))
      :ARG1-of (c2 / consistent-01
            :ARG2 (l / level
                  :ARG1-of (o2 / observe-01
                        :manner (i2 / in-vivo)
                        :location (a / animal
                              :ARG0-of (b / bear-01
                                    :ARG1 (t2 / tumor
                                          :mod (l2 / lung)))))
                  :ARG1-of (e / elevate-01)
                  :quant-of p2)))

# ::id a_pmid_2169_9731.149 ::date 2015-05-27T01:27:32 ::annotator SDL-AMR-09 ::preferred
# ::snt MØCM stimulation of neoplastic growth is diminished when IGF-1 content is decreased
# ::save-date Sat Feb 13, 2016 ::file a_pmid_2169_9731_149.txt
(d / diminish-01
      :ARG1 (s / stimulate-01
            :ARG0 (m / medium
                  :ARG1-of (c / condition-01
                        :ARG0 (m2 / macrophage)))
            :ARG1 (g / grow-01
                  :ARG1 (n2 / neoplasm)))
      :time (d2 / decrease-01
            :ARG1 (c2 / content
                  :quant-of (p / protein :name (n3 / name :op1 "IGF-1")))))

# ::id a_pmid_2169_9731.150 ::date 2015-05-27T01:33:27 ::annotator SDL-AMR-09 ::preferred
# ::snt In order to determine if IGF-1 was a molecular mediator directly responsible for growth stimulated by MØCM, we decreased MØCM IGF-1 content through two independent avenues: immuno-depletion and siRNA interference.
# ::save-date Fri Feb 12, 2016 ::file a_pmid_2169_9731_150.txt
(d / decrease-01
      :ARG0 (w / we)
      :ARG1 (c / contain-01
            :ARG0 m4
            :ARG1 p3)
      :instrument (a2 / avenue :quant 2
            :ARG0-of (d2 / depend-01 :polarity -)
            :ARG1-of (m2 / mean-01
                  :ARG2 (a3 / and
                        :op1 (i / immunodeplete-00)
                        :op2 (i2 / interfere-01
                              :ARG1 (n / nucleic-acid :name (n3 / name :op1 "siRNA"))))))
      :purpose (d3 / determine-01
            :ARG0 (w2 / we)
            :ARG1 (r2 / responsible-01 :mode interrogative
                  :ARG0 (p3 / protein :name (n4 / name :op1 "IGF-1")
                        :ARG0-of (m / mediate-01)
                        :mod (m3 / molecule))
                  :ARG1 (g / grow-01
                        :ARG1-of (s / stimulate-01
                              :ARG0 (m4 / medium
                                    :ARG1-of (c2 / condition-01
                                          :ARG0 (m5 / macrophage)))))
                  :ARG1-of (d4 / direct-02))))

# ::id a_pmid_2169_9731.151 ::date 2015-05-27T01:45:03 ::annotator SDL-AMR-09 ::preferred
# ::snt MØCM was concentrated to contain ~3.5 ng/mL IGF-1, and then incubated with control IgG (Con IgG) or α-IGF-1 IgG coated resin, as described [<xref ref-type="bibr" rid="B39">39</xref>].
# ::save-date Wed Mar 2, 2016 ::file a_pmid_2169_9731_151.txt
(a / and
      :op1 (c / concentrate-02
            :ARG1 (m / medium
                  :ARG1-of (c2 / condition-01
                        :ARG0 (m2 / macrophage)))
            :purpose (c3 / contain-01
                  :ARG0 m
                  :ARG1 (p4 / protein :name (n5 / name :op1 "IGF-1")
                        :quant (a3 / approximately
                              :op1 (c4 / concentration-quantity :quant 3.5
                                    :unit (n6 / nanogram-per-milliliter))))))
      :op2 (i / incubate-01
            :ARG1 m
            :ARG2 (o / or
                  :op1 (p / protein :name (n2 / name :op1 "IgG")
                        :ARG0-of (c5 / control-01))
                  :op2 (r2 / resin
                        :ARG1-of (c6 / coat-01
                              :ARG2 (a2 / and
                                    :op1 (p2 / protein :name (n4 / name :op1 "α-IGF-1"))
                                    :op2 p))))
            :time (t / then))
      :ARG1-of (r / resemble-01
            :ARG2 (t2 / thing
                  :ARG1-of (d / describe-01
                        :ARG0 (p3 / publication
                              :ARG1-of (c7 / cite-01
                                    :ARG2 39))))))

# ::id a_pmid_2169_9731.152 ::date 2015-05-27T08:56:32 ::annotator SDL-AMR-09 ::preferred
# ::snt This procedure successfully decreased MØCM IGF-1 levels to 40-50% of control (Figure <xref ref-type="fig" rid="F8">8A</xref>).
# ::save-date Sat Feb 13, 2016 ::file a_pmid_2169_9731_152.txt
(d / decrease-01
      :ARG0 (p2 / procedure
            :mod (t / this))
      :ARG1 (l / level
            :quant-of (p3 / protein :name (n2 / name :op1 "IGF-1")
                  :mod (m / medium
                        :ARG1-of (c / condition-01
                              :ARG0 (m2 / macrophage)))))
      :ARG4 (c3 / control
            :quant (p4 / percentage-entity
                  :value (v / value-interval :op1 40 :op2 50)))
      :ARG1-of (d2 / describe-01
            :ARG0 (f / figure :mod "8A"))
      :ARG1-of (s / succeed-01))

# ::id a_pmid_2169_9731.153 ::date 2015-05-27T09:03:09 ::annotator SDL-AMR-09 ::preferred
# ::snt When this IGF-1 depleted media was added to LM2 and JF32 cells, growth stimulation was significantly decreased compared to untreated MØCM or IgG controls, which were identical (Figure <xref ref-type="fig" rid="F8">8B</xref>).
# ::save-date Fri Feb 12, 2016 ::file a_pmid_2169_9731_153.txt
(d4 / decrease-01
      :ARG1 (s / stimulate-01
            :ARG1 (g / grow-01))
      :ARG2 (s2 / significant-02)
      :time (a / add-02
            :ARG1 (m / media
                  :ARG1-of (d2 / deplete-01
                        :ARG2 (p2 / protein :name (n3 / name :op1 "IGF-1")))
                  :mod (t2 / this))
            :ARG2 (a2 / and
                  :op1 (c / cell-line :name (n4 / name :op1 "LM2"))
                  :op2 (c4 / cell-line :name (n5 / name :op1 "JF32"))))
      :compared-to (c3 / control-01
            :ARG0 (o / or
                  :op1 (m2 / medium
                        :ARG1-of (t / treat-04 :polarity -)
                        :ARG1-of (c2 / condition-01
                              :ARG0 (m3 / macrophage)))
                  :op2 (p / protein :name (n2 / name :op1 "IgG")
                        :ARG1-of (i / identical-01
                              :ARG2 m2)
                        :ARG1-of t)))
      :ARG1-of (d3 / describe-01
            :ARG0 (f / figure :mod "8B")))

# ::id a_pmid_2169_9731.154 ::date 2015-05-27T09:24:03 ::annotator SDL-AMR-09 ::preferred
# ::snt In addition, MH-S macrophage IGF-1 secretion was interrupted by transfection with scrambled control (scr siRNA) or siRNA constructs designed against mouse IGF-1 (α-IGF siRNA).
# ::save-date Sun Jan 17, 2016 ::file a_pmid_2169_9731_154.txt
(a / and
      :op2 (i / interrupt-01
            :ARG0 (t / transfect-01
                  :ARG2 (o / or
                        :op1 (c / control
                              :ARG1-of (s2 / scramble-02)
                              :ARG1-of (m4 / mean-01
                                    :ARG2 (n8 / nucleic-acid :name (n7 / name :op1 "siRNA")
                                          :ARG1-of s2)))
                        :op2 (c2 / construct
                              :mod (n9 / nucleic-acid :name (n3 / name :op1 "siRNA"))
                              :ARG1-of (d / design-01
                                    :purpose (o2 / oppose-01
                                          :ARG1 (p2 / protein :name (n4 / name :op1 "IGF-1")
                                                :source (m2 / mouse)
                                                :ARG1-of (m3 / mean-01
                                                      :ARG2 (n10 / nucleic-acid :name (n5 / name :op1 "siRNA")
                                                            :mod (p3 / protein :name (n6 / name :op1 "α-IGF"))))))))))
            :ARG1 (s / secrete-01
                  :ARG0 (m / macrophage
                        :mod (c3 / cell-line :name (n / name :op1 "MH-S")))
                  :ARG1 (p / protein :name (n2 / name :op1 "IGF-1")))))

# ::id a_pmid_2169_9731.155 ::date 2015-05-27T09:30:54 ::annotator SDL-AMR-09 ::preferred
# ::snt One α-IGF siRNA construct was more effective than the scr siRNA, and significantly decreased MØCM IGF-1 levels to 25% of control (Figure <xref ref-type="fig" rid="F8">8C</xref>).
# ::save-date Fri Feb 12, 2016 ::file a_pmid_2169_9731_155.txt
(a / and
      :op1 (e / effective-04
            :ARG0 (c / construct-01 :quant 1
                  :ARG2 (n6 / nucleic-acid :name (n / name :op1 "siRNA")
                        :mod (p2 / protein :name (n2 / name :op1 "α-IGF"))))
            :degree (m / more)
            :compared-to (n7 / nucleic-acid :name (n3 / name :op1 "siRNA")
                  :ARG1-of (s / scramble-02)))
      :op2 (d / decrease-01
            :ARG1 (l / level
                  :quant-of (p3 / protein :name (n4 / name :op1 "IGF-1")
                        :mod (m2 / medium
                              :ARG1-of (c2 / condition-01
                                    :ARG0 (m3 / macrophage)))))
            :ARG2 (s2 / significant-02)
            :ARG4 (c3 / control
                  :quant (p / percentage-entity :value 25)))
      :ARG1-of (d2 / describe-01
            :ARG0 (f / figure :mod "8C")))

# ::id a_pmid_2169_9731.156 ::date 2015-05-27T10:14:06 ::annotator SDL-AMR-09 ::preferred
# ::snt The scr siRNA construct decreased macrophage IGF-1 secretion to a lesser extent (Figure <xref ref-type="fig" rid="F8">8C</xref>).
# ::save-date Wed May 27, 2015 ::file a_pmid_2169_9731_156.txt
(d / decrease-01
      :ARG0 (c / construct
            :topic (n3 / nucleic-acid :name (n / name :op1 "siRNA")
                  :ARG1-of (s / scramble-02)))
      :ARG1 (s2 / secrete-01
            :ARG0 (m / macrophage)
            :ARG1 (p / protein :name (n2 / name :op1 "IGF-1")))
      :ARG4 (e / extent
            :degree (l / less))
      :ARG1-of (d2 / describe-01
            :ARG0 (f / figure :mod "8C")))

# ::id a_pmid_2169_9731.157 ::date 2015-05-27T10:18:23 ::annotator SDL-AMR-09 ::preferred
# ::snt Transfection reagents and conditions were chosen to minimize cellular toxicity, and media IGF-1 content significantly decreased when normalized to MH-S viability (media IGF-1/MTS relative viability, data not shown).
# ::save-date Fri Feb 12, 2016 ::file a_pmid_2169_9731_157.txt
(a / and
      :op1 (c / choose-01
            :ARG1 (a2 / and
                  :op1 (r / reagent
                        :ARG2-of (t / transfect-01))
                  :op2 (c2 / condition
                        :mod t))
            :purpose (m / minimize-01
                  :ARG0 a2
                  :ARG1 (t2 / toxicity
                        :mod (c3 / cell))))
      :op2 (d / decrease-01
            :ARG1 (c4 / content
                  :quant-of (p / protein :name (n / name :op1 "IGF-1")
                        :mod (m2 / media)))
            :ARG2 (s / significant-02)
            :time (n2 / normalize-01
                  :ARG1 c4
                  :topic (v / viable
                        :domain (m3 / macrophage
                              :mod (c5 / cell-line :name (n3 / name :op1 "MH-S")))
                        :ARG1-of (m4 / mean-01
                              :ARG2 (s2 / slash
                                    :op1 p
                                    :op2 (v2 / viable
                                          :ARG2-of (r2 / relative-05))
                                    :ARG1-of (s3 / show-01 :polarity -
                                          :ARG0 (d2 / data))))))))

# ::id a_pmid_2169_9731.158 ::date 2015-05-27T10:24:34 ::annotator SDL-AMR-09 ::preferred
# ::snt Neoplastic growth reflected the level of IGF-1 in the media conditioned by siRNA-treated macrophages, with all three groups differing significantly in JF32 cells (Figure <xref ref-type="fig" rid="F8">8D</xref>).
# ::save-date Tue Jun 9, 2015 ::file a_pmid_2169_9731_158.txt
(a / and
      :op1 (r / reflect-01
            :ARG1 (g / grow-01
                  :ARG1 (n / neoplasm))
            :ARG2 (l / level
                  :quant-of (p / protein :name (n2 / name :op1 "IGF-1")))
            :location (m / media
                  :ARG1-of (c / condition-01
                        :ARG0 (m2 / macrophage
                              :ARG1-of (t / treat-04
                                    :ARG2 (n5 / nucleic-acid :name (n3 / name :op1 "siRNA"))))))
            :ARG1-of (d2 / describe-01
                  :ARG0 (f / figure :mod "8D")))
      :op2 (d / differ-02
            :ARG1 (g2 / group :quant 3
                  :mod (a2 / all))
            :ARG1-of (s / significant-02)
            :location (c2 / cell :name (n4 / name :op1 "JF32"))))

# ::id a_pmid_2169_9731.159 ::date 2015-05-27T22:39:13 ::annotator SDL-AMR-09 ::preferred
# ::snt While scr siRNA-treated media did not significantly lower LM2 cell growth, the correlation of media IGF-1 levels vs. LM2 proliferation was highly significant, as in JF32 cells (Figure <xref ref-type="fig" rid="F8">8D-F</xref>).
# ::save-date Sun Jan 17, 2016 ::file a_pmid_2169_9731_159.txt
(c / contrast-01
      :ARG1 (l2 / lower-05 :polarity -
            :ARG0 (m2 / medium
                  :ARG1-of (t / treat-04
                        :ARG2 (n5 / nucleic-acid :name (n / name :op1 "siRNA")
                              :ARG1-of (s2 / scramble-02))))
            :ARG1 (g / grow-01
                  :ARG1 (c2 / cell-line :name (n2 / name :op1 "LM2")))
            :ARG1-of (s / significant-02))
      :ARG2 (c3 / correlate-01
            :ARG1 (l3 / level
                  :quant-of (p / protein :name (n3 / name :op1 "IGF-1")
                        :mod (m / medium)))
            :ARG2 (p2 / proliferate-01
                  :ARG0 c2)
            :ARG1-of (s3 / significant-02
                  :ARG1-of (h / high-02))
            :ARG1-of (r2 / resemble-01
                  :ARG2 (p3 / proliferate-01
                        :ARG0 (c4 / cell-line :name (n4 / name :op1 "JF32")))))
      :ARG1-of (d / describe-01
            :ARG0 (a / and
                  :op1 (f / figure :mod "8D")
                  :op2 (f2 / figure :mod "8E")
                  :op3 (f3 / figure :mod "8F"))))

# ::id a_pmid_2169_9731.160 ::date 2015-05-27T22:58:47 ::annotator SDL-AMR-09 ::preferred
# ::snt Taken together, these experiments demonstrate that IGF-1 is responsible for the majority of neoplastic growth stimulated by MØCM.
# ::save-date Fri Feb 12, 2016 ::file a_pmid_2169_9731_160.txt
(t / take-01
      :ARG1 (e / experiment-01
            :ARG0-of (d / demonstrate-01
                  :ARG1 (r / responsible-01
                        :ARG0 (p / protein :name (n / name :op1 "IGF-1"))
                        :ARG1 (g / grow-01
                              :ARG1 (n2 / neoplasm)
                              :mod (m / majority)
                              :ARG1-of (s / stimulate-01
                                    :ARG0 (m2 / medium
                                          :ARG1-of (c / condition-01
                                                :ARG0 (m3 / macrophage)))))))
            :mod (t3 / this))
      :mod (t2 / together))

# ::id a_pmid_2169_9731.161 ::date 2015-05-27T23:12:21 ::annotator SDL-AMR-09 ::preferred
# ::snt Combined MEK and PI3K inhibition blocks IGF-1 and MØCM induced neoplastic proliferation by decreasing cyclin D1 expression
# ::save-date Fri Feb 12, 2016 ::file a_pmid_2169_9731_161.txt
(a / and
      :op1 (b / block-01
            :ARG0 (c / combine-01
                  :ARG1 (i2 / inhibit-01
                        :ARG1 (e2 / enzyme :name (n2 / name :op1 "MEK")))
                  :ARG2 (i3 / inhibit-01
                        :ARG1 (e3 / enzyme :name (n3 / name :op1 "PI3K"))))
            :ARG1 (p / protein :name (n4 / name :op1 "IGF-1")))
      :op2 (i / induce-01
            :ARG0 (m / medium
                  :ARG1-of (c2 / condition-01
                        :ARG0 (m2 / macrophage)))
            :ARG2 (p2 / proliferate-01
                  :ARG0 (n6 / neoplasm))
            :instrument (d / decrease-01
                  :ARG1 (e4 / express-03
                        :ARG2 (p3 / protein :name (n7 / name :op1 "cyclin-D1"))))))

# ::id a_pmid_2169_9731.162 ::date 2015-05-27T23:19:17 ::annotator SDL-AMR-09 ::preferred
# ::snt IGF-1 stimulated neoplastic proliferation and mediated a significant portion of macrophage-induced tumor cell growth in culture.
# ::save-date Sun Dec 20, 2015 ::file a_pmid_2169_9731_162.txt
(a / and
      :op1 (s / stimulate-01
            :ARG0 (p / protein :name (n / name :op1 "IGF-1"))
            :ARG1 (p2 / proliferate-01
                  :ARG0 (n2 / neoplasm)))
      :op2 (m / mediate-01
            :ARG0 p
            :ARG1 (p3 / portion
                  :ARG1-of (i / include-01
                        :ARG2 (g2 / grow-01
                              :ARG1 (c2 / cell
                                    :mod (t2 / tumor))
                              :ARG2-of (i3 / induce-01
                                    :ARG0 (m3 / macrophage))))
                  :ARG1-of (s2 / significant-02))
            :location (c3 / culture)))

# ::id a_pmid_2169_9731.163 ::date 2015-05-27T23:26:16 ::annotator SDL-AMR-09 ::preferred
# ::snt To determine if MØCM and/or IGF-1 were similarly blocked by MEK and PI3K inhibition, LM2 and JF32 cells were treated with combinations of MEK and/or PI3K inhibitors, in the presence of IGF-1 or MØCM.
# ::save-date Fri Feb 12, 2016 ::file a_pmid_2169_9731_163.txt
(t / treat-04
      :ARG1 (a / and
            :op1 (c / cell-line :name (n2 / name :op1 "LM2"))
            :op2 (c2 / cell-line :name (n3 / name :op1 "JF32")))
      :ARG2 (c3 / combine-01
            :ARG1 (a4 / and-or
                  :op1 (m / molecular-physical-entity
                        :ARG0-of (i / inhibit-01
                              :ARG1 (e / enzyme :name (n7 / name :op1 "MEK"))))
                  :op2 (m3 / molecular-physical-entity
                        :ARG0-of (i2 / inhibit-01
                              :ARG1 (e2 / enzyme :name (n8 / name :op1 "PI3K"))))))
      :condition (p / present-02
            :ARG1 (o / or
                  :op1 (p2 / protein :name (n5 / name :op1 "IGF-1"))
                  :op2 (m2 / medium
                        :ARG1-of (c4 / condition-01
                              :ARG0 (m4 / macrophage)))))
      :purpose (d / determine-01
            :ARG1 (b / block-01
                  :ARG0 (i3 / inhibit-01
                        :ARG1 (a3 / and
                              :op1 e
                              :op2 e2))
                  :ARG1 (a2 / and-or
                        :op1 m2
                        :op2 p2)
                  :ARG1-of (r / resemble-01))))

# ::id a_pmid_2169_9731.164 ::date 2015-05-27T23:37:43 ::annotator SDL-AMR-09 ::preferred
# ::snt Analogous to previous results with macrophage co-culture, growth stimulated by either IGF-1 or MØCM was blocked by combined inhibition of MEK and PI3K, to a greater extent than either pathway by itself (Figure <xref ref-type="fig" rid="F9">9A, B</xref>).
# ::save-date Fri Feb 12, 2016 ::file a_pmid_2169_9731_164.txt
(b3 / block-01
      :ARG0 (i / inhibit-01
            :ARG3-of (c2 / combine-01
                  :ARG1 (p2 / pathway :name (n / name :op1 "MEK"))
                  :ARG2 (p3 / pathway :name (n4 / name :op1 "PI3K"))))
      :ARG1 (g2 / grow-01
            :ARG1-of (s / stimulate-01
                  :ARG0 (o / or
                        :op1 (p / protein :name (n2 / name :op1 "IGF-1"))
                        :op2 (m3 / medium
                              :ARG1-of (c / condition-01
                                    :ARG0 (m4 / macrophage))))))
      :ARG1-of (d / describe-01
            :ARG0 (a / and
                  :op1 (f / figure :mod "9A")
                  :op2 (f2 / figure :mod "9B")))
      :degree (g / great
            :degree (m / more)
            :compared-to (b2 / block-01
                  :ARG1 (g3 / grow-01
                        :ARG1-of (s2 / stimulate-01
                              :ARG0 (o2 / or
                                    :op1 p
                                    :op2 m3)))))
      :mod (a2 / analogous
            :topic (t / thing
                  :ARG2-of (r2 / result-01
                        :ARG1 (c3 / co-culture
                              :mod (m2 / macrophage))
                        :mod (p4 / previous)))))

# ::id a_pmid_2169_9731.165 ::date 2015-05-27T23:53:49 ::annotator SDL-AMR-09 ::preferred
# ::snt Consistent with the proliferation results, cyclin D1 content (a biochemical correlate of lung cell proliferation [<xref ref-type="bibr" rid="B41">41</xref>]) was reduced by these inhibitors (Figure <xref ref-type="fig" rid="F9">9C-E</xref>).
# ::save-date Wed Dec 30, 2015 ::file a_pmid_2169_9731_165.txt
(c / consistent-01
      :ARG1 (r2 / reduce-01
            :ARG0 (m / molecular-physical-entity
                  :ARG0-of (i / inhibit-01)
                  :mod (t / this))
            :ARG1 (c2 / content
                  :quant-of (p2 / protein :name (n / name :op1 "cyclin-D1")
                        :ARG1-of (m2 / mean-01
                              :ARG2 (t3 / thing
                                    :ARG1-of (c3 / correlate-01
                                          :ARG2 (p3 / proliferate-01
                                                :ARG0 (c4 / cell
                                                      :mod (l / lung)))
                                          :ARG1-of (d / describe-01
                                                :ARG0 (p4 / publication
                                                      :ARG1-of (c5 / cite-01
                                                            :ARG2 41))))
                                    :mod (b / biochemistry))))))
      :ARG2 (t2 / thing
            :ARG2-of (r / result-01
                  :mod (p / proliferate-01)))
      :ARG1-of (d2 / describe-01
            :ARG0 (a / and
                  :op1 (f / figure :mod "9C")
                  :op2 (f2 / figure :mod "9D")
                  :op3 (f3 / figure :mod "9E"))))

# ::id a_pmid_2169_9731.166 ::date 2015-05-28T00:13:14 ::annotator SDL-AMR-09 ::preferred
# ::snt MØCM induced early increases in cRaf, Akt and GSK-3β phosphorylation, and Erk1/2 phosphorylation peaked at 24 hrs (Figure <xref ref-type="fig" rid="F9">9C, D</xref>).
# ::save-date Fri Feb 12, 2016 ::file a_pmid_2169_9731_166.txt
(a / and
      :op1 (i / induce-01
            :ARG0 (m / medium
                  :ARG1-of (c / condition-01
                        :ARG0 (m2 / macrophage)))
            :ARG2 (i2 / increase-01
                  :ARG1 (p / phosphorylate-01
                        :ARG1 (a2 / and
                              :op1 (e2 / enzyme :name (n2 / name :op1 "cRaf"))
                              :op2 (e3 / enzyme :name (n3 / name :op1 "Akt"))
                              :op3 (e4 / enzyme :name (n4 / name :op1 "GSK-3β"))))
                  :time (e / early)))
      :op2 (p2 / peak-01
            :ARG1 (p3 / phosphorylate-01
                  :ARG1 (s / slash
                        :op1 (e5 / enzyme :name (n5 / name :op1 "Erk1"))
                        :op2 (e6 / enzyme :name (n6 / name :op1 "Erk2"))))
            :time (a3 / after
                  :quant (t / temporal-quantity :quant 24
                        :unit (h / hour))))
      :ARG1-of (d / describe-01
            :ARG0 (a4 / and
                  :op1 (f / figure :mod "9C")
                  :op2 (f2 / figure :mod "9D"))))

# ::id a_pmid_2169_9731.167 ::date 2015-05-28T00:23:14 ::annotator SDL-AMR-09 ::preferred
# ::snt In both LM2 and JF32 cells, increased Akt phosphorylation corresponded to more phosphorylation of the Akt substrate, pGSK-3β (Figure <xref ref-type="fig" rid="F9">9H</xref> and <xref ref-type="fig" rid="F9">9I</xref>).
# ::save-date Sun Jan 17, 2016 ::file a_pmid_2169_9731_167.txt
(c / correspond-02
      :ARG1 (p / phosphorylate-01
            :ARG1 (e / enzyme :name (n / name :op1 "Akt"))
            :ARG1-of (i / increase-01))
      :ARG2 (p2 / phosphorylate-01
            :ARG1 (s / substrate
                  :poss e
                  :ARG1-of (m2 / mean-01
                        :ARG2 (e2 / enzyme :name (n2 / name :op1 "GSK-3β")
                              :ARG3-of (p3 / phosphorylate-01))))
            :degree (m / more))
      :location (a / and
            :op1 (c2 / cell-line :name (n3 / name :op1 "LM2"))
            :op2 (c3 / cell-line :name (n4 / name :op1 "JF32")))
      :ARG1-of (d / describe-01
            :ARG0 (a2 / and
                  :op1 (f / figure :mod "9H")
                  :op2 (f2 / figure :mod "9I"))))

# ::id a_pmid_2169_9731.168 ::date 2015-05-28T00:34:51 ::annotator SDL-AMR-09 ::preferred
# ::snt Phospho-cRaf levels, another marker of Akt activity, also increased in concert with heightened increased Akt activity from 4-24 hrs; although p-cRaf abruptly dropped at 48 hrs, pAkt and pGSK-3β levels remained highly elevated (Figure <xref ref-type="fig" rid="F9">9F, H</xref> and <xref ref-type="fig" rid="F9">9I</xref>).
# ::save-date Wed Mar 9, 2016 ::file a_pmid_2169_9731_168.txt
(a9 / and
      :op1 (i / increase-01
            :ARG1 (l / level
                  :quant-of (e / enzyme :name (n / name :op1 "cRaf")
                        :ARG3-of (p / phosphorylate-01)
                        :ARG1-of (m2 / mean-01
                              :ARG2 (m3 / marker
                                    :mod (a / activity-06
                                          :ARG0 (e2 / enzyme :name (n2 / name :op1 "Akt")))
                                    :mod (a2 / another)))))
            :mod (a3 / also)
            :manner (i2 / in-concert
                  :op1 i
                  :op2 (a5 / activity-06
                        :ARG0 e2
                        :ARG1-of (h / heighten-01)
                        :ARG1-of (i3 / increase-01)))
            :time (b / between
                  :op1 (t / temporal-quantity :quant 4
                        :unit (h6 / hour))
                  :op2 (t4 / temporal-quantity :quant 24
                        :unit h6)))
      :op2 (h2 / have-concession-91
            :ARG1 (r / remain-01
                  :ARG1 (a8 / and
                        :op1 (l2 / level
                              :quant-of (e3 / enzyme :name (n3 / name :op1 "Akt")
                                    :ARG3-of p))
                        :op2 (l3 / level
                              :quant-of (e4 / enzyme :name (n4 / name :op1 "GSK-3β")
                                    :ARG3-of p)))
                  :ARG3 (e5 / elevate-01
                        :ARG1-of (h4 / high-02)))
            :ARG2 (d / drop-01
                  :ARG1 e
                  :manner (a6 / abrupt)
                  :time (a7 / after
                        :quant (t2 / temporal-quantity :quant 48
                              :unit (h3 / hour)))))
      :ARG1-of (d2 / describe-01
            :ARG0 (a4 / and
                  :op1 (f / figure :mod "9F")
                  :op2 (f2 / figure :mod "9H")
                  :op3 (f3 / figure :mod "9I"))))

# ::id a_pmid_2169_9731.169 ::date 2015-05-28T00:52:13 ::annotator SDL-AMR-09 ::preferred
# ::snt We observed reciprocal changes in the Erk and Akt pathways in response to their respective enzyme inhibitors.
# ::save-date Sun Jan 17, 2016 ::file a_pmid_2169_9731_169.txt
(o / observe-01
      :ARG0 (w / we)
      :ARG1 (c / change-01
            :ARG1 (a / and
                  :op1 (p / pathway :name (n2 / name :op1 "Erk"))
                  :op2 (p2 / pathway :name (n3 / name :op1 "Akt")))
            :mod (r / reciprocal)
            :ARG2-of (r2 / respond-01
                  :ARG1 (t / thing
                        :ARG0-of (i / inhibit-01
                              :ARG1 (a2 / and
                                    :op1 (p3 / protein-family :name (n4 / name :op1 "Erk"))
                                    :op2 (p4 / protein-family :name (n5 / name :op1 "Akt"))))
                        :mod (r3 / respective)))))

# ::id a_pmid_2169_9731.170 ::date 2015-05-28T00:56:49 ::annotator SDL-AMR-09 ::preferred
# ::snt In LM2 cells, MEK inhibition (by U0126) suppressed early Erk1/2 phosphorylation while p-Akt levels increased.
# ::save-date Sun Jan 17, 2016 ::file a_pmid_2169_9731_170.txt
(c / contrast-01
      :ARG1 (s2 / suppress-01
            :ARG0 (i / inhibit-01
                  :ARG0 (s / small-molecule :name (n2 / name :op1 "U0126"))
                  :ARG1 (e / enzyme :name (n / name :op1 "MEK")))
            :ARG1 (p2 / phosphorylate-01
                  :ARG1 (s3 / slash
                        :op1 (e3 / enzyme :name (n3 / name :op1 "Erk1"))
                        :op2 (e4 / enzyme :name (n4 / name :op1 "Erk2")))
                  :time (e2 / early)))
      :ARG2 (i2 / increase-01
            :ARG1 (l / level
                  :quant-of (e5 / enzyme :name (n5 / name :op1 "Akt")
                        :ARG1-of (p / phosphorylate-01))))
      :location (c2 / cell-line :name (n6 / name :op1 "LM2")))

# ::id a_pmid_2169_9731.171 ::date 2015-05-28T01:03:47 ::annotator SDL-AMR-09 ::preferred
# ::snt Conversely, PI3K inhibition (by LY294002) increased basal p-Erk1/2 levels at the expense of p-Akt (4 hrs time point; Figure <xref ref-type="fig" rid="F9">9C</xref>).
# ::save-date Wed Jun 10, 2015 ::file a_pmid_2169_9731_171.txt
(c / contrast-01
      :ARG2 (i / increase-01
            :ARG0 (i2 / inhibit-01
                  :ARG0 (s / small-molecule :name (n2 / name :op1 "LY294002"))
                  :ARG1 (e2 / enzyme :name (n / name :op1 "PI3K")))
            :ARG1 (l / level
                  :quant-of (s2 / slash
                        :op1 (e3 / enzyme :name (n3 / name :op1 "Erk1")
                              :ARG3-of (p / phosphorylate-01))
                        :op2 (e4 / enzyme :name (n4 / name :op1 "Erk2")
                              :ARG3-of p))
                  :mod (b / basal))
            :ARG0-of (c2 / compromise-02
                  :ARG1 (e5 / enzyme :name (n5 / name :op1 "Akt")
                        :ARG3-of p)))
      :time (a / after
            :quant (t2 / temporal-quantity :quant 4 :unit 4))
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod "9C")))

# ::id a_pmid_2169_9731.172 ::date 2015-05-28T01:11:05 ::annotator SDL-AMR-09 ::preferred
# ::snt MEK inhibition raised p-Erk1/2 and total Erk1/2 levels at 24 and 48 hrs, while PI3K inhibition caused a compensatory increase in cellular p-Akt levels from 24-48 hrs.
# ::save-date Fri Jun 26, 2015 ::file a_pmid_2169_9731_172.txt
(c / contrast-01
      :ARG1 (r / raise-01
            :ARG0 (i / inhibit-01
                  :ARG1 (e2 / enzyme :name (n2 / name :op1 "MEK")))
            :ARG1 (a2 / and
                  :op1 (a / and
                        :op1 (l / level
                              :quant-of (e3 / enzyme :name (n3 / name :op1 "Erk1")
                                    :ARG3-of (p / phosphorylate-01)))
                        :op2 (l2 / level
                              :quant-of (e4 / enzyme :name (n4 / name :op1 "Erk2")
                                    :ARG3-of (p2 / phosphorylate-01))))
                  :op2 (s / slash
                        :op1 (l3 / level
                              :quant-of (e5 / enzyme :name (n5 / name :op1 "Erk1")))
                        :op2 (l4 / level
                              :quant-of (e6 / enzyme :name (n6 / name :op1 "Erk2")))
                        :mod (t / total)))
            :time (a4 / and
                  :op1 (a5 / after
                        :quant (t2 / temporal-quantity :quant 24
                              :unit (h / hour)))
                  :op2 (a6 / after
                        :quant (t3 / temporal-quantity :quant 48
                              :unit (h2 / hour)))))
      :ARG2 (c2 / cause-01
            :ARG0 (i2 / inhibit-01
                  :ARG1 (e7 / enzyme :name (n7 / name :op1 "PI3K")))
            :ARG1 (i3 / increase-01
                  :ARG1 (l5 / level
                        :quant-of (e8 / enzyme :name (n8 / name :op1 "Akt")
                              :mod (c4 / cell)
                              :ARG3-of p))
                  :ARG0-of (c3 / compensate-01)
                  :time (b / between
                        :op1 (t5 / temporal-quantity :quant 24
                              :unit (h4 / hour))
                        :op2 (t6 / temporal-quantity :quant 28
                              :unit h4)))))

# ::id a_pmid_2169_9731.173 ::date 2015-05-28T01:20:31 ::annotator SDL-AMR-09 ::preferred
# ::snt JF32 cell growth was also suppressed by each drug; although MEK inhibition did not affect p-Erk1/2 levels at 4 hrs, p-Erk1/2 levels decreased at 48 hrs (Figure <xref ref-type="fig" rid="F9">9D</xref>).
# ::save-date Sun Jan 17, 2016 ::file a_pmid_2169_9731_173.txt
(a5 / and
      :op1 (s / suppress-01
            :ARG0 (d / drug
                  :mod (e2 / each))
            :ARG1 (g / grow-01
                  :ARG1 (c / cell-line :name (n2 / name :op1 "JF32")))
            :mod (a / also))
      :op2 (h / have-concession-91
            :ARG1 (d2 / decrease-01
                  :ARG1 s2
                  :time (a4 / after
                        :quant (t2 / temporal-quantity :quant 48
                              :unit (h3 / hour))))
            :ARG2 (a2 / affect-01 :polarity -
                  :ARG0 (i / inhibit-01
                        :ARG1 (e3 / enzyme :name (n3 / name :op1 "MEK")))
                  :ARG1 (s2 / slash
                        :op1 (l / level
                              :quant-of (e4 / enzyme :name (n4 / name :op1 "Erk1")
                                    :ARG3-of (p / phosphorylate-01)))
                        :op2 (l2 / level
                              :quant-of (e5 / enzyme :name (n5 / name :op1 "Erk2")
                                    :ARG3-of p)))
                  :time (a3 / after
                        :quant (t / temporal-quantity :quant 4
                              :unit (h2 / hour)))))
      :ARG1-of (d3 / describe-01
            :ARG0 (f / figure :mod "9D")))

# ::id a_pmid_2169_9731.174 ::date 2015-05-28T01:29:59 ::annotator SDL-AMR-09 ::preferred
# ::snt PI3K inhibition stimulated Erk1/2 phosphorylation from 4-24 hrs, and increased Akt phosphorylation throughout the treatment time-course (Figure <xref ref-type="fig" rid="F9">9G, H</xref>).
# ::save-date Sat Jul 11, 2015 ::file a_pmid_2169_9731_174.txt
(a / and
      :op1 (s / stimulate-01
            :ARG0 (i2 / inhibit-01
                  :ARG1 (e / enzyme :name (n / name :op1 "PI3K")))
            :ARG1 (p2 / phosphorylate-01
                  :ARG1 (s2 / slash
                        :op1 (e2 / enzyme :name (n2 / name :op1 "Erk1"))
                        :op2 (e3 / enzyme :name (n3 / name :op1 "Erk2"))))
            :time (b / between
                  :op1 (t3 / temporal-quantity :quant 4
                        :unit (h2 / hour))
                  :op2 (t4 / temporal-quantity :quant 24
                        :unit h2)))
      :op2 (i / increase-01
            :ARG1 (p3 / phosphorylate-01
                  :ARG1 (e4 / enzyme :name (n4 / name :op1 "Akt")))
            :time (t2 / treat-04))
      :ARG1-of (d / describe-01
            :ARG0 (a2 / and
                  :op1 (f / figure :mod "9G")
                  :op2 (f2 / figure :mod "9H"))))

# ::id a_pmid_2169_9731.175 ::date 2015-05-28T01:34:55 ::annotator SDL-AMR-09 ::preferred
# ::snt While each inhibitor decreased basal proliferation rates (Figure <xref ref-type="fig" rid="F9">9A, B</xref>), combinations of kinase inhibitors and MØCM increased cRaf, Erk1/2, Akt and GSK-3β phosphorylation in an additive manner, with the highest levels observed in cells treated with both kinase inhibitors and MØCM ("U+L +", Figure <xref ref-type="fig" rid="F9">9C-I</xref>).
# ::save-date Fri Feb 12, 2016 ::file a_pmid_2169_9731_175.txt
(c / contrast-01
      :ARG1 (d / decrease-01
            :ARG0 (m2 / molecular-physical-entity
                  :ARG0-of (i2 / inhibit-01)
                  :mod (e / each))
            :ARG1 (r / rate
                  :mod (p2 / proliferate-01)
                  :mod (b / basal))
            :ARG1-of (d2 / describe-01
                  :ARG0 (a / and
                        :op1 (f / figure :mod "9A")
                        :op2 (f2 / figure :mod "9B"))))
      :ARG2 (i3 / increase-01
            :ARG0 (c2 / combine-01
                  :ARG1 (m3 / molecular-physical-entity
                        :ARG0-of (i4 / inhibit-01
                              :ARG1 (k / kinase)))
                  :ARG2 (m / medium
                        :ARG1-of (c3 / condition-01
                              :ARG0 (m4 / macrophage))))
            :ARG1 (p3 / phosphorylate-01
                  :ARG1 (a2 / and
                        :op1 (e3 / enzyme :name (n3 / name :op1 "cRaf"))
                        :op2 (s / slash
                              :op1 (e4 / enzyme :name (n4 / name :op1 "Erk1"))
                              :op2 (e5 / enzyme :name (n5 / name :op1 "Erk2")))
                        :op3 (e6 / enzyme :name (n6 / name :op1 "Akt"))
                        :op4 (e7 / enzyme :name (n7 / name :op1 "GSK-3β"))))
            :manner (a3 / add-02)
            :manner (o / observe-01
                  :ARG1 (l / level
                        :ARG1-of (h / high-02
                              :degree (m5 / most)))
                  :location (c4 / cell
                        :ARG1-of (t / treat-04
                              :ARG2 (a4 / and
                                    :op1 m3
                                    :op2 m)))))
      :ARG1-of (d3 / describe-01
            :ARG0 (a5 / and
                  :op1 (f3 / figure :mod "9C")
                  :op2 (f4 / figure :mod "9D")
                  :op3 (f5 / figure :mod "9E")
                  :op4 (f6 / figure :mod "9F")
                  :op5 (f7 / figure :mod "9G")
                  :op6 (f8 / figure :mod "9H")
                  :op7 (f9 / figure :mod "9I"))))

# ::id a_pmid_2169_9731.176 ::date 2015-05-28T02:51:56 ::annotator SDL-AMR-09 ::preferred
# ::snt Total and p-cRaf, p-Akt and p-GSK-3β were each significantly higher after 4-24 hrs of treatment in all groups receiving any combination of drug and MØCM, and p-Erk1/2 levels spiked after 24 hrs of treatment (Figure <xref ref-type="fig" rid="F9">9F-I</xref>).
# ::save-date Fri Feb 12, 2016 ::file a_pmid_2169_9731_176.txt
(a6 / and
      :op1 (h / high-02
            :ARG1 (a / and
                  :op1 (a2 / and
                        :op1 (e / enzyme :name (n / name :op1 "cRaf")
                              :mod (t / total))
                        :op2 (e2 / enzyme :name (n2 / name :op1 "Akt")
                              :mod t)
                        :op3 (e3 / enzyme :name (n3 / name :op1 "GSK-3β")
                              :mod t))
                  :op2 (a3 / and
                        :op1 (e4 / enzyme :name (n4 / name :op1 "cRaf")
                              :ARG3-of (p / phosphorylate-01))
                        :op2 (e5 / enzyme :name (n5 / name :op1 "Akt")
                              :ARG3-of p)
                        :op3 (e6 / enzyme :name (n6 / name :op1 "GSK-3β")
                              :ARG3-of p)))
            :degree (m2 / more)
            :ARG1-of (s / significant-02)
            :time (a4 / after
                  :op1 (t3 / treat-04)
                  :quant (t2 / temporal-quantity
                        :quant (v / value-interval :op1 4 :op2 24)
                        :unit (h3 / hour)))
            :location (g / group
                  :mod (a5 / all)
                  :ARG0-of (r / receive-01
                        :ARG1 (c / combine-01
                              :ARG1 (d / drug)
                              :ARG2 (m / medium
                                    :ARG1-of (c2 / condition-01
                                          :ARG0 (m3 / macrophage)))
                              :mod (a8 / any)))))
      :op2 (s2 / spike-04
            :ARG1 (l / level
                  :quant-of (s3 / slash
                        :op1 (e7 / enzyme :name (n8 / name :op1 "Erk1"))
                        :op2 (e8 / enzyme :name (n9 / name :op1 "Erk2"))))
            :time (a7 / after
                  :op1 (t4 / treat-04)
                  :quant (t5 / temporal-quantity :quant 24
                        :unit (h4 / hour))))
      :ARG1-of (d2 / describe-01
            :ARG0 (a9 / and
                  :op1 (f / figure :mod "9F")
                  :op2 (f2 / figure :mod "9G")
                  :op3 (f3 / figure :mod "9H")
                  :op4 (f4 / figure :mod "9I"))))

# ::id a_pmid_2169_9731.177 ::date 2015-05-28T03:03:52 ::annotator SDL-AMR-09 ::preferred
# ::snt Either inhibitor alone partially prevented the increase in cyclin D1 in cells treated with MØCM; cells receiving both inhibitors had the lowest cyclin D1 levels and were unresponsive to MØCM-induced growth (Figure <xref ref-type="fig" rid="F9">9E</xref>).
# ::save-date Fri Feb 12, 2016 ::file a_pmid_2169_9731_177.txt
(a / and
      :op1 (p / prevent-01
            :ARG0 (m / molecular-physical-entity
                  :ARG0-of (i2 / inhibit-01)
                  :mod (e / either)
                  :mod (a3 / alone))
            :ARG1 (i3 / increase-01
                  :ARG1 (p3 / protein :name (n / name :op1 "cyclin-D1"))
                  :location (c / cell
                        :ARG1-of (t / treat-04
                              :ARG2 (m4 / medium
                                    :ARG1-of (c2 / condition-01
                                          :ARG0 (m5 / macrophage))))))
            :degree (p2 / part))
      :op2 (a2 / and
            :op1 (h / have-03
                  :ARG0 (c3 / cell
                        :ARG0-of (r / receive-01
                              :ARG1 (m3 / molecular-physical-entity
                                    :ARG0-of i2
                                    :mod (b / both))))
                  :ARG1 (l / level
                        :quant-of p3
                        :ARG1-of (l2 / low-04
                              :degree (m2 / most))))
            :op2 (r2 / respond-01 :polarity -
                  :ARG0 c3
                  :ARG1 (g / grow-01
                        :ARG2-of (i4 / induce-01
                              :ARG0 m4))))
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod "9E")))

# ::id a_pmid_2169_9731.178 ::date 2015-05-28T03:20:16 ::annotator SDL-AMR-09 ::preferred
# ::snt Taken together, MØCM-induced neoplastic Akt and Erk1/2 phosphorylation was magnified several-fold by inhibitor treatment, dissociating kinase activity from proliferation in drug-treated cells; however, cyclin D1 levels were suppressed by either drug alone, which corresponded to decreased cell proliferation.
# ::save-date Fri Feb 12, 2016 ::file a_pmid_2169_9731_178.txt
(m2 / magnify-01
      :ARG0 (t / treat-04
            :ARG2 (m / molecular-physical-entity
                  :ARG0-of (i4 / inhibit-01)))
      :ARG1 (p2 / phosphorylate-01
            :ARG1 (a / and
                  :op1 (e / enzyme :name (n / name :op1 "Akt"))
                  :op2 (s / slash
                        :op1 (e2 / enzyme :name (n2 / name :op1 "Erk1"))
                        :op2 (e3 / enzyme :name (n3 / name :op1 "Erk2")))
                  :ARG1-of (t2 / take-01
                        :mod (t3 / together)))
            :mod (n4 / neoplasm)
            :ARG2-of (i2 / induce-01
                  :ARG0 (m3 / medium
                        :ARG1-of (c / condition-01
                              :ARG0 (m4 / macrophage))))
            :ARG0-of (d / dissociate-01
                  :ARG1 (a2 / activity-06
                        :ARG0 (k / kinase))
                  :ARG2 (p5 / proliferate-01
                        :ARG0 (p4 / protein)
                        :location (c2 / cell
                              :ARG1-of (t5 / treat-03
                                    :ARG3 (d2 / drug))))))
      :ARG1-of (c5 / contrast-01
            :ARG2 (s3 / suppress-01
                  :ARG0 (d4 / drug
                        :mod (e4 / either)
                        :mod (a3 / alone))
                  :ARG1 (l / level
                        :quant-of (p6 / protein :name (n7 / name :op1 "cyclin-D1")))
                  :ARG1-of (c3 / correspond-02
                        :ARG2 (p7 / proliferate-01
                              :ARG0 (c4 / cell)
                              :ARG1-of (d3 / decrease-01)))))
      :quant (p3 / product-of
            :op1 (s2 / several)))

# ::id a_pmid_2169_9731.179 ::date 2015-05-29T00:57:52 ::annotator SDL-AMR-09 ::preferred
# ::snt As with MØCM, IGF-1 stimulated both Akt and Erk1/2 activities.
# ::save-date Fri Feb 12, 2016 ::file a_pmid_2169_9731_179.txt
(r / resemble-01
      :ARG1 (s / stimulate-01
            :ARG0 (p / protein :name (n2 / name :op1 "IGF-1"))
            :ARG1 (a / act-02
                  :ARG0 (a2 / and
                        :op1 (e / enzyme :name (n3 / name :op1 "Akt"))
                        :op2 (s2 / slash
                              :op1 (e2 / enzyme :name (n4 / name :op1 "Erk1"))
                              :op2 (e3 / enzyme :name (n5 / name :op1 "Erk2"))))))
      :ARG2 (m / medium
            :ARG1-of (c / condition-01
                  :ARG0 (m2 / macrophage))))

# ::id a_pmid_2169_9731.180 ::date 2015-05-29T01:02:25 ::annotator SDL-AMR-09 ::preferred
# ::snt Kinase activation was greatest within 4 hrs of treatment, and remained elevated 48 hrs later, corresponding with increased cyclin D1 expression (Figure <xref ref-type="fig" rid="F10">10A-E</xref>).
# ::save-date Mon Dec 14, 2015 ::file a_pmid_2169_9731_180.txt
(a / and
      :op1 (g2 / great
            :domain (a2 / activate-01
                  :ARG1 (k / kinase))
            :degree (m / most)
            :time (a3 / after
                  :op1 (t / treat-03)
                  :quant (u / up-to
                        :op1 (t2 / temporal-quantity :quant 4
                              :unit (h / hour)))))
      :op2 (r / remain-01
            :ARG1 a2
            :ARG3 (e2 / elevate-01
                  :ARG1 a2)
            :time (a4 / after
                  :quant (t3 / temporal-quantity :quant 48
                        :unit (h2 / hour)))
            :ARG1-of (c / correspond-02
                  :ARG2 (e3 / express-03
                        :ARG2 (p / protein :name (n2 / name :op1 "cyclin-D1"))
                        :ARG1-of (i / increase-01))))
      :ARG1-of (d / describe-01
            :ARG0 (a5 / and
                  :op1 (f / figure :mod "10A")
                  :op2 (f2 / figure :mod "10B")
                  :op3 (f3 / figure :mod "10C")
                  :op4 (f4 / figure :mod "10D")
                  :op5 (f5 / figure :mod "10E"))))

# ::id a_pmid_2169_9731.181 ::date 2015-05-29T05:33:55 ::annotator SDL-AMR-09 ::preferred
# ::snt When treated with 2 ng/mL EGF, a concentration 1,000-times higher than the amount of EGF in cell-conditioned media and 40-times higher than what is detected in BAL fluid, Erk1/2 activity was not significantly elevated and Akt levels were unaffected (Figure <xref ref-type="fig" rid="F10">10C, D</xref>).
# ::save-date Fri Feb 12, 2016 ::file a_pmid_2169_9731_181.txt
(a2 / and
      :op1 (e / elevate-01 :polarity -
            :ARG1 (a / activity-06
                  :ARG0 (s / slash
                        :op1 (e2 / enzyme :name (n / name :op1 "Erk1"))
                        :op2 (e3 / enzyme :name (n2 / name :op1 "Erk2"))))
            :ARG1-of (s2 / significant-02))
      :op2 (a3 / affect-01 :polarity -
            :ARG1 (l / level
                  :quant-of (e4 / enzyme :name (n3 / name :op1 "Akt"))))
      :condition (t / treat-04
            :ARG2 (p / protein :name (n4 / name :op1 "EGF")
                  :quant (c / concentration-quantity :quant 2
                        :unit (n6 / nanogram-per-milliliter))
                  :ARG1-of (e5 / equal-01
                        :ARG2 (c2 / concentrate-02
                              :ARG1 p
                              :ARG1-of (h / high-02
                                    :degree (m2 / more
                                          :quant (p2 / product-of :op1 1000))
                                    :compared-to (a4 / and
                                          :op1 (a5 / amount
                                                :quant-of p
                                                :location (m3 / media
                                                      :ARG1-of (c3 / condition-01
                                                            :ARG2 (c4 / cell))))))
                              :ARG1-of (h2 / high-02
                                    :degree (m4 / more
                                          :quant (p3 / product-of :op1 40))
                                    :compared-to (t2 / thing
                                          :ARG1-of (d2 / detect-01
                                                :location (f / fluid
                                                      :mod (l2 / lavage
                                                            :mod (a7 / alveolus
                                                                  :mod (b / bronchus)))))))))))
      :ARG1-of (d / describe-01
            :ARG0 (a6 / and
                  :op1 (f2 / figure :mod "10C")
                  :op2 (f3 / figure :mod "10D"))))

# ::id a_pmid_2169_9731.182 ::date 2015-05-29T06:13:15 ::annotator SDL-AMR-09 ::preferred
# ::snt EGF may partially stimulate Erk1/2 activity at supra-physiological levels, but this was not sufficient to stimulate cellular growth.
# ::save-date Wed Mar 2, 2016 ::file a_pmid_2169_9731_182.txt
(c / contrast-01
      :ARG1 (p / possible-01
            :ARG1 (s / stimulate-01
                  :ARG0 (p2 / protein :name (n / name :op1 "EGF"))
                  :ARG1 (a / activity-06
                        :ARG0 (s2 / slash
                              :op1 (e / enzyme :name (n2 / name :op1 "Erk1"))
                              :op2 (e2 / enzyme :name (n3 / name :op1 "Erk2"))))
                  :degree (p3 / part)
                  :location (l / level
                        :mod (p4 / physiological
                              :degree (s3 / supra)))))
      :ARG2 (s4 / suffice-01 :polarity -
            :ARG0 (t / this)
            :ARG1 (s5 / stimulate-01
                  :ARG0 t
                  :ARG1 (g / grow-01
                        :ARG1 (c2 / cell)))))

# ::id a_pmid_2169_9731.183 ::date 2015-05-29T06:19:58 ::annotator SDL-AMR-09 ::preferred
# ::snt When administered at cell-and tissue-relevant levels, IGF-1 stimulated both Erk1/2 and Akt activation, elevated cellular cyclin D1 content, and induced neoplastic proliferation.
# ::save-date Sun Dec 20, 2015 ::file a_pmid_2169_9731_183.txt
(a4 / and
      :op1 (s / stimulate-01
            :ARG0 (p / protein :name (n / name :op1 "IGF-1"))
            :ARG1 (a / and
                  :op1 (a2 / activate-01
                        :ARG1 (s2 / slash
                              :op1 (e / enzyme :name (n2 / name :op1 "Erk1"))
                              :op2 (e2 / enzyme :name (n3 / name :op1 "Erk2"))))
                  :op2 (a3 / activate-01
                        :ARG1 (e3 / enzyme :name (n4 / name :op1 "Akt")))))
      :op2 (e4 / elevate-01
            :ARG0 p
            :ARG1 (c / content
                  :quant-of (p2 / protein :name (n5 / name :op1 "cyclin-D1")
                        :source (c2 / cell))))
      :op3 (i / induce-01
            :ARG0 p
            :ARG2 (p3 / proliferate-01
                  :ARG0 (n6 / neoplasm)))
      :condition (a5 / administer-01
            :ARG1 p
            :location (a6 / and
                  :op1 (l / level
                        :mod c2
                        :ARG1-of (r / relevant-01))
                  :op2 (l2 / level
                        :mod (t / tissue)
                        :ARG1-of r))))

# ::id a_pmid_2194_3101.13 ::date 2015-05-21T10:17:54 ::annotator SDL-AMR-09 ::preferred
# ::snt Evidence presented here indicate that BRAF<sup>V600E </sup>significantly induces cell migration and invasion properties <i>in vitro </i>in colon cancer cells, at least in part through activation of RhoA GTPase.
# ::save-date Sun Jan 17, 2016 ::file a_pmid_2194_3101_13.txt
(i / indicate-01
      :ARG0 (e / evidence
            :ARG1-of (p / present-01
                  :medium (h / here)))
      :ARG1 (i2 / induce-01
            :ARG0 (e3 / enzyme :name (n / name :op1 "BRAF")
                  :ARG1-of (m / mutate-01 :value "V600E"))
            :ARG2 (a / and
                  :op1 (p2 / property
                        :mod (m2 / migrate-01
                              :ARG0 (c / cell)))
                  :op2 (p3 / property
                        :mod (i3 / invade-01
                              :ARG0 c))
                  :manner (i4 / in-vitro)
                  :location (c2 / cell
                        :mod (d / disease :wiki "Cancer" :name (n2 / name :op1 "cancer")
                              :mod (c3 / colon))))
            :ARG1-of (s / significant-02)
            :manner (a2 / activate-01
                  :ARG0 e3
                  :ARG1 (p5 / pathway :name (n3 / name :op1 "RhoA" :op2 "GTPase"))
                  :degree (a3 / at-least
                        :op1 (p4 / part)))))

# ::id a_pmid_2194_3101.14 ::date 2015-05-22T03:41:49 ::annotator SDL-AMR-09 ::preferred
# ::snt The relationship established between BRAF<sup>V600E </sup>and RhoA activation is mediated by the MEK-ERK pathway.
# ::save-date Sat Jan 16, 2016 ::file a_pmid_2194_3101_14.txt
(m / mediate-01
      :ARG0 (p / pathway :name (n / name :op1 "MEK-ERK"))
      :ARG1 (r / relation-03
            :ARG0 (a / activate-01
                  :ARG1 (e2 / enzyme :name (n2 / name :op1 "BRAF")
                        :ARG1-of (m2 / mutate-01 :value "V600E")))
            :ARG2 (a2 / activate-01
                  :ARG1 (p2 / protein :name (n3 / name :op1 "RhoA")))
            :ARG1-of (e / establish-01)))

# ::id a_pmid_2194_3101.15 ::date 2015-05-22T03:49:36 ::annotator SDL-AMR-09 ::preferred
# ::snt In parallel, KRAS<sup>G12V </sup>enhances the ability of colon adenocarcinoma cells Caco-2 to migrate and invade through filopodia formation and PI3K-dependent Cdc42 activation.
# ::save-date Sun Jan 17, 2016 ::file a_pmid_2194_3101_15.txt
(e / enhance-01
      :ARG0 (e2 / enzyme :name (n / name :op1 "KRAS")
            :ARG1-of (m / mutate-01 :value "G12V"))
      :ARG1 (c / capable-01
            :ARG1 (c2 / cell-line :name (n2 / name :op1 "Caco-2")
                  :source (a / adenocarcinoma
                        :part-of (c3 / colon)))
            :ARG2 (a2 / and
                  :op1 (m2 / migrate-01
                        :ARG0 c2)
                  :op2 (i / invade-01
                        :ARG0 c2)
                  :manner (a3 / and
                        :op1 (f / form-01
                              :ARG0 c2
                              :ARG1 (f2 / filopodia))
                        :op2 (a4 / activate-01
                              :ARG0 c2
                              :ARG1 (p2 / protein :name (n3 / name :op1 "Cdc42"))
                              :ARG0-of (d / depend-01
                                    :ARG1 (e3 / enzyme :name (n4 / name :op1 "PI3K")))))))
      :mod (p / parallel))

# ::id a_pmid_2194_3101.16 ::date 2015-05-22T04:28:21 ::annotator SDL-AMR-09 ::preferred
# ::snt Ultimately increased cell migration and invasion, mediated by Rac1, along with the mesenchymal morphology obtained through the Epithelial-Mesenchymal Transition (EMT) were the main characteristics rendered by HRAS<sup>G12V </sup>in Caco-2 cells.
# ::save-date Sun Jan 17, 2016 ::file a_pmid_2194_3101_16.txt
(c / characteristic-02
      :ARG2 (a / and
            :op1 (m4 / migrate-01
                  :ARG0 (c3 / cell))
            :op2 (i2 / invade-01
                  :ARG0 c3)
            :op3 (m5 / morphology
                  :mod (m6 / mesenchyme)
                  :ARG1-of (o / obtain-01
                        :ARG2 (t / transition-01
                              :ARG2 (m7 / mesenchyme)
                              :ARG3 (e / epithelium))))
            :ARG1-of (m3 / mediate-01
                  :ARG0 (p / protein :name (n3 / name :op1 "Rac1")))
            :ARG1-of (i / increase-01
                  :manner (u / ultimate)))
      :mod (m2 / main)
      :ARG1-of (r / render-01
            :ARG0 (g / gene :name (n / name :op1 "HRAS")
                  :ARG1-of (m / mutate-01 :value "G12V"))
            :location (c2 / cell-line :name (n2 / name :op1 "Caco-2"))))

# ::id a_pmid_2194_3101.17 ::date 2015-05-22T04:34:22 ::annotator SDL-AMR-09 ::preferred
# ::snt Moreover, BRAF and KRAS oncogenes are shown to cooperate with the TGFβ-1 pathway to provide cells with additional transforming properties.
# ::save-date Sat Jan 16, 2016 ::file a_pmid_2194_3101_17.txt
(a / and
      :op2 (s / show-01
            :ARG1 (c / cooperate-01
                  :ARG0 (a2 / and
                        :op1 (g / gene :name (n / name :op1 "BRAF"))
                        :op2 (g2 / gene :name (n2 / name :op1 "KRAS"))
                        :ARG0-of (c3 / cause-01
                              :ARG1 (d / disease :wiki "Cancer" :name (n4 / name :op1 "cancer"))))
                  :ARG1 (p2 / pathway :name (n3 / name :op1 "TGFβ-1"))
                  :ARG2 (p / provide-01
                        :ARG0 (a4 / and
                              :op1 a2
                              :op2 p2)
                        :ARG1 (p3 / property
                              :mod (t / transform-01)
                              :mod (a3 / additional))
                        :ARG2 (c2 / cell)))))

# ::id a_pmid_2194_3101.131 ::date 2015-05-22T04:41:41 ::annotator SDL-AMR-09 ::preferred
# ::snt BRAF<sup>V600E </sup>induces distinct morphological changes in colon adenocarcinoma cells as compared to KRAS<sup>G12V </sup>and loss of their epithelial architecture in 3D culture
# ::save-date Sat Jan 16, 2016 ::file a_pmid_2194_3101_131.txt
(i / induce-01
      :ARG0 (e2 / enzyme :name (n / name :op1 "BRAF")
            :ARG1-of (m / mutate-01 :value "V600E"))
      :ARG2 (a4 / and
            :op1 (c / change-01
                  :ARG0 e2
                  :ARG1 (c2 / cell
                        :source (a / adenocarcinoma
                              :mod (c3 / colon)))
                  :mod (m2 / morphology)
                  :mod (d / distinct)
                  :compared-to (e3 / enzyme :name (n2 / name :op1 "KRAS")
                        :ARG1-of (m3 / mutate-01 :value "G12V")))
            :op2 (l / lose-02
                  :ARG0 c2
                  :ARG1 (a3 / architecture
                        :mod (e / epithelium)
                        :location (c4 / culture
                              :mod (d2 / dimension :quant 3))))))

# ::id a_pmid_2194_3101.132 ::date 2015-05-22T04:48:56 ::annotator SDL-AMR-09 ::preferred
# ::snt Previously established Caco-BR cells have adopted a substantially different morphology when compared to the parental Caco-2 cells [<xref ref-type="bibr" rid="B21">21</xref>].
# ::save-date Tue Jun 2, 2015 ::file a_pmid_2194_3101_132.txt
(a / adopt-01
      :ARG0 (c2 / cell-line :name (n / name :op1 "Caco-BR")
            :ARG1-of (e / establish-01
                  :time (p2 / previous)))
      :ARG1 (m / morphology
            :ARG1-of (d2 / differ-02
                  :degree (s / substantial)))
      :ARG1-of (d / describe-01
            :ARG0 (p / publication
                  :ARG1-of (c / cite-01
                        :ARG2 21)))
      :time (c3 / compare-01
            :ARG1 c2
            :ARG2 (c4 / cell-line :name (n2 / name :op1 "Caco-2")
                  :mod (p3 / parent))))

# ::id a_pmid_2194_3101.133 ::date 2015-05-22T04:54:27 ::annotator SDL-AMR-09 ::preferred
# ::snt The elongated morphology acquired by Caco-BR cells was characterized by long membrane protrusions (Figure <xref ref-type="fig" rid="F1">1A</xref>, Additional Figure <xref ref-type="supplementary-material" rid="S1">1</xref>).
# ::save-date Sun Dec 20, 2015 ::file a_pmid_2194_3101_133.txt
(c / characterize-01
      :ARG1 (m / morphology
            :ARG1-of (a3 / acquire-01
                  :ARG0 (c2 / cell-line :name (n / name :op1 "Caco-BR")))
            :ARG1-of (e / elongate-01))
      :ARG2 (p / protrude-01
            :ARG1 (m2 / membrane)
            :ARG1-of (l / long-03))
      :ARG1-of (d / describe-01
            :ARG0 (a / and
                  :op1 (f / figure :mod "1A")
                  :op2 (f2 / figure :mod 1
                        :mod (a2 / additional)))))

# ::id a_pmid_2194_3101.134 ::date 2015-05-22T03:33:13 ::annotator SDL-AMR-09 ::preferred
# ::snt We present evidence that the morphology of Caco-BR13 cells show properties of both Caco-2 epithelial nature and of the mesenchymal phenotype of Caco-H2 cells.
# ::save-date Sun Jan 17, 2016 ::file a_pmid_2194_3101_134.txt
(p / present-01
      :ARG0 (w / we)
      :ARG1 (e / evidence-01
            :ARG1 (s / show-01
                  :ARG0 (m / morphology
                        :poss (c / cell-line :name (n / name :op1 "Caco-BR13")))
                  :ARG1 (a / and
                        :op1 (p2 / property
                              :poss (n2 / nature
                                    :mod (e2 / epithelium)
                                    :poss (c2 / cell-line :name (n3 / name :op1 "Caco-2"))))
                        :op2 (p3 / property
                              :poss (p4 / phenotype
                                    :mod (m2 / mesenchyme)
                                    :poss (c3 / cell-line :name (n4 / name :op1 "Caco-H2"))))))))

# ::id a_pmid_2194_3101.135 ::date 2015-05-22T05:15:48 ::annotator SDL-AMR-09 ::preferred
# ::snt On the other hand, Caco-K15 cells, which overexpress KRAS<sup>G12V</sup>, have retained the overall parental morphology of Caco-2 cells.
# ::save-date Mon Dec 21, 2015 ::file a_pmid_2194_3101_135.txt
(c3 / contrast-01
      :ARG2 (r2 / retain-01
            :ARG0 (c / cell-line :name (n / name :op1 "Caco-K15")
                  :location-of (o / overexpress-01
                        :ARG1 (g / gene :name (n2 / name :op1 "KRAS")
                              :ARG1-of (m / mutate-01 :value "G12V"))))
            :ARG1 (m2 / morphology
                  :mod (o2 / overall)
                  :mod (p / parent)
                  :poss (c2 / cell-line :name (n3 / name :op1 "Caco-2")))))

# ::id a_pmid_2194_3101.136 ::date 2015-05-22T05:19:05 ::annotator SDL-AMR-09 ::preferred
# ::snt For comparison, established adenocarcinoma cell lines HT29 and DLD-1, bearing mutant <i>BRAF<sup>V600E </sup></i>and <i>KRAS<sup>G13D </sup></i>respectively, have also been analyzed in the present study.
# ::save-date Sun Dec 20, 2015 ::file a_pmid_2194_3101_136.txt
(a / analyze-01
      :ARG1 (a3 / and
            :op1 (c2 / cell-line :name (n / name :op1 "HT29")
                  :ARG0-of (b / bear-01
                        :ARG1 (g / gene :name (n3 / name :op1 "BRAF")
                              :ARG1-of (m / mutate-01 :value "V600E"))))
            :op2 (c3 / cell-line :name (n2 / name :op1 "DLD-1")
                  :ARG0-of (b2 / bear-01
                        :ARG1 (g2 / gene :name (n4 / name :op1 "KRAS")
                              :ARG1-of (m2 / mutate-01 :value "G13D"))))
            :mod (a4 / adenocarcinoma)
            :ARG1-of (e / establish-01)
            :mod (r / respective))
      :purpose (c / compare-01)
      :medium (s / study-01
            :time (p / present))
      :mod (a2 / also))

# ::id a_pmid_2194_3101.137 ::date 2015-05-22T05:24:04 ::annotator SDL-AMR-09 ::preferred
# ::snt It is of interest that the phenotype of Caco-BR cells resembles that of DLD-1 cells (KRAS<sup>G13D</sup>), especially since both of these cell types share high levels of p-BRAF (later analyzed).
# ::save-date Sat Jan 16, 2016 ::file a_pmid_2194_3101_137.txt
(i / interest-01
      :ARG0 (r / resemble-01
            :ARG1 (p / phenotype
                  :poss (c2 / cell-line :name (n / name :op1 "Caco-BR")))
            :ARG2 (p2 / phenotype
                  :poss (c3 / cell-line :name (n2 / name :op1 "DLD-1")
                        :mod (e3 / enzyme :name (n3 / name :op1 "KRAS")
                              :ARG1-of (m2 / mutate-01 :value "G13D")))))
      :ARG1-of (c / cause-01
            :ARG0 (s / share-01
                  :ARG0 (a / and
                        :op1 c2
                        :op2 c3)
                  :ARG1 (l / level
                        :ARG1-of (h / high-02)
                        :quant-of (e2 / enzyme :name (n4 / name :op1 "BRAF")
                              :ARG3-of (p4 / phosphorylate-01)
                              :ARG1-of (a2 / analyze-01
                                    :time (l2 / late
                                          :degree (m3 / more))))))
            :mod (e / especially)))

# ::id a_pmid_2194_3101.138 ::date 2015-05-22T05:32:19 ::annotator SDL-AMR-09 ::preferred
# ::snt Our previous study shows important similarities between Caco-BR and DLD-1 cells regarding their tumourigenic properties and signaling pathways, suggesting that their transformation process occurs mainly through the constitutive activation of the MAPK (Mitogen-Activated Protein Kinase) pathway [<xref ref-type="bibr" rid="B21">21</xref>].
# ::save-date Sun Jan 17, 2016 ::file a_pmid_2194_3101_138.txt
(s / show-01
      :ARG0 (s2 / study-01
            :ARG0 (w / we)
            :time (p / previous))
      :ARG1 (r / resemble-01
            :ARG1 (c / cell-line :name (n / name :op1 "Caco-BR"))
            :ARG2 (c2 / cell-line :name (n2 / name :op1 "DLD-1"))
            :topic (a / and
                  :op1 (p2 / possible-01
                        :ARG1 (c5 / create-01
                              :ARG1 (t / tumor)))
                  :op2 (p3 / pathway
                        :ARG0-of (s3 / signal-07)))
            :mod (i / important))
      :ARG0-of (s4 / suggest-01
            :ARG1 (p4 / process-02
                  :ARG1 (t2 / transform-01
                        :ARG1 (a3 / and
                              :op1 c
                              :op2 c2)))
            :manner (a4 / activate-01
                  :ARG1 (p5 / pathway :name (n3 / name :op1 "MAPK")
                        :ARG1-of (m / mean-01
                              :ARG2 (p6 / pathway :name (n4 / name :op1 "Mitogen-Activated" :op2 "Protein" :op3 "Kinase"))))
                  :mod (c3 / constitutive)))
      :ARG1-of (d / describe-01
            :ARG0 (p7 / publication
                  :ARG1-of (c4 / cite-01
                        :ARG2 21))))

# ::id a_pmid_2194_3101.139 ::date 2015-05-22T09:40:51 ::annotator SDL-AMR-09 ::preferred
# ::snt Staining with phalloidin resolved the morphological differences within the cell line panel indicating major actin cytoskeleton changes (Figure <xref ref-type="fig" rid="F1">1A</xref>).
# ::save-date Fri Feb 12, 2016 ::file a_pmid_2194_3101_139.txt
(r / resolve-01
      :ARG0 (s / stain-01
            :ARG2 (s2 / small-molecule :name (n / name :op1 "phalloidin")))
      :ARG1 (d2 / differ-02
            :ARG1 (p / panel
                  :mod (c / cell-line)
                  :ARG0-of (i / indicate-01
                        :ARG1 (c2 / change-01
                              :ARG1 (c3 / cytoskeleton
                                    :mod (p2 / protein :name (n2 / name :op1 "actin")))
                              :ARG1-of (m3 / major-02))))
            :mod (m2 / morphology))
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod "1A")))

# ::id a_pmid_2194_3101.140 ::date 2015-05-22T09:54:35 ::annotator SDL-AMR-09 ::preferred
# ::snt More specifically, in Caco-BR13 cells the formation of stress fibers was enhanced, whereas formation of filopodia-membrane protrusions enriched with actin- is evident in Caco-K15 cells (Figure <xref ref-type="fig" rid="F1">1A-ii</xref>, arrow).
# ::save-date Sun Jan 3, 2016 ::file a_pmid_2194_3101_140.txt
(c / contrast-01
      :ARG1 (e / enhance-01
            :ARG1 (f4 / form-01
                  :ARG1 (f5 / fiber
                        :mod (s2 / stress)))
            :location (c3 / cell-line :name (n3 / name :op1 "Caco-BR13")))
      :ARG2 (e2 / evident
            :domain (f / form-01
                  :ARG1 (p / protrusion
                        :mod (m2 / membrane
                              :mod (f2 / filopodia))
                        :ARG1-of (e3 / enrich-01
                              :ARG2 (p2 / protein :name (n / name :op1 "actin")))))
            :location (c2 / cell-line :name (n2 / name :op1 "Caco-K15")))
      :ARG1-of (d / describe-01
            :ARG0 (a / and
                  :op1 (f3 / figure :mod "1A.ii")
                  :op2 (a2 / arrow)))
      :ARG1-of (s / specific-02
            :degree (m / more)))

# ::id a_pmid_2194_3101.141 ::date 2015-05-22T13:33:03 ::annotator SDL-AMR-09 ::preferred
# ::snt In order to study in depth the morphology and architecture of the different cell lines under conditions that resemble the real tissue microenvironment, the three-dimensional (3D) culture system was adopted.
# ::save-date Mon Dec 21, 2015 ::file a_pmid_2194_3101_141.txt
(a / adopt-01
      :ARG1 (s / system
            :mod (c / culture
                  :mod (d3 / dimension :quant 3))
            :condition (c4 / condition
                  :ARG1-of (r2 / resemble-01
                        :ARG2 (m3 / microenvironment
                              :mod (t2 / tissue
                                    :ARG1-of (r / real-04))))))
      :purpose (s2 / study-01
            :ARG1 (a2 / and
                  :op1 (m2 / morphology
                        :poss (c2 / cell-line
                              :ARG1-of (d2 / differ-02)))
                  :op2 (a3 / architecture
                        :poss c2))
            :ARG1-of (d / deep-03)))

# ::id a_pmid_2194_3101.142 ::date 2015-05-22T12:03:37 ::annotator SDL-AMR-09 ::preferred
# ::snt As also previously shown [<xref ref-type="bibr" rid="B22">22</xref>], Caco-2 cells were organized into cyst-like structures that resemble normal colon cell architecture following their growth in Matrigel for about 12 days (Figure <xref ref-type="fig" rid="F1">1B</xref>).
# ::save-date Sun Jan 17, 2016 ::file a_pmid_2194_3101_142.txt
(s / show-01
      :ARG1 (o / organize-01
            :ARG1 (c2 / cell-line :name (n2 / name :op1 "Caco-2"))
            :ARG4 (s2 / structure
                  :ARG1-of (r / resemble-01
                        :ARG2 (c3 / cyst))
                  :ARG1-of (r2 / resemble-01
                        :ARG2 (a3 / architecture
                              :mod (c4 / cell
                                    :source (c5 / colon
                                          :ARG1-of (n3 / normal-02))))))
            :ARG1-of (f / follow-01
                  :ARG2 (g / grow-03
                        :ARG1 c2
                        :medium (p3 / protein :name (n / name :op1 "Matrigel"))
                        :duration (a / about
                              :op1 (t / temporal-quantity :quant 12
                                    :unit (d / day)))))
            :ARG1-of (d3 / describe-01
                  :ARG0 (f2 / figure :mod "1B")))
      :time (p / previous)
      :mod (a2 / also)
      :ARG1-of (d2 / describe-01
            :ARG0 (p2 / publication
                  :ARG1-of (c / cite-01
                        :ARG2 22))))

# ::id a_pmid_2194_3101.143 ::date 2015-05-22T13:20:04 ::annotator SDL-AMR-09 ::preferred
# ::snt In contrast, Caco-H cells (EMT model) formed invasive masses with elongated protrusions, an architecture not shared by Caco-BR13 and Caco-K15 cells (Figure <xref ref-type="fig" rid="F1">1B</xref>, upper panel, black arrow).
# ::save-date Sun Jan 17, 2016 ::file a_pmid_2194_3101_143.txt
(c / contrast-01
      :ARG2 (f / form-01
            :ARG0 (c2 / cell-line :name (n / name :op1 "Caco-H")
                  :mod (t / transition-01
                        :ARG2 (m2 / mesenchyme)
                        :ARG3 (e2 / epithelium)))
            :ARG1 (m / mass
                  :ARG0-of (i / invade-01)
                  :ARG1-of (p / protrude-01
                        :ARG1-of (e / elongate-01)
                        :mod (a / architecture
                              :ARG1-of (s / share-01 :polarity -
                                    :ARG0 (a2 / and
                                          :op1 (c3 / cell-line :name (n2 / name :op1 "Caco-BR13"))
                                          :op2 (c4 / cell-line :name (n3 / name :op1 "Caco-K15"))))))))
      :ARG1-of (d / describe-01
            :ARG0 (a3 / and
                  :op1 (f2 / figure :mod "1B")
                  :op2 (p2 / panel
                        :mod (u / upper))
                  :op3 (a4 / arrow
                        :ARG1-of (b / black-04)))))

# ::id a_pmid_2194_3101.144 ::date 2015-05-22T13:24:30 ::annotator SDL-AMR-09 ::preferred
# ::snt During 3D culture conditions, normal epithelial cells are organized into spheroids presenting a characteristic centrally-localized hollow lumen and distinct polarization of cells surrounding this lumen.
# ::save-date Mon Dec 21, 2015 ::file a_pmid_2194_3101_144.txt
(o2 / organize-01
      :ARG1 (c3 / cell
            :ARG1-of (n / normal-02)
            :source (e / epithelium))
      :ARG4 (s / spheroid
            :ARG0-of (p / present-01
                  :ARG1 (a / and
                        :op1 (l / lumen
                              :ARG1-of (h / hollow-02)
                              :location (c / center)
                              :ARG1-of (c6 / characteristic-02))
                        :op2 (p2 / polarize-01
                              :ARG1 (c4 / cell
                                    :ARG1-of (s2 / surround-01
                                          :ARG2 l))
                              :mod (d / distinct)))))
      :condition (c2 / culture
            :mod (d2 / dimension :quant 3)))

# ::id a_pmid_2194_3101.145 ::date 2015-05-22T06:05:15 ::annotator SDL-AMR-09 ::preferred
# ::snt Epithelial cancer cells do not form such structures; instead they develop non-polarized clusters with limited differentiation [<xref ref-type="bibr" rid="B23">23</xref>,<xref ref-type="bibr" rid="B24">24</xref>].
# ::save-date Fri Jul 24, 2015 ::file a_pmid_2194_3101_145.txt
(d / develop-02
      :ARG0 c
      :ARG1 (c2 / cluster
            :ARG1-of (p / polarize-01 :polarity -)
            :mod (d3 / differentiate-01
                  :ARG1-of (l / limit-01)))
      :ARG1-of (i / instead-of-91
            :ARG2 (f / form-01
                  :ARG0 (c / cell
                        :mod (d2 / disease :wiki "Cancer"
                              :name (n / name :op1 "cancer"))
                        :mod (e / epithelium))
                  :ARG1 (s / structure
                        :degree (s2 / such))))
      :ARG1-of (d4 / describe-01
            :ARG0 (a / and
                  :op1 (p2 / publication
                        :ARG1-of (c3 / cite-01 :ARG2 23))
                  :op2 (p3 / publication
                        :ARG1-of (c4 / cite-01 :ARG2 24)))))

# ::id a_pmid_2194_3101.146 ::date 2015-05-22T06:09:32 ::annotator SDL-AMR-09 ::preferred
# ::snt Following staining with Hoechst and phalloidin the ability of Caco-2 cells to form spheroids with lumen was observed, a property also retained by Caco-K15 cells but completely absent in Caco-BR13 and Caco-H2 cells (Figure <xref ref-type="fig" rid="F1">1B</xref>, lower panel).
# ::save-date Fri Feb 12, 2016 ::file a_pmid_2194_3101_146.txt
(o / observe-01
      :ARG1 (c / capable-01
            :ARG1 (c2 / cell-line :name (n3 / name :op1 "Caco-2"))
            :ARG2 (f3 / form-01
                  :ARG0 c2
                  :ARG1 (s2 / spheroid
                        :mod (l / lumen)))
            :ARG1-of (m4 / mean-01
                  :ARG2 (p2 / property
                        :ARG1-of (r / retain-01
                              :ARG0 (c3 / cell-line :name (n4 / name :op1 "Caco-K15"))
                              :mod (a2 / also))
                        :ARG1-of (a3 / absent-01
                              :ARG2 (a4 / and
                                    :op1 (c4 / cell-line :name (n5 / name :op1 "Caco-BR13"))
                                    :op2 (c6 / cell-line :name (n6 / name :op1 "Caco-H2")))
                              :ARG1-of (c5 / complete-02)))))
      :ARG2-of (f / follow-01
            :ARG1 (s / stain-01
                  :ARG2 (a / and
                        :op1 (s4 / small-molecule :name (n / name :op1 "Hoechst"))
                        :op2 (s3 / small-molecule :name (n2 / name :op1 "phalloidin")))))
      :ARG1-of (d / describe-01
            :ARG0 (a5 / and
                  :op1 (f2 / figure :mod "1B")
                  :op2 (p / panel
                        :ARG1-of (l2 / low-04
                              :degree (m3 / more))))))

# ::id a_pmid_2194_3101.147 ::date 2015-05-22T05:32:52 ::annotator SDL-AMR-09 ::preferred
# ::snt Significantly enlarged and more compact spheroids without lumen were formed by Caco-BR13 cells as compared to Caco-2 cells.
# ::save-date Fri Jul 24, 2015 ::file a_pmid_2194_3101_147.txt
(f / form-01
      :ARG0 (c2 / cell-line :name (n / name :op1 "Caco-BR13"))
      :ARG1 (s / spheroid
            :ARG1-of (e / enlarge-01
                  :ARG2 (s2 / significant-02))
            :ARG1-of (c / compact-01
                  :degree (m / more))
            :ARG0-of (h / have-03 :polarity -
                  :ARG1 (l2 / lumen)))
      :compared-to (c3 / cell-line :name (n2 / name :op1 "Caco-2")))

# ::id a_pmid_2194_3101.148 ::date 2015-05-22T05:57:00 ::annotator SDL-AMR-09 ::preferred
# ::snt In the case of Caco-H2 cells, no typical spheroids were formed, instead large masses with non-canonical shape were observed, typical of cancer cells.
# ::save-date Sun Jul 26, 2015 ::file a_pmid_2194_3101_148.txt
(o / observe-01
      :ARG1 (m / mass
            :mod (l / large)
            :ARG1-of (s2 / shape-01 :polarity -
                  :ARG2 (c3 / canonical))
            :ARG0-of (t2 / typify-01
                  :ARG1 (c4 / cell
                        :mod (d / disease :wiki "Cancer"
                              :name (n2 / name :op1 "cancer")))))
      :ARG1-of (i / instead-of-91
            :ARG2 (f / form-01
                  :ARG1 (s / spheroid
                        :ARG1-of (t / typical-02))))
      :topic (c2 / cell-line
            :name (n / name :op1 "Caco-H2")))

# ::id a_pmid_2194_3101.149 ::date 2015-05-22T06:01:40 ::annotator SDL-AMR-09 ::preferred
# ::snt Therefore, under 2D as well as 3D culture conditions BRAF<sup>V600E </sup>overexpression managed to alter the morphology of colon adenocarcinoma cells, rendering them a more mesenchymal-like phenotype, while KRAS<sup>G12V </sup>conserved the epithelial architecture of Caco-2 cells in general.
# ::save-date Sun Jan 17, 2016 ::file a_pmid_2194_3101_149.txt
(c / cause-01
      :ARG1 (c10 / contrast-01
            :ARG1 (m / manage-02
                  :ARG0 (o / overexpress-01
                        :ARG1 (e3 / enzyme :name (n3 / name :op1 "BRAF")
                              :ARG1-of (m3 / mutate-01 :value "V600E"))
                        :ARG0-of (a2 / alter-01
                              :ARG1 (m4 / morphology
                                    :poss (c5 / cell
                                          :source (a3 / adenocarcinoma
                                                :part-of (c6 / colon))))))
                  :ARG0-of (r / render-02
                        :ARG1 (p / phenotype
                              :ARG1-of (r2 / resemble-01
                                    :ARG2 (p2 / phenotype
                                          :mod (m5 / mesenchyme
                                                :degree (m6 / more)))))
                        :ARG2 c5))
            :ARG2 (c2 / conserve-01
                  :ARG0 (e2 / enzyme :name (n / name :op1 "KRAS")
                        :ARG1-of (m2 / mutate-01 :value "G12V"))
                  :ARG1 (a / architecture
                        :mod (e / epithelium)
                        :source (c3 / cell-line :name (n2 / name :op1 "Caco-2")))
                  :ARG1-of (g2 / general-02))
            :condition (a4 / and
                  :op1 (c8 / culture
                        :mod (d / dimension :quant 2))
                  :op2 (c9 / culture
                        :mod (d2 / dimension :quant 3)))))

# ::id a_pmid_2194_3101.150 ::date 2015-05-22T06:14:22 ::annotator SDL-AMR-09 ::preferred
# ::snt BRAF<sup>V600E </sup>downregulates E-cadherin at the mRNA level and impairs its distribution in human colon adenocarcinoma cells
# ::save-date Mon Jun 1, 2015 ::file a_pmid_2194_3101_150.txt
(a / and
      :op1 (d / downregulate-01
            :ARG1 (p / protein :name (n2 / name :op1 "E-cadherin"))
            :ARG2 (e / enzyme :name (n / name :op1 "BRAF")
                  :ARG1-of (m / mutate-01 :value "V600E"))
            :location (l / level
                  :quant-of (n4 / nucleic-acid :name (n3 / name :op1 "mRNA"))))
      :op2 (i / impair-01
            :ARG0 e
            :ARG1 (d2 / distribute-01
                  :ARG1 p
                  :location (c / cell
                        :source (a2 / adenocarcinoma
                              :mod (c2 / colon
                                    :mod (h / human)))))))

# ::id a_pmid_2194_3101.151 ::date 2015-05-22T06:20:35 ::annotator SDL-AMR-09 ::preferred
# ::snt It has been previously shown that HRAS<sup>G12V </sup>converts Caco-2 epithelial into mesenchymal cells by inducing loss of E-cadherin and overexpression of vimentin [<xref ref-type="bibr" rid="B25">25</xref>].
# ::save-date Sun Jan 17, 2016 ::file a_pmid_2194_3101_151.txt
(s / show-01
      :ARG1 (c2 / convert-01
            :ARG0 (g / gene :name (n3 / name :op1 "HRAS")
                  :ARG1-of (m / mutate-01 :value "G12V"))
            :ARG1 (c3 / cell-line :name (n4 / name :op1 "Caco-2")
                  :mod (e / epithelium))
            :ARG2 (c4 / cell
                  :location (m2 / mesenchyme))
            :manner (i / induce-01
                  :ARG0 g
                  :ARG2 (a / and
                        :op1 (l / lose-02
                              :ARG1 (p4 / protein :name (n2 / name :op1 "E-cadherin")))
                        :op2 (o / overexpress-01
                              :ARG1 (p3 / protein :name (n / name :op1 "vimentin"))))))
      :ARG1-of (d / describe-01
            :ARG0 (p / publication
                  :ARG1-of (c / cite-01
                        :ARG2 25)))
      :time (p2 / previous))

# ::id a_pmid_2194_3101.152 ::date 2015-05-22T08:10:51 ::annotator SDL-AMR-09 ::preferred
# ::snt In order to examine whether BRAF<sup>V600E </sup>had a similar effect on Caco-2 cells, the expression and localization of E-cadherin was analyzed (Figure <xref ref-type="fig" rid="F2">2A, B</xref>).
# ::save-date Sun Jan 17, 2016 ::file a_pmid_2194_3101_152.txt
(a / analyze-01
      :ARG1 (a3 / and
            :op1 (e / express-03
                  :ARG2 p)
            :op2 (b / be-located-at-91
                  :ARG2 (p / protein :name (n / name :op1 "E-cadherin"))))
      :ARG1-of (d / describe-01
            :ARG0 (a2 / and
                  :op1 (f / figure :mod "2A")
                  :op2 (f2 / figure :mod "2B")))
      :purpose (e2 / examine-01
            :ARG1 (p2 / possible-01 :mode interrogative
                  :ARG1 (a4 / affect-01
                        :ARG0 (e3 / enzyme :name (n2 / name :op1 "BRAF")
                              :ARG1-of (m / mutate-01 :value "V600E"))
                        :ARG1 (c / cell-line :name (n3 / name :op1 "Caco-2"))
                        :ARG1-of (r / resemble-01)))))

# ::id a_pmid_2194_3101.153 ::date 2015-05-22T08:30:44 ::annotator SDL-AMR-09 ::preferred
# ::snt Transformation of Caco-2 cells with BRAF<sup>V600E </sup>led to a significant decrease in the mRNA levels of E-cadherin but had no significant effect on the actual protein expression (Figure <xref ref-type="fig" rid="F2">2A</xref>).
# ::save-date Sun Jan 17, 2016 ::file a_pmid_2194_3101_153.txt
(c / contrast-01
      :ARG1 (l / lead-03
            :ARG0 (t / transform-01
                  :ARG0 (e2 / enzyme :name (n2 / name :op1 "BRAF")
                        :ARG1-of (m / mutate-01 :value "V600E"))
                  :ARG1 (c2 / cell-line :name (n / name :op1 "Caco-2")))
            :ARG1 (d / decrease-01
                  :ARG1 (l2 / level
                        :quant-of (n5 / nucleic-acid :name (n3 / name :op1 "mRNA")
                              :mod (p / protein :name (n4 / name :op1 "E-cadherin"))))
                  :ARG2 (s / significant-02)))
      :ARG2 (a / affect-01 :polarity -
            :ARG0 t
            :ARG1 (e / express-03
                  :ARG2 p
                  :ARG1-of (a2 / actual-02))
            :ARG1-of s)
      :ARG1-of (d2 / describe-01
            :ARG0 (f / figure :mod "2A")))

# ::id a_pmid_2194_3101.154 ::date 2015-05-22T09:19:19 ::annotator SDL-AMR-09 ::preferred
# ::snt Notably, in Caco-BR cells reduced intensity for E-cadherin was observed mostly in lower molecular weight protein bands representing the mature protein at 120 kDa (Figure <xref ref-type="fig" rid="F2">2A</xref>-lower panel, high exposure), whereas the decrease in the actual precursors at 135 kDa (Figure <xref ref-type="fig" rid="F2">2A</xref>-lower panel, low exposure), is considerably less.
# ::save-date Sun Jan 17, 2016 ::file a_pmid_2194_3101_154.txt
(c / contrast-01
      :ARG1 (o / observe-01
            :ARG1 (i / intensity
                  :ARG1-of (r2 / reduce-01)
                  :poss (p5 / protein :name (n4 / name :op1 "E-cadherin")))
            :location (b / band
                  :mod (p3 / protein
                        :ARG1-of (l4 / low-04
                              :ARG2 (w / weight-01
                                    :ARG1 (m4 / molecule))
                              :degree (m5 / more)))
                  :ARG0-of (r / represent-01
                        :ARG1 (p4 / protein :name (n2 / name :op1 "E-cadherin")
                              :ARG1-of (m / mature-02)
                              :quant (m7 / mass-quantity :quant 120
                                    :unit k))))
            :degree (m3 / most)
            :location (c3 / cell-line :name (n3 / name :op1 "Caco-BR"))
            :ARG1-of (d3 / describe-01
                  :ARG0 (a3 / and
                        :op1 (f2 / figure :mod "2A")
                        :op2 (p6 / panel
                              :ARG1-of (l5 / low-04
                                    :degree (m8 / more)))
                        :op3 (e2 / expose-01
                              :ARG1-of (h / high-02)))))
      :ARG2 (d / decrease-01
            :ARG1 (p / precursor
                  :ARG1-of (a / actual-02)
                  :quant (m9 / mass-quantity :quant 135
                        :unit (k / kilodalton)))
            :ARG2 (l6 / less
                  :degree (c2 / considerable))
            :ARG1-of (d2 / describe-01
                  :ARG0 (a2 / and
                        :op1 (f / figure :mod "2A")
                        :op2 (p2 / panel
                              :ARG1-of (l / low-04
                                    :degree (m2 / more)))
                        :op3 (e / exposure
                              :ARG1-of (l2 / low-04)))))
      :ARG1-of (n / notable-04))

# ::id a_pmid_2194_3101.155 ::date 2015-05-22T07:18:01 ::annotator SDL-AMR-09 ::preferred
# ::snt It appears that mutant BRAF<sup>V600E </sup>but not upstream KRAS<sup>G12V </sup>activation is able to suppress the mature E-cadherin, while the precursor remained mostly unaffected.
# ::save-date Sat Jan 16, 2016 ::file a_pmid_2194_3101_155.txt
(a / appear-01
      :ARG1 (c3 / contrast-01
            :ARG1 (c2 / capable-01
                  :ARG1 (a3 / activate-01
                        :ARG1 (e / enzyme :name (n / name :op1 "BRAF")
                              :ARG1-of (m / mutate-01 :value "V600E"))
                        :ARG1-of (c / contrast-01
                              :ARG2 (a4 / activate-01
                                    :ARG1 (e2 / enzyme :name (n2 / name :op1 "KRAS")
                                          :ARG1-of (m2 / mutate-01 :value "G12V"))
                                    :ARG1-of (c4 / capable-01 :polarity -
                                          :ARG2 s)
                                    :location (u / upstream))))
                  :ARG2 (s / suppress-01
                        :ARG1 (p / protein :name (n3 / name :op1 "E-cadherin")
                              :ARG1-of (m3 / mature-02))))
            :ARG2 (r / remain-01
                  :ARG1 (p2 / precursor)
                  :ARG3 (a2 / affect-01 :polarity -
                        :degree (m4 / most)))))

# ::id a_pmid_2194_3101.156 ::date 2015-05-22T08:10:15 ::annotator SDL-AMR-09 ::preferred
# ::snt Nevertheless, immunostaining with E-cadherin revealed a significant impairment of its distribution at the cell-cell boundaries since staining appeared discontinuous at the adherent junctions (Figure <xref ref-type="fig" rid="F2">2B</xref>, upper panel magnification).
# ::save-date Tue Jan 19, 2016 ::file a_pmid_2194_3101_156.txt
(h / have-concession-91
      :ARG1 (c2 / cause-01
            :ARG0 (a / appear-01
                  :ARG1 (c / continue-01 :polarity -
                        :ARG1 (s / stain-01))
                  :location (m3 / macro-molecular-complex :name (n2 / name :op1 "adherent" :op2 "junction")))
            :ARG1 (r / reveal-01
                  :ARG0 (i / immunostain-01
                        :ARG2 (p / protein :name (n / name :op1 "E-cadherin")))
                  :ARG1 (i2 / impair-01
                        :ARG1 (d2 / distribute-01
                              :ARG1 p
                              :ARG2 (b / boundary
                                    :mod (b2 / between
                                          :op1 c3
                                          :op2 (c3 / cell))))
                        :ARG1-of (s2 / significant-02))))
      :ARG1-of (d3 / describe-01
            :ARG0 (a3 / and
                  :op1 (f / figure :mod "2B")
                  :op2 (m / magnify-01
                        :ARG1 (p2 / panel
                              :mod (u / upper))))))

# ::id a_pmid_2194_3101.157 ::date 2015-05-22T09:26:49 ::annotator SDL-AMR-09 ::preferred
# ::snt Expression of E-cadherin in the Caco-BR grown in 3D spheroids was found significantly downregulated with diffused distribution (Figure <xref ref-type="fig" rid="F2">2B</xref>, lower panel).
# ::save-date Wed Oct 7, 2015 ::file a_pmid_2194_3101_157.txt
(f / find-01
      :ARG1 (d2 / downregulate-01
            :ARG1 (e / express-03
                  :ARG2 (p2 / protein :name (n / name :op1 "E-cadherin"))
                  :ARG3 (c / cell-line :name (n2 / name :op1 "Caco-BR")
                        :ARG1-of (g / grow-03
                              :location (s / spheroid
                                    :mod (d5 / dimension :quant 3)))))
            :manner (d3 / distribute-01
                  :ARG1-of (d4 / diffuse-01))
            :ARG1-of (s2 / significant-02))
      :ARG1-of (d / describe-01
            :ARG0 (a / and
                  :op1 (f2 / figure :mod "2B")
                  :op2 (p / panel
                        :ARG1-of (l / low-04
                              :degree (m / more))))))

# ::id a_pmid_2194_3101.158 ::date 2015-05-22T06:42:18 ::annotator SDL-AMR-09 ::preferred
# ::snt In contrast, the epithelial marker E-cadherin was normally localized at the cell-cell junctions of Caco-2 and Caco-K15 cells (Figure <xref ref-type="fig" rid="F2">2B</xref>, lower panel magnification).
# ::save-date Sun Jan 17, 2016 ::file a_pmid_2194_3101_158.txt
(c / contrast-01
      :ARG2 (b / be-located-at-91
            :ARG1 (m3 / marker :name (n2 / name :op1 "E-cadherin")
                  :mod (e / epithelium))
            :ARG2 (j3 / junction
                  :mod (b2 / between
                        :op1 (c2 / cell-line :name (n3 / name :op1 "Caco-2"))
                        :op2 (c3 / cell-line :name (n4 / name :op1 "Caco-K15"))))
            :ARG1-of (n / normal-02))
      :ARG1-of (d / describe-01
            :ARG0 (a / and
                  :op1 (f / figure :mod "2B")
                  :op2 (m / magnify-01
                        :ARG1 (p / panel
                              :ARG1-of (l2 / low-04))))))

# ::id a_pmid_2194_3101.159 ::date 2015-05-21T11:57:36 ::annotator SDL-AMR-09 ::preferred
# ::snt In order to determine whether Caco-BR cells have acquired more mesenchymal characteristics, RNA and protein levels of the mesenchymal marker Vimentin were examined (Figure <xref ref-type="fig" rid="F2">2C</xref>).
# ::save-date Sun Jan 17, 2016 ::file a_pmid_2194_3101_159.txt
(e / examine-01
      :ARG1 (a / and
            :op1 (l / level
                  :quant-of (n3 / nucleic-acid :name (n4 / name :op1 "RNA")))
            :op2 (l2 / level
                  :quant-of (p / protein))
            :poss (m4 / marker :name (n / name :op1 "Vimentin")
                  :mod (m / mesenchyme)))
      :purpose (d / determine-01
            :ARG1 (a2 / acquire-01 :mode interrogative
                  :ARG0 (c / cell-line :name (n2 / name :op1 "Caco-BR"))
                  :ARG1 (t / thing
                        :quant (m3 / more)
                        :ARG2-of (c2 / characteristic-02
                              :ARG1 m))))
      :ARG1-of (d2 / describe-01
            :ARG0 (f / figure :mod "2C")))

# ::id a_pmid_2194_3101.160 ::date 2015-05-22T10:03:33 ::annotator SDL-AMR-09 ::preferred
# ::snt An increase of about 3-fold was observed at the protein level, while confocal images did not show significant difference, as compared to Caco-2 (Figure <xref ref-type="fig" rid="F2">2D</xref>), since it is known that some cancer epithelial cells abnormally express N-cadherin which has been shown to promote motility and invasion [<xref ref-type="bibr" rid="B26">26</xref>,<xref ref-type="bibr" rid="B27">27</xref>], N-cadherin expression was examined (Figure <xref ref-type="fig" rid="F2">2E</xref>).
# ::save-date Sun Jan 17, 2016 ::file a_pmid_2194_3101_160.txt
(a5 / and
      :op1 (c2 / contrast-01
            :ARG1 (o / observe-01
                  :ARG1 (i2 / increase-01
                        :ARG1 (l / level
                              :quant-of (p5 / protein))
                        :ARG3 (a6 / about
                              :quant (a4 / about
                                    :op1 (p6 / product-of :op1 3)))))
            :ARG2 (s / show-01 :polarity -
                  :ARG0 (i3 / image
                        :mod (c8 / confocal))
                  :ARG1 (d4 / differ-02
                        :ARG1-of (s4 / significant-02))
                  :compared-to (c / cell-line :name (n3 / name :op1 "Caco-2"))
                  :ARG1-of (d / describe-01
                        :ARG0 (f / figure :mod "2D"))))
      :op2 (c9 / cause-01
            :ARG0 (k / know-01
                  :ARG1 (e2 / express-03
                        :ARG2 (p / protein :name (n2 / name :op1 "N-cadherin")
                              :ARG0-of (p2 / promote-01
                                    :ARG1 (a2 / and
                                          :op1 (m / motility)
                                          :op2 (i / invade-01))
                                    :ARG1-of (s3 / show-01
                                          :ARG0 (a3 / and
                                                :op1 (p3 / publication
                                                      :ARG1-of (c6 / cite-01
                                                            :ARG2 26))
                                                :op2 (p4 / publication
                                                      :ARG1-of (c7 / cite-01
                                                            :ARG2 27))))))
                        :ARG3 (c5 / cell
                              :quant (s2 / some)
                              :source (e3 / epithelium)
                              :mod (d2 / disease :wiki "Cancer" :name (n / name :op1 "cancer")))
                        :manner (a / abnormal)))
            :ARG1 (e / examine-01
                  :ARG1 e2
                  :ARG1-of (d3 / describe-01
                        :ARG0 (f2 / figure :mod "2E")))))

# ::id a_pmid_2194_3101.161 ::date 2015-05-22T06:22:40 ::annotator SDL-AMR-09 ::preferred
# ::snt In Caco-BR cells N-cadherin expression is increased about 2-fold both at mRNA and protein levels, as compared to Caco-2 cells.
# ::save-date Sun Jan 17, 2016 ::file a_pmid_2194_3101_161.txt
(i / increase-01
      :ARG1 (e / express-03
            :ARG2 (p / protein :name (n2 / name :op1 "N-cadherin"))
            :ARG3 (c2 / cell-line :name (n3 / name :op1 "Caco-BR")))
      :ARG2 (a2 / about
            :op1 (p2 / product-of :op1 12))
      :prep-at (a / and
            :op1 (l2 / level
                  :mod (n5 / nucleic-acid :name (n4 / name :op1 "mRNA")))
            :op2 (l / level
                  :mod (p3 / protein)))
      :compared-to (c / cell-line :name (n / name :op1 "Caco-2")))

# ::id a_pmid_2194_3101.162 ::date 2015-05-22T05:24:45 ::annotator SDL-AMR-09 ::preferred
# ::snt Confocal images confirmed this increase, as shown in Figure <xref ref-type="fig" rid="F2">2F</xref>.
# ::save-date Fri May 22, 2015 ::file a_pmid_2194_3101_162.txt
(c / confirm-01
      :ARG0 (i / images
            :mod (c2 / confocal))
      :ARG1 (i2 / increase-01
            :mod (t / this))
      :ARG1-of (s / show-01
            :ARG0 (f / figure :mod "2F")))

# ::id a_pmid_2194_3101.163 ::date 2015-05-22T05:26:05 ::annotator SDL-AMR-09 ::preferred
# ::snt Taken together these data suggest that BRAF<sup>V600E </sup>overexpression failed to induce an integrated EMT phenotype, which is the case with HRAS<sup>G12V </sup>overexpression [<xref ref-type="bibr" rid="B25">25</xref>], but managed to transform Caco-2 cells through the loss of some important epithelial characteristics.
# ::save-date Sun Jan 17, 2016 ::file a_pmid_2194_3101_163.txt
(s / suggest-01
      :ARG0 (d / data
            :mod (t2 / this)
            :ARG1-of (t / take-01
                  :mod (t3 / together)))
      :ARG1 (c4 / contrast-01
            :ARG1 (f / fail-01
                  :ARG1 (o / overexpress-01
                        :ARG1 (e3 / enzyme :name (n / name :op1 "BRAF")
                              :ARG1-of (m / mutate-01 :value "V600E")))
                  :ARG2 (i / induce-01
                        :ARG0 o
                        :ARG2 (p / phenotype
                              :mod (t5 / transition-01
                                    :ARG2 (m4 / mesenchyme)
                                    :ARG3 (e4 / epithelium))
                              :ARG1-of (i2 / integrate-01)))
                  :ARG2-of (c5 / contrast-01
                        :ARG1 (o2 / overexpress-01
                              :ARG1 (e2 / enzyme :name (n3 / name :op1 "HRAS")
                                    :ARG1-of (m2 / mutate-01 :value "G12V"))
                              :ARG1-of (d2 / describe-01
                                    :ARG0 (p2 / publication
                                          :ARG1-of (c / cite-01
                                                :ARG2 25))))))
            :ARG2 (m3 / manage-02
                  :ARG0 o
                  :ARG1 (t4 / transform-01
                        :ARG0 o
                        :ARG1 (c2 / cell-line :name (n4 / name :op1 "Caco-2")))
                  :manner (l / lose-02
                        :ARG0 c2
                        :ARG1 (t6 / thing
                              :mod (i3 / important)
                              :ARG2-of (c3 / characteristic-02
                                    :ARG1 (e / epithelium)
                                    :quant (s2 / some)))))))

# ::id a_pmid_2194_3101.164 ::date 2015-05-22T10:04:13 ::annotator SDL-AMR-09 ::preferred
# ::snt Differential BRAF<sup>V600E</sup>, KRAS<sup>G12V </sup>and HRAS<sup>G12V </sup>effect on the migration and invasion ability of Caco-2 cells <i>in vitro</i>
# ::save-date Sun Jan 17, 2016 ::file a_pmid_2194_3101_164.txt
(a / affect-01
      :ARG0 (a2 / and
            :op1 (e / enzyme :name (n / name :op1 "BRAF")
                  :ARG1-of (m / mutate-01 :value "V600E"))
            :op2 (e2 / enzyme :name (n2 / name :op1 "KRAS")
                  :ARG1-of (m2 / mutate-01 :value "G12V"))
            :op3 (e3 / enzyme :name (n3 / name :op1 "HRAS")
                  :ARG1-of (m3 / mutate-01 :value "G12V"))
            :ARG1-of (d / differ-02))
      :ARG1 (a3 / and
            :op1 (c / capable-01
                  :ARG1 (c3 / cell-line :name (n4 / name :op1 "Caco-2"))
                  :ARG2 (m4 / migrate-01
                        :ARG0 c3))
            :op2 (c2 / capable-01
                  :ARG1 c3
                  :ARG2 (i / invade-01
                        :ARG0 c3))
            :manner (i2 / in-vitro)))

# ::id a_pmid_2194_3101.165 ::date 2015-05-22T10:10:29 ::annotator SDL-AMR-09 ::preferred
# ::snt To further explore oncogenic effects on the cell cytoskeleton with regard to oncogenic transformation, the invasive and migratory properties of the previously established oncogenic cell models and in colon cancer cell lines HT29 and DLD-1 were analyzed.
# ::save-date Fri Jul 24, 2015 ::file a_pmid_2194_3101_165.txt
(a / analyze-01
      :ARG1 (a3 / and
            :op1 (p / property
                  :mod (i / invade-01)
                  :poss (a4 / and
                        :op1 (m2 / model
                              :ARG1-of (e2 / establish-01
                                    :time (p3 / previous))
                              :mod o
                              :mod (c7 / cell))
                        :op2 (c4 / cell-line
                              :name (n / name :op1 "HT29")
                              :mod (d / disease :wiki "Cancer"
                                    :name (n3 / name :op1 "cancer")
                                    :mod (c6 / colon)))
                        :op3 (c5 / cell-line
                              :name (n2 / name :op1 "DLD-1")
                              :mod d)))
            :op2 (p2 / property
                  :mod (m / migrate-01)
                  :poss a4))
      :purpose (e / explore-01
            :ARG1 (a2 / affect-01
                  :ARG0 (o / oncogene)
                  :ARG1 (c / cytoskeleton
                        :part-of (c2 / cell)))
            :ARG2 (t / transform-01
                  :mod o)
            :degree (f / further)))

# ::id a_pmid_2194_3101.166 ::date 2015-05-22T10:11:10 ::annotator SDL-AMR-09 ::preferred
# ::snt Transformation induced by each of the three oncogenes <i>KRAS<sup>G12V </sup></i>(Caco-K cells), <i>BRAF<sup>V600E </sup></i>(Caco-BR cells) and <i>HRAS<sup>G12V </sup></i>(Caco-H cells) managed to increase the ability of Caco-2 cells to migrate and invade <i>in vitro</i>, independently of their proliferating ability, which has been previously analyzed in [<xref ref-type="bibr" rid="B21">21</xref>].
# ::save-date Sun Jan 17, 2016 ::file a_pmid_2194_3101_166.txt
(m / manage-01
      :ARG0 (t / transform-01
            :ARG2-of (i / induce-01
                  :ARG0 (a / and
                        :op1 (g / gene :name (n4 / name :op1 "KRAS")
                              :location-of (c2 / cell :name (n / name :op1 "Caco-K")))
                        :op2 (g2 / gene :name (n5 / name :op1 "BRAF")
                              :location-of (c3 / cell-line :name (n2 / name :op1 "Caco-BR")
                                    :time (p3 / previous)))
                        :op3 (g3 / gene :name (n6 / name :op1 "HRAS")
                              :location-of (c4 / cell-line :name (n3 / name :op1 "Caco-H")))
                        :ARG0-of (c8 / cause-01
                              :ARG1 (d / disease :wiki "Cancer" :name (n8 / name :op1 "cancer"))))))
      :ARG1 (i2 / increase-01
            :ARG0 t
            :ARG1 (c5 / capable-01
                  :ARG1 (c6 / cell-line :name (n7 / name :op1 "Caco-2"))
                  :ARG2 (a2 / and
                        :op1 (m2 / migrate-01
                              :ARG0 c6)
                        :op2 (i3 / invade-01
                              :ARG0 c6)
                        :manner (i4 / in-vitro)
                        :manner (i5 / independent
                              :topic (c7 / capable-01
                                    :ARG1 c6
                                    :ARG2 (p2 / proliferate-01
                                          :ARG0 c6)
                                    :ARG1-of (a3 / analyze-01
                                          :medium (p / publication
                                                :ARG1-of (c / cite-01
                                                      :ARG2 21)))))))))

# ::id a_pmid_2194_3101.167 ::date 2015-05-23T07:23:36 ::annotator SDL-AMR-09 ::preferred
# ::snt More specifically, <i>BRAF<sup>V600E </sup></i>and <i>HRAS<sup>G12V </sup></i>provided Caco-2 cells with highly migrating and invasive properties, some similar to those in DLD-1 cells (Figure <xref ref-type="fig" rid="F3">3A, B</xref>), which is compatible with their more elongated morphology described earlier (Figure <xref ref-type="fig" rid="F1">1</xref>).
# ::save-date Sun Jan 17, 2016 ::file a_pmid_2194_3101_167.txt
(p / provide-01
      :ARG0 (a / and
            :op1 (g / gene :name (n / name :op1 "BRAF")
                  :ARG2-of (m / mutate-01 :value "V600E"))
            :op2 (g2 / gene :name (n2 / name :op1 "HRAS")
                  :ARG2-of (m2 / mutate-01 :value "G12V")))
      :ARG1 (p2 / property
            :mod (i / invade-01
                  :ARG1-of (h / high-02))
            :mod (m3 / migrate-01
                  :degree h)
            :ARG1-of (r / resemble-01
                  :ARG2 (p3 / property
                        :location (c / cell-line :name (n3 / name :op1 "DLD-1"))
                        :quant (s / some))
                  :ARG1-of (d / describe-01
                        :ARG0 (a2 / and
                              :op1 (f / figure :mod "3A")
                              :op2 (f2 / figure :mod "3B")))))
      :ARG2 (c2 / cell-line :name (n4 / name :op1 "Caco-2"))
      :mod (c3 / compatible
            :prep-with (m4 / morphology
                  :poss c2
                  :ARG1-of (e3 / elongate-01
                        :degree (m5 / more))
                  :ARG1-of (d2 / describe-01
                        :ARG0 (f3 / figure :mod 1)
                        :time (e4 / early
                              :degree m5))))
      :ARG1-of (s2 / specific-02
            :degree m5))

# ::id a_pmid_2194_3101.168 ::date 2015-05-23T09:00:41 ::annotator SDL-AMR-09 ::preferred
# ::snt Moreover, Caco-K cells, that retained typical epithelial morphology of Caco-2 parental cells also presented enhanced migrating and invasive properties, but to a lesser extent.
# ::save-date Sun Jan 17, 2016 ::file a_pmid_2194_3101_168.txt
(a / and
      :op2 (p / present-01
            :ARG0 (c / cell :name (n / name :op1 "Caco-K")
                  :ARG0-of (r / retain-01
                        :ARG1 (m / morphology
                              :mod (e / epithelium)
                              :ARG1-of (t / typical-02)
                              :poss (c2 / cell-line :name (n2 / name :op1 "Caco-2")
                                    :mod (p2 / parent)))))
            :ARG1 (p3 / property
                  :mod (i / invade-01)
                  :mod (m2 / migrate-01)
                  :ARG1-of (e2 / enhance-01))
            :mod (a2 / also)
            :ARG1-of (c3 / contrast-01
                  :ARG2 (p4 / present-01
                        :ARG0 c
                        :ARG1 p3
                        :degree (l / less)))))

# ::id a_pmid_2194_3101.169 ::date 2015-05-23T09:24:57 ::annotator SDL-AMR-09 ::preferred
# ::snt Taken together, morphological properties induced by either <i>BRAF<sup>V600E </sup></i>or <i>KRAS<sup>G12V </sup></i>oncogene affected the ability of Caco-2 cells to migrate and invade <i>in vitro</i>, but were not sufficient to fully reverse their epithelial phenotype.
# ::save-date Sun Jan 17, 2016 ::file a_pmid_2194_3101_169.txt
(c / contrast-01
      :ARG1 (a / affect-01
            :ARG0 (p / property
                  :mod (m / morphological)
                  :ARG2-of (i / induce-01
                        :ARG0 (o / or
                              :op1 (g / gene :name (n / name :op1 "BRAF")
                                    :ARG2-of (m2 / mutate-01 :value "V600E"))
                              :op2 (g2 / gene :name (n2 / name :op1 "KRAS")
                                    :ARG2-of (m3 / mutate-01 :value "G12V"))
                              :ARG0-of (c3 / cause-01
                                    :ARG1 (d / disease :wiki "Cancer" :name (n4 / name :op1 "cancer"))))))
            :ARG1 (p2 / possible-01
                  :ARG1 (a2 / and
                        :op1 (m4 / migrate-01
                              :ARG0 (c2 / cell-line :name (n3 / name :op1 "Caco-2")))
                        :op2 (i2 / invade-01
                              :ARG0 c2)
                        :manner (i3 / in-vitro))))
      :ARG2 (s / suffice-01 :polarity -
            :ARG0 p
            :ARG1 (r / reverse-01
                  :ARG0 p
                  :ARG1 (p3 / phenotype
                        :mod (e / epithelium)
                        :poss c2)
                  :degree (f / full)))
      :ARG1-of (t / take-01
            :mod (t2 / together)))

# ::id a_pmid_2194_3101.170 ::date 2015-05-23T09:49:32 ::annotator SDL-AMR-09 ::preferred
# ::snt The role of <i>BRAF </i>and <i>KRAS </i>oncogenes in altering cytoskeletal properties was further emphasized following depletion of BRAF<sup>V600E </sup>by shRNA in HT29 cells, where migration ability of HT-ShBR3 cells, with downregulated expression of mt<i>BRAF </i>gene, was significantly impaired as compared to the empty vector control HT-ps cells.
# ::save-date Sun Jan 17, 2016 ::file a_pmid_2194_3101_170.txt
(e / emphasize-01
      :ARG1 (r / role
            :poss (a / and
                  :op1 (g2 / gene :name (n / name :op1 "BRAF"))
                  :op2 (g3 / gene :name (n2 / name :op1 "KRAS"))
                  :ARG0-of (c7 / cause-01
                        :ARG1 (d3 / disease :wiki "Cancer" :name (n10 / name :op1 "cancer"))))
            :topic (a2 / alter-01
                  :ARG0 a
                  :ARG1 (p / property
                        :mod (c / cytoskeleton))))
      :degree (f / further)
      :ARG1-of (f2 / follow-01
            :ARG2 (d / deplete-01
                  :ARG0 (n9 / nucleic-acid :name (n3 / name :op1 "shRNA"))
                  :ARG1 (e2 / enzyme :name (n4 / name :op1 "BRAF")
                        :ARG2-of (m / mutate-01 :value "V600E"))
                  :location (c2 / cell-line :name (n5 / name :op1 "HT29")
                        :location-of (i / impair-01
                              :ARG1 (p2 / possible-01
                                    :ARG1 (m2 / migrate-01
                                          :ARG0 (c3 / cell-line :name (n6 / name :op1 "HT-ShBR3")))
                                    :accompanier (e3 / express-03
                                          :ARG1 (g / gene :name (n7 / name :op1 "BRAF")
                                                :ARG2-of (m3 / mutate-01))
                                          :ARG1-of (d2 / downregulate-01)))
                              :ARG1-of (s / significant-02)
                              :ARG1-of (c4 / compare-01
                                    :ARG2 (c5 / cell-line :name (n8 / name :op1 "HT-ps")
                                          :ARG2-of (c6 / control-01
                                                :ARG0 (v / vector
                                                      :ARG1-of (e4 / empty-02))))))))))

# ::id a_pmid_2194_3101.171 ::date 2015-05-23T10:29:36 ::annotator SDL-AMR-09 ::preferred
# ::snt Likewise, knock out of KRAS<sup>G13D </sup>in DLD-1 cells (DKO-4) [<xref ref-type="bibr" rid="B28">28</xref>] significantly reverted the migration ability of DLD-1 cells (Figure <xref ref-type="fig" rid="F3">3C</xref>).
# ::save-date Sun Jan 17, 2016 ::file a_pmid_2194_3101_171.txt
(r / revert-01
      :ARG0 (k / knock-out-03
            :ARG1 (e / enzyme :name (n2 / name :op1 "KRAS")
                  :ARG2-of (m2 / mutate-01 :value "G13D"))
            :location c
            :ARG1-of (d / describe-01
                  :ARG0 (c2 / cell-line :name (n3 / name :op1 "DKO-4")))
            :ARG1-of (d2 / describe-01
                  :ARG0 (p2 / publication
                        :ARG1-of (c3 / cite-01
                              :ARG2 28))))
      :ARG1 (p / possible-01
            :ARG1 (m / migrate-01
                  :ARG0 (c / cell-line :name (n / name :op1 "DLD-1"))))
      :ARG1-of (s / significant-02)
      :mod (l / likewise)
      :ARG1-of (d3 / describe-01
            :ARG0 (f / figure :mod "3C")))

# ::id a_pmid_2194_3101.172 ::date 2015-05-23T10:55:33 ::annotator SDL-AMR-09 ::preferred
# ::snt BRAF<sup>V600E </sup>enhances the ability of Caco-2 cells to migrate and invade <i>in vitro </i>through RhoA activation
# ::save-date Sun Jan 17, 2016 ::file a_pmid_2194_3101_172.txt
(e / enhance-01
      :ARG0 (e2 / enzyme :name (n / name :op1 "BRAF")
            :ARG2-of (m / mutate-01 :value "V600E"))
      :ARG1 (p / possible-01
            :ARG1 (a / and
                  :op1 (m2 / migrate-01
                        :ARG0 (c / cell-line :name (n2 / name :op1 "Caco-2")))
                  :op2 (i / invade-01
                        :ARG0 c)
                  :manner (i2 / in-vitro)))
      :manner (a2 / activate-01
            :ARG1 (p2 / protein :name (n3 / name :op1 "RhoA"))))

# ::id a_pmid_2194_3101.173 ::date 2015-05-23T11:05:09 ::annotator SDL-AMR-09 ::preferred
# ::snt Overexpression of BRAF<sup>V600E </sup>in Caco-2 cells had a profound effect on the RAS effector protein RhoA (Figure <xref ref-type="fig" rid="F4">4</xref>).
# ::save-date Sun Jan 17, 2016 ::file a_pmid_2194_3101_173.txt
(a / affect-01
      :ARG0 (o / overexpress-01
            :ARG1 (e / enzyme :name (n / name :op1 "BRAF")
                  :ARG2-of (m / mutate-01 :value "V600E"))
            :location (c / cell-line :name (n2 / name :op1 "Caco-2")))
      :ARG1 (p / protein :name (n3 / name :op1 "RhoA")
            :mod (e2 / effector
                  :mod (p3 / protein-family :name (n4 / name :op1 "RAS"))))
      :degree (p2 / profound)
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod 4)))

# ::id a_pmid_2194_3101.174 ::date 2015-05-23T11:24:36 ::annotator SDL-AMR-09 ::preferred
# ::snt In Caco-BR cells activation of RhoA is increased (Figure <xref ref-type="fig" rid="F4">4A</xref>) as well as phosphorylation of its downstream target Cofilin, a protein that is related to stress fibre formation (Figure <xref ref-type="fig" rid="F4">4B</xref>).
# ::save-date Sun Jan 17, 2016 ::file a_pmid_2194_3101_174.txt
(i / increase-01
      :ARG1 (a / and
            :op1 (a2 / activate-01
                  :ARG1 (p / protein :name (n / name :op1 "RhoA"))
                  :ARG1-of (d / describe-01
                        :ARG0 (f / figure :mod "4A")))
            :op2 (p2 / phosphorylate-01
                  :ARG1 (p3 / protein :name (n2 / name :op1 "Cofilin")
                        :ARG1-of (t / target-01
                              :ARG0 (c / cell-line :name (n3 / name :op1 "Caco-BR"))
                              :location (d2 / downstream))
                        :ARG1-of (r / relate-01
                              :ARG2 (f2 / form-01
                                    :ARG1 (f3 / fiber
                                          :mod (s / stress)))))
                  :ARG1-of (d3 / describe-01
                        :ARG0 (f4 / figure :mod "4B"))))
      :location c)

# ::id a_pmid_2194_3101.175 ::date 2015-05-23T11:34:33 ::annotator SDL-AMR-09 ::preferred
# ::snt These findings are closely related to the observation regarding increased stress fibre formation indicated by phalloidin staining in Caco-BR13 cells (Figure <xref ref-type="fig" rid="F1">1</xref>).
# ::save-date Fri Feb 12, 2016 ::file a_pmid_2194_3101_175.txt
(r / relate-01
      :ARG1 (t / thing
            :ARG1-of (f / find-01)
            :mod (t2 / this))
      :ARG2 (o / observe-01
            :ARG0-of (r2 / regard-01
                  :ARG1 (f2 / form-01
                        :ARG1 (f3 / fiber
                              :mod (s / stress))
                        :ARG1-of (i / increase-01)
                        :ARG1-of (i2 / indicate-01
                              :ARG0 (s2 / stain-01
                                    :ARG2 (s3 / small-molecule :name (n / name :op1 "phalloidin"))
                                    :location (c / cell-line :name (n2 / name :op1 "Caco-BR13")))))))
      :ARG1-of (c2 / close-10)
      :ARG1-of (d / describe-01
            :ARG0 (f4 / figure :mod 1)))

# ::id a_pmid_2194_3101.176 ::date 2015-05-23T12:33:16 ::annotator SDL-AMR-09 ::preferred
# ::snt Notably, an extra band of lower molecular weight is detected for RhoA in Caco-BR and DLD-1 cells, which potentially represents the main active GTPase form (Figure <xref ref-type="fig" rid="F4">4A</xref>).
# ::save-date Sun Jan 17, 2016 ::file a_pmid_2194_3101_176.txt
(d / detect-01
      :ARG1 (b / band
            :mod (e / extra)
            :ARG1-of (w / weight-01
                  :mod (m / molecule)
                  :ARG1-of (l / low-04
                        :degree (m2 / more)))
            :mod (p / protein :name (n / name :op1 "RhoA"))
            :ARG0-of (r / represent-01
                  :ARG1 (f / form
                        :mod (e2 / enzyme :name (n4 / name :op1 "GTPase"))
                        :ARG1-of (a / activate-01)
                        :mod (m3 / main))
                  :mod (p2 / potential)))
      :location (a2 / and
            :op1 (c / cell-line :name (n2 / name :op1 "Caco-BR"))
            :op2 (c2 / cell-line :name (n3 / name :op1 "DLD-1")))
      :ARG1-of (n5 / notable-04)
      :ARG1-of (d2 / describe-01
            :ARG0 (f2 / figure :mod "4A")))

# ::id a_pmid_2194_3101.177 ::date 2015-05-23T13:14:05 ::annotator SDL-AMR-09 ::preferred
# ::snt A variant of lower molecular weight for RhoA protein has previously been reported both in colon and breast tissues [<xref ref-type="bibr" rid="B7">7</xref>].
# ::save-date Mon Jun 1, 2015 ::file a_pmid_2194_3101_177.txt
(r / report-01
      :ARG1 (v / variant
            :ARG1-of (w / weight-01
                  :mod (m / molecule)
                  :ARG1-of (l / low-04
                        :degree (m2 / more)))
            :poss (p / protein :name (n / name :op1 "RhoA")))
      :time (p2 / previous)
      :location (a / and
            :op1 (t / tissue
                  :part-of (c / colon))
            :op2 (t2 / tissue
                  :part-of (b / breast)))
      :ARG1-of (d / describe-01
            :ARG0 (p3 / publication
                  :ARG1-of (c2 / cite-01
                        :ARG2 7))))

# ::id a_pmid_2194_3101.178 ::date 2015-05-23T13:25:12 ::annotator SDL-AMR-09 ::preferred
# ::snt However, RT-PCR analysis and treatment with the proteasome inhibitor MG-132, both in Caco-BR and DLD-1 cells, suggested no association of this faster migrating RhoA band with alternative splicing or proteasomal degradation (data not shown).
# ::save-date Wed Jan 20, 2016 ::file a_pmid_2194_3101_178.txt
(h / have-concession-91
      :ARG1 (s / suggest-01
            :ARG0 (a / and
                  :op1 (a2 / analyze-01
                        :instrument (t3 / thing :name (n / name :op1 "RT-PCR")))
                  :op2 (t / treat-04
                        :ARG2 (s2 / small-molecule :name (n2 / name :op1 "MG-132")
                              :ARG0-of (i / inhibit-01
                                    :ARG1 (e / enzyme :name (n3 / name :op1 "proteasome")))))
                  :location (a3 / and
                        :op1 (c / cell-line :name (n4 / name :op1 "Caco-BR"))
                        :op2 (c2 / cell-line :name (n5 / name :op1 "DLD-1"))))
            :ARG1 (a4 / associate-01 :polarity -
                  :ARG1 (b / band
                        :mod (p2 / protein :name (n6 / name :op1 "RhoA"))
                        :ARG0-of (m / migrate-01
                              :ARG1-of (f / fast-02
                                    :degree (m2 / more)))
                        :mod (t2 / this))
                  :ARG2 (o / or
                        :op1 (s3 / splice-01
                              :ARG1-of (a5 / alternate-01))
                        :op2 (d / degrade-01
                              :ARG1 e))))
      :ARG1-of (d2 / describe-01
            :ARG0 (d3 / data
                  :ARG1-of (s4 / show-01 :polarity -))))

# ::id a_pmid_2194_3101.179 ::date 2015-05-24T03:06:33 ::annotator SDL-AMR-09 ::preferred
# ::snt These data suggested that the additional band potentially represents a post-translational modification of RhoA protein.
# ::save-date Wed Mar 9, 2016 ::file a_pmid_2194_3101_179.txt
(s / suggest-01
      :ARG0 (d / data
            :mod (t / this))
      :ARG1 (r / represent-01
            :ARG0 (b / band
                  :ARG1-of (a / add-02))
            :ARG1 (m / modify-01
                  :ARG1 (p / protein :name (n / name :op1 "RhoA"))
                  :time (a2 / after
                        :op1 (t2 / translate-02)))
            :mod (p3 / potential)))

# ::id a_pmid_2194_3101.180 ::date 2015-05-24T03:32:22 ::annotator SDL-AMR-09 ::preferred
# ::snt To further explore the role of BRAF<sup>V600E </sup>in the activation of the RhoA pathway, transient transfection of the oncogene in Caco-2 cells was performed (Additional Figure <xref ref-type="supplementary-material" rid="S2">2</xref>).
# ::save-date Sun Jan 17, 2016 ::file a_pmid_2194_3101_180.txt
(p / perform-02
      :ARG1 (t / transfect-01
            :ARG1 (c / cell-line :name (n / name :op1 "Caco-2"))
            :ARG2 (o / oncogene)
            :ARG1-of (t2 / transient-02))
      :purpose (e / explore-01
            :ARG1 (r / role
                  :poss (e2 / enzyme :name (n2 / name :op1 "BRAF")
                        :ARG2-of (m / mutate-01 :value "V600E"))
                  :topic (a / activate-01
                        :ARG1 (p2 / pathway :name (n3 / name :op1 "RhoA"))))
            :degree (f / further))
      :ARG1-of (d / describe-01
            :ARG0 (f2 / figure :mod 2
                  :ARG1-of (a2 / add-02))))

# ::id a_pmid_2194_3101.181 ::date 2015-05-24T03:51:34 ::annotator SDL-AMR-09 ::preferred
# ::snt Subsequent analysis of the migration and invasion properties showed that moderate RhoA activation induced a partial cell migration and cell invasion response (Addition Figure <xref ref-type="supplementary-material" rid="S2">2A, B</xref>).
# ::save-date Sun Dec 20, 2015 ::file a_pmid_2194_3101_181.txt
(s / show-01
      :ARG0 (a / analyze-01
            :ARG1 (p / property
                  :mod (i / invade-01)
                  :mod (m / migrate-01))
            :time (s2 / subsequent))
      :ARG1 (i2 / induce-01
            :ARG0 (a2 / activate-01
                  :ARG1 (p2 / protein :name (n / name :op1 "RhoA"))
                  :ARG1-of (m2 / moderate-03))
            :ARG2 (a3 / and
                  :op1 (r / respond-01
                        :ARG2 (m3 / migrate-01
                              :ARG0 (c / cell)))
                  :op2 (r2 / respond-01
                        :ARG2 (i3 / invade-01
                              :ARG0 c))
                  :degree (p3 / part)))
      :ARG1-of (d / describe-01
            :ARG0 (a4 / and
                  :op1 (f / figure :mod "2A")
                  :op2 (f2 / figure :mod "2B")
                  :ARG1-of (a5 / add-02))))

# ::id a_pmid_2194_3101.182 ::date 2015-05-24T04:05:42 ::annotator SDL-AMR-09 ::preferred
# ::snt Notably in the invasion assay cell phenotype became slightly altered and resembled that of the stable Caco-BR clones (Additional Figure <xref ref-type="supplementary-material" rid="S2">2C</xref>), suggesting that a stable expression of BRAF<sup>V600E </sup>is required to achieve complete cell transformation and extensive RhoA activation.
# ::save-date Sun Jan 17, 2016 ::file a_pmid_2194_3101_182.txt
(a / and
      :op1 (b / become-01
            :ARG1 (p / phenotype
                  :mod (c / cell))
            :ARG2 (a2 / alter-01
                  :ARG1 p
                  :degree (s / slight)))
      :op2 (r / resemble-01
            :ARG1 p
            :ARG2 (p2 / phenotype
                  :poss (c2 / clone-01
                        :ARG1 (c3 / cell-line :name (n / name :op1 "Caco-BR"))
                        :ARG1-of (s2 / stable-03))))
      :ARG1-of (n2 / notable-04)
      :time (a3 / assay-01
            :ARG1 (i / invade-01))
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod "2C"
                  :ARG1-of (a4 / add-02)))
      :ARG0-of (s3 / suggest-01
            :ARG1 (r2 / require-01
                  :ARG0 (a5 / achieve-01
                        :ARG1 (a6 / and
                              :op1 (t / transform-01
                                    :ARG1 c
                                    :ARG1-of (c4 / complete-02))
                              :op2 (a7 / activate-01
                                    :ARG1 (p3 / protein :name (n3 / name :op1 "RhoA"))
                                    :ARG1-of (e / extensive-03))))
                  :ARG1 (e2 / express-03
                        :ARG2 (e3 / enzyme :name (n4 / name :op1 "BRAF")
                              :ARG2-of (m / mutate-01 :value "V600E"))
                        :ARG1-of s2))))

# ::id a_pmid_2194_3101.183 ::date 2015-05-24T04:55:35 ::annotator SDL-AMR-09 ::preferred
# ::snt Regarding the importance of RhoA activation in the induced cell migration and invasion observed in Caco-BR cells, siRNA against RhoA was performed leading to significant protein depletion in both Caco-2 and Caco-BR13 cells (Figure <xref ref-type="fig" rid="F5">5A</xref>).
# ::save-date Sun Jan 17, 2016 ::file a_pmid_2194_3101_183.txt
(p / perform-02
      :ARG1 (n6 / nucleic-acid :name (n / name :op1 "siRNA")
            :ARG0-of (o / oppose-01
                  :ARG1 (p2 / protein :name (n2 / name :op1 "RhoA"))))
      :topic (i / important
            :domain (a / activate-01
                  :ARG1 p2
                  :location (a2 / and
                        :op1 (m / migrate-01
                              :ARG0 (c / cell))
                        :op2 (i2 / invade-01
                              :ARG0 c)
                        :ARG2-of (i3 / induce-01)
                        :ARG1-of (o2 / observe-01
                              :location (c2 / cell-line :name (n3 / name :op1 "Caco-BR"))))))
      :ARG0-of (l / lead-03
            :ARG2 (d / deplete-01
                  :ARG1 (p3 / protein)
                  :ARG1-of (s / significant-02)
                  :location (a3 / and
                        :op1 (c3 / cell-line :name (n4 / name :op1 "Caco-2"))
                        :op2 (c4 / cell-line :name (n5 / name :op1 "Caco-BR13")))))
      :ARG1-of (d2 / describe-01
            :ARG0 (f / figure :mod "5A")))

# ::id a_pmid_2194_3101.184 ::date 2015-05-24T05:41:26 ::annotator SDL-AMR-09 ::preferred
# ::snt Depletion of RhoA substantially impaired both acquired properties with more profound effect in Caco-BR13 cells, further illustrating its central role in the BRAF<sup>V600E </sup>oncogene-induced transformation of colon adenocarcinoma cells (Figure <xref ref-type="fig" rid="F5">5B</xref>).
# ::save-date Sun Jan 17, 2016 ::file a_pmid_2194_3101_184.txt
(i / impair-01
      :ARG0 (d / deplete-01
            :ARG1 (p / protein :name (n / name :op1 "RhoA")))
      :ARG1 (p2 / property
            :ARG1-of (a / acquire-01)
            :mod (b / both))
      :degree (s / substantial)
      :ARG0-of (a2 / affect-01
            :degree (p3 / profound
                  :degree (m / more))
            :location (c / cell-line :name (n2 / name :op1 "Caco-BR13")))
      :ARG0-of (i2 / illustrate-01
            :ARG1 (r / role
                  :poss d
                  :topic (t / transform-01
                        :ARG1 (c2 / cell
                              :mod (a3 / adenocarcinoma
                                    :mod (c3 / colon)))
                        :ARG2-of (i3 / induce-01
                              :ARG0 (g / gene :name (n3 / name :op1 "BRAF")
                                    :ARG2-of (m2 / mutate-01 :value "V600E")
                                    :ARG0-of (c5 / cause-01
                                          :ARG1 (d3 / disease :wiki "Cancer" :name (n4 / name :op1 "cancer"))))))
                  :mod (c4 / central))
            :mod (f / further))
      :ARG1-of (d2 / describe-01
            :ARG0 (f2 / figure :mod "5B")))

# ::id a_pmid_2194_3101.185 ::date 2015-05-24T06:09:28 ::annotator SDL-AMR-09 ::preferred
# ::snt Moreover, following RhoA depletion in Caco-2 cells, the number and size of stress fibres were notably reduced as compared to Caco-BR cells, where no such alteration was observed (data not shown).
# ::save-date Sun Jan 17, 2016 ::file a_pmid_2194_3101_185.txt
(a / and
      :op2 (r / reduce-01
            :ARG1 (a2 / and
                  :op1 (n / number)
                  :op2 (s / size)
                  :quant-of (f / fiber
                        :mod (s2 / stress)))
            :ARG2 (n3 / notable-04)
            :compared-to (c / cell-line :name (n2 / name :op1 "Caco-BR")
                  :location-of (o / observe-01
                        :ARG1 (a3 / alter-01 :polarity -
                              :mod (s3 / such))))
            :ARG1-of (f2 / follow-01
                  :ARG2 (d / deplete-01
                        :ARG1 (p / protein :name (n4 / name :op1 "RhoA"))
                        :location (c2 / cell-line :name (n5 / name :op1 "Caco-2")))))
      :ARG1-of (d2 / describe-01
            :ARG0 (d3 / data
                  :ARG1-of (s4 / show-01 :polarity -))))

# ::id a_pmid_2194_3101.186 ::date 2015-05-24T06:23:54 ::annotator SDL-AMR-09 ::preferred
# ::snt In order to study further the impact of RhoA GTPase on cell migration, silencing of RhoA was performed in DLD-1 and HT29 cells.
# ::save-date Sun Jan 17, 2016 ::file a_pmid_2194_3101_186.txt
(p / perform-02
      :ARG1 (s / silence-01
            :ARG1 (p2 / protein :name (n / name :op1 "RhoA")))
      :location (a / and
            :op1 (c / cell-line :name (n2 / name :op1 "DLD-1"))
            :op2 (c2 / cell-line :name (n3 / name :op1 "HT29")))
      :purpose (s2 / study-01
            :ARG1 (i / impact-01
                  :ARG0 (p3 / pathway :name (n4 / name :op1 "RhoA" :op2 "GTPase"))
                  :ARG1 (m / migrate-01
                        :ARG0 (c3 / cell)))
            :degree (f / further)))

# ::id a_pmid_2194_3101.187 ::date 2015-05-24T06:37:30 ::annotator SDL-AMR-09 ::preferred
# ::snt Considering that these cell lines bear mutation in KRAS<sup>G13D </sup>and BRAF<sup>V600E </sup>respectively, RhoA depletion was also performed in selected clones where KRAS<sup>G13D </sup>(DKO4) or BRAF<sup>V600E </sup>(HTshBR3) was knocked out or down regulated via shRNA respectively.
# ::save-date Thu Dec 17, 2015 ::file a_pmid_2194_3101_187.txt
(p / perform-02
      :ARG1 (d / deplete-01
            :ARG1 (p2 / protein :name (n / name :op1 "RhoA")))
      :mod (a / also)
      :location (o / or
            :op1 (c / clone-01
                  :ARG1 (e / enzyme :name (n2 / name :op1 "KRAS")
                        :ARG2-of (m / mutate-01 :value "G13D")
                        :ARG1-of (d2 / describe-01
                              :ARG0 (c2 / cell :name (n3 / name :op1 "DKO4"))))
                  :ARG1-of (s / select-01))
            :op2 (c3 / clone-01
                  :ARG1 (e2 / enzyme :name (n4 / name :op1 "BRAF")
                        :ARG2-of (m2 / mutate-01 :value "V600E")
                        :ARG1-of (d3 / describe-01
                              :ARG0 (c4 / cell :name (n5 / name :op1 "HTshBR3"))))
                  :ARG1-of s)
            :ARG1-of (k / knock-out-03
                  :ARG2 (n7 / nucleic-acid :name (n6 / name :op1 "shRNA"))
                  :mod (r2 / respective))
            :ARG1-of (d4 / downregulate-01
                  :mod r2
                  :instrument n7))
      :ARG2-of (c5 / consider-02
            :ARG1 (b / bear-01
                  :ARG0 (c6 / cell-line
                        :mod (t / this))
                  :ARG1 (m3 / mutate-01)
                  :location (a2 / and
                        :op1 e
                        :op2 e2
                        :mod r2))))

# ::id a_pmid_2194_3101.188 ::date 2015-05-24T07:39:01 ::annotator SDL-AMR-09 ::preferred
# ::snt This approach can implement the connection between each oncogene and the small GTPase.
# ::save-date Sun Jan 3, 2016 ::file a_pmid_2194_3101_188.txt
(p / possible-01
      :ARG1 (i / implement-01
            :ARG0 (a / approach-02
                  :mod (t / this))
            :ARG1 (c / connect-01
                  :ARG1 (o / oncogene
                        :mod (e / each))
                  :ARG1 (p2 / protein-family :name (n / name :op1 "GTPase")
                        :mod (s / small)))))

# ::id a_pmid_2194_3101.189 ::date 2015-05-24T07:52:41 ::annotator SDL-AMR-09 ::preferred
# ::snt After silencing of RhoA, cell migration was significantly reduced in DLD-1, while no reduction was observed in DKO4 cells, where mutant KRAS<sup>G13D </sup>is knocked out, (Figure <xref ref-type="fig" rid="F5">5C</xref>).
# ::save-date Sun Jan 17, 2016 ::file a_pmid_2194_3101_189.txt
(c / contrast-01
      :ARG1 (r / reduce-01
            :ARG1 (m / migrate-01
                  :ARG0 (c2 / cell))
            :ARG2 (s / significant-02)
            :location (c3 / cell-line :name (n / name :op1 "DLD-1")))
      :ARG2 (o / observe-01
            :ARG1 (r2 / reduce-01 :polarity -)
            :location (c4 / cell-line :name (n2 / name :op1 "DKO4")
                  :location-of (k / knock-out-03
                        :ARG1 (e / enzyme :name (n3 / name :op1 "KRAS")
                              :ARG2-of (m2 / mutate-01 :value "G13D")))))
      :time (a / after
            :op1 (s2 / silence-01
                  :ARG1 (p / protein :name (n4 / name :op1 "RhoA"))))
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod "5C")))

# ::id a_pmid_2194_3101.190 ::date 2015-05-24T08:02:21 ::annotator SDL-AMR-09 ::preferred
# ::snt Depletion of RhoA in HTshBR3 (transfected with shRNA pSUPER BRAF<sup>V600E</sup>) cells with suppressed BRAF<sup>V600E </sup>activity did not reverse the ability of HT29 cell to migrate, while in HTps (HT29 cells transfected with empty vector pSUPER) a moderate reduction in cell migration was observed (Figure <xref ref-type="fig" rid="F5">5D</xref>).
# ::save-date Sun Jan 17, 2016 ::file a_pmid_2194_3101_190.txt
(c / contrast-01
      :ARG1 (r / reverse-01 :polarity -
            :ARG0 (d / deplete-01
                  :ARG1 (p / protein :name (n / name :op1 "RhoA"))
                  :location (c2 / cell :name (n2 / name :op1 "HTshBR3")
                        :ARG1-of (t / transfect-01
                              :ARG2 (e / enzyme :name (n3 / name :op1 "BRAF")
                                    :ARG2-of (m / mutate-01 :value "V600E")
                                    :mod (v / vector :name (n4 / name :op1 "pSUPER"))
                                    :ARG1-of (e2 / encode-01
                                          :ARG0 (n10 / nucleic-acid :name (n5 / name :op1 "shRNA")))))
                        :ARG0-of (h / have-03
                              :ARG1 (a / activity-06
                                    :ARG0 e
                                    :ARG1-of (s / suppress-01)))))
            :ARG1 (p2 / possible-01
                  :ARG1 (m2 / migrate-01
                        :ARG0 (c3 / cell-line :name (n6 / name :op1 "HT29")))))
      :ARG2 (o / observe-01
            :ARG1 (r3 / reduce-01
                  :ARG1 (m3 / migrate-01
                        :ARG0 (c4 / cell))
                  :ARG1-of (m4 / moderate-03)
                  :location (c5 / cell-line :name (n7 / name :op1 "HTps")
                        :ARG1-of (d2 / describe-01
                              :ARG0 (c6 / cell-line :name (n8 / name :op1 "HT29")
                                    :ARG1-of (t2 / transfect-01
                                          :ARG2 (v2 / vector :name (n9 / name :op1 "pSUPER")
                                                :ARG1-of (e3 / empty-02))))))))
      :ARG1-of (d3 / describe-01
            :ARG0 (f / figure :mod "5D")))

# ::id a_pmid_2194_3101.191 ::date 2015-05-24T08:25:41 ::annotator SDL-AMR-09 ::preferred
# ::snt Taken together, these results indicate that both <i>BRAF </i>and <i>KRAS </i>oncogenes utilize RhoA activation to promote cell migration.
# ::save-date Sat Jan 16, 2016 ::file a_pmid_2194_3101_191.txt
(i / indicate-01
      :ARG0 (t / thing
            :ARG2-of (r / result-01)
            :mod (t2 / this))
      :ARG1 (u / utilize-01
            :ARG0 (a / and
                  :op1 (g / gene :name (n / name :op1 "BRAF"))
                  :op2 (g2 / gene :name (n2 / name :op1 "KRAS"))
                  :ARG0-of (c2 / cause-01
                        :ARG1 (d / disease :wiki "Cancer" :name (n4 / name :op1 "cancer"))))
            :ARG1 (a2 / activate-01
                  :ARG1 (p / protein :name (n3 / name :op1 "RhoA")))
            :purpose (p2 / promote-01
                  :ARG0 a
                  :ARG1 (m / migrate-01
                        :ARG0 (c / cell))))
      :ARG1-of (t3 / take-01
            :mod (t4 / together)))

# ::id a_pmid_2194_3101.192 ::date 2015-05-24T08:31:00 ::annotator SDL-AMR-09 ::preferred
# ::snt In a different approach, inhibition of RhoA downstream signalling was achieved via treatment of cells with UO126, a MEK (mitogen-activated protein kinase/extracellular signal-regulated kinase kinase) inhibitor targeting the MAPK pathway, which is active in Caco-BR cells [<xref ref-type="bibr" rid="B21">21</xref>].
# ::save-date Sun Jan 17, 2016 ::file a_pmid_2194_3101_192.txt
(a / achieve-01
      :ARG1 (i / inhibit-01
            :ARG1 (s / signal-07
                  :ARG0 (p / protein :name (n / name :op1 "RhoA"))
                  :location (d / downstream)))
      :manner (t / treat-04
            :ARG1 (c / cell)
            :ARG2 (s2 / small-molecule :name (n2 / name :op1 "UO126")
                  :ARG0-of (i2 / inhibit-01
                        :ARG1 (p4 / protein-family :name (n3 / name :op1 "MEK")
                              :ARG1-of (m / mean-01
                                    :ARG2 (o / or
                                          :op1 (p5 / protein-family :name (n4 / name :op1 "mitogen-activated" :op2 "protein" :op3 "kinase"))
                                          :op2 (p6 / protein-family :name (n5 / name :op1 "extracellular" :op2 "signal-regulated" :op3 "kinase"))))))
                  :ARG0-of (t2 / target-01
                        :ARG1 (p2 / pathway :name (n6 / name :op1 "MAPK")
                              :ARG1-of (a2 / activate-01
                                    :location (c2 / cell-line :name (n7 / name :op1 "Caco-BR")))))))
      :ARG1-of (a3 / approach-02
            :ARG1-of (d2 / differ-02))
      :ARG1-of (d3 / describe-01
            :ARG0 (p3 / publication
                  :ARG1-of (c3 / cite-01
                        :ARG2 21))))

# ::id a_pmid_2194_3101.193 ::date 2015-05-24T08:55:39 ::annotator SDL-AMR-09 ::preferred
# ::snt Treatment with UO126, at the most optimal treatment condition (Additional Figure <xref ref-type="supplementary-material" rid="S3">3</xref>), resulted in the decreased activation of RhoA illustrating that mutant BRAF<sup>V600E </sup>utilises the MAPK pathway to activate RhoA (Figure <xref ref-type="fig" rid="F5">5E</xref>, upper panel).
# ::save-date Fri Feb 5, 2016 ::file a_pmid_2194_3101_193.txt
(r / result-01
      :ARG1 (t / treat-04
            :ARG2 (s / small-molecule :name (n / name :op1 "UO126"))
            :condition (o / optimal
                  :degree (m / most))
            :ARG1-of (d / describe-01
                  :ARG0 (f / figure :mod 3
                        :ARG1-of (a / add-02))))
      :ARG2 (a2 / activate-01
            :ARG0 t
            :ARG1 (p / protein :name (n2 / name :op1 "RhoA"))
            :ARG1-of (d2 / decrease-01))
      :ARG0-of (i / illustrate-01
            :ARG1 (u / utilize-01
                  :ARG0 (e / enzyme :name (n3 / name :op1 "BRAF")
                        :ARG2-of (m2 / mutate-01 :value "V600E"))
                  :ARG1 (p2 / pathway :name (n4 / name :op1 "MAPK"))
                  :purpose (a3 / activate-01
                        :ARG0 e
                        :ARG1 p)))
      :ARG1-of (d3 / describe-01
            :ARG0 (a4 / and
                  :op1 (f2 / figure :mod "5E"
                        :part (p3 / panel
                              :mod (u2 / upper))))))

# ::id a_pmid_2194_3101.194 ::date 2015-05-24T09:18:12 ::annotator SDL-AMR-09 ::preferred
# ::snt Alternative regulation of RhoA through the PI3K pathway was analysed in Caco-BR cells, and a mild effect on RhoA downstream components like p-Cofilin and p-Myl was observed (Figure <xref ref-type="fig" rid="F5">5E</xref>, lower panel).
# ::save-date Sun Jan 17, 2016 ::file a_pmid_2194_3101_194.txt
(a / and
      :op1 (a2 / analyze-01
            :ARG1 (r / regulate-01
                  :ARG0 (p / pathway :name (n / name :op1 "PI3K"))
                  :ARG1 (p2 / protein :name (n2 / name :op1 "RhoA"))
                  :ARG1-of (a3 / alternate-01))
            :location (c / cell-line :name (n3 / name :op1 "Caco-BR")))
      :op2 (o / observe-01
            :ARG1 (a4 / affect-01
                  :ARG1 (c2 / component
                        :location (d / downstream)
                        :part-of p2
                        :example (a5 / and
                              :op1 (p3 / protein :name (n4 / name :op1 "Cofilin")
                                    :ARG1-of (p4 / phosphorylate-01))
                              :op2 (p5 / protein :name (n5 / name :op1 "Myl")
                                    :ARG1-of p4)))
                  :degree (m / mild)))
      :ARG1-of (d2 / describe-01
            :ARG0 (a6 / and
                  :op1 (f / figure :mod "5E"
                        :part (p6 / panel
                              :ARG1-of (l / low-04
                                    :degree (m2 / more)))))))

# ::id a_pmid_2194_3101.195 ::date 2015-05-24T09:33:19 ::annotator SDL-AMR-09 ::preferred
# ::snt Analysis of RhoA-ROCK axis
# ::save-date Sun May 24, 2015 ::file a_pmid_2194_3101_195.txt
(a / analyze-01
      :ARG1 (a2 / axis :name (n / name :op1 "RhoA-ROCK")))

# ::id a_pmid_2194_3101.196 ::date 2015-05-24T09:36:27 ::annotator SDL-AMR-09 ::preferred
# ::snt Since RhoA appears to be essential for the attained migration in Caco-BR13 cells, RhoA-Rho kinase signalling was inhibited using the selective ROCK (Rho-associated coiled coil forming protein serine/threonine kinase) inhibitor Y-27632 aiming to inhibit cell migration.
# ::save-date Sun Jan 17, 2016 ::file a_pmid_2194_3101_196.txt
(c / cause-01
      :ARG0 (a / appear-02
            :ARG1 (e / essential
                  :domain (p / protein :name (n / name :op1 "RhoA"))
                  :purpose (m / migrate-01
                        :ARG1-of (a2 / attain-01)
                        :location (c2 / cell-line :name (n2 / name :op1 "Caco-BR13")))))
      :ARG1 (i / inhibit-01
            :ARG0 (s / small-molecule :name (n4 / name :op1 "Y-27632")
                  :ARG0-of (i2 / inhibit-01
                        :ARG1 (e2 / enzyme :name (n5 / name :op1 "ROCK")))
                  :ARG0-of (s2 / select-01))
            :ARG1 (s3 / signal-07
                  :ARG0 (k / kinase :name (n6 / name :op1 "RhoA-Rho")))
            :purpose (a3 / aim-01
                  :ARG1 (i3 / inhibit-01
                        :ARG1 (m2 / migrate-01
                              :ARG0 (c3 / cell))))))

# ::id a_pmid_2194_3101.197 ::date 2015-05-24T10:20:10 ::annotator SDL-AMR-09 ::preferred
# ::snt Treatment of Caco-2 and Caco-BR13 cells with the ROCK inhibitor had a moderate effect on downstream target p-Cofilin, while cell motility was found significantly increased in both cell lines (Figure <xref ref-type="fig" rid="F6">6A-B</xref>).
# ::save-date Tue Jan 12, 2016 ::file a_pmid_2194_3101_197.txt
(c / contrast-01
      :ARG1 (a / affect-01
            :ARG0 (t / treat-04
                  :ARG1 (a2 / and
                        :op1 (c2 / cell-line :wiki "Caco-2"
                              :name (n / name :op1 "Caco-2"))
                        :op2 (c3 / cell-line :wiki -
                              :name (n2 / name :op1 "Caco-BR13")))
                  :ARG2 (m / molecular-physical-entity
                        :ARG0-of (i / inhibit-01
                              :ARG1 (e / enzyme :wiki "ROCK1"
                                    :name (n3 / name :op1 "ROCK")))))
            :ARG1 (p / protein :wiki "Cofilin"
                  :name (n4 / name :op1 "Cofilin")
                  :ARG1-of (p2 / phosphorylate-01)
                  :ARG1-of (t3 / target-01
                        :location (d / downstream)))
            :ARG1-of (m2 / moderate-03))
      :ARG2 (f / find-01
            :ARG1 (i2 / increase-01
                  :ARG1 (m3 / motility
                        :mod (c4 / cell))
                  :ARG2 (s / significant-02))
            :location a2)
      :ARG1-of (d2 / describe-01
            :ARG0 (a3 / and
                  :op1 (f2 / figure :mod "6A")
                  :op2 (f3 / figure :mod "6B"))))

# ::id a_pmid_2194_3101.198 ::date 2015-05-24T10:38:29 ::annotator SDL-AMR-09 ::preferred
# ::snt To exclude the possibility of this observation being the non-specific effect of the inhibitor targeting several other kinases, siRNA against both ROCK isoforms (ROCK1 and ROCK2) was applied to both Caco-BR clones and parental Caco-2 cells (Figure <xref ref-type="fig" rid="F6">6C</xref>).
# ::save-date Sun Jan 17, 2016 ::file a_pmid_2194_3101_198.txt
(a / apply-02
      :ARG1 (n4 / nucleic-acid :name (n / name :op1 "siRNA")
            :ARG0-of (o / oppose-01
                  :ARG1 (a2 / and
                        :op1 (i / isoform :name (n2 / name :op1 "ROCK1"))
                        :op2 (i2 / isoform :name (n3 / name :op1 "ROCK2")))))
      :ARG2 (a3 / and
            :op1 (c / clone-01
                  :ARG1 (c2 / cell-line :name (n5 / name :op1 "Caco-BR")))
            :op2 (c3 / cell-line :name (n6 / name :op1 "Caco-2")
                  :mod (p / parent)))
      :purpose (e2 / exclude-01
            :ARG1 (p2 / possible-01
                  :ARG1 (o2 / observe-01
                        :ARG1 (a4 / affect-01
                              :ARG0 (m2 / molecular-physical-entity
                                    :ARG0-of (i3 / inhibit-01)
                                    :ARG0-of (t2 / target-01
                                          :ARG1 (k / kinase
                                                :mod (o3 / other)
                                                :quant (s / several))))
                              :ARG1-of (s2 / specific-02 :polarity -))
                        :mod (t / this))))
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod "6C")))

# ::id a_pmid_2194_3101.199 ::date 2015-05-24T11:14:19 ::annotator SDL-AMR-09 ::preferred
# ::snt Besides, the use of siRNA to deplete a protein and especially a small GTPase can prove more promising since the specific protein sequence is targeted.
# ::save-date Wed Mar 2, 2016 ::file a_pmid_2194_3101_199.txt
(a / and
      :op2 (p / possible-01
            :ARG1 (p2 / prove-01
                  :ARG0 (u / use-01
                        :ARG1 (n3 / nucleic-acid :name (n / name :op1 "siRNA"))
                        :ARG2 (d / deplete-01
                              :ARG0 n3
                              :ARG1 (a2 / and
                                    :op1 (p3 / protein)
                                    :op2 (e / enzyme :name (n2 / name :op1 "GTPase")
                                          :mod (s / small)
                                          :mod (e2 / especially)))))
                  :ARG1 (p4 / promise-01
                        :degree (m / more)))
            :ARG1-of (c / cause-01
                  :ARG0 (t / target-01
                        :ARG1 (s3 / sequence
                              :ARG1-of (s2 / specific-02)
                              :part-of (p5 / protein))))))

# ::id a_pmid_2194_3101.200 ::date 2015-05-24T11:25:59 ::annotator SDL-AMR-09 ::preferred
# ::snt In several reported studies, treatment with a selective inhibitor may produce more adverse effect through interaction with other (associated) components.
# ::save-date Sun Dec 20, 2015 ::file a_pmid_2194_3101_200.txt
(p / possible-01
      :ARG1 (p2 / produce-01
            :ARG0 (t / treat-04
                  :ARG2 (m / molecular-physical-entity
                        :ARG0-of (i / inhibit-01)
                        :ARG0-of (s / select-01)))
            :ARG1 (a / affect-01
                  :mod (a2 / adverse
                        :degree (m2 / more)))
            :manner (i2 / interact-01
                  :ARG0 m
                  :ARG1 (c / component
                        :mod (o / other)
                        :ARG1-of (a3 / associate-01))))
      :medium (s2 / study-01
            :ARG1-of (r / report-01)
            :quant (s3 / several)))

# ::id a_pmid_2194_3101.201 ::date 2015-05-24T11:36:25 ::annotator SDL-AMR-09 ::preferred
# ::snt Regardless efficient ROCK depletion, no inhibition in cell migration or invasion was observed in BRAF<sup>V600E </sup>transformed cells (Figure <xref ref-type="fig" rid="F6">6D</xref>).
# ::save-date Tue Jun 2, 2015 ::file a_pmid_2194_3101_201.txt
(o / observe-01
      :ARG1 (i / inhibit-01 :polarity -
            :ARG1 (o2 / or
                  :op1 (m / migrate-01
                        :ARG0 (c / cell))
                  :op2 (i2 / invade-01
                        :ARG0 c)))
      :location (c2 / cell
            :ARG1-of (t / transform-01
                  :ARG0 (e / enzyme :name (n / name :op1 "BRAF")
                        :ARG2-of (m2 / mutate-01 :value "V600E"))))
      :concession (d / deplete-01
            :ARG1 (e2 / enzyme :name (n2 / name :op1 "ROCK"))
            :ARG1-of (e3 / efficient-01))
      :ARG1-of (d2 / describe-01
            :ARG0 (f / figure :mod "6D")))

# ::id a_pmid_2194_3101.202 ::date 2015-05-25T03:08:17 ::annotator SDL-AMR-09 ::preferred
# ::snt Nevertheless increase motility was recorded in Caco-2 cells suggesting that Rac1 activation may be taking a lead role in the absence of the RhoA-Rho kinase signalling.
# ::save-date Thu Feb 4, 2016 ::file a_pmid_2194_3101_202.txt
(h / have-concession-91
      :ARG1 (r / record-01
            :ARG1 (i / increase-01
                  :ARG1 (m / motility))
            :location (c / cell-line :name (n / name :op1 "Caco-2"))
            :ARG0-of (s / suggest-01
                  :ARG1 (p / possible-01
                        :ARG1 (t / take-01
                              :ARG0 (a / activate-01
                                    :ARG1 (p2 / protein :name (n2 / name :op1 "Rac1")))
                              :ARG1 (r2 / role
                                    :purpose (l / lead-02))
                              :condition (a2 / absent-01
                                    :ARG1 (s2 / signal-07
                                          :ARG0 (k / kinase :name (n4 / name :op1 "RhoA-Rho")))))))))

# ::id a_pmid_2194_3101.203 ::date 2015-05-25T04:16:04 ::annotator SDL-AMR-09 ::preferred
# ::snt KRAS<sup>G12V </sup>induces Cdc42-dependent migration ability and filopodia formation in Caco-2 cells, partially dependent on PI3K pathway
# ::save-date Sun Dec 20, 2015 ::file a_pmid_2194_3101_203.txt
(i / induce-01
      :ARG0 (m2 / mutate-01 :value "G12V"
            :ARG1 (g / gene :name (n4 / name :op1 "KRAS"))
            :ARG0-of (d3 / depend-01
                  :ARG1 (p4 / pathway :name (n7 / name :op1 "PI3K"))
                  :degree (p2 / part)))
      :ARG2 (a / and
            :op1 (p3 / possible-01
                  :ARG1 (m / migrate-01
                        :ARG0 n2
                        :condition (d / depend-01
                              :ARG1 (p / protein :name (n / name :op1 "Cdc42")))))
            :op2 (f / form-01
                  :ARG1 (f2 / filopodium)
                  :location (c / cell-line :name (n2 / name :op1 "Caco-2")))))

# ::id a_pmid_2194_3101.204 ::date 2015-05-25T07:14:11 ::annotator SDL-AMR-09 ::preferred
# ::snt Previous studies have indicated that RhoA, Rac1 and Cdc42 signalling is essential for oncogenic Ras transforming capacity [<xref ref-type="bibr" rid="B29">29</xref>,<xref ref-type="bibr" rid="B30">30</xref>].
# ::save-date Thu Jan 14, 2016 ::file a_pmid_2194_3101_204.txt
(i / indicate-01
      :ARG0 (s / study-01
            :time (p / previous))
      :ARG1 (e / essential
            :domain (s2 / signal-07
                  :ARG0 (a / and
                        :op1 (p2 / protein :name (n / name :op1 "RhoA"))
                        :op2 (p3 / protein :name (n2 / name :op1 "Rac1"))
                        :op3 (p4 / protein :name (n3 / name :op1 "Cdc42"))))
            :purpose (c3 / capable-01
                  :ARG1 (e2 / enzyme :name (n4 / name :op1 "Ras")
                        :ARG0-of (c / cause-01
                              :ARG1 (d2 / disease :wiki "Disease" :name (n5 / name :op1 "Cancer"))))
                  :ARG2 (t / transform-01
                        :ARG1 e2)))
      :ARG1-of (d / describe-01
            :ARG0 (c2 / cite-01
                  :ARG1 (a2 / and :op1 29 :op2 30))))

# ::id a_pmid_2194_3101.205 ::date 2015-05-25T07:48:37 ::annotator SDL-AMR-09 ::preferred
# ::snt In the present study, Caco-2 cells overexpressing mutant KRAS<sup>G12V </sup>(Caco-K), selective activation for Cdc42 was detected (Figure <xref ref-type="fig" rid="F7">7A</xref>).
# ::save-date Sun Jan 17, 2016 ::file a_pmid_2194_3101_205.txt
(d / detect-01
      :ARG1 (a / activate-01
            :ARG1 (p / protein :name (n / name :op1 "Cdc42"))
            :manner (s / selective))
      :location (s2 / study-01
            :ARG1 (o2 / overexpress-01
                  :ARG1 (m / mutate-01 :value "G12V"
                        :ARG1 (g / gene :name (n3 / name :op1 "KRAS")))
                  :location (c / cell-line :name (n2 / name :op1 "Caco-2"))
                  :ARG1-of (m2 / mean-01
                        :ARG2 (c2 / cell-line :name (n4 / name :op1 "Caco-K"))))
            :time (p2 / present))
      :ARG1-of (d2 / describe-01
            :ARG0 (f / figure :mod "7A")))

# ::id a_pmid_2194_3101.206 ::date 2015-05-25T08:03:41 ::annotator SDL-AMR-09 ::preferred
# ::snt The formation of filopodia in these cells, earlier described, was in agreement with the high Cdc42 activity and is illustrated here by staining with antibody against Fascin, a filopodia marker (Figure <xref ref-type="fig" rid="F7">7B</xref>, upper panel).
# ::save-date Mon Dec 21, 2015 ::file a_pmid_2194_3101_206.txt
(a / and
      :op1 (a2 / agree-01
            :ARG1 (f / form-01
                  :ARG1 (f2 / filopodium)
                  :location (c / cell
                        :mod (t / this)))
            :ARG2 (a3 / activity-06
                  :ARG0 (p / protein :name (n / name :op1 "Cdc42"))
                  :ARG1-of (h / high-02)))
      :op2 (i / illustrate-01
            :ARG1 f
            :ARG0-of (s / stain-01
                  :ARG2 (a4 / antibody
                        :ARG0-of (c2 / counter-01
                              :ARG1 (m / marker :name (n2 / name :op1 "Fascin")
                                    :mod (f3 / filopodium)))))
            :medium (h2 / here))
      :ARG1-of (d / describe-01
            :ARG0 (p2 / panel
                  :location (u / upper)
                  :part-of (f4 / figure :mod "7B"))
            :mod (e / early
                  :degree (m3 / more))))

# ::id a_pmid_2194_3101.207 ::date 2015-05-25T08:49:06 ::annotator SDL-AMR-09 ::preferred
# ::snt A large number of relatively short filopodia distributed almost exclusively at the cell periphery was evident in Caco-K cells, while Caco-BR and Caco-H cells formed less but longer structures with a rather polarized shape potentially pointing towards the direction of cell migration (Figure <xref ref-type="fig" rid="F7">7B</xref>, upper panel).
# ::save-date Sun Jan 17, 2016 ::file a_pmid_2194_3101_207.txt
(c / contrast-01
      :ARG1 (e3 / evident
            :domain (f / filopodium
                  :ARG1-of (s / short-07
                        :ARG2-of (r / relative-05))
                  :quant (n2 / number
                        :mod (l2 / large))
                  :ARG1-of (d / distribute-01
                        :location (p6 / periphery
                              :domain (c7 / cell))
                        :ARG0-of (e / exclusive-02
                              :degree (a3 / almost))))
            :location (c2 / cell :name (n / name :op1 "Caco-K")))
      :ARG2 (f2 / form-01
            :ARG0 (a2 / and
                  :op1 (c4 / cell-line :name (n3 / name :op1 "Caco-BR"))
                  :op2 (c5 / cell-line :name (n4 / name :op1 "Caco-H")))
            :ARG1 (s2 / structure
                  :ARG0-of (h / have-03
                        :ARG1 (s4 / shape
                              :ARG1-of (p / polarize-01
                                    :degree (r3 / rather))
                              :ARG0-of (p7 / point-01
                                    :ARG2 (d4 / direction
                                          :direction-of (m2 / migrate-01
                                                :ARG0 (c3 / cell)))
                                    :mod (p8 / potential))))
                  :quant (l4 / less
                        :ARG1-of (c6 / contrast-01
                              :ARG2 (l / long-03
                                    :ARG1 s
                                    :degree (m / more))
                              :compared-to f))))
      :ARG1-of (d3 / describe-01
            :ARG0 (p5 / panel
                  :location (u / upper)
                  :part-of (f3 / figure :mod "7B"))))

# ::id a_pmid_2194_3101.208 ::date 2015-05-25T09:49:02 ::annotator SDL-AMR-09 ::preferred
# ::snt Nevertheless, no changes in Fascin protein expression were recorded in the different cell lines, (Figure <xref ref-type="fig" rid="F7">7B</xref>, lower panel).
# ::save-date Wed Aug 12, 2015 ::file a_pmid_2194_3101_208.txt
(h / have-concession-91
      :ARG2 (r / record-01
            :ARG1 (c / change-01 :polarity -
                  :ARG1 (e / express-03
                        :ARG2 (p / protein :name (n / name :op1 "Fascin"))))
            :location (c2 / cell-line
                  :ARG1-of (d / differ-02)))
      :ARG1-of (d2 / describe-01
            :ARG0 (p2 / panel
                  :ARG1-of (l / low-04
                        :degree (m2 / more))
                  :part-of (f / figure :mod "7B"))))

# ::id a_pmid_2194_3101.209 ::date 2015-05-25T09:58:39 ::annotator SDL-AMR-09 ::preferred
# ::snt Increased migration ability in Caco-BR and Caco-H cells may be indicative for the length and the location of filopodia.
# ::save-date Sun Jan 17, 2016 ::file a_pmid_2194_3101_209.txt
(p / possible-01
      :ARG1 (i / indicate-01
            :ARG0 (i2 / increase-01
                  :ARG1 (p2 / possible-01
                        :ARG1 (m / migrate-01
                              :location (a2 / and
                                    :op1 (c / cell-line :name (n / name :op1 "Caco-BR"))
                                    :op2 (c2 / cell-line :name (n2 / name :op1 "Caco-H"))))))
            :ARG1 (a3 / and
                  :op1 (l / length
                        :mod (f / filopodium))
                  :op2 (l2 / location
                        :location-of f))))

# ::id a_pmid_2194_3101.210 ::date 2015-05-25T10:10:43 ::annotator SDL-AMR-09 ::preferred
# ::snt It has been previously shown that in CHO-K1 cells (Chinese hamster ovary fibroblast- like cells) RhoA expression down-regulates Cdc42 and Rac1 activity in order to regulate membrane protrusions and cell polarity.
# ::save-date Mon Dec 21, 2015 ::file a_pmid_2194_3101_210.txt
(s / show-01
      :ARG1 (d / downregulate-01
            :ARG0 (e / express-03
                  :ARG2 (p2 / protein :name (n3 / name :op1 "RhoA"))
                  :location (c2 / cell-line :name (n6 / name :op1 "CHO-K1")
                        :ARG1-of (m2 / mean-01
                              :ARG2 (f2 / fibroblast
                                    :location (o2 / ovary
                                          :part-of (a5 / animal
                                                :mod (h2 / hamster
                                                      :mod (c5 / country :wiki "China" :name (n / name :op1 "China")))))
                                    :ARG1-of (r3 / resemble-01
                                          :ARG2 (c6 / cell))))))
            :ARG1 (a / activity-06
                  :ARG0 (a2 / and
                        :op1 (p3 / protein :name (n4 / name :op1 "Cdc42"))
                        :op2 (p4 / protein :name (n5 / name :op1 "Rac1"))))
            :purpose (r2 / regulate-01
                  :ARG0 e
                  :ARG1 (a4 / and
                        :op1 (p5 / protrude-01
                              :ARG1 (m / membrane))
                        :op2 (p6 / polarity
                              :mod (c4 / cell)))))
      :time (p / previous))

# ::id a_pmid_2194_3101.211 ::date 2015-05-25T10:11:53 ::annotator SDL-AMR-09 ::preferred
# ::snt In addition, Rac1 activity may down-regulate Cdc42 activity and promote the formation of stabilized rather than transient protrusions [<xref ref-type="bibr" rid="B31">31</xref>].
# ::save-date Mon Dec 21, 2015 ::file a_pmid_2194_3101_211.txt
(a / and
      :op2 (p / possible-01
            :ARG1 (a2 / and
                  :op1 (d2 / downregulate-01
                        :ARG0 (a3 / activity-06
                              :ARG0 (p2 / protein :name (n / name :op1 "Rac1")))
                        :ARG1 (a4 / activity-06
                              :ARG0 (p3 / protein :name (n2 / name :op1 "Cdc42"))))
                  :op2 (p4 / promote-02
                        :ARG1 (f / form-01
                              :ARG1 (p5 / protrude-01
                                    :ARG1-of (s / stabilize-01))
                              :ARG1-of (i / instead-of-91
                                    :ARG2 (p6 / protrude-01
                                          :ARG1-of (t / transient-02)))))))
      :ARG1-of (c / cite-01
            :ARG2 31))

# ::id a_pmid_2194_3101.212 ::date 2015-05-25T10:49:11 ::annotator SDL-AMR-09 ::preferred
# ::snt Indeed, low Cdc42 activity was recorded in Caco-BR and Caco-H cells where RhoA signaling is activated.
# ::save-date Sun Jan 17, 2016 ::file a_pmid_2194_3101_212.txt
(r / record-01
      :ARG1 (a / activity-06
            :ARG0 (p / protein :name (n / name :op1 "Cdc42"))
            :ARG1-of (l / low-04))
      :location (a2 / and
            :op1 (c / cell-line :name (n2 / name :op1 "Caco-BR"))
            :op2 (c2 / cell-line :name (n3 / name :op1 "Caco-H"))
            :location-of (a4 / activate-01
                  :ARG1 (s2 / signal-07
                        :ARG0 (p3 / protein :name (n5 / name :op1 "RhoA")))))
      :mod (i / indeed))

# ::id a_pmid_2194_3101.213 ::date 2015-05-25T11:26:03 ::annotator SDL-AMR-09 ::preferred
# ::snt To explore the role of Cdc42 in mutant KRAS<sup>G12V </sup>induced cell transformation, Caco-2 and Caco-K15 cells were treated with siRNA against this small GTPase.
# ::save-date Sun Jan 17, 2016 ::file a_pmid_2194_3101_213.txt
(h / have-purpose-91
      :ARG1 (t / treat-04
            :ARG1 (a / and
                  :op1 (c / cell-line :name (n2 / name :op1 "Caco-2"))
                  :op2 (c2 / cell-line :name (n3 / name :op1 "Caco-K15")))
            :ARG2 (n7 / nucleic-acid :name (n4 / name :op1 "small" :op2 "interfering" :op3 "RNA"))
            :purpose (d / defend-01
                  :ARG2 n7
                  :ARG3 (e2 / enzyme :name (n5 / name :op1 "GTPase")
                        :mod (s / small))))
      :ARG2 (e / explore-01
            :ARG1 (t2 / transform-01
                  :ARG0 (p / protein :name (n / name :op1 "Cdc42")
                        :domain (r / role))
                  :ARG1 (c3 / cell)
                  :ARG2-of (i / induce-01
                        :ARG0 (m / mutate-01 :value "G12V"
                              :ARG1 (g / gene :name (n6 / name :op1 "KRAS")))))))

# ::id a_pmid_2194_3101.214 ::date 2015-05-25T11:55:26 ::annotator SDL-AMR-09 ::preferred
# ::snt Significant downregulation of Cdc42 at the protein level was observed in both cell lines (Figure <xref ref-type="fig" rid="F7">7C</xref>-upper panel), that caused a significant decrease of cell migration and invasion ability of Caco-K15 and of Caco-2 cells but to a lesser extent (Figure <xref ref-type="fig" rid="F7">7C</xref>-lower panel).
# ::save-date Sun Jan 17, 2016 ::file a_pmid_2194_3101_214.txt
(c / cause-01
      :ARG0 (d / downregulate-01
            :ARG1 (p / protein :name (n / name :op1 "Cdc42"))
            :ARG1-of (s / significant-02)
            :prep-at (l2 / level
                  :mod (p2 / protein))
            :ARG1-of (o / observe-01
                  :location (c2 / cell-line
                        :mod (b / both)))
            :ARG1-of (d2 / describe-01
                  :ARG0 (f / figure :mod "7C"
                        :part-of (p3 / panel
                              :mod (u / upper)))))
      :ARG1 (d3 / decrease-01
            :ARG0 d
            :ARG1 (a / and
                  :op1 (a2 / and
                        :op1 (m3 / migrate-01
                              :ARG0 (c3 / cell-line :name (n2 / name :op1 "Caco-K15")))
                        :op2 (p5 / possible-01
                              :ARG1 (i3 / invade-01
                                    :ARG0 c3))
                        :ARG1-of (c6 / contrast-01
                              :ARG2 a4
                              :mod (e / extent
                                    :degree (l / less))))
                  :op2 (a4 / and
                        :op1 (m4 / migrate-01
                              :ARG0 (c4 / cell-line :name (n3 / name :op1 "Caco-2")))
                        :op2 (i2 / invade-01
                              :ARG0 c4)))
            :ARG2 (s2 / significant-02)
            :ARG1-of (d4 / describe-01
                  :ARG0 (f2 / figure :mod "7C"
                        :part-of (p4 / panel
                              :ARG1-of (l3 / low-04
                                    :degree (m5 / more)))))))

# ::id a_pmid_2194_3101.215 ::date 2015-05-25T11:55:49 ::annotator SDL-AMR-09 ::preferred
# ::snt Depletion of Cdc42 also affected the filopodia formation, when Caco-K cells were treated with siRNA against Cdc42 acquired rounded cell membrane lacking filapodia protrusion suggesting that filopodia formation in Caco-K cells is Cdc42-dependent (Figure <xref ref-type="fig" rid="F7">7D</xref>).
# ::save-date Mon Dec 21, 2015 ::file a_pmid_2194_3101_215.txt
(s / suggest-01
      :ARG0 (a / affect-01
            :ARG0 (d / deplete-01
                  :ARG1 (p / protein :name (n / name :op1 "Cdc42")))
            :ARG1 (f / form-01
                  :ARG1 (f2 / filopodium))
            :mod (a2 / also)
            :condition (a3 / acquire-01
                  :ARG0 (c2 / cell :name (n4 / name :op1 "Caco-K"))
                  :ARG1-of (c3 / condition-01
                        :ARG0 (t / treat-04
                              :ARG1 c2
                              :ARG2 (n2 / nucleic-acid :name (n5 / name :op1 "small" :op2 "interfere" :op3 "RNA"))
                              :ARG0-of (c4 / counter-01
                                    :ARG1 p))
                        :ARG1-of (r2 / result-01
                              :ARG2 (a4 / acquire-01
                                    :ARG0 c2
                                    :ARG1 (m / membrane
                                          :ARG1-of (r / round-04)
                                          :mod (c5 / cell)
                                          :ARG0-of (l / lack-01
                                                :ARG1 (p2 / protrude-01
                                                      :ARG1 (f5 / filopodium)))))))))
      :ARG2 (d2 / depend-01
            :ARG0 (f3 / form-01
                  :ARG1 (f4 / filopodium)
                  :location c2)
            :ARG1 p)
      :ARG1-of (d3 / describe-01
            :ARG0 (f6 / figure :mod "7D")))

# ::id a_pmid_2194_3101.216 ::date 2015-05-26T00:13:52 ::annotator SDL-AMR-09 ::preferred
# ::snt These findings suggest that KRAS<sup>G12V </sup>regulates motility and invasiveness of colon cancer cells through the Cdc42 GTPase.
# ::save-date Sun Jan 3, 2016 ::file a_pmid_2194_3101_216.txt
(s / suggest-01
      :ARG0 (t2 / thing
            :mod (t / this)
            :ARG1-of (f / find-01))
      :ARG1 (r / regulate-01
            :ARG0 (m / mutate-01 :value "G12V"
                  :ARG1 (g / gene :name (n3 / name :op1 "KRAS")))
            :ARG1 (a3 / and
                  :op1 (m2 / motility
                        :mod (c2 / cell
                              :mod (d / disease :name (n / name :op1 "Cancer")
                                    :location (c / colon))))
                  :op2 (i / invade-01
                        :ARG0 c2))
            :manner (p / protein :name (n4 / name :op1 "Cdc42" :op2 "GTPase"))))

# ::id a_pmid_2194_3101.217 ::date 2015-05-25T11:56:55 ::annotator SDL-AMR-09 ::preferred
# ::snt Considering that the PI3K pathway is also a KRAS effector pathway, the possibility of a cross-talk between the PI3K signalling pathway and Cdc42 was explored [<xref ref-type="bibr" rid="B16">16</xref>,<xref ref-type="bibr" rid="B21">21</xref>].
# ::save-date Sun Dec 20, 2015 ::file a_pmid_2194_3101_217.txt
(e / explore-01
      :ARG1 (p / possible-01
            :ARG1 (i / interfere-01
                  :ARG0 (p2 / pathway
                        :ARG1-of (s / signal-07
                              :ARG0 (p3 / pathway :name (n / name :op1 "PI3K"))))
                  :ARG1 (p4 / protein :name (n2 / name :op1 "Cdc42"))))
      :condition (c / consider-01
            :ARG1 (p5 / pathway
                  :mod (e2 / effector
                        :mod (g / gene :name (n3 / name :op1 "KRAS")))
                  :domain p3)
            :mod (a / also))
      :ARG1-of (c2 / cite-01
            :ARG2 (a2 / and :op1 16 :op2 21)))

# ::id a_pmid_2194_3101.218 ::date 2015-05-25T12:30:28 ::annotator SDL-AMR-09 ::preferred
# ::snt Following treatment with wortmanin at the most optimal treatment condition, as retrieved from inhibition of the active PI3K pathway in Caco-H2 cells that show high p-AKT levels (Additional Figure <xref ref-type="supplementary-material" rid="S4">4</xref>), resulted in reduced Cdc42 activity.
# ::save-date Sun Jan 17, 2016 ::file a_pmid_2194_3101_218.txt
(r / result-01
      :ARG1 (f3 / follow-01
            :ARG2 (t / treat-04
                  :ARG2 (w2 / wortmanin))
            :example (i / inhibit-01
                  :ARG1 (p2 / pathway :name (n2 / name :op1 "PI3K")
                        :ARG1-of (a2 / activate-01))
                  :ARG1-of (r3 / retrieve-01)
                  :location (c / cell-line :name (n3 / name :op1 "Caco-H2")
                        :ARG0-of (s / show-01
                              :ARG1 (l / level
                                    :ARG1-of (h / high-02)
                                    :quant-of (e / enzyme :name (n4 / name :op1 "AKT")
                                          :ARG3-of (p3 / phosphorylate-01))))))
            :ARG1-of (d / describe-01
                  :ARG0 (f2 / figure :mod 4
                        :mod (a4 / additional)))
            :condition (t3 / treat-04
                  :mod (o2 / optimal
                        :degree (m3 / most))))
      :ARG2 (r2 / reduce-01
            :ARG0 f3
            :ARG1 (a / activity-06
                  :ARG0 (p / protein :name (n / name :op1 "Cdc42")))))

# ::id a_pmid_2194_3101.219 ::date 2015-05-26T04:30:03 ::annotator SDL-AMR-09 ::preferred
# ::snt This illustrates how Cdc42 activation in response to the KRAS<sup>G12V</sup>-PI3K signalling pathway can be potentially essential for Cdc42-dependent cell migration and invasion properties (Figure <xref ref-type="fig" rid="F7">7E</xref>).
# ::save-date Tue Jun 16, 2015 ::file a_pmid_2194_3101_219.txt
(i / illustrate-01
      :ARG0 (t / this)
      :ARG1 (t2 / thing
            :manner-of (p4 / possible-01
                  :ARG1 (e2 / essential
                        :domain (a2 / activate-01
                              :ARG1 (p6 / protein :name (n3 / name :op1 "Cdc42"))
                              :ARG2-of (r2 / respond-01
                                    :ARG1 (p7 / pathway :name (n4 / name :op1 "KRASG12V-PI3K")
                                          :ARG1-of (s2 / signal-07))))
                        :purpose (a3 / and
                              :op1 (m / migrate-01
                                    :ARG0 (c / cell
                                          :ARG0-of (d3 / depend-01
                                                :ARG1 p6)))
                              :op2 (p8 / property
                                    :mod (i2 / invade-01
                                          :ARG0 c))))))
      :ARG1-of (d2 / describe-01
            :ARG0 (f / figure :mod "7E")))

# ::id a_pmid_2194_3101.220 ::date 2015-05-25T13:27:22 ::annotator SDL-AMR-09 ::preferred
# ::snt HRAS<sup>G12V </sup>induces high cell migration and invasion properties mediated by Rac1 associated with acquired EMT
# ::save-date Wed Feb 10, 2016 ::file a_pmid_2194_3101_220.txt
(i / induce-01
      :ARG0 (m / mutate-01 :value "G12V"
            :ARG1 (g / gene :name (n / name :op1 "HRAS")))
      :ARG2 (a3 / and
            :op1 (m2 / migrate-01
                  :ARG0 (c2 / cell)
                  :ARG1-of (h / high-02))
            :op2 (p3 / property
                  :mod (i2 / invade-01
                        :ARG1-of (m3 / mediate-01
                              :ARG0 (a4 / associate-01
                                    :ARG1 (p2 / protein :name (n4 / name :op1 "Rac1"))
                                    :ARG2 (e / event :wiki "Epithelial–mesenchymal_transition" :name (n3 / name :op1 "epithelial−mesenchymal" :op2 "transition")
                                          :ARG1-of (a6 / acquire-01))))))))

# ::id a_pmid_2194_3101.221 ::date 2015-05-26T00:33:47 ::annotator SDL-AMR-09 ::preferred
# ::snt Activation of Rac1, another RAS effector protein, was found slightly increased in Caco-H2 cells with EMT characteristics [<xref ref-type="bibr" rid="B15">15</xref>,<xref ref-type="bibr" rid="B25">25</xref>] (Figure <xref ref-type="fig" rid="F8">8A</xref>).
# ::save-date Sun Jan 17, 2016 ::file a_pmid_2194_3101_221.txt
(f / find-01
      :ARG1 (i3 / increase-01
            :ARG1 (a / activate-01
                  :ARG1 (p / protein :name (n2 / name :op1 "Rac1")
                        :mod (a6 / another)
                        :domain (e2 / effector
                              :mod (p2 / protein-family :name (n3 / name :op1 "Ras")))))
            :ARG2 (s2 / slight)
            :location (c / cell-line :name (n5 / name :op1 "Caco-H2")
                  :ARG1-of (c6 / characteristic-02
                        :ARG2 (e / event :name (n / name :op1 "epithelial−mesenchymal" :op2 "transition")))))
      :ARG1-of (d / describe-01
            :ARG0 (a4 / and
                  :op1 (p3 / publication
                        :ARG1-of (c4 / cite-01
                              :ARG2 (a5 / and :op1 15 :op2 25)))
                  :op2 (f2 / figure :mod "8A"))))

# ::id a_pmid_2194_3101.222 ::date 2015-05-26T11:23:06 ::annotator SDL-AMR-09 ::preferred
# ::snt Activation of Rac1 in Caco-H2 cells is in agreement with previous studies that correlate Rac1 with EMT and the inhibition of E-cadherin in mammary epithelial and pancreatic carcinoma cells respectively [<xref ref-type="bibr" rid="B32">32</xref>].
# ::save-date Sun Jan 17, 2016 ::file a_pmid_2194_3101_222.txt
(a / agree-01
      :ARG0 (a2 / activate-01
            :ARG1 (p / protein :name (n / name :op1 "Rac1")
                  :location (c / cell-line :name (n2 / name :op1 "Caco-H2"))))
      :ARG2 (s / study-01
            :ARG0-of (c2 / correlate-01
                  :ARG1 p
                  :ARG2 (a3 / and
                        :op1 (e3 / event :name (n3 / name :op1 "epithelial−mesenchymal" :op2 "transition"))
                        :op2 (i / inhibit-01
                              :ARG1 (p2 / protein :name (n4 / name :op1 "E-cadherin")
                                    :location (a4 / and
                                          :op1 (c3 / cell
                                                :mod (e / epithelium)
                                                :mod (m / mammary))
                                          :op2 (c4 / cell
                                                :mod (p3 / pancreas)
                                                :mod (c5 / carcinoma))
                                          :mod (r / respective))))))
            :time (p5 / previous))
      :ARG1-of (d / describe-01
            :ARG0 (p4 / publication
                  :ARG1-of (c6 / cite-01
                        :ARG2 32))))

# ::id a_pmid_2194_3101.223 ::date 2015-05-26T11:48:03 ::annotator SDL-AMR-09 ::preferred
# ::snt In contrast, a weak effect on Rac1 GTPase was recorded in Caco-BR cells (Figure <xref ref-type="fig" rid="F8">8A</xref>) and could be explained by the known antagonistic effect that exists between RhoA and Rac1 [<xref ref-type="bibr" rid="B33">33</xref>].
# ::save-date Sun Jan 17, 2016 ::file a_pmid_2194_3101_223.txt
(c / contrast-01
      :ARG2 (a / and
            :op1 (r / record-01
                  :ARG1 (a2 / affect-01
                        :ARG1 (p2 / protein :name (n / name :op1 "Rac1" :op2 "GTPase"))
                        :ARG1-of (w / weak-02))
                  :location (c2 / cell-line :name (n2 / name :op1 "Caco-BR"))
                  :ARG1-of (d / describe-01
                        :ARG0 (f / figure :mod "8A")))
            :op2 (p / possible-01
                  :ARG1 (e / explain-01
                        :ARG0 (a3 / affect-01
                              :ARG2 (a4 / antagonize-02
                                    :ARG1 (p3 / protein :name (n3 / name :op1 "RhoA"))
                                    :ARG2 (p4 / protein :name (n4 / name :op1 "Rac1")))
                              :ARG1-of (k / know-01))
                        :ARG1 a2)))
      :ARG1-of (d2 / describe-01
            :ARG0 (p5 / publication
                  :ARG1-of (c3 / cite-01
                        :ARG2 33))))

# ::id a_pmid_2194_3101.224 ::date 2015-05-26T12:34:23 ::annotator SDL-AMR-09 ::preferred
# ::snt As described earlier, HRAS<sup>G12V</sup>-transfected Caco-2 cells (Caco-H2) have undergone EMT, followed by the dramatic reduction of E-cadherin expression [<xref ref-type="bibr" rid="B16">16</xref>].
# ::save-date Sun Jan 17, 2016 ::file a_pmid_2194_3101_224.txt
(u / undergo-28
      :ARG1 (c / cell-line :name (n / name :op1 "Caco-2")
            :ARG1-of (t / transfect-01
                  :ARG2 (e3 / enzyme :name (n2 / name :op1 "HRAS")
                        :ARG2-of (m / mutate-01 :value "G12V"))))
      :ARG2 (e4 / event :name (n3 / name :op1 "epithelial−mesenchymal" :op2 "transition"))
      :ARG2-of (f / follow-01
            :ARG1 (r / reduce-01
                  :ARG1 (e / express-03
                        :ARG2 (p2 / protein :name (n4 / name :op1 "E-cadherin")))
                  :manner (d / dramatic)))
      :ARG1-of (d2 / describe-01
            :time (e2 / early
                  :degree (m2 / more)))
      :ARG1-of (d3 / describe-01
            :ARG0 (p3 / publication
                  :ARG1-of (c2 / cite-01
                        :ARG2 16))))

# ::id a_pmid_2194_3101.225 ::date 2015-05-26T12:58:03 ::annotator SDL-AMR-09 ::preferred
# ::snt Following PI3K pathway depletion using the specific inhibitor wortmanin at the most optimal treatment condition (Additional Figure <xref ref-type="supplementary-material" rid="S4">4</xref>), Rac1 activity was successfully inhibited only in Caco-2 cells, leaving Caco-H2 cells unaffected (Figure <xref ref-type="fig" rid="F8">8B</xref>, upper panel).
# ::save-date Sun Jan 17, 2016 ::file a_pmid_2194_3101_225.txt
(i / inhibit-01
      :ARG1 (a / activity-06
            :ARG0 (p / protein :name (n / name :op1 "Rac1")
                  :ARG0-of (l / leave-13
                        :ARG1 (a2 / affect-01 :polarity -
                              :ARG1 (c2 / cell-line :name (n3 / name :op1 "Caco-H2"))))))
      :ARG1-of (s / succeed-01)
      :location (c / cell-line :name (n2 / name :op1 "Caco-2")
            :mod (o / only))
      :ARG2-of (f / follow-01
            :ARG1 (d / deplete-01
                  :ARG1 (p2 / pathway :name (n4 / name :op1 "PI3K"))
                  :ARG0-of (u / use-01
                        :ARG1 (s2 / small-molecule :name (n5 / name :op1 "wortmanin")
                              :ARG0-of (i2 / inhibit-01)
                              :ARG1-of (s3 / specific-02))
                        :condition (t2 / treat-04
                              :mod (o2 / optimum
                                    :degree (m2 / most))))
                  :ARG1-of (d2 / describe-01
                        :ARG0 (f2 / figure :mod 4
                              :ARG1-of (a3 / add-02)))))
      :ARG1-of (d3 / describe-01
            :ARG0 (f3 / figure :mod "8B"
                  :location (p3 / panel
                        :mod (u2 / upper)))))

# ::id a_pmid_2194_3101.226 ::date 2015-05-26T13:36:04 ::annotator SDL-AMR-09 ::preferred
# ::snt Notably, under the same treatment conditions RhoA activity was found to be slightly increased, suggesting an involvement of the PI3K pathway in RhoA regulation (Figure <xref ref-type="fig" rid="F8">8B</xref>, lower panel).
# ::save-date Mon Dec 21, 2015 ::file a_pmid_2194_3101_226.txt
(f / find-02
      :ARG1 (i / increase-01
            :ARG1 (a / activity-06
                  :ARG0 (p / protein :wiki "RHOA"
                        :name (n / name :op1 "RhoA")))
            :ARG2 (s / slight)
            :ARG0-of (s3 / suggest-01
                  :ARG1 (i2 / involve-01
                        :ARG1 (p2 / pathway :wiki -
                              :name (n2 / name :op1 "PI3K"))
                        :ARG2 (r / regulate-01
                              :ARG1 p))))
      :condition (t / treat-04
            :ARG1-of (s2 / same-01))
      :ARG1-of (d / describe-01
            :ARG0 (f2 / figure :mod "8B"
                  :location (p3 / panel
                        :ARG1-of (l / low-04
                              :degree (m / more)))))
      :ARG1-of (n3 / notable-04))

# ::id a_pmid_2194_3101.227 ::date 2015-05-26T13:50:25 ::annotator SDL-AMR-09 ::preferred
# ::snt It is therefore concluded that in Caco-H2 cells, HRAS<sup>G12V </sup>deregulates PI3K-dependent activation of Rac1 as well as mediates RhoA inhibition.
# ::save-date Sun Jan 17, 2016 ::file a_pmid_2194_3101_227.txt
(c2 / cause-01
      :ARG1 (c / conclude-01
            :ARG1 (a2 / and
                  :op1 (d / deregulate-01
                        :ARG0 (e2 / enzyme :name (n / name :op1 "HRAS")
                              :ARG2-of (m / mutate-01 :value "G12V"))
                        :ARG1 (a / activate-01
                              :ARG1 (p2 / protein :name (n2 / name :op1 "Rac1")
                                    :ARG0-of (d2 / depend-01
                                          :ARG1 (e / enzyme :name (n3 / name :op1 "PI3K")))))
                        :location (c3 / cell-line :name (n5 / name :op1 "Caco-H2")))
                  :op2 (m2 / mediate-01
                        :ARG0 e2
                        :ARG1 (i / inhibit-01
                              :ARG1 (p3 / protein :name (n4 / name :op1 "RhoA")))))))

# ::id a_pmid_2194_3101.228 ::date 2015-05-26T14:11:12 ::annotator SDL-AMR-09 ::preferred
# ::snt To further explore the involvement of Rac1 activation in the transforming ability of HRAS<sup>G12V </sup>in Caco-2 cells, pharmacological inhibition of Rac1 was established using the selective inhibitor NSC23766 (Figure <xref ref-type="fig" rid="F8">8C</xref>) [<xref ref-type="bibr" rid="B34">34</xref>].
# ::save-date Sun Jan 17, 2016 ::file a_pmid_2194_3101_228.txt
(e / establish-01
      :ARG1 (i / inhibit-01
            :ARG1 (p / protein :name (n / name :op1 "Rac1"))
            :mod (p2 / pharmacologic))
      :ARG2-of (u / use-01
            :ARG1 (s2 / small-molecule :name (n2 / name :op1 "NSC23766")
                  :ARG0-of (i2 / inhibit-01)
                  :mod (s / selective)))
      :purpose (e2 / explore-01
            :ARG1 (i3 / involve-01
                  :ARG1 (a / activate-01
                        :ARG1 p)
                  :ARG2 (c / capable-01
                        :ARG1 (e3 / enzyme :name (n3 / name :op1 "HRAS")
                              :ARG2-of (m2 / mutate-01 :value "G12V"))
                        :ARG2 (t / transform-01
                              :ARG0 e3
                              :location (c2 / cell-line :name (n4 / name :op1 "Caco-2")))))
            :degree (f / further))
      :ARG1-of (d / describe-01
            :ARG0 (a2 / and
                  :op1 (f2 / figure :mod "8C")
                  :op2 (p3 / publication
                        :ARG1-of (c3 / cite-01
                              :ARG2 34)))))

# ::id a_pmid_2194_3101.229 ::date 2015-05-26T14:52:17 ::annotator SDL-AMR-09 ::preferred
# ::snt Inhibition of Rac1 not only managed to suppress Rac1 activation but also to abolish cell migration and invasion properties in a dose dependent manner (Figure <xref ref-type="fig" rid="F8">8D</xref>), indicating the critical role of Rac1 in EMT cell properties of Caco-H cells.
# ::save-date Sun Jan 17, 2016 ::file a_pmid_2194_3101_229.txt
(m / manage-01
      :ARG0 (i / inhibit-01
            :ARG1 (p / protein :name (n / name :op1 "Rac1")))
      :ARG1 (a / and
            :op1 (s / suppress-01
                  :ARG0 i
                  :ARG1 (a2 / activate-01
                        :ARG1 p))
            :op2 (a3 / abolish-01
                  :ARG0 i
                  :ARG1 (a4 / and
                        :op1 (p2 / property
                              :mod (c / cell
                                    :ARG0-of (m2 / migrate-01)))
                        :op2 (p3 / property
                              :mod (c5 / cell
                                    :ARG0-of (i2 / invade-01))))
                  :mod (a5 / also)
                  :manner (d / depend-01
                        :ARG1 (d2 / dose))))
      :ARG1-of (d3 / describe-01
            :ARG0 (f / figure :mod "8D"))
      :ARG0-of (i3 / indicate-01
            :ARG1 (r / role
                  :ARG1-of (c2 / critical-02
                        :ARG2 (p4 / property
                              :poss (c3 / cell-line :name (n3 / name :op1 "Caco-H"))
                              :mod (e / event :name (n2 / name :op1 "epithelial−mesenchymal" :op2 "transition"))))
                  :poss p)))

# ::id a_pmid_2194_3101.230 ::date 2015-05-26T15:02:00 ::annotator SDL-AMR-09 ::preferred
# ::snt TGFβ-1 co-operates with <i>BRAF<sup>V600E </sup></i>and <i>KRAS<sup>G12V </sup></i>oncogenes to provide Caco-2 cells with enhanced transformation properties
# ::save-date Sun Jan 17, 2016 ::file a_pmid_2194_3101_230.txt
(c / cooperate-01
      :ARG0 (p / protein :name (n / name :op1 "TGFβ-1"))
      :ARG1 (a / and
            :op1 (g / gene :name (n2 / name :op1 "BRAF")
                  :ARG2-of (m / mutate-01 :value "V600E"))
            :op2 (g2 / gene :name (n3 / name :op1 "KRAS")
                  :ARG2-of (m2 / mutate-01 :value "G12V"))
            :ARG0-of (c2 / cause-01
                  :ARG1 (d / disease :wiki "Cancer" :name (n5 / name :op1 "cancer"))))
      :ARG2 (p2 / provide-01
            :ARG0 p
            :ARG1 (p3 / property
                  :ARG0-of (t / transform-01)
                  :ARG1-of (e / enhance-01))
            :ARG2 (c3 / cell-line :name (n4 / name :op1 "Caco-2"))))

# ::id a_pmid_2194_3101.231 ::date 2015-05-26T15:37:43 ::annotator SDL-AMR-09 ::preferred
# ::snt Since <i>BRAF<sup>V600E </sup></i>and <i>KRAS<sup>G12V </sup></i>oncogenes did not manage to fully transform Caco-2 cells nor induced an EMT phenotype, as <i>HRAS<sup>G12V </sup></i>did, it was further investigated whether co-operation of oncogene-growth factor can produce synergistic effect.
# ::save-date Wed Feb 24, 2016 ::file a_pmid_2194_3101_231.txt
(i / investigate-01
      :ARG1 (p2 / possible-01
            :ARG1 (p / produce-01 :mode interrogative
                  :ARG0 (c / cooperate-01
                        :ARG0 (g4 / growth-factor
                              :ARG0-of (c2 / cause-01
                                    :ARG1 (d / disease :wiki "Cancer" :name (n7 / name :op1 "cancer")))))
                  :ARG1 (a / affect-01
                        :ARG2 (s / synergize-01))))
      :degree (f / further)
      :ARG1-of (c4 / cause-01
            :ARG0 (a2 / and
                  :op1 (m / manage-01 :polarity -
                        :ARG0 (a3 / and
                              :op1 (g / gene :name (n2 / name :op1 "BRAF")
                                    :ARG2-of (m2 / mutate-01 :value "V600E"))
                              :op2 (g2 / gene :name (n3 / name :op1 "KRAS")
                                    :ARG2-of (m3 / mutate-01 :value "G12V"))
                              :ARG0-of c2)
                        :ARG1 (t / transform-01
                              :ARG0 a3
                              :ARG1 (c3 / cell-line :name (n4 / name :op1 "Caco-2"))
                              :degree (f2 / full)))
                  :op2 (i2 / induce-01 :polarity -
                        :ARG0 a3
                        :ARG2 (p4 / phenotype
                              :mod (e / event :name (n5 / name :op1 "epithelial−mesenchymal" :op2 "transition"))))
                  :ARG1-of (c8 / contrast-01
                        :ARG2 (g3 / gene :name (n6 / name :op1 "HRAS")
                              :ARG2-of (m4 / mutate-01 :value "G12V"))))))

# ::id a_pmid_2194_3101.232 ::date 2015-05-26T15:59:38 ::annotator SDL-AMR-09 ::preferred
# ::snt The previously established oncogenic models of BRAF<sup>V600E </sup>and KRAS<sup>G12V </sup>along with the parental Caco-2 cells were treated with Transforming Growth Factor beta-1 (TGFβ-1) for 14 days.
# ::save-date Sun Jan 17, 2016 ::file a_pmid_2194_3101_232.txt
(t / treat-04
      :ARG1 (a / and
            :op1 (m / model
                  :poss (g / gene :name (n2 / name :op1 "BRAF")
                        :ARG2-of (m2 / mutate-01 :value "V600E"))
                  :ARG0-of (c / cause-01
                        :ARG1 (d2 / disease :wiki "Cancer" :name (n5 / name :op1 "cancer")))
                  :ARG1-of (e / establish-01
                        :time (p3 / previous)))
            :op2 (m3 / model
                  :poss (g2 / gene :name (n3 / name :op1 "KRAS")
                        :ARG2-of (m4 / mutate-01 :value "G12V"))
                  :ARG1-of e
                  :ARG0-of c)
            :op3 (c2 / cell-line :name (n4 / name :op1 "Caco-2")
                  :mod (p2 / parent)))
      :ARG2 (p / protein :name (n / name :op1 "Transforming" :op2 "Growth" :op3 "Factor" :op4 "beta-1"))
      :duration (t2 / temporal-quantity :quant 14
            :unit (d / day)))

# ::id a_pmid_2194_3101.233 ::date 2015-05-26T16:10:44 ::annotator SDL-AMR-09 ::preferred
# ::snt Staining with phalloidin revealed significant morphological changes in TGFβ-1 treated Caco-K15 cells that were not observed in Caco-2 cells following treatment with TGFβ-1, while no morphological changes were recorded in TGFβ-1 treated Caco-BR13 cells (Figure <xref ref-type="fig" rid="F9">9A</xref>).
# ::save-date Fri Feb 12, 2016 ::file a_pmid_2194_3101_233.txt
(c4 / contrast-01
      :ARG1 (r / reveal-01
            :ARG0 (s / stain-01
                  :ARG2 (s3 / small-molecule :name (n / name :op1 "phalloidin")))
            :ARG1 (c / change-01
                  :ARG1 (c2 / cell-line :name (n2 / name :op1 "Caco-K15")
                        :ARG1-of (t / treat-04
                              :ARG2 (p / protein :name (n3 / name :op1 "TGFβ-1"))))
                  :mod (m2 / morphological)
                  :ARG1-of (o / observe-01 :polarity -
                        :location (c3 / cell-line :name (n4 / name :op1 "Caco-2"))
                        :ARG1-of (f / follow-01
                              :ARG2 t))
                  :ARG1-of (s2 / significant-02)))
      :ARG2 (r2 / record-01
            :ARG1 (c5 / change-01 :polarity -
                  :ARG1 (c6 / cell-line :name (n5 / name :op1 "Caco-BR13")
                        :ARG1-of t)
                  :mod m2))
      :ARG1-of (d / describe-01
            :ARG0 (f2 / figure :mod "9A")))

# ::id a_pmid_2194_3101.234 ::date 2015-05-27T09:31:42 ::annotator SDL-AMR-09 ::preferred
# ::snt Protein analysis for E-cadherin, in fractionized soluble (intracellular) and insoluble (bound-membrane E-cadherin) extracts indicated a reduction of E-cadherin in the insoluble fraction in Caco-2 and Caco-K15 cells to a greater extend (Figure <xref ref-type="fig" rid="F9">9B</xref>, upper panel).
# ::save-date Sun Jan 17, 2016 ::file a_pmid_2194_3101_234.txt
(i / indicate-01
      :ARG0 (a / analyze-01
            :ARG1 (a2 / and
                  :op1 (e / extract
                        :mod (s / soluble)
                        :location (c / cell))
                  :op2 (e2 / extract
                        :mod (s2 / soluble :polarity -)
                        :ARG1-of (m / mean-01
                              :ARG2 (p2 / protein :name (n / name :op1 "E-cadherin")
                                    :mod (m2 / membrane
                                          :ARG1-of (b / bind-01)))))
                  :ARG1-of (f / fraction-01))
            :mod (p / protein)
            :purpose (p3 / protein :name (n2 / name :op1 "E-cadherin")))
      :ARG1 (r / reduce-01
            :ARG1 p3
            :ARG2 (g / great
                  :degree (m3 / more))
            :location (a3 / and
                  :op1 (f2 / fraction
                        :part-of (c2 / cell-line :name (n3 / name :op1 "Caco-2"))
                        :mod s2)
                  :op2 (f3 / fraction
                        :part-of (c3 / cell-line :name (n4 / name :op1 "Caco-K15"))
                        :mod s2)))
      :ARG1-of (d / describe-01
            :ARG0 (f4 / figure :mod "9B"
                  :location (p4 / panel
                        :mod (u / upper)))))

# ::id a_pmid_2194_3101.235 ::date 2015-05-27T11:07:03 ::annotator SDL-AMR-09 ::preferred
# ::snt Interestingly, even though levels of E-cadherin were not altered in Caco-BR13 cells, confocal images clearly presented disrupted cell-cell contacts and discontinuous staining which weakens cell junctions allowing cell migration (Figure <xref ref-type="fig" rid="F9">9B</xref>, lower panel-arrows).
# ::save-date Sun Jan 17, 2016 ::file a_pmid_2194_3101_235.txt
(p / present-102
      :ARG0 (i / image
            :mod (c / confocal))
      :ARG1 (a / and
            :op1 (c2 / contact-01
                  :ARG0 (c3 / cell)
                  :ARG1 c3
                  :ARG1-of (d / disrupt-01))
            :op2 (s / stain-01
                  :ARG1-of (c4 / continue-01 :polarity -)))
      :ARG0-of (w / weaken-01
            :ARG1 (j / junction
                  :mod c3))
      :ARG0-of (a2 / allow-01
            :ARG1 (m / migrate-01
                  :ARG0 c3))
      :manner (i2 / interesting)
      :ARG1-of (d2 / describe-01
            :ARG0 (f / figure :mod "9B"
                  :location (p3 / panel-arrow
                        :ARG1-of (l2 / low-04
                              :degree (m2 / more)))))
      :ARG1-of (c5 / clear-06)
      :concession (a3 / alter-01 :polarity -
                  :ARG1 (l / level
                        :quant-of (p2 / protein :name (n / name :op1 "E-cadherin")))
                  :location (c6 / cell-line :name (n2 / name :op1 "Caco-BR13"))))

# ::id a_pmid_2194_3101.236 ::date 2015-05-27T11:29:02 ::annotator SDL-AMR-09 ::preferred
# ::snt Altered localization of E-cadherin is an important mechanism contributing to cell metastasis [<xref ref-type="bibr" rid="B35">35</xref>].
# ::save-date Mon Jun 1, 2015 ::file a_pmid_2194_3101_236.txt
(m / mechanism
      :mod (i / important)
      :ARG0-of (c / contribute-01
            :ARG2 (m2 / metastasize-101
                  :ARG1 (c2 / cell)))
      :domain (l / localize-01
            :ARG1 (p / protein :name (n / name :op1 "E-cadherin"))
            :ARG1-of (a / alter-01))
      :ARG1-of (d / describe-01
            :ARG0 (p2 / publication
                  :ARG1-of (c3 / cite-01
                        :ARG2 35))))

# ::id a_pmid_2194_3101.237 ::date 2015-05-27T11:42:15 ::annotator SDL-AMR-09 ::preferred
# ::snt TGFβ-1 was also investigated for its potential effect on cell migration and invasion.
# ::save-date Wed May 27, 2015 ::file a_pmid_2194_3101_237.txt
(i / investigate-01
      :ARG1 (p / protein :name (n / name :op1 "TGFβ-1"))
      :ARG2 (a / affect-01
            :ARG0 p
            :ARG1 (a2 / and
                  :op1 (m / migrate-01
                        :ARG0 (c / cell))
                  :op2 (i2 / invade-01
                        :ARG0 c))
            :mod (p2 / potential))
      :mod (a3 / also))

# ::id a_pmid_2194_3101.238 ::date 2015-05-27T11:48:23 ::annotator SDL-AMR-09 ::preferred
# ::snt Treatment with TGFβ-1 increased the capacity of Caco-BR13 cells to invade <i>in vitro</i>, while no effect in the migrating ability of these cells was recorded (Figure <xref ref-type="fig" rid="F9">9C</xref>).
# ::save-date Sun Jan 17, 2016 ::file a_pmid_2194_3101_238.txt
(c / contrast-01
      :ARG1 (i / increase-01
            :ARG0 (t / treat-04
                  :ARG1 c3
                  :ARG2 (p / protein :name (n / name :op1 "TGFβ-1")))
            :ARG1 (c2 / capable-01
                  :ARG1 (c3 / cell-line :name (n2 / name :op1 "Caco-BR13"))
                  :ARG2 (i2 / invade-01
                        :ARG0 c3
                        :manner (i3 / in-vitro))))
      :ARG2 (r / record-01
            :ARG1 (a / affect-01 :polarity -
                  :ARG1 (c4 / capable-01
                        :ARG1 c3
                        :ARG2 (m / migrate-01
                              :ARG0 c3))))
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod "9C")))

# ::id a_pmid_2194_3101.239 ::date 2015-05-27T12:01:33 ::annotator SDL-AMR-09 ::preferred
# ::snt This enhanced invasive capacity of Caco-BR13 cells is independent of their cell proliferation (Additional Figure <xref ref-type="supplementary-material" rid="S5">5</xref>).
# ::save-date Sun Jan 17, 2016 ::file a_pmid_2194_3101_239.txt
(d / depend-01 :polarity -
      :ARG0 (c / capable-01
            :ARG1 (c2 / cell-line :name (n / name :op1 "Caco-BR13"))
            :ARG2 (i / invade-01
                  :ARG0 c2)
            :ARG1-of (e / enhance-01)
            :mod (t / this))
      :ARG1 (p / proliferate-01
            :ARG0 c2)
      :ARG1-of (d2 / describe-01
            :ARG0 (f / figure :mod 5
                  :ARG1-of (a / add-02))))

# ::id a_pmid_2194_3101.240 ::date 2015-05-27T12:06:53 ::annotator SDL-AMR-09 ::preferred
# ::snt In contrast, cell migration and invasion of Caco-2 and Caco-K15 cells were not affected by TGFβ-1 treatment, although KRAS<sup>G12V</sup>-transfected cells acquired a more elongated morphology and slightly downregulated E-cadherin.
# ::save-date Sun Jan 17, 2016 ::file a_pmid_2194_3101_240.txt
(c / contrast-01
      :ARG2 (a / affect-01 :polarity -
            :ARG0 (t3 / treat-04
                  :ARG2 (p3 / protein :name (n6 / name :op1 "TGFβ-1")))
            :ARG1 (a2 / and
                  :op1 (m / migrate-01
                        :ARG0 (a3 / and
                              :op1 (c2 / cell-line :name (n / name :op1 "Caco-2"))
                              :op2 (c3 / cell-line :name (n2 / name :op1 "Caco-K15"))))
                  :op2 (i / invade-01
                        :ARG0 a3))
            :concession (a5 / and
                        :op1 (a6 / acquire-01
                              :ARG0 (c4 / cell
                                    :ARG1-of (t / transfect-01
                                          :ARG2 (e2 / enzyme :name (n4 / name :op1 "KRAS")
                                                :ARG2-of (m2 / mutate-01 :value "G12V"))))
                              :ARG1 (m3 / morphology
                                    :ARG1-of (e / elongate-01
                                          :degree (m4 / more))))
                        :op2 (d / downregulate-01
                              :ARG1 (p2 / protein :name (n5 / name :op1 "E-cadherin"))
                              :ARG2 c4
                              :degree (s / slight)))))

# ::id a_pmid_2194_3101.241 ::date 2015-05-27T12:24:36 ::annotator SDL-AMR-09 ::preferred
# ::snt Taken together, these results suggest that TGFβ-1 can synergise with KRAS<sup>G12V </sup>and BRAF<sup>V600E </sup>oncogenes to provide Caco-2 cells with a more transforming phenotype.
# ::save-date Tue Feb 2, 2016 ::file a_pmid_2194_3101_241.txt
(s / suggest-01
      :ARG0 (t / thing
            :ARG2-of (r / result-01)
            :mod (t2 / this)
            :ARG1-of (t4 / take-01
                  :mod (t5 / together)))
      :ARG1 (p3 / possible-01
            :ARG1 (s2 / synergize-01
                  :ARG0 (g / gene :name (n / name :op1 "TGFβ-1"))
                  :ARG1 (a / and
                        :op1 (g2 / gene :name (n2 / name :op1 "KRAS")
                              :ARG2-of (m / mutate-01 :value "G12V"))
                        :op2 (g3 / gene :name (n3 / name :op1 "BRAF")
                              :ARG2-of (m2 / mutate-01 :value "V600E"))
                        :ARG0-of (c / cause-01
                              :ARG1 (d / disease :wiki "Cancer" :name (n5 / name :op1 "cancer"))))
                  :ARG2 (p / provide-01
                        :ARG0 g
                        :ARG1 (p2 / phenotype
                              :ARG1-of (t3 / transform-01
                                    :degree (m3 / more)))
                        :ARG2 (c2 / cell-line :name (n4 / name :op1 "Caco-2"))))))

# ::id a_pmid_2194_3101.242 ::date 2015-05-27T12:37:09 ::annotator SDL-AMR-09 ::preferred
# ::snt According to previous studies, the mutation in the C-terminal domain of Smad4, D351H, that is present in Caco-2 cells, results in complete Smad4 inactivation [<xref ref-type="bibr" rid="B36">36</xref>].
# ::save-date Sun Jan 17, 2016 ::file a_pmid_2194_3101_242.txt
(r / result-01
      :ARG1 (m / mutate-01 :value "D351H"
            :ARG1 (p / protein-segment :name (n / name :op1 "C-terminus")
                  :part-of (p2 / protein :name (n2 / name :op1 "Smad4")))
            :location (c2 / cell-line :name (n4 / name :op1 "Caco-2")))
      :ARG2 (a / activate-01 :polarity -
            :ARG1-of (c / complete-02))
      :ARG1-of (s / say-01
            :ARG0 (t / thing
                  :time (p3 / previous)
                  :ARG1-of (s2 / study-01)))
      :ARG1-of (d3 / describe-01
            :ARG0 (p4 / publication
                  :ARG1-of (c3 / cite-01
                        :ARG2 36))))

# ::id a_pmid_2194_3101.243 ::date 2015-05-27T13:24:28 ::annotator SDL-AMR-09 ::preferred
# ::snt However, TGFβ-1 has been shown to act through alternative non-Smad pathways, such as Rho GTPases and MAPK [<xref ref-type="bibr" rid="B37">37</xref>-<xref ref-type="bibr" rid="B39">39</xref>].
# ::save-date Mon Jun 1, 2015 ::file a_pmid_2194_3101_243.txt
(h / have-concession-91
      :ARG1 (s / show-01
            :ARG1 (a / act-01
                  :ARG0 (p / protein :name (n / name :op1 "TGFβ-1"))
                  :manner (p7 / pathway :polarity - :name (n5 / name :op1 "Smad")
                        :mod (a3 / alternative)
                        :example (a2 / and
                                    :op1 (p4 / pathway :name (n3 / name :op1 "Rho" :op2 "GTPase"))
                                    :op2 (p5 / pathway :name (n4 / name :op1 "MAPK")))))
            :ARG1-of (d / describe-01
                  :ARG0 (p6 / publication
                        :ARG1-of (c2 / cite-01
                              :ARG2 (v / value-interval :op1 37 :op2 39))))))

# ::id a_pmid_2194_3101.244 ::date 2015-05-27T13:35:14 ::annotator SDL-AMR-09 ::preferred
# ::snt Indeed, following TGFβ-1 treatment, enhanced activity for RhoA GTPase as well as pERK1/2 was recorded in Caco-2, Caco-K15 and Caco-BR13 cells.
# ::save-date Sun Jan 17, 2016 ::file a_pmid_2194_3101_244.txt
(r / record-01
      :ARG1 (a / activity-06
            :ARG0 (a2 / and
                  :op1 (p / pathway :name (n / name :op1 "RhoA" :op2 "GTPase"))
                  :op2 (e2 / enzyme :name (n2 / name :op1 "ERK1/2")
                        :ARG3-of (p3 / phosphorylate-01)))
            :ARG1-of (e / enhance-01))
      :location (a3 / and
            :op1 (c / cell-line :name (n3 / name :op1 "Caco-2"))
            :op2 (c2 / cell-line :name (n4 / name :op1 "Caco-K15"))
            :op3 (c3 / cell-line :name (n5 / name :op1 "Caco-BR13")))
      :ARG1-of (f / follow-01
            :ARG2 (t / treat-04
                  :ARG2 (p2 / protein :name (n6 / name :op1 "TGFβ-1"))))
      :mod (i / indeed))

# ::id a_pmid_2194_3101.245 ::date 2015-05-27T13:46:10 ::annotator SDL-AMR-09 ::preferred
# ::snt Based on these observations other than non-Smad signaling like RhoA GTPase and pERK1/2 pathways can be regulated by TGF-beta, to induce the morphological changes observed in the Caco-2 transformed and parental cells (Figure <xref ref-type="fig" rid="F9">9D</xref>).
# ::save-date Fri Feb 5, 2016 ::file a_pmid_2194_3101_245.txt
(p / possible-01
      :ARG1 (r / regulate-01
            :ARG0 (p2 / protein :name (n / name :op1 "TGF-beta"))
            :ARG1 (p7 / pathway
                  :ARG2-of (e / except-01
                        :ARG1 (p4 / pathway :polarity - :name (n4 / name :op1 "Smad")
                              :ARG0-of (s / signal-07)
                              :example (a2 / and
                                    :op1 (p5 / pathway :name (n5 / name :op1 "RhoA" :op2 "GTPase"))
                                    :op2 (p6 / pathway :name (n6 / name :op1 "pERK1/2"))))))
            :purpose (i / induce-01
                  :ARG0 r
                  :ARG2 (c / change-01
                        :ARG1-of (o / observe-01
                              :location (a / and
                                    :op1 (c2 / cell-line :name (n2 / name :op1 "Caco-2")
                                          :ARG1-of (t / transform-01))
                                    :op2 (c3 / cell-line :name (n3 / name :op1 "Caco-2")
                                          :mod (p3 / parent))))
                        :mod (m / morphological))))
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod "9D"))
      :ARG1-of (b / base-02
            :ARG2 (o2 / observe-01
                  :mod (t2 / this))))

# ::id a_pmid_2256_9000.96 ::date 2015-06-06T02:10:03 ::annotator SDL-AMR-09 ::preferred
# ::snt <i>In-vitro</i> inhibition of cell proliferation by selumetinib treatment in NSCLC and CRC cell lines
# ::save-date Sun Jan 17, 2016 ::file a_pmid_2256_9000_96.txt
(i / inhibit-01
      :ARG0 (t / treat-04
            :ARG2 (s / small-molecule :name (n / name :op1 "selumetinib")))
      :ARG1 (p / proliferate-01
            :ARG0 (c / cell))
      :location (a / and
            :op1 (c2 / cell-line
                  :mod (d / disease :name (n2 / name :op1 "NSCLC")))
            :op2 (c3 / cell-line
                  :mod (d2 / disease :name (n3 / name :op1 "CRC"))))
      :manner (i2 / in-vitro))

# ::id a_pmid_2256_9000.97 ::date 2015-06-06T02:57:48 ::annotator SDL-AMR-09 ::preferred
# ::snt We first evaluated the sensitivity to the selective MEK1/2 inhibitor, selumetinib, in a panel of five NSCLC (GLC82, H460, A549, H1299, Calu3) and six CRC (GEO, HCT15, HCT116, SW480, SW620, LS174T) cell lines by using the MTT assay.
# ::save-date Fri Feb 12, 2016 ::file a_pmid_2256_9000_97.txt
(e / evaluate-01
      :ARG0 (w / we)
      :ARG1 (s / sensitive-03
            :ARG1 (s2 / small-molecule :name (n / name :op1 "selumetinib")
                  :ARG0-of (i / inhibit-01
                        :ARG1 (e2 / enzyme :name (n2 / name :op1 "MEK1/2")))
                  :ARG0-of (s3 / select-01)))
      :mod (f / first)
      :location (p / panel
            :consist-of (a / and
                  :op1 (c / cell-line :quant 5
                        :ARG1-of (m / mean-01
                              :ARG2 (a2 / and
                                    :op1 (c2 / cell-line :name (n4 / name :op1 "GLC82"))
                                    :op2 (c3 / cell-line :name (n5 / name :op1 "H460"))
                                    :op3 (c4 / cell-line :name (n6 / name :op1 "A549"))
                                    :op4 (c5 / cell-line :name (n7 / name :op1 "H1299"))
                                    :op5 (c6 / cell-line :name (n8 / name :op1 "Calu3"))))
                        :mod (d / disease :name (n3 / name :op1 "NSCLC")))
                  :op2 (c7 / cell-line :quant 6
                        :ARG1-of (m2 / mean-01
                              :ARG2 (a3 / and
                                    :op1 (c8 / cell-line :name (n10 / name :op1 "GEO"))
                                    :op2 (c9 / cell-line :name (n11 / name :op1 "HCT15"))
                                    :op3 (c10 / cell-line :name (n12 / name :op1 "HCT116"))
                                    :op4 (c11 / cell-line :name (n13 / name :op1 "SW480"))
                                    :op5 (c12 / cell-line :name (n14 / name :op1 "SW620"))
                                    :op6 (c13 / cell-line :name (n15 / name :op1 "LS174T"))))
                        :mod (d2 / disease :name (n9 / name :op1 "CRC")))))
      :manner (u / use-01
            :ARG0 w
            :ARG1 (a4 / assay-01
                  :instrument (s4 / small-molecule :name (n16 / name :op1 "MTT")))))

# ::id a_pmid_2256_9000.98 ::date 2015-06-06T04:02:40 ::annotator SDL-AMR-09 ::preferred
# ::snt Cancer cells were treated with selumetinib at concentrations ranging from 0.01 to 10 <i>μ</i>ℳ for 48, 72, and 96 h.
# ::save-date Sun Jan 3, 2016 ::file a_pmid_2256_9000_98.txt
(t / treat-04
      :ARG1 (c / cell
            :mod (d / disease :wiki "Cancer" :name (n / name :op1 "cancer")))
      :ARG2 (s / small-molecule :name (n2 / name :op1 "selumetinib")
            :quant (c2 / concentration
                  :ARG1-of (r / range-01
                        :ARG3 (c3 / concentration-quantity :quant 0.01
                              :unit (m2 / micromolar))
                        :ARG4 (c4 / concentration-quantity :quant 10
                              :unit m2))))
      :duration (t2 / temporal-quantity
            :quant (a / and :op1 48 :op2 72 :op3 96)
            :unit (h / hour)))

# ::id a_pmid_2256_9000.99 ::date 2015-06-06T04:15:40 ::annotator SDL-AMR-09 ::preferred
# ::snt As shown in <xref ref-type="fig" rid="fig1">Figure 1</xref>, there was a wide range of sensitivity, with IC<sub>50</sub> values varying between 0.01 and >10 <i>μ</i>ℳ.
# ::save-date Wed Mar 2, 2016 ::file a_pmid_2256_9000_99.txt
(s / sensitive-03
      :ARG1-of (r / range-01
            :ARG1-of (w / wide-02)
            :ARG1-of (m / mean-01
                  :ARG2 (v / vary-01
                        :ARG1 (v2 / value
                              :ARG4-of (h / have-percentage-maximal-inhibitory-concentration-01
                                    :ARG2 50))
                        :ARG3 (c / concentration-quantity :quant 0.01
                              :unit (m2 / micromolar))
                        :ARG4 (m3 / more-than
                              :op1 (c2 / concentration-quantity :quant 10
                                    :unit (m4 / micromolar))))))
      :ARG1-of (s2 / show-01
            :ARG0 (f / figure :mod 1)))

# ::id a_pmid_2256_9000.100 ::date 2015-06-06T07:27:02 ::annotator SDL-AMR-09 ::preferred
# ::snt We classified as sensitive (S) or resistant (R) the cancer cell lines according to selumetinib IC<sub>50</sub> at 96 h ⩽1 or >1 <i>μ</i>ℳ, respectively.
# ::save-date Wed Mar 2, 2016 ::file a_pmid_2256_9000_100.txt
(a / and
      :op1 (c / classify-01
            :ARG0 (w / we)
            :ARG1 (c2 / cell-line
                  :mod (d / disease :wiki "Cancer" :name (n / name :op1 "cancer")))
            :ARG2 (s / sensitive-03
                  :ARG0 c2)
            :condition (h2 / have-percentage-maximal-inhibitory-concentration-01
                  :ARG1 (s2 / small-molecule :name (n3 / name :op1 "selumetinib"))
                  :ARG2 50
                  :ARG4 (o / or
                        :op1 (c3 / concentration-quantity :quant 1
                              :unit (m3 / micromolar))
                        :op2 (l / less-than
                              :op1 (c4 / concentration-quantity :quant 1
                                    :unit (m / micromolar))))
                  :time (a2 / after
                        :op1 (t2 / temporal-quantity :quant 96
                              :unit (h / hour)))))
      :op2 (c5 / classify-01
            :ARG0 w
            :ARG1 c2
            :ARG2 (r / resist-01
                  :ARG0 c2)
            :condition (h3 / have-percentage-maximal-inhibitory-concentration-01
                  :ARG1 s2
                  :ARG2 50
                  :ARG4 (m2 / more-than
                        :op1 (c7 / concentration-quantity :quant 1
                              :unit (m4 / micromolar)))
                  :time a2)))

# ::id a_pmid_2256_9000.101 ::date 2015-06-06T08:00:48 ::annotator SDL-AMR-09 ::preferred
# ::snt This concentration was chosen based on the data from phase I studies, which indicated that 1 <i>μ</i>ℳ was within the average plasma concentrations of selumetinib achieved in patients at the maximum tolerated dose for this agent (<xref ref-type="bibr" rid="bib2">Adjei <i>et al</i>, 2008</xref>).
# ::save-date Mon Dec 21, 2015 ::file a_pmid_2256_9000_101.txt
(c / choose-01
      :ARG1 (c2 / concentrate-02
            :mod (t / this))
      :ARG1-of (b / base-02
            :ARG2 (d / data
                  :source (s / study-01
                        :mod (p / phase
                              :ord (o / ordinal-entity :value 1)))
                  :ARG0-of (i / indicate-01
                        :ARG1 (i2 / include-01
                              :ARG1 (c3 / concentration-quantity :quant 1
                                    :unit (m / micromolar))
                              :ARG2 (c4 / concentrate-02
                                    :ARG1 (s2 / small-molecule :name (n / name :op1 "selumetinib"))
                                    :location (p2 / plasma)
                                    :ARG1-of (a / average-04)
                                    :ARG1-of (a2 / achieve-01
                                          :location (p3 / patient))
                                    :quant (d2 / dose
                                          :quant (m2 / maximum)
                                          :ARG1-of (t2 / tolerate-01
                                                :topic (a3 / agent
                                                      :mod (t3 / this)))))))))
      :ARG1-of (d3 / describe-01
            :ARG0 (p4 / publication-91
                  :ARG0 (a4 / and
                        :op1 (p5 / person :name (n2 / name :op1 "Adjei"))
                        :op2 (p6 / person
                              :mod (o2 / other)))
                  :time (d4 / date-entity :year 2008))))

# ::id a_pmid_2256_9000.102 ::date 2015-06-06T10:23:23 ::annotator SDL-AMR-09 ::preferred
# ::snt Overall, 67% (four of six) CRC and 40% (two of five) NSCLC cell lines had a selumetinib IC<sub>50</sub> of ⩽1 <i>μ</i>ℳ.
# ::save-date Sun Jan 17, 2016 ::file a_pmid_2256_9000_102.txt
(h / have-03
      :ARG0 (a / and
            :op1 (c / cell-line :quant 4
                  :ARG1-of (i / include-91
                        :ARG2 (c2 / cell-line :quant 6
                              :mod (d2 / disease :name (n / name :op1 "CRC")))
                        :ARG3 (p / percentage-entity :value 67)))
            :op2 (c3 / cell-line :quant 2
                  :ARG1-of (i2 / include-91
                        :ARG2 (c4 / cell-line :quant 5
                              :mod (d / disease :name (n3 / name :op1 "NSCLC")))
                        :ARG3 (p2 / percentage-entity :value 40))))
      :ARG1 (s / small-molecule :name (n6 / name :op1 "selumetinib")
            :ARG1-of (h2 / have-percentage-maximal-inhibitory-concentration-01
                  :ARG2 50
                  :ARG4 (c5 / concentration-quantity
                        :quant (o / or
                              :op1 (l / less-than :op1 1) :op2 1)
                        :unit (m / micromolar))))
      :mod (o2 / overall))

# ::id a_pmid_2256_9000.103 ::date 2015-06-06T10:49:58 ::annotator SDL-AMR-09 ::preferred
# ::snt In particular, among the sensitive cancer cell lines there were four, two NSCLC (Calu3 and H1299) and two CRC (HCT116 and SW620), extremely sensitive to selumetinib with an IC<sub>50</sub> of ⩽0.01 <i>μ</i>ℳ (<xref ref-type="fig" rid="fig1">Figure 1A and B</xref>).
# ::save-date Tue Mar 1, 2016 ::file a_pmid_2256_9000_103.txt
(i / include-91
      :ARG1 (c / cell-line :quant 4
            :mod (d / disease :wiki "Cancer" :name (n / name :op1 "cancer"))
            :ARG0-of (s / sensitive-03)
            :ARG2-of (i2 / include-91
                  :ARG1 (a / and
                        :op1 (c2 / cell-line :quant 2
                              :ARG1-of (m / mean-01
                                    :ARG2 (a2 / and
                                          :op1 (c3 / cell-line :name (n3 / name :op1 "Calu3"))
                                          :op2 (c4 / cell-line :name (n4 / name :op1 "H1299"))))
                              :mod (d3 / disease :name (n2 / name :op1 "NSCLC")))
                        :op2 (c5 / cell-line :quant 2
                              :ARG1-of (m2 / mean-01
                                    :ARG2 (a3 / and
                                          :op1 (c6 / cell-line :name (n6 / name :op1 "HCT116"))
                                          :op2 (c7 / cell-line :name (n7 / name :op1 "SW620"))))
                              :mod (d4 / disease :name (n5 / name :op1 "CRC")))
                        :ARG0-of (s2 / sensitive-03
                              :ARG1 (s3 / small-molecule :name (n8 / name :op1 "selumetinib")
                                    :ARG1-of (h / have-percentage-maximal-inhibitory-concentration-01
                                          :ARG2 50
                                          :ARG4 (c8 / concentration-quantity
                                                :quant (o / or
                                                      :op1 (l / less-than :op1 0.01) :op2 0.01)
                                                :unit (m3 / micromolar))))
                              :degree (e2 / extreme)))))
      :ARG2 (c9 / cell-line
            :mod d
            :ARG0-of s)
      :mod (p / particular)
      :ARG1-of (d2 / describe-01
            :ARG0 (a4 / and
                  :op1 (f / figure :mod "1A")
                  :op2 (f2 / figure :mod "1B"))))

# ::id a_pmid_2256_9000.104 ::date 2015-06-06T11:20:38 ::annotator SDL-AMR-09 ::preferred
# ::snt To investigate the mechanisms underlying the different sensitivities to the drug, we conducted experiments on a group of four cancer cell lines representing both selumetinib-sensitive (HCT116 and Calu3) and selumetinib-resistant (HCT15 and H460) models.
# ::save-date Wed Jun 10, 2015 ::file a_pmid_2256_9000_104.txt
(c / conduct-01
      :ARG0 (w / we)
      :ARG1 (e / experiment-01
            :ARG0 w
            :ARG1 (g / group
                  :consist-of (c2 / cell-line :quant 4
                        :mod (d / disease :wiki "Cancer"
                              :name (n / name :op1 "cancer"))
                        :ARG0-of (r / represent-01
                              :ARG1 (a / and
                                    :op1 (m / model-01
                                          :ARG0-of (s / sensitive-03
                                                :ARG1 (s2 / small-molecule
                                                      :name (n2 / name :op1 "selumetinib")))
                                          :ARG1-of (m2 / mean-01
                                                :ARG2 (a2 / and
                                                      :op1 (c3 / cell-line
                                                            :name (n3 / name :op1 "HCT116"))
                                                      :op2 (c4 / cell-line
                                                            :name (n4 / name :op1 "Calu3")))))
                                    :op2 (m3 / model-01
                                          :ARG0-of (r2 / resist-01
                                                :ARG1 s2)
                                          :ARG1-of (m4 / mean-01
                                                :ARG2 (a3 / and
                                                      :op1 (c5 / cell-line
                                                            :name (n5 / name :op1 "HCT15"))
                                                      :op2 (c6 / cell-line
                                                            :name (n6 / name :op1 "H460"))))))))))
      :purpose (i / investigate-01
            :ARG0 w
            :ARG1 (m5 / mechanism
                  :ARG0-of (u / underlie-01
                        :ARG1 (s3 / sensitive-03
                              :ARG1 (d2 / drug)
                              :ARG1-of (d3 / differ-02))))))

# ::id a_pmid_2256_9000.105 ::date 2015-06-06T11:32:55 ::annotator SDL-AMR-09 ::preferred
# ::snt Effects of selumetinib treatment on cell-cycle distribution in NSCLC and CRC cell lines
# ::save-date Sun Jan 17, 2016 ::file a_pmid_2256_9000_105.txt
(a / affect-01
      :ARG0 (t / treat-04
            :ARG2 (s / small-molecule :name (n / name :op1 "selumetinib")))
      :ARG1 (d / distribute-01
            :ARG1 (c / cycle-02
                  :ARG1 (c2 / cell)))
      :location (a2 / and
            :op1 (c3 / cell-line
                  :mod (d2 / disease :name (n2 / name :op1 "NSCLC")))
            :op2 (c4 / cell-line
                  :mod (d3 / disease :name (n3 / name :op1 "CRC")))))

# ::id a_pmid_2256_9000.106 ::date 2015-06-06T12:29:55 ::annotator SDL-AMR-09 ::preferred
# ::snt We conducted flow cytometric analysis to compare the cell-cycle distribution following treatment of the selumetinib-sensitive HCT116 and Calu3 cancer cell lines and of the selumetinib-resistant HCT15 and H460 cancer cell lines.
# ::save-date Mon Jan 4, 2016 ::file a_pmid_2256_9000_106.txt
(c / conduct-01
      :ARG0 (w / we)
      :ARG1 (a / analyze-01
            :manner (c9 / cytometry
                  :mod (f2 / flow)))
      :purpose (c2 / compare-01
            :ARG0 w
            :ARG1 (d / distribute-01
                  :ARG1 (c3 / cycle-02
                        :ARG1 (c4 / cell))
                  :ARG1-of (f / follow-01
                        :ARG2 (t / treat-04
                              :ARG1 (a2 / and
                                    :op1 (a3 / and
                                          :op1 (c5 / cell-line :name (n2 / name :op1 "HCT116"))
                                          :op2 (c6 / cell-line :name (n3 / name :op1 "Calu3"))
                                          :mod (d2 / disease :wiki "Cancer" :name (n4 / name :op1 "cancer"))
                                          :ARG0-of (s / sensitive-03
                                                :ARG1 (s2 / small-molecule :name (n5 / name :op1 "selumetinib"))))
                                    :op2 (a4 / and
                                          :op1 (c7 / cell-line :name (n6 / name :op1 "HCT15"))
                                          :op2 (c8 / cell-line :name (n7 / name :op1 "H460"))
                                          :mod d2
                                          :ARG0-of (r / resist-01
                                                :ARG1 s2))))))))

# ::id a_pmid_2256_9000.107 ::date 2015-06-06T12:47:55 ::annotator SDL-AMR-09 ::preferred
# ::snt Cancer cells were treated with selumetinib at the IC<sub>50</sub> values for inhibition of cell proliferation for 24, 48, and 72 h.
# ::save-date Tue Dec 15, 2015 ::file a_pmid_2256_9000_107.txt
(t / treat-04
      :ARG1 (c / cell
            :mod (d / disease :wiki "Cancer" :name (n / name :op1 "cancer")))
      :ARG2 (s / small-molecule :name (n2 / name :op1 "selumetinib")
            :ARG1-of (h2 / have-percentage-maximal-inhibitory-concentration-01
                  :ARG2 50
                  :ARG3 (i / inhibit-01
                        :ARG1 (p / proliferate-01
                              :ARG0 (c2 / cell)))))
      :duration (t3 / temporal-quantity
            :quant (a / and :op1 24 :op2 48 :op3 72)
            :unit (h / hour)))

# ::id a_pmid_2256_9000.108 ::date 2015-06-06T12:54:12 ::annotator SDL-AMR-09 ::preferred
# ::snt Twenty-four hours selumetinib treatment caused cell accumulation in the G1 phase and concomitant reduction in the S phase as compared with controls in selumetinib-sensitive cancer cell lines (<xref ref-type="fig" rid="fig2">Figure 2A</xref>).
# ::save-date Wed Jun 10, 2015 ::file a_pmid_2256_9000_108.txt
(c / cause-01
      :ARG0 (t / treat-04
            :ARG2 (s / small-molecule
                  :name (n / name :op1 "selumetinib"))
            :duration (t2 / temporal-quantity :quant 24
                  :unit (h / hour)))
      :ARG1 (a / and
            :op1 (a2 / accumulate-01
                  :ARG1 (c2 / cell)
                  :time (p / phase
                        :name (n2 / name :op1 "G1")))
            :op2 (r / reduce-01
                  :ARG1 c2
                  :mod (c3 / concomitant)
                  :time (p2 / phase
                        :name (n3 / name :op1 "S")))
            :compared-to (m / molecular-physical-entity
                  :ARG2-of (c4 / control-01)
                  :location (c5 / cell-line
                        :mod (d / disease :wiki "Cancer"
                              :name (n4 / name :op1 "cancer"))
                        :ARG0-of (s2 / sensitive-03
                              :ARG1 s))))
      :ARG1-of (d2 / describe-01
            :ARG0 (f / figure :mod "2A")))

# ::id a_pmid_2256_9000.109 ::date 2015-06-06T13:04:44 ::annotator SDL-AMR-09 ::preferred
# ::snt The arrest in the G1 phase was significantly increased with longer (48 and 72 h) treatment with selumetinib in both HCT116 and Calu3 cells.
# ::save-date Tue Aug 4, 2015 ::file a_pmid_2256_9000_109.txt
(i / increase-01
      :ARG1 (a / arrest-02
            :time (p / phase :name (n / name :op1 "G1")))
      :ARG2 (s / significant-02)
      :instrument (t / treat-04
            :ARG2 (s2 / small-molecule :name (n2 / name :op1 "selumetinib"))
            :ARG1-of (l / long-03
                  :degree (m / more)
                  :ARG1-of (m2 / mean-01
                        :ARG2 (a4 / and
                              :op1 (t2 / temporal-quantity :quant 48
                                    :unit (h / hour))
                              :op2 (t3 / temporal-quantity :quant 72
                                    :unit (h2 / hour))))))
      :location (a3 / and
            :op1 (c / cell-line :name (n3 / name :op1 "HCT116"))
            :op2 (c2 / cell-line :name (n4 / name :op1 "Calu3"))))

# ::id a_pmid_2256_9000.110 ::date 2015-06-06T13:11:29 ::annotator SDL-AMR-09 ::preferred
# ::snt This effect was also paralleled by a time-dependent reduction in the S phase in both selumetinib-sensitive cancer cell lines (<xref ref-type="fig" rid="fig2">Figure 2A</xref>).
# ::save-date Wed Jun 10, 2015 ::file a_pmid_2256_9000_110.txt
(p / parallel-01
      :ARG0 (a / affect-01
            :mod (t / this))
      :ARG1 (r / reduce-01
            :ARG0-of (d / depend-01
                  :ARG1 (t2 / time))
            :time (p2 / phase
                  :name (n / name :op1 "S"))
            :location (c / cell-line
                  :mod (d2 / disease :wiki "Cancer"
                        :name (n2 / name :op1 "cancer"))
                  :ARG0-of (s / sensitive-03
                        :ARG1 (s2 / small-molecule
                              :name (n3 / name :op1 "selumetinib")))
                  :mod (b / both)))
      :mod (a2 / also)
      :ARG1-of (d3 / describe-01
            :ARG0 (f / figure :mod "2A")))

# ::id a_pmid_2256_9000.111 ::date 2015-06-06T13:17:31 ::annotator SDL-AMR-09 ::preferred
# ::snt In contrast, no effect was observed on cell-cycle distribution in the two selumetinib-resistant HCT15 and H460 cells (<xref ref-type="fig" rid="fig2">Figure 2A</xref>).
# ::save-date Mon Dec 21, 2015 ::file a_pmid_2256_9000_111.txt
(c / contrast-01
      :ARG2 (o / observe-01
            :ARG1 (a / affect-01 :polarity -
                  :ARG1 (d / distribute-01
                        :ARG1 (c2 / cycle-02
                              :ARG1 (c3 / cell))))
            :location (a2 / and :quant 2
                  :op1 (c4 / cell-line :name (n / name :op1 "HCT15"))
                  :op2 (c5 / cell-line :name (n2 / name :op1 "H460"))
                  :ARG0-of (r / resist-01
                        :ARG1 (s / small-molecule :name (n3 / name :op1 "selumetinib")))))
      :ARG1-of (d2 / describe-01
            :ARG0 (f / figure :mod "2A")))

# ::id a_pmid_2256_9000.112 ::date 2015-06-06T13:34:03 ::annotator SDL-AMR-09 ::preferred
# ::snt These results were supported also by <xref ref-type="bibr" rid="bib18">Garon <i>et al</i> (2010)</xref>, in which the block in G1 phase inducted by selumetinib is evident only in sensitive cell lines.
# ::save-date Wed Jun 10, 2015 ::file a_pmid_2256_9000_112.txt
(s / support-01
      :ARG0 (p / publication-91
            :ARG0 (a / and
                  :op1 (p2 / person :name (n / name :op1 "Garon"))
                  :op2 (p3 / person
                        :mod (o / other)))
            :time (d / date-entity :year 2010)
            :location-of (e / evident
                  :domain (b / block-01
                        :time (p4 / phase :name (n2 / name :op1 "G1"))
                        :ARG2-of (i / induce-01
                              :ARG0 (s2 / small-molecule :name (n3 / name :op1 "selumetinib"))))
                  :location (c / cell-line
                        :ARG0-of (s3 / sensitive-03)
                        :mod (o2 / only))))
      :ARG1 (t / thing
            :ARG2-of (r / result-01)
            :mod (t2 / this))
      :mod (a2 / also))

# ::id a_pmid_2256_9000.113 ::date 2015-06-06T13:44:19 ::annotator SDL-AMR-09 ::preferred
# ::snt Effects of selumetinib treatment on the induction of apoptosis in NSCLC and CRC cell lines
# ::save-date Sun Jan 17, 2016 ::file a_pmid_2256_9000_113.txt
(a / affect-01
      :ARG0 (t / treat-04
            :ARG2 (s / small-molecule :name (n / name :op1 "selumetinib")))
      :ARG1 (i / induce-01
            :ARG2 (a2 / apoptosis))
      :location (a3 / and
            :op1 (c / cell-line
                  :mod (d / disease :name (n2 / name :op1 "NSCLC")))
            :op2 (c2 / cell-line
                  :mod (d2 / disease :name (n3 / name :op1 "CRC")))))

# ::id a_pmid_2256_9000.114 ::date 2015-06-06T13:49:46 ::annotator SDL-AMR-09 ::preferred
# ::snt Several preclinical models have demonstrated that selumetinib act as a cytotoxic drug rather than cytostatic by inducing proapoptotic activity (<xref ref-type="bibr" rid="bib23">Huynh <i>et al</i>, 2007a</xref>; <xref ref-type="bibr" rid="bib24">Huynh <i>et al</i>, 2007b</xref>; <xref ref-type="bibr" rid="bib29">Meng <i>et al</i>, 2009</xref>; <xref ref-type="bibr" rid="bib28">Meng <i>et al</i>, 2010</xref>).
# ::save-date Sun Jan 3, 2016 ::file a_pmid_2256_9000_114.txt
(d / demonstrate-01
      :ARG0 (m / model-01
            :mod (p / preclinical)
            :quant (s / several))
      :ARG1 (a / act-01
            :ARG0 (s2 / small-molecule :name (n / name :op1 "selumetinib"))
            :ARG1 (d2 / drug
                  :mod (c / cytotoxic)
                  :ARG1-of (i / instead-of-91
                        :ARG2 (d3 / drug
                              :mod (c2 / cytostatic))))
            :manner (i2 / induce-01
                  :ARG2 (a2 / activity-06
                        :ARG0-of (f / favor-01
                              :ARG1 (a3 / apoptosis)))))
      :ARG1-of (d4 / describe-01
            :ARG0 (a4 / and
                  :op1 (p2 / publication-91
                        :ARG0 (a5 / and
                              :op1 (p3 / person :name (n2 / name :op1 "Huynh"))
                              :op2 (p4 / person
                                    :mod (o / other)))
                        :time (d5 / date-entity :year 2007))
                  :op2 (p5 / publication-91
                        :ARG0 a5
                        :time d5)
                  :op3 (p6 / publication-91
                        :ARG0 (a6 / and
                              :op1 (p7 / person :name (n3 / name :op1 "Meng"))
                              :op2 p4)
                        :time (d6 / date-entity :year 2009))
                  :op4 (p8 / publication-91
                        :ARG0 a6
                        :time (d7 / date-entity :year 2010)))))

# ::id a_pmid_2256_9000.115 ::date 2015-06-06T14:15:55 ::annotator SDL-AMR-09 ::preferred
# ::snt To confirm this effect, the induction of apoptosis was evaluated using an FACS-based assay for Annexin V and PI staining.
# ::save-date Fri Jan 15, 2016 ::file a_pmid_2256_9000_115.txt
(e / evaluate-01
      :ARG1 (i / induce-01
            :ARG2 (a / apoptosis))
      :manner (u / use-01
            :ARG1 (a2 / assay-01
                  :ARG1-of (b / base-02
                        :ARG2 (t / thing :name (n / name :op1 "FACS"))))
            :purpose (s / stain-01
                  :ARG1 (a3 / and
                        :op1 (p / protein :name (n2 / name :op1 "Annexin" :op2 "V"))
                        :op2 (s2 / small-molecule :name (n3 / name :op1 "PI")))))
      :purpose (c / confirm-01
            :ARG1 (a4 / affect-01
                  :mod (t2 / this))))

# ::id a_pmid_2256_9000.116 ::date 2015-06-06T14:37:57 ::annotator SDL-AMR-09 ::preferred
# ::snt After 24 h of selumetinib treatment, a significant induction of apoptosis was detected in the sensitive HCT116 and Calu3 cancer cell lines, which was maximal following 72 h of treatment (<xref ref-type="fig" rid="fig2">Figure 2B</xref>).
# ::save-date Fri Dec 18, 2015 ::file a_pmid_2256_9000_116.txt
(d / detect-01
      :ARG1 (i / induce-01
            :ARG2 (a / apoptosis)
            :ARG1-of (s / significant-02)
            :mod (m / maximal)
            :ARG1-of (f / follow-01
                  :ARG2 (t / treat-04
                        :ARG2 (s2 / small-molecule :name (n / name :op1 "selumetinib"))
                        :duration (t2 / temporal-quantity :quant 72
                              :unit (h / hour)))))
      :location (a2 / and
            :op1 (c / cell-line :name (n2 / name :op1 "HCT116"))
            :op2 (c2 / cell-line :name (n3 / name :op1 "Calu3"))
            :ARG0-of (s3 / sensitive-03)
            :mod (d2 / disease :wiki "Cancer" :name (n4 / name :op1 "cancer")))
      :time (a3 / after
            :op1 (t3 / treat-04
                  :ARG2 s2
                  :duration (t4 / temporal-quantity :quant 24
                        :unit h)))
      :ARG1-of (d3 / describe-01
            :ARG0 (f2 / figure :mod "2B")))

# ::id a_pmid_2256_9000.117 ::date 2015-06-06T14:49:33 ::annotator SDL-AMR-09 ::preferred
# ::snt Moreover, apoptosis was not detectable following treatment with selumetinib in the two resistant HCT15 and H460 cancer cell lines (<xref ref-type="fig" rid="fig2">Figure 2B</xref>).
# ::save-date Wed Jun 10, 2015 ::file a_pmid_2256_9000_117.txt
(a / and
      :op2 (p / possible-01 :polarity -
            :ARG1 (d / detect-01
                  :ARG1 (a2 / apoptosis)
                  :location (a3 / and :quant 2
                        :op1 (c / cell-line
                              :name (n / name :op1 "HCT15"))
                        :op2 (c2 / cell-line
                              :name (n2 / name :op1 "H460"))
                        :ARG0-of (r / resist-01)
                        :mod (d2 / disease :wiki "Cancer"
                              :name (n3 / name :op1 "cancer"))))
            :ARG1-of (f / follow-01
                  :ARG2 (t / treat-04
                        :ARG2 (s / small-molecule
                              :name (n4 / name :op1 "selumetinib")))))
      :ARG1-of (d3 / describe-01
            :ARG0 (f2 / figure :mod "2B")))

# ::id a_pmid_2256_9000.118 ::date 2015-06-06T14:55:43 ::annotator SDL-AMR-09 ::preferred
# ::snt Effects of selumetinib treatment on intracellular signalling in NSCLC and CRC cell lines
# ::save-date Sun Jan 17, 2016 ::file a_pmid_2256_9000_118.txt
(a / affect-01
      :ARG0 (t / treat-04
            :ARG2 (s / small-molecule :name (n / name :op1 "selumetinib")))
      :ARG1 (s2 / signal-07
            :mod (i / intracellular))
      :location (a2 / and
            :op1 (c / cell-line
                  :mod (d / disease :name (n2 / name :op1 "NSCLC")))
            :op2 (c2 / cell-line
                  :mod (d2 / disease :name (n3 / name :op1 "CRC")))))

# ::id a_pmid_2256_9000.119 ::date 2015-06-06T14:59:49 ::annotator SDL-AMR-09 ::preferred
# ::snt To assess the effects of selumetinib treatment on key intracellular downstream signalling pathways, western blots were performed to assess total and phosphorylated EGFR and downstream effectors (total MEK1/2, phospho-MEK1/2, total MAPK, phospho-MAPK, total AKT, phospho-AKT, total 4EBP1, and phosho-4EBP1).
# ::save-date Sun Jan 17, 2016 ::file a_pmid_2256_9000_119.txt
(p / perform-01
      :ARG1 (i2 / immunoblot-01)
      :purpose (a / assess-01
            :ARG1 (a2 / and
                  :op1 (e / enzyme :name (n2 / name :op1 "EGFR")
                        :mod (t2 / total-01))
                  :op2 (e2 / enzyme :name (n3 / name :op1 "EGFR")
                        :ARG3-of (p2 / phosphorylate-01))
                  :op3 (e3 / effector
                        :location (d / downstream)
                        :ARG1-of (m / mean-01
                              :ARG2 (a3 / and
                                    :op1 (e4 / enzyme :name (n4 / name :op1 "MEK1/2")
                                          :mod t2)
                                    :op2 (e5 / enzyme :name (n5 / name :op1 "MEK1/2")
                                          :ARG3-of p2)
                                    :op3 (e6 / enzyme :name (n6 / name :op1 "MAPK")
                                          :mod t2)
                                    :op4 (e7 / enzyme :name (n7 / name :op1 "MAPK")
                                          :ARG3-of p2)
                                    :op5 (e8 / enzyme :name (n8 / name :op1 "AKT")
                                          :mod t2)
                                    :op6 (e9 / enzyme :name (n9 / name :op1 "AKT")
                                          :ARG3-of p2)
                                    :op7 (p3 / protein :name (n10 / name :op1 "4EBP1")
                                          :mod t2)
                                    :op8 (p4 / protein :name (n11 / name :op1 "4EBP1")
                                          :ARG3-of p2))))))
      :purpose (a4 / assess-01
            :ARG1 (a5 / affect-01
                  :ARG0 (t3 / treat-04
                        :ARG2 (s / small-molecule :name (n12 / name :op1 "selumetinib")))
                  :ARG1 (p5 / pathway
                        :ARG0-of (s2 / signal-07
                              :direction (d2 / downstream))
                        :mod (i / intracellular)
                        :ARG1-of (k / key-02)))))

# ::id a_pmid_2256_9000.120 ::date 2015-06-07T05:13:52 ::annotator SDL-AMR-09 ::preferred
# ::snt Cancer cells were evaluated at baseline and at different time points after treatment with selumetinib at 0.05 <i>μ</i>ℳ.
# ::save-date Tue Dec 15, 2015 ::file a_pmid_2256_9000_120.txt
(e / evaluate-01
      :ARG1 (c / cell
            :mod (d / disease :wiki "Cancer" :name (n / name :op1 "cancer")))
      :manner (a / and
            :op1 (b / baseline)
            :op2 (p / point
                  :mod (t / time)
                  :ARG1-of (d2 / differ-02)))
      :time (a2 / after
            :op1 (t2 / treat-04
                  :ARG2 (s / small-molecule :name (n2 / name :op1 "selumetinib")
                        :quant (c2 / concentration-quantity :quant 0.05
                              :unit (m / micromolar))))))

# ::id a_pmid_2256_9000.121 ::date 2015-06-07T05:28:29 ::annotator SDL-AMR-09 ::preferred
# ::snt No change in total and phosphorylated EGFR expression was observed in both selumetinib-sensitive and selumetinib-resistant cancer cell lines (<xref ref-type="fig" rid="fig3">Figure 3A–D</xref>).
# ::save-date Thu Jun 11, 2015 ::file a_pmid_2256_9000_121.txt
(o / observe-01
      :ARG1 (c / change-01 :polarity -
            :ARG1 (e / express-03
                  :ARG2 (a / and
                        :op1 (e2 / enzyme
                              :name (n / name :op1 "EGFR")
                              :mod (t / total-01))
                        :op2 (e3 / enzyme
                              :name (n2 / name :op1 "EGFR")
                              :ARG3-of (p / phosphorylate-01)))))
      :location (a2 / and
            :op1 (c2 / cell-line
                  :ARG0-of (s / sensitive-03
                        :ARG1 (s2 / small-molecule
                              :name (n3 / name :op1 "selumetinib"))))
            :op2 (c3 / cell-line
                  :ARG0-of (r / resist-01
                        :ARG1 s2))
            :mod (d / disease :wiki "Cancer"
                  :name (n4 / name :op1 "cancer")))
      :ARG1-of (d2 / describe-01
            :ARG0 (a3 / and
                  :op1 (f / figure :mod "3A")
                  :op2 (f2 / figure :mod "3B")
                  :op3 (f3 / figure :mod "3C")
                  :op4 (f4 / figure :mod "3D"))))

# ::id a_pmid_2256_9000.122 ::date 2015-06-07T05:38:40 ::annotator SDL-AMR-09 ::preferred
# ::snt Treatment with selumetinib caused a time-dependent inhibition in phospho-MEK1/2 with a complete signal suppression within 60 or 15 min of treatment in HCT116 and Calu3 cells, respectively (<xref ref-type="fig" rid="fig3">Figure 3A and B</xref>).
# ::save-date Sun Jan 17, 2016 ::file a_pmid_2256_9000_122.txt
(c / cause-01
      :ARG0 (t / treat-04
            :ARG2 (s / small-molecule :name (n / name :op1 "selumetinib")))
      :ARG1 (a4 / and
            :op1 (i / inhibit-01
                  :ARG0-of (d / depend-01
                        :ARG1 (t2 / time)))
            :op2 (s2 / suppress-01
                  :ARG1 (s3 / signal-07)
                  :degree (c2 / complete-01)
                  :time (a / after
                        :op1 (t3 / treat-04
                              :ARG2 s
                              :quant (u / up-to
                                    :op1 (t4 / temporal-quantity :quant 60
                                          :unit (m / minute)))))
                  :location (c3 / cell-line :name (n2 / name :op1 "HCT116")))
            :op3 (s4 / suppress-01
                  :ARG1 s3
                  :degree c2
                  :time (a2 / after
                        :op1 (t5 / treat-04
                              :ARG2 s)
                        :quant (u2 / up-to
                              :op1 (t6 / temporal-quantity :quant 15
                                    :unit m)))
                  :location (c4 / cell-line :name (n3 / name :op1 "Calu3"))))
      :location (e / enzyme :name (n4 / name :op1 "MEK1/2")
            :ARG3-of (p / phosphorylate-01))
      :ARG1-of (d2 / describe-01
            :ARG0 (a3 / and
                  :op1 (f / figure :mod "3A")
                  :op2 (f2 / figure :mod "3B"))))

# ::id a_pmid_2256_9000.123 ::date 2015-06-07T05:58:59 ::annotator SDL-AMR-09 ::preferred
# ::snt This inhibition was sustained for 24 h of selumetinib treatment in both cancer cell lines.
# ::save-date Wed Jun 10, 2015 ::file a_pmid_2256_9000_123.txt
(s / sustain-01
      :ARG1 (i / inhibit-01
            :mod (t / this))
      :duration (t2 / treat-04
            :ARG2 (s2 / small-molecule
                  :name (n / name :op1 "selumetinib"))
            :duration (t3 / temporal-quantity :quant 24
                  :unit (h / hour)))
      :location (c / cell-line
            :mod (d / disease :wiki "Cancer"
                  :name (n2 / name :op1 "cancer"))
            :mod (b / both)))

# ::id a_pmid_2256_9000.124 ::date 2015-06-07T06:03:58 ::annotator SDL-AMR-09 ::preferred
# ::snt In contrast, MEK1/2 inhibition of protein phosphorylation was less effective with only a slight reduction in pospho-MEK1/2 in the two selumetinib-resistant HCT15 and H460 cancer cell lines (<xref ref-type="fig" rid="fig3">Figure 3C and D</xref>).
# ::save-date Thu Jun 11, 2015 ::file a_pmid_2256_9000_124.txt
(c / contrast-01
      :ARG2 (e / effective-04
            :ARG0 (i / inhibit-01
                  :ARG0 (e3 / enzyme
                        :name (n6 / name :op1 "MEK1/2"))
                  :ARG1 (p2 / phosphorylate-01
                        :ARG1 (p3 / protein)))
            :ARG1 (r / reduce-01
                  :ARG1 (e2 / enzyme
                        :name (n / name :op1 "MEK1/2")
                        :ARG3-of (p / phosphorylate-01))
                  :ARG2 (s / slight)
                  :mod (o / only)
                  :location (a / and :quant 2
                        :op1 (c2 / cell-line
                              :name (n2 / name :op1 "HCT15"))
                        :op2 (c3 / cell-line
                              :name (n3 / name :op1 "H460"))
                        :mod (d / disease :wiki "Cancer"
                              :name (n4 / name :op1 "cancer"))
                        :ARG0-of (r2 / resist-01
                              :ARG1 (s2 / small-molecule
                                    :name (n5 / name :op1 "selumetinib")))))
            :degree (l / less))
      :ARG1-of (d2 / describe-01
            :ARG0 (a2 / and
                  :op1 (f / figure :mod "3C")
                  :op2 (f2 / figure :mod "3D"))))

# ::id a_pmid_2256_9000.125 ::date 2015-06-07T06:11:15 ::annotator SDL-AMR-09 ::preferred
# ::snt Moreover, MAPK phosphorylation was completely blocked following selumetinib treatment in HCT116 and Calu3.
# ::save-date Sun Jan 17, 2016 ::file a_pmid_2256_9000_125.txt
(a / and
      :op2 (b / block-01
            :ARG1 (p / phosphorylate-01
                  :ARG1 (e / enzyme :name (n / name :op1 "MAPK")))
            :degree (c / complete-01)
            :ARG1-of (f / follow-01
                  :ARG2 (t / treat-04
                        :ARG2 (s / small-molecule :name (n2 / name :op1 "selumetinib"))))
            :location (a2 / and
                  :op1 (c2 / cell-line :name (n3 / name :op1 "HCT116"))
                  :op2 (c3 / cell-line :name (n4 / name :op1 "Calu3")))))

# ::id a_pmid_2256_9000.126 ::date 2015-06-07T06:20:52 ::annotator SDL-AMR-09 ::preferred
# ::snt In contrast, in the two selumetinib-resistant HCT15 and H460 cells MAPK phosphorylation was only reduced but never completely abrogated (<xref ref-type="fig" rid="fig3">Figure 3C and D</xref>).
# ::save-date Sun Jan 17, 2016 ::file a_pmid_2256_9000_126.txt
(c / contrast-01
      :ARG2 (c2 / contrast-01
            :ARG1 (r / reduce-01
                  :ARG1 (p / phosphorylate-01
                        :ARG1 (e / enzyme :name (n / name :op1 "MAPK")))
                  :mod (o / only))
            :ARG2 (a2 / abrogate-01
                  :ARG1 p
                  :degree (c3 / complete-01)
                  :time (e2 / ever :polarity -))
            :location (a / and :quant 2
                  :op1 (c4 / cell-line :name (n2 / name :op1 "HCT15"))
                  :op2 (c5 / cell-line :name (n3 / name :op1 "H460"))
                  :ARG0-of (r2 / resist-01
                        :ARG1 (s / small-molecule :name (n4 / name :op1 "selumetinib")))))
      :ARG1-of (d / describe-01
            :ARG0 (a3 / and
                  :op1 (f / figure :mod "3C")
                  :op2 (f2 / figure :mod "3D"))))

# ::id a_pmid_2256_9000.127 ::date 2015-06-03T05:45:27 ::annotator SDL-AMR-09 ::preferred
# ::snt We next assessed the levels of AKT, phosphor-AKT, 4EBP1 and poshospho-4EBP1, which are downstream effectors of the PI3 kinase (PI3K) pathway.
# ::save-date Thu Jun 11, 2015 ::file a_pmid_2256_9000_127.txt
(a / assess-01
      :ARG0 (w / we)
      :ARG1 (a2 / and
            :op1 (l / level
                  :quant-of (e / enzyme :name (n2 / name :op1 "AKT")))
            :op2 (l2 / level
                  :quant-of (e2 / enzyme :name (n3 / name :op1 "AKT")
                        :ARG3-of (p / phosphorylate-01)))
            :op3 (l3 / level
                  :quant-of (p2 / protein :name (n4 / name :op1 "4EBP1")))
            :op4 (l4 / level
                  :quant-of (p3 / protein :name (n5 / name :op1 "4EBP1")
                        :ARG3-of p)))
      :time (n / next)
      :ARG0-of (a3 / affect-01
            :ARG1 (p5 / pathway :name (n6 / name :op1 "PI3" :op2 "kinase"))
            :mod (d / downstream)))

# ::id a_pmid_2256_9000.128 ::date 2015-06-03T12:50:47 ::annotator SDL-AMR-09 ::preferred
# ::snt Previous reports have suggested that resistance to selumetinib treatment in CRC and NSCLC cell lines was associated with baseline increased PI3K signalling (<xref ref-type="bibr" rid="bib7">Balmanno <i>et al</i>, 2009</xref>).
# ::save-date Sun Jan 17, 2016 ::file a_pmid_2256_9000_128.txt
(s / suggest-01
      :ARG0 (t / thing
            :ARG1-of (r / report-01)
            :time (p / previous))
      :ARG1 (a2 / associate-01
            :ARG1 (r2 / resist-01
                  :ARG1 (t2 / treat-04
                        :ARG2 (s4 / small-molecule :name (n5 / name :op1 "selumetinib")))
                  :location (a / and
                        :op1 (c / cell-line
                              :mod (d4 / disease :name (n / name :op1 "CRC")))
                        :op2 (c2 / cell-line
                              :mod (d3 / disease :name (n2 / name :op1 "NSCLC")))))
            :ARG2 (s3 / signal-07
                  :ARG0 (p2 / pathway :name (n3 / name :op1 "PI3K")
                        :ARG1-of (i / increase-01)
                        :mod (b / baseline))))
      :ARG1-of (d2 / describe-01
            :ARG0 (p3 / publication-91
                  :ARG0 (a3 / and
                        :op1 (p4 / person :name (n4 / name :op1 "Balmanno"))
                        :op2 (p5 / person
                              :mod (o / other)))
                  :time (d / date-entity :year 2009))))

# ::id a_pmid_2256_9000.129 ::date 2015-06-03T13:06:28 ::annotator SDL-AMR-09 ::preferred
# ::snt However, as depicted in <xref ref-type="fig" rid="fig3">Figure 3E–H</xref>, we failed to segregate the panel of 11 NSCLC and CRC cell lines into selumetinib-sensitive and selumetinib-resistant groups, by using the PI3K pathway.
# ::save-date Sun Jan 17, 2016 ::file a_pmid_2256_9000_129.txt
(h / have-concession-91
      :ARG1 (f / fail-01
            :ARG1 (w / we)
            :ARG2 (s / segregate-01
                  :ARG0 w
                  :ARG1 (p / panel
                        :consist-of (a3 / and :quant 11
                              :op1 (c / cell-line
                                    :mod (d2 / disease :name (n / name :op1 "NSCLC")))
                              :op2 (c2 / cell-line
                                    :mod (d3 / disease :name (n2 / name :op1 "CRC")))))
                  :ARG2 (a2 / and
                        :op1 (g / group
                              :ARG0-of (s2 / sensitive-03
                                    :ARG1 (s4 / small-molecule :name (n4 / name :op1 "selumetinib"))))
                        :op2 (g2 / group
                              :ARG0-of (r / resist-01
                                    :ARG1 s4)))
                  :manner (u / use-01
                        :ARG1 (p3 / pathway :name (n3 / name :op1 "PI3K")))))
      :ARG1-of (d / depict-01
            :ARG0 (v / value-interval
                  :op1 (f2 / figure :mod "3E")
                  :op2 (f3 / figure :mod "3H"))))

# ::id a_pmid_2256_9000.130 ::date 2015-06-03T13:18:03 ::annotator SDL-AMR-09 ::preferred
# ::snt Effects of selumetinib treatment on NSCLC and CRC tumour xenografts in nude mice
# ::save-date Sun Jan 17, 2016 ::file a_pmid_2256_9000_130.txt
(a / affect-01
      :ARG0 (t / treat-04
            :ARG2 (s2 / small-molecule :name (n4 / name :op1 "selumetinib")))
      :ARG1 (a2 / and
            :op1 (x3 / xenograft
                  :source (t2 / tumor
                        :mod (d / disease :name (n2 / name :op1 "NSCLC"))))
            :op2 (x / xenograft
                  :source (t3 / tumor
                        :mod (d2 / disease :name (n / name :op1 "CRC")))))
      :location (m / mouse
            :mod (n3 / nude)))

# ::id a_pmid_2256_9000.131 ::date 2015-06-03T13:21:01 ::annotator SDL-AMR-09 ::preferred
# ::snt As shown in <xref ref-type="fig" rid="fig4">Figure 4A and B</xref>, HCT116 and Calu3 xenograft growth was significantly inhibited by selumetinib treatment in a dose-dependent manner.
# ::save-date Fri Dec 18, 2015 ::file a_pmid_2256_9000_131.txt
(i / inhibit-01
      :ARG0 (t / treat-04
            :ARG2 (s4 / small-molecule :name (n3 / name :op1 "selumetinib")))
      :ARG1 (g / grow-01
            :ARG1 (a / and
                  :op1 (x3 / xenograft
                        :source (c / cell-line :name (n / name :op1 "HCT116")))
                  :op2 (x2 / xenograft
                        :source (c2 / cell-line :name (n4 / name :op1 "Calu3")))))
      :ARG1-of (s / signify-01)
      :manner (d / depend-01
            :ARG0 g
            :ARG1 (d2 / dose))
      :ARG1-of (s3 / show-01
            :ARG0 (a2 / and
                  :op1 (f / figure :mod "4A")
                  :op2 (f2 / figure :mod "4B"))))

# ::id a_pmid_2256_9000.132 ::date 2015-06-03T13:25:49 ::annotator SDL-AMR-09 ::preferred
# ::snt As an example, at day 50 from the injection of cancer cells, the mean tumour volume in mice bearing HCT116 tumour xenografts and treated with selumetinib, 25 or 50 mg kg<sup>−1</sup> were 40% and 15%, respectively, as compared with control untreated mice.
# ::save-date Sun Jan 17, 2016 ::file a_pmid_2256_9000_132.txt
(a4 / and
      :op1 (a / average-01
            :ARG1 (v / volume
                  :mod (t / tumor))
            :ARG2 (p / percentage-entity :value 40)
            :location (m2 / mouse
                  :ARG0-of (b / bear-01
                        :ARG1 (x2 / xenograft
                              :source (t3 / tumor
                                    :mod (c / cell-line :name (n / name :op1 "HCT116")))))))
      :op2 (a5 / average-01
            :ARG1 v
            :ARG2 (p2 / percentage-entity :value 15)
            :location (m4 / mouse
                  :ARG1-of (t4 / treat-04
                        :ARG2 (s2 / small-molecule :name (n4 / name :op1 "selumetinib")
                              :quant (o / or
                                    :op1 (c3 / concentration-quantity :quant 25
                                          :unit (m / milligram-per-kilogram))
                                    :op2 (c2 / concentration-quantity :quant 50
                                          :unit (m3 / milligram-per-kilogram)))))))
      :time (a2 / after
            :op1 (i / inject-01
                  :ARG2 (c4 / cell
                        :mod (d / disease :wiki "Cancer" :name (n2 / name :op1 "cancer"))))
            :quant (t5 / temporal-quantity :quant 50
                  :unit (d2 / day)))
      :mod (r / respective)
      :compared-to (m5 / mouse
            :ARG1-of (t6 / treat-04 :polarity -)
            :mod (c6 / control))
      :ARG0-of (e / exemplify-01))

# ::id a_pmid_2256_9000.133 ::date 2015-06-03T14:20:02 ::annotator SDL-AMR-09 ::preferred
# ::snt Similarly, at day 50 from the injection of cancer cells, the mean tumour volume in mice bearing Calu3 tumour xenografts and treated with selumetinib, 25 or 50 mg kg<sup>−1</sup> were 22% and 8%, respectively, as compared with control untreated mice.
# ::save-date Sun Jan 17, 2016 ::file a_pmid_2256_9000_133.txt
(a / and
      :op1 (a2 / average-01
            :ARG1 (v / volume
                  :mod (t / tumor))
            :ARG2 (p / percentage-entity :value 22)
            :location (m / mouse
                  :ARG0-of (b / bear-01
                        :ARG1 (x2 / xenograft
                              :source (t6 / tumor
                                    :mod (d3 / disease :name (n / name :op1 "cell-line" :op2 "Calu3")))))))
      :op2 (a3 / average-01
            :ARG1 v
            :ARG2 (p2 / percentage-entity :value 8)
            :location (m2 / mouse
                  :ARG1-of (t3 / treat-04
                        :ARG2 (s / small-molecule :name (n3 / name :op1 "selumetinib")
                              :quant (o / or
                                    :op1 (c2 / concentration-quantity :quant 25
                                          :unit (m3 / milligram-per-kilogram))
                                    :op2 (c3 / concentration-quantity :quant 50
                                          :unit (m4 / milligram-per-kilogram)))))))
      :mod (r / respective)
      :compared-to (m5 / mouse
            :ARG1-of (t2 / treat-04 :polarity -)
            :mod (c4 / control))
      :ARG1-of (r2 / resemble-01)
      :time (a4 / after
            :op1 (i / inject-01
                  :ARG2 (c5 / cell
                        :mod (d2 / disease :wiki "Cancer" :name (n2 / name :op1 "cancer"))))
            :quant (t5 / temporal-quantity :quant 50
                  :unit (d / day))))

# ::id a_pmid_2256_9000.134 ::date 2015-06-03T14:59:23 ::annotator SDL-AMR-09 ::preferred
# ::snt In contrast, selumetinib treatment was unable to affect tumour growth in both HCT15 and H460 tumour xenografts (<xref ref-type="fig" rid="fig4">Figure 4C and D</xref>).
# ::save-date Sun Jan 17, 2016 ::file a_pmid_2256_9000_134.txt
(c / contrast-01
      :ARG2 (c2 / capable-01 :polarity -
            :ARG1 (t / treat-04
                  :ARG2 (s / small-molecule :name (n / name :op1 "selumetinib")))
            :ARG2 (a / affect-01
                  :ARG0 t
                  :ARG1 (g / grow-01
                        :ARG1 (t2 / tumor)
                        :location (a2 / and
                              :op1 (x3 / xenograft
                                    :source (t3 / tumor
                                          :mod (c4 / cell-line :name (n3 / name :op1 "HCT15"))))
                              :op2 (x / xenograft
                                    :source (t4 / tumor
                                          :mod (c3 / cell-line :name (n2 / name :op1 "H460"))))))))
      :ARG1-of (d / describe-01
            :ARG0 (a3 / and
                  :op1 (f / figure :mod "4C")
                  :op2 (f2 / figure :mod "4D"))))

# ::id a_pmid_2256_9000.135 ::date 2015-06-04T08:25:28 ::annotator SDL-AMR-09 ::preferred
# ::snt EGFR, RAS, MEK, and AKT protein expression and selumetinib sensitivity in NSCLC and CRC cell lines
# ::save-date Sun Jan 17, 2016 ::file a_pmid_2256_9000_135.txt
(a / and
      :op1 (e4 / express-03
            :ARG2 (a2 / and
                  :op1 (e8 / enzyme :name (n4 / name :op1 "EGFR"))
                  :op2 (e5 / enzyme :name (n5 / name :op1 "RAS"))
                  :op3 (e6 / enzyme :name (n6 / name :op1 "MEK"))
                  :op4 (e7 / enzyme :name (n7 / name :op1 "AKT")))
            :ARG3 a3)
      :op2 (s / sensitive-03
            :ARG1 (s2 / small-molecule :name (n8 / name :op1 "selumetinib"))
            :location (a3 / and
                  :op1 (c / cell-line
                        :mod (d / disease :name (n / name :op1 "NSCLC")))
                  :op2 (c2 / cell-line
                        :mod (d2 / disease :name (n2 / name :op1 "CRC"))))))

# ::id a_pmid_2256_9000.136 ::date 2015-06-04T08:29:54 ::annotator SDL-AMR-09 ::preferred
# ::snt Identification of predictive biomarkers is becoming a fundamental aspect in the development of targeted agents.
# ::save-date Thu Jun 4, 2015 ::file a_pmid_2256_9000_136.txt
(b / become-01
      :ARG1 (i / identify-01
            :ARG1 (b2 / biomarker
                  :ARG0-of (p / predict-01)))
      :ARG2 (a / aspect
            :topic (d / develop-02
                  :ARG1 (a2 / agent
                        :ARG1-of (t / target-01)))
            :mod (f / fundamental)))

# ::id a_pmid_2256_9000.137 ::date 2015-06-04T08:34:01 ::annotator SDL-AMR-09 ::preferred
# ::snt So far, several preclinical studies have been published trying to address this aspect for the sensitivity to MEK inhibitors, but, since different results have been reported, no univocal interpretation could be made (<xref ref-type="bibr" rid="bib7">Balmanno <i>et al</i>, 2009</xref>; <xref ref-type="bibr" rid="bib17">Dry <i>et al</i>, 2010</xref>; <xref ref-type="bibr" rid="bib18">Garon <i>et al</i>, 2010</xref>; <xref ref-type="bibr" rid="bib44">Tendler <i>et al</i>, 2010)</xref>.
# ::save-date Sat Jan 16, 2016 ::file a_pmid_2256_9000_137.txt
(c / contrast-01
      :ARG1 (p2 / publish-01
            :ARG1 (s2 / study-01
                  :mod (p3 / preclinical)
                  :quant (s3 / several)
                  :ARG0-of (t2 / try-01
                        :ARG1 (a / address-02
                              :ARG0 s2
                              :ARG1 (a2 / aspect
                                    :mod (t3 / this)
                                    :topic (s4 / sensitive-03
                                          :ARG1 (m / molecular-physical-entity
                                                :ARG0-of (i / inhibit-01
                                                      :ARG1 (p / protein-family :name (n / name :op1 "MEK")))))))))
            :time (s / so-far))
      :ARG2 (p4 / possible-01
            :ARG1 (i2 / interpret-01 :polarity -
                  :mod (u / univocal))
            :ARG1-of (c2 / cause-01
                  :ARG0 (r / report-01
                        :ARG1 (t4 / thing
                              :ARG2-of (r2 / result-01)
                              :ARG1-of (d4 / differ-02)))))
      :ARG1-of (d3 / describe-01
            :ARG0 (a3 / and
                  :op1 (p5 / publication-91
                        :ARG0 (a4 / and
                              :op1 (p6 / person :name (n2 / name :op1 "Balmanno"))
                              :op2 (p7 / person
                                    :mod (o / other)))
                        :time (d / date-entity :year 2009))
                  :op2 (p8 / publication-91
                        :ARG0 (a5 / and
                              :op1 (p9 / person :name (n3 / name :op1 "Dry"))
                              :op2 p7)
                        :time (d2 / date-entity :year 2010))
                  :op3 (p11 / publication-91
                        :ARG0 (a6 / and
                              :op1 (p12 / person :name (n4 / name :op1 "Garon"))
                              :op2 p7)
                        :time d2)
                  :op4 (p14 / publication-91
                        :ARG0 (a7 / and
                              :op1 (p15 / person :name (n5 / name :op1 "Tendler"))
                              :op2 p7)
                        :time d2))))

# ::id a_pmid_2256_9000.138 ::date 2015-06-04T08:51:42 ::annotator SDL-AMR-09 ::preferred
# ::snt To identify specific profiles, which could allow identifying different molecular patterns of sensitivity or resistance to MEK inhibition, we first screened the intracellular signalling status of each cell lines.
# ::save-date Wed Mar 2, 2016 ::file a_pmid_2256_9000_138.txt
(s / screen-01
      :ARG0 (w / we)
      :ARG1 (s2 / status
            :mod (s3 / signal-07
                  :ARG1 (c / cell-line
                        :mod (e2 / each))
                  :mod (i4 / intracellular)))
      :purpose (i / identify-01
            :ARG0 w
            :ARG1 (p2 / profile
                  :ARG1-of (s4 / specific-02)
                  :ARG0-of (a / allow-01
                        :ARG1 (i2 / identify-01
                              :ARG1 (p3 / pattern-01
                                    :ARG1 (o3 / or
                                          :op1 (s5 / sensitive-03
                                                :ARG1 (p / pattern
                                                      :ARG0-of (i3 / inhibit-01
                                                            :ARG1 (e / enzyme :name (n / name :op1 "MEK")))
                                                      :mod (m2 / molecule)))
                                          :op2 (r2 / resist-01
                                                :ARG1 p))
                                    :mod (m / molecule)
                                    :ARG1-of (d / differ-02)))
                        :ARG1-of (p4 / possible-01))))
      :time (f / first))

# ::id a_pmid_2256_9000.139 ::date 2015-06-04T09:02:19 ::annotator SDL-AMR-09 ::preferred
# ::snt As depicted in <xref ref-type="supplementary-material" rid="sup1">Supplementary Figure 1A</xref>, the NCSLC and CRC cell lines displayed highly variable basal levels of total and phosphorylated EGFR, RAS, MEK, and AKT.
# ::save-date Sun Jan 17, 2016 ::file a_pmid_2256_9000_139.txt
(d / display-01
      :ARG0 (a / and
            :op1 (c / cell-line
                  :mod (d4 / disease :name (n4 / name :op1 "NCSLC")))
            :op2 (c2 / cell-line
                  :mod (d3 / disease :name (n5 / name :op1 "CRC"))))
      :ARG1 (a2 / and
            :op1 (l5 / level
                  :quant-of (e2 / enzyme :name (n2 / name :op1 "EGFR")
                        :mod (t2 / total)))
            :op2 (l / level
                  :quant-of (e / enzyme :name (n / name :op1 "EGFR")
                        :ARG3-of (p / phosphorylate-01)))
            :op3 (l6 / level
                  :quant-of (e3 / enzyme :name (n3 / name :op1 "RAS")
                        :mod t2))
            :op4 (l2 / level
                  :quant-of (e4 / enzyme :name (n6 / name :op1 "RAS")
                        :ARG3-of p))
            :op5 (l3 / level
                  :quant-of (e5 / enzyme :name (n7 / name :op1 "MEK")
                        :mod t2))
            :op6 (l7 / level
                  :quant-of (e7 / enzyme :name (n9 / name :op1 "MEK")
                        :ARG2-of p))
            :op7 (l4 / level
                  :quant-of (e6 / enzyme :name (n8 / name :op1 "AKT")
                        :mod t2))
            :op8 (l8 / level
                  :quant-of (e8 / enzyme :name (n10 / name :op1 "AKT")
                        :ARG3-of p))
            :ARG1-of (v / vary-01
                  :ARG2 (h / high-02))
            :mod (b / basal))
      :ARG1-of (d2 / depict-01
            :ARG0 (f / figure :mod "1A"
                  :ARG2-of (s / supplement-01))))

# ::id a_pmid_2256_9000.140 ::date 2015-06-04T09:19:17 ::annotator SDL-AMR-09 ::preferred
# ::snt As illustrated in <xref ref-type="supplementary-material" rid="sup1">Supplementary Figure 1B</xref>, there was no apparent correlation between basal levels of total and phosphorylated proteins listed above in both tumour types.
# ::save-date Mon Dec 21, 2015 ::file a_pmid_2256_9000_140.txt
(c2 / correlate-01 :polarity -
      :ARG1 (l / level
            :quant-of (p / protein
                  :mod (t / total))
            :mod (b / basal)
            :ARG1-of (l3 / list-01
                  :location (a2 / above))
            :location (t2 / type-03
                  :ARG1 (t3 / tumor)
                  :mod (b2 / both)))
      :ARG2 (l2 / level
            :ARG3-of (p3 / phosphorylate-01)
            :ARG1-of l3
            :mod b
            :location t2)
      :mod (a / apparent)
      :ARG1-of (i / illustrate-01
            :ARG0 (f / figure :mod "1B"
                  :ARG2-of (s / supplement-01))))

# ::id a_pmid_2256_9000.141 ::date 2015-06-04T10:12:56 ::annotator SDL-AMR-09 ::preferred
# ::snt Gene mutations and selumetinib sensitivity in NSCLC and CRC cell lines
# ::save-date Sun Jan 17, 2016 ::file a_pmid_2256_9000_141.txt
(a / and
      :op1 (m / mutate-01
            :ARG2 (g / gene))
      :op2 (s / sensitive-03
            :ARG1 (s2 / small-molecule :name (n / name :op1 "selumetinib")))
      :location (a2 / and
            :op1 (c / cell-line
                  :mod (d / disease :name (n2 / name :op1 "NSCLC")))
            :op2 (c2 / cell-line
                  :mod (d2 / disease :name (n3 / name :op1 "CRC")))))

# ::id a_pmid_2256_9000.142 ::date 2015-06-04T10:14:54 ::annotator SDL-AMR-09 ::preferred
# ::snt Activation of the classic MAPK cascade (RAS-RAF-MEK-ERK) is a common event in colorectal and lung cancer.
# ::save-date Thu Jan 14, 2016 ::file a_pmid_2256_9000_142.txt
(e / event
      :mod (c / common)
      :location (a / and
            :op1 (d / disease :wiki "Colorectal_cancer" :name (n2 / name :op1 "colon" :op2 "cancer"))
            :op2 (d2 / disease :wiki "Lung_cancer" :name (n7 / name :op1 "cancer")))
      :domain (a2 / activate-01
            :ARG1 (p / pathway :name (n / name :op1 "MAPK")
                  :mod (c6 / classic)
                  :ARG1-of (m / mean-01
                        :ARG2 (m2 / macro-molecular-complex
                              :part (e5 / enzyme :name (n3 / name :op1 "RAS"))
                              :part (e2 / enzyme :name (n4 / name :op1 "RAF"))
                              :part (e4 / enzyme :name (n5 / name :op1 "MEK"))
                              :part (e3 / enzyme :name (n6 / name :op1 "ERK")))))))

# ::id a_pmid_2256_9000.143 ::date 2015-06-04T10:22:20 ::annotator SDL-AMR-09 ::preferred
# ::snt Some genes within this pathway are mutated or aberrantly expressed.
# ::save-date Thu Jun 11, 2015 ::file a_pmid_2256_9000_143.txt
(o / or
      :op1 (m / mutate-01
            :ARG1 (g / gene
                  :quant (s / some)
                  :ARG1-of (i / include-91
                        :ARG2 (p / pathway
                              :mod (t / this)))))
      :op2 (e / express-03
            :ARG2 g
            :manner (a / aberrant)))

# ::id a_pmid_2256_9000.144 ::date 2015-06-04T10:25:42 ::annotator SDL-AMR-09 ::preferred
# ::snt Moreover, the MAPK pathway can be indirectly activated by mutations of genes encoding for PI3K/PTEN/AKT and p53.
# ::save-date Mon Dec 21, 2015 ::file a_pmid_2256_9000_144.txt
(a / and
      :op2 (p2 / possible-01
            :ARG1 (a2 / activate-01
                  :ARG0 (m / mutate-01
                        :ARG1 (g / gene
                              :ARG0-of (e / encode-01
                                    :ARG1 (a3 / and
                                          :op1 (p3 / pathway :name (n2 / name :op1 "PI3K/PTEN/AKT"))
                                          :op2 (p4 / protein :name (n3 / name :op1 "p53"))))))
                  :ARG1 (p / pathway :name (n / name :op1 "MAPK"))
                  :ARG1-of (d / direct-02 :polarity -))))

# ::id a_pmid_2256_9000.145 ::date 2015-06-04T10:31:29 ::annotator SDL-AMR-09 ::preferred
# ::snt We have screened the panel of 11 NSCLC and CRC cell lines for mutations in <i>KRAS, NRAS, BRAF, PIK3CA, p53, PTEN, MEK1/2, AKT, EGFR</i> (<xref ref-type="table" rid="tbl1">Table 1</xref>; <xref ref-type="supplementary-material" rid="sup1">Supplementary Table 1A–F</xref>).
# ::save-date Sun Jan 17, 2016 ::file a_pmid_2256_9000_145.txt
(s / screen-01
      :ARG0 (w2 / we)
      :ARG1 (p / panel
            :consist-of (a4 / and :quant 11
                  :op1 (c / cell-line
                        :mod (d2 / disease :name (n / name :op1 "NSCLC")))
                  :op2 (c2 / cell-line
                        :mod (d3 / disease :name (n2 / name :op1 "CRC")))))
      :ARG2 (m / mutate-01
            :ARG1 (a2 / and
                  :op1 (g2 / gene :name (n5 / name :op1 "KRAS"))
                  :op2 (g3 / gene :name (n6 / name :op1 "NRAS"))
                  :op3 (g4 / gene :name (n7 / name :op1 "BRAF"))
                  :op4 (g5 / gene :name (n8 / name :op1 "PIK3CA"))
                  :op5 (g6 / gene :name (n9 / name :op1 "p53"))
                  :op6 (g7 / gene :name (n10 / name :op1 "PTEN"))
                  :op7 (g8 / gene :name (n11 / name :op1 "MEK1/2"))
                  :op8 (g9 / gene :name (n12 / name :op1 "AKT"))
                  :op9 (g10 / gene :name (n13 / name :op1 "EGFR"))))
      :ARG1-of (d / describe-01
            :ARG0 (a3 / and
                  :op1 (t / table :mod 1)
                  :op2 (v / value-interval
                        :op1 (t2 / table :mod "1A")
                        :op2 (t3 / table :mod "1F")
                        :ARG2-of (s2 / supplement-01)))))

# ::id a_pmid_2256_9000.146 ::date 2015-06-04T10:39:47 ::annotator SDL-AMR-09 ::preferred
# ::snt In NSCLC cell lines, two out of five (40%) harboured a <i>KRAS</i> mutation, which was located in codon 12 or 13.
# ::save-date Sun Jan 17, 2016 ::file a_pmid_2256_9000_146.txt
(h / harbor-01
      :ARG0 (c4 / cell-line :quant 2
            :ARG1-of (i / include-91
                  :ARG2 (c5 / cell-line :quant 5)
                  :ARG3 (p / percentage-entity :value 40)))
      :ARG1 (m / mutate-01
            :ARG1 (g / gene :name (n / name :op1 "KRAS"))
            :ARG1-of (l / locate-01
                  :location (o / or
                        :op1 (c / codon :mod 12)
                        :op2 (c2 / codon :mod 13))))
      :location (c3 / cell-line
            :mod (d / disease :name (n2 / name :op1 "NSCLC"))))

# ::id a_pmid_2256_9000.147 ::date 2015-06-04T10:48:48 ::annotator SDL-AMR-09 ::preferred
# ::snt Moreover, three out of five (60%) of NSCLC cells harboured a <i>PI3KCA</i> mutation, which were located in exon 9 or 20.
# ::save-date Sun Jan 17, 2016 ::file a_pmid_2256_9000_147.txt
(a / and
      :op2 (h / harbor-01
            :ARG0 (c / cell-line :quant 3
                  :ARG1-of (i / include-91
                        :ARG2 (c2 / cell-line :quant 5
                              :mod (d / disease :name (n / name :op1 "NSCLC")))
                        :ARG3 (p / percentage-entity :value 60)))
            :ARG1 (m / mutate-01
                  :ARG1 (g / gene :name (n3 / name :op1 "PI3KCA"))
                  :ARG1-of (l / locate-01
                        :location (o / or
                              :op1 (e / exon :mod 9)
                              :op2 (e2 / exon :mod 20))))))

# ::id a_pmid_2256_9000.148 ::date 2015-06-04T10:54:23 ::annotator SDL-AMR-09 ::preferred
# ::snt A concomitant mutation in <i>KRAS</i> and <i>PI3KCA</i> gene was found in two out of five (40%) NSCLC.
# ::save-date Sun Jan 17, 2016 ::file a_pmid_2256_9000_148.txt
(f / find-01
      :ARG1 (m / mutate-01
            :ARG1 (a / and
                  :op1 (g / gene :name (n / name :op1 "KRAS"))
                  :op2 (g2 / gene :name (n2 / name :op1 "PI3KCA")))
            :mod (c / concomitant))
      :location (c2 / cell-line :quant 2
            :ARG1-of (i / include-91
                  :ARG2 (c3 / cell-line :quant 5
                        :mod (d / disease :name (n3 / name :op1 "NSCLC")))
                  :ARG3 (p / percentage-entity :value 40))))

# ::id a_pmid_2256_9000.149 ::date 2015-06-04T10:57:16 ::annotator SDL-AMR-09 ::preferred
# ::snt One NSCLC cell line had an <i>NRAS</i> mutation (<xref ref-type="table" rid="tbl1">Table 1</xref>; <xref ref-type="supplementary-material" rid="sup1">Supplementary Table 1A–F</xref>).
# ::save-date Sun Jan 17, 2016 ::file a_pmid_2256_9000_149.txt
(h / have-03
      :ARG0 (c / cell-line :quant 1
            :mod (d2 / disease :name (n / name :op1 "NSCLC")))
      :ARG1 (m / mutate-01
            :ARG1 (g / gene :name (n2 / name :op1 "NRAS")))
      :ARG1-of (d / describe-01
            :ARG0 (a / and
                  :op1 (t / table :mod 1)
                  :op2 (v / value-interval
                        :op1 (t2 / table :mod "1A")
                        :op2 (t3 / table :mod "1F")
                        :ARG2-of (s / supplement-01)))))

# ::id a_pmid_2256_9000.150 ::date 2015-06-04T11:00:44 ::annotator SDL-AMR-09 ::preferred
# ::snt In the panel of six CRC cell lines, all of them harboured a <i>KRAS</i> gene mutation that was located in codon 12 or 13.
# ::save-date Sun Jan 17, 2016 ::file a_pmid_2256_9000_150.txt
(h / harbor-01
      :ARG0 c3
      :ARG1 (m / mutate-01
            :ARG1 (g / gene :name (n / name :op1 "KRAS"))
            :ARG1-of (l / locate-01
                  :location (o / or
                        :op1 (c / codon :mod 12)
                        :op2 (c2 / codon :mod 13))))
      :location (p / panel
            :consist-of (c3 / cell-line :quant 6
                  :mod (d / disease :name (n2 / name :op1 "CRC")))))

# ::id a_pmid_2256_9000.151 ::date 2015-06-04T11:04:59 ::annotator SDL-AMR-09 ::preferred
# ::snt Moreover, half of CRC cell lines had both a <i>PI3KCA</i> mutation in exon 9 or 20 and a <i>KRAS</i> mutation.
# ::save-date Sun Jan 17, 2016 ::file a_pmid_2256_9000_151.txt
(a / and
      :op2 (h / have-03
            :ARG0 (c / cell-line :quant "1/2"
                  :ARG1-of (i / include-91
                        :ARG2 (c2 / cell-line
                              :mod (d / disease :name (n / name :op1 "CRC")))))
            :ARG1 (a2 / and
                  :op1 (m / mutate-01
                        :ARG1 (g / gene :name (n3 / name :op1 "PI3KCA"))
                        :location (a3 / and
                              :op1 (e / exon :mod 9)
                              :op2 (e2 / exon :mod 20)))
                  :op2 (m2 / mutate-01
                        :ARG1 (g2 / gene :name (n4 / name :op1 "KRAS"))))))

# ::id a_pmid_2256_9000.152 ::date 2015-06-04T11:22:42 ::annotator SDL-AMR-09 ::preferred
# ::snt None of the CRC cells had an <i>NRAS</i> mutation.
# ::save-date Sun Jan 17, 2016 ::file a_pmid_2256_9000_152.txt
(h / have-03
      :ARG0 (c / cell-line
            :quant (n2 / none)
            :mod (d / disease :name (n / name :op1 "CRC")))
      :ARG1 (m / mutate-01
            :ARG1 (g / gene :name (n3 / name :op1 "NRAS"))))

# ::id a_pmid_2256_9000.153 ::date 2015-06-04T11:38:35 ::annotator SDL-AMR-09 ::preferred
# ::snt No <i>BRAF</i> mutations were observed in the whole panel of NSCLC and CRC cells.
# ::save-date Sun Jan 17, 2016 ::file a_pmid_2256_9000_153.txt
(o / observe-01
      :ARG1 (m / mutate-01 :polarity -
            :ARG1 (g / gene :name (n / name :op1 "BRAF")))
      :location (p / panel
            :mod (w / whole)
            :consist-of (a2 / and
                  :op1 (c / cell-line
                        :mod (d / disease :name (n2 / name :op1 "NSCLC")))
                  :op2 (c2 / cell-line
                        :mod (d2 / disease :name (n3 / name :op1 "CRC"))))))

# ::id a_pmid_2256_9000.154 ::date 2015-06-04T11:43:00 ::annotator SDL-AMR-09 ::preferred
# ::snt As reported in <xref ref-type="supplementary-material" rid="sup1">Supplementary Table 1E and F</xref>, no other gene mutations were found in both NSCLC and CRC cell lines.
# ::save-date Sun Jan 17, 2016 ::file a_pmid_2256_9000_154.txt
(f / find-01
      :ARG1 (m / mutate-01 :polarity -
            :ARG1 (g / gene
                  :mod (o / other)))
      :location (a / and
            :op1 (c / cell-line
                  :mod (d2 / disease :name (n / name :op1 "NSCLC")))
            :op2 (c2 / cell-line
                  :mod (d / disease :name (n2 / name :op1 "CRC"))))
      :ARG1-of (r / report-01
            :ARG0 (a2 / and
                  :op1 (t / table :mod "1E")
                  :op2 (t2 / table :mod "1F")
                  :ARG2-of (s / supplement-01))))

# ::id a_pmid_2256_9000.155 ::date 2015-06-04T12:09:14 ::annotator SDL-AMR-09 ::preferred
# ::snt After this screening, we tried to correlate the mutational status with selumetinib sensitivity.
# ::save-date Thu Jun 11, 2015 ::file a_pmid_2256_9000_155.txt
(t / try-01
      :ARG0 (w / we)
      :ARG1 (c / correlate-01
            :ARG0 w
            :ARG1 (s / status
                  :mod (m / mutate-01))
            :ARG2 (s2 / sensitive-03
                  :ARG1 (s3 / small-molecule :name (n / name :op1 "selumetinib"))))
      :time (a / after
            :op1 (s4 / screen-01
                  :mod (t2 / this))))

# ::id a_pmid_2256_9000.156 ::date 2015-06-04T12:16:57 ::annotator SDL-AMR-09 ::preferred
# ::snt The analysis was made either considering separately the two sets of cell lines (data not shown) or all together (<xref ref-type="supplementary-material" rid="sup1">Supplementary Figure 2A and B</xref>).
# ::save-date Mon Dec 21, 2015 ::file a_pmid_2256_9000_156.txt
(a4 / analyze-01
      :manner (c / consider-01
            :ARG1 (o / or
                  :op1 (s / set :quant 2
                        :consist-of (c2 / cell-line)
                        :ARG1-of (s2 / separate-02)
                        :ARG1-of (d / describe-01
                              :ARG0 (d2 / data
                                    :ARG1-of (s3 / show-01 :polarity -))))
                  :op2 (s5 / set :quant 2
                        :consist-of c2
                        :mod (t2 / together)
                        :ARG1-of (d3 / describe-01
                              :ARG0 (a3 / and
                                    :op1 (f / figure :mod "2A")
                                    :op2 (f2 / figure :mod "2B")
                                    :ARG2-of (s4 / supplement-01)))))))

# ::id a_pmid_2256_9000.157 ::date 2015-06-04T12:40:13 ::annotator SDL-AMR-09 ::preferred
# ::snt Sensitivity to selumetinib did not seem to correlate with any specific gene mutations in this panel of NSCLC and CRC cell lines.
# ::save-date Sun Jan 17, 2016 ::file a_pmid_2256_9000_157.txt
(s / seem-01 :polarity -
      :ARG1 (c / correlate-01
            :ARG1 (s2 / sensitive-03
                  :ARG1 (s3 / small-molecule :name (n / name :op1 "selumetinib")))
            :ARG2 (m / mutate-01
                  :ARG1 (g / gene)
                  :ARG1-of (s4 / specific-02)
                  :mod (a / any))
            :location (p / panel
                  :consist-of (a3 / and
                        :op1 (c2 / cell-line
                              :mod (d / disease :name (n2 / name :op1 "NSCLC")))
                        :op2 (c3 / cell-line
                              :mod (d2 / disease :name (n3 / name :op1 "CRC"))))
                  :mod (t / this))))

# ::id a_pmid_2256_9000.158 ::date 2015-06-04T12:45:24 ::annotator SDL-AMR-09 ::preferred
# ::snt Identification of gene expression profiles that could be predictive of response to selumetinib in NSCLC and CRC cell lines
# ::save-date Sun Jan 17, 2016 ::file a_pmid_2256_9000_158.txt
(i2 / identify-01
      :ARG1 (p / profile
            :topic (e / express-03
                  :ARG2 (g / gene)))
      :ARG0-of (p5 / predict-01
            :ARG1 (r / respond-01
                  :ARG1 (s / small-molecule :name (n / name :op1 "selumetinib")))
            :ARG1-of (p2 / possible-01))
      :location (a / and
            :op1 (c / cell-line
                  :mod (d / disease :name (n2 / name :op1 "NSCLC")))
            :op2 (c2 / cell-line
                  :mod (d2 / disease :name (n3 / name :op1 "CRC")))))

# ::id a_pmid_2256_9000.159 ::date 2015-06-04T12:53:38 ::annotator SDL-AMR-09 ::preferred
# ::snt RNAs from the 11 cancer cell lines were extracted and used for microarray gene expression analysis.
# ::save-date Mon Dec 14, 2015 ::file a_pmid_2256_9000_159.txt
(a / and
      :op1 (e / extract-01
            :ARG1 (n3 / nucleic-acid :name (n2 / name :op1 "RNA")
                  :source (c / cell-line :quant 11
                        :mod (d / disease :wiki "Cancer" :name (n / name :op1 "cancer")))))
      :op2 (u / use-01
            :ARG1 n3
            :ARG2 (a2 / analyze-01
                  :ARG0 (m / microarray)
                  :ARG1 (e2 / express-03
                        :ARG2 (g / gene)))))

# ::id a_pmid_2256_9000.160 ::date 2015-06-04T13:11:13 ::annotator SDL-AMR-09 ::preferred
# ::snt Using Student's <i>t</i>-test with Benjamini–Hochberg multiple test correction, 21 and 18 genes were identified as upregulated or downregulated, respectively, in selumetinib-resistant cancer cell lines (<i>t</i>-test, <i>P</i><0.05) (<xref ref-type="supplementary-material" rid="sup1">Supplementary Figure 3</xref>).
# ::save-date Mon Dec 21, 2015 ::file a_pmid_2256_9000_160.txt
(a2 / and
      :op1 (i / identify-01
            :ARG1 (g / gene :quant 21)
            :ARG2 (u / upregulate-01))
      :op2 (i2 / identify-01
            :ARG1 (g2 / gene :quant 18)
            :ARG2 (d2 / downregulate-01))
      :location (c / cell-line
            :mod (d / disease :wiki "Cancer" :name (n / name :op1 "cancer"))
            :ARG0-of (r2 / resist-01
                  :ARG1 (s2 / small-molecule :name (n2 / name :op1 "selumetinib"))))
      :ARG1-of (s / statistical-test-91
            :ARG2 (l / less-than :op1 0.05)
            :ARG4 (t / thing :wiki "Student's_t-test" :name (n3 / name :op1 "Student's" :op2 "t-test")
                  :mod (c2 / correct-01
                        :mod (t2 / test-01
                              :quant (m / multiple))
                        :ARG1-of (a3 / accord-02
                              :ARG2 (a4 / and
                                    :op1 (p / person :name (n5 / name :op1 "Benjamini"))
                                    :op2 (p2 / person :name (n6 / name :op1 "Hochberg")))))))
      :ARG1-of (d3 / describe-01
            :ARG0 (f / figure :mod 3
                  :ARG2-of (s3 / supplement-01))))

# ::id a_pmid_2256_9000.161 ::date 2015-06-04T13:35:27 ::annotator SDL-AMR-09 ::preferred
# ::snt <xref ref-type="table" rid="tbl2">Table 2</xref> lists the differentially expressed genes in selumetinib-resistant cancer cell lines.
# ::save-date Wed Dec 9, 2015 ::file a_pmid_2256_9000_161.txt
(l / list-01
      :ARG0 (t / table :mod 2)
      :ARG1 (g / gene
            :ARG2-of (e / express-03
                  :ARG3 (c / cell-line
                        :ARG0-of (r / resist-01
                              :ARG1 (s / small-molecule :name (n2 / name :op1 "selumetinib")))
                        :mod (d / disease :wiki "Cancer" :name (n / name :op1 "cancer")))
                  :manner (d2 / differential))))

# ::id a_pmid_2256_9000.162 ::date 2015-06-02T05:36:06 ::annotator SDL-AMR-09 ::preferred
# ::snt Among the 21 genes that were upregulated in selumetinib-resistant cancer cell lines, we identified two genes, <i>ADCY7</i> and <i>AKAP13,</i> which are involved in the cAMP-dependent protein kinase (PKA) pathway (<xref ref-type="table" rid="tbl2">Table 2A</xref>; <xref ref-type="supplementary-material" rid="sup1">Supplementary Figure 3</xref>).
# ::save-date Wed Dec 9, 2015 ::file a_pmid_2256_9000_162.txt
(i / identify-01
      :ARG0 (w / we)
      :ARG1 (a / and
            :op1 (g / gene :name (n / name :op1 "ADCY7"))
            :op2 (g2 / gene :name (n2 / name :op1 "AKAP13"))
            :ARG1-of (i2 / involve-01
                  :ARG2 (p / pathway :name (n3 / name :op1 "cAMP-dependent" :op2 "protein" :op3 "kinase")))
            :ARG1-of (i3 / include-91
                  :ARG2 (g3 / gene :quant 21
                        :ARG1-of (u / upregulate-01
                              :location (c / cell-line
                                    :ARG0-of (r / resist-01
                                          :ARG1 (s / small-molecule :name (n4 / name :op1 "selumetinib")))
                                    :mod (d2 / disease :wiki "Cancer" :name (n5 / name :op1 "cancer")))))))
      :ARG1-of (d / describe-01
            :ARG0 (a2 / and
                  :op1 (t / table :mod "2A")
                  :op2 (f / figure :mod 3
                        :ARG2-of (s2 / supplement-01)))))

# ::id a_pmid_2256_9000.163 ::date 2015-06-02T05:47:27 ::annotator SDL-AMR-09 ::preferred
# ::snt The <i>ADCY7</i> gene encodes a membrane-bound adenylatecyclase that convert ATP into 3', 5'-adenosine monophosphate (cAMP) and pyrophosphate (<xref ref-type="supplementary-material" rid="sup1">Supplementary Figure 4</xref>).
# ::save-date Sun Jun 7, 2015 ::file a_pmid_2256_9000_163.txt
(e / encode-01
      :ARG0 (g / gene :name (n / name :op1 "ADCY7"))
      :ARG1 (e2 / enzyme :name (n2 / name :op1 "adenylatecyclase")
            :ARG1-of (b / bind-01
                  :ARG2 (m2 / membrane))
            :ARG0-of (c / convert-01
                  :ARG1 (s / small-molecule :name (n3 / name :op1 "ATP"))
                  :ARG2 (a / and
                        :op1 (s2 / small-molecule :name (n4 / name :op1 "3'" :op2 "5'" :op3 "adenosine" :op4 "monophosphate"))
                        :op2 (s3 / small-molecule :name (n5 / name :op1 "pyrophosphate")))))
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod 4
                  :ARG2-of (s4 / supplement-01))))

# ::id a_pmid_2256_9000.164 ::date 2015-06-02T05:53:53 ::annotator SDL-AMR-09 ::preferred
# ::snt The cAMP is a second messenger that has a key role in intracellular signalling transduction.
# ::save-date Wed Mar 2, 2016 ::file a_pmid_2256_9000_164.txt
(h / have-03
      :ARG0 (m / messenger
            :domain (s3 / small-molecule :name (n / name :op1 "cAMP"))
            :ord (o / ordinal-entity :value 2))
      :ARG1 (r / role
            :ARG1-of (k / key-02)
            :prep-in (t / transduce-01
                  :ARG1 (s2 / signal-07
                        :mod (i / intracellular)))))

# ::id a_pmid_2256_9000.165 ::date 2015-06-02T06:03:30 ::annotator SDL-AMR-09 ::preferred
# ::snt A major function in mammalian cells is the activation of the PKA (<xref ref-type="bibr" rid="bib42">Tasken <i>et al</i>, 1997</xref>).
# ::save-date Sun Dec 20, 2015 ::file a_pmid_2256_9000_165.txt
(f / function-01
      :ARG1 (a / activate-01
            :ARG1 (e / enzyme :name (n / name :op1 "PKA")))
      :ARG1-of (m / major-02)
      :location (c / cell
            :part-of (a2 / animal :name (n2 / name :op1 "Mammalia")))
      :ARG1-of (d / describe-01
            :ARG0 (p / publication-91
                  :ARG0 (a3 / and
                        :op1 (p3 / person :name (n3 / name :op1 "Tasken"))
                        :op2 (p2 / person
                              :mod (o / other)))
                  :time (d2 / date-entity :year 1997))))

# ::id a_pmid_2256_9000.166 ::date 2015-06-02T06:09:59 ::annotator SDL-AMR-09 ::preferred
# ::snt The <i>AKAP13</i> gene encodes the A-kinase anchor protein 13 that has the function of binding to the regulatory subunits of PKA (<xref ref-type="supplementary-material" rid="sup1">Supplementary Figure 4</xref>).
# ::save-date Tue Jun 2, 2015 ::file a_pmid_2256_9000_166.txt
(e / encode-01
      :ARG0 (g / gene :name (n / name :op1 "AKAP13"))
      :ARG1 (e2 / enzyme :name (n2 / name :op1 "A-kinase" :op2 "anchor" :op3 "protein" :op4 "13")
            :ARG0-of (f / function-01
                  :ARG1 (b / bind-01
                        :ARG1 e2
                        :ARG2 (s / subunit
                              :ARG0-of (r / regulate-01)
                              :part-of (e3 / enzyme :name (n3 / name :op1 "PKA"))))))
      :ARG1-of (d / describe-01
            :ARG0 (f2 / figure :mod 4
                  :ARG2-of (s2 / supplement-01))))

# ::id a_pmid_2256_9000.167 ::date 2015-06-02T06:12:35 ::annotator SDL-AMR-09 ::preferred
# ::snt Moreover, four genes (<i>NCOA3, TAF3, NR1H2</i>, and <i>RXRA</i>), which are upregulated in selumetinib-resistant cancer cell lines, belong to the retinoic acid pathway, which is also activated by PKA (<xref ref-type="bibr" rid="bib6">Altucci <i>et al</i>, 2007</xref>).
# ::save-date Wed Dec 9, 2015 ::file a_pmid_2256_9000_167.txt
(a / and
      :op2 (b / belong-01
            :ARG0 (g5 / gene :quant 4
                  :ARG1-of (m / mean-01
                        :ARG2 (a2 / and
                              :op1 (g / gene :name (n / name :op1 "NCOA3"))
                              :op2 (g2 / gene :name (n2 / name :op1 "TAF3"))
                              :op3 (g3 / gene :name (n3 / name :op1 "NR1H2"))
                              :op4 (g4 / gene :name (n4 / name :op1 "RXRA"))))
                  :ARG1-of (u / upregulate-01
                        :location (c / cell-line
                              :ARG0-of (r / resist-01
                                    :ARG1 (s / small-molecule :name (n5 / name :op1 "selumetinib")))
                              :mod (d3 / disease :wiki "Cancer" :name (n9 / name :op1 "cancer")))))
            :ARG1 (p / pathway :name (n6 / name :op1 "retinoic" :op2 "acid")
                  :ARG1-of (a3 / activate-01
                        :ARG0 (e / enzyme :name (n7 / name :op1 "PKA"))
                        :mod (a4 / also)))
            :ARG1-of (d / describe-01
                  :ARG0 (p2 / publication-91
                        :ARG0 (a5 / and
                              :op1 (p3 / person :name (n8 / name :op1 "Altucci"))
                              :op2 (p4 / person
                                    :mod (o / other)))
                        :time (d2 / date-entity :year 2007)))))

# ::id a_pmid_2256_9000.168 ::date 2015-06-02T06:18:04 ::annotator SDL-AMR-09 ::preferred
# ::snt Treatment with selective PKA inhibitors sensitises selumetinib-resistant cancer cell lines to selumetinib
# ::save-date Sun Jan 17, 2016 ::file a_pmid_2256_9000_168.txt
(s / sensitize-01
      :ARG0 (t / treat-04
            :ARG2 (m / molecular-physical-entity
                  :ARG0-of (i / inhibit-01
                        :ARG1 (p / protein-family :name (n / name :op1 "PKA")))
                  :mod (s2 / selective)))
      :ARG1 (c / cell-line
            :ARG0-of (r / resist-01
                  :ARG1 (s3 / small-molecule :name (n2 / name :op1 "selumetinib")))
            :mod (d / disease :wiki "Cancer" :name (n3 / name :op1 "cancer")))
      :ARG2 s3)

# ::id a_pmid_2256_9000.169 ::date 2015-06-02T06:27:56 ::annotator SDL-AMR-09 ::preferred
# ::snt To functionally evaluate if the cAMP-dependent PKA could mediate resistance to MEK inhibitor treatment, we have treated the panel of NSCLC and CRC with 8-Cl-cAMP, a site-selective cAMP analogue, which specifically inhibits PKAI, the PKA isoform that is directly involved in mitogenic signalling and the transformed phenotype (<xref ref-type="bibr" rid="bib46">Tortora and Ciardiello, 2000</xref>; <xref ref-type="bibr" rid="bib33">Naviglio <i>et al</i>, 2009</xref>).
# ::save-date Sun Jan 17, 2016 ::file a_pmid_2256_9000_169.txt
(t / treat-04
      :ARG0 (w / we)
      :ARG1 (p / panel
            :part (c / cell-line
                  :mod (d6 / disease :name (n / name :op1 "NSCLC")))
            :part (c2 / cell-line
                  :mod (d7 / disease :name (n2 / name :op1 "CRC"))))
      :ARG2 (s / small-molecule :name (n3 / name :op1 "8-Cl-cAMP")
            :mod (a2 / analogue
                  :poss (s2 / small-molecule :name (n4 / name :op1 "cAMP"))
                  :mod (s3 / selective
                        :mod (s4 / site)))
            :ARG0-of (i / inhibit-01
                  :ARG1 (e / enzyme :name (n5 / name :op1 "PKAI")
                        :mod (i2 / isoform
                              :poss (e2 / enzyme :name (n6 / name :op1 "PKA"))
                              :ARG1-of (i3 / involve-01
                                    :ARG2 (a3 / and
                                          :op1 (s6 / signal-07
                                                :mod (m / mitogenic))
                                          :op2 (p2 / phenotype
                                                :ARG1-of (t2 / transform-01)))
                                    :ARG1-of (d / direct-02))))
                  :ARG1-of (s5 / specific-02)))
      :purpose (e3 / evaluate-01
            :ARG0 w
            :ARG1 (p3 / possible-01 :mode interrogative
                  :ARG1 (m2 / mediate-01
                        :ARG0 (e4 / enzyme :name (n7 / name :op1 "PKA")
                              :ARG0-of (d2 / depend-01
                                    :ARG1 s2))
                        :ARG1 (r / resist-01
                              :ARG1 (t3 / treat-04
                                    :ARG2 (m3 / molecular-physical-entity
                                          :ARG0-of (i4 / inhibit-01
                                                :ARG1 (p10 / protein-family :name (n8 / name :op1 "MEK"))))))))
            :manner (f / functional))
      :ARG1-of (d3 / describe-01
            :ARG0 (a4 / and
                  :op1 (p4 / publication-91
                        :ARG0 (a5 / and
                              :op1 (p5 / person :name (n9 / name :op1 "Tortora"))
                              :op2 (p6 / person :name (n10 / name :op1 "Ciardiello")))
                        :time (d4 / date-entity :year 2000))
                  :op2 (p7 / publication-91
                        :ARG0 (a6 / and
                              :op1 (p8 / person :name (n11 / name :op1 "Naviglio"))
                              :op2 (p9 / person
                                    :mod (o / other)))
                        :time (d5 / date-entity :year 2009)))))

# ::id a_pmid_2256_9000.170 ::date 2015-06-02T06:40:26 ::annotator SDL-AMR-09 ::preferred
# ::snt A dose-dependent inhibition of growth was observed in all cancer cell lines with a different degree of sensitivity, as illustrated in <xref ref-type="fig" rid="fig5">Figure 5A</xref>.
# ::save-date Sun Jan 3, 2016 ::file a_pmid_2256_9000_170.txt
(o / observe-01
      :ARG1 (i / inhibit-01
            :ARG1 (g / grow-01)
            :ARG0-of (d / depend-01
                  :ARG1 (d2 / dose)))
      :location (c / cell-line
            :ARG0-of (h / have-03
                  :ARG1 (t / thing
                        :degree-of (s / sensitive-03)
                        :ARG1-of (d4 / differ-02)))
            :mod (a / all)
            :mod (d5 / disease :wiki "Cancer" :name (n / name :op1 "cancer")))
      :ARG1-of (i2 / illustrate-01
            :ARG0 (f / figure :mod "5A")))

# ::id a_pmid_2256_9000.171 ::date 2015-06-02T08:00:58 ::annotator SDL-AMR-09 ::preferred
# ::snt To evaluate the interaction between selumetinib and 8-Cl-cAMP, combination analyses were done.
# ::save-date Tue Jun 2, 2015 ::file a_pmid_2256_9000_171.txt
(a / analyze-01
      :mod (c / combine-01)
      :purpose (e / evaluate-01
            :ARG1 (i / interact-01
                  :ARG0 (s / small-molecule :name (n / name :op1 "selumetinib"))
                  :ARG1 (s2 / small-molecule :name (n2 / name :op1 "8-Cl-cAMP")))))

# ::id a_pmid_2256_9000.172 ::date 2015-06-02T08:14:50 ::annotator SDL-AMR-09 ::preferred
# ::snt The CRC and NSCLC cancer cells were treated with different concentrations of selumetinib (range, 0.01–10 <i>μ</i>ℳ) and 8-Cl-cAMP (range, 0.01–5 <i>μ</i>ℳ) each day, for a total of 3 days at a fixed drug ratio selumetinib to 8-Cl-cAMP of 1 : 1.
# ::save-date Sun Jan 17, 2016 ::file a_pmid_2256_9000_172.txt
(t / treat-04
      :ARG1 (a / and
            :op1 (c / cell-line
                  :mod (d6 / disease :name (n / name :op1 "NSCLC")))
            :op2 (c2 / cell-line
                  :mod (d7 / disease :name (n2 / name :op1 "CRC")))
            :mod (d5 / disease :wiki "Cancer" :name (n5 / name :op1 "cancer")))
      :ARG2 (a2 / and
            :op1 (s / small-molecule :name (n3 / name :op1 "selumetinib")
                  :mod (c4 / concentration-quantity
                        :quant (v / value-interval :op1 0.01 :op2 10)
                        :unit (m / micromolar)
                        :ARG1-of (d3 / differ-02)))
            :op2 (s2 / small-molecule :name (n4 / name :op1 "8-Cl-cAMP")
                  :mod (c5 / concentration-quantity
                        :ARG1-of (d4 / differ-02)
                        :quant (v2 / value-interval :op1 0.01 :op2 5)
                        :unit m)))
      :frequency (r2 / rate-entity-91
            :ARG3 (t2 / temporal-quantity :quant 1
                  :unit (d / day)))
      :condition (e / equal-01
            :ARG1 (r3 / ratio-of
                  :op1 s
                  :op2 s2
                  :ARG1-of (f / fix-03))
            :ARG2 (r4 / ratio-of :op1 1 :op2 1))
      :duration (t3 / temporal-quantity :quant 3
            :unit (d2 / day)
            :mod (t4 / total)))

# ::id a_pmid_2256_9000.173 ::date 2015-06-02T08:31:37 ::annotator SDL-AMR-09 ::preferred
# ::snt In all selumetinib-resistant cancer cell lines, the combination treatment caused synergistic growth inhibitory effects.
# ::save-date Tue Feb 2, 2016 ::file a_pmid_2256_9000_173.txt
(c / cause-01
      :ARG0 (t / treat-04
            :mod (c2 / combine-01))
      :ARG1 (a / affect-01
            :ARG2 (i / inhibit-01
                  :ARG1 (g / grow-01))
            :ARG0-of (s2 / synergize-01))
      :location (c3 / cell-line
            :ARG0-of (r / resist-01
                  :ARG1 (s / small-molecule :name (n / name :op1 "selumetinib")))
            :mod (a2 / all)
            :mod (d / disease :wiki "Cancer" :name (n2 / name :op1 "cancer"))))

# ::id a_pmid_2256_9000.174 ::date 2015-06-02T08:37:07 ::annotator SDL-AMR-09 ::preferred
# ::snt In fact, the CI values for the combinations treatments ranged between 0.013 and 0.350.
# ::save-date Sun Jan 3, 2016 ::file a_pmid_2256_9000_174.txt
(r / range-01
      :ARG1 (v / value
            :mod (i / interval
                  :mod (c / confidence))
            :poss (t / treat-04
                  :mod (c2 / combine-01)))
      :ARG3 0.013
      :ARG4 0.350
      :mod (i2 / in-fact))

# ::id a_pmid_2256_9000.175 ::date 2015-06-02T08:40:44 ::annotator SDL-AMR-09 ::preferred
# ::snt This was significantly different in the selumetinib-sensitive cancer cells in which the combination treatment was clearly antagonistic with CI between 1.3 and 3.6 (<xref ref-type="fig" rid="fig5">Figure 5B</xref>).
# ::save-date Mon Jan 4, 2016 ::file a_pmid_2256_9000_175.txt
(d2 / differ-02
      :ARG1 (t / this)
      :location (c / cell-line
            :ARG0-of (s2 / sensitive-03
                  :ARG1 (s3 / small-molecule :name (n / name :op1 "selumetinib")))
            :location-of (a / antagonize-02
                  :ARG1 (t2 / treat-04
                        :mod (c3 / combine-01))
                  :ARG1-of (c2 / clear-06))
            :ARG0-of (h / have-03
                  :ARG1 (i / interval
                        :mod (c4 / confidence)
                        :mod (v / value-interval :op1 1.3 :op2 3.6)))
            :mod (d3 / disease :wiki "Cancer" :name (n2 / name :op1 "cancer")))
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod "5B"))
      :ARG1-of (s4 / significant-02))

# ::id a_pmid_2256_9000.176 ::date 2015-06-02T08:49:49 ::annotator SDL-AMR-09 ::preferred
# ::snt We next assessed the phosphorylation state of MEK and MAPK following treatment with selumetinib, 8-Cl-cAMP as single agents or in combination with HCT15 and H460 cancer cell lines.
# ::save-date Sat Jan 16, 2016 ::file a_pmid_2256_9000_176.txt
(a / assess-01
      :ARG0 (w / we)
      :ARG1 (s / state
            :mod (p / phosphorylate-01
                  :ARG1 (a2 / and
                        :op1 (e / enzyme :name (n2 / name :op1 "MEK"))
                        :op2 (e2 / enzyme :name (n3 / name :op1 "MAPK"))))
            :ARG1-of (f / follow-01
                  :ARG2 (t / treat-04
                        :ARG2 (o / or
                              :op1 (o2 / or
                                    :op1 (s2 / small-molecule :name (n4 / name :op1 "selumetinib"))
                                    :op2 (s3 / small-molecule :name (n5 / name :op1 "8-Cl-cAMP"))
                                    :ARG0-of (a3 / act-01
                                          :ARG1 (a4 / agent
                                                :ARG1-of (s4 / single-02))))
                              :op2 (c / combine-01
                                    :ARG1 (a5 / and
                                          :op1 s2
                                          :op2 s3)
                                    :ARG2 (a6 / and
                                          :op1 (c2 / cell-line :name (n6 / name :op1 "HCT15"))
                                          :op2 (c3 / cell-line :name (n7 / name :op1 "H460"))
                                          :mod (d / disease :wiki "Cancer" :name (n8 / name :op1 "cancer"))))))))
      :mod (n / next))

# ::id a_pmid_2256_9000.177 ::date 2015-06-02T08:56:49 ::annotator SDL-AMR-09 ::preferred
# ::snt As shown in <xref ref-type="fig" rid="fig3">Figure 3C</xref>, single agent selumetinib or 8-Cl-cAMP slightly inhibited p-MEK and p-MAPK, whereas the combination induced a significant inhibition of both phosphorylated proteins.
# ::save-date Sun Jan 17, 2016 ::file a_pmid_2256_9000_177.txt
(c / contrast-01
      :ARG1 (i / inhibit-01
            :ARG0 (o / or
                  :op1 (s2 / small-molecule :name (n / name :op1 "selumetinib"))
                  :op2 (s3 / small-molecule :name (n2 / name :op1 "8-Cl-cAMP"))
                  :ARG0-of (a / act-01
                        :ARG1 (a2 / agent
                              :ARG1-of (s4 / single-02))))
            :ARG1 (a3 / and
                  :op1 (e / enzyme :name (n3 / name :op1 "MEK")
                        :ARG3-of (p5 / phosphorylate-01))
                  :op2 (e2 / enzyme :name (n4 / name :op1 "MAPK")
                        :ARG3-of p5))
            :degree (s / slight))
      :ARG2 (i2 / induce-01
            :ARG0 (c2 / combine-01
                  :ARG1 s2
                  :ARG2 s3)
            :ARG1 (i3 / inhibit-01
                  :ARG1 a3
                  :ARG1-of (s7 / significant-02)))
      :ARG1-of (s6 / show-01
            :ARG0 (f / figure :mod "3C")))

# ::id a_pmid_2256_9000.178 ::date 2015-06-02T09:02:19 ::annotator SDL-AMR-09 ::preferred
# ::snt A genetic approach to inhibiting PKAI expression was developed by the use of phosphorothioate antisense oligonucleotides targeting the synthesis of the PKAI regulatory subunit RI<i>α</i>.
# ::save-date Fri Feb 12, 2016 ::file a_pmid_2256_9000_178.txt
(d / develop-02
      :ARG1 (a / approach-02
            :ARG1 (i / inhibit-01
                  :ARG1 (e / express-03
                        :ARG2 (e2 / enzyme :name (n / name :op1 "PKAI"))))
            :mod (g / genetics))
      :manner (u / use-01
            :ARG1 (o / oligonucleotide
                  :ARG0-of (t / target-01
                        :ARG1 (s / synthesize-01
                              :ARG1 (p / protein-segment :name (n3 / name :op1 "RIα")
                                    :part-of e2
                                    :ARG0-of (r / regulate-01))))
                  :ARG0-of (c / counter-01
                        :ARG1 (s2 / sense-01))
                  :mod (p2 / phosphorothioate))))

# ::id a_pmid_2256_9000.179 ::date 2015-06-02T09:20:05 ::annotator SDL-AMR-09 ::preferred
# ::snt These oligonucleotides inhibit growth of several human cancer cell lines <i>in vitro</i> and <i>in vivo</i> (<xref ref-type="bibr" rid="bib49">Yokozaki <i>et al</i>, 1993</xref>; <xref ref-type="bibr" rid="bib34">Nesterova and Cho-Chung, 1995</xref>; <xref ref-type="bibr" rid="bib45">Tortora <i>et al</i>, 1997a</xref>).
# ::save-date Sun Jan 3, 2016 ::file a_pmid_2256_9000_179.txt
(i / inhibit-01
      :ARG0 (o / oligonucleotide
            :mod (t / this))
      :ARG1 (g / grow-01
            :ARG1 (c / cell-line
                  :mod (h / human)
                  :quant (s / several)
                  :mod (d5 / disease :wiki "Cancer" :name (n5 / name :op1 "cancer"))))
      :manner (a / and
            :op1 (i2 / in-vitro)
            :op2 (i3 / in-vivo))
      :ARG1-of (d / describe-01
            :ARG0 (a2 / and
                  :op1 (p / publication-91
                        :ARG0 (a3 / and
                              :op1 (p4 / person :name (n / name :op1 "Yokozaki"))
                              :op2 (p5 / person
                                    :mod (o2 / other)))
                        :time (d2 / date-entity :year 1993))
                  :op2 (p2 / publication-91
                        :ARG0 (a4 / and
                              :op1 (p6 / person :name (n2 / name :op1 "Nesterova"))
                              :op2 (p7 / person :name (n3 / name :op1 "Cho-Chung")))
                        :time (d3 / date-entity :year 1995))
                  :op3 (p3 / publication-91 :li "a"
                        :ARG0 (a5 / and
                              :op1 (p8 / person :name (n4 / name :op1 "Tortora"))
                              :op2 p5)
                        :time (d4 / date-entity :year 1997)))))

# ::id a_pmid_2256_9000.180 ::date 2015-06-02T09:26:05 ::annotator SDL-AMR-09 ::preferred
# ::snt Therefore, HYB 190, an 18-mer MBO antisense to the N-terminal 8–13 codons of the RI<i>α</i> subunit of PKAI, and the control HYB 239, containing four mismatched bases, were tested to study the effect on the growth of NSCLC and CRC cell lines.
# ::save-date Wed Mar 9, 2016 ::file a_pmid_2256_9000_180.txt
(c3 / cause-01
      :ARG1 (t / test-01
            :ARG1 (a3 / and
                  :op1 (o / oligonucleotide :name (n3 / name :op1 "HYB" :op2 "190")
                        :mod (b2 / backbone
                              :ARG3-of (m / mix-01))
                        :mod (a4 / antisense
                              :prep-to (c4 / codon
                                    :mod (v / value-interval :op1 8 :op2 13)
                                    :part-of (p / protein-segment :name (n4 / name :op1 "N-terminus"))
                                    :part-of (p2 / protein-segment :name (n5 / name :op1 "RIα")
                                          :part-of (e2 / enzyme :name (n6 / name :op1 "PKAI")))))
                        :mod (p3 / polymer
                              :ARG1-of (l / long-03
                                    :ARG2 18)))
                  :op2 (s2 / small-molecule :name (n7 / name :op1 "HYB" :op2 "239")
                        :ARG0-of (c6 / contain-01
                              :ARG1 (b / base :quant 4
                                    :mod (m4 / mismatch)))
                        :ARG0-of (c5 / control-01)))
            :purpose (s / study-01
                  :ARG1 (a / affect-01
                        :ARG1 (g / grow-01
                              :ARG1 (a2 / and
                                    :op1 (c / cell-line
                                          :mod (d / disease :name (n / name :op1 "NSCLC")))
                                    :op2 (c2 / cell-line
                                          :mod (d2 / disease :name (n2 / name :op1 "CRC")))))))))

# ::id a_pmid_2256_9000.181 ::date 2015-06-02T09:47:26 ::annotator SDL-AMR-09 ::preferred
# ::snt All cancer cell lines treated with HBY 190 displayed a dose-dependent inhibition of growth by MTT assay (<xref ref-type="fig" rid="fig6">Figure 6A</xref>).
# ::save-date Fri Feb 12, 2016 ::file a_pmid_2256_9000_181.txt
(d2 / display-01
      :ARG0 (c / cell-line
            :ARG1-of (t / treat-04
                  :ARG2 (s / small-molecule :name (n2 / name :op1 "HYB" :op2 "190")))
            :mod (a / all)
            :mod (d / disease :wiki "Cancer" :name (n / name :op1 "cancer")))
      :ARG1 (i / inhibit-01
            :ARG1 (g / grow-01)
            :ARG0-of (d3 / depend-01
                  :ARG1 (d4 / dose)))
      :ARG1-of (d5 / describe-01
            :ARG0 (f / figure :mod "6A"))
      :manner (a2 / assay-01
            :instrument (s2 / small-molecule :name (n3 / name :op1 "MTT"))))

# ::id a_pmid_2256_9000.182 ::date 2015-06-02T09:50:50 ::annotator SDL-AMR-09 ::preferred
# ::snt Growth inhibition was more pronounced in selumetinib-resistant cancer cell lines (IC<sub>50</sub> between 0.25 and 1 <i>μ</i>ℳ), while the IC<sub>50</sub> values were >5 <i>μ</i>ℳ in the selumetinib-sensitive cancer cells.
# ::save-date Sun Jan 3, 2016 ::file a_pmid_2256_9000_182.txt
(c / contrast-01
      :ARG1 (p / pronounced-02
            :ARG1 (i / inhibit-01
                  :ARG1 (g / grow-01))
            :degree (m / more)
            :location (c2 / cell-line
                  :ARG0-of (r / resist-01
                        :ARG1 (s / small-molecule :name (n2 / name :op1 "selumetinib")
                              :ARG1-of (h2 / have-percentage-maximal-inhibitory-concentration-01
                                    :ARG2 50
                                    :ARG4 (c4 / concentration-quantity
                                          :unit (m3 / micromolar)
                                          :quant (v / value-interval :op1 0.25 :op2 1)))))
                  :mod (d / disease :wiki "Cancer" :name (n / name :op1 "cancer"))))
      :ARG2 (h3 / have-percentage-maximal-inhibitory-concentration-01
            :ARG2 50
            :ARG4 (m5 / more-than
                  :op1 (c7 / concentration-quantity :quant 5
                        :unit m3))
            :location (c5 / cell-line
                  :ARG0-of (s2 / sensitive-03
                        :ARG1 s)
                  :mod d)))

# ::id a_pmid_2256_9000.183 ::date 2015-06-02T09:58:52 ::annotator SDL-AMR-09 ::preferred
# ::snt In contrast, the control oligonucleotide, HYB 239, at doses up to 5 <i>μ</i>ℳ, showed only 5–15% growth inhibition among all of the cell lines tested (<xref ref-type="fig" rid="fig6">Figure 6A</xref>).
# ::save-date Tue Dec 15, 2015 ::file a_pmid_2256_9000_183.txt
(c / contrast-01
      :ARG2 (s / show-01
            :ARG0 (o / oligonucleotide :wiki -
                  :name (n / name :op1 "HYB" :op2 239)
                  :ARG0-of (c2 / control-01))
            :ARG1 (i / inhibit-01
                  :ARG1 (g / grow-01)
                  :mod (p / percentage-entity
                        :value (v / value-interval :op1 5 :op2 15)
                        :mod (o2 / only)))
            :condition (d / dose
                  :quant (u / up-to
                        :op1 (c4 / concentration-quantity :quant 5
                              :unit (m / micromolar))))
            :location (c3 / cell-line
                  :mod (a / all)
                  :ARG1-of (t / test-01)))
      :ARG1-of (d2 / describe-01
            :ARG0 (f / figure :mod "6A")))

# ::id a_pmid_2256_9000.184 ::date 2015-06-02T12:42:11 ::annotator SDL-AMR-09 ::preferred
# ::snt To determine whether a combination of selumetinib and oligonucleotide HYB 190 could enhance the antiproliferative effect compared with either agent alone, selumetinib-resistant cells were treated with different combinations of the two agents at a fixed drug ratio of 1 : 1.
# ::save-date Mon Jun 8, 2015 ::file a_pmid_2256_9000_184.txt
(t / treat-04
      :ARG1 (c4 / cell
            :ARG0-of (r3 / resist-01
                  :ARG1 s))
      :ARG2 (c / combine-01
            :ARG1 s
            :ARG2 o
            :ARG1-of (d3 / differ-02))
      :purpose (d / determine-01
            :ARG1 (p2 / possible-01 :mode interrogative
                  :ARG1 (e / enhance-01
                        :ARG0 (c2 / combine-01
                              :ARG1 (s / small-molecule :name (n / name :op1 "selumetinib"))
                              :ARG2 (o / oligonucleotide :name (n2 / name :op1 "HYB" :op2 "190")))
                        :ARG1 (a / affect-01
                              :ARG2 (c3 / counter-01
                                    :ARG1 (p3 / proliferate-01)))
                        :compared-to (o2 / or
                              :op1 (e2 / enhance-01
                                    :ARG0 s
                                    :ARG1 a)
                              :op2 (e3 / enhance-01
                                    :ARG0 o
                                    :ARG1 a)))))
      :condition (e4 / equal-01
            :ARG1 (r2 / ratio
                  :mod (d2 / drug)
                  :ARG1-of (f / fix-03))
            :ARG2 (r4 / ratio-of :op1 1 :op2 1)))

# ::id a_pmid_2256_9000.185 ::date 2015-06-02T12:58:05 ::annotator SDL-AMR-09 ::preferred
# ::snt As shown in <xref ref-type="fig" rid="fig6">Figure 6B</xref>, the combination treatment caused synergistic growth inhibitory effects.
# ::save-date Mon Jun 8, 2015 ::file a_pmid_2256_9000_185.txt
(c / cause-01
      :ARG0 (t / treat-04
            :mod (c2 / combine-01))
      :ARG1 (a / affect-01
            :ARG2 (i / inhibit-01
                  :ARG1 (g / grow-01)))
      :ARG1-of (s / show-01
            :ARG0 (f / figure :mod "6B")))

# ::id a_pmid_2256_9000.186 ::date 2015-06-02T13:00:24 ::annotator SDL-AMR-09 ::preferred
# ::snt To determine whether the growth inhibitory effect of oligonucleotide HYB 190 correlated with a reduction in RI<i>α</i> protein levels, we performed protein blots on total cell extracts prepared from H460 cells treated with oligonucleotide HYB 190, oligonucleotide HYB 239, selumetinib, and combinations.
# ::save-date Tue Aug 4, 2015 ::file a_pmid_2256_9000_186.txt
(p / perform-01
      :ARG0 (w / we)
      :ARG1 (i2 / immunoblot-01
            :ARG1 (p2 / protein)
            :ARG2 (m / molecular-physical-entity
                  :ARG1-of (e / extract-01
                        :ARG2 (c2 / cell))
                  :mod (t / total)
                  :ARG1-of (p4 / prepare-01
                        :ARG2 (c3 / cell-line :name (n3 / name :op1 "H460")
                              :ARG1-of (t2 / treat-04
                                    :ARG2 (o2 / or
                                          :op1 o
                                          :op2 (o3 / oligonucleotide :name (n4 / name :op1 "HYB" :op2 "239"))
                                          :op3 (s / small-molecule :name (n5 / name :op1 "selumetinib"))
                                          :op4 (c4 / combine-01)))))))
      :purpose (d / determine-01
            :ARG0 w
            :ARG1 (c / correlate-01 :mode interrogative
                  :ARG1 (a / affect-01
                        :ARG0 (o / oligonucleotide :name (n / name :op1 "HYB" :op2 "190"))
                        :ARG2 (i / inhibit-01
                              :ARG0 o3
                              :ARG1 (g / grow-01)))
                  :ARG2 (r / reduce-01
                        :ARG1 (l / level
                              :quant-of (p3 / protein-segment :name (n2 / name :op1 "RIα")))))))

# ::id a_pmid_2256_9000.187 ::date 2015-06-02T13:11:21 ::annotator SDL-AMR-09 ::preferred
# ::snt Compared with untreated H460 cells, RI<i>α</i> levels were substantially unchanged, even in cells treated with a higher dose of the control oligonucleotide HYB 239 (1 <i>μ</i>ℳ) and selumetinib (5 <i>μ</i>ℳ).
# ::save-date Sun Jan 3, 2016 ::file a_pmid_2256_9000_187.txt
(c / change-01 :polarity -
      :ARG1 (l / level
            :quant-of (p / protein-segment :name (n / name :op1 "RIα"))
            :compared-to (c2 / cell-line :name (n2 / name :op1 "H460")
                  :ARG1-of (t / treat-04 :polarity -)))
      :degree (s / substantial)
      :concession (t2 / treat-04
            :ARG1 (c3 / cell)
            :ARG2 (a / and
                  :op1 (d / dose
                        :ARG1-of (h / high-02
                              :degree (m / more))
                        :quant-of (o / oligonucleotide :name (n3 / name :op1 "HYB" :op2 "239")
                              :ARG0-of (c4 / control-01))
                        :ARG1-of (m2 / mean-01
                              :ARG2 (c5 / concentration-quantity :quant 1
                                    :unit (m3 / micromolar))))
                  :op1 (d2 / dose
                        :ARG1-of h
                        :quant-of (s2 / small-molecule :name (n4 / name :op1 "selumetinib"))
                        :ARG1-of (m5 / mean-01
                              :ARG2 (m6 / mass-quantity :quant 5
                                    :unit m3))))))

# ::id a_pmid_2256_9000.188 ::date 2015-06-02T13:30:31 ::annotator SDL-AMR-09 ::preferred
# ::snt However, reduction of RI<i>α</i> expression was seen when H460 cells were treated with oligonucleotide HYB 190 (<xref ref-type="fig" rid="fig6">Figure 6C</xref>).
# ::save-date Mon Jun 8, 2015 ::file a_pmid_2256_9000_188.txt
(c2 / contrast-01
      :ARG2 (s / see-01
            :ARG1 (r / reduce-01
                  :ARG1 (e / express-03
                        :ARG2 (p / protein-segment :name (n / name :op1 "RIα"))))
            :condition (t / treat-04
                  :ARG1 (c / cell-line :name (n2 / name :op1 "H460"))
                  :ARG2 (o / oligonucleotide :name (n3 / name :op1 "HYB" :op2 "190")))
            :ARG1-of (d / describe-01
                  :ARG0 (f / figure :mod "6C"))))

# ::id a_pmid_2256_9000.189 ::date 2015-06-02T13:34:48 ::annotator SDL-AMR-09 ::preferred
# ::snt Moreover, a complete inhibition of RI<i>α</i> expression was seen in the combination treatment (<xref ref-type="fig" rid="fig6">Figure 6C</xref>).
# ::save-date Tue Sep 15, 2015 ::file a_pmid_2256_9000_189.txt
(a / and
      :op2 (s / see-01
            :ARG1 (i / inhibit-01
                  :ARG1 (e / express-03
                        :ARG2 (p / protein-segment :name (n / name :op1 "RIα")))
                  :degree (c / complete-02))
            :condition (t / treat-04
                  :mod (c2 / combine-01))
            :ARG1-of (d / describe-01
                  :ARG0 (f / figure :mod "6C"))))

# ::id a_pmid_2256_9000.190 ::date 2015-06-02T13:36:16 ::annotator SDL-AMR-09 ::preferred
# ::snt We finally evaluated whether the combined inhibition of both PKA and MEK pathways would have antitumour activity <i>in vivo</i> in selumetinib-resistant HCT15 and H460 xenografts (<xref ref-type="fig" rid="fig7">Figure 7</xref>).
# ::save-date Mon Dec 21, 2015 ::file a_pmid_2256_9000_190.txt
(e2 / evaluate-01 :li "-1"
      :ARG0 (w2 / we)
      :ARG1 (a / activity-06 :mode interrogative
            :ARG0 (i / inhibit-01
                  :ARG1 (a2 / and
                        :op1 (p / pathway :name (n2 / name :op1 "PKA"))
                        :op2 (p2 / pathway :name (n3 / name :op1 "MEK")))
                  :ARG1-of (c / combine-01))
            :ARG1 (c2 / counter-01
                  :ARG1 (t / tumor))
            :manner (i2 / in-vivo)
            :location (a3 / and
                  :op1 (x / xenograft
                        :source (c3 / cell-line :name (n / name :op1 "HCT15")))
                  :op2 (x2 / xenograft
                        :source (c4 / cell-line :name (n4 / name :op1 "H460")))
                  :ARG0-of (r / resist-01
                        :ARG1 (s / small-molecule :name (n6 / name :op1 "selumetinib")))))
      :ARG1-of (d / describe-01
            :ARG0 (f2 / figure :mod 7)))

# ::id a_pmid_2256_9000.191 ::date 2015-06-02T13:42:54 ::annotator SDL-AMR-09 ::preferred
# ::snt At day 50 from cancer cell injection, the mean tumour volume in mice bearing HCT15 and H460 tumour xenografts and treated with selumetinib, 25 mg kg<sup>−1</sup>, and 8-Cl-cAMP, 0.5 mg kg<sup>−1</sup>, were 20% and 16%, respectively, as compared with control untreated mice.
# ::save-date Sun Jan 17, 2016 ::file a_pmid_2256_9000_191.txt
(a / and
      :op1 (e / equal-01
            :ARG1 (v / volume
                  :mod (t / tumor)
                  :mod (m / mean))
            :ARG2 (p / percentage-entity :value 20)
            :location (m2 / mouse
                  :ARG0-of (b / bear-01
                        :ARG1 (a2 / and
                              :op1 (x / xenograft
                                    :source (t2 / tumor
                                          :mod (c6 / cell-line :name (n / name :op1 "HCT15"))))
                              :op2 (x2 / xenograft
                                    :source (t3 / tumor
                                          :mod (c4 / cell-line :name (n2 / name :op1 "H460"))))))
                  :ARG1-of (t4 / treat-04
                        :ARG2 (s / small-molecule :name (n4 / name :op1 "selumetinib")
                              :mod (c / concentration-quantity :quant 25
                                    :unit (m3 / milligram-per-kilogram))))))
      :op2 (e2 / equal-01
            :ARG1 v
            :ARG2 (p2 / percentage-entity :value 16)
            :location (m4 / mouse
                  :ARG0-of b
                  :ARG1-of (t5 / treat-04
                        :ARG2 (s2 / small-molecule :name (n5 / name :op1 "8-Cl-cAMP")
                              :mod (c2 / concentration-quantity :quant 0.5
                                    :unit (m5 / milligram-per-kilogram))))))
      :time (a3 / after
            :op1 (i / inject-01
                  :ARG1 (c3 / cell
                        :mod (d / disease :wiki "Cancer" :name (n3 / name :op1 "cancer"))))
            :quant (t6 / temporal-quantity :quant 50
                  :unit (d2 / day)))
      :compared-to (m6 / mouse
            :ARG0-of (c5 / control-01)
            :ARG1-of (t7 / treat-04 :polarity -)))

# ::id a_pmid_2458_8908.10 ::date 2015-06-04T08:56:43 ::annotator SDL-AMR-09 ::preferred
# ::snt In a cohort of 144 metastatic melanoma patients we found that patients with N-RAS mutant melanoma had a worse prognosis.
# ::save-date Thu Dec 10, 2015 ::file a_pmid_2458_8908_10.txt
(f / find-01
      :ARG0 (w / we)
      :ARG1 (h / have-03
            :ARG0 (p / person
                  :ARG0-of (h2 / have-03
                        :ARG1 (m5 / medical-condition :name (n / name :op1 "melanoma")
                              :mod (e / enzyme :name (n2 / name :op1 "N-RAS")
                                    :ARG2-of (m / mutate-01))))
                  :ARG0-of (h4 / have-rel-role-91
                        :ARG2 (p4 / patient))
                  :ARG1-of (i / include-91
                        :ARG2 (c / cohort
                              :consist-of (p3 / person :quant 144
                                    :ARG0-of (h3 / have-03
                                          :ARG1 (m4 / medical-condition :name (n3 / name :op1 "melanoma")
                                                :ARG1-of (m3 / metastasize-101)))
                                    :ARG0-of (h5 / have-rel-role-91
                                          :ARG2 (p5 / patient))))))
            :ARG1 (p2 / prognosis
                  :ARG1-of (b / bad-07
                        :degree (m2 / more)))))

# ::id a_pmid_2458_8908.11 ::date 2015-06-04T09:02:21 ::annotator SDL-AMR-09 ::preferred
# ::snt These patients were more likely to have brain metastases at the time of presentation with metastatic disease than their N-RAS-wild-type counterparts.
# ::save-date Wed Oct 14, 2015 ::file a_pmid_2458_8908_11.txt
(l / likely-01
      :ARG1 (h / have-03
            :ARG0 (p / person
                  :mod (t / this)
                  :compared-to (c / counterpart
                              :mod (e / enzyme :name (n / name :op1 "N-RAS")
                                    :mod (w / wild-type)))
                  :ARG0-of (h2 / have-rel-role-91
                        :ARG2 (p3 / patient)))
            :ARG1 (m / metastasize-101
                  :ARG2 (b / brain))
            :time (p2 / present-102
                  :ARG0 p
                  :ARG1 (d / disease
                        :ARG1-of (m2 / metastasize-101))))
      :degree (m3 / more))

# ::id a_pmid_2458_8908.12 ::date 2015-06-04T11:08:51 ::annotator SDL-AMR-09 ::preferred
# ::snt All N-RAS mutant melanoma cultures tested in our study (n = 7) were sensitive to MEK inhibition162.
# ::save-date Mon Feb 15, 2016 ::file a_pmid_2458_8908_12.txt
(s / sensitive-03
      :ARG0 (c / culture-01 :quant 7
            :ARG1 (m2 / medical-condition :name (n3 / name :op1 "melanoma")
                  :mod (e / enzyme :name (n4 / name :op1 "N-RAS")
                        :ARG2-of (m / mutate-01)))
            :ARG1-of (t / test-01
                  :medium (s2 / study-01
                        :ARG0 (w / we)))
            :mod (a / all))
      :ARG1 (i / inhibit-01
            :ARG0 (s3 / small-molecule :name (n2 / name :op1 "MEK" :op2 "162"))))

# ::id a_pmid_2458_8908.13 ::date 2015-06-04T09:06:40 ::annotator SDL-AMR-09 ::preferred
# ::snt Exposure to MEK162 reduced ERK1/2 phosphorylation, and induced apoptosis.
# ::save-date Sun Dec 20, 2015 ::file a_pmid_2458_8908_13.txt
(a / and
      :op1 (r2 / reduce-01
            :ARG0 (e2 / expose-01
                  :ARG2 (s2 / small-molecule :name (n3 / name :op1 "MEK162")))
            :ARG1 (p / phosphorylate-01
                  :ARG1 (e4 / enzyme :name (n4 / name :op1 "ERK1/2"))))
      :op2 (i2 / induce-01
            :ARG0 e2
            :ARG2 (a3 / apoptosis)))

# ::id a_pmid_2458_8908.14 ::date 2015-06-04T09:17:01 ::annotator SDL-AMR-09 ::preferred
# ::snt Clonogenic survival was significantly reduced in sensitive melanoma cell cultures.
# ::save-date Thu Dec 10, 2015 ::file a_pmid_2458_8908_14.txt
(r / reduce-01
      :ARG1 (s2 / survive-01
            :mod (c / clonogen))
      :ARG2 (s / significant-02)
      :location (c2 / culture-01
            :ARG1 (c3 / cell
                  :ARG0-of (s3 / sensitive-03)
                  :mod (m / medical-condition :name (n / name :op1 "melanoma")))))

# ::id a_pmid_2458_8908.58 ::date 2015-06-04T09:55:03 ::annotator SDL-AMR-09 ::preferred
# ::snt Clinical profiles of patients whose tumors harbor N-RAS and B-RAF mutations
# ::save-date Wed Oct 14, 2015 ::file a_pmid_2458_8908_58.txt
(p / profile-01
      :ARG1 (p2 / person
            :ARG0-of (h2 / have-03
                  :ARG1 (t / tumor
                        :ARG0-of (h / harbor-01
                              :ARG1 (m / mutate-01
                                    :ARG1 (a / and
                                          :op1 (e / enzyme :name (n3 / name :op1 "N-RAS"))
                                          :op2 (e2 / enzyme :name (n4 / name :op1 "B-RAF")))))))
            :ARG0-of (h3 / have-rel-role-91
                  :ARG2 (p3 / patient)))
      :mod (c / clinical))

# ::id a_pmid_2458_8908.59 ::date 2015-06-04T10:05:57 ::annotator SDL-AMR-09 ::preferred
# ::snt Characteristics of our cohort of 144 patients with stage IV melanoma are shown in Table <xref ref-type="table" rid="T1">1</xref>.
# ::save-date Tue Dec 22, 2015 ::file a_pmid_2458_8908_59.txt
(s / show-01
      :ARG0 (t / table :mod 1)
      :ARG1 (c / characteristic-02
            :ARG1 (p / person :quant 144
                  :ARG0-of (h / have-03
                        :ARG1 (m / medical-condition :name (n / name :op1 "melanoma")
                              :ARG1-of (s2 / stage-02
                                    :ARG2 "IV")))
                  :ARG0-of (h2 / have-rel-role-91
                        :ARG2 (p2 / patient))
                  :ARG1-of (i / include-91
                        :ARG2 (c2 / cohort
                              :poss (w / we))))))

# ::id a_pmid_2458_8908.60 ::date 2015-06-04T10:24:42 ::annotator SDL-AMR-09 ::preferred
# ::snt Mutations were found in B-RAF in 43.7%, N-RAS in 27.7%, and 28.4% were wild type (WT) for both.
# ::save-date Fri Jun 26, 2015 ::file a_pmid_2458_8908_60.txt
(f / find-01
      :ARG1 (m / mutate-01
            :ARG1 (a2 / and
                  :op1 (e / enzyme :name (n3 / name :op1 "B-RAF")
                        :quant (p4 / percentage-entity :value 43.7))
                  :op2 (e2 / enzyme :name (n4 / name :op1 "N-RAS")
                        :quant (p5 / percentage-entity :value 27.7))
                  :ARG2-of (i / include-91
                        :ARG1 (e3 / enzyme
                              :mod (w2 / wild-type))
                        :ARG3 (p6 / percentage-entity :value 28.4)))))

# ::id a_pmid_2458_8908.61 ::date 2015-06-04T10:42:40 ::annotator SDL-AMR-09 ::preferred
# ::snt The majority of B-RAF mutations were represented by substitution of valine at position 600 to glutamic acid (74.6% were B-RAF<sup>V600E</sup>) or to lysine (19% were B-RAF<sup>V600K</sup>).
# ::save-date Fri Jun 26, 2015 ::file a_pmid_2458_8908_61.txt
(o2 / or
      :op1 (r / represent-01
            :ARG0 (s / substitute-01
                  :ARG1 (a / amino-acid :name (n2 / name :op1 "glutamic" :op2 "acid"))
                  :ARG2 (a2 / amino-acid :mod 600 :name (n5 / name :op1 "valine")))
            :ARG1 (m / mutate-01
                  :ARG1-of (i / include-91
                        :ARG2 (m5 / mutate-01
                              :ARG2 (e2 / enzyme :name (n / name :op1 "B-RAF")))
                        :ARG3 (m2 / majority))
                  :ARG2-of (i2 / include-91
                        :ARG1 (m3 / mutate-01 :value "V600E"
                              :ARG2 e2)
                        :ARG3 (p / percentage-entity :value 74.6))))
      :op2 (r2 / represent-01
            :ARG0 (s2 / substitute-01
                  :ARG1 (a4 / amino-acid :name (n7 / name :op1 "lysine"))
                  :ARG2 a2)
            :ARG1 (m6 / mutate-01
                  :ARG1-of i
                  :ARG2-of (i3 / include-91
                        :ARG1 (m4 / mutate-01 :value "V600K"
                              :ARG2 e2)
                        :ARG3 (p2 / percentage-entity :value 19)))))

# ::id a_pmid_2458_8908.62 ::date 2015-06-14T01:04:39 ::annotator SDL-AMR-09 ::preferred
# ::snt Substitutions of glutamine 61 accounted for 95% of N-RAS mutations (most frequently Q61R/K/L/H).
# ::save-date Mon Dec 21, 2015 ::file a_pmid_2458_8908_62.txt
(a / account-01
      :ARG0 (s / substitute-01
            :ARG2 (a2 / amino-acid :mod 61 :name (n / name :op1 "glutamine")))
      :ARG2 (m / mutate-01
            :ARG1 (e / enzyme :name (n2 / name :op1 "N-RAS"))
            :ARG2-of (i / include-91
                  :ARG1 (a3 / and
                        :op1 (m2 / mutate-01 :value "Q61R")
                        :op2 (m5 / mutate-01 :value "Q61K")
                        :op3 (m6 / mutate-01 :value "Q61L")
                        :op4 (m7 / mutate-01 :value "Q61H"))
                  :ARG1-of (f / frequent-02
                        :degree (m3 / most)))
            :ARG1-of (i2 / include-91
                  :ARG2 (m4 / mutate-01
                        :ARG1 e)
                  :ARG3 (p2 / percentage-entity :value 95))))

# ::id a_pmid_2458_8908.63 ::date 2015-06-04T11:25:19 ::annotator SDL-AMR-09 ::preferred
# ::snt The slightly higher percentage of N-RAS mutant melanomas in our population than what is commonly reported may be a result of the relatively small sample size or a reflection of local demographics.
# ::save-date Mon Dec 21, 2015 ::file a_pmid_2458_8908_63.txt
(p / possible-01
      :ARG1 (o2 / or
            :op1 (r / result-01
                  :ARG1 (s2 / size-01
                        :ARG1 (t2 / thing
                              :ARG1-of (s3 / sample-01))
                        :ARG2 (s4 / small
                              :ARG2-of (r4 / relative-05)))
                  :ARG2 (p2 / percentage
                        :ARG1-of (h / high-02
                              :degree (m2 / more
                                    :degree (s / slight)))
                        :quant-of (m / medical-condition :name (n / name :op1 "melanoma")
                              :mod (e / enzyme :name (n2 / name :op1 "N-RAS")
                                    :ARG2-of (m3 / mutate-01)))
                        :location (p3 / population
                              :poss (w / we))
                        :compared-to (t / thing
                                    :ARG1-of (r2 / report-01
                                          :mod (c / common)))))
            :op2 (r3 / reflect-01
                  :ARG1 p2
                  :ARG2 (d / demographics
                        :ARG1-of (l / local-02)))))

# ::id a_pmid_2458_8908.64 ::date 2015-06-04T09:03:45 ::annotator SDL-AMR-09 ::preferred
# ::snt Clinical and pathological characteristics
# ::save-date Sun Jun 21, 2015 ::file a_pmid_2458_8908_64.txt
(c / characteristic-02
      :mod (c2 / clinical)
      :mod (p / pathology))

# ::id a_pmid_2458_8908.65 ::date 2015-06-04T09:05:27 ::annotator SDL-AMR-09 ::preferred
# ::snt Patients with B-RAF mutations tended to be younger; median age at initial diagnosis of melanoma was 57.6 in patients with B-RAF mutations, 68.2 in patients with N-RAS mutations and 66.3 years in patients wild-type for both (P <0.0001).
# ::save-date Thu Dec 10, 2015 ::file a_pmid_2458_8908_65.txt
(a3 / and
      :op1 (t / tend-02
            :ARG1 (p / person
                  :ARG0-of (h4 / have-rel-role-91
                        :ARG2 (p3 / patient
                              :mod (e3 / enzyme :name (n / name :op1 "B-RAF")
                                    :ARG2-of (m / mutate-01)))))
            :ARG2 (p2 / person
                  :mod (y / young
                        :degree (m3 / more))))
      :op2 (a / and
            :op1 (a4 / age-01
                  :ARG1 p
                  :ARG2 (t2 / temporal-quantity :quant 57.6
                        :unit (y2 / year)))
            :op2 (a5 / age-01
                  :ARG1 (p4 / person
                        :ARG0-of (h6 / have-rel-role-91
                              :ARG2 (p7 / patient
                                    :mod (e / enzyme :name (n4 / name :op1 "N-RAS")
                                          :ARG2-of (m6 / mutate-01)))))
                  :ARG2 (t3 / temporal-quantity :quant 68.2
                        :unit (y3 / year)))
            :op3 (a6 / age-01
                  :ARG1 (p5 / person
                        :ARG0-of (h7 / have-rel-role-91
                              :ARG2 (p8 / patient
                                    :mod e
                                    :mod e3
                                    :mod (w / wild-type))))
                  :ARG2 (t4 / temporal-quantity :quant 66.3
                        :unit (y4 / year)))
            :mod (m4 / median)
            :time (d / diagnose-01
                  :ARG2 (m2 / medical-condition :name (n2 / name :op1 "melanoma"))
                  :mod (i / initial))
            :ARG1-of (p6 / possible-01
                  :quant (l / less-than :value 0.0001))))

# ::id a_pmid_2458_8908.66 ::date 2015-06-14T02:18:32 ::annotator SDL-AMR-09 ::preferred
# ::snt Our cohort included 22 patients who received either dabrafenib (N = 1), vemurafenib (N = 19), a pan-RAF inhibitor (N = 1) or a pan-RAF inhibitor and vemurafenib (N = 1).
# ::save-date Wed Oct 14, 2015 ::file a_pmid_2458_8908_66.txt
(i2 / include-01
      :ARG1 (p / person :quant 22
            :ARG0-of (h / have-rel-role-91
                  :ARG2 (p6 / patient
                        :ARG2-of (i7 / include-91
                              :ARG1 (a2 / and
                                    :op1 (p2 / person :quant 1
                                          :ARG0-of (h2 / have-rel-role-91
                                                :ARG2 (p7 / patient))
                                          :ARG0-of (r2 / receive-01
                                                :ARG1 (s / small-molecule :name (n / name :op1 "dabrafenib"))))
                                    :op2 (p3 / person :quant 19
                                          :ARG0-of h2
                                          :ARG0-of (r3 / receive-01
                                                :ARG1 (s2 / small-molecule :name (n2 / name :op1 "vemurafenib"))))
                                    :op3 (p4 / person :quant 1
                                          :ARG0-of h2
                                          :ARG0-of (r4 / receive-01
                                                :ARG1 (m / molecular-physical-entity
                                                      :ARG0-of (i / inhibit-01
                                                            :ARG1 (e / enzyme :name (n4 / name :op1 "pan-RAF"))))))
                                    :op4 (p5 / person :quant 1
                                          :ARG0-of h2
                                          :ARG0-of (r5 / receive-01
                                                :ARG2 (a3 / and
                                                      :op1 m
                                                      :op2 s2))))))))
      :ARG2 (c / cohort
            :poss (w / we)))

# ::id a_pmid_2458_8908.67 ::date 2015-06-14T02:45:57 ::annotator SDL-AMR-09 ::preferred
# ::snt Patients with N-RAS mutated melanomas appear to have an increased rate of skin and soft tissue involvement (70%) compared to B-RAF mutated counterparts and WT patients (37% and 41% respectively, P = 0.0025).
# ::save-date Mon Dec 21, 2015 ::file a_pmid_2458_8908_67.txt
(a / appear-01
      :ARG1 (i / increase-01
            :ARG1 (r / rate
                  :degree-of (i2 / involve-01
                        :ARG1 (a2 / and
                              :op1 (s / skin)
                              :op2 (t / tissue
                                    :ARG1-of (s2 / soft-02))))
                  :mod (p6 / percentage-entity :value 70))
            :ARG1-of (h / have-03
                  :ARG0 (p2 / person
                        :ARG0-of (h2 / have-03
                              :ARG1 (m2 / medical-condition :name (n3 / name :op1 "melanoma")
                                    :mod (e / enzyme :name (n4 / name :op1 "N-RAS")
                                          :ARG2-of (m / mutate-01))))
                        :ARG0-of (h3 / have-rel-role-91
                              :ARG2 (p3 / patient))))
            :ARG1-of (c / compare-01
                  :ARG2 (a3 / and
                        :op1 (r3 / rate
                              :degree-of i2
                              :mod (c3 / counterpart
                                    :mod (e2 / enzyme :name (n5 / name :op1 "B-RAF")
                                          :ARG2-of (m3 / mutate-01)))
                              :mod (p7 / percentage-entity :value 37))
                        :op2 (r4 / rate
                              :degree-of i2
                              :mod (p4 / person
                                    :ARG0-of (h4 / have-rel-role-91
                                          :ARG2 (p5 / patient
                                                :mod (e3 / enzyme :name (n / name :op1 "B-RAF")
                                                      :mod (w2 / wild-type)))))
                              :mod (p8 / percentage-entity :value 41))
                        :mod (r2 / respective))))
      :ARG1-of (p / possible-01 :value 0.0025))

# ::id a_pmid_2458_8908.68 ::date 2015-06-14T02:55:18 ::annotator SDL-AMR-09 ::preferred
# ::snt The rate of lymph node metastasis was also noted to be higher in patients with N-RAS mutations (75%) compared to B-RAF mutant and WT patients (46% and 61%, respectively) (P = 0.01).
# ::save-date Mon Dec 21, 2015 ::file a_pmid_2458_8908_68.txt
(n3 / note-02
      :ARG1 (r / rate
            :mod (p4 / percentage-entity :value 75)
            :ARG1-of (h2 / high-02
                  :degree (m3 / more))
            :mod (m / metastasize-101
                  :ARG2 (n4 / node
                        :mod (l / lymph)))
            :condition (p / person
                  :ARG0-of (h / have-rel-role-91
                        :ARG2 (p2 / patient
                              :mod (e / enzyme :name (n5 / name :op1 "N-RAS")
                                    :ARG2-of (m4 / mutate-01)))))
            :ARG1-of (c / compare-01
                  :ARG2 (a / and
                        :op1 (r3 / rate
                              :mod (p3 / person
                                    :ARG0-of (h3 / have-rel-role-91
                                          :ARG2 (p5 / patient))
                                    :mod (e2 / enzyme :name (n6 / name :op1 "B-RAF")
                                          :ARG2-of (m5 / mutate-01)))
                              :mod (p7 / percentage-entity :value 46))
                        :op2 (r2 / rate
                              :mod (p6 / person
                                    :ARG0-of h3
                                    :mod (w / wild-type))
                              :mod (p8 / percentage-entity :value 61)))))
      :ARG1-of (p9 / possible-01 :value 0.01)
      :mod (a2 / also))

# ::id a_pmid_2458_8908.69 ::date 2015-06-15T08:03:17 ::annotator SDL-AMR-09 ::preferred
# ::snt No statistically significant difference was seen between the genotypes and other clinical characteristics, such as M stage and LDH levels.Seeing that B-RAF inhibitors can affect survival in patients with B-RAF mutant melanomas, this group of patients was removed from the survival analysis.
# ::save-date Mon Jan 4, 2016 ::file a_pmid_2458_8908_69.txt
(m / multi-sentence
      :snt1 (s / see-01 :polarity -
            :ARG1 (d / differ-02
                  :ARG1 (g / genotype)
                  :ARG2 (c / characteristic-02
                        :ARG2 (a / and
                              :op1 (e5 / event :name (n4 / name :op1 "M" :op2 "stage"))
                              :op2 (l / level
                                    :quant-of (e3 / enzyme :name (n3 / name :op1 "LDH")))
                              :ARG1-of (e / exemplify-01))
                        :mod (c2 / clinic)
                        :mod (o / other))
                  :ARG1-of (s2 / significant-02
                        :mod (s3 / statistic))))
      :snt2 (s7 / see-01
            :ARG1 (p / possible-01
                  :ARG1 (a2 / affect-01
                        :ARG0 (m3 / molecular-physical-entity
                              :ARG0-of (i2 / inhibit-01
                                    :ARG1 (e4 / enzyme :name (n / name :op1 "B-RAF"))))
                        :ARG1 (s5 / survive-01
                              :ARG0 (p2 / person
                                    :ARG0-of (h / have-03
                                          :ARG1 (m2 / medical-condition :name (n5 / name :op1 "melanoma")
                                                :mod (e2 / enzyme :name (n2 / name :op1 "B-RAF")
                                                      :ARG2-of (m4 / mutate-01))))
                                    :ARG0-of (h2 / have-rel-role-91
                                          :ARG2 (p3 / patient))))))
            :ARG0-of (c4 / cause-01
                  :ARG1 (r / remove-01
                        :ARG1 (g2 / group
                              :mod (t / this)
                              :ARG2-of (i / include-91
                                    :ARG1 p2))
                        :ARG2 (a3 / analyze-01
                              :ARG1 (s6 / survive-01))))))

# ::id a_pmid_2458_8908.70 ::date 2015-06-15T08:21:07 ::annotator SDL-AMR-09 ::preferred
# ::snt By Cox univariate analysis we found a trend towards shorter survival in the N-RAS mutant population, compared to the B-RAF and WT groups combined (p = 0.12).
# ::save-date Wed Aug 5, 2015 ::file a_pmid_2458_8908_70.txt
(f / find-01
      :ARG0 (w / we)
      :ARG1 (t / trend-01
            :ARG2 (s / survive-01
                  :ARG1 (p / population
                        :ARG0-of (h / have-03
                              :ARG1 (e3 / enzyme :name (n3 / name :op1 "N-RAS")
                                    :ARG2-of (m / mutate-01))))
                  :ARG1-of (s2 / short-07
                        :degree (m2 / more))
                  :ARG1-of (c / compare-01
                        :ARG2 (a / and
                              :op1 (g / group
                                    :mod (e4 / enzyme :name (n4 / name :op1 "B-RAF")))
                              :op2 (g2 / group
                                    :mod (w2 / wild-type))
                              :ARG1-of (c3 / combine-01)))))
      :ARG1-of (p2 / possible-01 :value 0.12)
      :manner (a3 / analyze-01 :name (n / name :op1 "Cox")
            :mod (u / univariate)))

# ::id a_pmid_2458_8908.71 ::date 2015-06-14T07:59:42 ::annotator SDL-AMR-09 ::preferred
# ::snt The median survival was 13 and 19.6 months, respectively.
# ::save-date Tue Jun 23, 2015 ::file a_pmid_2458_8908_71.txt
(s / survive-01
      :mod (m2 / median)
      :duration (a / and
            :op1 (t / temporal-quantity :quant 13
                  :unit (m / month))
            :op2 (t4 / temporal-quantity :quant 19.6
                  :unit m)
            :mod (r / respective)))

# ::id a_pmid_2458_8908.72 ::date 2015-06-14T08:03:21 ::annotator SDL-AMR-09 ::preferred
# ::snt Kaplan-Meier survival curves are shown in Figure <xref ref-type="fig" rid="F1">1</xref>a for the three groups of patients (BRAF or NRAS mutant or WT for both) and Figure <xref ref-type="fig" rid="F1">1</xref>b for the two groups (NRAS compared to BRAF mutant and WT combined) to visually demonstrate the differences between the groups.
# ::save-date Wed Oct 14, 2015 ::file a_pmid_2458_8908_72.txt
(s / show-01
      :ARG0 (a / and
            :op1 (f / figure :mod "1a"
                  :beneficiary (g / group-01 :quant 3
                        :ARG1 (p / person
                              :ARG0-of (h2 / have-rel-role-91
                                    :ARG2 (p2 / patient))
                              :mod (o2 / or
                                    :op1 (e / enzyme :name (n / name :op1 "BRAF")
                                          :ARG2-of (m4 / mutate-01))
                                    :op2 (e3 / enzyme :name (n4 / name :op1 "BRAF")
                                          :mod (w2 / wild-type))
                                    :op3 (e2 / enzyme :name (n2 / name :op1 "NRAS")
                                          :ARG2-of (m5 / mutate-01))
                                    :op4 (e4 / enzyme :name (n5 / name :op1 "NRAS")
                                          :mod (w3 / wild-type))))))
            :op2 (f2 / figure :mod "1b"
                  :beneficiary (g2 / group-01 :quant 2
                        :mod (c / compare-01
                              :ARG1 (e5 / enzyme :name (n3 / name :op1 "NRAS"))
                              :ARG2 (c2 / combine-01
                                    :ARG1 e
                                    :ARG2 e3)))))
      :ARG1 (c4 / curve :name (n6 / name :op1 "Kaplan-Meier")
            :mod (s2 / survive-01))
      :purpose (d / demonstrate-01
            :ARG1 (d2 / differ-02
                  :ARG1 g
                  :ARG2 g2)
            :mod (v / visual)))

# ::id a_pmid_2458_8908.73 ::date 2015-06-14T13:58:23 ::annotator SDL-AMR-09 ::preferred
# ::snt Interestingly, analysis of anatomic sites at the time of initial diagnosis of stage IV disease revealed a higher rate of brain involvement among B-RAF (16%) and N-RAS (15%) mutant melanoma patients, compared with patients with WT disease (2.5%) (P =0.04).
# ::save-date Tue Dec 22, 2015 ::file a_pmid_2458_8908_73.txt
(r / reveal-01
      :ARG0 (a / analyze-01
            :ARG1 (s / site
                  :mod (a2 / anatomy))
            :time (d / diagnose-01
                  :ARG2 (d2 / disease
                        :ARG1-of (s2 / stage-02
                              :ARG2 "IV"))
                  :mod (i / initial)))
      :ARG1 (a4 / and
            :op1 (r3 / rate
                  :mod (i4 / involve-01
                        :ARG1 (b / brain)
                        :prep-among (p3 / person
                              :ARG0-of (h / have-rel-role-91
                                    :ARG2 (p8 / patient
                                          :mod (m3 / medical-condition :name (n5 / name :op1 "melanoma")
                                                :mod (e / enzyme :name (n / name :op1 "B-RAF")
                                                      :ARG2-of (m / mutate-01)))))))
                  :mod (p4 / percentage-entity :value 16))
            :op2 (r4 / rate
                  :mod (i5 / involve-01
                        :ARG1 b
                        :prep-among (p9 / person
                              :ARG0-of (h5 / have-rel-role-91
                                    :ARG2 (p10 / patient
                                          :mod (m5 / medical-condition :name (n2 / name :op1 "melanoma")
                                                :mod (e2 / enzyme :name (n6 / name :op1 "N-RAS")
                                                      :ARG2-of (m4 / mutate-01)))))))
                  :mod (p5 / percentage-entity :value 15))
            :ARG1-of (h2 / high-02
                  :degree (m2 / more))
            :ARG1-of (c / compare-01
                  :ARG2 (r2 / rate
                        :mod (i3 / involve-01
                              :ARG1 b)
                        :condition (p6 / person
                              :ARG0-of (h3 / have-rel-role-91
                                    :ARG2 (p7 / patient
                                          :mod (d6 / disease
                                                :mod (w2 / wild-type)))))
                        :mod (p / percentage-entity :value 2.5))))
      :ARG2-of (i2 / interest-01)
      :ARG1-of (p2 / possible-01 :value 0.04))

# ::id a_pmid_2458_8908.74 ::date 2015-06-14T14:27:14 ::annotator SDL-AMR-09 ::preferred
# ::snt With longitudinal follow-up, however, the rate of development of brain metastases did not differ among the three groups, possibly because the WT groups lived longer and thus developed brain metastases over time.
# ::save-date Fri Jun 26, 2015 ::file a_pmid_2458_8908_74.txt
(c3 / contrast-01
      :ARG2 (d / differ-02 :polarity -
            :ARG1 (g / group :quant 3)
            :ARG3 (r / rate
                  :mod (d2 / develop-01
                        :ARG2 (m / metastasize-101
                              :ARG2 (b / brain))))
            :ARG1-of (c2 / cause-01
                  :ARG0 (a2 / and
                        :op1 (l2 / live-01
                              :ARG0 (g2 / group
                                    :mod (w / wild-type))
                              :ARG1-of (l3 / long-03
                                    :degree (m2 / more)))
                        :op2 (d3 / develop-01
                              :ARG2 m
                              :duration (o / over
                                    :mod (t / time))
                              :ARG1-of (c4 / cause-01
                                    :ARG0 l2)))
                  :ARG1-of (p / possible-01)))
      :ARG1-of (c / condition-01
            :ARG2 (f / follow-up-03
                  :mod (l / longitude))))

# ::id a_pmid_2458_8908.75 ::date 2015-06-14T02:56:32 ::annotator SDL-AMR-09 ::preferred
# ::snt <i>In vitro</i> activity of B-RAF and MEK inhibitors in a large panel of melanoma cultures
# ::save-date Sat Jan 16, 2016 ::file a_pmid_2458_8908_75.txt
(a / activity-06
      :ARG0 (a2 / and
            :op1 (m2 / molecular-physical-entity
                  :ARG0-of (i / inhibit-01
                        :ARG1 (e / enzyme :name (n / name :op1 "B-RAF"))))
            :op2 (m3 / molecular-physical-entity
                  :ARG0-of (i3 / inhibit-01
                        :ARG1 (p2 / protein-family :name (n2 / name :op1 "MEK")))))
      :manner (i2 / in-vitro)
      :location (p / panel
            :mod (l / large)
            :consist-of (c / culture
                  :mod (m / medical-condition :name (n3 / name :op1 "melanoma")))))

# ::id a_pmid_2458_8908.76 ::date 2015-06-14T03:05:52 ::annotator SDL-AMR-09 ::preferred
# ::snt To investigate the effect of B-RAF and MEK inhibition in melanoma cultures, we used RAF265 (a pan-RAF inhibitor), MEK162 (a MEK1/2 inhibitor) and the MEK inhibitor trametinib.
# ::save-date Tue Jan 12, 2016 ::file a_pmid_2458_8908_76.txt
(u / use-01
      :ARG0 (w / we)
      :ARG1 (a / and
            :op1 (s2 / small-molecule :wiki -
                  :name (n4 / name :op1 "RAF265")
                  :ARG0-of (i2 / inhibit-01
                        :ARG1 (e / enzyme :wiki -
                              :name (n5 / name :op1 "pan-RAF"))))
            :op2 (s3 / small-molecule :wiki "Binimetinib"
                  :name (n6 / name :op1 "MEK162")
                  :ARG0-of (i3 / inhibit-01
                        :ARG1 (e7 / enzyme :wiki "Mitogen-activated_protein_kinase_kinase"
                              :name (n7 / name :op1 "MEK1/2"))))
            :op3 (s / small-molecule :wiki "Trametinib"
                  :name (n8 / name :op1 "trametinib")
                  :ARG0-of (i4 / inhibit-01
                        :ARG1 (p / protein-family :wiki "Mitogen-activated_protein_kinase_kinase"
                              :name (n9 / name :op1 "MEK")))))
      :ARG2 (i5 / investigate-01
            :ARG0 w
            :ARG1 (a2 / affect-01
                  :ARG0 (i6 / inhibit-01
                        :ARG0 (a3 / and
                              :op1 (e9 / enzyme :wiki -
                                    :name (n10 / name :op1 "B-RAF"))
                              :op2 p))
                  :ARG1 (c / culture
                        :mod (m / medical-condition :wiki "Melanoma"
                              :name (n12 / name :op1 "melanoma"))))))

# ::id a_pmid_2458_8908.77 ::date 2015-06-14T03:27:04 ::annotator SDL-AMR-09 ::preferred
# ::snt A panel of 22 patient-derived melanoma cultures was used; the IC<sub>50</sub> for RAF265 and MEK162 are shown in Table <xref ref-type="table" rid="T2">2</xref>.
# ::save-date Tue Dec 15, 2015 ::file a_pmid_2458_8908_77.txt
(m / multi-sentence
      :snt1 (u / use-01
            :ARG1 (p / panel
                  :consist-of (c / culture-01 :quant 22
                        :ARG1 (m2 / medical-condition :name (n / name :op1 "melanoma"))
                        :ARG1-of (d / derive-01
                              :ARG2 (p2 / person
                                    :ARG0-of (h / have-rel-role-91
                                          :ARG2 (p3 / patient)))))))
      :snt2 (s / show-01
            :ARG0 (t2 / table :mod 1)
            :ARG1 (c2 / concentration-quantity
                  :ARG4-of (h2 / have-percentage-maximal-inhibitory-concentration-01
                        :ARG1 (a / and
                              :op1 (s2 / small-molecule :name (n3 / name :op1 "RAF265"))
                              :op2 (s3 / small-molecule :name (n4 / name :op1 "MEK162")))
                        :ARG2 50))))

# ::id a_pmid_2458_8908.78 ::date 2015-06-14T03:51:15 ::annotator SDL-AMR-09 ::preferred
# ::snt This was compared to the IC<sub>50</sub> for trametinib (Additional file <xref ref-type="supplementary-material" rid="S1">1</xref>: Table S1).
# ::save-date Sun Jan 3, 2016 ::file a_pmid_2458_8908_78.txt
(c / compare-01
      :ARG1 (t / this)
      :ARG2 (h / have-percentage-maximal-inhibitory-concentration-01
            :ARG1 (s / small-molecule :name (n2 / name :op1 "trametinib"))
            :ARG2 50)
      :ARG1-of (d / describe-01
            :ARG0 (t3 / table :mod "S1"
                  :location (f / file :mod 1
                        :mod (a / additional)))))

# ::id a_pmid_2458_8908.79 ::date 2015-06-14T03:57:10 ::annotator SDL-AMR-09 ::preferred
# ::snt Patient-derived melanoma cultures with their B-RAF/N-RAS mutational status and sensitivity to RAF265 and MEK162
# ::save-date Thu Dec 10, 2015 ::file a_pmid_2458_8908_79.txt
(d / derive-01
      :ARG1 (c / culture-01
            :ARG1 (m2 / medical-condition :name (n / name :op1 "melanoma")))
      :ARG2 (p / person
            :ARG0-of (h / have-rel-role-91
                  :ARG2 (p2 / patient)))
      :accompanier (a / and
            :op1 (s / status
                  :mod (m / mutate-01
                        :ARG1 (s5 / slash
                              :op1 (e / enzyme :name (n5 / name :op1 "B-RAF"))
                              :op2 (e2 / enzyme :name (n6 / name :op1 "N-RAS"))))
                  :poss c)
            :op2 (s2 / sensitive-03
                  :ARG0 c
                  :ARG1 (a2 / and
                        :op1 (s3 / small-molecule :name (n3 / name :op1 "RAF265"))
                        :op2 (s4 / small-molecule :name (n4 / name :op1 "MEK162"))))))

# ::id a_pmid_2458_8908.80 ::date 2015-06-14T04:31:40 ::annotator SDL-AMR-09 ::preferred
# ::snt Cells were treated with each drug individually at concentrations ranging from 1 nM to 1000 nM and analyzed three days later.
# ::save-date Tue Dec 15, 2015 ::file a_pmid_2458_8908_80.txt
(a / and
      :op1 (t / treat-04
            :ARG1 (c / cell)
            :ARG2 (d / drug
                  :mod (c2 / concentration
                        :ARG1-of (r / range-01
                              :ARG3 (c3 / concentration-quantity :quant 1
                                    :unit (n / nanomolar))
                              :ARG4 (c4 / concentration-quantity :quant 1000
                                    :unit n)))
                  :mod (e / each))
            :manner (i / individual))
      :op2 (a2 / analyze-01
            :ARG1 c
            :time (l3 / late
                  :op1 (t3 / temporal-quantity :quant 3
                        :unit (d3 / day))
                  :degree (m4 / more))))

# ::id a_pmid_2458_8908.81 ::date 2015-06-14T04:50:12 ::annotator SDL-AMR-09 ::preferred
# ::snt As shown in Table <xref ref-type="table" rid="T2">2</xref>, the IC<sub>50</sub> for RAF265 ranged from 24 to >10000 nM, 4 to 2004 nM, and 62 to 2082 nM for WT, B-RAF mutant and N-RAS mutant cultures, respectively.
# ::save-date Wed Mar 2, 2016 ::file a_pmid_2458_8908_81.txt
(s / show-01
      :ARG0 (t / table :mod 2)
      :ARG1 (a / and
            :op1 (r / range-01
                  :ARG1 (c10 / concentration-quantity
                        :ARG4-of (h / have-percentage-maximal-inhibitory-concentration-01
                              :ARG1 (s2 / small-molecule :name (n / name :op1 "RAF265"))
                              :ARG2 50))
                  :ARG3 (c4 / concentration-quantity :quant 24
                        :unit (n5 / nanomolar))
                  :ARG4 (m / more-than
                        :op1 (c5 / concentration-quantity :quant 10000
                              :unit n5))
                  :location (c / culture-01
                        :mod (w / wild-type)))
            :op2 (r2 / range-01
                  :ARG1 (c11 / concentration-quantity
                        :ARG4-of (h2 / have-percentage-maximal-inhibitory-concentration-01
                              :ARG1 s2
                              :ARG2 50))
                  :ARG3 (c6 / concentration-quantity :quant 4
                        :unit n5)
                  :ARG4 (c7 / concentration-quantity :quant 2004
                        :unit n5)
                  :location (c2 / culture-01
                        :mod (m2 / mutate-01
                              :ARG2 (e / enzyme :name (n2 / name :op1 "B-RAF")))))
            :op3 (r3 / range-01
                  :ARG1 (c12 / concentration-quantity
                        :ARG4-of (h3 / have-percentage-maximal-inhibitory-concentration-01
                              :ARG1 s2
                              :ARG2 50))
                  :ARG3 (c8 / concentration-quantity :quant 62
                        :unit n5)
                  :ARG4 (c9 / concentration-quantity :quant 2082
                        :unit n5)
                  :location (c3 / culture-01
                        :mod (m3 / mutate-01
                              :ARG2 (e2 / enzyme :name (n3 / name :op1 "N-RAS")))))
            :mod (r4 / respective)))

# ::id a_pmid_2458_8908.82 ::date 2015-06-15T10:43:18 ::annotator SDL-AMR-09 ::preferred
# ::snt The IC<sub>50</sub> for MEK162 ranged from 10 to >10000 nM, < 1 to 150 nM, and 4 to 13 nM for WT, B-RAF mutant and N-RAS mutant melanoma cultures, respectively.
# ::save-date Tue Dec 15, 2015 ::file a_pmid_2458_8908_82.txt
(a / and
      :op1 (r / range-01
            :ARG1 (c10 / concentration-quantity
                  :ARG4-of (h / have-percentage-maximal-inhibitory-concentration-01
                        :ARG1 (s / small-molecule :name (n3 / name :op1 "MEK162"))
                        :ARG2 50)
                  :location (c / culture-01
                        :mod (w / wild-type)))
            :ARG3 (c4 / concentration-quantity :quant 10
                  :unit (n2 / nanomolar))
            :ARG4 (m / more-than
                  :op1 (c5 / concentration-quantity :quant 10000
                        :unit n2)))
      :op2 (r2 / range-01
            :ARG1 (c11 / concentration-quantity
                  :ARG4-of (h2 / have-percentage-maximal-inhibitory-concentration-01
                        :ARG1 s
                        :ARG2 50)
                  :location (c2 / culture-01
                        :mod (m2 / medical-condition :name (n5 / name :op1 "melanoma")
                              :mod (e2 / enzyme :name (n6 / name :op1 "B-RAF")
                                    :ARG2-of (m3 / mutate-01)))))
            :ARG3 (l / less-than
                  :op1 (c6 / concentration-quantity :quant 1
                        :unit n2))
            :ARG4 (c7 / concentration-quantity :quant 150
                  :unit n2))
      :op3 (r3 / range-01
            :ARG1 (c12 / concentration-quantity
                  :ARG4-of (h3 / have-percentage-maximal-inhibitory-concentration-01
                        :ARG1 s
                        :ARG2 50)
                  :location (c3 / culture-01
                        :mod (m5 / medical-condition :name n5
                              :mod (e / enzyme :name (n9 / name :op1 "N-RAS")
                                    :ARG2-of (m4 / mutate-01)))))
            :ARG3 (c8 / concentration-quantity :quant 4
                  :unit n2)
            :ARG4 (c9 / concentration-quantity :quant 13
                  :unit n2))
      :mod (r4 / respective))

# ::id a_pmid_2458_8908.83 ::date 2015-06-14T04:51:15 ::annotator SDL-AMR-09 ::preferred
# ::snt The sensitivity to RAF265 in wild type (2 out of 5) and N-RAS (2 out of 7) melanoma cultures was low.
# ::save-date Thu Dec 10, 2015 ::file a_pmid_2458_8908_83.txt
(s / sensitive-03
      :ARG0 (a2 / and
            :op1 (c2 / culture-01 :quant 2
                  :ARG1 (m / medical-condition :name (n4 / name :op1 "melanoma")
                        :mod (w2 / wild-type))
                  :ARG1-of (i3 / include-91
                        :ARG2 (c / culture-01 :quant 5)))
            :op2 (c3 / culture-01 :quant 2
                  :ARG1 (m2 / medical-condition :name (n5 / name :op1 "melanoma")
                        :mod (e / enzyme :name (n6 / name :op1 "N-RAS")))
                  :ARG1-of (i4 / include-91
                        :ARG2 (c4 / culture-01 :quant 7))))
      :ARG1 (s2 / small-molecule :name (n / name :op1 "RAF265"))
      :ARG1-of (l / low-04))

# ::id a_pmid_2458_8908.84 ::date 2015-06-14T05:44:21 ::annotator SDL-AMR-09 ::preferred
# ::snt Two wild type cultures (YUROB and YUSOC) are sensitive to both RAF265 and MEK162.
# ::save-date Mon Jun 22, 2015 ::file a_pmid_2458_8908_84.txt
(s / sensitive-03
      :ARG0 (c / culture-01 :quant 2
            :mod (w / wild-type)
            :ARG1-of (m / mean-01
                  :ARG2 (a / and
                        :op1 (c2 / cell-line :name (n / name :op1 "YUROB"))
                        :op2 (c3 / cell-line :name (n2 / name :op1 "YUSOC")))))
      :ARG1 (a2 / and
            :op1 (s2 / small-molecule :name (n3 / name :op1 "RAF265"))
            :op2 (s3 / small-molecule :name (n4 / name :op1 "MEK162"))
            :mod (b / both)))

# ::id a_pmid_2458_8908.85 ::date 2015-06-14T05:48:43 ::annotator SDL-AMR-09 ::preferred
# ::snt Six of ten B-RAF mutant cultures were sensitive to RAF265, and seven out of ten were sensitive to MEK162.
# ::save-date Fri Jun 26, 2015 ::file a_pmid_2458_8908_85.txt
(a / and
      :op1 (s / sensitive-03
            :ARG0 (c / culture-01 :quant 6
                  :mod (m / mutate-01
                        :ARG2 (e3 / enzyme :name (n3 / name :op1 "B-RAF")))
                  :ARG1-of (i3 / include-91
                        :ARG2 (c2 / culture-01 :quant 10)))
            :ARG1 (s3 / small-molecule :name (n4 / name :op1 "RAF265")))
      :op2 (s2 / sensitive-03
            :ARG0 (c3 / culture-01 :quant 7
                  :ARG1-of (i / include-91
                        :ARG2 c2)
                  :mod m)
            :ARG1 (s4 / small-molecule :name (n5 / name :op1 "MEK162"))))

# ::id a_pmid_2458_8908.86 ::date 2015-06-14T05:57:55 ::annotator SDL-AMR-09 ::preferred
# ::snt In N-RAS mutant melanoma cultures, 2 out of 7 were sensitive to RAF265 and, strikingly, all were sensitive to MEK162.
# ::save-date Thu Dec 10, 2015 ::file a_pmid_2458_8908_86.txt
(a / and
      :op1 (s / sensitive-03
            :ARG0 (c / culture-01 :quant 2
                  :ARG1 (m2 / medical-condition :name (n3 / name :op1 "melanoma"))
                  :mod (m / mutate-01
                        :ARG1 (e3 / enzyme :name (n4 / name :op1 "N-RAS")))
                  :ARG1-of (i2 / include-91
                        :ARG2 (c2 / culture-01 :quant 7)))
            :ARG1 (s4 / small-molecule :name (n / name :op1 "RAF265")))
      :op2 (s2 / sensitive-03
            :ARG0 (a2 / all)
            :ARG1 (s5 / small-molecule :name (n2 / name :op1 "MEK162"))
            :ARG1-of (s3 / strike-04)))

# ::id a_pmid_2458_8908.87 ::date 2015-06-14T06:03:39 ::annotator SDL-AMR-09 ::preferred
# ::snt Of the 7 N-RAS mutant cultures, 5 were sensitive to trametinib.
# ::save-date Mon Jun 22, 2015 ::file a_pmid_2458_8908_87.txt
(s / sensitive-03
      :ARG0 (c / culture-01 :quant 5
            :mod (m / mutate-01
                  :ARG2 (e / enzyme :name (n2 / name :op1 "N-RAS")))
            :ARG1-of (i / include-91
                  :ARG2 (c2 / culture-01 :quant 7)))
      :ARG1 (s2 / small-molecule :name (n / name :op1 "trametinib")))

# ::id a_pmid_2458_8908.88 ::date 2015-06-14T06:11:25 ::annotator SDL-AMR-09 ::preferred
# ::snt YUFIC and YUTICA were more resistant.
# ::save-date Mon Jun 22, 2015 ::file a_pmid_2458_8908_88.txt
(r / resist-01
      :ARG0 (a / and
            :op1 (c / cell-line :name (n / name :op1 "YUFIC"))
            :op2 (c2 / cell-line :name (n2 / name :op1 "YUTICA")))
      :degree (m / more))

# ::id a_pmid_2458_8908.89 ::date 2015-06-14T06:13:12 ::annotator SDL-AMR-09 ::preferred
# ::snt Molecular effects of MEK162
# ::save-date Mon Jun 22, 2015 ::file a_pmid_2458_8908_89.txt
(a / affect-01
      :ARG0 (s / small-molecule :name (n / name :op1 "MEK162"))
      :ARG1 (m / molecule))

# ::id a_pmid_2458_8908.90 ::date 2015-06-14T06:18:36 ::annotator SDL-AMR-09 ::preferred
# ::snt Due to the striking sensitivity patterns of MEK162, we conducted additional studies to verify target down-regulation in the sensitive and resistant cultures.
# ::save-date Mon Jan 4, 2016 ::file a_pmid_2458_8908_90.txt
(c / cause-01
      :ARG0 (p / pattern-01
            :ARG1 (s / sensitive-03
                  :ARG1 (s5 / small-molecule :name (n / name :op1 "MEK162")))
            :ARG1-of (s2 / strike-04))
      :ARG1 (c2 / conduct-01
            :ARG0 (w / we)
            :ARG1 (s3 / study-01
                  :ARG0 w
                  :mod (a / additional))
            :purpose (v / verify-01
                  :ARG0 w
                  :ARG1 (d / downregulate-01
                        :ARG1 (t / target-01)
                        :location (a2 / and
                              :op1 (c3 / culture-01
                                    :ARG0-of (s6 / sensitive-03))
                              :op2 (c4 / culture-01
                                    :ARG0-of (r2 / resist-01)))))))

# ::id a_pmid_2458_8908.91 ::date 2015-06-14T06:28:34 ::annotator SDL-AMR-09 ::preferred
# ::snt ERK1/2 isoforms are the immediate downstream substrates and best studied effectors of dual specificity kinases MEK1/2.
# ::save-date Thu Dec 10, 2015 ::file a_pmid_2458_8908_91.txt
(a2 / and
      :op1 (s / substrate
            :location (d / downstream)
            :mod (i2 / immediacy))
      :op2 (e3 / effector
            :ARG1-of (s4 / study-01
                  :ARG1-of (g / good-02
                        :degree (m / most)))
            :poss (k / kinase :name (n2 / name :op1 "MEK1/2")
                  :mod (s3 / specificity
                        :mod (d2 / dual))))
      :domain (i / isoform
            :mod (e2 / enzyme :name (n / name :op1 "ERK1/2"))))

# ::id a_pmid_2458_8908.92 ::date 2015-06-14T06:30:15 ::annotator SDL-AMR-09 ::preferred
# ::snt To assess the effect of MEK1/2 inhibition on ERK1/2 activation state (phosphorylation at T202/Y204 sites), melanoma cultures were treated with MEK162 and compared with untreated controls.
# ::save-date Thu Dec 10, 2015 ::file a_pmid_2458_8908_92.txt
(a / and
      :op1 (t / treat-04
            :ARG1 (c2 / culture-01
                  :ARG1 (m2 / medical-condition :name (n3 / name :op1 "melanoma")))
            :ARG2 (s3 / small-molecule :name (n4 / name :op1 "MEK162")))
      :op2 (c / compare-01
            :ARG1 c2
            :ARG2 (c3 / control
                  :ARG1-of (t2 / treat-04 :polarity -)))
      :purpose (a2 / assess-01
            :ARG1 (a3 / affect-01
                  :ARG0 (i / inhibit-01
                        :ARG1 (e / enzyme :name (n / name :op1 "MEK1/2")))
                  :ARG1 (s / state
                        :mod (a4 / activate-01
                              :ARG1 (e2 / enzyme :name (n2 / name :op1 "ERK1/2"))))
                  :ARG2-of (m / mean-01
                        :ARG1 (p2 / phosphorylate-01
                              :ARG1 (s4 / slash
                                    :op1 (a5 / amino-acid :mod 202 :name (n6 / name :op1 "threonine"))
                                    :op2 (a6 / amino-acid :mod 204 :name (n7 / name :op1 "tyrosine"))))))))

# ::id a_pmid_2458_8908.93 ::date 2015-06-14T06:43:14 ::annotator SDL-AMR-09 ::preferred
# ::snt We selected one sensitive and one resistant culture in the WT and B-RAF mutant categories.
# ::save-date Mon Jun 22, 2015 ::file a_pmid_2458_8908_93.txt
(s / select-01
      :ARG0 (w / we)
      :ARG1 (a3 / and
            :op1 (c3 / culture-01 :quant 1
                  :ARG0-of (s3 / sensitive-03))
            :op2 (c4 / culture-01 :quant 1
                  :ARG0-of (r2 / resist-01)))
      :ARG2 (a / and
            :op1 (c / category
                  :mod (w4 / wild-type))
            :op2 (c5 / category
                  :mod (m / mutate-01
                        :ARG2 (e3 / enzyme :wiki -
                              :name (n3 / name :op1 "B-RAF"))))))

# ::id a_pmid_2458_8908.94 ::date 2015-06-14T07:01:32 ::annotator SDL-AMR-09 ::preferred
# ::snt Seeing that all N-RAS mutant cultures were sensitive to MEK162, we selected two sensitive cultures for these studies.
# ::save-date Mon Jun 22, 2015 ::file a_pmid_2458_8908_94.txt
(c / cause-01
      :ARG0 (s / see-01
            :ARG1 (s3 / sensitive-03
                  :ARG0 (c2 / culture-01
                        :mod (m / mutate-01
                              :ARG2 (e / enzyme :name (n / name :op1 "N-RAS")))
                        :mod (a / all))
                  :ARG1 (s6 / small-molecule :name (n2 / name :op1 "MEK162"))))
      :ARG1 (s2 / select-01
            :ARG0 (w / we)
            :ARG1 (c3 / culture-01 :quant 2
                  :ARG0-of (s4 / sensitive-03))
            :ARG3 (s5 / study-01
                  :mod (t / this))))

# ::id a_pmid_2458_8908.95 ::date 2015-06-14T07:07:30 ::annotator SDL-AMR-09 ::preferred
# ::snt WT (YUVON and YUROB), B-RAF mutant (YUKSI and YUMAC) and N-RAS mutant (YUDOSO and YUKIM) cells were treated with increasing doses (10-1000 nM) of MEK162 or left untreated for 4 and 24 hours.
# ::save-date Wed Aug 5, 2015 ::file a_pmid_2458_8908_95.txt
(o / or
      :op1 (t2 / treat-04
            :ARG1 (a6 / and
                  :op1 (a7 / and
                        :op1 (c2 / cell-line :name (n / name :op1 "YUVON"))
                        :op2 (c3 / cell-line :name (n2 / name :op1 "YUROB"))
                        :mod (w2 / wild-type))
                  :op2 (a2 / and
                        :op1 (c4 / cell-line :name (n6 / name :op1 "YUKSI"))
                        :op2 (c5 / cell-line :name (n7 / name :op1 "YUMAC"))
                        :mod (e / enzyme :name (n8 / name :op1 "B-RAF")
                              :ARG2-of (m3 / mutate-01)))
                  :op3 (a3 / and
                        :op1 (c6 / cell-line :name (n3 / name :op1 "YUDOSO"))
                        :op3 (c7 / cell-line :name (n9 / name :op1 "YUKIM"))
                        :mod (e2 / enzyme :name (n10 / name :op1 "N-RAS")
                              :ARG2-of (m / mutate-01))))
            :ARG2 (s / small-molecule :name (n5 / name :op1 "MEK162")
                  :quant (d / dose
                        :quant (b / between
                              :op1 (c8 / concentration-quantity :quant 10
                                    :unit (n4 / nanomolar))
                              :op2 (c9 / concentration-quantity :quant 1000
                                    :unit n4))
                        :ARG1-of (i / increase-01))))
      :op2 (l / leave-14
            :ARG1 (t3 / treat-04 :polarity -
                  :ARG1 a6))
      :duration (a5 / and
            :op1 (t / temporal-quantity :quant 4
                  :unit (h / hour))
            :op2 (t4 / temporal-quantity :quant 24
                  :unit h)))

# ::id a_pmid_2458_8908.96 ::date 2015-06-14T07:20:15 ::annotator SDL-AMR-09 ::preferred
# ::snt Western blot analysis was performed using phospho-ERK1/2, total ERK1/2 and β-actin antibodies, and results are shown in Figure <xref ref-type="fig" rid="F2">2</xref>A.In the MEK162 resistant melanoma cultures (YUVON and YUKSI), the baseline level of phospho-ERK1/2 and the ratio of phospho-ERK1/2 to total ERK1/2 was lower compared to sensitive cultures (YUROB, YUMAC, YUDOSO, YUKIM).
# ::save-date Thu Dec 10, 2015 ::file a_pmid_2458_8908_96.txt
(m2 / multi-sentence
      :snt1 (a / and
            :op1 (p / perform-01
                  :ARG1 (i / immunoblot-01)
                  :ARG2 (a3 / and
                        :op1 (e3 / enzyme :name (n2 / name :op1 "ERK1/2")
                              :ARG3-of (p2 / phosphorylate-01))
                        :op2 (e4 / enzyme :name (n3 / name :op1 "ERK1/2")
                              :mod (t / total))
                        :op3 (a4 / antibody
                              :ARG0-of (c4 / counter-01
                                    :ARG2 (p7 / protein :name (n4 / name :op1 "β-actin"))))))
            :op2 (s / show-01
                  :ARG0 (f / figure :mod "2A")
                  :ARG1 (t2 / thing
                        :ARG2-of (r / result-01))))
      :snt2 (l2 / low-04
            :ARG1 (a5 / and
                  :op1 (l3 / level
                        :domain (b2 / baseline)
                        :quant-of (e / enzyme :name (n8 / name :op1 "ERK1/2")
                              :ARG3-of (p8 / phosphorylate-01)))
                  :op2 (r2 / ratio-of
                        :op1 e
                        :op2 (e2 / enzyme :name (n9 / name :op1 "ERK1/2")
                              :mod (t3 / total)))
                  :ARG1-of (c2 / compare-01
                        :ARG2 (c3 / culture-01
                              :ARG0-of (s3 / sensitive-03)
                              :ARG1-of (m4 / mean-01
                                    :ARG2 (a6 / and
                                          :op1 (c7 / cell-line :name (n11 / name :op1 "YUROB"))
                                          :op2 (c8 / cell-line :name (n12 / name :op1 "YUMAC"))
                                          :op3 (c9 / cell-line :name (n13 / name :op1 "YUDOSO"))
                                          :op4 (c10 / cell-line :name (n14 / name :op1 "YUKIM")))))))
            :degree (m3 / more)
            :location (c / culture-01
                  :ARG1 (m5 / medical-condition :name (n6 / name :op1 "melanoma"))
                  :ARG0-of (r3 / resist-01
                        :ARG1 (s2 / small-molecule :name (n7 / name :op1 "MEK162")))
                  :ARG1-of (m / mean-01
                        :ARG2 (a8 / and
                              :op1 (c5 / cell-line :name (n5 / name :op1 "YUVON"))
                              :op2 (c6 / cell-line :name (n10 / name :op1 "YUKSI")))))))

# ::id a_pmid_2458_8908.97 ::date 2015-06-14T07:22:57 ::annotator SDL-AMR-09 ::preferred
# ::snt In MEK162-sensitive melanomas exposure to MEK162 resulted in a significant decrease in the level of ERK1/2 phosphorylation (Figure <xref ref-type="fig" rid="F2">2</xref>A).
# ::save-date Fri Dec 18, 2015 ::file a_pmid_2458_8908_97.txt
(r / result-01
      :ARG1 (e / expose-01
            :ARG1 (m / medical-condition :name (n / name :op1 "melanoma")
                  :ARG0-of (s / sensitive-03
                        :ARG1 (s4 / small-molecule :name (n2 / name :op1 "MEK162"))))
            :ARG2 s4)
      :ARG2 (d2 / decrease-01
            :ARG0 e
            :ARG1 (l / level
                  :degree-of (p2 / phosphorylate-01
                        :ARG1 (e2 / enzyme :name (n4 / name :op1 "ERK1/2"))))
            :ARG2 (s2 / significant-02))
      :ARG1-of (d3 / describe-01
            :ARG0 (f / figure :mod "2A")))

# ::id a_pmid_2514_2146.9 ::date 2015-06-08T10:07:47 ::annotator SDL-AMR-09 ::preferred
# ::snt Sensitivity fell into three groups: sensitive, 50% inhibitory concentration (IC<sub>50</sub>) < 1 μM; intermediately sensitive, IC<sub>50</sub> 1-2 μM; and resistant, >2 μM. Fifteen of 21 (71%) <i>BRAF</i> mutants, including 4 with innate vemurafenib resistance, were sensitive to SCH772984.
# ::save-date Tue Dec 15, 2015 ::file a_pmid_2514_2146_9.txt
(m6 / multi-sentence
      :snt1 (f / fall-04
            :ARG1 (s / sensitive-03)
            :ARG2 (g / group :quant 3
                  :ARG1-of (m9 / mean-01
                        :ARG2 (a / and
                              :op1 (s2 / sensitive-03
                                    :ARG1-of (m / mean-01
                                          :ARG2 (h / have-percentage-maximal-inhibitory-concentration-01
                                                :ARG2 50
                                                :ARG4 (l / less-than
                                                      :op1 (c / concentration-quantity :quant 1
                                                            :unit (m2 / micromolar))))))
                              :op2 (s3 / sensitive-03
                                    :mod (i / intermediate)
                                    :ARG1-of (m3 / mean-01
                                          :ARG2 (h2 / have-percentage-maximal-inhibitory-concentration-01
                                                :ARG2 50
                                                :ARG4 (c3 / concentration-quantity
                                                      :quant (b / between :op1 1 :op2 2)
                                                      :unit m2))))
                              :op3 (r / resist-01
                                    :ARG1-of (m4 / mean-01
                                          :ARG2 (h3 / have-percentage-maximal-inhibitory-concentration-01
                                                :ARG2 50
                                                :ARG4 (m5 / more-than
                                                      :op1 (c2 / concentration-quantity :quant 2
                                                            :unit m2)))))))))
      :snt2 (s4 / sensitive-03
            :ARG0 (g2 / gene :quant 15 :name (n4 / name :op1 "BRAF")
                  :ARG2-of (m7 / mutate-01)
                  :ARG1-of (i2 / include-91
                        :ARG2 (g3 / gene :quant 21 :name (n5 / name :op1 "BRAF")
                              :ARG2-of m7)
                        :ARG3 (p / percentage-entity :value 71))
                  :ARG2-of (i3 / include-01
                        :ARG1 (g4 / gene :quant 4 :name (n6 / name :op1 "BRAF")
                              :ARG0-of (r2 / resist-01
                                    :ARG1 (s5 / small-molecule :name (n7 / name :op1 "vemurafenib"))
                                    :mod (i4 / innate))
                              :ARG2-of m7)))
            :ARG1 (s6 / small-molecule :name (n8 / name :op1 "SCH772984"))))

# ::id a_pmid_2514_2146.10 ::date 2015-06-08T10:19:11 ::annotator SDL-AMR-09 ::preferred
# ::snt All three (100%) <i>BRAF/NRAS</i> double mutants, 11 of 14 (78%) <i>NRAS</i> mutants and 5 of 7 (71%) wild-type melanomas were sensitive.
# ::save-date Thu Dec 10, 2015 ::file a_pmid_2514_2146_10.txt
(s / sensitive-03
      :ARG0 (a / and
            :op1 (s2 / slash
                  :op1 (g / gene :quant 3 :name (n / name :op1 "BRAF"))
                  :op2 (g4 / gene :name (n6 / name :op1 "NRAS"))
                  :ARG2-of (m / mutate-01
                        :mod (d / double))
                  :ARG1-of (i3 / include-91
                        :ARG3 (p / percentage-entity :value 100))
                  :mod (a2 / all))
            :op2 (g2 / gene :quant 11 :name (n2 / name :op1 "NRAS")
                  :ARG2-of (m2 / mutate-01)
                  :ARG1-of (i / include-91
                        :ARG2 (g3 / gene :quant 14 :name (n3 / name :op1 "NRAS")
                              :ARG2-of m2)
                        :ARG3 (p2 / percentage-entity :value 78)))
            :op2 (m4 / medical-condition :quant 5 :name (n4 / name :op1 "melanoma")
                  :mod (w / wild-type)
                  :ARG1-of (i2 / include-91
                        :ARG2 (m3 / medical-condition :quant 7 :name (n5 / name :op1 "melanoma"))
                        :ARG3 (p3 / percentage-entity :value 71)))))

# ::id a_pmid_2514_2146.11 ::date 2015-06-08T10:57:20 ::annotator SDL-AMR-09 ::preferred
# ::snt Among <i>BRAF</i><sup><i>V600</i></sup> mutants with <i>in vitro</i> acquired resistance to vemurafenib, those with MAPK pathway reactivation as the mechanism of resistance were sensitive to SCH772984.
# ::save-date Mon Jun 15, 2015 ::file a_pmid_2514_2146_11.txt
(s / sensitive-03
      :ARG0 (g2 / gene :wiki "BRAF_(gene)"
            :name (n3 / name :op1 "BRAF")
            :ARG2-of (m2 / mutate-01 :value "V600")
            :ARG0-of (r2 / reactivate-01
                  :ARG1 (p / pathway :wiki "MAPK/ERK_pathway"
                        :name (n4 / name :op1 "MAPK"))
                  :ARG1-of (m3 / mean-01
                        :ARG2 (m4 / mechanism
                              :mod (r3 / resist-01))))
            :ARG1-of (i2 / include-91
                  :ARG2 (g / gene :wiki "BRAF_(gene)"
                        :name (n / name :op1 "BRAF")
                        :ARG2-of m2
                        :ARG0-of (r / resist-01
                              :ARG1 (s2 / small-molecule :wiki "Vemurafenib"
                                    :name (n2 / name :op1 "vemurafenib"))
                              :ARG1-of (a / acquire-01
                                    :ARG0 g
                                    :manner (i / in-vitro))))))
      :ARG1 (s3 / small-molecule :wiki -
            :name (n5 / name :op1 "SCH772984")))

# ::id a_pmid_2514_2146.12 ::date 2015-06-08T11:29:35 ::annotator SDL-AMR-09 ::preferred
# ::snt SCH772984 caused G1 arrest and induced apoptosis.
# ::save-date Sun Dec 20, 2015 ::file a_pmid_2514_2146_12.txt
(a / and
      :op1 (c / cause-01
            :ARG0 (s / small-molecule :name (n / name :op1 "SCH772984"))
            :ARG1 (a2 / arrest-02
                  :ARG1 (t / thing :name (n2 / name :op1 "G1"))))
      :op2 (i / induce-01
            :ARG0 s
            :ARG2 (a3 / apoptosis)))

# ::id a_pmid_2514_2146.54 ::date 2015-06-08T11:38:34 ::annotator SDL-AMR-09 ::preferred
# ::snt BRAF-mutant melanoma cell lines are sensitive to ERK inhibition
# ::save-date Sat Jan 16, 2016 ::file a_pmid_2514_2146_54.txt
(s / sensitive-03
      :ARG0 (c / cell-line
            :mod (m / medical-condition :name (n3 / name :op1 "melanoma"))
            :mod (e / enzyme :name (n / name :op1 "BRAF")
                  :ARG2-of (m2 / mutate-01)))
      :ARG1 (i / inhibit-01
            :ARG1 (e2 / enzyme :name (n2 / name :op1 "ERK"))))

# ::id a_pmid_2514_2146.55 ::date 2015-06-08T11:54:22 ::annotator SDL-AMR-09 ::preferred
# ::snt Twenty-one melanoma cell lines containing mutations in the <i>BRAF</i> gene were evaluated to determine sensitivity to SCH772984 (ERKi).
# ::save-date Mon Jan 4, 2016 ::file a_pmid_2514_2146_55.txt
(e / evaluate-01
      :ARG1 (c / cell-line :quant 21
            :ARG0-of (c2 / contain-01
                  :ARG1 (m2 / mutate-01
                        :ARG1 (g / gene :name (n / name :op1 "BRAF"))))
            :mod (m / medical-condition :name (n4 / name :op1 "melanoma")))
      :purpose (d / determine-01
            :ARG1 (s / sensitive-03
                  :ARG0 c
                  :ARG1 (s2 / small-molecule :name (n2 / name :op1 "SCH772984")
                        :ARG0-of (i / inhibit-01
                              :ARG1 (p / protein-family :name (n3 / name :op1 "ERK")))))))

# ::id a_pmid_2514_2146.56 ::date 2015-06-08T10:19:39 ::annotator SDL-AMR-09 ::preferred
# ::snt As a comparison, sensitivity to vemurafenib was also determined.
# ::save-date Mon Jun 15, 2015 ::file a_pmid_2514_2146_56.txt
(d / determine-01
      :ARG1 (s / sensitive-03
            :ARG1 (s2 / small-molecule :name (n / name :op1 "vemurafenib")))
      :mod (a / also)
      :ARG1-of (c / compare-01))

# ::id a_pmid_2514_2146.57 ::date 2015-06-08T12:47:23 ::annotator SDL-AMR-09 ::preferred
# ::snt <i>BRAF</i><sup><i>V600E</i></sup> was the most frequently observed BRAF mutation, present in 17 of 21 cell lines.
# ::save-date Mon Dec 21, 2015 ::file a_pmid_2514_2146_57.txt
(m4 / mutate-01
      :ARG2 (g3 / gene :name (n3 / name :op1 "BRAF"))
      :ARG1-of (o / observe-01
            :ARG1-of (f / frequent-02
                  :degree (m2 / most)))
      :ARG1-of (p / present-02
            :ARG2 (c / cell-line :quant 17
                  :ARG1-of (i2 / include-91
                        :ARG2 (c2 / cell-line :quant 21))))
      :domain (g / gene :name (n2 / name :op1 "BRAF")
            :ARG2-of (m / mutate-01 :value "V600E")))

# ::id a_pmid_2514_2146.58 ::date 2015-06-08T13:04:17 ::annotator SDL-AMR-09 ::preferred
# ::snt M381 contains <i>BRAF</i><sup><i>V600R</i></sup> substitution, M414 contains <i>BRAF</i><sup><i>V600K</i></sup>, M417 contains <i>BRAF</i><sup><i>G466E</i></sup> and M420 contains <i>BRAF</i><sup><i>L597S</i></sup> mutation.
# ::save-date Sun Jun 14, 2015 ::file a_pmid_2514_2146_58.txt
(a / and
      :op1 (c / contain-01
            :ARG0 (c2 / cell-line :name (n / name :op1 "M381"))
            :ARG1 (s / substitute-01
                  :ARG2 (g / gene :name (n2 / name :op1 "BRAF")
                        :ARG2-of (m2 / mutate-01 :value "V600R"))))
      :op2 (c3 / contain-01
            :ARG0 (c4 / cell-line :name (n3 / name :op1 "M414"))
            :ARG1 (m3 / mutate-01 :value "V600K"
                  :ARG1 g))
      :op3 (c5 / contain-01
            :ARG0 (c6 / cell-line :name (n4 / name :op1 "M417"))
            :ARG1 (m4 / mutate-01 :value "G466E"
                  :ARG1 g))
      :op4 (c7 / contain-01
            :ARG0 (c8 / cell-line :name (n5 / name :op1 "M420"))
            :ARG1 (m5 / mutate-01 :value "L597S"
                  :ARG1 g)))

# ::id a_pmid_2514_2146.59 ::date 2015-06-08T13:31:30 ::annotator SDL-AMR-09 ::preferred
# ::snt Among the 21 cell lines, sensitivity to vemurafenib or SCH-772984 fell into 3 groups: highly sensitive (50% inhibitory concentration, IC<sub>50</sub> < 1 μM), intermediate sensitivity (IC<sub>50</sub> 1–2 μM) and resistant (IC<sub>50</sub> > 2 μM).
# ::save-date Tue Dec 15, 2015 ::file a_pmid_2514_2146_59.txt
(f / fall-04
      :ARG1 (s / sensitive-03
            :ARG0 (c2 / cell-line :quant 21)
            :ARG1 (o / or
                  :op1 (s2 / small-molecule :name (n / name :op1 "vemurafenib"))
                  :op2 (s3 / small-molecule :name (n2 / name :op1 "SCH-772984"))))
      :ARG2 (g / group :quant 3
            :ARG1-of (m6 / mean-01
                  :ARG2 (a / and
                        :op1 (s4 / sensitive-03
                              :ARG1-of (h / high-02)
                              :ARG1-of (m / mean-01
                                    :ARG2 (h2 / have-percentage-maximal-inhibitory-concentration-01
                                          :ARG2 50
                                          :ARG4 (l / less-than
                                                :op1 (c / concentration-quantity :quant 1
                                                      :unit (m2 / micromolar))))))
                        :op2 (s5 / sensitive-03
                              :mod (i2 / intermediate)
                              :ARG1-of (m3 / mean-01
                                    :ARG2 (h3 / have-percentage-maximal-inhibitory-concentration-01
                                          :ARG2 50
                                          :ARG4 (c3 / concentration-quantity
                                                :quant (b / between :op1 1 :op2 2)
                                                :unit m2))))
                        :op3 (r / resist-01
                              :ARG1-of (m4 / mean-01
                                    :ARG2 (h4 / have-percentage-maximal-inhibitory-concentration-01
                                          :ARG2 50
                                          :ARG4 (m5 / more-than
                                                :op1 (c4 / concentration-quantity :quant 2
                                                      :unit m2)))))))))

# ::id a_pmid_2514_2146.60 ::date 2015-06-08T13:55:17 ::annotator SDL-AMR-09 ::preferred
# ::snt 15 cell lines were highly sensitive to SCH-772984 with IC<sub>50</sub> less than or equal to 1 μM. Of the 12 cell lines highly sensitive to vemurafenib, all contain <i>BRAF</i><sup><i>V600E</i></sup> and were also sensitive to SCH-772984.
# ::save-date Mon Dec 21, 2015 ::file a_pmid_2514_2146_60.txt
(m / multi-sentence
      :snt1 (s / sensitive-03
            :ARG0 (c / cell-line :quant 15)
            :ARG1 (s2 / small-molecule :name (n / name :op1 "SCH-772984")
                  :ARG1-of (h3 / have-percentage-maximal-inhibitory-concentration-01
                        :ARG2 50
                        :ARG4 (c4 / concentration-quantity :quant 1
                              :unit (m2 / micromolar))))
            :ARG1-of (h / high-02))
      :snt2 (a / and
            :op1 (c2 / contain-01
                  :ARG0 (c3 / cell-line :quant 12
                        :mod (a2 / all)
                        :ARG0-of (s3 / sensitive-03
                              :ARG1 (s4 / small-molecule :name (n2 / name :op1 "vemurafenib"))
                              :ARG1-of h))
                  :ARG1 (g / gene :name (n3 / name :op1 "BRAF")
                        :ARG2-of (m5 / mutate-01 :value "V600E")))
            :op2 (s5 / sensitive-03
                  :ARG0 c3
                  :ARG1 (s6 / small-molecule :name (n4 / name :op1 "SCH-772984"))
                  :mod (a3 / also))))

# ::id a_pmid_2514_2146.61 ::date 2015-06-08T13:58:46 ::annotator SDL-AMR-09 ::preferred
# ::snt Interestingly, M399, M414, M308, and M409 were sensitive to SCH-772984 but only intermediately sensitive (M399, M409 and M414) or resistant (M308) to vemurafenib.
# ::save-date Sun Jun 14, 2015 ::file a_pmid_2514_2146_61.txt
(s / sensitive-03
      :ARG0 (a / and
            :op1 (c / cell-line :name (n / name :op1 "M399"))
            :op2 (c2 / cell-line :name (n2 / name :op1 "M414"))
            :op3 (c3 / cell-line :name (n3 / name :op1 "M308"))
            :op4 (c5 / cell-line :name (n6 / name :op1 "M409")))
      :ARG1 (s2 / small-molecule :name (n4 / name :op1 "SCH-772984"))
      :ARG1-of (c4 / contrast-01
            :ARG2 (o / or
                  :op1 (s3 / sensitive-03
                        :ARG0 (a3 / and
                              :op1 c
                              :op2 c5
                              :op3 c2)
                        :ARG1 (s4 / small-molecule :name (n5 / name :op1 "vemurafenib"))
                        :mod (i2 / intermediate
                              :mod (o2 / only)))
                  :op2 (r / resist-01
                        :ARG0 c3
                        :ARG1 s4)))
      :mod (i / interesting))

# ::id a_pmid_2514_2146.62 ::date 2015-06-08T14:47:51 ::annotator SDL-AMR-09 ::preferred
# ::snt With the exception of M414, all non-V600E mutants were resistant to both vemurafenib and SCH772984 (Figure <xref ref-type="fig" rid="Fig1">1</xref>A).
# ::save-date Sun Jun 14, 2015 ::file a_pmid_2514_2146_62.txt
(r / resist-01
      :ARG0 (m / mutate-01 :value "V600E" :polarity -
            :mod (a2 / all)
            :ARG2-of (e / except-01
                  :ARG1 (c / cell-line :name (n3 / name :op1 "M414"))))
      :ARG1 (a / and
            :op1 (s / small-molecule :name (n / name :op1 "vemurafenib"))
            :op2 (s2 / small-molecule :name (n2 / name :op1 "SCH772984")))
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod "1A")))

# ::id a_pmid_2514_2146.63 ::date 2015-06-08T15:01:08 ::annotator SDL-AMR-09 ::preferred
# ::snt As a comparison, sensitivity to the MEKi trametinib segregated all cell lines into three different groups: highly sensitive (IC<sub>50</sub> < 2nM), intermediately sensitive (IC<sub>50</sub> 2-30nM) and resistant (IC<sub>50</sub> > 30 nM) (Additional file <xref ref-type="media" rid="MOESM1">1</xref>: Figure S1).
# ::save-date Mon Dec 21, 2015 ::file a_pmid_2514_2146_63.txt
(s / segregate-01
      :ARG0 (s2 / sensitive-03
            :ARG1 (s3 / small-molecule :name (n / name :op1 "trametinib")
                  :ARG0-of (i / inhibit-01
                        :ARG1 (e / enzyme :name (n2 / name :op1 "MEK")))))
      :ARG1 (c2 / cell-line
            :mod (a / all))
      :ARG2 (g / group :quant 3
            :ARG1-of (d / differ-02)
            :ARG1-of (m5 / mean-01
                  :ARG2 (a2 / and
                        :op1 (s4 / sensitive-03
                              :ARG1-of (h / high-02)
                              :ARG1-of (m / mean-01
                                    :ARG2 (h2 / have-percentage-maximal-inhibitory-concentration-01
                                          :ARG2 50
                                          :ARG4 (l / less-than
                                                :op1 (c3 / concentration-quantity :quant 2
                                                      :unit (n3 / nanomolar))))))
                        :op2 (s5 / sensitive-03
                              :manner (i2 / intermediate)
                              :ARG1-of (m2 / mean-01
                                    :ARG2 (h3 / have-percentage-maximal-inhibitory-concentration-01
                                          :ARG2 50
                                          :ARG4 (c4 / concentration-quantity
                                                :quant (b / between :op1 2 :op2 30)
                                                :unit n3))))
                        :op3 (r / resist-01
                              :ARG1-of (m3 / mean-01
                                    :ARG2 (h4 / have-percentage-maximal-inhibitory-concentration-01
                                          :ARG2 50
                                          :ARG4 (m4 / more-than
                                                :op1 (c5 / concentration-quantity :quant 30
                                                      :unit n3))))))))
      :ARG1-of (d2 / describe-01
            :ARG0 (f3 / file :mod 1
                  :ARG1-of (a4 / add-02)
                  :ARG1-of (m6 / mean-01
                        :ARG2 (f2 / figure :mod "S1"))))
      :ARG1-of (c / compare-01))

# ::id a_pmid_2514_2146.64 ::date 2015-06-08T15:23:12 ::annotator SDL-AMR-09 ::preferred
# ::snt In general, cell lines sensitive to SCH772984 were also sensitive to trametinib.<fig id="Fig1"><label>Figure 1</label><caption><p><bold>Effect of SCH-722984 on BRAF-mutant melanoma cell lines.
# ::save-date Sat Jan 16, 2016 ::file a_pmid_2514_2146_64.txt
(m / multi-sentence
      :snt1 (s / sensitive-03
            :ARG0 (c / cell-line
                  :ARG0-of (s3 / sensitive-03
                        :ARG1 (s4 / small-molecule :name (n2 / name :op1 "SCH772984"))))
            :ARG1 (s2 / small-molecule :name (n / name :op1 "trametinib"))
            :ARG1-of (g / general-02)
            :mod (a / also))
      :snt2 (f2 / figure :mod 1
            :ARG1-of (d2 / describe-01
                  :ARG2 (a2 / affect-01
                        :ARG0 (s5 / small-molecule :name (n3 / name :op1 "SCH-722984"))
                        :ARG1 (c2 / cell-line
                              :mod (m2 / medical-condition :name (n5 / name :op1 "melanoma"))
                              :mod (e / enzyme :name (n4 / name :op1 "BRAF")
                                    :ARG2-of (m3 / mutate-01)))))))

# ::id a_pmid_2514_2146.65 ::date 2015-06-08T15:35:44 ::annotator SDL-AMR-09 ::preferred
# ::snt A</bold>.
# ::save-date Fri Oct 23, 2015 ::file a_pmid_2514_2146_65.txt
(h / have-li-91
      :ARG2 "A")

# ::id a_pmid_2514_2146.66 ::date 2015-06-08T15:37:31 ::annotator SDL-AMR-09 ::preferred
# ::snt IC<sub>50</sub> (nM).
# ::save-date Tue Dec 15, 2015 ::file a_pmid_2514_2146_66.txt
(h / have-percentage-maximal-inhibitory-concentration-01
      :ARG2 50
      :ARG4 (c / concentration-quantity
            :unit (n / nanomolar)))

# ::id a_pmid_2514_2146.67 ::date 2015-06-08T15:41:35 ::annotator SDL-AMR-09 ::preferred
# ::snt 21 BRAF-mutant melanoma cell lines were exposed to 0–10 μM SCH-722984 (black bars) or vemurafenib (grey bars) and cell viability determined by ATP-based bioluminescence assay.
# ::save-date Sat Jan 16, 2016 ::file a_pmid_2514_2146_67.txt
(a / and
      :op1 (e / expose-01
            :ARG1 (c / cell-line :quant 21
                  :mod (m3 / medical-condition :name (n5 / name :op1 "melanoma"))
                  :mod (e2 / enzyme :name (n / name :op1 "BRAF")
                        :ARG2-of (m2 / mutate-01)))
            :ARG2 (o / or
                  :op1 (s / small-molecule :name (n2 / name :op1 "SCH-722984")
                        :quant (c2 / concentration-quantity
                              :quant (b / between :op1 0 :op2 10)
                              :unit (m / micromolar))
                        :ARG1-of (d / describe-01
                              :ARG0 (b2 / bar
                                    :ARG1-of (b3 / black-04))))
                  :op2 (s2 / small-molecule :name (n3 / name :op1 "vemurafenib")
                        :quant c2
                        :ARG1-of (d4 / describe-01
                              :ARG0 (b4 / bar
                                    :ARG1-of (g2 / gray-02))))))
      :op2 (d2 / determine-01
            :ARG1 (v / viability
                  :mod c)
            :instrument (a2 / assay-01
                  :ARG1 (b5 / bioluminescence)
                  :ARG1-of (b6 / base-02
                        :ARG2 (s3 / small-molecule :name (n4 / name :op1 "ATP"))))))

# ::id a_pmid_2514_2146.68 ::date 2015-06-08T16:02:35 ::annotator SDL-AMR-09 ::preferred
# ::snt Results are the mean of three experiments, performed in duplicates (n = 6).
# ::save-date Mon Nov 2, 2015 ::file a_pmid_2514_2146_68.txt
(r / result-01
      :ARG2 (m / mean
            :poss (e / experiment-01 :quant 3
                  :ARG1-of (p / perform-01
                        :manner (d / duplicate :quant 6)))))

# ::id a_pmid_2514_2146.69 ::date 2015-06-08T16:07:12 ::annotator SDL-AMR-09 ::preferred
# ::snt Error bars are standard deviation.
# ::save-date Mon Dec 21, 2015 ::file a_pmid_2514_2146_69.txt
(d / deviate-01
      :ARG1-of (s / standard-02)
      :domain (b / bar
            :mod (e / error)))

# ::id a_pmid_2514_2146.70 ::date 2015-06-08T16:10:24 ::annotator SDL-AMR-09 ::preferred
# ::snt Non-V600E substitutions are denoted in the bar graph for each corresponding cell line (M420, BRAF<sup>L597S</sup>; M381, BRAF<sup>V600R</sup> , M417, BRAF<sup>G466E</sup>, M414, BRAF<sup>V600K</sup>).
# ::save-date Sat Jan 16, 2016 ::file a_pmid_2514_2146_70.txt
(d / denote-01
      :ARG1 (s / substitute-01
            :ARG2 (m / mutate-01 :value "V600E" :polarity -)
            :ARG1-of (c / correspond-02
                  :ARG2 (c2 / cell-line)))
      :location (g / graph
            :mod (b / bar))
      :ARG1-of (m2 / mean-01
            :ARG2 (a / and
                  :op1 (c3 / correspond-02
                        :ARG1 (c4 / cell-line :name (n / name :op1 "M420"))
                        :ARG2 (e / enzyme :name (n5 / name :op1 "BRAF")
                              :ARG2-of (m3 / mutate-01 :value "L597S")))
                  :op2 (c5 / correspond-02
                        :ARG1 (c8 / cell-line :name (n2 / name :op1 "M381"))
                        :ARG2 (e2 / enzyme :name (n6 / name :op1 "BRAF")
                              :ARG2-of (m4 / mutate-01 :value "V600R")))
                  :op3 (c6 / correspond-02
                        :ARG1 (c9 / cell-line :name (n3 / name :op1 "M417"))
                        :ARG2 (e3 / enzyme :name (n7 / name :op1 "BRAF")
                              :ARG2-of (m5 / mutate-01 :value "G466E")))
                  :op4 (c7 / correspond-02
                        :ARG1 (c10 / cell-line :name (n4 / name :op1 "M414"))
                        :ARG2 (e4 / enzyme :name (n8 / name :op1 "BRAF")
                              :ARG2-of (m6 / mutate-01 :value "V600K"))))))

# ::id a_pmid_2514_2146.71 ::date 2015-06-09T09:52:56 ::annotator SDL-AMR-09 ::preferred
# ::snt Bar at 1 μM denotes threshold between sensitive and intermediate.
# ::save-date Tue Dec 15, 2015 ::file a_pmid_2514_2146_71.txt
(d / denote-01
      :ARG0 (b / bar
            :quant (c / concentration-quantity :quant 1
                  :unit (m / micromolar)))
      :ARG1 (t / threshold
            :topic (b2 / between
                  :op1 (s / sensitive-03)
                  :op2 (i / intermediate))))

# ::id a_pmid_2514_2146.72 ::date 2015-06-09T10:12:32 ::annotator SDL-AMR-09 ::preferred
# ::snt Resistant cell lines have IC<sub>50</sub> higher than 2 μM.
# ::save-date Tue Dec 15, 2015 ::file a_pmid_2514_2146_72.txt
(h2 / have-percentage-maximal-inhibitory-concentration-01
      :ARG1 (c / cell-line
            :ARG0-of (r / resist-01))
      :ARG2 50
      :ARG4 (m / more-than
            :op1 (c2 / concentration-quantity :quant 2
                  :unit (m2 / micromolar))))

# ::id a_pmid_2514_2146.73 ::date 2015-06-09T10:32:40 ::annotator SDL-AMR-09 ::preferred
# ::snt <bold>B</bold>.
# ::save-date Fri Oct 23, 2015 ::file a_pmid_2514_2146_73.txt
(h / have-li-91
      :ARG2 "B")

# ::id a_pmid_2514_2146.74 ::date 2015-06-09T10:37:43 ::annotator SDL-AMR-09 ::preferred
# ::snt Timecourse effects of SCH722984 on the MAPK signaling.
# ::save-date Sun Dec 20, 2015 ::file a_pmid_2514_2146_74.txt
(a / affect-01
      :ARG0 (s / small-molecule :name (n / name :op1 "SCH722984"))
      :ARG1 (s2 / signal-07
            :ARG0 (p / pathway :name (n2 / name :op1 "MAPK")))
      :mod (t / timecourse))

# ::id a_pmid_2514_2146.75 ::date 2015-06-09T10:43:47 ::annotator SDL-AMR-09 ::preferred
# ::snt SCH722984-sensitive M238, SCH722984-resistant M233, were treated in a timecourse manner with 500nM SCH722984 at 1, 2, 6, 12, 24 and 48 hours compared to DMSO as solvent control <bold>(C)</bold>.
# ::save-date Tue Dec 15, 2015 ::file a_pmid_2514_2146_75.txt
(t / treat-04
      :ARG1 (a / and
            :op1 (c / cell-line :name (n / name :op1 "M238")
                  :ARG0-of (s2 / sensitive-03
                        :ARG1 (s / small-molecule :name (n2 / name :op1 "SCH722984"))))
            :op2 (c2 / cell-line :name (n3 / name :op1 "M233")
                  :ARG0-of (r / resist-01
                        :ARG1 s)))
      :ARG2 (s3 / small-molecule :name (n4 / name :op1 "SCH722984")
            :quant (c5 / concentration-quantity :quant 500
                  :unit (n5 / nanomolar))
            :ARG1-of (c3 / compare-01
                  :ARG2 (s5 / small-molecule :name (n6 / name :op1 "DMSO")
                        :ARG0-of (c4 / control-01
                              :ARG1 (d / dissolve-01)))))
      :time (a2 / after
            :op1 (a3 / and
                  :op1 (t2 / temporal-quantity :quant 1
                        :unit (h / hour))
                  :op2 (t3 / temporal-quantity :quant 2
                        :unit h)
                  :op3 (t4 / temporal-quantity :quant 6
                        :unit h)
                  :op4 (t5 / temporal-quantity :quant 12
                        :unit h)
                  :op5 (t6 / temporal-quantity :quant 24
                        :unit h)
                  :op6 (t7 / temporal-quantity :quant 48
                        :unit h)))
      :manner (t8 / timecourse))

# ::id a_pmid_2514_2146.76 ::date 2015-06-09T11:43:33 ::annotator SDL-AMR-09 ::preferred
# ::snt Phosphorylated or total MEK, ERK1/2, RSK, AKT, or beta-actin as loading control were determined by western blot analysis.
# ::save-date Sun Dec 20, 2015 ::file a_pmid_2514_2146_76.txt
(d / determine-01
      :ARG1 (o / or
            :op1 (a / and
                  :op1 (e / enzyme :name (n / name :op1 "MEK")
                        :ARG3-of (p / phosphorylate-01))
                  :op2 (e2 / enzyme :name (n2 / name :op1 "ERK1/2")
                        :ARG3-of p)
                  :op3 (e3 / enzyme :name (n3 / name :op1 "RSK")
                        :ARG3-of p)
                  :op4 (e4 / enzyme :name (n4 / name :op1 "AKT")
                        :ARG3-of p))
            :op2 (a2 / and
                  :op1 (e8 / enzyme :name (n8 / name :op1 "MEK")
                        :mod (t / total))
                  :op2 (e7 / enzyme :name (n7 / name :op1 "ERK1/2")
                        :mod t)
                  :op3 (e6 / enzyme :name (n6 / name :op1 "RSK")
                        :mod t)
                  :op4 (e5 / enzyme :name (n5 / name :op1 "AKT")
                        :mod t))
            :op3 (p2 / protein :name (n9 / name :op1 "beta-actin")
                  :ARG0-of (c / control-01
                        :ARG1 (l / load-01))))
      :manner (a3 / analyze-01
            :manner (i / immunoblot-01)))

# ::id a_pmid_2514_2146.77 ::date 2015-06-09T12:17:16 ::annotator SDL-AMR-09 ::preferred
# ::snt <bold>C</bold>.
# ::save-date Fri Oct 23, 2015 ::file a_pmid_2514_2146_77.txt
(h / have-li-91
      :ARG2 "C")

# ::id a_pmid_2514_2146.78 ::date 2015-06-09T12:17:50 ::annotator SDL-AMR-09 ::preferred
# ::snt Effects of SCH722984 on the MAPK signaling at 24 hours.
# ::save-date Tue Jun 9, 2015 ::file a_pmid_2514_2146_78.txt
(a2 / affect-01
      :ARG0 (s / small-molecule :name (n / name :op1 "SCH722984"))
      :ARG1 (s2 / signal-07
            :ARG0 (p / pathway :name (n2 / name :op1 "MAPK")))
      :time (a / after
            :quant (t / temporal-quantity :quant 24
                  :unit (h / hour))))

# ::id a_pmid_2514_2146.79 ::date 2015-06-09T12:20:29 ::annotator SDL-AMR-09 ::preferred
# ::snt SCH722984-sensitive M262, SCH722984-resistant M381, SCH722984-intermediately sensitive M409 cells were treated for 24 h with DMSO as solvent control (-) or 500 nM SCH722984 (+).</p></caption><graphic /></fig>
# ::save-date Tue Dec 15, 2015 ::file a_pmid_2514_2146_79.txt
(t / treat-04
      :ARG1 (a / and
            :op1 (c / cell-line :name (n / name :op1 "M262")
                  :ARG0-of (s / sensitive-03
                        :ARG1 (s2 / small-molecule :name (n2 / name :op1 "SCH722984"))))
            :op2 (c2 / cell-line :name (n3 / name :op1 "M381")
                  :ARG0-of (r / resist-01
                        :ARG1 s2))
            :op3 (c3 / cell-line :name (n4 / name :op1 "M409")
                  :ARG0-of (s3 / sensitive-03
                        :ARG1 s2
                        :mod (i / intermediate))))
      :ARG2 (o / or
            :op1 (s4 / small-molecule :name (n5 / name :op1 "DMSO")
                  :ARG0-of (c4 / control-01
                        :ARG1 (d / dissolve-01)))
            :op2 (s5 / small-molecule :name (n6 / name :op1 "SCH722984")
                  :quant (c5 / concentration-quantity :quant 500
                        :unit (n7 / nanomolar))))
      :duration (t2 / temporal-quantity :quant 24
            :unit (h / hour)))

# ::id a_pmid_2514_2146.80 ::date 2015-06-09T12:37:21 ::annotator SDL-AMR-09 ::preferred
# ::snt We next determined a time-course of SCH772984 on MAPK and PI3K/AKT pathway signaling for M238, a SCH772984-sensitive <i>BRAF</i><sup><i>V600E</i></sup>-mutant melanoma cell line and M233, a SCH772984-resistant <i>BRAF</i><sup><i>V600E</i></sup>-mutant melanoma cell line (Figure <xref ref-type="fig" rid="Fig1">1</xref>B).
# ::save-date Wed Mar 2, 2016 ::file a_pmid_2514_2146_80.txt
(d / determine-01
      :ARG0 (w / we)
      :ARG1 (t / timecourse
            :poss (s / small-molecule :name (n2 / name :op1 "SCH772984")
                  :ARG2-of (t2 / treat-04
                        :ARG1 (a / and
                              :op1 (p / pathway :name (n4 / name :op1 "MAPK")
                                    :ARG0-of (s2 / signal-07))
                              :op2 (p2 / pathway :name (n5 / name :op1 "PI3K/AKT")
                                    :ARG0-of s2))))
            :beneficiary (a2 / and
                  :op1 (c2 / cell-line :name (n6 / name :op1 "M238")
                        :ARG2-of (m / mean-01
                              :ARG1 (c3 / cell-line
                                    :ARG0-of (s3 / sensitive-03
                                          :ARG1 s)
                                    :mod (g / gene :name (n7 / name :op1 "BRAF")
                                          :ARG2-of (m3 / mutate-01 :value "V600E"))
                                    :mod (m2 / medical-condition :name (n3 / name :op1 "melanoma")))))
                  :op2 (c5 / cell-line :name (n8 / name :op1 "M233")
                        :ARG1-of (m4 / mean-01
                              :ARG2 (c4 / cell-line
                                    :ARG0-of (r / resist-01
                                          :ARG1 s)
                                    :mod m2
                                    :mod g)))))
      :time (n / next)
      :ARG1-of (d3 / describe-01
            :ARG0 (f / figure :mod "1B")))

# ::id a_pmid_2514_2146.81 ::date 2015-06-09T13:23:01 ::annotator SDL-AMR-09 ::preferred
# ::snt For both M233 and M238, treatment with 500nM SCH772984 inhibited pRSK, a known ERK1/2 downstream target, as well as pERK1/2 itself.
# ::save-date Tue Dec 22, 2015 ::file a_pmid_2514_2146_81.txt
(i / inhibit-01
      :ARG0 (t / treat-04
            :ARG1 (a / and
                  :op1 (c / cell-line :name (n2 / name :op1 "M233"))
                  :op2 (c2 / cell-line :name (n3 / name :op1 "M238")))
            :ARG2 (s / small-molecule :name (n / name :op1 "SCH772984")
                  :quant (c3 / concentration-quantity :quant 500
                        :unit (n4 / nanomolar))))
      :ARG1 (a2 / and
            :op1 (e / enzyme :name (n5 / name :op1 "RSK")
                  :ARG3-of (p / phosphorylate-01)
                  :ARG1-of (t2 / target-01
                        :ARG0 (e3 / enzyme :name (n7 / name :op1 "ERK1/2"))
                        :ARG1-of (k / know-01)
                        :location (d / downstream)))
            :op2 (e2 / enzyme :name (n6 / name :op1 "ERK1/2")
                  :ARG3-of p)))

# ::id a_pmid_2514_2146.82 ::date 2015-06-09T14:07:27 ::annotator SDL-AMR-09 ::preferred
# ::snt For the resistant M233, the MAPK inhibition was strong as early as 1 hour post treatment, with decreased pERK and near-complete disappearance of pRSK.
# ::save-date Sun Jan 17, 2016 ::file a_pmid_2514_2146_82.txt
(a2 / and
      :op1 (s / strong
            :domain (i / inhibit-01
                  :ARG1 (p / protein-family :name (n / name :op1 "MAPK")
                        :part-of (c / cell-line :name (n2 / name :op1 "M233")
                              :ARG0-of (r / resist-01))))
            :time (a / after
                  :op1 (t / treat-04)
                  :quant (t2 / temporal-quantity :quant 1
                        :unit (h / hour))))
      :op2 (d / decrease-01
            :ARG1 (e / enzyme :name (n3 / name :op1 "ERK")
                  :ARG3-of (p2 / phosphorylate-01)
                  :part-of c))
      :op3 (d2 / disappear-01
            :ARG1 (e2 / enzyme :name (n5 / name :op1 "RSK")
                  :ARG3-of p2
                  :part-of c)
            :ARG1-of (c2 / complete-01
                  :degree (n4 / near))))

# ::id a_pmid_2514_2146.83 ::date 2015-06-09T14:18:38 ::annotator SDL-AMR-09 ::preferred
# ::snt However, between 12 and 24 hours we observe a rebound in the pathway with a return to baseline pERK1/2 levels and an induction in pMEK above baseline levels by 24 hours.
# ::save-date Mon Jun 15, 2015 ::file a_pmid_2514_2146_83.txt
(h3 / have-concession-91
      :ARG2 (o / observe-01
            :ARG0 (w / we)
            :ARG1 (r / rebound-01
                  :ARG1 (p / pathway)
                  :ARG0-of (c2 / cause-01
                        :ARG1 (a / and
                              :op1 (r2 / return-01
                                    :ARG1 (l / level
                                          :quant-of (e / enzyme :name (n / name :op1 "ERK1/2")
                                                :ARG3-of (p2 / phosphorylate-01))
                                          :mod (b2 / baseline)))
                              :op2 (i / induce-01
                                    :ARG1 (e2 / enzyme :name (n2 / name :op1 "MEK")
                                          :ARG3-of p2)
                                    :ARG2 (a2 / above
                                          :op1 (l2 / level
                                                :quant-of e2
                                                :mod b2)))
                              :time (a3 / after
                                    :quant (t3 / temporal-quantity :quant 24
                                          :unit (h2 / hour))))))
            :time (b / between
                  :op1 (t / temporal-quantity :quant 12
                        :unit (h / hour))
                  :op2 (t2 / temporal-quantity :quant 24
                        :unit h))))

# ::id a_pmid_2514_2146.84 ::date 2015-06-09T14:35:03 ::annotator SDL-AMR-09 ::preferred
# ::snt Little change in pAKT was seen at any timepoint up to 24 hours, though a mild induction was seen at 48 hours.
# ::save-date Sun Dec 20, 2015 ::file a_pmid_2514_2146_84.txt
(s / see-01
      :ARG1 (c / change-01
            :ARG1 (e / enzyme :name (n / name :op1 "AKT")
                  :ARG3-of (p / phosphorylate-01))
            :mod (l / little))
      :time (t / timepoint
            :mod (a / any)
            :quant (u / up-to
                  :op1 (t2 / temporal-quantity :quant 24
                        :unit (h / hour))))
      :concession (s2 / see-01
                  :ARG1 (i / induce-01
                        :ARG2 e
                        :degree (m / mild))
                  :time (a2 / after
                        :op1 (t3 / temporal-quantity :quant 48
                              :unit h))))

# ::id a_pmid_2514_2146.85 ::date 2015-06-09T14:42:33 ::annotator SDL-AMR-09 ::preferred
# ::snt For the sensitive M238, pRSK levels also decreased as early as 1 hour and levels continued to decrease thereafter.
# ::save-date Mon Jun 15, 2015 ::file a_pmid_2514_2146_85.txt
(a / and
      :op1 (d / decrease-01
            :ARG1 (l / level
                  :quant-of (e / enzyme :name (n / name :op1 "RSK")
                        :ARG3-of (p / phosphorylate-01)
                        :part-of (c / cell-line :name (n2 / name :op1 "M238")
                              :ARG0-of (s / sensitive-03))))
            :mod (a2 / also)
            :time (a3 / after
                  :op1 (t / temporal-quantity :quant 1
                        :unit (h / hour))))
      :op2 (c2 / continue-01
            :ARG1 (d2 / decrease-01
                  :ARG1 l)
            :time (t2 / thereafter)))

# ::id a_pmid_2514_2146.86 ::date 2015-06-09T14:51:34 ::annotator SDL-AMR-09 ::preferred
# ::snt Meanwhile, pERK1/2 remained suppressed through 24 hours.
# ::save-date Sun Jun 14, 2015 ::file a_pmid_2514_2146_86.txt
(r / remain-01
      :ARG1 (e / enzyme :name (n / name :op1 "ERK1/2")
            :ARG3-of (p / phosphorylate-01))
      :ARG3 (s / suppress-01
            :ARG1 e)
      :duration (t / temporal-quantity :quant 24
            :unit (h / hour))
      :time (m / meanwhile))

# ::id a_pmid_2514_2146.87 ::date 2015-06-09T14:54:51 ::annotator SDL-AMR-09 ::preferred
# ::snt By 48 hours, pERK1/2 levels increased, though at reduced levels compared to baseline.
# ::save-date Sun Jun 14, 2015 ::file a_pmid_2514_2146_87.txt
(i / increase-01
      :ARG1 (l / level
            :quant-of (e / enzyme :name (n / name :op1 "ERK1/2")
                  :ARG3-of (p / phosphorylate-01)))
      :time (a / after
            :op1 (t / temporal-quantity :quant 48
                  :unit (h / hour)))
      :concession (l2 / level
                  :ARG1-of (r / reduce-01
                        :ARG1-of (c / compare-01
                              :ARG2 (b / baseline)))))

# ::id a_pmid_2514_2146.88 ::date 2015-06-09T15:01:39 ::annotator SDL-AMR-09 ::preferred
# ::snt Concomitant with this, pMEK levels remained unchanged until 24 hours and increased further by 48 hours.
# ::save-date Mon Jun 15, 2015 ::file a_pmid_2514_2146_88.txt
(a / and
      :op1 (r / remain-01
            :ARG1 (l / level
                  :quant-of (e / enzyme :name (n / name :op1 "MEK")
                        :ARG3-of (p / phosphorylate-01)))
            :ARG3 (c / change-01 :polarity -
                  :ARG1 l)
            :time (u / until
                  :op1 (t / temporal-quantity :quant 24
                        :unit (h / hour))))
      :op2 (i / increase-01
            :ARG1 l
            :time (a2 / after
                  :op1 (t2 / temporal-quantity :quant 48
                        :unit h))
            :degree (f / further))
      :manner (c2 / concomitant
            :prep-with (t3 / this)))

# ::id a_pmid_2514_2146.89 ::date 2015-06-09T15:11:28 ::annotator SDL-AMR-09 ::preferred
# ::snt Regarding pAKT, an early induction at 1 hour occurred, followed by decreases thereafter though never becoming completely suppressed even at 48 hours.
# ::save-date Sun Dec 20, 2015 ::file a_pmid_2514_2146_89.txt
(i / induce-01
      :ARG2 (e2 / enzyme :name (n / name :op1 "AKT")
            :ARG3-of (p / phosphorylate-01))
      :time (e / early)
      :time (a / after
            :op1 (t / temporal-quantity :quant 1
                  :unit (h / hour)))
      :ARG2-of (f / follow-01
            :ARG1 (d / decrease-01
                  :ARG1 e
                  :time (t2 / thereafter)
                  :concession (b / become-01 :polarity -
                              :ARG1 e2
                              :ARG2 (s / suppress-01
                                    :ARG1 e2
                                    :time (a2 / after
                                          :op1 (t3 / temporal-quantity :quant 48
                                                :unit h))
                                    :mod (e4 / even)
                                    :degree (c / complete))
                              :time (e3 / ever)))))

# ::id a_pmid_2514_2146.90 ::date 2015-06-08T13:42:46 ::annotator SDL-AMR-09 ::preferred
# ::snt In both cell lines, pRSK remained blocked at all timepoints, demonstrating ongoing, potent inhibition of ERK1/2 activity by SCH772984.
# ::save-date Mon Dec 21, 2015 ::file a_pmid_2514_2146_90.txt
(r / remain-01
      :ARG1 (p / protein :name (n / name :op1 "pRSK"))
      :ARG3 (b / block-01
            :ARG1 p
            :ARG0-of (d / demonstrate-01
                  :ARG1 (i / inhibit-01
                        :ARG0 (s / small-molecule :name (n3 / name :op1 "SCH772984"))
                        :ARG1 (a2 / activity-06
                              :ARG0 (e / enzyme :name (n2 / name :op1 "ERK1/2")))
                        :ARG1-of (g / go-on-15)
                        :mod (p2 / potent))
                  :time (t / timepoint
                        :mod (a / all))))
      :location (c2 / cell-line
            :mod (b2 / both)))

# ::id a_pmid_2514_2146.91 ::date 2015-06-08T14:20:49 ::annotator SDL-AMR-09 ::preferred
# ::snt These data supports that the distinction between sensitive and resistant cell lines could be best made based on pERK recovery at 24 hours, as recovery of the feedback loop that restores MAPK activity occurred by 24 hours in the resistant cell line whereas the sensitive cell line required longer than 24 hours.
# ::save-date Sat Jan 16, 2016 ::file a_pmid_2514_2146_91.txt
(s / support-01
      :ARG0 (d2 / data
            :mod (t2 / this))
      :ARG1 (p / possible-01
            :ARG1 (b / base-02
                  :ARG1 (d / distinguish-01
                        :ARG1 (a / and
                              :op1 (c / cell-line
                                    :ARG0-of (s2 / sensitive-03))
                              :op2 (c2 / cell-line
                                    :ARG0-of (r / resist-01))))
                  :ARG2 (r2 / recover-02
                        :ARG0 (e / enzyme :name (n2 / name :op1 "ERK")
                              :ARG3-of (p3 / phosphorylate-01))
                        :time (a3 / after
                              :op1 (t / temporal-quantity :quant 24
                                    :unit (h / hour)))
                        :ARG1-of (m3 / mean-01
                              :ARG2 (r5 / recover-02
                                    :ARG0 (l / loop
                                          :mod (f / feedback)
                                          :ARG0-of (r3 / restore-01
                                                :ARG1 (a2 / activity-06
                                                      :ARG0 (p2 / pathway :name (n / name :op1 "MAPK")))
                                                :location c2
                                                :ARG1-of (c3 / contrast-01
                                                      :ARG2 (r4 / require-01
                                                            :ARG0 c
                                                            :ARG1 (l2 / long-03
                                                                  :ARG2 t
                                                                  :degree (m2 / more))))
                                                :time a3)))))
                  :ARG1-of (g / good-02
                        :degree (m / most)))))

# ::id a_pmid_2514_2146.92 ::date 2015-06-09T10:34:09 ::annotator SDL-AMR-09 ::preferred
# ::snt Therefore, for subsequent analyses, we selected 24 hours as the optimal timepoint to compare signaling in our cell lines.
# ::save-date Fri Feb 5, 2016 ::file a_pmid_2514_2146_92.txt
(c / cause-01
      :ARG1 (s / select-01
            :ARG0 (w / we)
            :ARG1 (t / temporal-quantity :quant 24
                  :unit (h / hour))
            :ARG3 (t2 / timepoint
                  :mod (o / optimal))
            :purpose (c2 / compare-01
                  :ARG0 w
                  :ARG1 (s2 / signal-07
                        :location (c3 / cell-line
                              :poss w)))
            :purpose (a / analyze-01
                  :ARG0 w
                  :time (s3 / subsequent))))

# ::id a_pmid_2514_2146.93 ::date 2015-06-09T10:47:48 ::annotator SDL-AMR-09 ::preferred
# ::snt As shown in Figure <xref ref-type="fig" rid="Fig1">1</xref>C, three <i>BRAF</i> mutant cell lines representative of the different sensitivity groups to SCH772984 were profiled in terms of downstream signaling inhibition at 24 hours: a highly sensitive cell line (M262, <i>BRAF</i><sup><i>V600E</i></sup>), an intermediately sensitive cell line (M409, <i>BRAF</i><sup><i>V600E</i></sup>), and a resistant cell line (M381, <i>BRAF</i><sup><i>V600R</i></sup>).
# ::save-date Mon Dec 21, 2015 ::file a_pmid_2514_2146_93.txt
(p2 / profile-01
      :ARG1 (c / cell-line :quant 3
            :ARG0-of (r2 / represent-01
                  :ARG1 (g / group
                        :ARG1-of (d2 / differ-02)
                        :ARG0-of (s / sensitive-03
                              :ARG1 (s6 / small-molecule :name (n2 / name :op1 "SCH772984")))))
            :ARG1-of (m7 / mean-01
                  :ARG2 (a / and
                        :op1 (c3 / cell-line
                              :ARG0-of (s3 / sensitive-03
                                    :ARG1-of (h2 / high-02))
                              :ARG1-of (m2 / mean-01
                                    :ARG2 (c4 / cell-line :name (n3 / name :op1 "M262")
                                          :mod (g2 / gene :name (n4 / name :op1 "BRAF")
                                                :ARG2-of (m3 / mutate-01 :value "V600E")))))
                        :op2 (c5 / cell-line
                              :ARG0-of (s4 / sensitive-03
                                    :mod (i2 / intermediate))
                              :ARG1-of (m4 / mean-01
                                    :ARG2 (c6 / cell-line :name (n5 / name :op1 "M409")
                                          :mod g2)))
                        :op3 (c7 / cell-line
                              :ARG0-of (r4 / resist-01)
                              :ARG1-of (m5 / mean-01
                                    :ARG2 (c8 / cell-line :name (n6 / name :op1 "M381")
                                          :mod (g4 / gene :name (n7 / name :op1 "BRAF")
                                                :ARG2-of (m6 / mutate-01 :value "V600R")))))))
            :mod (g3 / gene :name (n / name :op1 "BRAF")
                  :ARG2-of (m / mutate-01)))
      :topic (i / inhibit-01
            :ARG1 (s2 / signal-07
                  :location (d / downstream))
            :time (a2 / after
                  :op1 (t / temporal-quantity :quant 24
                        :unit (h / hour))))
      :ARG1-of (s5 / show-01
            :ARG0 (f / figure :mod "1C")))

# ::id a_pmid_2514_2146.94 ::date 2015-06-09T11:23:26 ::annotator SDL-AMR-09 ::preferred
# ::snt For M262, treatment with SCH772984 resulted in disappearance of pRSK, disappearance of pERK1/2, decrease in pAKT, and slight induction of pMEK at 24 hours.
# ::save-date Sun Jan 17, 2016 ::file a_pmid_2514_2146_94.txt
(r / result-01
      :ARG1 (t2 / treat-04
            :ARG1 (c / cell-line :name (n / name :op1 "M262"))
            :ARG2 (s / small-molecule :name (n2 / name :op1 "SCH772984")))
      :ARG2 (a / and
            :op1 (d / disappear-01
                  :ARG1 (e4 / enzyme :name (n3 / name :op1 "RSK")
                        :ARG3-of (p2 / phosphorylate-01)))
            :op2 (d2 / disappear-01
                  :ARG1 (e / enzyme :name (n4 / name :op1 "ERK1/2")
                        :ARG3-of p2))
            :op3 (d3 / decrease-01
                  :ARG1 (e2 / enzyme :name (n5 / name :op1 "AKT")
                        :ARG3-of p2))
            :op4 (i / induce-01
                  :ARG2 (e3 / enzyme :name (n6 / name :op1 "MEK")
                        :ARG3-of p2)
                  :degree (s2 / slight))
            :time (a2 / after
                  :op1 (t / temporal-quantity :quant 24
                        :unit (h / hour)))))

# ::id a_pmid_2514_2146.95 ::date 2015-06-09T11:33:05 ::annotator SDL-AMR-09 ::preferred
# ::snt M409 had a similar cell signaling profile as M262, consistent with its modest sensitivity.
# ::save-date Sun Jun 14, 2015 ::file a_pmid_2514_2146_95.txt
(h / have-03
      :ARG0 (c / cell-line :name (n / name :op1 "M409"))
      :ARG1 (p / profile-01
            :ARG0-of (s / signal-07
                  :ARG1 (c2 / cell))
            :ARG1-of (r / resemble-01
                  :ARG2 (c3 / cell-line :name (n2 / name :op1 "M262")))
            :ARG1-of (c4 / consistent-01
                  :ARG2 (s2 / sensitive-03
                        :ARG0 p
                        :mod (m / modest)))))

# ::id a_pmid_2514_2146.96 ::date 2015-06-09T11:39:15 ::annotator SDL-AMR-09 ::preferred
# ::snt For M381induction of pMEK and pERK1/2 were seen with no change in pRSK at 24 h.
# ::save-date Sun Dec 20, 2015 ::file a_pmid_2514_2146_96.txt
(s / see-01
      :ARG1 (i / induce-01
            :ARG2 (a2 / and
                  :op1 (e / enzyme :name (n / name :op1 "MEK")
                        :ARG3-of (p / phosphorylate-01))
                  :op2 (e2 / enzyme :name (n2 / name :op1 "ERK1/2")
                        :ARG3-of p))
            :location (c2 / cell-line :name (n4 / name :op1 "M381")))
      :ARG2 (c / change-01 :polarity -
            :ARG1 (e3 / enzyme :name (n3 / name :op1 "RSK")
                  :ARG3-of p))
      :time (a / after
            :op1 (t / temporal-quantity :quant 24
                  :unit (h / hour))))

# ::id a_pmid_2514_2146.97 ::date 2015-06-09T11:47:25 ::annotator SDL-AMR-09 ::preferred
# ::snt To determine the effect of SCH772984 on the PI3K/AKT pathway, we first evaluated the baseline pAKT levels for a group of cell lines (Additional file <xref ref-type="media" rid="MOESM2">2</xref>: Figure S2).
# ::save-date Mon Jun 15, 2015 ::file a_pmid_2514_2146_97.txt
(e / evaluate-01
      :ARG0 (w / we)
      :ARG1 (l / level
            :quant-of (e2 / enzyme :name (n2 / name :op1 "AKT")
                  :ARG3-of (p2 / phosphorylate-01)
                  :part-of (g / group
                        :consist-of (c / cell-line)))
            :mod (b / baseline))
      :purpose (d / determine-01
            :ARG0 w
            :ARG1 (a / affect-01
                  :ARG0 (s / small-molecule :name (n3 / name :op1 "SCH772984"))
                  :ARG1 (p / pathway :name (n / name :op1 "PI3K/AKT"))))
      :ARG1-of (d2 / describe-01
            :ARG0 (f / file :mod 2
                  :ARG1-of (m / mean-01
                        :ARG2 (f2 / figure :mod "S2"))
                  :ARG1-of (a3 / add-02)))
      :time (f3 / first))

# ::id a_pmid_2514_2146.98 ::date 2015-06-09T12:08:35 ::annotator SDL-AMR-09 ::preferred
# ::snt We found a weak correlation with the activity of the PI3K/AKT pathway and sensitivity to SCH772984 for BRAF mutants.
# ::save-date Sat Jan 16, 2016 ::file a_pmid_2514_2146_98.txt
(f / find-01
      :ARG0 (w / we)
      :ARG1 (a2 / and
            :op1 (c / correlate-01
                  :ARG1 e
                  :ARG2 (a / activity-06
                        :ARG0 (p / pathway :name (n / name :op1 "PI3K/AKT")))
                  :ARG1-of (w2 / weak-02))
            :op2 (s / sensitive-03
                  :ARG0 (e / enzyme :name (n2 / name :op1 "BRAF")
                        :ARG2-of (m / mutate-01))
                  :ARG1 (s2 / small-molecule :name (n3 / name :op1 "SCH772984")))))

# ::id a_pmid_2514_2146.99 ::date 2015-06-09T12:12:03 ::annotator SDL-AMR-09 ::preferred
# ::snt For example, M238 and M409 are two clear examples of cell lines with low levels of pAKT related to sensitivity to SCH772984.
# ::save-date Mon Jun 15, 2015 ::file a_pmid_2514_2146_99.txt
(a2 / and
      :op1 (c / cell-line :name (n / name :op1 "M238"))
      :op2 (c2 / cell-line :name (n2 / name :op1 "M409"))
      :ARG0-of (e2 / exemplify-01 :quant 2
            :ARG1 (c3 / cell-line
                  :ARG0-of (h / have-03
                        :ARG1 (l / level
                              :quant-of (e3 / enzyme :name (n3 / name :op1 "AKT")
                                    :ARG3-of (p / phosphorylate-01))
                              :ARG1-of (l2 / low-04))))
            :ARG1-of (c4 / clear-06))
      :ARG1-of (r / relate-01
            :ARG2 (s / sensitive-03
                  :ARG1 (s2 / small-molecule :name (n4 / name :op1 "SCH772984"))))
      :ARG0-of (e / exemplify-01))

# ::id a_pmid_2514_2146.100 ::date 2015-06-09T12:17:57 ::annotator SDL-AMR-09 ::preferred
# ::snt For both of them, ERK inhibition with SCH772984 was accompanied by an upregulation of pAKT levels even at 24 hours treatment (Figure <xref ref-type="fig" rid="Fig1">1</xref>B).
# ::save-date Sat Jan 16, 2016 ::file a_pmid_2514_2146_100.txt
(a / accompany-01
      :ARG0 (u / upregulate-01
            :ARG1 (l / level
                  :quant-of (e3 / enzyme :name (n4 / name :op1 "AKT")
                        :ARG3-of (p / phosphorylate-01))))
      :ARG1 (i / inhibit-01
            :ARG0 (s / small-molecule :name (n3 / name :op1 "SCH772984"))
            :ARG1 (e2 / enzyme :name (n2 / name :op1 "ERK")))
      :time (a2 / after
            :op1 (t2 / treat-04)
            :mod (e / even)
            :quant (t / temporal-quantity :quant 24
                  :unit (h / hour)))
      :beneficiary (t3 / they
            :mod (b / both))
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod "1B")))

# ::id a_pmid_2514_2146.101 ::date 2015-06-09T12:37:14 ::annotator SDL-AMR-09 ::preferred
# ::snt M233 was among the resistant <i>BRAF</i><sup><i>V600E</i></sup> melanoma cell lines, which appeared to have increased pAKT at baseline compared to other <i>BRAF</i> mutant cell lines.
# ::save-date Thu Jan 14, 2016 ::file a_pmid_2514_2146_101.txt
(c4 / cell-line :name (n5 / name :op1 "M233")
      :ARG0-of (h / have-03
            :ARG1 (e / enzyme :name (n3 / name :op1 "AKT")
                  :ARG3-of (p / phosphorylate-01)
                  :ARG1-of (i2 / increase-01
                        :location (b / baseline)
                        :compared-to (c3 / cell-line
                              :mod (g2 / gene :name (n4 / name :op1 "BRAF")
                                    :ARG2-of (m3 / mutate-01))
                              :mod (o / other))))
            :ARG1-of (a / appear-01))
      :ARG1-of (i / include-91
            :ARG2 (c2 / cell-line
                  :mod (g / gene :name (n2 / name :op1 "BRAF")
                        :ARG2-of (m2 / mutate-01 :value "V600E"))
                  :mod (m4 / medical-condition :name (n / name :op1 "melanoma"))))
      :ARG0-of (r / resist-01))

# ::id a_pmid_2514_2146.102 ::date 2015-06-09T12:44:42 ::annotator SDL-AMR-09 ::preferred
# ::snt Consistent with this, M233 is a PTEN null cell line and has a concomitant <i>AKT1</i> amplification [<xref ref-type="bibr" rid="CR31">31</xref>].
# ::save-date Sun Jan 17, 2016 ::file a_pmid_2514_2146_102.txt
(a / and
      :op1 (c2 / cell-line
            :mod (n2 / null)
            :mod (p / protein :name (n3 / name :op1 "PTEN"))
            :domain (c / cell-line :name (n / name :op1 "M233")))
      :op2 (h / have-03
            :ARG0 c
            :ARG1 (a2 / amplify-01
                  :ARG1 (g / gene :name (n4 / name :op1 "AKT1"))
                  :mod (c3 / concomitant)))
      :ARG1-of (c4 / consistent-01
            :ARG2 (t / this))
      :ARG1-of (d / describe-01
            :ARG0 (p2 / publication
                  :ARG1-of (c5 / cite-01
                        :ARG2 31))))

# ::id a_pmid_2514_2146.103 ::date 2015-06-09T12:56:40 ::annotator SDL-AMR-09 ::preferred
# ::snt After treatment with SCH772984 (Figure <xref ref-type="fig" rid="Fig1">1</xref>B), these levels stay constant, indicating that dual inhibition with SCH772984 and AKT/mTOR inhibitors may be a useful strategy.
# ::save-date Mon Dec 21, 2015 ::file a_pmid_2514_2146_103.txt
(s / stay-01
      :ARG1 (l / level
            :mod (t2 / this))
      :ARG3 (c / constant)
      :ARG0-of (i2 / indicate-01
            :ARG1 (s2 / strategy
                  :domain (a / and
                        :op1 (i3 / inhibit-01
                              :ARG0 (s3 / small-molecule :name (n / name :op1 "SCH772984"))
                              :mod (d2 / dual))
                        :op2 (m / molecular-physical-entity
                              :ARG0-of (i / inhibit-01
                                    :ARG1 (p2 / pathway :name (n2 / name :op1 "AKT/mTOR")))))
                  :ARG1-of (u / useful-05)
                  :ARG1-of (p / possible-01)))
      :time (a2 / after
            :op1 (t3 / treat-04
                  :ARG2 s3)
            :ARG1-of (d3 / describe-01
                  :ARG0 (f / figure :mod "1B"))))

# ::id a_pmid_2514_2146.104 ::date 2015-06-09T13:11:03 ::annotator SDL-AMR-09 ::preferred
# ::snt In contrast, M262 is an <i>AKT1</i> amplified cell line [<xref ref-type="bibr" rid="CR31">31</xref>] with high sensitivity to SCH772984 and vemurafenib.
# ::save-date Sun Jan 17, 2016 ::file a_pmid_2514_2146_104.txt
(c / contrast-01
      :ARG2 (c2 / cell-line
            :ARG1-of (a / amplify-01
                  :ARG0 (g / gene :name (n / name :op1 "AKT1")))
            :domain (c3 / cell-line :name (n2 / name :op1 "M262")
                  :ARG0-of (s / sensitive-03
                        :ARG1 (a2 / and
                              :op1 (s2 / small-molecule :name (n3 / name :op1 "SCH772984"))
                              :op2 (s3 / small-molecule :name (n4 / name :op1 "vemurafenib")))
                        :ARG1-of (h / high-02)))
            :ARG1-of (d / describe-01
                  :ARG0 (p / publication
                        :ARG1-of (c4 / cite-01
                              :ARG2 31)))))

# ::id a_pmid_2514_2146.105 ::date 2015-06-09T13:15:15 ::annotator SDL-AMR-09 ::preferred
# ::snt Treatment of M262 with SCH772984 reduced both pERK1/2 and pAKT levels, indicating blockade of the MAPK pathway and PI3K/AKT pathway at the same time (Figure <xref ref-type="fig" rid="Fig1">1</xref>C).
# ::save-date Sun Jun 14, 2015 ::file a_pmid_2514_2146_105.txt
(r / reduce-01
      :ARG0 (t2 / treat-04
            :ARG1 (c / cell-line :name (n3 / name :op1 "M262"))
            :ARG2 (s2 / small-molecule :name (n4 / name :op1 "SCH772984")))
      :ARG1 (a / and
            :op1 (l / level
                  :quant-of (e / enzyme :name (n5 / name :op1 "ERK1/2")
                        :ARG3-of (p3 / phosphorylate-01)))
            :op2 (l2 / level
                  :quant-of (e2 / enzyme :name (n6 / name :op1 "AKT")
                        :ARG3-of p3)))
      :ARG0-of (i / indicate-01
            :ARG1 (b / blockade-01
                  :ARG1 (a2 / and
                        :op1 (p / pathway :name (n / name :op1 "MAPK"))
                        :op2 (p2 / pathway :name (n2 / name :op1 "PI3K/AKT")))
                  :time (t3 / time
                        :ARG1-of (s3 / same-01))))
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod "1C")))

# ::id a_pmid_2514_2146.106 ::date 2015-06-09T13:20:27 ::annotator SDL-AMR-09 ::preferred
# ::snt In general, the presence of <i>AKT1</i> or <i>AKT2</i> amplification did not preclude sensitivity to SCH772984, as three of five such cell lines were highly sensitive to SCH772984 (M229, M249, and M262), one was intermediately sensitive (M255), and M233 and M308 were resistant (Figure <xref ref-type="fig" rid="Fig1">1</xref>A).
# ::save-date Sun Jan 17, 2016 ::file a_pmid_2514_2146_106.txt
(p / preclude-01 :polarity -
      :ARG0 (a / amplify-01
            :ARG1 (a2 / and
                  :op1 (g2 / gene :name (n / name :op1 "AKT1"))
                  :op2 (g3 / gene :name (n2 / name :op1 "AKT2"))))
      :ARG1 (s / sensitive-03
            :ARG1 (s2 / small-molecule :name (n3 / name :op1 "SCH772984")))
      :ARG1-of (c / cause-01
            :ARG0 (a3 / and
                  :op1 (s3 / sensitive-03
                        :ARG0 (c2 / cell-line :quant 3
                              :ARG1-of (i / include-91
                                    :ARG2 (c3 / cell-line :quant 5))
                              :ARG1-of (m / mean-01
                                    :ARG2 (a4 / and
                                          :op1 (c4 / cell-line :name (n5 / name :op1 "M229"))
                                          :op2 (c5 / cell-line :name (n6 / name :op1 "M249"))
                                          :op3 (c6 / cell-line :name (n7 / name :op1 "M262")))))
                        :ARG1 s2
                        :ARG1-of (h / high-02))
                  :op2 (c7 / cell-line :quant 1
                        :ARG0-of (s5 / sensitive-03
                              :ARG1 s2
                              :mod (i2 / intermediate))
                        :ARG1-of (m2 / mean-01
                              :ARG2 (c8 / cell-line :name (n8 / name :op1 "M255"))))
                  :op3 (a5 / and
                        :op1 (c9 / cell-line :name (n9 / name :op1 "M233"))
                        :op2 (c10 / cell-line :name (n10 / name :op1 "M308"))
                        :ARG0-of (r / resist-01
                              :ARG1 s2))))
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod "1A"))
      :ARG1-of (g / general-02))

# ::id a_pmid_2514_2146.107 ::date 2015-06-09T13:37:14 ::annotator SDL-AMR-09 ::preferred
# ::snt Given high baseline pAKT levels were seen in some cells resistant to ERK inhibition (Additional file <xref ref-type="media" rid="MOESM2">2</xref>: Figure S2) and the persistence of pAKT activity with SCH722984 treatment, we evaluated the effect of SCH772984 in combination with the AKT inhibitor MK-2206 or the mTOR inhibitor MK-8669.
# ::save-date Sat Jan 16, 2016 ::file a_pmid_2514_2146_107.txt
(c / cause-01
      :ARG0 (a / and
            :op1 (s / see-01
                  :ARG1 (l / level
                        :quant-of (e2 / enzyme :name (n2 / name :op1 "AKT")
                              :ARG3-of (p / phosphorylate-01))
                        :mod (b / baseline)
                        :ARG1-of (h / high-02))
                  :location (c2 / cell
                        :quant (s2 / some)
                        :ARG0-of (r / resist-01
                              :ARG1 (i2 / inhibit-01
                                    :ARG1 (e / enzyme :name (n3 / name :op1 "ERK")))))
                  :ARG1-of (d / describe-01
                        :ARG0 (f / file :mod 2
                              :ARG1-of (m / mean-01
                                    :ARG2 (f2 / figure :mod "S2"))
                              :ARG1-of (a5 / add-02))))
            :op2 (p2 / persist-01
                  :ARG1 (a2 / activity-06
                        :ARG0 (e4 / enzyme :name (n4 / name :op1 "AKT")
                              :ARG3-of (p3 / phosphorylate-01)
                              :ARG1-of (t2 / treat-04
                                    :ARG2 (s3 / small-molecule :name (n5 / name :op1 "SCH722984")))))))
      :ARG1 (e5 / evaluate-01
            :ARG0 (w / we)
            :ARG1 (a4 / affect-01
                  :ARG0 (s4 / small-molecule :name (n6 / name :op1 "SCH772984")
                        :ARG1-of (c3 / combine-01
                              :ARG2 (o / or
                                    :op1 (s6 / small-molecule :name (n7 / name :op1 "MK-2206")
                                          :ARG0-of (i3 / inhibit-01
                                                :ARG1 (e6 / enzyme :name (n8 / name :op1 "AKT"))))
                                    :op2 (s5 / small-molecule :name (n9 / name :op1 "MK-8669")
                                          :ARG0-of (i4 / inhibit-01
                                                :ARG1 (p4 / protein :name (n10 / name :op1 "mTOR"))))))))))

# ::id a_pmid_2514_2146.108 ::date 2015-06-09T13:50:54 ::annotator SDL-AMR-09 ::preferred
# ::snt The addition of either the AKTi or mTORi always resulted in more potent cell growth inhibition compared to ERKi alone (Additional file <xref ref-type="media" rid="MOESM3">3</xref>: Figures S3A and 3B).
# ::save-date Sun Jan 17, 2016 ::file a_pmid_2514_2146_108.txt
(r / result-01
      :ARG1 (a / add-02
            :ARG1 (o / or
                  :op1 (m3 / molecular-physical-entity
                        :ARG0-of (i / inhibit-01
                              :ARG1 (p3 / protein-family :name (n / name :op1 "AKT"))))
                  :op2 (m4 / molecular-physical-entity
                        :ARG0-of (i2 / inhibit-01
                              :ARG1 (p / protein :name (n2 / name :op1 "mTOR"))))))
      :ARG2 (i3 / inhibit-01
            :ARG1 (g / grow-01
                  :ARG1 (c / cell))
            :mod (p2 / potent
                  :mod (m / more))
            :compared-to (m5 / molecular-physical-entity
                  :ARG0-of (i4 / inhibit-01
                        :ARG1 (e2 / enzyme :name (n3 / name :op1 "ERK")
                              :mod (a3 / alone)))))
      :time (a2 / always)
      :ARG1-of (d / describe-01
            :ARG0 (f / file :mod 3
                  :ARG1-of (m2 / mean-01
                        :ARG2 (a5 / and
                              :op1 (f2 / figure :mod "S3A")
                              :op2 (f3 / figure :mod "S3B")))
                  :ARG1-of (a6 / add-02))))

# ::id a_pmid_2514_2146.109 ::date 2015-06-09T14:04:24 ::annotator SDL-AMR-09 ::preferred
# ::snt Combining SCH772984 with the mTOR inhibitor MK-8669 was particularly synergistic.
# ::save-date Tue Feb 2, 2016 ::file a_pmid_2514_2146_109.txt
(s2 / synergize-01
      :ARG0 (c / combine-01
            :ARG1 (s / small-molecule :name (n / name :op1 "SCH772984"))
            :ARG2 (s3 / small-molecule :name (n2 / name :op1 "MK-8669")
                  :ARG0-of (i2 / inhibit-01
                        :ARG1 (p / protein :name (n3 / name :op1 "mTOR")))))
      :mod (p2 / particular))

# ::id a_pmid_2514_2146.110 ::date 2015-06-09T14:07:27 ::annotator SDL-AMR-09 ::preferred
# ::snt For BRAF-mutant cell line M233, both combinations resulted in more complete decrease in pERK compared to treatment with SCH772984 alone.
# ::save-date Sat Jan 16, 2016 ::file a_pmid_2514_2146_110.txt
(r / result-01
      :ARG1 (c / combine-01
            :mod (b / both))
      :ARG2 (d / decrease-01
            :ARG1 (e / enzyme :name (n / name :op1 "ERK")
                  :ARG3-of (p / phosphorylate-01))
            :degree (c2 / complete
                  :mod (m / more))
            :compared-to (t / treat-04
                  :ARG2 (s / small-molecule :name (n2 / name :op1 "SCH772984")
                        :mod (a / alone))))
      :beneficiary (c3 / cell-line :name (n3 / name :op1 "M233")
            :mod (e2 / enzyme :name (n4 / name :op1 "BRAF")
                  :ARG2-of (m2 / mutate-01))))

# ::id a_pmid_2514_2146.111 ::date 2015-06-09T14:14:59 ::annotator SDL-AMR-09 ::preferred
# ::snt Despite the improved inhibition of the MAPK pathway, the levels of pAKT were largely unaffected by the addition of MK-2206 or MK-8669 (Additional file <xref ref-type="media" rid="MOESM3">3</xref>: Figure S3C).
# ::save-date Sun Jun 14, 2015 ::file a_pmid_2514_2146_111.txt
(h / have-concession-91
      :ARG1 (a / affect-01 :polarity -
            :ARG0 (a2 / add-02
                  :ARG1 (o / or
                        :op1 (s / small-molecule :name (n3 / name :op1 "MK-2206"))
                        :op2 (s2 / small-molecule :name (n4 / name :op1 "MK-8669"))))
            :ARG1 (l / level
                  :quant-of (e / enzyme :name (n2 / name :op1 "AKT")
                        :ARG3-of (p2 / phosphorylate-01)))
            :degree (l2 / large))
      :ARG2 (i / inhibit-01
            :ARG1 (p / pathway :name (n / name :op1 "MAPK"))
            :ARG1-of (i2 / improve-01))
      :ARG1-of (d / describe-01
            :ARG0 (f / file :mod 3
                  :ARG1-of (m3 / mean-01
                        :ARG2 (f2 / figure :mod "S3C"))
                  :ARG1-of (a4 / add-02))))

# ::id a_pmid_2514_2146.112 ::date 2015-06-09T14:34:19 ::annotator SDL-AMR-09 ::preferred
# ::snt Potent SCH772984-mediated ERK inhibition in <i>BRAF</i>-wild type melanoma cell lines
# ::save-date Sat Jan 16, 2016 ::file a_pmid_2514_2146_112.txt
(i2 / inhibit-01
      :ARG1 (e / enzyme :name (n / name :op1 "ERK"))
      :ARG1-of (m / mediate-01
            :ARG0 (s / small-molecule :name (n2 / name :op1 "SCH772984"))
            :location (c / cell-line
                  :mod (m2 / melanoma
                        :mod (g / gene :name (n3 / name :op1 "BRAF")
                              :mod (w / wild-type)))))
      :mod (p / potent))

# ::id a_pmid_2514_2146.113 ::date 2015-06-09T14:37:53 ::annotator SDL-AMR-09 ::preferred
# ::snt Currently, there is no effective targeted therapy for <i>BRAF</i> wild-type melanoma, which comprises 50% of all melanomas.
# ::save-date Thu Jan 14, 2016 ::file a_pmid_2514_2146_113.txt
(t3 / therapy :polarity -
      :ARG0-of (a / affect-01)
      :ARG1-of (t2 / target-01)
      :ARG1-of (c2 / comprise-01
            :ARG2 (m / medical-condition :name (n3 / name :op1 "melanoma")
                  :ARG1-of (i / include-91
                        :ARG2 (m2 / medical-condition :name (n4 / name :op1 "melanoma")
                              :mod (a2 / all))
                        :ARG3 (p / percentage-entity :value 50))))
      :time (c / current)
      :beneficiary (m4 / medical-condition :name (n2 / name :op1 "melanoma")
            :mod (g / gene :name (n / name :op1 "BRAF")
                  :mod (w / wild-type))))

# ::id a_pmid_2514_2146.114 ::date 2015-06-09T14:48:52 ::annotator SDL-AMR-09 ::preferred
# ::snt Fourteen <i>NRAS</i> mutant melanoma and seven cells lines with wild-type <i>BRA</i>F and <i>NRAS</i> were evaluated for SCH772984 sensitivity.
# ::save-date Thu Jan 14, 2016 ::file a_pmid_2514_2146_114.txt
(e / evaluate-01
      :ARG1 (a / and
            :op1 (m3 / medical-condition :quant 14 :name (n5 / name :op1 "melanoma")
                  :mod (e2 / enzyme :name (n / name :op1 "NRAS")
                        :ARG2-of (m2 / mutate-01)))
            :op2 (c / cell-line :quant 7
                  :ARG0-of (h / have-03
                        :ARG1 (a2 / and
                              :op1 (g / gene :name (n2 / name :op1 "BRAF")
                                    :mod (w / wild-type))
                              :op2 (g2 / gene :name (n3 / name :op1 "NRAS")
                                    :mod w)))))
      :purpose (s / sensitive-03
            :ARG0 a
            :ARG1 (s2 / small-molecule :name (n4 / name :op1 "SCH772984"))))

# ::id a_pmid_2514_2146.115 ::date 2015-06-09T14:52:25 ::annotator SDL-AMR-09 ::preferred
# ::snt As shown in Figure <xref ref-type="fig" rid="Fig2">2</xref>A, while all <i>NRAS</i>-mutant cell lines were resistant to vemurafenib, 11 of 14 were highly sensitive to SCH772984 (IC<sub>50</sub> < 1 μM).
# ::save-date Tue Dec 15, 2015 ::file a_pmid_2514_2146_115.txt
(c / contrast-01
      :ARG1 (r / resist-01
            :ARG0 (c2 / cell-line
                  :mod (a / all)
                  :mod (g / gene :name (n / name :op1 "NRAS")
                        :ARG2-of (m / mutate-01)))
            :ARG1 (s / small-molecule :name (n2 / name :op1 "vemurafenib")))
      :ARG2 (s2 / sensitive-03
            :ARG0 (c3 / cell-line :quant 11
                  :ARG1-of (i / include-91
                        :ARG2 (c4 / cell-line :quant 14
                              :mod m)))
            :ARG1 (s3 / small-molecule :name (n3 / name :op1 "SCH772984")
                  :ARG1-of (h2 / have-percentage-maximal-inhibitory-concentration-01
                        :ARG2 50
                        :ARG4 (l / less-than
                              :op1 (c5 / concentration-quantity :quant 1
                                    :unit (m3 / micromolar)))))
            :ARG1-of (h / high-02))
      :ARG1-of (s4 / show-01
            :ARG0 (f / figure :mod "2A")))

# ::id a_pmid_2514_2146.116 ::date 2015-06-09T15:17:27 ::annotator SDL-AMR-09 ::preferred
# ::snt Across the 11 NRAS sensitive cell lines, two of them were Q61L (M296 and M311), four were Q61K (M408, Sbcl2, WM1366, M245 and M244), one was Q61H (M243) and three were Q61R (SKMEL173, M296 and M412a).
# ::save-date Mon Jun 15, 2015 ::file a_pmid_2514_2146_116.txt
(a2 / and
      :op1 (c3 / cell-line :quant 2
            :ARG1-of (m / mutate-01 :value "Q61L")
            :ARG1-of (m5 / mean-01
                  :ARG2 (a3 / and
                        :op1 (c5 / cell-line :name (n3 / name :op1 "M296"))
                        :op2 (c6 / cell-line :name (n4 / name :op1 "M311")))))
      :op2 (c7 / cell-line :quant 5
            :ARG1-of (m2 / mutate-01 :value "Q61K")
            :ARG1-of (m6 / mean-01
                  :ARG2 (a4 / and
                        :op1 (c8 / cell-line :name (n5 / name :op1 "M408"))
                        :op2 (c9 / cell-line :name (n6 / name :op1 "Sbcl2"))
                        :op3 (c10 / cell-line :name (n7 / name :op1 "WM1366"))
                        :op4 (c11 / cell-line :name (n8 / name :op1 "M245"))
                        :op5 (c12 / cell-line :name (n9 / name :op1 "M244")))))
      :op3 (c13 / cell-line :quant 1
            :ARG1-of (m3 / mutate-01 :value "Q61H")
            :ARG1-of (m7 / mean-01
                  :ARG2 (c14 / cell-line :name (n10 / name :op1 "M243"))))
      :op4 (c15 / cell-line :quant 3
            :ARG1-of (m4 / mutate-01 :value "Q61R")
            :ARG1-of (m8 / mean-01
                  :ARG2 (a5 / and
                        :op1 (c16 / cell-line :name (n11 / name :op1 "SKMEL173"))
                        :op2 c5
                        :op3 (c18 / cell-line :name (n13 / name :op1 "M412a")))))
      :ARG1-of (i2 / include-91
            :ARG2 (c4 / cell-line :quant 11
                  :ARG0-of (s2 / sensitive-03)
                  :mod (e2 / enzyme :name (n2 / name :op1 "NRAS")))))

# ::id a_pmid_2514_2146.117 ::date 2015-06-09T15:37:01 ::annotator SDL-AMR-09 ::preferred
# ::snt Interestingly, the three cell lines with IC50 > 1uM (M202, M207 and M318) were exclusively NRAS Q61L mutated.
# ::save-date Sun Jan 17, 2016 ::file a_pmid_2514_2146_117.txt
(m / mutate-01 :value "Q61L"
      :ARG2 (e2 / enzyme :name (n / name :op1 "NRAS")
            :part-of (c / cell-line :quant 3
                  :ARG0-of (h / have-03
                        :ARG1 (c6 / concentrate-02
                              :quant (m2 / more-than
                                    :op1 (c2 / concentration-quantity :quant 1
                                          :unit (m3 / micromolar)))
                              :mod (i2 / inhibit-01
                                    :degree (p / percentage-entity :value 50))))
                  :ARG1-of (m4 / mean-01
                        :ARG2 (a / and
                              :op1 (c3 / cell-line :name (n3 / name :op1 "M202"))
                              :op2 (c4 / cell-line :name (n4 / name :op1 "M207"))
                              :op3 (c5 / cell-line :name (n5 / name :op1 "M318"))))))
      :ARG0-of (e / exclusive-02)
      :ARG2-of (i / interest-01))

# ::id a_pmid_2514_2146.118 ::date 2015-06-09T15:42:35 ::annotator SDL-AMR-09 ::preferred
# ::snt Sensitivity to trametinib are shown in Additional file <xref ref-type="media" rid="MOESM4">4</xref>: Figures S4A and 4B for NRAS-mutant and wild-type melanoma cell lines, respectively.
# ::save-date Sun Jan 17, 2016 ::file a_pmid_2514_2146_118.txt
(s / show-01
      :ARG0 (f / file :mod 4
            :ARG1-of (m / mean-01
                  :ARG2 (a2 / and
                        :op1 (f2 / figure :mod "S4A")
                        :op2 (f3 / figure :mod "S4B")))
            :ARG1-of (a4 / add-02))
      :ARG1 (s2 / sensitive-03
            :ARG0 (a3 / and
                  :op1 (c2 / cell-line
                        :mod (e / enzyme :name (n2 / name :op1 "NRAS")
                              :ARG2-of (m3 / mutate-01)))
                  :op2 (c / cell-line
                        :mod (m4 / medical-condition :name (n3 / name :op1 "melanoma")
                              :mod (w / wild-type)))
                  :mod (r / respective))
            :ARG1 (s3 / small-molecule :name (n / name :op1 "trametinib"))))

# ::id a_pmid_2514_2146.119 ::date 2015-06-09T15:47:37 ::annotator SDL-AMR-09 ::preferred
# ::snt Consistent with the profile for sensitive cell lines, treatment with SCH772984 for the sensitive M408 resulted in decreased pRSK, disappearance of pERK1/2, and slight induction of pMEK, with no change in total RSK, MEK, ERK 1/2, or AKT.
# ::save-date Sun Dec 20, 2015 ::file a_pmid_2514_2146_119.txt
(r / result-01
      :ARG1 (t / treat-04
            :ARG1 (c / cell-line :name (n3 / name :op1 "M408")
                  :ARG0-of (s / sensitive-03))
            :ARG2 (s2 / small-molecule :name (n4 / name :op1 "SCH772984")))
      :ARG2 (a / and
            :op1 (d / decrease-01
                  :ARG1 (e3 / enzyme :name (n5 / name :op1 "RSK")
                        :ARG3-of (p / phosphorylate-01)))
            :op2 (d2 / disappear-01
                  :ARG1 (e / enzyme :name (n / name :op1 "ERK1/2")
                        :ARG3-of (p4 / phosphorylate-01)))
            :op3 (i / induce-01
                  :ARG2 (e4 / enzyme :name (n6 / name :op1 "MEK")
                        :ARG3-of (p2 / phosphorylate-01))
                  :degree (s3 / slight))
            :ARG0-of (c2 / change-01 :polarity -
                  :ARG1 (a2 / and
                        :op1 (e5 / enzyme :name (n7 / name :op1 "RSK")
                              :mod (t2 / total))
                        :op2 (e6 / enzyme :name (n8 / name :op1 "MEK")
                              :mod t2)
                        :op3 (e7 / enzyme :name (n9 / name :op1 "ERK1/2")
                              :mod t2)
                        :op4 (e8 / enzyme :name (n10 / name :op1 "AKT")
                              :mod t2))))
      :ARG1-of (c3 / consistent-01
            :ARG2 (p3 / profile-01
                  :beneficiary (c4 / cell-line
                        :ARG0-of (s4 / sensitive-03)))))

# ::id a_pmid_2514_2146.120 ::date 2015-06-11T01:41:00 ::annotator SDL-AMR-09 ::preferred
# ::snt For the resistant M202, a modest induction of pMEK with some decrease in pERK and pRSK was observed at 24 hours (Figure <xref ref-type="fig" rid="Fig2">2</xref>B).
# ::save-date Sat Jan 16, 2016 ::file a_pmid_2514_2146_120.txt
(o / observe-01
      :ARG1 (a / and
            :op1 (i / induce-01
                  :ARG2 (e / enzyme :name (n / name :op1 "MEK")
                        :ARG3-of (p / phosphorylate-01))
                  :mod (m / modest))
            :op2 (d / decrease-01
                  :ARG1 (a2 / and
                        :op1 (e2 / enzyme :name (n2 / name :op1 "ERK"))
                        :op2 (e3 / enzyme :name (n3 / name :op1 "RSK"))
                        :ARG3-of p)
                  :ARG2 (s / some)))
      :time (a3 / after
            :quant (t / temporal-quantity :quant 24
                  :unit (h / hour)))
      :location (c / cell-line :name (n4 / name :op1 "M202")
            :ARG0-of (r / resist-01))
      :ARG1-of (d2 / describe-01
            :ARG0 (f / figure :mod "2B")))

# ::id a_pmid_2514_2146.121 ::date 2015-06-11T01:49:13 ::annotator SDL-AMR-09 ::preferred
# ::snt Treatment with SCH772984 resulted in upregulation of pAKT levels for M408 and WM1366 (Additional file <xref ref-type="media" rid="MOESM3">3</xref>: Figure S3C).
# ::save-date Mon Jun 22, 2015 ::file a_pmid_2514_2146_121.txt
(r / result-01
      :ARG1 (t / treat-04
            :ARG1 (a / and
                  :op1 (c / cell-line :name (n3 / name :op1 "M408"))
                  :op2 (c2 / cell-line :name (n4 / name :op1 "WM1366")))
            :ARG2 (s / small-molecule :name (n / name :op1 "SCH772984")))
      :ARG2 (u / upregulate-01
            :ARG1 (l / level
                  :quant-of (e / enzyme :name (n2 / name :op1 "AKT")
                        :ARG3-of (p / phosphorylate-01))))
      :ARG1-of (d / describe-01
            :ARG0 (f / file :mod 3
                  :mod (f2 / figure :mod "S3C")
                  :mod (a2 / additional))))

# ::id a_pmid_2514_2146.122 ::date 2015-06-11T01:58:54 ::annotator SDL-AMR-09 ::preferred
# ::snt Consistent with the synergistic growth inhibition seen with combining SCH772984 and either MK-2206 or MK-8669, pAKT levels were abrogated with the addition of MK-2206 (AKT inhibitor) and MK-8669 (mTOR inhibitor) (Additional file <xref ref-type="media" rid="MOESM3">3</xref>: Figure S3A-C).<fig id="Fig2"><label>Figure 2</label><caption><p><bold>Susceptibility of NRAS-mutant melanoma cell lines to SCH-722984.
# ::save-date Tue Feb 2, 2016 ::file a_pmid_2514_2146_122.txt
(m / multi-sentence
      :snt1 (c / consistent-01
            :ARG1 (a / abrogate-01
                  :ARG1 (l / level
                        :quant-of (e / enzyme :name (n / name :op1 "AKT")
                              :ARG3-of (p / phosphorylate-01)))
                  :ARG2 (a2 / add-02
                        :ARG1 (a3 / and
                              :op1 (s6 / small-molecule :name (n2 / name :op1 "MK-2206")
                                    :ARG0-of (i2 / inhibit-01
                                          :ARG1 e))
                              :op2 (s7 / small-molecule :name (n3 / name :op1 "MK-8669")
                                    :ARG0-of (i3 / inhibit-01
                                          :ARG1 (p2 / protein :name (n4 / name :op1 "mTOR")))))))
            :ARG2 (i / inhibit-01
                  :ARG1 (g / grow-01)
                  :ARG0-of (s / synergize-01)
                  :ARG1-of (s2 / see-01
                        :manner (c2 / combine-01
                              :ARG1 (s3 / small-molecule :name (n5 / name :op1 "SCH772984"))
                              :ARG2 (o / or
                                    :op1 s6
                                    :op2 s7))))
            :ARG1-of (d / describe-01
                  :ARG0 (f / file :mod 3
                        :mod (a4 / additional)
                        :part (f2 / figure :mod "S3A")
                        :part (f4 / figure :mod "S3B")
                        :part (f5 / figure :mod "S3C"))))
      :snt2 (s4 / susceptibility
            :mod (c3 / cell-line
                  :mod (e3 / enzyme :name (n8 / name :op1 "NRAS")
                        :ARG2-of (m7 / mutate-01))
                  :source (m2 / medical-condition :name (n6 / name :op1 "melanoma")))
            :ARG2-of (r / respond-01
                  :ARG1 (s5 / small-molecule :name (n9 / name :op1 "SCH722984")))
            :ARG1-of (d2 / describe-01
                  :ARG0 (f3 / figure :mod 2))))

# ::id a_pmid_2514_2146.123 ::date 2015-09-01T08:21:22 ::annotator SDL-AMR-09 ::preferred
# ::snt A</bold>.
# ::save-date Sun Jan 3, 2016 ::file a_pmid_2514_2146_123.txt
(s / string-entity :value "A")

# ::id a_pmid_2514_2146.124 ::date 2015-06-11T02:33:05 ::annotator SDL-AMR-09 ::preferred
# ::snt IC<sub>50</sub> (nM).
# ::save-date Tue Dec 15, 2015 ::file a_pmid_2514_2146_124.txt
(h / have-percentage-maximal-inhibitory-concentration-01
      :ARG2 50
      :ARG4 (c / concentration-quantity
            :unit (n / nanomolar)))

# ::id a_pmid_2514_2146.125 ::date 2015-06-11T02:39:31 ::annotator SDL-AMR-09 ::preferred
# ::snt Melanoma cell lines containing mutations in <i>NRAS</i> were exposed to 0–10 μM SCH-722984 (black bars) or vemurafenib (grey bars), and the cell viability determined.
# ::save-date Sun Dec 20, 2015 ::file a_pmid_2514_2146_125.txt
(a / and
      :op1 (e / expose-01
            :ARG1 (c / cell-line
                  :ARG0-of (c2 / contain-01
                        :ARG1 (m2 / mutate-01
                              :ARG1 (g / gene :name (n / name :op1 "NRAS"))))
                  :source (m3 / medical-condition :name (n4 / name :op1 "melanoma")))
            :ARG2 (o / or
                  :op1 (s / small-molecule :name (n2 / name :op1 "SCH722984")
                        :ARG1-of (d / describe-01
                              :ARG2 (b / bar
                                    :ARG1-of (b2 / black-04))))
                  :op2 (s2 / small-molecule :name (n3 / name :op1 "vemurafenib")
                        :ARG1-of (d2 / describe-01
                              :ARG2 (b3 / bar
                                    :ARG1-of (g2 / gray-02))))
                  :mod (c3 / concentration-quantity
                        :quant (v / value-interval :op1 0 :op2 10)
                        :unit (m / micromolar))))
      :op2 (d3 / determine-01
            :ARG1 (v2 / viability
                  :poss c)))

# ::id a_pmid_2514_2146.126 ::date 2015-06-11T02:53:46 ::annotator SDL-AMR-09 ::preferred
# ::snt Results are the mean of three experiments, performed in duplicate (n = 6).
# ::save-date Mon Nov 2, 2015 ::file a_pmid_2514_2146_126.txt
(m / mean
      :domain (t / thing
            :ARG2-of (r / result-01))
      :mod (e / experiment-01 :quant 3
            :ARG1-of (p / perform-01
                  :frequency (p2 / product-of :op1 2))
            :ARG1-of (m2 / mean-01
                  :ARG2 (e2 / equal-01
                        :ARG1 e
                        :ARG2 6))))

# ::id a_pmid_2514_2146.127 ::date 2015-06-11T02:57:31 ::annotator SDL-AMR-09 ::preferred
# ::snt Error bars are standard deviation.
# ::save-date Mon Dec 21, 2015 ::file a_pmid_2514_2146_127.txt
(d / deviate-01
      :ARG1-of (s / standard-02)
      :ARG1-of (d2 / describe-01
            :ARG0 (b / bar
                  :mod (e / error))))

# ::id a_pmid_2514_2146.128 ::date 2015-06-11T03:01:20 ::annotator SDL-AMR-09 ::preferred
# ::snt Bar at 1 μM denotes threshold between sensitive and intermediate.
# ::save-date Tue Dec 15, 2015 ::file a_pmid_2514_2146_128.txt
(d / denote-01
      :ARG0 (b / bar
            :location (c / concentration-quantity :quant 1
                  :unit (m / micromolar)))
      :ARG1 (t / threshold
            :location (b2 / between
                  :op1 (s / sensitive-03)
                  :op2 (i / intermediate))))

# ::id a_pmid_2514_2146.129 ::date 2015-06-11T03:04:53 ::annotator SDL-AMR-09 ::preferred
# ::snt Resistant cell lines have IC<sub>50</sub> higher than 2 μM.
# ::save-date Tue Dec 15, 2015 ::file a_pmid_2514_2146_129.txt
(h / have-percentage-maximal-inhibitory-concentration-01
      :ARG1 (c / cell-line
            :ARG0-of (r / resist-01))
      :ARG2 50
      :ARG4 (m2 / more-than
            :op1 (c2 / concentration-quantity :quant 2
                  :unit (m / micromolar))))

# ::id a_pmid_2514_2146.130 ::date 2015-09-01T08:22:36 ::annotator SDL-AMR-09 ::preferred
# ::snt <bold>B</bold>.
# ::save-date Tue Sep 1, 2015 ::file a_pmid_2514_2146_130.txt
(f / figure :mod "B")

# ::id a_pmid_2514_2146.131 ::date 2015-06-11T03:27:11 ::annotator SDL-AMR-09 ::preferred
# ::snt Effects of SCH722984 on MAPK signaling.
# ::save-date Tue Sep 15, 2015 ::file a_pmid_2514_2146_131.txt
(a / affect-01
      :ARG0 (s2 / small-molecule :name (n2 / name :op1 "SCH722984"))
      :ARG1 (s / signal-07
            :ARG0 (p / pathway :name (n / name :op1 "MAPK"))))

# ::id a_pmid_2514_2146.132 ::date 2015-06-11T03:30:16 ::annotator SDL-AMR-09 ::preferred
# ::snt SCH722984-resistant M202 and SCH722984-sensitive M408 were treated for 24 h with DMSO as solvent control (-) or 500 nM SCH722984 (+).
# ::save-date Sun Jan 3, 2016 ::file a_pmid_2514_2146_132.txt
(t / treat-04
      :ARG1 (a / and
            :op1 (c / cell-line :name (n / name :op1 "M202")
                  :ARG0-of (r / resist-01
                        :ARG1 s5))
            :op2 (c2 / cell-line :name (n2 / name :op1 "M408")
                  :ARG0-of (s / sensitive-03
                        :ARG1 s5)))
      :ARG2 (o / or
            :op1 (s2 / small-molecule :name (n4 / name :op1 "DMSO")
                  :mod (c3 / control
                        :mod (s3 / solvent))
                  :ARG1-of (l / label-01
                        :ARG2 (s4 / string-entity :value -)))
            :op2 (s5 / small-molecule :name (n5 / name :op1 "SCH722984")
                  :quant (c4 / concentration-quantity :quant 500
                        :unit (n3 / nanomolar))
                  :ARG1-of (l2 / label-01
                        :ARG2 (s6 / string-entity :value +))))
      :duration (t2 / temporal-quantity :quant 24
            :unit (h / hour)))

# ::id a_pmid_2514_2146.133 ::date 2015-06-11T03:42:33 ::annotator SDL-AMR-09 ::preferred
# ::snt Phosphorylated or total MEK, ERK 1/2, RSK, AKT or beta-actin as loading control were determined by western blot analysis.</p></caption><graphic /></fig>
# ::save-date Sun Dec 20, 2015 ::file a_pmid_2514_2146_133.txt
(d / determine-01
      :ARG1 (o / or
            :op1 (o2 / or
                  :op1 (e / enzyme :name (n / name :op1 "MEK"))
                  :op2 (s / slash
                        :op1 (e2 / enzyme :name (n2 / name :op1 "ERK1"))
                        :op2 (e3 / enzyme :name (n4 / name :op1 "ERK2")))
                  :op3 (e4 / enzyme :name (n5 / name :op1 "RSK"))
                  :op4 (e5 / enzyme :name (n6 / name :op1 "AKT"))
                  :op5 (p / protein :name (n7 / name :op1 "beta-actin"))
                  :ARG1-of (p2 / phosphorylate-01))
            :op2 (o3 / or
                  :op1 (e6 / enzyme :name (n8 / name :op1 "MEK"))
                  :op2 (s2 / slash
                        :op1 e2
                        :op2 e3)
                  :op3 (e9 / enzyme :name (n11 / name :op1 "RSK"))
                  :op4 (e10 / enzyme :name (n12 / name :op1 "AKT"))
                  :op5 (p3 / protein :name (n13 / name :op1 "beta-actin"))
                  :mod (t / total))
            :mod (c / control-01
                  :ARG1 (l / load-01)))
      :ARG2 (a / analyze-01
            :manner (i / immunoblot-01)))

# ::id a_pmid_2514_2146.134 ::date 2015-06-11T03:53:57 ::annotator SDL-AMR-09 ::preferred
# ::snt For <i>BRAF</i> and <i>NRAS</i> wild-type melanoma cell lines, all seven were sensitive to ERK inhibition, with six of seven highly sensitive to SCH772984 (Figure <xref ref-type="fig" rid="Fig3">3</xref>A), including M418, which is a <i>KRAS</i><sup><i>G12A</i></sup> mutant.
# ::save-date Sat Jan 16, 2016 ::file a_pmid_2514_2146_134.txt
(s / sensitive-03
      :ARG0 (c2 / cell-line :quant 7
            :mod (a / all)
            :mod (g / gene :name (n2 / name :op1 "BRAF")
                  :mod (w / wild-type))
            :mod (g2 / gene :name (n3 / name :op1 "NRAS")
                  :mod w)
            :source (m / medical-condition :name (n8 / name :op1 "melanoma")))
      :ARG1 (i / inhibit-01
            :ARG1 (e / enzyme :name (n / name :op1 "ERK")))
      :ARG2-of (i2 / include-91
            :ARG1 (s2 / sensitive-03
                  :ARG0 (c / cell-line :quant 6)
                  :ARG1 (s3 / small-molecule :name (n4 / name :op1 "SCH772984"))
                  :ARG1-of (h / high-02)
                  :ARG1-of (d / describe-01
                        :ARG0 (f / figure :mod "3A"))
                  :ARG2-of (i3 / include-01
                        :ARG1 (c3 / cell-line :name (n6 / name :op1 "M418")
                              :mod (g3 / gene :name (n7 / name :op1 "KRAS")
                                    :ARG2-of (m3 / mutate-01 :value "G12A")))))))

# ::id a_pmid_2514_2146.135 ::date 2015-06-11T04:03:55 ::annotator SDL-AMR-09 ::preferred
# ::snt Consistent with this, treatment with SCH772984 in the highly sensitive M285 line resulted in complete disappearance of pRSK, decreased pERK1/2 and induction of pMEK.
# ::save-date Mon Dec 21, 2015 ::file a_pmid_2514_2146_135.txt
(c / consistent-01
      :ARG1 (r / result-01
            :ARG1 (t2 / treat-04
                  :ARG1 (c2 / cell-line :name (n2 / name :op1 "M285")
                        :ARG0-of (s / sensitive-03
                              :ARG1-of (h / high-02)))
                  :ARG2 (s3 / small-molecule :name (n / name :op1 "SCH772984")))
            :ARG2 (a / and
                  :op1 (d / disappear-01
                        :ARG1 (e / enzyme :name (n3 / name :op1 "RSK")
                              :ARG3-of (p / phosphorylate-01))
                        :degree (c3 / complete))
                  :op2 (d2 / decrease-01
                        :ARG1 (s2 / slash
                              :op1 (e2 / enzyme :name (n4 / name :op1 "ERK1"))
                              :op2 (e3 / enzyme :name (n5 / name :op1 "ERK2"))
                              :ARG3-of p))
                  :op3 (i / induce-01
                        :ARG2 (e4 / enzyme :name (n6 / name :op1 "MEK")
                              :ARG3-of p))))
      :ARG2 (t / this))

# ::id a_pmid_2514_2146.136 ::date 2015-06-11T04:09:18 ::annotator SDL-AMR-09 ::preferred
# ::snt M257, which is intermediately sensitive to SCH722984, had near-complete disappearance of pRSK, though pERK1/2 was slightly induced at 24 hours.
# ::save-date Mon Dec 21, 2015 ::file a_pmid_2514_2146_136.txt
(d / disappear-01
      :ARG1 (e / enzyme :name (n / name :op1 "RSK")
            :ARG3-of (p / phosphorylate-01))
      :degree (c / complete
            :degree (n2 / near))
      :location (c2 / cell-line :name (n3 / name :op1 "M257")
            :ARG0-of (s / sensitive-03
                  :ARG1 (s4 / small-molecule :name (n4 / name :op1 "SCH722984"))
                  :degree (i / intermediate)))
      :concession (i2 / induce-01
            :ARG2 (s3 / slash
                  :op1 (e2 / enzyme :name (n5 / name :op1 "ERK1"))
                  :op2 (e3 / enzyme :name (n6 / name :op1 "ERK2"))
                  :ARG3-of p)
            :degree (s2 / slight)
            :time (a / after
                  :op1 (t / temporal-quantity :quant 24
                        :unit (h / hour)))))

# ::id a_pmid_2514_2146.137 ::date 2015-06-11T04:14:38 ::annotator SDL-AMR-09 ::preferred
# ::snt Phospho-MEK was also induced in treated cells.
# ::save-date Sun Dec 20, 2015 ::file a_pmid_2514_2146_137.txt
(i / induce-01
      :ARG2 (e / enzyme :name (n / name :op1 "MEK")
            :ARG3-of (p / phosphorylate-01))
      :mod (a / also)
      :location (c / cell
            :ARG1-of (t / treat-04)))

# ::id a_pmid_2514_2146.138 ::date 2015-06-11T04:15:33 ::annotator SDL-AMR-09 ::preferred
# ::snt No changes in pAKT with SCH772984 were seen in either M285 or M257 (Figure <xref ref-type="fig" rid="Fig3">3</xref>B).
# ::save-date Mon Jun 22, 2015 ::file a_pmid_2514_2146_138.txt
(s / see-01
      :ARG1 (c / change-01 :polarity -
            :ARG0 (s2 / small-molecule :name (n2 / name :op1 "SCH772984"))
            :ARG1 (e / enzyme :name (n / name :op1 "AKT")
                  :ARG3-of (p / phosphorylate-01)))
      :location (o / or
            :op1 (c2 / cell-line :name (n3 / name :op1 "M285"))
            :op2 (c3 / cell-line :name (n4 / name :op1 "M257"))
            :mod (e2 / either))
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod "3B")))

# ::id a_pmid_2514_2146.139 ::date 2015-06-11T04:18:45 ::annotator SDL-AMR-09 ::preferred
# ::snt These data indicate that SCH772984 may be effective against a majority of <i>BRAF</i> wild-type cell lines including <i>NRAS</i> mutants and <i>BRAF/NRA</i>S wild-type melanoma cell lines which remain dependent on the MAPK pathway for continued growth.<fig id="Fig3"><label>Figure 3</label><caption><p><bold>Susceptibility of BRAF/NRAS wild-type melanoma to SCH-722984.
# ::save-date Thu Dec 10, 2015 ::file a_pmid_2514_2146_139.txt
(m / multi-sentence
      :snt1 (i / indicate-01
            :ARG0 (d2 / data
                  :mod (t / this))
            :ARG1 (p2 / possible-01
                  :ARG1 (e / effective-04
                        :ARG0 (s4 / small-molecule :name (n2 / name :op1 "SCH772984"))
                        :ARG1 (c / counter-01
                              :ARG0 s4
                              :ARG1 (c2 / cell-line
                                    :mod (g / gene :name (n3 / name :op1 "BRAF")
                                          :mod (w / wild-type))
                                    :ARG2-of (i2 / include-01
                                          :ARG1 (a / and
                                                :op1 (c3 / cell-line
                                                      :mod (g2 / gene :name (n4 / name :op1 "NRAS")
                                                            :ARG2-of (m4 / mutate-01)))
                                                :op2 (c4 / cell-line
                                                      :mod (s / slash
                                                            :op1 g
                                                            :op2 (g6 / gene :name (n10 / name :op1 "NRAS")
                                                                  :mod w)))
                                                :ARG1-of (r / remain-01
                                                      :ARG3 (d3 / depend-01
                                                            :ARG0 a
                                                            :ARG1 (p / pathway :name (n / name :op1 "MAPK"))
                                                            :purpose (g3 / grow-01
                                                                  :ARG1 a
                                                                  :ARG1-of (c5 / continue-01))))
                                                :source (m3 / medical-condition :name (n8 / name :op1 "melanoma"))))
                                    :quant (m2 / majority))))))
      :snt2 (s2 / susceptibility
            :ARG2-of (r2 / respond-01
                  :ARG1 (s5 / small-molecule :name (n7 / name :op1 "SCH722984")))
            :ARG1-of (d / describe-01
                  :ARG0 (f / figure :mod 3))
            :mod (m5 / medical-condition :name (n9 / name :op1 "melanoma")
                  :mod (s3 / slash
                        :op1 (g4 / gene :name (n5 / name :op1 "BRAF"))
                        :op2 (g5 / gene :name (n6 / name :op1 "NRAS"))
                        :mod (w2 / wild-type)))))

# ::id a_pmid_2514_2146.141 ::date 2015-06-11T04:33:09 ::annotator SDL-AMR-09 ::preferred
# ::snt IC<sub>50</sub> (nM).
# ::save-date Tue Dec 15, 2015 ::file a_pmid_2514_2146_141.txt
(h / have-percentage-maximal-inhibitory-concentration-01
      :ARG2 50
      :ARG4 (c2 / concentration-quantity
            :unit (n / nanomolar)))

# ::id a_pmid_2514_2146.142 ::date 2015-06-11T04:34:20 ::annotator SDL-AMR-09 ::preferred
# ::snt Cells were treated with 0–10 μM SCH-722984 (black bars) or vemurafenib (grey bars) and cell viability determined by ATP-based bioluminescence assay.
# ::save-date Sun Dec 20, 2015 ::file a_pmid_2514_2146_142.txt
(a / and
      :op1 (t / treat-04
            :ARG1 (c / cell)
            :ARG2 (o / or
                  :op1 (s2 / small-molecule :name (n / name :op1 "SCH722984")
                        :ARG1-of (d / describe-01
                              :ARG0 (b / bar
                                    :ARG1-of (b2 / black-04))))
                  :op2 (s3 / small-molecule :name (n2 / name :op1 "vemurafenib")
                        :ARG1-of (d2 / describe-01
                              :ARG0 (b3 / bar
                                    :ARG1-of (g / gray-02))))
                  :mod (c2 / concentration-quantity
                        :quant (v / value-interval :op1 0 :op2 10)
                        :unit (m / micromolar))))
      :op2 (d3 / determine-01
            :ARG1 (v2 / viability
                  :poss c)
            :manner (a2 / assay-01
                  :ARG1 (b4 / bioluminescence)
                  :ARG1-of (b5 / base-02
                        :ARG2 (s / small-molecule :name (n3 / name :op1 "ATP"))))))

# ::id a_pmid_2514_2146.143 ::date 2015-06-11T04:42:01 ::annotator SDL-AMR-09 ::preferred
# ::snt Results are the mean of duplicate experiments, performed in triplicate (n = 6).
# ::save-date Mon Nov 2, 2015 ::file a_pmid_2514_2146_143.txt
(m / mean
      :domain (t / thing
            :ARG2-of (r / result-01))
      :mod (e / experiment-01
            :ARG1-of (p / perform-01
                  :frequency (p3 / product-of :op1 3))
            :frequency (p2 / product-of :op1 2)
            :ARG1-of (m2 / mean-01
                  :ARG2 (e2 / equal-01
                        :ARG1 e
                        :ARG2 6))))

# ::id a_pmid_2514_2146.144 ::date 2015-06-11T04:44:48 ::annotator SDL-AMR-09 ::preferred
# ::snt Error bars are standard deviation.
# ::save-date Mon Dec 21, 2015 ::file a_pmid_2514_2146_144.txt
(d / deviate-01
      :ARG1-of (s / standard-02)
      :ARG1-of (d2 / describe-01
            :ARG0 (b / bar
                  :mod (e / error))))

# ::id a_pmid_2514_2146.145 ::date 2015-06-11T04:45:48 ::annotator SDL-AMR-09 ::preferred
# ::snt Bar at 1 μM denotes threshold between sensitive and intermediate.
# ::save-date Tue Dec 15, 2015 ::file a_pmid_2514_2146_145.txt
(d / denote-01
      :ARG0 (b / bar
            :location (c / concentration-quantity :quant 1
                  :unit (m / micromolar)))
      :ARG1 (t / threshold
            :location (b2 / between
                  :op1 (s / sensitive-03)
                  :op2 (i / intermediate))))

# ::id a_pmid_2514_2146.146 ::date 2015-06-11T04:48:17 ::annotator SDL-AMR-09 ::preferred
# ::snt Resistant cell lines have IC<sub>50</sub> higher than 2 μM.
# ::save-date Tue Dec 15, 2015 ::file a_pmid_2514_2146_146.txt
(h / have-percentage-maximal-inhibitory-concentration-01
      :ARG1 (c / cell-line
            :ARG0-of (r / resist-01))
      :ARG2 50
      :ARG4 (m2 / more-than
            :op1 (c2 / concentration-quantity :quant 2
                  :unit (m / micromolar))))

# ::id a_pmid_2514_2146.148 ::date 2015-06-11T04:50:33 ::annotator SDL-AMR-09 ::preferred
# ::snt Effects of SCH722984 on MAPK signaling.
# ::save-date Wed Sep 16, 2015 ::file a_pmid_2514_2146_148.txt
(a / affect-01
      :ARG0 (s2 / small-molecule :name (n2 / name :op1 "SCH722984"))
      :ARG1 (s / signal-07
            :ARG0 (p / pathway :name (n / name :op1 "MAPK"))))

# ::id a_pmid_2514_2146.149 ::date 2015-06-11T04:51:53 ::annotator SDL-AMR-09 ::preferred
# ::snt SCH-722984-resistant M257 and SCH-722984-sensitive M285, were treated for 24 h with DMSO (-) or 500 nM SCH722984 (+).
# ::save-date Sun Jan 3, 2016 ::file a_pmid_2514_2146_149.txt
(t / treat-04
      :ARG1 (a / and
            :op1 (c / cell-line :name (n / name :op1 "M257")
                  :ARG0-of (r / resist-01
                        :ARG1 s4))
            :op2 (c2 / cell-line :name (n2 / name :op1 "M285")
                  :ARG0-of (s / sensitive-03
                        :ARG1 s4)))
      :ARG2 (o / or
            :op1 (s2 / small-molecule :name (n4 / name :op1 "DMSO")
                  :ARG1-of (l / label-01
                        :ARG2 (s3 / string-entity :value -)))
            :op2 (s4 / small-molecule :name (n5 / name :op1 "SCH722984")
                  :quant (c3 / concentration-quantity :quant 500
                        :unit (n3 / nanomolar))
                  :ARG1-of (l2 / label-01
                        :ARG2 (s5 / string-entity :value +))))
      :duration (t2 / temporal-quantity :quant 24
            :unit (h / hour)))

# ::id a_pmid_2514_2146.150 ::date 2015-06-11T04:56:55 ::annotator SDL-AMR-09 ::preferred
# ::snt Phosphorylated or total MEK, ERK 1/2, RSK, AKT or beta-actin as loading control were determined by western blot analysis.</p></caption><graphic /></fig>
# ::save-date Sun Dec 20, 2015 ::file a_pmid_2514_2146_150.txt
(d / determine-01
      :ARG1 (o / or
            :op1 (o2 / or
                  :op1 (e / enzyme :name (n / name :op1 "MEK"))
                  :op2 (s / slash
                        :op1 (e2 / enzyme :name (n2 / name :op1 "ERK1"))
                        :op2 (e3 / enzyme :name (n4 / name :op1 "ERK2")))
                  :op3 (e4 / enzyme :name (n5 / name :op1 "RSK"))
                  :op4 (e5 / enzyme :name (n6 / name :op1 "AKT"))
                  :op5 (p / protein :name (n7 / name :op1 "beta-actin"))
                  :ARG1-of (p2 / phosphorylate-01))
            :op2 (o3 / or
                  :op1 (e6 / enzyme :name (n8 / name :op1 "MEK"))
                  :op2 (s2 / slash
                        :op1 e2
                        :op2 e3)
                  :op3 (e9 / enzyme :name (n11 / name :op1 "RSK"))
                  :op4 (e10 / enzyme :name (n12 / name :op1 "AKT"))
                  :op5 (p3 / protein :name (n13 / name :op1 "beta-actin"))
                  :mod (t / total))
            :mod (c / control-01
                  :ARG1 (l / load-01)))
      :manner (a / analyze-01
            :manner (i / immunoblot-01)))

# ::id a_pmid_2514_2146.151 ::date 2015-06-11T05:02:14 ::annotator SDL-AMR-09 ::preferred
# ::snt SCH722984 is effective in <i>BRAF</i>-mutant melanoma with acquired vemurafenib-resistance
# ::save-date Thu Dec 10, 2015 ::file a_pmid_2514_2146_151.txt
(e / effective-04
      :ARG0 (s / small-molecule :name (n / name :op1 "SCH722984"))
      :location (m / medical-condition :name (n4 / name :op1 "melanoma")
            :mod (g / gene :name (n2 / name :op1 "BRAF")
                  :ARG2-of (m3 / mutate-01))
            :ARG0-of (a / acquire-01
                  :ARG1 (r / resist-01
                        :ARG0 m
                        :ARG1 (s2 / small-molecule :name (n3 / name :op1 "vemurafenib"))))))

# ::id a_pmid_2514_2146.152 ::date 2015-06-11T05:05:37 ::annotator SDL-AMR-09 ::preferred
# ::snt The IC<sub>50</sub> of SCH722984 or vemurafenib was next determined in eight <i>BRAF</i>-mutant vemurafenib-resistant melanoma cell lines (Figure <xref ref-type="fig" rid="Fig4">4</xref>A).
# ::save-date Tue Dec 15, 2015 ::file a_pmid_2514_2146_152.txt
(d / determine-01
      :ARG1 (c3 / concentration-quantity
            :ARG4-of (h / have-percentage-maximal-inhibitory-concentration-01
                  :ARG1 (o / or
                        :op1 (s / small-molecule :name (n2 / name :op1 "SCH722984"))
                        :op2 (s2 / small-molecule :name (n3 / name :op1 "vemurafenib")))
                  :ARG2 50))
      :time (n4 / next)
      :location (c / cell-line :quant 8
            :mod (g / gene :name (n5 / name :op1 "BRAF")
                  :ARG2-of (m5 / mutate-01))
            :ARG0-of (r / resist-01
                  :ARG1 s2)
            :source (m / medical-condition :name (n / name :op1 "melanoma")))
      :ARG1-of (d2 / describe-01
            :ARG0 (f / figure :mod "4A")))

# ::id a_pmid_2514_2146.153 ::date 2015-06-11T05:09:34 ::annotator SDL-AMR-09 ::preferred
# ::snt M376 and M398, two <i>BRAF/NRAS</i> double mutant cell lines derived from the same patient tumors, were highly sensitive to SCH722984, despite high resistance to vemurafenib.
# ::save-date Mon Dec 21, 2015 ::file a_pmid_2514_2146_153.txt
(s / sensitive-03
      :ARG0 (a / and
            :op1 (c / cell-line :name (n / name :op1 "M376"))
            :op2 (c2 / cell-line :name (n2 / name :op1 "M398"))
            :ARG1-of (m / mean-01
                  :ARG2 (c3 / cell-line :quant 2
                        :mod (s2 / slash
                              :op1 (g / gene :name (n4 / name :op1 "BRAF"))
                              :op2 (g2 / gene :name (n5 / name :op1 "NRAS"))
                              :ARG2-of (m2 / mutate-01
                                    :mod (d / double)))
                        :ARG1-of (d2 / derive-01
                              :ARG2 (t / tumor
                                    :poss (p / person
                                          :ARG0-of (h2 / have-rel-role-91
                                                :ARG2 (p2 / patient)))
                                    :ARG1-of (s3 / same-01
                                          :ARG3 p))))))
      :ARG1 (s4 / small-molecule :name (n3 / name :op1 "SCH722984"))
      :ARG1-of (h / high-02)
      :concession (r / resist-01
            :ARG0 a
            :ARG1 (s5 / small-molecule :name (n6 / name :op1 "vemurafenib")
                  :ARG1-of h)))

# ::id a_pmid_2514_2146.154 ::date 2015-06-11T05:16:04 ::annotator SDL-AMR-09 ::preferred
# ::snt M376 is a spontaneously arising double mutant, whereas M398 was established from tumor from the same patient upon progression on vemurafenib.
# ::save-date Wed Nov 4, 2015 ::file a_pmid_2514_2146_154.txt
(c / contrast-01
      :ARG1 (m / mutate-01
            :ARG2 (c2 / cell-line :name (n / name :op1 "M376")
                  :ARG1-of (a / arise-02
                        :manner (s / spontaneous)))
            :mod (d / double))
      :ARG2 (e / establish-01
            :ARG0 (p3 / progress-01
                  :ARG1 (s3 / small-molecule :name (n3 / name :op1 "vemurafenib")))
            :ARG1 (c3 / cell-line :name (n2 / name :op1 "M398"))
            :source (t / tumor
                  :source (p / person
                        :ARG0-of (h / have-rel-role-91
                              :ARG2 (p2 / patient))
                        :ARG1-of (s2 / same-01)))))

# ::id a_pmid_2514_2146.155 ::date 2015-06-11T05:21:26 ::annotator SDL-AMR-09 ::preferred
# ::snt Similar to their isogenic parental cell lines, potent growth inhibition with SCH772984 was also seen for three <i>BRAF</i><sup><i>V600E</i></sup> mutant melanoma cell lines with <i>in vitro</i>-derived vemurafenib resistance (polyclonal population): M395AR, M397AR, and M249AR4.
# ::save-date Thu Dec 10, 2015 ::file a_pmid_2514_2146_155.txt
(s / see-01
      :ARG1 (i / inhibit-01
            :ARG0 (s2 / small-molecule :name (n / name :op1 "SCH772984"))
            :ARG1 (g / grow-01)
            :mod (p / potent))
      :mod (a / also)
      :location (c / cell-line :quant 3
            :mod (g2 / gene :name (n2 / name :op1 "BRAF")
                  :ARG2-of (m3 / mutate-01 :value "V600E"))
            :ARG0-of (r2 / resist-01
                  :ARG1 (s3 / small-molecule :name (n3 / name :op1 "vemurafenib"))
                  :ARG1-of (d / derive-01
                        :ARG2 (i2 / in-vitro)))
            :ARG1-of (m5 / mean-01
                  :ARG2 (a2 / and
                        :op1 (c3 / cell-line :name (n4 / name :op1 "M395AR"))
                        :op2 (c4 / cell-line :name (n5 / name :op1 "M397AR"))
                        :op3 (c5 / cell-line :name (n6 / name :op1 "M249AR4"))))
            :source (m / medical-condition :name (n7 / name :op1 "melanoma"))
            :ARG1-of (d3 / describe-01
                  :ARG2 (p3 / population
                        :mod (p4 / polyclone))))
      :ARG1-of (r / resemble-01
            :ARG2 (c2 / cell-line
                  :poss (t / they)
                  :mod (i3 / isogenic)
                  :mod (p2 / parental))))

# ::id a_pmid_2514_2146.156 ::date 2015-06-11T05:28:28 ::annotator SDL-AMR-09 ::preferred
# ::snt Previously data demonstrated that these cell lines reactivate the MAPK pathway via generation of BRAF splice variants (M395AR and M397AR) [<xref ref-type="bibr" rid="CR7">7</xref>, <xref ref-type="bibr" rid="CR24">24</xref>], or via secondary <i>NRAS</i> mutation (M249AR4) [<xref ref-type="bibr" rid="CR6">6</xref>].
# ::save-date Fri Jun 12, 2015 ::file a_pmid_2514_2146_156.txt
(d / demonstrate-01
      :ARG0 (d2 / data
            :mod (p2 / previous))
      :ARG1 (r / reactivate-01
            :ARG0 (c / cell-line
                  :mod (t / this))
            :ARG1 (p / pathway :name (n / name :op1 "MAPK"))
            :manner (o / or
                  :op1 (g / generate-01
                        :ARG1 (v / variant
                              :ARG2-of (r2 / result-01
                                    :ARG1 (s / splice-01
                                          :ARG1 (e / enzyme :name (n2 / name :op1 "BRAF")))))
                        :ARG1-of (d3 / describe-01
                              :ARG0 (a2 / and
                                    :op1 (p3 / publication
                                          :ARG1-of (c2 / cite-01
                                                :ARG2 7))
                                    :op2 (p4 / publication
                                          :ARG1-of (c3 / cite-01
                                                :ARG2 24))))
                        :ARG1-of (m / mean-01
                              :ARG2 (a / and
                                    :op1 (c5 / cell-line :name (n3 / name :op1 "M395AR"))
                                    :op2 (c6 / cell-line :name (n4 / name :op1 "M397AR")))))
                  :op2 (m2 / mutate-01
                        :ARG1 (g2 / gene :name (n5 / name :op1 "NRAS"))
                        :mod (s2 / secondary)
                        :ARG1-of (d4 / describe-01
                              :ARG0 (p5 / publication
                                    :ARG1-of (c4 / cite-01
                                          :ARG2 6)))
                        :ARG1-of (m3 / mean-01
                              :ARG2 (c7 / cell-line :name (n6 / name :op1 "M249AR4")))))))

# ::id a_pmid_2514_2146.157 ::date 2015-06-11T05:37:42 ::annotator SDL-AMR-09 ::preferred
# ::snt In contrast, M229AR9, M238AR2 and M409AR1 remained highly resistant to SCH722984 with IC50s >2uM.
# ::save-date Tue Dec 15, 2015 ::file a_pmid_2514_2146_157.txt
(c / contrast-01
      :ARG2 (r / remain-01
            :ARG1 (a / and
                  :op1 (c2 / cell-line :name (n / name :op1 "M229AR9"))
                  :op2 (c3 / cell-line :name (n2 / name :op1 "M238AR2"))
                  :op3 (c4 / cell-line :name (n3 / name :op1 "M409AR1")))
            :ARG3 (r2 / resist-01
                  :ARG0 a
                  :ARG1 (s / small-molecule :name (n4 / name :op1 "SCH722984")
                        :ARG1-of (c6 / concentrate-02
                              :mod (i / inhibit-01
                                    :degree (p / percentage-entity :value 50))
                              :quant (m2 / more-than
                                    :op1 (c5 / concentration-quantity :quant 2
                                          :unit (m / micromolar)))))
                  :ARG1-of (h / high-02))))

# ::id a_pmid_2514_2146.158 ::date 2015-06-11T05:43:23 ::annotator SDL-AMR-09 ::preferred
# ::snt For M229AR9 and M238AR2 upregulation of RTK is the mechanism of vemurafenib resistance [<xref ref-type="bibr" rid="CR6">6</xref>].
# ::save-date Fri Jun 12, 2015 ::file a_pmid_2514_2146_158.txt
(m / mechanism
      :domain (u / upregulate-01
            :ARG1 (e / enzyme :name (n / name :op1 "RTK")))
      :mod (r / resist-01
            :ARG0 (a / and
                  :op1 (c / cell-line :name (n2 / name :op1 "M229AR9"))
                  :op2 (c2 / cell-line :name (n3 / name :op1 "M238AR2")))
            :ARG1 (s / small-molecule :name (n4 / name :op1 "vemurafenib")))
      :ARG1-of (d / describe-01
            :ARG0 (p / publication
                  :ARG1-of (c3 / cite-01
                        :ARG2 6))))

# ::id a_pmid_2514_2146.159 ::date 2015-06-11T05:51:31 ::annotator SDL-AMR-09 ::preferred
# ::snt The mechanism of resistance for M409AR is unknown at this time, and studies are ongoing to delineate the mechanism underlying BRAFi-resistance.<fig id="Fig4"><label>Figure 4</label><caption><p><bold>SCH722984 in BRAF-mutant melanoma cell lines with vemurafenib-acquired resistance.
# ::save-date Sat Jan 16, 2016 ::file a_pmid_2514_2146_159.txt
(m / multi-sentence
      :snt1 (a / and
            :op1 (k / know-01 :polarity -
                  :ARG1 (m2 / mechanism
                        :mod (r / resist-01
                              :ARG0 (c / cell-line :name (n / name :op1 "M409AR"))))
                  :time (t / this))
            :op2 (g / go-on-15
                  :ARG1 (s / study-01)
                  :purpose (d / delineate-01
                        :ARG0 s
                        :ARG1 (m3 / mechanism
                              :ARG0-of (u / underlie-01
                                    :ARG1 (r2 / resist-01
                                          :ARG1 (m4 / molecular-physical-entity
                                                :ARG0-of (i / inhibit-01
                                                      :ARG1 (e / enzyme :name (n2 / name :op1 "BRAF"))))))))))
      :snt2 (s2 / small-molecule :name (n3 / name :op1 "SCH722984")
            :location (c2 / cell-line
                  :mod (g2 / gene :name (n4 / name :op1 "BRAF")
                        :ARG2-of (m5 / mutate-01))
                  :source (m6 / medical-condition :name (n5 / name :op1 "melanoma"))
                  :ARG0-of (r3 / resist-01
                        :ARG1 (s3 / small-molecule :name (n6 / name :op1 "vemurafenib"))
                        :ARG1-of (a2 / acquire-01)))
            :ARG1-of (d3 / describe-01
                  :ARG0 (f / figure :mod 4))))

# ::id a_pmid_2514_2146.161 ::date 2015-06-11T05:56:49 ::annotator SDL-AMR-09 ::preferred
# ::snt IC<sub>50</sub> (nM) to SCH-722984 or vemurafenib.
# ::save-date Tue Dec 15, 2015 ::file a_pmid_2514_2146_161.txt
(h / have-percentage-maximal-inhibitory-concentration-01
      :ARG1 (o / or
            :op1 (s / small-molecule :name (n / name :op1 "SCH722984"))
            :op2 (s2 / small-molecule :name (n2 / name :op1 "vemurafenib")))
      :ARG2 50
      :ARG4 (c2 / concentration-quantity
            :unit (n3 / nanomolar)))

# ::id a_pmid_2514_2146.162 ::date 2015-06-11T07:06:20 ::annotator SDL-AMR-09 ::preferred
# ::snt M398 and M376, two melanoma cell lines established from tumors progressing on vemurafenib, as well as six parental <i>BRAF</i> mutant melanoma cell lines and their paired <i>in vitro</i> derived vemurafenib-acquired resistance sublines (AR) were grown in the presence of 0–10 μM SCH-722984 (black bars) or vemurafenib (grey bars).
# ::save-date Mon Dec 21, 2015 ::file a_pmid_2514_2146_162.txt
(g / grow-03
      :ARG1 (a / and
            :op1 (a2 / and
                  :op1 (c / cell-line :name (n / name :op1 "M398"))
                  :op2 (c2 / cell-line :name (n2 / name :op1 "M376"))
                  :ARG1-of (m / mean-01
                        :ARG2 (c3 / cell-line :quant 2
                              :ARG1-of (e / establish-01
                                    :source (t / tumor
                                          :ARG1-of (p / progress-01
                                                :ARG1-of (c4 / cause-01
                                                      :ARG0 s2))))
                              :source (m4 / medical-condition :name (n6 / name :op1 "melanoma")))))
            :op2 (c5 / cell-line :quant 6
                  :mod (p2 / parental)
                  :mod (g2 / gene :name (n4 / name :op1 "BRAF")
                        :ARG2-of (m3 / mutate-01))
                  :source m4)
            :op3 (s / subline
                  :poss c5
                  :ARG1-of (p3 / pair-01)
                  :ARG0-of (a3 / acquire-01
                        :ARG1 (r / resist-01
                              :ARG0 s
                              :ARG1 s2
                              :ARG1-of (d / derive-01
                                    :ARG2 (i / in-vitro))))))
      :condition (o / or
            :op1 (p4 / present-02
                  :ARG1 (s3 / small-molecule :name (n5 / name :op1 "SCH722984")
                        :mod (c6 / concentration-quantity
                              :quant (v / value-interval :op1 0 :op2 10)
                              :unit (m2 / micromolar)))
                  :ARG1-of (d2 / describe-01
                        :ARG0 (b / bar
                              :ARG1-of (b2 / black-04))))
            :op2 (p5 / present-02
                  :ARG1 (s2 / small-molecule :name (n3 / name :op1 "vemurafenib")
                        :quant v)
                  :ARG1-of (d3 / describe-01
                        :ARG0 (b3 / bar
                              :ARG1-of (g3 / gray-02))))))

# ::id a_pmid_2514_2146.163 ::date 2015-06-11T07:21:32 ::annotator SDL-AMR-09 ::preferred
# ::snt Values are mean of three experiments, performed in duplicate (n = 6).
# ::save-date Mon Nov 2, 2015 ::file a_pmid_2514_2146_163.txt
(m / mean
      :domain (v / value)
      :mod (e / experiment-01 :quant 3
            :ARG1-of (p / perform-01
                  :frequency (p2 / product-of :op1 2))
            :ARG1-of (m2 / mean-01
                  :ARG2 (e2 / equal-01
                        :ARG1 e
                        :ARG2 6))))

# ::id a_pmid_2514_2146.164 ::date 2015-06-11T07:23:03 ::annotator SDL-AMR-09 ::preferred
# ::snt Error bars are standard deviation.
# ::save-date Mon Dec 21, 2015 ::file a_pmid_2514_2146_164.txt
(d / deviate-01
      :ARG1-of (s / standard-02)
      :ARG1-of (d2 / describe-01
            :ARG0 (b / bar
                  :mod (e / error))))

# ::id a_pmid_2514_2146.165 ::date 2015-06-11T07:24:17 ::annotator SDL-AMR-09 ::preferred
# ::snt Bar at 1 μM denotes threshold between sensitive and intermediate.
# ::save-date Tue Dec 15, 2015 ::file a_pmid_2514_2146_165.txt
(d / denote-01
      :ARG0 (b / bar
            :location (c / concentration-quantity :quant 1
                  :unit (m / micromolar)))
      :ARG1 (t / threshold
            :location (b2 / between
                  :op1 (s / sensitive-03)
                  :op2 (i / intermediate))))

# ::id a_pmid_2514_2146.166 ::date 2015-06-11T07:26:03 ::annotator SDL-AMR-09 ::preferred
# ::snt Resistant cell lines have IC<sub>50</sub> higher than 2 μM.
# ::save-date Tue Dec 15, 2015 ::file a_pmid_2514_2146_166.txt
(h / have-percentage-maximal-inhibitory-concentration-01
      :ARG1 (c3 / cell-line
            :ARG0-of (r / resist-01))
      :ARG2 50
      :ARG4 (m / more-than
            :op1 (c2 / concentration-quantity :quant 2
                  :unit (m2 / micromolar))))

# ::id a_pmid_2514_2146.167 ::date 2015-06-11T07:31:08 ::annotator SDL-AMR-09 ::preferred
# ::snt *: BRAF/NRAS double mutant, **: BRAF-splice variant, §: Receptor tyrosine kinase upreguation, +: resistance mechanism unknown.
# ::save-date Sat Jan 16, 2016 ::file a_pmid_2514_2146_167.txt
(m / multi-sentence
      :snt1 (s / slash
            :op1 (e2 / enzyme :name (n / name :op1 "BRAF"))
            :op2 (e3 / enzyme :name (n2 / name :op1 "NRAS"))
            :ARG2-of (m2 / mutate-01
                  :mod (d / double)))
      :snt2 (v / variant
            :ARG2-of (r / result-01
                  :ARG1 (s2 / splice-01
                        :ARG1 (e4 / enzyme :name (n3 / name :op1 "BRAF")))))
      :snt3 (u / upregulate-01
            :ARG1 (e / enzyme :name (n4 / name :op1 "receptor" :op2 "tyrosine" :op3 "kinase")))
      :snt4 (m3 / mechanism
            :ARG1-of (k2 / know-01 :polarity -)
            :mod (r2 / resist-01)))

# ::id a_pmid_2514_2146.169 ::date 2015-06-11T07:38:22 ::annotator SDL-AMR-09 ::preferred
# ::snt Effect of SCH722984 on MAPK signaling.
# ::save-date Wed Sep 16, 2015 ::file a_pmid_2514_2146_169.txt
(a / affect-01
      :ARG0 (s2 / small-molecule :name (n2 / name :op1 "SCH722984"))
      :ARG1 (s / signal-07
            :ARG0 (p / pathway :name (n / name :op1 "MAPK"))))

# ::id a_pmid_2514_2146.170 ::date 2015-06-11T07:39:24 ::annotator SDL-AMR-09 ::preferred
# ::snt Western blot analysis was performed to evaluate the effect of 24 hour exposure to 500 nM SCH&22984 (+) or DMSO (-) on phospho- or total MEK, ERK 1/2, RSK, AKT or beta-actin as loading control.</p></caption><graphic /></fig>
# ::save-date Mon Jan 4, 2016 ::file a_pmid_2514_2146_170.txt
(p / perform-01
      :ARG1 (a2 / analyze-01
            :manner (i / immunoblot-01))
      :purpose (e3 / evaluate-01
            :ARG1 (a / affect-01
                  :ARG0 (e4 / expose-01
                        :ARG1 (o2 / or
                              :op1 (o3 / or
                                    :op1 (e / enzyme :name (n2 / name :op1 "MEK"))
                                    :op2 (s2 / slash
                                          :op1 (e2 / enzyme :name (n3 / name :op1 "ERK1"))
                                          :op2 (e5 / enzyme :name (n7 / name :op1 "ERK2")))
                                    :op3 (e6 / enzyme :name (n8 / name :op1 "RSK"))
                                    :op4 (e7 / enzyme :name (n9 / name :op1 "AKT"))
                                    :op5 (p2 / protein :name (n10 / name :op1 "beta-actin"))
                                    :ARG3-of (p3 / phosphorylate-01))
                              :op2 (o4 / or
                                    :op1 (e10 / enzyme :name (n14 / name :op1 "MEK"))
                                    :op2 (s3 / slash
                                          :op1 e2
                                          :op2 e5)
                                    :op3 (e9 / enzyme :name (n13 / name :op1 "RSK"))
                                    :op4 (e8 / enzyme :name (n12 / name :op1 "AKT"))
                                    :op5 (p4 / protein :name (n11 / name :op1 "beta-actin"))
                                    :mod (t / total))
                              :manner (c2 / control-01
                                    :ARG1 (l / load-01)))
                        :ARG2 (o / or
                              :op1 (s4 / small-molecule :name (n / name :op1 "SCH722984")
                                    :quant (c / concentration-quantity :quant 500
                                          :unit (n4 / nanomolar))
                                    :ARG1-of (l2 / label-01
                                          :ARG2 (s5 / string-entity :value +)))
                              :op2 (s / small-molecule :name (n6 / name :op1 "DMSO")
                                    :ARG1-of (l3 / label-01
                                          :ARG2 (s6 / string-entity :value -))))
                        :duration (t3 / temporal-quantity :quant 24
                              :unit (h2 / hour))))))

# ::id a_pmid_2514_2146.171 ::date 2015-06-11T07:47:08 ::annotator SDL-AMR-09 ::preferred
# ::snt Consistent with the signaling for other sensitive cell lines, all three <i>BRAF/NRAS</i> double mutants (M376, M398, M249AR4) displayed decreased pRSK and pERK1/2 at 24 hours with no detectable change in pMEK.
# ::save-date Mon Jun 22, 2015 ::file a_pmid_2514_2146_171.txt
(c / consistent-01
      :ARG1 (d / display-01
            :ARG0 (c3 / cell-line :quant 3
                  :mod (s3 / slash
                        :op1 (g / gene :name (n / name :op1 "BRAF"))
                        :op2 (g2 / gene :name (n2 / name :op1 "NRAS"))
                        :ARG2-of (m / mutate-01
                              :mod (d2 / double)))
                  :ARG1-of (m2 / mean-01
                        :ARG2 (a / and
                              :op1 (c4 / cell-line :name (n3 / name :op1 "M376"))
                              :op2 (c5 / cell-line :name (n4 / name :op1 "M398"))
                              :op3 (c6 / cell-line :name (n5 / name :op1 "M249AR4"))))
                  :mod (a2 / all))
            :ARG1 (a5 / and
                  :op1 (a3 / and
                        :op1 (e / enzyme :name (n6 / name :op1 "RSK"))
                        :op2 (s4 / slash
                              :op1 (e2 / enzyme :name (n7 / name :op1 "ERK1"))
                              :op2 (e3 / enzyme :name (n8 / name :op1 "ERK2")))
                        :ARG3-of (p / phosphorylate-01)
                        :ARG1-of (d3 / decrease-01)
                        :time (a4 / after
                              :op1 (t / temporal-quantity :quant 24
                                    :unit (h / hour))))
                  :op2 (p2 / possible-01 :polarity -
                        :ARG1 (d4 / detect-01
                              :ARG1 (c7 / change-01
                                    :ARG1 (e4 / enzyme :name (n9 / name :op1 "MEK")
                                          :ARG3-of p))))))
      :ARG2 (s / signal-07
            :ARG1 (c2 / cell-line
                  :mod (o / other)
                  :ARG0-of (s2 / sensitive-03))))

# ::id a_pmid_2514_2146.172 ::date 2015-06-11T08:02:55 ::annotator SDL-AMR-09 ::preferred
# ::snt In the paired parental and acquired-resistance cell lines, treatment of the parental cell lines (M397, M249, M229, M238 and M409) with SCH722984 resulted in disappearance of pRSK, decrease in pERK1/2.
# ::save-date Mon Jun 22, 2015 ::file a_pmid_2514_2146_172.txt
(r / result-01
      :ARG1 (t / treat-04
            :ARG1 (a / and
                  :op1 (c / cell-line :name (n / name :op1 "M397"))
                  :op2 (c2 / cell-line :name (n2 / name :op1 "M249"))
                  :op3 (c3 / cell-line :name (n3 / name :op1 "M229"))
                  :op4 (c4 / cell-line :name (n4 / name :op1 "M238"))
                  :op5 (c5 / cell-line :name (n5 / name :op1 "M409"))
                  :mod (p / parental))
            :ARG2 (s2 / small-molecule :name (n9 / name :op1 "SCH722984")))
      :ARG2 (a2 / and
            :op1 (d / disappear-01
                  :ARG1 (e / enzyme :name (n6 / name :op1 "RSK")
                        :ARG3-of (p2 / phosphorylate-01)))
            :op2 (d2 / decrease-01
                  :ARG1 (s / slash
                        :op1 (e2 / enzyme :name (n7 / name :op1 "ERK1"))
                        :op2 (e3 / enzyme :name (n8 / name :op1 "ERK2"))
                        :ARG3-of p2)))
      :location (a3 / and
            :op1 (c6 / cell-line
                  :mod p)
            :op2 (c7 / cell-line
                  :ARG0-of (a4 / acquire-01
                        :ARG1 (r2 / resist-01)))
            :ARG1-of (p3 / pair-01)))

# ::id a_pmid_2514_2146.173 ::date 2015-06-11T08:07:26 ::annotator SDL-AMR-09 ::preferred
# ::snt Interestingly, we observed again upregulation of pAKT levels after treatment with SCH772984 in M398, M376, M397AR, M249AR4, and M409AR1, suggesting a rapid upregulation of the PI3K/AKT/mTOR pathway.
# ::save-date Mon Jun 22, 2015 ::file a_pmid_2514_2146_173.txt
(o / observe-01
      :ARG0 (w / we)
      :ARG1 (u / upregulate-01
            :ARG1 (l / level
                  :quant-of (e / enzyme :name (n / name :op1 "AKT")
                        :ARG3-of (p / phosphorylate-01))))
      :mod (a / again)
      :time (a2 / after
            :op1 (t / treat-04
                  :ARG1 (a3 / and
                        :op1 (c / cell-line :name (n3 / name :op1 "M398"))
                        :op2 (c2 / cell-line :name (n4 / name :op1 "M376"))
                        :op3 (c3 / cell-line :name (n5 / name :op1 "M397AR"))
                        :op4 (c4 / cell-line :name (n6 / name :op1 "M249AR4"))
                        :op5 (c5 / cell-line :name (n7 / name :op1 "M409AR1")))
                  :ARG2 (s2 / small-molecule :name (n2 / name :op1 "SCH772984"))))
      :ARG0-of (s / suggest-01
            :ARG1 (u2 / upregulate-01
                  :ARG1 (p2 / pathway :name (n8 / name :op1 "PI3K/AKT/mTOR"))
                  :mod (r / rapid)))
      :ARG2-of (i / interest-01))

# ::id a_pmid_2514_2146.174 ::date 2015-06-12T03:09:17 ::annotator SDL-AMR-09 ::preferred
# ::snt This suggests that dual inhibition with SCH772984 and an AKT or mTOR inhibitor may result in more potent growth inhibition.
# ::save-date Sun Jan 17, 2016 ::file a_pmid_2514_2146_174.txt
(s / suggest-01
      :ARG0 (t / this)
      :ARG1 (p / possible-01
            :ARG1 (r / result-01
                  :ARG1 (i / inhibit-01
                        :ARG0 (a / and
                              :op1 (s2 / small-molecule :name (n / name :op1 "SCH772984"))
                              :op2 (m2 / molecular-physical-entity
                                    :ARG0-of (i3 / inhibit-01
                                          :ARG1 (o / or
                                                :op1 (p2 / protein-family :name (n2 / name :op1 "AKT"))
                                                :op2 (p4 / protein :name (n3 / name :op1 "mTOR"))))))
                        :mod (d / dual))
                  :ARG2 (i2 / inhibit-01
                        :ARG1 (g / grow-01)
                        :mod (p3 / potent
                              :degree (m / more))))))

# ::id a_pmid_2514_2146.175 ::date 2015-06-13T15:15:09 ::annotator SDL-AMR-09 ::preferred
# ::snt For M397AR and M249AR4, the disappearance of pERK was robust.
# ::save-date Sat Jan 16, 2016 ::file a_pmid_2514_2146_175.txt
(r / robust
      :domain (d / disappear-01
            :ARG1 (e / enzyme :name (n3 / name :op1 "ERK")
                  :ARG3-of (p / phosphorylate-01)))
      :location (a / and
            :op1 (c / cell-line :name (n / name :op1 "M397AR"))
            :op2 (c2 / cell-line :name (n2 / name :op1 "M249AR4"))))

# ::id a_pmid_2514_2146.176 ::date 2015-06-13T15:25:21 ::annotator SDL-AMR-09 ::preferred
# ::snt In contrast, for the resistant M229AR9, M238AR2 and M409AR1, though treatment with SCH772984 resulted in disappearance of pRSK, pMEK appeared to be induced and pERK1/2 remained almost unchanged (Figure <xref ref-type="fig" rid="Fig4">4</xref>B).
# ::save-date Sat Jan 16, 2016 ::file a_pmid_2514_2146_176.txt
(c / contrast-01
      :ARG2 (c2 / contrast-01
            :ARG1 (r2 / result-01
                  :ARG1 (t / treat-04
                        :ARG1 (a4 / and
                              :op1 (c5 / cell-line :name (n4 / name :op1 "M229AR9"))
                              :op2 (c6 / cell-line :name (n5 / name :op1 "M238AR2"))
                              :op3 (c7 / cell-line :name (n6 / name :op1 "M409AR1")))
                        :ARG2 (s / small-molecule :name (n3 / name :op1 "SCH772984")))
                  :ARG2 (d2 / disappear-01
                        :ARG1 (a5 / and
                              :op1 (e / enzyme :name (n / name :op1 "MEK")
                                    :ARG3-of (p / phosphorylate-01))
                              :op2 (e3 / enzyme :name (n7 / name :op1 "RSK")
                                    :ARG3-of p))))
            :ARG2 (a / appear-02
                  :ARG1 (a2 / and
                        :op1 (i / induce-01
                              :ARG2 (e2 / enzyme :name (n2 / name :op1 "ERK")
                                    :ARG3-of p))
                        :op2 (r / remain-01
                              :ARG3 (c3 / change-01 :polarity -
                                    :ARG1 (e4 / enzyme :name (n8 / name :op1 "ERK1/2")
                                          :ARG3-of p)
                                    :degree (a3 / almost))))))
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod "4B")))

# ::id a_pmid_2514_2146.177 ::date 2015-06-13T15:30:36 ::annotator SDL-AMR-09 ::preferred
# ::snt Synergistic inhibition with combination BRAF and ERK inhibition
# ::save-date Tue Feb 2, 2016 ::file a_pmid_2514_2146_177.txt
(i3 / inhibit-01
      :ARG0-of (s / synergize-01)
      :manner (c / combine-01
            :ARG1 (i / inhibit-01
                  :ARG1 (e2 / enzyme :name (n2 / name :op1 "BRAF")))
            :ARG2 (i2 / inhibit-01
                  :ARG1 (e / enzyme :name (n / name :op1 "ERK")))))

# ::id a_pmid_2514_2146.178 ::date 2015-06-13T15:52:17 ::annotator SDL-AMR-09 ::preferred
# ::snt We next determined whether combining BRAF and ERK inhibition could result in synergistic inhibition by dual MAPK pathway inhibition.
# ::save-date Tue Feb 2, 2016 ::file a_pmid_2514_2146_178.txt
(d / determine-01
      :ARG0 (w / we)
      :ARG1 (p3 / possible-01 :mode interrogative
            :ARG1 (r / result-01
                  :ARG1 (c / combine-01
                        :ARG1 (a / and
                              :op1 (i / inhibit-01
                                    :ARG1 (e2 / enzyme :name (n4 / name :op1 "BRAF")))
                              :op2 (i2 / inhibit-01
                                    :ARG1 (e / enzyme :name (n / name :op1 "ERK")))))
                  :ARG2 (i3 / inhibit-01
                        :ARG0-of (s / synergize-01))
                  :manner (i4 / inhibit-01
                        :ARG1 (p2 / pathway :name (n2 / name :op1 "MAPK"))
                        :mod (d2 / dual))))
      :mod (n3 / next))

# ::id a_pmid_2514_2146.179 ::date 2015-06-13T16:03:56 ::annotator SDL-AMR-09 ::preferred
# ::snt Treatment of M238 and M792, two <i>BRAF</i><sup><i>V600E</i></sup>-mutant melanoma cell lines highly sensitive to singular treatment with vemurafenib and SCH772984, with equimolar concentrations of combined vemurafenib and SCH772984 treatment resulted in potent synergistic growth inhibition with IC<sub>50</sub> of 10nM (Figure <xref ref-type="fig" rid="Fig5">5</xref>A, <xref ref-type="fig" rid="Fig5">5</xref>B).
# ::save-date Tue Feb 2, 2016 ::file a_pmid_2514_2146_179.txt
(r / result-01
      :ARG1 (t / treat-04
            :ARG1 (a / and
                  :op1 (c / cell-line :name (n / name :op1 "M238"))
                  :op2 (c2 / cell-line :name (n2 / name :op1 "M792"))
                  :ARG1-of (m / mean-01
                        :ARG2 (c3 / cell-line :quant 2
                              :mod (g / gene :name (n3 / name :op1 "BRAF")
                                    :ARG1-of (m2 / mutate-01 :value "V600E"))
                              :ARG0-of (s / sensitive-03
                                    :ARG1 (t2 / treat-04
                                          :ARG1 a
                                          :ARG2 (a2 / and
                                                :op1 (s4 / small-molecule :name (n6 / name :op1 "vemurafenib"))
                                                :op2 (s3 / small-molecule :name (n4 / name :op1 "SCH772984"))))
                                    :ARG1-of (h / high-02))
                              :prep-with (c5 / concentrate-02
                                    :ARG1 (t3 / treat-04
                                          :ARG2 (a3 / and
                                                :op1 s4
                                                :op2 s3)
                                          :ARG1-of (c6 / combine-01))
                                    :mod (e / equimolar))
                              :part-of (m3 / medical-condition :name (n7 / name :op1 "melanoma"))))))
      :ARG2 (i / inhibit-01
            :ARG1 (g2 / grow-03)
            :mod (p / potent)
            :ARG0-of (s2 / synergize-01)
            :ARG3-of (h3 / have-percentage-maximal-inhibitory-concentration-01
                  :ARG2 50
                  :ARG4 (c7 / concentration-quantity :quant 10
                        :unit (n5 / nanomolar))))
      :ARG1-of (d / describe-01
            :ARG0 (a4 / and
                  :op1 (f / figure :mod "5A")
                  :op2 (f2 / figure :mod "5B"))))

# ::id a_pmid_2514_2146.180 ::date 2015-06-15T05:37:28 ::annotator SDL-AMR-09 ::preferred
# ::snt Combining vemurafenib with SCH772984 resulted in a more profound decrease in pRSK and pERK for the highly sensitive M262 and M792 lines compared to untreated controls or treatment with either agent alone.
# ::save-date Sat Jan 16, 2016 ::file a_pmid_2514_2146_180.txt
(r / result-01
      :ARG1 (c / combine-01
            :ARG1 (s3 / small-molecule :name (n6 / name :op1 "vemurafenib"))
            :ARG2 (s2 / small-molecule :name (n / name :op1 "SCH772984")))
      :ARG2 (d / decrease-01
            :ARG1 (a / and
                  :op1 (e / enzyme :name (n2 / name :op1 "RSK")
                        :ARG3-of (p2 / phosphorylate-01))
                  :op2 (e2 / enzyme :name (n3 / name :op1 "ERK")
                        :ARG3-of p2))
            :location (a2 / and
                  :op1 (c3 / cell-line :name (n4 / name :op1 "M262"))
                  :op2 (c4 / cell-line :name (n5 / name :op1 "M792"))
                  :ARG0-of (s / sensitive-03
                        :ARG1-of (h / high-02)))
            :mod (p / profound
                  :degree (m / more))
            :compared-to (o / or
                  :op1 (c5 / control
                        :ARG1-of (t2 / treat-04 :polarity -))
                  :op2 (t / treat-04
                        :ARG2 (a3 / agent
                              :mod (a4 / alone)
                              :mod (e3 / either))))))

# ::id a_pmid_2514_2146.181 ::date 2015-06-14T02:59:30 ::annotator SDL-AMR-09 ::preferred
# ::snt M262 resulted in decreased pAKT levels after all three treatments.
# ::save-date Wed Jun 24, 2015 ::file a_pmid_2514_2146_181.txt
(r / result-01
      :ARG1 (c / cell-line :name (n / name :op1 "M262"))
      :ARG2 (l / level
            :ARG1-of (d / decrease-01)
            :quant-of (e / enzyme :name (n2 / name :op1 "AKT")
                  :ARG3-of (p2 / phosphorylate-01)))
      :time (a / after
            :op1 (t / treat-04 :quant 3
                  :mod (a2 / all))))

# ::id a_pmid_2514_2146.182 ::date 2015-06-14T03:06:09 ::annotator SDL-AMR-09 ::preferred
# ::snt For M308, which is resistant to vemurafenib and sensitive to SCH772984, as pRSK was already completely absent with treatment with SCH772984 alone, no additional effect of the combination was apparent (Figure <xref ref-type="fig" rid="Fig5">5</xref>C).
# ::save-date Thu Jun 25, 2015 ::file a_pmid_2514_2146_182.txt
(c / cause-01
      :ARG0 (a / absent-01
            :ARG1 (e / enzyme :name (n / name :op1 "RSK")
                  :ARG3-of (p / phosphorylate-01))
            :manner (c2 / complete)
            :ARG1-of (c3 / cause-01
                  :ARG0 (t / treat-04
                        :ARG2 (s2 / small-molecule :name (n2 / name :op1 "SCH772984"))))
            :time (a3 / already))
      :ARG1 (a4 / appear-01 :polarity -
            :ARG1 (a5 / affect-01
                  :ARG0 (c5 / combine-01)
                  :ARG1 (c6 / cell-line :name (n3 / name :op1 "M308")
                        :ARG0-of (r / resist-01
                              :ARG1 (s3 / small-molecule :name (n4 / name :op1 "vemurafenib")))
                        :ARG0-of (s / sensitive-03
                              :ARG1 (s4 / small-molecule :name (n5 / name :op1 "SCH772984")
                                    :mod (a2 / alone))))
                  :mod (a6 / additional)))
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod "5C")))

# ::id a_pmid_2514_2146.183 ::date 2015-06-15T14:05:35 ::annotator SDL-AMR-09 ::preferred
# ::snt Interestingly, at 24 hours post treatment, induction of pMEK and pERK was already seen, indicating rapid feedback recovery for M308, despite its sensitivity to SCH772984.
# ::save-date Sat Jan 16, 2016 ::file a_pmid_2514_2146_183.txt
(s / see-01
      :ARG1 (i2 / induce-01
            :ARG2 (a / and
                  :op1 (e / enzyme :name (n / name :op1 "MEK")
                        :ARG3-of (p2 / phosphorylate-01))
                  :op2 (e2 / enzyme :name (n2 / name :op1 "ERK")
                        :ARG3-of p2)))
      :manner (i / interesting)
      :time (a3 / after
            :op1 (t3 / treat-04)
            :quant (t2 / temporal-quantity :quant 24
                  :unit (h2 / hour)))
      :time (a2 / already)
      :ARG0-of (i3 / indicate-01
            :ARG1 (r / recover-02
                  :ARG0 (c2 / cell-line :name (n3 / name :op1 "M308"))
                  :ARG1 (f / feedback)
                  :mod (r2 / rapid)
                  :concession (s2 / sensitive-03
                              :ARG0 c2
                              :ARG1 (s3 / small-molecule :name (n4 / name :op1 "SCH772984"))))))

# ::id a_pmid_2514_2146.184 ::date 2015-06-14T02:43:23 ::annotator SDL-AMR-09 ::preferred
# ::snt A slight decrease in pERK1/2 was seen with SCH772984 treatment, with a compensatory increase in pMEK.
# ::save-date Thu Jun 25, 2015 ::file a_pmid_2514_2146_184.txt
(s / see-01
      :ARG1 (a / and
            :op1 (d / decrease-01
                  :ARG1 (e / enzyme :name (n / name :op1 "ERK1/2")
                        :ARG3-of p)
                  :ARG2 (s2 / slight)
                  :ARG1-of (c / cause-01
                        :ARG0 (t / treat-04
                              :ARG2 (s3 / small-molecule :name (n2 / name :op1 "SCH772984")))))
            :op2 (i / increase-01
                  :ARG1 (e2 / enzyme :name (n3 / name :op1 "MEK")
                        :ARG3-of (p / phosphorylate-01))
                  :ARG0-of (c2 / compensate-01))))

# ::id a_pmid_2514_2146.185 ::date 2015-06-14T02:58:48 ::annotator SDL-AMR-09 ::preferred
# ::snt The generally more resistant M308 and M370 lines, in contrast to the generally more sensitive M262 and M792 lines, did not show a decrease in pMEK when combining the two drugs, which seems to be due to the lack of activity of vemurafenib in these resistant cells.
# ::save-date Mon Dec 21, 2015 ::file a_pmid_2514_2146_185.txt
(s / show-01 :polarity -
      :ARG0 (a2 / and
            :op1 (c5 / cell-line :name (n2 / name :op1 "M308"))
            :op2 (c6 / cell-line :name (n3 / name :op1 "M370"))
            :ARG0-of (r2 / resist-01
                  :degree (m / more)
                  :ARG1-of (g / general-02))
            :ARG1-of (c3 / cause-01
                  :ARG0 (l / lack-01
                        :ARG0 a2
                        :ARG1 (a / activity-06
                              :ARG0 (s4 / small-molecule :name (n6 / name :op1 "vemurafenib"))))
                  :ARG1-of (s2 / seem-01))
            :ARG1-of (c / contrast-01
                  :ARG2 (a3 / and
                        :op1 (c7 / cell-line :name (n4 / name :op1 "M262"))
                        :op2 (c8 / cell-line :name (n5 / name :op1 "M792"))
                        :ARG0-of (s3 / sensitive-03
                              :degree m
                              :ARG1-of g))))
      :ARG1 (d / decrease-01
            :ARG1 (e / enzyme :name (n / name :op1 "MEK")
                  :ARG3-of (p / phosphorylate-01)))
      :time (c2 / combine-01
            :ARG1 (d2 / drug :quant 2)))

# ::id a_pmid_2514_2146.186 ::date 2015-06-14T03:53:14 ::annotator SDL-AMR-09 ::preferred
# ::snt No additive effect from the dual upstream blockade could be noticed in the immediate downstream targets, indicating that the pathway remained active (Figure <xref ref-type="fig" rid="Fig5">5</xref>C).
# ::save-date Thu Jun 25, 2015 ::file a_pmid_2514_2146_186.txt
(p2 / possible-01
      :ARG1 (n / notice-01 :polarity -
            :ARG1 (a2 / affect-01
                  :ARG0 (b / blockade-01
                        :location (u / upstream)
                        :mod (d2 / dual))
                  :ARG1-of (a3 / add-02))
            :location (t / target
                  :location (d3 / downstream
                        :mod (i2 / immediacy)))
            :ARG0-of (i / indicate-01
                  :ARG1 (r / remain-01
                        :ARG1 (p / pathway)
                        :ARG3 (a / active))))
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod "5C")))

# ::id a_pmid_2514_2146.187 ::date 2015-06-13T16:08:12 ::annotator SDL-AMR-09 ::preferred
# ::snt All cell lines sensitive to BRAFi were also sensitive to the combination.
# ::save-date Wed Jun 24, 2015 ::file a_pmid_2514_2146_187.txt
(s / sensitive-03
      :ARG0 (c / cell-line
            :mod (a / all)
            :ARG0-of (s2 / sensitive-03
                  :ARG1 (m / molecular-physical-entity
                        :ARG0-of (i / inhibit-01
                              :ARG1 (e / enzyme :name (n / name :op1 "BRAF"))))))
      :ARG1 (c2 / combine-01)
      :mod (a2 / also))

# ::id a_pmid_2514_2146.188 ::date 2015-06-13T16:11:12 ::annotator SDL-AMR-09 ::preferred
# ::snt Four intermediately sensitive cell lines to BRAFi became highly sensitive to the combination, with improved pathway inhibition compared to ERK inhibition alone in all cases.
# ::save-date Sat Jan 30, 2016 ::file a_pmid_2514_2146_188.txt
(b / become-01
      :ARG1 (c / cell-line :quant 4
            :ARG0-of (s / sensitive-03
                  :ARG1 (m / molecular-physical-entity
                        :ARG0-of (i5 / inhibit-01
                              :ARG1 (e2 / enzyme :name (n2 / name :op1 "BRAF"))))
                  :degree (i / intermediate)))
      :ARG2 (s2 / sensitive-03
            :ARG0 c
            :ARG1 (c2 / combine-01)
            :ARG1-of (h / high-02))
      :prep-with (i2 / inhibit-01
            :ARG1 (p / pathway)
            :ARG1-of (i3 / improve-01)
            :compared-to (i4 / inhibit-01
                  :ARG1 (e / enzyme :name (n / name :op1 "ERK"))
                  :mod (a / alone)
                  :prep-in (c3 / case-04
                        :mod (a2 / all)))))

# ::id a_pmid_2514_2146.189 ::date 2015-06-15T15:23:14 ::annotator SDL-AMR-09 ::preferred
# ::snt More importantly, highly resistant cell lines to BRAFi became sensitive (M420, M308, M410) or intermediately sensitive (M417, M370, M229AR, M409AR1) to the combination.
# ::save-date Mon Dec 21, 2015 ::file a_pmid_2514_2146_189.txt
(b / become-01
      :ARG1 (c / cell-line
            :ARG0-of (r / resist-01
                  :ARG1 (m2 / molecular-physical-entity
                        :ARG0-of (i3 / inhibit-01
                              :ARG1 (e / enzyme :name (n / name :op1 "BRAF"))))
                  :ARG1-of (h / high-02)))
      :ARG2 (o / or
            :op1 (s / sensitive-03
                  :ARG0 (a / and
                        :op1 (c2 / cell-line :name (n2 / name :op1 "M420"))
                        :op2 (c3 / cell-line :name (n3 / name :op1 "M308"))
                        :op3 (c4 / cell-line :name (n4 / name :op1 "M410")))
                  :ARG1 (c5 / combine-01))
            :op2 (s2 / sensitive-03
                  :ARG0 (a2 / and
                        :op1 (c6 / cell-line :name (n5 / name :op1 "M417"))
                        :op2 (c7 / cell-line :name (n6 / name :op1 "M370"))
                        :op3 (c8 / cell-line :name (n7 / name :op1 "M229AR"))
                        :op4 (c9 / cell-line :name (n8 / name :op1 "M409AR1")))
                  :ARG1 c5
                  :degree (i / intermediate)))
      :manner (i2 / important
            :degree (m / more)))

# ::id a_pmid_2514_2146.190 ::date 2015-06-15T15:49:26 ::annotator SDL-AMR-09 ::preferred
# ::snt Three remained resistant but with a slightly improved IC<sub>50.</sub> C.I.s demonstrated synergy with combined BRAF and ERK inhibition for all cell lines except M308, in which dual treatment with vemurafenib and SCH772984 is only additive (Figure <xref ref-type="fig" rid="Fig5">5</xref>D).<fig id="Fig5"><label>Figure 5</label><caption><p><bold>Susceptibility of</bold><bold><i>BRAF</i></bold><bold>mutant melanoma cell lines to MAPK inhibitors.</bold>
# ::save-date Tue Feb 2, 2016 ::file a_pmid_2514_2146_190.txt
(m / multi-sentence
      :snt2 (d / demonstrate-01
            :ARG0 (i3 / index
                  :mod (c3 / combine-01))
            :ARG1 (s / synergize-01
                  :ARG0 i3
                  :ARG1 (i4 / inhibit-01
                        :ARG1 (a3 / and
                              :op1 (e4 / enzyme :name (n3 / name :op1 "BRAF"))
                              :op2 (e / enzyme :name (n / name :op1 "ERK")))
                        :location (c7 / cell-line
                              :mod (a / all)
                              :ARG2-of (e2 / except-01
                                    :ARG1 (c8 / cell-line :name (n4 / name :op1 "M308")
                                          :location-of (a2 / add-02
                                                :ARG1 (t2 / treat-04
                                                      :ARG2 (a4 / and
                                                            :op1 (s3 / small-molecule :name (n6 / name :op1 "vemurafenib"))
                                                            :op2 (s4 / small-molecule :name (n9 / name :op1 "SCH772984")))
                                                      :mod (d2 / dual))
                                                :mod (o / only)))))))
            :ARG1-of (d3 / describe-01
                  :ARG0 (f / figure :mod "5D")))
      :snt3 (s2 / susceptible
            :domain (c9 / cell-line
                  :part-of (m6 / medical-condition :name (n8 / name :op1 "melanoma")
                        :mod (e3 / enzyme :name (n5 / name :op1 "BRAF")
                              :ARG2-of (m3 / mutate-01))))
            :prep-to (m4 / molecular-physical-entity
                  :ARG0-of (i / inhibit-01
                        :ARG1 (p / protein-family :name (n2 / name :op1 "MAPK"))))
            :ARG1-of (d4 / describe-01
                  :ARG0 (f2 / figure :mod 5)))
      :snt1 (r3 / remain-01
            :ARG1 (c2 / cell-line :quant 3)
            :ARG3 (r / resist-01
                  :ARG0 c2
                  :ARG1-of (c / contrast-01
                        :ARG2 (h2 / have-percentage-maximal-inhibitory-concentration-01
                              :ARG1 c2
                              :ARG2 50
                              :ARG1-of (i2 / improve-01))))))

# ::id a_pmid_2514_2146.191 ::date 2015-06-15T15:53:38 ::annotator SDL-AMR-09 ::preferred
# ::snt Percent growth inhibition of <bold>(A)</bold> M238 and <bold>(B)</bold> M792.
# ::save-date Thu Aug 6, 2015 ::file a_pmid_2514_2146_191.txt
(i / inhibit-01
      :ARG1 (g / grow-01
            :ARG1 (a / and
                  :op1 (c / cell-line :name (n / name :op1 "M238")
                        :ARG1-of (d / describe-01
                              :ARG0 (f / figure :mod "5A")))
                  :op2 (c2 / cell-line :name (n2 / name :op1 "M792")
                        :ARG1-of (d2 / describe-01
                              :ARG0 (f2 / figure :mod "5B"))))
            :quant (p / percent)))

# ::id a_pmid_2514_2146.192 ::date 2015-06-15T16:00:09 ::annotator SDL-AMR-09 ::preferred
# ::snt After 120 hours treatment with 0–10 μM vemurafenib (V, squares), SCH722984 (E, circles), or the combination (V + E, triangles), cell viability was determined by bioluminescence assay.
# ::save-date Sun Jan 3, 2016 ::file a_pmid_2514_2146_192.txt
(d / determine-01
      :ARG1 (v / viability
            :poss (c / cell))
      :ARG2 (a / assay-01
            :ARG1 (b / bioluminescence))
      :time (a2 / after
            :op1 (t2 / treat-04
                  :ARG2 (o / or
                        :op1 (s3 / small-molecule :name (n4 / name :op1 "vemurafenib")
                              :ARG1-of (l / label-01
                                    :ARG0 (a4 / and
                                          :op2 (s / string-entity :value "V")
                                          :op2 (s4 / square)))
                              :quant (v2 / value-interval
                                    :op1 (c4 / concentration-quantity :quant 0
                                          :unit (m / micromolar))
                                    :op2 (c5 / concentration-quantity :quant 10
                                          :unit m)))
                        :op2 (s2 / small-molecule :name (n / name :op1 "SCH722984")
                              :ARG1-of (d3 / describe-01
                                    :ARG0 (a5 / and
                                          :op1 (s5 / string-entity :value "E")
                                          :op2 (c2 / circle))))
                        :op3 (c3 / combine-01
                              :ARG1 s3
                              :ARG2 s2
                              :ARG1-of (d4 / describe-01
                                    :ARG0 (a6 / and
                                          :op1 (s6 / string-entity :value "V+E")
                                          :op2 (t4 / triangle)))))
                  :duration (t / temporal-quantity :quant 120
                        :unit (h / hour)))))

# ::id a_pmid_2514_2146.193 ::date 2015-06-15T11:31:23 ::annotator SDL-AMR-09 ::preferred
# ::snt Results are representative data in duplicate from three independent experiments (n = 6).
# ::save-date Thu Jun 25, 2015 ::file a_pmid_2514_2146_193.txt
(d / data
      :ARG0-of (r / represent-01)
      :ARG0-of (d2 / duplicate-01
            :ARG1 (e / experiment-01 :quant 3
                  :ARG0-of (d3 / depend-01 :polarity -))
            :ARG1-of (m / mean-01
                  :ARG2 (e2 / experiment-01 :quant 6)))
      :domain (t / thing
            :ARG2-of (r2 / result-01)))

# ::id a_pmid_2514_2146.194 ::date 2015-06-15T05:34:20 ::annotator SDL-AMR-09 ::preferred
# ::snt <bold>C</bold>.
# ::save-date Thu Aug 6, 2015 ::file a_pmid_2514_2146_194.txt
(f / figure :mod "5C")

# ::id a_pmid_2514_2146.195 ::date 2015-06-14T04:32:18 ::annotator SDL-AMR-09 ::preferred
# ::snt Effect of BRAF-, ERK- inhibition or the combination on MAPK signaling.
# ::save-date Sat Jan 16, 2016 ::file a_pmid_2514_2146_195.txt
(a / affect-01
      :ARG0 (o2 / or
            :op1 (i / inhibit-01
                  :ARG1 (e2 / enzyme :name (n3 / name :op1 "BRAF")))
            :op2 (i2 / inhibit-01
                  :ARG1 (e / enzyme :name (n / name :op1 "ERK")))
            :op3 (c / combine-01
                  :ARG1 i
                  :ARG2 i2))
      :ARG1 (s / signal-07
            :ARG0 (p / pathway :name (n2 / name :op1 "MAPK"))))

# ::id a_pmid_2514_2146.196 ::date 2015-06-14T05:03:53 ::annotator SDL-AMR-09 ::preferred
# ::snt Cell lines were treated with DMSO (control, C), 500 nM Vemurafenib (BRAFi, B), 500 nM SCH722984 (ERKi, E) or the combination of vemurafenib and SCH722984 (B + E) for 24 hours.
# ::save-date Sun Jan 17, 2016 ::file a_pmid_2514_2146_196.txt
(t2 / treat-04
      :ARG1 (c / cell-line)
      :ARG2 (o / or
            :op1 (s4 / small-molecule :name (n5 / name :op1 "DMSO")
                  :ARG1-of (l / label-01
                        :ARG2 (c2 / control)))
            :op2 (s2 / small-molecule :name (n4 / name :op1 "vemurafenib")
                  :quant (c4 / concentration-quantity :quant 500
                        :unit (n2 / nanomolar))
                  :ARG1-of (l2 / label-01
                        :ARG2 (m3 / molecular-physical-entity
                              :ARG0-of (i2 / inhibit-01
                                    :ARG1 (e2 / enzyme :name (n7 / name :op1 "BRAF"))))))
            :op3 (s / small-molecule :name (n / name :op1 "SCH722984")
                  :quant (c5 / concentration-quantity :quant 500
                        :unit (n3 / nanomolar))
                  :ARG1-of (l3 / label-01
                        :ARG2 (m2 / molecular-physical-entity
                              :ARG0-of (i / inhibit-01
                                    :ARG1 (p / protein-family :name (n6 / name :op1 "ERK"))))))
            :op4 (c3 / combine-01
                  :ARG1 s2
                  :ARG2 s
                  :ARG1-of (l4 / label-01
                        :ARG2 (s3 / string-entity :value "B+E"))))
      :duration (t3 / temporal-quantity :quant 24
            :unit (h2 / hour)))

# ::id a_pmid_2514_2146.197 ::date 2015-06-14T05:34:14 ::annotator SDL-AMR-09 ::preferred
# ::snt Western blots analyzed for phospho- and total MEK, ERK1/2, RSK, AKT and actin as loading control.
# ::save-date Sun Dec 20, 2015 ::file a_pmid_2514_2146_197.txt
(a7 / analyze-01
      :purpose (a3 / and
            :op1 (a4 / and
                  :op1 (e2 / enzyme :name (n / name :op1 "MEK"))
                  :op2 (e / enzyme :name (n2 / name :op1 "ERK1/2"))
                  :op3 (e3 / enzyme :name (n4 / name :op1 "RSK"))
                  :op4 (e4 / enzyme :name (n5 / name :op1 "AKT"))
                  :op5 p2
                  :ARG3-of (p / phosphorylate-01))
            :op2 (a5 / and
                  :op1 e2
                  :op2 e
                  :op3 e3
                  :op4 e4
                  :op5 (p2 / protein :name (n6 / name :op1 "actin"))
                  :mod (t / total))
            :ARG0-of (c / control-01
                  :ARG1 (l / load-01)))
      :manner (i / immunoblot-01))

# ::id a_pmid_2514_2146.198 ::date 2015-06-14T06:02:13 ::annotator SDL-AMR-09 ::preferred
# ::snt <bold>D</bold>.
# ::save-date Sun Jan 3, 2016 ::file a_pmid_2514_2146_198.txt
(s / string-entity :value "D")

# ::id a_pmid_2514_2146.199 ::date 2015-06-14T06:02:45 ::annotator SDL-AMR-09 ::preferred
# ::snt IC<sub>50</sub> (nM) to MAPK inhibitors and synergistic effect.
# ::save-date Tue Feb 2, 2016 ::file a_pmid_2514_2146_199.txt
(a / and
      :op1 (h / have-percentage-maximal-inhibitory-concentration-01 :ARG2 50
            :ARG1 (m / molecular-physical-entity
                  :ARG0-of (i2 / inhibit-01
                        :ARG1 (p / protein-family :wiki "Mitogen-activated_protein_kinase"
                              :name (n / name :op1 "MAPK"))))
            :ARG4 (c / concentration-quantity
                  :unit (n2 / nanomolar)))
      :op2 (a2 / affect-01
            :ARG2 (s / synergize-01)))

# ::id a_pmid_2514_2146.200 ::date 2015-06-15T09:33:41 ::annotator SDL-AMR-09 ::preferred
# ::snt BRAF-mutant melanoma cell lines were treated with 0–10 μM vemurafenib (BRAFi) or SCH722984 (ERKi), the combination (B + E) or 0–1 μM trametinib (MEKi).
# ::save-date Thu Jan 14, 2016 ::file a_pmid_2514_2146_200.txt
(t / treat-04
      :ARG1 (c / cell-line
            :part-of (m5 / medical-condition :name (n4 / name :op1 "melanoma")
                  :mod (e3 / enzyme :name (n / name :op1 "BRAF")
                        :ARG2-of (m2 / mutate-01))))
      :ARG2 (o / or
            :op1 (s2 / small-molecule :name (n7 / name :op1 "vemurafenib")
                  :quant (c2 / concentration-quantity
                        :unit (m3 / micromolar)
                        :quant (v / value-interval :op1 1 :op2 10))
                  :ARG0-of (i2 / inhibit-01
                        :ARG1 (e4 / enzyme :name (n9 / name :op1 "BRAF"))))
            :op2 (s / small-molecule :name (n2 / name :op1 "SCH722984")
                  :ARG0-of (i / inhibit-01
                        :ARG1 (p / protein-family :name (n3 / name :op1 "ERK"))))
            :op3 (c3 / combine-01
                  :ARG1 s2
                  :ARG2 s
                  :ARG1-of (l / label-01
                        :ARG2 (s4 / string-entity :value "B+E")))
            :op4 (s3 / small-molecule :name (n8 / name :op1 "trametinib")
                  :ARG0-of (i3 / inhibit-01
                        :ARG1 (e2 / enzyme :name (n6 / name :op1 "MEK")))
                  :quant (c4 / concentration-quantity
                        :unit (m4 / micromolar)
                        :quant (b2 / between :op1 0 :op2 1)))))

# ::id a_pmid_2514_2146.201 ::date 2015-06-14T03:07:21 ::annotator SDL-AMR-09 ::preferred
# ::snt Green indicates sensitivity, yellow intermediately sensitive, and red for resistant.
# ::save-date Mon Dec 21, 2015 ::file a_pmid_2514_2146_201.txt
(a / and
      :op1 (i / indicate-01
            :ARG0 (g / green-02)
            :ARG1 (s / sensitive-03))
      :op2 (i2 / indicate-01
            :ARG0 (y / yellow-02)
            :ARG1 (s2 / sensitive-03
                  :degree (i4 / intermediate)))
      :op3 (i3 / indicate-01
            :ARG0 (r / red-02)
            :ARG1 (r2 / resist-01)))

# ::id a_pmid_2514_2146.202 ::date 2015-06-14T03:10:24 ::annotator SDL-AMR-09 ::preferred
# ::snt The CI column indicates the combination index of vemurafenib and SCH722984.</p></caption><graphic /></fig>
# ::save-date Sun Jan 3, 2016 ::file a_pmid_2514_2146_202.txt
(i / indicate-01
      :ARG0 (c / column
            :mod (s3 / string-entity :value "CI"))
      :ARG1 (i2 / index
            :mod (c2 / combine-01
                  :ARG1 (s / small-molecule :name (n3 / name :op1 "vemurafenib"))
                  :ARG2 (s2 / small-molecule :name (n2 / name :op1 "SCH722984")))))

# ::id a_pmid_2514_2146.203 ::date 2015-06-14T03:18:42 ::annotator SDL-AMR-09 ::preferred
# ::snt We next examined whether cells inherently resistant to BRAFi could be sensitive to a MEK inhibitor (MEKi) or ERKi.
# ::save-date Sat Jan 16, 2016 ::file a_pmid_2514_2146_203.txt
(e2 / examine-01
      :ARG0 (w / we)
      :ARG1 (p / possible-01 :mode interrogative
            :ARG1 (s / sensitive-03
                  :ARG0 (c / cell
                        :ARG0-of (r / resist-01
                              :ARG1 (m3 / molecular-physical-entity
                                    :ARG0-of (i3 / inhibit-01
                                          :ARG1 (e4 / enzyme :name (n3 / name :op1 "BRAF"))))
                              :mod (i4 / inherent)))
                  :ARG1 (o / or
                        :op1 (m / molecular-physical-entity
                              :ARG0-of (i / inhibit-01
                                    :ARG1 (p3 / protein-family :name (n / name :op1 "MEK"))))
                        :op2 (m2 / molecular-physical-entity
                              :ARG0-of (i2 / inhibit-01
                                    :ARG1 (p2 / protein-family :name (n4 / name :op1 "ERK")))))))
      :mod (n2 / next))

# ::id a_pmid_2514_2146.204 ::date 2015-06-14T03:19:57 ::annotator SDL-AMR-09 ::preferred
# ::snt Sensitivity of <i>BRAF</i> mutant melanoma cell lines to BRAFi predicted sensitivity to MEK and ERK inhibitors.
# ::save-date Fri Feb 12, 2016 ::file a_pmid_2514_2146_204.txt
(p / predict-01
      :ARG0 (s2 / sensitive-03
            :ARG0 (c / cell-line
                  :mod (g / gene :name (n / name :op1 "BRAF")
                        :ARG2-of (m2 / mutate-01))
                  :part-of (m / medical-condition :name (n5 / name :op1 "melanoma")))
            :ARG1 (m5 / molecular-physical-entity
                  :ARG0-of (i / inhibit-01
                        :ARG1 (e2 / enzyme :name (n2 / name :op1 "BRAF")))))
      :ARG1 (s / sensitive-03
            :ARG1 (a / and
                  :op1 (m3 / molecular-physical-entity
                        :ARG0-of (i2 / inhibit-01
                              :ARG1 (p3 / protein-family :name (n3 / name :op1 "MEK"))))
                  :op2 (m4 / molecular-physical-entity
                        :ARG0-of (i3 / inhibit-01
                              :ARG1 (p2 / protein-family :name (n4 / name :op1 "ERK")))))))

# ::id a_pmid_2514_2146.205 ::date 2015-06-14T03:36:53 ::annotator SDL-AMR-09 ::preferred
# ::snt Furthermore, 10 cell lines inherently resistant to BRAFi were often sensitive to MEK and ERK inhibition, and cell lines resistant to BRAFi or MEKi were relatively more sensitive to SCH722984.
# ::save-date Sat Jan 16, 2016 ::file a_pmid_2514_2146_205.txt
(a / and
      :op2 (a2 / and
            :op1 (s / sensitive-03
                  :ARG0 (c / cell-line :quant 10
                        :ARG0-of (r / resist-01
                              :ARG1 (m2 / molecular-physical-entity
                                    :ARG0-of (i3 / inhibit-01
                                          :ARG1 (e / enzyme :name (n3 / name :op1 "BRAF"))))
                              :manner (i / inherent)))
                  :ARG1 (i2 / inhibit-01
                        :ARG1 (a3 / and
                              :op1 (e3 / enzyme :name (n4 / name :op1 "MEK"))
                              :op2 (e2 / enzyme :name (n5 / name :op1 "ERK"))))
                  :frequency (o / often)))
      :op2 (s2 / sensitive-03
            :ARG0 (c2 / cell-line
                  :ARG0-of (r3 / resist-01
                        :ARG1 (o2 / or
                              :op1 m2
                              :op2 (m3 / molecular-physical-entity
                                    :ARG0-of (i4 / inhibit-01
                                          :ARG1 e3)))))
            :ARG1 (s3 / small-molecule :name (n / name :op1 "SCH722984"))
            :degree (m / more)
            :ARG2-of (r2 / relative-05)))

# ::id a_pmid_2514_2146.206 ::date 2015-06-15T09:52:29 ::annotator SDL-AMR-09 ::preferred
# ::snt Indeed, combining BRAF with ERK inhibition potently decreased the equimolar IC<sub>50</sub> of all cell lines and resulted in synergy in all but one case (M308), including M255, M399 and M420, which are completely resistant to individual inhibitors (Figure <xref ref-type="fig" rid="Fig5">5</xref>D).
# ::save-date Tue Feb 2, 2016 ::file a_pmid_2514_2146_206.txt
(a / and
      :op1 (d / decrease-01
            :ARG0 (c2 / combine-01
                  :ARG1 (i5 / inhibit-01
                        :ARG1 (e2 / enzyme :name (n / name :op1 "BRAF")))
                  :ARG2 (i / inhibit-01
                        :ARG1 (e / enzyme :name (n2 / name :op1 "ERK"))))
            :ARG1 (h / have-percentage-maximal-inhibitory-concentration-01
                  :ARG1 (c3 / cell-line
                        :mod (a3 / all))
                  :ARG2 50
                  :mod (e4 / equimolar))
            :manner (p / potent))
      :op2 (r / result-01
            :ARG1 c2
            :ARG2 (s / synergize-01)
            :prep-in (c / case-04
                  :ARG1-of (i2 / include-91
                        :ARG2 (a4 / and
                              :op1 (c6 / cell-line :name (n5 / name :op1 "M255"))
                              :op2 (c7 / cell-line :name (n6 / name :op1 "M399"))
                              :op3 (c8 / cell-line :name (n7 / name :op1 "M420"))
                              :ARG0-of (r2 / resist-01
                                    :ARG1 (m2 / molecular-physical-entity
                                          :mod (i3 / individual)
                                          :ARG0-of (i4 / inhibit-01)))))
                  :mod a3
                  :ARG2-of (e3 / except-01
                        :ARG1 (c5 / cell-line :name (n4 / name :op1 "M308")))))
      :ARG1-of (d2 / describe-01
            :ARG0 (f / figure :mod "5D"))
      :mod (i6 / indeed))

# ::id a_pmid_2514_2146.207 ::date 2015-06-14T04:09:18 ::annotator SDL-AMR-09 ::preferred
# ::snt Because the combination on BRAF combined with MEK inhibition is currently FDA approved for <i>BRAF</i><sup><i>V600</i></sup> mutant melanoma, we also determined the IC<sub>50</sub> for the combination of vemurafenib and trametinib.
# ::save-date Sat Jan 16, 2016 ::file a_pmid_2514_2146_207.txt
(c / cause-01
      :ARG0 (a2 / approve-01
            :ARG0 (o / organization :name (n4 / name :op1 "FDA"))
            :ARG1 (c3 / combine-01
                  :ARG1 (e2 / enzyme :name (n3 / name :op1 "BRAF")
                        :ARG1-of (c4 / combine-01
                              :ARG2 (i / inhibit-01
                                    :ARG1 (e / enzyme :name (n / name :op1 "MEK"))))))
            :time (c5 / current)
            :purpose (m3 / medical-condition :name (n2 / name :op1 "melanoma")
                  :mod (g / gene :name (n5 / name :op1 "BRAF")
                        :ARG2-of (m2 / mutate-01 :value "V600"))))
      :ARG1 (d / determine-01
            :ARG0 (w / we)
            :ARG1 (h / have-percentage-maximal-inhibitory-concentration-01
                  :ARG1 (c2 / combine-01
                        :ARG1 (s / small-molecule :name (n6 / name :op1 "vemurafenib"))
                        :ARG2 (s2 / small-molecule :name (n7 / name :op1 "trametinib")))
                  :ARG2 50)
            :mod (a / also)))

# ::id a_pmid_2514_2146.208 ::date 2015-06-13T14:55:05 ::annotator SDL-AMR-09 ::preferred
# ::snt The results showed potent growth inhibition and synergy in all cell lines.
# ::save-date Tue Feb 2, 2016 ::file a_pmid_2514_2146_208.txt
(s / show-01
      :ARG0 (t / thing
            :ARG2-of (r / result-01))
      :ARG1 (a / and
            :op1 (i / inhibit-01
                  :ARG1 (g / grow-01)
                  :mod (p / potent))
            :op2 (s2 / synergize-01)
            :location (c / cell-line
                  :mod (a2 / all))))

# ::id a_pmid_2514_2146.209 ::date 2015-06-13T14:58:19 ::annotator SDL-AMR-09 ::preferred
# ::snt Sensitivity to the vemurafenib + trametinib combination generally overlapped with sensitivity to the vemurafenib + SCH722984 combination (Figure <xref ref-type="fig" rid="Fig5">5</xref>D), consistent with the idea that both combinations cause dual MAPK blockade.
# ::save-date Fri Dec 18, 2015 ::file a_pmid_2514_2146_209.txt
(o / overlap-01
      :ARG0 (s / sensitive-03
            :ARG1 (t / thing
                  :ARG3-of (c / combine-01
                        :ARG1 (s4 / small-molecule :name (n3 / name :op1 "vemurafenib"))
                        :ARG2 (s5 / small-molecule :name (n4 / name :op1 "trametinib")))))
      :ARG1 (s2 / sensitive-03
            :ARG1 (t2 / thing
                  :ARG3-of (c2 / combine-01
                        :ARG1 s4
                        :ARG2 (s3 / small-molecule :name (n2 / name :op1 "SCH722984")))))
      :ARG1-of (g / general-02)
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod "5D"))
      :ARG1-of (c4 / consistent-01
            :ARG2 (i / idea
                  :topic (c5 / cause-01
                        :ARG0 (a / and
                              :op1 t
                              :op2 t2)
                        :ARG1 (b / blockade-01
                              :ARG1 (p / pathway :name (n / name :op1 "MAPK"))
                              :mod (d2 / dual))))))

# ::id a_pmid_2514_2146.210 ::date 2015-06-15T14:14:50 ::annotator SDL-AMR-09 ::preferred
# ::snt The growth curves for the vemurafenib + trametinib combinations are shown in Additional file <xref ref-type="media" rid="MOESM5">5</xref>: Figure S5.
# ::save-date Wed Jun 24, 2015 ::file a_pmid_2514_2146_210.txt
(s / show-01
      :ARG0 (f / file :mod 5
            :mod (a / additional)
            :ARG1-of (m / mean-01
                  :ARG2 (f2 / figure :mod "S5")))
      :ARG1 (c / curve
            :topic (g / grow-01
                  :ARG1 (c2 / combine-01
                        :ARG1 (s2 / small-molecule :name (n / name :op1 "vemurafenib"))
                        :ARG2 (s3 / small-molecule :name (n2 / name :op1 "trametinib"))))))

# ::id a_pmid_2514_2146.211 ::date 2015-06-14T04:03:50 ::annotator SDL-AMR-09 ::preferred
# ::snt Effects of MAPK pathway inhibition on cell cycle progression and apoptosis
# ::save-date Mon Dec 21, 2015 ::file a_pmid_2514_2146_211.txt
(a / affect-01
      :ARG0 (i / inhibit-01
            :ARG0 (p / pathway :name (n / name :op1 "MAPK")))
      :ARG1 (a2 / and
            :op1 (p2 / progress-01
                  :ARG1 (c / cycle-02
                        :ARG1 (c2 / cell)))
            :op2 (a3 / apoptosis)))

# ::id a_pmid_2514_2146.212 ::date 2015-06-14T04:08:21 ::annotator SDL-AMR-09 ::preferred
# ::snt To determine the effect of BRAF or ERK inhibition on cell cycle progression and apoptosis, cells were treated with SCH772984, alone or in combination with vemurafenib for 48 hours then stained with DAPI and intracellularly for cleaved PARP and analyzed by flow cytometry.
# ::save-date Fri Feb 12, 2016 ::file a_pmid_2514_2146_212.txt
(a / and
      :op1 (t2 / treat-04
            :ARG1 (c6 / cell-line)
            :ARG2 (o2 / or
                  :op1 (s2 / small-molecule :name (n3 / name :op1 "SCH772984")
                        :mod (a5 / alone))
                  :op2 (c4 / combine-01
                        :ARG1 s2
                        :ARG2 (s3 / small-molecule :name (n6 / name :op1 "vemurafenib"))))
            :duration (t / temporal-quantity :quant 48
                  :unit (h / hour)))
      :op2 (s / stain-01
            :ARG1 c6
            :ARG2 (s4 / small-molecule :name (n4 / name :op1 "DAPI"))
            :manner (i3 / intracellular)
            :purpose (p2 / protein :name (n5 / name :op1 "PARP")
                  :ARG1-of (c3 / cleave-01))
            :time (t3 / then))
      :op3 (a6 / analyze-01
            :ARG1 c6
            :manner (c5 / cytometry
                  :mod (f / flow)))
      :purpose (d / determine-01
            :ARG1 (a2 / affect-01
                  :ARG0 (i / inhibit-01
                        :ARG1 (o3 / or
                              :op1 (e2 / enzyme :name (n / name :op1 "BRAF"))
                              :op2 (e / enzyme :name (n2 / name :op1 "ERK"))))
                  :ARG1 (a3 / and
                        :op1 (p / progress-01
                              :ARG1 (c / cycle-02
                                    :ARG1 (c2 / cell)))
                        :op2 (a4 / apoptosis)))))

# ::id a_pmid_2514_2146.213 ::date 2015-06-15T15:22:10 ::annotator SDL-AMR-09 ::preferred
# ::snt Treatment with either of these two inhibitors resulted in an increase in the sub-G0 population, the G1 population, as well as an increase in cleaved PARP levels which indicates apoptotic cells (Figure <xref ref-type="fig" rid="Fig6">6</xref>A).
# ::save-date Sun Jan 3, 2016 ::file a_pmid_2514_2146_213.txt
(r / result-01
      :ARG1 (t2 / treat-04
            :ARG1 (m / molecular-physical-entity
                  :ARG0-of (i / inhibit-01)
                  :ARG1-of (i4 / include-91
                        :ARG2 (m2 / molecular-physical-entity :quant 2
                              :mod (t3 / this)))
                  :mod (e / either)))
      :ARG2 (i2 / increase-01
            :ARG1 (a / and
                  :op1 (p / population
                        :mod (e2 / event :name (n / name :op1 "sub-G0")))
                  :op2 (p4 / population
                        :mod (e3 / event :name (n3 / name :op1 "G1")))
                  :op3 (l / level
                        :quant-of (p3 / protein :name (n2 / name :op1 "PARP"))
                        :ARG1-of (c2 / cleave-01))
                  :ARG0-of (i3 / indicate-01
                        :ARG1 (c / cell
                              :mod (a2 / apoptosis)))))
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod "6A")))

# ::id a_pmid_2514_2146.214 ::date 2015-06-13T16:12:03 ::annotator SDL-AMR-09 ::preferred
# ::snt A modest increase of 3-10% was seen in the sub-G0 population for all cell lines treated with vemurafenib, SCH772984 or the combination.
# ::save-date Sun Jan 3, 2016 ::file a_pmid_2514_2146_214.txt
(s / see-01
      :ARG1 (i / increase-01
            :ARG2 (v / value-interval
                  :op1 (p2 / percentage-entity :value 3)
                  :op2 (p / percentage-entity :value 10))
            :mod (m / modest))
      :location (p3 / populate-01
            :ARG1 (c / cell-line
                  :mod (a / all)
                  :ARG1-of (t / treat-04
                        :ARG2 (o / or
                              :op1 (s3 / small-molecule :name (n2 / name :op1 "vemurafenib"))
                              :op2 (s2 / small-molecule :name (n / name :op1 "SCH772984"))
                              :op3 (c3 / combine-01
                                    :ARG1 s3
                                    :ARG2 s2))))
            :time (e / event :name (n3 / name :op1 "sub-GO"))))

# ::id a_pmid_2514_2146.215 ::date 2015-06-13T16:17:37 ::annotator SDL-AMR-09 ::preferred
# ::snt The amount of subG1 increase did not correlate with sensitivity or resistance to the MAPK pathway inhibitors.
# ::save-date Sun Jan 3, 2016 ::file a_pmid_2514_2146_215.txt
(c / correlate-01 :polarity -
      :ARG1 (a / amount-01
            :ARG1 (i2 / increase-01
                  :time (e / event :name (n2 / name :op1 "subG1"))))
      :ARG2 (o / or
            :op1 (s / sensitive-03
                  :ARG1 (m / molecular-physical-entity
                        :ARG0-of (i3 / inhibit-01
                              :ARG1 (p2 / pathway :name (n3 / name :op1 "MAPK")))))
            :op2 (r / resist-01
                  :ARG1 m)))

# ::id a_pmid_2514_2146.216 ::date 2015-06-14T02:35:28 ::annotator SDL-AMR-09 ::preferred
# ::snt In contrast, for the G0-G1 populations, there was a correlation with sensitivity, with an up to 40% increase in G0-G1 population seen in the sensitive cell lines M238 and M792, while the resistant cell lines M233 and M299 demonstrated only a 10% increase in the G0-G1 population for the combination treatment.
# ::save-date Sun Jan 3, 2016 ::file a_pmid_2514_2146_216.txt
(c / contrast-01
      :ARG1 (c2 / correlate-01
            :ARG1 (p / population
                  :mod (e / event :name (n3 / name :op1 "G0-G1")))
            :ARG2 (s3 / sensitive-03)
            :prep-with (i / increase-01
                  :ARG1 p
                  :ARG2 (u / up-to
                        :op1 (p3 / percentage-entity :value 40))
                  :ARG1-of (s / see-01
                        :location (a / and
                              :op1 (c3 / cell-line :name (n / name :op1 "M238"))
                              :op2 (c4 / cell-line :name (n2 / name :op1 "M792"))
                              :ARG0-of (s2 / sensitive-03)))))
      :ARG2 (d / demonstrate-01
            :ARG0 (a2 / and
                  :op1 (c5 / cell-line :name (n4 / name :op1 "M233"))
                  :op2 (c6 / cell-line :name (n5 / name :op1 "M299"))
                  :ARG1-of (t / treat-04
                        :ARG2 (c7 / combine-01))
                  :ARG0-of (r / resist-01))
            :ARG1 (i2 / increase-01
                  :ARG1 p
                  :ARG2 (p4 / percentage-entity :value 10))))

# ::id a_pmid_2514_2146.217 ::date 2015-06-15T16:21:56 ::annotator SDL-AMR-09 ::preferred
# ::snt Concomitant with the increase in G0-G1, a decreased proportion of cells were observed in S-phase, with the largest decreases of over 20% seen in the sensitive cell lines M792 and M238 (Figure <xref ref-type="fig" rid="Fig6">6</xref>B).
# ::save-date Fri Jan 15, 2016 ::file a_pmid_2514_2146_217.txt
(o / observe-01
      :ARG1 (a2 / and
            :op1 (p3 / proportion-01
                  :ARG1 (c / cell)
                  :ARG1-of (d2 / decrease-01
                        :time (e / event :name (n5 / name :op1 "S-phase"))))
            :op2 (i / increase-01
                  :time (e2 / event :name (n / name :op1 "G0-G1")))
            :op3 (d3 / decrease-01
                  :ARG2 (o2 / over
                        :op1 (p5 / percentage-entity :value 20))
                  :mod (l2 / large
                        :degree (m2 / most))
                  :ARG1-of (s / see-01
                        :location (a / and
                              :op1 (c2 / cell-line :name (n3 / name :op1 "M792"))
                              :op2 (c3 / cell-line :name (n4 / name :op1 "M238"))
                              :ARG0-of (s2 / sensitive-03)))))
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod "6B"))
      :mod (c4 / concomitant))

# ::id a_pmid_2514_2146.218 ::date 2015-06-14T00:01:32 ::annotator SDL-AMR-09 ::preferred
# ::snt Treatment of the sensitive cell lines, M238 and M792, with SCH772984 alone or in combination with vemurafenib resulted in a dramatic increase in cleaved PARP reaching induced percentages around 40-50%.
# ::save-date Sun Dec 20, 2015 ::file a_pmid_2514_2146_218.txt
(r / result-01
      :ARG1 (t / treat-04
            :ARG1 (a2 / and
                  :op1 (c2 / cell-line :name (n / name :op1 "M238"))
                  :op2 (c3 / cell-line :name (n2 / name :op1 "M792"))
                  :ARG0-of (s / sensitive-03))
            :ARG2 (o / or
                  :op1 (s2 / small-molecule :name (n3 / name :op1 "SCH772984")
                        :mod (a3 / alone))
                  :op2 (c / combine-01
                        :ARG1 s2
                        :ARG2 (s3 / small-molecule :name (n4 / name :op1 "vemurafenib")))))
      :ARG2 (i / increase-01
            :ARG1 (p2 / protein :name (n5 / name :op1 "PARP")
                  :ARG1-of (c4 / cleave-01)
                  :ARG0-of (r2 / reach-01
                        :ARG1 (p3 / percentage
                              :ARG2-of (i2 / induce-01)
                              :ARG1-of (e2 / equal-01
                                    :ARG2 (a4 / around
                                          :op1 (v / value-interval
                                                :op1 (p4 / percentage-entity :value 40)
                                                :op2 (p5 / percentage-entity :value 50)
                                                :mod (a / around)))))))
            :degree (d / dramatic)))

# ::id a_pmid_2514_2146.219 ::date 2015-06-14T00:39:07 ::annotator SDL-AMR-09 ::preferred
# ::snt In comparison, the resistant cell lines (M233 and M299) had cleaved PARP at 20-25% (Figure <xref ref-type="fig" rid="Fig6">6</xref>C).
# ::save-date Sun Jun 14, 2015 ::file a_pmid_2514_2146_219.txt
(c / compare-01
      :ARG2 (h / have-03
            :ARG0 (a / and
                  :op1 (c3 / cell-line :name (n / name :op1 "M233"))
                  :op2 (c4 / cell-line :name (n2 / name :op1 "M299"))
                  :ARG0-of (r / resist-01))
            :ARG1 (p2 / protein :name (n3 / name :op1 "PARP")
                  :ARG1-of (c2 / cleave-01)
                  :quant (v / value-interval
                        :op1 (p / percentage-entity :value 20)
                        :op2 (p3 / percentage-entity :value 25))))
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod "6C")))

# ::id a_pmid_2514_2146.220 ::date 2015-06-14T00:46:28 ::annotator SDL-AMR-09 ::preferred
# ::snt With the exception of M299, a statistically significant increase in cleaved PARP was seen in all cell lines treated with SCH772984, or the combination of SCH772984 and vemurafenib, compared to vemurafenib alone.
# ::save-date Fri Dec 18, 2015 ::file a_pmid_2514_2146_220.txt
(s / see-01
      :ARG1 (i / increase-01
            :ARG1 (p / protein :name (n / name :op1 "PARP")
                  :ARG1-of (c / cleave-01))
            :ARG2 (s2 / significant-02
                  :mod (s3 / statistics))
            :location (c2 / cell-line
                  :ARG1-of (t / treat-04
                        :ARG2 (o / or
                              :op1 (s4 / small-molecule :name (n2 / name :op1 "SCH772984"))
                              :op2 (c3 / combine-01
                                    :ARG1 s4
                                    :ARG2 (s5 / small-molecule :name (n3 / name :op1 "vemurafenib")))))
                  :ARG2-of (e3 / except-01
                        :ARG1 (c4 / cell-line :name (n5 / name :op1 "M299")))
                  :mod (a2 / all))
            :compared-to (t2 / treat-04
                  :ARG2 s5
                  :mod (a / alone))))

# ::id a_pmid_2514_2146.221 ::date 2015-06-14T01:02:18 ::annotator SDL-AMR-09 ::preferred
# ::snt Combinatorial treatment offered a statistically significant increase in cleaved PARP compared to vemurafenib alone in all cell lines (20% increase in sensitive cell lines and 10% increase in resistant cell lines compared to vemurafenib alone).
# ::save-date Fri Dec 18, 2015 ::file a_pmid_2514_2146_221.txt
(o / offer-01
      :ARG0 (t / treat-04
            :mod (c / combine-01))
      :ARG1 (i / increase-01
            :ARG1 (p3 / protein :name (n / name :op1 "PARP")
                  :ARG1-of (c2 / cleave-01))
            :ARG2 (s / significant-02
                  :mod (s2 / statistics))
            :compared-to (o2 / offer-01
                  :ARG0 (t2 / treat-04
                        :ARG2 (s4 / small-molecule :name (n2 / name :op1 "vemurafenib")
                              :mod (a2 / alone))))
            :location (c3 / cell-line
                  :mod (a / all))
            :ARG1-of (e2 / equal-01
                  :ARG2 (a3 / and
                        :op1 (i3 / increase-01
                              :ARG2 (p4 / percentage-entity :value 20)
                              :location (c4 / cell-line
                                    :ARG1-of (s3 / sensitive-03)))
                        :op2 (i4 / increase-01
                              :ARG2 (p5 / percentage-entity :value 10)
                              :location (c5 / cell-line
                                    :ARG0-of (r / resist-01)))))))

# ::id a_pmid_2514_2146.222 ::date 2015-06-14T01:16:42 ::annotator SDL-AMR-09 ::preferred
# ::snt However only a trend towards increased cleaved PARP fractions was observed comparing combinatorial treatment with SCH772984 alone without reaching statistical significance.<fig id="Fig6"><label>Figure 6</label><caption><p><bold>Effect of SCH722984, vemurafenib or the combination on cell cycle progression and apoptosis in BRAF-mutant melanoma cell lines.</bold>
# ::save-date Mon Dec 21, 2015 ::file a_pmid_2514_2146_222.txt
(m / multi-sentence
      :snt1 (c8 / contrast-01
            :ARG2 (o / observe-01
                  :ARG1 (t / trend-01
                        :ARG2 (f / fraction-01
                              :ARG1 (p / protein :name (n / name :op1 "PARP")
                                    :ARG1-of (c / cleave-01))
                              :ARG1-of (i / increase-01
                                    :ARG0-of (r / reach-01 :polarity -
                                          :ARG1 (s2 / significant-02
                                                :mod (s3 / statistics)))))
                        :mod (o3 / only))
                  :condition (c2 / compare-01
                        :ARG1 (t2 / treat-04
                              :mod (c3 / combine-01))
                        :ARG2 (t3 / treat-04
                              :ARG2 (s / small-molecule :name (n2 / name :op1 "SCH772984")
                                    :mod (a3 / alone))))))
      :snt2 (a / affect-01
            :ARG0 (o2 / or
                  :op1 (s4 / small-molecule :name (n3 / name :op1 "SCH722984"))
                  :op2 (s5 / small-molecule :name (n4 / name :op1 "vemurafenib"))
                  :op3 (c4 / combine-01
                        :ARG1 s4
                        :ARG2 s5))
            :ARG1 (a2 / and
                  :op1 (p2 / progress-01
                        :ARG1 (c5 / cycle-02
                              :ARG1 (c6 / cell)))
                  :op2 (a4 / apoptosis))
            :location (c7 / cell-line
                  :mod (m3 / medical-condition :name (n6 / name :op1 "melanoma")
                        :mod (e2 / enzyme :name (n7 / name :op1 "BRAF")
                              :ARG2-of (m2 / mutate-01))))
            :ARG1-of (d / describe-01
                  :ARG0 (f2 / figure :mod 6))))

# ::id a_pmid_2514_2146.223 ::date 2015-06-14T01:36:07 ::annotator SDL-AMR-09 ::preferred
# ::snt Two sensitive cell lines (M238 and M792) and two resistant cell lines (M233 and M299) were exposed to DMSO as vehicle control (Unst, control unstained: Control, control stained), 1 μM vemurafenib (Vem), SCH722984 (ERKi), the combination (V + E) or 1 μM staurosporine for 48 hours.
# ::save-date Mon Jan 4, 2016 ::file a_pmid_2514_2146_223.txt
(a4 / and
      :op1 (e / expose-01
            :ARG1 (a / and
                  :op1 (c2 / cell-line :name (n / name :op1 "M238"))
                  :op2 (c3 / cell-line :name (n2 / name :op1 "M792"))
                  :ARG0-of (s / sensitive-03))
            :ARG2 (o / or
                  :op1 (s2 / small-molecule :name (n5 / name :op1 "DMSO")
                        :ARG0-of (c5 / control-01
                              :ARG1 (v / vehicle)
                              :ARG1-of (m / mean-01
                                    :ARG2 (a2 / and
                                          :op1 (s3 / stain-01
                                                :ARG1 c5)
                                          :op2 (s8 / stain-01 :polarity -
                                                :ARG1 c5)))))
                  :op2 (s4 / small-molecule :name (n7 / name :op1 "vemurafenib")
                        :quant (c7 / concentration-quantity :quant 1
                              :unit (m2 / micromolar)))
                  :op3 (s6 / small-molecule :name (n9 / name :op1 "SCH722984")
                        :ARG0-of (i / inhibit-01
                              :ARG1 (p / protein-family :name (n6 / name :op1 "ERK"))))
                  :op4 (c8 / combine-01
                        :ARG1 s4
                        :ARG2 s6
                        :ARG1-of (l / label-01
                              :ARG2 (s5 / string-entity :value "V+E")))
                  :op5 (s7 / small-molecule :name (n10 / name :op1 "staurosporine")
                        :quant (c9 / concentration-quantity :quant 1
                              :unit (m3 / micromolar))))
            :duration (t2 / temporal-quantity :quant 48
                  :unit (h2 / hour)))
      :op2 (e3 / expose-01
            :ARG1 (a3 / and
                  :op1 (c / cell-line :name (n3 / name :op1 "M233"))
                  :op2 (c4 / cell-line :name (n4 / name :op1 "M299"))
                  :ARG0-of (r / resist-01))
            :ARG2 (o2 / or
                  :op1 s2
                  :op2 s4
                  :op3 s6
                  :op4 c8
                  :op5 s7)
            :duration t2))

# ::id a_pmid_2514_2146.224 ::date 2015-06-14T03:37:23 ::annotator SDL-AMR-09 ::preferred
# ::snt <bold>A</bold>.
# ::save-date Fri Oct 23, 2015 ::file a_pmid_2514_2146_224.txt
(h / have-li-91
      :ARG2 "A")

# ::id a_pmid_2514_2146.225 ::date 2015-06-14T03:41:22 ::annotator SDL-AMR-09 ::preferred
# ::snt Cell cycle progression was tested by DAPI staining solution and induced apoptosis by cleaved PARP (PARP-Ax700).
# ::save-date Fri Feb 12, 2016 ::file a_pmid_2514_2146_225.txt
(a / and
      :op1 (t / test-01
            :ARG0 (s / solution
                  :mod (s2 / stain-01
                        :ARG2 (s3 / small-molecule :name (n4 / name :op1 "DAPI"))))
            :ARG1 (p / progress-01
                  :ARG1 (c / cycle-02
                        :ARG1 (c2 / cell))))
      :op2 (i / induce-01
            :ARG0 p
            :ARG2 (a2 / apoptosis)
            :instrument (p2 / protein :name (n2 / name :op1 "PARP")
                  :ARG1-of (c3 / cleave-01)
                  :ARG1-of (e / equal-01
                        :ARG2 (p3 / protein :name (n3 / name :op1 "PARP")
                              :mod (s4 / small-molecule :name (n5 / name :op1 "Ax700")))))))

# ::id a_pmid_2514_2146.226 ::date 2015-06-14T03:48:25 ::annotator SDL-AMR-09 ::preferred
# ::snt Figures are representative of triplicate experiments.
# ::save-date Sun Jun 14, 2015 ::file a_pmid_2514_2146_226.txt
(r2 / represent-01
      :ARG0 (f / figure)
      :ARG1 (e / experiment :quant 3))

# ::id a_pmid_2514_2146.227 ::date 2015-06-14T03:54:47 ::annotator SDL-AMR-09 ::preferred
# ::snt <bold>B</bold>.
# ::save-date Fri Oct 23, 2015 ::file a_pmid_2514_2146_227.txt
(h / have-li-91
      :ARG2 "B")

# ::id a_pmid_2514_2146.228 ::date 2015-06-14T03:55:13 ::annotator SDL-AMR-09 ::preferred
# ::snt Quantitative analysis of the cell cycle progression by DAPI staining using flow cytometry shows the percentage of cells in sub-G0 (blue), G0/G1 (red), S phase (yellow), or G2/M (green).
# ::save-date Fri Feb 12, 2016 ::file a_pmid_2514_2146_228.txt
(s / show-01
      :ARG0 (a / analyze-01
            :ARG1 (p / progress-01
                  :ARG1 (c / cycle-02
                        :ARG1 (c2 / cell))
                  :instrument (s2 / stain-01
                        :ARG2 (s5 / small-molecule :name (n / name :op1 "DAPI"))
                        :ARG0-of (u / use-01
                              :ARG1 (c3 / cytometry
                                    :mod (f / flow)))))
            :mod (q / quantitative))
      :ARG1 (o / or
            :op1 (p2 / percentage
                  :quant-of (c4 / cell
                        :ARG1-of (c5 / color-01
                              :ARG2 (b / blue))
                        :mod (e / event :name (n2 / name :op1 "sub-G0"))))
            :op2 (p3 / percentage
                  :quant-of (c6 / cell
                        :ARG1-of (c7 / color-01
                              :ARG2 (r / red-02))
                        :mod (s3 / slash
                              :op1 (e2 / event :name (n6 / name :op1 "G0"))
                              :op2 (e3 / event :name (n7 / name :op1 "G1")))))
            :op3 (p4 / percentage
                  :quant-of (c8 / cell
                        :ARG1-of (c9 / color-01
                              :ARG2 (y / yellow-02))
                        :mod (e4 / event :name (n5 / name :op1 "S" :op2 "phase"))))
            :op4 (p5 / percentage
                  :quant-of (c10 / cell
                        :ARG1-of (c11 / color-01
                              :ARG2 (g / green-02))
                        :mod (s4 / slash
                              :op1 (e5 / event :name (n3 / name :op1 "G2"))
                              :op2 (e6 / event :name (n8 / name :op1 "M")))))))

# ::id a_pmid_2514_2146.229 ::date 2015-06-14T04:05:29 ::annotator SDL-AMR-09 ::preferred
# ::snt Numbers on the bar graph represent percentage of cells in G0/G1.
# ::save-date Sun Jan 3, 2016 ::file a_pmid_2514_2146_229.txt
(r / represent-01
      :ARG0 (n / number
            :mod (g / graph
                  :mod (b / bar)))
      :ARG1 (p / percentage
            :quant-of (c / cell)
            :mod (s / slash
                  :op1 (e / event :name (n2 / name :op1 "G0"))
                  :op2 (e2 / event :name (n3 / name :op1 "G1")))))

# ::id a_pmid_2514_2146.230 ::date 2015-06-14T04:08:39 ::annotator SDL-AMR-09 ::preferred
# ::snt Columns represent mean values of three independent experiments (n = 3); bars, SEM.
# ::save-date Sat Jan 30, 2016 ::file a_pmid_2514_2146_230.txt
(a / and
      :op1 (r / represent-01
            :ARG0 (c / column)
            :ARG1 (v / value
                  :mod (m / mean)
                  :poss (e / experiment :quant 3
                        :ARG0-of (d / depend-01 :polarity -)))
            :ARG1-of (m2 / mean-01
                  :ARG2 (e2 / equal-01
                        :ARG1 (v2 / variable :name (n / name :op1 "n"))
                        :ARG2 3)))
      :op2 (b / bar)
      :op3 (m3 / mean
            :mod (e3 / error
                  :ARG1-of (s / standard-02))))

# ::id a_pmid_2514_2146.231 ::date 2015-06-14T04:15:19 ::annotator SDL-AMR-09 ::preferred
# ::snt <bold>C</bold>.
# ::save-date Sun Jan 3, 2016 ::file a_pmid_2514_2146_231.txt
(s / string-entity :value "C")

# ::id a_pmid_2514_2146.232 ::date 2015-06-14T04:15:39 ::annotator SDL-AMR-09 ::preferred
# ::snt Apoptosis in response to MAPK inhibitors.
# ::save-date Sun Jan 17, 2016 ::file a_pmid_2514_2146_232.txt
(r / respond-01
      :ARG1 (m / molecular-physical-entity
            :ARG0-of (i / inhibit-01
                  :ARG1 (p / protein-family :name (n3 / name :op1 "MAPK"))))
      :ARG2 (a / apoptosis))

# ::id a_pmid_2514_2146.233 ::date 2015-06-14T04:19:53 ::annotator SDL-AMR-09 ::preferred
# ::snt Percentage of apoptotic cells positive for cleaved PARP (PARP-Ax700) in this four melanoma cell lines.
# ::save-date Fri Feb 12, 2016 ::file a_pmid_2514_2146_233.txt
(p6 / percentage
      :quant-of (c / cell
            :mod (p5 / positive
                  :topic (p3 / protein :name (n2 / name :op1 "PARP")
                        :ARG1-of (c2 / cleave-01
                              :ARG2 (p4 / protein :name (n3 / name :op1 "PARP")
                                    :mod (s / small-molecule :name (n5 / name :op1 "Ax700"))))))
            :mod (a / apoptosis))
      :location (c3 / cell-line :quant 4
            :mod (m2 / medical-condition :name (n4 / name :op1 "melanoma"))
            :mod (t2 / this)))

# ::id a_pmid_2514_2146.234 ::date 2015-06-14T04:26:25 ::annotator SDL-AMR-09 ::preferred
# ::snt Columns represent mean values of three independent experiments (n = 3); bars, SEM; *, P < 0.05.</p></caption><graphic /></fig>
# ::save-date Mon Dec 21, 2015 ::file a_pmid_2514_2146_234.txt
(a / and
      :op1 (r / represent-01
            :ARG0 (c / column)
            :ARG1 (v / value
                  :mod (m / mean)
                  :poss (e / experiment :quant 3
                        :ARG0-of (d / depend-01 :polarity -))))
      :op2 (b / bar)
      :op3 (m2 / mean-01
            :mod (e2 / error
                  :ARG1-of (s / standard-02)))
      :op3 (s2 / statistical-test-91
            :ARG2 (l / less-than :op1 0.05)))

# ::id a_pmid_2514_2146.235 ::date 2015-06-14T04:29:49 ::annotator SDL-AMR-09 ::preferred
# ::snt To address whether there are differences in MEK inhibition or ERK inhibition on apoptosis, we performed cell cycle analysis on three melanoma cell lines with distinct sensitivity profile to SCH772984: M263 (sensitive), M255 (intermediately sensitive) and M370 (resistant).
# ::save-date Sat Jan 16, 2016 ::file a_pmid_2514_2146_235.txt
(p / perform-01
      :ARG0 (w / we)
      :ARG1 (a / analyze-01
            :ARG0 w
            :ARG1 (c / cycle-02
                  :ARG1 (c2 / cell))
            :location (c3 / cell-line :quant 3
                  :mod (m2 / medical-condition :name (n3 / name :op1 "melanoma"))
                  :ARG0-of (h / have-03
                        :ARG1 (p2 / profile-01
                              :ARG1 (s / sensitive-03
                                    :ARG0 c3
                                    :ARG1 (s2 / small-molecule :name (n4 / name :op1 "SCH772984"))
                                    :mod (d2 / distinct))))
                  :ARG1-of (m / mean-01
                        :ARG2 (a2 / and
                              :op1 (c4 / cell-line :name (n5 / name :op1 "M263")
                                    :ARG0-of (s3 / sensitive-03
                                          :ARG1 s2))
                              :op2 (c5 / cell-line :name (n6 / name :op1 "M255")
                                    :ARG0-of (s4 / sensitive-03
                                          :ARG1 s2
                                          :mod (i / intermediate)))
                              :op3 (c6 / cell-line :name (n7 / name :op1 "M370")
                                    :ARG0-of (r / resist-01
                                          :ARG1 s2))))))
      :purpose (a3 / address-02
            :ARG0 w
            :ARG1 (d3 / differ-02 :mode interrogative
                  :ARG1 (i2 / inhibit-01
                        :ARG1 (e / enzyme :name (n / name :op1 "MEK")))
                  :ARG2 (i3 / inhibit-01
                        :ARG1 (e2 / enzyme :name (n2 / name :op1 "ERK")))
                  :ARG3 (a4 / apoptosis))))

# ::id a_pmid_2514_2146.236 ::date 2015-06-14T04:43:33 ::annotator SDL-AMR-09 ::preferred
# ::snt All three cell lines demonstrated good synergy for the combination of vemurafenib and SCH772984.
# ::save-date Tue Feb 2, 2016 ::file a_pmid_2514_2146_236.txt
(d / demonstrate-01
      :ARG0 (c / cell-line :quant 3
            :mod (a / all))
      :ARG1 (s / synergize-01
            :ARG1-of (g / good-02))
      :condition (c2 / combine-01
            :ARG1 (s3 / small-molecule :name (n / name :op1 "vemurafenib"))
            :ARG2 (s2 / small-molecule :name (n2 / name :op1 "SCH772984"))))

# ::id a_pmid_2514_2146.237 ::date 2015-06-14T04:53:50 ::annotator SDL-AMR-09 ::preferred
# ::snt Cell lines treated with SCH772984 or the combination of vemurafenib + SCH772984 had the highest levels of cleaved PARP.
# ::save-date Mon Dec 21, 2015 ::file a_pmid_2514_2146_237.txt
(h2 / have-03
      :ARG0 (c / cell-line
            :ARG1-of (t / treat-04
                  :ARG2 (o / or
                        :op1 (s / small-molecule :name (n / name :op1 "SCH772984"))
                        :op2 (c2 / combine-01
                              :ARG1 (s2 / small-molecule :name (n2 / name :op1 "vemurafenib"))
                              :ARG2 s))))
      :ARG1 (l / level
            :ARG1-of (h / high-02
                  :degree (m / most))
            :quant-of (p / protein :name (n3 / name :op1 "PARP")
                  :ARG1-of (c3 / cleave-01))))

# ::id a_pmid_2514_2146.238 ::date 2015-06-14T04:58:07 ::annotator SDL-AMR-09 ::preferred
# ::snt In comparison, trametinib, did not induce the same levels of apoptosis in any case.
# ::save-date Sat Jan 30, 2016 ::file a_pmid_2514_2146_238.txt
(c / compare-01
      :ARG2 (i / induce-01 :polarity -
            :ARG0 (s2 / small-molecule :name (n / name :op1 "trametinib"))
            :ARG2 (l / level
                  :ARG2-of (s / same-01)
                  :degree-of (a2 / apoptosis))
            :prep-in (c2 / case-04
                  :mod (a / any))))

# ::id a_pmid_2514_2146.239 ::date 2015-06-14T05:03:37 ::annotator SDL-AMR-09 ::preferred
# ::snt In terms of effects on the cell cycle, G0-G1 arrest was maximally induced by ERK inhibition also (Additional file <xref ref-type="media" rid="MOESM6">6</xref>: Figure S6).
# ::save-date Sat Jan 16, 2016 ::file a_pmid_2514_2146_239.txt
(a3 / affect-01
      :ARG1 (c / cycle-02
            :ARG1 (c2 / cell))
      :ARG2 (i / induce-01
            :ARG0 (i2 / inhibit-01
                  :ARG1 (e / enzyme :name (n / name :op1 "ERK")))
            :ARG2 (a / arrest-02
                  :time (v / value-interval
                        :op1 (e2 / event :name (n2 / name :op1 "G0"))
                        :op2 (e3 / event :name (n3 / name :op1 "G1"))))
            :mod (a2 / also)
            :manner (m / maximal))
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod "S6"
                  :location (f2 / file :mod 6
                        :ARG1-of (a4 / add-02)))))

# ::id a_pmid_2514_2146.240 ::date 2015-06-14T05:11:13 ::annotator SDL-AMR-09 ::preferred
# ::snt This data support the potent activity of SCH772984 both as a single agent and in combination.
# ::save-date Mon Dec 21, 2015 ::file a_pmid_2514_2146_240.txt
(s / support-01
      :ARG0 (d / data
            :mod (t / this))
      :ARG1 (a / activity-06
            :ARG0 (a2 / and
                  :op1 (s2 / small-molecule :name (n / name :op1 "SCH772984")
                        :mod (a3 / agent
                              :ARG1-of (s3 / single-02)))
                  :op2 (c / combine-01
                        :ARG1 s2))
            :mod (p / potent)))

# ::id a_pmid_2514_2146.241 ::date 2015-06-14T05:15:34 ::annotator SDL-AMR-09 ::preferred
# ::snt Combining BRAF and ERK inhibition delays the development of resistance
# ::save-date Sat Jan 16, 2016 ::file a_pmid_2514_2146_241.txt
(d / delay-01
      :ARG0 (c / combine-01
            :ARG1 (i / inhibit-01
                  :ARG1 (e / enzyme :name (n2 / name :op1 "BRAF")))
            :ARG2 (i2 / inhibit-01
                  :ARG1 (e2 / enzyme :name (n / name :op1 "ERK"))))
      :ARG1 (d2 / develop-01
            :ARG2 (r / resist-01)))

# ::id a_pmid_2514_2146.242 ::date 2015-06-14T05:33:13 ::annotator SDL-AMR-09 ::preferred
# ::snt Given the potent synergistic inhibition seen when combining vemurafenib and SCH772984, we hypothesized that chronic exposure to dual inhibition would significantly delay the development of resistance compared to either single agent alone.
# ::save-date Tue Feb 2, 2016 ::file a_pmid_2514_2146_242.txt
(h / hypothesize-01
      :ARG0 (w / we)
      :ARG1 (d2 / delay-01
            :ARG0 (e / expose-01
                  :ARG2 (i / inhibit-01
                        :mod (d / dual))
                  :mod (c / chronic))
            :ARG1 (d3 / develop-01
                  :ARG2 (r / resist-01))
            :ARG1-of (s / significant-02
                  :compared-to (a / agent
                        :mod (e3 / either)
                        :ARG1-of (s5 / single-02))))
      :ARG1-of (c2 / cause-01
            :ARG0 (i2 / inhibit-01
                  :ARG0-of (s2 / synergize-01)
                  :mod (p / potent)
                  :ARG1-of (s3 / see-01
                        :time (c3 / combine-01
                              :ARG1 (s6 / small-molecule :name (n / name :op1 "vemurafenib"))
                              :ARG2 (s4 / small-molecule :name (n2 / name :op1 "SCH772984")))))))

# ::id a_pmid_2514_2146.243 ::date 2015-06-14T05:46:37 ::annotator SDL-AMR-09 ::preferred
# ::snt To test this hypothesis, long term cultures were established in 96-well plates to allow both qualitative and quantitative assessment of the effect of each drug alone or their combination on M238 and M792, which are highly sensitive to both inhibitors and for which dual therapy was highly synergistic (Figure <xref ref-type="fig" rid="Fig7">7</xref>A).
# ::save-date Tue Feb 2, 2016 ::file a_pmid_2514_2146_243.txt
(e / establish-01
      :ARG1 (c / culture
            :ARG1-of (l / long-03))
      :location (p / plate :quant 96
            :mod (w / well))
      :purpose (a / allow-01
            :ARG1 (a8 / and
                  :op1 (a2 / assess-01
                        :ARG1 (a4 / affect-01
                              :ARG0 (o / or
                                    :op1 (d / drug
                                          :mod (e2 / each)
                                          :mod (a5 / alone))
                                    :op2 (c2 / combine-01
                                          :ARG1 d
                                          :ARG2 d))
                              :ARG1 (a6 / and
                                    :op1 (c3 / cell-line :name (n / name :op1 "M238"))
                                    :op2 (c4 / cell-line :name (n2 / name :op1 "M792"))
                                    :ARG0-of (s / sensitive-03
                                          :ARG1 (m / molecular-physical-entity
                                                :ARG0-of (i2 / inhibit-01)
                                                :mod (b / both)))
                                    :ARG0-of (h2 / have-03
                                          :ARG1 (t3 / therapy
                                                :mod (d2 / dual)
                                                :ARG0-of (s2 / synergize-01
                                                      :ARG1-of (h3 / high-02))))))
                        :mod (q / qualitative))
                  :op2 (a9 / assess-01
                        :ARG1 a4
                        :mod (q2 / quantitative))))
      :purpose (t4 / test-01
            :ARG1 (h / hypothesize-01
                  :mod (t5 / this)))
      :ARG1-of (d3 / describe-01
            :ARG0 (f / figure :mod "7A")))

# ::id a_pmid_2514_2146.244 ::date 2015-06-14T06:08:25 ::annotator SDL-AMR-09 ::preferred
# ::snt Treatment with 500nM vemurafenib initially suppressed growth of M238 and M792, however, by 42 days of treatment, several wells were confluent and cells had normal morphology, indicating development of BRAFi-resistance.
# ::save-date Fri Feb 5, 2016 ::file a_pmid_2514_2146_244.txt
(h / have-concession-91
      :ARG1 (a2 / and
            :op1 (c4 / confluent
                  :domain (w / well
                        :quant (s2 / several)))
            :op2 (h2 / have-03
                  :ARG0 (c5 / cell)
                  :ARG1 (m / morphology
                        :ARG1-of (n5 / normal-02)))
            :ARG0-of (i2 / indicate-01
                  :ARG1 (d2 / develop-01
                        :ARG2 (r / resist-01
                              :ARG1 (m2 / molecular-physical-entity
                                    :ARG0-of (i3 / inhibit-01
                                          :ARG1 (e / enzyme :name (n6 / name :op1 "BRAF")))))))
            :time (a3 / after
                  :op1 (t4 / treat-04)
                  :quant (t3 / temporal-quantity :quant 42
                        :unit (d3 / day))))
      :ARG2 (s / suppress-01
            :ARG0 (t2 / treat-04
                  :ARG2 (s3 / small-molecule :name (n / name :op1 "vemurafenib")
                        :quant (c / concentration-quantity :quant 500
                              :unit (n2 / nanomolar))))
            :ARG1 (g / grow-01
                  :ARG1 (a / and
                        :op1 (c2 / cell-line :name (n3 / name :op1 "M238"))
                        :op2 (c3 / cell-line :name (n4 / name :op1 "M792"))))
            :time (i / initial)))

# ::id a_pmid_2514_2146.245 ::date 2015-06-14T06:17:35 ::annotator SDL-AMR-09 ::preferred
# ::snt In contrast, very few cells were seen in plates treated with ERKi alone or in combination at 42 days (Figure <xref ref-type="fig" rid="Fig7">7</xref>B).
# ::save-date Mon Jan 4, 2016 ::file a_pmid_2514_2146_245.txt
(c / contrast-01
      :ARG2 (s / see-01
            :ARG1 (c2 / cell
                  :mod (f / few
                        :mod (v / very)))
            :location (p / plate
                  :ARG1-of (t2 / treat-04
                        :ARG2 (o / or
                              :op1 (m / molecular-physical-entity
                                    :mod (a / alone)
                                    :ARG0-of (i / inhibit-01
                                          :ARG1 (p2 / protein-family :name (n / name :op1 "ERK"))))
                              :op2 (c3 / combine-01
                                    :ARG1 m))))
            :time (a2 / after
                  :quant (t3 / temporal-quantity :quant 42
                        :unit (d2 / day))))
      :ARG1-of (d3 / describe-01
            :ARG0 (f2 / figure :mod "7B")))

# ::id a_pmid_2514_2146.246 ::date 2015-06-14T06:22:24 ::annotator SDL-AMR-09 ::preferred
# ::snt For ERKi-treated M792 plates, confluent wells were not seen until 84 days.
# ::save-date Sun Jun 21, 2015 ::file a_pmid_2514_2146_246.txt
(s / see-01 :polarity -
      :ARG1 (w / well
            :mod (c / confluent))
      :time (u / until
            :quant (t2 / temporal-quantity :quant 84
                  :unit (d2 / day)))
      :location (p / plate
            :part (c2 / cell-line :name (n / name :op1 "M792"))
            :ARG1-of (t3 / treat-04
                  :ARG2 (e / enzyme :name (n2 / name :op1 "ERKi")))))

# ::id a_pmid_2514_2146.247 ::date 2015-06-14T06:26:12 ::annotator SDL-AMR-09 ::preferred
# ::snt When cell viability was quantified at day 44 for BRAFi-treated cells, over 90% of the wells had >10,000 viable cells.
# ::save-date Sun Jan 17, 2016 ::file a_pmid_2514_2146_247.txt
(h / have-03
      :ARG0 (w / well
            :ARG1-of (i / include-91
                  :ARG2 (w2 / well))
            :quant (o2 / over
                  :op1 (p / percentage-entity :value 90)))
      :ARG1 (c / cell
            :mod (v / viable)
            :quant (m / more-than :op1 10000))
      :time (q / quantify-01
            :ARG1 (v2 / viable
                  :domain (c2 / cell))
            :time (a / after
                  :quant (t / temporal-quantity :quant 44
                        :unit (d / day)))
            :beneficiary (c3 / cell
                  :ARG1-of (t2 / treat-04
                        :ARG2 (m2 / molecular-physical-entity
                              :ARG0-of (i2 / inhibit-01
                                    :ARG1 (e / enzyme :name (n / name :op1 "BRAF"))))))))

# ::id a_pmid_2514_2146.248 ::date 2015-06-14T06:37:23 ::annotator SDL-AMR-09 ::preferred
# ::snt In contrast, many fewer viable cells were seen for M792 treated with ERKi alone or in combination with BRAFi measured at day 84.
# ::save-date Sun Jan 17, 2016 ::file a_pmid_2514_2146_248.txt
(c / contrast-01
      :ARG2 (s / see-01
            :ARG1 (c2 / cell
                  :mod (f / few
                        :mod (m / more)
                        :mod (m2 / many))
                  :mod (v / viable))
            :location (c3 / cell-line :name (n / name :op1 "M792")
                  :ARG1-of (t / treat-04
                        :ARG2 (o / or
                              :op1 (e / enzyme :name (n2 / name :op1 "ERKi")
                                    :mod (a / alone))
                              :op2 (c4 / combine-01
                                    :ARG1 e
                                    :ARG2 (m4 / molecular-physical-entity
                                          :ARG0-of (i / inhibit-01
                                                :ARG1 (e2 / enzyme :name (n3 / name :op1 "BRAF")))))))
                  :ARG1-of (m3 / measure-01
                        :time (a2 / after
                              :quant (t2 / temporal-quantity :quant 84
                                    :unit (d / day)))))))

# ::id a_pmid_2514_2146.249 ::date 2015-06-14T06:42:56 ::annotator SDL-AMR-09 ::preferred
# ::snt Only 20% of the wells treated with ERKi alone and <5% of wells treated with the combination had >10,000 cells (Figure <xref ref-type="fig" rid="Fig7">7</xref>C).
# ::save-date Sun Jun 21, 2015 ::file a_pmid_2514_2146_249.txt
(h / have-03
      :ARG0 (a / and
            :op1 (w / well
                  :quant (p2 / percentage-entity :value 20
                        :ARG1-of (i / include-91
                              :ARG2 (w2 / well
                                    :ARG1-of (t / treat-04
                                          :ARG2 (e / enzyme :name (n / name :op1 "ERKi")
                                                :mod (a2 / alone))))))
                  :mod (o2 / only))
            :op2 (w3 / well
                  :quant (l / less-than
                        :op1 (p3 / percentage-entity :value 5))
                  :ARG1-of (i2 / include-91
                        :ARG2 (w4 / well
                              :ARG1-of (t2 / treat-04
                                    :ARG2 (c / combine-01
                                          :ARG1 e))))))
      :ARG1 (c2 / cell
            :quant (m / more-than :op1 10000))
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod "7C")))

# ::id a_pmid_2514_2146.250 ::date 2015-06-14T06:49:59 ::annotator SDL-AMR-09 ::preferred
# ::snt For M238, similar data were seen, though in this case, treatment with 500nM ERKi alone delayed the development of resistance until 140 days.
# ::save-date Sat Jan 30, 2016 ::file a_pmid_2514_2146_250.txt
(s / see-01
      :ARG1 (d / data
            :ARG2-of (r2 / resemble-01))
      :location (c / cell-line :name (n / name :op1 "M238"))
      :concession (d3 / delay-01
                  :ARG0 (t2 / treat-04
                        :ARG2 (e / enzyme :name (n2 / name :op1 "ERKi")
                              :quant (c2 / concentration-quantity :quant 500
                                    :unit (n3 / nanomolar))
                              :mod (a / alone)))
                  :ARG1 (d4 / develop-01
                        :ARG2 (r3 / resist-01))
                  :ARG2 (u / until
                        :quant (t3 / temporal-quantity :quant 140
                              :unit (d5 / day)))
                  :condition (c3 / case-04
                        :ARG1 (t4 / this))))

# ::id a_pmid_2514_2146.251 ::date 2015-06-14T07:33:27 ::annotator SDL-AMR-09 ::preferred
# ::snt Most strikingly, for M238, 280 days, twice that for SCH772984 alone, were required for resistance to the combination of vemurafenib and SCH772984 to develop (Figure <xref ref-type="fig" rid="Fig7">7</xref>D).
# ::save-date Mon Jun 22, 2015 ::file a_pmid_2514_2146_251.txt
(r / require-01
      :ARG0 (d3 / develop-01
            :ARG1 (c / cell-line :name (n / name :op1 "M238"))
            :ARG2 (r3 / resist-01
                  :ARG1 (c2 / combine-01
                        :ARG1 (s3 / small-molecule :name (n3 / name :op1 "vemurafenib"))
                        :ARG2 s)))
      :ARG1 (t2 / temporal-quantity :quant 280
            :unit (d2 / day)
            :ARG1-of (e / equal-01
                  :ARG2 (p / product-of :op1 2
                        :op2 (t / temporal-quantity
                              :ARG1-of (r2 / require-01
                                    :ARG0 (s / small-molecule :name (n2 / name :op1 "SCH772984")
                                          :mod (a / alone)))))))
      :ARG1-of (s2 / strike-04
            :degree (m2 / most))
      :ARG1-of (d4 / describe-01
            :ARG0 (f / figure :mod "7D")))

# ::id a_pmid_2514_2146.252 ::date 2015-06-14T07:47:36 ::annotator SDL-AMR-09 ::preferred
# ::snt Taken together, these data provide preliminary <i>in vitro</i> evidence that SCH772984 may more potently and more durably inhibit <i>BRAF</i>-mutant melanoma compared to single agent vemurafenib, and that the combination of BRAF and ERK inhibition results in better inhibition than either alone.
# ::save-date Sat Jan 16, 2016 ::file a_pmid_2514_2146_252.txt
(p / provide-01
      :ARG0 (d2 / data
            :mod (t / this)
            :ARG1-of (t2 / take-01
                  :manner (t3 / together)))
      :ARG1 (e2 / evidence-01
            :ARG1 (a2 / and
                  :op1 (p3 / possible-01
                        :ARG1 (i2 / inhibit-01
                              :ARG0 (s3 / small-molecule :name (n / name :op1 "SCH772984"))
                              :ARG1 (m5 / medical-condition :name (n2 / name :op1 "melanoma")
                                    :mod (g2 / gene :name (n3 / name :op1 "BRAF")
                                          :ARG2-of (m4 / mutate-01)))
                              :mod (p4 / potent
                                    :degree (m2 / more)
                                    :compared-to (i3 / inhibit-01
                                          :ARG0 (s2 / small-molecule :name (n4 / name :op1 "vemurafenib")
                                                :ARG1-of (s / single-02)
                                                :mod (a / agent))))
                              :mod (d3 / durable
                                    :degree (m3 / more))))
                  :op2 (r / result-01
                        :ARG1 (c / combine-01
                              :ARG1 (i4 / inhibit-01
                                    :ARG1 (e / enzyme :name (n5 / name :op1 "BRAF")))
                              :ARG2 (i5 / inhibit-01
                                    :ARG1 (e3 / enzyme :name (n6 / name :op1 "ERK"))))
                        :ARG2 (i6 / inhibit-01
                              :ARG1-of (g / good-02
                                    :degree (m / more)
                                    :compared-to (i7 / inhibit-01
                                          :ARG0 (o / or
                                                :op1 e
                                                :op2 e3)
                                          :mod (a3 / alone))))))
            :mod (p2 / preliminary)
            :mod (i / in-vitro)))

# ::id a_pmid_2514_2146.253 ::date 2015-06-14T07:59:49 ::annotator SDL-AMR-09 ::preferred
# ::snt These data are intriguing and should be further validated <i>in vivo</i>.<fig id="Fig7"><label>Figure 7</label><caption><p><bold>Effect of combined MAPK inhibition on long-term melanoma cultures.</bold>
# ::save-date Thu Dec 10, 2015 ::file a_pmid_2514_2146_253.txt
(m / multi-sentence
      :snt1 (a / and
            :op1 (i / intrigue-01
                  :ARG0 (d / data
                        :mod (t / this)))
            :op2 (r2 / recommend-01
                  :ARG1 (v / validate-01
                        :ARG1 d
                        :manner (f / further)
                        :manner (i2 / in-vivo)))
            :ARG1-of (d2 / describe-01
                  :ARG0 (f2 / figure :mod 7)))
      :snt2 (a2 / affect-01
            :ARG0 (i3 / inhibit-01
                  :ARG1 (p / pathway :name (n / name :op1 "MAPK"))
                  :ARG1-of (c / combine-01))
            :ARG1 (c2 / culture-01
                  :ARG1 (m2 / medical-condition :name (n2 / name :op1 "melanoma"))
                  :ARG1-of (l / long-03))))

# ::id a_pmid_2514_2146.254 ::date 2015-06-14T08:06:35 ::annotator SDL-AMR-09 ::preferred
# ::snt M238 and M792, two MAPK inhibitor-sensitive cell lines, were chronically exposed to 500nM of Vemurafenib (V), SCH722984 (E) or combination (V + E) in 96-well plates.
# ::save-date Sun Jan 17, 2016 ::file a_pmid_2514_2146_254.txt
(e / expose-01
      :ARG1 (a / and
            :op1 (c2 / cell-line :name (n2 / name :op1 "M238"))
            :op2 (c3 / cell-line :name (n3 / name :op1 "M792"))
            :ARG0-of (s / sensitive-03
                  :ARG1 (m / molecular-physical-entity
                        :ARG0-of (i / inhibit-01
                              :ARG1 (p / protein-family :name (n / name :op1 "MAPK"))))))
      :ARG2 (o / or
            :op1 (s3 / small-molecule :name (n4 / name :op1 "Vemurafenib")
                  :quant (c4 / concentration-quantity :quant 500
                        :unit (n5 / nanomolar)))
            :op2 (s2 / small-molecule :name (n6 / name :op1 "SCH722984"))
            :op3 (c5 / combine-01
                  :ARG1 s3
                  :ARG2 s2))
      :manner (c / chronic)
      :location (p2 / plate :quant 96
            :mod (w / well)))

# ::id a_pmid_2514_2146.255 ::date 2015-06-14T08:12:39 ::annotator SDL-AMR-09 ::preferred
# ::snt <bold>A</bold>.
# ::save-date Fri Oct 23, 2015 ::file a_pmid_2514_2146_255.txt
(h / have-li-91
      :ARG2 "A")

# ::id a_pmid_2514_2146.256 ::date 2015-06-14T08:13:07 ::annotator SDL-AMR-09 ::preferred
# ::snt Schematic.
# ::save-date Sun Jun 14, 2015 ::file a_pmid_2514_2146_256.txt
(s / schematic)

# ::id a_pmid_2514_2146.257 ::date 2015-06-14T08:14:07 ::annotator SDL-AMR-09 ::preferred
# ::snt For each cell line, 20,000 cells/well were plated on 96-well plates.
# ::save-date Sun Jun 14, 2015 ::file a_pmid_2514_2146_257.txt
(p / plate-00
      :ARG1 (o / or
            :op1 (c / cell :quant 20000)
            :op2 (w / well :quant 20000))
      :condition (c2 / cell-line
            :mod (e / each))
      :location (p2 / plate :quant 96
            :mod (w2 / well)))

# ::id a_pmid_2514_2146.258 ::date 2015-06-14T08:18:50 ::annotator SDL-AMR-09 ::preferred
# ::snt The following day, all cells on the plate were treated with 500nM of each drug or combination.
# ::save-date Tue Dec 15, 2015 ::file a_pmid_2514_2146_258.txt
(t / treat-04
      :ARG1 (c / cell
            :location (p / plate)
            :mod (a / all))
      :ARG2 (o / or
            :op1 (d / drug
                  :mod (e / each)
                  :quant (c2 / concentration-quantity :quant 500
                        :unit (n / nanomolar)))
            :op2 (c3 / combine-01
                  :ARG1 d))
      :time (d2 / day
            :ARG1-of (f / follow-01)))

# ::id a_pmid_2514_2146.259 ::date 2015-06-14T08:35:34 ::annotator SDL-AMR-09 ::preferred
# ::snt Fresh media containing the appropriate inhibitor(s) was added weekly.
# ::save-date Mon Dec 21, 2015 ::file a_pmid_2514_2146_259.txt
(a / add-02
      :ARG1 (m / medium
            :ARG1-of (f / fresh-04)
            :ARG0-of (c / contain-01
                  :ARG1 (m2 / molecular-physical-entity
                        :ARG0-of (i / inhibit-01)
                        :ARG1-of (a2 / appropriate-02))))
      :frequency (r / rate-entity-91
            :ARG1 1
            :ARG2 (t / temporal-quantity :quant 1
                  :unit (w / week))))

# ::id a_pmid_2514_2146.260 ::date 2015-06-14T08:42:36 ::annotator SDL-AMR-09 ::preferred
# ::snt When cells in several wells were confluent, viable cells were quantified by MTS assay and cell numbers were determined by comparing with a standard curve of known cell numbers.
# ::save-date Fri Feb 12, 2016 ::file a_pmid_2514_2146_260.txt
(a2 / and
      :op1 (q / quantify-01
            :ARG0 (a / assay-01
                  :instrument (s3 / small-molecule :name (n / name :op1 "MTS")))
            :ARG1 (c / cell
                  :mod (v / viable)))
      :op2 (d / determine-01
            :ARG1 (n2 / number
                  :quant-of (c2 / cell))
            :instrument (c3 / compare-01
                  :ARG1 n2
                  :ARG2 (c4 / curve
                        :ARG1-of (s / standard-02)
                        :quant-of (n3 / number
                              :mod (c5 / cell)
                              :ARG1-of (k / know-01)))))
      :time (c6 / confluent
            :domain (c7 / cell
                  :location (w / well
                        :quant (s2 / several)))))

# ::id a_pmid_2514_2146.261 ::date 2015-06-14T08:48:36 ::annotator SDL-AMR-09 ::preferred
# ::snt <bold>B</bold>.
# ::save-date Fri Oct 23, 2015 ::file a_pmid_2514_2146_261.txt
(h / have-li-91
      :ARG2 "B")

# ::id a_pmid_2514_2146.262 ::date 2015-06-14T08:49:00 ::annotator SDL-AMR-09 ::preferred
# ::snt Microscopic imaging of treated M238 cells photographed at 14 days (top) or 44 days (bottom) of treatment.
# ::save-date Mon Dec 21, 2015 ::file a_pmid_2514_2146_262.txt
(i / image-101
      :ARG1 (a3 / and
            :op1 (c / cell-line :name (n / name :op1 "M238")
                  :ARG1-of (t3 / treat-04)
                  :ARG1-of (p / photograph-01
                        :time (a / after
                              :op1 (t7 / treat-04)
                              :quant (t4 / temporal-quantity :quant 14
                                    :unit (d3 / day))))
                  :location (t5 / top))
            :op2 (c2 / cell-line :name (n2 / name :op1 "M238")
                  :ARG1-of t3
                  :ARG1-of (p2 / photograph-01
                        :time (a2 / after
                              :op1 (t / treat-04)
                              :quant (t6 / temporal-quantity :quant 44
                                    :unit (d4 / day))))
                  :location (b / bottom)))
      :mod (m / microscopic))

# ::id a_pmid_2514_2146.263 ::date 2015-06-14T08:57:44 ::annotator SDL-AMR-09 ::preferred
# ::snt <bold>C</bold>.
# ::save-date Fri Oct 23, 2015 ::file a_pmid_2514_2146_263.txt
(h / have-li-91
      :ARG2 "C")

# ::id a_pmid_2514_2146.264 ::date 2015-06-14T08:58:08 ::annotator SDL-AMR-09 ::preferred
# ::snt Quantitative analysis of viable cells for M792 at 44 days (V) or 84 days (E and V + E).
# ::save-date Mon Jan 4, 2016 ::file a_pmid_2514_2146_264.txt
(a / analyze-01
      :ARG1 (c / cell
            :mod (v / viable))
      :mod (q / quantitative)
      :purpose (a5 / and
            :op1 (c2 / cell-line :name (n / name :op1 "M792")
                  :ARG1-of (e / expose-01
                        :ARG2 (s2 / small-molecule :name (n2 / name :op1 "Vemurafenib"))
                        :duration (t3 / temporal-quantity :quant 44
                              :unit (d3 / day))))
            :op1 (c4 / cell-line :name (n4 / name :op1 "M792")
                  :ARG1-of (e3 / expose-01
                        :ARG2 (a3 / and
                              :op1 (s / small-molecule :name (n3 / name :op1 "SCH722984"))
                              :op2 (c3 / combine-01
                                    :ARG1 s2
                                    :ARG2 s))
                        :duration (t4 / temporal-quantity :quant 84
                              :unit (d4 / day))))))

# ::id a_pmid_2514_2146.265 ::date 2015-06-14T09:06:59 ::annotator SDL-AMR-09 ::preferred
# ::snt <bold>D</bold>.
# ::save-date Fri Oct 23, 2015 ::file a_pmid_2514_2146_265.txt
(h / have-li-91
      :ARG2 "D")

# ::id a_pmid_2514_2146.266 ::date 2015-06-14T09:07:22 ::annotator SDL-AMR-09 ::preferred
# ::snt Quantitative analysis of viable cells for M238 at 44 days (V), 140 days (E) or 280 days (V + E).
# ::save-date Mon Jan 4, 2016 ::file a_pmid_2514_2146_266.txt
(a3 / analyze-01
      :ARG1 (o2 / or
            :op1 (c / cell
                  :mod (v / viable)))
      :mod (q / quantitative)
      :purpose (a / and
            :op1 (c2 / cell-line :name (n / name :op1 "M238")
                  :ARG1-of (e / expose-01
                        :ARG2 (s2 / small-molecule :name (n2 / name :op1 "Vemurafenib"))
                        :duration (t4 / temporal-quantity :quant 44
                              :unit (d4 / day))))
            :op2 (c3 / cell-line :name (n6 / name :op1 "M238")
                  :ARG1-of (e3 / expose-01
                        :ARG2 (s / small-molecule :name (n3 / name :op1 "SCH722984"))
                        :duration (t5 / temporal-quantity :quant 140
                              :unit (d5 / day))))
            :op3 (c6 / cell-line :name (n7 / name :op1 "M238")
                  :ARG1-of (e4 / expose-01
                        :ARG2 (a6 / and
                              :op1 s2
                              :op2 s)
                        :duration (t6 / temporal-quantity :quant 280
                              :unit (d6 / day))))))

# ::id a_pmid_2514_2146.267 ::date 2015-06-14T09:19:57 ::annotator SDL-AMR-09 ::preferred
# ::snt The percentage of wells with 1–1,000 (white), 2,000-3,999 (tan), 4,000-5,999 (yellow), 6,000-7,999 (orange), 8,000-9,999 (red) and >10,000 (brown) viable cells are shown.
# ::save-date Sun Dec 20, 2015 ::file a_pmid_2514_2146_267.txt
(s / show-01
      :ARG1 (p2 / percentage
            :quant-of (w / well
                  :ARG0-of (h / have-03
                        :ARG1 (a / and
                              :op1 (c / cell
                                    :mod (v / viable)
                                    :quant (v2 / value-interval :op1 1 :op2 1000)
                                    :ARG1-of (c2 / color-01
                                          :ARG2 (w2 / white-03)))
                              :op2 (c3 / cell
                                    :mod v
                                    :quant (v3 / value-interval :op1 2000 :op2 3999)
                                    :ARG1-of (c4 / color-01
                                          :ARG2 (t / tan)))
                              :op3 (c5 / cell
                                    :mod v
                                    :quant (v4 / value-interval :op1 4000 :op2 5999)
                                    :ARG1-of (c6 / color-01
                                          :ARG2 (y / yellow-02)))
                              :op4 (c7 / cell
                                    :mod v
                                    :quant (v5 / value-interval :op1 6000 :op2 7999)
                                    :ARG1-of (c8 / color-01
                                          :ARG2 (o / orange)))
                              :op5 (c9 / cell
                                    :mod v
                                    :quant (v6 / value-interval :op1 8000 :op2 9999)
                                    :ARG1-of (c10 / color-01
                                          :ARG2 (r / red-02)))
                              :op6 (c11 / cell
                                    :mod v
                                    :quant (m / more-than :op1 10000)
                                    :ARG1-of (c12 / color-01
                                          :ARG2 (b4 / brown))))))))

# ::id a_pmid_2514_2146.268 ::date 2015-06-14T09:32:03 ::annotator SDL-AMR-09 ::preferred
# ::snt Data are representative of triplicate independent experiments.</p></caption><graphic /></fig>
# ::save-date Sun Jun 14, 2015 ::file a_pmid_2514_2146_268.txt
(r2 / represent-01
      :ARG0 (d / data)
      :ARG1 (e / experiment :quant 3
            :ARG0-of (d2 / depend-01 :polarity -)))

# ::id bel_pmid_1088_2715.4484 ::date 2015-04-16T13:40:07 ::annotator SDL-AMR-09 ::preferred
# ::snt GEF activity of Ras-GRF1 toward Ha-Ras, as defined by in vitro GDP binding and release assays, was augmented after tyrosine phosphorylation by ACK1.
# ::save-date Sun Jan 17, 2016 ::file bel_pmid_1088_2715_4484.txt
(a / augment-01
      :ARG1 (a3 / activity-06
            :ARG0 (p3 / protein :name (n3 / name :op1 "GEF"))
            :ARG1 (p2 / protein :name (n4 / name :op1 "Ras-GRF1"))
            :beneficiary (e2 / enzyme :name (n5 / name :op1 "Ha-Ras"))
            :manner (d / define-01
                  :ARG0 (a4 / and
                        :op1 (b / bind-01
                              :ARG1 (s2 / small-molecule :name (n6 / name :op1 "GDP"))
                              :manner (i / in-vitro))
                        :op2 (a5 / assay-01
                              :ARG1 (r / release-01)))
                  :ARG1 a3))
      :time (a6 / after
            :op1 (p / phosphorylate-01
                  :ARG1 (a2 / amino-acid :name (n2 / name :op1 "tyrosine"))
                  :ARG2 (e / enzyme :name (n / name :op1 "ACK1")))))

# ::id bel_pmid_1088_2715.4486 ::date 2015-04-16T14:49:15 ::annotator SDL-AMR-09 ::preferred
# ::snt Ras-GRF1 acts as a GEF for Rac when tyrosine-phosphorylated following G protein-coupled receptor stimulation.
# ::save-date Sun Jan 17, 2016 ::file bel_pmid_1088_2715_4486.txt
(a / act-01
      :ARG0 (p / protein :name (n / name :op1 "Ras-GRF1"))
      :ARG1 (p2 / protein :name (n2 / name :op1 "GEF"))
      :time (p3 / phosphorylate-01
            :ARG1 (a2 / amino-acid :name (n4 / name :op1 "tyrosine")
                  :part-of p))
      :ARG1-of (f / follow-01
            :ARG2 (s2 / stimulate-01
                  :ARG1 (r / receptor
                        :ARG1-of (c / couple-01
                              :ARG2 (p4 / protein :name (n5 / name :op1 "G"))))))
      :beneficiary (e / enzyme :name (n3 / name :op1 "Rac")))

# ::id bel_pmid_1088_2715.21490 ::date 2015-04-16T11:11:33 ::annotator SDL-AMR-09 ::preferred
# ::snt We show here that activated ACK1, a nonreceptor tyrosine kinase that belongs to the focal adhesion kinase family, causes tyrosine phosphorylation of Ras-GRF1.
# ::save-date Mon Jan 4, 2016 ::file bel_pmid_1088_2715_21490.txt
(s / show-01
      :ARG0 (w / we)
      :ARG1 (c / cause-01
            :ARG0 (n5 / nonreceptor-tyrosine-kinase :name (n4 / name :op1 "ACK1")
                  :ARG0-of (b / belong-01
                        :ARG1 (p3 / protein-family :name (n3 / name :op1 "focal" :op2 "adhesion" :op3 "kinase")))
                  :ARG0-of (r / receive-01 :polarity -)
                  :ARG1-of (a2 / activate-01))
            :ARG1 (p / phosphorylate-01
                  :ARG1 (a / amino-acid :name (n / name :op1 "tyrosine")
                        :part-of (p2 / protein :name (n2 / name :op1 "Ras-GRF1")))))
      :location (h / here))

# ::id bel_pmid_1090_3731.2472 ::date 2015-04-16T11:23:52 ::annotator SDL-AMR-09 ::preferred
# ::snt Stimulation by IL-18 strongly enhanced tyrosine phosphorylation of STAT3 and of the mitogen-activated protein kinases (MAPK) p44erk-1and p42erk-2.
# ::save-date Sun Jan 17, 2016 ::file bel_pmid_1090_3731_2472.txt
(e / enhance-01
      :ARG0 (s2 / stimulate-01
            :ARG2 (p5 / protein :name (n4 / name :op1 "IL-18")))
      :ARG1 (p / phosphorylate-01
            :ARG1 (a / and
                  :op1 (a3 / amino-acid :name (n6 / name :op1 "tyrosine")
                        :part-of (p6 / protein :name (n5 / name :op1 "STAT3")))
                  :op2 (a2 / and
                        :op1 (a4 / amino-acid :name (n3 / name :op1 "tyrosine")
                              :part-of (a6 / and
                                    :op1 (e3 / enzyme :name (n / name :op1 "p44" :op2 "ERK-1"))
                                    :op2 (e4 / enzyme :name (n2 / name :op1 "p44" :op2 "ERK-2"))
                                    :ARG1-of (m3 / mean-01
                                          :ARG2 (p2 / protein-family :name (n8 / name :op1 "MAPK"))))))))
      :ARG1-of (s / strong-02))

# ::id bel_pmid_1090_3731.37032 ::date 2015-04-16T21:53:29 ::annotator SDL-AMR-09 ::preferred
# ::snt MAPK activation appears to play a prominent role in IL-18 signaling, being involved in transcription and translation of IL-18-induced IFN-gamma mRNA and IL-18-induced cytolytic effects.
# ::save-date Sun Dec 20, 2015 ::file bel_pmid_1090_3731_37032.txt
(c / cause-01
      :ARG0 (i / involve-01
            :ARG1 a2
            :ARG2 (a3 / and
                  :op1 (t / transcribe-01
                        :ARG0 a2
                        :ARG1 (n5 / nucleic-acid :name (n3 / name :op1 "mRNA")
                              :mod (p5 / protein :name (n4 / name :op1 "IFN-gamma"))
                              :ARG2-of (i2 / induce-01
                                    :ARG0 p4)))
                  :op2 (t2 / translate-01
                        :ARG0 a2
                        :ARG1 n5)
                  :op3 (a4 / affect-01
                        :ARG2 (c2 / cytolysis)
                        :ARG1-of i2)))
      :ARG1 (a / appear-01
            :ARG1 (p2 / play-02
                  :ARG0 (a2 / activate-01
                        :ARG0 (p / pathway :name (n / name :op1 "MAPK")))
                  :ARG1 (r / role
                        :mod (p3 / prominent))
                  :topic (s / signal-07
                        :ARG0 (p4 / protein :name (n2 / name :op1 "IL-18"))))))

# ::id bel_pmid_1090_3734.4380 ::date 2015-04-16T22:01:39 ::annotator SDL-AMR-09 ::preferred
# ::snt Moreover, cord blood T cells cultured with IGF-1 and PHA had a higher resistance to anti-Fas-induced apoptosis as compared with PHA-activated cord blood T cells. IGF-1 also significantly inhibited PHA-induced Fas expression on cord blood T cells
# ::save-date Sun Jan 17, 2016 ::file bel_pmid_1090_3734_4380.txt
(m / multi-sentence
      :snt1 (a2 / and
            :op2 (r / resist-01
                  :ARG0 (c4 / cell :name (n4 / name :op1 "T")
                        :ARG1-of (c3 / culture-01
                              :ARG0 (a6 / and
                                    :op1 (p2 / protein :name (n5 / name :op1 "IGF-1"))
                                    :op2 (p3 / protein :name (n6 / name :op1 "PHA")))
                              :mod (b2 / blood
                                    :location (c5 / cord))))
                  :ARG1 (a4 / apoptosis
                        :ARG0-of (c6 / counter-01
                              :ARG1 p5)
                        :ARG2-of (i3 / induce-01))
                  :compared-to (c7 / cell :name (n7 / name :op1 "T")
                        :ARG1-of (a5 / activate-01
                              :ARG0 p3)
                        :mod b2)
                  :ARG1-of (h / high-02
                        :degree (m2 / more))))
      :snt2 (i / inhibit-01
            :ARG0 (p4 / protein :name (n8 / name :op1 "IGF-1"))
            :ARG1 (e / express-03
                  :ARG1 (p5 / protein :name (n2 / name :op1 "Fas"))
                  :ARG3 (c / cell :name (n3 / name :op1 "T")
                        :mod (b / blood
                              :location (c2 / cord)))
                  :ARG2-of (i2 / induce-01
                        :ARG0 (p / protein :name (n / name :op1 "PHA"))))
            :mod (a / also)
            :ARG1-of (s / significant-02)))

# ::id bel_pmid_1090_3734.23408 ::date 2015-04-16T10:37:26 ::annotator SDL-AMR-09 ::preferred
# ::snt Our previous study indicated that IGF-1 could significantly increase IL-6 mRNA expression and protein production in PHA- activated cord blood MNC ( 12 ).
# ::save-date Fri Dec 18, 2015 ::file bel_pmid_1090_3734_23408.txt
(i / indicate-01
      :ARG0 (s / study-01
            :ARG0 (w / we)
            :time (p / previous))
      :ARG1 (p5 / possible-01
            :ARG1 (i2 / increase-01
                  :ARG0 (p2 / protein :name (n3 / name :op1 "IGF-1"))
                  :ARG1 (a / and
                        :op1 (e / express-03
                              :ARG2 (n6 / nucleic-acid :name (n2 / name :op1 "mRNA")
                                    :mod (p4 / protein :name (n / name :op1 "IL-6"))))
                        :op2 (p3 / produce-01
                              :ARG1 (p6 / protein)
                              :ARG3 (c3 / cell :name (n4 / name :op1 "MNC")
                                    :ARG1-of (a2 / activate-01
                                          :ARG0 (p7 / protein :name (n5 / name :op1 "PHA")))
                                    :mod (b / blood
                                          :location (c / cord)))))
                  :ARG2 (s2 / significant-02)))
      :ARG1-of (d / describe-01
            :ARG0 (p8 / publication
                  :ARG1-of (c2 / cite-01
                        :ARG2 12))))

# ::id bel_pmid_1091_2795.5930 ::date 2015-04-16T10:59:04 ::annotator SDL-AMR-09 ::preferred
# ::snt constitutively active kinases within the ERK1/2 pathway (MEKK1, MEK1) or the p38 pathway (ASK1, MEKK1, MKK3) are potent activators of the MMP-1 promoter
# ::save-date Mon Jul 20, 2015 ::file bel_pmid_1091_2795_5930.txt
(a / activate-01
      :ARG0 (o / or
            :op1 (k / kinase
                  :ARG0-of (a2 / activity-06
                        :manner (c / constitutive))
                  :location (o2 / or
                        :op1 (p4 / pathway :name (n3 / name :op1 "ERK1/2")
                              :ARG1-of (m2 / mean-01
                                    :ARG2 (a3 / and
                                          :op1 (e5 / enzyme :name (n5 / name :op1 "MEKK1"))
                                          :op2 (e6 / enzyme :name (n6 / name :op1 "MEK1")))))
                        :op2 (p3 / pathway :name (n2 / name :op1 "p38")
                              :ARG1-of (m3 / mean-01
                                    :ARG2 (a4 / and
                                          :op1 (e2 / enzyme :name (n7 / name :op1 "ASK1"))
                                          :op2 e5
                                          :op3 (e4 / enzyme :name (n9 / name :op1 "MKK3"))))))))
      :ARG1 (m / molecular-physical-entity
            :ARG0-of (p2 / promote-01
                  :ARG1 (e / enzyme :name (n / name :op1 "MMP-1"))))
      :mod (p / potent))

# ::id bel_pmid_1092_5306.24430 ::date 2015-04-16T18:32:24 ::annotator SDL-AMR-09 ::preferred
# ::snt TGF-b1 also stimulates H2O2 production in bovine pulmonary artery endothelial cells (22), vascular endothelial cells (23), mouse osteoblastic cells (24), and human lung fibroblast (HLF) cells (25, 26).
# ::save-date Wed Oct 28, 2015 ::file bel_pmid_1092_5306_24430.txt
(s / stimulate-01
      :ARG0 (p5 / protein :name (n / name :op1 "TGF-b1"))
      :ARG1 (p / produce-01
            :ARG1 (s2 / small-molecule :name (n2 / name :op1 "H2O2")))
      :mod (a / also)
      :location (a2 / and
            :op1 (c / cell
                  :ARG1-of (d / describe-01
                        :ARG0 (p2 / publication
                              :ARG1-of (c8 / cite-01
                                    :ARG2 22)))
                  :mod (e / endothelium)
                  :part-of (a3 / artery
                        :mod (l2 / lung)
                        :mod (c9 / cattle)))
            :op2 (c2 / cell
                  :ARG1-of (d2 / describe-01
                        :ARG0 (p3 / publication
                              :ARG1-of (c7 / cite-01
                                    :ARG2 23)))
                  :mod e
                  :part-of (v / vessel))
            :op3 (c3 / cell
                  :ARG1-of (d3 / describe-01
                        :ARG0 (p4 / publication
                              :ARG1-of (c6 / cite-01
                                    :ARG2 24)))
                  :mod (o / osteoblast)
                  :part-of (m3 / mouse))
            :op4 (c4 / cell
                  :ARG1-of (d5 / describe-01
                        :ARG0 (p6 / publication
                              :ARG1-of (c5 / cite-01
                                    :ARG2 (a4 / and :op1 25 :op2 26))))
                  :part-of (l / lung
                        :mod (h / human))
                  :mod (f / fibroblast))))

# ::id bel_pmid_1092_5306.24432 ::date 2015-04-16T22:45:07 ::annotator SDL-AMR-09 ::preferred
# ::snt TGF-b1 (1 ng/ml)-induced intracellular ROS levels in HLF cells were measured with DCFH-DA and laser-scanning confocal microscopy...As shown in Fig. 1, A and B, DCF fluorescence displayed a rapid increase with maximal intensity at 5 min after treatment and was followed by a decline in fluorescence to the basal level by 20 min.
# ::save-date Fri Feb 12, 2016 ::file bel_pmid_1092_5306_24432.txt
(m / multi-sentence
      :snt1 (m2 / measure-01
            :ARG1 (l / level
                  :quant-of (s3 / small-molecule :name (n / name :op1 "ROS"))
                  :location (c / cell :name (n2 / name :op1 "HLF"))
                  :mod (i / intracellular)
                  :ARG2-of (i2 / induce-01
                        :ARG0 (p / protein :name (n3 / name :op1 "TGF-b1")
                              :quant (c2 / concentration-quantity :quant 1
                                    :unit (n4 / nanogram-per-milliliter)))))
            :ARG2 (a / and
                  :op1 (s4 / small-molecule :name (n5 / name :op1 "DCFH-DA"))
                  :op2 (m6 / microscope
                        :mod (c3 / confocal)
                        :ARG2-of (s / scan-01
                              :ARG0 (l2 / laser)))))
      :snt2 (a2 / and
            :op1 (d / display-01
                  :ARG1 (i3 / increase-01
                        :ARG1 (f4 / fluoresce-01
                              :ARG1 (s5 / small-molecule :name (n6 / name :op1 "DCF")))
                        :mod (r / rapid)
                        :ARG1-of (i4 / intense-02
                              :degree (m8 / maximal))
                        :time (a4 / after
                              :op1 (t2 / treat-04
                                    :ARG1 f4
                                    :ARG2 s5)
                              :quant (t / temporal-quantity :quant 5
                                    :unit (m4 / minute)))))
            :op2 (f / follow-01
                  :ARG1 (d3 / decline-01
                        :ARG1 (f5 / fluoresce-01)
                        :degree (l3 / level
                              :mod (b / basal))
                        :time (a5 / after
                              :op1 (t3 / treat-04)
                              :quant (t4 / temporal-quantity :quant 20
                                    :unit (m3 / minute))))
                  :ARG2 f4)
            :ARG1-of (s2 / show-01
                  :ARG0 (a3 / and
                        :op1 (f2 / figure :mod "1A")
                        :op2 (f3 / figure :mod "1B")))))

# ::id bel_pmid_1092_5306.24450 ::date 2015-04-16T12:56:04 ::annotator SDL-AMR-09 ::preferred
# ::snt Also, stimulation with TGF-b1 (1 ng/ml) caused a time-dependent increase in IL-6 protein accumulation in the culture supernatants (Fig. 2C).
# ::save-date Thu Apr 23, 2015 ::file bel_pmid_1092_5306_24450.txt
(c / cause-01
      :ARG0 (s / stimulate-01
            :ARG2 (p2 / protein :name (n / name :op1 "TGF-b1")
                  :quant (c2 / concentration-quantity :quant 1
                        :unit (n2 / nanogram-per-milliliter))))
      :ARG1 (i / increase-01
            :ARG1 (a2 / accumulate-01
                  :ARG0 (p / protein :name (n3 / name :op1 "IL-6")))
            :ARG0-of (d2 / depend-01
                  :ARG1 (t / time))
            :location (s2 / supernatant
                  :mod (c3 / culture)))
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod "2C"))
      :mod (a / also))

# ::id bel_pmid_1092_5306.24464 ::date 2015-04-16T22:23:36 ::annotator SDL-AMR-09 ::preferred
# ::snt The amount of 1 ng/ml TGF-b1 was sufficient to induce the IL-6 mRNA (Fig. 2A). TGF-b1 (1 ng/ml) treatment produced a progressive increase in IL-6 mRNA concentrations, beginning as early as 30 min, peaking at 12 h, and decreasing after 24 h (Fig. 2B).
# ::save-date Sun Jan 17, 2016 ::file bel_pmid_1092_5306_24464.txt
(m / multi-sentence
      :snt1 (s / suffice-01
            :ARG0 (a / amount-01
                  :ARG1 (p6 / protein :name (n / name :op1 "TGF-b1"))
                  :ARG2 (c / concentration-quantity :quant 1
                        :unit (n2 / nanogram-per-milliliter)))
            :ARG1 (i / induce-01
                  :ARG0 a
                  :ARG2 (n9 / nucleic-acid :name (n4 / name :op1 "mRNA")
                        :mod (p / protein :name (n3 / name :op1 "IL-6"))))
            :ARG1-of (d / describe-01
                  :ARG0 (f / figure :mod "2A")))
      :snt2 (p2 / produce-01
            :ARG0 (t / treat-04
                  :ARG2 (p7 / protein :name (n6 / name :op1 "TGF-b1")
                        :quant (c2 / concentration-quantity :quant 1
                              :unit (n5 / nanogram-per-milliliter))))
            :ARG1 (i2 / increase-01
                  :ARG1 (c3 / concentrate-02
                        :ARG1 (n10 / nucleic-acid :name (n7 / name :op1 "mRNA")
                              :mod (p3 / protein :name (n8 / name :op1 "IL-6"))))
                  :ARG0-of (b / begin-01
                        :time (e / early
                              :op1 (t2 / temporal-quantity :quant 30
                                    :unit (m4 / minute))))
                  :ARG1-of (p4 / peak-01
                        :time (a3 / after
                              :op1 (t3 / temporal-quantity :quant 12
                                    :unit (h / hour))))
                  :ARG1-of (d3 / decrease-01
                        :time (a2 / after
                              :op1 (t4 / temporal-quantity :quant 24
                                    :unit (h2 / hour))))
                  :ARG1-of (p5 / progress-01))
            :ARG1-of (d2 / describe-01
                  :ARG0 (f2 / figure :mod "2B"))))

# ::id bel_pmid_1093_8266.21268 ::date 2015-04-16T13:43:02 ::annotator SDL-AMR-09 ::preferred
# ::snt Our results indicate that autocrine secretion of PRL stimulates tyrosine phosphorylation of ErbB-2 by Jak2, provides docking sites for Grb2 and stimulates Ras-MAP kinase cascade, thereby causing unrestricted cellular proliferation.
# ::save-date Sun Jan 17, 2016 ::file bel_pmid_1093_8266_21268.txt
(i / indicate-01
      :ARG0 (t / thing
            :ARG2-of (r / result-01)
            :poss (w / we))
      :ARG1 (a / and
            :op1 (s / stimulate-01
                  :ARG0 (s3 / secrete-01
                        :ARG0 (a2 / autocrine)
                        :ARG1 (p4 / protein :name (n / name :op1 "PRL")))
                  :ARG1 (p3 / phosphorylate-01
                        :ARG1 (a3 / amino-acid :name (n2 / name :op1 "tyrosine")
                              :part-of (e2 / enzyme :name (n3 / name :op1 "ErbB-2")))
                        :ARG2 (e / enzyme :name (n4 / name :op1 "Jak2"))))
            :op2 (p / provide-01
                  :ARG0 a2
                  :ARG1 (s4 / site
                        :ARG0-of (d / dock-01))
                  :ARG2 (p7 / protein :name (n5 / name :op1 "Grb2")))
            :op3 (s2 / stimulate-01
                  :ARG0 a2
                  :ARG1 (p6 / pathway :name (n7 / name :op1 "Ras-MAP" :op2 "kinase")))
            :ARG0-of (c / cause-01
                  :ARG1 (p2 / proliferate-01
                        :ARG0 (c2 / cell)
                        :ARG1-of (r2 / restrict-01 :polarity -)))))

# ::id bel_pmid_1094_3842.21324 ::date 2015-04-16T14:11:14 ::annotator SDL-AMR-09 ::preferred
# ::snt inhibition of MAPK14 activity also interfered with stabilization of EPO mRNA in human hepatoma cells undergoing hypoxic stress
# ::save-date Sun Jan 3, 2016 ::file bel_pmid_1094_3842_21324.txt
(i / interfere-01
      :ARG0 (i2 / inhibit-01
            :ARG1 (a / activity-06
                  :ARG0 (e / enzyme :name (n / name :op1 "MAPK14"))))
      :ARG1 (s / stabilize-01
            :ARG1 (n4 / nucleic-acid :name (n2 / name :op1 "mRNA")
                  :mod (s3 / small-molecule :name (n3 / name :op1 "EPO")))
            :location (c / cell
                  :mod (h / hepatoma)
                  :mod (h2 / human)
                  :ARG1-of (s2 / stress-02
                        :ARG0 (h3 / hypoxia))))
      :mod (a2 / also))

# ::id bel_pmid_1094_5974.21384 ::date 2015-04-16T15:21:00 ::annotator SDL-AMR-09 ::preferred
# ::snt Consistent with the earlier results, p42/44 MAPK and its upstream kinase MEK1/2 were activated in a time-dependent manner by the induction of Pak1 (Fig. 3C).
# ::save-date Sun Dec 20, 2015 ::file bel_pmid_1094_5974_21384.txt
(a3 / activate-01
      :ARG0 (i / induce-01
            :ARG2 (e2 / enzyme :name (n / name :op1 "Pak1")))
      :ARG1 (a2 / and
            :op1 (s / slash
                  :op1 (e3 / enzyme :name (n3 / name :op1 "p42" :op2 "MAPK"))
                  :op2 (e4 / enzyme :name (n4 / name :op1 "p44" :op2 "MAPK")))
            :op2 (s2 / slash
                  :op1 (k5 / kinase :name (n2 / name :op1 "MEK1"))
                  :op2 (k6 / kinase :name (n6 / name :op1 "MEK2"))
                  :location (u / upstream)
                  :poss s))
      :manner (d / depend-01
            :ARG1 (t2 / time))
      :ARG1-of (c / consistent-01
            :ARG2 (t / thing
                  :ARG2-of (r / result-01
                        :time (e / early
                              :degree (m / more))))
            :ARG1-of (d2 / describe-01
                  :ARG0 (f / figure :mod "3C"))))

# ::id bel_pmid_1097_1465.18050 ::date 2015-04-16T14:25:55 ::annotator SDL-AMR-09 ::preferred
# ::snt Jaffe et al. [22,23] reported IL-5 and IL-13 production from human lung mast cells following IgE-mediated activation.
# ::save-date Fri Feb 12, 2016 ::file bel_pmid_1097_1465_18050.txt
(r / report-01
      :ARG0 (a / and
            :op1 (p / person :name (n / name :op1 "Jaffe"))
            :op2 (p2 / person
                  :mod (o / other)))
      :ARG1 (p4 / produce-01
            :ARG1 (a3 / and
                  :op1 (p5 / protein :name (n2 / name :op1 "IL-5"))
                  :op2 (p6 / protein :name (n3 / name :op1 "IL-13")))
            :ARG2 (c2 / cell
                  :mod (m / mast)
                  :part-of (l / lung
                        :mod (h / human)))
            :ARG1-of (f / follow-01
                  :ARG2 (a4 / activate-01
                        :ARG1-of (m2 / mediate-01
                              :ARG0 (s / small-molecule :name (n4 / name :op1 "IgE"))))))
      :ARG1-of (d / describe-01
            :ARG0 (p3 / publication
                  :ARG1-of (c / cite-01
                        :ARG2 (a2 / and :op1 22 :op2 23)))))

# ::id bel_pmid_1097_1465.18052 ::date 2015-04-16T14:48:41 ::annotator SDL-AMR-09 ::preferred
# ::snt Using immunocytochemistry, Bradding et al. [1±4] reported that interleukin (IL)-4, IL-5, IL-6, and tumour necrosis factor (TNF)-a were present within mast cells in nasal and bronchial mucosa taken from both normal subjects and patients with allergic perennial rhinitis,
# ::save-date Thu Jan 14, 2016 ::file bel_pmid_1097_1465_18052.txt
(c / cause-01
      :ARG0 (u / use-01
            :ARG0 a
            :ARG1 (i / immunocytochemistry)
            :ARG1-of (d2 / describe-01
                  :ARG0 (p8 / publication
                        :ARG1-of (c3 / cite-01
                              :ARG2 (o2 / or :op1 1
                                    :op2 (a6 / and :op1 1 :op2 4))))))
      :ARG1 (r / report-01
            :ARG0 (a / and
                  :op1 (p / person :name (n / name :op1 "Bradding"))
                  :op2 (p2 / person
                        :mod (o / other)))
            :ARG1 (p9 / present-02
                  :ARG1 (a2 / and
                        :op1 (p4 / protein :name (n4 / name :op1 "IL-4"))
                        :op2 (p5 / protein :name (n5 / name :op1 "IL-5"))
                        :op3 (p6 / protein :name (n6 / name :op1 "IL-6"))
                        :op4 (p7 / protein :name (n7 / name :op1 "tumour" :op2 "necrosis" :op3 "factor-a")))
                  :ARG2 (c2 / cell
                        :mod (m / mast
                              :location (a4 / and
                                          :op1 (m2 / mucosa
                                                :mod (n8 / nose))
                                          :op2 (m3 / mucosa
                                                :mod (b3 / bronchus))
                                          :ARG1-of (t / take-01
                                                :ARG2 (a3 / and
                                                      :op1 (s / subject
                                                            :ARG1-of (n2 / normal-02))
                                                      :op2 (p3 / patient
                                                            :ARG1-of (a5 / allergic-01
                                                                  :ARG2 (m4 / medical-condition :name (n3 / name :op1 "perennial" :op2 "rhinitis"))))))))))))

# ::id bel_pmid_1099_3906.5890 ::date 2015-04-16T16:35:07 ::annotator SDL-AMR-09 ::preferred
# ::snt STAM2 is downstream of the Jak family of kinases since coexpression of STAM2 with Jak1 or Jak2 but not an unrelated Tec family kinase, Etk, resulted in its tyrosine phosphorylation.
# ::save-date Sun Jan 3, 2016 ::file bel_pmid_1099_3906_5890.txt
(c4 / cause-01
      :ARG0 (c5 / contrast-01
            :ARG1 (r / result-01
                  :ARG1 (e3 / express-03
                        :ARG2 (a2 / and
                              :op1 (p5 / protein :name (n3 / name :op1 "STAM2"))
                              :op2 (o / or
                                    :op1 (e / enzyme :name (n / name :op1 "Jak1"))
                                    :op2 (e2 / enzyme :name (n2 / name :op1 "Jak2")))))
                  :ARG2 (p4 / phosphorylate-01
                        :ARG1 (a / amino-acid :name (n5 / name :op1 "tyrosine")
                              :part-of p5)))
            :ARG2 (r2 / result-01 :polarity -
                  :ARG1 (k2 / kinase :name (n7 / name :op1 "Etk")
                        :ARG1-of (r3 / relate-01 :polarity -)
                        :ARG1-of (i / include-91
                              :ARG2 (p2 / protein-family :name (n6 / name :op1 "Tec"))))
                  :ARG2 p4))
      :ARG1 (b / be-located-at-91
            :ARG1 p5
            :ARG2 (r4 / relative-position
                  :op1 (p / protein-family :name (n4 / name :op1 "Jak"))
                  :direction (d / downstream))))

# ::id bel_pmid_1099_3906.6852 ::date 2015-04-16T16:07:43 ::annotator SDL-AMR-09 ::preferred
# ::snt Tyrosine phosphorylation of STAM2 is induced by growth factors such as epidermal growth factor and platelet-derived growth factor as well as by cytokines like IL-3.
# ::save-date Wed Feb 24, 2016 ::file bel_pmid_1099_3906_6852.txt
(i / induce-01
      :ARG0 (g / growth-factor
            :example (a2 / and
                  :op1 (p3 / protein :name (n7 / name :op1 "epidermal" :op2 "growth" :op3 "factor"))
                  :op2 (p4 / protein :name (n6 / name :op1 "platelet-derived" :op2 "growth" :op3 "factor"))
                  :op2 (p5 / protein :name (n5 / name :op1 "cytokine")
                        :example (p6 / protein :name (n4 / name :op1 "IL-3")))))
      :ARG2 (p8 / phosphorylate-01
            :ARG1 (a / amino-acid :name (n / name :op1 "tyrosine")
                  :part-of (p / protein :name (n2 / name :op1 "STAM2")))))

# ::id bel_pmid_1099_3906.7612 ::date 2015-04-16T15:51:09 ::annotator SDL-AMR-09 ::preferred
# ::snt Finally, overexpression of wild type STAM2 led to an increase in IL-2-mediated induction of c-Myc promoter activation indicating that it potentiates cytokine receptor signaling.
# ::save-date Thu Dec 17, 2015 ::file bel_pmid_1099_3906_7612.txt
(l / lead-03 :li "-1"
      :ARG0 (o / overexpress-01
            :ARG1 (p5 / protein :name (n / name :op1 "STAM2")
                  :mod (w / wild-type)))
      :ARG2 (i / increase-01
            :ARG1 (i2 / induce-01
                  :ARG2 (a / activate-01
                        :ARG1 (m2 / molecular-physical-entity
                              :ARG0-of (p2 / promote-01
                                    :ARG1 (p6 / protein :name (n3 / name :op1 "c-Myc")))))
                  :ARG1-of (m / mediate-01
                        :ARG0 (p / protein :name (n2 / name :op1 "IL-2")))))
      :ARG0-of (i3 / indicate-01
            :ARG1 (p3 / potentiate-01
                  :ARG1 (s / signal-07
                        :ARG0 (r / receptor
                              :mod (p4 / protein :name (n4 / name :op1 "cytokine"))))
                  :ARG2 o)))

# ::id bel_pmid_1101_5448.8236 ::date 2015-04-19T13:37:46 ::annotator SDL-AMR-09 ::preferred
# ::snt Additionally, T cells from CCR2(-/)- immunized mice showed decreased antigen-induced proliferation and production of IFN-gamma compared with wild-type immunized controls, suggesting that CCR2 enhances the T helper cell type 1 immune response in EAE.
# ::save-date Mon Dec 21, 2015 ::file bel_pmid_1101_5448_8236.txt
(a / and
      :op2 (s / show-01
            :ARG0 (c / cell :name (n / name :op1 "T")
                  :source (m / mouse
                        :ARG1-of (i / immunize-01)
                        :mod (p / protein :name (n2 / name :op1 "CCR2")
                              :ARG2-of (m2 / mutate-01 :mod "-/-"))))
            :ARG1 (a2 / and
                  :op1 (p2 / proliferate-01
                        :ARG2-of (i2 / induce-01
                              :ARG0 (a3 / antigen)))
                  :op2 (p3 / produce-01
                        :ARG1 (p4 / protein :name (n3 / name :op1 "IFN-gamma")))
                  :ARG1-of (d / decrease-01
                        :ARG1-of (c2 / compare-01
                              :ARG2 (m3 / mouse
                                    :ARG2-of (c3 / control-01)
                                    :ARG1-of i
                                    :mod (w / wild-type))
                              :ARG0-of (s2 / suggest-01
                                    :ARG1 (e / enhance-01
                                          :ARG0 p
                                          :ARG1 (r / respond-01
                                                :ARG0 (c4 / cell :name (n4 / name :op1 "T-helper")
                                                      :ARG1-of (t2 / type-03))
                                                :ARG1-of (i3 / immune-02
                                                      :ARG2 (d2 / disease :name (n6 / name :op1 "experimental" :op2 "autoimmune" :op3 "encephalomyelitis")))))))))))

# ::id bel_pmid_1101_5448.18896 ::date 2015-04-19T14:24:47 ::annotator SDL-AMR-09 ::preferred
# ::snt At days 8, 11, 20, 23, and 26 after disease induction, splenocytes from CCR2-deficient mice also proliferated less robustly to Ag and secreted lower levels of IFN-{gamma} and IL-6 than splenocytes from wild-type controls
# ::save-date Fri Feb 12, 2016 ::file bel_pmid_1101_5448_18896.txt
(a / and
      :op1 (p / proliferate-01
            :ARG0 (c / cell :name (n / name :op1 "splenocyte")
                  :source (m / mouse
                        :mod (p2 / protein :name (n2 / name :op1 "CCR2")
                              :ARG2-of (m2 / mutate-01 :mod "-/-"))))
            :manner (r / robust
                  :degree (l / less))
            :mod (a2 / also)
            :ARG1-of (r2 / result-01
                  :ARG2 (s2 / small-molecule :name (n5 / name :op1 "Ag"))))
      :op2 (s / secrete-01
            :ARG0 c
            :ARG1 (a4 / and
                  :op1 (l2 / level
                        :quant-of (p3 / protein :name (n3 / name :op1 "IFN-γ"))
                        :ARG1-of (l3 / low-04
                              :degree (m4 / more)
                              :compared-to (c2 / cell :name (n6 / name :op1 "splenocyte")
                                    :source (m5 / mouse
                                          :mod (c3 / control)
                                          :mod (w / wild-type)))))
                  :op2 (l4 / level
                        :quant-of (p4 / protein :name (n4 / name :op1 "IL-6"))
                        :ARG1-of l3)))
      :time (a5 / after
            :op1 (i / induce-01
                  :ARG2 (d2 / disease))
            :quant (a3 / and
                  :op1 (t / temporal-quantity :quant 8
                        :unit (d3 / day))
                  :op2 (t2 / temporal-quantity :quant 11
                        :unit (d4 / day))
                  :op3 (t3 / temporal-quantity :quant 20
                        :unit (d5 / day))
                  :op4 (t4 / temporal-quantity :quant 23
                        :unit (d6 / day))
                  :op5 (t5 / temporal-quantity :quant 26
                        :unit (d7 / day)))))

# ::id bel_pmid_1102_9459.7644 ::date 2015-04-19T15:49:48 ::annotator SDL-AMR-09 ::preferred
# ::snt The wild-type Ki-ras transfectants lack functional TGF-beta receptors, whereas all three Ki-ras(G12V) transfectants expressed functional TGF-beta receptors that bound (125)I-TGF-beta1.
# ::save-date Sun Jan 3, 2016 ::file bel_pmid_1102_9459_7644.txt
(c / contrast-01
      :ARG1 (l / lack-01
            :ARG0 (c2 / cell
                  :ARG1-of (t / transfect-01
                        :ARG2 (p / protein :name (n / name :op1 "Ki-ras")
                              :mod (w / wild-type))))
            :ARG1 (p4 / protein :name (n6 / name :op1 "TGF-β" :op2 "receptor")
                  :mod (f / function-01)))
      :ARG2 (e / express-03
            :ARG2 (p5 / protein :name (n2 / name :op1 "TGF-β" :op2 "receptor")
                  :mod f
                  :ARG1-of (b / bind-01
                        :ARG2 (p2 / protein :name (n4 / name :op1 "(125)I-TGF-β1"))))
            :ARG3 (c3 / cell :quant 3
                  :ARG1-of (t2 / transfect-01
                        :ARG2 (p3 / protein :name (n5 / name :op1 "Ki-ras")
                              :ARG2-of (m / mutate-01 :value "G12V")))
                  :mod (a / all))))

# ::id bel_pmid_1102_9459.20858 ::date 2015-04-19T16:12:26 ::annotator SDL-AMR-09 ::preferred
# ::snt GnT-V transcription was stimulated by several oncogenes including src , her -2/ neu , H- ras , and v- sis (9 , 10 , 11) , and this overexpression was regulated through the ras-raf-ets pathways.
# ::save-date Fri Jan 15, 2016 ::file bel_pmid_1102_9459_20858.txt
(a / and
      :op1 (s / stimulate-01
            :ARG0 (o / oncogene
                  :mod (s2 / several)
                  :ARG2-of (i / include-91
                        :ARG1 (a2 / and
                              :op1 (g / gene :name (n / name :op1 "src"))
                              :op2 (g2 / gene :name (n2 / name :op1 "her-2/neu"))
                              :op3 (g3 / gene :name (n3 / name :op1 "H-ras"))
                              :op4 (g4 / gene :name (n4 / name :op1 "v-sis"))
                              :ARG0-of (c / cause-01
                                    :ARG1 (d2 / disease :wiki "Cancer" :name (n7 / name :op1 "cancer"))))))
            :ARG1 (t / transcribe-01
                  :ARG1 (e / enzyme :name (n5 / name :op1 "GnT-V")))
            :ARG1-of (d / describe-01
                  :ARG0 (a3 / and
                        :op1 (f / figure :mod 9)
                        :op2 (f2 / figure :mod 10)
                        :op3 (f3 / figure :mod 11))))
      :op2 (r / regulate-01
            :ARG0 (p / pathway :name (n6 / name :op1 "ras-raf-ets"))
            :ARG1 (o2 / overexpress-01
                  :mod (t2 / this))))

# ::id bel_pmid_1102_9459.21486 ::date 2015-04-19T16:37:10 ::annotator SDL-AMR-09 ::preferred
# ::snt Each of three Ki-ras(G12V) transfectants responded to TGF-beta1 by an increase in proliferation and by decreasing the abundance of the Cdk inhibitor p21 and the tumor suppressor PTEN, whereas each of three wild-type Ki-ras transfectants remained unresponsive to TGF-beta1.
# ::save-date Sat Jan 16, 2016 ::file bel_pmid_1102_9459_21486.txt
(c / contrast-01
      :ARG1 (r / respond-01
            :ARG0 (c2 / cell :quant 3
                  :ARG1-of (t / transfect-01
                        :ARG2 (e5 / enzyme :name (n / name :op1 "Ki-ras")
                              :ARG2-of (m / mutate-01 :value "G12V")))
                  :mod (e / each))
            :ARG1 (p2 / protein :name (n3 / name :op1 "TGF-β1"))
            :ARG2 (a / and
                  :op1 (i / increase-01
                        :ARG1 (p3 / proliferate-01))
                  :op2 (d / decrease-01
                        :ARG1 (a2 / abound-01
                              :ARG1 (a3 / and
                                    :op1 (p4 / protein :name (n4 / name :op1 "p21")
                                          :ARG0-of (i2 / inhibit-01
                                                :ARG1 (e2 / enzyme :name (n5 / name :op1 "Cdk"))))
                                    :op2 (s / suppress-01
                                          :ARG0 (g / gene :name (n6 / name :op1 "PTEN"))
                                          :ARG1 (t2 / tumor)))))))
      :ARG2 (r2 / remain-01
            :ARG1 (c3 / cell :quant 3
                  :ARG1-of (t3 / transfect-01
                        :ARG2 (e4 / enzyme :name (n7 / name :op1 "Ki-ras")))
                  :mod (e3 / each)
                  :mod (w / wild-type))
            :ARG3 (r3 / respond-01 :polarity -
                  :ARG0 c3
                  :ARG1 p2)))

# ::id bel_pmid_1103_6942.20042 ::date 2015-04-19T16:58:12 ::annotator SDL-AMR-09 ::preferred
# ::snt SIRP is a transmembrane protein that is now known to bind to integrin-associated protein. It appears to bind directly to JAK2 by a process that does not require tyrosyl phosphorylation, although is itself highly phosphorylated on tyrosines in response to GH. The phosphorylated SIRP recruits one or more molecules of the tyrosine phosphatase SHP2 that, in turn, de-phosphorylates SIRP and most likely JAK2.
# ::save-date Sun Jan 17, 2016 ::file bel_pmid_1103_6942_20042.txt
(m / multi-sentence
      :snt1 (k / know-01
            :ARG1 (b / bind-01
                  :ARG1 (p / protein :name (n / name :op1 "SIRP")
                        :mod (t / transmembrane))
                  :ARG2 (p2 / protein
                        :ARG1-of (a / associate-01
                              :ARG2 (p3 / protein :name (n2 / name :op1 "integrin")))))
            :time (n3 / now))
      :snt2 (a2 / appear-02
            :ARG1 (b2 / bind-01
                  :ARG1 (p4 / protein :name (n5 / name :op1 "SIRP"))
                  :ARG2 (e / enzyme :name (n4 / name :op1 "JAK2"))
                  :ARG1-of (d / direct-02)
                  :ARG1-of (p5 / process-02
                        :ARG0-of (r / require-01 :polarity -
                              :ARG1 (p6 / phosphorylate-01
                                    :ARG1 (a6 / amino-acid :name (n6 / name :op1 "tyrosine"))))))
            :concession (p7 / phosphorylate-01
                  :ARG1 (a3 / amino-acid :name (n7 / name :op1 "tyrosine")
                        :part-of p4)
                  :ARG1-of (h / high-02)
                  :ARG2-of (r2 / respond-01
                        :ARG1 (p10 / protein :name (n8 / name :op1 "GH")))))
      :snt3 (r3 / recruit-01
            :ARG0 (p8 / protein :name (n9 / name :op1 "SIRP")
                  :ARG1-of (p9 / phosphorylate-01))
            :ARG1 (m4 / molecule
                  :mod (t2 / tyrosine-phosphatase :name (n10 / name :op1 "SHP2")
                        :ARG1-of (r4 / respond-01
                              :ARG2 (d2 / dephosphorylate-01
                                    :ARG0 t2
                                    :ARG1 (a4 / and
                                          :op1 p8
                                          :op2 (e3 / enzyme :name (n11 / name :op1 "JAK2")
                                                :ARG1-of (l / likely-01
                                                      :degree (m5 / most))))
                                    :mod (i / in-turn))))
                  :quant (a5 / at-least :op1 1))))

# ::id bel_pmid_1104_3579.5226 ::date 2015-04-19T17:48:52 ::annotator SDL-AMR-09 ::preferred
# ::snt Consistent with acting through a G protein-coupled receptor, estradiol signaling to Erk-1/-2 occurred via a Gbetagamma-dependent, pertussis toxin-sensitive pathway that required Src-related tyrosine kinase activity and tyrosine phosphorylation of tyrosine 317 of the Shc adapter protein.
# ::save-date Fri Jan 15, 2016 ::file bel_pmid_1104_3579_5226.txt
(s / signal-07
      :ARG0 (s3 / small-molecule :name (n / name :op1 "estradiol"))
      :ARG2 (e / enzyme :name (n2 / name :op1 "Erk-1/-2"))
      :manner (p / pathway
            :ARG0-of (d / depend-01
                  :ARG1 (m2 / macro-molecular-complex
                        :part (p2 / protein :name (n3 / name :op1 "Gβ"))
                        :part (p3 / protein :name (n4 / name :op1 "Gγ"))))
            :ARG0-of (s2 / sensitive-03
                  :ARG1 (s4 / small-molecule :name (n5 / name :op1 "pertussis" :op2 "toxin")))
            :ARG0-of (r / require-01
                  :ARG1 (a / and
                        :op1 (a2 / activity-06
                              :ARG0 (e2 / enzyme :name (n6 / name :op1 "tyrosine" :op2 "kinase"))
                              :ARG1-of (r2 / relate-01
                                    :ARG2 (p4 / protein :name (n7 / name :op1 "Src"))))
                        :op2 (p5 / phosphorylate-01
                              :ARG1 (a3 / amino-acid :mod 317 :name (n8 / name :op1 "tyrosine")
                                    :part-of (p6 / protein :name (n9 / name :op1 "Shc" :op2 "adapter")))))))
      :ARG1-of (c / consistent-01
            :ARG2 (a4 / act-01
                  :instrument (r3 / receptor
                        :ARG1-of (c2 / couple-01
                              :ARG2 (p7 / protein :name (n10 / name :op1 "G")))))))

# ::id bel_pmid_1104_3579.5228 ::date 2015-04-19T18:40:01 ::annotator SDL-AMR-09 ::preferred
# ::snt Reinforcing this idea, estradiol signaling to Erk-1/-2 was dependent upon trans-activation of the epidermal growth factor (EGF) receptor via release of heparan-bound EGF (HB-EGF).
# ::save-date Sun Jan 3, 2016 ::file bel_pmid_1104_3579_5228.txt
(d / depend-01
      :ARG0 (s / signal-07
            :ARG0 (s2 / small-molecule :name (n / name :op1 "estradiol"))
            :ARG2 (e / enzyme :name (n2 / name :op1 "Erk-1/-2")))
      :ARG1 (a / activate-01
            :ARG1 (p2 / protein :name (n4 / name :op1 "epidermal" :op2 "growth" :op3 "factor" :op4 "receptor"))
            :mod (t / trans)
            :manner (r3 / release-01
                  :ARG1 (b / bind-01
                        :ARG1 (r2 / receptor)
                        :ARG2 (h / heparin)
                        :ARG1-of (d3 / describe-01
                              :ARG0 (p / protein :name (n5 / name :op1 "HB-EGF"))))))
      :ARG2-of (r4 / reinforce-01
            :ARG1 (i / idea
                  :mod (t2 / this))))

# ::id bel_pmid_1104_3579.19856 ::date 2015-04-19T19:00:20 ::annotator SDL-AMR-09 ::preferred
# ::snt Estrogen rapidly activates the mitogen-activated protein kinases, Erk-1 and Erk-2, via an as yet unknown mechanism. requires the expression of the G protein-coupled receptor homolog, GPR30. We show that 17beta-estradiol activates Erk-1/-2 not only in MCF-7 cells, which express both estrogen receptor alpha (ER alpha) and ER beta, but
# ::save-date Fri Feb 12, 2016 ::file bel_pmid_1104_3579_19856.txt
(m / multi-sentence
      :snt1 (a / activate-01
            :ARG0 (e / estrogen)
            :ARG1 (a2 / and
                  :op1 (e2 / enzyme :name (n / name :op1 "Erk-1"))
                  :op2 (e3 / enzyme :name (n2 / name :op1 "Erk-2"))
                  :domain (e4 / enzyme :name (n3 / name :op1 "protein" :op2 "kinase")
                        :ARG1-of (a3 / activate-01
                              :ARG0 (m2 / mitogen))))
            :manner (r / rapid)
            :manner (m3 / mechanism
                  :ARG1-of (k / know-01 :polarity -
                        :mod (y / yet))))
      :snt2 (r2 / require-01
            :ARG1 (e5 / express-03
                  :ARG2 (p / protein :name (n4 / name :op1 "G" :op2 "protein-coupled" :op3 "receptor" :op4 "homolog")
                        :ARG1-of (d / describe-01
                              :ARG0 (p2 / protein :name (n5 / name :op1 "GPR30"))))))
      :snt3 (s / show-01
            :ARG0 (w / we)
            :ARG1 (a4 / activate-01
                  :ARG0 (s2 / small-molecule :name (n6 / name :op1 "17β-estradiol"))
                  :ARG1 (e6 / enzyme :name (n7 / name :op1 "Erk-1/-2"))
                  :location (c / cell-line :name (n8 / name :op1 "MCF-7")
                        :mod (o / only :polarity -)
                        :ARG2-of (e7 / express-03
                              :ARG1 (a5 / and
                                    :op1 (p3 / protein :name (n9 / name :op1 "estrogen" :op2 "receptor" :op3 "α")
                                          :ARG1-of (d2 / describe-01
                                                :ARG0 (p4 / protein :name (n10 / name :op1 "ERα"))))
                                    :op2 (p5 / protein :name (n11 / name :op1 "ERβ"))))))))

# ::id bel_pmid_1106_2502.20878 ::date 2015-04-21T12:35:44 ::annotator SDL-AMR-09 ::preferred
# ::snt Correspondingly, in vitro kinase assays showed that N17Rac1 inhibited the kinase activities of MEK1/2 and ERK1/2 stimulated by target signals (Fig. 4b).
# ::save-date Sun Jan 17, 2016 ::file bel_pmid_1106_2502_20878.txt
(s / show-01
      :ARG0 (a / assay-01
            :ARG1 (k / kinase)
            :manner (i / in-vitro))
      :ARG1 (i2 / inhibit-01
            :ARG0 (e3 / enzyme :name (n / name :op1 "N17Rac1"))
            :ARG1 (a2 / activity-06
                  :ARG0 (a3 / and
                        :op1 (e / enzyme :name (n2 / name :op1 "MEK1/2"))
                        :op2 (e2 / enzyme :name (n3 / name :op1 "ERK1/2")))
                  :ARG1 k
                  :ARG1-of (s2 / stimulate-01
                        :ARG0 (s3 / signal-07
                              :ARG1-of (t / target-01)))))
      :ARG1-of (c / correspond-02)
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod "4b")))

# ::id bel_pmid_1106_2502.20880 ::date 2015-04-21T13:13:15 ::annotator SDL-AMR-09 ::preferred
# ::snt Introduction of N17Rac1 into NK92 cells totally blocked PAK1 activation triggered by target ligation, whereas introduction of V12Rac1 strongly stimulated PAK1 activity even in the absence of target cells (Fig. 7d).
# ::save-date Sun Jan 17, 2016 ::file bel_pmid_1106_2502_20880.txt
(c / contrast-01
      :ARG1 (b / block-01
            :ARG0 (i / introduce-02
                  :ARG1 (e3 / enzyme :name (n / name :op1 "N17Rac1"))
                  :ARG2 (c2 / cell :name (n2 / name :op1 "NK92")))
            :ARG1 (a / activate-01
                  :ARG1 (e / enzyme :name (n3 / name :op1 "PAK1"))
                  :ARG1-of (t / trigger-01
                        :ARG0 (l / ligate-01
                              :ARG1 (t2 / target-01))))
            :degree (t3 / total))
      :ARG2 (s / stimulate-01
            :ARG0 (i2 / introduce-02
                  :ARG1 (e2 / enzyme :name (n4 / name :op1 "V12Rac1"))
                  :ARG2 c2)
            :ARG1 (a2 / activity-06
                  :ARG1 e)
            :ARG1-of (s2 / strong-02)
            :concession (a3 / absent-01
                        :ARG1 (c3 / cell
                              :ARG1-of (t4 / target-01))
                        :ARG2 s))
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod "7d")))

# ::id bel_pmid_1106_2502.21386 ::date 2015-04-21T17:24:36 ::annotator SDL-AMR-09 ::preferred
# ::snt Examination of whole cell lysates from the same NK92 cells showed that kinase-deficient (KD) PAK1, unlike control CD56, also effectively suppressed MEK and ERK activation by target ligation (Fig. 7b). Thus, PAK1 is upstream of both MEK and ERK in the NK lytic process.
# ::save-date Sun Dec 20, 2015 ::file bel_pmid_1106_2502_21386.txt
(m / multi-sentence
      :snt1 (s / show-01
            :ARG0 (e / examine-01
                  :ARG1 (l / lysate
                        :mod (c / cell)
                        :source (c2 / cell :name (n / name :op1 "NK92")
                              :ARG1-of (s2 / same-01))
                        :mod (w / whole)))
            :ARG1 (c3 / contrast-01
                  :ARG1 (s3 / suppress-01
                        :ARG0 (e2 / enzyme :name (n2 / name :op1 "PAK1")
                              :mod (k / kinase
                                    :ARG2-of (m2 / mutate-01 :mod "-/-")))
                        :ARG1 (a / activate-01
                              :ARG0 (l2 / ligate-01
                                    :ARG1 (t / target-01))
                              :ARG1 (a2 / and
                                    :op1 (e3 / enzyme :name (n3 / name :op1 "MEK"))
                                    :op2 (e4 / enzyme :name (n4 / name :op1 "ERK"))))
                        :mod (a3 / also)
                        :manner (e5 / effective-04))
                  :ARG2 (s4 / suppress-01 :polarity -
                        :ARG0 (p / protein :name (n5 / name :op1 "CD56")
                              :ARG2-of (c4 / control-01))
                        :ARG1 a))
            :ARG1-of (d / describe-01
                  :ARG0 (f / figure :mod "7b")))
      :snt2 (c5 / cause-01
            :ARG1 (b / be-located-at-91
                  :ARG1 (e6 / enzyme :name (n6 / name :op1 "PAK1"))
                  :ARG2 (r / relative-position
                        :op1 (a4 / and
                              :op1 (e7 / enzyme :name (n7 / name :op1 "MEK"))
                              :op2 (e8 / enzyme :name (n8 / name :op1 "ERK")))
                        :direction (u / upstream))
                  :time (p2 / process-02
                        :ARG1 (l3 / lyse-00
                              :ARG1 (c6 / cell :name (n9 / name :op1 "NK")))))))

# ::id bel_pmid_1111_7534.6206 ::date 2015-04-21T18:11:37 ::annotator SDL-AMR-09 ::preferred
# ::snt PRL enhanced tyrosine phosphorylation of NKCC1, and this effect was attenuated by the JAK2 inhibitor AG490.
# ::save-date Sun Jan 17, 2016 ::file bel_pmid_1111_7534_6206.txt
(a / and
      :op1 (e / enhance-01
            :ARG0 (p3 / protein :name (n / name :op1 "PRL"))
            :ARG1 (p / phosphorylate-01
                  :ARG1 (a2 / amino-acid :name (n2 / name :op1 "tyrosine")
                        :part-of (p2 / protein :name (n3 / name :op1 "NKCC1"))))
            :ARG2-of (a4 / affect-01))
      :op2 (a3 / attenuate-01
            :ARG0 (s / small-molecule :name (n4 / name :op1 "AG490")
                  :ARG0-of (i / inhibit-01
                        :ARG1 (e2 / enzyme :name (n5 / name :op1 "JAK2"))))
            :ARG1 e))

# ::id bel_pmid_1111_7534.6208 ::date 2015-04-21T18:22:31 ::annotator SDL-AMR-09 ::preferred
# ::snt PRL treatment of HC11 cells increased phosphorylation of STAT5. The JAK2 inhibitor AG490 blocked phosphorylation of STAT5 and PRL-induced, but not PGE1-induced, Cl- transport
# ::save-date Fri Feb 12, 2016 ::file bel_pmid_1111_7534_6208.txt
(m / multi-sentence
      :snt1 (i / increase-01
            :ARG0 (t / treat-04
                  :ARG1 (c / cell :name (n / name :op1 "HC11"))
                  :ARG2 (p5 / protein :name (n2 / name :op1 "PRL")))
            :ARG1 (p / phosphorylate-01
                  :ARG1 (p2 / protein :name (n3 / name :op1 "STAT5"))))
      :snt2 (b / block-01
            :ARG0 (s2 / small-molecule :name (n4 / name :op1 "AG490")
                  :ARG0-of (i2 / inhibit-01
                        :ARG1 (e / enzyme :name (n5 / name :op1 "JAK2"))))
            :ARG1 (a / and
                  :op1 (p3 / phosphorylate-01
                        :ARG1 (p4 / protein :name (n6 / name :op1 "STAT5")))
                  :op2 (t2 / transport-01
                        :ARG1 (s3 / small-molecule :name (n7 / name :op1 "Cl"))
                        :ARG2-of (i3 / induce-01
                              :ARG0 (s4 / small-molecule :name (n8 / name :op1 "PRL")))
                        :ARG1-of (c2 / contrast-01
                              :ARG2 (b2 / block-01 :polarity -
                                    :ARG1 (t3 / transport-01
                                          :ARG1 s3
                                          :ARG2-of (i4 / induce-01
                                                :ARG0 (s / small-molecule :name (n10 / name :op1 "PGE1"))))))))))

# ::id bel_pmid_1112_3332.21962 ::date 2015-04-21T18:40:34 ::annotator SDL-AMR-09 ::preferred
# ::snt These results suggest that ERK2 has a regulatory role in activating CREB in vivo in lung neutrophils after hemorrhage or endotoxemia.
# ::save-date Sat Apr 25, 2015 ::file bel_pmid_1112_3332_21962.txt
(s / suggest-01
      :ARG0 (t / thing
            :ARG2-of (r / result-01)
            :mod (t2 / this))
      :ARG1 (r2 / role
            :topic (r3 / regulate-01
                  :ARG0 (e / enzyme :name (n3 / name :op1 "ERK2"))
                  :ARG1 (a / activate-01
                        :ARG1 (p / protein :name (n / name :op1 "CREB"))
                        :manner (i / in-vivo)
                        :location (c / cell :name (n2 / name :op1 "neutrophil")
                              :part-of (l / lung))
                        :time (a2 / after
                              :mod (o / or
                                    :op1 (h / hemorrhage-01)
                                    :op2 (e2 / endotoxemia)))))
            :poss e))

# ::id bel_pmid_1112_3332.37042 ::date 2015-04-21T18:56:11 ::annotator SDL-AMR-09 ::preferred
# ::snt These results suggest that ERK2 has a regulatory role in activating CREB in vivo in lung neutrophils after hemorrhage or endotoxemia.
# ::save-date Sat Apr 25, 2015 ::file bel_pmid_1112_3332_37042.txt
(s / suggest-01
      :ARG0 (t / thing
            :ARG2-of (r / result-01)
            :mod (t2 / this))
      :ARG1 (r2 / role
            :topic (r3 / regulate-01
                  :ARG0 (e / enzyme :name (n / name :op1 "ERK2"))
                  :ARG1 (a / activate-01
                        :ARG1 (p / protein :name (n2 / name :op1 "CREB"))
                        :manner (i / in-vivo)
                        :location (c / cell :name (n3 / name :op1 "neutrophil")
                              :part-of (l / lung))
                        :time (a2 / after
                              :mod (o / or
                                    :op1 (h / hemorrhage-01)
                                    :op2 (e2 / endotoxemia)))))
            :poss e))

# ::id bel_pmid_1112_7821.23468 ::date 2015-04-21T19:02:13 ::annotator SDL-AMR-09 ::preferred
# ::snt Tyrosine phosphorylation of JAK1 was detected at a very low concentration of IL-4 (1 ng/ml), while IL-13 induced phosphorylation only at concentrations of 50 ng/ml and above, both in normal (Figure 2a,b, upper blots) and tumor lung myo®broblasts (Figure 2c,d, upper blots).
# ::save-date Sun Dec 20, 2015 ::file bel_pmid_1112_7821_23468.txt
(c / contrast-01
      :ARG1 (d / detect-01
            :ARG1 (p / phosphorylate-01
                  :ARG1 (a / amino-acid :name (n / name :op1 "tyrosine")
                        :part-of (e / enzyme :name (n2 / name :op1 "JAK1"))))
            :condition (p2 / protein :name (n3 / name :op1 "IL-4")
                  :quant (c2 / concentration-quantity :quant 1
                        :unit (n4 / nanogram-per-milliliter)
                        :ARG1-of (l / low-04
                              :degree (v / very)))))
      :ARG2 (d2 / detect-01
            :ARG1 (p3 / phosphorylate-01
                  :ARG2-of (i / induce-01
                        :ARG0 p4))
            :condition (p4 / protein :name (n5 / name :op1 "IL-13")
                  :quant (a2 / and
                        :op1 (c3 / concentration-quantity :quant 50
                              :unit n4)
                        :op2 (a3 / above
                              :op1 c3)
                        :mod (o / only))))
      :location (a4 / and
            :op1 (m / myofibroblast
                  :part-of (l2 / lung)
                  :ARG1-of (n6 / normal-02)
                  :ARG1-of (d3 / describe-01
                        :ARG0 (a5 / and
                              :op1 (f / figure :mod "2a")
                              :op2 (f2 / figure :mod "2b")
                              :op3 (b / blot
                                    :mod (u / upper)))))
            :op2 (m2 / myofibroblast
                  :part-of l2
                  :mod (t / tumor)
                  :ARG1-of (d4 / describe-01
                        :ARG0 (a6 / and
                              :op1 (f3 / figure :mod "2c")
                              :op2 (f4 / figure :mod "2d")
                              :op3 b)))))

# ::id bel_pmid_1112_7821.23470 ::date 2015-04-21T19:39:15 ::annotator SDL-AMR-09 ::preferred
# ::snt the constitutive phosphorylation of STAT3 was observed repeatedly in tumor myo®bro- blasts (Figure 6f), but only occasionally in normal ®broblasts (Figure 6e). In the latter cells, IL-4 and IL- 13 induced (Figure 6d) or increased (Figure 6e) the tyrosine phosphorylation of STAT3, whereas in tumor myo®broblasts the two cytokines only caused an increase in the phosphorylation of STAT3 (Figure 6f).
# ::save-date Sun Dec 20, 2015 ::file bel_pmid_1112_7821_23470.txt
(m / multi-sentence
      :snt1 (c / contrast-01
            :ARG1 (o / observe-01
                  :ARG1 (p / phosphorylate-01
                        :ARG1 (p2 / protein :name (n / name :op1 "STAT3"))
                        :mod (c2 / constitute-01))
                  :ARG1-of (r / repeat-01)
                  :location (m2 / myofibroblast
                        :mod (t / tumor))
                  :ARG1-of (d / describe-01
                        :ARG0 (f / figure :mod "6f")))
            :ARG2 (o2 / observe-01
                  :ARG1 p
                  :frequency (o3 / occasional
                        :mod (o4 / only))
                  :location (f2 / fibroblast
                        :ARG1-of (n2 / normal-02))
                  :ARG1-of (d2 / describe-01
                        :ARG0 (f3 / figure :mod "6e"))))
      :snt2 (c3 / contrast-01
            :ARG1 (o5 / or
                  :op1 (i / induce-01
                        :ARG0 (a / and
                              :op1 (c4 / cytokine :name (n3 / name :op1 "IL-4"))
                              :op2 (c5 / cytokine :name (n4 / name :op1 "IL-13")))
                        :ARG2 (p3 / phosphorylate-01
                              :ARG0 (a2 / amino-acid :name (n6 / name :op1 "tyrosine")
                                    :part-of (p4 / protein :name (n5 / name :op1 "STAT3"))))
                        :ARG1-of (d3 / describe-01
                              :ARG0 (f4 / figure :mod "6d")))
                  :op2 (i2 / increase-01
                        :ARG0 a
                        :ARG1 p3
                        :ARG1-of (d4 / describe-01
                              :ARG0 (f5 / figure :mod "6e")))
                  :location (c6 / cell
                        :mod (l / latter)))
            :ARG2 (c7 / cause-01
                  :ARG0 a
                  :ARG1 (i3 / increase-01
                        :ARG0 a
                        :ARG1 p3)
                  :mod (o6 / only)
                  :location (m3 / myofibroblast
                        :mod (t2 / tumor))
                  :ARG1-of (d5 / describe-01
                        :ARG0 (f6 / figure :mod "6f")))))

# ::id bel_pmid_1112_7821.23472 ::date 2015-04-21T20:05:26 ::annotator SDL-AMR-09 ::preferred
# ::snt In normal lung ®broblasts and in tumor myo®broblasts, STAT6 was indeed phosphorylated on tyrosine residues in response to IL-4 and IL-13 (Figure 4a,b, upper blots).
# ::save-date Fri Jul 24, 2015 ::file bel_pmid_1112_7821_23472.txt
(p / phosphorylate-01
      :ARG1 (r / residue
            :mod (a / amino-acid :name (n / name :op1 "tyrosine"))
            :part-of (p2 / protein :name (n2 / name :op1 "STAT6"))
            :location (a2 / and
                  :op1 (f / fibroblast
                        :ARG1-of (n3 / normal-02)
                        :part-of (l / lung))
                  :op2 (m / myofibroblast
                        :mod (t / tumor))))
      :ARG2-of (r2 / respond-01
            :ARG1 (a3 / and
                  :op1 (p3 / protein :name (n4 / name :op1 "IL-4"))
                  :op2 (p4 / protein :name (n5 / name :op1 "IL-13"))))
      :mod (i / indeed)
      :ARG1-of (d / describe-01
            :ARG0 (a4 / and
                  :op1 (f2 / figure :mod "4a")
                  :op2 (f3 / figure :mod "4b")
                  :op3 (b / blot
                        :mod (u / upper)))))

# ::id bel_pmid_1112_7821.23474 ::date 2015-04-21T20:17:49 ::annotator SDL-AMR-09 ::preferred
# ::snt Finally, Tyk2, the fourth member of the JAK family, was found to be constitutively tyrosine-phosphorylated in these cells. However, IL-4 and IL-13 increased its phosphorylation level in lung myo®broblasts (Figure 2j), but not in normal cells, where both cytokines appear to slightly decrease its extent of phosphoryla- tion (Figure 2i).
# ::save-date Sun Jan 3, 2016 ::file bel_pmid_1112_7821_23474.txt
(m / multi-sentence
      :snt1 (f / find-01 :li "-1"
            :ARG1 (p / phosphorylate-01
                  :ARG1 (a / amino-acid :name (n / name :op1 "tyrosine")
                        :part-of (e / enzyme :name (n2 / name :op1 "Tyk2")
                              :ARG1-of (m2 / mean-01
                                    :ARG2 (m3 / member
                                          :ord (o / ordinal-entity :value 4)
                                          :ARG1-of (i / include-91
                                                :ARG2 (p3 / protein-family :name (n3 / name :op1 "JAK")))))))
                  :manner (c / constitutive)
                  :location (c2 / cell
                        :mod (t / this))))
      :snt2 (c3 / contrast-01
            :ARG1 (i2 / increase-01
                  :ARG0 (a2 / and
                        :op1 (c4 / cytokine :name (n4 / name :op1 "IL-4"))
                        :op2 (c5 / cytokine :name (n5 / name :op1 "IL-13")))
                  :ARG1 (l / level
                        :degree-of (p2 / phosphorylate-01
                              :ARG1 (a3 / amino-acid :name (n6 / name :op1 "tyrosine"))))
                  :location (m4 / myofibroblast
                        :part-of (l2 / lung))
                  :ARG1-of (d / describe-01
                        :ARG0 (f4 / figure :mod "2j")))
            :ARG2 (i3 / increase-01 :polarity -
                  :ARG0 a2
                  :ARG1 l
                  :location (c6 / cell
                        :ARG1-of (n7 / normal-02)
                        :location-of (d2 / decrease-01
                              :ARG0 a2
                              :ARG1 (e3 / extent
                                    :degree-of p2)
                              :ARG1-of (a4 / appear-02)
                              :degree (s / slight)))
                  :ARG1-of (d3 / describe-01
                        :ARG0 (f5 / figure :mod "2i")))))

# ::id bel_pmid_1112_7821.23486 ::date 2015-04-21T20:18:17 ::annotator SDL-AMR-09 ::preferred
# ::snt IL-4 and IL-13 induced tyrosine phosphorylation of STAT6 (green cytoplasmic staining) but probably also nuclear translocation of some phosphorylated STAT6 mole- cules, accounting for the yellow signal detected. Similar results were obtained with normal lung ®broblasts.
# ::save-date Sun Jan 3, 2016 ::file bel_pmid_1112_7821_23486.txt
(m / multi-sentence
      :snt1 (i / induce-01
            :ARG0 (a / and
                  :op1 (p / protein :name (n / name :op1 "IL-4"))
                  :op2 (p2 / protein :name (n2 / name :op1 "IL-13")))
            :ARG2 (a2 / and
                  :op1 (p3 / phosphorylate-01
                        :ARG1 (a3 / amino-acid :name (n3 / name :op1 "tyrosine")
                              :part-of (p4 / protein :name (n4 / name :op1 "STAT6")))
                        :ARG1-of (d / describe-01
                              :ARG0 (s / stain-01
                                    :ARG2 (c / cytoplasm)
                                    :ARG1-of (g / green-02))))
                  :op2 (t / translocate-01
                        :ARG1 (m2 / molecule
                              :mod p4
                              :ARG1-of p3
                              :quant (s2 / some))
                        :ARG2 (n5 / nucleus)
                        :mod (p5 / probable)
                        :mod (a4 / also)
                        :ARG2-of (a5 / account-01
                              :ARG1 (s3 / signal-07
                                    :ARG1-of (d2 / detect-01)
                                    :ARG1-of (y / yellow-02))))))
      :snt2 (o / obtain-01
            :ARG1 (t2 / thing
                  :ARG2-of (r / result-01)
                  :ARG1-of (r2 / resemble-01))
            :ARG2 (f / fibroblast
                  :part-of (l / lung)
                  :ARG1-of (n6 / normal-02))))

# ::id bel_pmid_1113_4016.21280 ::date 2015-04-17T07:07:34 ::annotator SDL-AMR-09 ::preferred
# ::snt Using purified wild-type and mutant c-Raf-1 proteins, we demonstrate that Thr(269) is the major c-Raf-1 site phosphorylated by KSR in vitro and that phosphorylation of this site is essential for c-Raf-1 activation by KSR.
# ::save-date Thu Jul 30, 2015 ::file bel_pmid_1113_4016_21280.txt
(d / demonstrate-01
      :ARG0 (w / we)
      :ARG1 (a / and
            :op1 (p2 / protein-segment
                  :part-of (e5 / enzyme :name (n2 / name :op1 "c-Raf-1"))
                  :domain (a2 / amino-acid :mod 269 :name (n / name :op1 "threonine"))
                  :ARG1-of (m / major-02)
                  :ARG1-of (p / phosphorylate-01
                        :ARG2 (e2 / enzyme :name (n3 / name :op1 "KSR"))
                        :manner (i / in-vitro)))
            :op1 (e3 / essential
                  :domain (p5 / phosphorylate-01
                        :ARG1 a2
                        :mod (e / essential)
                        :purpose (a3 / activate-01
                              :ARG0 e2
                              :ARG1 e5)
                        :mod a2)))
      :manner (u / use-01
            :ARG0 w
            :ARG1 (a4 / and
                  :op1 (p6 / protein
                        :mod (w2 / wild-type)
                        :ARG1-of (p8 / purify-01))
                  :op2 (e4 / enzyme :name (n4 / name :op1 "c-Raf-1")
                        :ARG2-of (m2 / mutate-01)))))

# ::id bel_pmid_1113_4016.22950 ::date 2015-04-21T05:59:02 ::annotator SDL-AMR-09 ::preferred
# ::snt In vivo, low physiologic doses of EGF (0.001-0.1 ng/ml) stimulated KSR activation and induced Thr(269) phosphorylation and activation of c-Raf-1.
# ::save-date Sun Jan 17, 2016 ::file bel_pmid_1113_4016_22950.txt
(a / and
      :op1 (s / stimulate-01
            :ARG0 (p / protein :name (n / name :op1 "EGF")
                  :quant (d / dose
                        :ARG1-of (l / low-04)
                        :mod (p2 / physiology))
                  :quant (v / value-interval :op1 0.001 :op1 0.1
                        :unit (n3 / nanogram-per-milliliter)))
            :ARG1 (a2 / activate-01
                  :ARG1 (e / enzyme :name (n2 / name :op1 "KSR"))))
      :op2 (i / induce-01
            :ARG0 p
            :ARG2 (a3 / and
                  :op1 (p4 / phosphorylate-01
                        :ARG1 (a4 / amino-acid :mod 269 :name (n5 / name :op1 "threonine"))
                        :part-of (e2 / enzyme :name (n4 / name :op1 "c-Raf-1")))
                  :op2 (a5 / activate-01
                        :ARG1 e2)))
      :manner (i2 / in-vivo))

# ::id bel_pmid_1114_5587.7292 ::date 2015-04-21T06:16:53 ::annotator SDL-AMR-09 ::preferred
# ::snt In conclusion , our results show that IL-6 stimulates hepatic IGFBP-4 gene expression and production in vitro and in vivo , thereby suggesting another mechanism by which cytokines could control IGF-I action.
# ::save-date Tue Jun 23, 2015 ::file bel_pmid_1114_5587_7292.txt
(c / conclude-02
      :ARG0 w
      :ARG1 (s / show-01
            :ARG0 (t / thing
                  :ARG1-of (r / result-01)
                  :poss (w / we))
            :ARG1 (s2 / stimulate-01
                  :ARG0 (p / protein :name (n / name :op1 "IL-6"))
                  :ARG1 (a / and
                        :op1 (e / express-03
                              :ARG1 (g / gene :name (n2 / name :op1 "IGFBP-4")
                                    :mod (h / hepatic)))
                        :op2 (p2 / produce-01
                              :ARG1 g)
                        :manner (a2 / and
                              :op1 (i / in-vitro)
                              :op2 (i2 / in-vivo))))
            :ARG0-of (s3 / suggest-01
                  :ARG1 (p5 / possible-01
                        :ARG1 (c2 / control-01
                              :ARG0 (c3 / cytokine)
                              :ARG1 (a3 / act-02
                                    :ARG0 (p4 / protein :name (n4 / name :op1 "IGF-I")))
                              :manner (m / mechanism
                                    :mod (a4 / another)))))))

# ::id bel_pmid_1115_4060.8844 ::date 2015-04-21T06:30:49 ::annotator SDL-AMR-09 ::preferred
# ::snt GAGA box of the rat serine protease inhibitor 2 (spi 2) genes not only acts as a basal promoter element, but also mediates transcriptional activation by growth hormone and interleukin-6.
# ::save-date Sun Jan 3, 2016 ::file bel_pmid_1115_4060_8844.txt
(a / and
      :op1 (a2 / act-02
            :ARG0 (d2 / dna-sequence :name (n3 / name :op1 "GAGA" :op2 "box")
                  :part-of (g2 / gene :name (n / name :op1 "serine" :op2 "protease" :op3 "inhibitor" :op4 "2")
                        :mod (r / rat)))
            :ARG1 (e2 / element
                  :ARG0-of (p / promote-01
                        :mod (b2 / basal))))
      :op2 (m / mediate-01
            :ARG0 d2
            :ARG1 (a3 / activate-01
                  :ARG0 (a4 / and
                        :op1 (h / hormone
                              :ARG0-of (g / grow-01))
                        :op2 (p2 / protein :name (n2 / name :op1 "interleukin-6")))
                  :mod (t / transcribe-01))
            :mod (a5 / also)))

# ::id bel_pmid_1116_0334.6798 ::date 2015-04-21T06:51:13 ::annotator SDL-AMR-09 ::preferred
# ::snt SDF-1alpha treatment induced expression of the chemokines monocyte chemoattractant protein-1, IL-8, and IFN-gamma-inducible protein-10.
# ::save-date Sun Jan 3, 2016 ::file bel_pmid_1116_0334_6798.txt
(i / induce-01
      :ARG0 (t / treat-04
            :ARG2 (p / protein :name (n / name :op1 "SDF-1" :op2 "alpha")))
      :ARG2 (e / express-03
            :ARG2 (a / and
                  :op1 (p2 / protein :name (n2 / name :op1 "monocyte" :op2 "chemoattractant" :op3 "protein-1"))
                  :op2 (p3 / protein :name (n4 / name :op1 "IL-8"))
                  :op3 (p4 / protein :name (n3 / name :op1 "IFN-gamma-inducible" :op2 "protein-10"))
                  :mod (p5 / protein :name (n5 / name :op1 "chemokine")))))

# ::id bel_pmid_1116_0334.7176 ::date 2015-04-21T07:44:10 ::annotator SDL-AMR-09 ::preferred
# ::snt CXCR4 protein expression was also enhanced upon treatment with TNF-alpha and IL-1beta (2- to 3-fold).
# ::save-date Thu Dec 17, 2015 ::file bel_pmid_1116_0334_7176.txt
(e / enhance-01
      :ARG1 (e2 / express-03
            :ARG2 (p / protein :name (n / name :op1 "CXCR4")))
      :mod (a / also)
      :condition (t / treat-04
            :ARG2 (a2 / and
                  :op1 (p2 / protein :name (n2 / name :op1 "TNF-alpha"))
                  :op2 (p3 / protein :name (n3 / name :op1 "IL-1beta"))
                  :quant (p4 / product-of
                        :op1 (v / value-interval :op1 2 :op2 3)))))

# ::id bel_pmid_1116_0334.7194 ::date 2015-04-21T07:55:30 ::annotator SDL-AMR-09 ::preferred
# ::snt Enhancement of CXC chemokine receptor 4 (CXCR4) mRNA expression was observed upon treatment with the cytokines TNF-alpha and IL-1beta.
# ::save-date Thu May 7, 2015 ::file bel_pmid_1116_0334_7194.txt
(o / observe-01
      :ARG1 (e / enhance-01
            :ARG1 (e2 / express-03
                  :ARG1 (n6 / nucleic-acid :name (n5 / name :op1 "mRNA"))
                  :ARG2 (p / protein :name (n / name :op1 "CXC" :op2 "chemokine" :op3 "receptor" :op4 "4")
                        :ARG1-of (d / describe-01
                              :ARG2 (p2 / protein :name (n4 / name :op1 "CXCR4"))))))
      :condition (t / treat-04
            :ARG2 (a / and
                  :op1 (c / cytokine :name (n2 / name :op1 "TNF-alpha"))
                  :op2 (c2 / cytokine :name (n3 / name :op1 "IL-1beta")))))

# ::id bel_pmid_1116_0334.22876 ::date 2015-04-21T08:01:25 ::annotator SDL-AMR-09 ::preferred
# ::snt Stimulation of cells with the ligand for CXCR4, stromal cell-derived factor-1alpha (SDF-1alpha), resulted in an elevation in intracellular Ca(2+) concentration
# ::save-date Sun Jan 3, 2016 ::file bel_pmid_1116_0334_22876.txt
(r / result-01
      :ARG1 (s / stimulate-01
            :ARG0 (p2 / protein :name (n / name :op1 "stromal" :op2 "cell-derived" :op3 "factor-1alpha")
                  :ARG1-of (b / bind-01
                        :ARG2 (p / protein :name (n2 / name :op1 "CXCR4"))))
            :ARG1 (c / cell))
      :ARG2 (e / elevate-01
            :ARG1 (c2 / concentrate-02
                  :ARG1 (c3 / calcium
                        :mod (i / intracellular)
                        :ARG1-of (i2 / ionize-01 :value "2+")))))

# ::id bel_pmid_1116_0334.22880 ::date 2015-04-21T08:03:27 ::annotator SDL-AMR-09 ::preferred
# ::snt resulted in an elevation in intracellular Ca(2+) concentration and activation of the mitogen-activated protein kinase cascade, specifically, extracellular signal-regulated kinase 2 (ERK2) mitogen-activated protein kinase.
# ::save-date Mon Dec 21, 2015 ::file bel_pmid_1116_0334_22880.txt
(r / result-01
      :ARG1 (a3 / and
            :op1 (e / elevate-01
                  :ARG1 (c2 / concentrate-02
                        :ARG1 (c / calcium
                              :mod (i / intracellular)
                              :ARG1-of (i2 / ionize-01 :value "2+"))))
            :op2 (a2 / activate-01
                  :ARG1 (c3 / cascade
                        :mod (p / pathway :name (n / name :op1 "mitogen-activated" :op2 "protein" :op3 "kinase")
                              :ARG1-of (m / mean-01
                                    :ARG2 (p2 / pathway :name (n2 / name :op1 "extracellular" :op2 "signal-regulated" :op3 "kinase" :op4 "2" :op5 "mitogen-activated" :op6 "protein" :op7 "kinase"))
                                    :ARG1-of (s / specific-02)))))))

# ::id bel_pmid_1116_0334.23556 ::date 2015-04-21T08:12:32 ::annotator SDL-AMR-09 ::preferred
# ::snt IL-1beta stimulation also enhanced CXCR4 expression (28.8% for CRT-J and 41.6% for U87-MG cells).
# ::save-date Sun Jan 3, 2016 ::file bel_pmid_1116_0334_23556.txt
(s / stimulate-01
      :ARG0 (p / protein :name (n / name :op1 "IL-1beta"))
      :ARG0-of (e / enhance-01
            :ARG1 (e2 / express-03
                  :ARG2 (p2 / protein :name (n2 / name :op1 "CXCR4")
                        :ARG0-of (m / mean-01
                              :ARG1 (a / and
                                    :op1 (c / cell :name (n3 / name :op1 "CRT-J")
                                          :mod (p3 / percentage-entity :value 28.8))
                                    :op2 (c2 / cell :name (n5 / name :op1 "U87-MG")
                                          :mod (p4 / percentage-entity :value 41.6))))))
            :mod (a2 / also)))

# ::id bel_pmid_1116_0334.37038 ::date 2015-04-21T08:18:07 ::annotator SDL-AMR-09 ::preferred
# ::snt SDF-1alpha-induced chemokine expression was abrogated upon inclusion of U0126, a pharmacological inhibitor of ERK1/2, indicating that the ERK signaling cascade is involved in this response.
# ::save-date Sun Jan 17, 2016 ::file bel_pmid_1116_0334_37038.txt
(a / abrogate-01
      :ARG1 (e / express-03
            :ARG2 (c / chemokine)
            :ARG2-of (i / induce-01
                  :ARG0 (p / protein :name (n / name :op1 "SDF-1" :op2 "alpha"))))
      :time (i2 / include-01
            :ARG1 (s3 / small-molecule :name (n5 / name :op1 "U0126")
                  :ARG0-of (i3 / inhibit-01
                        :ARG1 (s / slash
                              :op1 (e2 / enzyme :name (n2 / name :op1 "ERK1"))
                              :op2 (e3 / enzyme :name (n3 / name :op1 "ERK2")))
                        :mod (p2 / pharmacology))))
      :ARG0-of (i4 / indicate-01
            :ARG1 (i5 / involve-01
                  :ARG1 (p3 / pathway :name (n4 / name :op1 "ERK")
                        :ARG0-of (s2 / signal-07))
                  :ARG2 (r / respond-01
                        :mod (t / this)))))

# ::id bel_pmid_1119_6191.2576 ::date 2015-04-21T08:39:33 ::annotator SDL-AMR-09 ::preferred
# ::snt In T47D cells, IL-6 stimulated the activation of Janus-activated kinase 1 tyrosine kinase and signal transducers and activators of transcription (STAT) 1 and STAT3 transcription factors. Expression of dominant negative STAT3 in the cells strongly reduced IL-6-mediated growth inhibition but did not prevent IL-6-induced cell migration.
# ::save-date Fri Feb 5, 2016 ::file bel_pmid_1119_6191_2576.txt
(m / multi-sentence
      :snt1 (s / stimulate-01
            :ARG0 (p / protein :name (n / name :op1 "IL-6"))
            :ARG1 (a / activate-01
                  :ARG1 (a2 / and
                        :op1 (e / enzyme :name (n2 / name :op1 "Janus-activated" :op2 "kinase" :op3 "1" :op4 "tyrosine" :op5 "kinase"))
                        :op2 (p2 / protein :name (n3 / name :op1 "signal" :op2 "transducers" :op3 "activator" :op4 "transcription"))
                        :op3 (e2 / enzyme :name (n4 / name :op1 "STAT3" :op2 "transcription" :op3 "factors"))))
            :location (c4 / cell :name (n8 / name :op1 "T47D")))
      :snt2 (c / contrast-01
            :ARG1 (r / reduce-01
                  :ARG0 (e3 / express-03
                        :ARG2 (p3 / protein :name (n5 / name :op1 "STAT3")
                              :ARG2-of (m4 / mutate-01 :mod "-/-")
                              :ARG0-of (d / dominate-01))
                        :location (c2 / cell))
                  :ARG1 (i / inhibit-01
                        :ARG1 (g / grow-01)
                        :ARG1-of (m2 / mediate-01
                              :ARG0 p))
                  :ARG1-of (s2 / strong-02))
            :ARG2 (p4 / prevent-01 :polarity -
                  :ARG0 e3
                  :ARG1 (m3 / migrate-01
                        :ARG0 (c3 / cell)
                        :ARG2-of (i2 / induce-01
                              :ARG0 p)))))

# ::id bel_pmid_1119_6191.23672 ::date 2015-04-21T09:38:51 ::annotator SDL-AMR-09 ::preferred
# ::snt The IL-6-type cytokines, IL-6 and oncostatin M, simultaneously inhibited cell proliferation and increased cell migration
# ::save-date Sun Jan 3, 2016 ::file bel_pmid_1119_6191_23672.txt
(i / inhibit-01
      :ARG0 (a / and
            :op1 (p2 / protein :name (n3 / name :op1 "IL-6-type" :op2 "cytokine"))
            :op2 (p3 / protein :name (n4 / name :op1 "IL-6"))
            :op3 (p4 / protein :name (n5 / name :op1 "oncostatin" :op2 "M")))
      :ARG1 (a2 / and
            :op1 (p / proliferate-01
                  :ARG0 (c3 / cell))
            :op2 (i2 / increase-01
                  :ARG1 (m / migrate-01
                        :ARG0 (c4 / cell))))
      :manner (s / simultaneous))

# ::id bel_pmid_1119_6191.38528 ::date 2015-04-21T09:44:41 ::annotator SDL-AMR-09 ::preferred
# ::snt Pretreatment of cells with EGF receptor specific inhibitor CGP59326 or with the bispecific EGF receptor/ERBB2  inhibitor PD153035, diminished IL6 induced MAPK activation. Even the PKB phosphorylation was also affected by these two inhibitors.
# ::save-date Fri Feb 12, 2016 ::file bel_pmid_1119_6191_38528.txt
(m / multi-sentence
      :snt1 (d / diminish-01
            :ARG0 (o / or
                  :op1 (p / pretreat-01
                        :ARG1 (c / cell)
                        :ARG3 (s4 / small-molecule :name (n / name :op1 "CGP59326")
                              :ARG0-of (i / inhibit-01)
                              :ARG1-of (s / specific-02
                                    :ARG2 (e2 / enzyme :name (n7 / name :op1 "EGF" :op2 "receptor")))))
                  :op2 (p3 / pretreat-01
                        :ARG1 c
                        :ARG3 (s3 / small-molecule :name (n3 / name :op1 "PD153035")
                              :ARG0-of (i2 / inhibit-01)
                              :mod (b / bispecific
                                    :prep-to (s2 / slash
                                          :op1 e2
                                          :op2 (p2 / protein :name (n2 / name :op1 "ERBB2")))))))
            :ARG1 (a / activate-01
                  :ARG1 (e / enzyme :name (n4 / name :op1 "MAPK"))
                  :ARG2-of (i3 / induce-01
                        :ARG0 (p5 / protein :name (n5 / name :op1 "il6")))))
      :snt2 (a2 / affect-01
            :ARG1 (p6 / phosphorylate-01
                  :ARG1 (e3 / enzyme :name (n6 / name :op1 "PKB")))
            :ARG2 (t / thing :quant 2
                  :ARG0-of (i4 / inhibit-01)
                  :mod (t2 / this))
            :mod (a3 / also)))

# ::id bel_pmid_1120_8678.16854 ::date 2015-04-21T09:56:46 ::annotator SDL-AMR-09 ::preferred
# ::snt Tissue factor (TF) can be induced in monocytes by external signals such as growth factors, inflammatory cytokines (interleukin [IL]-1b and tumor necrosis factor [TNF]-a), oxidized LDLs, and endotoxin. 2
# ::save-date Wed Feb 24, 2016 ::file bel_pmid_1120_8678_16854.txt
(p6 / possible-01
      :ARG1 (i / induce-01
            :ARG2 (p5 / protein :name (n6 / name :op1 "tissue" :op2 "factor"))
            :location (m / monocyte)
            :manner (s / signal-07
                  :mod (e / external)
                  :example (a / and
                        :op1 (g / growth-factor)
                        :op2 (c / cytokine
                              :ARG1-of (i2 / inflame-01)
                              :ARG0-of (m2 / mean-01
                                    :ARG1 (a2 / and
                                          :op1 (p / protein :name (n2 / name :op1 "interleukin" :op2 "IL-1b"))
                                          :op2 (p4 / protein :name (n3 / name :op1 "tumor" :op2 "necrosis" :op3 "factor")))))
                        :op3 (p2 / protein :name (n4 / name :op1 "LDL")
                              :ARG1-of (o / oxidize-01))
                        :op4 (s2 / small-molecule :name (n5 / name :op1 "endotoxin"))))
            :ARG1-of (d2 / describe-01
                  :ARG0 (p3 / publication
                        :ARG1-of (c2 / cite-01
                              :ARG2 2)))))

# ::id bel_pmid_1120_8678.23564 ::date 2015-04-21T10:07:33 ::annotator SDL-AMR-09 ::preferred
# ::snt Incubation of monocytes with LPS or IL-1b resulted in a 10- and 5-fold increase of TF activity, respectively.
# ::save-date Fri Feb 12, 2016 ::file bel_pmid_1120_8678_23564.txt
(r / result-01
      :ARG1 (i / incubate-01
            :ARG1 (m / monocyte)
            :ARG2 (o / or
                  :op1 (l / lipopolysaccharide)
                  :op2 (p / protein :name (n2 / name :op1 "IL-1b"))))
      :ARG2 (i2 / increase-01
            :ARG1 (a / activity-06
                  :ARG0 (p3 / protein :name (n3 / name :op1 "TF")))
            :ARG2 (p2 / product-of :op1 10 :op2 5)))

# ::id bel_pmid_1120_8678.24148 ::date 2015-04-21T10:55:26 ::annotator SDL-AMR-09 ::preferred
# ::snt In human aortic smooth muscle cells, fibrates inhibit the IL-1b?induced expression of cyclooxygenase (COX)-2 and IL-6 by inhibiting the NF-kB and AP-1 signaling pathway.9,10
# ::save-date Sun Jan 17, 2016 ::file bel_pmid_1120_8678_24148.txt
(i / inhibit-01
      :ARG0 (f / fibrate)
      :ARG1 (e / express-03
            :ARG2 (a / and
                  :op1 (e2 / enzyme :name (n / name :op1 "cyclooxygenase" :op2 "2"))
                  :op2 (p2 / protein :name (n3 / name :op1 "IL-6")))
            :ARG2-of (i2 / induce-01
                  :ARG0 (p / protein :name (n2 / name :op1 "IL-1b"))))
      :manner (i3 / inhibit-01
            :ARG1 (a2 / and
                  :op1 (p3 / protein :name (n4 / name :op1 "NF-kB"))
                  :op2 (p4 / pathway :name (n5 / name :op1 "AP-1")
                        :ARG0-of (s / signal-07))))
      :location (c / cell
            :mod (m / muscle
                  :ARG1-of (s2 / smooth-06))
            :mod (a3 / aortic
                  :mod (h / human)))
      :ARG1-of (d / describe-01
            :ARG0 (p5 / publication
                  :ARG0-of (c2 / cite-01
                        :ARG2 (a4 / and :op1 9 :op2 10)))))

# ::id bel_pmid_1120_8678.24150 ::date 2015-04-22T04:19:37 ::annotator SDL-AMR-09 ::preferred
# ::snt PPARa activators prevent TNF-a?induced VCAM-1 expression in human saphenous vein endothelial cells, partly via inhibition of the NF-kB pathway.14
# ::save-date Sun Jan 3, 2016 ::file bel_pmid_1120_8678_24150.txt
(p / prevent-01
      :ARG0 (a / activate-01
            :ARG1 (p2 / protein :name (n / name :op1 "PPARa")))
      :ARG1 (e / express-03
            :ARG2 (p3 / protein :name (n2 / name :op1 "VCAM-1"))
            :ARG2-of (i / induce-01
                  :ARG0 (p4 / protein :name (n3 / name :op1 "TNF-a"))))
      :location (c / cell
            :mod (e2 / endothelium)
            :mod (v / vein
                  :mod (s / saphenous))
            :mod (h / human))
      :degree (p5 / part)
      :manner (i2 / inhibit-01
            :ARG1 (p6 / pathway :name (n5 / name :op1 "NF-kB")))
      :ARG1-of (d / describe-01
            :ARG0 (p7 / publication
                  :ARG1-of (c2 / cite-01
                        :ARG2 14))))

# ::id bel_pmid_1120_8678.24166 ::date 2015-04-22T05:04:52 ::annotator SDL-AMR-09 ::preferred
# ::snt In human vascular endothelial cells, PPARa inhibits the thrombin-mediated activation of endothelin-1 via negative interference with the AP-1 signaling pathway.13
# ::save-date Thu Feb 4, 2016 ::file bel_pmid_1120_8678_24166.txt
(i / inhibit-01
      :ARG0 (p / protein :name (n / name :op1 "PPARa"))
      :ARG1 (a / activate-01
            :ARG1 (p2 / protein :name (n2 / name :op1 "endothelin-1"))
            :ARG1-of (m / mediate-01
                  :ARG0 (e / enzyme :name (n3 / name :op1 "thrombin"))))
      :manner (i2 / interfere-01
            :ARG0 p
            :ARG1 (p3 / pathway :name (n5 / name :op1 "AP-1")
                  :ARG0-of (s / signal-07))
            :ARG0-of (n4 / negative-02))
      :location (c / cell :name (n6 / name :op1 "human" :op2 "vascular" :op3 "endothelial"))
      :ARG1-of (d / describe-01
            :ARG0 (p4 / publication
                  :ARG1-of (c2 / cite-01
                        :ARG2 13))))

# ::id bel_pmid_1120_8678.24170 ::date 2015-04-22T05:15:01 ::annotator SDL-AMR-09 ::preferred
# ::snt Incubation of THP-1 cells with PPARa activators 1 hour before LPS stimulation for 2 hours resulted in a decreased level of TF mRNA compared with cells incubated with only LPS (Figure 2A).
# ::save-date Fri Feb 12, 2016 ::file bel_pmid_1120_8678_24170.txt
(r / result-01
      :ARG1 (i / incubate-01
            :ARG1 (c / cell :name (n / name :op1 "THP-1"))
            :ARG2 (a / activate-01
                  :ARG1 (p / protein :name (n2 / name :op1 "PPARa")))
            :time (b / before
                  :op1 (s / stimulate-01
                        :ARG1 (l2 / lipopolysaccharide)
                        :duration (t2 / temporal-quantity :quant 2
                              :unit (h2 / hour)))
                  :quant (t / temporal-quantity :quant 1
                        :unit (h / hour))))
      :ARG2 (d / decrease-01
            :ARG1 (l / level
                  :quant-of (n5 / nucleic-acid :name (n4 / name :op1 "mRNA")
                        :ARG0-of (e / encode-01
                              :ARG1 (p2 / protein :name (n6 / name :op1 "TF")))))
            :compared-to (c2 / cell
                  :ARG1-of (i2 / incubate-01
                        :ARG2 l2
                        :mod (o / only))))
      :ARG1-of (d2 / describe-01
            :ARG2 (f / figure :mod "2A")))

# ::id bel_pmid_1123_1577.20122 ::date 2015-04-22T05:51:53 ::annotator SDL-AMR-09 ::preferred
# ::snt Bag1, a co-chaperone for heat-shock protein 70 (Hsp70), coordinates signals for cell growth in response to cell stress, by downregulating the activity of Raf-1 kinase. Raf-1 and Hsp70 compete for binding to Bag1, such that Bag1 binds to and activates Raf-1, subsequently activating the downstream extracellular signal-related kinases
# ::save-date Sun Jan 3, 2016 ::file bel_pmid_1123_1577_20122.txt
(m / multi-sentence
      :snt1 (c / coordinate-01
            :ARG1 (p / protein :name (n / name :op1 "Bag1")
                  :ARG0-of (m2 / mean-01
                        :ARG1 (p2 / protein :name (n2 / name :op1 "co-chaperone")
                              :beneficiary (p3 / protein :name (n3 / name :op1 "heat-shock")
                                    :mod (m3 / molecular-mass :mod 70)))))
            :ARG2 (s / signal-07
                  :beneficiary (g / grow-01
                        :ARG1 (c2 / cell))
                  :ARG0-of (r / respond-01
                        :ARG1 (s2 / stress-02
                              :ARG1 (c3 / cell))))
            :manner (d / downregulate-01
                  :ARG1 (a / activity-06
                        :ARG0 (e3 / enzyme :name (n4 / name :op1 "Raf-1")))))
      :snt2 (c4 / compete-01
            :ARG0 (e / enzyme :name (n5 / name :op1 "Raf-1"))
            :ARG1 (p4 / protein :name (n6 / name :op1 "Hsp70"))
            :ARG2 (b / bind-01
                  :ARG1 (p5 / protein :name (n7 / name :op1 "Bag1")))
            :ARG1-of (c5 / cause-01
                  :ARG0 (a3 / and
                        :op1 (b2 / bind-01
                              :ARG0 p5
                              :ARG1 e)
                        :op2 (a4 / activate-01
                              :ARG0 p5
                              :ARG1 e)))
            :time (s3 / subsequent
                  :op1 (a5 / activate-01
                        :ARG1 (e2 / enzyme :name (n8 / name :op1 "extracellular" :op2 "signal-related" :op3 "kinase")
                              :mod (d2 / downstream))))))

# ::id bel_pmid_1123_9409.20136 ::date 2015-04-21T10:39:53 ::annotator SDL-AMR-09 ::preferred
# ::snt Phosphorylation of Shc produces its binding to the adaptor protein Grb2, causing activation of the protooncogene ras, which is also upstream of the MAP kinase pathway.
# ::save-date Wed Apr 22, 2015 ::file bel_pmid_1123_9409_20136.txt
(c / cause-01
      :ARG0 (p / produce-01
            :ARG0 (p2 / phosphorylate-01
                  :ARG1 (p3 / protein :name (n / name :op1 "shc")))
            :ARG1 (b / bind-01
                  :ARG1 p3
                  :ARG2 (p4 / protein :name (n2 / name :op1 "grb2")
                        :mod (a / adaptor))))
      :ARG1 (a2 / activate-01
            :ARG1 (p5 / protooncogene :name (n3 / name :op1 "ras")
                  :ARG1-of (b2 / be-located-at-91
                        :ARG2 (p6 / pathway :name (n4 / name :op1 "MAP" :op2 "kinase"))
                        :direction (u / upstream)
                        :mod (a3 / also)))))

# ::id bel_pmid_1123_9409.21258 ::date 2015-04-21T10:48:33 ::annotator SDL-AMR-09 ::preferred
# ::snt insulin receptor phosphorylates a number of intracellular substrates on tyrosine including members of the insulin receptor substrate family (IRS1/2/3/4), the Shc adaptor...
# ::save-date Sat Jan 2, 2016 ::file bel_pmid_1123_9409_21258.txt
(p / phosphorylate-01
      :ARG1 (a2 / and
            :op1 (n / number
                  :quant-of (s / substrate
                        :mod (i2 / intracellular)))
            :op2 (i4 / include-01
                  :ARG1 (m / member
                        :ARG1-of (m2 / mean-01
                              :ARG2 (s2 / slash
                                    :op1 (p4 / protein :name (n5 / name :op1 "IRS1"))
                                    :op2 (p5 / protein :name (n6 / name :op1 "IRS2"))
                                    :op3 (p6 / protein :name (n7 / name :op1 "IRS3"))
                                    :op4 (p7 / protein :name (n8 / name :op1 "IRS4")))))
                  :ARG2 (p2 / protein-family :name (n3 / name :op1 "insulin" :op2 "receptor" :op3 "substrate")))
            :op3 (p3 / protein :name (n4 / name :op1 "Shc" :op2 "adaptor")))
      :ARG2 (r / receptor
            :mod (i / insulin))
      :location (a / amino-acid :name (n2 / name :op1 "tyrosine")))

# ::id bel_pmid_1123_9409.23154 ::date 2015-04-22T04:49:02 ::annotator SDL-AMR-09 ::preferred
# ::snt Insulin stimulates the tyrosine kinase activity of its receptor, leading to the phosphorylation of a number of cellular substrates, including Gab1, Shc, IRS 1 - 4, and Cbl. Gab1 appears to interact with the SH2 containing tyrosine phosphatase SHP2, leading to the activation of the MAP kinase pathway.
# ::save-date Wed Jan 13, 2016 ::file bel_pmid_1123_9409_23154.txt
(m / multi-sentence
      :snt1 (s / stimulate-01
            :ARG0 (i / insulin)
            :ARG1 (a / activity-06
                  :ARG0 (r / receptor
                        :poss i)
                  :ARG1 (e / enzyme :name (n / name :op1 "tyrosine" :op2 "kinase")))
            :ARG0-of (l / lead-03
                  :ARG2 (p / phosphorylate-01
                        :ARG1 (n2 / number
                              :quant-of (s2 / substrate
                                    :mod (c / cell)
                                    :ARG2-of (i2 / include-01
                                          :ARG1 (a2 / and
                                                :op1 (p2 / protein :name (n3 / name :op1 "Gab1"))
                                                :op2 (p3 / protein :name (n4 / name :op1 "Shc"))
                                                :op3 (p4 / protein :name (n5 / name :op1 "IRS")
                                                      :mod (v / value-interval :op1 1 :op2 4))
                                                :op4 (p5 / protein :name (n6 / name :op1 "Cbl")))))))))
      :snt2 (a3 / appear-02
            :ARG1 (p6 / protein :name (n7 / name :op1 "Gab1"))
            :ARG2 (i3 / interact-01
                  :ARG0 p6
                  :ARG1 (t / tyrosine-phosphatase :name (n8 / name :op1 "SHP2")
                        :ARG1-of (c2 / contain-01
                              :ARG0 (p8 / protein :name (n9 / name :op1 "Sh2"))))
                  :ARG0-of (l2 / lead-03
                        :ARG2 (a4 / activate-01
                              :ARG1 (p9 / pathway :name (n10 / name :op1 "MAP" :op2 "kinase")))))))

# ::id bel_pmid_1123_9409.24744 ::date 2015-04-21T10:08:31 ::annotator SDL-AMR-09 ::preferred
# ::snt Overexpression of these enzymes [LAR and PTP1B] in cultured cells prevents insulin receptor kinase activation.
# ::save-date Wed Jun 24, 2015 ::file bel_pmid_1123_9409_24744.txt
(p / prevent-01
      :ARG0 (o / overexpress-01
            :ARG1 (a / and
                  :op1 (e / enzyme :name (n / name :op1 "LAR"))
                  :op2 (e2 / enzyme :name (n2 / name :op1 "PTP1B")))
            :location (c / cell
                  :ARG1-of (c2 / culture-01)))
      :ARG1 (a2 / activate-01
            :ARG1 (p2 / protein :name (n3 / name :op1 "insulin" :op2 "receptor" :op3 "kinase"))))

# ::id bel_pmid_1123_9409.32116 ::date 2015-04-21T10:11:51 ::annotator SDL-AMR-09 ::preferred
# ::snt The translocation of phosphorylated cbl recruits additional signaling proteins to the lipid raft, resulting in the activation of the G protein TC10.
# ::save-date Thu Dec 17, 2015 ::file bel_pmid_1123_9409_32116.txt
(r / recruit-01
      :ARG0 (t / translocate-01
            :ARG1 (p / protein :name (n / name :op1 "cbl")
                  :ARG1-of (p2 / phosphorylate-01)))
      :ARG1 (p3 / protein
            :ARG0-of (s / signal-07)
            :mod (a / additional))
      :ARG2 (r2 / raft
            :mod (l / lipid))
      :ARG2-of (r3 / result-01
            :ARG1 (a2 / activate-01
                  :ARG1 (p4 / protein :name (n2 / name :op1 "G" :op2 "TC10")))))

# ::id bel_pmid_1125_0916.23582 ::date 2015-04-21T10:19:34 ::annotator SDL-AMR-09 ::preferred
# ::snt Contrary to the hypothesis, both IL-1beta and IL-6 treatment resulted in a significant decrease in OT receptor messenger RNA measured by ribonuclease protection analysis.
# ::save-date Sun Jan 3, 2016 ::file bel_pmid_1125_0916_23582.txt
(r / result-01
      :ARG1 (t / treat-04
            :ARG1 (a / and
                  :op1 (p / protein :name (n / name :op1 "IL-1beta"))
                  :op2 (p2 / protein :name (n2 / name :op1 "IL-6"))))
      :ARG2 (d / decrease-01
            :ARG1 (n5 / nucleic-acid :name (n3 / name :op1 "messeger" :op2 "RNA")
                  :ARG0-of (e / encode-01
                        :ARG1 (r5 / receptor :name (n4 / name :op1 "OT"))))
            :ARG2 (s / significant-02)
            :ARG1-of (m / measure-01
                  :manner (a2 / analyze-01
                        :ARG1 (p3 / protection
                              :mod (r3 / ribonuclease)))))
      :ARG0-of (c / counter-01
            :ARG1 (t2 / thing
                  :ARG1-of (h / hypothesize-01))))

# ::id bel_pmid_1125_2722.32494 ::date 2015-04-22T01:33:42 ::annotator SDL-AMR-09 ::preferred
# ::snt We demonstrated that ROR alpha is expressed in human primary smooth-muscle cells and that ectopic expression of ROR alpha1 inhibits TNFalpha-induced IL-6, IL-8 and COX-2 expression in these cells.
# ::save-date Sun Jan 3, 2016 ::file bel_pmid_1125_2722_32494.txt
(d / demonstrate-01
      :ARG0 (w / we)
      :ARG1 (a / and
            :op1 (e / express-03
                  :ARG2 (p4 / protein :name (n2 / name :op1 "ROR" :op2 "alpha" :op3 "receptor"))
                  :location (c / cell
                        :mod (m / muscle
                              :ARG1-of (s / smooth-06
                                    :mod (p / primary)))
                        :mod (h / human)))
            :op2 (i / inhibit-01
                  :ARG0 (e2 / express-03
                        :ARG2 (p2 / protein :name (n7 / name :op1 "ROR" :op2 "alpha1" :op3 "receptor"))
                        :manner (e3 / ectopic))
                  :ARG1 (a2 / and
                        :op1 (p5 / protein :name (n3 / name :op1 "IL-6")
                              :ARG2-of (i2 / induce-01
                                    :ARG0 (p3 / protein :name (n4 / name :op1 "TNFalpha"))))
                        :op2 (p6 / protein :name (n5 / name :op1 "IL-8"))
                        :op3 (e4 / express-03
                              :ARG2 (e5 / enzyme :name (n6 / name :op1 "COX-2"))))
                  :location (c4 / cell
                        :mod (t / this)))))

# ::id bel_pmid_1127_9172.6266 ::date 2015-04-20T09:43:50 ::annotator SDL-AMR-09 ::preferred
# ::snt SB203580, a specific p38 MAPK inhibitor, attenuated these effects, further confirming that both MMK6 and MMK3 act via p38 MAPK, whereas they had no effect on the increase in glucose transport induced by a constitutively active MAPK kinase 1 (MEK1) mutant or by myristoylated Akt.
# ::save-date Fri Feb 12, 2016 ::file bel_pmid_1127_9172_6266.txt
(a6 / attenuate-01
      :ARG0 (s2 / small-molecule :name (n / name :op1 "SB203580")
            :ARG0-of (i2 / inhibit-01
                  :ARG1 (p / protein-family :name (n2 / name :op1 "p38" :op2 "MAPK")))
            :ARG1-of (s / specific-02))
      :ARG1 (a2 / affect-01
            :mod (t / this))
      :ARG0-of (c / confirm-01
            :ARG1 (a4 / act-01
                  :ARG0 (a7 / and
                        :op1 (e / enzyme :name (n3 / name :op1 "MKK6"))
                        :op2 (e2 / enzyme :name (n4 / name :op1 "MKK3")))
                  :manner p
                  :ARG1-of (c2 / contrast-01
                        :ARG2 (a3 / affect-01 :polarity -
                              :ARG0 a7
                              :ARG1 (i3 / increase-01
                                    :ARG1 (t2 / transport-01
                                          :ARG1 (g / glucose))
                                    :ARG2-of (i4 / induce-01
                                          :ARG0 (o / or
                                                :op1 (e4 / enzyme :name (n5 / name :op1 "MAPK" :op2 "kinase" :op3 "1")
                                                      :ARG2-of (m3 / mutate-01)
                                                      :ARG0-of (a / activity-06
                                                            :mod (c3 / constitutive)))
                                                :op2 (e5 / enzyme :name (n6 / name :op1 "Akt")
                                                      :ARG1-of (m5 / myristoylate-00))))))))
            :degree (f / further)))

# ::id bel_pmid_1127_9172.21850 ::date 2015-04-21T10:58:48 ::annotator SDL-AMR-09 ::preferred
# ::snt Constitutively active MKK6/3 mutants up-regulated GLUT1 expression and down-regulated GLUT4 expression, thereby significantly increasing basal glucose transport but diminishing transport induced by insulin.
# ::save-date Mon Jan 4, 2016 ::file bel_pmid_1127_9172_21850.txt
(c / cause-01
      :ARG0 (a / and
            :op1 (u / upregulate-01
                  :ARG1 (e2 / express-03
                        :ARG2 (p / protein :name (n2 / name :op1 "GLUT1")))
                  :ARG2 (s2 / slash
                        :op1 (e4 / enzyme :name (n5 / name :op1 "MKK6")
                              :ARG0-of (a2 / activity-06
                                    :mod (c2 / constitutive)))
                        :op2 (e5 / enzyme :name (n6 / name :op1 "MKK3")
                              :ARG1-of a2)
                        :ARG2-of (m / mutate-01)))
            :op2 (d / downregulate-01
                  :ARG1 (e3 / express-03
                        :ARG2 (p2 / protein :name (n3 / name :op1 "GLUT4")))
                  :ARG2 m))
      :ARG1 (c3 / contrast-01
            :ARG1 (i / increase-01
                  :ARG1 (t / transport-01
                        :ARG1 (g / glucose
                              :mod (b / basal)))
                  :ARG2 (s / significant-02))
            :ARG2 (d2 / diminish-01
                  :ARG1 (t2 / transport-01
                        :ARG2-of (i2 / induce-01
                              :ARG0 (p3 / protein :name (n4 / name :op1 "insulin")))))))

# ::id bel_pmid_1128_2560.28384 ::date 2015-04-21T11:14:00 ::annotator SDL-AMR-09 ::preferred
# ::snt A similar 24P3 induction was observed in other T cell lymphomas (EL4 and TH201) in response to IL-9, as well as in EL4 cells stimulated with IL-6 or IL-1.
# ::save-date Sun Jan 3, 2016 ::file bel_pmid_1128_2560_28384.txt
(o / observe-01
      :ARG1 (i / induce-01
            :ARG2 (p / protein :name (n / name :op1 "24P3"))
            :ARG1-of (r / resemble-01))
      :location (a2 / and
            :op1 (l / lymphoma
                  :example (a / and
                        :op1 (c2 / cell :name (n3 / name :op1 "EL4"))
                        :op2 (c3 / cell :name (n4 / name :op1 "TH201")))
                  :mod (o2 / other)
                  :ARG2-of (r2 / respond-01
                        :ARG1 (p2 / protein :name (n5 / name :op1 "IL-9")))
                  :mod (c5 / cell :name (n9 / name :op1 "T")))
            :op2 (c4 / cell :name (n6 / name :op1 "EL4")
                  :ARG1-of (s / stimulate-01
                        :ARG0 (o3 / or
                              :op1 (p3 / protein :name (n7 / name :op1 "IL-6"))
                              :op2 (p4 / protein :name (n8 / name :op1 "IL-1")))))))

# ::id bel_pmid_1128_2560.28446 ::date 2015-04-21T11:39:29 ::annotator SDL-AMR-09 ::preferred
# ::snt Searching for genes specifically modulated by IL-9, we observed that the 24P3 mRNA is strongly upregulated in BW5147 T lymphoma cells upon IL-9 stimulation.
# ::save-date Mon Dec 21, 2015 ::file bel_pmid_1128_2560_28446.txt
(o / observe-01
      :ARG0 (w / we)
      :ARG1 (h / have-condition-91
            :ARG1 (u / upregulate-01
                  :ARG1 (n4 / nucleic-acid :name (n5 / name :op1 "mRNA")
                        :ARG0-of (e / encode-01
                              :ARG1 (p / protein :name (n / name :op1 "24P3"))))
                  :location (c / cell :name (n2 / name :op1 "BW5147" :op2 "T")
                        :mod (l / lymphoma))
                  :ARG1-of (s2 / strong-02))
            :ARG2 (s / stimulate-01
                  :ARG0 (p2 / protein :name (n3 / name :op1 "IL-9"))))
      :time (s3 / search-01
            :ARG0 w
            :ARG1 (g / gene
                  :ARG1-of (m2 / modulate-01
                        :ARG0 p2
                        :ARG1-of (s4 / specific-02)))))

# ::id bel_pmid_1128_7618.22858 ::date 2015-04-21T12:03:34 ::annotator SDL-AMR-09 ::preferred
# ::snt ResnetDB sentence: Gadd45gamma expression is induced by several cytokines, including IL-3, IL-6, and GM-CSF (20).
# ::save-date Sat Jan 2, 2016 ::file bel_pmid_1128_7618_22858.txt
(d / describe-01
      :ARG0 (s / sentence
            :mod (t / thing :name (n / name :op1 "ResnetDB")))
      :ARG1 (i / induce-01
            :ARG0 (c / cytokine
                  :ARG2-of (i2 / include-91
                        :ARG1 (a / and
                              :op1 (p2 / protein :name (n2 / name :op1 "IL-3"))
                              :op2 (p3 / protein :name (n3 / name :op1 "IL-6"))
                              :op3 (p4 / protein :name (n4 / name :op1 "GM-CSF"))))
                  :quant (s2 / several))
            :ARG2 (e / express-03
                  :ARG2 (p7 / protein :name (n6 / name :op1 "Gadd45" :op2 "gamma"))))
      :ARG1-of (d2 / describe-01
            :ARG0 (p5 / publication
                  :ARG1-of (c2 / cite-01
                        :ARG2 20))))

# ::id bel_pmid_1128_7618.23626 ::date 2015-04-21T12:15:46 ::annotator SDL-AMR-09 ::preferred
# ::snt Gadd45gamma, a family member of the growth arrest and DNA damage-inducible gene family 45 (Gadd45), is strongly induced by interleukin-2 (IL-2) in peripheral T cells.
# ::save-date Sat Jan 2, 2016 ::file bel_pmid_1128_7618_23626.txt
(i / induce-01
      :ARG0 (p2 / protein :name (n3 / name :op1 "interleukin-2"))
      :ARG2 (p / protein :name (n / name :op1 "Gadd45gamma")
            :ARG1-of (i3 / include-91
                  :ARG2 (p4 / protein-family :name (n2 / name :op1 "growth" :op2 "arrest" :op3 "and" :op4 "DNA" :op5 "damage-inducible" :op6 "gene" :op7 "45"))))
      :location (c / cell :name (n4 / name :op1 "T")
            :mod (p3 / peripheral))
      :ARG1-of (s / strong-02))

# ::id bel_pmid_1128_9146.5754 ::date 2015-04-21T12:47:25 ::annotator SDL-AMR-09 ::preferred
# ::snt K-Ras-mediated increase in cyclooxygenase 2 mRNA stability involves activation of the protein kinase B1.
# ::save-date Thu Apr 30, 2015 ::file bel_pmid_1128_9146_5754.txt
(i2 / involve-01
      :ARG1 (a / activate-01
            :ARG1 (e4 / enzyme :name (n3 / name :op1 "protein" :op2 "kinase" :op3 "B1")))
      :ARG2 (i / increase-01
            :ARG1 (s / stability
                  :mod (n5 / nucleic-acid :name (n4 / name :op1 "mRNA")
                        :ARG0-of (e2 / encode-01
                              :ARG1 (e3 / enzyme :name (n2 / name :op1 "cyclooxygenase" :op2 "2")))))
            :ARG1-of (m / mediate-01
                  :ARG0 (e / enzyme :name (n / name :op1 "K-Ras")))))

# ::id bel_pmid_1128_9146.7350 ::date 2015-04-21T12:53:57 ::annotator SDL-AMR-09 ::preferred
# ::snt Thus, Akt/PKB activity is involved in K-Ras-induced expression of COX-2 and stabilization of COX-2 mRNA largely depends on the activation of Akt/PKB.
# ::save-date Sun Jan 17, 2016 ::file bel_pmid_1128_9146_7350.txt
(c / cause-01
      :ARG1 (a / and
            :op1 (i / involve-01
                  :ARG1 (a2 / activity-06
                        :ARG0 (p / pathway :name (n / name :op1 "Akt/PKB")))
                  :ARG2 (e3 / express-03
                        :ARG2 (e4 / enzyme :name (n3 / name :op1 "COX-2"))
                        :ARG2-of (i2 / induce-01
                              :ARG0 (e2 / enzyme :name (n2 / name :op1 "K-Ras")))))
            :op2 (d / depend-01
                  :ARG0 (s / stabilize-01
                        :ARG2 (n5 / nucleic-acid :name (n4 / name :op1 "mRNA")
                              :ARG0-of (e5 / encode-01
                                    :ARG1 e4)))
                  :ARG1 (a3 / activate-01
                        :ARG1 p)
                  :degree (l / large))))

# ::id bel_pmid_1129_4897.21214 ::date 2015-04-21T13:05:07 ::annotator SDL-AMR-09 ::preferred
# ::snt Addition of a single tyrosine residue, Y724, restored its [Fgfr3] ability to stimulate cellular transformation, phosphatidylinositol 3-kinase activation, and phosphorylation of Shp2, MAPK, Stat1, and Stat3.
# ::save-date Sun Jun 28, 2015 ::file bel_pmid_1129_4897_21214.txt
(r3 / restore-01
      :ARG0 (a / add-02
            :ARG1 (r / residue
                  :mod (a2 / amino-acid :mod 724 :name (n / name :op1 "tyrosine"))
                  :ARG1-of (s / single-02)))
      :ARG1 (c / capable-01
            :ARG1 (p / protein :name (n3 / name :op1 "Fgfr3"))
            :ARG2 (s2 / stimulate-01
                  :ARG0 p
                  :ARG1 (a4 / and
                        :op1 (t / transform-01
                              :mod (c2 / cell))
                        :op2 (a5 / activate-01
                              :ARG1 (e / enzyme :name (n4 / name :op1 "phosphatidylinositol" :op2 "3-kinase")))
                        :op3 (p2 / phosphorylate-01
                              :ARG1 (a6 / and
                                    :op1 (e2 / enzyme :name (n5 / name :op1 "Shp2"))
                                    :op2 (e3 / enzyme :name (n6 / name :op1 "MAPK"))
                                    :op3 (p3 / protein :name (n7 / name :op1 "Stat1"))
                                    :op4 (p4 / protein :name (n8 / name :op1 "Stat3"))))))))

# ::id bel_pmid_1129_4897.23128 ::date 2015-04-21T13:23:38 ::annotator SDL-AMR-09 ::preferred
# ::snt We also found that Y770 may function as a negative regulatory site for FGFR3-stimulated transformation and PI 3-kinase activation.
# ::save-date Thu Apr 30, 2015 ::file bel_pmid_1129_4897_23128.txt
(f / find-01
      :ARG0 (w / we)
      :ARG1 (p / possible-01
            :ARG1 (f2 / function-01
                  :ARG0 (a / amino-acid :mod 770 :name (n / name :op1 "tyrosine"))
                  :ARG1 (p3 / protein-segment
                        :ARG2-of (d / downregulate-01
                              :ARG1 (a2 / and
                                    :op1 (t / transform-01
                                          :ARG1-of (s2 / stimulate-01
                                                :ARG0 (p2 / protein :name (n2 / name :op1 "FGFR3"))))
                                    :op2 (a3 / activate-01
                                          :ARG1 (e / enzyme :name (n3 / name :op1 "PI" :op2 "3-kinase"))))))))
      :mod (a4 / also))

# ::id bel_pmid_1129_7520.6398 ::date 2015-04-21T13:35:06 ::annotator SDL-AMR-09 ::preferred
# ::snt The reintroduction of wild-type LKB1 into a cancer cell line that lacks LKB1 suppressed growth, but mutants of LKB1 in which Ser(431) was mutated to Ala to prevent phosphorylation of LKB1 were ineffective in inhibiting growth.
# ::save-date Sun Dec 20, 2015 ::file bel_pmid_1129_7520_6398.txt
(c / contrast-01
      :ARG1 (s / suppress-01
            :ARG0 (r / reintroduce-01
                  :ARG1 (e / enzyme :name (n / name :op1 "LKB1")
                        :mod (w / wild-type))
                  :ARG2 (c4 / cell-line
                        :ARG0-of (l2 / lack-01
                              :ARG1 (e3 / enzyme :name (n4 / name :op1 "LKB1")))
                        :mod (d / disease :wiki "Cancer" :name (n6 / name :op1 "cancer"))))
            :ARG1 (g / grow-01))
      :ARG2 (e2 / effective-04 :polarity -
            :ARG0 (e4 / enzyme :name (n5 / name :op1 "LKB1")
                  :part (a / amino-acid :mod 431 :name (n2 / name :op1 "serine")
                        :ARG1-of (m2 / mutate-01
                              :ARG2 (a2 / amino-acid :name (n3 / name :op1 "Ala"))
                              :ARG0-of (p / prevent-01
                                    :ARG1 (p2 / phosphorylate-01
                                          :ARG1 e))))
                  :ARG1-of (m / mutate-01))
            :ARG1 (i / inhibit-01
                  :ARG0 e4
                  :ARG1 g)))

# ::id bel_pmid_1129_7520.22158 ::date 2015-04-21T13:54:33 ::annotator SDL-AMR-09 ::preferred
# ::snt We present pharmacological and genetic evidence that p90(RSK) mediated this phosphorylation in response to agonists that activate ERK1/2 and that cAMP-dependent protein kinase mediated this phosphorylation in response to agonists that activate adenylate cyclase
# ::save-date Mon Jan 4, 2016 ::file bel_pmid_1129_7520_22158.txt
(p / present-01
      :ARG0 (w / we)
      :ARG1 (e / evidence-01
            :ARG1 (a / and
                  :op1 (m / mediate-01
                        :ARG0 (p7 / protein :name (n8 / name :op1 "p90" :op2 "RSK"))
                        :ARG1 (p4 / phosphorylate-01
                              :mod (t / this))
                        :ARG2-of (r / respond-01
                              :ARG1 (a5 / agonist
                                    :ARG0-of (a2 / activate-01
                                          :ARG1 (e2 / enzyme :name (n3 / name :op1 "ERK1/2"))))))
                  :op2 (m3 / mediate-01
                        :ARG0 (e3 / enzyme :name (n4 / name :op1 "protein" :op2 "kinase")
                              :ARG0-of (d / depend-01
                                    :ARG1 (s / small-molecule :name (n / name :op1 "cAMP"))))
                        :ARG1 p4
                        :ARG2-of (r2 / respond-01
                              :ARG1 (a4 / agonist
                                    :ARG0-of (a3 / activate-01
                                          :ARG1 (e4 / enzyme :name (n6 / name :op1 "adenylate" :op2 "cyclase")))))))
            :mod (g / genetics)
            :mod (p2 / pharmacology)))

# ::id bel_pmid_1129_7530.22688 ::date 2015-04-21T14:08:08 ::annotator SDL-AMR-09 ::preferred
# ::snt Immunoblot analysis of extracts from control and HT15 cells showed an increase in the activated forms of ERK1/2 in the Sod2-overexpressing cells that was reversed upon coexpression of catalase (Fig. 5A).
# ::save-date Tue Feb 2, 2016 ::file bel_pmid_1129_7530_22688.txt
(s / show-01
      :ARG0 (a / and
            :op1 (a2 / analyze-01
                  :ARG1 (t / thing
                        :ARG1-of (e / extract-01
                              :ARG2 (c / control)))
                  :manner (i / immunoblot-01))
            :op2 (c2 / cell-line :name (n / name :op1 "HT15")))
      :ARG1 (i2 / increase-01
            :ARG1 (e2 / enzyme :name (n2 / name :op1 "ERK1/2")
                  :ARG1-of (a3 / activate-01))
            :location (c3 / cell
                  :location-of (o / overexpress-01
                        :ARG1 (e3 / enzyme :name (n3 / name :op1 "Sod2"))))
            :ARG1-of (r / reverse-01
                  :ARG0 (c4 / coexpress-01
                        :ARG2 (e4 / enzyme :name (n4 / name :op1 "catalase")))))
      :ARG1-of (d / describe-01
            :ARG0 (f2 / figure :mod "5A")))

# ::id bel_pmid_1129_7530.22690 ::date 2015-04-21T14:17:40 ::annotator SDL-AMR-09 ::preferred
# ::snt Analysis of IL-1a levels in Sod2-overexpressing cells showed a 3-fold increase in basal IL-1a levels that was reversed when catalase was coexpressed in these cell lines (Fig. 2A).
# ::save-date Tue Feb 2, 2016 ::file bel_pmid_1129_7530_22690.txt
(s / show-01
      :ARG0 (a / analyze-01
            :ARG1 (l / level
                  :quant-of (p / protein :name (n / name :op1 "IL-1a")))
            :location (c / cell
                  :location-of (o / overexpress-01
                        :ARG1 (e2 / enzyme :name (n5 / name :op1 "Sod2")))))
      :ARG1 (i / increase-01
            :ARG1 (l2 / level
                  :mod (b / basal)
                  :quant-of p)
            :ARG2 (p3 / product-of :op1 3)
            :ARG1-of (r / reverse-01
                  :time (c2 / coexpress-01
                        :ARG2 (e / enzyme :name (n4 / name :op1 "catalase"))
                        :ARG3 (c4 / cell-line
                              :mod (t / this)))))
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod "2A")))

# ::id bel_pmid_1129_7530.24362 ::date 2015-04-21T14:26:17 ::annotator SDL-AMR-09 ::preferred
# ::snt Thus, a 15-fold increase in Sod2 levels, which is well within the range of activity observed in response to cytokines and growth factors, can enhance MMP-1 expression in an H2O2-dependent fashion.
# ::save-date Wed Feb 24, 2016 ::file bel_pmid_1129_7530_24362.txt
(c / cause-01
      :ARG1 (p / possible-01
            :ARG1 (e / enhance-01
                  :ARG0 (i / increase-01
                        :ARG1 (l / level
                              :quant-of (e2 / enzyme :name (n / name :op1 "Sod2")))
                        :ARG2 (p2 / product-of :op1 15)
                        :part-of (r / range-01
                              :ARG1 (a / activity-06)
                              :ARG1-of (o / observe-01
                                    :ARG2-of (r2 / respond-01
                                          :ARG1 (a2 / and
                                                :op1 (c2 / cytokine)
                                                :op2 (g / growth-factor))))
                              :degree (w / well)))
                  :ARG1 (e3 / express-03
                        :ARG2 (e4 / enzyme :name (n3 / name :op1 "MMP-1")))
                  :manner (d / depend-01
                        :ARG0 e3
                        :ARG1 (s2 / small-molecule :name (n4 / name :op1 "H2O2"))))))

# ::id bel_pmid_1129_7530.24364 ::date 2015-04-22T08:40:56 ::annotator SDL-AMR-09 ::preferred
# ::snt In support of this hypothesis, the gelatinolytic activity of MMP-2 and the mRNA levels of MMP-3 and MMP-7 were increased in the Sod2 overexpressors compared with control cell lines (Fig. 5C, left panel).
# ::save-date Sat Jan 30, 2016 ::file bel_pmid_1129_7530_24364.txt
(s / support-01
      :ARG0 (i / increase-01
            :ARG1 (a / and
                  :op1 (a2 / activity-06
                        :ARG0 (e / enzyme :name (n / name :op1 "MMP-2"))
                        :ARG1 (g / gelatinolysis))
                  :op2 (l / level
                        :quant-of (n6 / nucleic-acid :name (n5 / name :op1 "mRNA")
                              :ARG0-of (e4 / encode-01
                                    :ARG1 (a3 / and
                                          :op1 (e2 / enzyme :name (n2 / name :op1 "MMP-3"))
                                          :op2 (e3 / enzyme :name (n3 / name :op1 "MMP-7")))))))
            :location (c3 / cell-line
                  :location-of (o / overexpress-01
                        :ARG1 (e5 / enzyme :name (n4 / name :op1 "Sod2")))
                  :compared-to (c4 / cell-line
                        :ARG2-of (c2 / control-01))))
      :ARG1 (h / hypothesize-01
            :mod (t / this))
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod "5C"
                  :location (p / panel
                        :ARG1-of (l2 / left-20)))))

# ::id bel_pmid_1129_7530.24366 ::date 2015-04-22T08:49:39 ::annotator SDL-AMR-09 ::preferred
# ::snt The observed decline in MMP-9 activity in the HT15 cell line may represent a negative regulatory aspect of Sod2 in MMP expression.
# ::save-date Mon Jul 6, 2015 ::file bel_pmid_1129_7530_24366.txt
(p / possible-01
      :ARG1 (r / represent-01
            :ARG0 (d / decline-01
                  :ARG1 (a / activity-06
                        :ARG0 (e / enzyme :name (n / name :op1 "MMP-9"))
                        :location (c2 / cell-line :name (n5 / name :op1 "HT15")))
                  :ARG1-of (o / observe-01))
            :ARG1 (a2 / aspect
                  :ARG0-of (d2 / downregulate-01
                        :ARG2 (e2 / enzyme :name (n3 / name :op1 "Sod2"))
                        :topic (e3 / express-03
                              :ARG2 (e4 / enzyme :name (n4 / name :op1 "MMP")))))))

# ::id bel_pmid_1129_7530.28094 ::date 2015-04-22T09:11:29 ::annotator SDL-AMR-09 ::preferred
# ::snt The induction of MMP-13 by IL-1a and phorbol myristate acetate was severely impaired in the Sod2-/+ fibroblasts compared with the Sod2+/+ fibroblasts (Fig. 3, A and B).
# ::save-date Fri Feb 12, 2016 ::file bel_pmid_1129_7530_28094.txt
(i / impair-01
      :ARG1 (i2 / induce-01
            :ARG0 (a / and
                  :op1 (p / protein :name (n2 / name :op1 "IL-1a"))
                  :op2 (s2 / small-molecule :name (n3 / name :op1 "phorbol" :op2 "myristate" :op3 "acetate")))
            :ARG2 (e / enzyme :name (n / name :op1 "MMP-13")))
      :location (f / fibroblast
            :mod (e2 / enzyme :name (n4 / name :op1 "Sod2")
                  :ARG2-of (m2 / mutate-01 :mod "-/+")))
      :ARG1-of (d / describe-01
            :ARG0 (a3 / and
                  :op1 (f3 / figure :mod "3A")
                  :op2 (f4 / figure :mod "3B")))
      :degree (s / severe)
      :compared-to (f2 / fibroblast
            :mod (e3 / enzyme :name (n5 / name :op1 "Sod2")
                  :mod (w / wild-type))))

# ::id bel_pmid_1129_7530.30812 ::date 2015-04-22T09:57:46 ::annotator SDL-AMR-09 ::preferred
# ::snt the wild-type MEFs responded to the induction of MMP-13 by TNF, whereas the heterozygotes did not.
# ::save-date Sun Jan 17, 2016 ::file bel_pmid_1129_7530_30812.txt
(c / contrast-01
      :ARG1 (r / respond-01
            :ARG0 (c2 / cell :name (n / name :op1 "MEF")
                  :mod (w / wild-type))
            :ARG1 (i / induce-01
                  :ARG0 (p2 / protein :name (n3 / name :op1 "TNF"))
                  :ARG2 (e / enzyme :name (n2 / name :op1 "MMP-13"))))
      :ARG2 (r2 / respond-01 :polarity -
            :ARG0 (h / heterozygote)
            :ARG1 i))

# ::id bel_pmid_1129_7548.19988 ::date 2015-04-22T10:06:54 ::annotator SDL-AMR-09 ::preferred
# ::snt Although the growth factors epidermal growth factor (EGF) and neuregulin (NRG) 1 similarly stimulated Erk1/2 in MDA-MB-361 cells, EGF acting through an EGF receptor/ErbB2 heterodimer preferentially stimulated protein kinase C, and NRG1beta acting through an ErbB2/ErbB3 heterodimer preferentially stimulated Akt.
# ::save-date Wed Feb 24, 2016 ::file bel_pmid_1129_7548_19988.txt
(h / have-concession-91
      :ARG1 (a2 / and
            :op1 (s2 / stimulate-01
                  :ARG0 (p3 / protein :name (n5 / name :op1 "EGF")
                        :ARG0-of (a3 / act-01
                              :instrument (h2 / heterodimer
                                    :part (p4 / protein :name (n7 / name :op1 "ErbB2")))))
                  :ARG1 (e2 / enzyme :name (n8 / name :op1 "protein" :op2 "kinase" :op3 "C"))
                  :ARG1-of (p5 / prefer-01))
            :op2 (s3 / stimulate-01
                  :ARG0 (p6 / protein :name (n9 / name :op1 "NRG1beta")
                        :ARG0-of (a4 / act-01
                              :instrument (m / macro-molecular-complex :name (n13 / name :op1 "heterodimer")
                                    :part (p8 / protein :name (n11 / name :op1 "ErbB3"))
                                    :part p4)))
                  :ARG1 (e3 / enzyme :name (n14 / name :op1 "Akt"))
                  :ARG1-of p5))
      :ARG2 (s / stimulate-01
            :ARG0 (g / growth-factor
                  :example (a / and
                        :op1 (p / protein :name (n / name :op1 "epidermal" :op2 "growth" :op3 "factor"))
                        :op2 (p2 / protein :name (n2 / name :op1 "neuregulin" :op2 "1"))))
            :ARG1 (e / enzyme :name (n3 / name :op1 "Erk1/2"))
            :manner (r / resemble-01)
            :location (c / cell :name (n4 / name :op1 "MDA-MB-361"))))

# ::id bel_pmid_1129_7548.24054 ::date 2015-04-22T10:33:08 ::annotator SDL-AMR-09 ::preferred
# ::snt In MDA-MB-453 cells, NRG1beta acting through an ErbB2/ErbB3 heterodimer stimulated prolonged signaling of all pathways examined relative to NRG2beta acting through the same heterodimeric receptor species. Surprisingly, NRG1beta and NRG2beta also regulated partially overlapping but distinct sets of genes in these cells.
# ::save-date Thu Nov 5, 2015 ::file bel_pmid_1129_7548_24054.txt
(m / multi-sentence
      :snt1 (s / stimulate-01
            :ARG0 (p / protein :name (n / name :op1 "NRG1beta")
                  :ARG0-of (a / act-01
                        :instrument (h / heterodimer
                              :part (p2 / protein :name (n3 / name :op1 "ErbB2"))
                              :part (p3 / protein :name (n4 / name :op1 "ErbB3")))))
            :ARG1 (s2 / signal-07
                  :ARG0 (p5 / pathway
                        :mod (a2 / all)
                        :ARG1-of (e / examine-01))
                  :ARG1-of (p4 / prolong-01))
            :ARG1-of (r / relative-05
                  :ARG3 (p6 / protein :name (n5 / name :op1 "NRG2beta")
                        :ARG0-of (a3 / act-01
                              :instrument (s3 / specie
                                    :mod (r2 / receptor
                                          :ARG1-of (s5 / same-01)
                                          :mod (h2 / heterodimer))))))
            :location (c / cell :name (n7 / name :op1 "MDA-MB-453")))
      :snt2 (r3 / regulate-01
            :ARG0 (a4 / and
                  :op1 (p7 / protein :name (n8 / name :op1 "NRG1beta"))
                  :op2 (p8 / protein :name (n9 / name :op1 "NRG2beta")))
            :ARG1 (s4 / set
                  :mod (g / gene)
                  :ARG0-of (o / overlap-01
                        :degree (p9 / part)
                        :ARG1-of (c3 / contrast-01
                              :ARG2 (d / distinct
                                    :domain s4))))
            :location (c2 / cell
                  :mod (t / this))
            :ARG0-of (s6 / surprise-01)
            :mod (a5 / also)))

# ::id bel_pmid_1129_7548.24056 ::date 2015-04-22T12:33:36 ::annotator SDL-AMR-09 ::preferred
# ::snt As expected, EGF preferentially stimulated the recruitment of the adaptor protein Grb2 to EGF receptor whereas NRG1beta preferentially stimulated the recruitment of this protein to ErbB3. NRG1beta also preferentially stimulated the association of p85, the 85-kDa subunit of PI3K, with ErbB3, as demonstrated previously (40).
# ::save-date Sun Jan 17, 2016 ::file bel_pmid_1129_7548_24056.txt
(m / multi-sentence
      :snt1 (c / contrast-01
            :ARG1 (s / stimulate-01
                  :ARG0 (p / protein :name (n / name :op1 "EGF"))
                  :ARG1 (r / recruit-01
                        :ARG1 (p4 / protein :name (n2 / name :op1 "Grb2")
                              :mod (a / adaptor))
                        :ARG2 (e3 / enzyme :name (n8 / name :op1 "EGF" :op2 "receptor")))
                  :ARG1-of (p2 / prefer-01))
            :ARG2 (s2 / stimulate-01
                  :ARG0 (p3 / protein :name (n4 / name :op1 "NRG1beta"))
                  :ARG1 (r3 / recruit-01
                        :ARG1 p4
                        :ARG2 (p5 / protein :name (n5 / name :op1 "ErbB3")))
                  :ARG1-of p2)
            :ARG1-of (e / expect-01))
      :snt2 (s3 / stimulate-01
            :ARG0 (p7 / protein :name (n6 / name :op1 "NRG1beta"))
            :ARG1 (a3 / associate-01
                  :ARG1 (p8 / protein-segment :name (n7 / name :op1 "p85")
                        :ARG1-of (m2 / mean-01
                              :ARG2 (e2 / enzyme :name (n9 / name :op1 "PI3K")
                                    :quant (m3 / mass-quantity :quant 85
                                          :unit (k / kilodalton)))))
                  :ARG2 (p11 / protein :name (n10 / name :op1 "ErbB3")))
            :mod (a2 / also)
            :ARG1-of (p6 / prefer-01)
            :ARG1-of (d / demonstrate-01
                  :time (p12 / previous))
            :ARG1-of (d2 / describe-01
                  :ARG0 (p13 / publication
                        :ARG1-of (c2 / cite-01
                              :ARG2 40)))))

# ::id bel_pmid_1129_7548.38074 ::date 2015-04-22T13:02:54 ::annotator SDL-AMR-09 ::preferred
# ::snt Although the growth factors epidermal growth factor (EGF) and neuregulin (NRG) 1 similarly stimulated Erk1/2 in MDA-MB-361 cells, EGF acting through an EGF receptor/ErbB2 heterodimer preferentially stimulated protein kinase C, and NRG1beta acting through an ErbB2/ErbB3 heterodimer preferentially stimulated Akt.
# ::save-date Wed Feb 24, 2016 ::file bel_pmid_1129_7548_38074.txt
(h / have-concession-91
      :ARG1 (a / and
            :op1 (s / stimulate-01
                  :ARG0 (p / protein :name (n / name :op1 "EGF")
                        :ARG0-of (a2 / act-01
                              :instrument (h2 / heterodimer
                                    :part (p2 / protein :name (n4 / name :op1 "ErbB2"))
                                    :part (p7 / protein :name (n3 / name :op1 "EGF" :op2 "receptor")))))
                  :ARG1 (e / enzyme :name (n5 / name :op1 "protein" :op2 "kinase" :op3 "C"))
                  :ARG1-of (p3 / prefer-01))
            :op2 (s2 / stimulate-01
                  :ARG0 (p4 / protein :name (n6 / name :op1 "NRG1beta")
                        :ARG0-of (a3 / act-01
                              :instrument (h3 / heterodimer
                                    :part (p6 / protein :name (n9 / name :op1 "ErbB3"))
                                    :part p2)))
                  :ARG1 (e2 / enzyme :name (n10 / name :op1 "Akt"))
                  :ARG1-of p3))
      :ARG2 (s3 / stimulate-01
            :ARG0 (g / growth-factor
                  :example (a4 / and
                        :op1 (p8 / protein :name (n11 / name :op1 "epidermal" :op2 "growth" :op3 "factor"))
                        :op2 (p9 / protein :name (n12 / name :op1 "neuregulin" :op2 "1"))))
            :ARG1 (e3 / enzyme :name (n13 / name :op1 "Erk1/2"))
            :manner (r2 / resemble-01)
            :location (c / cell :name (n14 / name :op1 "MDA-MB-361"))))

# ::id bel_pmid_1131_3931.5286 ::date 2015-04-22T13:13:05 ::annotator SDL-AMR-09 ::preferred
# ::snt We find that Cdk10 binds full length Ets2 in vitro and in vivo and inhibits Ets2 transactivation in mammalian cells.
# ::save-date Thu Dec 17, 2015 ::file bel_pmid_1131_3931_5286.txt
(f3 / find-01
      :ARG0 (w / we)
      :ARG1 (a3 / and
            :op1 (b / bind-01
                  :ARG0 (e / enzyme :name (n / name :op1 "Cdk10"))
                  :ARG1 (l / length
                        :poss (p / protein :name (n2 / name :op1 "Ets2"))
                        :degree (f2 / full))
                  :manner (a2 / and
                        :op1 (i / in-vitro)
                        :op2 (i2 / in-vivo)))
            :op2 (i3 / inhibit-01
                  :ARG0 e
                  :ARG1 (t / transactivate-01
                        :ARG1 p
                        :location (c / cell
                              :mod (m / mammal))))))

# ::id bel_pmid_1132_3411.1008 ::date 2015-04-22T13:22:03 ::annotator SDL-AMR-09 ::preferred
# ::snt Consistently, substrate-trapping experiments with a SHP2 catalytic inactive mutant suggested that Gab1 was a SHP2 PTPase substrate in the cells. Therefore, Gab1 not only is a SHP2 activator but also is a target of its PTPase.
# ::save-date Mon Feb 1, 2016 ::file bel_pmid_1132_3411_1008.txt
(m / multi-sentence
      :snt1 (s / suggest-01
            :ARG0 (a / and
                  :op1 (e / experiment-01
                        :ARG1 (s2 / substrate
                              :ARG1-of (t / trap-01
                                    :ARG0 (e2 / enzyme :name (n / name :op1 "SHP2")
                                          :ARG2-of (m2 / mutate-01)
                                          :ARG1-of (a2 / activate-01 :polarity -
                                                :mod (c / catalysis)))))))
            :ARG1 (s3 / substrate
                  :domain (p / protein :name (n2 / name :op1 "Gab1"))
                  :mod (e3 / enzyme :name (n3 / name :op1 "SHP2" :op2 "PTPase"))
                  :location (c2 / cell))
            :manner (c4 / consistent-02))
      :snt2 (c3 / cause-01
            :ARG1 (a3 / and
                  :op1 (a4 / activate-01
                        :ARG0 (p2 / protein :name (n5 / name :op1 "Gab1"))
                        :ARG1 (e4 / enzyme :name (n4 / name :op1 "SHP2")))
                  :op2 (t2 / target-01
                        :ARG0 (e5 / enzyme :name (n6 / name :op1 "PTPase")
                              :part-of e4)
                        :ARG1 p2))))

# ::id bel_pmid_1132_3411.6960 ::date 2015-04-22T13:40:51 ::annotator SDL-AMR-09 ::preferred
# ::snt We found that both Tyr-627 and Tyr-659 of Gab1 were required for SHP2 binding to Gab1 and for ERK2 activation by EGF.
# ::save-date Sun Jan 17, 2016 ::file bel_pmid_1132_3411_6960.txt
(f / find-01
      :ARG0 (w / we)
      :ARG1 (r / require-01
            :ARG0 (a4 / and
                  :op1 (b / bind-01
                        :ARG1 (e / enzyme :name (n4 / name :op1 "SHP2"))
                        :ARG2 (p2 / protein :name (n5 / name :op1 "Gab1")))
                  :op2 (a5 / activate-01
                        :ARG0 (p3 / protein :name (n6 / name :op1 "EGF"))
                        :ARG1 (e2 / enzyme :name (n7 / name :op1 "ERK2"))))
            :ARG1 (a / and
                  :op1 (a2 / amino-acid :mod 627 :name (n / name :op1 "tyrosine")
                        :part-of p2)
                  :op2 (a3 / amino-acid :mod 659 :name (n3 / name :op1 "tyrosine")
                        :part-of p2))))

# ::id bel_pmid_1134_1776.3378 ::date 2015-04-22T13:47:25 ::annotator SDL-AMR-09 ::preferred
# ::snt We demonstrated that lung myofibroblasts, incubated in the presence of E2, showed a rapid phosphorylation on serine-259 of Raf1 and tyrosine-204 of ERK1/2 MAP kinase at 15 min, by approximately 3- and 5-fold, respectively
# ::save-date Sun Jan 3, 2016 ::file bel_pmid_1134_1776_3378.txt
(d / demonstrate-01
      :ARG0 (w / we)
      :ARG1 (s / show-01
            :ARG0 (m2 / myofibroblast
                  :mod (l / lung)
                  :ARG1-of (i / incubate-01
                        :condition (p / present-02
                                    :ARG1 (e / enzyme :name (n3 / name :op1 "E2")))))
            :ARG1 (a / and
                  :op1 (p2 / phosphorylate-01
                        :ARG0 (a2 / amino-acid :mod 259 :name (n4 / name :op1 "serine"))
                        :ARG1 (e2 / enzyme :name (n5 / name :op1 "Raf1"))
                        :mod (r2 / rapid)
                        :quant (a4 / approximately
                              :op1 (p4 / product-of :op1 3)))
                  :op2 (p3 / phosphorylate-01
                        :ARG0 (a3 / amino-acid :mod 204 :name (n6 / name :op1 "tyrosine"))
                        :ARG1 (e3 / enzyme :name (n7 / name :op1 "ERK1/2" :op2 "MAP" :op3 "kinase"))
                        :quant (a5 / approximately
                              :op1 (p5 / product-of :op1 5)))
                  :mod (r / respective)
                  :time (a6 / after
                        :quant (t / temporal-quantity :quant 15
                              :unit (m / minute))))))

# ::id bel_pmid_1135_0938.21662 ::date 2015-04-21T04:51:58 ::annotator SDL-AMR-09 ::preferred
# ::snt since in PKR-null MEFs there is a marked defect in Erk1 and Erk2 activation by PDGF (Figure1D), it appears that PKR is involved in serine phosphorylation of Stat3 through the activation of Erks.
# ::save-date Sun Jan 17, 2016 ::file bel_pmid_1135_0938_21662.txt
(a / appear-02
      :ARG1 (i / involve-01
            :ARG0 (e / enzyme :name (n / name :op1 "PKR"))
            :ARG2 (p / phosphorylate-01
                  :ARG1 (a3 / amino-acid :name (n4 / name :op1 "serine")
                        :part-of (p2 / protein :name (n2 / name :op1 "Stat3")))
                  :ARG2 (a2 / activate-01
                        :ARG1 a5)))
      :ARG1-of (c / cause-01
            :ARG0 (d / defect
                  :prep-in (a4 / activate-01
                        :ARG0 (p3 / protein :name (n5 / name :op1 "PDGF"))
                        :ARG1 (a5 / and
                              :op1 (e3 / enzyme :name (n6 / name :op1 "Erk1"))
                              :op2 (e4 / enzyme :name (n7 / name :op1 "Erk2"))))
                  :mod (m2 / marked)
                  :ARG1-of (d2 / describe-01
                        :ARG0 (f2 / figure :mod "1D"))
                  :location (c2 / cell :name (n8 / name :op1 "MEF")
                        :ARG3-of (e6 / express-03
                              :ARG2 (e5 / enzyme :name (n9 / name :op1 "PKR")
                                    :ARG2-of (m / mutate-01 :mod "-/-")))))))

# ::id bel_pmid_1135_0938.21664 ::date 2015-04-21T05:27:58 ::annotator SDL-AMR-09 ::preferred
# ::snt Whereas PKR+/+ cells exhibited a clear induction in phospho-Ser727 Stat3, PKR-null cells were defective in this process (Figure1B)
# ::save-date Sun Dec 20, 2015 ::file bel_pmid_1135_0938_21664.txt
(c / contrast-01
      :ARG1 (e3 / exhibit-01 :polarity -
            :ARG0 (c4 / cell
                  :ARG3-of (e5 / express-03
                        :ARG2 (e4 / enzyme :name (n4 / name :op1 "PKR")
                              :ARG2-of (m / mutate-01 :mod "-/-"))))
            :ARG1 (i2 / induce-01
                  :ARG2 (p3 / phosphorylate-01
                        :ARG1 a)))
      :ARG2 (e / exhibit-01
            :ARG0 (c2 / cell
                  :ARG3-of (e6 / express-03
                        :ARG2 (e2 / enzyme :name (n / name :op1 "PKR")
                              :mod (w / wild-type))))
            :ARG1 (i / induce-01
                  :ARG2 (p / phosphorylate-01
                        :ARG1 (a / amino-acid :mod 727 :name (n2 / name :op1 "serine")
                              :part-of (p2 / protein :name (n3 / name :op1 "Stat3"))))
                  :ARG1-of (c3 / clear-06)))
      :ARG1-of (d2 / describe-01
            :ARG0 (f / figure :mod "1B")))

# ::id bel_pmid_1135_0938.21666 ::date 2015-04-21T05:41:20 ::annotator SDL-AMR-09 ::preferred
# ::snt Accordingly, nuclear extracts prepared from PDGF-treated PKR- null cells were severely deficient in Stat3 containing DNA-binding complexes compared with wild-type MEFs (data not shown). Taken together, we conclude that PDGF-induced activation of Stat3 DNA binding is PKR dependent.
# ::save-date Sun Jan 17, 2016 ::file bel_pmid_1135_0938_21666.txt
(m / multi-sentence
      :snt1 (l / lack-01
            :ARG0 (e / extract
                  :mod (n / nucleus)
                  :ARG1-of (p / prepare-01
                        :ARG2 (c / cell
                              :ARG1-of (t / treat-04
                                    :ARG2 (p2 / protein :name (n2 / name :op1 "PDGF")))
                              :ARG2-of (e5 / express-03
                                    :ARG1 (e2 / enzyme :name (n3 / name :op1 "PKR")
                                          :ARG2-of (m4 / mutate-01 :mod "-/-"))))))
            :ARG1 (m3 / macro-molecular-complex
                  :ARG0-of (b / bind-01
                        :ARG1 (n9 / nucleic-acid :wiki "DNA" :name (n10 / name :op1 "DNA")))
                  :ARG0-of (c3 / contain-01
                        :ARG1 (p3 / protein :name (n4 / name :op1 "Stat3"))))
            :ARG1-of (s / show-01 :polarity -)
            :degree (s2 / severe)
            :manner (a2 / accordingly)
            :compared-to (c2 / cell :name (n8 / name :op1 "MEF")
                  :mod (w2 / wild-type)))
      :snt2 (c4 / conclude-01
            :ARG0 (w / we)
            :ARG1 (d2 / depend-01
                  :ARG0 (a / activate-01
                        :ARG0 (p4 / protein :name (n6 / name :op1 "PDGF"))
                        :ARG1 (b2 / bind-01
                              :ARG1 (n11 / nucleic-acid :wiki "DNA" :name (n12 / name :op1 "DNA")
                                    :mod (p5 / protein :name (n7 / name :op1 "Stat3")))))
                  :ARG1 (e3 / enzyme :name (n5 / name :op1 "PKR")))
            :ARG1-of (t2 / take-01
                  :mod (t3 / together))))

# ::id bel_pmid_1135_0938.26648 ::date 2015-04-21T05:57:48 ::annotator SDL-AMR-09 ::preferred
# ::snt PDGF treatment induced two Tyr705-phosphorylated forms of Stat3 in PKR+/+ cells, a faster migrating species termed Stat3fm and a slower migrating species termed Stat3sm (Figure1A).....Importantly, PDGF treatment did not induce either form of tyrosine-phosphorylated Stat3 in PKR-null cells (Figure1A), implicating a requirement for PKR in both tyrosine and serine phosphorylation of Stat3.
# ::save-date Wed Jan 20, 2016 ::file bel_pmid_1135_0938_26648.txt
(m2 / multi-sentence
      :snt1 (i / induce-01
            :ARG0 (t / treat-04
                  :ARG1 (p2 / protein :name (n2 / name :op1 "PDGF")))
            :ARG2 (a2 / and
                  :op1 (p4 / protein :name (n5 / name :op1 "Stat3")
                        :ARG0-of (m3 / migrate-01
                              :ARG1-of (f2 / fast-02
                                    :degree (m4 / more)))
                        :ARG1-of (t2 / term-01
                              :ARG3 (s2 / string-entity :value "Stat3fm"))
                        :part (a3 / amino-acid :mod 705 :name (n4 / name :op1 "tyrosine")
                              :ARG1-of (p3 / phosphorylate-01)))
                  :op2 (p5 / protein :name (n6 / name :op1 "Stat3")
                        :ARG0-of (m5 / migrate-01
                              :ARG1-of (s3 / slow-05
                                    :degree (l / less)))
                        :ARG1-of (t3 / term-01
                              :ARG3 (s / string-entity :value "Stat3sm"))
                        :part a3))
            :location (c / cell
                  :ARG2-of (e4 / express-03
                        :ARG1 (e / enzyme :name (n3 / name :op1 "PKR")
                              :mod (w / wild-type))))
            :ARG1-of (d / describe-01
                  :ARG0 (f3 / figure :mod "1A")))
      :snt2 (i2 / induce-01 :polarity -
            :ARG0 (t4 / treat-04
                  :ARG1 (p6 / protein :name (n7 / name :op1 "PDGF")))
            :ARG2 (f / form :quant 2
                  :mod (p7 / protein :name (n8 / name :op1 "Stat3")
                        :part (a4 / amino-acid :name (n9 / name :op1 "tyrosine")
                              :ARG1-of (p8 / phosphorylate-01)))
                  :mod (e2 / either))
            :location (c2 / cell
                  :ARG2-of (e5 / express-03
                        :ARG1 (e3 / enzyme :name (n10 / name :op1 "PKR")
                              :ARG2-of (m / mutate-01 :mod "-/-"))))
            :ARG1-of (d2 / describe-01
                  :ARG0 (f4 / figure :mod "1A"))
            :ARG0-of (i3 / imply-01
                  :ARG1 (r / require-01
                        :ARG0 (p9 / phosphorylate-01
                              :ARG1 (a / and
                                    :op1 (a5 / amino-acid :name (n11 / name :op1 "tyrosine")
                                          :part-of (p10 / protein :name (n13 / name :op1 "Stat3")))
                                    :op2 (a6 / amino-acid :name (n12 / name :op1 "serine")
                                          :part-of p10)))
                        :ARG1 e3))
            :mod (i4 / important)))

# ::id bel_pmid_1135_0938.26650 ::date 2015-04-21T06:29:03 ::annotator SDL-AMR-09 ::preferred
# ::snt The results (Figure4A and B) showed a 16-fold induction in PKR wild-type cells in contrast to a 0.8-fold induction in c-fos message in PKR-null cells at 15 min of PDGF treatment
# ::save-date Tue Apr 28, 2015 ::file bel_pmid_1135_0938_26650.txt
(s / show-01
      :ARG0 (t / thing
            :ARG1-of (r / result-01
                  :ARG1-of (d / describe-01
                        :ARG0 (a2 / and
                              :op1 (f / figure :mod "4A")
                              :op2 (f2 / figure :mod "4B")))))
      :ARG1 (c / contrast-01
            :ARG1 (i / induce-01
                  :location (c2 / cell
                        :ARG3-of (e5 / express-03
                              :ARG2 (e / enzyme :name (n / name :op1 "PKR")
                                    :mod (w / wild-type))))
                  :mod (p2 / product-of :op1 16))
            :ARG2 (i2 / induce-01
                  :ARG1 (e4 / express-03
                        :ARG1 (g / gene :name (n4 / name :op1 "c-fos")))
                  :location (c3 / cell
                        :ARG2-of (e3 / express-03
                              :ARG1 (e2 / enzyme :name (n2 / name :op1 "PKR")
                                    :ARG2-of (m4 / mutate-01 :mod "-/-"))))
                  :mod (p3 / product-of :op1 0.8))
            :time (a / after
                  :op1 (t2 / treat-04
                        :ARG2 (p / protein :name (n3 / name :op1 "PDGF")))
                  :quant (t3 / temporal-quantity :quant 15
                        :unit (m2 / minute)))))

# ::id bel_pmid_1135_0938.29866 ::date 2015-04-21T06:47:48 ::annotator SDL-AMR-09 ::preferred
# ::snt Immunoblotting with anti-Stat3 as well as anti-PKR anti bodies (Figure2E) showed an increase in interaction within 5-15 min of treatment with the growth factor, followed by a decrease to below basal level at later time points.
# ::save-date Wed Feb 24, 2016 ::file bel_pmid_1135_0938_29866.txt
(s2 / show-01
      :ARG0 (i / immunoblot-01
            :ARG3 (a / and
                  :op1 (a2 / antibody
                        :ARG0-of (c / counter-01
                              :ARG1 (p / protein :name (n2 / name :op1 "Stat3"))))
                  :op2 (a3 / antibody
                        :ARG0-of (c2 / counter-01
                              :ARG1 (e / enzyme :name (n3 / name :op1 "PKR")))))
            :ARG1-of (d / describe-01
                  :ARG0 (f / figure :mod "2E")))
      :ARG1 (i2 / increase-01
            :ARG1 (i3 / interact-01)
            :time (a4 / after
                  :op1 (t / treat-04
                        :ARG2 (g / growth-factor))
                  :quant (t2 / temporal-quantity
                        :quant (b / between :op1 5 :op2 15)
                        :unit (m2 / minute)))
            :ARG2-of (f2 / follow-01
                  :ARG1 (d2 / decrease-01
                        :ARG4 (b3 / below
                              :op1 (l2 / level
                                    :mod (b2 / basal)))
                        :time (l / late
                              :degree (m / more))))))

# ::id bel_pmid_1140_4390.9676 ::date 2015-04-21T07:10:14 ::annotator SDL-AMR-09 ::preferred
# ::snt The induction of TNF-alpha production by NGF was blocked by K252a, an inhibitor of the TrkA receptor.
# ::save-date Sun Dec 20, 2015 ::file bel_pmid_1140_4390_9676.txt
(b / block-01
      :ARG0 (s / small-molecule :name (n3 / name :op1 "K252a")
            :ARG0-of (i / inhibit-01
                  :ARG1 (r / receptor :name (n4 / name :op1 "TrkA"))))
      :ARG1 (i2 / induce-01
            :ARG0 (p / protein :name (n / name :op1 "NGF"))
            :ARG2 (p2 / produce-01
                  :ARG1 (p3 / protein :name (n2 / name :op1 "TNF-alpha")))))

# ::id bel_pmid_1140_4390.22028 ::date 2015-04-21T07:22:21 ::annotator SDL-AMR-09 ::preferred
# ::snt To examine the role of TrkA in NGF's effects, we used K252a, which inhibits the tyrosine kinase activity of this receptor. Pretreatment of the cells with K252a (50 ng/mL) inhibited the production of TNF-a by NGF
# ::save-date Tue Jan 19, 2016 ::file bel_pmid_1140_4390_22028.txt
(m / multi-sentence
      :snt1 (u / use-01
            :ARG0 (w / we)
            :ARG1 (s / small-molecule :name (n / name :op1 "K252a")
                  :ARG0-of (i / inhibit-01
                        :ARG1 (a / activity-06
                              :ARG0 r2
                              :ARG1 (e2 / enzyme :name (n9 / name :op1 "tyrosine" :op2 "kinase")))))
            :ARG2 (e / examine-01
                  :ARG0 w
                  :ARG1 (r / role
                        :poss (r2 / receptor :name (n2 / name :op1 "TrkA"))
                        :topic (t / thing
                              :ARG2-of (a2 / affect-01
                                    :ARG0 (p2 / protein :name (n3 / name :op1 "NGF")))))))
      :snt2 (i2 / inhibit-01
            :ARG0 (p / pretreat-01
                  :ARG1 (c / cell)
                  :ARG3 (s2 / small-molecule :name (n5 / name :op1 "K252a")
                        :quant (m2 / mass-quantity :quant 50
                              :unit (n8 / nanogram-per-milliliter))))
            :ARG1 (p3 / produce-01
                  :ARG0 (p4 / protein :name (n6 / name :op1 "NGF"))
                  :ARG1 (p5 / protein :name (n7 / name :op1 "TNF-a")))))

# ::id bel_pmid_1140_4390.29562 ::date 2015-04-21T11:30:05 ::annotator SDL-AMR-09 ::preferred
# ::snt NGF activates Erk1/Erk2 and JNK but not p38MAPK in J774 cells... NGF also induced phosphorylation of JNK
# ::save-date Sun Dec 20, 2015 ::file bel_pmid_1140_4390_29562.txt
(m / multi-sentence
      :snt1 (c / contrast-01
            :ARG1 (a / activate-01
                  :ARG0 (p2 / protein :name (n / name :op1 "NGF"))
                  :ARG1 (a3 / and
                        :op1 (e / enzyme :name (n2 / name :op1 "Erk1"))
                        :op2 (e2 / enzyme :name (n3 / name :op1 "Erk2"))
                        :op3 (e3 / enzyme :name (n4 / name :op1 "JNK")))
                  :location (c2 / cell-line :name (n6 / name :op1 "J774")))
            :ARG2 (a2 / activate-01 :polarity -
                  :ARG0 p2
                  :ARG1 (e4 / enzyme :name (n5 / name :op1 "p38MAPK"))
                  :location c2))
      :snt2 (i / induce-01
            :ARG0 (p3 / protein :name (n7 / name :op1 "NGF"))
            :ARG2 (p4 / phosphorylate-01
                  :ARG1 (e5 / enzyme :name (n8 / name :op1 "JNK")))
            :mod (a4 / also)))

# ::id bel_pmid_1140_4390.29566 ::date 2015-04-21T11:49:11 ::annotator SDL-AMR-09 ::preferred
# ::snt The MAP kinase-Erk kinase (MEK) inhibitor PD 098059 inhibits the production of TNF-alpha induced by NGF
# ::save-date Sat Jan 16, 2016 ::file bel_pmid_1140_4390_29566.txt
(i2 / inhibit-01
      :ARG0 (s / small-molecule :name (n4 / name :op1 "PD098059")
            :ARG0-of (i / inhibit-01
                  :ARG1 (a / and
                        :op1 (p4 / protein-family :name (n6 / name :op1 "MAP" :op2 "kinase"))
                        :op2 (p5 / protein-family :name (n3 / name :op1 "Erk")))))
      :ARG1 (p / produce-01
            :ARG1 (p2 / protein :name (n5 / name :op1 "TNF-alpha"))
            :ARG2-of (i3 / induce-01
                  :ARG0 (p3 / protein :name (n / name :op1 "NGF")))))

# ::id bel_pmid_1140_8560.1760 ::date 2015-04-21T12:06:06 ::annotator SDL-AMR-09 ::preferred
# ::snt Both early passage and immortalized MEF cells from GSTpi(-/-) animals expressed significantly elevated activity of extracellular signal-regulated kinases ERK1/ERK2, kinases linked to cell proliferation pathways
# ::save-date Thu Jan 28, 2016 ::file bel_pmid_1140_8560_1760.txt
(e / exhibit-01
      :ARG0 (a / and
            :op1 (c / cell
                  :mod (p / passage
                        :mod (e2 / early))
                  :source (c4 / cell :name (n4 / name :op1 "MEF")
                        :ARG3-of (e4 / express-03
                              :ARG2 (p2 / protein :name (n3 / name :op1 "GSTpi")
                                    :ARG2-of (m2 / mutate-01 :mod "-/-")))))
            :op2 (c2 / cell
                  :ARG1-of (i / immortalize-03)
                  :source c4))
      :ARG1 (a2 / activity-06
            :ARG0 (a3 / and
                  :op1 (e3 / enzyme :name (n / name :op1 "ERK1")
                        :ARG1-of (l / link-01
                              :ARG2 (p3 / pathway
                                    :mod (p4 / proliferate-01
                                          :ARG0 (c3 / cell))))
                        :ARG1-of (i2 / include-91
                              :ARG2 (p5 / protein-family :name (n5 / name :op1 "extracellular" :op2 "signal-regulated" :op3 "kinase"))))
                  :op2 (e6 / enzyme :name (n2 / name :op1 "ERK2")
                        :ARG1-of l
                        :ARG1-of i2))
            :ARG1-of (e5 / elevate-01
                  :ARG1-of (s / significant-02))))

# ::id bel_pmid_1143_8543.2568 ::date 2015-04-22T02:04:21 ::annotator SDL-AMR-09 ::preferred
# ::snt A tetrameric Stat3 complex was found to be essential in transfection experiments for maximal interleukin-6-inducible activation of alpha2-macroglobulin gene promoter.
# ::save-date Sun Dec 20, 2015 ::file bel_pmid_1143_8543_2568.txt
(f / find-01
      :ARG1 (e / essential
            :domain (m3 / macro-molecular-complex
                  :mod (t / tetrameric)
                  :mod (p / protein :name (n / name :op1 "Stat3")))
            :purpose (a / activate-01
                  :ARG1 (m2 / molecular-physical-entity
                        :ARG0-of (p4 / promote-01
                              :ARG1 (g / gene
                                    :ARG0-of (e3 / encode-01
                                          :ARG1 (p5 / protein :name (n3 / name :op1 "alpha2-macroglobulin"))))))
                  :degree (m / maximum)
                  :ARG2-of (i / induce-01
                        :ARG0 (p3 / protein :name (n2 / name :op1 "interleukin-6"))
                        :ARG1-of (p2 / possible-01)))
            :prep-in (e2 / experiment-01
                  :ARG2 (t2 / transfect-01))))

# ::id bel_pmid_1144_7289.27070 ::date 2015-04-22T02:22:20 ::annotator SDL-AMR-09 ::preferred
# ::snt We have previously demonstrated that complex formation between the SH2 domain of Grb2 and FRS2a is mediated via Y196-, Y306-, Y349-, and Y392-designated Grb2 binding sites (4, 5).
# ::save-date Sun Jan 3, 2016 ::file bel_pmid_1144_7289_27070.txt
(d / demonstrate-01
      :ARG0 (w2 / we)
      :ARG1 (m / mediate-01
            :ARG0 (b / bind-01
                  :ARG2 (a2 / and
                        :op1 (a4 / amino-acid :mod 196 :name (n8 / name :op1 "tyrosine")
                              :part-of p2)
                        :op2 (a5 / amino-acid :mod 306 :name (n9 / name :op1 "tyrosine")
                              :part-of p2)
                        :op3 (a6 / amino-acid :mod 349 :name (n10 / name :op1 "tyrosine")
                              :part-of p2)))
            :ARG1 (f / form-01
                  :ARG0 (a / and
                        :op1 (p4 / protein-segment :name (n4 / name :op1 "SH2" :op2 "domain")
                              :part-of (p2 / protein :name (n2 / name :op1 "Grb2")))
                        :op2 (p3 / protein :name (n3 / name :op1 "FRS2a")))
                  :ARG1 (m2 / macro-molecular-complex)))
      :time (p / previous)
      :ARG1-of (d2 / describe-01
            :ARG0 (p8 / publication
                  :ARG1-of (c2 / cite-01
                        :ARG2 (a3 / and :op1 4 :op2 5)))))

# ::id bel_pmid_1144_7289.27072 ::date 2015-04-22T02:53:10 ::annotator SDL-AMR-09 ::preferred
# ::snt In addition, FRS2a recruits Grb2 indirectly by means of two binding sites for the SH2 domains of the protein tyrosine phosphatase Shp2 at Y436- and Y471-designated Shp2 binding sites (5).
# ::save-date Wed Jan 13, 2016 ::file bel_pmid_1144_7289_27072.txt
(a / and
      :op2 (r / recruit-01
            :ARG0 (p / protein :name (n / name :op1 "FRS2a"))
            :ARG1 (p2 / protein :name (n2 / name :op1 "Grb2"))
            :ARG1-of (d / direct-02 :polarity -)
            :manner (b / bind-01)
            :ARG1-of (d3 / describe-01
                  :ARG0 (p7 / publication
                        :ARG1-of (c / cite-01
                              :ARG2 5)))
            :instrument (a3 / and
                  :op1 (a4 / amino-acid :mod 436 :name (n7 / name :op1 "tyrosine")
                        :part-of (p3 / protein-segment :name (n5 / name :op1 "SH2" :op2 "domain")
                              :part-of (p4 / protein-tyrosine-phosphatase :name (n6 / name :op1 "Shp2"))
                              :ARG1-of (b2 / bind-01)))
                  :op2 (a5 / amino-acid :mod 471 :name (n8 / name :op1 "tyrosine")
                        :part-of p3))))

# ::id bel_pmid_1149_0023.3486 ::date 2015-04-22T03:18:07 ::annotator SDL-AMR-09 ::preferred
# ::snt Serum amyloid A-activating factor-1 (SAF-1) is a zinc finger transcription factor that is activated by many mediators of inflammation including IL-1, IL-6, and bacterial LPS.
# ::save-date Fri Feb 12, 2016 ::file bel_pmid_1149_0023_3486.txt
(a / activate-01
      :ARG0 (m2 / molecular-physical-entity
            :ARG0-of (m3 / mediate-01
                  :ARG1 (i / inflame-01))
            :quant (m4 / many)
            :ARG2-of (i2 / include-01
                  :ARG1 (a2 / and
                        :op1 (p2 / protein :name (n2 / name :op1 "IL-1"))
                        :op2 (p3 / protein :name (n3 / name :op1 "IL-6"))
                        :op3 (l / lipopolysaccharide
                              :mod (b / bacteria)))))
      :ARG1 (p / protein :name (n / name :op1 "serum" :op2 "amyloid" :op3 "A-activating" :op4 "factor-1")
            :ARG0-of (t / transcribe-01
                  :ARG1 (p4 / protein :name (n5 / name :op1 "zinc" :op2 "finger")))))

# ::id bel_pmid_1149_0023.22070 ::date 2015-04-22T03:28:06 ::annotator SDL-AMR-09 ::preferred
# ::snt We further show that SAF-1 is phosphorylated in vitro by PKA-Calpha and that addition of cAMP markedly induces in vivo phosphorylation of SAF-1 and transcription of SAF-regulated reporter genes.
# ::save-date Sun Jan 3, 2016 ::file bel_pmid_1149_0023_22070.txt
(a / and
      :op2 (s / show-01
            :ARG0 (w / we)
            :ARG1 (a2 / and
                  :op1 (p3 / phosphorylate-01
                        :ARG1 (p4 / protein :name (n / name :op1 "SAF-1"))
                        :ARG2 (e / enzyme :name (n2 / name :op1 "PKA-Calpha"))
                        :manner (i2 / in-vitro))
                  :op2 (i / induce-01
                        :ARG0 (a3 / add-02
                              :ARG1 (s2 / small-molecule :name (n3 / name :op1 "cAMP")))
                        :ARG2 (a4 / and
                              :op1 (p5 / phosphorylate-01
                                    :ARG1 p4
                                    :manner (i3 / in-vivo))
                              :op2 (t / transcribe-01
                                    :ARG1 (g / gene
                                          :ARG1-of (r2 / regulate-01
                                                :ARG0 p4)
                                          :ARG0-of (r3 / report-01))
                                    :manner i3))
                        :manner (m / marked)))
            :mod (f / further)))

# ::id bel_pmid_1149_3654.6262 ::date 2015-04-22T03:38:36 ::annotator SDL-AMR-09 ::preferred
# ::snt Inhibition of p38 MAPK by SB203580 in differentiating C2C12 myoblasts blocks MyoD expression, SHPS-1 tyrosyl phosphorylation and the association of SHPS-1 with SHP-2.
# ::save-date Mon Jan 4, 2016 ::file bel_pmid_1149_3654_6262.txt
(b / block-01
      :ARG0 (i / inhibit-01
            :ARG0 (s / small-molecule :name (n2 / name :op1 "SB203580"))
            :ARG1 (e / enzyme :name (n3 / name :op1 "p38MAPK"))
            :location (m / myoblast
                  :part-of (c / cell-line :name (n4 / name :op1 "C2C12")
                        :ARG1-of (d / differentiate-101))))
      :ARG1 (a / and
            :op1 (e2 / express-03
                  :ARG2 (p4 / protein :name (n5 / name :op1 "MyoD")))
            :op2 (p3 / phosphorylate-01
                  :ARG1 (a3 / amino-acid :name (n6 / name :op1 "tyrosine")
                        :part-of (p5 / protein :name (n7 / name :op1 "SHPS-1"))))
            :op3 (a2 / associate-01
                  :ARG1 p5
                  :ARG2 (p6 / protein :name (n8 / name :op1 "SHP-2")))))

# ::id bel_pmid_1149_3654.11578 ::date 2015-04-22T04:02:12 ::annotator SDL-AMR-09 ::preferred
# ::snt Either constitutive expression or inducible activation of MyoD in 10T(1/2) fibroblasts promotes SHPS-1 tyrosyl phosphorylation and its association with SHP-2.
# ::save-date Mon Jan 4, 2016 ::file bel_pmid_1149_3654_11578.txt
(p2 / promote-01
      :ARG0 (a / and
            :op1 (e / express-03
                  :ARG2 p
                  :ARG3 (f / fibroblast
                        :part-of (c2 / cell-line :name (n2 / name :op1 "10T(1/2)")))
                  :mod (c / constitutive))
            :op2 (a2 / activate-01
                  :ARG1 (p / protein :name (n / name :op1 "MyoD"))
                  :ARG2-of (i / induce-01
                        :ARG1-of (p3 / possible-01))
                  :location f))
      :ARG1 (a3 / and
            :op1 (p5 / phosphorylate-01
                  :ARG1 (a4 / amino-acid :name (n3 / name :op1 "tyrosine")
                        :part-of (p6 / protein :name (n4 / name :op1 "SHPS-1"))))
            :op2 (a5 / associate-01
                  :ARG1 p6
                  :ARG2 (p7 / protein :name (n5 / name :op1 "SHP-2")))))

# ::id bel_pmid_1149_3654.30640 ::date 2015-04-22T04:11:16 ::annotator SDL-AMR-09 ::preferred
# ::snt We have identified that the 120 kDa complex consists of the SHP-2 substrate-1 (SHPS-1) and the Grb2-associated binder-1 (Gab-1). SHPS-1, but not Gab-1, undergoes tyrosyl phosphorylation and association with SHP-2 during myogenesis,
# ::save-date Mon Jan 4, 2016 ::file bel_pmid_1149_3654_30640.txt
(m / multi-sentence
      :snt1 (i / identify-01
            :ARG0 (w2 / we)
            :ARG1 (c / consist-01
                  :ARG1 (m4 / macro-molecular-complex
                        :ARG1-of (e / equal-01
                              :ARG2 (m2 / mass-quantity :quant 120
                                    :unit (k / kilodalton))))
                  :ARG2 (a / and
                        :op1 (p2 / protein :name (n / name :op1 "SHP-2" :op2 "substrate-1"))
                        :op2 (p3 / protein :name (n2 / name :op1 "Grb2-associated" :op2 "binder-1")))))
      :snt2 (c3 / contrast-01
            :ARG1 (a3 / and
                  :op1 (p4 / phosphorylate-01
                        :ARG1 (a2 / amino-acid :name (n3 / name :op1 "tyrosine")
                              :part-of (p / protein :name (n6 / name :op1 "SHP-2" :op2 "substrate-1")))
                        :time (m3 / myogenesis))
                  :op2 (a4 / associate-01
                        :ARG1 p
                        :ARG2 (p5 / protein :name (n4 / name :op1 "SHP-2"))
                        :time m3))
            :ARG2 (a5 / and
                  :op1 (p6 / phosphorylate-01 :polarity -
                        :ARG1 (a6 / amino-acid :name (n5 / name :op1 "tyrosine")
                              :part-of (p7 / protein :name (n7 / name :op1 "Grb2-associated" :op2 "binder-1")))
                        :time m3)
                  :op2 (a7 / associate-01
                        :ARG1 p7
                        :ARG2 p5
                        :time m3))))

# ::id bel_pmid_1150_0506.8864 ::date 2015-04-23T00:37:06 ::annotator SDL-AMR-09 ::preferred
# ::snt The expression and activity of the protein-tyrosine phosphatase 1B (PTP1B), but not protein-tyrosine phosphatases SHP-1, SHP-2, and LAR, were constitutively decreased in tissues expressing the Q205L Galpha(i2).
# ::save-date Sun Jan 3, 2016 ::file bel_pmid_1150_0506_8864.txt
(c2 / contrast-01
      :ARG1 (d / decrease-01
            :ARG1 (a / and
                  :op1 (e / express-03
                        :ARG2 (e4 / enzyme :name (n6 / name :op1 "protein" :op2 "tyrosyne" :op3 "phosphatase" :op4 "1B"))
                        :ARG3 (t / tissue
                              :ARG3-of (e2 / express-03
                                    :ARG2 (p2 / protein :name (n2 / name :op1 "Galpha(i2)")
                                          :ARG1-of (m / mutate-01 :value "Q205L")))))
                  :op2 (a2 / activity-06
                        :ARG0 e4
                        :location t))
            :mod (c / constitutive))
      :ARG2 (d2 / decrease-01 :polarity -
            :ARG1 (a3 / and
                  :op1 (e3 / express-03
                        :ARG2 (a4 / and
                              :op1 (p3 / protein-tyrosine-phophatase :name (n3 / name :op1 "SHP-1"))
                              :op2 (p4 / protein-tyrosine-phosphatase :name (n4 / name :op1 "SHP-2"))
                              :op3 (p5 / protein-tyrosine-phosphatase :name (n5 / name :op1 "LAR")))
                        :ARG3 t)
                  :op2 (a5 / activity-06
                        :ARG0 a4
                        :location t))))

# ::id bel_pmid_1153_6047.16526 ::date 2015-04-23T01:01:38 ::annotator SDL-AMR-09 ::preferred
# ::snt IL-6 induced STAT3 transactivation was reduced from sixfold to 2.5-fold when cells were pre-treated with the JAK2 inhibitor (Figure 2b).
# ::save-date Tue Jan 19, 2016 ::file bel_pmid_1153_6047_16526.txt
(r / reduce-01
      :ARG1 (t / transactivate-01
            :ARG1 (p / protein :name (n / name :op1 "STAT3"))
            :ARG2-of (i2 / induce-01
                  :ARG0 (p2 / protein :name (n2 / name :op1 "IL-6"))))
      :ARG3 (p4 / product-of :op1 6)
      :ARG4 (p5 / product-of :op1 2.5)
      :condition (p3 / pretreat-01
            :ARG1 (c / cell)
            :ARG3 (m3 / molecular-physical-entity
                  :ARG0-of (i / inhibit-01
                        :ARG1 (e / enzyme :name (n4 / name :op1 "JAK2"))))
            :time (b / before))
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod "2b")))

# ::id bel_pmid_1153_6047.22124 ::date 2015-04-23T01:26:41 ::annotator SDL-AMR-09 ::preferred
# ::snt Overexpression of both MEN2A-RET and STAT3 strongly enhanced reporter activation, indicating that MEN2A-RET induces cyclin-D1 gene expression via STAT3 (Figure 4a).
# ::save-date Sun Jan 3, 2016 ::file bel_pmid_1153_6047_22124.txt
(e / enhance-01
      :ARG0 (o / overexpress-01
            :ARG1 (a / and
                  :op1 (p2 / protein :name (n / name :op1 "MEN2A-RET"))
                  :op2 (p3 / protein :name (n2 / name :op1 "STAT3"))
                  :mod (b / both)))
      :ARG1 (a2 / activate-01
            :ARG1 (g / gene
                  :ARG0-of (r2 / report-01)))
      :ARG1-of (s / strong-02)
      :ARG0-of (i / indicate-01
            :ARG1 (i2 / induce-01
                  :ARG0 p2
                  :ARG2 (e2 / express-03
                        :ARG1 (g2 / gene :name (n3 / name :op1 "cyclin-D1")))
                  :instrument p3))
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod "4a")))

# ::id bel_pmid_1153_6047.22126 ::date 2015-04-23T01:39:46 ::annotator SDL-AMR-09 ::preferred
# ::snt These data indicate that MEN2A-RET enhances proliferation via STAT3, and that a full length STAT3 is required to mediate the MEN2A-RET induced proliferation.
# ::save-date Sun Dec 20, 2015 ::file bel_pmid_1153_6047_22126.txt
(i / indicate-01
      :ARG0 (d / data
            :mod (t / this))
      :ARG1 (a / and
            :op1 (e / enhance-01
                  :ARG0 (p / protein :name (n / name :op1 "MEN2A-RET"))
                  :ARG1 (p2 / proliferate-01)
                  :ARG2 (p3 / protein :name (n2 / name :op1 "STAT3")))
            :op2 (r / require-01
                  :ARG0 (m / mediate-01
                        :ARG0 p4
                        :ARG1 (p5 / proliferate-01
                              :ARG2-of (i2 / induce-01
                                    :ARG0 p)))
                  :ARG1 (p4 / protein :name (n3 / name :op1 "STAT3")
                        :ARG1-of (l / long-03
                              :degree (f / full))))))

# ::id bel_pmid_1153_6047.30396 ::date 2015-04-23T01:45:44 ::annotator SDL-AMR-09 ::preferred
# ::snt Over-expression of MEN2A-RET mutants reduced STAT3 ser727 phosphorylation to basal levels, suggesting that STAT3 tyr705 phosphorylation is a prerequisite for maximal MEN2A-RET induced STAT3 ser727 phosphorylation (Figure 3b).
# ::save-date Sun Jan 3, 2016 ::file bel_pmid_1153_6047_30396.txt
(r / reduce-01
      :ARG0 (o / overexpress-01
            :ARG1 (p3 / protein :name (n / name :op1 "MEN2A-RET")
                  :ARG2-of (m / mutate-01)))
      :ARG1 (p2 / phosphorylate-01
            :ARG1 (a / amino-acid :mod 727 :name (n2 / name :op1 "serine")
                  :part-of (p4 / protein :name (n3 / name :op1 "STAT-3"))))
      :ARG4 (l / level
            :mod (b / basal))
      :ARG0-of (s / suggest-01
            :ARG1 (r2 / require-01
                  :ARG0 (p5 / phosphorylate-01
                        :ARG1 a
                        :degree (m2 / maximum)
                        :ARG2-of (i / induce-01
                              :ARG0 p3))
                  :ARG1 (p / phosphorylate-01
                        :ARG1 (a3 / amino-acid :mod 705 :name (n6 / name :op1 "tyrosine")
                              :part-of p4))))
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod "3b")))

# ::id bel_pmid_1153_6047.30398 ::date 2015-04-23T02:16:27 ::annotator SDL-AMR-09 ::preferred
# ::snt STAT3 tyr705 phosphorylation was reduced when the MEN2A-RET single mutants tyr752phe or tyr928phe were overexpressed, while no STAT3 tyr705 phosphorylation was observed in the presence of the MEN2A-RET double mutant (Figure 3b).
# ::save-date Mon Dec 21, 2015 ::file bel_pmid_1153_6047_30398.txt
(c / contrast-01
      :ARG1 (r / reduce-01
            :ARG1 (p2 / phosphorylate-01
                  :ARG1 (a / amino-acid :mod 705 :name (n / name :op1 "tyrosine")
                        :part-of (p3 / protein :name (n2 / name :op1 "STAT3"))))
            :condition (o / overexpress-01
                  :ARG1 (o2 / or
                        :op1 (p / protein :name (n4 / name :op1 "MEN2A-RET")
                              :ARG2-of (m2 / mutate-01 :value "tyr752phe")
                              :ARG1-of (s / single-02))
                        :op2 (p5 / protein :name (n9 / name :op1 "MEN2A-RET")
                              :ARG2-of (m5 / mutate-01 :value "tyr928phe")
                              :ARG1-of s))))
      :ARG2 (o3 / observe-01 :polarity -
            :ARG1 p2
            :condition (p4 / present-02
                  :ARG1 (p7 / protein :name (n5 / name :op1 "MEN2A-RET")
                        :ARG1-of (m3 / mutate-01
                              :mod (d / double)))))
      :ARG1-of (d2 / describe-01
            :ARG0 (f / figure :mod "3b")))

# ::id bel_pmid_1153_6047.30400 ::date 2015-04-23T02:24:21 ::annotator SDL-AMR-09 ::preferred
# ::snt As depicted in Figure 3a, mutation of tyr928 (RET) reduced STAT3 transactivation approximately 1.5-fold, indicating that other STAT3 docking sites must be present in MEN2A-RET as well.
# ::save-date Thu Dec 17, 2015 ::file bel_pmid_1153_6047_30400.txt
(r / reduce-01
      :ARG0 (m / mutate-01
            :ARG1 (a / amino-acid :mod 928 :name (n / name :op1 "tyrosine")
                  :part-of (p / protein :name (n2 / name :op1 "RET"))))
      :ARG1 (t / transactivate-01
            :ARG1 (p2 / protein :name (n3 / name :op1 "STAT3")))
      :ARG2 (p5 / product-of :op1 1.5
            :mod (a3 / approximate))
      :ARG0-of (i / indicate-01
            :ARG1 (o / obligate-01
                  :ARG2 (p6 / present-02
                        :ARG1 (p4 / protein-segment
                              :ARG2-of (d / dock-01
                                    :ARG1 p2)
                              :mod (o2 / other))
                        :ARG2 (p3 / protein :name (n4 / name :op1 "MEN2A-RET"))
                        :mod (a2 / as-well))))
      :ARG1-of (d2 / depict-01
            :ARG0 (f / figure :mod "3a")))

# ::id bel_pmid_1153_6047.30402 ::date 2015-04-23T02:37:07 ::annotator SDL-AMR-09 ::preferred
# ::snt As depicted in Figure 1a,b, over-expression of both MEN2A-RET and STAT3 strongly enhanced IRE transactivation, while overexpression of STAT3 alone did not affect reporter activation.
# ::save-date Mon Jul 13, 2015 ::file bel_pmid_1153_6047_30402.txt
(c / contrast-01
      :ARG1 (e / enhance-01
            :ARG0 (o / overexpress-01
                  :ARG1 (a / and
                        :op1 (p2 / protein :name (n / name :op1 "MEN2A-RET"))
                        :op2 (p3 / protein :name (n2 / name :op1 "STAT3"))))
            :ARG1 (t / transactivate-01
                  :ARG1 (p4 / protein-segment :name (n3 / name :op1 "IRE")))
            :ARG1-of (s / strong-02))
      :ARG2 (a2 / affect-01 :polarity -
            :ARG0 (o2 / overexpress-01
                  :ARG1 p3)
            :ARG1 (a4 / activate-01
                  :ARG1 (g / gene
                        :ARG0-of (r2 / report-01))))
      :ARG1-of (d / depict-01
            :ARG0 (a5 / and
                  :op1 (f / figure :mod "1a")
                  :op2 (f2 / figure :mod "1b"))))

# ::id bel_pmid_1155_7580.38186 ::date 2015-04-22T05:07:19 ::annotator SDL-AMR-09 ::preferred
# ::snt After bFGF was added to pulmonary fibroblasts, the kinase activities of p44/p42 ERK1/2 were determined by an in-gel assay at various times after exposure (Fig. 1). The data demonstrate that the addition of bFGF results in activation of ERK1/2 within 5 min, with the highest activity at 30 min, followed by a lower level of activity that persists for 8-12 h.
# ::save-date Sun Jan 17, 2016 ::file bel_pmid_1155_7580_38186.txt
(m3 / multi-sentence
      :snt1 (d / determine-01
            :ARG1 (a14 / and
                  :op1 (a / activity-06
                        :ARG0 (k2 / kinase :name (n / name :op1 "p44" :op2 "ERK1")))
                  :op2 (a13 / activity-06
                        :ARG0 (k3 / kinase :name (n3 / name :op1 "p42" :op2 "ERK2"))))
            :manner (a3 / assay-01
                  :manner (i / in-gel))
            :time (a5 / after
                  :op1 (a6 / add-02
                        :ARG1 (p3 / protein :name (n2 / name :op1 "bFGF"))
                        :ARG2 (f3 / fibroblast
                              :part-of (l3 / lung))))
            :ARG1-of (d2 / describe-01
                  :ARG0 (f / figure :mod 1))
            :frequency (v / various
                  :time (a4 / after
                        :op1 (e2 / expose-01))))
      :snt2 (d3 / demonstrate-01
            :ARG0 (d4 / data)
            :ARG1 (r / result-01
                  :ARG1 (a7 / add-02
                        :ARG1 (p / protein :name (n5 / name :op1 "bFGF")))
                  :ARG2 (a8 / activate-01
                        :ARG1 (a9 / and
                              :op1 (e4 / enzyme :name (n6 / name :op1 "ERK1"))
                              :op2 (e5 / enzyme :name (n7 / name :op1 "ERK2"))
                              :ARG0-of (a2 / activity-06
                                    :ARG2-of (f2 / follow-01
                                          :ARG1 (a12 / activity-06
                                                :ARG0 a9
                                                :ARG1-of (l / low-04
                                                      :degree (m2 / more))
                                                :ARG1-of (p2 / persist-01
                                                      :duration (b2 / between
                                                            :op1 (t4 / temporal-quantity :quant 8
                                                                  :unit (h3 / hour))
                                                            :op2 (t5 / temporal-quantity :quant 12
                                                                  :unit (h4 / hour))))))
                                    :ARG1-of (h / high-02
                                          :degree (m / most)
                                          :time (a11 / after
                                                :op1 a7
                                                :quant (t2 / temporal-quantity :quant 30
                                                      :unit m4)))))
                        :time (a10 / after
                              :op1 a7
                              :quant (u / up-to
                                    :op1 (t / temporal-quantity :quant 5
                                          :unit (m4 / minute))))))))

# ::id bel_pmid_1155_7774.11824 ::date 2015-04-22T05:39:51 ::annotator SDL-AMR-09 ::preferred
# ::snt PPARalpha (NR1C1) controls lipid oxidation and clearance in hepatocytes and PPARgamma (NR1C3) promotes preadipocyte differentiation and lipogenesis.
# ::save-date Thu Apr 30, 2015 ::file bel_pmid_1155_7774_11824.txt
(a / and
      :op1 (c / control-01
            :ARG0 (p / protein :name (n / name :op1 "PPARalpha")
                  :ARG1-of (d2 / describe-01
                        :ARG2 (p4 / protein :name (n5 / name :op1 "NR1C1"))))
            :ARG1 (a2 / and
                  :op1 (o / oxidize-01
                        :ARG1 (l / lipid))
                  :op2 (c2 / clear-01
                        :ARG2 l))
            :location (h / hepatocyte))
      :op2 (p2 / promote-02
            :ARG0 (p3 / protein :name (n3 / name :op1 "PPARgamma")
                  :ARG1-of (d3 / describe-01
                        :ARG2 (p5 / protein :name (n6 / name :op1 "NR1C3"))))
            :ARG1 (a3 / and
                  :op1 (d / differentiate-01
                        :ARG1 (p6 / preadipocyte))
                  :op2 (l2 / lipogenesis
                        :location p6))))

# ::id bel_pmid_1155_7774.16262 ::date 2015-04-22T05:52:03 ::annotator SDL-AMR-09 ::preferred
# ::snt Furthermore, it has been shown that activation of PPARg by the thiozolidinedione, rosiglitazaone, decreased scavenger receptor class A expresion.
# ::save-date Wed Apr 22, 2015 ::file bel_pmid_1155_7774_16262.txt
(a / and
      :op2 (s / show-01
            :ARG1 (d / decrease-01
                  :ARG0 (a2 / activate-01
                        :ARG0 (s3 / small-molecule :name (n3 / name :op1 "rosiglitazone")
                              :ARG1-of (i / include-91
                                    :ARG2 (s2 / small-molecule :name (n2 / name :op1 "thiazolidinedione"))))
                        :ARG1 (p / protein :name (n / name :op1 "PPARgamma")))
                  :ARG1 (e / express-03
                        :ARG2 (p2 / protein :name (n4 / name :op1 "scavenger" :op2 "receptor" :op3 "class" :op4 "A"))))))

# ::id bel_pmid_1155_7774.16418 ::date 2015-04-22T06:04:25 ::annotator SDL-AMR-09 ::preferred
# ::snt Pparg, which is activated by 15-deoxy-D12,14-prostaglandin J2 and the thiazolidione class of insulin-sensitizing drugs,...Among its known target genes are adipocyte factty-acid binidng protein and fatty acid synthase, which are efeeectors of lipid accumulaiton during adipogeesis.
# ::save-date Tue Dec 22, 2015 ::file bel_pmid_1155_7774_16418.txt
(m / multi-sentence
      :snt1 (a / activate-01
            :ARG0 (a2 / and
                  :op1 (s / small-molecule :name (n2 / name :op1 "15-deoxy-D12" :op2 "14-prostaglandin" :op3 "J2"))
                  :op2 (c / class
                        :mod (s2 / small-molecule :name (n3 / name :op1 "thiazolidione"))
                        :ARG1-of (i / include-91
                              :ARG2 (d / drug
                                    :ARG0-of (s3 / sensitize-01
                                          :ARG2 (p4 / protein :name (n4 / name :op1 "insulin")))))))
            :ARG1 (p / protein :name (n / name :op1 "PPAR-gamma")))
      :snt2 (i2 / include-91
            :ARG1 (a3 / and
                  :op1 (g2 / gene
                        :ARG0-of (e3 / encode-01
                              :ARG1 (p5 / protein :name (n8 / name :op1 "adipocyte" :op2 "fatty-acid" :op3 "biniding" :op4 "protein"))))
                  :op2 (g3 / gene
                        :ARG0-of (e4 / encode-01
                              :ARG1 (e / enzyme :name (n7 / name :op1 "fatty" :op2 "acid" :op3 "synthase"))))
                  :mod (e2 / effector
                        :ARG0-of (c2 / cause-01
                              :ARG1 (a4 / accumulate-01
                                    :ARG1 (l / lipid))
                              :time (a5 / adipogenesis)))
                  :part-of (a6 / adipocyte))
            :ARG2 (g / gene
                  :ARG1-of (t / target-01
                        :ARG2 (p2 / protein :name (n5 / name :op1 "PPARgamma")))
                  :ARG1-of (k / know-01))))

# ::id bel_pmid_1155_7774.30036 ::date 2015-04-22T06:23:11 ::annotator SDL-AMR-09 ::preferred
# ::snt Therefore the profound repression of CYP27 and apoE expressoin by activatoin or overexpression of PPARd might contribute to the lipid accumulation observed in these cells in culture
# ::save-date Wed Jun 24, 2015 ::file bel_pmid_1155_7774_30036.txt
(i / infer-01
      :ARG1 (p / possible-01
            :ARG1 (c / contribute-01
                  :ARG0 (r / repress-01
                        :ARG0 (o / or
                              :op1 (a3 / activate-01
                                    :ARG1 (p2 / protein :name (n3 / name :op1 "PPARdelta")))
                              :op2 (o2 / overexpress-01
                                    :ARG1 p2))
                        :ARG1 (e / express-03
                              :ARG1 (a2 / and
                                    :op1 (g / gene :name (n / name :op1 "CYP27"))
                                    :op2 (g2 / gene :name (n2 / name :op1 "apoE"))))
                        :mod (p3 / profound))
                  :ARG2 (a / accumulate-01
                        :ARG1 (l / lipid)
                        :ARG1-of (o3 / observe-01
                              :location (c2 / cell
                                    :mod (t / this))
                              :manner (i2 / in-culture))))))

# ::id bel_pmid_1155_7774.33822 ::date 2015-04-22T06:40:44 ::annotator SDL-AMR-09 ::preferred
# ::snt However, plaque formation is also appreciated to be an inflammoratory response and it has been shown that activators of Pparg inhibit the production of inflammoratory cytokines such as TNFa, Il6 and Il1b.
# ::save-date Sun Jan 3, 2016 ::file bel_pmid_1155_7774_33822.txt
(c2 / contrast-01
      :ARG2 (a2 / and
            :op1 (u / understand-01
                  :ARG1 (f / form-01
                        :ARG1 (p / plaque))
                  :ARG2 (r / respond-01
                        :ARG2 (i / inflame-01))
                  :mod (a4 / also))
            :op2 (s / show-01
                  :ARG1 (i2 / inhibit-01
                        :ARG0 (t / thing
                              :ARG0-of (a / activate-01
                                    :ARG1 (p2 / protein :name (n / name :op1 "PPARgamma"))))
                        :ARG1 (p3 / produce-01
                              :ARG1 (c / cytokine
                                    :example (a3 / and
                                          :op1 (p5 / protein :name (n3 / name :op1 "TNFa"))
                                          :op2 (p6 / protein :name (n4 / name :op1 "Il6"))
                                          :op3 (p7 / protein :name (n5 / name :op1 "Il6b")))
                                    :ARG0-of i))))))

# ::id bel_pmid_1155_7774.33878 ::date 2015-04-22T06:56:30 ::annotator SDL-AMR-09 ::preferred
# ::snt These studies started with the observation that Pparg up-regulates CD36 (savenger receptor calss-B) expression in macrophages.
# ::save-date Thu Apr 30, 2015 ::file bel_pmid_1155_7774_33878.txt
(s / start-01
      :ARG1 (s2 / study-01
            :mod (t / this))
      :ARG2 (o / observe-02
            :ARG1 (u / upregulate-01
                  :ARG1 (e / express-03
                        :ARG2 (p2 / protein :name (n2 / name :op1 "CD36")
                              :ARG1-of (d / describe-01
                                    :ARG2 (p3 / protein :name (n3 / name :op1 "savenger" :op2 "receptor" :op3 "class" :op4 "B"))))
                        :ARG3 (m / macrophage))
                  :ARG2 (p / protein :name (n / name :op1 "PPARgamma")))))

# ::id bel_pmid_1158_3971.7986 ::date 2015-04-22T07:00:57 ::annotator SDL-AMR-09 ::preferred
# ::snt Exogenous ANXA1 but not ANXA5, administered to IL-6 KO mice before LPS challenge inhibited TNF-alpha release.
# ::save-date Fri Feb 12, 2016 ::file bel_pmid_1158_3971_7986.txt
(i / inhibit-01
      :ARG0 (p / protein :name (n / name :op1 "ANXA1")
            :mod (e / exogenous)
            :ARG1-of (c / contrast-01
                  :ARG2 (p2 / protein :name (n2 / name :op1 "ANXA5")))
            :ARG1-of (a / administer-01
                  :ARG2 (m / mouse
                        :mod (p3 / protein :name (n3 / name :op1 "IL-6")
                              :ARG2-of (m2 / mutate-01 :mod "-/+")))
                  :time (b / before
                        :op1 (c2 / challenge-01
                              :ARG2 (l / lipopolysaccharide)))))
      :ARG1 (r / release-01
            :ARG1 (p4 / protein :name (n5 / name :op1 "TNF-alpha"))))

# ::id bel_pmid_1158_3971.9278 ::date 2015-04-22T07:13:20 ::annotator SDL-AMR-09 ::preferred
# ::snt recombinant IL-6 to IL-6 KO animals before LPS or TNF-alpha challenge, replenished ANXA1 liver synthesis to that of WT animals.
# ::save-date Fri Feb 12, 2016 ::file bel_pmid_1158_3971_9278.txt
(r / replenish-01
      :ARG0 (p / protein :name (n / name :op1 "IL-6")
            :ARG1-of (r2 / recombine-01)
            :ARG1-of (a / administer-01
                  :ARG2 (a2 / animal
                        :mod (p4 / protein :name (n5 / name :op1 "IL-6")
                              :ARG2-of (m / mutate-01 :mod "-/+")))
                  :time (b / before
                        :op1 (c / challenge-01
                              :ARG2 (o / or
                                    :op1 (l3 / lipopolysaccharide)
                                    :op2 (p2 / protein :name (n3 / name :op1 "TNF-alpha")))))))
      :ARG1 (s2 / synthesize-01
            :ARG0 (l / liver)
            :ARG1 (p3 / protein :name (n4 / name :op1 "ANXA1")))
      :extent (s3 / synthesize-01
            :ARG0 (l2 / liver
                  :part-of (a3 / animal
                        :mod (w / wild-type)))
            :ARG1 p3))

# ::id bel_pmid_1159_1769.19228 ::date 2015-04-22T07:21:10 ::annotator SDL-AMR-09 ::preferred
# ::snt Here we show that IL-10 directly affects progenitor myeloid cells by protecting them from death following the removal of growth factors.
# ::save-date Wed Feb 24, 2016 ::file bel_pmid_1159_1769_19228.txt
(s / show-01
      :ARG0 (w / we)
      :ARG1 (a / affect-01
            :ARG0 (p2 / protein :name (n / name :op1 "IL-10"))
            :ARG1 (c / cell
                  :mod (p3 / progenitor)
                  :mod (m / myeloid))
            :ARG2 (p4 / protect-01
                  :ARG0 p2
                  :ARG1 c
                  :ARG2 (d / die-01
                        :ARG1-of (f / follow-01
                              :ARG2 (r / remove-01
                                    :ARG1 (g / growth-factor)))))
            :ARG1-of (d2 / direct-02))
      :medium (h / here))

# ::id bel_pmid_1159_1769.21788 ::date 2015-04-22T07:26:19 ::annotator SDL-AMR-09 ::preferred
# ::snt Following ligand binding to the IL-10R, Jak1 and Tyk2, which are constitutively associated with IL-10R1 and IL-10R2, respectively (3, 14), are phosphorylated on tyrosine The phosphorylated IL-10R/Jak1/Tyk2 complex serves as a docking site for the transcription factors Stat-1 and Stat-3 Jak1, which is required for the biological activity of IL-10 (20), also tyrosine phosphorylates the insulin receptor substrate-1 (IRS-1)
# ::save-date Mon Jul 6, 2015 ::file bel_pmid_1159_1769_21788.txt
(m / multi-sentence
      :snt1 (p / phosphorylate-01
            :ARG1 (a / and
                  :op1 (a2 / amino-acid :name (n3 / name :op1 "tyrosine")
                        :part-of (e / enzyme :name (n / name :op1 "Jak1")
                              :ARG1-of (a4 / associate-01
                                    :ARG2 (r2 / receptor :name (n6 / name :op1 "IL-10R1"))
                                    :manner (c / constitutive)
                                    :manner (r4 / respective)
                                    :ARG1-of (d / describe-01
                                          :ARG0 (p2 / publication
                                                :ARG1-of (c2 / cite-01
                                                      :ARG2 (a6 / and :op1 3 :op2 14)))))))
                  :op2 (a3 / amino-acid :name (n4 / name :op1 "tyrosine")
                        :part-of (e2 / enzyme :name (n2 / name :op1 "Tyk2")
                              :ARG1-of (a5 / associate-01
                                    :ARG2 (r3 / receptor :name (n7 / name :op1 "IL-10R2"))
                                    :manner c
                                    :ARG1-of d
                                    :manner r4))))
            :ARG1-of (f / follow-01
                  :ARG2 (b / bind-01
                        :ARG1 (l / ligand)
                        :ARG2 (r / receptor :name (n5 / name :op1 "IL-10R")))))
      :snt2 (s / serve-01
            :ARG0 (m2 / macro-molecular-complex
                  :part (r5 / receptor :name (n8 / name :op1 "IL-10R"))
                  :part (e3 / enzyme :name (n9 / name :op1 "Jak1"))
                  :part (e4 / enzyme :name (n10 / name :op1 "Tyk2"))
                  :ARG1-of (p3 / phosphorylate-01))
            :ARG1 (s2 / site
                  :ARG2-of (d2 / dock-01
                        :ARG1 (a7 / and
                              :op1 (p4 / protein :name (n11 / name :op1 "Stat-1"))
                              :op2 (p5 / protein :name (n12 / name :op1 "Stat-3"))
                              :mod (f2 / factor
                                    :ARG0-of (t / transcribe-01))))))
      :snt3 (p6 / phosphorylate-01
            :ARG1 (a9 / amino-acid :name (n14 / name :op1 "tyrosine")
                  :part-of (p7 / protein :name (n15 / name :op1 "insulin" :op2 "receptor" :op3 "substrate" :op4 "1")
                        :ARG1-of (d3 / describe-01
                              :ARG2 (p8 / protein :name (n16 / name :op1 "IRS-1")))))
            :ARG2 (e5 / enzyme :name (n13 / name :op1 "Jak1")
                  :ARG1-of (r6 / require-01
                        :ARG0 (a10 / activity-06
                              :ARG0 (p9 / protein :name (n17 / name :op1 "IL-10"))
                              :mod (b2 / biology))
                        :ARG1-of (d4 / describe-01
                              :ARG0 (p10 / publication
                                    :ARG1-of (c3 / cite-01
                                          :ARG2 20)))))
            :mod (a8 / also)))

# ::id bel_pmid_1159_1769.27658 ::date 2015-04-23T23:45:22 ::annotator SDL-AMR-09 ::preferred
# ::snt We and others have shown that activation of IL-4 (23) and IFN-{alpha} receptors stimulates tyrosyl phosphorylation of IRS docking proteins, which depends upon Jak,
# ::save-date Fri Apr 24, 2015 ::file bel_pmid_1159_1769_27658.txt
(s / show-01
      :ARG0 (a / and
            :op1 (w / we)
            :op2 (p2 / person
                  :mod (o / other)))
      :ARG1 (s2 / stimulate-01
            :ARG0 (a2 / activate-01
                  :ARG1 (a3 / and
                        :op1 (p3 / protein :name (n / name :op1 "IL-4")
                              :ARG1-of (d / describe-01
                                    :ARG0 (p4 / publication
                                          :ARG1-of (c / cite-01
                                                :ARG2 23))))
                        :op2 (r / receptor :name (n2 / name :op1 "IFN-alpha"))))
            :ARG1 (p / phosphorylate-01
                  :ARG1 (a4 / amino-acid :name (n3 / name :op1 "tyrosine")
                        :part-of (p5 / protein :name (n4 / name :op1 "IRS")
                              :ARG1-of (d2 / dock-01)))
                  :ARG0-of (d3 / depend-01
                        :ARG1 (e / enzyme :name (n5 / name :op1 "Jak"))))))

# ::id bel_pmid_1159_1769.27854 ::date 2015-04-24T00:24:51 ::annotator SDL-AMR-09 ::preferred
# ::snt IL-10 can directly promote the death of inflammatory cells, including activated macrophages (4), neutrophils (5), and T cells
# ::save-date Fri Jul 24, 2015 ::file bel_pmid_1159_1769_27854.txt
(p / possible-01
      :ARG1 (p2 / promote-02
            :ARG0 (p3 / protein :name (n / name :op1 "IL-10"))
            :ARG1 (d2 / die-01
                  :ARG1 (c / cell
                        :ARG0-of (i / inflame-01)
                        :ARG2-of (i2 / include-01
                              :ARG1 (a / and
                                    :op1 (m / macrophage
                                          :ARG1-of (a2 / activate-01)
                                          :ARG1-of (d3 / describe-01
                                                :ARG0 (p4 / publication
                                                      :ARG1-of (c2 / cite-01
                                                            :ARG2 4))))
                                    :op2 (n2 / neutrophil
                                          :ARG1-of (d4 / describe-01
                                                :ARG0 (p5 / publication
                                                      :ARG1-of (c3 / cite-01
                                                            :ARG2 5))))
                                    :op3 (c4 / cell :name (n3 / name :op1 "T"))))))
            :ARG1-of (d / direct-02)))

# ::id bel_pmid_1159_1769.27880 ::date 2015-04-24T00:31:14 ::annotator SDL-AMR-09 ::preferred
# ::snt In contrast, IL-10 increases the survival of some types of human cancer cells, such as Burkitt lymphoma (7). Non-Hodgkin s lymphoma cells secrete IL-10, and inhibition of this autocrine IL-10 has recently been shown to promote cell death and reduce expression of the anti-apoptotic protein Bcl-2
# ::save-date Sat Jan 2, 2016 ::file bel_pmid_1159_1769_27880.txt
(m / multi-sentence
      :snt1 (c / contrast-01
            :ARG2 (i / increase-01
                  :ARG0 (p / protein :name (n2 / name :op1 "IL-10"))
                  :ARG1 (s / survive-01
                        :ARG0 (c2 / cell
                              :ARG1-of (t / type-03
                                    :quant (s2 / some))
                              :mod (d5 / disease :wiki "Cancer" :name (n6 / name :op1 "cancer")
                                    :mod (h / human)
                                    :mod (d / disease :name (n / name :op1 "Burkitt" :op2 "lymphoma"))))))
            :ARG1-of (d2 / describe-01
                  :ARG0 (p2 / publication
                        :ARG1-of (c4 / cite-01
                              :ARG2 7))))
      :snt2 (a / and
            :op1 (s3 / secrete-01
                  :ARG0 (c5 / cell
                        :mod (d4 / disease :name (n4 / name :op1 "non-Hodgkin" :op2 "lymphoma")))
                  :ARG1 (p3 / protein :name (n3 / name :op1 "IL-10")
                        :mod (a3 / autocrine)))
            :op2 (s4 / show-01
                  :ARG1 (a2 / and
                        :op1 (p4 / promote-01
                              :ARG0 (i2 / inhibit-01
                                    :ARG1 p3)
                              :ARG1 (d3 / die-01
                                    :ARG1 (c6 / cell)))
                        :op2 (r / reduce-01
                              :ARG0 i2
                              :ARG1 (e / express-03
                                    :ARG2 (p5 / protein :name (n5 / name :op1 "Bcl-2")
                                          :ARG0-of (c7 / counter-01
                                                :ARG1 (a4 / apoptosis))))))
                  :time (r2 / recent))))

# ::id bel_pmid_1159_1769.27882 ::date 2015-04-24T00:47:49 ::annotator SDL-AMR-09 ::preferred
# ::snt Similarly, IL-10 increases the expression of Bcl-xL in thyrocytes from patients with Graves disease
# ::save-date Wed Oct 14, 2015 ::file bel_pmid_1159_1769_27882.txt
(i / increase-01
      :ARG0 (p / protein :name (n / name :op1 "IL-10"))
      :ARG1 (e / express-03
            :ARG2 (p2 / protein :name (n2 / name :op1 "Bcl-xL"))
            :ARG3 (t / thyrocyte
                  :source (p3 / person
                        :ARG0-of (s / suffer-01
                              :ARG1 (d / disease :name (n5 / name :op1 "Graves")))
                        :ARG0-of (h / have-rel-role-91
                              :ARG2 (p4 / patient)))))
      :ARG1-of (r / resemble-01))

# ::id bel_pmid_1160_6453.38354 ::date 2015-04-24T00:52:35 ::annotator SDL-AMR-09 ::preferred
# ::snt LDL, in pathophysiological concentrations, affect the IGF-I signaling pathway at multiple levels: 1) they induce phosphorylation of IGF-I receptor beta and IRS-1 in a time- and dose-dependent manner; 2) they up-regulate IRS-1-associated PI3 kinase/Akt activation in response to IGF-I at early times; and 3) they show additive effects with IGF-I on extracellular signal-regulated MAPK 1/2 phosphorylation.
# ::save-date Sun Jan 17, 2016 ::file bel_pmid_1160_6453_38354.txt
(a / affect-01
      :ARG0 (p6 / protein :name (n2 / name :op1 "LDL")
            :quant (c / concentration
                  :mod (p2 / pathophysiology)))
      :ARG1 (p4 / pathway :name (n3 / name :op1 "IGF-I")
            :ARG0-of (s2 / signal-07))
      :manner (l / level
            :quant (m / multiple)
            :ARG1-of (m2 / mean-01
                  :ARG2 (a2 / and
                        :op1 (i / induce-01 :li 1
                              :ARG0 p6
                              :ARG2 (p / phosphorylate-01
                                    :ARG2 (a3 / and
                                          :op1 (p3 / protein :name (n4 / name :op1 "IGF-I" :op2 "receptor" :op3 "beta"))
                                          :op2 (p7 / protein :name (n5 / name :op1 "IRS-1"))))
                              :manner (d / depend-01
                                    :ARG0 p
                                    :ARG1 (a4 / and
                                          :op1 (t / time)
                                          :op2 (d2 / dose))))
                        :op2 (u / upregulate-01 :li 2
                              :ARG1 (a5 / activate-01
                                    :ARG1 (p8 / pathway :name (n6 / name :op1 "PI3-kinase/Akt"))
                                    :ARG1-of (a6 / associate-01
                                          :ARG2 p7))
                              :ARG2 p6
                              :ARG2-of (r / respond-01
                                    :ARG1 (p5 / protein))
                              :time (e / early))
                        :op3 (s3 / show-01 :li 3
                              :ARG0 p6
                              :ARG1 (a7 / affect-01
                                    :ARG0 p6
                                    :ARG1 (p9 / phosphorylate-01
                                          :ARG1 (a9 / and
                                                :op1 (e3 / enzyme :name (n / name :op1 "MAPK1"))
                                                :op2 (e4 / enzyme :name (n7 / name :op1 "MAPK2")))
                                          :ARG1-of (r2 / regulate-01
                                                :ARG0 (s4 / signal-07
                                                      :mod (e2 / extracellular))))
                                    :ARG1-of (a8 / add-02
                                          :ARG2 p5)))))))

# ::id bel_pmid_1168_9697.19254 ::date 2015-04-24T01:17:44 ::annotator SDL-AMR-09 ::preferred
# ::snt identification of an acidic domain of gp130 as a binding region for Hck, which mediates proliferative signaling the deletion of this region of gp130 resulted in a significant reduction of Hck kinase activity and cell proliferation upon stimulation of gp130 compared to wild-type gp130
# ::save-date Fri Dec 18, 2015 ::file bel_pmid_1168_9697_19254.txt
(m / multi-sentence
      :snt1 (i / identify-01
            :ARG1 (p / protein-segment
                  :mod (a / acid)
                  :part-of (p2 / protein :name (n / name :op1 "gp130")))
            :ARG2 (r / region
                  :ARG2-of (b / bind-01
                        :ARG1 (k2 / kinase :name (n2 / name :op1 "Hck")))
                  :ARG0-of (m2 / mediate-01
                        :ARG1 (s / signal-07
                              :mod (p3 / proliferate-01)))))
      :snt2 (r2 / result-01
            :ARG1 (d / delete-01
                  :ARG1 (p4 / protein-segment
                        :mod (t / this)
                        :part-of (p5 / protein :name (n3 / name :op1 "gp130"))))
            :ARG2 (r3 / reduce-01
                  :ARG1 (a4 / and
                        :op1 (a2 / activity-06
                              :ARG0 (k3 / kinase :name (n4 / name :op1 "Hck")))
                        :op2 (p6 / proliferate-01
                              :ARG0 (c / cell)))
                  :ARG2 (s2 / significant-02)
                  :compared-to (p7 / protein :name (n5 / name :op1 "gp130")
                        :mod (w / wild-type))
                  :condition (s3 / stimulate-01
                        :ARG1 p5))))

# ::id bel_pmid_1168_9697.28350 ::date 2015-04-24T01:34:59 ::annotator SDL-AMR-09 ::preferred
# ::snt Il6 induces the activation of the Src family kinase Hck, which is associated with the Il6 receptor beta-chain, gp130
# ::save-date Mon Jan 4, 2016 ::file bel_pmid_1168_9697_28350.txt
(i / induce-01
      :ARG0 (p / protein :name (n / name :op1 "IL-6"))
      :ARG2 (a / activate-01
            :ARG1 (k2 / kinase :name (n2 / name :op1 "Hck")
                  :ARG1-of (i2 / include-91
                        :ARG2 (p4 / protein-family :name (n3 / name :op1 "Src")))
                  :ARG1-of (a2 / associate-01
                        :ARG2 (p3 / protein :name (n4 / name :op1 "IL-6" :op2 "receptor" :op3 "beta-chain")
                              :ARG1-of (m / mean-01
                                    :ARG2 (p2 / protein :name (n5 / name :op1 "gp130"))))))))

# ::id bel_pmid_1168_9697.28396 ::date 2015-04-24T02:02:24 ::annotator SDL-AMR-09 ::preferred
# ::snt this acidic domain of gp130 is responsible for the activation of Hck, Erk, Pyk2 and signals cell proliferation upon growth factor stimulation
# ::save-date Wed Feb 24, 2016 ::file bel_pmid_1168_9697_28396.txt
(a / and
      :op1 (r / responsible-01
            :ARG0 (p / protein-segment
                  :mod (a3 / acid)
                  :part-of (p2 / protein :name (n3 / name :op1 "gp130"))
                  :mod (t / this))
            :ARG1 (a2 / activate-01
                  :ARG1 (a4 / and
                        :op1 (e2 / enzyme :name (n4 / name :op1 "Hck"))
                        :op2 (e3 / enzyme :name (n5 / name :op1 "Erk"))
                        :op3 (e4 / enzyme :name (n6 / name :op1 "Pyk2")))))
      :op2 (s2 / signal-07
            :ARG0 p
            :ARG1 (p3 / proliferate-01
                  :ARG0 (c / cell))
            :condition (s3 / stimulate-01
                  :ARG2 (g / growth-factor))))

# ::id bel_pmid_1169_8287.20332 ::date 2015-04-24T02:08:19 ::annotator SDL-AMR-09 ::preferred
# ::snt It hasrecently been reported that a cytosolic isoform of PTPepsilon (PTPepsilonC) whenover-expressed in murine M1 myeloid cells inhibits interleukin-6 (IL-6)- and leukemia inhibitory factor-induced activation of Janus kinases (JAKs), thereby suppressing STAT3 tyrosine phosphorylation and STAT3 signaling.
# ::save-date Sun Jan 3, 2016 ::file bel_pmid_1169_8287_20332.txt
(r / report-01
      :ARG1 (i / inhibit-01
            :ARG0 (i2 / isoform
                  :part-of (c / cytosol)
                  :mod (e / enzyme :name (n2 / name :op1 "PTPepsilon"))
                  :ARG1-of (d2 / describe-01
                        :ARG2 (e2 / enzyme :name (n3 / name :op1 "PTPepsilonC"))))
            :ARG1 (a / activate-01
                  :ARG1 (e3 / enzyme :name (n6 / name :op1 "Janus" :op2 "kinase"))
                  :ARG2-of (i3 / induce-01
                        :ARG0 (a3 / and
                              :op1 (p2 / protein :name (n7 / name :op1 "interleukin-6")
                                    :ARG1-of (d4 / describe-01
                                          :ARG2 (p3 / protein :name (n8 / name :op1 "IL-6"))))
                              :op2 (p5 / protein :name (n / name :op1 "leukemia" :op2 "inhibitory" :op3 "factor")))))
            :condition (o / overexpress-01
                  :ARG1 i2
                  :location (c2 / cell-line :name (n4 / name :op1 "M1")
                        :mod (m / myeloid)
                        :part-of (m2 / mouse)))
            :ARG0-of (c3 / cause-01
                  :ARG1 (s / suppress-01
                        :ARG0 i2
                        :ARG1 (a5 / and
                              :op1 (p / phosphorylate-01
                                    :ARG1 (a2 / amino-acid :name (n11 / name :op1 "tyrosine")
                                          :part-of (p4 / protein :name (n10 / name :op1 "STAT3"))))
                              :op2 (s2 / signal-07
                                    :ARG2 p4)))))
      :time (r2 / recent))

# ::id bel_pmid_1174_2412.20342 ::date 2015-04-24T02:25:46 ::annotator SDL-AMR-09 ::preferred
# ::snt Others are themselves enzymes, including the phosphotyrosine phosphatase SHP2 and the cytoplasmic tyrosine kinase Fyn.
# ::save-date Fri Feb 12, 2016 ::file bel_pmid_1174_2412_20342.txt
(e / enzyme
      :ARG2-of (i / include-01
            :ARG1 (a / and
                  :op1 (t2 / tyrosine-phosphatase :name (n3 / name :op1 "SHP2")
                        :ARG3-of (p / phosphorylate-01))
                  :op2 (t3 / tyrosine-kinase :name (n4 / name :op1 "Fyn")
                        :part-of (c / cytoplasm)))))

# ::id bel_pmid_1174_2412.25070 ::date 2015-04-24T02:40:40 ::annotator SDL-AMR-09 ::preferred
# ::snt Blockade of the pathway with dominant negative mutants or pharmacological inhibitors prevents the stimulation of cell growth by insulin, but has no effect on the metabolic actions of the hormone deletion of Akt2 produces hepatic insulin resistance in mice
# ::save-date Fri Feb 5, 2016 ::file bel_pmid_1174_2412_25070.txt
(m2 / multi-sentence
      :snt1 (c / contrast-01
            :ARG1 (p / prevent-01
                  :ARG0 (b / block-01
                        :ARG1 (p2 / pathway)
                        :ARG3 (o / or
                              :op1 (g2 / gene
                                    :ARG2-of (m / mutate-01 :mod "-/-")
                                    :ARG0-of (d / dominate-01))
                              :op2 (m5 / molecular-physical-entity
                                    :ARG0-of (i / inhibit-01)
                                    :mod (p3 / pharmacological))))
                  :ARG1 (s / stimulate-01
                        :ARG1 (g / grow-01
                              :ARG1 (c2 / cell))
                        :ARG2 (p6 / protein :name (n / name :op1 "insulin"))))
            :ARG2 (a / affect-01 :polarity -
                  :ARG0 b
                  :ARG1 (a2 / act-01
                        :ARG0 (h / hormone
                              :ARG1-of (m6 / mean-01
                                    :ARG2 p6))
                        :ARG1 (m3 / metabolize-01))))
      :snt2 (p4 / produce-01
            :ARG0 (d2 / delete-01
                  :ARG1 (e / enzyme :name (n2 / name :op1 "Akt2")))
            :ARG1 (r / resist-01
                  :ARG0 (l / liver)
                  :ARG1 (p5 / protein :name (n3 / name :op1 "insulin")))
            :location (m4 / mouse)))

# ::id bel_pmid_1174_2412.38246 ::date 2015-04-24T02:59:06 ::annotator SDL-AMR-09 ::preferred
# ::snt Upon its activation downstream of PI(3)K, Akt phosphorylates and inactivates GSK-3, decreasing the rate of phosphorylation of glycogen synthase, thus increasing its activity state59.
# ::save-date Sun Jan 3, 2016 ::file bel_pmid_1174_2412_38246.txt
(a / and
      :op1 (p / phosphorylate-01
            :ARG1 (e4 / enzyme :name (n2 / name :op1 "GSK-3"))
            :ARG2 (e / enzyme :name (n / name :op1 "Akt")))
      :op2 (i / inactivate-00
            :ARG0 e
            :ARG1 e4)
      :ARG0-of (c / cause-01
            :ARG1 (d / decrease-01
                  :ARG1 (r / rate
                        :degree-of (p2 / phosphorylate-01
                              :ARG1 (e2 / enzyme :name (n3 / name :op1 "glycogen" :op2 "synthase"))))
                  :ARG0-of (c2 / cause-01
                        :ARG1 (i2 / increase-01
                              :ARG1 (s / state
                                    :mod (a2 / activity-06
                                          :ARG0 e2))))))
      :condition (a3 / activate-01
            :ARG1 e
            :location (r2 / relative-position
                  :op1 (e3 / enzyme :name (n4 / name :op1 "PI(3)K"))
                  :direction (d2 / downstream)))
      :ARG1-of (d3 / describe-01
            :ARG0 (p3 / publication
                  :ARG1-of (c3 / cite-01
                        :ARG2 59))))

# ::id bel_pmid_1175_3615.28390 ::date 2015-04-24T03:16:55 ::annotator SDL-AMR-09 ::preferred
# ::snt interleukin-6 (IL-6) or leukemia inhibitory factor (LIF)-induced differentiation of the myeloid cell line M1 was associated with a rapid increase in the level of mRNA encoding the signaling adaptor protein, SKAP55R
# ::save-date Sun Jan 17, 2016 ::file bel_pmid_1175_3615_28390.txt
(a / associate-01
      :ARG1 (d2 / differentiate-01
            :ARG1 (c / cell-line :name (n2 / name :op1 "M1")
                  :mod (m / myeloid))
            :ARG2-of (i / induce-01
                  :ARG0 (o / or
                        :op1 (p / protein :name (n3 / name :op1 "interleukin-6")
                              :ARG1-of (d3 / describe-01
                                    :ARG2 (p2 / protein :name (n4 / name :op1 "IL-6"))))
                        :op2 (p5 / protein :name (n5 / name :op1 "leukemia" :op2 "inhibitory" :op3 "factor")
                              :ARG1-of (d4 / describe-01
                                    :ARG2 (p3 / protein :name (n6 / name :op1 "LIF")))))))
      :ARG2 (i2 / increase-01
            :ARG1 (l / level
                  :quant-of (n / nucleic-acid :name (n7 / name :op1 "mRNA")
                        :ARG0-of (e / encode-01
                              :ARG1 (p4 / protein :name (n9 / name :op1 "SKAP55R")
                                    :mod (a2 / adaptor)
                                    :ARG0-of (s3 / signal-07)))))
            :mod (r / rapid)))

# ::id bel_pmid_1177_9161.28386 ::date 2015-04-24T08:55:26 ::annotator SDL-AMR-09 ::preferred
# ::snt inflammatory cytokines, notably Tnf-alpha, and Il6, induce the expression of Cox2 and the secretion of Pge2 in human prostate cancer cell lines
# ::save-date Fri Feb 12, 2016 ::file bel_pmid_1177_9161_28386.txt
(i / induce-01
      :ARG0 (c3 / cytokine
            :ARG2-of (i2 / include-91
                  :ARG1 (a2 / and
                        :op1 (p2 / protein :name (n2 / name :op1 "Tnf-alpha"))
                        :op2 (p3 / protein :name (n4 / name :op1 "Il6"))
                        :ARG1-of (n / notable-04)))
            :ARG0-of (i3 / inflame-01))
      :ARG2 (a / and
            :op1 (e / express-03
                  :ARG2 (e2 / enzyme :name (n5 / name :op1 "Cox2")))
            :op2 (s / secrete-01
                  :ARG1 (s2 / small-molecule :name (n6 / name :op1 "Pge2")))
            :location (c / cell-line
                  :mod (h / human)
                  :mod (d / disease :wiki "Prostate_cancer" :name (n3 / name :op1 "prostate" :op2 "cancer")))))

# ::id bel_pmid_1177_9161.28388 ::date 2015-04-24T09:59:40 ::annotator SDL-AMR-09 ::preferred
# ::snt the human COx2 gene contains a putative NF-IL-6 element in the 5'-flanking promoter region which can be activated by Il6
# ::save-date Thu Apr 30, 2015 ::file bel_pmid_1177_9161_28388.txt
(c / contain-01
      :ARG0 (g / gene :name (n / name :op1 "COx2")
            :mod (h / human))
      :ARG1 (e2 / element
            :mod (p / protein :name (n2 / name :op1 "NF-IL-6"))
            :ARG1-of (t / think-01)
            :ARG1-of (p3 / possible-01)
            :ARG1-of (a2 / activate-01
                  :ARG0 (p5 / protein :name (n4 / name :op1 "Il6"))
                  :ARG1-of (p4 / possible-01)))
      :location (r / region
            :mod (d / dna-sequence :name (n3 / name :op1 "5'-flanking"))
            :ARG0-of (p2 / promote-01)))

# ::id bel_pmid_1177_9161.34138 ::date 2015-04-24T10:48:11 ::annotator SDL-AMR-09 ::preferred
# ::snt events lead to activation of Stat signaling and result in the induction of proteins, such as bcl-2 and cMyc, both of which are critical regulators of cell cycle progression and apoptosis
# ::save-date Mon Dec 21, 2015 ::file bel_pmid_1177_9161_34138.txt
(a / and
      :op1 (l / lead-03
            :ARG0 (e / event)
            :ARG2 (a2 / activate-01
                  :ARG1 (s / signal-07
                        :ARG0 (p / protein :name (n / name :op1 "Stat")))))
      :op2 (r / result-01
            :ARG1 e
            :ARG2 (i / induce-01
                  :ARG2 (p2 / protein
                        :example (a3 / and
                              :op1 (p3 / protein :name (n2 / name :op1 "bcl-2"))
                              :op2 (p4 / protein :name (n3 / name :op1 "cMyc"))
                              :ARG0-of (r2 / regulate-01
                                    :ARG1 (a4 / and
                                          :op1 (p5 / progress-01
                                                :ARG1 (c2 / cycle-02
                                                      :ARG1 (c3 / cell)))
                                          :op2 (a5 / apoptosis
                                                :mod c2))
                                    :mod (b / both))
                              :ARG1-of (c / critical-02))))))

# ::id bel_pmid_1179_0801.20476 ::date 2015-04-24T11:25:29 ::annotator SDL-AMR-09 ::preferred
# ::snt Further work revealed that TGF-R signaling (Massague and Wotton, 2000) was required for EMT, invasion in vitro, and metastasis in vivo,
# ::save-date Sun Jan 17, 2016 ::file bel_pmid_1179_0801_20476.txt
(r / reveal-01
      :ARG0 (w / work-01
            :degree (f / further))
      :ARG1 (r2 / require-01
            :ARG0 (a2 / and
                  :op1 (e / event :name (n4 / name :op1 "epithelial−mesenchymal" :op2 "transition"))
                  :op2 (i / invade-01
                        :manner (i2 / in-vitro))
                  :op3 (m / metastasis
                        :manner (i3 / in-vivo)))
            :ARG1 (s / signal-07
                  :ARG1 (p / pathway :name (n / name :op1 "TGF-R"))))
      :ARG1-of (d / describe-01
            :ARG0 (p2 / publication-91
                  :ARG0 (a / and
                        :op1 (p3 / person :name (n2 / name :op1 "Massague"))
                        :op2 (p4 / person :name (n3 / name :op1 "Wotton")))
                  :time (d2 / date-entity :year 2000))))

# ::id bel_pmid_1179_0801.21076 ::date 2015-04-24T12:09:36 ::annotator SDL-AMR-09 ::preferred
# ::snt Raf/mitogen-activated protein kinase (MAPK) is required for EMT, whereas activation of phosphatidylinositol 3-kinase (PI3K) causes scattering and protects from TGFbeta-induced apoptosis.
# ::save-date Sun Jan 17, 2016 ::file bel_pmid_1179_0801_21076.txt
(r / require-01
      :ARG0 (e2 / event :name (n / name :op1 "epithelial−mesenchymal" :op2 "transition"))
      :ARG1 (p3 / pathway :name (n6 / name :op1 "Raf/MAPK"))
      :ARG1-of (c / contrast-01
            :ARG2 (a2 / and
                  :op1 (c2 / cause-01
                        :ARG0 (a3 / activate-01
                              :ARG1 (e / enzyme :name (n4 / name :op1 "phosphatidylinositol" :op2 "3-kinase")))
                        :ARG1 (s / scatter-01))
                  :op2 (p5 / protect-01
                        :ARG0 a3
                        :ARG2 (a4 / apoptosis
                              :ARG2-of (i / induce-01
                                    :ARG0 (p6 / protein :name (n5 / name :op1 "TGFbeta"))))))))

# ::id bel_pmid_1179_0801.26880 ::date 2015-04-25T01:06:29 ::annotator SDL-AMR-09 ::preferred
# ::snt In addition to oncogenic Ras (Oft et al., 1996), hepatocyte growth factor (HGF)/scatter factor (SF), fibroblast growth factor (FGF), and TGF alone induce mesenchymal features in diverse epithelial cell systems (Brinkmann et al., 1995; Piek et al., 1999; Thiery and Chopin, 1999).
# ::save-date Thu Jan 14, 2016 ::file bel_pmid_1179_0801_26880.txt
(i / induce-01
      :ARG0 (a / and
            :op1 (e2 / enzyme :name (n / name :op1 "Ras")
                  :ARG0-of (c / cause-01
                        :ARG1 (d7 / disease :wiki "Cancer" :name (n7 / name :op1 "cancer")))
                  :ARG1-of (d / describe-01
                        :ARG0 (p2 / publication-91
                              :ARG0 (a2 / and
                                    :op1 (p3 / person :name (n3 / name :op1 "Oft"))
                                    :op2 (p4 / person
                                          :mod (o / other)))
                              :time (d2 / date-entity :year 1996))))
            :op2 (s / slash
                  :op1 (s4 / small-molecule :name (n2 / name :op1 "hepatocyte" :op2 "growth" :op3 "factor")))
            :op3 (s2 / small-molecule :name (n5 / name :op1 "scatter" :op2 "factor")
                  :ARG1-of d3)
            :op4 (p13 / protein-family :name (n8 / name :op1 "fibroblast" :op2 "growth" :op3 "factor"))
            :op5 (p12 / protein :name (n6 / name :op1 "TGF")
                  :mod (a3 / alone)))
      :ARG2 (f / feature
            :mod (m4 / mesenchyme))
      :location (s5 / system
            :consist-of (c6 / cell
                  :mod (e / epithelium))
            :mod (d6 / diverse))
      :ARG1-of (d3 / describe-01
            :ARG0 (a4 / and
                  :op1 (p5 / publication-91
                        :ARG0 (a5 / and
                              :op1 (p6 / person :name (n9 / name :op1 "Brinkmann"))
                              :op2 (p14 / person
                                    :mod (o2 / other))
                              :time (d4 / date-entity :year 1995)))
                  :op2 (p7 / publication-91
                        :ARG0 (a6 / and
                              :op1 (p8 / person :name (n11 / name :op1 "Piek"))
                              :op2 (p15 / person
                                    :mod (o3 / other))
                              :time (d5 / date-entity :year 1999)))
                  :op3 (p9 / publication-91
                        :ARG0 (a7 / and
                              :op1 (p10 / person :name (n13 / name :op1 "Thiery"))
                              :op2 (p11 / person :name (n10 / name :op1 "Chopin")))
                        :time d5))))

# ::id bel_pmid_1179_0801.27514 ::date 2015-04-25T03:01:02 ::annotator SDL-AMR-09 ::preferred
# ::snt Ha-Ras cooperates with transforming growth factor beta (TGFbeta) to cause epithelial mesenchymal transition (EMT) characterized by spindle-like cell morphology, loss of epithelial markers, and induction of mesenchymal markers.
# ::save-date Sun Jan 17, 2016 ::file bel_pmid_1179_0801_27514.txt
(c / cooperate-01
      :ARG0 (e2 / enzyme :name (n / name :op1 "Ha-Ras"))
      :ARG1 (p / protein :name (n3 / name :op1 "transforming" :op2 "growth" :op3 "factor" :op4 "beta"))
      :ARG2 (c2 / cause-01
            :ARG0 (a2 / and
                  :op1 e2
                  :op2 p)
            :ARG1 (t2 / transition-01
                  :ARG2 m4
                  :ARG3 e
                  :ARG1-of (c3 / characterize-01
                        :ARG2 (a / and
                              :op1 (m / morphology
                                    :mod (c4 / cell)
                                    :ARG1-of (r / resemble-01
                                          :ARG2 (s / spindle)))
                              :op2 (l / lose-02
                                    :ARG1 (m2 / marker
                                          :mod (e / epithelium)))
                              :op3 (i / induce-01
                                    :ARG2 (m3 / marker
                                          :mod (m4 / mesenchyme))))))))

# ::id bel_pmid_1179_0801.31150 ::date 2015-04-25T05:52:40 ::annotator SDL-AMR-09 ::preferred
# ::snt the spindle-like phenotype induced by TGF treatment (Fig. 1 A, inset) persisted after factor removal (Fig. 1 B, inset) and involved loss of E-cadherin/4-integrin, whereas vimentin was strongly induced
# ::save-date Sun Dec 20, 2015 ::file bel_pmid_1179_0801_31150.txt
(a / and
      :op1 (p / persist-01
            :ARG1 (p2 / phenotype
                  :ARG1-of (r / resemble-01
                        :ARG2 (s / spindle))
                  :ARG1-of (i2 / induce-01
                        :ARG0 (t / treat-04
                              :ARG2 (p5 / protein :name (n3 / name :op1 "TGF")))
                        :ARG1-of (d / describe-01
                              :ARG0 (f2 / figure :mod "1A"
                                    :location (i3 / inset)))))
            :time (a2 / after
                  :op1 (r2 / remove-01
                        :ARG1 p5
                        :ARG1-of (d2 / describe-01
                              :ARG0 (f3 / figure :mod "1B"
                                    :location i3)))))
      :op2 (i / involve-01
            :ARG0 p2
            :ARG1 (l / lose-02
                  :ARG1 (s2 / slash
                        :op1 (p3 / protein :name (n / name :op1 "E-cadherin"))
                        :op2 (p4 / protein :name (n2 / name :op1 "4-integrin")))))
      :ARG1-of (c / contrast-01
            :ARG2 (i4 / induce-01
                  :ARG2 (p6 / protein :name (n4 / name :op1 "vimentin"))
                  :ARG1-of (s3 / strong-02))))

# ::id bel_pmid_1179_8191.15678 ::date 2015-04-25T11:24:44 ::annotator SDL-AMR-09 ::preferred
# ::snt Two peroxisome proliferator-activated receptor a agonsists: Wy-14643 and a marketed fribrate drug, fenofibrate
# ::save-date Thu Apr 30, 2015 ::file bel_pmid_1179_8191_15678.txt
(a / and
      :op1 (s / small-molecule :name (n / name :op1 "Wy-14643"))
      :op3 (s2 / small-molecule :name (n2 / name :op1 "fenofibrate")
            :domain (d / drug
                  :ARG1-of (m / market-01)
                  :mod (f / fibrate)))
      :domain (a2 / agonist :quant 2
            :mod (p / protein :name (n3 / name :op1 "peroxisome" :op2 "proliferator-activated" :op3 "receptor" :op4 "alpha"))))

# ::id bel_pmid_1179_8191.28334 ::date 2015-04-25T11:30:27 ::annotator SDL-AMR-09 ::preferred
# ::snt Several pro-inflammatory mediators up-regulate SAA transcription, including Il1, Il6, TNFalpha, and Lif.
# ::save-date Sun May 3, 2015 ::file bel_pmid_1179_8191_28334.txt
(u / upregulate-01
      :ARG0 (m2 / molecular-physical-entity
            :ARG0-of (m / mediate-01
                  :quant (s / several))
            :ARG0-of (f / favor-01
                  :ARG1 (i / inflame-01))
            :ARG2-of (i2 / include-91
                  :ARG1 (a / and
                        :op1 (p / protein :name (n2 / name :op1 "Il1"))
                        :op2 (p2 / protein :name (n3 / name :op1 "Il6"))
                        :op3 (p3 / protein :name (n4 / name :op1 "TNFalpha"))
                        :op4 (p4 / protein :name (n5 / name :op1 "Lif"))))
            :quant (s2 / several))
      :ARG1 (t / transcribe-01
            :ARG1 (g / gene :name (n / name :op1 "SAA"))))

# ::id bel_pmid_1179_8191.33678 ::date 2015-04-25T11:47:11 ::annotator SDL-AMR-09 ::preferred
# ::snt Fibrates induce the peroxisomal b-oxidation system of fatty acids in rodents, resulting in proliferation of peroxisomes, hepatomegaly and eventually hepatocarcinoma.
# ::save-date Wed Mar 9, 2016 ::file bel_pmid_1179_8191_33678.txt
(i / induce-01
      :ARG0 (f / fibrate)
      :ARG2 (s / system
            :mod (o / oxidize-01
                  :ARG1 (a / acid
                        :ARG1-of (f2 / fat-03))
                  :mod (b / beta)
                  :mod (p / peroxisome)))
      :ARG1-of (r / result-01
            :ARG2 (a2 / and
                  :op1 (p2 / proliferate-01
                        :ARG0 p)
                  :op2 (h / hepatomegaly)
                  :op3 (h2 / hepatocarcinoma
                        :time (e / eventual))))
      :location (r2 / rodent))

# ::id bel_pmid_1180_3570.9290 ::date 2015-04-25T12:10:20 ::annotator SDL-AMR-09 ::preferred
# ::snt We note a marked and differential increase in Itih-4 labeling in proliferating hepatocytes, compared with bile duct cells in liver explant cultures treated with interleukin-6 (IL-6)
# ::save-date Thu Apr 30, 2015 ::file bel_pmid_1180_3570_9290.txt
(n / note-01
      :ARG1 (w / we)
      :ARG2 (i / increase-01
            :ARG1 (l / label-01
                  :ARG1 (p / protein :name (n2 / name :op1 "Itih-4")))
            :location (h / hepatocyte
                  :ARG0-of (p2 / proliferate-01))
            :compared-to (c2 / cell
                  :mod (d2 / duct
                        :mod (b / bile))
                  :location (c3 / culture
                        :mod (e / explant)
                        :mod (l2 / liver)
                        :ARG1-of (t / treat-04
                              :ARG2 (p3 / protein :name (n4 / name :op1 "interleukin-6")))))
            :ARG2-of (m / mark-02)
            :ARG1-of (d / differ-02)))

# ::id bel_pmid_1180_3570.9376 ::date 2015-04-26T00:04:28 ::annotator SDL-AMR-09 ::preferred
# ::snt Inter-alpha-trypsin inhibitor-4 (Itih-4) is a liver-restricted member of the serine protease inhibitor family with diverse functions as an anti-apoptotic and matrix stabilizing molecule that are important throughout development.
# ::save-date Mon Jan 4, 2016 ::file bel_pmid_1180_3570_9376.txt
(i / include-91
      :ARG1 (p2 / protein :name (n4 / name :op1 "Inter-alpha-trypsin" :op2 "inhibitor-4")
            :ARG1-of (r / restrict-01
                  :ARG2 (l / liver))
            :ARG0-of (f2 / function-01
                  :ARG1 (a2 / and
                        :op1 (c / counter-01
                              :ARG1 (a3 / apoptosis))
                        :op2 (s / stabilize-01
                              :ARG0 (m / molecule)
                              :ARG1 (m2 / matrix)))
                  :mod (i3 / important
                        :time (d / develop-01))
                  :mod (d2 / diverse)))
      :ARG2 (p3 / protein-family :name (n3 / name :op1 "serine" :op2 "protease" :op3 "inhibitor")))

# ::id bel_pmid_1182_0727.27898 ::date 2015-04-26T00:58:40 ::annotator SDL-AMR-09 ::preferred
# ::snt tryosine phosphorylation of gp130 was observed in fibroblasts after stimulation with all the cytokines
# ::save-date Sun Jan 3, 2016 ::file bel_pmid_1182_0727_27898.txt
(o / observe-01
      :ARG1 (p / phosphorylate-01
            :ARG1 (a / amino-acid :name (n2 / name :op1 "tyrosine")
                  :part-of (p2 / protein :name (n / name :op1 "gp130"))))
      :location (f / fibroblast)
      :time (a2 / after
            :op1 (s / stimulate-01
                  :ARG2 (c / cytokine
                        :mod (a3 / all)))))

# ::id bel_pmid_1183_2424.8080 ::date 2015-04-26T01:10:58 ::annotator SDL-AMR-09 ::preferred
# ::snt We have previously shown that B cell lymphoma/leukemia-2 (bcl-2) -/- mice develop cystic kidneys and exhibit sustained phosphorylation of FAK and paxillin.
# ::save-date Sun Jan 17, 2016 ::file bel_pmid_1183_2424_8080.txt
(s / show-01
      :ARG0 (w / we)
      :ARG1 (a / and
            :op1 (d / develop-01
                  :ARG1 (m / mouse
                        :mod (p5 / protein :name (n3 / name :op1 "bcl-2")
                              :ARG2-of (m3 / mutate-01 :mod "-/-")))
                  :ARG2 (k2 / kidney
                        :mod (c / cyst)))
            :op2 (e / exhibit-01
                  :ARG0 m
                  :ARG1 (p / phosphorylate-01
                        :ARG1 (a2 / and
                              :op1 (e2 / enzyme :name (n / name :op1 "FAK"))
                              :op2 (p3 / protein :name (n2 / name :op1 "paxillin")))
                        :ARG1-of (s2 / sustain-01))))
      :time (p4 / previous))

# ::id bel_pmid_1183_2424.8082 ::date 2015-04-26T02:25:04 ::annotator SDL-AMR-09 ::preferred
# ::snt Cystic kidneys from postnatal day 20 bcl-2 -/- mice demonstrate a reduced expression, sixfold decrease in activity, and altered distribution of SHP-2 and PTP 1B
# ::save-date Sun Aug 9, 2015 ::file bel_pmid_1183_2424_8082.txt
(d / demonstrate-01
      :ARG0 (k / kidney
            :mod (c / cyst)
            :time (d2 / day :value 20)
            :source (m / mouse
                  :mod (p2 / protein :name (n / name :op1 "bcl-2")
                        :ARG2-of (m2 / mutate-01 :mod "-/-")))
            :time (a5 / after
                  :op1 (b / bear-02)))
      :ARG1 (a / and
            :op1 (r2 / reduce-01
                  :ARG1-of (e / express-03))
            :op2 (d3 / decrease-01
                  :ARG1 (a2 / activity-06)
                  :ARG2 (p / product-of :op1 6))
            :op3 (d4 / distribute-01
                  :ARG1 (a3 / and
                        :op1 (p3 / protein :name (n2 / name :op1 "SHP-2"))
                        :op2 (e2 / enzyme :name (n3 / name :op1 "PTP" :op2 "1B")))
                  :ARG1-of (a4 / alter-01))))

# ::id bel_pmid_1183_2424.8084 ::date 2015-04-26T03:04:37 ::annotator SDL-AMR-09 ::preferred
# ::snt Cystic kidneys from postnatal day 20 bcl-2 -/- mice demonstrate a reduced expression, sixfold decrease in activity, and altered distribution of SHP-2 and PTP 1B.
# ::save-date Sun Aug 9, 2015 ::file bel_pmid_1183_2424_8084.txt
(d / demonstrate-01
      :ARG0 (k / kidney
            :mod (c / cyst)
            :time (d2 / day :value 20)
            :source (m / mouse
                  :mod (p2 / protein :name (n / name :op1 "bcl-2")
                        :ARG0-of (m2 / mutate-01 :mod "-/-")))
            :time (a5 / after
                  :op1 (b / bear-02)))
      :ARG1 (a / and
            :op1 (r / reduce-01
                  :ARG1 (e / express-03))
            :op2 (d3 / decrease-01
                  :ARG1 (a2 / activity-06)
                  :ARG2 (p / product-of :op1 6))
            :op3 (d4 / distribute-01
                  :ARG1 (a3 / and
                        :op1 (p3 / protein :name (n3 / name :op1 "SHP-2"))
                        :op2 (e2 / enzyme :name (n2 / name :op1 "PTP" :op2 "1B")))
                  :ARG1-of (a4 / alter-01))))

# ::id bel_pmid_1190_2577.36732 ::date 2015-04-26T03:15:51 ::annotator SDL-AMR-09 ::preferred
# ::snt The primary substrates of CDK4/6 and CDK2 in G1 progression are the members of the retinoblastoma protein family  RB,p107 and p130 The activity of the RB proteins is modulated by sequential phosphorylation by CDK4/6cyclinD and CDK2cyclinE complexes
# ::save-date Sun Jan 3, 2016 ::file bel_pmid_1190_2577_36732.txt
(m / multi-sentence
      :snt1 (i / include-91
            :ARG1 (s5 / substrate
                  :poss (a5 / and
                        :op1 (e3 / enzyme :name (n9 / name :op1 "CDK4/6"))
                        :op2 (e4 / enzyme :name (n10 / name :op1 "CDK2")))
                  :time (p9 / progress-01
                        :ARG1 (e5 / event :name (n12 / name :op1 "G1")))
                  :mod (p10 / primary))
            :ARG2 (p / protein-family :name (n / name :op1 "retinoblastoma")
                  :ARG1-of (m2 / mean-01
                        :ARG2 (a / and
                              :op1 (p2 / protein :name (n2 / name :op1 "RB"))
                              :op2 (p3 / protein :name (n3 / name :op1 "p107"))
                              :op2 (p4 / protein :name (n4 / name :op1 "p130"))))))
      :snt2 (m3 / modulate-01
            :ARG0 (p5 / phosphorylate-01
                  :ARG2 (a2 / and
                        :op1 (m4 / macro-molecular-complex
                              :op1 (e / enzyme :name (n5 / name :op1 "CDK4/6"))
                              :op2 (p7 / protein :name (n7 / name :op1 "cyclinD")))
                        :op2 (m5 / macro-molecular-complex
                              :op1 (e2 / enzyme :name (n11 / name :op1 "CDK2"))
                              :op2 (p8 / protein :name (n8 / name :op1 "cyclinE"))))
                  :mod (s3 / sequence))
            :ARG1 (a3 / activity-06
                  :ARG0 (p6 / protein :name (n6 / name :op1 "RB")))))

# ::id bel_pmid_1190_2577.37122 ::date 2015-04-26T04:19:24 ::annotator SDL-AMR-09 ::preferred
# ::snt Inhibitory phosphorylation of adjacent threonine and tyrosine residues (T14/Y15 in CDK1) is mediated by dualspecificity kinases (such as WEE1 and MYT1). This inhibition is relieved when the CDC25 phosphatases (CDC25A,CDC25B and CDC25C) dephosphorylate these residues, which triggers entry into mitosis
# ::save-date Wed Jan 13, 2016 ::file bel_pmid_1190_2577_37122.txt
(m / multi-sentence
      :snt1 (m2 / mediate-01
            :ARG0 (k / kinase
                  :mod (d / dualspecificity)
                  :example (a5 / and
                        :op1 (k2 / kinase :name (n4 / name :op1 "WEE1"))
                        :op2 (k3 / kinase :name (n5 / name :op1 "MYT1"))))
            :ARG1 (p / phosphorylate-01
                  :ARG1 (a7 / and
                        :op1 (r / residue
                              :mod (a / amino-acid :name (n / name :op1 "threonine")
                                    :part-of (e5 / enzyme :name (n3 / name :op1 "CDK1"))))
                        :op2 (r3 / residue
                              :mod (a2 / amino-acid :name (n2 / name :op1 "tyrosine")
                                    :part-of e5))
                        :mod (a4 / adjacent))
                  :ARG0-of (i / inhibit-01)))
      :snt2 (r2 / relieve-01
            :ARG1 (i2 / inhibit-01
                  :mod (t / this))
            :time (d2 / dephosphorylate-01
                  :ARG1 (r4 / residue
                        :mod (t2 / this))
                  :ARG2 (p3 / phosphatase :name (n6 / name :op1 "CDC25")
                        :ARG2-of (i3 / include-91
                              :ARG1 (a3 / and
                                    :op1 (e / enzyme :name (n7 / name :op1 "CDC25A"))
                                    :op2 (e2 / enzyme :name (n8 / name :op1 "CDC25B"))
                                    :op3 (e3 / enzyme :name (n9 / name :op1 "CDC25C")))))
                  :ARG0-of (t4 / trigger-01
                        :ARG1 (e4 / enter-01
                              :ARG1 (m4 / mitosis))))))

# ::id bel_pmid_1190_2577.37858 ::date 2015-04-26T04:55:20 ::annotator SDL-AMR-09 ::preferred
# ::snt CDK2 is sequentially activated by the E-type cyclins  cyclin E1 and E2  during the G1/S transition, and the A-type cyclins  cyclin A1 and A2 during S phase
# ::save-date Sat Jan 2, 2016 ::file bel_pmid_1190_2577_37858.txt
(a / activate-01
      :ARG0 (a2 / and
            :op1 (p5 / protein :name (n4 / name :op1 "cyclin" :op2 "E")
                  :time (t / transition-01
                        :ARG2 (e3 / event :name (n9 / name :op1 "S"))
                        :ARG3 (e / event :name (n7 / name :op1 "G1")))
                  :ARG2-of (t4 / type-03
                        :ARG1 (a3 / and
                              :op1 (p7 / protein :name (n11 / name :op1 "cyclin" :op2 "E1"))
                              :op2 (p8 / protein :name (n12 / name :op1 "cyclin" :op2 "E2")))))
            :op2 (p / protein :name (n2 / name :op1 "cyclin" :op2 "A")
                  :ARG2-of (t2 / type-03
                        :ARG1 (a4 / and
                              :op1 (p2 / protein :name (n / name :op1 "cyclin" :op2 "A1"))
                              :op2 (p3 / protein :name (n3 / name :op1 "cyclin" :op2 "A2"))))
                  :time e3))
      :ARG1 (e2 / enzyme :name (n8 / name :op1 "CDK2"))
      :manner (s / sequence))

# ::id bel_pmid_1190_2577.37928 ::date 2015-04-26T05:17:56 ::annotator SDL-AMR-09 ::preferred
# ::snt CKIs are of two types(reviewed in REF. 17). The four members of the INK4 family  INK4A (also known as p16),INK4B(also known as p15),INK4C (also known as p18) and INK4D (also known as p19)  exert their inhibitory activity by binding to the CDK4 and CDK6 kinases and preventing their association with D-type cyclins
# ::save-date Mon Jan 4, 2016 ::file bel_pmid_1190_2577_37928.txt
(m / multi-sentence
      :snt2 (e2 / exert-01
            :ARG0 (a / and
                  :op1 (p / protein :name (n2 / name :op1 "INK4A")
                        :ARG1-of (k / know-02
                              :ARG2 (p5 / protein :name (n6 / name :op1 "p16"))
                              :mod (a5 / also)))
                  :op2 (p2 / protein :name (n3 / name :op1 "INK4B")
                        :ARG1-of (k2 / know-02
                              :ARG2 (p6 / protein :name (n7 / name :op1 "p15"))
                              :mod a5))
                  :op3 (p3 / protein :name (n4 / name :op1 "INK4C")
                        :ARG1-of (k3 / know-02
                              :ARG2 (p7 / protein :name (n8 / name :op1 "p18"))
                              :mod a5))
                  :op4 (p4 / protein :name (n5 / name :op1 "INK4D")
                        :ARG1-of (k4 / know-02
                              :ARG2 (p8 / protein-family :name (n9 / name :op1 "p19"))
                              :mod a5))
                  :ARG1-of (i2 / include-91
                        :ARG2 (p10 / protein :name (n12 / name :op1 "INK4"))))
            :ARG1 (a3 / activity-06
                  :ARG0 a
                  :ARG1 (i / inhibit-01
                        :ARG0 a))
            :manner (a4 / and
                  :op1 (b / bind-01
                        :ARG1 (a2 / and
                              :op1 (k5 / kinase :name (n10 / name :op1 "CDK4"))
                              :op2 (k6 / kinase :name (n11 / name :op1 "CDK6"))))
                  :op2 (p9 / prevent-01
                        :ARG1 (a6 / associate-01
                              :ARG1 a2
                              :ARG2 (p13 / protein :name (n13 / name :op1 "cyclin" :op2 "D"))))))
      :snt1 (t / type-03 :quant 2
            :ARG1 (e / enzyme :name (n / name :op1 "CKI"))
            :ARG1-of (r / review-02
                  :medium (r2 / ref :mod 17))))

# ::id bel_pmid_1190_9529.24784 ::date 2015-04-24T06:45:50 ::annotator SDL-AMR-09 ::preferred
# ::snt Cotransfection of JAK1 or JAK3 with TCPTP-WT resulted in substantial dephosphorylation of the kinases
# ::save-date Sun Jan 3, 2016 ::file bel_pmid_1190_9529_24784.txt
(r / result-01
      :ARG1 (c / cotransfect-01
            :ARG2 (a / and
                  :op1 (o / or
                        :op1 (e2 / enzyme :name (n / name :op1 "JAK1"))
                        :op2 (e / enzyme :name (n2 / name :op1 "JAK3")))
                  :op2 (p3 / protein :name (n3 / name :op1 "TCPTP")
                        :mod (w / wild-type))))
      :ARG2 (d / dephosphorylate-01
            :ARG1 o
            :degree (s / substantial)))

# ::id bel_pmid_1190_9529.30256 ::date 2015-04-25T08:44:14 ::annotator SDL-AMR-09 ::preferred
# ::snt Immunoblotting with a phospho-STAT1 antibody revealed an increase in STAT1 phosphorylation in TCPTP-deficient thymocytes
# ::save-date Thu Dec 17, 2015 ::file bel_pmid_1190_9529_30256.txt
(r / reveal-01
      :ARG0 (i / immunoblot-01
            :ARG3 (a / antibody
                  :ARG0-of (c / counter-01
                        :ARG1 (p / protein :name (n / name :op1 "STAT1")
                              :ARG3-of (p5 / phosphorylate-01)))))
      :ARG1 (i2 / increase-01
            :ARG1 (p2 / phosphorylate-01
                  :ARG1 p)
            :location (c2 / cell :name (n4 / name :op1 "thymocyte")
                  :ARG0-of (l2 / lack-01
                        :ARG1 (p4 / protein :name (n3 / name :op1 "TCPTP"))))))

# ::id bel_pmid_1197_1957.1966 ::date 2015-04-26T02:39:36 ::annotator SDL-AMR-09 ::preferred
# ::snt PKA also decreased Raf-1 serine 338 phosphorylation of Raf-1, previously shown to be required for Raf-1 activation.
# ::save-date Sat May 2, 2015 ::file bel_pmid_1197_1957_1966.txt
(d / decrease-01
      :ARG0 (e2 / enzyme :name (n2 / name :op1 "PKA"))
      :ARG1 (p / phosphorylate-01
            :ARG1 (a / amino-acid :mod 338 :name (n3 / name :op1 "serine")
                  :part-of (e / enzyme :name (n / name :op1 "Raf-1")))
            :ARG2 e
            :ARG1-of (r / require-01
                  :purpose (a4 / activate-01
                        :ARG1 e)
                  :ARG1-of (s2 / show-01
                        :time (p2 / previous))))
      :mod (a2 / also))

# ::id bel_pmid_1197_1957.37446 ::date 2015-04-26T04:55:14 ::annotator SDL-AMR-09 ::preferred
# ::snt The cyclic AMP (cAMP)-dependent protein kinase (PKA) can inhibit Raf-1 by direct phosphorylation.  We have mapped all cAMP-induced phosphorylation sites in Raf-1, showing that serines 43, 259, and 621 are phosphorylated by PKA in vitro and induced by cAMP in vivo.
# ::save-date Sun Jan 3, 2016 ::file bel_pmid_1197_1957_37446.txt
(m / multi-sentence
      :snt1 (p2 / possible-01
            :ARG1 (i / inhibit-01
                  :ARG0 (e5 / enzyme :name (n5 / name :op1 "protein" :op2 "kinase")
                        :ARG0-of (d2 / depend-01
                              :ARG1 s))
                  :ARG1 (e / enzyme :name (n / name :op1 "Raf-1"))
                  :manner (p4 / phosphorylate-01
                        :ARG1-of (d / direct-02))))
      :snt2 (m3 / map-01
            :ARG0 (w / we)
            :ARG1 (p3 / protein-segment
                  :location (e2 / enzyme :name (n4 / name :op1 "Raf-1"))
                  :ARG1-of (p / phosphorylate-01)
                  :ARG2-of (i2 / induce-01
                        :ARG0 (s / small-molecule :name (n10 / name :op1 "cAMP")))
                  :mod (a / all))
            :ARG0-of (c2 / cause-01
                  :ARG1 (s2 / show-01
                        :ARG0 w
                        :ARG1 (a7 / and
                              :op1 (p6 / phosphorylate-01
                                    :ARG1 (a2 / and
                                          :op1 (a3 / amino-acid :mod 43 :name (n6 / name :op1 "serine"))
                                          :op2 (a4 / amino-acid :mod 259 :name (n7 / name :op1 "serine"))
                                          :op3 (a5 / amino-acid :mod 621 :name (n8 / name :op1 "serine")))
                                    :ARG2 (e3 / enzyme :name (n9 / name :op1 "PKA"))
                                    :manner (i3 / in-vitro))
                              :op2 (i4 / induce-01
                                    :ARG0 s
                                    :ARG2 a2
                                    :manner (i5 / in-vivo)))))))

# ::id bel_pmid_1202_1251.10412 ::date 2015-04-26T07:44:27 ::annotator SDL-AMR-09 ::preferred
# ::snt In contrast, LPS from Escherichia coli stimulated mast cells in a TLR4-dependent manner to produce TNF-alpha, IL-1beta, IL-6, and IL-13, but not IL-4 nor IL-5.
# ::save-date Fri Feb 12, 2016 ::file bel_pmid_1202_1251_10412.txt
(c / contrast-01
      :ARG2 (s / stimulate-01
            :ARG0 (l / lipopolysaccharide
                  :source (o / organism :name (n2 / name :op1 "Escherichia" :op2 "coli")))
            :ARG1 (c3 / cell
                  :mod (m2 / mast))
            :manner (d / depend-01
                  :ARG1 (p / protein :name (n3 / name :op1 "TLR4")))
            :purpose (c4 / contrast-01
                  :ARG1 (p8 / produce-01
                        :ARG0 c3
                        :ARG1 (a / and
                              :op1 (p2 / protein :name (n4 / name :op1 "TNF-alpha"))
                              :op2 (p3 / protein :name (n5 / name :op1 "IL-1beta"))
                              :op3 (p4 / protein :name (n6 / name :op1 "IL-6"))
                              :op4 (p5 / protein :name (n7 / name :op1 "IL-13"))))
                  :ARG2 (p9 / produce-01 :polarity -
                        :ARG0 c3
                        :ARG1 (a2 / and
                              :op1 (p6 / protein :name (n8 / name :op1 "IL-4"))
                              :op2 (p7 / protein :name (n9 / name :op1 "IL-5")))))))

# ::id bel_pmid_1202_3369.1246 ::date 2015-04-24T10:00:31 ::annotator SDL-AMR-09 ::preferred
# ::snt Like IL-12, IL-23 binds to the IL-12R subunit IL-12Rbeta1.
# ::save-date Sat May 2, 2015 ::file bel_pmid_1202_3369_1246.txt
(b / bind-01
      :ARG1 (p / protein :name (n2 / name :op1 "IL-23")
            :ARG1-of (r / resemble-01
                  :ARG2 (p2 / protein :name (n / name :op1 "IL-12"))))
      :ARG2 (p4 / protein :name (n3 / name :op1 "IL-12Rbeta1")
            :ARG1-of (i / include-91
                  :ARG2 (p3 / protein :name (n4 / name :op1 "IL-12R")))))

# ::id bel_pmid_1202_3369.35656 ::date 2015-04-24T10:27:04 ::annotator SDL-AMR-09 ::preferred
# ::snt IL-23 activates the same Jak-stat signaling molecules as IL-12: Jak2, Tyk2, and stat1, -3, -4, and -5, but stat4 activation is substantially weaker and different DNA-binding stat complexes form in response to IL-23 compared with IL-12. IL-23R associates constitutively with Jak2 and in a ligand-dependent manner with stat3.
# ::save-date Sun Jan 3, 2016 ::file bel_pmid_1202_3369_35656.txt
(m / multi-sentence
      :snt1 (h / have-concession-91
            :ARG1 (a3 / and
                  :op1 (w / weak-02
                        :ARG1 (a4 / activate-01
                              :ARG1 p12)
                        :degree (m2 / more)
                        :degree (s / substantial))
                  :op2 (f / form-01
                        :ARG1 (m3 / macro-molecular-complex
                              :ARG1-of (b / bind-01
                                    :ARG2 (n14 / nucleic-acid :wiki "DNA" :name (n15 / name :op1 "DNA")))
                              :mod (p7 / protein :name (n13 / name :op1 "stat"))
                              :ARG1-of (d3 / differ-02))
                        :ARG2-of (r2 / respond-01
                              :ARG1 (p5 / protein :name (n5 / name :op1 "IL-23")))
                        :compared-to (p6 / protein :name (n6 / name :op1 "IL-12"))))
            :ARG2 (a2 / activate-01
                  :ARG0 p5
                  :ARG1 (m4 / molecule
                        :ARG0-of (s3 / signal-07
                              :ARG1 (p4 / pathway :name (n7 / name :op1 "Jak-stat")))
                        :ARG1-of (m5 / mean-01
                              :ARG2 (a5 / and
                                    :op1 (e2 / enzyme :name (n4 / name :op1 "Jak2"))
                                    :op2 (e3 / enzyme :name (n12 / name :op1 "Tyk2"))
                                    :op3 (p10 / protein :name (n8 / name :op1 "stat1"))
                                    :op4 (p11 / protein :name (n9 / name :op1 "stat3"))
                                    :op5 (p12 / protein :name (n10 / name :op1 "stat4"))
                                    :op6 (p13 / protein :name (n11 / name :op1 "stat5"))))
                        :ARG1-of (r3 / resemble-01
                              :ARG2 (m6 / molecule
                                    :ARG1-of (a8 / activate-01
                                          :ARG0 p6)))
                        :ARG1-of (s2 / same-01))))
      :snt2 (a / and
            :op1 (a6 / associate-01
                  :ARG1 (p / protein :name (n / name :op1 "IL-23R"))
                  :ARG2 (e / enzyme :name (n2 / name :op1 "Jak2"))
                  :manner (c / constitutive))
            :op2 (a7 / associate-01
                  :ARG1 p
                  :ARG2 (p3 / protein :name (n3 / name :op1 "stat3"))
                  :manner (d / depend-01
                        :ARG0 (l / ligand)))))

# ::id bel_pmid_1207_7275.28056 ::date 2015-04-28T00:47:26 ::annotator SDL-AMR-09 ::preferred
# ::snt At day 7 following infection, lung tissue from mice given hIL-17F Ad showed substantial increases in the mRNA for inflammatory cytokines and chemokines, including IL-6, IFN-g, inflammatory protein 10, and monokine induced by IFN-g (Fig. 3).
# ::save-date Sun Dec 20, 2015 ::file bel_pmid_1207_7275_28056.txt
(s / show-01
      :ARG0 (t / tissue
            :location (l / lung)
            :source (m / mouse
                  :ARG2-of (g / give-01
                        :ARG1 (g2 / gene :name (n / name :op1 "Ad")
                              :ARG3-of (e / express-03
                                    :ARG2 (p6 / protein :name (n8 / name :op1 "hil-17F")))))))
      :ARG1 (i2 / increase-01
            :ARG1 (a2 / and
                  :op1 (n3 / nucleic-acid :name (n2 / name :op1 "mRNA")
                        :purpose (a3 / and
                              :op1 (c / cytokine)
                              :op2 (c2 / chemokine)
                              :ARG0-of (i3 / inflame-01)
                              :ARG2-of (i4 / include-91
                                    :ARG1 (a4 / and
                                          :op1 (p3 / protein :name (n5 / name :op1 "IL-6"))
                                          :op2 (p4 / protein :name (n6 / name :op1 "IFN-g"))
                                          :op3 (p5 / protein :name (n7 / name :op1 "inflammatory" :op2 "protein" :op3 "10"))
                                          :op4 (m2 / monokine
                                                :ARG2-of (i5 / induce-01
                                                      :ARG0 p4)))))))
            :degree (s2 / substantial))
      :ARG1-of (d2 / describe-01
            :ARG0 (f2 / figure :mod 3))
      :time (a / after
            :op1 (i / infect-01
                  :ARG1 t)
            :quant (t2 / temporal-quantity :quant 7
                  :unit (d / day))))

# ::id bel_pmid_1207_7275.28070 ::date 2015-04-26T03:07:16 ::annotator SDL-AMR-09 ::preferred
# ::snt We cultured sorted mast cells and basophils with IL-25, IL-18, or IL-25 IL-18 and detected both IL-5 and IL-13 from IL-18 cultured cell supernatants
# ::save-date Tue May 5, 2015 ::file bel_pmid_1207_7275_28070.txt
(a / and
      :op1 (c / culture-01
            :ARG0 (w / we)
            :ARG1 (o / or
                  :op1 (a3 / and
                        :op1 (p / protein :name (n / name :op1 "IL-25"))
                        :op2 (p2 / protein :name (n2 / name :op1 "IL-18")))
                  :op2 (a4 / and
                        :op1 p
                        :op2 p2))
            :location (a2 / and
                  :op1 (c2 / cell
                        :mod (m / mast)
                        :ARG1-of (s2 / sort-01))
                  :op2 (c5 / cell :name (n3 / name :op1 "basophil"))))
      :op2 (d / detect-01
            :ARG0 w
            :ARG1 (a5 / and
                  :op1 (p3 / protein :name (n4 / name :op1 "IL-5"))
                  :op2 (p4 / protein :name (n5 / name :op1 "IL-13"))
                  :source (s / supernatant
                        :mod (c3 / cell)
                        :location-of (c4 / culture-01
                              :ARG0 w
                              :ARG1 p2)))))

# ::id bel_pmid_1208_2107.1700 ::date 2015-04-26T03:32:14 ::annotator SDL-AMR-09 ::preferred
# ::snt The dual phosphorylation of Thr-183 and Tyr-185 in ERK2 is catalyzed by MAPK/ERK kinase 1 (MEK1).
# ::save-date Sun Dec 13, 2015 ::file bel_pmid_1208_2107_1700.txt
(c / catalyze-01
      :ARG0 (e2 / enzyme :name (n / name :op1 "MAPK/ERK" :op2 "kinase" :op3 "1"))
      :ARG1 (p2 / phosphorylate-01
            :ARG1 (a / and
                  :op1 (a2 / amino-acid :mod 183 :name (n2 / name :op1 "threonine")
                        :part-of (e / enzyme :name (n4 / name :op1 "ERK2")))
                  :op2 (a3 / amino-acid :mod 185 :name (n3 / name :op1 "tyrosine")
                        :part-of e))
            :mod (d / dual)))

# ::id bel_pmid_1208_7097.38812 ::date 2015-04-26T04:42:38 ::annotator SDL-AMR-09 ::preferred
# ::snt the phosphorylation of Raf-1 on Ser-259 induced by paclitaxel he region surrounding Ser-259 in Raf-1 conforms to a consensus sequence for phosphorylation by Akt
# ::save-date Sun Dec 20, 2015 ::file bel_pmid_1208_7097_38812.txt
(c / conform-01
      :ARG1 (p / phosphorylate-01
            :ARG2 (a / amino-acid :mod 259 :name (n2 / name :op1 "serine")
                  :part-of (e2 / enzyme :name (n3 / name :op1 "Raf-1")))
            :ARG2-of (i / induce-01
                  :ARG0 (p3 / paclitaxel
                        :location (r / region
                              :ARG0-of (s2 / surround-01
                                    :ARG1 a)))))
      :ARG2 (s / sequence
            :mod (c2 / consensus)
            :purpose (p2 / phosphorylate-01
                  :ARG2 (e / enzyme :name (n / name :op1 "Akt")))))

# ::id bel_pmid_1208_9357.6280 ::date 2015-04-26T09:01:03 ::annotator SDL-AMR-09 ::preferred
# ::snt The MAPK kinase inhibitors did not affect Nur77 and Nurr1 mRNA induction but blocked CRH or cAMP-stimulated Nur transcriptional activity.
# ::save-date Fri Feb 12, 2016 ::file bel_pmid_1208_9357_6280.txt
(c / contrast-01
      :ARG1 (a / affect-01 :polarity -
            :ARG0 (m / molecular-physical-entity
                  :ARG0-of (i3 / inhibit-01
                        :ARG1 (p3 / protein-family :name (n8 / name :op1 "MAPK" :op2 "kinase"))))
            :ARG1 (i / induce-01
                  :ARG2 (a2 / and
                        :op1 (n9 / nucleic-acid :name (n6 / name :op1 "mRNA")
                              :ARG0-of (e2 / encode-01
                                    :ARG1 (p / protein :name (n / name :op1 "Nur77"))))
                        :op2 (n10 / nucleic-acid :name (n7 / name :op1 "mRNA")
                              :ARG0-of (e3 / encode-01
                                    :ARG1 (p2 / protein :name (n2 / name :op1 "Nurr1")))))))
      :ARG2 (b / block-01
            :ARG0 m
            :ARG1 (a3 / activity-06
                  :ARG0 (p6 / protein :name (n5 / name :op1 "Nur"))
                  :ARG1 (t2 / transcribe-01)
                  :ARG1-of (s / stimulate-01
                        :ARG0 (o / or
                              :op1 (s2 / small-molecule :name (n3 / name :op1 "CRH"))
                              :op2 (s3 / small-molecule :name (n4 / name :op1 "cAMP")))))))

# ::id bel_pmid_1208_9357.19824 ::date 2015-04-26T09:21:30 ::annotator SDL-AMR-09 ::preferred
# ::snt calcium-independent pathways are accounted for in part by MAPK activation (Rap1/B-Raf/MAPK-ERK kinase/ERK1/2) AtT-20 corticotrophs express B-Raf, as do other cells in which cAMP stimulates MAPK. CRH/cAMP stimulated ERK2 (Mapk1) activity and increased transcriptional activity of a Gal4-Elk1 protein, which was blocked by overexpression of dominant negative mutants and kinase inhibitors and stimulated by expression of B-Raf.
# ::save-date Fri Feb 12, 2016 ::file bel_pmid_1208_9357_19824.txt
(m / multi-sentence
      :snt1 (a5 / account-01
            :ARG1 (p / pathway
                  :ARG0-of (d2 / depend-01 :polarity -
                        :ARG1 (c / calcium))
                  :example (p4 / pathway :name (n16 / name :op1 "Rap1/B-Raf/MAPK-ERK-kinase/ERK1/2")))
            :ARG2 (a6 / activate-01
                  :ARG1 (e7 / enzyme :name (n3 / name :op1 "MAPK")))
            :degree (p3 / part))
      :snt2 (e / express-03
            :ARG1 (c2 / corticotroph :name (n / name :op1 "AtT-20"))
            :ARG2 (e2 / enzyme :name (n2 / name :op1 "B-Raf"))
            :ARG1-of (r / resemble-01
                  :ARG2 (e11 / express-03
                        :ARG1 (c3 / cell
                              :mod (o2 / other)
                              :location-of (s4 / stimulate-01
                                    :ARG0 (s6 / small-molecule :name (n10 / name :op1 "cAMP"))
                                    :ARG1 (e4 / enzyme :name (n14 / name :op1 "MAPK")))))))
      :snt3 (a / and
            :op1 (s / stimulate-01
                  :ARG0 (s2 / slash
                        :op1 (s7 / small-molecule :name (n4 / name :op1 "CRH"))
                        :op2 (s5 / small-molecule :name (n5 / name :op1 "cAMP")))
                  :ARG1 (a2 / activity-06
                        :ARG0 (e3 / enzyme :name (n6 / name :op1 "ERK2"))))
            :op2 (i2 / increase-01
                  :ARG0 s2
                  :ARG1 (a3 / activity-06
                        :ARG0 (p5 / protein :name (n8 / name :op1 "Gal4-Elk1")
                              :ARG1-of (b / block-01
                                    :ARG0 (a4 / and
                                          :op1 (o / overexpress-01
                                                :ARG1 (p6 / protein
                                                      :ARG2-of (m3 / mutate-01 :mod "-/-")))
                                          :op2 (m2 / molecular-physical-entity
                                                :ARG0-of (i3 / inhibit-01
                                                      :ARG1 (k / kinase)))))
                              :ARG1-of (s3 / stimulate-01
                                    :ARG0 (e5 / express-03
                                          :ARG2 (e6 / enzyme :name (n9 / name :op1 "B-Raf")))))
                        :ARG1 (t2 / transcribe-01)))))

# ::id bel_pmid_1208_9357.26116 ::date 2015-04-28T02:24:41 ::annotator SDL-AMR-09 ::preferred
# ::snt CRH and cAMP induce Nur77 and Nurr1 expression and transcription at the NurRE site by protein kinase A (PKA) and calcium-dependent and -independent mechanisms.
# ::save-date Fri Feb 12, 2016 ::file bel_pmid_1208_9357_26116.txt
(i / induce-01
      :ARG0 (a / and
            :op1 (s / small-molecule :name (n / name :op1 "CRH"))
            :op2 (s2 / small-molecule :name (n2 / name :op1 "cAMP")))
      :ARG2 (a4 / and
            :op1 (e / express-03
                  :ARG2 (a2 / and
                        :op1 (p3 / protein :name (n3 / name :op1 "Nur77"))
                        :op2 (p4 / protein :name (n4 / name :op1 "Nurr1"))))
            :op2 (t / transcribe-01
                  :ARG0 (a3 / and
                        :op1 (e2 / enzyme :name (n6 / name :op1 "protein" :op2 "kinase" :op3 "A"))
                        :op2 (m / mechanism
                              :ARG0-of (d / depend-01
                                    :ARG1 (c / calcium)))
                        :op3 (m2 / mechanism
                              :ARG0-of (d2 / depend-01 :polarity -
                                    :ARG1 (c2 / calcium))))
                  :ARG1 a2
                  :location (p / protein-segment :name (n5 / name :op1 "NurRE")))))

# ::id bel_pmid_1210_1242.29522 ::date 2015-04-27T12:13:10 ::annotator SDL-AMR-09 ::preferred
# ::snt The levels of collagen alpha1 (I), alpha1 (III), and fibronectin mRNAs were reduced in 1-day wounds of Nrf2 knockout mice compared to control littermates.
# ::save-date Sun Jan 3, 2016 ::file bel_pmid_1210_1242_29522.txt
(r / reduce-01
      :ARG1 (a / and
            :op1 (l2 / level
                  :quant-of (p2 / protein :name (n3 / name :op1 "collagen" :op2 "alpha1(I)")))
            :op2 (l3 / level
                  :quant-of (p3 / protein :name (n / name :op1 "alpha1(III)")))
            :op3 (l4 / level
                  :quant-of (n5 / nucleic-acid :name (n4 / name :op1 "mRNA")
                        :mod (f / fibronectin))))
      :location (w / wound-01
            :ARG1 (m / mouse
                  :ARG1-of (k / knock-out-03
                        :ARG0 (p / protein :name (n2 / name :op1 "Nrf2"))))
            :age (t / temporal-quantity :quant 1
                        :unit (d / day))
            :compared-to (l / littermate
                  :ARG1-of (c / control-01))))

# ::id bel_pmid_1210_1242.29526 ::date 2015-04-27T12:37:21 ::annotator SDL-AMR-09 ::preferred
# ::snt Interestingly, the normally observed induction of IL-1beta and TNF-alpha expression (22) was delayed in the knockout mice. The levels of IL-1beta mRNA were 50% lower in the 1-day wounds of Nrf2-/- mice than for control littermates.
# ::save-date Sun Jan 3, 2016 ::file bel_pmid_1210_1242_29526.txt
(m2 / multi-sentence
      :snt1 (d2 / delay-01
            :ARG1 (i / induce-01
                  :ARG2 (e / express-03
                        :ARG2 (a / and
                              :op1 (p4 / protein :name (n5 / name :op1 "IL-1beta"))
                              :op2 (p5 / protein :name (n6 / name :op1 "TNF-alpha"))))
                  :ARG1-of (o / observe-01
                        :ARG1-of (n4 / normal-02))
                  :ARG1-of (d3 / describe-01
                        :ARG0 (p6 / publication
                              :ARG1-of (c2 / cite-01
                                    :ARG2 22))))
            :ARG2-of (i2 / interest-01)
            :location (m5 / mouse
                  :ARG2-of (m6 / mutate-01 :mod "+/-")))
      :snt2 (l2 / low-04
            :ARG1 (l / level
                  :quant-of (n7 / nucleic-acid :name (n / name :op1 "mRNA")
                        :mod (p2 / protein :name (n2 / name :op1 "IL-1beta"))))
            :degree (m / more)
            :quant (p / percentage-entity :value 50)
            :location (w / wound-01
                  :ARG1 (m3 / mouse
                        :ARG1-of (k / knock-out-03
                              :ARG0 (p3 / protein :name (n3 / name :op1 "Nrf2"))))
                  :age (t / temporal-quantity :quant 1
                              :unit (d / day)))
            :compared-to (l3 / littermate
                  :ARG1-of (c / control-01))))

# ::id bel_pmid_1210_1242.29528 ::date 2015-04-26T07:11:09 ::annotator SDL-AMR-09 ::preferred
# ::snt Expression of IL-6 was also lower in 1-day wounds of Nrf2 null mice, but in contrast to IL-1beta the mRNA of this cytokine was no longer detectable at later stages of repair.
# ::save-date Wed Mar 9, 2016 ::file bel_pmid_1210_1242_29528.txt
(h / have-concession-91
      :ARG1 (c2 / contrast-01
            :ARG1 (p3 / protein :name (n3 / name :op1 "IL1-beta"))
            :ARG2 (p4 / possible-01
                  :ARG1 (d2 / detect-01
                        :ARG1 (n5 / nucleic-acid :name (n4 / name :op1 "mRNA")
                              :poss p)
                        :time (n6 / no-longer)
                        :time (s / stage
                              :mod (l / late
                                    :degree (m3 / more))
                              :subevent-of (r2 / repair-01)))))
      :ARG2 (l2 / low-04
            :ARG1 (e / express-03
                  :ARG2 (p / protein :name (n / name :op1 "IL-6")))
            :degree (m / more)
            :mod (a / also)
            :location (w / wound-01
                  :ARG1 (m2 / mouse
                        :mod (p2 / protein :name (n2 / name :op1 "Nrf2")
                              :ARG2-of (m4 / mutate-01 :mod "-/-")))
                  :age (t / temporal-quantity :quant 1
                        :unit (d / day)))))

# ::id bel_pmid_1210_1242.29532 ::date 2015-04-24T10:28:50 ::annotator SDL-AMR-09 ::preferred
# ::snt Indeed, TGF-beta1 mRNA was present at lower levels in unwounded back skin and in 1-day wounds of Nrf2-/- mice (Fig.7).
# ::save-date Fri Dec 18, 2015 ::file bel_pmid_1210_1242_29532.txt
(p3 / present-02
      :ARG1 (n4 / nucleic-acid :name (n2 / name :op1 "mRNA")
            :mod (p / protein :name (n3 / name :op1 "TGF-beta1"))
            :quant (l / level
                  :ARG1-of (l2 / low-04
                        :degree (m / more))))
      :ARG2 (a2 / and
            :op1 (s / skin
                  :location (b2 / back)
                  :ARG1-of (w / wound-01 :polarity -))
            :op2 (w2 / wound-01
                  :ARG1 (m2 / mouse
                        :mod (p2 / protein :name (n / name :op1 "Nrf2")
                              :ARG2-of (m3 / mutate-01 :mod "-/-"))
                        :age (t / temporal-quantity :quant 1
                                    :unit (d / day)))))
      :ARG1-of (d2 / describe-01
            :ARG0 (f / figure :mod 7))
      :mod (i / indeed))

# ::id bel_pmid_1210_1242.29534 ::date 2015-04-24T10:41:23 ::annotator SDL-AMR-09 ::preferred
# ::snt Expression of VEGF, a major regulator of angiogenesis, was also reduced in nonwounded skin and in 1-day wounds of Nrf2 null mice (Fig.7).
# ::save-date Thu Jul 30, 2015 ::file bel_pmid_1210_1242_29534.txt
(r2 / reduce-01
      :ARG1 (e / express-03
            :ARG2 (p / protein :name (n2 / name :op1 "VEGF")
                  :ARG0-of (r / regulate-01
                        :ARG1 (a4 / angiogenesis)
                        :ARG1-of (m3 / major-02))))
      :mod (a2 / also)
      :location (a3 / and
            :op1 (s / skin
                  :ARG1-of (w / wound-01 :polarity -))
            :op2 (m / mouse
                  :mod (p2 / protein :name (n3 / name :op1 "Nrf2")
                        :ARG2-of (m2 / mutate-01 :mod "-/-"))
                  :age (t / temporal-quantity :quant 1
                              :unit (d / day))))
      :ARG1-of (d2 / describe-01
            :ARG0 (f / figure :mod 7)))

# ::id bel_pmid_1211_0143.268 ::date 2015-04-26T05:25:35 ::annotator SDL-AMR-09 ::preferred
# ::snt binding of Il6 to Il6R induces homodimerization ofgp130, activating JAK associated with gp130 at Box1.
# ::save-date Sun Jan 3, 2016 ::file bel_pmid_1211_0143_268.txt
(i / induce-01
      :ARG0 (b / bind-01
            :ARG1 (p / protein :name (n / name :op1 "Il6"))
            :ARG2 (p2 / protein :name (n2 / name :op1 "Il6R")))
      :ARG2 (h2 / homodimerize-01
            :ARG1 (p3 / protein :name (n3 / name :op1 "gp130")))
      :ARG0-of (a / activate-01
            :ARG1 (e / enzyme :name (n4 / name :op1 "JAK")
                  :ARG1-of (a2 / associate-01
                        :ARG2 p3
                        :location (p5 / protein-segment :name (n5 / name :op1 "Box1")
                              :part-of p3)))))

# ::id bel_pmid_1211_0143.20340 ::date 2015-04-26T06:48:31 ::annotator SDL-AMR-09 ::preferred
# ::snt in Il6 signal cascade, the SHP2 interaction site of gp130 has also been shown to be a Socs3 contact site so that Socs3 may compete for the SHP2-gp130 interaction site
# ::save-date Sat Jan 2, 2016 ::file bel_pmid_1211_0143_20340.txt
(s / show-01
      :ARG1 (p5 / protein-segment
            :location-of (i / interact-01
                  :ARG1 (e / enzyme :name (n / name :op1 "SHP2")))
            :domain (p6 / protein-segment
                  :ARG0-of (c / contact-01
                        :ARG1 (p2 / protein :name (n3 / name :op1 "Socs3")
                              :purpose (p3 / possible-01
                                          :ARG1 (c2 / compete-01
                                                :ARG0 p2
                                                :ARG1 p5)))))
            :part-of (p / protein :name (n2 / name :op1 "gp130")))
      :location (c3 / cascade
            :mod (s2 / signal-07
                  :ARG0 (p4 / protein :name (n4 / name :op1 "IL-6"))))
      :mod (a / also))

# ::id bel_pmid_1211_0143.28372 ::date 2015-04-26T08:13:52 ::annotator SDL-AMR-09 ::preferred
# ::snt nonreceptor tyrosine kinases, such as Btk, Tec, Fes, and Hck are activated through the Il6R receptor
# ::save-date Sun Jan 17, 2016 ::file bel_pmid_1211_0143_28372.txt
(a / activate-01
      :ARG0 (r / receptor :name (n / name :op1 "IL-6R"))
      :ARG1 (e5 / enzyme :name (n2 / name :op1 "nonreceptor" :op2 "tyrosine" :op3 "kinase")
            :example (a3 / and
                  :op1 (k / kinase :name (n3 / name :op1 "Btk"))
                  :op2 (k2 / kinase :name (n4 / name :op1 "Tec"))
                  :op3 (k3 / kinase :name (n5 / name :op1 "Fes"))
                  :op4 (k4 / kinase :name (n6 / name :op1 "Hck")))))

# ::id bel_pmid_1211_0143.28412 ::date 2015-04-26T08:19:58 ::annotator SDL-AMR-09 ::preferred
# ::snt tyrosine phosphorylation of SHP2, a phosphotyrosine phosphatase, and that of STAT3 depend on the second tyrosine residue Y2 from the membrane in gp130
# ::save-date Tue May 5, 2015 ::file bel_pmid_1211_0143_28412.txt
(d / depend-01
      :ARG0 (a / and
            :op1 (p / phosphorylate-01
                  :ARG1 (a3 / amino-acid :name (n6 / name :op1 "tyrosine")
                        :part-of (e / enzyme :name (n4 / name :op1 "SHP2")
                              :ARG1-of (m / mean-01
                                    :ARG2 (p3 / phosphatase
                                          :mod (p5 / phosphotyrosine))))))
            :op2 (p4 / phosphorylate-01
                  :ARG1 (a4 / amino-acid :name (n7 / name :op1 "tyrosine")
                        :part-of (p6 / protein :name (n5 / name :op1 "STAT3")))))
      :ARG1 (r / residue :name (n2 / name :op1 "Y2")
            :mod (a2 / amino-acid :name (n / name :op1 "tyrosine"))
            :mod (o / ordinal-entity :value 2)
            :location (m2 / membrane
                  :part-of (p2 / protein :name (n3 / name :op1 "gp130")))))

# ::id bel_pmid_1211_0143.32746 ::date 2015-04-27T11:48:31 ::annotator SDL-AMR-09 ::preferred
# ::snt presence of type 1 Il6R, which is a binding site for NF-IL-6, IL-6DBP, and CEBPbeta has been confirmed in the genes for CRP, hemoplexin A and haptoglobin binding activity of NF-IL-6 is probably induced by Il6 through the increased expression of the NF-IL-6 gene
# ::save-date Mon Dec 21, 2015 ::file bel_pmid_1211_0143_32746.txt
(m / multi-sentence
      :snt1 (c / confirm-01
            :ARG1 (p3 / present-02
                  :ARG1 (p4 / protein :name (n3 / name :op1 "IL-6R")
                        :ARG1-of (t / type-03 :mod 1)
                        :domain (p8 / protein-segment
                              :ARG1-of (b2 / bind-01
                                    :ARG2 (a3 / and
                                          :op1 (p5 / protein :name (n / name :op1 "NF-IL-6"))
                                          :op2 (p6 / protein :name (n4 / name :op1 "IL-6DBP"))
                                          :op3 (p7 / protein :name (n5 / name :op1 "CEBPbeta")))))))
            :ARG2 (a / and
                  :op1 (p9 / protein :name (n6 / name :op1 "CRP"))
                  :op2 (p10 / protein :name (n7 / name :op1 "hemoplexin" :op2 "A"))
                  :op3 (p11 / protein :name (n9 / name :op1 "haptoglobin")))
            :location (g2 / gene))
      :snt2 (i / induce-01
            :ARG0 (p2 / protein :name (n10 / name :op1 "Il6"))
            :ARG2 (a2 / activity-06
                  :ARG0 (p12 / protein :name (n8 / name :op1 "NF-IL-6"))
                  :ARG1 (b / bind-01))
            :mod (p / probable)
            :manner (e / express-03
                  :ARG2 (g / gene
                        :ARG0-of (e2 / encode-01
                              :ARG1 p12))
                  :ARG1-of (i2 / increase-01))))

# ::id bel_pmid_1211_0143.35664 ::date 2015-04-27T12:38:01 ::annotator SDL-AMR-09 ::preferred
# ::snt binding of Il6 to Il6R induces homodimerization ofgp130, activating JAK associated with gp130 at Box1.......Our group and others found that JAK1, JAK2, and Tky-2 are activated and are tyrosine-phosphorylated in response to IL-6, CNTF, LIF, and OSM [14]
# ::save-date Sun Jan 17, 2016 ::file bel_pmid_1211_0143_35664.txt
(m / multi-sentence
      :snt1 (i / induce-01
            :ARG0 (b / bind-01
                  :ARG1 (p / protein :name (n / name :op1 "Il6"))
                  :ARG2 (p2 / protein :name (n2 / name :op1 "Il6R")))
            :ARG2 (h / homodimerize-01
                  :ARG1 (p3 / protein :name (n3 / name :op1 "gp130")))
            :ARG0-of (a / activate-01
                  :ARG1 (e2 / enzyme :name (n4 / name :op1 "JAK")
                        :ARG1-of (a2 / associate-01
                              :ARG2 p3
                              :location (p5 / protein-segment :name (n5 / name :op1 "Box1"))))))
      :snt2 (f / find-01
            :ARG0 (a3 / and
                  :op1 (g / group
                        :poss (w / we))
                  :op2 (g2 / group
                        :mod (o / other)))
            :ARG1 (a4 / and
                  :op1 (a5 / activate-01
                        :ARG1 (a6 / and
                              :op1 (e3 / enzyme :name (n6 / name :op1 "JAK1"))
                              :op2 (e4 / enzyme :name (n7 / name :op1 "JAK2"))
                              :op3 (p9 / protein :name (n8 / name :op1 "Tky2"))))
                  :op2 (p6 / phosphorylate-01
                        :ARG1 (a9 / and
                              :op1 (a7 / amino-acid :name (n9 / name :op1 "tyrosine")
                                    :part-of e3)
                              :op2 (a10 / amino-acid :name (n14 / name :op1 "tyrosine")
                                    :part-of e4)
                              :op3 (a11 / amino-acid :name (n15 / name :op1 "tyrosine")
                                    :part-of (e / enzyme :name (n16 / name :op1 "Tky-2"))))
                        :ARG2-of (r / respond-01
                              :ARG1 (a8 / and
                                    :op1 (p10 / protein :name (n10 / name :op1 "IL-6"))
                                    :op2 (p11 / protein :name (n11 / name :op1 "CNTF"))
                                    :op3 (p12 / protein :name (n12 / name :op1 "LIF"))
                                    :op4 (p7 / protein :name (n13 / name :op1 "OSM"))))))
            :ARG1-of (d2 / describe-01
                  :ARG0 (p14 / publication
                        :ARG1-of (c2 / cite-01
                              :ARG2 14)))))

# ::id bel_pmid_1211_0143.38318 ::date 2015-04-26T06:48:54 ::annotator SDL-AMR-09 ::preferred
# ::snt Socs1 is essential for inhibition of IFN-gamma-induced inhibition of STAT6
# ::save-date Sun Dec 20, 2015 ::file bel_pmid_1211_0143_38318.txt
(e / essential
      :domain (p / protein :name (n / name :op1 "Socs1"))
      :purpose (i / inhibit-01
            :ARG1 (i2 / inhibit-01
                  :ARG1 (p3 / protein :name (n3 / name :op1 "STAT6"))
                  :ARG2-of (i3 / induce-01
                        :ARG0 (p2 / protein :name (n2 / name :op1 "IFN-gamma"))))))

# ::id bel_pmid_1211_0143.38516 ::date 2015-04-24T06:57:38 ::annotator SDL-AMR-09 ::preferred
# ::snt Socs1 inhibits activation of STAT6 by Il4 stimulation
# ::save-date Fri May 1, 2015 ::file bel_pmid_1211_0143_38516.txt
(i / inhibit-01
      :ARG0 (p3 / protein :name (n / name :op1 "Socs1"))
      :ARG1 (a / activate-01
            :ARG0 (s / stimulate-01
                  :ARG1 (p2 / protein :name (n3 / name :op1 "IL-4")))
            :ARG1 (p / protein :name (n2 / name :op1 "STAT6"))))

# ::id bel_pmid_1211_0143.38548 ::date 2015-04-24T07:11:00 ::annotator SDL-AMR-09 ::preferred
# ::snt Il6 activates STAT1 and STAT5 in addition to STAT3
# ::save-date Tue Apr 28, 2015 ::file bel_pmid_1211_0143_38548.txt
(a / activate-01
      :ARG0 (p / protein :name (n5 / name :op1 "IL-6"))
      :ARG1 (a2 / and
            :op1 (p2 / protein :name (n2 / name :op1 "STAT1"))
            :op2 (p3 / protein :name (n3 / name :op1 "STAT5"))
            :op3 (p4 / protein :name (n4 / name :op1 "STAT3"))))

# ::id bel_pmid_1214_7685.34134 ::date 2015-04-24T09:59:30 ::annotator SDL-AMR-09 ::preferred
# ::snt the down-regulation of D1 and D2 cyclins by OSM was mediated by STAT3 but not by SHP2/Ras STAT3 activation is necessary and sufficient for down-regulation of D1 and D2 cyclins in fetal hepatocytes
# ::save-date Tue May 5, 2015 ::file bel_pmid_1214_7685_34134.txt
(m3 / multi-sentence
      :snt1 (c4 / contrast-01
            :ARG1 (m / mediate-01
                  :ARG0 (p7 / protein :name (n10 / name :op1 "STAT3"))
                  :ARG1 (d2 / downregulate-01
                        :ARG1 (a5 / and
                              :op1 (p5 / protein :name (n8 / name :op1 "D1" :op2 "cyclin"))
                              :op2 (p6 / protein :name (n9 / name :op1 "D2" :op2 "cyclin")))
                        :ARG2 (e / enzyme :name (n4 / name :op1 "OSM"))))
            :ARG2 (m2 / mediate-01 :polarity -
                  :ARG0 (p4 / pathway :name (n7 / name :op1 "SHP2/Ras"))
                  :ARG1 d2))
      :snt2 (a / and
            :op1 (n / need-01
                  :ARG0 (d / downregulate-01
                        :ARG1 (a2 / and
                              :op1 (p2 / protein :name (n2 / name :op1 "D1" :op2 "cyclin"))
                              :op2 (p3 / protein :name (n3 / name :op1 "D2" :op2 "cyclin"))
                              :location (h / hepatocyte
                                    :mod (f / fetus))))
                  :ARG1 (a4 / activate-01
                        :ARG1 (p / protein :name (n6 / name :op1 "STAT3"))))
            :op2 (s / suffice-01
                  :ARG0 a2
                  :ARG1 d)))

# ::id bel_pmid_1217_7059.29876 ::date 2015-04-24T13:12:00 ::annotator SDL-AMR-09 ::preferred
# ::snt Substitution of Arg-238, equivalent to conserved Arg in the 14-3-3 binding motif, with Glu (R238E) decreased 14-3-3theta binding to PDK1 (Fig. 3 C, upper panel, lane 4). In contrast, substitution of Val-243 with Pro (V243P), a residue conserved in many 14-3-3 targets, such as Raf-1 and Bad (Fig.3 A), dramatically increased the amount of 14-3-3theta bound to PDK1
# ::save-date Sun Jan 17, 2016 ::file bel_pmid_1217_7059_29876.txt
(m / multi-sentence
      :snt1 (d / decrease-01
            :ARG0 (s / substitute-01 :value "R238E"
                  :ARG1 (a8 / amino-acid :name (n14 / name :op1 "glutamic" :op2 "acid"))
                  :ARG3 (a / amino-acid :mod 238 :name (n2 / name :op1 "arginine")
                        :ARG1-of (e / equal-01
                              :ARG2 (a2 / amino-acid :name (n3 / name :op1 "arginine")
                                    :ARG1-of (c / conserve-01
                                          :location (p9 / protein-segment
                                                :ARG1-of (b2 / bind-01
                                                      :ARG2 (p / protein :name (n / name :op1 "14-3-3")))))))))
            :ARG1 (b3 / bind-01
                  :ARG1 (p2 / protein :name (n5 / name :op1 "14-3-3theta"))
                  :ARG2 (e3 / enzyme :name (n6 / name :op1 "PDK1")))
            :ARG1-of (d2 / describe-01
                  :ARG0 (f / figure :mod "3C")
                  :location (l / lane :mod 4
                        :location (p8 / panel
                              :mod (u2 / upper)))))
      :snt2 (c2 / contrast-01
            :ARG2 (i / increase-01
                  :ARG0 (s2 / substitute-01 :value "V243P"
                        :ARG1 (a4 / amino-acid :name (n7 / name :op1 "proline"))
                        :ARG2 (a5 / amino-acid :mod 243 :name (n8 / name :op1 "valine")
                              :ARG1-of (m3 / mean-01
                                    :ARG2 (r / residue
                                          :ARG1-of (c3 / conserve-01
                                                :location (m2 / molecular-physical-entity
                                                      :ARG1-of (t / target-01
                                                            :ARG0 (p4 / protein :name (n9 / name :op1 "14-3-3")))
                                                      :example (a6 / and
                                                            :op1 (e2 / enzyme :name (n10 / name :op1 "Raf-1"))
                                                            :op2 (p5 / protein :name (n11 / name :op1 "Bad")))
                                                      :quant (m4 / many)))
                                          :ARG1-of (d3 / describe-01
                                                :ARG0 (f2 / figure :mod "3A"))))))
                  :ARG1 (a7 / amount
                        :quant-of (p6 / protein :name (n12 / name :op1 "14-3-3theta")
                              :ARG1-of (b4 / bind-01
                                    :ARG2 (e4 / enzyme :name (n13 / name :op1 "PDK1")))))
                  :manner (d4 / dramatic))))

# ::id bel_pmid_1217_7059.29878 ::date 2015-04-24T14:04:14 ::annotator SDL-AMR-09 ::preferred
# ::snt Co-immunoprecipitation analysis indicated that mutation at Ser-241 impairs the PDK1 binding ability for 14-3-3theta and 14-3-3eta (Fig. 3 B, upper panel, lane 3, and data not shown).
# ::save-date Sun Jan 17, 2016 ::file bel_pmid_1217_7059_29878.txt
(i / indicate-01
      :ARG0 (a / analyze-01
            :manner (c / coimmunoprecipitate-01))
      :ARG1 (i2 / impair-01
            :ARG0 (m / mutate-01
                  :ARG1 (a2 / amino-acid :mod 241 :name (n2 / name :op1 "serine")))
            :ARG1 (c2 / capable-01
                  :ARG1 (e / enzyme :name (n3 / name :op1 "PDK1"))
                  :ARG2 (b2 / bind-01
                        :ARG1 e
                        :ARG2 (a3 / and
                              :op1 (p3 / protein :name (n4 / name :op1 "14-3-3theta"))
                              :op2 (p4 / protein :name (n5 / name :op1 "14-3-3eta"))))))
      :ARG1-of (d / describe-01
            :ARG0 (a4 / and
                  :op1 (f / figure :mod "3B"
                        :location (l / lane :mod 3
                              :location (p5 / panel
                                    :mod (u2 / upper))))
                  :op2 (d2 / data
                        :ARG1-of (s / show-01 :polarity -)))))

# ::id bel_pmid_1219_8646.11798 ::date 2015-04-25T00:40:31 ::annotator SDL-AMR-09 ::preferred
# ::snt Hepatic expression of Ccnd1, cMyc, IL-1r1, and IL-6r was induced in wild-type mice, but not Pparalpha-null mice, after acute exposure to the potent Pparalpha agonist Wy-14,643, indicating a role for Pparalpha in regulating the expression of these genes.
# ::save-date Sun Dec 20, 2015 ::file bel_pmid_1219_8646_11798.txt
(i / induce-01
      :ARG2 (e / express-03
            :ARG2 (a / and
                  :op1 (g / gene :name (n / name :op1 "Ccnd1"))
                  :op2 (g2 / gene :name (n2 / name :op1 "cMyc"))
                  :op3 (g3 / gene :name (n3 / name :op1 "IL-1r1"))
                  :op4 (g4 / gene :name (n4 / name :op1 "IL-6r")))
            :mod (h / hepatic))
      :location (m / mouse
            :mod (w / wild-type)
            :ARG1-of (c / contrast-01
                  :ARG2 (m2 / mouse :polarity -
                        :ARG3-of (e4 / express-03
                              :ARG2 (p5 / protein :name (n6 / name :op1 "Pparalpha")
                                    :ARG2-of (m3 / mutate-01 :mod "-/-"))))))
      :time (a2 / after
            :op1 (e2 / expose-01
                  :ARG2 (a4 / agonist :name (n7 / name :op1 "Wy-14,643")
                        :mod (p6 / potent)
                        :mod (p7 / protein :name (n8 / name :op1 "Pparalpha")))
                  :mod (a3 / acute)
                  :ARG0-of (i2 / indicate-01
                        :ARG1 (r / role
                              :topic (r2 / regulate-01
                                    :ARG0 p7
                                    :ARG1 (e3 / express-03
                                          :ARG2 a)))))))

# ::id bel_pmid_1220_4103.24772 ::date 2015-04-25T02:16:02 ::annotator SDL-AMR-09 ::preferred
# ::snt Jak1 phosphorylation was reduced in wildtype indivduals after Il13 treatement, implying that SHP-2 is responsible for this effect.
# ::save-date Sun Jan 17, 2016 ::file bel_pmid_1220_4103_24772.txt
(r / reduce-01
      :ARG1 (p / phosphorylate-01
            :ARG1 (e3 / enzyme :name (n / name :op1 "Jak1")))
      :location (i / individual
            :mod (w / wild-type))
      :time (a / after
            :op1 (t / treat-04
                  :ARG2 (p3 / protein :name (n2 / name :op1 "Il13"))))
      :ARG0-of (i2 / imply-01
            :ARG1 (r2 / responsible-01
                  :ARG0 (p2 / protein :name (n3 / name :op1 "SHP-2"))
                  :ARG1 (a2 / affect-01
                        :ARG0 p2
                        :ARG2 r))))

# ::id bel_pmid_1220_4103.27950 ::date 2015-04-25T02:40:16 ::annotator SDL-AMR-09 ::preferred
# ::snt as for Jak1, the phosphoryaltions of Tyk2 and IRS-2 were reduced after IL13 stimulaiton in wildtype cells.
# ::save-date Tue May 5, 2015 ::file bel_pmid_1220_4103_27950.txt
(r / reduce-01
      :ARG1 (p / phosphorylate-01
            :ARG1 (a / and
                  :op1 (e / enzyme :name (n / name :op1 "Tyk2"))
                  :op2 (p2 / protein :name (n2 / name :op1 "IRS-2"))))
      :topic (e2 / enzyme :name (n3 / name :op1 "Jak1"))
      :time (a2 / after
            :op1 (s / stimulate-01
                  :ARG1 (p4 / protein :name (n4 / name :op1 "IL13"))
                  :location (c / cell
                        :mod (w / wild-type)))))

# ::id bel_pmid_1220_4103.27958 ::date 2015-04-25T02:48:28 ::annotator SDL-AMR-09 ::preferred
# ::snt Results In cytoplasmic extracts, phosphoryalation of the p85alpha subunit of PI3-kinase was markedly increased after stimulation with Il13 in both groups of probands.
# ::save-date Tue May 5, 2015 ::file bel_pmid_1220_4103_27958.txt
(i / increase-01
      :ARG1 (p / phosphorylate-01
            :ARG1 (p2 / protein-segment :name (n / name :op1 "p85alpha")
                  :part-of (e / enzyme :name (n2 / name :op1 "PI3-kinase"))))
      :manner (m / marked)
      :time (a / after
            :op1 (s / stimulate-01
                  :ARG2 (p3 / protein :name (n3 / name :op1 "Il13"))
                  :location (g / group
                        :mod (b / both)
                        :ARG2-of (i2 / include-91
                              :ARG1 (p4 / proband)))))
      :ARG2-of (r / result-01)
      :location (m2 / molecular-physical-entity
            :ARG1-of (e2 / extract-01
                  :ARG2 (c / cytoplasm))))

# ::id bel_pmid_1221_8157.20330 ::date 2015-04-25T03:11:24 ::annotator SDL-AMR-09 ::preferred
# ::snt when Il6 and Il6R were combined, significant stimulation of both mineral and matrix release from bone explants was noted
# ::save-date Fri Dec 18, 2015 ::file bel_pmid_1221_8157_20330.txt
(n / note-02
      :ARG1 (s / stimulate-01
            :ARG1 (r / release-01
                  :ARG1 (a / and
                        :op1 (m / mineral)
                        :op2 (m2 / matrix))
                  :ARG2 (e / explant
                        :mod (b / bone)))
            :ARG1-of (s2 / significant-02))
      :time (c / combine-01
            :ARG1 (p / protein :name (n2 / name :op1 "Il6"))
            :ARG2 (p2 / protein :name (n3 / name :op1 "Il6R"))))

# ::id bel_pmid_1221_8157.20336 ::date 2015-04-25T03:25:27 ::annotator SDL-AMR-09 ::preferred
# ::snt Il6 plus Il6R enhanced the expression of RANKL and OPG in calvarial bones, but decreased RANK expression
# ::save-date Sat Apr 25, 2015 ::file bel_pmid_1221_8157_20336.txt
(c / contrast-01
      :ARG1 (e / enhance-01
            :ARG0 (a / and
                  :op1 (p / protein :name (n / name :op1 "Il6"))
                  :op2 (p2 / protein :name (n2 / name :op1 "Il6R")))
            :ARG1 (e2 / express-03
                  :ARG2 (a2 / and
                        :op1 (p3 / protein :name (n3 / name :op1 "RANKL"))
                        :op2 (p4 / protein :name (n4 / name :op1 "OPG"))))
            :location (b / bone
                  :mod (c2 / calvarial)))
      :ARG2 (d / decrease-01
            :ARG0 a
            :ARG1 (e3 / express-03
                  :ARG2 (p5 / protein :name (n5 / name :op1 "RANK")))))

# ::id bel_pmid_1221_8157.28344 ::date 2015-04-25T03:37:06 ::annotator SDL-AMR-09 ::preferred
# ::snt Il6, leukemia inhibitory factor [LIF}, and oncostatin M [OSM] are Il6-type cytokines that stimulate osteoclast formation and function
# ::save-date Mon Dec 21, 2015 ::file bel_pmid_1221_8157_28344.txt
(t2 / type-03
      :ARG1 (a3 / and
            :op1 (p / protein :name (n2 / name :op1 "Il6"))
            :op2 (p2 / protein :name (n3 / name :op1 "leukemia" :op2 "inhibitory" :op3 "factor"))
            :op3 (p3 / protein :name (n4 / name :op1 "oncostatin" :op2 "M")))
      :ARG2 (c / cytokine
            :ARG0-of (s / stimulate-01
                  :ARG1 (a2 / and
                        :op1 (f / form-01
                              :ARG1 (o / osteoclast))
                        :op2 (f2 / function-01
                              :ARG0 o)))
            :mod p))

# ::id bel_pmid_1221_8157.29756 ::date 2015-04-25T04:19:56 ::annotator SDL-AMR-09 ::preferred
# ::snt OSM also stimulated Ca release and enhanced the mRNA expression of RANKL and OPG in mouse calcaria, but have no effect on the expression of RANK
# ::save-date Tue May 5, 2015 ::file bel_pmid_1221_8157_29756.txt
(c / contrast-01
      :ARG1 (a / and
            :op1 (s2 / stimulate-01
                  :ARG0 (p / protein :name (n2 / name :op1 "OSM"))
                  :ARG1 (r / release-01
                        :ARG1 (c3 / calcium))
                  :mod (a2 / also))
            :op2 (e / enhance-01
                  :ARG0 p
                  :ARG1 (e2 / express-03
                        :ARG1 (n3 / nucleic-acid :name (n / name :op1 "mRNA"))
                        :ARG2 (a3 / and
                              :op1 (p2 / protein :name (n4 / name :op1 "RANKL"))
                              :op2 (p3 / protein :name (n5 / name :op1 "OPG")))
                        :ARG3 (c2 / calcaria
                              :mod (m2 / mouse)))))
      :ARG2 (a4 / affect-01 :polarity -
            :ARG0 p
            :ARG1 (e3 / express-03
                  :ARG2 (p4 / protein :name (n6 / name :op1 "RANK")))))

# ::id bel_pmid_1221_9085.28406 ::date 2015-04-25T04:35:46 ::annotator SDL-AMR-09 ::preferred
# ::snt functions of the 2 major signaling pathways, the signal transducers and activators of transcription 1 and 3 [STAT1/3] and the Src-homology tyrosine phosphatase 2 [SHP2]-Ras-ERK [Ptpn11], emanating from the common signal transducer, gp130, in the gastrointestinal tract
# ::save-date Tue Jan 19, 2016 ::file bel_pmid_1221_9085_28406.txt
(f2 / function-01
      :ARG0 (p / pathway :quant 2
            :ARG0-of (s / signal-07)
            :ARG1-of (m / major-02)
            :example (a2 / and
                  :op1 (a / and
                        :op1 (p3 / pathway :name (n2 / name :op1 "signal" :op2 "transducer" :op3 "and" :op4 "activator" :op5 "of" :op6 "transcription" :op7 "1"))
                        :op2 (p6 / pathway :name (n5 / name :op1 "signal" :op2 "transducer" :op3 "and" :op4 "activator" :op5 "of" :op6 "transcription" :op7 "3")))
                  :op2 (p4 / pathway :name (n3 / name :op1 "Src-homology" :op2 "tyrosine" :op3 "phosphatase" :op4 "2-Ras-ERK"))))
      :ARG1-of (e / emanate-01
            :ARG2 (m3 / molecular-physical-entity
                  :ARG2-of (t / transduce-01
                        :ARG1 (s2 / signal-07)
                        :ARG1-of (m2 / mean-01
                              :ARG2 (p2 / protein :name (n / name :op1 "gp130"))))
                  :mod (c / common))
            :location (t3 / tract
                  :mod (g / gastrointestinal))))

# ::id bel_pmid_1222_0517.8134 ::date 2015-04-25T05:15:59 ::annotator SDL-AMR-09 ::preferred
# ::snt Sp1-mediated transcription is one of the mechanisms, which is responsible for BMP2-induced up-regulation of Erk2 expression.
# ::save-date Sun Dec 20, 2015 ::file bel_pmid_1222_0517_8134.txt
(t2 / transcribe-01
      :ARG1-of (m / mediate-01
            :ARG0 (p / protein :name (n / name :op1 "Sp1")))
      :ARG1-of (i / include-91
            :ARG2 (m2 / mechanism))
      :ARG0-of (r / responsible-01
            :ARG1 (e / express-03
                  :ARG2 (u / upregulate-01
                        :ARG1 (e2 / enzyme :name (n3 / name :op1 "Erk2"))
                        :ARG2-of (i2 / induce-01
                              :ARG0 (p2 / protein :name (n2 / name :op1 "BMP2")))))))

# ::id bel_pmid_1222_0517.25504 ::date 2015-04-25T07:05:16 ::annotator SDL-AMR-09 ::preferred
# ::snt increased Erk2 protein level under BMP2 inducement comes from BMP2-up-regulated Erk2 mRNA expression.
# ::save-date Sun Jan 17, 2016 ::file bel_pmid_1222_0517_25504.txt
(c / come-01
      :ARG1 (l / level
            :quant-of (e3 / enzyme :name (n / name :op1 "Erk2"))
            :ARG1-of (i / increase-01)
            :ARG2-of (i2 / induce-01
                  :ARG0 (p2 / protein :name (n2 / name :op1 "BMP2"))))
      :ARG3 (e / express-03
            :ARG2 (n3 / nucleic-acid :name (n5 / name :op1 "mRNA")
                  :ARG1-of (u / upregulate-01
                        :ARG2 p2)
                  :ARG0-of (e2 / encode-01
                        :ARG1 e3))))

# ::id bel_pmid_1222_6756.17890 ::date 2015-04-25T11:00:20 ::annotator SDL-AMR-09 ::preferred
# ::snt NIH3T3 cells expressing either Raf :ER-DD or Raf : ER-YY synthesized RALT upon stimulation with Tamoxifen for 4 ± 8 h in serum-deprived medium (Figure 4b). The effect of tamoxifen was as strong as serum stimulation and was reverted by the administra- tion of U0126 (Figure 4b)
# ::save-date Sun Jan 17, 2016 ::file bel_pmid_1222_6756_17890.txt
(m / multi-sentence
      :snt1 (s2 / synthesize-01
            :ARG0 (c / cell-line :name (n3 / name :op1 "NIH3T3")
                  :ARG3-of (e2 / express-03
                        :ARG2 (o / or
                              :op1 (p2 / protein :name (n / name :op1 "Raf:ER-DD"))
                              :op2 (p3 / protein :name (n4 / name :op1 "Raf:ER-YY")))))
            :ARG1 (p / protein :name (n8 / name :op1 "RALT"))
            :time (s3 / stimulate-01
                  :ARG2 (s9 / small-molecule :name (n9 / name :op1 "tamoxifen"))
                  :duration (b / between
                        :op1 (t / temporal-quantity :quant 4
                              :unit (h / hour))
                        :op2 (t2 / temporal-quantity :quant 8
                              :unit (h2 / hour)))
                  :location (m5 / medium
                        :ARG1-of (d / deprive-01
                              :ARG2 (s4 / serum))))
            :ARG1-of (d2 / describe-01
                  :ARG0 (f / figure :mod "4b")))
      :snt2 (a / and
            :op1 (s5 / strong-02
                  :ARG1 (a2 / affect-01
                        :ARG0 (s7 / small-molecule :name (n10 / name :op1 "tamoxifen")))
                  :degree (e3 / equal)
                  :compared-to (s6 / stimulate-01
                        :ARG0 (s8 / serum)))
            :op2 (r / revert-01
                  :ARG0 (a3 / administrate-01
                        :ARG1 (s / small-molecule :name (n2 / name :op1 "U0126")))
                  :ARG1 a2)
            :ARG1-of (d3 / describe-01
                  :ARG0 (f2 / figure :mod "4b"))))

# ::id bel_pmid_1222_6756.17894 ::date 2015-04-25T10:26:29 ::annotator SDL-AMR-09 ::preferred
# ::snt Ablation of RALT expression by MEK- 1 inhibitors is caused by suppression of RALT transcription, as indicated by the Northern blot analysis presented in Figure 3.
# ::save-date Thu Dec 17, 2015 ::file bel_pmid_1222_6756_17894.txt
(c2 / cause-01
      :ARG0 (s / suppress-01
            :ARG1 (t2 / transcribe-01
                  :ARG1 p))
      :ARG1 (a / ablate-01
            :ARG1 (e3 / express-03
                  :ARG2 (p / protein :name (n3 / name :op1 "RALT")))
            :ARG3 (m / molecular-physical-entity
                  :ARG0-of (i2 / inhibit-01
                        :ARG1 (e2 / enzyme :name (n2 / name :op1 "MEK-1")))))
      :ARG1-of (i3 / indicate-01
            :ARG0 (a2 / analyze-01
                  :instrument (t3 / thing :name (n4 / name :op1 "Northern" :op2 "blot"))
                  :ARG1-of (p2 / present-01
                        :location (f / figure :mod 3)))))

# ::id bel_pmid_1222_6756.26554 ::date 2015-04-25T11:52:45 ::annotator SDL-AMR-09 ::preferred
# ::snt Upon stimulation with EGF (0.3 ng/ml) or bFGF (0.3 ng/ml) about 20% of uninjected EGFR/ErbB-2 cells entered S phase (data not shown). We observed a similar rate of entrance into S phase when counting cells microinjected with a control antiserum (RAM, Figure 1e). Cells micro- injected with anti-RALT antibodies and stimulated with EGF progressed to S phase at a frequency which was 2.8-fold higher than control cells.
# ::save-date Tue Feb 2, 2016 ::file bel_pmid_1222_6756_26554.txt
(m / multi-sentence
      :snt1 (e / enter-01
            :ARG0 (a / about
                  :op1 (p2 / percentage-entity :value 20
                        :quant-of (c3 / cell
                              :ARG2-of (i / inject-01 :polarity -)
                              :mod (s4 / slash
                                    :op1 (e6 / enzyme :name (n8 / name :op1 "EGFR"))
                                    :op2 (e7 / enzyme :name (n9 / name :op1 "ErbB-2"))))))
            :ARG1 (e4 / event :name (n10 / name :op1 "S" :op2 "phase"))
            :time (s / stimulate-01
                  :ARG2 (o / or
                        :op1 (p3 / protein :name (n / name :op1 "EGF")
                              :quant (c / concentration-quantity :quant 0.3
                                    :unit (n2 / nanogram-per-milliliter)))
                        :op2 (p5 / protein :name (n3 / name :op1 "bFGF")
                              :quant (c2 / concentration-quantity :quant 0.3
                                    :unit (n4 / nanogram-per-milliliter)))))
            :ARG1-of (d / describe-01
                  :ARG0 (d2 / data
                        :ARG1-of (s2 / show-01 :polarity -))))
      :snt2 (o2 / observe-01
            :ARG0 (w / we)
            :ARG1 (r / rate
                  :degree-of (e2 / enter-01
                        :ARG1 (e5 / event :name (n11 / name :op1 "S" :op2 "phase")))
                  :ARG1-of (r2 / resemble-01))
            :time (c4 / count-01
                  :ARG1 (c5 / cell
                        :ARG2-of (m2 / microinject-01
                              :ARG1 (a2 / antiserum
                                    :mod (c6 / control-01)
                                    :ARG1-of (l / label-01
                                          :ARG2 (s5 / string-entity :value "RAM"))))))
            :ARG1-of (d3 / describe-01
                  :ARG0 (f / figure :mod "1e")))
      :snt3 (p4 / progress-01
            :ARG1 (a4 / and
                  :op1 (m3 / microinject-01
                        :ARG1 (a5 / antibody
                              :ARG0-of (c10 / counter-01
                                    :ARG1 (p9 / protein :name (n5 / name :op1 "RALT"))))
                        :ARG2 (c7 / cell))
                  :op2 (s3 / stimulate-01
                        :ARG1 c7
                        :ARG2 (p / protein :name (n7 / name :op1 "EGF"))))
            :ARG4 (e3 / event :name (n6 / name :op1 "S" :op2 "phase"))
            :ARG1-of (h2 / have-frequency-91
                  :ARG2 (p6 / product-of :op1 2.8)
                  :ARG1-of (h / high-02)
                  :compared-to (c8 / cell
                        :mod (c9 / control-01)))))

# ::id bel_pmid_1222_6756.26768 ::date 2015-04-26T03:21:14 ::annotator SDL-AMR-09 ::preferred
# ::snt We conclude that endogenous RALT protein behaves as a bonafide feedback inhibitor of the ErbB-2 kinase.
# ::save-date Sun Jan 3, 2016 ::file bel_pmid_1222_6756_26768.txt
(c / conclude-01
      :ARG0 (w / we)
      :ARG1 (b / behave-01
            :ARG0 (p / protein :name (n / name :op1 "RALT")
                  :mod (m / monocot))
            :ARG1 (m2 / molecular-physical-entity
                  :ARG0-of (i / inhibit-01
                        :ARG1 (e / enzyme :name (n2 / name :op1 "ErbB-2" :op2 "kinase"))
                        :mod (f / feedback
                              :mod (b2 / bonafide))))))

# ::id bel_pmid_1222_6756.29724 ::date 2015-04-26T03:28:58 ::annotator SDL-AMR-09 ::preferred
# ::snt These observations were extended to HC-11 cells, a murine cell line derived from breast epithelium. In these cells TGF-a, an activator of EGFR, and HRG- 1b, which triggers ErbB-2/ErbB-3 dimers (Marte et al., 1995a,b), are able to induce RALT expression (Fiorentino et al., 2000).
# ::save-date Sun Jan 17, 2016 ::file bel_pmid_1222_6756_29724.txt
(m / multi-sentence
      :snt1 (e2 / extend-01
            :ARG1 (t / thing
                  :ARG1-of (o / observe-01)
                  :mod (t2 / this))
            :ARG4 (c / cell :name (n2 / name :op1 "HC-11")
                  :ARG1-of (m2 / mean-01
                        :ARG2 (c3 / cell-line
                              :mod (o4 / organism :name (n / name :op1 "Muridae"))
                              :ARG1-of (d3 / derive-01
                                    :ARG2 (e3 / epithelium
                                          :mod (b / breast)))))))
      :snt2 (p / possible-01
            :ARG1 (i / induce-01
                  :ARG0 (a2 / and
                        :op1 (p2 / protein :name (n3 / name :op1 "TGF-a")
                              :ARG0-of (a3 / activate-01
                                    :ARG1 (e4 / enzyme :name (n4 / name :op1 "EGFR"))))
                        :op2 (p3 / protein :name (n5 / name :op1 "HRG-1b"))
                        :ARG0-of (t3 / trigger-01
                              :ARG1 (a6 / and
                                    :op1 (e / enzyme :name (n10 / name :op1 "ErbB-2"))
                                    :op2 (e6 / enzyme :name (n11 / name :op1 "ErbB-3"))
                                    :ARG3-of (d4 / dimerize-01))
                              :ARG1-of (d5 / describe-01
                                    :ARG0 (a7 / and
                                          :op1 (p4 / publication-91 :li "a"
                                                :ARG0 (a4 / and
                                                      :op1 (p5 / person :name (n7 / name :op1 "Marte"))
                                                      :op2 (p6 / person
                                                            :mod (o2 / other))))
                                          :op2 (p12 / publication-91 :li "b"
                                                :ARG0 a4)
                                          :time (d / date-entity :year 1995)))))
                  :ARG2 (e5 / express-03
                        :ARG2 (p7 / protein :name (n8 / name :op1 "RALT")))
                  :ARG1-of (d6 / describe-01
                        :ARG0 (p8 / publication-91
                              :ARG0 (a5 / and
                                    :op1 (p9 / person :name (n9 / name :op1 "Fiorentino"))
                                    :op2 (p10 / person
                                          :mod (o3 / other)))
                              :time (d2 / date-entity :year 2000)))
                  :location (c2 / cell
                        :mod (t4 / this)))))

# ::id bel_pmid_1223_7173.1150 ::date 2015-04-26T04:17:21 ::annotator SDL-AMR-09 ::preferred
# ::snt We tested if human coronary artery endothelial cells (HCAEC) may become a source of cytokine and adhesion molecule expression when stimulated with bacterial lipopolysaccharide (LPS). Analysis of HCAEC supernatants by ELISA identified enhanced secretion of IL-6, IL-8, and MCP-1 while
# ::save-date Fri Feb 12, 2016 ::file bel_pmid_1223_7173_1150.txt
(m / multi-sentence
      :snt1 (t / test-01
            :ARG0 (w / we)
            :ARG1 (p / possible-01
                  :ARG1 (b / become-01 :mode interrogative
                        :ARG1 (c / cell
                              :mod (e3 / endothelium)
                              :mod (a / artery
                                    :mod (c4 / coronary))
                              :mod (h / human))
                        :ARG2 (s / source-02
                              :ARG1 (e / express-03
                                    :ARG2 (a5 / and
                                          :op1 (c2 / cytokine)
                                          :op2 (p5 / protein :name (n8 / name :op1 "adhesion" :op2 "molecule")))))
                        :time (s2 / stimulate-01
                              :ARG1 c
                              :ARG2 (l / lipopolysaccharide
                                    :mod (b2 / bacteria))))))
      :snt2 (i / identify-01
            :ARG1 (a3 / analyze-01
                  :ARG1 (s3 / supernatant
                        :mod (c3 / cell :name (n3 / name :op1 "HCAEC")))
                  :instrument (t2 / thing :name (n4 / name :op1 "ELISA")))
            :ARG2 (s4 / secrete-01
                  :ARG1 (a4 / and
                        :op1 (p2 / protein :name (n5 / name :op1 "IL-6"))
                        :op2 (p3 / protein :name (n6 / name :op1 "IL-8"))
                        :op3 (p4 / protein :name (n7 / name :op1 "MCP-1")))
                  :ARG1-of (e2 / enhance-01))))

# ::id bel_pmid_1223_7173.1152 ::date 2015-04-26T04:40:04 ::annotator SDL-AMR-09 ::preferred
# ::snt IL-1beta and TNF-alpha but not IL-10. FACS analysis showed an LPS-induced upregulation of ICAM-1, VCAM, and ELAM-1.
# ::save-date Fri Feb 12, 2016 ::file bel_pmid_1223_7173_1152.txt
(m / multi-sentence
      :snt1 (c / contrast-01
            :ARG1 (a / and
                  :op1 (p / protein :name (n / name :op1 "IL-1beta"))
                  :op2 (p2 / protein :name (n2 / name :op1 "TNF-alpha")))
            :ARG2 (p3 / protein :polarity - :name (n3 / name :op1 "IL-10")))
      :snt2 (s / show-01
            :ARG0 (a2 / analyze-01
                  :instrument (t / thing :name (n4 / name :op1 "FACS")))
            :ARG1 (u / upregulate-01
                  :ARG1 (a3 / and
                        :op1 (p4 / protein :name (n6 / name :op1 "ICAM-1"))
                        :op2 (p5 / protein :name (n7 / name :op1 "VCAM"))
                        :op3 (p6 / protein :name (n8 / name :op1 "ELAM-1")))
                  :ARG2-of (i / induce-01
                        :ARG0 (l / lipopolysaccharide)))))

# ::id bel_pmid_1227_0932.7862 ::date 2015-04-26T04:51:12 ::annotator SDL-AMR-09 ::preferred
# ::snt SHP-2 is a dual-specificity phosphatase involved in Stat1 dephosphorylation at both tyrosine and serine residues in nuclei
# ::save-date Sun Jan 17, 2016 ::file bel_pmid_1227_0932_7862.txt
(p3 / phosphatase
      :domain (p / protein :name (n2 / name :op1 "SHP-2"))
      :ARG1-of (i / involve-01
            :ARG2 (d2 / dephosphorylate-01
                  :ARG1 (a2 / and
                        :op1 (r2 / residue
                              :mod (a3 / amino-acid :name (n4 / name :op1 "tyrosine")))
                        :op2 (r3 / residue
                              :mod (a / amino-acid :name (n / name :op1 "serine")))
                        :part-of (p2 / protein :name (n3 / name :op1 "Stat1")))
                  :location (n5 / nucleus)))
      :ARG1-of (s / specific-02
            :mod (d / dual)))

# ::id bel_pmid_1227_0932.9942 ::date 2015-04-26T05:39:35 ::annotator SDL-AMR-09 ::preferred
# ::snt In SHP-2-/- mouse fibroblast cells, Stat1 phosphorylation at both the tyrosine residue Tyr(701) and the serine residue Ser(727) by IFNgamma was enhanced and prolonged.
# ::save-date Sun Jan 17, 2016 ::file bel_pmid_1227_0932_9942.txt
(a2 / and
      :op1 (e / enhance-01
            :ARG1 (p / phosphorylate-01
                  :ARG1 (a3 / and
                        :op1 (r / residue
                              :mod (a4 / amino-acid :mod 701 :name (n3 / name :op1 "tyrosine")))
                        :op2 (r2 / residue
                              :mod (a / amino-acid :mod 727 :name (n / name :op1 "serine")))
                        :part-of (p2 / protein :name (n2 / name :op1 "Stat1")))
                  :ARG2 (p3 / protein :name (n4 / name :op1 "IFNgamma"))))
      :op2 (p4 / prolong-01
            :ARG1 p)
      :location (c2 / cell :name (n5 / name :op1 "fibroblast")
            :mod (m / mouse)
            :mod (p5 / protein :name (n6 / name :op1 "SHP-2")
                  :ARG2-of (m2 / mutate-01 :mod "-/-"))))

# ::id bel_pmid_1227_0932.39476 ::date 2015-04-26T05:53:40 ::annotator SDL-AMR-09 ::preferred
# ::snt Consistently, purified GST-SHP-2 dephosphorylated Stat1 at both tyrosine and serine residues when immunoprecipitated phospho-Stat1 or a peptide corresponding to the sequence surrounding Tyr(P)(701) or Ser(P)(727) of Stat1 was used as the substrate.
# ::save-date Mon Feb 1, 2016 ::file bel_pmid_1227_0932_39476.txt
(d / dephosphorylate-01
      :ARG1 (a2 / and
            :op1 (r / residue
                  :mod (a3 / amino-acid :name (n3 / name :op1 "tyrosine")))
            :op2 (r2 / residue
                  :mod (a4 / amino-acid :name (n4 / name :op1 "serine")))
            :part-of (p2 / protein :name (n5 / name :op1 "Stat1")))
      :ARG2 (e / enzyme :name (n2 / name :op1 "GST-SHP-2")
            :ARG1-of (p / purify-01))
      :time (u / use-01
            :ARG1 (o / or
                  :op1 (p3 / protein :name (n6 / name :op1 "Stat1")
                        :ARG1-of (i / immunoprecipitate-01)
                        :ARG3-of (p4 / phosphorylate-01))
                  :op2 (p5 / peptide
                        :ARG1-of (c / correspond-02
                              :ARG2 (s / sequence
                                    :ARG1-of (s2 / surround-01
                                          :ARG2 (o2 / or
                                                :op1 (a5 / amino-acid :mod 701 :name (n7 / name :op1 "tyrosine")
                                                      :part-of p2
                                                      :ARG3-of p4)
                                                :op2 (a6 / amino-acid :mod 727 :name (n8 / name :op1 "serine")
                                                      :part-of p2
                                                      :ARG3-of p4)))))))
            :ARG2 (s3 / substrate))
      :manner (c2 / consistent-02))

# ::id bel_pmid_1240_2043.4190 ::date 2015-04-26T08:18:35 ::annotator SDL-AMR-09 ::preferred
# ::snt Here we show that after stimulation by growth factors Spry1 and Spry2 translocate to the plasma membrane and become phosphorylated on a conserved tyrosine.
# ::save-date Wed Feb 24, 2016 ::file bel_pmid_1240_2043_4190.txt
(s / show-01
      :ARG0 (w / we)
      :ARG1 (a / and
            :op1 (t / translocate-01
                  :ARG1 (a2 / and
                        :op1 (p / protein :name (n / name :op1 "Spry1"))
                        :op2 (p2 / protein :name (n2 / name :op1 "Spry2")))
                  :ARG2 (m / membrane
                        :mod (p3 / plasma)))
            :op2 (b / become-01
                  :ARG1 a2
                  :ARG2 (p4 / phosphorylate-01
                        :ARG1 (a3 / amino-acid :name (n3 / name :op1 "tyrosine")
                              :ARG1-of (c / conserve-01)
                              :part-of a2)))
            :time (a4 / after
                  :op1 (s2 / stimulate-01
                        :ARG0 (g / growth-factor)
                        :ARG1 a2)))
      :location (h / here))

# ::id bel_pmid_1240_2043.10224 ::date 2015-04-26T08:42:25 ::annotator SDL-AMR-09 ::preferred
# ::snt Next, they bind to the adaptor protein Grb2 and inhibit the recruitment of the Grb2-Sos complex either to the fibroblast growth factor receptor (FGFR) docking adaptor protein FRS2 or to Shp2. Membrane translocation of Spry is necessary for its phosphorylation, which is essential for its inhibitor activity.
# ::save-date Wed Jan 13, 2016 ::file bel_pmid_1240_2043_10224.txt
(m / multi-sentence
      :snt1 (a / and
            :op1 (b / bind-01
                  :ARG1 (t2 / they)
                  :ARG2 (p2 / protein :name (n3 / name :op1 "adaptor" :op2 "protein" :op3 "Grb2")))
            :op2 (i2 / inhibit-01
                  :ARG0 t2
                  :ARG1 (r / recruit-01
                        :ARG1 (m2 / macro-molecular-complex
                              :part (p3 / protein :name (n4 / name :op1 "Grb2"))
                              :part (p4 / protein :name (n5 / name :op1 "Sos"))))
                  :location (o / or
                        :op1 (p5 / protein :name (n6 / name :op1 "fibroblast" :op2 "growth" :op3 "factor" :op4 "receptor")
                              :ARG0-of (d / dock-01
                                    :ARG1 (p6 / protein :name (n7 / name :op1 "adaptor" :op2 "protein" :op3 "FRS2"))))
                        :op2 (e2 / enzyme :name (n8 / name :op1 "Shp2"))))
            :time (n / next))
      :snt2 (n2 / need-01
            :ARG0 (t / translocate-01
                  :ARG1 (p8 / protein :name (n9 / name :op1 "Spry"))
                  :ARG2 (m3 / membrane))
            :ARG1 (p9 / phosphorylate-01
                  :ARG1 p8
                  :mod (e / essential)
                  :purpose (a2 / activity-06
                        :ARG0 p8
                        :ARG1 (i3 / inhibit-01)))))

# ::id bel_pmid_1240_2043.26582 ::date 2015-04-26T09:09:57 ::annotator SDL-AMR-09 ::preferred
# ::snt Using an antibody against Spry2, we showed that endogenous Spry2 becomes phosphorylated on tyrosine in response to EGF or FGF stimulation in C2C12 cells (Fig. 4b, left) and in COS7 cells (Fig. 4b, right).
# ::save-date Sat Jan 30, 2016 ::file bel_pmid_1240_2043_26582.txt
(s / show-01
      :ARG0 (w / we)
      :ARG1 (b / become-01
            :ARG1 (p / protein :name (n / name :op1 "Spry2")
                  :mod (m / monocot))
            :ARG2 (p2 / phosphorylate-01
                  :ARG1 (a / amino-acid :name (n2 / name :op1 "tyrosine")
                        :part-of p)
                  :ARG2-of (r / respond-01
                        :ARG1 (s2 / stimulate-01
                              :ARG1 p
                              :ARG2 (o / or
                                    :op1 (p3 / protein :name (n3 / name :op1 "EGF"))
                                    :op2 (p4 / protein :name (n4 / name :op1 "FGF")))
                              :location (a2 / and
                                    :op1 (c / cell-line :name (n5 / name :op1 "C2C12")
                                          :ARG1-of (d / describe-01
                                                :ARG0 (f / figure :mod "4b"
                                                      :ARG1-of (l / left-20))))
                                    :op2 (c2 / cell :name (n6 / name :op1 "COS7")
                                          :ARG1-of (d2 / describe-01
                                                :ARG0 (f2 / figure :mod "4b"
                                                      :ARG1-of (r2 / right-04)))))))))
      :manner (u / use-01
            :ARG1 (a3 / antibody
                  :ARG0-of (c3 / counter-01
                        :ARG1 (p5 / protein :name (n7 / name :op1 "Spry2"))))))

# ::id bel_pmid_1240_2043.26584 ::date 2015-04-26T09:36:05 ::annotator SDL-AMR-09 ::preferred
# ::snt In addition, neither xSpry1Y53F nor mSpry2Y55F was tyrosine phosphorylated in cells stimulated with EGF (data not shown).
# ::save-date Thu May 7, 2015 ::file bel_pmid_1240_2043_26584.txt
(a / and
      :op2 (p / phosphorylate-01 :polarity -
            :ARG1 (a6 / and
                  :op1 (a5 / amino-acid :name (n5 / name :op1 "tyrosine")
                        :part-of (p4 / protein :name (n7 / name :op1 "xSpry1Y53F")))
                  :op2 (a7 / amino-acid :name (n8 / name :op1 "tyrosine")
                        :part-of (p5 / protein :name (n9 / name :op1 "mSpry2Y55F"))))
            :location (c / cell
                  :ARG1-of (s / stimulate-01
                        :ARG0 (p2 / protein :name (n6 / name :op1 "EGF")))))
      :ARG1-of (d / describe-01
            :ARG0 (d2 / data
                  :ARG1-of (s3 / show-01 :polarity -))))

# ::id bel_pmid_1240_2043.26602 ::date 2015-04-26T10:28:50 ::annotator SDL-AMR-09 ::preferred
# ::snt When Myc-tagged mSpry2 and haemagluttinin A (HA)- tagged Grb2 were expressed in cultured cells, both molecules translocated to the ruffling membrane region in response to stimulation with FGF or EGF and colocalized there (Fig. 1c).
# ::save-date Tue Feb 2, 2016 ::file bel_pmid_1240_2043_26602.txt
(a5 / and
      :op1 (t3 / translocate-01
            :ARG1 a2
            :ARG2 (r / region
                  :part-of (m / membrane)
                  :ARG0-of (r2 / ruffle-02))
            :ARG2-of (r3 / respond-01
                  :ARG1 (s / stimulate-01
                        :ARG0 (o / or
                              :op1 (p5 / protein :wiki "Fibroblast_growth_factor" :name (n5 / name :op1 "FGF"))
                              :op2 (p6 / protein :wiki "Epidermal_growth_factor" :name (n6 / name :op1 "EGF"))))))
      :op2 (c3 / colocalize-01
            :ARG1 a2
            :ARG2 r)
      :time (e / express-03
            :ARG2 (a2 / and
                  :op1 (p2 / protein :wiki "SPRY2" :name (n2 / name :op1 "Spry2")
                        :ARG1-of (t / tag-01
                              :ARG2 (p / protein :wiki - :name (n / name :op1 "Myc")))
                        :mod (m2 / mouse))
                  :op2 (p4 / protein :wiki "GRB2" :name (n4 / name :op1 "Grb2")
                        :ARG1-of (t2 / tag-01
                              :ARG0 (p3 / protein :wiki - :name (n3 / name :op1 "haemagluttinin" :op2 "A")))))
            :ARG3 (c / cell
                  :ARG1-of (c2 / culture-01)))
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod "1c")))

# ::id bel_pmid_1240_2043.30896 ::date 2015-04-26T10:50:14 ::annotator SDL-AMR-09 ::preferred
# ::snt both xSpry1Y53F and mSpry2Y55F were unable to inhibit the binding of Grb2 to FRS2 or Shp2 in response to FGF stimulation (Fig. 2a, b) or the recruitment of Grb2–Sos complex to FRS2 (Fig. 2c).
# ::save-date Wed Jan 13, 2016 ::file bel_pmid_1240_2043_30896.txt
(p / possible-01 :polarity -
      :ARG1 (i / inhibit-01
            :ARG0 (a / and
                  :op1 (p3 / protein :name (n12 / name :op1 "xSpry1")
                        :ARG2-of (m2 / mutate-01 :value "Y53F"))
                  :op2 (p8 / protein :name (n / name :op1 "Spry2")
                        :ARG1-of (t / tag-01
                              :ARG2 (p10 / protein :name (n3 / name :op1 "myc")))
                        :ARG2-of (m3 / mutate-01 :value "Y55F")))
            :ARG1 (a5 / and
                  :op1 (b / bind-01
                        :ARG1 (p4 / protein :name (n5 / name :op1 "Grb2"))
                        :ARG2 (o / or
                              :op1 (p5 / protein :name (n6 / name :op1 "FRS2"))
                              :op2 (e / enzyme :name (n7 / name :op1 "Shp2")))
                        :ARG2-of (r / respond-01
                              :ARG1 (o2 / or
                                    :op1 (s / stimulate-01
                                          :ARG0 (p7 / protein :name (n8 / name :op1 "FGF"))
                                          :ARG1-of (d / describe-01
                                                :ARG0 (a4 / and
                                                      :op1 (f / figure :mod "2a")
                                                      :op2 (f2 / figure :mod "2b")))))))
                  :op2 (r2 / recruit-01
                        :ARG1 (m / macro-molecular-complex
                              :part p4
                              :part (p9 / protein :name (n10 / name :op1 "Sos")))
                        :ARG2 p5
                        :ARG1-of (d2 / describe-01
                              :ARG0 (f3 / figure :mod "2c"))))))

# ::id bel_pmid_1240_2043.30898 ::date 2015-04-26T11:02:37 ::annotator SDL-AMR-09 ::preferred
# ::snt We investigated the ability of the Spry mutants to bind to Grb2. Both xSpry1Y53F and mSpry2Y55F failed to bind to Grb2 in response to FGF stimulation (Fig. 5c).
# ::save-date Sun Jan 3, 2016 ::file bel_pmid_1240_2043_30898.txt
(m / multi-sentence
      :snt1 (i / investigate-01
            :ARG0 (w / we)
            :ARG1 (c / capable-01
                  :ARG1 (p / protein :name (n / name :op1 "Spry")
                        :ARG2-of (m2 / mutate-01))
                  :ARG2 (b / bind-01
                        :ARG1 p
                        :ARG2 (p2 / protein :name (n2 / name :op1 "Grb2")))))
      :snt2 (f / fail-01
            :ARG1 (a / and
                  :op1 (p4 / protein :name (n9 / name :op1 "xSpry1")
                        :ARG2-of (m3 / mutate-01 :value "Y53F"))
                  :op2 (p7 / protein :name (n3 / name :op1 "Spry2")
                        :ARG2-of (m4 / mutate-01 :value "Y55F")
                        :ARG1-of (t / tag-01
                              :ARG2 (p3 / protein :name (n5 / name :op1 "myc")))))
            :ARG2 (b2 / bind-01
                  :ARG1 a
                  :ARG2 (p5 / protein :name (n7 / name :op1 "Grb2"))
                  :ARG2-of (r / respond-01
                        :ARG1 (s / stimulate-01
                              :ARG0 (p6 / protein :name (n8 / name :op1 "FGF")))))
            :ARG1-of (d / describe-01
                  :ARG0 (f2 / figure :mod "5c"))))

# ::id bel_pmid_1240_2043.30900 ::date 2015-04-26T11:10:13 ::annotator SDL-AMR-09 ::preferred
# ::snt We also found that the tyrosine- phosphorylated, endogenous Spry2 binds to endogenous Grb2 in a manner dependent on FGF stimulation (Fig. 4c).
# ::save-date Thu May 7, 2015 ::file bel_pmid_1240_2043_30900.txt
(f / find-01
      :ARG0 (w / we)
      :ARG1 (b / bind-01
            :ARG1 (a / amino-acid :name (n / name :op1 "tyrosine")
                  :ARG1-of (p / phosphorylate-01)
                  :part-of (p2 / protein :name (n2 / name :op1 "Spry2")
                        :mod (m / monocot)))
            :ARG2 (p3 / protein :name (n3 / name :op1 "Grb2")
                  :mod m)
            :manner (d / depend-01
                  :ARG1 (s / stimulate-01
                        :ARG0 (p4 / protein :name (n4 / name :op1 "FGF")))))
      :ARG1-of (d2 / describe-01
            :ARG0 (f2 / figure :mod "4c"))
      :mod (a2 / also))

# ::id bel_pmid_1242_3677.2596 ::date 2015-06-13T07:11:54 ::annotator SDL-AMR-09 ::preferred
# ::snt gp130-mediated Stat1/3 activation is required to maintain the normal balance of hematopoietic progenitors during fetal and adult hematopoiesis
# ::save-date Fri Jul 24, 2015 ::file bel_pmid_1242_3677_2596.txt
(r / require-01
      :ARG0 (m / maintain-01
            :ARG1 (b / balance-01
                  :ARG1 (p / progenitor
                        :mod (h / hematopoiesis))
                  :ARG1-of (n2 / normal-02)))
      :ARG1 (a / activate-01
            :ARG1 (p2 / protein :name (n / name :op1 "Stat1/3"))
            :ARG1-of (m2 / mediate-01
                  :ARG0 (p3 / protein :name (n3 / name :op1 "gp130"))))
      :time (a2 / and
            :op1 (h2 / hematopoiesis
                  :mod (f / fetus))
            :op2 (h3 / hematopoiesis
                  :mod (a3 / adult))))

# ::id bel_pmid_1244_4555.28358 ::date 2015-06-13T07:41:17 ::annotator SDL-AMR-09 ::preferred
# ::snt Immunoblots using antibodies to BATF detected an increase in BATF protein in response to LIF/IL-6 stimulation.
# ::save-date Wed Jun 17, 2015 ::file bel_pmid_1244_4555_28358.txt
(d / detect-01
      :ARG0 (i / immunoblot-01
            :ARG0-of (u / use-01
                  :ARG1 (a / antibody
                        :ARG0-of (c / counter-01
                              :ARG1 (p / protein :name (n / name :op1 "BATF"))))))
      :ARG1 (i2 / increase-01
            :ARG1 p
            :ARG2-of (r / respond-01
                  :ARG1 (s / stimulate-01
                        :ARG2 (p2 / protein :name (n2 / name :op1 "LIF/IL-6"))))))

# ::id bel_pmid_1247_9220.29758 ::date 2015-06-13T08:15:28 ::annotator SDL-AMR-09 ::preferred
# ::snt These data demonstrate that OSM induces up-regulation of C/EBPdelta via a Stat3-dependent pathway in mammary epithelial cells and that the growth inhibition induced by OSM depends on the presence of C/EBPdelta.
# ::save-date Sun Jan 3, 2016 ::file bel_pmid_1247_9220_29758.txt
(d / demonstrate-01
      :ARG0 (d2 / data
            :mod (t / this))
      :ARG1 (a / and
            :op1 (i / induce-01
                  :ARG0 (p / protein :name (n / name :op1 "OSM"))
                  :ARG2 (u / upregulate-01
                        :ARG1 (p2 / protein :name (n2 / name :op1 "C/EBPδ")))
                  :instrument (p3 / pathway
                        :ARG0-of (d3 / depend-01
                              :ARG1 (p4 / protein :name (n3 / name :op1 "Stat3"))))
                  :location (c / cell
                        :mod (e / epithelium
                              :mod (m / mammary))))
            :op2 (d4 / depend-01
                  :ARG0 (i2 / inhibit-01
                        :ARG1 (g / grow-01)
                        :ARG2-of (i3 / induce-01
                              :ARG0 p))
                  :ARG1 (p5 / present-02
                        :ARG1 p2))))

# ::id bel_pmid_1247_9220.29764 ::date 2015-06-13T08:28:54 ::annotator SDL-AMR-09 ::preferred
# ::snt Oncostatin M (OSM), an interleukin 6-type cytokine, induces sustained up-regulation of CCAAT/enhancer-binding protein (C/EBP) delta mRNA and protein
# ::save-date Fri Jan 15, 2016 ::file bel_pmid_1247_9220_29764.txt
(i / induce-01
      :ARG0 (p / protein :name (n / name :op1 "Oncostatin" :op2 "M")
            :ARG1-of (m / mean-01
                  :ARG2 (p3 / protein :name (n2 / name :op1 "interleukin" :op2 "6-type" :op3 "cytokine"))))
      :ARG2 (u / upregulate-01
            :ARG1 (a / and
                  :op1 (n5 / nucleic-acid :name (n3 / name :op1 "mRNA")
                        :ARG0-of (e / encode-01
                              :ARG1 (p2 / protein :name (n4 / name :op1 "CCAAT/enhancer-binding" :op2 "protein" :op3 "δ"))))
                  :op2 p2)
            :ARG1-of (s / sustain-01)))

# ::id bel_pmid_1247_9220.29772 ::date 2015-06-13T08:38:16 ::annotator SDL-AMR-09 ::preferred
# ::snt % Oncostatin M (OSM), an interleukin 6-type cytokine, induces sustained up-regulation of CCAAT/enhancer-binding protein (C/EBP) delta mRNA and protein in nonneoplastic HC11 mouse mammary epithelial cells.
# ::save-date Sun Jan 3, 2016 ::file bel_pmid_1247_9220_29772.txt
(i / induce-01
      :ARG0 (p / protein :name (n / name :op1 "Oncostatin" :op2 "M")
            :ARG1-of (m / mean-01
                  :ARG2 (p3 / protein :name (n2 / name :op1 "interleukin" :op2 "6-type" :op3 "cytokine"))))
      :ARG2 (u / upregulate-01
            :ARG1 (a / and
                  :op1 (n7 / nucleic-acid :name (n3 / name :op1 "mRNA")
                        :ARG0-of (e / encode-01
                              :ARG1 (p2 / protein :name (n4 / name :op1 "CCAAT/enhancer-binding" :op2 "protein" :op3 "δ"))))
                  :op2 p2)
            :ARG1-of (s / sustain-01))
      :location (c2 / cell :name (n5 / name :op1 "HC11")
            :mod (e2 / epithelium
                  :mod (m2 / mammary
                        :part-of (m3 / mouse)))
            :mod (n6 / neoplasm :polarity -)))

# ::id bel_pmid_1247_9220.29776 ::date 2015-06-13T09:28:48 ::annotator SDL-AMR-09 ::preferred
# ::snt This up-regulation is dependent on signaling by phospho-Stat3 (signal transducers and activators of transcription).
# ::save-date Tue Jan 19, 2016 ::file bel_pmid_1247_9220_29776.txt
(d / depend-01
      :ARG0 (u / upregulate-01
            :mod (t / this))
      :ARG1 (s / signal-07
            :ARG0 (p / protein :name (n / name :op1 "Stat3")
                  :ARG3-of (p2 / phosphorylate-01)
                  :ARG2-of (t2 / transduce-01
                        :ARG1 (s2 / signal-07))
                  :ARG0-of (a / activate-01
                        :ARG1 (t3 / transcribe-01)))))

# ::id bel_pmid_1249_6442.9810 ::date 2015-06-13T09:47:21 ::annotator SDL-AMR-09 ::preferred
# ::snt Recombinant murine OSM stimulated eotaxin protein production and mRNA levels in the NIH 3T3 fibroblast cell line
# ::save-date Sun Jun 14, 2015 ::file bel_pmid_1249_6442_9810.txt
(s / stimulate-01
      :ARG0 (p / protein :name (n / name :op1 "OSM")
            :part-of (o / organism :name (n2 / name :op1 "Muridae"))
            :ARG3-of (r / recombine-01))
      :ARG1 (a / and
            :op1 (p2 / produce-01
                  :ARG1 (p3 / protein :name (n3 / name :op1 "eotaxin")))
            :op2 (l / level
                  :quant-of (n6 / nucleic-acid :name (n4 / name :op1 "mRNA"))))
      :location (c / cell-line :name (n5 / name :op1 "NIH-3T3")
            :mod (f / fibroblast)))

# ::id bel_pmid_1249_6442.19422 ::date 2015-06-13T10:00:22 ::annotator SDL-AMR-09 ::preferred
# ::snt overexpression of Osm in lungs of mice resulted in a vigorous inflammatory response strongly supports a role of Osm in lung inflammatory responses that involve eosinophil infiltration
# ::save-date Mon Jul 13, 2015 ::file bel_pmid_1249_6442_19422.txt
(m / multi-sentence
      :snt1 (r / result-01
            :ARG1 (o / overexpress-01
                  :ARG1 (p / protein :name (n / name :op1 "OSM"))
                  :location (l / lung
                        :part-of (m2 / mouse)))
            :ARG2 (r2 / respond-01
                  :ARG0-of (i / inflame-01)
                  :mod (v / vigorous)))
      :snt2 (s / support-01
            :ARG1 (r3 / role
                  :poss (p2 / protein :name (n2 / name :op1 "OSM"))
                  :topic (r4 / respond-01
                        :ARG0-of (i2 / inflame-01
                              :ARG1 (l2 / lung))
                        :ARG2-of (i3 / involve-01
                              :ARG1 (i4 / infiltrate-01
                                    :ARG0 (c / cell :name (n3 / name :op1 "eosinophil"))))))
            :ARG1-of (s2 / strong-02)))

# ::id bel_pmid_1249_6442.19424 ::date 2015-06-13T10:56:22 ::annotator SDL-AMR-09 ::preferred
# ::snt Osm stimluated eotaxin protein prudction and mRNA levels in fibroblasts Il6 could regulate a small induction of eotaxin, but other Il6/Lif cytokines [Lif, cariotrophin-1] had no effect
# ::save-date Sun Jan 3, 2016 ::file bel_pmid_1249_6442_19424.txt
(m / multi-sentence
      :snt1 (s / stimulate-01
            :ARG0 (p / protein :name (n / name :op1 "OSM"))
            :ARG1 (a / and
                  :op1 (p2 / produce-01
                        :ARG1 (p3 / protein :name (n2 / name :op1 "eotaxin")))
                  :op2 (l / level
                        :quant-of (n9 / nucleic-acid :name (n3 / name :op1 "mRNA"))))
            :location (f / fibroblast))
      :snt2 (c / contrast-01
            :ARG1 (p4 / possible-01
                  :ARG1 (r2 / regulate-01
                        :ARG0 (p5 / protein :name (n4 / name :op1 "Il6"))
                        :ARG1 (i / induce-01
                              :ARG2 (p6 / protein :name (n5 / name :op1 "eotaxin"))
                              :degree (s2 / small))))
            :ARG2 (a2 / affect-01 :polarity -
                  :ARG0 (c2 / cytokine :name (n6 / name :op1 "Il6/Lif")
                        :mod (o / other)
                        :ARG1-of (m2 / mean-01
                              :ARG2 (a3 / and
                                    :op1 (p7 / protein :name (n7 / name :op1 "Lif"))
                                    :op2 (p8 / protein :name (n8 / name :op1 "cariotrophin-1"))))))))

# ::id bel_pmid_1249_6958.18008 ::date 2015-06-13T11:22:49 ::annotator SDL-AMR-09 ::preferred
# ::snt GSK3-beta is also phosphorylated in response to hormonal stimuli not involving mechanical stress, such as insulin28; this pathway, however, was unaffected in the melusin-null background.
# ::save-date Mon Jan 4, 2016 ::file bel_pmid_1249_6958_18008.txt
(p / phosphorylate-01
      :ARG1 (p2 / pathway :name (n / name :op1 "GSK-3β"))
      :mod (a / also)
      :ARG2-of (r / respond-01
            :ARG1 (s / stimulate-01
                  :ARG0 (h / hormone
                        :example (p3 / protein :name (n2 / name :op1 "insulin")))
                  :ARG2-of (i / involve-01 :polarity -
                        :ARG1 (s2 / stress-02
                              :mod (m / mechanics)))
                  :ARG1-of (d / describe-01
                        :ARG0 (p5 / publication
                              :ARG1-of (c2 / cite-01
                                    :ARG2 28)))))
      :ARG1-of (c / contrast-01
            :ARG2 (a2 / affect-01 :polarity -
                  :ARG1 p2
                  :location (b / background
                        :mod (p4 / protein :name (n3 / name :op1 "melusin")
                              :ARG2-of (m2 / mutate-01 :mod "-/-"))))))

# ::id bel_pmid_1249_6958.19264 ::date 2015-06-13T12:32:13 ::annotator SDL-AMR-09 ::preferred
# ::snt but did not substantially affect phosphorylation of p38 and ERK 1/2. In addition, phosphorylation of AKT was greatly impaired in aortic-banded heart of melusin-null mice.
# ::save-date Sat Jun 13, 2015 ::file bel_pmid_1249_6958_19264.txt
(m / multi-sentence
      :snt1 (c / contrast-01
            :ARG2 (a / affect-01 :polarity -
                  :ARG1 (p / phosphorylate-01
                        :ARG1 (a2 / and
                              :op1 (e / enzyme :name (n / name :op1 "p38"))
                              :op2 (e2 / enzyme :name (n2 / name :op1 "ERK1/2"))))
                  :degree (s / substantial)))
      :snt2 (a3 / and
            :op2 (i / impair-01
                  :ARG1 (p2 / phosphorylate-01
                        :ARG1 (e3 / enzyme :name (n3 / name :op1 "AKT")))
                  :location (h / heart
                        :ARG1-of (b / band-01
                              :ARG2 (a4 / aorta))
                        :part-of (m2 / mouse
                              :mod (p3 / protein :name (n4 / name :op1 "melusin")
                                    :ARG2-of (m3 / mutate-01 :mod "-/-"))))
                  :degree (g / great))))

# ::id bel_pmid_1249_6958.19266 ::date 2015-06-13T12:55:08 ::annotator SDL-AMR-09 ::preferred
# ::snt Analysis of intracellular signaling events induced by pressure overload indicated that phosphorylation of glycogen synthase kinase-3beta (GSK-3beta) was specifically blunted in melusin-null hearts.
# ::save-date Fri Jul 24, 2015 ::file bel_pmid_1249_6958_19266.txt
(i / indicate-01
      :ARG0 (a / analyze-01
            :ARG1 (e / event
                  :mod (s / signal-07)
                  :mod (i2 / intracellular)
                  :ARG2-of (i3 / induce-01
                        :ARG0 (o / overload-01
                              :ARG2 (p / pressure-01)))))
      :ARG1 (b / blunt-01
            :ARG1 (p2 / phosphorylate-01
                  :ARG1 (e2 / enzyme :name (n / name :op1 "glycogen" :op2 "synthase" :op3 "kinase-3β")))
            :location (h / heart
                  :mod (p3 / protein :name (n2 / name :op1 "melusin")
                        :ARG2-of (m / mutate-01 :mod "-/-")))
            :ARG1-of (s2 / specific-02)))

# ::id bel_pmid_1252_4227.38280 ::date 2015-06-13T13:07:03 ::annotator SDL-AMR-09 ::preferred
# ::snt HGF induced activation of ERK1 and ERK2 was shown to be dependent on the presence of HS moieties.
# ::save-date Fri Feb 12, 2016 ::file bel_pmid_1252_4227_38280.txt
(s / show-01
      :ARG1 (d / depend-01
            :ARG0 (a / activate-01
                  :ARG1 (a2 / and
                        :op1 (e / enzyme :name (n / name :op1 "ERK1"))
                        :op2 (e2 / enzyme :name (n2 / name :op1 "ERK2")))
                  :ARG2-of (i / induce-01
                        :ARG0 (p / protein :name (n3 / name :op1 "HGF"))))
            :ARG1 (p2 / present-02
                  :ARG1 (m / moiety
                        :mod (s2 / small-molecule :name (n4 / name :op1 "HS"))))))

# ::id bel_pmid_1254_0842.9294 ::date 2015-06-13T13:15:45 ::annotator SDL-AMR-09 ::preferred
# ::snt STAP-2 mRNA was strongly induced in the liver in response to lipopolysaccharide and in isolated hepatocytes in response to interleukin-6.
# ::save-date Sun Jan 3, 2016 ::file bel_pmid_1254_0842_9294.txt
(a / and
      :op1 (i / induce-01
            :ARG2 (n5 / nucleic-acid :name (n / name :op1 "mRNA")
                  :ARG0-of (e / encode-01
                        :ARG1 (p / protein :name (n2 / name :op1 "STAP-2"))))
            :location (l / liver)
            :ARG1-of (s / strong-02)
            :ARG0-of (r2 / respond-01
                  :ARG1 (s2 / small-molecule :name (n3 / name :op1 "lipopolysaccharide"))))
      :op2 (i2 / induce-01
            :ARG2 n5
            :degree s
            :location (h / hepatocyte
                  :ARG1-of (i3 / isolate-01))
            :ARG0-of (r3 / respond-01
                  :ARG1 (p2 / protein :name (n4 / name :op1 "interleukin-6")))))

# ::id bel_pmid_1254_0842.10250 ::date 2015-06-13T13:21:32 ::annotator SDL-AMR-09 ::preferred
# ::snt These data suggest that STAP-2 is a new class of adaptor molecule that modulates STAT3 activity through its YXXQ motif.
# ::save-date Mon Jul 6, 2015 ::file bel_pmid_1254_0842_10250.txt
(s / suggest-01
      :ARG0 (d / data
            :mod (t / this))
      :ARG1 (p / protein :name (n / name :op1 "STAP-2")
            :domain (c / class
                  :mod (m / molecule
                        :ARG0-of (a / adapt-01))
                  :ARG1-of (n2 / new-01))
            :ARG0-of (m2 / modulate-01
                  :ARG1 (a2 / activity-06
                        :ARG0 (p2 / protein :name (n3 / name :op1 "STAT3")))
                  :instrument (m3 / motif :name (n4 / name :op1 "YXXQ")
                        :part-of p2))))

# ::id bel_pmid_1254_0842.28154 ::date 2015-06-13T13:50:15 ::annotator SDL-AMR-09 ::preferred
# ::snt Because STAP-2 expression is induced by proinflammatory cytokines such as IL-6 or IL-1beta, STAP-2 may play a role in the regulation of inflammation.
# ::save-date Sun Jan 3, 2016 ::file bel_pmid_1254_0842_28154.txt
(c / cause-01
      :ARG0 (i / induce-01
            :ARG0 (c2 / cytokine
                  :ARG0-of (f / favor-01
                        :ARG1 (i2 / inflame-01))
                  :example (o / or
                        :op1 (c3 / cytokine :name (n / name :op1 "IL-6"))
                        :op2 (c4 / cytokine :name (n2 / name :op1 "IL-1β"))))
            :ARG2 (e / express-03
                  :ARG2 (p / protein :name (n3 / name :op1 "STAP-2"))))
      :ARG1 (p2 / possible-01
            :ARG1 (p3 / play-08
                  :ARG0 p
                  :ARG1 (r / regulate-01
                        :ARG1 i2))))

# ::id bel_pmid_1258_6835.2750 ::date 2015-06-13T14:05:55 ::annotator SDL-AMR-09 ::preferred
# ::snt conditional inactivation of Cdc2 reduces phosphorylation of S6K1 at S/TP sites while simultaneously increasing phosphorylation of Thr(389) and of the S6K1 substrate, RPS6.
# ::save-date Wed Jun 17, 2015 ::file bel_pmid_1258_6835_2750.txt
(c / contrast-01
      :ARG1 (r / reduce-01
            :ARG0 (a / activate-01 :polarity -
                  :ARG1 (e / enzyme :name (n / name :op1 "Cdc2"))
                  :mod (c2 / conditional))
            :ARG1 (p / phosphorylate-01
                  :ARG1 (p2 / protein-segment :name (n2 / name :op1 "S/TP")
                        :part-of (e2 / enzyme :name (n3 / name :op1 "S6K1")))))
      :ARG2 (i / increase-01
            :ARG0 a
            :ARG1 (p3 / phosphorylate-01
                  :ARG1 (a2 / and
                        :op1 (a3 / amino-acid :mod 389 :name (n4 / name :op1 "threonine"))
                        :op2 (s / substrate :name (n5 / name :op1 "RPS6")
                              :part-of e2)))
            :manner (s2 / simultaneous)))

# ::id bel_pmid_1259_5539.28136 ::date 2015-06-13T15:11:52 ::annotator SDL-AMR-09 ::preferred
# ::snt iNOS protein was undetectable at 1 h but was increased after 2, 4, and 24 h of incubation with IL-6. The iNOS expression induced by a 2-h incubation with 10 ng/ml IL-1beta, a well known inducer of iNOS in cardiac myocytes (38), was used as a positive control in these experiments.
# ::save-date Sun Jan 17, 2016 ::file bel_pmid_1259_5539_28136.txt
(m / multi-sentence
      :snt1 (c / contrast-01
            :ARG1 (p / possible-01 :polarity -
                  :ARG1 (d / detect-01
                        :ARG1 (e3 / enzyme :name (n / name :op1 "iNOS")))
                  :time (a / after
                        :op1 (t / temporal-quantity :quant 1
                              :unit (h / hour))))
            :ARG2 (i / increase-01
                  :ARG1 e3
                  :time (a2 / after
                        :op1 (i2 / incubate-01
                              :ARG2 (p3 / protein :name (n2 / name :op1 "IL-6"))
                              :duration (t2 / temporal-quantity
                                    :quant (a3 / and :op1 2 :op2 4 :op3 24)
                                    :unit h)))))
      :snt2 (u / use-01
            :ARG1 (e / express-03
                  :ARG2 (e4 / enzyme :name (n3 / name :op1 "iNOS"))
                  :ARG2-of (i3 / induce-01
                        :ARG0 (i4 / incubate-01
                              :ARG2 (p5 / protein :name (n4 / name :op1 "IL-1β")
                                    :quant (c2 / concentration-quantity :quant 10
                                          :unit (n5 / nanogram-per-milliliter))
                                    :ARG0-of (i5 / induce-01
                                          :ARG1 e4
                                          :location (m2 / myocyte
                                                :part-of (h2 / heart))
                                          :ARG1-of (k / know-02
                                                :degree (w / well))
                                          :ARG1-of (d2 / describe-01
                                                :ARG0 (p6 / publication
                                                      :ARG1-of (c3 / cite-01
                                                            :ARG2 38)))))
                              :duration (t3 / temporal-quantity :quant 2
                                    :unit (h3 / hour)))))
            :ARG2 (c4 / control-01
                  :mod (p7 / positive))
            :location (e2 / experiment-01
                  :mod (t4 / this))))

# ::id bel_pmid_1259_5539.28352 ::date 2015-06-13T15:48:28 ::annotator SDL-AMR-09 ::preferred
# ::snt Fig.3 A shows that an increase in phosphorylation of ERK2 at Tyr204 was detected after 5 min of exposure to 10 ng/ml IL-6; this effect peaked at 30 min and was followed by a decline to basal levels by 2 h.
# ::save-date Mon Jun 22, 2015 ::file bel_pmid_1259_5539_28352.txt
(m / multi-sentence
      :snt1 (s / show-01
            :ARG0 (f / figure :mod "3A")
            :ARG1 (d / detect-01
                  :ARG1 (i / increase-01
                        :ARG1 (p / phosphorylate-01
                              :ARG1 (a / amino-acid :mod 204 :name (n / name :op1 "tyrosine")
                                    :part-of (e / enzyme :name (n2 / name :op1 "ERK2")))))
                  :time (a2 / after
                        :op1 (e2 / expose-01
                              :ARG2 (p2 / protein :name (n3 / name :op1 "IL-6")
                                    :quant (c / concentration-quantity :quant 10
                                          :unit (n4 / nanogram-per-milliliter)))
                              :duration (t / temporal-quantity :quant 5
                                    :unit (m2 / minute))))))
      :snt2 (a3 / and
            :op1 (p3 / peak-01
                  :ARG1 (a4 / affect-01
                        :mod (t2 / this))
                  :time (a5 / after
                        :quant (t3 / temporal-quantity :quant 30
                              :unit m2)))
            :op2 (f2 / follow-01
                  :ARG1 (d2 / decline-01
                        :ARG4 (l / level
                              :mod (b / basal))
                        :time (a6 / after
                              :quant (u / up-to
                                    :op1 (t4 / temporal-quantity :quant 2
                                          :unit (h / hour)))))
                  :ARG2 a4)))

# ::id bel_pmid_1259_5539.28364 ::date 2015-06-13T16:03:45 ::annotator SDL-AMR-09 ::preferred
# ::snt IL-6 increased phosphorylation of STAT3 (at Tyr(705)) and ERK1/2 (at Tyr(204)) within 5 min that peaked at 15-30 min and returned to basal levels at 2 h
# ::save-date Wed Jun 17, 2015 ::file bel_pmid_1259_5539_28364.txt
(i / increase-01
      :ARG0 (p / protein :name (n / name :op1 "IL-6"))
      :ARG1 (p2 / phosphorylate-01
            :ARG1 (a / and
                  :op1 (a2 / amino-acid :mod 705 :name (n2 / name :op1 "tyrosine")
                        :part-of (p3 / protein :name (n3 / name :op1 "STAT3")))
                  :op2 (a3 / amino-acid :mod 204 :name (n4 / name :op1 "tyrosine")
                        :part-of (e / enzyme :name (n5 / name :op1 "ERK1/2")))))
      :time (a4 / after
            :quant (u / up-to
                  :op1 (t / temporal-quantity :quant 5
                        :unit (m / minute))))
      :ARG1-of (p4 / peak-01
            :time (a5 / after
                  :quant (t2 / temporal-quantity
                        :quant (v / value-interval :op1 15 :op2 30)
                        :unit m)))
      :ARG1-of (r / return-01
            :ARG4 (l / level
                  :mod (b / basal))
            :time (a6 / after
                  :quant (t3 / temporal-quantity :quant 2
                        :unit (h / hour)))))

# ::id bel_pmid_1259_5539.28368 ::date 2015-06-13T16:16:01 ::annotator SDL-AMR-09 ::preferred
# ::snt Fig. 1 Ashows that phosphorylation of STAT3 at Tyr705 was detected after 5 min of exposure to 10 ng/ml IL-6, reached a maximum at 15 min, and then declined within 1 h. These results demonstrate that IL-6 activates a STAT3 signaling in adult rat ventricular myocytes.
# ::save-date Mon Jun 22, 2015 ::file bel_pmid_1259_5539_28368.txt
(m / multi-sentence
      :snt1 (s / show-01
            :ARG0 (f / figure :mod "1A")
            :ARG1 (a / and
                  :op1 (d / detect-01
                        :ARG1 (p / phosphorylate-01
                              :ARG1 (a2 / amino-acid :mod 705 :name (n / name :op1 "tyrosine")
                                    :part-of (p2 / protein :name (n2 / name :op1 "STAT3"))))
                        :time (a3 / after
                              :op1 (e / expose-01
                                    :ARG2 (p3 / protein :name (n3 / name :op1 "IL-6")
                                          :quant (c / concentration-quantity :quant 10
                                                :unit (n4 / nanogram-per-milliliter)))
                                    :duration (t / temporal-quantity :quant 5
                                          :unit (m2 / minute)))))
                  :op2 (r / reach-01
                        :ARG0 p
                        :ARG1 (m3 / maximum)
                        :time (a4 / after
                              :quant (t2 / temporal-quantity :quant 15
                                    :unit m2)))
                  :op3 (d2 / decline-01
                        :ARG1 p
                        :time (a5 / after
                              :quant (u / up-to
                                    :op1 (t3 / temporal-quantity :quant 1
                                          :unit (h / hour))))
                        :mod (t4 / then))))
      :snt2 (d3 / demonstrate-01
            :ARG0 (t5 / thing
                  :ARG2-of (r2 / result-01)
                  :mod (t6 / this))
            :ARG1 (a6 / activate-01
                  :ARG0 (p4 / protein :name (n5 / name :op1 "IL-6"))
                  :ARG1 (s2 / signal-07
                        :ARG0 (p5 / protein :name (n6 / name :op1 "STAT3")))
                  :location (m4 / myocyte
                        :mod (v / ventricle)
                        :part-of (r3 / rat
                              :mod (a7 / adult))))))

# ::id bel_pmid_1259_5539.38542 ::date 2015-06-13T16:31:28 ::annotator SDL-AMR-09 ::preferred
# ::snt Fig. 1  Ashows that phosphorylation of STAT3 at Tyr705 was detected after 5 min of exposure to 10 ng/ml IL-6, reached a maximum at 15 min, and then declined within 1 h. These results demonstrate that IL-6 activates a STAT3 signaling in adult rat ventricular myocytes.
# ::save-date Mon Dec 21, 2015 ::file bel_pmid_1259_5539_38542.txt
(m / multi-sentence
      :snt1 (s / show-01
            :ARG0 (f / figure :mod "1A")
            :ARG1 (a / and
                  :op1 (d / detect-01
                        :ARG1 (p / phosphorylate-01
                              :ARG1 (a2 / amino-acid :mod 705 :name (n / name :op1 "tyrosine")
                                    :part-of (p2 / protein :name (n2 / name :op1 "STAT3"))))
                        :time (a3 / after
                              :op1 (e / expose-01
                                    :ARG2 (p3 / protein :name (n3 / name :op1 "IL-6")
                                          :quant (c / concentration-quantity :quant 10
                                                :unit (n4 / nanogram-per-milliliter)))
                                    :duration (t / temporal-quantity :quant 5
                                          :unit (m2 / minute)))))
                  :op2 (r / reach-01
                        :ARG0 p
                        :ARG1 (m3 / maximum)
                        :time (a4 / after
                              :op1 (t2 / temporal-quantity :quant 15
                                    :unit m2)))
                  :op3 (d2 / decline-01
                        :ARG1 p
                        :time (a5 / after
                              :op1 (u / up-to
                                    :op1 (t3 / temporal-quantity :quant 1
                                          :unit (h / hour))))
                        :mod (t4 / then))))
      :snt2 (d3 / demonstrate-01
            :ARG0 (t5 / thing
                  :ARG2-of (r2 / result-01)
                  :mod (t6 / this))
            :ARG1 (a6 / activate-01
                  :ARG0 (p4 / protein :name (n5 / name :op1 "IL-6"))
                  :ARG1 (s2 / signal-07
                        :ARG0 (p5 / protein :name (n6 / name :op1 "STAT3")))
                  :location (m4 / myocyte
                        :mod (v / ventricle)
                        :part-of (r3 / rat
                              :mod (a7 / adult))))))

# ::id bel_pmid_1260_4616.9184 ::date 2015-06-13T16:43:55 ::annotator SDL-AMR-09 ::preferred
# ::snt Overexpression of mSef in NIH3T3 cells results in a decrease in FGF-induced cell proliferation associated with a decrease in Tyr phosphorylation of FGFR1 and FRS2. As a consequence, there is a reduction in the phosphorylation of Raf-1 at Ser(338), MEK1/2 at Ser(217) and Ser(221), and ERK1/2 at Thr(202) and Tyr(204).
# ::save-date Sun Jan 17, 2016 ::file bel_pmid_1260_4616_9184.txt
(m / multi-sentence
      :snt1 (r / result-01
            :ARG1 (o / overexpress-01
                  :ARG1 (p / protein :name (n / name :op1 "Sef")
                        :part-of (m2 / mouse))
                  :location (c / cell-line :name (n2 / name :op1 "NIH3T3")))
            :ARG2 (a / associate-01
                  :ARG1 (d / decrease-01
                        :ARG1 (p2 / proliferate-01
                              :ARG0 (c2 / cell)
                              :ARG2-of (i / induce-01
                                    :ARG0 (p3 / protein :name (n3 / name :op1 "FGF")))))
                  :ARG2 (d2 / decrease-01
                        :ARG1 (p4 / phosphorylate-01
                              :ARG1 (a2 / and
                                    :op1 (a3 / amino-acid :name (n4 / name :op1 "tyrosine")
                                          :part-of (e4 / enzyme :name (n5 / name :op1 "FGFR1")))
                                    :op2 (a4 / amino-acid :name (n6 / name :op1 "tyrosine")
                                          :part-of (p6 / protein :name (n7 / name :op1 "FRS2"))))))))
      :snt2 (c3 / cause-01
            :ARG1 (r2 / reduce-01
                  :ARG1 (p7 / phosphorylate-01
                        :ARG1 (a5 / and
                              :op1 (a6 / amino-acid :mod 338 :name (n8 / name :op1 "serine")
                                    :part-of (e / enzyme :name (n9 / name :op1 "Raf-1")))
                              :op2 (a7 / amino-acid :mod 217 :name (n10 / name :op1 "serine")
                                    :part-of (e2 / enzyme :name (n11 / name :op1 "MEK1/2")))
                              :op3 (a8 / amino-acid :mod 221 :name (n12 / name :op1 "serine")
                                    :part-of e2)
                              :op4 (a9 / amino-acid :mod 202 :name (n13 / name :op1 "threonine")
                                    :part-of (e3 / enzyme :name (n14 / name :op1 "ERK1/2")))
                              :op5 (a10 / amino-acid :mod 204 :name (n15 / name :op1 "tyrosine")
                                    :part-of e3))))))

# ::id bel_pmid_1260_4616.26900 ::date 2015-06-14T06:27:27 ::annotator SDL-AMR-09 ::preferred
# ::snt These data indicate that adenovirus-mediated expression of mSef reduced FGF-induced tyrosine phosphorylation of FGFR without affecting the overall level of FGFR expression (Fig.4 A).
# ::save-date Wed Jun 17, 2015 ::file bel_pmid_1260_4616_26900.txt
(i / indicate-01
      :ARG0 (d / data
            :mod (t / this))
      :ARG1 (r / reduce-01
            :ARG0 (e / express-03
                  :ARG2 (p / protein :name (n / name :op1 "Sef")
                        :part-of (m / mouse))
                  :ARG1-of (m2 / mediate-01
                        :ARG0 (a / adenovirus)))
            :ARG1 (p2 / phosphorylate-01
                  :ARG1 (a2 / amino-acid :name (n2 / name :op1 "tyrosine")
                        :part-of (p3 / protein :name (n3 / name :op1 "FGFR")))
                  :ARG2-of (i2 / induce-01
                        :ARG0 (p4 / protein :name (n4 / name :op1 "FGF"))))
            :manner (a3 / affect-01 :polarity -
                  :ARG1 (l / level
                        :quant-of (e2 / express-03
                              :ARG2 p3)
                        :mod (o / overall))))
      :ARG1-of (d2 / describe-01
            :ARG0 (f / figure :mod "4A")))

# ::id bel_pmid_1260_4616.28060 ::date 2015-06-14T06:38:51 ::annotator SDL-AMR-09 ::preferred
# ::snt Adenovirus-mediated expression of mSef but not GFP resulted in a reduction in the levels of activated ERK1/2, whereas overall levels of ERK1/2 were unaffected (Fig. 2 A).
# ::save-date Wed Jun 17, 2015 ::file bel_pmid_1260_4616_28060.txt
(c / contrast-01
      :ARG1 (r / result-01
            :ARG1 (c2 / contrast-01
                  :ARG1 (e / express-03
                        :ARG2 (p / protein :name (n / name :op1 "Sef")
                              :part-of (m / mouse))
                        :ARG1-of (m2 / mediate-01
                              :ARG0 (a / adenovirus)))
                  :ARG2 (e2 / express-03 :polarity -
                        :ARG2 (p2 / protein :name (n2 / name :op1 "GFP"))
                        :ARG1-of m2))
            :ARG2 (r2 / reduce-01
                  :ARG1 (l / level
                        :quant-of (e3 / enzyme :name (n3 / name :op1 "ERK1/2")
                              :ARG1-of (a2 / activate-01)))))
      :ARG2 (a3 / affect-01 :polarity -
            :ARG1 (l2 / level
                  :quant-of (e4 / enzyme :name (n4 / name :op1 "ERK1/2"))
                  :mod (o / overall)))
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod "2A")))

# ::id bel_pmid_1261_2908.9036 ::date 2015-06-14T06:46:00 ::annotator SDL-AMR-09 ::preferred
# ::snt We found that liver from ICAM-1-deficient mice exhibited impaired regeneration after partial hepatectomy. This finding is associated with dramatic decrease in leukocyte recruitment and tissue TNF-alpha and IL-6 levels.
# ::save-date Sun Jan 3, 2016 ::file bel_pmid_1261_2908_9036.txt
(m / multi-sentence
      :snt1 (f / find-01
            :ARG0 (w / we)
            :ARG1 (e / exhibit-01
                  :ARG0 (l / liver
                        :source (m2 / mouse
                              :mod (p / protein :name (n / name :op1 "ICAM-1")
                                    :ARG2-of (m3 / mutate-01 :mod "-/-"))))
                  :ARG1 (r / regenerate-01
                        :ARG1-of (i / impair-01))
                  :time (a / after
                        :op1 (h / hepatectomy
                              :degree (p2 / part)))))
      :snt2 (a2 / associate-01
            :ARG1 (f2 / find-01
                  :mod (t / this))
            :ARG2 (d / decrease-01
                  :ARG1 (a3 / and
                        :op1 (r2 / recruit-01
                              :ARG1 (c / cell :name (n2 / name :op1 "leukocyte")))
                        :op2 (l2 / level
                              :quant-of (a4 / and
                                    :op1 (p3 / protein :name (n3 / name :op1 "TNF-α"))
                                    :op2 (p4 / protein :name (n4 / name :op1 "IL-6"))
                                    :mod (t2 / tissue))))
                  :degree (d2 / dramatic))))

# ::id bel_pmid_1261_8892.1630 ::date 2015-04-27T11:37:26 ::annotator SDL-AMR-09 ::preferred
# ::snt The treatment of NCI-N87 cells with EGF resulted in increases in phosphorylation of Erk1/2, Akt, and P38. Blockade of the Erk, phosphatidylinositol-3 kinase/Akt, or P38 pathways in this cell line
# ::save-date Sat May 2, 2015 ::file bel_pmid_1261_8892_1630.txt
(m / multi-sentence
      :snt1 (r / result-01
            :ARG1 (t / treat-04
                  :ARG1 (c / cell :name (n / name :op1 "NCI-N87"))
                  :ARG2 (p / protein :name (n2 / name :op1 "EGF")))
            :ARG2 (i / increase-01
                  :ARG0 t
                  :ARG1 (p2 / phosphorylate-01
                        :ARG1 (a / and
                              :op1 (e / enzyme :name (n3 / name :op1 "Erk1/2"))
                              :op2 (e2 / enzyme :name (n4 / name :op1 "Akt"))
                              :op3 (e3 / enzyme :name (n5 / name :op1 "P38"))))))
      :snt2 (b / blockade-01
            :ARG1 (o / or
                  :op1 (p3 / pathway :name (n6 / name :op1 "Erk"))
                  :op2 (p4 / pathway :name (n7 / name :op1 "phosphatidylinositol-3-kinase/Akt"))
                  :op3 (p5 / pathway :name (n8 / name :op1 "P38")))
            :location (c2 / cell-line
                  :mod (t2 / this))))

# ::id bel_pmid_1262_9177.8352 ::date 2015-04-28T03:44:03 ::annotator SDL-AMR-09 ::preferred
# ::snt ciliary neurotrophic factor, CNTF, activation of gp130 in NSCs rapidly increased Notch1 expression
# ::save-date Sat May 2, 2015 ::file bel_pmid_1262_9177_8352.txt
(i / increase-01
      :ARG0 (a / activate-01
            :ARG0 (p / protein :name (n / name :op1 "ciliary" :op2 "neurotrophic" :op3 "factor"))
            :ARG1 (p2 / protein :name (n2 / name :op1 "gp130"))
            :location (c / cell :name (n3 / name :op1 "NSC")))
      :ARG1 (e / express-03
            :ARG2 (p3 / protein :name (n4 / name :op1 "Notch1")))
      :manner (r / rapid))

# ::id bel_pmid_1262_9177.26086 ::date 2015-04-28T05:12:11 ::annotator SDL-AMR-09 ::preferred
# ::snt infusion of EGF and CNTF into adult forebrain lateral ventricles increased periventricular NOTCH1 compared with EGF alone
# ::save-date Tue Jun 23, 2015 ::file bel_pmid_1262_9177_26086.txt
(i / increase-01
      :ARG0 (i2 / infuse-01
            :ARG1 (a / and
                  :op1 (p / protein :name (n / name :op1 "EGF"))
                  :op2 (p2 / protein :name (n2 / name :op1 "CNTF")))
            :ARG2 (v / ventricle
                  :location (l / lateral)
                  :part-of (f / forebrain
                        :mod (a2 / adult))))
      :ARG1 (p3 / protein :name (n3 / name :op1 "NOTCH1")
            :location (p4 / periventricular))
      :compared-to (i3 / infuse-01
            :ARG1 p
            :ARG2 v))

# ::id bel_pmid_1262_9177.28408 ::date 2015-04-28T05:53:24 ::annotator SDL-AMR-09 ::preferred
# ::snt NOTCH1 activation, indicated by tumor necrosis factor alpha-converting enzyme, TACE [Adam17], and presenilin-mediated processing, also increased
# ::save-date Sat May 2, 2015 ::file bel_pmid_1262_9177_28408.txt
(i / increase-01
      :ARG1 (a / activate-01
            :ARG1 (p / protein :name (n / name :op1 "NOTCH1"))
            :ARG1-of (i2 / indicate-01
                  :ARG0 (a2 / and
                        :op1 (e / enzyme :name (n2 / name :op1 "tumor" :op2 "necrosis" :op3 "factor" :op4 "alpha-converting" :op5 "enzyme"))
                        :op2 (p2 / process-01
                              :ARG1-of (m / mediate-01
                                    :ARG0 (p3 / protein :name (n3 / name :op1 "presenilin")))))))
      :mod (a4 / also))

# ::id bel_pmid_1268_6512.15962 ::date 2015-04-28T07:07:22 ::annotator SDL-AMR-09 ::preferred
# ::snt We used a murine macrophage-like cell line, RAW264.7, to demonstrate that Janus kinase (JAK)2 is tyrosine phosphorylated immediately after LPS stimulation. Anti-Toll-like receptor (TLR)4 neutralization antibody inhibits the phosphorylation of JAK2 and the c-Jun NH2-terminal protein kinase (JNK).
# ::save-date Fri Feb 12, 2016 ::file bel_pmid_1268_6512_15962.txt
(m / multi-sentence
      :snt1 (u / use-01
            :ARG0 (w / we)
            :ARG1 (c / cell-line :name (n / name :op1 "RAW264.7")
                  :ARG1-of (r / resemble-01
                        :ARG2 (c2 / cell :name (n2 / name :op1 "macrophage")))
                  :part-of (o / organism :name (n3 / name :op1 "Muridae")))
            :ARG2 (d / demonstrate-01
                  :ARG0 w
                  :ARG1 (p / phosphorylate-01
                        :ARG1 (a / amino-acid :name (n4 / name :op1 "tyrosine")
                              :part-of (e / enzyme :name (n5 / name :op1 "Janus" :op2 "kinase" :op3 "2")))
                        :time (a2 / after
                              :op1 (s / stimulate-01
                                    :ARG0 (l / lipopolysaccharide)
                                    :ARG1 e)
                              :mod (i / immediate)))))
      :snt2 (i2 / inhibit-01
            :ARG0 (a3 / antibody
                  :ARG0-of (n7 / neutralize-01
                        :ARG1 (p2 / protein :name (n8 / name :op1 "Toll-like" :op2 "receptor" :op3 "4"))))
            :ARG1 (p3 / phosphorylate-01
                  :ARG1 (a4 / and
                        :op1 (e2 / enzyme :name (n9 / name :op1 "JAK2"))
                        :op2 (e3 / enzyme :name (n10 / name :op1 "c-Jun" :op2 "NH2-terminal" :op3 "protein" :op4 "kinase"))))))

# ::id bel_pmid_1268_7404.28336 ::date 2015-04-28T07:57:00 ::annotator SDL-AMR-09 ::preferred
# ::snt Il6 can elicit proinflammatory or anti-inflammatory effects, depending on the in vivo environmental circumstances
# ::save-date Tue Jun 16, 2015 ::file bel_pmid_1268_7404_28336.txt
(p / possible-01
      :ARG1 (e / elicit-01
            :ARG0 (p2 / protein :name (n / name :op1 "Il6"))
            :ARG1 (a / and
                  :op1 (a2 / affect-01
                        :ARG0-of (f / favor-01
                              :ARG1 (i / inflame-01)))
                  :op2 (a3 / affect-01
                        :ARG0-of (c / counter-01
                              :ARG1 i))))
      :ARG0-of (d / depend-01
            :ARG1 (c2 / circumstance
                  :manner (i2 / in-vivo)
                  :mod (e4 / environment))))

# ::id bel_pmid_1268_7404.38564 ::date 2015-04-28T08:21:02 ::annotator SDL-AMR-09 ::preferred
# ::snt Il6 promotes the growth arrest and differentiation of M1 cells through gp130-mediated Stat3 activation, whereas the Y759/SHP-2-mediated cascade by gp130 stimulation has growth-enhancing effects
# ::save-date Sun Jan 17, 2016 ::file bel_pmid_1268_7404_38564.txt
(c / contrast-01
      :ARG1 (p / promote-01
            :ARG0 (p2 / protein :name (n / name :op1 "Il6"))
            :ARG1 (a / and
                  :op1 (a2 / arrest-02
                        :ARG1 (g / grow-01
                              :ARG1 (c2 / cell :name (n2 / name :op1 "M1"))))
                  :op2 (d / differentiate-01
                        :ARG1 c2))
            :manner (a3 / activate-01
                  :ARG1 (p3 / protein :name (n3 / name :op1 "Stat3"))
                  :ARG1-of (m / mediate-01
                        :ARG0 (p4 / protein :name (n4 / name :op1 "gp130")))))
      :ARG2 (a5 / affect-01
            :ARG0 (c3 / cascade
                  :ARG1-of (m2 / mediate-01
                        :ARG0 (a4 / amino-acid :mod 759 :name (n5 / name :op1 "tyrosine")
                              :part-of (p5 / protein :name (n6 / name :op1 "SHP-2"))))
                  :ARG1-of (s / stimulate-01
                        :ARG0 p4))
            :ARG2 (e3 / enhance-01
                  :ARG0 c3
                  :ARG1 (g2 / grow-01))))

# ::id bel_pmid_1276_9686.36092 ::date 2015-04-28T12:26:18 ::annotator SDL-AMR-09 ::preferred
# ::snt Mutational inactivation of the MYCantagonist Mxi-1 in prostate carcinoma may be another mechanism of MYC activation [54]. Mxi-1 inactivation would presumably shift the equilibrium between Mxi-1/MAX and c-MYC/MAX in prostate cells towards c- MYC/MAX hetero-dimers, and therefore lead to elevated expression of c-MYC-target genes.
# ::save-date Wed Mar 2, 2016 ::file bel_pmid_1276_9686_36092.txt
(m / multi-sentence
      :snt1 (m2 / mechanism
            :ARG1-of (p / possible-01)
            :ARG0-of (a / activate-01
                  :ARG1 (p10 / protein :name (n / name :op1 "MYC")))
            :domain (a2 / activate-01 :polarity -
                  :ARG1 (p11 / protein :name (n2 / name :op1 "Mxi-1")
                        :ARG1-of (a3 / antagonize-02
                              :ARG2 p10))
                  :ARG1-of (m3 / mutate-01)
                  :location (m6 / medical-condition :name (n3 / name :op1 "carcinoma")
                        :location (p2 / prostate)))
            :mod (a4 / another)
            :ARG1-of (d2 / describe-01
                  :ARG0 (p3 / publication
                        :ARG1-of (c / cite-01
                              :ARG2 54))))
      :snt2 (a5 / and
            :op1 (s / shift-01
                  :ARG0 (a6 / activate-01 :polarity -
                        :ARG1 (p9 / protein :name (n4 / name :op1 "Mxi-1")))
                  :ARG1 (e / equilibrium
                        :mod (b / between
                              :op1 (m4 / macro-molecular-complex
                                    :part p9
                                    :part (p4 / protein :name (n5 / name :op1 "MAX")))
                              :op2 (m5 / macro-molecular-complex
                                    :part (p8 / protein :name (n6 / name :op1 "c-MYC"))
                                    :part p4)))
                  :ARG2 (h / heterodimer
                        :mod m5)
                  :location (c2 / cell
                        :part-of (p5 / prostate))
                  :ARG1-of (p6 / presume-01))
            :op2 (c3 / cause-01
                  :ARG0 s
                  :ARG1 (l / lead-03
                        :ARG2 (e2 / express-03
                              :ARG1 (p7 / protein :name (n7 / name :op1 "c-MYC")
                                    :ARG1-of (t / target-01))
                              :ARG1-of (e3 / elevate-01))))))

# ::id bel_pmid_1276_9686.37908 ::date 2015-04-28T14:08:29 ::annotator SDL-AMR-09 ::preferred
# ::snt The encoded protein (CDKN1A) binds to and inhibits the activity of cyclin-CDK2 or -CDK4 complexes
# ::save-date Mon Jul 6, 2015 ::file bel_pmid_1276_9686_37908.txt
(a / and
      :op1 (b / bind-01
            :ARG1 (p / protein
                  :ARG1-of (e / encode-01
                        :ARG0 (g / gene :name (n / name :op1 "CDKN1A"))))
            :ARG2 (o / or
                  :op1 (m / macro-molecular-complex
                        :part (p2 / protein :name (n2 / name :op1 "cyclin"))
                        :part (e2 / enzyme :name (n3 / name :op1 "CDK2")))
                  :op2 (m2 / macro-molecular-complex
                        :part p2
                        :part (e3 / enzyme :name (n4 / name :op1 "CDK4")))))
      :op2 (i / inhibit-01
            :ARG0 p
            :ARG1 (a2 / activity-06
                  :ARG0 o)))

# ::id bel_pmid_1276_9686.37918 ::date 2015-04-28T14:29:04 ::annotator SDL-AMR-09 ::preferred
# ::snt The encoded protein binds to and prevents the activation of cyclin E-CDK2 or cyclin D-CDK4 complexes
# ::save-date Tue Apr 28, 2015 ::file bel_pmid_1276_9686_37918.txt
(a / and
      :op1 (b / bind-01
            :ARG1 (p / protein
                  :ARG1-of (e / encode-01))
            :ARG2 (o / or
                  :op1 (m / macro-molecular-complex
                        :part (p2 / protein :name (n / name :op1 "cyclin" :op2 "E"))
                        :part (e2 / enzyme :name (n2 / name :op1 "CDK2")))
                  :op2 (m2 / macro-molecular-complex
                        :part (p3 / protein :name (n3 / name :op1 "cyclin" :op2 "D"))
                        :part (e3 / enzyme :name (n4 / name :op1 "CDK4")))))
      :op2 (p4 / prevent-01
            :ARG0 p
            :ARG1 (a2 / activate-01
                  :ARG1 o)))

# ::id bel_pmid_1281_2976.37028 ::date 2015-04-28T14:42:22 ::annotator SDL-AMR-09 ::preferred
# ::snt In many cells PKA inhibits the extracellular receptor kinase (ERK1/2) cascade of the mitogen-activated protein kinase (MAPK) pathway leading to inhibition of cell proliferation.
# ::save-date Sat May 2, 2015 ::file bel_pmid_1281_2976_37028.txt
(i / inhibit-01
      :ARG0 (e / enzyme :name (n / name :op1 "PKA"))
      :ARG1 (c / cascade
            :mod (e2 / enzyme :name (n2 / name :op1 "extracellular" :op2 "receptor" :op3 "kinase"))
            :poss (p / pathway :name (n3 / name :op1 "mitogen-activated" :op2 "protein" :op3 "kinase")))
      :location (c2 / cell
            :quant (m / many))
      :ARG0-of (l / lead-03
            :ARG2 (i2 / inhibit-01
                  :ARG1 (p2 / proliferate-01
                        :ARG0 (c3 / cell)))))

# ::id bel_pmid_1288_1425.6346 ::date 2015-04-28T14:55:56 ::annotator SDL-AMR-09 ::preferred
# ::snt Here we demonstrate that Ser311 accounts for zetaPKC phosphorylation of RelA and that this site is phosphorylated in vivo in response to TNF-alpha.
# ::save-date Sat May 2, 2015 ::file bel_pmid_1288_1425_6346.txt
(d / demonstrate-01
      :ARG0 (w / we)
      :ARG1 (a / and
            :op1 (a2 / account-01
                  :ARG0 (a3 / amino-acid :mod 311 :name (n / name :op1 "serine"))
                  :ARG1 (p / phosphorylate-01
                        :ARG1 (p2 / protein :name (n2 / name :op1 "RelA"))
                        :ARG2 (e / enzyme :name (n3 / name :op1 "zetaPKC"))))
            :op2 (p3 / phosphorylate-01
                  :ARG1 (p4 / protein-segment
                        :mod (t / this))
                  :manner (i / in-vivo)
                  :ARG2-of (r / respond-01
                        :ARG1 (p5 / protein :name (n4 / name :op1 "TNF-alpha")))))
      :location (h / here))

# ::id bel_pmid_1288_1425.9992 ::date 2015-04-28T15:29:15 ::annotator SDL-AMR-09 ::preferred
# ::snt Also, an inactivating mutation of that residue severely impairs RelA transcriptional activity, blocks its anti-apoptotic function and abrogates the interaction of RelA with the co-activator CBP as well as its recruitment, and that of RNA polymerase II (Pol II) with the interleukin-6 (IL-6) promoter.
# ::save-date Tue Feb 2, 2016 ::file bel_pmid_1288_1425_9992.txt
(a2 / and
      :op1 (i / impair-01
            :ARG0 (m / mutate-01
                  :ARG1 (r / residue
                        :mod (t / that))
                  :ARG1-of (a3 / activate-01 :polarity -))
            :ARG1 (a4 / activity-06
                  :ARG0 (p / protein :name (n / name :op1 "RelA"))
                  :ARG1 (t2 / transcribe-01)))
      :op2 (b / block-01
            :ARG0 m
            :ARG1 (f / function-01
                  :ARG0 r
                  :ARG1 (o / oppose-01
                        :ARG1 (a5 / apoptosis))))
      :op3 (a6 / abrogate-01
            :ARG0 m
            :ARG1 (a7 / and
                  :op1 (i2 / interact-01
                        :ARG0 p
                        :ARG1 (a8 / and
                              :op1 (p2 / protein :name (n2 / name :op1 "CBP")
                                    :ARG0-of (c / coactivate-01))
                              :op2 (r2 / recruit-01
                                    :ARG0 p2)))
                  :op2 (i3 / interact-01
                        :ARG0 (e / enzyme :name (n3 / name :op1 "RNA" :op2 "polymerase" :op3 "II"))
                        :ARG1 (m2 / molecular-physical-entity
                              :ARG0-of (p3 / promote-01
                                    :ARG1 (p4 / protein :name (n4 / name :op1 "interleukin-6")))))))
      :manner (s / severe)
      :mod (a9 / also))

# ::id bel_pmid_1292_3167.9944 ::date 2015-04-28T16:21:04 ::annotator SDL-AMR-09 ::preferred
# ::snt Immunoblot analyses confirm that Tyr-542 and Tyr-580 are the major sites of Shp2 tyrosyl phosphorylation and that Tyr-542 is the major Grb2 binding site.
# ::save-date Sun Jan 3, 2016 ::file bel_pmid_1292_3167_9944.txt
(c / confirm-01
      :ARG0 (a / analyze-01
            :manner (i / immunoblot-01))
      :ARG1 (a2 / and
            :op1 (p / protein-segment
                  :domain (a3 / and
                        :op1 (a4 / amino-acid :mod 542 :name (n / name :op1 "tyrosine"))
                        :op2 (a5 / amino-acid :mod 580 :name (n2 / name :op1 "tyrosine")))
                  :ARG1-of (m / major-02)
                  :location-of (p2 / phosphorylate-01
                        :ARG1 (a6 / amino-acid :name (n3 / name :op1 "tyrosine")
                              :part-of (e / enzyme :name (n4 / name :op1 "Shp2")))))
            :op2 (p3 / protein-segment
                  :domain a4
                  :ARG1-of m
                  :ARG1-of (b / bind-01)
                  :part-of (p4 / protein :name (n5 / name :op1 "Grb2")))))

# ::id bel_pmid_1292_3167.29880 ::date 2015-04-28T16:44:44 ::annotator SDL-AMR-09 ::preferred
# ::snt Y542F-expressing cells exhibited an ?50% decrease in Tyr-580 phosphorylation (Fig. 3C, right panel).
# ::save-date Sat May 2, 2015 ::file bel_pmid_1292_3167_29880.txt
(e / exhibit-01
      :ARG0 (c / cell
            :ARG3-of (e2 / express-03
                  :ARG2 (a / amino-acid
                        :ARG2-of (m / mutate-01 :value "Y542F"))))
      :ARG1 (d / decrease-01
            :ARG1 (p / phosphorylate-01
                  :ARG1 (a2 / amino-acid :mod 580 :name (n / name :op1 "tyrosine")))
            :quant (a3 / approximately
                  :op1 (p2 / percentage-entity :value 50)))
      :ARG1-of (d2 / describe-01
            :ARG0 (a4 / and
                  :op1 (f / figure :mod "3C"
                        :part (p3 / panel
                              :ARG1-of (r / right-04))))))

# ::id bel_pmid_1293_4012.314 ::date 2015-04-28T16:59:56 ::annotator SDL-AMR-09 ::preferred
# ::snt Therefore, the cell cycle progression from S to M phase was impaired during liver regeneration in Cry-deficient mice
# ::save-date Sun Jan 3, 2016 ::file bel_pmid_1293_4012_314.txt
(c / cause-01
      :ARG1 (i / impair-01
            :ARG1 (p / progress-01
                  :ARG1 (c2 / cycle-02
                        :ARG1 (c3 / cell))
                  :ARG3 (e / event :name (n / name :op1 "S" :op2 "phase"))
                  :ARG4 (e2 / event :name (n2 / name :op1 "M" :op2 "phase")))
            :time (r / regenerate-01
                  :ARG1 (l / liver)
                  :location (m / mouse
                        :mod (p2 / protein :name (n3 / name :op1 "Cry")
                              :ARG2-of (m2 / mutate-01 :mod "-/-"))))))

# ::id bel_pmid_1293_4012.20242 ::date 2015-04-28T17:14:59 ::annotator SDL-AMR-09 ::preferred
# ::snt from full text - Three E-box elements were found within 1.2 kb of the mouse wee1 gene 5-upstream region (Fig. 3B). CLOCK and BMAL1 together, but neither of them alone, produced a major increase in transcriptional activity through this fragment in transfected NIH3T3 cells
# ::save-date Sun Jan 17, 2016 ::file bel_pmid_1293_4012_20242.txt
(m / multi-sentence
      :snt1 (f / find-01
            :ARG1 (e / element :quant 3
                  :mod (d / dna-sequence :name (n / name :op1 "E-box")))
            :location (r / region
                  :direction (u / upstream :mod 5)
                  :location (g / gene :name (n2 / name :op1 "wee1")
                        :part-of (m2 / mouse)
                        :quant (d2 / distance-quantity :quant 1.2
                              :unit (k / kilo-base-pair))))
            :ARG1-of (d3 / describe-01
                  :ARG0 (f2 / figure :mod "3B")))
      :snt2 (p / produce-01
            :ARG0 (c / contrast-01
                  :ARG1 (a / and
                        :op1 (g2 / gene :name (n3 / name :op1 "CLOCK"))
                        :op2 (g3 / gene :name (n4 / name :op1 "BMAL1"))
                        :mod (t / together))
                  :ARG2 (o / or
                        :op1 g2
                        :op2 g3
                        :mod (a2 / alone)))
            :ARG1 (i / increase-01
                  :ARG1 (a3 / activity-06
                        :ARG0 a
                        :ARG1 (t2 / transcribe-01))
                  :medium (f3 / fragment
                        :mod (t3 / this))
                  :location (c2 / cell-line :name (n5 / name :op1 "NIH3T3")
                        :ARG1-of (t4 / transfect-01))
                  :ARG1-of (m3 / major-02)))
      :source (t5 / text
            :ARG1-of (f4 / full-09)))

# ::id bel_pmid_1293_4012.22244 ::date 2015-04-29T03:31:21 ::annotator SDL-AMR-09 ::preferred
# ::snt from full text - The wee1 gene product phosphorylates Cdc2 on Tyr-15 [p-Cdc2(Tyr 15)] and keeps it in an inactive form
# ::save-date Mon Dec 21, 2015 ::file bel_pmid_1293_4012_22244.txt
(a / and
      :op1 (p / phosphorylate-01
            :ARG1 (a2 / amino-acid :mod 15 :name (n / name :op1 "tyrosine")
                  :part-of (e / enzyme :name (n2 / name :op1 "Cdc2")))
            :ARG2 (p2 / product
                  :poss (g / gene :name (n3 / name :op1 "wee1"))))
      :op2 (k / keep-01
            :ARG0 p2
            :ARG1 (a4 / amino-acid :mod 15 :name (n5 / name :op1 "tyrosine")
                  :part-of e
                  :ARG3-of (p3 / phosphorylate-01)
                  :mod (f / form
                        :ARG1-of (a3 / activate-01 :polarity -))))
      :source (t / text
            :ARG1-of (f2 / full-09)))

# ::id bel_pmid_1293_4012.26132 ::date 2015-04-29T04:38:56 ::annotator SDL-AMR-09 ::preferred
# ::snt from full text - Furthermore, Cdc2 kinase activity was reduced (Figs. 2B and 1C). Therefore, the cell cycle progression from S to M phase was impaired during liver regeneration in Cry-deficient mice
# ::save-date Sun Jan 3, 2016 ::file bel_pmid_1293_4012_26132.txt
(m / multi-sentence
      :snt1 (a / and
            :op2 (r / reduce-01
                  :ARG1 (a2 / activity-06
                        :ARG1 (k / kinase :name (n / name :op1 "Cdc2"))))
            :ARG1-of (d / describe-01
                  :ARG0 (a3 / and
                        :op1 (f / figure :mod "2B")
                        :op2 (f2 / figure :mod "1C"))))
      :snt2 (c / cause-01
            :ARG1 (i / impair-01
                  :ARG1 (p / progress-01
                        :ARG1 (c2 / cycle-02
                              :ARG1 (c3 / cell))
                        :ARG3 (e / event :name (n2 / name :op1 "S" :op2 "phase"))
                        :ARG4 (e2 / event :name (n3 / name :op1 "M" :op2 "phase")))
                  :time (r2 / regenerate-01
                        :ARG1 (l / liver)
                        :location (m2 / mouse
                              :mod (p2 / protein :name (n4 / name :op1 "Cry")
                                    :ARG2-of (m3 / mutate-01 :mod "-/-"))))))
      :source (t3 / text
            :ARG1-of (f3 / full-09)))

# ::id bel_pmid_1293_4012.26134 ::date 2015-04-29T05:11:30 ::annotator SDL-AMR-09 ::preferred
# ::snt from full text - The expression profiles of cyclin D1 and wee1 transcripts were markedly different between Cry-deficient and wildtype mice throughout the liver regeneration process: cyclin D1 expression decreased up to 86% and wee1 expression increased up to 4.6-fold
# ::save-date Mon Dec 21, 2015 ::file bel_pmid_1293_4012_26134.txt
(d / differ-02
      :ARG1 (p / profile-01
            :ARG1 (p2 / protein :name (n / name :op1 "cyclin" :op2 "D1")
                  :ARG1-of (t / transcribe-01)))
      :ARG2 (p3 / profile-01
            :ARG1 (p4 / protein :name (n2 / name :op1 "wee1")
                  :ARG1-of t))
      :degree (e / express-03
            :ARG2 (a / and
                  :op1 p2
                  :op2 p4))
      :degree (m / marked)
      :location (b / between
            :op1 (m2 / mouse
                  :mod (p5 / protein :name (n3 / name :op1 "Cry")
                        :ARG2-of (m3 / mutate-01 :mod "-/-")))
            :op2 (m4 / mouse
                  :mod (w / wild-type)))
      :time (p6 / process-02
            :ARG1 (r / regenerate-01
                  :ARG1 (l / liver)))
      :ARG1-of (m5 / mean-01
            :ARG2 (a2 / and
                  :op1 (d2 / decrease-01
                        :ARG1 (e2 / express-03
                              :ARG1 p2)
                        :ARG2 (u / up-to
                              :op1 (p7 / percentage-entity :value 86)))
                  :op2 (i / increase-01
                        :ARG1 (e3 / express-03
                              :ARG1 p4)
                        :ARG2 (u2 / up-to
                              :op1 (p8 / product-of :op1 4.6)))))
      :source (t2 / text
            :ARG1-of (f / full-09)))

# ::id bel_pmid_1293_4012.32782 ::date 2015-04-29T06:50:16 ::annotator SDL-AMR-09 ::preferred
# ::snt from full text - However, in Clock mutant (Clock/Clock) mice (26), which carry dominantnegative Clock mutations (27), wee1 expression was low at both ZTs
# ::save-date Sun Jan 3, 2016 ::file bel_pmid_1293_4012_32782.txt
(h / have-concession-91
      :ARG1 (l / low-04
            :ARG1 (e / express-03
                  :ARG2 (p / protein :name (n / name :op1 "wee1")))
            :time (z / zeitgeber-time
                  :mod (b / both))
            :location (m / mouse
                  :mod (g / gene :name (n2 / name :op1 "Clock")
                        :mod (w / wild-type))
                  :ARG1-of (d / describe-01
                        :ARG0 (p2 / publication
                              :ARG1-of (c / cite-01
                                    :ARG2 26)))
                  :ARG0-of (c2 / carry-01
                        :ARG1 (g2 / gene :name (n3 / name :op1 "Clock")
                              :ARG2-of (m3 / mutate-01 :mod "-/-"))
                        :ARG1-of (d2 / describe-01
                              :ARG0 (p3 / publication
                                    :ARG1-of (c3 / cite-01
                                          :ARG2 27))))))
      :source (t / text
            :ARG1-of (f / full-09)))

# ::id bel_pmid_1295_7325.25184 ::date 2015-04-29T07:11:28 ::annotator SDL-AMR-09 ::preferred
# ::snt Studies crossing PPAR-–deficient mice with apolipoprotein E atherosclerosis-prone mice and placing them on high-fat diets found less atherosclerosis, despite the PPAR- null mice having higher atherogenic lipids.101
# ::save-date Sun Jul 26, 2015 ::file bel_pmid_1295_7325_25184.txt
(f / find-01
      :ARG0 (s / study-01
            :ARG0-of (c / cross-01
                  :ARG1 (a / and
                        :op1 (m / mouse
                              :mod (p / protein :name (n / name :op1 "PPAR")
                                    :ARG2-of (m2 / mutate-01 :mod "-/-")))
                        :op2 (m3 / mouse
                              :ARG1-of (p2 / prone-01
                                    :ARG2 (d / disease :name (n2 / name :op1 "atherosclerosis")))
                              :mod (p3 / protein :name (n3 / name :op1 "apolipoprotein" :op2 "E")))))
            :ARG0-of (p4 / place-01
                  :ARG1 a
                  :ARG2 (d2 / diet
                        :instrument (f2 / fat
                              :ARG1-of (h / high-02)))))
      :ARG1 (d3 / disease :name (n4 / name :op1 "atherosclerosis")
            :quant (l / less))
      :concession (h3 / have-03
                  :ARG0 m
                  :ARG1 (l2 / lipid
                        :mod (a2 / atherogenic)
                        :ARG1-of (h4 / high-02
                              :degree (m4 / more))))
      :ARG1-of (d4 / describe-01
            :ARG0 (p5 / publication
                  :ARG1-of (c2 / cite-01
                        :ARG2 101))))

# ::id bel_pmid_1295_7325.30032 ::date 2015-04-29T07:44:00 ::annotator SDL-AMR-09 ::preferred
# ::snt These investigators went on to demonstrate that interleukin-6 production is increased in aortic explants of PPAR-–deficient mice.95
# ::save-date Thu Jun 18, 2015 ::file bel_pmid_1295_7325_30032.txt
(g / go-on-15
      :ARG1 (p / person
            :ARG0-of (i / investigate-01)
            :mod (t / this))
      :purpose (d / demonstrate-01
            :ARG0 p
            :ARG1 (i2 / increase-01
                  :ARG1 (p2 / produce-01
                        :ARG1 (p3 / protein :name (n / name :op1 "interleukin-6")))
                  :location (e / explant
                        :part-of (a / aorta
                              :part-of (m / mouse
                                    :mod (p4 / protein :name (n2 / name :op1 "PPAR")
                                          :ARG2-of (m2 / mutate-01 :mod "-/-")))))))
      :ARG1-of (d2 / describe-01
            :ARG0 (p5 / publication
                  :ARG1-of (c / cite-01
                        :ARG2 95))))

# ::id bel_pmid_1463_5034.19774 ::date 2015-04-29T07:59:03 ::annotator SDL-AMR-09 ::preferred
# ::snt As demonstrated in Fig. 3A, blockade of the OX40/OX40L interaction significantly reduced the Th1-specific transcription factor T-bet to 30.8% compared with controls (p=0.007). On the other hand, expression of IL-10, a cytokine that was shown to be protective in chronic DSS-induced colitis [29], increased 3.6-fold (p=0.008).
# ::save-date Fri Feb 12, 2016 ::file bel_pmid_1463_5034_19774.txt
(m / multi-sentence
      :snt1 (r / reduce-01
            :ARG0 (b / blockade-01
                  :ARG1 (i / interact-01
                        :ARG0 (p8 / protein :name (n / name :op1 "OX40"))
                        :ARG1 (p9 / protein :name (n2 / name :op1 "OX40L"))))
            :ARG1 (p2 / protein :name (n3 / name :op1 "T-bet")
                  :ARG0-of (t / transcribe-01)
                  :ARG1-of (s / specific-02
                        :ARG2 (p7 / protein :name (n4 / name :op1 "Th1"))))
            :ARG2 (s2 / significant-02)
            :ARG4 (p / percentage-entity :value 30.8)
            :ARG1-of (c2 / compare-01
                  :ARG2 (c3 / control-01))
            :ARG1-of (d / demonstrate-01
                  :ARG0 (f2 / figure :mod "3A"))
            :ARG1-of (s4 / statistical-test-91
                  :ARG2 0.007))
      :snt2 (c4 / contrast-01
            :ARG2 (i2 / increase-01
                  :ARG1 (e / express-03
                        :ARG2 (p3 / protein :name (n5 / name :op1 "IL-10")
                              :ARG1-of (m4 / mean-01
                                    :ARG2 (c5 / cytokine
                                          :ARG0-of (p4 / protect-01
                                                :ARG1-of (s3 / show-01)
                                                :location (d2 / disease :name (n6 / name :op1 "colitis")
                                                      :mod (c6 / chronic)
                                                      :ARG2-of (i3 / induce-01
                                                            :ARG0 (s6 / small-molecule :name (n7 / name :op1 "DSS"))))))
                                    :ARG1-of (d3 / describe-01
                                          :ARG0 (p5 / publication
                                                :ARG1-of (c7 / cite-01
                                                      :ARG2 29))))))
                  :ARG2 (p6 / product-of :op1 3.6)
                  :ARG1-of (s5 / statistical-test-91
                        :ARG2 0.008))))

# ::id bel_pmid_1463_5034.19776 ::date 2015-04-29T09:15:18 ::annotator SDL-AMR-09 ::preferred
# ::snt IL- 10 secretion increased 20-fold (p X 0.0001). This was accompanied by a significant, 18-fold, increase of IL-5 secretion. IFNG levels were not altered, but IL-6 secretion was reduced to 60% compared with controls.
# ::save-date Sat Jan 2, 2016 ::file bel_pmid_1463_5034_19776.txt
(m / multi-sentence
      :snt1 (i / increase-01
            :ARG1 (s / secrete-01
                  :ARG1 (p / protein :name (n / name :op1 "IL-10")))
            :ARG2 (p2 / product-of :op1 20)
            :ARG1-of (s5 / statistical-test-91
                  :ARG2 (l / less-than :op1 0.0001)))
      :snt2 (a / accompany-01
            :ARG0 (i2 / increase-01
                  :ARG1 (s2 / secrete-01
                        :ARG1 (p4 / protein :name (n2 / name :op1 "IL-5")))
                  :ARG2 (p5 / product-of :op1 18)
                  :ARG1-of (s3 / significant-02))
            :ARG1 (t / this))
      :snt3 (c / contrast-01
            :ARG1 (r / reduce-01
                  :ARG1 (s4 / secrete-01
                        :ARG1 (p6 / protein :name (n3 / name :op1 "IL-6")))
                  :ARG4 (p7 / percentage-entity :value 60)
                  :ARG1-of (c2 / compare-01
                        :ARG2 (c3 / control-01)))
            :ARG2 (a2 / alter-01 :polarity -
                  :ARG1 (l2 / level
                        :quant-of (p8 / protein :name (n4 / name :op1 "IFN-γ"))))))

# ::id bel_pmid_1465_6721.15754 ::date 2015-04-29T09:38:46 ::annotator SDL-AMR-09 ::preferred
# ::snt In neutrophils challenged with LPS, IkB-a underwent time-dependent degradation (Fig. 8C). However, in neutrophils incubated with both LPS and H2O2, no degradation of IkB-a was apparent.
# ::save-date Fri Feb 12, 2016 ::file bel_pmid_1465_6721_15754.txt
(m / multi-sentence
      :snt1 (u / undergo-28
            :ARG1 (p / protein :name (n / name :op1 "IκB-α"))
            :ARG2 (d / degrade-01
                  :ARG1 p
                  :ARG0-of (d2 / depend-01
                        :ARG1 (t / time)))
            :location (c / cell :name (n2 / name :op1 "neutrophil")
                  :ARG1-of (c2 / challenge-01
                        :ARG0 (l / lipopolysaccharide)))
            :ARG1-of (d3 / describe-01
                  :ARG0 (f / figure :mod "8C")))
      :snt2 (h / have-concession-91
            :ARG1 (a / appear-02 :polarity -
                  :ARG1 (d4 / degrade-01
                        :ARG1 (p2 / protein :name (n4 / name :op1 "IκB-α")))
                  :location (c3 / cell :name (n5 / name :op1 "neutrophil")
                        :ARG1-of (i / incubate-01
                              :ARG2 (a2 / and
                                    :op1 (l2 / lipopolysaccharide)
                                    :op2 (s / small-molecule :name (n7 / name :op1 "H2O2"))))))))

# ::id bel_pmid_1465_6721.15758 ::date 2015-04-29T11:45:21 ::annotator SDL-AMR-09 ::preferred
# ::snt neutrophils stimulated with LPS demonstrated increased TNF-a secretion (Fig. 6A). The response was significantly attenuated by concurrent incubation of neutrophils with H2O2.
# ::save-date Fri Dec 18, 2015 ::file bel_pmid_1465_6721_15758.txt
(m / multi-sentence
      :snt1 (d / demonstrate-01
            :ARG0 (c / cell :name (n / name :op1 "neutrophil")
                  :ARG1-of (s / stimulate-01
                        :ARG2 (m2 / molecular-physical-entity :name (n2 / name :op1 "LPS"))))
            :ARG1 (s2 / secrete-01
                  :ARG1 (p / protein :name (n3 / name :op1 "TNF-α"))
                  :ARG1-of (i / increase-01))
            :ARG1-of (d2 / describe-01
                  :ARG0 (f / figure :mod "6A")))
      :snt2 (a / attenuate-01
            :ARG0 (i2 / incubate-01
                  :ARG1 (c2 / cell :name (n4 / name :op1 "neutrophil"))
                  :ARG2 (s4 / small-molecule :name (n5 / name :op1 "H2O2")
                        :ARG1-of (c3 / concurrent-02)))
            :ARG1 (t / thing
                  :ARG2-of (r / respond-01))
            :ARG1-of (s3 / significant-02)))

# ::id bel_pmid_1465_6721.15794 ::date 2015-04-29T11:59:04 ::annotator SDL-AMR-09 ::preferred
# ::snt As was the case for p38, ERK1/2 was both rapidly and persistently activated in neutrophils exposed to H2O2 (Fig. 2A).
# ::save-date Wed Oct 28, 2015 ::file bel_pmid_1465_6721_15794.txt
(a / activate-01
      :ARG1 (e / enzyme :name (n / name :op1 "ERK1/2"))
      :location (c / cell :name (n2 / name :op1 "neutrophil")
            :ARG1-of (e2 / expose-01
                  :ARG2 (s / small-molecule :name (n3 / name :op1 "H2O2"))))
      :manner (a2 / and
            :op1 (r / rapid)
            :op2 (p / persistent))
      :ARG1-of (r2 / resemble-01
            :ARG2 (e3 / enzyme :name (n4 / name :op1 "p38")))
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod "2A")))

# ::id bel_pmid_1465_6721.15796 ::date 2015-04-29T12:10:44 ::annotator SDL-AMR-09 ::preferred
# ::snt Similar to the patterns seen with ERK1/2 and p38, JNK activation in neutrophils exposed to H2O2 was both rapid and persistent (Fig. 2B).
# ::save-date Wed Oct 28, 2015 ::file bel_pmid_1465_6721_15796.txt
(a / and
      :op1 (r / rapid)
      :op2 (p / persistent)
      :domain (a2 / activate-01
            :ARG1 (e / enzyme :name (n / name :op1 "JNK"))
            :location (c / cell :name (n2 / name :op1 "neutrophil")
                  :ARG1-of (e2 / expose-01
                        :ARG2 (s2 / small-molecule :name (n3 / name :op1 "H2O2")))))
      :ARG1-of (r2 / resemble-01
            :ARG2 (p2 / pattern
                  :ARG1-of (s / see-01)
                  :poss (a3 / and
                        :op1 (e3 / enzyme :name (n4 / name :op1 "ERK1/2"))
                        :op2 (e4 / enzyme :name (n5 / name :op1 "p38")))))
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod "2B")))

# ::id bel_pmid_1465_6721.15930 ::date 2015-04-29T12:36:46 ::annotator SDL-AMR-09 ::preferred
# ::snt whereas exposure of neutrophils to LPS or TNF-a resulted in increased levels of the transcriptionally active serine 133-phosphorylated form of CREB
# ::save-date Mon Jul 20, 2015 ::file bel_pmid_1465_6721_15930.txt
(c / contrast-01
      :ARG2 (r / result-01
            :ARG1 (e / expose-01
                  :ARG1 (c2 / cell :name (n / name :op1 "neutrophil"))
                  :ARG2 (o / or
                        :op1 (m / molecular-physical-entity :name (n2 / name :op1 "LPS"))
                        :op2 (p / protein :name (n3 / name :op1 "TNF-α"))))
            :ARG2 (l / level
                  :ARG1-of (i / increase-01)
                  :quant-of (p2 / protein :name (n4 / name :op1 "CREB")
                        :part (a / amino-acid :mod 133 :name (n5 / name :op1 "serine"))
                        :ARG1-of (p3 / phosphorylate-01)
                        :ARG0-of (a2 / activity-06
                              :manner (t / transcribe-01))))))

# ::id bel_pmid_1465_6721.15966 ::date 2015-04-29T13:03:52 ::annotator SDL-AMR-09 ::preferred
# ::snt Exposure of neutrophils to LPS resulted in persistence of p38 activation that was similar to that produced by H2O2, but the increase in phosphorylated p38 was less rapid, rising above baseline values more than 5 min after LPS was added to the neutrophils.
# ::save-date Sun Jan 3, 2016 ::file bel_pmid_1465_6721_15966.txt
(c / contrast-01
      :ARG1 (r / result-01
            :ARG1 (e / expose-01
                  :ARG1 (c2 / cell :name (n / name :op1 "neutrophil"))
                  :ARG2 (m / molecular-physical-entity :name (n2 / name :op1 "LPS")))
            :ARG2 (p / persist-01
                  :ARG1 (a / activate-01
                        :ARG1 (e2 / enzyme :name (n3 / name :op1 "p38")))
                  :ARG1-of (r2 / resemble-01
                        :ARG2 (p2 / produce-01
                              :ARG0 (s / small-molecule :name (n4 / name :op1 "H2O2"))
                              :ARG1 p))))
      :ARG2 (r3 / rapid
            :degree (l / less)
            :domain (i / increase-01
                  :ARG1 (e3 / enzyme :name (n5 / name :op1 "p38")
                        :ARG1-of (r4 / rise-01
                              :ARG4 (a2 / above
                                    :op1 (v / value
                                          :mod (b / baseline)))
                              :time (a3 / after
                                    :op1 (a4 / add-02
                                          :ARG1 m
                                          :ARG2 c2)
                                    :op1 (m2 / more-than
                                          :op1 (t / temporal-quantity :quant 5
                                                :unit (m3 / minute)))))
                        :ARG3-of (p3 / phosphorylate-01)))))

# ::id bel_pmid_1465_6721.15968 ::date 2015-04-29T14:02:07 ::annotator SDL-AMR-09 ::preferred
# ::snt Phosphorylation of ERK1/2 after exposure of neutrophils with LPS was only apparent after 20-min incubation and was less intense than that produced by stimulation of neutrophils with H2O2.
# ::save-date Wed Oct 28, 2015 ::file bel_pmid_1465_6721_15968.txt
(a / and
      :op1 (a2 / appear-02
            :ARG1 (p / phosphorylate-01
                  :ARG1 (e / enzyme :name (n / name :op1 "ERK1/2"))
                  :time (a3 / after
                        :op1 (e2 / expose-01
                              :ARG1 (c / cell :name (n2 / name :op1 "neutrophil"))
                              :ARG2 (m / molecular-physical-entity :name (n3 / name :op1 "LPS")))))
            :mod (o / only)
            :time (a4 / after
                  :op1 (i / incubate-01
                        :duration (t / temporal-quantity :quant 20
                              :unit (m2 / minute)))))
      :op2 (i2 / intense-02
            :ARG1 p
            :degree (l / less)
            :compared-to (p2 / phosphorylate-01
                  :ARG1 e
                  :ARG1-of (p3 / produce-01
                        :ARG0 (s / stimulate-01
                              :ARG1 c
                              :ARG2 (s2 / small-molecule :name (n4 / name :op1 "H2O2")))))))

# ::id bel_pmid_1465_6721.15970 ::date 2015-04-29T14:28:20 ::annotator SDL-AMR-09 ::preferred
# ::snt JNK activation induced by LPS only became apparent 20 min after LPS was added to the cells and was of a lesser degree than that induced by H2O2 at all time points.
# ::save-date Wed Mar 9, 2016 ::file bel_pmid_1465_6721_15970.txt
(a / and
      :op1 (b / become-01
            :ARG1 (a2 / activate-01
                  :ARG1 (e / enzyme :name (n / name :op1 "JNK"))
                  :ARG2-of (i / induce-01
                        :ARG0 (m / molecular-physical-entity :name (n2 / name :op1 "LPS"))))
            :ARG2 (a3 / appear-02
                  :ARG1 a2)
            :mod (o / only)
            :time (a4 / after
                  :op1 (a5 / add-02
                        :ARG1 m
                        :ARG2 (c / cell))
                  :quant (t / temporal-quantity :quant 20
                        :unit (m2 / minute))))
      :op2 (a8 / activate-01
            :ARG1 e
            :ARG2-of i
            :degree (l / less
                  :degree (m3 / more)
                  :time (a7 / always))
            :compared-to (a6 / activate-01
                  :ARG1 e
                  :ARG2-of (i2 / induce-01
                        :ARG0 (s / small-molecule :name (n3 / name :op1 "H2O2"))))))

# ::id bel_pmid_1465_7354.10332 ::date 2015-04-28T09:21:19 ::annotator SDL-AMR-09 ::preferred
# ::snt Further, evidence is presented for TGF-beta-stimulated p160ROCK translocation to the nucleus and inhibitory phosphorylation of the cyclin-dependent kinase-activating phosphatase, Cdc25A.
# ::save-date Sun Jan 3, 2016 ::file bel_pmid_1465_7354_10332.txt
(p / present-01
      :ARG1 (e / evidence-01
            :ARG1 (a / and
                  :op1 (t / translocate-01
                        :ARG1 (p2 / protein :name (n / name :op1 "p160ROCK")
                              :ARG1-of (s / stimulate-01
                                    :ARG0 (p4 / protein :name (n2 / name :op1 "TGF-beta"))))
                        :ARG2 (n3 / nucleus))
                  :op2 (p3 / phosphorylate-01
                        :ARG1 (p6 / phosphatase :name (n4 / name :op1 "Cdc25A"))
                        :ARG0-of (d / depend-01
                              :ARG1 (c / cyclin
                                    :ARG0-of (a2 / activate-01
                                          :ARG1 (k / kinase))))
                        :ARG0-of (i / inhibit-01))))
      :mod (f / further))

# ::id bel_pmid_1467_1317.33588 ::date 2015-04-28T10:31:00 ::annotator SDL-AMR-09 ::preferred
# ::snt p57Kip2 (Cdkn1c) is expressed in postmitotic differentiating midbrain dopamine cells. Induction of p57Kip2 expression depends on Nurr1,
# ::save-date Sun Dec 20, 2015 ::file bel_pmid_1467_1317_33588.txt
(m3 / multi-sentence
      :snt1 (e / express-03
            :ARG2 (p / protein :name (n / name :op1 "p57Kip2")
                  :ARG1-of (m / mean-01
                        :ARG2 (p2 / protein :name (n2 / name :op1 "Cdkn1c"))))
            :ARG3 (c / cell
                  :mod (d / dopamine)
                  :mod (m2 / midbrain)
                  :mod (p3 / postmitotic)
                  :ARG0-of (d2 / differentiate-01)))
      :snt2 (d3 / depend-01
            :ARG0 (i / induce-01
                  :ARG2 (e2 / express-03
                        :ARG2 (p5 / protein :name (n4 / name :op1 "p57Kip2"))))
            :ARG1 (p4 / protein :name (n3 / name :op1 "Nurr1"))))

# ::id bel_pmid_1475_9523.36890 ::date 2015-04-30T02:40:11 ::annotator SDL-AMR-09 ::preferred
# ::snt The expression of MUP2 is known to be stimulated by growth hormone (GH), through the GH receptor (GHR), Janus kinase 2 (JAK2) and signal transducer and activator of transcription 5 (STAT5) signal transduction pathway.
# ::save-date Tue Jan 19, 2016 ::file bel_pmid_1475_9523_36890.txt
(k / know-01
      :ARG1 (s / stimulate-01
            :ARG0 (s2 / small-molecule :name (n3 / name :op1 "growth" :op2 "hormone"))
            :ARG1 (e / express-03
                  :ARG2 (p / protein :name (n / name :op1 "MUP2")))
            :ARG2 (a / and
                  :op1 (r / receptor :name (n2 / name :op1 "GH"))
                  :op2 (e2 / enzyme :name (n4 / name :op1 "Janus" :op2 "kinase" :op3 "2"))
                  :op3 (p2 / pathway :name (n5 / name :op1 "signal" :op2 "transducer" :op3 "and" :op4 "activator" :op5 "of" :op6 "transcription" :op7 "5")
                        :ARG0-of (s3 / signal-07
                              :ARG1-of (t / transduce-01))))))

# ::id bel_pmid_1496_3018.30938 ::date 2015-04-30T04:12:05 ::annotator SDL-AMR-09 ::preferred
# ::snt Phosphorylation at Ser727 in signal transducer and activator of transcription 1 (STAT1) is essential for its activation and signal transduction.
# ::save-date Tue Jan 19, 2016 ::file bel_pmid_1496_3018_30938.txt
(e / essential
      :domain (p / phosphorylate-01
            :ARG1 (a / amino-acid :mod 727 :name (n / name :op1 "serine")
                  :part-of (p2 / protein :name (n2 / name :op1 "signal" :op2 "transducer" :op3 "and" :op4 "activator" :op5 "of" :op6 "transcription" :op7 "1"))))
      :purpose (a2 / and
            :op1 (a3 / activate-01
                  :ARG1 p2)
            :op2 (t / transduce-01
                  :ARG1 (s / signal-07))))

# ::id bel_pmid_1496_3018.37018 ::date 2015-05-04T01:46:14 ::annotator SDL-AMR-09 ::preferred
# ::snt In vitro kinase assays using the combined STAT1 proteins as substrates from immunoprecipitation and glutathione S-transferase pull down show that active ERK1, JNK1, p38 kinase, MEK1 and MSK1 stimulated phosphorylation of STAT1 (Ser727) indirectly through an unidentified factor or a downstream kinase.
# ::save-date Sun Jan 3, 2016 ::file bel_pmid_1496_3018_37018.txt
(s / show-01
      :ARG0 (a / assay-01
            :ARG1 (k / kinase)
            :manner (i / in-vitro)
            :ARG0-of (u / use-01
                  :ARG1 (p / protein :name (n / name :op1 "STAT1")
                        :ARG3-of (c / combine-01))
                  :ARG2 (s2 / substrate
                        :source (a2 / and
                              :op1 (i2 / immunoprecipitate-01)
                              :op2 (p2 / pull-down-08
                                    :ARG1 (e / enzyme :name (n2 / name :op1 "glutathione" :op2 "S-transferase")))))))
      :ARG1 (s3 / stimulate-01
            :ARG0 (a3 / and
                  :op1 (e2 / enzyme :name (n3 / name :op1 "ERK1"))
                  :op2 (e3 / enzyme :name (n4 / name :op1 "JNK1"))
                  :op3 (e6 / enzyme :name (n5 / name :op1 "p38" :op2 "kinase"))
                  :op4 (e4 / enzyme :name (n6 / name :op1 "MEK1"))
                  :op5 (e5 / enzyme :name (n7 / name :op1 "MSK1")))
            :ARG1 (p3 / phosphorylate-01
                  :ARG1 (a4 / amino-acid :mod 727 :name (n8 / name :op1 "serine")
                        :part-of p)
                  :ARG2 (o / or
                        :op1 (f / factor
                              :ARG1-of (i4 / identify-01 :polarity -))
                        :op2 (k3 / kinase
                              :mod (d / downstream))))
            :ARG1-of (d2 / direct-02 :polarity -)
            :ARG0-of (a5 / activity-06)))

# ::id bel_pmid_1496_6563.336 ::date 2015-05-03T08:25:01 ::annotator SDL-AMR-09 ::preferred
# ::snt Inactivation of Icmt inhibited cell growth and K-Ras-induced oncogenic transformation, both in soft agar assays and in a nude mice model.
# ::save-date Sun Dec 20, 2015 ::file bel_pmid_1496_6563_336.txt
(a2 / and
      :op1 (a / activate-01 :polarity -
            :ARG1 (e / enzyme :name (n / name :op1 "Icmt"))
            :ARG0-of (i / inhibit-01
                  :ARG1 (g / grow-01
                        :ARG1 (c / cell))
                  :location (a5 / and
                        :op1 (a3 / assay-01
                              :ARG1 (a4 / agar
                                    :ARG1-of (s / soft-02)))
                        :op2 (m / model
                              :topic (m2 / mouse)
                              :mod (n3 / nude)))))
      :op2 (t / transform-01
            :ARG1 c
            :ARG2-of (i2 / induce-01
                  :ARG0 (e2 / enzyme :name (n2 / name :op1 "K-Ras")))
            :ARG0-of (c2 / cause-01
                  :ARG1 (d / disease :wiki "Cancer" :name (n4 / name :op1 "cancer")))))

# ::id bel_pmid_1496_6563.338 ::date 2015-05-03T09:28:45 ::annotator SDL-AMR-09 ::preferred
# ::snt The effect of inactivating Icmt was not limited to the inhibition of K-Ras-induced transformation: inactivation of Icmt blocked transformation by an oncogenic form of B-Raf
# ::save-date Sun Dec 20, 2015 ::file bel_pmid_1496_6563_338.txt
(a3 / and
      :op1 (l / limit-01 :polarity -
            :ARG1 (a / affect-01
                  :ARG0 (a2 / activate-01 :polarity -
                        :ARG1 (e / enzyme :name (n / name :op1 "Icmt"))))
            :ARG2 (i / inhibit-01
                  :ARG1 (t / transform-01
                        :ARG2-of (i2 / induce-01
                              :ARG0 (e2 / enzyme :name (n2 / name :op1 "K-Ras"))))))
      :op2 (b / block-01
            :ARG0 a2
            :ARG1 (t2 / transform-01)
            :ARG3 (f / form
                  :ARG0-of (c2 / cause-01
                        :ARG1 (d / disease :wiki "Cancer" :name (n4 / name :op1 "cancer")))
                  :mod (e3 / enzyme :name (n3 / name :op1 "B-Raf")))))

# ::id bel_pmid_1496_6563.4878 ::date 2015-05-03T10:41:41 ::annotator SDL-AMR-09 ::preferred
# ::snt In the case of the Ras proteins, carboxyl methylation is important for targeting of the proteins to the plasma membrane.
# ::save-date Thu Jan 14, 2016 ::file bel_pmid_1496_6563_4878.txt
(i / important
      :purpose (t / target-01
            :ARG0 (p / protein :name (n / name :op1 "carboxyl" :op2 "methylation"))
            :ARG1 (p3 / protein-family :name (n2 / name :op1 "Ras"))
            :direction (m / membrane
                  :part-of (p2 / plasma))))

# ::id bel_pmid_1496_6563.4882 ::date 2015-05-10T10:29:07 ::annotator SDL-AMR-09 ::preferred
# ::snt levels of RhoA were greatly reduced as a consequence of accelerated protein turnover. In addition, there was a large Ras/Erk1/2-dependent increase in p21(Cip1), which was probably a consequence of the reduced levels of RhoA. Deletion of p21(Cip1) restored the ability of K-Ras-Icmt(Delta/Delta) fibroblasts to grow in soft agar.
# ::save-date Thu Jan 14, 2016 ::file bel_pmid_1496_6563_4882.txt
(m / multi-sentence
      :snt1 (r / reduce-01
            :ARG1 (l / level
                  :degree-of (p / protein :name (n / name :op1 "RhoA")))
            :ARG2 (g / great)
            :ARG1-of (c / cause-01
                  :ARG0 (t / turnover
                        :mod (p2 / protein)
                        :ARG1-of (a / accelerate-01))))
      :snt3 (r2 / restore-01
            :ARG0 (d2 / delete-01
                  :ARG1 (p6 / protein :name (n5 / name :op1 "p21(Cip1)")))
            :ARG1 (c3 / capable-01
                  :ARG1 (f / fibroblast
                        :ARG0-of (c4 / contain-01
                              :ARG1 (e2 / enzyme :name (n6 / name :op1 "K-Ras-Icmt(Delta/Delta)"))))
                  :ARG2 (g2 / grow-01
                        :ARG1 f
                        :location (a3 / agar
                              :ARG1-of (s / soft-02)))))
      :snt2 (a2 / and
            :op2 (i / increase-01
                  :ARG1 (p3 / protein :name (n2 / name :op1 "p21(Cip1)"))
                  :ARG2 (l2 / large)
                  :ARG0-of (d / depend-01
                        :ARG1 (p7 / pathway :name (n3 / name :op1 "Ras/Erk1/2")))
                  :ARG1-of (c2 / cause-01
                        :ARG0 (r3 / reduce-01
                              :ARG1 (l3 / level
                                    :quant-of (p5 / protein :name (n4 / name :op1 "RhoA"))))
                        :mod (p4 / probable)))))

# ::id bel_pmid_1496_6572.18984 ::date 2015-05-04T00:31:42 ::annotator SDL-AMR-09 ::preferred
# ::snt The increase in IL-6 in septic DPPI(-/-) mice, which appears to protect these mice from death, may be related to reduced DPPI-mediated activation of mast cell tryptase and other peptidases, which we show cleave IL-6 in vitro.
# ::save-date Wed May 20, 2015 ::file bel_pmid_1496_6572_18984.txt
(p / possible-01
      :ARG1 (r / relate-01
            :ARG1 (i / increase-01
                  :ARG1 (p2 / protein :name (n / name :op1 "IL-6")
                        :ARG0-of (p3 / protect-01
                              :ARG1 m
                              :ARG2 (d / die-01
                                    :ARG1 m)
                              :ARG1-of (a2 / appear-02)))
                  :location (m / mouse
                        :mod (s / septic)
                        :mod (e / enzyme :name (n2 / name :op1 "DPPI")
                              :ARG2-of (m2 / mutate-01 :mod "-/-"))))
            :ARG2 (a / activate-01
                  :ARG1 (a3 / and
                        :op1 (e3 / enzyme :name (n4 / name :op1 "tryptase")
                              :mod (c2 / cell)
                              :mod (m4 / mast))
                        :op2 (p4 / peptidase
                              :mod (o / other))
                        :ARG0-of (c / cleave-01
                              :ARG1 p2
                              :manner (i2 / in-vitro)
                              :ARG1-of (s2 / show-01
                                    :ARG0 (w / we))))
                  :ARG1-of (m3 / mediate-01
                        :ARG0 e)
                  :ARG1-of (r2 / reduce-01))))

# ::id bel_pmid_1503_9780.28646 ::date 2015-05-03T23:41:52 ::annotator SDL-AMR-09 ::preferred
# ::snt Importantly, over-expression of c-Jun rescued the defects in proliferation and premature senescence observed in mkk7-/- MEFs (Fig. 7b-d).
# ::save-date Sun Jan 3, 2016 ::file bel_pmid_1503_9780_28646.txt
(r / rescue-01
      :ARG0 (o2 / overexpress-01
            :ARG1 (p / protein :name (n / name :op1 "c-Jun")))
      :ARG1 (d / defect
            :topic (a / and
                  :op1 (p2 / proliferate-01)
                  :op2 (s / senescence
                        :mod (p3 / premature))
                  :ARG1-of (o / observe-01
                        :location (c / cell :name (n2 / name :op1 "MEF")
                              :part (e2 / enzyme :name (n3 / name :op1 "mkk7")
                                    :ARG2-of (m / mutate-01 :mod "-/-"))))))
      :mod (i / important)
      :ARG1-of (d2 / describe-01
            :ARG0 (a2 / and
                  :op1 (f / figure :mod "7b")
                  :op2 (f3 / figure :mod "7c")
                  :op3 (f2 / figure :mod "7d"))))

# ::id bel_pmid_1503_9780.29004 ::date 2015-05-06T00:16:11 ::annotator SDL-AMR-09 ::preferred
# ::snt Moreover, genetic inactivation of MKK4 in MEFs resulted in reduced proliferation doubling times and premature senescence, indicating that both MKK4 and MKK7 are essential for these cellular processes (data not shown).
# ::save-date Mon Jul 13, 2015 ::file bel_pmid_1503_9780_29004.txt
(a4 / and
      :op2 (r / result-01
            :ARG1 (a / activate-01 :polarity -
                  :ARG1 (e / enzyme :name (n / name :op1 "MKK4")
                        :location (c / cell :name (n2 / name :op1 "MEF")))
                  :mod (g / genetic)
                  :location c)
            :ARG2 (a2 / and
                  :op1 (t2 / time
                        :ARG1-of (r2 / reduce-01)
                        :duration-of (d / double-01
                              :ARG1 (p / proliferate-01
                                    :ARG0 c)))
                  :op2 (s / senescence
                        :mod (p3 / premature)))
            :ARG0-of (i / indicate-01
                  :ARG1 (e2 / essential
                        :purpose (p2 / process-02
                              :location (c2 / cell)
                              :mod (t / this))
                        :domain (a3 / and
                              :op1 e
                              :op2 (e3 / enzyme :name (n3 / name :op1 "MKK7")))
                        :ARG1-of (s2 / show-01 :polarity -)))))

# ::id bel_pmid_1503_9780.29010 ::date 2015-05-07T07:22:31 ::annotator SDL-AMR-09 ::preferred
# ::snt In contrast, proliferation of hepatocytes was markedly impaired in E11.5 mkk7-/- embryos, as determined by BrdU in vivo labelling (data not shown).
# ::save-date Sun Jan 17, 2016 ::file bel_pmid_1503_9780_29010.txt
(c2 / contrast-01
      :ARG2 (i / impair-01
            :ARG1 (p / proliferate-01
                  :ARG0 (c / cell :name (n / name :op1 "hepatocyte")))
            :manner (m / marked)
            :location (e / embryo
                  :mod (e2 / enzyme :name (n2 / name :op1 "mkk7")
                        :ARG2-of (m2 / mutate-01 :mod "-/-"))
                  :age (t2 / temporal-quantity :quant 11.5
                        :unit (d2 / day)))
            :ARG1-of (d / determine-01
                  :ARG0 (l / label-01
                        :instrument (s2 / small-molecule :name (n4 / name :op1 "BrdU"))
                        :manner (i2 / in-vivo)))
            :ARG1-of (s / show-01 :polarity -)))

# ::id bel_pmid_1503_9780.29012 ::date 2015-05-06T01:38:47 ::annotator SDL-AMR-09 ::preferred
# ::snt Re-expression of wild-type MKK7 (Fig. 2c) restored the reduced proliferation of mkk7- /- MEFs to levels observed in wild-type MEFs.
# ::save-date Sun May 10, 2015 ::file bel_pmid_1503_9780_29012.txt
(r / restore-01
      :ARG0 (e / express-03
            :ARG2 (e2 / enzyme :name (n / name :op1 "MKK7")
                  :mod (w / wild-type))
            :mod (a / again)
            :ARG1-of (d / describe-01
                  :ARG0 (f / figure :mod "2c")))
      :ARG1 (p / proliferate-01
            :ARG0 (c / cell :name (n2 / name :op1 "MEF")
                  :part (e3 / enzyme :name (n3 / name :op1 "mkk7")
                        :ARG2-of (m / mutate-01 :mod "-/-")))
            :ARG1-of (r2 / reduce-01))
      :ARG2 (l / level
            :ARG1-of (o / observe-01
                  :location c)))

# ::id bel_pmid_1503_9780.29014 ::date 2015-05-07T07:21:47 ::annotator SDL-AMR-09 ::preferred
# ::snt loss of MKK7 expression resulted in impaired JNK activation in MEFs at the basal level and after stimulation with tumour necrosis factor alpha (TNF-alpha) or UV irradiation (Fig. 2a).
# ::save-date Thu Jan 14, 2016 ::file bel_pmid_1503_9780_29014.txt
(r / result-01
      :ARG1 (l / lose-02
            :ARG1 (e / express-03
                  :ARG2 (e2 / enzyme :name (n / name :op1 "MKK7"))))
      :ARG2 (a / activate-01
            :ARG1 (e3 / enzyme :name (n2 / name :op1 "JNK"))
            :ARG1-of (i / impair-01)
            :location (c / cell :name (n3 / name :op1 "MEF"))
            :location (l2 / level
                  :mod (b / basal))
            :time (a2 / after
                  :op1 (s / stimulate-01
                        :ARG1 e3
                        :ARG2 (o / or
                              :op1 (p / protein :name (n4 / name :op1 "tumour" :op2 "necrosis" :op3 "factor" :op4 "alpha"))
                              :op2 (i2 / irradiate-01
                                    :ARG2 (l3 / light
                                          :mod (u / ultraviolet)))))))
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod "2a")))

# ::id bel_pmid_1503_9780.29016 ::date 2015-05-11T22:59:07 ::annotator SDL-AMR-09 ::preferred
# ::snt Importantly, cyclin B1-associated CDC2 kinase activity was markedly reduced in mkk7-/- MEFs (Fig. 4d), indicating that reduced CDC2 expression correlates with impaired cyclin B1/CDC2 activity.
# ::save-date Mon Jul 6, 2015 ::file bel_pmid_1503_9780_29016.txt
(r / reduce-01
      :ARG1 (a / activity-06
            :ARG0 (k / kinase :name (n / name :op1 "CDC2")
                  :ARG1-of (a2 / associate-01
                        :ARG2 (p / protein :name (n2 / name :op1 "cyclin" :op2 "B1")))))
      :mod (i / important)
      :manner (m / marked)
      :location (c / cell :name (n3 / name :op1 "MEF")
            :part (e / enzyme :name (n4 / name :op1 "mkk7")
                  :ARG2-of (m2 / mutate-01 :mod "-/-")))
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod "4d"))
      :ARG0-of (i2 / indicate-01
            :ARG1 (c2 / correlate-01
                  :ARG1 (e2 / express-03
                        :ARG2 k
                        :ARG1-of (r2 / reduce-01))
                  :ARG2 (a3 / activity-06
                        :ARG0 (s / slash
                              :op1 p
                              :op2 k)
                        :ARG1-of (i3 / impair-01)))))

# ::id bel_pmid_1503_9780.29022 ::date 2015-05-07T10:01:03 ::annotator SDL-AMR-09 ::preferred
# ::snt Similarly to mkk7-/- MEFs, cdc2 mRNA expression was downregulated in primary mkk7-/- hepatocytes (Fig. 4g).
# ::save-date Sun Jan 17, 2016 ::file bel_pmid_1503_9780_29022.txt
(d / downregulate-01
      :ARG1 (e / express-03
            :ARG1 (n6 / nucleic-acid :name (n / name :op1 "mRNA")
                  :ARG0-of (e2 / encode-01
                        :ARG1 (e5 / enzyme :name (n2 / name :op1 "cdc2")))))
      :location (c / cell :name (n3 / name :op1 "hepatocyte")
            :mod (p2 / primary)
            :mod (e3 / enzyme :name (n4 / name :op1 "mkk7")
                  :ARG2-of (m / mutate-01 :mod "-/-")))
      :ARG1-of (r2 / resemble-01
            :ARG2 (e4 / express-03
                  :ARG3 (c2 / cell :name (n5 / name :op1 "MEF")
                        :part e3)))
      :ARG1-of (d2 / describe-01
            :ARG0 (f / figure :mod "4g")))

# ::id bel_pmid_1503_9780.29098 ::date 2015-05-08T10:53:52 ::annotator SDL-AMR-09 ::preferred
# ::snt These results are consistent with previous data showing that loss of JNK1/JNK2 in MEFs results in reduced proliferation17 and that inactivation of c-Jun in MEFs results in premature senescence and impaired proliferation19.
# ::save-date Sun Jan 17, 2016 ::file bel_pmid_1503_9780_29098.txt
(c / consistent-01
      :ARG1 (t / thing
            :ARG2-of (r / result-01)
            :mod (t2 / this))
      :ARG2 (d / data
            :time (p / previous)
            :ARG0-of (s / show-01
                  :ARG2 (a / and
                        :op1 (r2 / result-01
                              :ARG1 (l / lose-02
                                    :ARG1 (s2 / slash
                                          :op1 (e / enzyme :name (n / name :op1 "JNK1"))
                                          :op2 (e2 / enzyme :name (n2 / name :op1 "JNK2"))
                                          :location (c2 / cell :name (n3 / name :op1 "MEF")))
                                    :ARG2 (p2 / proliferate-01
                                          :ARG1-of (r4 / reduce-01)))
                              :ARG1-of (d2 / describe-01
                                    :ARG0 (p4 / publication-91
                                          :ARG1-of (c3 / cite-01
                                                :ARG2 17))))
                        :op2 (r3 / result-01
                              :ARG1 (a2 / activate-01 :polarity -
                                    :ARG1 (p7 / protein :name (n4 / name :op1 "c-Jun")
                                          :location c2))
                              :ARG2 (a3 / and
                                    :op1 (s3 / senescence
                                          :mod (p3 / premature))
                                    :op2 (p5 / proliferate-01
                                          :ARG1-of (i2 / impair-01)))
                              :ARG1-of (d3 / describe-01
                                    :ARG0 (p6 / publication-91
                                          :ARG1-of (c4 / cite-01
                                                :ARG2 19))))))))

# ::id bel_pmid_1503_9780.33214 ::date 2015-05-09T04:14:05 ::annotator SDL-AMR-09 ::preferred
# ::snt Over-expression of c-Jun in mkk7-/- MEFs restored CDC2 expression (Fig. 6c) and transactivation of the cdc2 AP-1 promoter construct to levels observed in wild-type MEFs (Fig. 6d).
# ::save-date Sun Jan 17, 2016 ::file bel_pmid_1503_9780_33214.txt
(r / restore-01
      :ARG0 (o2 / overexpress-01
            :ARG1 (p / protein :name (n / name :op1 "c-Jun"))
            :location (c / cell :name (n2 / name :op1 "MEF")
                  :part (e2 / enzyme :name (n3 / name :op1 "mkk7")
                        :ARG2-of (m / mutate-01 :mod "-/-"))))
      :ARG1 (a / and
            :op1 (e3 / express-03
                  :ARG2 (e / enzyme :name (n4 / name :op1 "CDC2"))
                  :ARG1-of (d / describe-01
                        :ARG0 (f / figure :mod "6c")))
            :op2 (t / transactivate-01
                  :ARG1 (m2 / molecular-physical-entity
                        :ARG0-of (p3 / promote-01
                              :ARG1 (p4 / protein :name (n5 / name :op1 "cdc2" :op2 "AP-1")
                                    :ARG1-of (c2 / construct-01))))
                  :ARG1-of (d2 / describe-01
                        :ARG0 (f2 / figure :mod "6d"))))
      :ARG2 (l / level
            :ARG1-of (o / observe-01
                  :location (c3 / cell :name (n6 / name :op1 "MEF")
                        :mod (w / wild-type)))))

# ::id bel_pmid_1511_5616.1726 ::date 2015-05-05T00:21:55 ::annotator SDL-AMR-09 ::preferred
# ::snt In this study, we found that H-Ras interacted with ASK1 to cause the inhibition of both ASK1 activity and ASK1-induced apoptosis in vivo
# ::save-date Sun Dec 20, 2015 ::file bel_pmid_1511_5616_1726.txt
(f / find-01
      :ARG0 (w / we)
      :ARG1 (i / interact-01
            :ARG0 (e / enzyme :name (n / name :op1 "H-Ras"))
            :ARG1 (e2 / enzyme :name (n2 / name :op1 "ASK1"))
            :purpose (c / cause-01
                  :ARG0 e
                  :ARG1 (i2 / inhibit-01
                        :ARG1 (a2 / and
                              :op1 (a / activity-06
                                    :ARG0 e2)
                              :op2 (a3 / apoptosis
                                    :ARG2-of (i3 / induce-01
                                          :ARG0 e2
                                          :manner (i4 / in-vivo)))))))
      :medium (s / study-01
            :mod (t / this)))

# ::id bel_pmid_1512_8871.1604 ::date 2015-05-13T22:27:24 ::annotator SDL-AMR-09 ::preferred
# ::snt In this report, we demonstrate that the CDC25B phosphatase, an activator of cyclin dependent kinases at mitosis, is phosphorylated both in vitro and in vivo by Aurora-A on serine 353 and that this phosphorylated form of CDC25B is located at the centrosome during mitosis.
# ::save-date Mon May 25, 2015 ::file bel_pmid_1512_8871_1604.txt
(d / demonstrate-01
      :ARG0 (w / we)
      :ARG1 (a4 / and
            :op1 (p / phosphorylate-01
                  :ARG1 (a2 / amino-acid :mod 353 :name (n2 / name :op1 "serine")
                        :part-of (p3 / phosphatase :name (n4 / name :op1 "CDC25B")
                              :ARG0-of (a / activate-01
                                    :ARG1 (k / kinase
                                          :ARG0-of (d2 / depend-01
                                                :ARG1 (c / cyclin)))
                                    :time (m / mitosis))))
                  :ARG2 (e / enzyme :name (n3 / name :op1 "Aurora-A"))
                  :manner (a3 / and
                        :op1 (i / in-vitro)
                        :op2 (i2 / in-vivo)))
            :op2 (b2 / be-located-at-91
                  :ARG1 (p2 / protein)
                  :ARG2 (c2 / centrosome)
                  :time m))
      :medium (r / report
            :mod (t / this)))

# ::id bel_pmid_1514_3158.1864 ::date 2015-05-09T03:18:32 ::annotator SDL-AMR-09 ::preferred
# ::snt PTPD1 activates src tyrosine kinase and increases the magnitude and duration of epidermal growth factor (EGF) signaling. EGF receptor phosphorylation and downstream activation of ERK 1/2 and Elk1-dependent gene transcription are enhanced by PTPD1.
# ::save-date Sun Jan 17, 2016 ::file bel_pmid_1514_3158_1864.txt
(m / multi-sentence
      :snt1 (a / and
            :op1 (a2 / activate-01
                  :ARG0 (p / protein :name (n / name :op1 "PTPD1"))
                  :ARG1 (p2 / protein :name (n3 / name :op1 "src" :op2 "tyrosine" :op3 "kinase")))
            :op2 (i / increase-01
                  :ARG0 p
                  :ARG1 (a3 / and
                        :op1 (m2 / magnitude
                              :poss (s / signal-07
                                    :ARG0 (p3 / protein :name (n2 / name :op1 "epidermal" :op2 "growth" :op3 "factor"))))
                        :op2 (d / duration
                              :poss s))))
      :snt2 (e / enhance-01
            :ARG0 (p4 / protein :name (n4 / name :op1 "PTPD1"))
            :ARG1 (a4 / and
                  :op1 (p5 / phosphorylate-01
                        :ARG1 (e3 / enzyme :name (n8 / name :op1 "EFG" :op2 "rececptor")))
                  :op2 (a5 / activate-01
                        :ARG1 (t / transcribe-01
                              :ARG1 (g / gene)
                              :ARG0-of (d3 / depend-01
                                    :ARG1 (a6 / and
                                          :op1 (e2 / enzyme :name (n6 / name :op1 "ERK" :op2 "1/2"))
                                          :op2 (p6 / protein :name (n7 / name :op1 "Elk1")))))
                        :mod (d2 / downstream)))))

# ::id bel_pmid_1515_6153.27354 ::date 2015-05-11T23:49:03 ::annotator SDL-AMR-09 ::preferred
# ::snt Importantly, expression of Myc–Hes1 greatly increased the amount of endogenous JAK2 coprecipitated with endogenous STAT3 (Fig. 4e), suggesting that Hes1 facilitates the interaction between JAK2 and its substrate STAT3
# ::save-date Tue Feb 2, 2016 ::file bel_pmid_1515_6153_27354.txt
(i / increase-01
      :ARG0 (e / express-03
            :ARG2 (m / macro-molecular-complex
                  :part (p / protein :name (n / name :op1 "Myc"))
                  :part (p3 / protein :name (n5 / name :op1 "Hes1"))))
      :ARG1 (a / amount
            :quant-of (e2 / enzyme :name (n2 / name :op1 "JAK2")
                  :mod (e3 / endogenous)
                  :op1-of (a2 / and
                        :op2 (p2 / protein :name (n3 / name :op1 "STAT3")
                              :mod e3)
                        :ARG1-of (c / coprecipitate-01))))
      :ARG2 (g / great)
      :mod (i2 / important)
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod "4e"))
      :ARG0-of (s / suggest-01
            :ARG1 (f2 / facilitate-01
                  :ARG0 p3
                  :ARG1 (i3 / interact-01
                        :ARG0 e2
                        :ARG1 p2))))

# ::id bel_pmid_1515_6153.27358 ::date 2015-05-08T12:10:25 ::annotator SDL-AMR-09 ::preferred
# ::snt Expression of either Hes1 or Hes5 significantly activated the STAT reporter gene construct in both E13 neuroepithelial cells and MNS-70 cells,
# ::save-date Fri Dec 18, 2015 ::file bel_pmid_1515_6153_27358.txt
(a / activate-01
      :ARG0 (e / express-03
            :ARG2 (o / or
                  :op1 (p / protein :name (n / name :op1 "Hes1"))
                  :op2 (p2 / protein :name (n2 / name :op1 "Hes5"))))
      :ARG1 (g / gene :name (n3 / name :op1 "STAT")
            :ARG0-of (r / report-01)
            :ARG1-of (c / construct-01))
      :ARG1-of (s / significant-02)
      :location (a2 / and
            :op1 (c3 / cell :name (n5 / name :op1 "E13")
                  :part-of (n4 / neuroepithelium))
            :op2 (c2 / cell :name (n6 / name :op1 "MNS-70"))))

# ::id bel_pmid_1515_6153.29634 ::date 2015-05-14T00:03:24 ::annotator SDL-AMR-09 ::preferred
# ::snt Expression of an active form of Notch (Notch?E; the transmembrane and intracellular domains of mouse Notch1, comprising residues 1,704–2,531)15, significantly induced activation of a STAT-dependent reporter gene (APRE-Luc)16 in mouse cortical neuroepithelial cells derived on embryonic day (E) 13 or in the rat neural precursor MNS-70 cells17
# ::save-date Thu Feb 4, 2016 ::file bel_pmid_1515_6153_29634.txt
(i / induce-01
      :ARG0 (e / express-03
            :ARG2 (f / form
                  :mod (p2 / protein :name (n3 / name :op1 "Notch")
                        :ARG1-of (m3 / mean-01
                              :ARG2 (p9 / protein :name (n4 / name :op1 "Notch" :op2 "Delta" :op3 "E")
                                    :ARG1-of (m / mean-01
                                          :ARG2 (a4 / and
                                                :op1 (p3 / protein-segment
                                                      :mod (t / transmembrane)
                                                      :part-of (p5 / protein :name (n6 / name :op1 "Notch1")
                                                            :mod (m2 / mouse)))
                                                :op2 (p10 / protein-segment
                                                      :mod (c2 / cell
                                                            :part-of p5))
                                                :ARG1-of (c / comprise-01
                                                      :ARG2 (v2 / value-interval
                                                            :op1 (r2 / residue :mod 1704)
                                                            :op2 (r4 / residue :mod 2531))))))))
                  :ARG0-of (a3 / activity-06))
            :ARG1-of (d4 / describe-01
                  :ARG0 (p4 / publication-91
                        :ARG1-of (c6 / cite-01
                              :ARG2 15))))
      :ARG2 (a / activate-01
            :ARG1 (g / gene :name (n / name :op1 "APRE-Luc")
                  :ARG0-of (d / depend-01
                        :ARG1 (p / protein :name (n2 / name :op1 "STAT")
                              :ARG1-of (a2 / activate-01)))
                  :ARG0-of (r / report-01))
            :location (o / or
                  :op1 (c3 / cell
                        :part-of (n7 / neuroepithelium)
                        :mod (c4 / cortex)
                        :ARG1-of (d2 / derive-01
                              :ARG1-of (d6 / describe-01
                                    :ARG0 (p8 / publication-91
                                          :ARG1-of (c8 / cite-01
                                                :ARG2 17)))
                              :time (d3 / day
                                    :ord (o2 / ordinal-entity :value 13)
                                    :mod (e2 / embryo))))
                  :op2 (c5 / cell :name (n8 / name :op1 "MNS-70")
                        :mod (p6 / precursor)
                        :mod (r3 / rat)
                        :mod (n9 / neural))))
      :ARG1-of (s / significant-02)
      :ARG1-of (d5 / describe-01
            :ARG0 (p7 / publication-91
                  :ARG1-of (c7 / cite-01
                        :ARG2 16))))

# ::id bel_pmid_1516_6036.20904 ::date 2015-04-29T02:41:57 ::annotator SDL-AMR-09 ::preferred
# ::snt Following depletion of both serum and Epo for 2 hours, p44/42 ERK (Phospho ERK1 (Thr202/Tyr204); phospho-ERK2 (Thr185/Tyr187)) remained active in H-ras.V12-transduced cells but not in the control cells. No difference was seen in the expression of total p44/42 ERK in the 2 populations of cells
# ::save-date Tue Jan 19, 2016 ::file bel_pmid_1516_6036_20904.txt
(m3 / multi-sentence
      :snt1 (r / remain-01
            :ARG1 (s2 / slash
                  :op1 (e6 / enzyme :name (n10 / name :op1 "p44ERK"))
                  :op2 (e7 / enzyme :name (n11 / name :op1 "p42ERK"))
                  :ARG1-of (m / mean-01
                        :ARG2 (a5 / and
                              :op1 (s3 / slash
                                    :op1 (a6 / amino-acid :mod 202 :name (n / name :op1 "threonine")
                                          :part-of e
                                          :ARG3-of (p / phosphorylate-01))
                                    :op2 (a7 / amino-acid :mod 204 :name (n2 / name :op1 "tyrosine")
                                          :part-of (e / enzyme :name (n6 / name :op1 "ERK1"))
                                          :ARG1-of p))
                              :op2 (s4 / slash
                                    :op1 (a8 / amino-acid :mod 185 :name (n7 / name :op1 "threonine")
                                          :part-of e4
                                          :ARG3-of p)
                                    :op2 (a9 / amino-acid :name (n8 / name :op1 "tyrosine")
                                          :part-of (e4 / enzyme :name (n9 / name :op1 "ERK2"))
                                          :ARG3-of p)))))
            :ARG3 (c / contrast-01
                  :ARG1 (r2 / remain-01
                        :ARG1 s2
                        :ARG2 (a3 / activity-06
                              :ARG0 s2)
                        :location (c5 / cell
                              :ARG2-of (m2 / mutate-01 :value "V12")
                              :ARG1-of (t / transduce-01
                                    :ARG2 (e2 / enzyme :name (n5 / name :op1 "H-Ras")))))
                  :ARG2 (a4 / activity-06 :polarity -
                        :ARG0 s2
                        :location (c2 / cell
                              :ARG0-of (c3 / control-01))))
            :time (a / after
                  :op1 (d / deplete-01
                        :ARG1 (a2 / and
                              :op1 (s / serum)
                              :op2 (s7 / small-molecule :name (n3 / name :op1 "Epo")))
                        :duration (t2 / temporal-quantity :quant 2
                              :unit (h2 / hour)))))
      :snt2 (s5 / see-01
            :ARG0 (d2 / differ-02 :polarity -
                  :ARG1 (e5 / express-03
                        :ARG2 (s6 / slash
                              :op1 e6
                              :op2 e7
                              :mod (t3 / total))
                        :ARG3 (p2 / population :quant 2
                              :consist-of (c4 / cell))))))

# ::id bel_pmid_1519_6705.1680 ::date 2015-04-29T02:59:12 ::annotator SDL-AMR-09 ::preferred
# ::snt Furthermore, GH induced rapid, time- and dose-dependent signaling events in LNCaP cells, including phosphorylation of JAK2 tyrosine kinase, of GHR itself and of STAT5A (JAK2-STAT5A pathway), of p42/p44 MAPK and of Akt/PKB.
# ::save-date Fri Feb 12, 2016 ::file bel_pmid_1519_6705_1680.txt
(a2 / and
      :op2 (i / induce-01
            :ARG0 (p / protein :name (n2 / name :op1 "GH"))
            :ARG2 (e / event
                  :mod (s / signal-07
                        :ARG0-of (d / depend-01
                              :ARG1 (a / and
                                    :op1 (t / time)
                                    :op2 (d2 / dose)))
                        :mod (r / rapid))
                  :location (c / cell-line :name (n3 / name :op1 "LNCaP"))
                  :ARG2-of (i2 / include-01
                        :ARG1 (p3 / phosphorylate-01
                              :ARG1 (a3 / and
                                    :op1 (t2 / tyrosine-kinase :name (n / name :op1 "JAK2"))
                                    :op2 (p2 / protein :name (n5 / name :op1 "GHR"))
                                    :op3 (p4 / protein :name (n6 / name :op1 "STAT5A"))
                                    :op4 (e5 / enzyme :name (n7 / name :op1 "p42/p44" :op2 "MAPK"))
                                    :op5 (e4 / enzyme :name (n8 / name :op1 "Akt/PKB"))))))))

# ::id bel_pmid_1528_4181.1506 ::date 2015-04-29T03:16:10 ::annotator SDL-AMR-09 ::preferred
# ::snt COX-2 protein and activity measured as prostaglandin E(2) level were up-regulated in cells expressing mutant K-ras(V12);
# ::save-date Sun Jan 17, 2016 ::file bel_pmid_1528_4181_1506.txt
(u / upregulate-01
      :ARG1 (a / and
            :op1 (e3 / enzyme :name (n / name :op1 "COX-2"))
            :op2 (a2 / activity-06
                  :ARG0 e3
                  :ARG1-of (m / measure-01
                        :ARG3 (l / level
                              :quant-of (s / small-molecule :name (n2 / name :op1 "prostaglandin" :op2 "E2"))))))
      :location (c / cell
            :ARG1-of (e / express-03
                  :ARG2 (e2 / enzyme :name (n3 / name :op1 "K-ras")
                        :ARG2-of (m3 / mutate-01 :value "V12")))))

# ::id bel_pmid_1528_4181.19506 ::date 2015-04-29T03:22:44 ::annotator SDL-AMR-09 ::preferred
# ::snt In conclusion, the results suggest that ROS generation, through COX-2 up-regulation, may contribute to the active oncogenicity of mutant K-ras in the lung as a result of DNA damage
# ::save-date Wed Jan 13, 2016 ::file bel_pmid_1528_4181_19506.txt
(c / conclude-02
      :ARG1 (t / thing
            :ARG2-of (r / result-01)
            :ARG0-of (s / suggest-01
                  :ARG1 (p / possible-01
                        :ARG1 (c2 / contribute-01
                              :ARG0 (g / generate-01
                                    :ARG1 (s2 / small-molecule :name (n2 / name :op1 "ROS"))
                                    :instrument (u / upregulate-01
                                          :ARG1 (e2 / enzyme :name (n3 / name :op1 "COX-2"))))
                              :ARG2 (o / oncogenicity
                                    :ARG0-of (a / activate-01)
                                    :poss (e3 / enzyme :name (n4 / name :op1 "K-ras")
                                          :ARG1-of (m2 / mutate-01))
                                    :location (l / lung)
                                    :ARG2-of (r2 / result-01
                                          :ARG1 (d2 / damage-01
                                                :ARG1 (n / nucleic-acid :wiki "DNA" :name (n5 / name :op1 "DNA"))))))))))

# ::id bel_pmid_1528_4181.28764 ::date 2015-04-30T01:12:43 ::annotator SDL-AMR-09 ::preferred
# ::snt Constitutively active mutant K-ras(V12) in E10 cells led to a highly significant (P < 0.001) increased level of peroxides, and a corresponding increase in the amount of DNA strand-break damage, compared with the parental line E10 and the vector control
# ::save-date Wed Mar 9, 2016 ::file bel_pmid_1528_4181_28764.txt
(l / lead-03
      :ARG0 (e / enzyme :name (n / name :op1 "K-ras")
            :ARG0-of (a / activity-06
                  :manner (c / constitutive))
            :ARG2-of (m / mutate-01 :value "V12"))
      :ARG1 (c2 / cell-line :name (n2 / name :op1 "E10"))
      :ARG2 (a2 / and
            :op1 (i / increase-01
                  :ARG1 (l2 / level
                        :quant-of (p / peroxide))
                  :ARG2 (s2 / significant-02
                        :ARG1-of (h / high-02))
                  :ARG1-of (s3 / statistical-test-91
                        :ARG2 (l3 / less-than :op1 0.001)))
            :op2 (i2 / increase-01
                  :ARG1 (a3 / amount
                        :degree-of (d / damage-01
                              :ARG1-of (c3 / cause-01
                                    :ARG0 (b / break-01
                                          :ARG1 (s / strand
                                                :part-of (n5 / nucleic-acid :name (n3 / name :op1 "DNA")))))))
                  :ARG2-of (c4 / correspond-02
                        :ARG1 i)))
      :ARG1-of (c5 / compare-01
            :ARG2 (a4 / and
                  :op1 (c6 / cell-line :name (n4 / name :op1 "E10")
                        :mod (p2 / parent))
                  :op2 (c7 / control-01
                        :ARG0 (v / vector)))))

# ::id bel_pmid_1528_4232.30936 ::date 2015-04-30T01:33:09 ::annotator SDL-AMR-09 ::preferred
# ::snt STAT3 activation is much stronger and more prolonged in STAT1-null mouse embryo fibroblasts than in wild-type cells.
# ::save-date Sat Jan 2, 2016 ::file bel_pmid_1528_4232_30936.txt
(a3 / and
      :op1 (s / strong-02
            :ARG1 (a2 / activate-01
                  :ARG1 (p2 / protein :name (n / name :op1 "STAT3")))
            :mod (m5 / much
                  :degree (m6 / more))
            :location (f / fibroblast
                  :mod (p3 / protein :name (n2 / name :op1 "STAT1")
                        :ARG2-of (m3 / mutate-01 :mod "-/-"))
                  :part-of (e / embryo
                        :mod (m4 / mouse))))
      :op2 (p / prolong-01
            :ARG1 a2
            :degree (m2 / more)
            :location f)
      :ARG1-of (c / compare-01
            :ARG2 (c2 / cell
                  :mod (w / wild-type))))

# ::id bel_pmid_1528_4232.36882 ::date 2015-05-03T01:48:03 ::annotator SDL-AMR-09 ::preferred
# ::snt In response to IFNgamma, SRC-family kinases are required to activate STAT3 (but not STAT1) through tyrosine phosphorylation, whereas the receptor-bound kinases JAK1 and JAK2 are required to activate both STATs.
# ::save-date Mon Jan 4, 2016 ::file bel_pmid_1528_4232_36882.txt
(r2 / require-01
      :ARG1 (c / contrast-01
            :ARG1 (a / activate-01
                  :ARG0 (k / kinase
                        :ARG1-of (i / include-91
                              :ARG2 (p / protein-family :name (n7 / name :op1 "SRC"))))
                  :ARG1 (p5 / protein :name (n2 / name :op1 "STAT3"))
                  :instrument (p3 / phosphorylate-01
                        :ARG1 (a6 / amino-acid :name (n4 / name :op1 "tyrosine"))))
            :ARG2 (a2 / activate-01 :polarity -
                  :ARG0 k
                  :ARG1 (p6 / protein :name (n3 / name :op1 "STAT1"))
                  :instrument p3))
      :ARG1-of (c2 / contrast-01
            :ARG2 (r3 / require-01
                  :ARG1 (a3 / activate-01
                        :ARG0 (a4 / and
                              :op1 (k4 / kinase :name (n6 / name :op1 "JAK1")
                                    :ARG1-of (b / bind-01
                                          :ARG2 (r4 / receptor)))
                              :op2 (k3 / kinase :name (n5 / name :op1 "JAK2")
                                    :ARG1-of b))
                        :ARG1 (a5 / and
                              :op1 p5
                              :op2 p6))))
      :ARG2-of (r / respond-01
            :ARG1 (p2 / protein :name (n / name :op1 "IFNgamma"))))

# ::id bel_pmid_1529_2179.378 ::date 2015-05-03T02:08:31 ::annotator SDL-AMR-09 ::preferred
# ::snt hyperoxia stimulated ERK-1 and ERK-2 phosphorylation
# ::save-date Thu May 7, 2015 ::file bel_pmid_1529_2179_378.txt
(s / stimulate-01
      :ARG0 (h / hyperoxia)
      :ARG1 (p2 / phosphorylate-01
            :ARG1 (a / and
                  :op1 (e / enzyme :name (n / name :op1 "ERK-1"))
                  :op2 (e2 / enzyme :name (n2 / name :op1 "ERK-2")))))

# ::id bel_pmid_1529_2179.380 ::date 2015-05-03T02:12:40 ::annotator SDL-AMR-09 ::preferred
# ::snt Collectively, these results indicate that ERK-1 regulates hyperoxia-stimulated Nrf2 phosphorylation and the subsequent ARE-driven transcriptional response.
# ::save-date Fri Feb 12, 2016 ::file bel_pmid_1529_2179_380.txt
(i / indicate-01
      :ARG0 (t / thing
            :ARG2-of (r / result-01)
            :mod (t3 / this))
      :ARG1 (r2 / regulate-01
            :ARG0 (e / enzyme :name (n3 / name :op1 "ERK-1"))
            :ARG1 (a / and
                  :op1 (p2 / phosphorylate-01
                        :ARG1 (p / protein :name (n / name :op1 "Nrf2")
                              :ARG1-of (s / stimulate-01
                                    :ARG0 (h / hyperoxia))))
                  :op2 (r3 / respond-01
                        :mod (s2 / subsequent)
                        :mod (t2 / transcribe-01)
                        :ARG1-of (d / drive-02
                              :ARG0 (p3 / protein :name (n2 / name :op1 "ARE"))))))
      :mod (c / collective))

# ::id bel_pmid_1529_2179.382 ::date 2015-05-03T02:28:16 ::annotator SDL-AMR-09 ::preferred
# ::snt As was seen for wild-type MEFs, hyperoxia enhanced the phosphorylation of endogenous Nrf2 (lane 6) when compared with room air-exposed controls (lane 5).
# ::save-date Sun May 10, 2015 ::file bel_pmid_1529_2179_382.txt
(e5 / enhance-01
      :ARG0 (h / hyperoxia)
      :ARG1 (p2 / phosphorylate-01
            :ARG1 (p / protein :name (n / name :op1 "Nrf2")
                  :mod (e2 / endogene)
                  :ARG1-of (d / describe-01
                        :ARG0 (l / lane
                              :ARG1-of (l2 / label-01
                                    :ARG2 6)))))
      :condition (c3 / compare-01
            :ARG1 h
            :ARG2 (c2 / control
                  :ARG1-of (e3 / expose-01
                        :ARG2 (a / air
                              :mod (r / room)))
                  :ARG1-of (d2 / describe-01
                        :ARG0 (l3 / lane
                              :ARG1-of (l4 / label-01
                                    :ARG2 5)))))
      :ARG1-of (r2 / resemble-01
            :ARG2 (t / thing
                  :ARG1-of (s2 / see-01
                        :location (f / fibroblast
                              :part-of (e4 / embryo
                                    :mod (m / mouse))
                              :mod (w / wild-type))))))

# ::id bel_pmid_1529_2179.384 ::date 2015-05-03T03:11:55 ::annotator SDL-AMR-09 ::preferred
# ::snt In ERK-1+/+ MEFs, hyperoxia stimulated phosphorylation of Nrf2 (lane 4), when compared with room air-exposed controls (lane 3).
# ::save-date Sat Jan 2, 2016 ::file bel_pmid_1529_2179_384.txt
(s2 / stimulate-01
      :ARG0 (h / hyperoxia)
      :ARG1 (p2 / phosphorylate-01
            :ARG1 (p / protein :name (n / name :op1 "Nrf2")))
      :ARG1-of (d / describe-01
            :ARG0 (l / lane
                  :ARG1-of (l2 / label-01
                        :ARG2 4)))
      :location (f2 / fibroblast
            :part-of (e / embryo
                  :mod (m / mouse))
            :mod (e3 / enzyme :name (n2 / name :op1 "ERK-1")
                  :mod (w / wild-type)))
      :condition (c / compare-01
                  :ARG1 s2
                  :ARG2 (c2 / control
                        :ARG1-of (e2 / expose-01
                              :ARG2 (a / air
                                    :mod (r / room)))
                        :ARG1-of (d2 / describe-01
                              :ARG0 (l3 / lane
                                    :ARG1-of (l4 / label-01
                                          :ARG2 3))))))

# ::id bel_pmid_1529_2179.386 ::date 2015-05-03T03:19:46 ::annotator SDL-AMR-09 ::preferred
# ::snt However, a high proportion of Nrf2 accumulated in the nucleus of both cell types following the exposure of cells to hyperoxia (Fig. 1A, right panels).
# ::save-date Mon Dec 21, 2015 ::file bel_pmid_1529_2179_386.txt
(h3 / have-concession-91
      :ARG1 (a / accumulate-01
            :ARG1 (p / proportion
                  :ARG1-of (h / high-02)
                  :quant-of (p3 / protein :name (n / name :op1 "Nrf2")))
            :location (n2 / nucleus
                  :part-of (c2 / cell
                        :ARG1-of (t / type-03
                              :mod (b / both))))
            :time (a2 / after
                  :op1 (e / expose-01
                        :ARG1 c2
                        :ARG2 (h2 / hyperoxia))))
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod "1A"
                  :location (p2 / panel
                        :ARG1-of (r / right-04)))))

# ::id bel_pmid_1529_2179.388 ::date 2015-05-03T03:25:25 ::annotator SDL-AMR-09 ::preferred
# ::snt hyperoxia caused the translocation of Nrf2 from the cytoplasm to the nucleus within 30-60 min of exposure
# ::save-date Thu Dec 17, 2015 ::file bel_pmid_1529_2179_388.txt
(c / cause-01
      :ARG0 (h / hyperoxia)
      :ARG1 (t / translocate-01
            :ARG1 (p / protein :name (n / name :op1 "Nrf2"))
            :ARG2 (n2 / nucleus)
            :ARG3 (c2 / cytoplasm)
            :time (a / after
                  :op1 (e / expose-01)
                  :quant (u / up-to
                        :op1 (v / value-interval
                              :op1 (t2 / temporal-quantity :quant 30
                                    :unit (m2 / minute))
                              :op2 (t3 / temporal-quantity :quant 60
                                    :unit (m3 / minute)))))))

# ::id bel_pmid_1529_2179.16234 ::date 2015-05-03T05:07:08 ::annotator SDL-AMR-09 ::preferred
# ::snt Taken together, these observations strongly support a role for NADPH oxidase-generated ROS in mediating hyperoxia-induced Nrf2 activation in pulmonary epithelial cells.
# ::save-date Sat Feb 13, 2016 ::file bel_pmid_1529_2179_16234.txt
(s4 / support-01
      :ARG0 (t3 / thing
            :ARG1-of (o / observe-02)
            :ARG0-of (s / support-01
                  :ARG1-of (s2 / strong-02))
            :mod (t4 / this))
      :ARG1 (r / role
            :topic (m4 / mediate-01
                  :ARG1 (a / activate-01
                        :ARG1 (p / protein :name (n3 / name :op1 "Nrf2"))
                        :ARG2-of (i / induce-01
                              :ARG0 (h2 / hyperoxia))
                        :location (c / cell
                              :part-of (e2 / epithelium
                                    :part-of (l / lung)))))
            :beneficiary (s3 / small-molecule :name (n / name :op1 "ROS")
                  :ARG1-of (g / generate-01
                        :ARG0 (m2 / macro-molecular-complex
                              :part (o2 / oxidase)
                              :part (s5 / small-molecule :name (n4 / name :op1 "NADPH"))))))
      :condition (t6 / take-01
            :ARG1 t3
            :mod (t2 / together)))

# ::id bel_pmid_1529_2179.22402 ::date 2015-05-03T05:23:49 ::annotator SDL-AMR-09 ::preferred
# ::snt hyperoxia stimulated ERK-1 and ERK-2 phosphorylation {SE: Canonical ERK phosphorylation leading directly to activation}
# ::save-date Fri Jul 24, 2015 ::file bel_pmid_1529_2179_22402.txt
(m / multi-sentence
      :snt1 (s / stimulate-01
            :ARG0 (h / hyperoxia)
            :ARG1 (p2 / phosphorylate-01
                  :ARG1 (a / and
                        :op1 (e2 / enzyme :name (n2 / name :op1 "ERK-1"))
                        :op2 (e3 / enzyme :name (n3 / name :op1 "ERK-2")))))
      :snt2 (p / phosphorylate-01
            :ARG1 (e / enzyme :name (n / name :op1 "ERK"))
            :mod (c2 / canon)
            :ARG0-of (l / lead-03
                  :ARG2 (a2 / activate-01)
                  :ARG1-of (d / direct-02))))

# ::id bel_pmid_1529_2179.37048 ::date 2015-05-03T05:29:47 ::annotator SDL-AMR-09 ::preferred
# ::snt Overexpression of the ERK-1 mutant, but not the ERK-2 mutant, significantly inhibited hyperoxia-induced ARE transcription, suggesting that ERK-1 at least in part mediates Nrf2 translocation and its downstream target expression (Fig. 7B).
# ::save-date Fri Feb 12, 2016 ::file bel_pmid_1529_2179_37048.txt
(c / contrast-01
      :ARG1 (i / inhibit-01
            :ARG0 (o / overexpress-01
                  :ARG1 (e2 / enzyme :name (n / name :op1 "ERK-1")
                        :ARG2-of (m / mutate-01)))
            :ARG1 (t3 / transcribe-01
                  :ARG1 (p3 / protein :name (n3 / name :op1 "ARE"))
                  :ARG2-of (i3 / induce-01
                        :ARG0 (h / hyperoxia)))
            :ARG1-of (s2 / significant-02))
      :ARG2 (i2 / inhibit-01 :polarity -
            :ARG0 (o2 / overexpress-01
                  :ARG1 (e4 / enzyme :name (n2 / name :op1 "ERK-2")
                        :ARG1-of (m2 / mutate-01)))
            :ARG1 t3)
      :ARG0-of (s / suggest-01
            :ARG1 (m3 / mediate-01
                  :ARG0 e2
                  :ARG1 (a2 / and
                        :op1 (t2 / translocate-01
                              :ARG1 (p / protein :name (n4 / name :op1 "Nrf2")))
                        :op2 (e5 / express-03
                              :ARG2 p
                              :location (d / downstream)
                              :mod (t / target-01)))
                  :degree (a / at-least
                        :op1 (p2 / part))))
      :ARG1-of (d2 / describe-01
            :ARG0 (f / figure :mod "7B")))

# ::id bel_pmid_1529_2206.19252 ::date 2015-05-03T05:43:20 ::annotator SDL-AMR-09 ::preferred
# ::snt The interleukin-6 (IL6) family of cytokines signals through the common receptor subunit gp130, and subsequently activates Stat3, MAPK, and PI3K.
# ::save-date Mon Jan 4, 2016 ::file bel_pmid_1529_2206_19252.txt
(a / and
      :op1 (s / signal-07
            :ARG0 (p / protein-family :name (n2 / name :op1 "interleukin-6"))
            :instrument (p4 / protein :name (n3 / name :op1 "gp130")
                  :mod (s2 / subunit
                        :part-of (r2 / receptor
                              :mod (c2 / common)))))
      :op2 (a2 / activate-01
            :ARG1 (a3 / and
                  :op1 (p3 / protein :name (n4 / name :op1 "Stat3"))
                  :op2 (e / enzyme :name (n / name :op1 "MAPK"))
                  :op3 (e2 / enzyme :name (n5 / name :op1 "PI3K")))
            :manner (s4 / subsequent)))

# ::id bel_pmid_1529_2206.21658 ::date 2015-05-03T05:58:35 ::annotator SDL-AMR-09 ::preferred
# ::snt Experiments in primary mammary epithelial cells and transfected COS-7 cells revealed a p44/42 MAPK and EGFR-dependent Stat3 activation.
# ::save-date Thu Dec 17, 2015 ::file bel_pmid_1529_2206_21658.txt
(r / reveal-01
      :ARG0 (e / experiment-01
            :ARG1 (a / and
                  :op1 (c / cell
                        :part-of (e2 / epithelium)
                        :mod (p2 / primary)
                        :mod (m / mammary))
                  :op2 (c2 / cell-line :name (n2 / name :op1 "COS-7")
                        :ARG1-of (t / transfect-01))))
      :ARG1 (a2 / activate-01
            :ARG1 (p / protein :name (n3 / name :op1 "Stat3"))
            :ARG0-of (d / depend-01
                  :ARG1 (a3 / and
                        :op1 (e5 / enzyme :name (n4 / name :op1 "EGFR"))
                        :op2 (s / slash
                              :op1 (e3 / enzyme :name (n / name :op1 "p44MAPK"))
                              :op2 (e4 / enzyme :name (n5 / name :op1 "p42MAPK")))))))

# ::id bel_pmid_1529_2206.28426 ::date 2015-05-03T06:07:23 ::annotator SDL-AMR-09 ::preferred
# ::snt Stat3 controls cell death and tissue remodeling in the mouse mammary gland during involution, which is partially induced by IL6 and LIF.
# ::save-date Sun Dec 20, 2015 ::file bel_pmid_1529_2206_28426.txt
(c / control-01
      :ARG0 (p2 / protein :name (n / name :op1 "Stat3"))
      :ARG1 (a / and
            :op1 (d / die-01
                  :ARG1 (c2 / cell))
            :op2 (r / remodel-01
                  :ARG1 (t / tissue)))
      :location (g2 / gland
            :mod (m / mammary)
            :part-of (m2 / mouse))
      :time (i / involution
            :ARG2-of (i2 / induce-01
                  :ARG0 (a2 / and
                        :op1 (p3 / protein :name (n2 / name :op1 "IL6"))
                        :op2 (p4 / protein :name (n3 / name :op1 "LIF")))
                  :degree (p / part))))

# ::id bel_pmid_1532_0963.2798 ::date 2015-05-03T06:17:45 ::annotator SDL-AMR-09 ::preferred
# ::snt We found that the Tyr701 phosphorylation kinetics of Stat1 mediated by IFN stimulation was higher when cells were incubated with IFN-alpha5 than when using IFN-alpha2. Similarly, Tyr(1054/1055) phosphorylation kinetics of Tyk2 were more intense after exposure to IFN-alpha5 than when using IFN-alpha2. Concomitantly, Tyr705 phosphorylation of Stat3 was higher after stimulation with IFN-alpha5 than with IFN-alpha2.
# ::save-date Sun Jul 26, 2015 ::file bel_pmid_1532_0963_2798.txt
(m / multi-sentence
      :snt1 (f / find-01
            :ARG0 (w / we)
            :ARG1 (h2 / high-02
                  :ARG1 (k / kinetics
                        :mod (p2 / phosphorylate-01
                              :ARG1 (a / amino-acid :mod 701 :name (n / name :op1 "tyrosine")
                                    :part-of (p / protein :name (n12 / name :op1 "Stat1"))))
                        :ARG1-of (m2 / mediate-01
                              :ARG0 (s / stimulate-01
                                    :ARG0 (p3 / protein :name (n3 / name :op1 "IFN")))))
                  :degree (m3 / more)
                  :condition (i / incubate-01
                        :ARG1 (c / cell)
                        :ARG2 (p4 / protein :name (n4 / name :op1 "IFN-alpha5")))
                  :compared-to (u / use-01
                        :ARG1 (p5 / protein :name (n7 / name :op1 "IFN-alpha2")))))
      :snt2 (i2 / intense-02
            :ARG1 (k3 / kinetics
                  :mod (p6 / phosphorylate-01
                        :ARG1 (s2 / slash
                              :op1 (a4 / amino-acid :mod 1054 :name (n2 / name :op1 "tyrosine")
                                    :part-of (e2 / enzyme :name (n6 / name :op1 "Tyk2")))
                              :op2 (a5 / amino-acid :mod 1055 :name (n5 / name :op1 "tyrosine")
                                    :part-of e2))))
            :degree (m4 / more)
            :compared-to (u2 / use-01
                  :ARG1 (p7 / protein :name (n8 / name :op1 "IFN-alpha2")))
            :time (a3 / after
                  :op1 (e / expose-01
                        :ARG1 (p8 / protein :name (n9 / name :op1 "IFN-alpha5"))))
            :ARG1-of (r / resemble-01))
      :snt3 (h / high-02
            :ARG1 (p9 / phosphorylate-01
                  :ARG1 (a6 / amino-acid :mod 705 :name (n13 / name :op1 "tyrosine")
                        :part-of (p10 / protein :name (n14 / name :op1 "Stat3"))))
            :degree (m5 / more)
            :time (a7 / after
                  :op1 (s3 / stimulate-01
                        :ARG0 (p11 / protein :name (n15 / name :op1 "IFN-alpha5"))))
            :compared-to (s4 / stimulate-01
                  :ARG0 (p12 / protein :name (n16 / name :op1 "IFN-alpha2")))
            :mod (c2 / concomitant)))

# ::id bel_pmid_1535_5339.5770 ::date 2015-05-03T08:26:03 ::annotator SDL-AMR-09 ::preferred
# ::snt The accumulation of the ST6Gal I transcript in response to activated Ras was accompanied by an increase of alpha2,6-sialyltransferase activity and of Neu5Acalpha2,6Gal at the cell surface.
# ::save-date Mon Jul 6, 2015 ::file bel_pmid_1535_5339_5770.txt
(a6 / accompany-01
      :ARG0 (i / increase-01
            :ARG1 (a2 / activity-06
                  :ARG0 (a5 / and
                        :op1 (e3 / enzyme :name (n4 / name :op1 "alpha2,6-sialyltransferase"))
                        :op2 (e4 / enzyme :name (n5 / name :op1 "Neu5Acalpha2,6Gal")))
                  :location (s / surface
                        :part-of (c / cell))))
      :ARG1 (a / accumulate-01
            :ARG1 (m / molecular-physical-entity
                  :ARG0-of (t / transcribe-01
                        :ARG1 (e / enzyme :name (n2 / name :op1 "ST6Gal-I"))))
            :ARG2-of (r / respond-01
                  :ARG1 (e2 / enzyme :name (n3 / name :op1 "Ras")
                        :ARG1-of (a3 / activate-01)))))

# ::id bel_pmid_1535_5339.19518 ::date 2015-05-03T08:35:23 ::annotator SDL-AMR-09 ::preferred
# ::snt Results obtained with H-RasV12 partial loss of function mutants H-RasV12S35 (Raf signal only), H-RasV12C40 (PI3-kinase signal only) and H-RasV12G37 (RalGEFs signal only) suggest that the H-Ras induction of the mouse ST6Gal I gene (Siat1) transcription is primarily routed through RalGEFs.
# ::save-date Sun Jan 3, 2016 ::file bel_pmid_1535_5339_19518.txt
(s / suggest-01
      :ARG0 (t / thing
            :ARG2-of (r / result-01)
            :ARG1-of (o / obtain-01
                  :instrument (a / and
                        :op1 (e / enzyme :name (n3 / name :op1 "H-Ras")
                              :ARG2-of (m / mutate-01 :value "V12S35")
                              :ARG1-of (m5 / mean-01
                                    :ARG2 (e2 / enzyme :name (n / name :op1 "H-Ras")
                                          :ARG2-of (m6 / mutate-01 :value "V12")
                                          :ARG0-of (l2 / lose-02
                                                :ARG1 (f2 / function)
                                                :degree (p / part))))
                              :ARG1-of (s2 / signal-07
                                    :ARG0 (e5 / enzyme :name (n2 / name :op1 "Raf"))))
                        :op2 (e3 / enzyme :name (n4 / name :op1 "H-Ras")
                              :ARG2-of (m2 / mutate-01 :value "V12C40")
                              :ARG1-of (s3 / signal-07
                                    :ARG0 (k / kinase :name (n6 / name :op1 "P13"))))
                        :op3 (e4 / enzyme :name (n5 / name :op1 "H-Ras")
                              :ARG2-of (m3 / mutate-01 :value "V12G37")
                              :ARG1-of (s4 / signal-07
                                    :ARG0 (p2 / pathway :name (n9 / name :op1 "RalGEF"))
                                    :mod (o2 / only))))))
      :ARG1 (r2 / route-01
            :ARG0 p2
            :ARG1 (i / induce-01
                  :ARG0 (e6 / enzyme :name (n7 / name :op1 "H-Ras"))
                  :ARG2 (t2 / transcribe-01
                        :ARG1 (g / gene :name (n8 / name :op1 "ST6Gal" :op2 "I")
                              :mod (m4 / mouse))))
            :mod (p3 / primary)))

# ::id bel_pmid_1535_5339.20914 ::date 2015-05-03T09:52:19 ::annotator SDL-AMR-09 ::preferred
# ::snt Transformation by human K-Ras or H-Ras (S12 and V12 point mutations, respectively) results in a 10-fold increase in ST6Gal I mRNA, but no alteration in the expression of related sialyltransferases.
# ::save-date Sun May 10, 2015 ::file bel_pmid_1535_5339_20914.txt
(r / result-01
      :ARG1 (t / transform-01
            :ARG0 (o / or
                  :op1 (e / enzyme :name (n / name :op1 "K-Ras")
                        :ARG2-of (m / mutate-01 :value "S2")
                        :mod (h / human))
                  :op2 (e2 / enzyme :name (n2 / name :op1 "H-Ras")
                        :ARG2-of (m2 / mutate-01 :value "V12")
                        :mod h)))
      :ARG2 (c / contrast-01
            :ARG1 (i / increase-01
                  :ARG1 (n6 / nucleic-acid :name (n4 / name :op1 "mRNA")
                        :ARG0-of (e5 / encode-01
                              :ARG1 (e6 / enzyme :name (n3 / name :op1 "ST6Gal" :op2 "I"))))
                  :ARG2 (p / product-of :op1 10))
            :ARG2 (a / alter-01 :polarity -
                  :ARG1 (e3 / express-03
                        :ARG2 (e4 / enzyme :name (n5 / name :op1 "sialyltransferase")
                              :ARG1-of (r3 / relate-01))))))

# ::id bel_pmid_1536_9798.8104 ::date 2015-05-03T10:01:46 ::annotator SDL-AMR-09 ::preferred
# ::snt Survivin disruption by DN T34A Survivin blocked CA-Ras-induced IL-3-independent cell survival and proliferation; however, it did not affect CA-Ras-mediated enhancement of S-phase, indicating that the anti-apoptotic activity of CA-Ras is Survivin dependent while its S-phase enhancing effect is not.
# ::save-date Sun Dec 20, 2015 ::file bel_pmid_1536_9798_8104.txt
(h / have-concession-91
      :ARG1 (a2 / affect-01 :polarity -
            :ARG0 d
            :ARG1 (e2 / enhance-01
                  :ARG1 (e5 / event :name (n / name :op1 "S-phase"))
                  :ARG1-of (m / mediate-01
                        :ARG0 e))
            :ARG0-of (i2 / indicate-01
                  :ARG1 (c3 / contrast-01
                        :ARG1 (a3 / activity-06
                              :ARG0 e
                              :ARG1 (o / oppose-01
                                    :ARG1 (a4 / apoptosis))
                              :ARG0-of (d4 / depend-01
                                    :ARG1 p))
                        :ARG2 (d5 / depend-01 :polarity -
                              :ARG0 (a5 / affect-01
                                    :ARG2 (e4 / enhance-01
                                          :ARG0 e5))
                              :ARG1 p2))))
      :ARG2 (b / block-01
            :ARG0 (d / disrupt-01
                  :ARG0 (p2 / protein :name (n2 / name :op1 "Survivin")
                        :ARG2-of (m2 / mutate-01 :value "T34A" :mod "-/-"))
                  :ARG1 (p / protein :name (n5 / name :op1 "Survivin")))
            :ARG1 (a / and
                  :op1 (s / survive-01
                        :ARG0 (c / cell)
                        :ARG2-of (i / induce-01
                              :ARG0 (e / enzyme :name (n3 / name :op1 "CA-Ras")))
                        :ARG0-of (d3 / depend-01
                              :ARG1 (p5 / protein :name (n4 / name :op1 "IL-3"))))
                  :op2 (p3 / proliferate-01
                        :ARG0 c
                        :ARG1-of i
                        :ARG0-of d3))))

# ::id bel_pmid_1536_9798.9254 ::date 2015-05-03T10:28:07 ::annotator SDL-AMR-09 ::preferred
# ::snt Survivin expression is up-regulated by IL-3 in Ba/F3 and CD34+ cells and inhibited by the Ras inhibitor, farnesylthiosalicylic acid.
# ::save-date Fri Feb 12, 2016 ::file bel_pmid_1536_9798_9254.txt
(a2 / and
      :op1 (u / upregulate-01
            :ARG1 (e2 / express-03
                  :ARG2 (p / protein :wiki "Survivin" :name (n2 / name :op1 "Survivin")))
            :ARG2 (p2 / protein :wiki "Interleukin_3" :name (n3 / name :op1 "IL-3"))
            :location (a / and
                  :op1 (c2 / cell-line :wiki - :name (n4 / name :op1 "Ba/F3"))
                  :op2 (c / cell-line :wiki "CD34" :name (n5 / name :op1 "CD34+"))))
      :op2 (i2 / inhibit-01
            :ARG0 (s / small-molecule :wiki - :name (n7 / name :op1 "farnesylthiosalicylic" :op2 "acid")
                  :ARG0-of (i / inhibit-01
                        :ARG1 (p3 / protein-family :wiki "Ras_subfamily" :name (n6 / name :op1 "Ras"))))
            :ARG1 e2))

# ::id bel_pmid_1536_9798.27516 ::date 2015-05-03T10:41:10 ::annotator SDL-AMR-09 ::preferred
# ::snt Over-expression of constitutively activated H-Ras (CA-Ras) in Ba/F3 cells blocked down-modulation of Survivin expression, G0/G1 arrest, and apoptosis induced by IL-3 withdrawal, while dominant-negative (DN) H-Ras down-regulated Survivin.
# ::save-date Sat Jan 2, 2016 ::file bel_pmid_1536_9798_27516.txt
(c4 / contrast-01
      :ARG1 (b / block-01
            :ARG0 (o / overexpress-01
                  :ARG1 (e / enzyme :name (n / name :op1 "H-Ras")
                        :ARG1-of (a / activate-01
                              :manner (c / constitutive)))
                  :location (c5 / cell-line :name (n7 / name :op1 "Ba/F3")))
            :ARG1 (a2 / and
                  :op1 (d2 / downmodulate-01
                        :ARG1 (e3 / express-03
                              :ARG2 (p / protein :name (n3 / name :op1 "Survivin"))))
                  :op2 (a3 / arrest-02
                        :ARG1 (c3 / cell-line :name (n4 / name :op1 "G0/G1")))
                  :op3 (a4 / apoptosis
                        :ARG2-of (i / induce-01
                              :ARG0 (w / withdraw-01
                                    :ARG1 (p2 / protein :name (n5 / name :op1 "IL-3")))))))
      :ARG2 (d / downregulate-01
            :ARG0 (e4 / enzyme :name (n6 / name :op1 "H-Ras")
                  :ARG2-of (m / mutate-01 :mod "-/-"))
            :ARG1 p))

# ::id bel_pmid_1538_3658.21950 ::date 2015-05-03T11:25:23 ::annotator SDL-AMR-09 ::preferred
# ::snt By contrast, serum- and glucocorticoid-inducible kinase 1 (SGK1) was significantly induced in a p53-dependent manner after DNA damage, and this induction was through extracellular signal-regulated kinase 1/2-mediated posttranslational regulation.
# ::save-date Sun Dec 20, 2015 ::file bel_pmid_1538_3658_21950.txt
(c / contrast-01
      :ARG2 (i / induce-01
            :ARG2 (e3 / enzyme
                  :name (n3 / name :op1 "SGK1"))
            :manner (d / depend-01
                  :ARG1 (p / protein
                        :name (n / name :op1 "p53")))
            :time (a2 / after
                  :op1 (d2 / damage-01
                        :ARG1 (n5 / nucleic-acid :wiki "DNA"
                              :name (n6 / name :op1 "DNA"))))
            :ARG1-of (s3 / significant-02)
            :instrument (r2 / regulate-01
                  :mod (e / extracellular)
                  :ARG1-of (r / regulate-01
                        :ARG0 (s / signal-07))
                  :ARG1-of (m / mediate-01
                        :ARG0 (s2 / slash
                              :op1 (e2 / enzyme
                                    :name (n2 / name :op1 "kinase" :op2 1))
                              :op2 (e4 / enzyme
                                    :name (n4 / name :op1 "kinase" :op2 2))))
                  :time (a4 / after
                        :op1 (t / translate-02)))))

# ::id bel_pmid_1538_9879.2572 ::date 2015-05-03T11:56:37 ::annotator SDL-AMR-09 ::preferred
# ::snt IL-6 family cytokines (Interleukin-6 and Oncostatin M (OSM))-increase STAT3 phosphorylation (pSTAT3), increase CCAAT enhancer binding protein delta (C/EBPdelta) gene expression
# ::save-date Mon Jan 4, 2016 ::file bel_pmid_1538_9879_2572.txt
(i / increase-01
      :ARG0 (c / cytokine
            :ARG1-of (i2 / include-91
                  :ARG2 (p3 / protein-family :name (n7 / name :op1 "IL-6")))
            :ARG1-of (m2 / mean-01
                  :ARG2 (a3 / and
                        :op1 (p5 / protein :name (n8 / name :op1 "Interleukin-6"))
                        :op2 (p6 / protein :name (n9 / name :op1 "Oncostatin-M")))))
      :ARG1 (a2 / and
            :op1 (p / phosphorylate-01
                  :ARG1 (p2 / protein :name (n5 / name :op1 "STAT3")))
            :op2 (e / express-03
                  :ARG2 (g3 / gene :name (n6 / name :op1 "C/EBPdelta")))))

# ::id bel_pmid_1550_7530.2578 ::date 2015-05-03T12:22:05 ::annotator SDL-AMR-09 ::preferred
# ::snt results indicate that BCL-6 negatively regulates proliferation of the monocytic/macrophage lineage by suppressing an autocrine IL-6/STAT3-mediated gene expression program.
# ::save-date Sun May 10, 2015 ::file bel_pmid_1550_7530_2578.txt
(i / indicate-01
      :ARG0 (t / thing
            :ARG2-of (r / result-01))
      :ARG1 (d / downregulate-01
            :ARG0 (p3 / protein :name (n / name :op1 "BCL-6"))
            :ARG1 (p / proliferate-01
                  :ARG0 (s2 / slash
                        :op1 (l2 / lineage
                              :mod (m2 / monocyte))
                        :op2 (l3 / lineage
                              :mod (m3 / macrophage))))
            :manner (s / suppress-01
                  :ARG1 (p2 / program
                        :mod (e / express-03
                              :ARG2 (g2 / gene))
                        :ARG1-of (m / mediate-01
                              :ARG0 (s3 / slash
                                    :op1 (p4 / protein :name (n3 / name :op1 "IL-6"))
                                    :op2 (p5 / protein :name (n4 / name :op1 "STAT3"))))
                        :mod (a / autocrine)))))

# ::id bel_pmid_1550_7530.32694 ::date 2015-05-03T12:31:46 ::annotator SDL-AMR-09 ::preferred
# ::snt Crucial to this enhanced proliferation is spontaneous interleukin 6 (IL-6) production and signal transducer and activator of transcription 3 (STAT3) activation in BCL-6(-/-) macrophages. Gene expression studies demonstrate that BCL-6 binds to several sequence motifs scattered in the IL-6 locus and can repress IL-6 transcription both in 293T cells and in macrophages.
# ::save-date Sun Jan 3, 2016 ::file bel_pmid_1550_7530_32694.txt
(m3 / multi-sentence
      :snt1 (c / crucial
            :prep-to (p3 / proliferate-01
                  :ARG1-of (e / enhance-01)
                  :mod (t2 / this))
            :domain (a2 / and
                  :op1 (p / produce-01
                        :ARG1 (p2 / protein :name (n / name :op1 "interleukin-6"))
                        :mod (s / spontaneous))
                  :op2 (a3 / activate-01
                        :ARG1 (p8 / protein :name (n9 / name :op1 "signal" :op2 "transducer" :op3 "and" :op4 "activator" :op5 "of" :op6 "transcription" :op7 "3"))
                        :location (m4 / macrophage
                              :mod (p4 / protein :name (n4 / name :op1 "BCL-6")
                                    :ARG2-of (m / mutate-01 :mod "-/-"))))))
      :snt2 (d / demonstrate-01
            :ARG0 (s2 / study-01
                  :ARG1 (e2 / express-03
                        :ARG2 (g2 / gene)))
            :ARG1 (a4 / and
                  :op1 (b / bind-01
                        :ARG0 (p7 / protein :name (n8 / name :op1 "BCL-6"))
                        :ARG1 (m2 / motif
                              :mod (s4 / sequence)
                              :quant (s5 / several)
                              :ARG1-of (s6 / scatter-01
                                    :ARG2 (l / locus
                                          :location-of (g3 / gene :name (n5 / name :op1 "IL-6"))))))
                  :op2 (p5 / possible-01
                        :ARG1 (r / repress-01
                              :ARG0 p7
                              :ARG1 (t4 / transcribe-01
                                    :ARG1 g3)
                              :location (a5 / and
                                    :op1 (c2 / cell-line :name (n2 / name :op1 "293T"))
                                    :op2 (c3 / cell :name (n3 / name :op1 "macrophage"))))))))

# ::id bel_pmid_1559_0693.2660 ::date 2015-04-29T06:45:16 ::annotator SDL-AMR-09 ::preferred
# ::snt ERK1/2 and JNK inactivation was associated with Ets-like transcription factor-1 (ELK-1) dephosphorylation.
# ::save-date Thu May 7, 2015 ::file bel_pmid_1559_0693_2660.txt
(a / associate-01
      :ARG1 (a3 / activate-01 :polarity -
            :ARG1 (a2 / and
                  :op1 (e / enzyme :name (n / name :op1 "ERK1"))
                  :op2 (e2 / enzyme :name (n2 / name :op1 "ERK2"))
                  :op3 (e3 / enzyme :name (n3 / name :op1 "JNK"))))
      :ARG2 (d / dephosphorylate-01
            :ARG1 (p2 / protein :name (n6 / name :op1 "Ets-like" :op2 "transcription" :op3 "factor-1")
                  :ARG1-of (d2 / describe-01
                        :ARG2 (p / protein :name (n5 / name :op1 "ELK-1"))))))

# ::id bel_pmid_1562_3503.11656 ::date 2015-04-29T06:55:46 ::annotator SDL-AMR-09 ::preferred
# ::snt Rev-erbbeta is an orphan nuclear receptor that selectively blocks trans-activation mediated by the retinoic acid-related orphan receptor-alpha (RORalpha)
# ::save-date Thu Dec 17, 2015 ::file bel_pmid_1562_3503_11656.txt
(r / receptor
      :mod (o / orphan)
      :mod (n / nucleus)
      :domain (p / protein :name (n2 / name :op1 "Rev-erbbeta"))
      :ARG0-of (b / block-01
            :ARG1 (t / transactivate-01
                  :ARG1-of (m / mediate-01
                        :ARG0 (p2 / protein :name (n3 / name :op1 "retinoic" :op2 "acid-related" :op3 "orphan" :op4 "receptor-alpha")
                              :ARG1-of (d / describe-01
                                    :ARG2 (r2 / receptor :name (n4 / name :op1 "RORalpha"))))))
            :manner (s / selective)))

# ::id bel_pmid_1562_3503.33508 ::date 2015-04-29T07:05:29 ::annotator SDL-AMR-09 ::preferred
# ::snt Exogenous expression of a dominant negative version of mouse Rev-erbbeta decreases the expression of many genes involved in fatty acid/lipid absorption (including Cd36, and Fabp-3 and -4). Interestingly, we observed a robust induction (15-fold) in mRNA expression of interleukin-6
# ::save-date Wed Mar 9, 2016 ::file bel_pmid_1562_3503_33508.txt
(m / multi-sentence
      :snt1 (d / decrease-01
            :ARG0 (e / express-03
                  :ARG2 (v / version
                        :ARG0-of (d2 / dominate-01)
                        :mod (p / protein :name (n / name :op1 "Rev-erbbeta")
                              :source (m2 / mouse))
                        :ARG2-of (m5 / mutate-01 :mod "-/-"))
                  :mod (e2 / exogenous))
            :ARG1 (e3 / express-03
                  :ARG1 (g / gene
                        :quant (m3 / many)
                        :ARG1-of (i / involve-01
                              :ARG2 (a / absorb-01
                                    :ARG1 (s / slash
                                          :op1 (a2 / acid
                                                :ARG1-of (f / fat-03))
                                          :op2 (l / lipid))))
                        :ARG2-of (i2 / include-01
                              :ARG1 (a4 / and
                                    :op1 (g2 / gene :name (n3 / name :op1 "Cd36"))
                                    :op2 (g3 / gene :name (n4 / name :op1 "Fabp-3"))
                                    :op3 (g4 / gene :name (n5 / name :op1 "Fabp-4")))))))
      :snt2 (o / observe-01
            :ARG0 (w / we)
            :ARG1 (i3 / induce-01
                  :ARG2 (e4 / express-03
                        :ARG2 (n8 / nucleic-acid :name (n6 / name :op1 "mRNA")
                              :ARG0-of (e5 / encode-01
                                    :ARG1 (p3 / protein :name (n7 / name :op1 "interleukin-6")))))
                  :mod (r / robust
                        :ARG1-of (m4 / mean-01
                              :ARG2 (p2 / product-of :op1 15))))
            :ARG2-of (i4 / interest-01)))

# ::id bel_pmid_1564_7320.19184 ::date 2015-04-29T07:22:33 ::annotator SDL-AMR-09 ::preferred
# ::snt We report here that loss of Lsh specifically alters expression of the Cdkn1c gene The reactivation of the silenced paternal Cdkn1c allele correlates closely with a loss of CpG methylation at the 5' DMR at the Cdkn1c promoter Chromatin immunoprecipitations demonstrate a direct association of Lsh with the 5' DMR at the Cdkn1c promoter
# ::save-date Sun Jan 3, 2016 ::file bel_pmid_1564_7320_19184.txt
(m / multi-sentence
      :snt1 (r / report-01
            :ARG0 (w / we)
            :ARG1 (a / alter-01
                  :ARG0 (l / lose-01
                        :ARG1 (p2 / protein :name (n / name :op1 "Lsh")))
                  :ARG1 (e / express-03
                        :ARG1 (g / gene :name (n2 / name :op1 "Cdkn1c")))
                  :manner (s / specific-02))
            :medium (h / here))
      :snt2 (c / correlate-01
            :ARG1 (r2 / reactivate-01
                  :ARG1 (a2 / allele
                        :mod (g2 / gene :name (n3 / name :op1 "Cdkn1c"))
                        :mod (p3 / paternal)
                        :ARG1-of (s2 / silence-01)))
            :ARG2 (l2 / lose-02
                  :ARG1 (m2 / methylate-01
                        :ARG1 (d5 / dna-sequence :name (n8 / name :op1 "5'" :op2 "DMR")
                              :part-of (m4 / molecular-physical-entity
                                    :ARG0-of (p4 / promote-02
                                          :ARG1 g2))
                              :part-of (d / dna-sequence :name (n4 / name :op1 "CpG")))))
            :ARG1-of (c2 / close-10))
      :snt3 (d3 / demonstrate-01
            :ARG0 (i / immunoprecipitate-01
                  :ARG1 (m3 / macro-molecular-complex :name (n6 / name :op1 "chromatin")))
            :ARG1 (a4 / associate-01
                  :ARG1 (p6 / protein :name (n7 / name :op1 "Lsh"))
                  :ARG2 (d6 / dna-sequence :name (n10 / name :op1 "5'" :op2 "DMR")
                        :part-of (m5 / molecular-physical-entity
                              :ARG0-of (p7 / promote-02
                                    :ARG1 (g3 / gene :name (n9 / name :op1 "Cdkn1c")))))
                  :ARG1-of (d4 / direct-02))))

# ::id bel_pmid_1564_7320.25946 ::date 2015-04-29T07:49:23 ::annotator SDL-AMR-09 ::preferred
# ::snt Entrez gene: Cyclin-dependent kinase inhibitor 1C is a tight-binding inhibitor of several G1 cyclin/Cdk complexes and a negative regulator of cell proliferation.
# ::save-date Sat Jan 2, 2016 ::file bel_pmid_1564_7320_25946.txt
(a / and
      :op1 (i2 / inhibit-01
            :ARG0 (p / protein :name (n / name :op1 "cyclin-dependent" :op2 "kinase" :op3 "inhibitor" :op4 "1C")
                  :ARG1-of (b / bind-01
                        :ARG0-of (t / tight-05)))
            :ARG1 (m / macro-molecular-complex
                  :part (p2 / protein :name (n2 / name :op1 "cyclin"))
                  :part (e / enzyme :name (n3 / name :op1 "Cdk"))
                  :quant (s / several)
                  :mod (e2 / event :name (n5 / name :op1 "G1"))))
      :op2 (d / downregulate-01
            :ARG1 (p3 / proliferate-01
                  :ARG0 (c / cell))
            :ARG2 p)
      :ARG1-of (d2 / describe-01
            :ARG0 (p4 / publication-91
                  :ARG8 (n4 / name :op1 "Entrez" :op2 "gene"))))

# ::id bel_pmid_1566_5273.5396 ::date 2015-04-29T08:04:11 ::annotator SDL-AMR-09 ::preferred
# ::snt CDK2-cyclin A1/E1 and CDK1-cyclin B1 phosphorylate BARD1 on its NH(2) terminus in vivo and in vitro.
# ::save-date Sun May 3, 2015 ::file bel_pmid_1566_5273_5396.txt
(p / phosphorylate-01
      :ARG1 (p5 / protein-segment :name (n7 / name :op1 "NH2-terminus")
            :part-of (p6 / protein :name (n8 / name :op1 "BARD1")))
      :ARG2 (a / and
            :op1 (m / macro-molecular-complex
                  :part (e / enzyme :name (n / name :op1 "CDK2"))
                  :part (p2 / protein :name (n3 / name :op1 "cyclin" :op2 "A1")))
            :op2 (m2 / macro-molecular-complex
                  :part (p3 / protein :name (n4 / name :op1 "cyclin" :op2 "E1"))
                  :part e)
            :op3 (m3 / macro-molecular-complex
                  :part (e3 / enzyme :name (n5 / name :op1 "CDK1"))
                  :part (p4 / protein :name (n6 / name :op1 "cyclin" :op2 "B1"))))
      :manner (a2 / and
            :op1 (i / in-vivo)
            :op2 (i2 / in-vitro)))

# ::id bel_pmid_1566_5823.1056 ::date 2015-04-29T08:15:10 ::annotator SDL-AMR-09 ::preferred
# ::snt We also provide evidence that IRF-5 interacts with and is activated by MyD88 and TRAF6
# ::save-date Wed Apr 29, 2015 ::file bel_pmid_1566_5823_1056.txt
(p / provide-01
      :ARG0 (w / we)
      :ARG1 (e / evidence
            :topic (a2 / and
                  :op1 (i / interact-01
                        :ARG0 (p2 / protein :name (n / name :op1 "IRF-5"))
                        :ARG1 (a3 / and
                              :op1 (p3 / protein :name (n2 / name :op1 "MyD88"))
                              :op2 (p4 / protein :name (n3 / name :op1 "TRAF6"))))
                  :op2 (a4 / activate-01
                        :ARG0 a3
                        :ARG1 p2)))
      :mod (a / also))

# ::id bel_pmid_1566_5823.33196 ::date 2015-04-29T08:19:54 ::annotator SDL-AMR-09 ::preferred
# ::snt Here, we demonstrate that the transcription factor IRF-5 is generally involved downstream of the TLR-MyD88 signalling pathway for gene induction of proinflammatory cytokines, such as interleukin-6 (IL-6), IL-12 and tumour-necrosis factor-alpha. In haematopoietic cells from mice deficient in the Irf5 gene (Irf5-/- mice), the induction of these cytokines by various TLR ligands is severely impaired
# ::save-date Sun Jan 17, 2016 ::file bel_pmid_1566_5823_33196.txt
(m / multi-sentence
      :snt1 (d / demonstrate-01
            :ARG0 (w / we)
            :ARG1 (i / involve-01
                  :ARG1 (p2 / protein :name (n / name :op1 "IRF-5")
                        :mod (f / factor
                              :ARG0-of (t2 / transcribe-01)))
                  :ARG1-of (g / general-02)
                  :location (r / relative-position
                        :op1 (p3 / pathway :name (n2 / name :op1 "TLR-MyD88")
                              :ARG0-of (s / signal-07
                                    :ARG1 (i2 / induce-01
                                          :ARG2 (g2 / gene
                                                :ARG0-of (e / encode-01
                                                      :ARG1 (c2 / cytokine
                                                            :ARG0-of (f2 / favor-01
                                                                  :ARG1 (i3 / inflame-01))
                                                            :example (a / and
                                                                  :op1 (p5 / protein :name (n4 / name :op1 "interleukin-6")
                                                                        :ARG1-of (d3 / describe-01
                                                                              :ARG2 (p8 / protein :name (n7 / name :op1 "IL-6"))))
                                                                  :op2 (p6 / protein :name (n5 / name :op1 "IL-12"))
                                                                  :op3 (p7 / protein :name (n6 / name :op1 "tumour-necrosis" :op2 "factor-alpha")))))))))
                        :direction (d2 / downstream)))
            :medium (h2 / here))
      :snt2 (i4 / impair-01
            :ARG1 (i5 / induce-01
                  :ARG0 (l / ligand :name (n9 / name :op1 "TLR")
                        :mod (v / various))
                  :ARG2 (c3 / cytokine
                        :mod (t3 / this)))
            :manner (s2 / severe)
            :location (c / cell
                  :mod (h / haematopoietic)
                  :source (m2 / mouse
                        :ARG0-of (l2 / lack-01
                              :ARG1 (g4 / gene :name (n3 / name :op1 "IRF5")))
                        :ARG1-of (d4 / describe-01
                              :ARG2 (m3 / mouse
                                    :mod (g3 / gene :name (n10 / name :op1 "IRF5")
                                          :ARG2-of (m4 / mutate-01 :mod "-/-"))))))))

# ::id bel_pmid_1567_1526.28746 ::date 2015-04-29T08:40:12 ::annotator SDL-AMR-09 ::preferred
# ::snt Stable knockdown of mutant KRAS(D12) in murine C26 CRC cells by RNA interference lead to a dramatic reduction of COX-2 synthesis and prostaglandin E2 production.
# ::save-date Sun Jan 17, 2016 ::file bel_pmid_1567_1526_28746.txt
(l / lead-03
      :ARG0 (k / knock-down-02
            :ARG1 (e2 / enzyme :name (n / name :op1 "KRAS")
                  :ARG1-of (m / mutate-01 :value "D12"))
            :ARG5 (i / interfere-01
                  :ARG0 (n5 / nucleic-acid :name (n6 / name :op1 "RNA")))
            :ARG1-of (s / stable-03)
            :location (c / cell-line :name (n4 / name :op1 "C26")
                  :source (m2 / mouse)
                  :mod (d2 / disease :name (n7 / name :op1 "CRC"))))
      :ARG2 (r2 / reduce-01
            :ARG1 (a2 / and
                  :op1 (s2 / synthesize-01
                        :ARG1 (e / enzyme :name (n2 / name :op1 "COX-2")))
                  :op2 (p2 / produce-01
                        :ARG1 (s3 / small-molecule :name (n3 / name :op1 "prostaglandin" :op2 "E2"))))
            :degree (d / dramatic)))

# ::id bel_pmid_1568_5173.4092 ::date 2015-04-29T08:57:34 ::annotator SDL-AMR-09 ::preferred
# ::snt These findings indicate that lipid accumulation in the liver leads to subacute hepatic 'inflammation' through NF-kappaB activation and downstream cytokine production. This causes insulin resistance both locally in liver and systemically.
# ::save-date Sun Jul 26, 2015 ::file bel_pmid_1568_5173_4092.txt
(m / multi-sentence
      :snt1 (i / indicate-01
            :ARG0 (t / thing
                  :mod (t2 / this)
                  :ARG1-of (f / find-01))
            :ARG1 (l / lead-03
                  :ARG0 (a / accumulate-01
                        :ARG0 (l3 / liver)
                        :ARG1 (l2 / lipid))
                  :ARG1 (i2 / inflame-01
                        :ARG0 (a2 / and
                              :op1 (a3 / activate-01
                                    :ARG1 (m2 / macro-molecular-complex :name (n / name :op1 "NF-kappaB")))
                              :op2 (p / produce-01
                                    :ARG1 (c2 / cytokine)
                                    :location (d / downstream)))
                        :ARG1 l3
                        :mod (s / subacute))))
      :snt2 (c / cause-01
            :ARG0 (t3 / this)
            :ARG1 (r / resist-01
                  :ARG1 (p2 / protein :name (n3 / name :op1 "insulin")))
            :manner (a4 / and
                  :op1 (l4 / local-02
                        :ARG2 (l5 / liver))
                  :op2 (s2 / system))))

# ::id bel_pmid_1568_5173.6180 ::date 2015-04-29T09:09:44 ::annotator SDL-AMR-09 ::preferred
# ::snt Insulin resistance was improved by systemic neutralization of IL-6 or salicylate inhibition of IKK-beta.
# ::save-date Wed Jan 13, 2016 ::file bel_pmid_1568_5173_6180.txt
(i / improve-01
      :ARG0 (o / or
            :op1 (n2 / neutralize-01
                  :ARG1 (p / protein :name (n3 / name :op1 "IL-6"))
                  :mod (s2 / system))
            :op2 (i2 / inhibit-01
                  :ARG0 (s3 / small-molecule :name (n5 / name :op1 "salicylate"))
                  :ARG1 (e / enzyme :name (n4 / name :op1 "IKK-beta"))))
      :ARG1 (r / resist-01
            :ARG1 (p3 / protein :name (n / name :op1 "insulin"))))

# ::id bel_pmid_1568_8424.11152 ::date 2015-04-29T09:13:46 ::annotator SDL-AMR-09 ::preferred
# ::snt We here report that the NFkappaB and C/EBP beta controlled gene IL6 is upregulated in DDIT3- and FUS-DDIT3-expressing fibrosarcoma cell lines
# ::save-date Fri Jan 15, 2016 ::file bel_pmid_1568_8424_11152.txt
(r / report-01
      :ARG0 (w / we)
      :ARG1 (u / upregulate-01
            :ARG1 (g / gene :name (n / name :op1 "IL6")
                  :ARG1-of (c / control-01
                        :ARG0 (a / and
                              :op1 (m / macro-molecular-complex :name (n2 / name :op1 "NF-kappaB"))
                              :op2 (p2 / protein :name (n3 / name :op1 "C/EBP" :op2 "beta")))))
            :location (c2 / cell-line
                  :part-of (f / fibrosarcoma)
                  :ARG3-of (e / express-03
                        :ARG1 (a2 / and
                              :op1 (p / protein :name (n4 / name :op1 "DDIT3"))
                              :op2 (p3 / protein :name (n5 / name :op1 "FUS-DDIT3"))))))
      :medium (h / here))

# ::id bel_pmid_1568_8424.11196 ::date 2015-04-29T09:24:44 ::annotator SDL-AMR-09 ::preferred
# ::snt Knockdown experiments using siRNA against CEBPB transcripts showed that the effect of FUS-DDIT3 on IL6 expression is C/EBP beta dependent
# ::save-date Sun Jan 17, 2016 ::file bel_pmid_1568_8424_11196.txt
(s / show-01
      :ARG0 (e / experiment-01
            :ARG1 (k / knock-down-02)
            :ARG0-of (u / use-01
                  :ARG1 (n2 / nucleic-acid :name (n / name :op1 "siRNA")
                        :ARG0-of (c / counter-01
                              :ARG1 (g / gene :name (n3 / name :op1 "CEBPB")
                                    :ARG1-of (t / transcribe-01))))))
      :ARG1 (d / depend-01
            :ARG0 (a / affect-01
                  :ARG0 (p2 / protein :name (n6 / name :op1 "FUS-DDIT3"))
                  :ARG1 (e2 / express-03
                        :ARG2 (p3 / protein :name (n5 / name :op1 "IL6"))))
            :ARG1 (p / protein :name (n4 / name :op1 "C/EBP" :op2 "beta"))))

# ::id bel_pmid_1573_6430.6098 ::date 2015-04-29T09:56:35 ::annotator SDL-AMR-09 ::preferred
# ::snt Our results suggest that Chk1 associates with BAD and phosphorylates the BAD protein at serine-155
# ::save-date Thu May 7, 2015 ::file bel_pmid_1573_6430_6098.txt
(s / suggest-01
      :ARG0 (t / thing
            :ARG1-of (r / result-01)
            :poss (w / we))
      :ARG1 (a / and
            :op1 (a2 / associate-01
                  :ARG1 (e / enzyme :name (n / name :op1 "Chk1"))
                  :ARG2 (p / protein :name (n2 / name :op1 "BAD")))
            :op2 (p2 / phosphorylate-01
                  :ARG1 (a3 / amino-acid :mod 155 :name (n3 / name :op1 "serine")
                        :part-of p)
                  :ARG2 e)))

# ::id bel_pmid_1573_6430.6100 ::date 2015-04-29T10:04:01 ::annotator SDL-AMR-09 ::preferred
# ::snt Furthermore, Chk1 also phosphorylates Cdc25A on serine 123 which accelerates its degradation through the ubiquitin-proteasome pathway and arrests cells in late G2-phase after DNA damage.
# ::save-date Sat Jan 2, 2016 ::file bel_pmid_1573_6430_6100.txt
(a2 / and
      :op2 (p / phosphorylate-01
            :ARG1 (a / amino-acid :mod 123 :name (n / name :op1 "serine")
                  :part-of (e / enzyme :name (n3 / name :op1 "Cdc25A")))
            :ARG2 (e2 / enzyme :name (n2 / name :op1 "Chk1"))
            :ARG0-of (a3 / accelerate-01
                  :ARG1 (d / degrade-01
                        :ARG1 e
                        :ARG2 (p2 / pathway :name (n4 / name :op1 "ubiquitin-proteasome"))))
            :ARG0-of (a4 / arrest-02
                  :ARG1 (c / cell)
                  :time (a5 / after
                        :op1 (d2 / damage-01
                              :ARG1 (n5 / nucleic-acid :wiki "DNA" :name (n6 / name :op1 "DNA"))))
                  :time (e3 / event :name (n7 / name :op1 "phase" :op2 "G2")
                        :mod (l / late)))
            :mod (a6 / also)))

# ::id bel_pmid_1574_9903.11636 ::date 2015-04-29T10:15:47 ::annotator SDL-AMR-09 ::preferred
# ::snt IkappaBNS was recruited to the IL-6 promoter, but not to the TNF-alpha promoter, together with p50.
# ::save-date Thu May 7, 2015 ::file bel_pmid_1574_9903_11636.txt
(r / recruit-01
      :ARG1 (p / protein :name (n / name :op1 "IkappaBNS")
            :accompanier (p6 / protein :name (n4 / name :op1 "p50")))
      :ARG2 (m / molecular-physical-entity
            :ARG0-of (p2 / promote-01
                  :ARG1 (p3 / protein :name (n2 / name :op1 "IL-6"))))
      :ARG1-of (c / contrast-01
            :ARG2 (r2 / recruit-01 :polarity -
                  :ARG1 p
                  :ARG2 (m2 / molecular-physical-entity
                        :ARG0-of (p4 / promote-01
                              :ARG1 (p5 / protein :name (n3 / name :op1 "TNF-alpha")))))))

# ::id bel_pmid_1574_9903.11638 ::date 2015-04-29T10:23:42 ::annotator SDL-AMR-09 ::preferred
# ::snt IkappaBNS resulted in impaired LPS-induced IL-6 production, but not TNF-alpha production in the murine macrophage cell line RAW264.7.
# ::save-date Sun Dec 20, 2015 ::file bel_pmid_1574_9903_11638.txt
(r / result-01
      :ARG1 (p / protein :name (n / name :op1 "IkappaBNS"))
      :ARG2 (p2 / produce-01
            :ARG1 (p3 / protein :name (n2 / name :op1 "IL-6"))
            :ARG1-of (i / impair-01)
            :ARG2-of (i2 / induce-01
                  :ARG0 (m3 / molecular-physical-entity :name (n3 / name :op1 "LPS")))
            :location (c / cell-line :name (n5 / name :op1 "RAW264.7")
                  :consist-of (m / macrophage
                        :mod (m2 / mouse))))
      :ARG1-of (c2 / contrast-01
            :ARG2 (r2 / result-01 :polarity -
                  :ARG1 p
                  :ARG2 (p4 / produce-01
                        :ARG1 (p5 / protein :name (n4 / name :op1 "TNF-alpha"))
                        :location c))))

# ::id bel_pmid_1574_9903.27884 ::date 2015-04-29T10:30:48 ::annotator SDL-AMR-09 ::preferred
# ::snt We compared CLPMphi gene expression profiles of wild-type mice with IL-10-deficient mice, and identified genes that are selectively expressed in wild-type CLPMphi. These genes included nuclear IkappaB proteins such as Bcl-3 and IkappaBNS.
# ::save-date Thu Apr 30, 2015 ::file bel_pmid_1574_9903_27884.txt
(m / multi-sentence
      :snt1 (a / and
            :op1 (c / compare-01
                  :ARG0 (w / we)
                  :ARG1 (p / profile
                        :mod (e / express-03
                              :ARG1 (g / gene :name (n / name :op1 "CLPMphi")))
                        :poss (m2 / mouse
                              :mod (w2 / wild-type)))
                  :ARG2 (m3 / mouse
                        :ARG0-of (l / lack-01
                              :ARG1 (p2 / protein :name (n2 / name :op1 "IL-10")))))
            :op2 (i / identify-01
                  :ARG0 w
                  :ARG1 (g2 / gene
                        :ARG1-of (e2 / express-03
                              :ARG3 (m4 / mouse
                                    :mod w2
                                    :mod g)
                              :manner (s / selective)))))
      :snt2 (i2 / include-01
            :ARG1 (p3 / protein :name (n3 / name :op1 "IkappaB")
                  :mod (n4 / nucleus)
                  :example (a2 / and
                        :op1 (p4 / protein :name (n5 / name :op1 "Bcl-3"))
                        :op2 (p5 / protein :name (n6 / name :op1 "IkappaBNS"))))
            :ARG2 (g3 / gene
                  :mod (t / this))))

# ::id bel_pmid_1575_7894.10588 ::date 2015-04-29T10:41:20 ::annotator SDL-AMR-09 ::preferred
# ::snt One of the phenotypes of mice with targeted disruption of the uncoupling protein-2 gene (Ucp2-/-) is greater macrophage phagocytic activity and free radical production, resulting in a striking resistance to infectious microorganisms.
# ::save-date Sun Dec 20, 2015 ::file bel_pmid_1575_7894_10588.txt
(i / include-91
      :ARG1 (a / and
            :op1 (a2 / activity-06
                  :ARG0 (m2 / macrophage)
                  :ARG1 (p / phagocytosis)
                  :mod (g / great
                        :degree (m / more)))
            :op2 (p2 / produce-01
                  :ARG1 (r3 / radical
                        :ARG1-of (f / free-04)))
            :ARG1-of (r / result-01
                  :ARG2 (r2 / resist-01
                        :ARG1 (m5 / microorganism
                              :ARG0-of (i2 / infect-01))
                        :ARG1-of (s / strike-04)))
            :domain (p4 / phenotype))
      :ARG2 (p3 / phenotype
            :poss (m3 / mouse
                  :mod (d / disrupt-01
                        :ARG1 (g2 / gene :name (n2 / name :op1 "uncoupling" :op2 "protein-2")
                              :ARG1-of (d2 / describe-01
                                    :ARG2 (g3 / gene :name (n3 / name :op1 "Ucp-2")
                                          :ARG2-of (m4 / mutate-01 :mod "-/-"))))
                        :ARG1-of (t / target-01)))))

# ::id bel_pmid_1575_7894.31794 ::date 2015-04-29T12:24:04 ::annotator SDL-AMR-09 ::preferred
# ::snt We found that levels of nitric oxide measured in either plasma or isolated macrophages from Ucp2-/- mice are significantly elevated in response to bacterial lipopolysaccharide challenge compared with similarly treated Ucp2+/+ mice.
# ::save-date Sun Jan 3, 2016 ::file bel_pmid_1575_7894_31794.txt
(f / find-01
      :ARG0 (w / we)
      :ARG1 (e / elevate-01
            :ARG1 (l / level
                  :quant-of (s2 / small-molecule :name (n / name :op1 "nitric" :op2 "oxide"))
                  :ARG1-of (m / measure-01
                        :location (o / or
                              :op1 (p / plasma)
                              :op2 (m2 / macrophage
                                    :ARG1-of (i / isolate-01))
                              :source (m3 / mouse
                                    :mod (g / gene :name (n2 / name :op1 "Ucp2")
                                          :ARG2-of (m4 / mutate-01 :mod "-/-"))))))
            :ARG1-of (s / significant-02)
            :ARG2-of (r / respond-01
                  :ARG1 (c2 / challenge-01
                        :ARG2 (s3 / small-molecule :name (n3 / name :op1 "lipopolysaccharide")
                              :mod (b / bacterium))))
            :compared-to (m5 / mouse
                  :ARG1-of (t / treat-03
                        :manner (r2 / resemble-01))
                  :mod (g2 / gene :name (n4 / name :op1 "Ucp2")
                        :mod (w2 / wild-type)))))

# ::id bel_pmid_1575_7894.31802 ::date 2015-04-29T12:33:58 ::annotator SDL-AMR-09 ::preferred
# ::snt Protein levels of iNOS and {beta}-actin were measured by Western blotting. (increased Nos2 expression)
# ::save-date Mon Dec 21, 2015 ::file bel_pmid_1575_7894_31802.txt
(m / measure-01
      :ARG1 (a2 / and
            :op1 (l / level
                  :quant-of (e3 / enzyme :name (n2 / name :op1 "iNOS")))
            :op2 (l2 / level
                  :quant-of (p2 / protein :name (n3 / name :op1 "beta-actin"))))
      :ARG3 (e / express-03
            :ARG2 (e2 / enzyme :name (n / name :op1 "Nos2"))
            :ARG1-of (i / increase-01))
      :manner (i2 / immunoblot-01))

# ::id bel_pmid_1575_7894.31804 ::date 2015-04-29T12:43:40 ::annotator SDL-AMR-09 ::preferred
# ::snt nduction of inflammatory cytokines by LPS is increased in Ucp2-/- mice. A, Northern blotting. Spleen total RNA was isolated from mice treated with 4 µg/g bw LPS or PBS. RNA for IFNg, IL1b, TNF and IL6 were elevated in Ucp2-/- mice in response to LPS.
# ::save-date Mon Jan 4, 2016 ::file bel_pmid_1575_7894_31804.txt
(m / multi-sentence
      :snt1 (i / increase-01
            :ARG1 (i2 / induce-01
                  :ARG0 (m8 / molecular-physical-entity :name (n2 / name :op1 "LPS"))
                  :ARG2 (c4 / cytokine
                        :ARG0-of (i3 / inflame-01)))
            :location (m2 / mouse
                  :mod (g / gene :name (n3 / name :op1 "Ucp2")
                        :ARG2-of (m3 / mutate-01 :mod "-/-"))))
      :snt2 (t / thing :name (n4 / name :op1 "Northern" :op2 "blotting")
            :ARG1-of (d / describe-01
                  :ARG0 (f / figure :mod "A")))
      :snt3 (i4 / isolate-01
            :ARG1 (n / nucleic-acid :name (n7 / name :op1 "RNA")
                  :quant (t2 / total)
                  :mod (s2 / spleen))
            :ARG2 (m4 / mouse
                  :ARG1-of (t3 / treat-03
                        :ARG3 (o / or
                              :op1 (m9 / molecular-physical-entity :name (n5 / name :op1 "LPS")
                                    :quant (c2 / concentration-quantity :quant 4
                                          :unit (m5 / microgram-per-gram)
                                          :mod (w / weight
                                                :mod (b / basis))))
                              :op2 (m10 / molecular-physical-entity :name (n6 / name :op1 "PBS")
                                    :quant c2)))))
      :snt4 (e / elevate-01
            :ARG1 (a / and
                  :op1 (n14 / nucleic-acid :name (n15 / name :op1 "RNA")
                        :ARG0-of (e2 / encode-01
                              :ARG1 (p2 / protein :name (n8 / name :op1 "IFNg"))))
                  :op2 (n16 / nucleic-acid :name (n17 / name :op1 "RNA")
                        :ARG0-of (e3 / encode-01
                              :ARG1 (p3 / protein :name (n9 / name :op1 "IL-1b"))))
                  :op3 (n18 / nucleic-acid :name (n19 / name :op1 "RNA")
                        :ARG0-of (e4 / encode-01
                              :ARG1 (p4 / protein :name (n10 / name :op1 "TNF"))))
                  :op4 (n20 / nucleic-acid :name (n21 / name :op1 "RNA")
                        :ARG0-of (e5 / encode-01
                              :ARG1 (p5 / protein :name (n11 / name :op1 "IL-6")))))
            :location (m6 / mouse
                  :mod (g2 / gene :name (n12 / name :op1 "Ucp2")
                        :ARG2-of (m7 / mutate-01 :mod "-/-")))
            :ARG2-of (r6 / respond-01
                  :ARG1 (m11 / molecular-physical-entity :name (n13 / name :op1 "LPS")))))

# ::id bel_pmid_1576_4709.2580 ::date 2015-04-29T12:56:13 ::annotator SDL-AMR-09 ::preferred
# ::snt Signal transducer and activator of transcription 3 (STAT3) is activated by the IL-6 family of cytokines and growth factors. STAT3 requires phosphorylation on Ser-727, in addition to tyrosine phosphorylation on Tyr-705, to be transcriptionally active.
# ::save-date Wed Feb 24, 2016 ::file bel_pmid_1576_4709_2580.txt
(m / multi-sentence
      :snt1 (a2 / activate-01
            :ARG0 (a3 / and
                  :op1 (p4 / protein-family :name (n4 / name :op1 "IL-6"))
                  :op2 (g / growth-factor))
            :ARG1 (p2 / protein :name (n / name :op1 "signal" :op2 "transducer" :op3 "and" :op4 "activator" :op5 "of" :op6 "transcription" :op7 "3")
                  :ARG1-of (d / describe-01
                        :ARG2 (p3 / protein :name (n2 / name :op1 "STAT-3")))))
      :snt2 (r / require-01
            :ARG1 (p / phosphorylate-01
                  :ARG1 (a4 / amino-acid :mod 727 :name (n7 / name :op1 "serine")
                        :part-of (p7 / protein :name (n6 / name :op1 "STAT-3")))
                  :ARG1-of (a5 / add-02
                        :ARG2 (p8 / phosphorylate-01
                              :ARG1 (a6 / amino-acid :mod 705 :name (n8 / name :op1 "tyrosine")
                                    :part-of p7))))
            :purpose (a / activity-06
                  :ARG0 p7
                  :ARG1 (t2 / transcribe-01))))

# ::id bel_pmid_1577_8365.952 ::date 2015-04-29T13:23:12 ::annotator SDL-AMR-09 ::preferred
# ::snt We found that CCR7 induced a Gi-dependent activation of MAPK members ERK1/2, JNK, and p38, with ERK1/2 and p38 controlling JNK. MAPK members regulated chemotaxis, but not the migratory speed, of DCs.
# ::save-date Mon Jan 4, 2016 ::file bel_pmid_1577_8365_952.txt
(m3 / multi-sentence
      :snt1 (f / find-01
            :ARG0 (w / we)
            :ARG1 (i / induce-01
                  :ARG0 (p2 / protein :name (n2 / name :op1 "CCR7"))
                  :ARG2 (a / activate-01
                        :ARG1 (a2 / and
                              :op1 (e / enzyme :name (n4 / name :op1 "ERK1"))
                              :op2 (e2 / enzyme :name (n5 / name :op1 "ERK2"))
                              :op3 (e3 / enzyme :name (n6 / name :op1 "JNK"))
                              :op4 (e5 / enzyme :name (n7 / name :op1 "p38"))
                              :ARG1-of (i2 / include-91
                                    :ARG2 (p / protein-family :name (n / name :op1 "MAPK"))))
                        :ARG0-of (d / depend-01
                              :ARG1 (p3 / protein :name (n3 / name :op1 "Gi")))
                        :manner (c / control-01
                              :ARG0 (a3 / and
                                    :op1 e
                                    :op2 e2
                                    :op3 e5)
                              :ARG1 e3))))
      :snt2 (r / regulate-01
            :ARG0 (m4 / member
                  :ARG1-of (i3 / include-91
                        :ARG2 (p4 / protein-family :name (n8 / name :op1 "MAPK"))))
            :ARG1 (c2 / chemotaxis
                  :mod (c3 / cell :name (n9 / name :op1 "DC")))
            :ARG1-of (c4 / contrast-01
                  :ARG2 (r2 / regulate-01 :polarity -
                        :ARG0 m4
                        :ARG1 (s / speed
                              :mod (m6 / migrate-01
                                    :ARG0 c3))))))

# ::id bel_pmid_1577_8365.1824 ::date 2015-04-29T13:42:29 ::annotator SDL-AMR-09 ::preferred
# ::snt Interference with Rho or Pyk2 inhibited cofilin inactivation and the migratory speed of DCs, but did not affect chemotaxis.
# ::save-date Thu May 7, 2015 ::file bel_pmid_1577_8365_1824.txt
(c / contrast-01
      :ARG1 (i / inhibit-01
            :ARG0 (i2 / interfere-01
                  :ARG1 (o / or
                        :op1 (p / protein :name (n / name :op1 "Rho"))
                        :op2 (e / enzyme :name (n2 / name :op1 "Pyk2"))))
            :ARG1 (a3 / and
                  :op1 (a2 / activate-01 :polarity -
                        :ARG1 (p2 / protein :name (n3 / name :op1 "cofilin")))
                  :op2 (s / speed
                        :mod (m / migrate-01
                              :ARG0 (c2 / cell :name (n4 / name :op1 "DC"))))))
      :ARG2 (a4 / affect-01 :polarity -
            :ARG0 i2
            :ARG1 (c3 / chemotaxis)))

# ::id bel_pmid_1579_3228.19202 ::date 2015-04-29T13:47:26 ::annotator SDL-AMR-09 ::preferred
# ::snt AdipoQ (23), has been suggested to serve as an insulin-sensitizing factor (24). The mRNA level in mesenteric fat from Tg mice was markedly decreased
# ::save-date Thu May 7, 2015 ::file bel_pmid_1579_3228_19202.txt
(m / multi-sentence
      :snt1 (s / suggest-01
            :ARG1 (s2 / serve-01
                  :ARG0 (p / protein :name (n / name :op1 "AdipoQ")
                        :ARG1-of (d2 / describe-01
                              :ARG0 (p3 / publication
                                    :ARG1-of (c / cite-01
                                          :ARG2 23))))
                  :ARG1 (f / factor
                        :ARG0-of (s3 / sensitize-01
                              :ARG2 (p2 / protein :name (n2 / name :op1 "insulin")))))
            :ARG1-of (d3 / describe-01
                  :ARG0 (p4 / publication
                        :ARG1-of (c2 / cite-01
                              :ARG2 24))))
      :snt2 (d / decrease-01
            :ARG1 (l / level
                  :quant-of (n4 / nucleic-acid :name (n3 / name :op1 "mRNA"))
                  :location (f2 / fat
                        :mod (m3 / mesentery)
                        :source (m4 / mouse
                              :mod (t / transgenic))))
            :manner (m2 / marked)))

# ::id bel_pmid_1579_3228.19204 ::date 2015-04-30T05:45:29 ::annotator SDL-AMR-09 ::preferred
# ::snt Angiotensinogen mRNA, which is up-regulated by glucocorticoids (26), was substantially increased in Tg mice.
# ::save-date Fri May 1, 2015 ::file bel_pmid_1579_3228_19204.txt
(i / increase-01
      :ARG1 (n4 / nucleic-acid :name (n / name :op1 "mRNA")
            :ARG0-of (e / encode-01
                  :ARG1 (p / protein :name (n2 / name :op1 "angiotensinogen")))
            :ARG1-of (u / upregulate-01
                  :ARG2 (s2 / small-molecule :name (n3 / name :op1 "glucocorticoid"))
                  :ARG1-of (d / describe-01
                        :ARG0 (p3 / publication
                              :ARG1-of (c / cite-01
                                    :ARG2 26)))))
      :degree (s / substantial)
      :location (m / mouse
            :mod (t / transgenic)))

# ::id bel_pmid_1579_3228.19208 ::date 2015-04-30T05:50:58 ::annotator SDL-AMR-09 ::preferred
# ::snt The mRNA for resistin, which has been suggested to be involved in glucose homeostasis (25), was significantly decreased in Tg mice.
# ::save-date Fri Dec 18, 2015 ::file bel_pmid_1579_3228_19208.txt
(d / decrease-01
      :ARG1 (n3 / nucleic-acid :wiki "Messenger_RNA"
            :name (n / name :op1 "mRNA")
            :ARG0-of (e / encode-01
                  :ARG1 (p / protein :wiki "Resistin"
                        :name (n2 / name :op1 "resistin")))
            :ARG1-of (i / involve-01
                  :ARG2 (h / homeostasis
                        :mod (g / glucose))
                  :ARG1-of (s / suggest-01)
                  :ARG1-of (d2 / describe-01
                        :ARG0 (p2 / publication
                              :ARG1-of (c / cite-01 :ARG2 25)))))
      :ARG2 (s2 / significant-02)
      :location (m / mouse
            :mod (t / transgenic)))

# ::id bel_pmid_1579_3228.19210 ::date 2015-04-30T06:05:49 ::annotator SDL-AMR-09 ::preferred
# ::snt model. Tumor necrosis factor- alpha (TNF-a), a fat cell- derived cytokine that can cause insulin resistance (3, 22), was significantly elevated in serum of Tg mice
# ::save-date Mon Jan 4, 2016 ::file bel_pmid_1579_3228_19210.txt
(m / multi-sentence
      :snt1 (m2 / model)
      :snt2 (e / elevate-01
            :ARG1 (p / protein :name (n / name :op1 "tumor" :op2 "necrosis" :op3 "factor" :op4 "alpha")
                  :ARG1-of (d / describe-01
                        :ARG2 (p2 / protein :name (n2 / name :op1 "TNF-a")))
                  :mod (c / cytokine
                        :ARG1-of (d2 / derive-01
                              :ARG2 (c2 / cell
                                    :mod (f / fat)))
                        :ARG0-of (c3 / cause-01
                              :ARG1 (r / resist-01
                                    :ARG1 (p4 / protein :name (n3 / name :op1 "insulin")))
                              :ARG1-of (p3 / possible-01))
                        :ARG1-of (d3 / describe-01
                              :ARG0 (p5 / publication
                                    :ARG1-of (c4 / cite-01
                                          :ARG2 (a / and :op1 3 :op2 22))))))
            :ARG1-of (s / significant-02)
            :location (s2 / serum
                  :source (m3 / mouse
                        :mod (t / transgenic)))))

# ::id bel_pmid_1579_3228.21750 ::date 2015-04-30T06:16:15 ::annotator SDL-AMR-09 ::preferred
# ::snt Genetic disruption of these pathways improves insulin resistance (86,87). Heterozygous IKKbeta+/- mice, fed with a high-fat diet or crossed with obese ob/ob mice, showed a significant decrease in blood glucose levels and improved insulin resistance (87).
# ::save-date Mon Jan 4, 2016 ::file bel_pmid_1579_3228_21750.txt
(m / multi-sentence
      :snt1 (i / improve-01
            :ARG0 (d / disrupt-01
                  :ARG1 (p / pathway
                        :mod (t / this))
                  :mod (g / gene))
            :ARG1 (r / resist-01
                  :ARG1 (p2 / protein :name (n / name :op1 "insulin")))
            :ARG1-of (d2 / describe-01
                  :ARG0 (p3 / publication
                        :ARG1-of (c / cite-01
                              :ARG2 (a / and :op1 86 :op2 87)))))
      :snt2 (s / show-01
            :ARG0 (m2 / mouse
                  :mod (p6 / protein :name (n2 / name :op1 "IKKbeta")
                        :ARG2-of (m3 / mutate-01 :mod "+/-"))
                  :ARG2-of (f / feed-01
                        :ARG1 (d5 / diet
                              :ARG0-of (c3 / contain-01
                                    :ARG1 (f2 / fat
                                          :ARG1-of (h2 / high-02))))
                        :op1-of (o / or
                              :op2 (c4 / cross-01
                                    :ARG1 (a3 / and
                                          :op1 m2
                                          :op2 (m4 / mouse
                                                :mod (o2 / obese)
                                                :mod (o3 / ob-ob))))))
                  :mod (h / heterozygous))
            :ARG1 (a2 / and
                  :op1 (d3 / decrease-01
                        :ARG1 (l / level
                              :quant-of (g3 / glucose)
                              :location (b / blood))
                        :ARG2 (s2 / significant-02))
                  :op2 (r2 / resist-01
                        :ARG1 (p4 / protein :name (n3 / name :op1 "insulin"))
                        :ARG1-of (i2 / improve-01)))
            :ARG1-of (d4 / describe-01
                  :ARG0 (p5 / publication
                        :ARG1-of (c2 / cite-01
                              :ARG2 87)))))

# ::id bel_pmid_1579_3228.21980 ::date 2015-04-30T06:42:27 ::annotator SDL-AMR-09 ::preferred
# ::snt JNK1 knockout mice gain less weight and are protected against diet-induced insulin resistance or insulin resistance associated with a genetic model of obesity (ob/ob) (86).
# ::save-date Mon Jan 4, 2016 ::file bel_pmid_1579_3228_21980.txt
(a / and
      :op1 (g / gain-02
            :ARG0 (m / mouse
                  :ARG1-of (k / knock-out-03
                        :ARG0 (e / enzyme :name (n / name :op1 "JNK1"))))
            :ARG1 (w / weight
                  :quant (l / less)))
      :op2 (p / protect-01
            :ARG1 m
            :ARG2 (o / or
                  :op1 (r / resist-01
                        :ARG1 (p2 / protein :name (n2 / name :op1 "insulin"))
                        :ARG2-of (i / induce-01
                              :ARG0 (d / diet)))
                  :op2 (r2 / resist-01
                        :ARG1 p2
                        :ARG1-of (a2 / associate-01
                              :ARG2 (m3 / model
                                    :mod (g2 / genetic)
                                    :mod (o2 / obesity)
                                    :ARG1-of (d2 / describe-01
                                          :ARG2 (s / string-entity :value "ob/ob")))))))
      :ARG1-of (d3 / describe-01
            :ARG0 (p4 / publication
                  :ARG1-of (c / cite-01
                        :ARG2 86))))

# ::id bel_pmid_1579_3228.28348 ::date 2015-04-30T06:53:33 ::annotator SDL-AMR-09 ::preferred
# ::snt and in mice, IL-6 treatment causes insulin resistance in skeletal muscle and in liver most likely due to defects in IRS-1 (and IRS-2, respectively)-associated PI 3-kinase activity (56).
# ::save-date Mon Jan 4, 2016 ::file bel_pmid_1579_3228_28348.txt
(a / and
      :op2 (c / cause-01
            :ARG0 (t / treat-03
                  :ARG1 (m2 / mouse)
                  :ARG3 (p / protein :name (n / name :op1 "IL-6")))
            :ARG1 (r / resist-01
                  :ARG1 (p2 / protein :name (n2 / name :op1 "insulin"))
                  :ARG1-of (c2 / cause-01
                        :ARG0 (d / defect-01
                              :ARG0 (a3 / activity-06
                                    :ARG0 (e / enzyme :name (n3 / name :op1 "PI" :op2 "3-kinase"))
                                    :ARG1-of (a4 / associate-01
                                          :ARG2 (a5 / and
                                                :op1 (p3 / protein :name (n4 / name :op1 "IRS-1"))
                                                :op2 (p4 / protein :name (n5 / name :op1 "IRS-2"))
                                                :manner (r2 / respective)))))
                        :ARG1-of (l / likely-01
                              :degree (m / most)))
                  :location (a2 / and
                        :op1 (m3 / muscle
                              :mod (s / skeleton))
                        :op2 (l2 / liver))))
      :ARG1-of (d2 / describe-01
            :ARG0 (p5 / publication
                  :ARG1-of (c3 / cite-01
                        :ARG2 56))))

# ::id bel_pmid_1583_1486.36764 ::date 2015-04-30T07:03:23 ::annotator SDL-AMR-09 ::preferred
# ::snt As previously reported, expression of Dok-R in EGF-stimulated cells resulted in a dramatic decrease in the induction of Erk-2 activation as well as a delay in the activation kinetics (Fig. 1), while Dok-R {Delta}PRR completely lost this Erk-2 attenuating capacity, which demonstrates that the key residues for mediating this attenuation are found within the PRR.
# ::save-date Sun Jan 17, 2016 ::file bel_pmid_1583_1486_36764.txt
(c / contrast-01
      :ARG1 (r / result-01
            :ARG1 (e / express-03
                  :ARG2 (p / protein :name (n / name :op1 "Dok-R"))
                  :ARG3 (c2 / cell
                        :ARG1-of (s / stimulate-01
                              :ARG2 (p5 / protein :name (n2 / name :op1 "EGF")))))
            :ARG2 (a2 / and
                  :op1 (d / decrease-01
                        :ARG1 (i / induce-01
                              :ARG2 (a / activate-01
                                    :ARG1 (e2 / enzyme :name (n3 / name :op1 "Erk-2"))))
                        :degree (d2 / dramatic))
                  :op2 (d3 / delay-01
                        :ARG1 (k / kinetics
                              :mod (a3 / activate-01))))
            :ARG1-of (d4 / describe-01
                  :ARG0 (f / figure :mod 1)))
      :ARG2 (l / lose-02
            :ARG0 (p2 / protein :name (n4 / name :op1 "Dok-R" :op2 "delta" :op3 "PRR"))
            :ARG1 (c5 / capable-01
                  :ARG2 (a4 / attenuate-01
                        :ARG1 e2))
            :ARG1-of (c3 / complete-02)
            :ARG0-of (d5 / demonstrate-01
                  :ARG1 (f2 / find-01
                        :ARG1 (r2 / residue
                              :ARG1-of (k2 / key-02
                                    :ARG2 (m / mediate-01
                                          :ARG1 a4)))
                        :location (p3 / protein :name (n5 / name :op1 "PRR")))))
      :ARG1-of (r3 / report-01
            :time (p4 / previous)))

# ::id bel_pmid_1584_5922.27198 ::date 2015-04-30T07:28:29 ::annotator SDL-AMR-09 ::preferred
# ::snt The isoform SH2-Bbeta modulates JAK2 activity by binding to the phosphorylated enzyme, further increasing its activity. in an animal model of GH excess in which JAK2 is not phosphorylated, although it is increased in the membrane-fraction, both the level of SH2-Bbeta, and especially its association to membranes, are augmented.
# ::save-date Mon Jul 6, 2015 ::file bel_pmid_1584_5922_27198.txt
(m / multi-sentence
      :snt1 (m2 / modulate-01
            :ARG0 (p / protein :name (n / name :op1 "SH2-Bbeta")
                  :mod (i / isoform))
            :ARG1 (a / activity-06
                  :ARG0 e)
            :manner (b / bind-01
                  :ARG1 p
                  :ARG2 (e / enzyme :name (n2 / name :op1 "JAK2")
                        :ARG1-of (p2 / phosphorylate-01))
                  :ARG0-of (i2 / increase-01
                        :ARG1 a
                        :degree (f / further))))
      :snt2 (a2 / augment-01
            :ARG1 (a3 / and
                  :op1 (l / level
                        :quant-of (p3 / protein :name (n3 / name :op1 "SH2-Bbeta")))
                  :op2 (a4 / associate-01
                        :ARG1 p3
                        :ARG2 (m3 / membrane)
                        :mod (e3 / especially)))
            :location (m4 / model
                  :mod (a5 / animal)
                  :mod (e4 / exceed-01
                        :ARG0 (p4 / protein :name (n4 / name :op1 "GH")))
                  :location-of (p5 / phosphorylate-01 :polarity -
                        :ARG1 (e5 / enzyme :name (n5 / name :op1 "JAK2"))
                        :concession (i3 / increase-01
                              :ARG1 e5
                              :location (f2 / fraction
                                    :mod m3))))))

# ::id bel_pmid_1587_9117.18042 ::date 2015-04-30T07:47:15 ::annotator SDL-AMR-09 ::preferred
# ::snt In response to IFN-gamma, C/EBP-beta undergoes phosphorylation at a critical ERK1/2 phosphorylation motif.
# ::save-date Wed Jun 24, 2015 ::file bel_pmid_1587_9117_18042.txt
(u / undergo-28
      :ARG1 (p2 / protein :name (n / name :op1 "C/EBP-beta"))
      :ARG2 (p / phosphorylate-01
            :ARG1 (p4 / protein-segment
                  :part-of p2
                  :ARG1-of (c / critical-02
                        :ARG2 p))
            :ARG2 (a / and
                  :op1 (e / enzyme :name (n3 / name :op1 "ERK1"))
                  :op2 (e2 / enzyme :name (n4 / name :op1 "ERK2"))))
      :ARG2-of (r / respond-01
            :ARG1 (p3 / protein :name (n2 / name :op1 "IFN-gamma"))))

# ::id bel_pmid_1596_4826.36122 ::date 2015-04-30T07:55:26 ::annotator SDL-AMR-09 ::preferred
# ::snt Serine-642 was identified as an Akt-dependent phosphorylation site. WEE1Hu kinase activity was not affected by serine-642 phosphorylation. We revealed that serine-642 phosphorylation promoted cytoplasmic localization of WEE1Hu. The nuclear-to-cytoplasmic translocation was mediated by phosphorylation-dependent WEE1Hu binding to 14-3-3theta but not 14-3-3beta or -sigma preventing Y15 phosphorylation of Cdc2 by WEE1.
# ::save-date Thu Dec 17, 2015 ::file bel_pmid_1596_4826_36122.txt
(m / multi-sentence
      :snt1 (i / identify-01
            :ARG1 (a / amino-acid :mod 642 :name (n2 / name :op1 "serine"))
            :ARG2 (s / site
                  :ARG1-of (p / phosphorylate-01)
                  :ARG0-of (d / depend-01
                        :ARG1 (e / enzyme :name (n3 / name :op1 "Akt")))))
      :snt2 (a2 / affect-01 :polarity -
            :ARG0 (p3 / phosphorylate-01
                  :ARG1 (a4 / amino-acid :mod 642 :name (n5 / name :op1 "serine")))
            :ARG1 (a3 / activity-06
                  :ARG0 (k / kinase :name (n4 / name :op1 "WEE1Hu"))))
      :snt3 (r / reveal-01
            :ARG0 (w / we)
            :ARG1 (p4 / promote-02
                  :ARG0 (p5 / phosphorylate-01
                        :ARG1 (a5 / amino-acid :mod 642 :name (n6 / name :op1 "serine")))
                  :ARG1 (b2 / be-located-at-91
                        :ARG1 (k2 / kinase :name (n7 / name :op1 "WEE1Hu"))
                        :ARG2 (c / cytoplasm))))
      :snt4 (m2 / mediate-01
            :ARG0 (b / bind-01
                  :ARG1 (k3 / kinase :name (n8 / name :op1 "WEE1Hu"))
                  :ARG2 (p6 / protein :name (n9 / name :op1 "14-3-3" :op2 "theta"))
                  :ARG0-of (d2 / depend-01
                        :ARG1 (p2 / phosphorylate-01)))
            :ARG1 (t / translocate-01
                  :ARG2 (c2 / cytoplasm)
                  :ARG3 (n / nucleus))
            :ARG0-of (p9 / prevent-01
                  :ARG1 (p10 / phosphorylate-01
                        :ARG1 (a6 / amino-acid :mod 15 :name (n12 / name :op1 "tyrosine")
                              :part-of (e2 / enzyme :name (n13 / name :op1 "Cdc2")))
                        :ARG2 (k4 / kinase :name (n14 / name :op1 "WEE1"))))
            :ARG1-of (c3 / contrast-01
                  :ARG2 (m3 / mediate-01 :polarity -
                        :ARG0 (b3 / bind-01
                              :ARG1 k3
                              :ARG2 (o / or
                                    :op1 (p7 / protein :name (n10 / name :op1 "14-3-3" :op2 "beta"))
                                    :op2 (p8 / protein :name (n11 / name :op1 "14-3-3" :op2 "sigma"))))
                        :ARG1 t))))

# ::id bel_pmid_1610_2754.11486 ::date 2015-04-30T08:14:02 ::annotator SDL-AMR-09 ::preferred
# ::snt KLF5 accelerates mitotic entry in H-Ras-transformed cells by transcriptionally activating cyclin B1 and Cdc2, which leads to an increase in cyclin B1/Cdc2 kinase activity
# ::save-date Mon Jul 6, 2015 ::file bel_pmid_1610_2754_11486.txt
(a / accelerate-01
      :ARG0 (p / protein :name (n / name :op1 "KLF5"))
      :ARG1 (e / enter-01
            :ARG0 (m / mitosis)
            :ARG1 (c / cell
                  :ARG1-of (t / transform-01
                        :ARG0 (e2 / enzyme :name (n2 / name :op1 "H-Ras")))))
      :manner (a2 / activate-01
            :ARG0 p
            :ARG1 (a3 / and
                  :op1 (p2 / protein :name (n3 / name :op1 "cyclin" :op2 "B1"))
                  :op2 (k / kinase :name (n4 / name :op1 "Cdc2")))
            :mod (t2 / transcribe-01)
            :ARG0-of (l / lead-03
                  :ARG2 (i / increase-01
                        :ARG1 (a4 / activity-06
                              :ARG0 a3)))))

# ::id bel_pmid_1613_9224.21092 ::date 2015-04-30T08:30:42 ::annotator SDL-AMR-09 ::preferred
# ::snt We report that phosphorylation-induced turnover of endogenous N-myc protein in CGNPs increases during mitosis, due to increased priming phosphorylation of N-myc for GSK-3beta. The priming phosphorylation requires the Cdk1 complex, whose cyclin subunits are indirect Sonic hedgehog targets
# ::save-date Wed Jan 13, 2016 ::file bel_pmid_1613_9224_21092.txt
(m / multi-sentence
      :snt1 (r / report-01
            :ARG0 (w / we)
            :ARG1 (i / increase-01
                  :ARG1 (t / turnover
                        :ARG2-of (i2 / induce-01
                              :ARG0 (p / phosphorylate-01))
                        :mod (p2 / protein :name (n / name :op1 "N-myc")
                              :mod (e / endogenous))
                        :location (c2 / cell :name (n6 / name :op1 "CGNP")))
                  :time (m2 / mitosis)
                  :ARG1-of (c / cause-01
                        :ARG0 (p3 / phosphorylate-01
                              :ARG1 p2
                              :ARG2 (e2 / enzyme :name (n2 / name :op1 "GSK-3beta"))
                              :mod (p4 / priming)
                              :ARG1-of (i3 / increase-01)))))
      :snt2 (r2 / require-01
            :ARG0 (p5 / phosphorylate-01
                  :mod (p6 / priming))
            :ARG1 (m3 / macro-molecular-complex
                  :part (p7 / protein :name (n4 / name :op1 "cyclin")
                        :ARG1-of (t2 / target-01
                              :ARG2 (p8 / protein :name (n5 / name :op1 "Sonic" :op2 "hedgehog"))
                              :mod (i4 / indirect)))
                  :part (e3 / enzyme :name (n3 / name :op1 "Cdk1")))))

# ::id bel_pmid_1614_1211.1764 ::date 2015-04-30T08:44:28 ::annotator SDL-AMR-09 ::preferred
# ::snt We conclude that TNFalpha and IGF-I may additively contribute to fibrosis during intestinal inflammation. TNFR2 is a primary mediator of fibrogenic actions of TNFalpha acting through ERK1/2 to stimulate proliferation and through STAT3 to stimulate TIMP-1 and inhibit collagen degradation.
# ::save-date Mon Jan 4, 2016 ::file bel_pmid_1614_1211_1764.txt
(m2 / multi-sentence
      :snt1 (c / conclude-01
            :ARG0 (w / we)
            :ARG1 (p2 / possible-01
                  :ARG1 (c2 / contribute-01
                        :ARG0 (a / and
                              :op1 (p3 / protein :name (n / name :op1 "TNF-alpha"))
                              :op2 (p4 / protein :name (n2 / name :op1 "IGF-I")))
                        :ARG2 (f / fibrosis)
                        :manner (a2 / add-02)
                        :time (i / inflame-01
                              :ARG1 (i2 / intestine)))))
      :snt2 (m3 / mediate-01
            :ARG0 (p5 / protein :name (n3 / name :op1 "TNFR2"))
            :ARG1 (a3 / act-01
                  :ARG0 (p7 / protein :name (n4 / name :op1 "TNF-alpha"))
                  :ARG1 (f2 / fibrogenesis))
            :mod (p6 / primary)
            :manner (a8 / and
                  :op1 (a4 / act-02
                        :ARG0 p5
                        :path (a5 / and
                              :op1 (e / enzyme :name (n5 / name :op1 "ERK1"))
                              :op2 (e2 / enzyme :name (n6 / name :op1 "ERK2")))
                        :purpose (s / stimulate-01
                              :ARG0 p5
                              :ARG1 (p8 / proliferate-01)))
                  :op2 (a6 / act-02
                        :ARG0 p5
                        :path (p9 / protein :name (n7 / name :op1 "STAT3"))
                        :purpose (a7 / and
                              :op1 (s2 / stimulate-01
                                    :ARG0 p5
                                    :ARG1 (p10 / protein :name (n8 / name :op1 "TIMP-1")))
                              :op2 (i3 / inhibit-01
                                    :ARG0 p5
                                    :ARG1 (d2 / degrade-01
                                          :ARG1 (p11 / protein :name (n9 / name :op1 "collagen")))))))))

# ::id bel_pmid_1614_1211.2914 ::date 2015-04-30T09:03:20 ::annotator SDL-AMR-09 ::preferred
# ::snt Tumor necrosis factor (TNF) alpha has defined proinflammatory
# ::save-date Sun May 3, 2015 ::file bel_pmid_1614_1211_2914.txt
(d / define-01
      :ARG1 (p3 / protein :name (n3 / name :op1 "tumor" :op2 "necrosis" :op3 "factor" :op4 "alpha")
            :ARG1-of (d2 / describe-01
                  :ARG2 (p2 / protein :name (n2 / name :op1 "TNF"))))
      :ARG2 (f / favor-01
            :ARG0 (p / protein)
            :ARG1 (i / inflame-01)))

# ::id bel_pmid_1614_1211.10448 ::date 2015-04-30T09:03:46 ::annotator SDL-AMR-09 ::preferred
# ::snt TNFalpha, but not IGF-I, induced tissue inhibitor of metalloproteinase-1 (TIMP-1) expression and reduced matrix metalloproteinases-2 activity and collagen degradation. TNFalpha also activated ERK1/2.
# ::save-date Sun Dec 20, 2015 ::file bel_pmid_1614_1211_10448.txt
(m / multi-sentence
      :snt1 (a / and
            :op1 (i2 / induce-01
                  :ARG0 (p / protein :name (n / name :op1 "TNF-alpha")
                        :ARG1-of (c / contrast-01
                              :ARG2 (p2 / protein :name (n2 / name :op1 "IGF-I"))))
                  :ARG2 (e / express-03
                        :ARG2 (p3 / protein :name (n3 / name :op1 "tissue" :op2 "inhibitor" :op3 "of" :op4 "metalloproteinase-1")
                              :ARG1-of (d / describe-01
                                    :ARG2 (p4 / protein :name (n4 / name :op1 "TIMP-1"))))))
            :op2 (r / reduce-01
                  :ARG0 p
                  :ARG1 (a2 / and
                        :op1 (a3 / activity-06
                              :ARG0 (e2 / enzyme :name (n5 / name :op1 "matrix" :op2 "metalloproteinase-2")))
                        :op2 (d2 / degrade-01
                              :ARG1 (p5 / protein :name (n6 / name :op1 "collagen"))))))
      :snt2 (a4 / activate-01
            :ARG0 (p6 / protein :name (n7 / name :op1 "TNF-alpha"))
            :ARG1 (a6 / and
                  :op1 (e3 / enzyme :name (n8 / name :op1 "ERK1"))
                  :op2 (e4 / enzyme :name (n9 / name :op1 "ERK2")))
            :mod (a5 / also)))

# ::id bel_pmid_1614_1211.19760 ::date 2015-04-30T09:12:07 ::annotator SDL-AMR-09 ::preferred
# ::snt These responses to TNFalpha were absent in TNFR2-/- and TNFR1/2-/- myofibroblasts, whereas TNFR1-/- cells showed similar responses to WT.
# ::save-date Thu May 7, 2015 ::file bel_pmid_1614_1211_19760.txt
(c / contrast-01
      :ARG1 (a3 / absent-01
            :ARG1 (t / thing
                  :ARG2-of (r2 / respond-01
                        :ARG1 (p / protein :name (n / name :op1 "TNF-alpha")))
                  :mod (t3 / this))
            :ARG2 (a / and
                  :op1 (m2 / myofibroblast
                        :mod p2)
                  :op2 (m3 / myofibroblast
                        :mod (p3 / protein :name (n3 / name :op1 "TNFR1")
                              :ARG2-of m)
                        :mod (p2 / protein :name (n2 / name :op1 "TNFR2")
                              :ARG2-of (m / mutate-01 :mod "-/-")))))
      :ARG2 (s / show-01
            :ARG0 (c2 / cell
                  :mod p3)
            :ARG1 (t2 / thing
                  :ARG2-of (r3 / respond-01)
                  :ARG1-of (r / resemble-01
                        :ARG2 (c3 / cell
                              :mod (w / wild-type))))))

# ::id bel_pmid_1614_9052.2664 ::date 2015-04-30T09:23:31 ::annotator SDL-AMR-09 ::preferred
# ::snt Additionally, genistein enhanced RA-induced neuronal differentiation by increasing the activation of extracellular signal-related kinase 1/2 (ERK1/2) via phosphorylation at Thr183 and Tyr185 in 3-7 days.
# ::save-date Fri Feb 12, 2016 ::file bel_pmid_1614_9052_2664.txt
(e / enhance-01
      :ARG0 (s / small-molecule :name (n / name :op1 "genistein"))
      :ARG1 (d3 / differentiate-01
            :ARG1 (n2 / neuron)
            :ARG2-of (i / induce-01
                  :ARG0 (s2 / small-molecule :name (n3 / name :op1 "RA"))))
      :manner (i2 / increase-01
            :ARG1 (a / activate-01
                  :ARG1 (a2 / and
                        :op1 (e2 / enzyme :name (n4 / name :op1 "extracellular" :op2 "signal-related" :op3 "kinase" :op4 "1")
                              :ARG1-of (d4 / describe-01
                                    :ARG2 (e4 / enzyme :name (n6 / name :op1 "ERK1"))))
                        :op2 (e3 / enzyme :name (n5 / name :op1 "extracellular" :op2 "signal-related" :op3 "kinase" :op4 "2")
                              :ARG1-of (d5 / describe-01
                                    :ARG2 (e5 / enzyme :name (n7 / name :op1 "ERK2"))))))
            :manner (p / phosphorylate-01
                  :ARG1 (a3 / and
                        :op1 (a4 / amino-acid :mod 183 :name (n8 / name :op1 "tyrosine"))
                        :op2 (a5 / amino-acid :mod 185 :name (n9 / name :op1 "tyrosine")))))
      :ARG1-of (a6 / add-02)
      :time (b / between
            :op1 (t / temporal-quantity :quant 3
                  :unit (d / day))
            :op2 (t2 / temporal-quantity :quant 7
                  :unit (d2 / day))))

# ::id bel_pmid_1617_7098.35020 ::date 2015-04-29T03:38:18 ::annotator SDL-AMR-09 ::preferred
# ::snt Ag stimulation of Lyn unique domain transfectants was accompanied by enhanced phosphorylation of MEK and ERK-2, which are required for leukotriene C4 (LTC4) release, and production of LTC4 was increased 3- to 5-fold, compared with cells transfected with vector alone.
# ::save-date Thu Dec 17, 2015 ::file bel_pmid_1617_7098_35020.txt
(a / and
      :op1 (a2 / accompany-01
            :ARG0 (p / phosphorylate-01
                  :ARG1 (a3 / and
                        :op1 (e / enzyme :name (n / name :op1 "MEK"))
                        :op2 (e2 / enzyme :name (n2 / name :op1 "ERK-2"))
                        :ARG1-of (r / require-01
                              :ARG0 (r2 / release-01
                                    :ARG1 (s2 / small-molecule :name (n4 / name :op1 "leukotriene" :op2 "C4")))))
                  :ARG1-of (e4 / enhance-01))
            :ARG1 (s / stimulate-01
                  :ARG0 (a4 / antigen)
                  :ARG1 (m / molecular-physical-entity
                        :ARG1-of (t / transfect-01
                              :ARG2 (d / domain
                                    :mod (u / unique)
                                    :part-of (e3 / enzyme :name (n3 / name :op1 "Lyn")))))))
      :op2 (i / increase-01
            :ARG1 (p2 / produce-01
                  :ARG1 s2)
            :ARG2 (v / value-interval
                  :op1 (p3 / product-of :op1 3)
                  :op2 (p4 / product-of :op1 5))
            :compared-to (c / cell
                  :ARG1-of (t2 / transfect-01
                        :ARG2 (v2 / vector
                              :mod (a5 / alone))))))

# ::id bel_pmid_1618_2244.3476 ::date 2015-04-29T04:08:13 ::annotator SDL-AMR-09 ::preferred
# ::snt Our analyses using epiregulin-deficient mice with mixed and inbred genetic backgrounds revealed that epiregulin deficiency results in the reduction of IL-6 production levels in both cell types upon peptidoglycan stimulation, and that the extent of this reduction is more evident under the BALB/c background compared with the C57BL/6J background.
# ::save-date Fri May 8, 2015 ::file bel_pmid_1618_2244_3476.txt
(r / reveal-01
      :ARG0 (t / thing
            :ARG1-of (a / analyze-01
                  :ARG0 (w2 / we)
                  :instrument (m / mouse
                        :ARG0-of (l / lack-01
                              :ARG1 (p / protein :name (n / name :op1 "epiregulin")))
                        :ARG0-of (h / have-03
                              :ARG1 (a2 / and
                                    :op1 (b / background
                                          :ARG3-of (m2 / mix-01)
                                          :mod (g / genetic))
                                    :op2 (b2 / background
                                          :ARG1-of (i / inbreed-00)
                                          :mod g))))))
      :ARG1 (a3 / and
            :op1 (r2 / result-01
                  :ARG1 l
                  :ARG2 (r3 / reduce-01
                        :ARG1 (l2 / level
                              :degree-of (p2 / produce-01
                                    :ARG1 (p3 / protein :name (n2 / name :op1 "IL-6"))))
                        :prep-in a2
                        :condition (s / stimulate-01
                              :ARG1 (m3 / macro-molecular-complex :name (n3 / name :op1 "peptidoglycan")))))
            :op2 (e / evident
                  :domain (e2 / extent
                        :degree-of r3)
                  :degree (m4 / more)
                  :prep-under (b3 / background
                        :mod (c / cell-line :name (n4 / name :op1 "BALB/c")))
                  :compared-to (b4 / background
                        :mod (c2 / cell-line :name (n5 / name :op1 "C57BL/6J"))))))

# ::id bel_pmid_1618_2244.26736 ::date 2015-04-29T04:26:09 ::annotator SDL-AMR-09 ::preferred
# ::snt rmEP reduced IL-18 expression in WT- and EP –/–-derived keratinocytes at 8 h after stimulation, and there was no obvious difference between WT and EP –/– (Fig. 3D).
# ::save-date Fri May 8, 2015 ::file bel_pmid_1618_2244_26736.txt
(a / and
      :op1 (r / reduce-01
            :ARG0 (p / protein :name (n / name :op1 "rmEP"))
            :ARG1 (e / express-03
                  :ARG2 (p2 / protein :name (n2 / name :op1 "IL-18"))
                  :ARG3 (a2 / and
                        :op1 (k / keratinocyte
                              :mod (w / wild-type))
                        :op2 (k2 / keratinocyte
                              :ARG3-of (e2 / express-03
                                    :ARG2 (p3 / protein :name (n3 / name :op1 "EP")
                                          :ARG2-of (m / mutate-01 :mod "-/-"))))))
            :time (a3 / after
                  :op1 (s / stimulate-01)
                  :quant (t / temporal-quantity :quant 8
                        :unit (h / hour))))
      :op2 (d / differ-02
            :ARG1 a2
            :ARG1-of (o2 / obvious-01 :polarity -))
      :ARG1-of (d2 / describe-01
            :ARG0 (f / figure :mod "3D")))

# ::id bel_pmid_1620_4059.41796 ::date 2015-04-29T04:42:35 ::annotator SDL-AMR-09 ::preferred
# ::snt Here, we show that ras-transformed cancer cells can also induce TSP-1 down-regulation in their adjacent nontransformed stromal fibroblasts, but not in endothelial cells, in a paracrine and distance-dependent manner.
# ::save-date Mon Jan 4, 2016 ::file bel_pmid_1620_4059_41796.txt
(s / show-01
      :ARG0 (w / we)
      :ARG1 (c3 / contrast-01
            :ARG1 (p / possible-01
                  :ARG1 (i / induce-01
                        :ARG0 (c / cell
                              :ARG1-of (t / transform-01
                                    :ARG0 (e / enzyme :name (n / name :op1 "ras")))
                              :mod (d5 / disease :wiki "Cancer" :name (n3 / name :op1 "cancer")))
                        :ARG2 (d / downregulate-01
                              :ARG1 (p3 / protein :name (n2 / name :op1 "TSP-1"))
                              :location (f / fibroblast
                                    :mod (s2 / stroma)
                                    :ARG1-of (t2 / transform-01 :polarity -)
                                    :ARG2-of (b / border-01)
                                    :poss e))
                        :mod (a / also)
                        :manner (p5 / paracrine)
                        :ARG0-of (d3 / depend-01
                              :ARG1 (d4 / distance))))
            :ARG2 (p4 / possible-01 :polarity -
                  :ARG1 (i2 / induce-01
                        :ARG0 c
                        :ARG2 (d2 / downregulate-01
                              :ARG1 p3
                              :location (c4 / cell
                                    :mod (e2 / endothelium))))))
      :location (h / here))

# ::id bel_pmid_1620_4059.41800 ::date 2015-04-29T05:04:55 ::annotator SDL-AMR-09 ::preferred
# ::snt Indeed, MDF528 nontransformed dermal fibroblasts, like many other types of normal nonangiogenic cells (12), express copious amounts of TSP-1 (Fig. 1B, lane 1), which becomes undetectable in their H-ras -expressing counterparts (528ras1 cells; Fig. 1B, lane 2; refs.
# ::save-date Mon Dec 21, 2015 ::file bel_pmid_1620_4059_41800.txt
(e / express-03
      :ARG2 (a / amount
            :mod (c3 / copious)
            :quant-of (p / protein :name (n3 / name :op1 "TSP-1")
                  :ARG1-of (b / become-01
                        :ARG2 (d3 / detect-01
                              :ARG1 p
                              :ARG1-of (p4 / possible-01 :polarity -))
                        :location (c4 / counterpart
                              :ARG3-of (e2 / express-03
                                    :ARG2 (e4 / enzyme :name (n4 / name :op1 "H-ras")))
                              :poss f
                              :ARG1-of (d4 / describe-01
                                    :ARG0 (f3 / figure :mod "1B"
                                          :mod (l2 / lane :mod 2))
                                    :ARG2 (n7 / name :op1 "528ras1" :op2 "cells"))
                              :ARG1-of (d6 / describe-01
                                    :ARG0 (p2 / publication
                                          :ARG1-of (c5 / cite-01)))))))
      :ARG3 (f / fibrolast
            :mod (d / dermis)
            :ARG1-of (t / transform-01 :polarity -)
            :mod (c / cell-line :name (n5 / name :op1 "MDF528")))
      :mod (i / indeed)
      :ARG1-of (d2 / describe-01
            :ARG0 (f2 / figure :mod "1B"
                  :mod (l / lane :mod 1)))
      :ARG1-of (r / resemble-01
            :ARG2 (e3 / express-03
                  :ARG3 (c2 / cell
                        :mod (a2 / angiogenic :polarity -)
                        :ARG1-of (n / normal-02)
                        :ARG1-of (t2 / type-03
                              :mod (m / many)
                              :mod (o / other))))
            :ARG1-of (d5 / describe-01
                  :ARG0 (p3 / publication
                        :ARG1-of (c7 / cite-01
                              :ARG2 12)))))

# ::id bel_pmid_1620_4059.41802 ::date 2015-04-29T05:36:03 ::annotator SDL-AMR-09 ::preferred
# ::snt Down-regulation of thrombospondin-1 promoter activity in nontumorigenic dermal fibroblasts exposed to tumor cell-derived soluble mediator(s).
# ::save-date Mon Jul 6, 2015 ::file bel_pmid_1620_4059_41802.txt
(e / expose-01
      :ARG1 (d / downregulate-01
            :ARG1 (a / activity-06
                  :ARG0 (m / molecular-physical-entity
                        :ARG0-of (p / promote-01
                              :ARG1 (p2 / protein :name (n / name :op1 "thrombospondin-1"))))
                  :location (f / fibroblast
                        :mod (d2 / dermis)
                        :ARG0-of (c2 / cause-01 :polarity -
                              :ARG1 (t / tumor)))))
      :ARG2 (m2 / molecular-physical-entity
            :ARG0-of (m3 / mediate-01)
            :ARG1-of (d3 / derive-01
                  :ARG2 (c / cell
                        :source t))
            :mod (s / soluble)))

# ::id bel_pmid_1620_4059.41804 ::date 2015-04-29T05:55:09 ::annotator SDL-AMR-09 ::preferred
# ::snt Interestingly, exposure of MDF-EGFP/TSP-1 fibroblasts to conditioned medium derived rom H-ras-expressing 528ras1 cancer cells (528ras1 conditioned medium) induced a near complete inhibition of GFP fluorescence as indicated by both confocal microscopy and flow cytometry (Fig. 2C, left).
# ::save-date Sat Jan 30, 2016 ::file bel_pmid_1620_4059_41804.txt
(i / induce-01
      :ARG0 (e / expose-01
            :ARG1 (f / fibroblast
                  :mod (c2 / cell-line :name (n2 / name :op1 "MDF-EGFP/TSP-1")))
            :ARG2 (m / medium
                  :ARG1-of (c / condition-01)
                  :ARG1-of (d2 / derive-01
                        :ARG2 (c3 / cell
                              :ARG3-of (e2 / express-03
                                    :ARG2 (e3 / enzyme :name (n3 / name :op1 "H-ras")))
                              :mod (c5 / cell-line :name (n4 / name :op1 "528ras1"))
                              :mod (d4 / disease :wiki "Cancer" :name (n / name :op1 "cancer"))))
                  :ARG1-of (d / describe-01
                        :ARG2 (n9 / name :op1 "528ras1" :op2 "conditioned" :op3 "medium"))))
      :ARG2 (i3 / inhibit-01
            :ARG1 (f2 / fluoresce-01
                  :ARG1 (p2 / protein :name (n6 / name :op1 "GFP")))
            :ARG1-of (c6 / complete-02
                  :degree (n5 / near)))
      :ARG2-of (i2 / interest-01)
      :ARG1-of (i4 / indicate-01
            :instrument (a / and
                  :op1 (m2 / microscopy
                        :mod (c4 / cofocal))
                  :op2 (c7 / cytometry
                        :mod (f4 / flow)))
            :ARG1-of (d3 / describe-01
                  :ARG0 (f3 / figure :mod "2C"
                        :ARG1-of (l / left-20)))))

# ::id bel_pmid_1620_4059.41806 ::date 2015-04-29T06:16:04 ::annotator SDL-AMR-09 ::preferred
# ::snt Again, this effect was paralleled by comparable decreases in TSP-1 mRNA and protein expression in these cells exposed to 528ras1 conditioned medium (Fig. 2C).
# ::save-date Wed Jul 8, 2015 ::file bel_pmid_1620_4059_41806.txt
(p / parallel-01
      :ARG0 (e / effect
            :mod (t / this))
      :ARG1 (d / decrease-01
            :ARG1 (e2 / express-03
                  :ARG2 (a / and
                        :op1 (n4 / nucleic-acid :name (n / name :op1 "mRNA")
                              :ARG0-of (e4 / encode-01
                                    :ARG1 p3))
                        :op2 (p3 / protein :name (n3 / name :op1 "TSP-1")))
                  :ARG3 (c2 / cell
                        :mod (t2 / this)
                        :ARG1-of (e3 / expose-01
                              :ARG2 (m / medium
                                    :ARG1-of (c3 / condition-01)
                                    :mod (c4 / cell-line :name (n2 / name :op1 "528ras1"))))))
            :ARG1-of (c / comparable-03))
      :mod (a2 / again)
      :ARG1-of (d2 / describe-01
            :ARG0 (f / figure :mod "2C")))

# ::id bel_pmid_1620_4059.41808 ::date 2015-04-29T06:22:23 ::annotator SDL-AMR-09 ::preferred
# ::snt In addition to the aforementioned paracrine properties of 528ras1 cells, we observed that also conditioned medium of human colorectal cancer cells harboring a mutant K-ras oncogene (DLD-1), but not that of a DLD-1 variant with genetically disrupted K-ras allele (DKO-3 cells), efficiently suppressed the activity of the TSP-1 reporter gene in MDF-EGFP/ TSP-1 cells (Fig. 4A).
# ::save-date Sun Jan 3, 2016 ::file bel_pmid_1620_4059_41808.txt
(o / observe-01
      :ARG0 (w / we)
      :ARG1 (a / and
            :op1 (p2 / property
                  :mod (p3 / paracrine)
                  :ARG1-of (m / mention-01
                        :time (b / before))
                  :poss (c2 / cell-line :name (n3 / name :op1 "528ras1")))
            :op1 (c10 / contrast-01
                  :ARG1 (s / suppress-01
                        :ARG0 (m2 / medium
                              :ARG1-of (c / condition-01)
                              :mod (c5 / cell
                                    :source (h / human)
                                    :ARG0-of (h2 / harbor-01
                                          :ARG1 (g4 / gene :name (n6 / name :op1 "K-ras")
                                                :ARG2-of (m3 / mutate-01)
                                                :ARG0-of (c6 / cause-01
                                                      :ARG1 (d6 / disease :wiki "Cancer" :name (n8 / name :op1 "cancer")))))
                                    :ARG1-of (d4 / describe-01
                                          :ARG2 (n12 / name :op1 "DLD-1"))
                                    :mod (d / disease :wiki "Colorectal_cancer" :name (n / name :op1 "colorectal" :op2 "cancer")))
                              :mod (a4 / also))
                        :ARG1 (a2 / activity-06
                              :ARG0 (g / gene
                                    :ARG0-of (r2 / report-01
                                          :ARG1 (p4 / protein :name (n4 / name :op1 "TSP-1")))))
                        :location (c3 / cell-line :name (n5 / name :op1 "MDF-EGFP/TSP-1"))
                        :ARG2-of (e / efficient-01))
                  :ARG2 (s2 / suppress-01 :polarity -
                        :ARG0 (m4 / medium
                              :ARG1-of (c4 / condition-01)
                              :mod (v / variant
                                    :poss (c9 / cell-line :name (n7 / name :op1 "DLD-1"))
                                    :ARG1-of (d5 / describe-01
                                          :ARG2 (n10 / name :op1 "DKO-3" :op2 "cells"))
                                    :ARG0-of (h3 / have-03
                                          :ARG1 (a5 / allele
                                                :mod (g3 / gene :name (n2 / name :op1 "K-ras"))
                                                :ARG1-of (d3 / disrupt-01
                                                      :mod (g2 / genetic))))))
                        :ARG1 a2
                        :location c3)))
      :ARG1-of (d2 / describe-01
            :ARG0 (f / figure :mod "4A")))

# ::id bel_pmid_1620_4059.41810 ::date 2015-04-29T07:21:22 ::annotator SDL-AMR-09 ::preferred
# ::snt Once again, we observed that expression of TSP-1 by the nontransformed MDFB6 fibroblasts was precipitously down-regulated when these cells were incubated with B6ras conditioned medium (Fig. 5A).
# ::save-date Wed Apr 29, 2015 ::file bel_pmid_1620_4059_41810.txt
(o2 / observe-01
      :ARG0 (w / we)
      :ARG1 (d / downregulate-01
            :ARG1 (e2 / express-03
                  :ARG2 (p / protein :wiki "Thrombospondin_1"
                        :name (n2 / name :op1 "TSP-1"))
                  :ARG3 (f / fibroblast
                        :mod (c / cell-line :wiki -
                              :name (n3 / name :op1 "MDFB6"))
                        :ARG1-of (t / transform-01 :polarity -)))
            :manner (p2 / precipitous)
            :condition (i / incubate-01
                  :ARG1 f
                  :ARG2 (m / medium
                        :ARG1-of (c2 / condition-01)
                        :mod (c3 / cell-line :wiki -
                              :name (n4 / name :op1 "B6ras")))))
      :mod (a / again
            :mod (o / once))
      :ARG1-of (d2 / describe-01
            :ARG0 (f2 / figure :mod "5A")))

# ::id bel_pmid_1620_4059.41812 ::date 2015-04-29T07:46:33 ::annotator SDL-AMR-09 ::preferred
# ::snt A, immortalized dermal fibroblasts (MDFB6) down-regulate TSP-1 protein expression in the presence of conditioned medium from their H-ras-transformed counterparts (B6ras CM); quantification of representative Western blot.
# ::save-date Thu Jan 28, 2016 ::file bel_pmid_1620_4059_41812.txt
(m / multi-sentence
      :snt1 (d / downregulate-01
            :ARG1 (e2 / express-03
                  :ARG2 (p2 / protein :name (n3 / name :op1 "TSP-1")))
            :location (f / fibroblast
                  :mod (d2 / dermis)
                  :ARG1-of (i / immortalize-03)
                  :ARG1-of (d3 / describe-01
                        :ARG2 (n5 / name :op1 "MDFB6")))
            :condition (p / present-02
                  :ARG1 (m2 / medium
                        :ARG1-of (c / condition-01)
                        :mod (c2 / counterpart
                              :poss f
                              :ARG1-of (t / transform-01
                                    :ARG0 (e / enzyme :name (n6 / name :op1 "H-ras"))))
                        :ARG1-of (d5 / describe-01
                              :ARG2 (n8 / name :op1 "B6ras" :op2 "CM")))))
      :ARG1-of (d4 / describe-01
            :ARG0 (f2 / figure :mod "A"))
      :snt2 (q / quantify-01
            :ARG1 (i2 / immunoblot-01
                  :ARG0-of (r2 / represent-01))))

# ::id bel_pmid_1620_4059.41814 ::date 2015-04-29T07:53:25 ::annotator SDL-AMR-09 ::preferred
# ::snt B, absence of TSP-1 down-regulation in Id1-deficient dermal fibroblasts exposed to conditioned medium of ras-transformed (528ras1 CM and B6ras CM) and neu-transformed (528neu CM) tumor cells.
# ::save-date Fri May 8, 2015 ::file bel_pmid_1620_4059_41814.txt
(a / absent-01
      :ARG1 (d2 / downregulate-01
            :ARG1 (p / protein :name (n2 / name :op1 "TSP-1"))
            :location (f2 / fibroblast
                  :mod (d3 / dermis)
                  :ARG0-of (l / lack-01
                        :ARG1 (p2 / protein :name (n3 / name :op1 "Id1")))
                  :ARG1-of (e2 / expose-01
                        :ARG2 (m / medium
                              :ARG1-of (c / condition-01)
                              :mod (c2 / cell
                                    :source (t / tumor)
                                    :ARG1-of (t2 / transform-01
                                          :ARG0 (e / enzyme :name (n / name :op1 "ras")))
                                    :ARG1-of (t3 / transform-01
                                          :ARG0 (p3 / protein :name (n4 / name :op1 "neu"))))))))
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod "B")))

# ::id bel_pmid_1620_4059.41816 ::date 2015-04-29T08:22:53 ::annotator SDL-AMR-09 ::preferred
# ::snt Paracrine effects of various ras-driven cancer cells were detected at the level of TSP-1 protein, mRNA, and promoter activity (Fig. 2C).
# ::save-date Wed Dec 9, 2015 ::file bel_pmid_1620_4059_41816.txt
(d2 / detect-01
      :ARG1 (e / effect
            :mod (p / paracrine)
            :poss (c / cell
                  :mod (v / various)
                  :ARG1-of (d3 / drive-02
                        :ARG0 (e2 / enzyme :name (n2 / name :op1 "ras")))
                  :mod (d / disease :wiki "Cancer" :name (n / name :op1 "cancer"))))
      :location (a / and
            :op1 (p3 / protein :name (n3 / name :op1 "TSP-1"))
            :op2 (n5 / nucleic-acid :name (n4 / name :op1 "mRNA")
                  :ARG0-of (e3 / encode-01
                        :ARG1 p3))
            :op3 (a2 / activity-06
                  :ARG0 (m / molecular-physical-entity
                        :ARG0-of (p4 / promote-01
                              :ARG1 p3))))
      :ARG1-of (d4 / describe-01
            :ARG0 (f / figure :mod "2C")))

# ::id bel_pmid_1620_4059.41820 ::date 2015-04-29T08:37:24 ::annotator SDL-AMR-09 ::preferred
# ::snt In contrast, abrogation of TSP-1 suppression was observed (Fig. 6C) when MDF528 cells were incubated with dimethylsphingosine, a specific inhibitor of sphingosine kinase.
# ::save-date Sun Jan 3, 2016 ::file bel_pmid_1620_4059_41820.txt
(c / contrast-01
      :ARG2 (o / observe-01
            :ARG1 (a / abrogate-01
                  :ARG1 (s / suppress-01
                        :ARG1 (p / protein :name (n / name :op1 "TSP-1")))
                  :condition (i2 / incubate-01
                        :ARG1 (c2 / cell-line :name (n2 / name :op1 "MDF528"))
                        :ARG2 (s2 / small-molecule :name (n3 / name :op1 "dimethylsphingosine")
                              :ARG0-of (i3 / inhibit-01
                                    :ARG1 (e / enzyme :name (n4 / name :op1 "sphingosine" :op2 "kinase")))
                              :ARG1-of (s3 / specific-02))))
            :ARG1-of (d / describe-01
                  :ARG0 (f / figure :mod "6C"))))

# ::id bel_pmid_1620_4059.41822 ::date 2015-04-29T08:43:53 ::annotator SDL-AMR-09 ::preferred
# ::snt Thus, suppression of TSP-1 promoter activity by fraction 2 of 528ras1 conditioned medium was moderately sensitive to pertussis toxin but was completely abolished by dimethylsphingosine.
# ::save-date Sun Dec 20, 2015 ::file bel_pmid_1620_4059_41822.txt
(i / infer-01
      :ARG1 (c / contrast-01
            :ARG1 (s / sensitive-03
                  :ARG0 (s2 / suppress-01
                        :ARG0 (f / fraction :mod 2
                              :ARG1-of (i2 / include-91
                                    :ARG2 (m2 / medium
                                          :ARG1-of (c2 / condition-01)
                                          :mod (c3 / cell-line :name (n2 / name :op1 "528ras1")))))
                        :ARG1 (a2 / activity-06
                              :ARG0 (m / molecular-physical-entity
                                    :ARG0-of (p / promote-01
                                          :ARG1 (p2 / protein :name (n / name :op1 "TSP-1"))))))
                  :ARG1 (s3 / small-molecule :name (n3 / name :op1 "pertussis" :op2 "toxin"))
                  :ARG1-of (m3 / moderate-03))
            :ARG2 (a / abolish-01
                  :ARG0 (s4 / small-molecule :name (n4 / name :op1 "dimethylsphingosine"))
                  :ARG1 s2
                  :ARG1-of (c4 / complete-02))))

# ::id bel_pmid_1625_4190.34278 ::date 2015-04-29T08:51:46 ::annotator SDL-AMR-09 ::preferred
# ::snt Table 3. Alteration of Gene Expression Specially Associated with p53 and H-ras Status in Skin Tumorigenesis upregulated
# ::save-date Mon Dec 21, 2015 ::file bel_pmid_1625_4190_34278.txt
(a / alter-01
      :ARG1 (e2 / express-03
            :ARG1 (g / gene)
            :ARG1-of (a2 / associate-01
                  :ARG2 (a3 / and
                        :op1 (s / status
                              :mod (p / protein :name (n2 / name :op1 "p53")))
                        :op2 (s2 / status
                              :mod (e / enzyme :name (n3 / name :op1 "H-ras"))))
                  :ARG1-of (s4 / special-02)))
      :subevent-of (c / create-01
            :ARG1 (t / tumor
                  :mod (s3 / skin)))
      :ARG1-of (d / describe-01
            :ARG0 (t2 / table :mod 3)))

# ::id bel_pmid_1628_7813.37026 ::date 2015-04-29T09:06:48 ::annotator SDL-AMR-09 ::preferred
# ::snt It is known that there are two isoforms of ERK, ERK1 and ERK2, and they phosphorylate and activate various transcription factors, such as Elk-1 and Elk-2. These transcription factors regulate expression of diverse genes that relates to the proliferation and growth of the cells.
# ::save-date Sat Jan 16, 2016 ::file bel_pmid_1628_7813_37026.txt
(m / multi-sentence
      :snt1 (k / know-01
            :ARG1 (a4 / and
                  :op1 (e2 / enzyme :name (n2 / name :op1 "ERK1")
                        :mod (i / isoform
                              :mod (p5 / protein-family :name (n4 / name :op1 "ERK")))
                        :ARG0-of (p / phosphorylate-01
                              :ARG1 (f / factor
                                    :ARG0-of (t / transcribe-01)
                                    :example (a / and
                                          :op1 (p2 / protein :name (n5 / name :op1 "Elk-1"))
                                          :op2 (p3 / protein :name (n6 / name :op1 "Elk-2")))
                                    :mod (v / various)))
                        :ARG0-of (a3 / activate-01
                              :ARG1 f))
                  :op2 (e3 / enzyme :name (n3 / name :op1 "ERK2")
                        :mod i
                        :ARG0-of p
                        :ARG0-of a3)))
      :snt2 (r / regulate-01
            :ARG0 (f2 / factor
                  :ARG0-of (t2 / transcribe-01)
                  :mod (t3 / this))
            :ARG1 (e5 / express-03
                  :ARG1 (g / gene
                        :mod (d / diverse))
                  :ARG1-of (r2 / relate-01
                        :ARG2 (a2 / and
                              :op1 (p4 / proliferate-01
                                    :ARG0 (c / cell))
                              :op2 (g2 / grow-01
                                    :ARG1 c))))))

# ::id bel_pmid_1632_4152.36878 ::date 2015-04-29T09:26:46 ::annotator SDL-AMR-09 ::preferred
# ::snt IL-12 activates the Janus family tyrosine kinases JAK2 and Tyk2, which in turn phosphorylate STAT4 on tyrosine 693.
# ::save-date Mon Jan 4, 2016 ::file bel_pmid_1632_4152_36878.txt
(a / activate-01
      :ARG0 (p / protein :name (n / name :op1 "IL-12"))
      :ARG1 (a2 / and
            :op1 (t / tyrosine-kinase :name (n2 / name :op1 "JAK2"))
            :op2 (t2 / tyrosine-kinase :name (n3 / name :op1 "Tyk2"))
            :ARG2-of (p2 / phosphorylate-01
                  :ARG1 (a3 / amino-acid :mod 693 :name (n4 / name :op1 "tyrosine")
                        :part-of (p3 / protein :name (n5 / name :op1 "STAT4")))
                  :mod (i / in-turn))
            :ARG1-of (i2 / include-91
                  :ARG2 (p4 / protein-family :name (n6 / name :op1 "Janus")))))

# ::id bel_pmid_1633_9523.28962 ::date 2015-04-30T01:24:04 ::annotator SDL-AMR-09 ::preferred
# ::snt Among the cytokines expressed after 4 h of Ag stimulation in BMMCs, our data show that levels of mRNA and protein for IL-4, IL-6, and for IL-13 are all significantly higher in Lyn-/- than in WT BMMCs.
# ::save-date Fri Dec 18, 2015 ::file bel_pmid_1633_9523_28962.txt
(s / show-01
      :ARG0 (d / data
            :poss (w / we))
      :ARG1 (h / high-02
            :ARG1 (a4 / and
                  :op1 (l2 / level
                        :quant-of (p / protein :name (n / name :op1 "IL-4")))
                  :op2 (l3 / level
                        :quant-of (p2 / protein :name (n2 / name :op1 "IL-6")))
                  :op3 (l4 / level
                        :quant-of (p3 / protein :name (n3 / name :op1 "IL-13")))
                  :op4 (l5 / level
                        :quant-of (n11 / nucleic-acid :name (n4 / name :op1 "mRNA")
                              :ARG0-of (e4 / encode-01
                                    :ARG1 p)))
                  :op5 (l6 / level
                        :quant-of (n12 / nucleic-acid :name (n5 / name :op1 "mRNA")
                              :ARG0-of (e5 / encode-01
                                    :ARG1 p2)))
                  :op6 (l7 / level
                        :quant-of (n13 / nucleic-acid :name (n6 / name :op1 "mRNA")
                              :ARG0-of (e6 / encode-01
                                    :ARG1 p3)))
                  :ARG1-of (i / include-91
                        :ARG2 (c / cytokine
                              :ARG2-of (e / express-03
                                    :time (a2 / after
                                          :op1 (s2 / stimulate-01
                                                :ARG0 (a3 / antigen)
                                                :location (c2 / cell-line :name (n7 / name :op1 "BMMC")))
                                          :quant (t / temporal-quantity :quant 4
                                                :unit (h2 / hour)))))))
            :degree (m / more)
            :location (c3 / cell-line :name (n8 / name :op1 "BMMC")
                  :ARG3-of (e2 / express-03
                        :ARG2 (e3 / enzyme :name (n9 / name :op1 "Lyn")
                              :ARG2-of (m2 / mutate-01 :mod "-/-"))))
            :compared-to (c4 / cell-line :name (n10 / name :op1 "BMMC")
                  :mod (w2 / wild-type))
            :ARG1-of (s3 / significant-02)))

# ::id bel_pmid_1633_9523.28966 ::date 2015-04-30T01:39:23 ::annotator SDL-AMR-09 ::preferred
# ::snt Our data show that mRNA coding for at least one transcription factor, the cytoplasmic NF-AT (NF-ATC, also known as NFATC1 and NFAT2) is induced 3-fold more in Lyn–/– BMMCs than in WT BMMCs (Table II).
# ::save-date Mon Jan 4, 2016 ::file bel_pmid_1633_9523_28966.txt
(s / show-01
      :ARG0 (d / data
            :poss (w / we))
      :ARG1 (i / induce-01
            :ARG2 (c / code-01
                  :ARG1 (f / factor
                        :ARG0-of (t / transcribe-01)
                        :quant (a / at-least :op1 1)
                        :ARG1-of (m / mean-01
                              :ARG2 (p4 / protein :name (n2 / name :op1 "NF-AT")
                                    :mod (c2 / cytoplasm)
                                    :ARG1-of (k / know-02
                                          :ARG2 (a4 / and
                                                :op1 (p2 / protein :name (n3 / name :op1 "NFATC1"))
                                                :op2 (p3 / protein :name (n4 / name :op1 "NFAT2")))
                                          :mod (a3 / also)))))
                  :instrument (n8 / nucleic-acid :name (n / name :op1 "mRNA")))
            :degree (p / product-of :op1 3)
            :location (c3 / cell-line :name (n5 / name :op1 "BMMC")
                  :ARG3-of (e / express-03
                        :ARG2 (e2 / enzyme :name (n6 / name :op1 "Lyn")
                              :ARG2-of (m2 / mutate-01 :mod "-/-"))))
            :compared-to (c4 / cell-line :name (n7 / name :op1 "BMMC")
                  :mod (w2 / wild-type))
            :mod (m3 / more))
      :ARG1-of (d2 / describe-01
            :ARG0 (t2 / table :mod "II")))

# ::id bel_pmid_1633_9523.28968 ::date 2015-04-30T01:49:54 ::annotator SDL-AMR-09 ::preferred
# ::snt The 33-fold up-regulation of sphingosine kinase 1 in Ag-stimulated Lyn–/– BMMCs may also contribute to increased chemokine production
# ::save-date Sun Jan 3, 2016 ::file bel_pmid_1633_9523_28968.txt
(p / possible-01
      :ARG1 (c / contribute-01
            :ARG0 (u / upregulate-01
                  :ARG1 (e3 / enzyme :name (n / name :op1 "sphingosine" :op2 "kinase" :op3 "1"))
                  :degree (p2 / product-of :op1 33)
                  :location (c2 / cell-line :name (n2 / name :op1 "BMMC")
                        :ARG3-of (e / express-03
                              :ARG2 (e2 / enzyme :name (n3 / name :op1 "Lyn")
                                    :ARG2-of (m / mutate-01 :mod "-/-")))
                        :ARG1-of (s / stimulate-01
                              :ARG0 (a / antigen))))
            :ARG2 (p3 / produce-01
                  :ARG1 (c3 / chemokine)
                  :ARG1-of (i / increase-01))
            :mod (a2 / also)))

# ::id bel_pmid_1637_4521.27952 ::date 2015-04-30T01:53:14 ::annotator SDL-AMR-09 ::preferred
# ::snt After 24 hours of IL-13 induction, phosphorylation of ERK1 (p44) and ERK2 (p42) but not JNK1/2 or p38 MAPK was observed (Figure 1).
# ::save-date Sun Dec 20, 2015 ::file bel_pmid_1637_4521_27952.txt
(c / contrast-01
      :ARG1 (o / observe-01
            :ARG1 (p / phosphorylate-01
                  :ARG1 (a2 / and
                        :op1 (e / enzyme :name (n3 / name :op1 "p44ERK1"))
                        :op2 (e2 / enzyme :name (n4 / name :op1 "p42ERK2")))))
      :ARG2 (o2 / observe-01 :polarity -
            :ARG1 (p4 / phosphorylate-01
                  :ARG1 (o3 / or
                        :op1 (e3 / enzyme :name (n5 / name :op1 "JNK1"))
                        :op2 (e4 / enzyme :name (n6 / name :op1 "JNK2"))
                        :op3 (e5 / enzyme :name (n7 / name :op1 "p38MAPK")))))
      :time (a / after
            :op1 (i / induce-01
                  :ARG2 (p3 / protein :name (n2 / name :op1 "IL-13")))
            :quant (t / temporal-quantity :quant 24
                  :unit (h / hour)))
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod 1)))

# ::id bel_pmid_1637_4521.27960 ::date 2015-04-30T02:06:26 ::annotator SDL-AMR-09 ::preferred
# ::snt Our previous studies demonstrated that IL-13 causes MMP- and cathepsin-dependent lung remodeling and inhibits the expression of a1–AT (4).
# ::save-date Fri May 8, 2015 ::file bel_pmid_1637_4521_27960.txt
(d / demonstrate-01
      :ARG0 (s / study-01
            :ARG0 (w / we)
            :time (p / previous))
      :ARG1 (a / and
            :op1 (c / cause-01
                  :ARG0 (p2 / protein :name (n / name :op1 "IL-13"))
                  :ARG1 (r / remodel-01
                        :ARG1 (l / lung)
                        :ARG0-of (d2 / depend-01
                              :ARG1 (a2 / and
                                    :op1 (e / enzyme :name (n2 / name :op1 "MMP"))
                                    :op2 (e2 / enzyme :name (n3 / name :op1 "cathepsin"))))))
            :op2 (i / inhibit-01
                  :ARG1 (e3 / express-03
                        :ARG2 (p3 / protein :name (n4 / name :op1 "a1–AT")))))
      :ARG1-of (d3 / describe-01
            :ARG0 (p4 / publication
                  :ARG1-of (c2 / cite-01
                        :ARG2 4))))

# ::id bel_pmid_1637_4521.27968 ::date 2015-04-30T02:12:02 ::annotator SDL-AMR-09 ::preferred
# ::snt IL-13 Tg can be inducibly expressed in the adult murine lung by the administration of doxycycline-containing (dox-containing) water. As expected, increased levels of phospho-STAT6 were readily detected by Western blot analysis after Tg activation (Figure 1).
# ::save-date Sun Jan 17, 2016 ::file bel_pmid_1637_4521_27968.txt
(m / multi-sentence
      :snt1 (p / possible-01
            :ARG1 (e / express-03
                  :ARG2 (p3 / protein :name (n2 / name :op1 "IL-13")
                        :mod (t / transgenic))
                  :ARG3 (l / lung
                        :part-of (o / organism :name (n / name :op1 "Muridae")
                              :mod (a2 / adult)))
                  :manner (i / induce-01
                        :ARG1-of (p2 / possible-01))
                  :instrument (a3 / administer-01
                        :ARG1 (w2 / water
                              :ARG0-of (c / contain-01
                                    :ARG1 (s / small-molecule :name (n3 / name :op1 "doxycycline")))))))
      :snt2 (d / detect-01
            :ARG1 (l2 / level
                  :ARG1-of (i2 / increase-01)
                  :quant-of (p4 / protein :name (n4 / name :op1 "STAT6")
                        :ARG3-of (p5 / phosphorylate-01)))
            :ARG2 (a4 / analyze-01
                  :manner (i3 / immunoblot-01))
            :ARG1-of (e2 / expect-01)
            :manner (r / ready)
            :time (a5 / after
                  :op1 (a6 / activate-01
                        :ARG0 (p6 / protein :name (n6 / name :op1 "IL-6")
                              :mod (t2 / transgenic))))
            :ARG1-of (d2 / describe-01
                  :ARG0 (f / figure :mod 1))))

# ::id bel_pmid_1637_4521.27988 ::date 2015-04-30T02:32:06 ::annotator SDL-AMR-09 ::preferred
# ::snt Tg IL-13 caused increases in lung volume, alveolar size, goblet cell number, and Gob-5, Muc-5ac, and Muc-1 gene expression in Tg+ ERK1/2 MAPK-sufficient animals (Figure 8, A–H).
# ::save-date Sat Jan 2, 2016 ::file bel_pmid_1637_4521_27988.txt
(c / cause-01
      :ARG0 (p / protein :name (n / name :op1 "IL-13")
            :mod (t / transgenic))
      :ARG1 (i / increase-01
            :ARG1 (a / and
                  :op1 (v / volume
                        :mod (l / lung))
                  :op2 (s / size
                        :mod (a2 / alveolus))
                  :op3 (n2 / number
                        :quant-of (c2 / cell
                              :mod (g / goblet)))
                  :op3 (e / express-03
                        :ARG1 (a3 / and
                              :op1 (g2 / gene :name (n3 / name :op1 "Gob-5"))
                              :op2 (g3 / gene :name (n4 / name :op1 "Muc-5ac"))
                              :op3 (g4 / gene :name (n5 / name :op1 "Muc-1")))))
            :location (a4 / animal
                  :ARG1-of (s2 / suffice-01
                        :ARG0 (p2 / pathway :name (n6 / name :op1 "ERK1/2" :op2 "MAPK")))
                  :mod (t2 / transgenic
                        :mod (p3 / positive))))
      :ARG1-of (d / describe-01
            :ARG0 (a5 / and
                  :op1 (f / figure :mod "8A")
                  :op2 (f3 / figure :mod "8B")
                  :op3 (f4 / figure :mod "8C")
                  :op4 (f5 / figure :mod "8D")
                  :op5 (f6 / figure :mod "8E")
                  :op6 (f7 / figure :mod "8F")
                  :op7 (f8 / figure :mod "8G")
                  :op8 (f9 / figure :mod "8H"))))

# ::id bel_pmid_1643_0878.29026 ::date 2015-04-30T02:39:09 ::annotator SDL-AMR-09 ::preferred
# ::snt BMMCs from mice lacking Map3k2 showed reduced production (50-60%) of IL-6, IL-13, and TNF-alpha after stimulation
# ::save-date Thu Apr 30, 2015 ::file bel_pmid_1643_0878_29026.txt
(s / show-01
      :ARG0 (c / cell-line :name (n / name :op1 "BMMC")
            :source (m / mouse
                  :ARG0-of (l / lack-01
                        :ARG1 (g / gene :name (n2 / name :op1 "Map3k2")))))
      :ARG1 (p2 / produce-01
            :ARG1 (a / and
                  :op1 (p4 / protein :name (n3 / name :op1 "IL-6"))
                  :op2 (p5 / protein :name (n4 / name :op1 "IL-13"))
                  :op3 (p6 / protein :name (n5 / name :op1 "TNF-alpha")))
            :ARG1-of (r / reduce-01
                  :ARG1-of (m2 / mean-01
                        :ARG2 (v / value-interval
                              :op1 (p / percentage-entity :value 50)
                              :op2 (p3 / percentage-entity :value 60)))))
      :time (a2 / after
            :op1 (s2 / stimulate-01)))

# ::id bel_pmid_1648_4683.21972 ::date 2015-04-30T02:44:55 ::annotator SDL-AMR-09 ::preferred
# ::snt In asbestos-associated transformation of rodent mesothelial cells, the use of dominant negative ERK1 or Fra-1 constructs reverses the phenotype of mesothelioma cells to that of normal mesothelial cells (12). Moreover, Fra-1 expression is increased in human mesotheliomas and in other tumor types.
# ::save-date Fri Feb 5, 2016 ::file bel_pmid_1648_4683_21972.txt
(m / multi-sentence
      :snt1 (r / reverse-01
            :ARG0 (u / use-01
                  :ARG1 (o / or
                        :op1 (m2 / molecular-physical-entity
                              :ARG1-of (c / construct-01
                                    :mod (e / enzyme :name (n / name :op1 "ERK1")))
                              :ARG2-of (m4 / mutate-01 :mod "-/-"
                                    :ARG0-of (d / dominate-01)))
                        :op2 (m6 / molecular-physical-entity
                              :ARG1-of (c5 / construct-01
                                    :mod (p5 / protein :name (n2 / name :op1 "Fra-1")))
                              :mod m4)))
            :ARG1 (p / phenotype
                  :poss (c2 / cell
                        :mod (m3 / mesothelium)
                        :source (r2 / rodent)))
            :prep-to (p2 / phenotype
                  :poss (c3 / cell
                        :ARG1-of (n4 / normal-02)
                        :mod m3))
            :prep-in (t / transform-01
                  :ARG1 c2
                  :ARG1-of (a / associate-01
                        :ARG2 (a2 / asbestos)))
            :ARG1-of (d2 / describe-01
                  :ARG0 (p3 / publication
                        :ARG1-of (c4 / cite-01
                              :ARG2 12))))
      :snt2 (a3 / and
            :op2 (i / increase-01
                  :ARG1 (e3 / express-03
                        :ARG2 (p4 / protein :name (n5 / name :op1 "Fra-1"))
                        :ARG3 (a4 / and
                              :op1 (m5 / mesothelioma
                                    :source (h / human))
                              :op2 (t2 / tumor
                                    :mod (o2 / other)))))))

# ::id bel_pmid_1648_4683.26962 ::date 2015-04-30T02:56:45 ::annotator SDL-AMR-09 ::preferred
# ::snt We have used siRNA approaches to show that Fra-1 expression is critical to the expression of genes, such as cd44 and c-met, that are critical to migration and autocrine growth factor production in transformation and invasion of mesotheliomas (13).
# ::save-date Wed Feb 24, 2016 ::file bel_pmid_1648_4683_26962.txt
(u / use-01
      :ARG0 (w2 / we)
      :ARG1 (a / approach-02
            :instrument (n6 / nucleic-acid :name (n2 / name :op1 "siRNA")))
      :purpose (s2 / show-01
            :ARG0 w2
            :ARG1 (c / critical-02
                  :ARG1 (e / express-03
                        :ARG2 (p / protein :name (n3 / name :op1 "Fra-1")))
                  :ARG2 (e2 / express-03
                        :ARG1 (g / gene
                              :ARG1-of (c2 / critical-02
                                    :ARG2 (a3 / and
                                          :op1 (m2 / migrate-01)
                                          :op2 (p2 / produce-01
                                                :ARG1 (g4 / growth-factor
                                                      :mod (a4 / autocrine)))
                                          :prep-in (a5 / and
                                                :op1 (t / transform-01
                                                      :ARG1 (m3 / mesothelioma))
                                                :op2 (i / invade-01
                                                      :ARG1 m3))))
                              :example (a2 / and
                                    :op1 (g2 / gene :name (n4 / name :op1 "cd44"))
                                    :op2 (g3 / gene :name (n5 / name :op1 "c-met")))))))
      :ARG1-of (d / describe-01
            :ARG0 (p3 / publication
                  :ARG1-of (c3 / cite-01
                        :ARG2 13))))

# ::id bel_pmid_1648_4683.37584 ::date 2015-04-30T03:06:52 ::annotator SDL-AMR-09 ::preferred
# ::snt In contrast, EGFR activation by gram-positive bacteria occurred through cleavage of the transmembrane ligand HBEGF by ADAM 10.
# ::save-date Sat May 9, 2015 ::file bel_pmid_1648_4683_37584.txt
(c / contrast-01
      :ARG2 (a / activate-01
            :ARG0 (b / bacteria
                  :mod (g / gram-positive))
            :ARG1 (e / enzyme :name (n / name :op1 "EGFR"))
            :manner (c2 / cleave-01
                  :ARG0 (p / protein :name (n3 / name :op1 "ADAM" :op2 "10"))
                  :ARG1 (l / ligand :name (n2 / name :op1 "HBEGF")
                        :mod (t / transmembrane)))))

# ::id bel_pmid_1649_2667.37650 ::date 2015-04-30T03:12:47 ::annotator SDL-AMR-09 ::preferred
# ::snt from full text - Furthermore, the decreased expression of either b-arrestin 1 or b-arrestin 2 (via siRNA) resulted in a decrease in ERK1/2 activity
# ::save-date Mon Dec 21, 2015 ::file bel_pmid_1649_2667_37650.txt
(a / and
      :op2 (r / result-01
            :ARG1 (e / express-03
                  :ARG2 (o / or
                        :op1 (p / protein :name (n / name :op1 "b-arrestin" :op2 "1"))
                        :op2 (p2 / protein :name (n2 / name :op1 "b-arrestin" :op2 "2")))
                  :ARG1-of (d / decrease-01)
                  :instrument (n5 / nucleic-acid :name (n3 / name :op1 "siRNA")))
            :ARG2 (d2 / decrease-01
                  :ARG1 (a2 / activity-06
                        :ARG0 (e2 / enzyme :name (n4 / name :op1 "ERK1/2")))))
      :ARG1-of (d3 / describe-01
            :ARG0 (t / text
                  :ARG1-of (f / full-09))))

# ::id bel_pmid_1651_0581.41864 ::date 2015-04-30T03:18:13 ::annotator SDL-AMR-09 ::preferred
# ::snt FBLN-3 expression in MB114 cells also prevented their activation of p38 MAPK, but not that of extracellular signal-regulated kinase 1/2 (ERK1/2), stimulated by VEGF (Fig. 2E).
# ::save-date Sat May 2, 2015 ::file bel_pmid_1651_0581_41864.txt
(c / contrast-01
      :ARG1 (p2 / prevent-01
            :ARG0 (e / express-03
                  :ARG2 (p3 / protein :name (n2 / name :op1 "FBLN-3"))
                  :ARG3 (c2 / cell-line :name (n3 / name :op1 "MB114")))
            :ARG1 (a / activate-01
                  :ARG0 c2
                  :ARG1 (e2 / enzyme :name (n4 / name :op1 "p38MAPK")))
            :mod (a2 / also))
      :ARG2 (p4 / prevent-01 :polarity -
            :ARG1 (a3 / activate-01
                  :ARG1 (e3 / enzyme :name (n5 / name :op1 "extracellular" :op2 "signal-regulated" :op3 "kinase" :op4 "1/2"))
                  :ARG1-of (s / stimulate-01
                        :ARG0 (p5 / protein :name (n6 / name :op1 "VEGF")))))
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod "2E")))

# ::id bel_pmid_1651_0581.41866 ::date 2015-05-02T11:07:17 ::annotator SDL-AMR-09 ::preferred
# ::snt Figure 3A shows that relative to control cells, FBLN-3 and FBLN-5 both decreased MB114 cell expression of MMP-2 and MMP-3 while simultaneously increasing that of the MMP antagonists, TIMP-1 and TIMP-3.
# ::save-date Sun Jan 17, 2016 ::file bel_pmid_1651_0581_41866.txt
(s / show-01
      :ARG0 (f / figure :mod "3A")
      :ARG1 (a / and
            :op1 (d / decrease-01
                  :ARG0 (a2 / and
                        :op1 (p / protein :name (n / name :op1 "FBLN-3"))
                        :op2 (p2 / protein :name (n2 / name :op1 "FBLN-5")))
                  :ARG1 (e / express-03
                        :ARG2 (a3 / and
                              :op1 (e3 / enzyme :name (n4 / name :op1 "MMP-2"))
                              :op2 (e4 / enzyme :name (n5 / name :op1 "MMP-3")))
                        :ARG3 (c3 / cell-line :name (n3 / name :op1 "MB114"))))
            :op2 (i / increase-01
                  :ARG0 a2
                  :ARG2 (a4 / and
                        :op1 (p5 / protein :name (n6 / name :op1 "TIMP-1")
                              :ARG1-of (a5 / antagonize-02
                                    :ARG2 (e2 / enzyme :name (n7 / name :op1 "MMP"))))
                        :op2 (p7 / protein :name (n8 / name :op1 "TIMP-3")
                              :ARG1-of a5))
                  :manner (s2 / simultaneous))
            :compared-to (c / cell
                  :mod (c2 / control-01))))

# ::id bel_pmid_1651_0581.41868 ::date 2015-05-03T01:35:17 ::annotator SDL-AMR-09 ::preferred
# ::snt Although MB114 cell expression of TIMP-2 was unaffected by either FBLN-3 or FBLN-5, both FBLNs induced MB114 cell expression of the angiostatic molecule, TSP-1 (Fig. 3A).
# ::save-date Sun Dec 20, 2015 ::file bel_pmid_1651_0581_41868.txt
(h / have-concession-91
      :ARG1 (i / induce-01
            :ARG0 (a / and
                  :op1 (p / protein :name (n / name :op1 "FBLN-3"))
                  :op2 (p2 / protein :name (n2 / name :op1 "FBLN-5")))
            :ARG2 (e / express-03
                  :ARG2 (p3 / protein :name (n4 / name :op1 "TSP-1")
                        :mod (a2 / angiostatic))
                  :ARG3 (c2 / cell-line :name (n3 / name :op1 "MB114"))))
      :ARG2 (a3 / affect-01 :polarity -
            :ARG0 a
            :ARG1 (e2 / express-03
                  :ARG2 (p4 / protein :name (n5 / name :op1 "TIMP-2"))
                  :ARG3 c2))
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod "3A")))

# ::id bel_pmid_1651_0581.41870 ::date 2015-05-03T02:32:05 ::annotator SDL-AMR-09 ::preferred
# ::snt Interestingly, although TIMP-3 expression was elevated basally in FBLN-5-expressing MB114 cells, only FBLN-3 stimulated TIMP-3 expression in tubulating MB114 cells (Fig. 3B).
# ::save-date Tue Feb 2, 2016 ::file bel_pmid_1651_0581_41870.txt
(h / have-concession-91
      :ARG1 (s / stimulate-01
            :ARG0 (p / protein :name (n / name :op1 "FBLN-3")
                  :mod (o / only))
            :ARG1 (e / express-03
                  :ARG2 (p2 / protein :name (n3 / name :op1 "TIMP-3"))
                  :ARG3 (c2 / cell-line :name (n2 / name :op1 "MB114")
                        :ARG0-of (t / tubulate-01))))
      :ARG2 (e2 / elevate-01
            :ARG1 (e3 / express-03
                  :ARG2 p2
                  :ARG3 (c3 / cell-line :name (n4 / name :op1 "MB114")
                        :ARG3-of (e4 / express-03
                              :ARG2 (p3 / protein :name (n5 / name :op1 "FBLN-5")))))
            :manner (b / basal))
      :ARG2-of (i / interest-01))

# ::id bel_pmid_1651_0581.41872 ::date 2015-05-03T02:46:15 ::annotator SDL-AMR-09 ::preferred
# ::snt Gelatin zymography of MB114 cell conditioned medium confirmed that expression of either FBLN-3 or FBLN-5 significantly reduced MMP-2 protease activity in tubulating MB114 cells (Fig. 3C).
# ::save-date Tue Feb 2, 2016 ::file bel_pmid_1651_0581_41872.txt
(c / confirm-01
      :ARG1 (r / reduce-01
            :ARG0 (e / express-03
                  :ARG2 (o / or
                        :op1 (p / protein :name (n3 / name :op1 "FBLN-3"))
                        :op2 (p2 / protein :name (n4 / name :op1 "FBLN-5"))))
            :ARG1 (a / activity-06
                  :ARG0 (p3 / protease :name (n5 / name :op1 "MMP-2"))
                  :location (c4 / cell-line :name (n6 / name :op1 "MB114")
                        :ARG0-of (t / tubulate-01)))
            :ARG2 (s / significant-02))
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod "3C"))
      :mod (z / zymography
            :mod (g / gelatin)
            :topic (m / medium
                  :ARG1-of (c2 / condition-01)
                  :mod (c3 / cell-line :name (n2 / name :op1 "MB114")))))

# ::id bel_pmid_1651_0581.41874 ::date 2015-05-03T02:52:43 ::annotator SDL-AMR-09 ::preferred
# ::snt FBLN-3 and FBLN-5 antagonize angiogenesis in vivo.
# ::save-date Sun May 3, 2015 ::file bel_pmid_1651_0581_41874.txt
(a / antagonize-02
      :ARG1 (a2 / and
            :op1 (p / protein :name (n / name :op1 "FBLN-3"))
            :op2 (p2 / protein :name (n2 / name :op1 "FBLN-5")))
      :ARG2 (a3 / angiogenesis)
      :manner (i / in-vivo))

# ::id bel_pmid_1651_0581.41878 ::date 2015-05-03T02:57:26 ::annotator SDL-AMR-09 ::preferred
# ::snt Moreover, recombinant FBLN-3 and FBLN-5 (Fig. 4B) both inhibited human HMEC-1 endothelial cell migration to fibronectin (Fig. 4C), whereas FBLN-5, but not FBLN-3, mediated their adhesion in an RGD-dependent manner (Fig. 4D; refs.
# ::save-date Mon Jan 4, 2016 ::file bel_pmid_1651_0581_41878.txt
(a3 / and
      :op2 (c / contrast-01
            :ARG1 (i / inhibit-01
                  :ARG0 (a / and
                        :op1 (p / protein :name (n / name :op1 "FBLN-3"))
                        :op2 (p2 / protein :name (n2 / name :op1 "FBLN-5"))
                        :ARG3-of (r / recombine-01)
                        :ARG1-of (d / describe-01
                              :ARG0 (f / figure :mod "4B")))
                  :ARG1 (m / migrate-01
                        :ARG0 (c2 / cell-line :name (n3 / name :op1 "HMEC-1")
                              :mod (h / human))
                        :ARG1 (e / endothelium)
                        :ARG2 (p3 / protein :name (n4 / name :op1 "fibronectin")))
                  :ARG1-of (d2 / describe-01
                        :ARG0 (f2 / figure :mod "4C")))
            :ARG2 (c3 / contrast-01
                  :ARG1 (m2 / mediate-01
                        :ARG0 p2
                        :ARG1 (a2 / adhere-01
                              :ARG1 c2
                              :manner (d3 / depend-01
                                    :ARG0 c2
                                    :ARG1 (s / small-molecule :name (n5 / name :op1 "RGD")))))
                  :ARG2 (m3 / mediate-01 :polarity -
                        :ARG0 p
                        :ARG1 a2)
                  :ARG1-of (d4 / describe-01
                        :ARG0 (f3 / figure :mod "4D"))
                  :ARG1-of (d5 / describe-01
                        :ARG0 (p4 / publication
                              :ARG1-of (c4 / cite-01))))))

# ::id bel_pmid_1651_0581.41880 ::date 2015-05-03T06:29:52 ::annotator SDL-AMR-09 ::preferred
# ::snt Figure 5A shows that bFGF stimulated significant vascularization of implanted Matrigel plugs, which was quantified by measuring plug hemoglobin contents (Fig. 5A) and microvessel densities (Fig. 5B).
# ::save-date Tue Feb 2, 2016 ::file bel_pmid_1651_0581_41880.txt
(s / show-01
      :ARG0 (f / figure :mod "5A")
      :ARG1 (s2 / stimulate-01
            :ARG0 (p / protein :name (n / name :op1 "bFGF"))
            :ARG1 (v / vascularize-01
                  :ARG1 (p2 / plug
                        :ARG1-of (i / implant-01)
                        :mod (p4 / protein :name (n2 / name :op1 "Matrigel")))
                  :ARG1-of (s3 / significant-02)
                  :ARG1-of (q / quantify-01
                        :manner (m / measure-01
                              :ARG1 (a / and
                                    :op1 (c / content
                                          :mod (h / hemoglobin)
                                          :ARG1-of (d2 / describe-01
                                                :ARG0 f)
                                          :location (p3 / plug))
                                    :op2 (d / density
                                          :mod (m2 / microvessel)
                                          :ARG1-of (d3 / describe-01
                                                :ARG0 (f2 / figure :mod "5B")))))))))

# ::id bel_pmid_1651_0581.41890 ::date 2015-05-03T06:53:58 ::annotator SDL-AMR-09 ::preferred
# ::snt More importantly, tumors derived from FBLN-expressing MCA102 fibrosarcoma cells also exhibited significantly reduced blood vessel densities compared with tumors derived from control cells (Fig. 6D ).
# ::save-date Mon Jan 4, 2016 ::file bel_pmid_1651_0581_41890.txt
(e / exhibit-01
      :ARG0 (t / tumor
            :ARG1-of (d / derive-01
                  :ARG2 (c / cell-line :name (n / name :op1 "MCA102")
                        :ARG3-of (e2 / express-03
                              :ARG2 (p / protein :name (n2 / name :op1 "FBLN")))
                        :mod (f2 / fibrosarcoma))))
      :ARG1 (d2 / density
            :mod (v / vessel
                  :mod (b / blood))
            :ARG1-of (r / reduce-01
                  :ARG2 (s / significant-02)
                  :compared-to (t2 / tumor
                        :ARG1-of (d4 / derive-01
                              :ARG2 (c2 / cell
                                    :mod (c3 / control-01))))))
      :mod (i / important
            :degree (m / more))
      :ARG1-of (d3 / describe-01
            :ARG0 (f / figure :mod "6D"))
      :mod (a / also))

# ::id bel_pmid_1651_0581.41892 ::date 2015-05-03T06:58:31 ::annotator SDL-AMR-09 ::preferred
# ::snt In addition, FBLN-3-expressing MCA102 tumors contained significantly enlarged regions of central and peripheral necrosis that were typically absent in their control counterparts.
# ::save-date Fri Dec 18, 2015 ::file bel_pmid_1651_0581_41892.txt
(a / and
      :op2 (c / contain-01
            :ARG0 (t / tumor
                  :source (c2 / cell-line :name (n / name :op1 "MCA102"))
                  :ARG3-of (e / express-03
                        :ARG2 (p / protein :name (n2 / name :op1 "FBLN-3"))))
            :ARG1 (r / region
                  :ARG1-of (e2 / enlarge-01
                        :ARG2 (s / significant-02))
                  :ARG1-of (a3 / absent-01
                        :ARG2 (c4 / counterpart
                              :poss r
                              :mod (c5 / control-01))
                        :ARG1-of (t2 / typical-02))
                  :location-of (a2 / and
                        :op1 (n3 / necrosis
                              :mod (c3 / center))
                        :op2 (n4 / necrosis
                              :mod (p2 / periphery))))))

# ::id bel_pmid_1651_0838.19670 ::date 2015-05-03T07:03:40 ::annotator SDL-AMR-09 ::preferred
# ::snt The TLR3 agonist poly (I:C) significantly increased bidirectional secretion of CCL2, IL6, TNFA and CSF2 and basolateral secretion of CSF3.
# ::save-date Sun Jan 3, 2016 ::file bel_pmid_1651_0838_19670.txt
(i / increase-01
      :ARG0 (a / agonist :name (n / name :op1 "poly" :op2 "(I:C)")
            :mod (p / protein :name (n2 / name :op1 "TLR3")))
      :ARG1 (a3 / and
            :op1 (s2 / secrete-01
                  :ARG1 (a2 / and
                        :op1 (p3 / protein :name (n4 / name :op1 "CCL2"))
                        :op2 (p2 / protein :name (n3 / name :op1 "IL6"))
                        :op3 (p4 / protein :name (n5 / name :op1 "TNFA"))
                        :op4 (p5 / protein :name (n6 / name :op1 "CSF2")))
                  :mod (b2 / bidirectional))
            :op2 (s3 / secrete-01
                  :ARG1 (p6 / protein :name (n7 / name :op1 "CSF3"))
                  :mod (b / basolateral)))
      :ARG2 (s / significant-02))

# ::id bel_pmid_1654_7273.28276 ::date 2015-05-01T10:50:35 ::annotator SDL-AMR-09 ::preferred
# ::snt To verify the absence of the STAT6-signaling cascade in STAT6-/- MLF, we assessed mOSM and mIL-4 induced responses with respect to STAT3 and STAT6 activation. Fig. 6 confirms the absence of STAT6 protein and STAT6 induction in STAT6-/- MLF but equivalent activation of STAT3 in both wt and STAT6-/- MLF.
# ::save-date Sun Dec 20, 2015 ::file bel_pmid_1654_7273_28276.txt
(m / multi-sentence
      :snt1 (a / assess-01
            :ARG0 (w / we)
            :ARG1 (t / thing
                  :ARG2-of (r / respond-01)
                  :ARG2-of (i2 / induce-01
                        :ARG0 (a2 / and
                              :op1 (p11 / protein :name (n8 / name :op1 "OSM")
                                    :mod (m2 / mouse))
                              :op2 (p / protein :name (n / name :op1 "IL-4")
                                    :mod m2))))
            :purpose (v / verify-01
                  :ARG0 w
                  :ARG1 (a5 / absent-01
                        :ARG1 (c / cascade
                              :ARG0-of (s / signal-07
                                    :ARG1 (p2 / protein :name (n7 / name :op1 "STAT6"))))
                        :ARG2 (f2 / fibroblast
                              :mod (l / lung
                                    :mod m2)
                              :mod (p6 / protein :name (n9 / name :op1 "STAT6")
                                    :ARG2-of (m3 / mutate-01 :mod "-/-")))))
            :topic (a3 / activate-01
                  :ARG1 (a4 / and
                        :op1 (p3 / protein :name (n5 / name :op1 "STAT3"))
                        :op2 p2)))
      :snt2 (c2 / confirm-01
            :ARG0 (f / figure :mod 6)
            :ARG1 (c3 / contrast-01
                  :ARG1 (a6 / and
                        :op1 (a7 / absent-01
                              :ARG1 (p7 / protein :name (n10 / name :op1 "STAT6"))
                              :ARG2 f3)
                        :op2 (i / induce-01
                              :ARG2 p7
                              :location (f3 / fibroblast
                                    :mod (l2 / lung
                                          :mod (m11 / mouse))
                                    :mod (p8 / protein :name (n12 / name :op1 "STAT6")
                                          :ARG2-of (m5 / mutate-01 :mod "-/-")))))
                  :ARG2 (a8 / activate-01
                        :ARG1 (p9 / protein :name (n13 / name :op1 "STAT3"))
                        :ARG2-of (e3 / equal-01)
                        :location (a9 / and
                              :op1 f3
                              :op2 (f5 / fibroblast
                                    :mod (w2 / wild-type)
                                    :mod l2))))))

# ::id bel_pmid_1654_7273.28294 ::date 2015-05-03T05:58:43 ::annotator SDL-AMR-09 ::preferred
# ::snt Twenty-four hour stimulation with 25.0 ng/ml mOSM induced detectable increases in eotaxin-1 expression at the mRNA and protein level in both wt and STAT6-/- MLF (Fig. 5, A and C). Stimulation of wt MLF using 10.0 ng/ml mIL-4 induced eotaxin mRNA expression and protein production that was nondetectable in STAT6-/- MLF (Fig. 5, A and C)
# ::save-date Sun Dec 20, 2015 ::file bel_pmid_1654_7273_28294.txt
(m / multi-sentence
      :snt1 (i / induce-01
            :ARG0 (s / stimulate-01
                  :ARG2 (p / protein :name (n2 / name :op1 "OSM")
                        :mod (m5 / mouse)
                        :quant (c / concentration-quantity :quant 25
                              :unit (n3 / nanogram-per-milliliter)))
                  :duration (t3 / temporal-quantity :quant 24
                        :unit (h3 / hour)))
            :ARG2 (i2 / increase-01
                  :ARG1 (e2 / express-03
                        :ARG2 (p11 / protein :name (n / name :op1 "eotaxin-1"))
                        :manner (a4 / and
                              :op1 (l6 / level
                                    :mod (n4 / nucleic-acid :name (n5 / name :op1 "mRNA")))
                              :op2 (l / level
                                    :mod (p2 / protein))))
                  :ARG3 (a2 / and
                        :op1 (f5 / fibroblast
                              :mod (l2 / lung
                                    :mod m5)
                              :mod (p3 / protein :name (n7 / name :op1 "STAT6")
                                    :ARG2-of (m3 / mutate-01 :mod "-/-")))
                        :op2 (f6 / fibroblast
                              :mod (w / wild-type)
                              :mod l2))
                  :ARG1-of (d / detect-01
                        :ARG1-of (p4 / possible-01)))
            :ARG1-of (d2 / describe-01
                  :ARG0 (a3 / and
                        :op1 (f / figure :mod "5A")
                        :op2 (f2 / figure :mod "5C"))))
      :snt2 (i3 / induce-01
            :ARG0 (s2 / stimulate-01
                  :ARG1 (f7 / fibroblast
                        :mod (l4 / lung
                              :mod (m4 / mouse))
                        :mod (w2 / wild-type))
                  :ARG2-of (u / use-01
                        :ARG1 (p5 / protein :name (n12 / name :op1 "IL-4")
                              :quant (c2 / concentration-quantity :quant 10
                                    :unit (n13 / nanogram-per-milliliter))
                              :mod m4)))
            :ARG2 (a / and
                  :op1 (e5 / express-03
                        :ARG1 (n6 / nucleic-acid :name (n14 / name :op1 "mRNA")
                              :ARG0-of (e6 / encode-01
                                    :ARG1 (p6 / protein :name (n15 / name :op1 "eotaxin")))))
                  :op2 (p7 / produce-01
                        :ARG1 (p8 / protein))
                  :ARG1-of (d3 / detect-01 :polarity -
                        :location (f8 / fibroblast
                              :mod (p10 / protein :name (n17 / name :op1 "STAT6")
                                    :ARG2-of (m8 / mutate-01 :mod "-/-"))
                              :mod l4)
                        :ARG1-of (p9 / possible-01)))
            :ARG1-of (d4 / describe-01
                  :ARG0 (a5 / and
                        :op1 (f3 / figure :mod "5A")
                        :op2 (f4 / figure :mod "5C")))))

# ::id bel_pmid_1654_7273.29762 ::date 2015-05-03T09:42:42 ::annotator SDL-AMR-09 ::preferred
# ::snt We and others have shown that OSM can induce eotaxin-1 in mouse lung fibroblasts (MLF) (28) and lung smooth muscle cells (29).
# ::save-date Sat Jan 2, 2016 ::file bel_pmid_1654_7273_29762.txt
(s / show-01
      :ARG0 (a / and
            :op1 (w / we)
            :op2 (p / person
                  :mod (o / other)))
      :ARG1 (p2 / possible-01
            :ARG1 (i / induce-01
                  :ARG0 (p3 / protein :name (n / name :op1 "OSM"))
                  :ARG2 (p6 / protein :name (n2 / name :op1 "eotaxin-1"))
                  :location (a2 / and
                        :op1 (f / fibroblast
                              :mod (l / lung
                                    :mod (m / mouse))
                              :ARG1-of (d / describe-01
                                    :ARG0 (p4 / publication
                                          :ARG1-of (c / cite-01
                                                :ARG2 28))))
                        :op2 (c2 / cell
                              :mod (m2 / muscle
                                    :ARG1-of (s2 / smooth-06)
                                    :mod (l2 / lung))
                              :ARG1-of (d2 / describe-01
                                    :ARG0 (p5 / publication
                                          :ARG1-of (c3 / cite-01
                                                :ARG2 29))))))))

# ::id bel_pmid_1654_7273.29766 ::date 2015-05-03T09:58:48 ::annotator SDL-AMR-09 ::preferred
# ::snt We also compared the effects of mOSM on IL-6 expression in both wt and STAT6-/- MLF (Fig. 5, B and D) and show that STAT6-/- MLF respond similarly to wt MLF in IL-6 expression at both the mRNA and protein levels.
# ::save-date Tue May 12, 2015 ::file bel_pmid_1654_7273_29766.txt
(a / and
      :op1 (c / compare-01
            :ARG0 (w / we)
            :ARG1 (a3 / affect-01
                  :ARG0 (p / protein :name (n2 / name :op1 "OSM")
                        :mod (m4 / mouse))
                  :ARG1 (e2 / express-03
                        :ARG2 (p2 / protein :name (n3 / name :op1 "IL-6"))
                        :ARG3 (a4 / and
                              :op1 (f3 / fibroblast
                                    :mod (l2 / lung
                                          :mod m4)
                                    :mod (w2 / wild-type))
                              :op2 (f4 / fibroblast
                                    :mod (p3 / protein :name (n6 / name :op1 "STAT6")
                                          :ARG2-of (m3 / mutate-01 :mod "-/-"))
                                    :mod l2))))
            :mod (a2 / also)
            :ARG1-of (d / describe-01
                  :ARG0 (a5 / and
                        :op1 (f / figure :mod "5B")
                        :op2 (f2 / figure :mod "5D"))))
      :op2 (s / show-01
            :ARG0 w
            :ARG1 (r2 / respond-01
                  :ARG0 f4
                  :ARG1-of (r3 / resemble-01
                        :ARG2 f3)
                  :condition (e3 / express-01
                              :ARG2 p2
                              :manner (a7 / and
                                    :op1 (l3 / level
                                          :mod (n / nucleic-acid :name (n7 / name :op1 "mRNA")))
                                    :op2 (l / level
                                          :mod (p5 / protein)))))))

# ::id bel_pmid_1654_7273.29768 ::date 2015-05-03T10:26:47 ::annotator SDL-AMR-09 ::preferred
# ::snt mOSM induced STAT1 (Y701), STAT3 (Y705), and STAT5 (Y694) phosphorylation as reported by others (57, 58, 59).
# ::save-date Sun Dec 20, 2015 ::file bel_pmid_1654_7273_29768.txt
(i / induce-01
      :ARG0 (p2 / protein :name (n2 / name :op1 "OSM")
            :mod (m / mouse))
      :ARG2 (p / phosphorylate-01
            :ARG1 (a / and
                  :op1 (a2 / amino-acid :mod 701 :name (n3 / name :op1 "tyrosine")
                        :part-of (p3 / protein :name (n4 / name :op1 "STAT1")))
                  :op2 (a3 / amino-acid :mod 705 :name (n5 / name :op1 "tyrosine")
                        :part-of (p4 / protein :name (n6 / name :op1 "STAT3")))
                  :op3 (a4 / amino-acid :mod 694 :name (n7 / name :op1 "tyrosine")
                        :part-of (p5 / protein :name (n8 / name :op1 "STAT5")))))
      :ARG1-of (r2 / report-01
            :ARG0 (p6 / person
                  :mod (o / other)))
      :ARG1-of (d / describe-01
            :ARG0 (p7 / publication
                  :ARG1-of (c / cite-01
                        :ARG2 (a5 / and :op1 57 :op2 58 :op3 59)))))

# ::id bel_pmid_1654_7273.29770 ::date 2015-05-03T10:35:40 ::annotator SDL-AMR-09 ::preferred
# ::snt Levels of VCAM-1 in STAT-6-deficient MLF were somewhat reduced compared with those observed in wt MLF, however, the ability of mOSM or mTNF-{alpha} to induce VCAM-1 was maintained (Fig. 7B).
# ::save-date Sun Dec 20, 2015 ::file bel_pmid_1654_7273_29770.txt
(h / have-concession-91
      :ARG1 (r / reduce-01
            :ARG1 (l / level
                  :quant-of (p / protein :name (n / name :op1 "VCAM-1"))
                  :location (f / fibroblast
                        :mod (l2 / lung
                              :mod m4)
                        :mod (p2 / protein :name (n2 / name :op1 "STAT6")
                              :ARG2-of (m6 / mutate-01 :mod "-/-")))
                  :ARG1-of (c / compare-01
                        :ARG2 (l3 / level
                              :ARG1-of (o / observe-01
                                    :location (f2 / fibroblast
                                          :mod (w / wild-type)
                                          :mod l2))
                              :quant-of p)))
            :ARG2 (s / somewhat))
      :ARG2 (m3 / maintain-01
            :ARG1 (c2 / capable-01
                  :ARG1 (o2 / or
                        :op1 (p4 / protein :name (n4 / name :op1 "OSM")
                              :mod (m4 / mouse))
                        :op2 (p5 / protein :name (n5 / name :op1 "TNF-{alpha}")
                              :mod m4))
                  :ARG2 (i / induce-01
                        :ARG0 o2
                        :ARG2 p)))
      :ARG1-of (d2 / describe-01
            :ARG0 (f3 / figure :mod "7B")))

# ::id bel_pmid_1654_7273.38510 ::date 2015-05-03T11:31:22 ::annotator SDL-AMR-09 ::preferred
# ::snt IL-4 has been documented to regulate the expression of eotaxin-1 (41), eotaxin-2 (42), and eotaxin-3 (34) in endothelial cells and fibroblasts in a STAT6-dependent manner (42, 43, 44, 45). IL-4 signal transduction includes activation of STAT6 (46, 47, 48, 49, 50).
# ::save-date Tue Jan 19, 2016 ::file bel_pmid_1654_7273_38510.txt
(m / multi-sentence
      :snt1 (d / document-01
            :ARG1 (p / protein :name (n / name :op1 "IL-4")
                  :ARG0-of (r / regulate-01
                        :ARG1 (e / express-03
                              :ARG2 (a / and
                                    :op1 (p2 / protein :name (n2 / name :op1 "eotaxin-1")
                                          :ARG1-of (d2 / describe-01
                                                :ARG0 (p3 / publication
                                                      :ARG1-of (c / cite-01
                                                            :ARG2 41))))
                                    :op2 (p4 / protein :name (n3 / name :op1 "eotaxin-2")
                                          :ARG1-of (d3 / describe-01
                                                :ARG0 (p5 / publication
                                                      :ARG1-of (c2 / cite-01
                                                            :ARG2 42))))
                                    :op3 (p6 / protein :name (n4 / name :op1 "eotaxin-3")
                                          :ARG1-of (d4 / describe-01
                                                :ARG0 (p7 / publication
                                                      :ARG1-of (c3 / cite-01
                                                            :ARG2 34)))))
                              :ARG3 (a2 / and
                                    :op1 (c4 / cell
                                          :mod (e2 / endothelium))
                                    :op2 (f / fibroblast)))
                        :manner (d5 / depend-01
                              :ARG0 r
                              :ARG1 (p8 / protein :name (n5 / name :op1 "STAT6")))))
            :ARG1-of (d6 / describe-01
                  :ARG0 (p9 / publication
                        :ARG1-of (c5 / cite-01
                              :ARG2 (a3 / and :op1 42 :op2 43 :op3 44 :op4 45)))))
      :snt2 (i / include-01
            :ARG1 (a4 / activate-01
                  :ARG1 (p11 / protein :name (n7 / name :op1 "STAT6")))
            :ARG2 (t / transduce-01
                  :ARG1 (s / signal-07
                        :ARG0 (p10 / protein :name (n6 / name :op1 "IL-4"))))
            :ARG1-of (d7 / describe-01
                  :ARG0 (p12 / publication
                        :ARG1-of (c6 / cite-01
                              :ARG2 (a5 / and :op1 46 :op2 47 :op3 48 :op4 49 :op5 50))))))

# ::id bel_pmid_1654_7273.38520 ::date 2015-05-03T11:49:14 ::annotator SDL-AMR-09 ::preferred
# ::snt To verify the absence of the STAT6-signaling cascade in STAT6-/-  MLF, we assessed mOSM and mIL-4 induced responses with respect to STAT3 and STAT6 activation. Fig. 6 confirms the absence of STAT6 protein and STAT6 induction in STAT6-/- MLF but equivalent activation of STAT3 in both wt and STAT6-/- MLF.
# ::save-date Sun Dec 20, 2015 ::file bel_pmid_1654_7273_38520.txt
(m / multi-sentence
      :snt1 (a / assess-01
            :ARG0 (w / we)
            :ARG1 (t / thing
                  :ARG1-of (r / respond-01)
                  :ARG2-of (i2 / induce-01
                        :ARG0 (a2 / and
                              :op1 (p / protein :name (n / name :op1 "OSM")
                                    :mod (m2 / mouse))
                              :op2 (p2 / protein :name (n2 / name :op1 "IL-4")
                                    :mod m2))))
            :purpose (v / verify-01
                  :ARG0 w
                  :ARG1 (a5 / absent-01
                        :ARG1 (c / cascade
                              :ARG0-of (s / signal-07
                                    :ARG1 (p4 / protein :name (n5 / name :op1 "STAT6"))))
                        :ARG2 (f / fibroblast
                              :mod (l / lung
                                    :mod m2)
                              :mod (p6 / protein :name (n6 / name :op1 "STAT6")
                                    :ARG2-of (m5 / mutate-01 :mod "-/-")))))
            :topic (a3 / activate-01
                  :ARG1 (a4 / and
                        :op1 (p3 / protein :name (n3 / name :op1 "STAT3"))
                        :op2 p4)))
      :snt2 (c2 / confirm-01
            :ARG0 (f2 / figure :mod 6)
            :ARG1 (c3 / contrast-01
                  :ARG1 (a6 / and
                        :op1 (a7 / absent-01
                              :ARG1 (p7 / protein :name (n7 / name :op1 "STAT6"))
                              :ARG2 f3)
                        :op2 (i / induce-01
                              :ARG2 p7
                              :location (f3 / fibroblast
                                    :mod (l2 / lung
                                          :mod (m6 / mouse))
                                    :mod (p8 / protein :name (n8 / name :op1 "STAT6")
                                          :ARG2-of (m7 / mutate-01 :mod "-/-")))))
                  :ARG2 (a8 / activate-01
                        :ARG1 (p9 / protein :name (n9 / name :op1 "STAT3"))
                        :ARG1-of (e / equal-01)
                        :location (a9 / and
                              :op1 (f4 / fibroblast
                                    :mod (w2 / wild-type)
                                    :mod l2)
                              :op2 f3)))))

# ::id bel_pmid_1654_7273.39184 ::date 2015-05-03T12:04:56 ::annotator SDL-AMR-09 ::preferred
# ::snt Levels of VCAM-1 in STAT-6-deficient MLF were somewhat reduced compared with those observed in wt MLF, however, the ability of mOSM or mTNF-{alpha} to induce VCAM-1 was maintained (Fig. 7B).
# ::save-date Sun Dec 20, 2015 ::file bel_pmid_1654_7273_39184.txt
(h / have-concession-91
      :ARG1 (r / reduce-01
            :ARG1 (l / level
                  :quant-of (p / protein :name (n / name :op1 "VCAM-1"))
                  :location (f / fibroblast
                        :mod (l2 / lung
                              :mod m4)
                        :mod (p2 / protein :name (n2 / name :op1 "STAT-6")
                              :ARG2-of (m6 / mutate-01 :mod "-/-")))
                  :ARG1-of (c / compare-01
                        :ARG2 (l3 / level
                              :ARG1-of (o / observe-01
                                    :location (f2 / fibroblast
                                          :mod (w / wild-type)
                                          :mod l2))
                              :quant-of p)))
            :ARG2 (s / somewhat))
      :ARG2 (m3 / maintain-01
            :ARG1 (c2 / capable-01
                  :ARG1 (o2 / or
                        :op1 (p4 / protein :name (n4 / name :op1 "OSM")
                              :mod (m4 / mouse))
                        :op2 (p5 / protein :name (n5 / name :op1 "TNF-{alpha}")
                              :mod m4))
                  :ARG2 (i / induce-01
                        :ARG0 o2
                        :ARG2 p)))
      :ARG1-of (d2 / describe-01
            :ARG0 (f3 / figure :mod "7B")))

# ::id bel_pmid_1658_5161.22112 ::date 2015-05-03T12:12:14 ::annotator SDL-AMR-09 ::preferred
# ::snt Focus formation was consistently observed with both mutants. However, C-RAF mutant proteins caused the formation of much smaller cell aggregates (Fig. 5A) as compared with v-Raf.
# ::save-date Mon Feb 1, 2016 ::file bel_pmid_1658_5161_22112.txt
(m / multi-sentence
      :snt1 (o / observe-01
            :ARG1 (f / form-01
                  :ARG1 (f2 / focus))
            :manner (c / consistent-02)
            :instrument (m5 / molecular-physical-entity
                  :ARG2-of (m2 / mutate-01)
                  :mod (b / both)))
      :snt2 (c5 / contrast-01
            :ARG2 (c2 / cause-01
                  :ARG0 (e / enzyme :name (n / name :op1 "C-RAF")
                        :ARG2-of (m3 / mutate-01))
                  :ARG1 (f3 / form-01
                        :ARG1 (a / aggregate-01
                              :ARG1 (c3 / cell)
                              :mod (s2 / small
                                    :degree (m4 / much)
                                    :compared-to (e2 / enzyme :name (n2 / name :op1 "C-Raf"))))
                        :ARG1-of (d / describe-01
                              :ARG0 (f4 / figure :mod "5A"))))))

# ::id bel_pmid_1658_5540.18258 ::date 2015-05-03T12:23:36 ::annotator SDL-AMR-09 ::preferred
# ::snt Wild-type MEFs induced Ifnb, Tnfa, and Il-6 in response to poly(I:C) {an viral mimetic activator of FADD signaling-SE}, whereas the induction was severely impaired in FADD-deficient MEFs as examined by RT-PCR analyses (Fig. 1A).
# ::save-date Sun Dec 20, 2015 ::file bel_pmid_1658_5540_18258.txt
(c / contrast-01
      :ARG1 (i / induce-01
            :ARG0 (f / fibroblast
                  :mod (e / embryo
                        :mod (m / mouse))
                  :mod (w / wild-type))
            :ARG2 (a2 / and
                  :op1 (p / protein :name (n / name :op1 "Ifnb"))
                  :op2 (p2 / protein :name (n2 / name :op1 "Tnfa"))
                  :op3 (p3 / protein :name (n3 / name :op1 "IL-6")))
            :ARG2-of (r / respond-01
                  :ARG1 (s3 / small-molecule :name (n4 / name :op1 "poly(I:C)")
                        :ARG1-of (m2 / mean-01
                              :ARG2 (m6 / molecular-physical-entity
                                    :ARG0-of (a3 / activate-01
                                          :ARG1 (s / signal-07
                                                :ARG0 (p4 / protein :name (n5 / name :op1 "FADD"))
                                                :ARG1 (t3 / thing :name (n6 / name :op1 "SE"))))
                                    :ARG0-of (m3 / mimic-01
                                          :ARG1 (v / virus)))))))
      :ARG2 (i2 / impair-01
            :ARG1 i
            :degree (s2 / severe)
            :location (f2 / fibroblast
                  :mod (e2 / embryo
                        :mod (m4 / mouse))
                  :mod (p5 / protein :name (n7 / name :op1 "FADD")
                        :ARG2-of (m5 / mutate-01 :mod "-/-")))
            :ARG1-of (e3 / examine-01
                  :ARG0 (a4 / analyze-01
                        :mod (t / thing :name (n8 / name :op1 "RT-PCR")))))
      :ARG1-of (d2 / describe-01
            :ARG0 (f3 / figure :mod "1A")))

# ::id bel_pmid_1658_5540.25628 ::date 2015-05-03T12:54:08 ::annotator SDL-AMR-09 ::preferred
# ::snt the induction of Tnfa and Il-6 was severely impaired after 2 h of poly(I:C) stimulation and reduced after 6 h of stimulation in caspase-8-deficient cells (Fig. 4B).
# ::save-date Sun Dec 20, 2015 ::file bel_pmid_1658_5540_25628.txt
(a / and
      :op1 (i / impair-01
            :ARG1 (i2 / induce-01
                  :ARG2 (a2 / and
                        :op1 (p / protein :name (n / name :op1 "Tnfa"))
                        :op2 (p2 / protein :name (n2 / name :op1 "IL-6"))))
            :degree (s / severe)
            :time (a3 / after
                  :op1 (s2 / stimulate-01
                        :ARG0 (s4 / small-molecule :name (n3 / name :op1 "poly(I:C)"))
                        :duration (t / temporal-quantity :quant 2
                              :unit (h / hour)))))
      :op2 (r / reduce-01
            :ARG1 i2
            :time (a4 / after
                  :op1 (s3 / stimulate-01
                        :duration (t2 / temporal-quantity :quant 6
                              :unit (h2 / hour))
                        :location (c / cell
                              :mod (p4 / protein :name (n4 / name :op1 "caspase-8")
                                    :ARG2-of (m / mutate-01 :mod "-/-"))))))
      :ARG1-of (d2 / describe-01
            :ARG0 (f / figure :mod "4B")))

# ::id bel_pmid_1658_5540.25630 ::date 2015-05-03T13:05:29 ::annotator SDL-AMR-09 ::preferred
# ::snt nuclear translocation of p65, a component of NF-{kappa}B, was reduced in caspase-8-deficient cells (Fig. 4C)
# ::save-date Thu Dec 17, 2015 ::file bel_pmid_1658_5540_25630.txt
(r / reduce-01
      :ARG1 (t / translocate-01
            :ARG1 (p / protein-segment :name (n / name :op1 "p65")
                  :part-of (p2 / protein :name (n3 / name :op1 "NF-{kappa}B")))
            :ARG2 (n2 / nucleus))
      :location (c / cell
            :mod (p3 / protein :name (n4 / name :op1 "caspase-8")
                  :ARG2-of (m / mutate-01 :mod "-/-")))
      :ARG1-of (d2 / describe-01
            :ARG0 (f / figure :mod "4C")))

# ::id bel_pmid_1663_6663.7850 ::date 2015-05-03T13:12:25 ::annotator SDL-AMR-09 ::preferred
# ::snt LMW-DSP2 overexpression in 293T cells suppressed IL-6-induced phosphorylation and activation of STAT3.
# ::save-date Sun Dec 20, 2015 ::file bel_pmid_1663_6663_7850.txt
(s / suppress-01
      :ARG0 (o / overexpress-01
            :ARG1 (e / enzyme :name (n / name :op1 "LMW-DSP2"))
            :location (c / cell-line :name (n2 / name :op1 "293T")))
      :ARG1 (a / and
            :op1 (p / phosphorylate-01
                  :ARG1 p3)
            :op2 (a2 / activate-01
                  :ARG1 (p3 / protein :name (n4 / name :op1 "STAT3")))
            :ARG2-of (i / induce-01
                  :ARG0 (p2 / protein :name (n3 / name :op1 "IL-6")))))

# ::id bel_pmid_1663_6663.24748 ::date 2015-05-03T13:20:23 ::annotator SDL-AMR-09 ::preferred
# ::snt In contrast, small-interfering RNA-mediated reduction of LMW-DSP2 expression enhanced IL-6-induced STAT3-dependent transcription.
# ::save-date Sun Dec 20, 2015 ::file bel_pmid_1663_6663_24748.txt
(c / contrast-01
      :ARG2 (e / enhance-01
            :ARG0 (r2 / reduce-01
                  :ARG1 (e2 / express-03
                        :ARG2 (e3 / enzyme :name (n2 / name :op1 "LMW-DSP2")))
                  :ARG1-of (m / mediate-01
                        :ARG0 (n / nucleic-acid :name (n5 / name :op1 "small-interfering" :op2 "RNA"))))
            :ARG1 (t / transcribe-01
                  :ARG2-of (i / induce-01
                        :ARG0 (p / protein :name (n3 / name :op1 "IL-6")))
                  :ARG0-of (d / depend-01
                        :ARG1 (p2 / protein :name (n4 / name :op1 "STAT3"))))))

# ::id bel_pmid_1663_6672.36768 ::date 2015-05-03T13:24:50 ::annotator SDL-AMR-09 ::preferred
# ::snt Expression of wild-type (wt) Cbp remarkably suppressed EGF-induced activation of Src, ERK1/2, and Akt-1 enzymes, and NIH3T3 cell transformation, as well as colony formation of a breast cancer cell line (MDA-MB-468) in soft agar.
# ::save-date Fri Jan 15, 2016 ::file bel_pmid_1663_6672_36768.txt
(s / suppress-01
      :ARG0 (e / express-03
            :ARG2 (p / protein :name (n2 / name :op1 "Cbp")
                  :mod (w / wild-type)))
      :ARG1 (a2 / and
            :op1 (a4 / activate-01
                  :ARG1 (a / and
                        :op1 (p3 / protein :name (n4 / name :op1 "Src"))
                        :op2 (s2 / slash
                              :op1 (e4 / enzyme :name (n5 / name :op1 "ERK1"))
                              :op2 (e5 / enzyme :name (n6 / name :op1 "ERK2")))
                        :op3 (e2 / enzyme :name (n7 / name :op1 "Akt-1")))
                  :ARG2-of (i2 / induce-01
                        :ARG0 (p2 / protein :name (n3 / name :op1 "EGF"))))
            :op2 (t / transform-01
                  :ARG1 (c / cell-line :name (n8 / name :op1 "NIH3T3")))
            :op3 (f / form-01
                  :ARG1 (c3 / cell-line :name (n9 / name :op1 "MDA-MB-468")
                        :mod (d / disease :wiki "Breast_cancer" :name (n / name :op1 "breast" :op2 "cancer")))
                  :mod (c2 / colony)
                  :location (a3 / agar
                        :ARG1-of (s3 / soft-02))))
      :ARG1-of (r / remarkable-02))

# ::id bel_pmid_1671_3670.8846 ::date 2015-05-03T13:34:06 ::annotator SDL-AMR-09 ::preferred
# ::snt Interestingly, 500 ng/ml GH and 30 ng/ml IL-6 increased PAI-1 secretion five-fold and 3.6-fold, respectively. Furthermore, GH and IL-6 induced PAI-1 mRNA by up to 7.3-fold, and 3.6-fold, respectively, in a time-dependent fashion with significant stimulation seen at concentrations as low as 5 ng/ml GH and 10 ng/ml IL-6.
# ::save-date Sat Jan 2, 2016 ::file bel_pmid_1671_3670_8846.txt
(m / multi-sentence
      :snt1 (a2 / and
            :op1 (i / increase-01
                  :ARG0 (p / protein :name (n / name :op1 "GH")
                        :quant (c / concentration-quantity :quant 500
                              :unit (n2 / nanogram-per-milliliter)))
                  :ARG1 (s / secrete-01
                        :ARG1 (p3 / protein :name (n5 / name :op1 "PAI-1")))
                  :ARG2 (p4 / product-of :op1 5))
            :op2 (i2 / increase-01
                  :ARG0 (p2 / protein :name (n3 / name :op1 "IL-6")
                        :quant (c2 / concentration-quantity :quant 30
                              :unit (n4 / nanogram-per-milliliter)))
                  :ARG1 s
                  :ARG2 (p6 / product-of :op1 3.6))
            :ARG2-of (i5 / interest-01))
      :snt2 (a / and
            :op2 (a3 / and
                  :op1 (i3 / induce-01
                        :ARG0 (p5 / protein :name (n6 / name :op1 "GH"))
                        :ARG2 (n15 / nucleic-acid :name (n7 / name :op1 "mRNA")
                              :ARG0-of (e / encode-01
                                    :ARG1 (p7 / protein :name (n8 / name :op1 "PAI-1")))
                              :quant (u / up-to
                                    :op1 (p8 / product-of :op1 7.3))))
                  :op2 (i4 / induce-01
                        :ARG0 (p9 / protein :name (n9 / name :op1 "IL-6"))
                        :ARG2 (n16 / nucleic-acid :name (n10 / name :op1 "mRNA")
                              :ARG0-of (e2 / encode-01
                                    :ARG1 p7)
                              :quant (u2 / up-to
                                    :op1 (p10 / product-of :op1 3.6))))
                  :mod (r4 / respective)
                  :instrument (s3 / stimulate-01
                        :ARG1-of (s2 / significant-02))
                  :manner (a5 / and
                        :op1 (d / depend-01
                              :ARG1 (t / time))
                        :op2 (s5 / see-01
                              :time (c3 / concentrate-02
                                    :ARG1 (a4 / and
                                          :op1 (p11 / protein :name (n11 / name :op1 "GH")
                                                :quant (c4 / concentration-quantity :quant 5
                                                      :unit (n12 / nanogram-per-milliliter)))
                                          :op2 (p12 / protein :name (n13 / name :op1 "IL-6")
                                                :quant (c5 / concentration-quantity :quant 10
                                                      :unit (n14 / nanogram-per-milliliter))))
                                    :ARG1-of (l / low-04)))))))

# ::id bel_pmid_1679_8732.4954 ::date 2015-05-04T09:56:00 ::annotator SDL-AMR-09 ::preferred
# ::snt RNA interference-mediated inhibition of TLR2 and MyD88 expression in C2C12 muscle cells resulted in a near complete inhibition of palmitate-induced insulin resistance and IL-6 production.
# ::save-date Fri Feb 12, 2016 ::file bel_pmid_1679_8732_4954.txt
(r / result-01
      :ARG1 (i2 / inhibit-01
            :ARG1 (e / express-03
                  :ARG2 (a3 / and
                        :op1 (p / protein :name (n / name :op1 "TLR2"))
                        :op2 (p2 / protein :name (n2 / name :op1 "MyD88")))
                  :ARG3 (c / cell :name (n3 / name :op1 "C2C12")
                        :mod (m2 / muscle)))
            :ARG1-of (m / mediate-01
                  :ARG0 (i / interfere-01
                        :ARG0 (n8 / nucleic-acid :name (n9 / name :op1 "RNA")))))
      :ARG2 (a / and
            :op1 (i3 / inhibit-01
                  :ARG1 (r3 / resist-01
                        :ARG1 (p5 / protein :name (n5 / name :op1 "insulin"))
                        :ARG2-of (i4 / induce-01
                              :ARG0 (s / small-molecule :name (n6 / name :op1 "palmitate"))))
                  :ARG1-of (c2 / complete-02
                        :degree (n4 / near)))
            :op2 (p3 / produce-01
                  :ARG1 (p4 / protein :name (n7 / name :op1 "IL-6")))))

# ::id bel_pmid_1679_8732.19654 ::date 2015-05-04T10:46:23 ::annotator SDL-AMR-09 ::preferred
# ::snt When compared with an equimolar concentration of palmitate, fibroblast-stimulating lipopeptide-1, a known TLR2 ligand, was a slightly more potent activator of signal transduction and interleukin (IL)-6 production.
# ::save-date Fri Feb 12, 2016 ::file bel_pmid_1679_8732_19654.txt
(a2 / activate-01
      :ARG0 (p / protein :name (n / name :op1 "fibroblast-stimulating" :op2 "lipopeptide-1")
            :ARG1-of (k / know-01)
            :mod (p2 / potent
                  :degree (m / more
                        :degree (s / slight))
                  :compared-to (c2 / concentrate-02
                        :ARG1 (s3 / small-molecule :name (n4 / name :op1 "palmitate"))
                        :mod (e / equimolar)))
            :mod (l / ligand :name (n2 / name :op1 "TLR2")))
      :ARG1 (a3 / and
            :op1 (t / transduce-01
                  :ARG1 (s2 / signal-07))
            :op2 (p3 / produce-01
                  :ARG1 (p4 / protein :name (n3 / name :op1 "interleukin-6")))))

# ::id bel_pmid_167_9532.20916 ::date 2015-05-04T11:02:09 ::annotator SDL-AMR-09 ::preferred
# ::snt When c-H-ras expression was induced with heavy metal ions there was a marked reduction in the expression of two glycosylphosphatidylinositol (GPI) anchored proteins, TAP/Ly-6A.2 and Thy-1, on the plasma membrane of the transformed cells.
# ::save-date Sun Dec 20, 2015 ::file bel_pmid_167_9532_20916.txt
(r2 / reduce-01
      :ARG1 (e / express-03
            :ARG2 (p5 / protein :quant 2 :name (n5 / name :op1 "glycosylphosphatidylinositol" :op2 "anchored" :op3 "protein")
                  :ARG2-of (i / include-91
                        :ARG1 (a2 / and
                              :op1 (p2 / protein :name (n2 / name :op1 "TAP/Ly-6A.2"))
                              :op2 (p3 / protein :name (n3 / name :op1 "Thy-1")))))
            :ARG3 (m2 / membrane
                  :mod (p / plasma)
                  :part-of (c / cell
                        :ARG1-of (t / transform-01))))
      :ARG1-of (m / mark-01)
      :time (i2 / induce-01
            :ARG2 (e2 / express-03
                  :ARG2 (e3 / enzyme :name (n / name :op1 "c-H-ras")))
            :instrument (i3 / ion
                  :mod (m3 / metal
                        :mod (h / heavy)))))

# ::id bel_pmid_1688_7332.6142 ::date 2015-05-04T11:13:18 ::annotator SDL-AMR-09 ::preferred
# ::snt We demonstrate that siRNA targeting ULK2 in mouse P19 cells results in elevated FGFR1 mediated FRS3 and SHP2 tyrosyl phosphorylation.
# ::save-date Mon May 11, 2015 ::file bel_pmid_1688_7332_6142.txt
(d / demonstrate-01
      :ARG0 (w / we)
      :ARG1 (r2 / result-01
            :ARG1 (t / target-01
                  :ARG0 (n9 / nucleic-acid :name (n / name :op1 "siRNA"))
                  :ARG1 (e / enzyme :name (n2 / name :op1 "ULK2"))
                  :location (c / cell :name (n3 / name :op1 "P19")
                        :mod (m / mouse)))
            :ARG2 (p / phosphorylate-01
                  :ARG1 (a3 / and
                        :op1 (a2 / amino-acid :name (n6 / name :op1 "tyrosine")
                              :part-of (e3 / enzyme :name (n7 / name :op1 "SHP2")))
                        :op2 (a4 / amino-acid :name (n8 / name :op1 "tyrosine")
                              :part-of (p2 / protein :name (n4 / name :op1 "FRS3"))))
                  :ARG1-of (m2 / mediate-01
                        :ARG0 (e2 / enzyme :name (n5 / name :op1 "FGFR1")))
                  :ARG1-of (e4 / elevate-01
                        :ARG0 e2))))

# ::id bel_pmid_1692_4534.3554 ::date 2015-05-04T11:22:59 ::annotator SDL-AMR-09 ::preferred
# ::snt PGD(2) induced a reduction in adiponectin and leptin mRNA, and the secretion of these adipokines was also inhibited, the effect being greater with leptin (up to 10-fold) than with adiponectin (twofold).
# ::save-date Fri Feb 12, 2016 ::file bel_pmid_1692_4534_3554.txt
(a / and
      :op1 (i / induce-01
            :ARG0 (s2 / small-molecule :name (n / name :op1 "PGD2"))
            :ARG2 (r / reduce-01
                  :ARG1 (a2 / and
                        :op1 (n6 / nucleic-acid :name (n2 / name :op1 "mRNA")
                              :ARG0-of (e / encode-01
                                    :ARG1 (p / protein :name (n3 / name :op1 "adiponectin"))))
                        :op2 (n7 / nucleic-acid :name (n4 / name :op1 "mRNA")
                              :ARG0-of (e2 / encode-01
                                    :ARG1 (p2 / protein :name (n5 / name :op1 "leptin")))))))
      :op2 (i2 / inhibit-01
            :ARG1 (s / secrete-01
                  :ARG1 (a7 / and
                        :op1 p
                        :op2 p2))
            :mod (a4 / also))
      :op3 (g / great
            :degree (m / more)
            :domain (a3 / affect-01
                  :ARG1 p2
                  :quant (u / up-to
                        :op1 (p3 / product-of :op1 10)))
            :compared-to (a8 / affect-01
                  :ARG1 p
                  :quant (p4 / product-of :quant 2))))

# ::id bel_pmid_1692_4534.16206 ::date 2015-05-04T11:41:07 ::annotator SDL-AMR-09 ::preferred
# ::snt In contrast, PGD(2) induced a marked stimulation of IL-6 and MCP-1 expression; with IL-6, this was rapid, the mRNA level increasing by >50-fold by 1 h. The rise in mRNA was accompanied by an increase in IL-6 and MCP-1 release (up to 100- and 6.5-fold, respectively).
# ::save-date Fri Feb 12, 2016 ::file bel_pmid_1692_4534_16206.txt
(m / multi-sentence
      :snt2 (a2 / accompany-01
            :ARG0 (a4 / and
                  :op1 (i3 / increase-01
                        :ARG1 (r6 / release-01
                              :ARG1 (p4 / protein :name (n6 / name :op1 "IL-6")))
                        :ARG2 (p6 / product-of :op1 100))
                  :op2 (i4 / increase-01
                        :ARG1 (r7 / release-01
                              :ARG1 (p5 / protein :name (n7 / name :op1 "MCP-1")))
                        :ARG2 (p7 / product-of :op1 6.5))
                  :mod (r8 / respective))
            :ARG1 (r4 / rise-01
                  :ARG1 (n8 / nucleic-acid :name (n5 / name :op1 "mRNA"))))
      :snt1 (a3 / and
            :op1 (c / contrast-01
                  :ARG2 (i / induce-01
                        :ARG0 (s3 / small-molecule :name (n / name :op1 "PGD2"))
                        :ARG2 (s / stimulate-01
                              :ARG1 (a5 / and
                                    :op1 (e3 / express-03
                                          :ARG2 (p / protein :name (n2 / name :op1 "IL-6"))
                                          :mod (r / rapid))
                                    :op2 (e / express-03
                                          :ARG2 (p2 / protein :name (n3 / name :op1 "MCP-1"))))
                              :ARG1-of (m3 / mark-01))))
            :op2 (i2 / increase-01
                  :ARG1 (l / level
                        :quant-of (n9 / nucleic-acid :name (n4 / name :op1 "mRNA")
                              :ARG0-of (e2 / encode-01
                                    :ARG1 p)))
                  :ARG2 (m4 / more-than
                        :op1 (p3 / product-of :quant 50))
                  :time (a / after
                        :op1 (s2 / stimulate-01
                              :ARG1 e3)
                        :quant (u / up-to
                              :op1 (t / temporal-quantity :quant 1
                                    :unit (h / hour)))))))

# ::id bel_pmid_1695_1379.27948 ::date 2015-05-04T12:04:35 ::annotator SDL-AMR-09 ::preferred
# ::snt IL-13 increased Egr-1 mRNA levels in a biphasic manner in Stat6/ fibroblasts; early induction of Egr-1 mRNA was observed 30 min following exposure to IL-13 and declined after 3–6 h (Fig. 6A). Egr-1 protein was increased in Stat6/ fibroblasts as compared with Stat6/ fibroblasts from 30 min to 3 h after IL-13 treatment (Fig. 6, B and C).
# ::save-date Sun Dec 20, 2015 ::file bel_pmid_1695_1379_27948.txt
(m / multi-sentence
      :snt2 (i3 / increase-01
            :ARG1 (p6 / protein :name (n8 / name :op1 "Erg-1"))
            :location (f4 / fibroblast
                  :mod (p7 / protein :name (n9 / name :op1 "Stat6"))
                  :compared-to (f5 / fibroblast
                        :mod (p8 / protein :name (n10 / name :op1 "Stat6")
                              :ARG2-of (m3 / mutate-01 :mod "-/-")))
                  :mod (w2 / wild-type))
            :time (a3 / after
                  :op1 (t6 / treat-04
                        :ARG1 f4
                        :ARG2 (p9 / protein :name (n11 / name :op1 "IL-13")))
                  :quant (b2 / between
                        :op1 (t4 / temporal-quantity :quant 30
                              :unit (m4 / minute))
                        :op2 (t5 / temporal-quantity :quant 3
                              :unit (h3 / hour))))
            :ARG1-of (d3 / describe-01
                  :ARG0 (a4 / and
                        :op1 (f6 / figure :mod "6B")
                        :op2 (f7 / figure :mod "6C"))))
      :snt1 (a5 / and
            :op1 (i / increase-01
                  :ARG0 (p / protein :name (n / name :op1 "IL-13"))
                  :ARG1 (l / level
                        :quant-of n2)
                  :manner (b / biphasic)
                  :location (f / fibroblast
                        :mod (p3 / protein :name (n4 / name :op1 "Stat6"))
                        :mod (w / wild-type)))
            :op2 (a / and
                  :op1 (o / observe-01
                        :ARG1 (i2 / induce-01
                              :ARG2 (n2 / nucleic-acid :name (n5 / name :op1 "mRNA")
                                    :ARG0-of (e2 / encode-01
                                          :ARG1 (p4 / protein :name (n6 / name :op1 "Egr-1"))))
                              :time (e3 / early)
                              :ARG1-of (f2 / follow-01
                                    :ARG2 (e4 / expose-01
                                          :ARG1 f
                                          :ARG2 p)))
                        :duration (t / temporal-quantity :quant 30
                              :unit (m2 / minute)))
                  :op2 (d / decline-01
                        :ARG1 i2
                        :time (a2 / after
                              :op1 e4
                              :quant (b3 / between
                                    :op1 (t2 / temporal-quantity :quant 3
                                          :unit (h / hour))
                                    :op2 (t3 / temporal-quantity :quant 6
                                          :unit (h2 / hour)))))
                  :ARG1-of (d2 / describe-01
                        :ARG0 (f3 / figure :mod "6A")))))

# ::id bel_pmid_1695_1379.27954 ::date 2015-05-04T12:40:26 ::annotator SDL-AMR-09 ::preferred
# ::snt PDGF-AA immunostaining was strongly expressed in the lungs of IL-13 transgene-positive mice and localized to the airway epithelium, airway smooth muscle, and interstitial cells (Fig. 1, B–E).
# ::save-date Tue Jan 19, 2016 ::file bel_pmid_1695_1379_27954.txt
(a / and
      :op1 (e / express-03
            :ARG2 (i / immunostain-01
                  :ARG3 (p / protein :name (n / name :op1 "PDGF-AA")))
            :ARG3 (l / lung
                  :mod (m / mouse
                        :mod (p3 / protein :name (n3 / name :op1 "IL-13")
                              :ARG2-of (m3 / mutate-01))
                        :mod (p2 / positive)))
            :ARG1-of (s / strong-02))
      :op2 (b / be-located-at-91
            :ARG1 p
            :ARG2 (a2 / and
                  :op1 (e2 / epithelium
                        :mod (a3 / airway))
                  :op2 (m2 / muscle
                        :ARG1-of (s2 / smooth-06)
                        :mod a3)
                  :op3 (c / cell
                        :mod (i2 / interstice))))
      :ARG1-of (d / describe-01
            :ARG0 (v / value-interval
                  :op1 (f / figure :mod "1B")
                  :op2 (f2 / figure :mod "1E"))))

# ::id bel_pmid_1695_1379.27956 ::date 2015-05-04T12:52:03 ::annotator SDL-AMR-09 ::preferred
# ::snt PDGF-CC immunostaining was strongly expressed in the lungs of IL-13 transgene-positive mice and localized to airway epithelium, type II pneumocytes, alveolar macrophages, and fibroblasts (Fig. 1G).
# ::save-date Tue Jan 19, 2016 ::file bel_pmid_1695_1379_27956.txt
(a / and
      :op1 (e / express-03
            :ARG2 (i / immunostain-01
                  :ARG3 (p / protein :name (n / name :op1 "PDGF-CC")))
            :ARG3 (l / lung
                  :poss-of (m / mouse
                        :mod (p3 / protein :name (n2 / name :op1 "IL-13")
                              :ARG2-of (m2 / mutate-01))
                        :mod (p2 / positive)))
            :ARG1-of (s / strong-02))
      :op2 (b / be-located-at-91
            :ARG1 p
            :ARG2 (a2 / and
                  :op1 (e2 / epithelium
                        :mod (a3 / airway))
                  :op2 (c / cell :name (n3 / name :op1 "type" :op2 "II" :op3 "pneumocyte"))
                  :op3 (c2 / cell :name (n4 / name :op1 "macrophage")
                        :mod (a4 / alveolus))
                  :op4 (f / fibroblast)))
      :ARG1-of (d / describe-01
            :ARG0 (f2 / figure :mod "1G")))

# ::id bel_pmid_1695_1379.27964 ::date 2015-05-04T12:58:32 ::annotator SDL-AMR-09 ::preferred
# ::snt we observed that IL-13 caused tyrosine phosphorylation of Stat1 in Stat6/ and Stat6/ fibroblasts (Fig. 3, A and C).
# ::save-date Mon May 11, 2015 ::file bel_pmid_1695_1379_27964.txt
(o / observe-01
      :ARG0 (w / we)
      :ARG1 (c / cause-01
            :ARG0 (p2 / protein :name (n / name :op1 "IL-13"))
            :ARG1 (p / phosphorylate-01
                  :ARG1 (a / amino-acid :name (n2 / name :op1 "tyrosine")
                        :part-of (p3 / protein :name (n3 / name :op1 "Stat1")))
                  :location (a2 / and
                        :op1 (f / fibroblast
                              :mod (p4 / protein :name (n4 / name :op1 "Stat6")
                                    :ARG2-of (m / mutate-01 :mod "-/-")))
                        :op2 (f2 / fibroblast
                              :mod (p5 / protein :name (n5 / name :op1 "Stat6"))
                              :mod (w2 / wild-type)))))
      :ARG1-of (d / describe-01
            :ARG0 (a3 / and
                  :op1 (f3 / figure :mod "3A")
                  :op2 (f4 / figure :mod "3C"))))

# ::id bel_pmid_1695_1379.27966 ::date 2015-05-04T13:10:27 ::annotator SDL-AMR-09 ::preferred
# ::snt Next, we observed that Stat6 was tyrosine phosphorylated in Stat1/ and Stat1/ fibroblasts (Fig. 3, B and D).
# ::save-date Mon May 11, 2015 ::file bel_pmid_1695_1379_27966.txt
(o / observe-01
      :ARG0 (w / we)
      :ARG1 (p2 / phosphorylate-01
            :ARG1 (p / protein :name (n / name :op1 "Stat6")
                  :part (a / amino-acid :name (n2 / name :op1 "tyrosine")))
            :location (a2 / and
                  :op1 (f / fibroblast
                        :mod (p3 / protein :name (n3 / name :op1 "Stat1")
                              :ARG2-of (m / mutate-01 :mod "-/-")))
                  :op2 (f2 / fibroblast
                        :mod (p4 / protein :name (n4 / name :op1 "Stat1"))
                        :mod (w2 / wild-type))))
      :time (n5 / next)
      :ARG1-of (d / describe-01
            :ARG0 (a3 / and
                  :op1 (f3 / figure :mod "3B")
                  :op2 (f4 / figure :mod "3D"))))

# ::id bel_pmid_1695_1379.27992 ::date 2015-05-04T13:15:50 ::annotator SDL-AMR-09 ::preferred
# ::snt A late peak of Egr-1 mRNA occurred 12–24 h after IL-13 treatment but was not accompanied by an increase in Egr-1 protein.
# ::save-date Wed Jul 15, 2015 ::file bel_pmid_1695_1379_27992.txt
(c / contrast-01
      :ARG1 (p / peak
            :mod (l / late)
            :mod (n4 / nucleic-acid :name (n / name :op1 "mRNA")
                  :ARG0-of (e / encode-01
                        :ARG1 (p2 / protein :name (n2 / name :op1 "Egr-1"))))
            :time (a / after
                  :op1 (t / treat-04
                        :ARG2 (p3 / protein :name (n3 / name :op1 "IL-13")))
                  :quant (b / between
                        :op1 (t2 / temporal-quantity :quant 12
                              :unit (h / hour))
                        :op2 (t3 / temporal-quantity :quant 24
                              :unit (h2 / hour)))))
      :ARG2 (a2 / accompany-01 :polarity -
            :ARG0 (i / increase-01
                  :ARG1 p2)
            :ARG1 p))

# ::id bel_pmid_1695_1379.28002 ::date 2015-05-04T13:23:36 ::annotator SDL-AMR-09 ::preferred
# ::snt IL-13-induced PDGF-A and PDGF-C mRNA levels were significantly reduced in fibroblasts isolated from the lungs of Stat6/ mice compared with fibroblasts isolated from the lungs of the wild-type Stat6/ mice (Fig. 2, A and B).
# ::save-date Sun Dec 20, 2015 ::file bel_pmid_1695_1379_28002.txt
(r / reduce-01
      :ARG1 (a / and
            :op1 (l / level
                  :quant-of (n8 / nucleic-acid :wiki "Messenger_RNA"
                        :name (n2 / name :op1 "mRNA")
                        :ARG0-of (e / encode-01
                              :ARG1 (p / protein :wiki "PDGFA"
                                    :name (n / name :op1 "PDGF-A")))))
            :op2 (l2 / level
                  :quant-of (n9 / nucleic-acid :wiki "Messenger_RNA"
                        :name (n4 / name :op1 "mRNA")
                        :ARG0-of (e2 / encode-01
                              :ARG1 (p3 / protein :wiki "PDGFC"
                                    :name (n5 / name :op1 "PDGF-C")))))
            :ARG2-of (i / induce-01
                  :ARG0 (p2 / protein :wiki "Interleukin_13"
                        :name (n3 / name :op1 "IL-13"))))
      :ARG2 (s / significant-02)
      :location (f / fibroblast
            :ARG1-of (i2 / isolate-01
                  :ARG2 (l3 / lung
                        :mod (m / mouse
                              :mod (p4 / protein :wiki "STAT6"
                                    :name (n6 / name :op1 "Stat6")
                                    :ARG2-of (m2 / mutate-01 :mod "-/-")))))
            :compared-to (f2 / fibroblast
                  :ARG1-of (i3 / isolate-01
                        :ARG2 (l4 / lung
                              :mod (m3 / mouse
                                    :mod (p5 / protein :wiki "STAT6"
                                          :name (n7 / name :op1 "Stat6")
                                          :mod (w / wild-type)))))))
      :ARG1-of (d / describe-01
            :ARG0 (a2 / and
                  :op1 (f3 / figure :mod "2A")
                  :op2 (f4 / figure :mod "2B"))))

# ::id bel_pmid_1695_1379.32888 ::date 2015-05-04T13:32:44 ::annotator SDL-AMR-09 ::preferred
# ::snt Egr-1 has been characterized as a transcriptional regulator of both PDGF-A and PDGF-C gene expression (18, 19).
# ::save-date Mon May 4, 2015 ::file bel_pmid_1695_1379_32888.txt
(c / characterize-01
      :ARG1 (p / protein :name (n / name :op1 "Erg-1"))
      :ARG2 (r / regulate-01
            :ARG1 (e / express-03
                  :ARG1 (a / and
                        :op1 (g / gene :name (n2 / name :op1 "PDGF-A"))
                        :op2 (g2 / gene :name (n3 / name :op1 "PDGF-C"))))
            :mod (t / transcribe-01))
      :ARG1-of (d / describe-01
            :ARG0 (p2 / publication
                  :ARG1-of (c2 / cite-01
                        :ARG2 (a2 / and :op1 18 :op2 19)))))

# ::id bel_pmid_1695_1379.38388 ::date 2015-05-04T13:35:59 ::annotator SDL-AMR-09 ::preferred
# ::snt Western blot analysis demonstrated that PD98059 blocked IL-13-induced phosphorylation of ERK1/2 (Fig. 8A) yet enhanced the phosphorylation of Stat6 and increased protein expression of Egr-1 in a time-dependent manner after IL-13 treatment (Fig. 8, B and C).
# ::save-date Sun Jan 17, 2016 ::file bel_pmid_1695_1379_38388.txt
(d / demonstrate-01
      :ARG0 (a / analyze-01
            :manner (i3 / immunoblot-01))
      :ARG1 (c / contrast-01
            :ARG1 (b / block-01
                  :ARG0 (s / small-molecule :name (n3 / name :op1 "PD98059"))
                  :ARG1 (p / phosphorylate-01
                        :ARG1 (e3 / enzyme :name (n2 / name :op1 "ERK1/2"))
                        :ARG2-of (i / induce-01
                              :ARG0 (p4 / protein :name (n6 / name :op1 "IL-13"))))
                  :ARG1-of (d2 / describe-01
                        :ARG0 (f / figure :mod "8A")))
            :ARG2 (a2 / and
                  :op1 (e / enhance-01
                        :ARG0 s
                        :ARG1 (p5 / phosphorylate-01
                              :ARG1 (p6 / protein :name (n7 / name :op1 "Stat6"))))
                  :op2 (i2 / increase-01
                        :ARG0 s
                        :ARG1 (e2 / express-03
                              :ARG2 (p7 / protein :name (n8 / name :op1 "Erg-1")))
                        :time (a3 / after
                              :op1 (t / treat-04
                                    :ARG2 p4))
                        :manner (d3 / depend-01
                              :ARG0 i2
                              :ARG1 (t2 / time)))
                  :ARG1-of (d4 / describe-01
                        :ARG0 (a4 / and
                              :op1 (f2 / figure :mod "8B")
                              :op2 (f3 / figure :mod "8C"))))))

# ::id bel_pmid_1698_7002.500 ::date 2015-05-01T11:07:21 ::annotator SDL-AMR-09 ::preferred
# ::snt In cycling cells, the effects of Nox1 were dose dependent: levels of Nox1 that induced 3- to 10-fold increases in ROS promoted phosphorylation of ERK1/2 and expression of cyclin D1,
# ::save-date Wed Mar 2, 2016 ::file bel_pmid_1698_7002_500.txt
(d / depend-01
      :ARG0 (a / affect-01
            :ARG0 (e / enzyme :name (n / name :op1 "Nox1")))
      :ARG1 (d2 / dose)
      :location (c / cell
            :ARG1-of (c2 / cycle-02))
      :ARG1-of (m / mean-01
            :ARG2 (p / promote-01
                  :ARG0 (l / level
                        :quant-of e
                        :ARG0-of (i / induce-01
                              :ARG2 (i2 / increase-01
                                    :ARG1 (s / small-molecule :name (n4 / name :op1 "ROS"))
                                    :ARG2 (b / between
                                          :op1 (p4 / product-of :op1 3)
                                          :op2 (p5 / product-of :op1 10)))))
                  :ARG1 (a2 / and
                        :op1 (p2 / phosphorylate-01
                              :ARG1 (e3 / enzyme :name (n2 / name :op1 "ERK1/2")))
                        :op2 (e2 / express-03
                              :ARG2 (p3 / protein :name (n3 / name :op1 "cyclin" :op2 "D1")))))))

# ::id bel_pmid_1700_8315.1518 ::date 2015-05-01T11:14:03 ::annotator SDL-AMR-09 ::preferred
# ::snt Induction of STAT3 Tyr705 and Ser727 phosphorylations by Galpha(s)QL was suppressed by inhibition of protein kinase A, Janus kinase 2/3, Rac1, c-Jun N-terminal kinase (JNK), or phosphatidylinositol 3-kinase, and a similar profile was observed in response to beta2-adrenergic receptor stimulation
# ::save-date Sun Jan 3, 2016 ::file bel_pmid_1700_8315_1518.txt
(a / and
      :op1 (s / suppress-01
            :ARG0 (i2 / inhibit-01
                  :ARG1 (o2 / or
                        :op1 (e / enzyme :name (n5 / name :op1 "protein" :op2 "kinase" :op3 "A"))
                        :op2 (e2 / enzyme :name (n6 / name :op1 "Janus" :op2 "kinase" :op3 "2/3"))
                        :op3 (p4 / protein :name (n7 / name :op1 "Rac1"))
                        :op4 (e3 / enzyme :name (n8 / name :op1 "c-Jun" :op2 "N-terminal" :op3 "kinase"))
                        :op5 (e4 / enzyme :name (n9 / name :op1 "phosphatidylinositol" :op2 "3-kinase"))))
            :ARG1 (i / induce-01
                  :ARG2 (p / phosphorylate-01
                        :ARG1 (a2 / and
                              :op1 (a3 / amino-acid :mod 705 :name (n2 / name :op1 "tyrosine"))
                              :op2 (a4 / amino-acid :mod 727 :name (n3 / name :op1 "serine"))
                              :part-of (p2 / protein :name (n / name :op1 "STAT3")))
                        :ARG2 (p3 / protein :name (n4 / name :op1 "Galpha(s)QL")))))
      :op2 (o / observe-01
            :ARG1 (p5 / profile
                  :ARG1-of (r2 / resemble-01)
                  :ARG2-of (r / respond-01
                        :ARG1 (s3 / stimulate-01
                              :ARG1 (p6 / protein :name (n10 / name :op1 "beta2-adrenergic" :op2 "receptor")))))))

# ::id bel_pmid_1703_0180.5428 ::date 2015-05-03T12:23:41 ::annotator SDL-AMR-09 ::preferred
# ::snt Activated KRAS is known to induce tyrosine phosphorylation of beta-catenin, leading to its release from E-cadherin at the adherens junction
# ::save-date Sun Dec 20, 2015 ::file bel_pmid_1703_0180_5428.txt
(i / induce-01
      :ARG0 (e / enzyme :name (n / name :op1 "KRAS")
            :ARG1-of (a / activate-01))
      :ARG2 (p2 / phosphorylate-01
            :ARG1 (a2 / amino-acid :name (n4 / name :op1 "tyrosine")
                  :part-of (p3 / protein :name (n2 / name :op1 "beta-catenin"))))
      :ARG1-of (l / lead-03
            :ARG2 (r / release-01
                  :ARG1 p3
                  :ARG2 (p4 / protein :name (n3 / name :op1 "E-cadherin"))
                  :location (m / macro-molecular-complex :name (n5 / name :op1 "adherens" :op2 "junction"))))
      :ARG1-of (k / know-01))

# ::id bel_pmid_1708_2637.21974 ::date 2015-05-03T12:58:41 ::annotator SDL-AMR-09 ::preferred
# ::snt TNF-a strongly stimulated FRA-1 promoter activity in WT MEFs as compared with the erk1-/- MEFs (Fig. 9B).
# ::save-date Sun Jan 17, 2016 ::file bel_pmid_1708_2637_21974.txt
(s / stimulate-01
      :ARG0 (p / protein :name (n / name :op1 "TNF-a"))
      :ARG1 (a / activity-06
            :ARG0 (m2 / molecular-physical-entity
                  :ARG0-of (p2 / promote-01
                        :ARG1 (p3 / protein :name (n2 / name :op1 "FRA-1"))))
            :location (f2 / fibroblast
                  :source (e / embryo
                        :mod (m3 / mouse))
                  :mod (w / wild-type)
                  :ARG2-of (c / compare-01
                        :ARG1 (f3 / fibroblast
                              :source (e2 / embryo
                                    :mod (m / mouse))
                              :mod (e3 / enzyme :name (n3 / name :op1 "erk1")
                                    :ARG2-of (m4 / mutate-01 :mod "-/-"))))))
      :ARG1-of (s2 / strong-02)
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod "9B")))

# ::id bel_pmid_1708_2637.21978 ::date 2015-05-03T13:23:33 ::annotator SDL-AMR-09 ::preferred
# ::snt the recruitment of c-Jun was strongly enhanced following TNF-a treatment (Fig. 10B, lanes 3 and 4). In contrast, the binding of c-Jun to the fra-1 promoter was significantly diminished in MEFS lacking the erk1-/- signaling (cf lanes 7 and 8 with lanes 3 and 4).
# ::save-date Fri Feb 12, 2016 ::file bel_pmid_1708_2637_21978.txt
(m / multi-sentence
      :snt1 (e2 / enhance-01
            :ARG1 (r / recruit-01
                  :ARG1 (p5 / protein :name (n / name :op1 "c-Jun")))
            :ARG1-of (d / describe-01
                  :ARG0 (a / and
                        :op1 (l / lane :mod 3)
                        :op2 (l5 / lane :mod 5)
                        :part-of (f / figure :mod "10B")))
            :ARG1-of (f2 / follow-01
                  :ARG2 (t / treat-04
                        :ARG2 (p / protein :name (n2 / name :op1 "TNF-a"))))
            :ARG1-of (s / strong-02))
      :snt2 (c / contrast-01
            :ARG2 (d2 / diminish-01
                  :ARG1 (b / bind-01
                        :ARG1 (p4 / protein :name (n4 / name :op1 "c-Jun"))
                        :ARG2 (m2 / molecular-physical-entity
                              :ARG0-of (p2 / promote-01
                                    :ARG1 (p3 / protein :name (n3 / name :op1 "fra-1")))))
                  :ARG2 (s2 / significant-02)
                  :location (f3 / fibroblast
                        :source (e4 / embryo
                              :mod (m3 / mouse))
                        :ARG0-of (l2 / lack-01
                              :ARG1 (s3 / signal-07
                                    :ARG0 (e5 / enzyme :name (n5 / name :op1 "erk1")
                                          :ARG2-of (m4 / mutate-01 :mod "-/-"))))))
            :ARG1-of (c2 / conform-01
                  :ARG0 (c3 / compare-01
                        :ARG1 (a2 / and
                              :op1 (l3 / lane :mod 7)
                              :op2 (l4 / lane :mod 8))
                        :ARG2 (a3 / and
                              :op1 (l6 / lane :mod 3)
                              :op2 (l7 / lane :mod 4))))))

# ::id bel_pmid_1708_2637.31490 ::date 2015-05-03T14:04:15 ::annotator SDL-AMR-09 ::preferred
# ::snt As shown in Fig. 9A, TNF-a strongly stimulated both ERK1 and ERK2 phosphorylation in WT cells (cf lanes 1 and 2).
# ::save-date Mon Jul 13, 2015 ::file bel_pmid_1708_2637_31490.txt
(s / stimulate-01
      :ARG0 (p / protein :name (n / name :op1 "TNF-a"))
      :ARG1 (p2 / phosphorylate-01
            :ARG1 (a / and
                  :op1 (e / enzyme :name (n2 / name :op1 "ERK1"))
                  :op2 (e2 / enzyme :name (n3 / name :op1 "ERK2"))
                  :mod (b / both))
            :location (c / cell
                  :mod (w / wild-type)))
      :ARG1-of (c3 / conform-01
            :ARG0 (c2 / compare-01
                  :ARG1 (l / lane :mod 1)
                  :ARG2 (l2 / lane :mod 2)))
      :ARG1-of (s2 / show-01
            :location (f / figure :mod "9A"))
      :ARG1-of (s3 / strong-02))

# ::id bel_pmid_1708_2637.39256 ::date 2015-05-03T14:17:15 ::annotator SDL-AMR-09 ::preferred
# ::snt The -318 TRE mediates c-Jun-dependent, TNF-alpha-inducible FRA-1 promoter activity.....Consistent with this result, ectopic expression of a c-Jun mutant lacking the transactivation domain greatly reduced (~80%) TNF-alpha-stimulated promoter activity (Fig. 2B)....However, TNF-a induced the binding of c-Jun to the promoter as early as 30 min (Fig. 3A, lane 2), and it remained high through 60 min (Fig. 3A, lane 3).
# ::save-date Fri Feb 12, 2016 ::file bel_pmid_1708_2637_39256.txt
(m / multi-sentence
      :snt1 (m2 / mediate-01
            :ARG0 (d / dna-sequence :mod "-318" :name (n / name :op1 "TRE"))
            :ARG1 (a / activity-06
                  :ARG0 (m8 / molecular-physical-entity
                        :ARG0-of (p / promote-01
                              :ARG1 (p2 / protein :name (n2 / name :op1 "FRA-1"))))
                  :ARG0-of (d2 / depend-01
                        :ARG1 (p11 / protein :name (n3 / name :op1 "c-Jun")))
                  :ARG2-of (i / induce-01
                        :ARG0 (p4 / protein :name (n4 / name :op1 "TNF-alpha"))
                        :ARG1-of (p12 / possible-01))))
      :snt2 (r / reduce-01
            :ARG0 (e / express-03
                  :ARG2 (e4 / enzyme :name (n5 / name :op1 "c-Jun")
                        :ARG2-of (m3 / mutate-01)
                        :ARG0-of (l / lack-01
                              :ARG1 (p7 / protein-segment
                                    :ARG2-of (t / transactivate-01))))
                  :mod (e2 / ectopic))
            :ARG1 (a3 / activity-06
                  :ARG0 (m6 / molecular-physical-entity
                        :ARG0-of (p3 / promote-01))
                  :ARG1-of (s / stimulate-01
                        :ARG0 (p8 / protein :name (n6 / name :op1 "TNF-alpha"))))
            :ARG2 (a2 / approximately
                  :op1 (p6 / percentage-entity :value 80))
            :degree (g / great)
            :ARG1-of (c / consistent-01
                  :ARG2 (t5 / thing
                        :mod (t2 / this)
                        :ARG2-of (r2 / result-01)))
            :ARG1-of (d4 / describe-01
                  :ARG0 (f / figure :mod "2B")))
      :snt3 (c2 / contrast-01
            :ARG2 (a4 / and
                  :op1 (i2 / induce-01
                        :ARG0 (p9 / protein :name (n7 / name :op1 "TNF-a"))
                        :ARG2 (b / bind-01
                              :ARG1 (p10 / protein :name (n8 / name :op1 "c-Jun"))
                              :ARG2 (m7 / molecular-physical-entity
                                    :ARG0-of (p5 / promote-01)))
                        :time (a5 / after
                              :mod (e3 / early)
                              :quant (t3 / temporal-quantity :quant 30
                                    :unit (m4 / minute)))
                        :ARG1-of (d5 / describe-01
                              :ARG0 (l2 / lane :mod 2
                                    :part-of (f2 / figure :mod "3A"))))
                  :op2 (r3 / remain-01
                        :ARG1 b
                        :ARG3 (h / high-02
                              :ARG1 b)
                        :duration (t4 / temporal-quantity :quant 60
                              :unit (m5 / minute))
                        :ARG1-of (d6 / describe-01
                              :ARG0 (l3 / lane :mod 3
                                    :part-of f2))))))

# ::id bel_pmid_1710_5652.28156 ::date 2015-05-03T15:17:27 ::annotator SDL-AMR-09 ::preferred
# ::snt Real-time RT-PCR revealed that IL-1beta induced SYN expression at the transcriptional level, because the mRNA level of SYN was upregulated by IL-1?. TNF-? had a weaker effect on SYN transcription, whereas IL-6 had no effect
# ::save-date Sun Jan 17, 2016 ::file bel_pmid_1710_5652_28156.txt
(m / multi-sentence
      :snt1 (r / reveal-01
            :ARG0 (t3 / thing :name (n / name :op1 "RT-PCR")
                  :mod (r2 / real-time))
            :ARG1 (i / induce-01
                  :ARG0 (p / protein :name (n2 / name :op1 "IL-1beta"))
                  :ARG2 (e2 / express-03
                        :ARG2 (e3 / enzyme :name (n3 / name :op1 "SYN")))
                  :mod (l / level
                        :mod (t / transcribe-01)))
            :ARG1-of (c / cause-01
                  :ARG0 (u / upregulate-01
                        :ARG1 (n9 / nucleic-acid :name (n4 / name :op1 "mRNA")
                              :mod (l2 / level)
                              :ARG0-of (e5 / encode-01
                                    :ARG1 e3))
                        :ARG2 (p2 / protein :name (n5 / name :op1 "IL1B")))))
      :snt2 (c2 / contrast-01
            :ARG1 (a / affect-01
                  :ARG0 (p3 / protein :name (n6 / name :op1 "TNF-α"))
                  :ARG1 (t2 / transcribe-01
                        :ARG1 (e4 / enzyme :name (n7 / name :op1 "SYN")))
                  :ARG1-of (w / weak-02
                        :degree (m2 / more)))
            :ARG2 (a2 / affect-01 :polarity -
                  :ARG0 (p4 / protein :name (n8 / name :op1 "IL-6"))
                  :ARG1 t2)))

# ::id bel_pmid_1711_8707.35424 ::date 2015-05-03T16:06:50 ::annotator SDL-AMR-09 ::preferred
# ::snt STAT3 is also able to prevent cell death through inhibition of the extrinsic apoptotic pathway. This pathway is activated upon binding of extracellular ligands such as FAS ligand (FAS-L) to cell-surface death receptors. Upon interaction with FAS-L, the FAS death receptor induces cell death through caspase-8 activation and truncation of the death agonist BID.
# ::save-date Sun Dec 20, 2015 ::file bel_pmid_1711_8707_35424.txt
(m / multi-sentence
      :snt1 (p / possible-01
            :ARG1 (p2 / prevent-01
                  :ARG0 (p3 / protein :name (n / name :op1 "STAT3"))
                  :ARG1 (d / die-01
                        :ARG1 (c / cell))
                  :ARG3 (i / inhibit-01
                        :ARG1 (p4 / pathway
                              :mod (e2 / extrinsic)
                              :mod (a5 / apoptosis)))
                  :mod (a / also)))
      :snt2 (a2 / activate-01
            :ARG1 (p5 / pathway
                  :mod (t / this))
            :time (b / bind-01
                  :ARG1 (l / ligand
                        :mod (e / extracellular)
                        :example (l2 / ligand :name (n3 / name :op1 "FAS")))
                  :ARG2 (r / receptor
                        :location (s / surface
                              :part-of (c2 / cell))
                        :ARG1-of (d2 / die-01))))
      :snt3 (i2 / induce-01
            :ARG0 (p6 / protein :name (n4 / name :op1 "FAS" :op2 "death" :op3 "receptor"))
            :ARG2 (d3 / die-01
                  :ARG1 (c3 / cell))
            :manner (a3 / and
                  :op1 (a4 / activate-01
                        :ARG1 (p7 / protein :name (n5 / name :op1 "caspase-8")))
                  :op2 (t2 / truncate-01
                        :ARG1 (p8 / protein :name (n6 / name :op1 "death" :op2 "agonist" :op3 "BID"))))
            :time (i3 / interact-01
                  :ARG1 (p9 / protein :name (n7 / name :op1 "FAS-L")))))

# ::id bel_pmid_1711_8707.37686 ::date 2015-05-04T01:14:17 ::annotator SDL-AMR-09 ::preferred
# ::snt These genes can be divided in three classes: one that controls cell-cycle arrest and senescence, one that controls apoptosis and one that regulates glucose metabolism and autophagy [42]. p53 is essentially known as a pro-apoptotic transcription factor that upregulates the expression of proteins such as BCL2-associated X protein (BAX), p53 upregulated modulator of apoptosis (PUMA) or NOXA.
# ::save-date Mon Jul 20, 2015 ::file bel_pmid_1711_8707_37686.txt
(m / multi-sentence
      :snt2 (k / know-02
            :ARG1 (p2 / protein :name (n / name :op1 "p53"))
            :ARG2 (p3 / protein :name (n2 / name :op1 "transcription" :op2 "factor")
                  :ARG0-of (f / favor-01
                        :ARG1 (a7 / apoptosis))
                  :ARG0-of (u / upregulate-01
                        :ARG1 (e / express-03
                              :ARG2 (p4 / protein
                                    :example (o2 / or
                                          :op1 (p5 / protein :name (n3 / name :op1 "Bcl-2-associated" :op2 "X"))
                                          :op2 (p6 / protein :name (n4 / name :op1 "p53" :op2 "upregulated" :op3 "modulator" :op4 "of" :op5 "apoptosis"))
                                          :op3 (p7 / protein :name (n5 / name :op1 "NOXA")))))))
            :manner (e2 / essential))
      :snt1 (p8 / possible-01
            :ARG1 (d / divide-02
                  :ARG1 (g / gene
                        :mod (t / this))
                  :ARG2 (c / class :quant 3
                        :ARG1-of (m2 / mean-01
                              :ARG2 (a / and
                                    :op1 (c3 / class
                                          :ARG0-of (c2 / control-01
                                                :ARG1 (a2 / and
                                                      :op1 (a3 / arrest-02
                                                            :ARG1 (c4 / cycle-02
                                                                  :ARG1 (c7 / cell)))
                                                      :op2 (s / senescence))))
                                    :op2 (c8 / class
                                          :ARG0-of (c9 / control-01
                                                :ARG1 (a4 / apoptosis)))
                                    :op3 (c10 / class
                                          :ARG0-of (r / regulate-01
                                                :ARG1 (a5 / and
                                                      :op1 (m3 / metabolize-01
                                                            :ARG1 (g2 / glucose))
                                                      :op2 (a6 / autophagy)))))))
                  :ARG1-of (d2 / describe-01
                        :ARG0 (p / publication
                              :ARG1-of (c5 / cite-01
                                    :ARG2 42))))))

# ::id bel_pmid_1711_8707.38556 ::date 2015-05-04T02:07:52 ::annotator SDL-AMR-09 ::preferred
# ::snt that IL-6 and IL-10, two cytokines that are known to activate STAT3, confer a drug-resistant phenotype in renal carcinomas, which was subsequently confirmed in different cancer cell lines such as multiple myeloma [72,73].
# ::save-date Mon Jan 4, 2016 ::file bel_pmid_1711_8707_38556.txt
(c / confer-02
      :ARG0 (a / and
            :op1 (c9 / cytokine :name (n / name :op1 "IL-6"))
            :op2 (c10 / cytokine :name (n2 / name :op1 "IL-10"))
            :ARG0-of (a2 / activate-01
                  :ARG1 (p / protein :name (n3 / name :op1 "STAT3"))
                  :ARG1-of (k / know-01)))
      :ARG1 (p4 / phenotype
            :ARG0-of (r / resist-01
                  :ARG1 (d / drug))
            :ARG1-of (c3 / confirm-01
                  :location (c6 / cell-line
                        :ARG1-of (d3 / differ-02)
                        :mod (d5 / disease :wiki "Cancer" :name (n4 / name :op1 "cancer")
                              :example (d4 / disease :name (n5 / name :op1 "multiple" :op2 "myeloma"))))
                  :time (s / subsequent)))
      :ARG1-of (d2 / describe-01
            :ARG0 (p5 / publication
                  :ARG1-of (c8 / cite-01
                        :ARG2 (a3 / and :op1 72 :op2 73))))
      :location (m / medical-condition :name (n6 / name :op1 "carcinoma")
            :mod (k2 / kidney)))

# ::id bel_pmid_1711_8707.39772 ::date 2015-05-04T02:09:46 ::annotator SDL-AMR-09 ::preferred
# ::snt Importantly, the expression of survivin correlates with STAT3 activation in breast tumors, and the inhibition of this signaling pathway induces apoptosis [47,48]. Finally, it has also been shown that AKT is a direct target gene of STAT3, which binds directly to its promoter to enhance its expression [49].
# ::save-date Mon Jan 4, 2016 ::file bel_pmid_1711_8707_39772.txt
(m / multi-sentence
      :snt1 (a / and
            :op1 (c / correlate-01
                  :ARG1 (e / express-03
                        :ARG2 (p5 / protein :name (n4 / name :op1 "survivin")
                              :ARG0-of (s / signal-07)))
                  :ARG2 (a2 / activate-01
                        :ARG1 (p / protein :name (n / name :op1 "STAT3")))
                  :location (t / tumor
                        :mod (b / breast)))
            :op2 (i / induce-01
                  :ARG0 (i2 / inhibit-01
                        :ARG1 (p7 / pathway
                              :mod (t2 / this)
                              :ARG0-of s))
                  :ARG2 (a3 / apoptosis))
            :manner (i3 / important)
            :ARG1-of (d / describe-01
                  :ARG0 (p3 / publication
                        :ARG1-of (c2 / cite-01
                              :ARG2 (a4 / and :op1 47 :op2 48)))))
      :snt2 (s3 / show-01 :li "-1"
            :ARG1 (t3 / target-01
                  :ARG0 (p4 / protein :name (n2 / name :op1 "STAT3")
                        :ARG1-of (b2 / bind-01
                              :ARG2 (m2 / molecular-physical-entity
                                    :ARG0-of (p2 / promote-01
                                          :ARG1 g))
                              :purpose (e2 / enhance-01
                                    :ARG0 p4
                                    :ARG1 (e3 / express-03
                                          :ARG1 g))))
                  :ARG1 (g / gene :name (n3 / name :op1 "AKT"))
                  :ARG1-of (d2 / direct-02))
            :mod (a5 / also)
            :ARG1-of (d3 / describe-01
                  :ARG0 (p6 / publication
                        :ARG1-of (c3 / cite-01
                              :ARG2 49)))))

# ::id bel_pmid_1712_7443.3208 ::date 2015-05-04T03:05:58 ::annotator SDL-AMR-09 ::preferred
# ::snt Several transcription factors have also been implicated in megakaryopoiesis including, GATA-1, friend of GATA-1 (FOG-1), nuclear factor-erythroid 2 (NF-E2), and Fli-1.
# ::save-date Sat May 9, 2015 ::file bel_pmid_1712_7443_3208.txt
(i / implicate-01
      :ARG1 (p / protein :name (n / name :op1 "transcription" :op2 "factor")
            :quant (s / several)
            :ARG2-of (i2 / include-91
                  :ARG1 (a2 / and
                        :op1 (p2 / protein :name (n2 / name :op1 "GATA-1"))
                        :op2 (p3 / protein :name (n5 / name :op1 "friend" :op2 "of" :op3 "GATA-1"))
                        :op3 (p4 / protein :name (n3 / name :op1 "nuclear" :op2 "factor-erythroid" :op3 "2"))
                        :op4 (p5 / protein :name (n4 / name :op1 "Fli-1")))))
      :ARG2 (m / megakaryopoiesis)
      :mod (a / also))

# ::id bel_pmid_1712_7443.21794 ::date 2015-05-04T03:19:04 ::annotator SDL-AMR-09 ::preferred
# ::snt Tyk2, along with JAK2, does appear to regulate TPO receptor localization at the plasma membrane by stimulating recycling and enhancing the stability of the receptor in Ba/F3 cells
# ::save-date Sun Jan 17, 2016 ::file bel_pmid_1712_7443_21794.txt
(a / appear-02
      :ARG1 (r / regulate-01
            :ARG0 (a3 / and
                  :op1 (e / enzyme :name (n / name :op1 "Tyk2"))
                  :op2 (e4 / enzyme :name (n5 / name :op1 "JAK2")))
            :ARG1 (b / be-located-at-91
                  :ARG1 (p / protein :name (n3 / name :op1 "TPO" :op2 "receptor"))
                  :ARG2 (m / membrane
                        :mod (p2 / plasma)))
            :manner (a2 / and
                  :op1 (s / stimulate-01
                        :ARG0 a3
                        :ARG1 (r2 / recycle-01))
                  :op2 (e3 / enhance-01
                        :ARG0 a3
                        :ARG1 (s2 / stability
                              :poss p
                              :location (c / cell-line :name (n4 / name :op1 "Ba/F3")))))))

# ::id bel_pmid_1712_7443.27130 ::date 2015-05-04T03:37:35 ::annotator SDL-AMR-09 ::preferred
# ::snt Other notable genes downregulated with GATA-1 knockdown are the p45 subunit of nuclear factor erythroid-derived 2 (NF- E2), JAK2, and beta1-tubulin.
# ::save-date Thu Jul 9, 2015 ::file bel_pmid_1712_7443_27130.txt
(i / include-91
      :ARG1 (a / and
            :op1 (s / subunit
                  :part-of (g4 / gene :name (n4 / name :op1 "nuclear" :op2 "factor" :op3 "erythroid-derived" :op4 "2"))
                  :mod (p2 / protein :name (n6 / name :op1 "p45")))
            :op2 (g2 / gene :name (n2 / name :op1 "JAK2"))
            :op3 (g3 / gene :name (n3 / name :op1 "beta1-tubulin")))
      :ARG2 (g / gene
            :mod (o / other)
            :ARG1-of (n / notable-04)
            :ARG1-of (d / downregulate-01
                  :ARG2 (p / protein :name (n5 / name :op1 "GATA-1")
                        :ARG1-of (k / knock-down-02)))))

# ::id bel_pmid_1712_7443.29536 ::date 2015-05-04T04:45:39 ::annotator SDL-AMR-09 ::preferred
# ::snt There are two isoforms of 3beta- HSD expressed in wild-type megakaryocytes (I and VI), but neither are expressed in NF-E2 null megakaryocytes.
# ::save-date Sun Jan 3, 2016 ::file bel_pmid_1712_7443_29536.txt
(c / contrast-01
      :ARG1 (e / express-03
            :ARG2 (i / isoform :quant 2
                  :mod (e2 / enzyme :name (n / name :op1 "3beta-HSD"))
                  :ARG1-of (m / mean-01
                        :ARG2 (a / and
                              :op1 (e4 / enzyme :name (n2 / name :op1 "3beta-HSD" :op2 "I"))
                              :op2 (e5 / enzyme :name (n3 / name :op1 "3beta-HSD" :op2 "IV")))))
            :ARG3 (m4 / megakaryocyte
                  :mod (w / wild-type)))
      :ARG2 (e3 / express-03 :polarity -
            :ARG2 i
            :ARG3 (m3 / megakaryocyte
                  :mod (p / protein :name (n5 / name :op1 "NF-E2")
                        :ARG1-of (m2 / mutate-01 :mod "-/-")))))

# ::id bel_pmid_1712_7443.31646 ::date 2015-05-04T05:09:18 ::annotator SDL-AMR-09 ::preferred
# ::snt TPO is necessary for megakaryocyte maturation in that TPO deficient mice display greatly reduced megakaryocyte production as well as reduced numbers of mature megakaryocytes
# ::save-date Sun Jan 17, 2016 ::file bel_pmid_1712_7443_31646.txt
(n / need-01
      :ARG0 (m / mature-01
            :ARG1 (m4 / megakaryocyte))
      :ARG1 (p2 / protein :name (n2 / name :op1 "TPO"))
      :ARG1-of (c2 / cause-01
            :ARG0 (d / display-01
                  :ARG0 (m2 / mouse
                        :ARG0-of (l / lack-01
                              :ARG1 p2))
                  :ARG1 (a / and
                        :op1 (p / produce-01
                              :ARG1 m4
                              :ARG1-of (r / reduce-01
                                    :degree (g / great)))
                        :op2 (n3 / number
                              :ARG1-of (r2 / reduce-01)
                              :quant-of (m5 / megakaryocyte
                                    :ARG1-of (m3 / mature-02)))))))

# ::id bel_pmid_1712_7443.35706 ::date 2015-05-04T05:30:39 ::annotator SDL-AMR-09 ::preferred
# ::snt TPO to c-Mpl (a receptor tyrosine kinase) activates both Janus Kinase 2 (JAK2) and Tyk2
# ::save-date Sun Jan 17, 2016 ::file bel_pmid_1712_7443_35706.txt
(a / activate-01
      :ARG0 (a3 / and
            :op1 (p / protein :name (n3 / name :op1 "TPO"))
            :op2 (p3 / protein :name (n4 / name :op1 "c-Mpl")
                  :ARG1-of (m / mean-01
                        :ARG2 (e4 / enzyme :name (n5 / name :op1 "receptor" :op2 "tyrosine" :op3 "kinase")))))
      :ARG1 (a2 / and
            :op1 (e2 / enzyme :name (n / name :op1 "Janus" :op2 "Kinase" :op3 "2"))
            :op2 (e3 / enzyme :name (n2 / name :op1 "Tyk2")))
      :mod (b / both))

# ::id bel_pmid_1714_2955.38942 ::date 2015-05-04T06:03:13 ::annotator SDL-AMR-09 ::preferred
# ::snt . Furthermore, the bFGF-induced activation of ERK1/2 seems to enhance the transcriptional activity of STAT3. Co-stimulation of KMS-11 with bFGF and IL-6 leads to marked expression of STAT3 target genes, such as c-myc and bcl-2, further suggesting the relevance of STAT3 phosphorylated at both Tyr705 and Ser727 for the full activation as a transcription factor (Fig. 5). In addition, the
# ::save-date Sun Jan 3, 2016 ::file bel_pmid_1714_2955_38942.txt
(m / multi-sentence
      :snt1 (a / and
            :op2 (s / seem-01
                  :ARG1 (e / enhance-01
                        :ARG0 (a3 / activate-01
                              :ARG1 (e3 / enzyme :name (n2 / name :op1 "ERK1/2"))
                              :ARG2-of (i / induce-01
                                    :ARG0 (p3 / protein :name (n3 / name :op1 "bFGF"))))
                        :ARG1 (a2 / activity-06
                              :ARG0 (p / protein :name (n / name :op1 "STAT3"))
                              :ARG1 (t / transcribe-01)))))
      :snt2 (l / lead-03
            :ARG0 (s2 / stimulate-01
                  :ARG1 (c / cell-line :name (n4 / name :op1 "KMS-11"))
                  :ARG2 (a4 / and
                        :op1 (p4 / protein :name (n5 / name :op1 "bFGF"))
                        :op2 (p5 / protein :name (n6 / name :op1 "IL-6")))
                  :manner (j / joint))
            :ARG1 (e2 / express-03
                  :ARG1 (g4 / gene
                        :ARG2-of (i2 / include-91
                              :ARG1 (a5 / and
                                    :op1 (g2 / gene :name (n8 / name :op1 "c-myc"))
                                    :op2 (g3 / gene :name (n9 / name :op1 "bcl-2"))))
                        :ARG1-of (t2 / target-01
                              :ARG0 (p2 / protein :name (n7 / name :op1 "STAT3"))))
                  :ARG1-of (m2 / mark-01))
            :ARG0-of (s3 / suggest-01
                  :ARG1 (r / relevant-01
                        :ARG1 (a8 / and
                              :op1 (a6 / amino-acid :name (n11 / name :op1 "tyrosine")
                                    :ARG1-of (p7 / phosphorylate-01))
                              :op2 (a7 / amino-acid :name (n12 / name :op1 "serine")
                                    :ARG1-of p7)
                              :part-of p2)
                        :ARG2 (a9 / activate-01
                              :ARG1 (f3 / factor
                                    :ARG0-of (t3 / transcribe-01))
                              :ARG1-of (f2 / full-09)))
                  :degree (f / further))
            :ARG1-of (d / describe-01
                  :ARG0 (f4 / figure :mod 5))))

# ::id bel_pmid_1714_3332.29844 ::date 2015-05-04T06:55:31 ::annotator SDL-AMR-09 ::preferred
# ::snt Expression of PGC-1?, PEPCK, and glucose-6-phosphatase mRNAs were also significantly increased in fasted KO compared with fasted WT livers (Table 2), consistent with enhanced glucose production in KO livers.
# ::save-date Wed Jan 20, 2016 ::file bel_pmid_1714_3332_29844.txt
(i / increase-01
      :ARG1 (e / express-03
            :ARG2 (a / and
                  :op1 (p / protein :name (n / name :op1 "PGC-1a"))
                  :op2 (e2 / enzyme :name (n2 / name :op1 "PEPCK"))
                  :op3 (n5 / nucleic-acid :name (n3 / name :op1 "mRNA")
                        :ARG0-of (e3 / encode-01
                              :ARG1 (e5 / enzyme :name (n4 / name :op1 "glucose-6-phosphatase"))))))
      :ARG2 (s / significant-02)
      :location (l2 / liver
            :ARG0-of (f / fast-01)
            :ARG1-of (c / compare-01
                  :ARG2 (l / liver
                        :ARG0-of f
                        :mod (w / wild-type)))
            :ARG1-of (d / describe-01
                  :ARG0 (t / table :mod 2))
            :ARG2-of (m / mutate-01 :mod "-/-"))
      :ARG1-of (c2 / consistent-01
            :ARG2 (p2 / produce-01
                  :ARG1 (g / glucose)
                  :ARG1-of (e4 / enhance-01)
                  :location l2))
      :mod (a2 / also))

# ::id bel_pmid_1714_3332.29846 ::date 2015-05-04T07:24:55 ::annotator SDL-AMR-09 ::preferred
# ::snt As analyzed by real-time RT-PCR, levels of SOCS-3 mRNA and mRNAs of proinflammatory cytokines IL-1, IL-6, TNF-?, and plasminogen activator inhibitor–1 (PAI-1) were increased in fasted KO liver (Table 2).
# ::save-date Wed Jan 20, 2016 ::file bel_pmid_1714_3332_29846.txt
(i / increase-01
      :ARG1 (a / and
            :op1 (l2 / level
                  :quant-of (n9 / nucleic-acid :name (n / name :op1 "mRNA")
                        :ARG0-of (e2 / encode-01
                              :ARG1 (p / protein :name (n2 / name :op1 "SOCS-3")))))
            :op2 (l3 / level
                  :quant-of (n10 / nucleic-acid :name (n3 / name :op1 "mRNA")
                        :ARG0-of (e3 / encode-01
                              :ARG1 (a2 / and
                                    :op1 (c / cytokine
                                          :ARG2-of (i2 / include-91
                                                :ARG1 (a3 / and
                                                      :op1 (p3 / protein :name (n4 / name :op1 "IL-1"))
                                                      :op2 (p4 / protein :name (n5 / name :op1 "IL-6"))
                                                      :op3 (p5 / protein :name (n7 / name :op1 "TNF-a"))))
                                          :ARG0-of (f2 / favor-01
                                                :ARG1 (i3 / inflame-01)))
                                    :op2 (p2 / protein :name (n8 / name :op1 "plasminogen" :op2 "activator" :op3 "inhibitor–1")))))))
      :location (l / liver
            :ARG0-of (f / fast-01)
            :ARG1-of (k / knock-out-03))
      :ARG1-of (d / describe-01
            :ARG0 (t / table :mod 2))
      :ARG1-of (a4 / analyze-01
            :instrument (t2 / thing :name (n6 / name :op1 "RT-PCR")
                  :mod (r / real-time))))

# ::id bel_pmid_1714_3332.29848 ::date 2015-05-04T07:31:47 ::annotator SDL-AMR-09 ::preferred
# ::snt In addition, expression of tribbles 3 (TRB3) protein (Figure 8C) and mRNA (Table 2) was increased in fasted KO livers.
# ::save-date Wed Jan 20, 2016 ::file bel_pmid_1714_3332_29848.txt
(a / and
      :op2 (i / increase-01
            :ARG1 (e / express-03
                  :ARG2 (a2 / and
                        :op1 (p / protein :name (n / name :op1 "tribbles" :op2 "3")
                              :ARG1-of (d / describe-01
                                    :ARG0 (f / figure :mod "8C")))
                        :op2 (n3 / nucleic-acid :name (n2 / name :op1 "mrna")
                              :ARG1-of (d2 / describe-01
                                    :ARG0 (t / table :mod 2)))))
            :location (l / liver
                  :ARG0-of (f2 / fast-01)
                  :ARG1-of (k / knock-out-03))))

# ::id bel_pmid_1720_0144.37610 ::date 2015-05-04T10:52:25 ::annotator SDL-AMR-09 ::preferred
# ::snt mTORC2 can be activated by PI3K directly and phosphorylates Akt at S473, which together with phosphorylation at T308 results in the full activation of Akt [12,13].
# ::save-date Mon Dec 21, 2015 ::file bel_pmid_1720_0144_37610.txt
(a / and
      :op1 (p / possible-01
            :ARG1 (a2 / activate-01
                  :ARG0 (e / enzyme :name (n / name :op1 "PI3K"))
                  :ARG1 (m / macro-molecular-complex
                        :part (m2 / macro-molecular-complex :name (n2 / name :op1 "mTORC2")))
                  :ARG1-of (d / direct-02)))
      :op2 (p3 / phosphorylate-01
            :ARG1 (a3 / amino-acid :mod 473 :name (n4 / name :op1 "serine")
                  :part-of (e2 / enzyme :name (n3 / name :op1 "Akt")))
            :ARG2 m2
            :accompanier (p5 / phosphorylate-01
                  :ARG1 (a4 / amino-acid :mod 308 :name (n5 / name :op1 "tyrosine")
                        :part-of e2))
            :ARG1-of (r / result-01
                  :ARG2 (a5 / activate-01
                        :ARG1 e2
                        :ARG1-of (f / full-09))))
      :ARG1-of (d2 / describe-01
            :ARG0 (p6 / publication
                  :ARG1-of (c / cite-01
                        :ARG2 (a6 / and :op1 12 :op2 13)))))

# ::id bel_pmid_1720_0144.38486 ::date 2015-05-04T11:23:37 ::annotator SDL-AMR-09 ::preferred
# ::snt The intracellular signaling induced by IL-4/IL-4R interactions on CD4  T cells has been characterized in great detail. The binding of IL-4 to the Type I receptor in CD4  T cells induces the activation of the nonreceptor tyrosine kinase Jak1, which promotes the phosphorylation of STAT6.
# ::save-date Sun Jan 3, 2016 ::file bel_pmid_1720_0144_38486.txt
(m / multi-sentence
      :snt1 (c / characterize-01
            :ARG1 (s / signal-07
                  :mod (i / intracellular)
                  :ARG2-of (i2 / induce-01
                        :ARG0 (i3 / interact-01
                              :ARG0 (p / protein :name (n / name :op1 "IL-4"))
                              :ARG1 (p2 / protein :name (n2 / name :op1 "IL-4R"))
                              :location (c2 / cell :name (n3 / name :op1 "CD4T")))))
            :manner (d / detail-01
                  :degree (g / great)))
      :snt2 (i4 / induce-01
            :ARG0 (b / bind-01
                  :ARG1 (p3 / protein :name (n4 / name :op1 "IL-4"))
                  :ARG2 (p4 / protein :name (n5 / name :op1 "Type" :op2 "I" :op3 "receptor"))
                  :location (c3 / cell :name (n6 / name :op1 "CD4" :op2 "T")))
            :ARG2 (a / activate-01
                  :ARG1 (e / enzyme :name (n7 / name :op1 "nonreceptor" :op2 "tyrosine" :op3 "kinase" :op4 "Jak1")
                        :ARG0-of (p5 / promote-01
                              :ARG1 (p6 / phosphorylate-01
                                    :ARG1 (p7 / protein :name (n8 / name :op1 "STAT6"))))))))

# ::id bel_pmid_1723_4180.3578 ::date 2015-05-04T11:45:28 ::annotator SDL-AMR-09 ::preferred
# ::snt Marimastat (100 mg/kg), dexamethasone (10 mg/kg) and rolipram (0.3 mg/kg) reduced significantly IL-6, KC/CXCL1, MIP-1alpha/CCL3 and MMP-9 levels in bronchoalveolar lavage fluid.
# ::save-date Fri Dec 18, 2015 ::file bel_pmid_1723_4180_3578.txt
(r / reduce-01
      :ARG0 (a / and
            :op1 (s2 / small-molecule :name (n5 / name :op1 "marimastat")
                  :quant (c2 / concentration-quantity :quant 100
                        :unit (m / milligram-per-kilogram)))
            :op2 (s3 / small-molecule :name (n6 / name :op1 "dexamethasone")
                  :quant (c / concentration-quantity :quant 10
                        :unit (m2 / milligram-per-kilogram)))
            :op3 (s4 / small-molecule :name (n7 / name :op1 "rolipram")
                  :quant (c3 / concentration-quantity :quant 0.3
                        :unit (m3 / milligram-per-kilogram))))
      :ARG1 (a2 / and
            :op1 (l / level
                  :quant-of (p / protein :name (n / name :op1 "IL-6")))
            :op2 (l3 / level
                  :quant-of (p2 / protein :name (n2 / name :op1 "KC/CXCL1")))
            :op3 (l4 / level
                  :quant-of (p3 / protein :name (n3 / name :op1 "MIP-1alpha/CCL3")))
            :op4 (l5 / level
                  :quant-of (e2 / enzyme :name (n4 / name :op1 "MMP-9"))))
      :ARG2 (s / significant-02)
      :location (f / fluid
            :mod (l2 / lavage)
            :mod (b / bronchoalveolar)))

# ::id bel_pmid_1729_2829.29076 ::date 2015-05-05T10:38:03 ::annotator SDL-AMR-09 ::preferred
# ::snt Nox1 and Nox4 mRNAs were upregulated in H-RasV12-transformed p38??/? MEFs, suggesting that these two NOX family members may be involved in H-RasV12-induced ROS production in fibroblasts (Figure S5B).
# ::save-date Wed Jan 13, 2016 ::file bel_pmid_1729_2829_29076.txt
(u / upregulate-01
      :ARG1 (a / and
            :op1 (n10 / nucleic-acid :name (n4 / name :op1 "mRNA")
                  :ARG0-of (e5 / encode-01
                        :ARG1 (e / enzyme :name (n6 / name :op1 "Nox1"))))
            :op2 (n11 / nucleic-acid :name (n5 / name :op1 "mRNA")
                  :ARG0-of (e6 / encode-01
                        :ARG1 (e2 / enzyme :name (n7 / name :op1 "Nox4")))))
      :ARG0-of (s / suggest-01
            :ARG1 (p / possible-01
                  :ARG1 (i / involve-01
                        :ARG1 (m / member :quant 2
                              :ARG1-of (m4 / mean-01
                                    :ARG2 a)
                              :ARG1-of (i3 / include-91
                                    :ARG2 (p4 / protein-family :name (n / name :op1 "NOX"))))
                        :ARG2 (p2 / produce-01
                              :ARG1 (s2 / small-molecule :name (n2 / name :op1 "ROS"))
                              :ARG2-of (i2 / induce-01
                                    :ARG0 (e4 / enzyme :name (n3 / name :op1 "H-Ras")
                                          :ARG2-of (m3 / mutate-01 :value "V12")))))))
      :ARG1-of (d / describe-01
            :ARG0 (f2 / figure :mod "S5B"))
      :location (c / cell :name (n8 / name :op1 "MEF")
            :mod (e3 / enzyme :name (n9 / name :op1 "p38"))
            :ARG1-of (t2 / transform-01
                  :ARG0 e4)))

# ::id bel_pmid_1729_9132.25542 ::date 2015-05-06T06:23:16 ::annotator SDL-AMR-09 ::preferred
# ::snt Papillary adenomas (1.2.1.2.2) were detected 6–8 wk after BRafVE expression and appeared to increase in number and size. These lesions were bronchiolocentric, but did not appear to involve the terminal bronchioles. Rather, the lesions appeared to arise in alveolar ducts and expand outward and around bronchioles (Fig. 4B).
# ::save-date Sat Jan 2, 2016 ::file bel_pmid_1729_9132_25542.txt
(m / multi-sentence
      :snt1 (a / and
            :op1 (d / detect-01
                  :ARG1 (m3 / medical-condition :name (n3 / name :op1 "adenoma")
                        :mod (p / papilla)
                        :ARG1-of (l2 / label-01
                              :ARG2 (s2 / string-entity :value "1.2.1.2.2")))
                  :time (a4 / after
                        :op1 (e / express-03
                              :ARG2 (e2 / enzyme :name (n / name :op1 "BRaf")
                                    :ARG2-of (m2 / mutate-01 :value "VE")))
                        :quant (b5 / between
                              :op1 (t / temporal-quantity :quant 6
                                    :unit (w / week))
                              :op2 (t3 / temporal-quantity :quant 8
                                    :unit (w2 / week)))))
            :op2 (a2 / appear-02
                  :ARG1 (i / increase-01
                        :ARG1 (a12 / and
                              :op1 (n2 / number
                                    :quant-of (a3 / adenoma))
                              :op2 (s / size
                                    :poss-of a3)))))
      :ARG1-of (d2 / describe-01
            :ARG0 (f / figure :mod "4B"))
      :snt2 (c / contrast-01
            :ARG1 (b / bronchiolocentric
                  :domain (l / lesion
                        :mod (t5 / this)))
            :ARG2 (a5 / appear-02 :polarity -
                  :ARG1 (i2 / involve-01
                        :ARG1 (b3 / bronchiole
                              :mod (t2 / terminus))
                        :ARG2 l)))
      :snt3 (a6 / appear-02
            :ARG1 (a8 / and
                  :op1 (a7 / arise-02
                        :ARG1 (l3 / lesion)
                        :location (d3 / duct
                              :part-of (a9 / alveolus)))
                  :op2 (e3 / expand-01
                        :ARG1 l3
                        :location (a10 / and
                              :op1 (o / outward
                                    :op1 (b4 / bronchiole))
                              :op2 (a11 / around
                                    :op1 b4))))
            :mod (r / rather))
      :ARG1-of (d4 / describe-01
            :ARG0 (f2 / figure :mod "4B")))

# ::id bel_pmid_1729_9132.25544 ::date 2015-05-05T13:24:45 ::annotator SDL-AMR-09 ::preferred
# ::snt At early times after induced BRafVE expression, we detected evidence of epithelial hyperplasia (classified as 1.1.1.1) arising within the terminal bronchioles and within the central lung parenchyma.
# ::save-date Wed Mar 9, 2016 ::file bel_pmid_1729_9132_25544.txt
(d / detect-01
      :ARG0 (w / we)
      :ARG1 (e / evidence-01
            :ARG1 (h / hyperplasia
                  :mod (e2 / epithelium)
                  :ARG1-of (a / arise-02
                        :location (a2 / and
                              :op1 (b / bronchiole
                                    :mod (t / terminal))
                              :op2 (p / parenchyma
                                    :mod (l / lung
                                          :mod (c / central)))))
                  :ARG1-of (c2 / classify-01
                        :ARG2 (s / string-entity :value "1.1.1.1"))))
      :time (t2 / time
            :mod (e3 / early))
      :time (a3 / after
            :op1 (e4 / express-03
                  :ARG2 (e5 / enzyme :name (n / name :op1 "BRafVE")
                        :ARG2-of (m / mutate-01 :value "VE"))
                  :ARG2-of (i / induce-01))))

# ::id bel_pmid_1729_9132.25548 ::date 2015-05-05T13:33:29 ::annotator SDL-AMR-09 ::preferred
# ::snt the majority of cells within BRafVE-induced tumors expressed SP-C, suggesting that they have properties of ATII pneumocytes (Fig. 2K,L).
# ::save-date Sat Jan 2, 2016 ::file bel_pmid_1729_9132_25548.txt
(e / express-03
      :ARG2 (p5 / protein :name (n4 / name :op1 "SP-C"))
      :ARG3 (c2 / cell
            :quant (m / majority)
            :ARG1-of (i / include-91
                  :ARG2 (c3 / cell
                        :location (t / tumor
                              :ARG2-of (i2 / induce-01
                                    :ARG0 (e2 / enzyme :name (n2 / name :op1 "Braf")
                                          :ARG2-of (m2 / mutate-01 :value "VE")))))))
      :ARG0-of (s / suggest-01
            :ARG1 (h / have-03
                  :ARG0 c2
                  :ARG1 (p / property
                        :poss (c / cell :name (n / name :op1 "ATII" :op2 "pneumocyte")))))
      :ARG1-of (d / describe-01
            :ARG0 (a / and
                  :op1 (f / figure :mod "2K")
                  :op2 (f2 / figure :mod "2L"))))

# ::id bel_pmid_1729_9132.28748 ::date 2015-05-05T13:43:53 ::annotator SDL-AMR-09 ::preferred
# ::snt It is reported that KRasG12D-induced lung tumors do not routinely display elevated pERK1/2 but display stress-activated MAP kinase (SAPK/JNK) activation (Lee et al. 2002)... Interestingly, the major difference appears to be that expression of KRasG12D in the lung leads to more rapid and consistent progression to adenocarcinoma than that elicited by BRafVE.
# ::save-date Mon Feb 1, 2016 ::file bel_pmid_1729_9132_28748.txt
(m / multi-sentence
      :snt2 (a / appear-01
            :ARG1 (d / differ-02
                  :ARG1 (l2 / lead-03
                        :ARG0 (e2 / express-03
                              :ARG2 (e6 / enzyme :name (n2 / name :op1 "KRAS")
                                    :ARG2-of (m3 / mutate-01 :value "G12D"))
                              :ARG3 (l / lung))
                        :ARG2 (p / progress-01
                              :ARG4 (m8 / medical-condition :name (n6 / name :op1 "adenocarcinoma"))
                              :mod (r / rapid
                                    :degree (m5 / more))
                              :ARG1-of (c / consistent-02
                                    :degree m5)))
                  :ARG2 (p6 / progress-01
                        :ARG4 (a3 / adenocarcinoma)
                        :ARG1-of (e3 / elicit-01
                              :ARG0 (e4 / enzyme :name (n / name :op1 "Braf")
                                    :ARG2-of (m6 / mutate-01 :value "VE"))))
                  :ARG1-of (m2 / major-02))
            :ARG2-of (i / interest-01))
      :snt1 (r2 / report-01
            :ARG1 (c3 / contrast-01
                  :ARG1 (d4 / display-01 :polarity -
                        :ARG0 (t / tumor
                              :location (l4 / lung)
                              :ARG2-of (i2 / induce-01
                                    :ARG0 (e7 / enzyme :name (n4 / name :op1 "KRAS")
                                          :ARG1-of (m4 / mutate-01 :value "G12D"))))
                        :ARG1 (e / enzyme :name (n5 / name :op1 "ERK1/2")
                              :ARG1-of (e5 / elevate-01)
                              :ARG3-of (p4 / phosphorylate-01))
                        :mod (r3 / routine))
                  :ARG2 (d5 / display-01
                        :ARG1 (a5 / activate-01
                              :ARG1 (p9 / pathway :name (n8 / name :op1 "MAP" :op2 "kinase")
                                    :ARG1-of (a6 / activate-01
                                          :ARG0 (s / stress-02))
                                    :ARG1-of (m7 / mean-01
                                          :ARG2 (p7 / pathway :name (n7 / name :op1 "SAPK/JNK")))))))
            :ARG1-of (d2 / describe-01
                  :ARG0 (p5 / publication-91
                        :ARG0 (a2 / and
                              :op1 (p2 / person :name (n3 / name :op1 "Lee"))
                              :op2 (p3 / person
                                    :mod (o / other))))
                  :time (d3 / date-entity :year 2002))))

# ::id bel_pmid_1730_3558.25228 ::date 2015-05-06T05:15:30 ::annotator SDL-AMR-09 ::preferred
# ::snt from full text - As shown in Fig. 1A, ERK1/2 in wild-type MEFs is phosphorylated after IGF-1 stimulation with a peak at 5–10 min, after which pERK declined substantially. In b-arrestin1 KO MEFs, on the other hand, ERK1/2 remained essentially inactivated upon IGF-1 stimulation (Fig. 1A).
# ::save-date Sun Jan 17, 2016 ::file bel_pmid_1730_3558_25228.txt
(m / multi-sentence
      :snt2 (c3 / contrast-01
            :ARG2 (r / remain-01
                  :ARG1 (a / activate-01 :polarity -
                        :ARG1 (e2 / enzyme :name (n / name :op1 "ERK1/2"))
                        :time (s / stimulate-01
                              :ARG0 (p3 / protein :name (n2 / name :op1 "IGF-1"))))
                  :manner (e / essential)
                  :ARG1-of (d / describe-01
                        :ARG0 (f / figure :mod "1A"))
                  :location (c / cell :name (n8 / name :op1 "MEF")
                        :mod (p4 / protein :name (n3 / name :op1 "b-arrestin1")
                              :ARG2-of (m4 / mutate-01 :mod "-/-")))))
      :source (t2 / text
            :ARG1-of (f3 / full-09))
      :snt1 (a3 / and
            :op1 (p / phosphorylate-01
                  :ARG1 (e3 / enzyme :name (n7 / name :op1 "ERK1/2"))
                  :ARG1-of (s2 / show-01
                        :ARG0 (f2 / figure :mod "1A"))
                  :location (c2 / cell :name (n4 / name :op1 "MEF")
                        :mod (w / wild-type))
                  :time (a2 / after
                        :op1 (s3 / stimulate-01
                              :ARG0 (p5 / protein :name (n5 / name :op1 "IGF-1"))))
                  :ARG1-of (p6 / peak-01
                        :time (b / between
                              :op1 (t / temporal-quantity :quant 5
                                    :unit (m2 / minute))
                              :op2 (t3 / temporal-quantity :quant 10
                                    :unit (m3 / minute)))))
            :op2 (d2 / decline-01
                  :ARG1 (e4 / enzyme :name (n6 / name :op1 "ERK")
                        :ARG3-of (p2 / phosphorylate-01))
                  :degree (s4 / substantial)
                  :time (a4 / after
                        :op1 p6))))

# ::id bel_pmid_1730_3558.27774 ::date 2015-05-05T12:23:11 ::annotator SDL-AMR-09 ::preferred
# ::snt from full text - Similarly, we find that both b-arrestin1 and 2 are ubiquitinated in IGF-1-stimulated WT MEF cells.
# ::save-date Mon Dec 21, 2015 ::file bel_pmid_1730_3558_27774.txt
(f / find-01
      :ARG0 (w / we)
      :ARG1 (u / ubiquitinate-01
            :ARG1 (a / and
                  :op1 (p / protein :name (n / name :op1 "b-arrestin1"))
                  :op2 (p2 / protein :name (n2 / name :op1 "b-arrestin2")))
            :location (c / cell :name (n3 / name :op1 "MEF")
                  :mod (w2 / wild-type)
                  :ARG1-of (s / stimulate-01
                        :ARG0 (p3 / protein :name (n4 / name :op1 "IGF-1")))))
      :ARG1-of (r / resemble-01)
      :source (t / text
            :ARG1-of (f2 / full-09)))

# ::id bel_pmid_1732_0860.11808 ::date 2015-05-05T12:25:02 ::annotator SDL-AMR-09 ::preferred
# ::snt the preincubation of RAW264.7 cells with a specific PPARalpha agonist, K-111 (2,2-dichloro-12-(4-chlorophenyl)dodecanoic acid). K-111 reduced both the IL-6 production and mRNA expression in RAW264.7 cells
# ::save-date Fri Feb 12, 2016 ::file bel_pmid_1732_0860_11808.txt
(m / multi-sentence
      :snt1 (p4 / preincubate-01
            :ARG1 (c / cell-line :name (n / name :op1 "RAW264.7"))
            :ARG2 (a / agonist :name (n3 / name :op1 "K-111")
                  :mod (p / protein :name (n2 / name :op1 "PPARalpha"))
                  :ARG1-of (s / specific-02)))
      :snt2 (r / reduce-01
            :ARG0 (a2 / agonist :name (n4 / name :op1 "K-111")
                  :ARG1-of (m2 / mean-01
                        :ARG2 (s2 / small-molecule :name (n8 / name :op1 "2,2-dichloro-12-(4-chlorophenyl)dodecanoic" :op2 "acid"))))
            :ARG1 (a3 / and
                  :op1 (p2 / produce-01
                        :ARG1 (p3 / protein :name (n5 / name :op1 "IL-6")))
                  :op2 (e / express-03
                        :ARG1 (n9 / nucleic-acid :name (n6 / name :op1 "mRNA"))
                        :ARG3 (c2 / cell-line :name (n7 / name :op1 "RAW264.7"))))))

# ::id bel_pmid_1732_2026.36370 ::date 2015-05-05T12:35:45 ::annotator SDL-AMR-09 ::preferred
# ::snt Since activation of NF-B in A549 cells is dependent on IKK2, which phosphorylates serines 32 and 36 of IB as a prelude to IB degradation and activation of NF-B (Catley et al., 2005
# ::save-date Sun Jan 17, 2016 ::file bel_pmid_1732_2026_36370.txt
(d / depend-01
      :ARG0 (a / activate-01
            :ARG1 (p / protein :name (n / name :op1 "NF-B")
                  :location (c / cell-line :name (n2 / name :op1 "A549"))))
      :ARG1 (e / enzyme :name (n3 / name :op1 "IKK2")
            :ARG2-of (p3 / phosphorylate-01
                  :ARG1 (a2 / and
                        :op1 (a6 / amino-acid :mod 32 :name (n6 / name :op1 "serine"))
                        :op2 (a7 / amino-acid :mod 36 :name (n7 / name :op1 "serine"))
                        :part-of (e2 / enzyme :name (n4 / name :op1 "IB")))
                  :purpose (p4 / prelude
                        :prep-to (a3 / and
                              :op1 (d2 / degrade-01
                                    :ARG1 e2)
                              :op2 (a4 / activate-01
                                    :ARG1 p)))))
      :ARG1-of (d3 / describe-01
            :ARG0 (p2 / publication-91
                  :ARG0 (a5 / and
                        :op1 (p5 / person :name (n5 / name :op1 "Catley"))
                        :op2 (p6 / person
                              :mod (o / other))))
            :time (d4 / date-entity :year 2005)))

# ::id bel_pmid_1732_2026.38418 ::date 2015-05-05T13:24:14 ::annotator SDL-AMR-09 ::preferred
# ::snt Thus, IL-6 release was substantially increased by both IL-1 and to a lesser extent by TNF. In each case, prior infection with the null adenovirus showed no significant effect, whereas dominant IBN reduced IL-6 release to near-background levels. Likewise, the dominant-negative IKK2 adenovirus prevented IL-6 release
# ::save-date Fri Feb 12, 2016 ::file bel_pmid_1732_2026_38418.txt
(m / multi-sentence
      :snt3 (p / prevent-01
            :ARG0 (a / adenovirus
                  :mod (e2 / enzyme :name (n / name :op1 "IKK2")
                        :ARG0-of (d2 / dominate-01)
                        :ARG2-of (m2 / mutate-01 :mod "-/-")))
            :ARG1 (r / release-01
                  :ARG1 (p2 / protein :name (n10 / name :op1 "IL-6")))
            :manner (l3 / likewise))
      :snt2 (c2 / contrast-01
            :ARG1 (s / show-01
                  :ARG0 (i2 / infect-01
                        :ARG0 (a2 / adenovirus
                              :ARG2-of (m3 / mutate-01 :mod "-/-"))
                        :time (p3 / prior))
                  :ARG1 (a3 / affect-01 :polarity -
                        :ARG1-of (s3 / significant-02))
                  :prep-in (c / case-04
                        :mod (e / each)))
            :ARG2 (r3 / reduce-01
                  :ARG0 (p8 / protein :name (n2 / name :op1 "IκBαΔN")
                        :ARG0-of (d / dominate-01))
                  :ARG1 (r4 / release-01
                        :ARG1 (p4 / protein :name (n3 / name :op1 "IL-6")))
                  :ARG4 (n4 / near
                        :op1 (l / level
                              :mod (b / background)))))
      :snt1 (c3 / cause-01
            :ARG1 (a4 / and
                  :op1 (i / increase-01
                        :ARG0 (p6 / protein :name (n6 / name :op1 "IL-1"))
                        :ARG1 (r5 / release-01
                              :ARG1 (p5 / protein :name (n5 / name :op1 "IL-6")))
                        :ARG2 (s2 / substantial))
                  :op2 (i3 / increase-01
                        :ARG0 (p7 / protein :name (n7 / name :op1 "TNF"))
                        :ARG1 r5
                        :ARG2 (l2 / less
                              :degree (m4 / more))))))

# ::id bel_pmid_1732_2026.39144 ::date 2015-05-06T08:24:53 ::annotator SDL-AMR-09 ::preferred
# ::snt Similar levels of RANTES and MCP-1 release were induced by IL-1 and TNF treatments. However, the induction of IL-6, IL-8, and GMCSF by TNF was 50 to 80% lower than for IL-1, whereas TNF-induced GRO was some 35- to 40-fold lower than that for IL-1. In all instances, preincubation with PS-1145 or ML120B resulted in a significant attenuation of cytokine release (Fig. 6).
# ::save-date Fri Feb 12, 2016 ::file bel_pmid_1732_2026_39144.txt
(m2 / multi-sentence
      :snt1 (i / induce-01
            :ARG0 (a / and
                  :op1 (t / treat-04
                        :ARG2 (p2 / protein :name (n / name :op1 "TNF")))
                  :op2 (t2 / treat-04
                        :ARG2 (p3 / protein :name (n2 / name :op1 "IL-1"))))
            :ARG2 (a2 / and
                  :op1 (l2 / level
                        :quant-of (p14 / protein :name (n3 / name :op1 "RANTES")
                              :ARG1-of r2)
                        :ARG1-of (r3 / resemble-01
                              :ARG2 (l3 / level
                                    :quant-of (p4 / protein :name (n4 / name :op1 "MCP-1")
                                          :ARG1-of (r2 / release-01)))))))
      :snt2 (c / contrast-01
            :ARG1 (l / lower-05
                  :ARG1 (i2 / induce-01
                        :ARG0 (p9 / protein :name (n8 / name :op1 "TNF"))
                        :ARG2 (a3 / and
                              :op1 (p6 / protein :name (n5 / name :op1 "IL-6"))
                              :op2 (p7 / protein :name (n6 / name :op1 "IL-8"))
                              :op3 (p8 / protein :name (n7 / name :op1 "GMCSF"))))
                  :ARG2 (b / between
                        :op1 (p5 / percentage-entity :value 50)
                        :op2 (p / percentage-entity :value 80))
                  :compared-to (i4 / induce-01
                        :ARG0 p9
                        :ARG2 (p10 / protein :name (n9 / name :op1 "IL-1"))))
            :ARG2 (l4 / lower-05
                  :ARG1 (p13 / protein :name (n10 / name :op1 "GRO")
                        :ARG2-of (i3 / induce-01
                              :ARG0 p9))
                  :ARG2 (b2 / between
                        :op1 (p11 / percentage-entity :value 35)
                        :op2 (p12 / percentage-entity :value 40))
                  :compared-to i4)
            :ARG2-of (c2 / contrast-01))
      :snt3 (r / result-01
            :ARG1 (p15 / preincubate-01
                  :ARG2 (o / or
                        :op1 (s3 / small-molecule :name (n11 / name :op1 "PS-1145"))
                        :op2 (s2 / small-molecule :name (n12 / name :op1 "ML120B"))))
            :ARG2 (a5 / attenuate-01
                  :ARG1 (r4 / release-01
                        :ARG1 (c3 / cytokine))
                  :ARG1-of (s / significant-02))
            :prep-in (i6 / instance
                  :mod (a4 / all)))
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod 6)))

# ::id bel_pmid_1733_2487.25838 ::date 2015-05-05T11:48:28 ::annotator SDL-AMR-09 ::preferred
# ::snt Exposure of CD40L enhanced the constitutive production of IL-6 and MCP-1 protein (Figure 4A and 4B).
# ::save-date Tue May 12, 2015 ::file bel_pmid_1733_2487_25838.txt
(e / enhance-01
      :ARG0 (e2 / expose-01
            :ARG1 (p / protein :name (n / name :op1 "CD40L")))
      :ARG1 (p2 / produce-01
            :ARG1 (a / and
                  :op1 (p3 / protein :name (n2 / name :op1 "IL-6"))
                  :op2 (p4 / protein :name (n3 / name :op1 "MCP-1")))
            :mod (c / constitutive))
      :ARG1-of (d / describe-01
            :ARG0 (a2 / and
                  :op1 (f / figure :name (n4 / name :op1 "4A"))
                  :op2 (f2 / figure :name (n5 / name :op1 "4B")))))

# ::id bel_pmid_1739_6137.31084 ::date 2015-05-05T11:58:09 ::annotator SDL-AMR-09 ::preferred
# ::snt Figure 1 TRF2 (myc-tagged) induces telomere dysfunction and cellular senescence in p53 P/P primary mouse embryonic fibroblasts.
# ::save-date Thu Feb 4, 2016 ::file bel_pmid_1739_6137_31084.txt
(i / induce-01
      :ARG0 (p / protein :name (n / name :op1 "TRF2")
            :ARG1-of (t2 / tag-01
                  :ARG2 (p4 / protein :name (n2 / name :op1 "myc"))))
      :ARG2 (a / and
            :op1 (f2 / function-01 :polarity -
                  :ARG0 (t / telomere))
            :op2 (s / senescence
                  :mod (c2 / cell)))
      :location (f3 / fibroblast
            :mod (e / embryo
                  :source (m / mouse
                        :mod (p2 / primary)
                        :mod (p3 / protein :name (n3 / name :op1 "p35")
                              :ARG2-of (m2 / mutate-01 :value "P/P")))))
      :ARG1-of (d2 / describe-01
            :ARG0 (f4 / figure :mod 1)))

# ::id bel_pmid_1739_6137.31086 ::date 2015-05-06T06:38:23 ::annotator SDL-AMR-09 ::preferred
# ::snt overexpression of TRF2 in p53 P/P MEFs resulted in upregulation of p21 (Fig 1D). In addition, reduction of BrdU incorporation, induction of p21 level and increased number of SA-beta-gal-positive senescent cells were also observed when oncogenic H-Ras was overexpressed in p53 P/P MEFs (Fig 1A?C).
# ::save-date Thu Feb 4, 2016 ::file bel_pmid_1739_6137_31086.txt
(m / multi-sentence
      :snt1 (r / result-01
            :ARG1 (o / overexpress-01
                  :ARG1 (p / protein :name (n2 / name :op1 "TRF2"))
                  :location (c / cell :name (n3 / name :op1 "MEF")
                        :mod (p2 / protein :name (n4 / name :op1 "p53")
                              :ARG2-of (m3 / mutate-01 :value "P/P"))))
            :ARG2 (u / upregulate-01
                  :ARG1 (p3 / protein :name (n5 / name :op1 "p21")))
            :ARG1-of (d / describe-01
                  :ARG0 (f / figure :mod "1D")))
      :snt2 (a / and
            :op2 (o2 / observe-01
                  :ARG1 (a2 / and
                        :op1 (r2 / reduce-01
                              :ARG1 (i / incorporate-01
                                    :ARG1 (s2 / small-molecule :name (n / name :op1 "BrdU"))))
                        :op2 (i2 / induce-01
                              :ARG2 (l / level
                                    :degree-of (p6 / protein :name (n9 / name :op1 "p21"))))
                        :op3 (n10 / number
                              :quant-of (c3 / cell
                                    :mod (s / senescent)
                                    :mod (p7 / positive
                                          :mod (e / enzyme :name (n11 / name :op1 "SA-beta-gal"))))
                              :ARG1-of (i3 / increase-01)))
                  :time (o3 / overexpress-01
                        :ARG1 (e2 / enzyme :name (n6 / name :op1 "H-Ras")
                              :mod (o4 / oncogenic))
                        :location (c2 / cell :name (n8 / name :op1 "MEF")
                              :mod (p4 / protein :name (n7 / name :op1 "p53"))))
                  :mod (a3 / also)))
      :ARG1-of (d2 / describe-01
            :ARG0 (a4 / and
                  :op1 (f3 / figure :mod "1A")
                  :op2 (f4 / figure :mod "1B")
                  :op3 (f5 / figure :mod "1C"))))

# ::id bel_pmid_1740_4266.3636 ::date 2015-05-05T11:58:52 ::annotator SDL-AMR-09 ::preferred
# ::snt In addition, i.p. administration of UA increased the levels of IL-1beta secretion and MPO activity in colonic mucosa of ICR mice.
# ::save-date Fri Feb 12, 2016 ::file bel_pmid_1740_4266_3636.txt
(a2 / and
      :op2 (i / increase-01
            :ARG0 (a / administrate-01
                  :ARG1 (s2 / small-molecule :name (n / name :op1 "UA"))
                  :mod (i2 / injection
                        :mod (i3 / intraperitoneal)))
            :ARG1 (a3 / and
                  :op1 (l / level
                        :degree-of (s / secrete-01
                              :ARG1 (p / protein :name (n3 / name :op1 "IL-1beta"))))
                  :op2 (l2 / level
                        :degree-of (a4 / activity-06
                              :ARG0 (e / enzyme :name (n4 / name :op1 "MPO"))
                              :location (m2 / mucosa
                                    :part-of (c / colon)
                                    :source (o / organism :name (n2 / name :op1 "ICR" :op2 "mouse"))))))))

# ::id bel_pmid_1740_4266.3638 ::date 2015-05-05T12:13:49 ::annotator SDL-AMR-09 ::preferred
# ::snt UA increased the protein release of IL-1beta, IL-6, and MIF, but not of TNF-alpha, in dose- and time-dependent manners.
# ::save-date Fri Feb 12, 2016 ::file bel_pmid_1740_4266_3638.txt
(c / contrast-01
      :ARG1 (i2 / increase-01
            :ARG0 (s / small-molecule :name (n / name :op1 "UA"))
            :ARG1 (r / release-01
                  :ARG1 (a / and
                        :op1 (p2 / protein :name (n2 / name :op1 "IL-1beta"))
                        :op2 (p3 / protein :name (n3 / name :op1 "IL-6"))
                        :op3 (p4 / protein :name (n4 / name :op1 "MIF")))))
      :ARG2 (i3 / increase-01 :polarity -
            :ARG0 s
            :ARG1 (r2 / release-01
                  :ARG1 (p5 / protein :name (n5 / name :op1 "TNF-alpha"))))
      :manner (a2 / and
            :op1 (d / depend-01
                  :ARG0 i2
                  :ARG1 (d3 / dose))
            :op2 (d2 / depend-01
                  :ARG0 i2
                  :ARG1 (t / time))))

# ::id bel_pmid_1740_4266.16378 ::date 2015-05-05T12:22:29 ::annotator SDL-AMR-09 ::preferred
# ::snt As shown in Fig. 3, A and B, IL-1B mRNA and proIL-1B protein were detected in a constitutive manner at low levels in nontreated pMphi. Those treated with 4 microM UA for 3 and 6 h were markedly up-regulated, whereas, intriguingly, the levels diminished after 12 h.
# ::save-date Fri Feb 12, 2016 ::file bel_pmid_1740_4266_16378.txt
(m / multi-sentence
      :snt1 (d / detect-01
            :ARG1 (a4 / and
                  :op1 (n6 / nucleic-acid :name (n3 / name :op1 "mRNA")
                        :part (p3 / protein :name (n4 / name :op1 "IL-B1")))
                  :op2 (p2 / protein :name (n2 / name :op1 "proIL-1B"))
                  :quant (l2 / level
                        :ARG1-of (l3 / low-04)))
            :ARG1-of (s / show-01
                  :ARG0 (a3 / and
                        :op1 (f / figure :mod "3A")
                        :op2 (f2 / figure :mod "3B")))
            :manner (c3 / constitutive)
            :location (c4 / cell :name (n5 / name :op1 "pMphi")
                  :ARG1-of (t5 / treat-04 :polarity -)))
      :snt2 (c / contrast-01
            :ARG1 (u / upregulate-01
                  :ARG1 (c5 / cell
                        :ARG1-of (t / treat-04
                              :ARG2 (s2 / small-molecule :name (n / name :op1 "UA")
                                    :quant (c2 / concentration-quantity :quant 4
                                          :unit (m3 / micromolar)))
                              :duration (a / and
                                    :op1 (t2 / temporal-quantity :quant 3
                                          :unit (h / hour))
                                    :op2 (t3 / temporal-quantity :quant 6
                                          :unit (h2 / hour)))))
                  :manner (m4 / marked))
            :ARG2 (d2 / diminish-01
                  :ARG1 (l / level)
                  :time (a2 / after
                        :op1 (t4 / temporal-quantity :quant 12
                              :unit (h3 / hour)))
                  :ARG0-of (i / intrigue-01))))

# ::id bel_pmid_1740_6055.15774 ::date 2015-05-06T04:34:07 ::annotator SDL-AMR-09 ::preferred
# ::snt JAK-2 activation and phosphorylation have been demonstrated in response to exogenous H2O2 in fibroblasts and VSMCs, respectively (27,63).
# ::save-date Wed Oct 28, 2015 ::file bel_pmid_1740_6055_15774.txt
(d2 / demonstrate-01
      :ARG1 (a / and
            :op1 (a2 / activate-01
                  :ARG1 (e2 / enzyme :name (n / name :op1 "JAK-2")))
            :op2 (p / phosphorylate-01
                  :ARG1 e2))
      :ARG2-of (r / respond-01
            :ARG1 (s / small-molecule :name (n2 / name :op1 "H2O2")
                  :mod (e / exogenous)
                  :location (a3 / and
                        :op1 (f / fibroblast)
                        :op2 (c / cell :name (n3 / name :op1 "VSMC")))))
      :ARG1-of (d / describe-01
            :ARG0 (a4 / and
                  :op1 (p3 / publication
                        :ARG1-of (c2 / cite-01
                              :ARG2 27))
                  :op2 (p4 / publication
                        :ARG1-of (c3 / cite-01
                              :ARG2 63)))))

# ::id bel_pmid_1740_6055.15784 ::date 2015-05-06T04:56:50 ::annotator SDL-AMR-09 ::preferred
# ::snt in view of the ability of H2O2 to inhibit protein tyrosine phosphatases (PTPases), such as PTP-1B (68), and SH-2 domain-containing tyrosine phosphatase (SHP)-2 (69),
# ::save-date Wed Oct 28, 2015 ::file bel_pmid_1740_6055_15784.txt
(h / have-purpose-91
      :ARG2 (c / capable-01
            :ARG1 (s / small-molecule :name (n / name :op1 "H2O2"))
            :ARG2 (i / inhibit-01
                  :ARG0 s
                  :ARG1 (a / and
                        :op1 (e / enzyme :name (n2 / name :op1 "protein" :op2 "tyrosine" :op3 "phosphatase")
                              :example (e2 / enzyme :name (n3 / name :op1 "PTP-1B"))
                              :ARG1-of (d2 / describe-01
                                    :ARG0 (p2 / publication
                                          :ARG1-of (c3 / cite-01
                                                :ARG2 68))))
                        :op2 (e3 / enzyme :name (n5 / name :op1 "tyrosine" :op2 "phosphatase")
                              :ARG0-of (c4 / contain-01
                                    :ARG1 (d3 / domain :name (n4 / name :op1 "SH-2")))
                              :ARG1-of (d / describe-01
                                    :ARG0 (p / publication
                                          :ARG1-of (c2 / cite-01
                                                :ARG2 69))))))))

# ::id bel_pmid_1740_6055.34632 ::date 2015-05-06T09:43:44 ::annotator SDL-AMR-09 ::preferred
# ::snt c-Src has also been shown to be activated in response to ROS, including H2O2, in different cell types (19,20, 33,37,50).
# ::save-date Wed Jan 13, 2016 ::file bel_pmid_1740_6055_34632.txt
(s / show-01
      :ARG1 (a2 / activate-01
            :ARG1 (e / enzyme :name (n3 / name :op1 "c-Src"))
            :ARG2-of (r / respond-01
                  :ARG1 (s3 / small-molecule :name (n / name :op1 "ROS")
                        :ARG2-of (i / include-91
                              :ARG1 (s2 / small-molecule :name (n2 / name :op1 "H2O2")))
                        :location (c6 / cell
                              :ARG1-of (t / type-03
                                    :ARG1-of (d2 / differ-02))))))
      :ARG1-of (d / describe-01
            :ARG0 (a / and
                  :op1 (p / publication
                        :ARG1-of (c / cite-01
                              :ARG2 19))
                  :op2 (p3 / publication
                        :ARG1-of (c3 / cite-01
                              :ARG2 20))
                  :op3 (p2 / publication
                        :ARG1-of (c2 / cite-01
                              :ARG2 33))
                  :op4 (p4 / publication
                        :ARG1-of (c4 / cite-01
                              :ARG2 37))
                  :op5 (p5 / publication
                        :ARG1-of (c5 / cite-01
                              :ARG2 50))))
      :mod (a3 / also))

# ::id bel_pmid_1746_8755.1748 ::date 2015-05-05T10:49:52 ::annotator SDL-AMR-09 ::preferred
# ::snt deletion of p38alpha mitogen-activated protein (MAP) kinase in adult mice results in increased proliferation
# ::save-date Tue May 12, 2015 ::file bel_pmid_1746_8755_1748.txt
(r / result-01
      :ARG1 (d / delete-01
            :ARG1 (e / enzyme :name (n / name :op1 "p38" :op2 "alpha" :op3 "mitogen-activated" :op4 "protein" :op5 "kinase"))
            :location (m / mouse
                  :mod (a / adult)))
      :ARG2 (p / proliferate-01
            :ARG1-of (i / increase-01)))

# ::id bel_pmid_1746_8755.1750 ::date 2015-05-05T11:47:19 ::annotator SDL-AMR-09 ::preferred
# ::snt In addition, p38alpha controls self-renewal of the lung stem and progenitor cell population by inhibiting proliferation-inducing signals, most notably epidermal growth factor receptor
# ::save-date Sun Dec 20, 2015 ::file bel_pmid_1746_8755_1750.txt
(a / and
      :op2 (c / control-01
            :ARG0 (e / enzyme :name (n2 / name :op1 "P38" :op2 "Alpha"))
            :ARG1 (r / renew-01
                  :ARG0 (a2 / and
                        :op1 (p2 / population
                              :consist-of (c2 / cell
                                    :mod (s2 / stem
                                          :source (l / lung))))
                        :op2 (p / population
                              :consist-of (c3 / cell
                                    :mod (p4 / progenitor))))
                  :ARG1 a2)
            :ARG2 (i / inhibit-01
                  :ARG0 e
                  :ARG1 (s3 / signal
                        :ARG0-of (i2 / induce-01
                              :ARG2 (p5 / proliferate-01))
                        :ARG2-of (i3 / include-91
                              :ARG1 (e2 / enzyme :name (n / name :op1 "epidermal" :op2 "growth" :op3 "factor" :op4 "receptor"))))
                  :ARG1-of (n3 / notable-04
                        :degree (m / most)))))

# ::id bel_pmid_1746_8755.1754 ::date 2015-05-06T04:57:26 ::annotator SDL-AMR-09 ::preferred
# ::snt We found that p38alpha positively regulates factors such as CCAAT/enhancer-binding protein that are required for lung cell differentiation.
# ::save-date Sun May 17, 2015 ::file bel_pmid_1746_8755_1754.txt
(f / find-01
      :ARG0 (w / we)
      :ARG1 (r / regulate-01
            :ARG0 (e2 / enzyme :name (n / name :op1 "p38" :op2 "alpha"))
            :ARG1 (f2 / factor
                  :example (p / protein :name (n3 / name :op1 "CCAAT/enhancer-binding" :op2 "protein")
                        :ARG1-of (r2 / require-01
                              :ARG0 (d / differentiate-01
                                    :ARG1 (c / cell
                                          :mod (l / lung))))))
            :manner (p2 / positive)))

# ::id bel_pmid_1746_8755.21936 ::date 2015-05-06T05:15:05 ::annotator SDL-AMR-09 ::preferred
# ::snt The reduction in C/EBPa could be accounted for by lower levels of phospho-C/EBPb (Fig. 3a), a known target for p38a (refs. 12,20), which in turn regulates the expression of C/EBPa (ref. 21).
# ::save-date Sun Jan 17, 2016 ::file bel_pmid_1746_8755_21936.txt
(p / possible-01
      :ARG1 (a / account-01
            :ARG1 (r / reduce-01
                  :ARG1 (p2 / protein :name (n / name :op1 "C/EBPa")))
            :ARG2 (l / level
                  :ARG1-of (l2 / low-04
                        :degree (m / more))
                  :quant-of (p8 / protein :name (n3 / name :op1 "C/EBPa")
                        :ARG3-of (p3 / phosphorylate-01)
                        :ARG1-of (t / target-01
                              :ARG0 (p4 / protein :name (n2 / name :op1 "p38a")
                                    :ARG0-of (r2 / regulate-01
                                          :ARG1 (e / express-03
                                                :ARG2 p2)
                                          :manner (i / in-turn)
                                          :ARG1-of (d3 / describe-01
                                                :ARG0 (p7 / publication
                                                      :ARG1-of (c3 / cite-01
                                                            :ARG2 21)))))
                              :ARG1-of (d2 / describe-01
                                    :ARG0 (a2 / and
                                          :op1 (p5 / publication
                                                :ARG1-of (c / cite-01
                                                      :ARG2 12))
                                          :op2 (p6 / publication
                                                :ARG1-of (c2 / cite-01
                                                      :ARG2 20))))
                              :ARG1-of (k / know-01))))
            :ARG1-of (d / describe-01
                  :ARG0 (f / figure :mod "3a"))))

# ::id bel_pmid_1746_8755.22008 ::date 2015-05-06T07:47:34 ::annotator SDL-AMR-09 ::preferred
# ::snt Mnk1 was also activated at lower levels in Mapk14-null mice (Fig. 3b). This p38a-activated protein kinase phosphorylates and stabilizes Sprouty2 (ref. 26), which in turn can negatively regulate tyrosine kinase receptor signaling in lung cells27.
# ::save-date Sun Jan 17, 2016 ::file bel_pmid_1746_8755_22008.txt
(m2 / multi-sentence
      :snt1 (a / activate-01
            :ARG1 (e3 / enzyme :name (n3 / name :op1 "Mnk1"))
            :ARG1-of (d / describe-01
                  :ARG0 (f / figure :mod "3b"))
            :mod (a5 / also)
            :degree (l3 / level
                  :ARG1-of (l / low-04
                        :degree (m / more)))
            :location (m3 / mouse
                  :mod (e2 / enzyme :name (n5 / name :op1 "Mapk14")
                        :ARG2-of (m4 / mutate-01 :mod "-/-")))
            :ARG1-of (d5 / describe-01
                  :ARG0 (f2 / figure :mod "3b")))
      :snt2 (a2 / and
            :op1 (p / phosphorylate-01
                  :ARG1 e
                  :ARG2 k)
            :op2 (s / stabilize-01
                  :ARG0 (k / kinase
                        :mod (p6 / protein)
                        :ARG1-of (a4 / activate-01
                              :ARG0 (p7 / protein :name (n4 / name :op1 "p38a"))))
                  :ARG1 (e / enzyme :name (n / name :op1 "Sprouty2")
                        :ARG2-of (d2 / downregulate-01
                              :ARG1 (s2 / signal-07
                                    :ARG0 (p4 / pathway :name (n2 / name :op1 "tyrosine" :op2 "kinase" :op3 "receptor"))
                                    :location (c2 / cell
                                          :source (l2 / lung)))
                              :mod (i / in-turn)
                              :ARG1-of (p3 / possible-01)
                              :ARG1-of (d3 / describe-01
                                    :ARG0 (p5 / publication
                                          :ARG1-of (c3 / cite-01
                                                :ARG2 27)))))
                  :ARG1-of (d4 / describe-01
                        :ARG0 (p2 / publication
                              :ARG1-of (c / cite-01
                                    :ARG2 26))))))

# ::id bel_pmid_1746_8755.25974 ::date 2015-05-06T09:42:50 ::annotator SDL-AMR-09 ::preferred
# ::snt Our results indicated that the p38a-deficient lungs had hyperproliferative alveolar tissue with loss of differentiation markers. A similar but more marked lung phenotype, with hyperproliferation and defective cell maturation, has been described previously in CCAAT/ enhancer-binding protein (C/EBP)a knockout mice, which die shortly after birth because of respiratory failure16–18.
# ::save-date Thu Feb 4, 2016 ::file bel_pmid_1746_8755_25974.txt
(m / multi-sentence
      :snt1 (i / indicate-01
            :ARG0 (t3 / thing
                  :poss (w / we)
                  :ARG2-of (r / result-01))
            :ARG1 (h / have-03
                  :ARG0 (l / lung
                        :ARG0-of (l2 / lack-01
                              :ARG1 (p8 / protein :name (n / name :op1 "p38a"))))
                  :ARG1 (t / tissue
                        :ARG0-of (p6 / proliferate-01
                              :degree (h2 / hyper))
                        :mod (a / alveolus)
                        :mod (l3 / lose-02
                              :ARG1 (m8 / marker
                                    :ARG1-of (d / differentiate-01))))))
      :ARG1-of (d5 / describe-01
            :ARG0 (p7 / publication
                  :ARG1-of (c4 / cite-01
                        :ARG2 (v / value-interval :op1 16 :op2 18))))
      :snt2 (d2 / describe-01
            :ARG1 (p4 / phenotype
                  :mod (l4 / lung)
                  :mod (p5 / proliferate-01
                        :ARG0 c2
                        :degree (h3 / hyper))
                  :ARG0-of (m5 / maturate-03
                        :ARG1 (c2 / cell)
                        :mod (d3 / defective))
                  :ARG1-of (r2 / resemble-01
                        :ARG1-of (c6 / contrast-01
                              :ARG2 (m3 / marked
                                    :degree (m4 / more)
                                    :domain p4))))
            :time (p3 / previous)
            :location (m6 / mouse
                  :ARG1-of (d4 / die-01
                        :time (a2 / after
                              :op1 (b / bear-02
                                    :ARG1 m6)
                              :ARG1-of (s / short-07))
                        :ARG1-of (c3 / cause-01
                              :ARG0 (f / fail-01
                                    :ARG1 m6
                                    :ARG2 (r3 / respiration))))
                  :mod (p2 / protein :name (n4 / name :op1 "CCAAT/" :op2 "enhancer-binding" :op3 "protein")
                        :ARG2-of (m7 / mutate-01 :mod "+/-")
                        :ARG1-of (m2 / mean-01
                              :ARG2 (p / protein :name (n3 / name :op1 "C/EBP"))))
                  :ARG1-of (k / knock-out-03))))

# ::id bel_pmid_1746_8755.25986 ::date 2015-05-06T12:42:28 ::annotator SDL-AMR-09 ::preferred
# ::snt the amount of Tgfb1 (TGFb) mRNA was higher in p38a-deficient lungs compared with Mapk14D/+ lungs (Fig. 3e). TGFb has been found to be overexpressed in C/EBPa knockout lungs17, so the reduced C/EBPa levels in the Mapk14-null lungs could account for the higher TGFb expression.
# ::save-date Sun Jul 26, 2015 ::file bel_pmid_1746_8755_25986.txt
(m2 / multi-sentence
      :snt1 (h / high-02
            :ARG1 (a / amount
                  :quant-of (n8 / nucleic-acid :name (n4 / name :op1 "mRNA")
                        :part-of (p2 / protein :name (n3 / name :op1 "Tgfb1"))))
            :degree (m / more)
            :location (l / lung
                  :ARG0-of (l2 / lack-01
                        :ARG1 (p / protein :name (n / name :op1 "p38a")))
                  :ARG1-of (c / compare-01
                        :ARG2 (l3 / lung
                              :mod (e / enzyme :name (n2 / name :op1 "Mapk14D")
                                    :ARG2-of (m3 / mutate-01 :mod "-/+")))))
            :ARG1-of (d / describe-01
                  :ARG0 (f / figure :mod "3e")))
      :snt2 (c2 / cause-01
            :ARG0 (f2 / find-01
                  :ARG1 (o / overexpress-01
                        :ARG1 (p3 / protein :name (n5 / name :op1 "Tgfb"))
                        :location (l4 / lung
                              :mod (p5 / protein :name (n6 / name :op1 "C/EBPa")
                                    :ARG2-of (m6 / mutate-01 :mod "-/-")))
                        :ARG1-of (d2 / describe-01
                              :ARG0 (p4 / publication :mod 17))))
            :ARG1 (p6 / possible-01
                  :ARG1 (a2 / account-01
                        :ARG0 (l6 / level
                              :ARG1-of (r2 / reduce-01)
                              :quant-of p5
                              :location (l5 / lung
                                    :mod (e2 / enzyme :name (n7 / name :op1 "Mapk14")
                                          :ARG2-of (m4 / mutate-01 :mod "-/-"))))
                        :ARG1 (e3 / express-03
                              :ARG2 p3
                              :ARG1-of (h2 / high-02
                                    :degree (m5 / more)))))))

# ::id bel_pmid_1746_8755.28766 ::date 2015-05-06T12:58:04 ::annotator SDL-AMR-09 ::preferred
# ::snt Expression of KrasG12V induced also a loss of epithelial markers (as assessed by E-cadherin staining, which was similar in Mapk14D/+ and Mapk14D/D alveoli; Fig. 6c) and an increase in SP-C+ cells (Fig. 6d).
# ::save-date Sun Dec 20, 2015 ::file bel_pmid_1746_8755_28766.txt
(i / induce-01
      :ARG0 (e / express-03
            :ARG2 (e5 / enzyme :name (n / name :op1 "KRAS")
                  :ARG2-of (m / mutate-01 :value "G12V")))
      :ARG2 (a2 / and
            :op1 (l / lose-02
                  :ARG1 (m4 / marker
                        :mod (e2 / epithelium))
                  :ARG1-of (a3 / assess-01
                        :ARG0 (s / stain-01
                              :ARG2 (p / protein :name (n3 / name :op1 "E-cadherin"))
                              :location (a5 / alveoli
                                    :mod (e3 / enzyme :name (n5 / name :op1 "Mapk14D"))
                                    :ARG2-of (m3 / mutate-01 :mod "+/-")
                                    :ARG1-of (r / resemble-01
                                          :ARG2 (a6 / alveoli
                                                :mod (e4 / enzyme :name (n4 / name :op1 "Mapk14D/D"))))))
                        :ARG1-of (d2 / describe-01
                              :ARG0 (f2 / figure :mod "6c"))))
            :op2 (i2 / increase-01
                  :location (c / cell
                        :mod (p2 / protein :name (n2 / name :op1 "SPC+")))))
      :mod (a / also)
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod "6d")))

# ::id bel_pmid_1746_8755.29060 ::date 2015-05-06T13:07:34 ::annotator SDL-AMR-09 ::preferred
# ::snt However, the SP-C+ cells were more numerous in the Mapk14-/- lungs (with almost twice as many as in Mapk14-/+ lungs; Fig. 2c). Notably, immunohistological staining showed reduced levels of the epithelial marker E-cadherin in the alveolar cells (Fig. 2c), indicating defective differentiation of these cells.
# ::save-date Mon Jan 4, 2016 ::file bel_pmid_1746_8755_29060.txt
(m / multi-sentence
      :snt1 (c / contrast-01
            :ARG2 (n / numerous
                  :degree (m2 / more)
                  :domain (c2 / cell
                        :mod (p2 / protein :name (n2 / name :op1 "SPC+")))
                  :location (l / lung
                        :mod (e / enzyme :name (n3 / name :op1 "Mapk14")
                              :ARG2-of (m3 / mutate-01 :mod "-/-"))))
            :ARG1-of (m5 / mean-01
                  :ARG2 (c4 / cell
                        :quant (n6 / numerous
                              :quant (p3 / product-of :op1 2
                                    :op2 (c5 / cell
                                          :location (l3 / lung
                                                :mod (e3 / enzyme :name (n7 / name :op1 "Mapk14")
                                                      :ARG2-of (m6 / mutate-01 :mod "-/+"))))
                                    :mod (a2 / almost))))))
      :snt2 (s / show-01
            :ARG0 (s2 / stain-01
                  :mod (i2 / immunohistology))
            :ARG1 (l2 / level
                  :ARG1-of (r / reduce-01)
                  :quant-of (m7 / marker
                        :mod (e2 / epithelium)
                        :mod (p / protein :name (n5 / name :op1 "E-cadherin")
                              :location c3)))
            :ARG0-of (i / indicate-01
                  :ARG1 (d / differentiate-01
                        :ARG1 (c3 / cell
                              :mod (a / alveolus))
                        :mod (d2 / defective)))
            :ARG1-of (n4 / notable-04)
            :ARG1-of (d3 / describe-01
                  :ARG0 (f / figure :mod "2c"))))

# ::id bel_pmid_1746_8755.29062 ::date 2015-05-06T13:09:51 ::annotator SDL-AMR-09 ::preferred
# ::snt Notably, we found that p38a-deficient lungs contained lower levels of C/EBPa and HNF3b, another transcription factor involved in lung differentiation whose expression is controlled by C/EBPa (ref. 19) (Fig. 3a and Supplementary Fig. 1a online).
# ::save-date Sun Jan 17, 2016 ::file bel_pmid_1746_8755_29062.txt
(f / find-01
      :ARG0 (w / we)
      :ARG1 (c / contain-01
            :ARG0 (l2 / lung
                  :ARG0-of (l3 / lack-01
                        :ARG1 (p / protein :name (n2 / name :op1 "p38a"))))
            :ARG1 (a / and
                  :op1 (l4 / level
                        :quant-of (p2 / protein :name (n3 / name :op1 "C/EBPa")))
                  :op2 (l5 / level
                        :quant-of (p3 / protein :name (n4 / name :op1 "HNF3b")
                              :domain (p4 / protein :name (n5 / name :op1 "transcription" :op2 "factor")
                                    :ARG1-of (i / involve-01
                                          :ARG2 (d / differentiate-01
                                                :ARG1 (l6 / lung)))
                                    :ARG2-of (e / express-03
                                          :ARG1-of (c2 / control-01
                                                :ARG0 p2))
                                    :mod (a2 / another))))
                  :ARG1-of (l / low-04
                        :degree (m / more))))
      :ARG1-of (n / notable-04)
      :ARG1-of (d2 / describe-01
            :ARG0 (p5 / publication
                  :ARG1-of (c3 / cite-01
                        :ARG2 19)))
      :ARG1-of (d3 / describe-01
            :ARG0 (a3 / and
                  :op1 (f2 / figure :mod "3a")
                  :op2 (f3 / figure :mod "1a"
                        :ARG2-of (s / supplement-01)
                        :medium (o / online)))))

# ::id bel_pmid_1746_8755.29066 ::date 2015-05-06T10:17:52 ::annotator SDL-AMR-09 ::preferred
# ::snt Furthermore, the higher number of AT2 cells correlated with an almost fivefold increase in Ki67+ cells in Mapk14-/- lungs compared with the number of Ki67+ cells in their heterozygous Mapk14D/+ counterparts (Fig. 2d).
# ::save-date Sun Jan 3, 2016 ::file bel_pmid_1746_8755_29066.txt
(a / and
      :op2 (c / correlate-01
            :ARG1 (n / number
                  :quant-of (c3 / cell :name (n3 / name :op1 "AT2"))
                  :ARG1-of (h / high-02
                        :degree (m / more)))
            :ARG2 (i / increase-01
                  :ARG1 (c4 / cell :name (n4 / name :op1 "Ki67+")
                        :ARG2-of (m2 / mutate-01 :mod "+/-")
                        :location (l / lung
                              :mod (e / enzyme :name (n5 / name :op1 "Mapk14")
                                    :ARG2-of (m3 / mutate-01 :mod "-/-"))))
                  :ARG2 (a2 / almost
                        :op1 (p / product-of :op1 5))
                  :ARG1-of (c2 / compare-01
                        :ARG2 (n2 / number
                              :quant-of (c5 / cell :name (n6 / name :op1 "Ki67+")
                                    :location (l2 / lung
                                          :mod (e2 / enzyme :name (n7 / name :op1 "Mapk14D"))
                                          :mod (h2 / heterozygous)
                                          :ARG2-of (m4 / mutate-01 :mod "-/+")))))))
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod "2d")))

# ::id bel_pmid_1746_8755.29068 ::date 2015-05-06T06:56:12 ::annotator SDL-AMR-09 ::preferred
# ::snt We also detected a reduction in STAT3 protein in Mapk14D/D lungs (Fig. 3a) that correlated with the reduction in Il6 mRNA (Fig. 3).
# ::save-date Tue May 12, 2015 ::file bel_pmid_1746_8755_29068.txt
(d / detect-01
      :ARG0 (w / we)
      :ARG1 (r / reduce-01
            :ARG1 (p / protein :name (n / name :op1 "STAT3"))
            :location (l / lung
                  :mod (p2 / pathway :name (n2 / name :op1 "Mapk14D/D")))
            :ARG1-of (c / correlate-01
                  :ARG2 (r2 / reduce-01
                        :ARG1 (n5 / nucleic-acid :name (n3 / name :op1 "mRNA")
                              :part (p3 / protein :name (n4 / name :op1 "IL-6")))))
            :ARG1-of (d2 / describe-01
                  :ARG0 (f / figure :mod "3a")))
      :mod (a / also)
      :ARG1-of (d3 / describe-01
            :ARG0 (f2 / figure :mod 3)))

# ::id bel_pmid_1746_8755.29072 ::date 2015-05-06T07:27:06 ::annotator SDL-AMR-09 ::preferred
# ::snt three times as much Egfr mRNA was present in Mapk14D/D lungs (Fig. 3d) compared with Mapk14D/+ lungs, suggesting that EGFR expression was transcriptionally enhanced in the absence of p38a.
# ::save-date Sun Jan 17, 2016 ::file bel_pmid_1746_8755_29072.txt
(p / present-02
      :ARG1 (n6 / nucleic-acid :name (n7 / name :op1 "mRNA")
            :quant (p3 / product-of :quant 3)
            :ARG0-of (e6 / encode-01
                  :ARG1 (e5 / enzyme :name (n4 / name :op1 "Egfr"))))
      :ARG2 (l / lung
            :mod (e7 / enzyme :name (n3 / name :op1 "Mapk14D/D")))
      :ARG1-of (c / compare-01
            :ARG2 (l2 / lung
                  :mod (e8 / enzyme :name (n5 / name :op1 "Mapk14D")
                        :ARG2-of (m / mutate-01 :mod "+/+"))))
      :ARG0-of (s / suggest-01
            :ARG1 (e / enhance-01
                  :ARG1 (e2 / express-03
                        :ARG2 (e3 / enzyme :name (n / name :op1 "EGFR")))
                  :manner (t / transcribe-01)
                  :condition (a / absent-01
                        :ARG1 (p2 / protein :name (n2 / name :op1 "p38a")))))
      :mod e3
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod "3d")))

# ::id bel_pmid_1746_8755.29082 ::date 2015-05-06T08:49:21 ::annotator SDL-AMR-09 ::preferred
# ::snt Notably, EGFR transcription is regulated by AP-1 (ref. 28), and we observed higher levels of phospho-c-Jun, one of the AP-1 components, in the p38a-deficient lungs (Fig. 3c), suggesting that p38a downregulation might activate AP-1.
# ::save-date Sun Jan 17, 2016 ::file bel_pmid_1746_8755_29082.txt
(a / and
      :op1 (r / regulate-01
            :ARG0 (p3 / protein :name (n3 / name :op1 "AP-1"))
            :ARG1 (t / transcribe-01
                  :ARG1 (e / enzyme :name (n / name :op1 "EGFR")))
            :ARG1-of (d / describe-01
                  :ARG0 (p2 / publication
                        :ARG1-of (c / cite-01
                              :ARG2 28)))
            :ARG1-of (n2 / notable-04))
      :op2 (o / observe-01
            :ARG0 (w / we)
            :ARG1 (l / level
                  :ARG1-of (h / high-02
                        :degree (m / more))
                  :quant-of (p / protein :name (n4 / name :op1 "c-Jun")
                        :ARG1-of (i / include-91
                              :ARG2 (c2 / component
                                    :poss p3))
                        :ARG1-of (p4 / phosphorylate-01))
                  :location (l2 / lung
                        :ARG0-of (l3 / lack-01
                              :ARG1 (p6 / protein :name (n5 / name :op1 "p38a")))))
            :ARG1-of (d2 / describe-01
                  :ARG0 (f / figure :mod "3c")))
      :ARG0-of (s / suggest-01
            :ARG1 (p5 / possible-01
                  :ARG1 (a2 / activate-01
                        :ARG0 (d3 / downregulate-01
                              :ARG1 p6)
                        :ARG1 p3))))

# ::id bel_pmid_1746_8757.6426 ::date 2015-05-04T08:07:32 ::annotator SDL-AMR-09 ::preferred
# ::snt Furthermore, inactivation of JNK or c-Jun suppressed the increased proliferation of Mapk14-deficient hepatocytes and tumor cells.
# ::save-date Mon May 4, 2015 ::file bel_pmid_1746_8757_6426.txt
(a / and
      :op2 (s / suppress-01
            :ARG0 (a2 / activate-01 :polarity -
                  :ARG1 (o / or
                        :op1 (e / enzyme :name (n / name :op1 "JNK"))
                        :op2 (p / protein :name (n2 / name :op1 "c-Jun"))))
            :ARG1 (p2 / proliferate-01
                  :ARG0 (a3 / and
                        :op1 (c / cell :name (n3 / name :op1 "hepatocyte")
                              :ARG0-of (l / lack-01
                                    :ARG1 (e2 / enzyme :name (n4 / name :op1 "Mapk14"))))
                        :op2 (c2 / cell
                              :mod (t / tumor)))
                  :ARG1-of (i / increase-01))))

# ::id bel_pmid_1750_7094.5814 ::date 2015-05-04T11:03:32 ::annotator SDL-AMR-09 ::preferred
# ::snt Upon stimulation with TLR ligands, p105 is phosphorylated by I kappa B kinase (IKK) complex and partially degraded, which releases TPL2. The free TPL2 is active and stimulates the ERK pathway via MEK1/2.
# ::save-date Mon Jan 4, 2016 ::file bel_pmid_1750_7094_5814.txt
(m / multi-sentence
      :snt1 (a / and
            :op1 (p / phosphorylate-01
                  :ARG1 (p2 / protein :name (n / name :op1 "p105"))
                  :ARG2 (e4 / enzyme :name (n2 / name :op1 "IκB" :op2 "kinase")))
            :op2 (d / degrade-01
                  :ARG1 p2
                  :degree (p3 / part))
            :ARG0-of (r / release-01
                  :ARG1 (e / enzyme :name (n3 / name :op1 "TPL2")))
            :time (s / stimulate-01
                  :ARG2 (l / ligand :name (n4 / name :op1 "TLR"))))
      :snt2 (a2 / and
            :op1 (a3 / activity-06
                  :ARG0 (e2 / enzyme :name (n5 / name :op1 "TPL2")
                        :ARG1-of (f / free-04)))
            :op2 (s2 / stimulate-01
                  :ARG0 e2
                  :ARG1 (p4 / pathway :name (n6 / name :op1 "ERK"))
                  :ARG2 (e3 / enzyme :name (n7 / name :op1 "MEK1/2")))))

# ::id bel_pmid_1751_1588.20428 ::date 2015-05-04T11:34:52 ::annotator SDL-AMR-09 ::preferred
# ::snt Angiopoietin-1 stimulates association of SHP-2 to the phosphorylated Tie-2 receptor (47), which in turn inhibits PI3 kinase-dependent signaling pathways leading to EC migration.
# ::save-date Sun Jan 17, 2016 ::file bel_pmid_1751_1588_20428.txt
(s / stimulate-01
      :ARG0 (p / protein :name (n / name :op1 "angiopoietin-1"))
      :ARG1 (a / associate-01
            :ARG0 p
            :ARG1 (p5 / protein :name (n2 / name :op1 "SHP-2"))
            :ARG2 (r / receptor :name (n3 / name :op1 "Tie-2")
                  :ARG1-of (p2 / phosphorylate-01))
            :ARG0-of (i / inhibit-01
                  :ARG1 (p3 / pathway
                        :ARG0-of (s2 / signal-07)
                        :ARG0-of (d / depend-01
                              :ARG1 (k / kinase :name (n4 / name :op1 "PI3"))))
                  :ARG0-of (l / lead-03
                        :ARG2 (m / migrate-01
                              :ARG0 (c / cell :name (n5 / name :op1 "EC"))))
                  :mod (i2 / in-turn)))
      :ARG1-of (d2 / describe-01
            :ARG0 (p4 / publication
                  :ARG1-of (c2 / cite-01
                        :ARG2 47))))

# ::id bel_pmid_1751_1588.36510 ::date 2015-05-04T12:09:40 ::annotator SDL-AMR-09 ::preferred
# ::snt Overexpression of dominant negative N17Rac1 significantly inhibits VEGF-induced ROS production that is involved in VEGFR2 activation, EC migration, and proliferation (100).
# ::save-date Fri Feb 5, 2016 ::file bel_pmid_1751_1588_36510.txt
(i / inhibit-01
      :ARG0 (o / overexpress-01
            :ARG1 (e / enzyme :name (n / name :op1 "N17Rac1")
                  :ARG0-of (d / dominate-01)
                  :ARG2-of (m / mutate-01 :mod "-/-")))
      :ARG1 (p / produce-01
            :ARG1 (s2 / small-molecule :name (n3 / name :op1 "ROS"))
            :ARG2-of (i2 / induce-01
                  :ARG0 (p2 / protein :name (n4 / name :op1 "VEGF")))
            :ARG1-of (i3 / involve-01
                  :ARG2 (a / and
                        :op1 (a2 / activate-01
                              :ARG1 (p3 / protein :name (n5 / name :op1 "VEGFR2")))
                        :op2 (a3 / and
                              :op1 (m2 / migrate-01
                                    :ARG0 (c / cell :name (n6 / name :op1 "EC")))
                              :op2 (p4 / proliferate-01
                                    :ARG0 c)))))
      :ARG1-of (s / significant-02)
      :ARG1-of (d2 / describe-01
            :ARG0 (p5 / publication
                  :ARG1-of (c2 / cite-01
                        :ARG2 100))))

# ::id bel_pmid_1751_1588.36636 ::date 2015-05-04T12:37:52 ::annotator SDL-AMR-09 ::preferred
# ::snt VEGFR2 forms a complex with VE-cadherin, -catenin, and PI3 kinase that is required for phosphorylation of Akt, which plays an important role in EC survival (15) and migration (27, 28, 80).
# ::save-date Mon Jan 4, 2016 ::file bel_pmid_1751_1588_36636.txt
(f / form-01
      :ARG0 (p / protein :name (n / name :op1 "VEGFR2"))
      :ARG1 (m / macro-molecular-complex
            :part p
            :part (p2 / protein :name (n2 / name :op1 "VE-cadherin"))
            :part (p3 / protein :name (n3 / name :op1 "VE-catenin"))
            :part (k / kinase :name (n4 / name :op1 "PI3"))
            :ARG1-of (r / require-01
                  :ARG0 (p4 / phosphorylate-01
                        :ARG2 (e / enzyme :name (n5 / name :op1 "Akt"))
                        :ARG0-of (p5 / play-08
                              :ARG1 (a / and
                                    :op1 (s / survive-02
                                          :ARG0 (c / cell :name (n6 / name :op1 "EC"))
                                          :ARG1-of (d / describe-01
                                                :ARG0 (p6 / publication
                                                      :ARG1-of (c2 / cite-01
                                                            :ARG2 15))))
                                    :op2 (m2 / migrate-01
                                          :ARG0 c
                                          :ARG1-of (d2 / describe-01
                                                :ARG0 (p7 / publication
                                                      :ARG1-of (c3 / cite-01
                                                            :ARG2 (a2 / and :op1 27 :op2 28 :op3 80)))))
                                    :mod (i / important)))))))

# ::id bel_pmid_1751_3865.31240 ::date 2015-05-04T13:10:29 ::annotator SDL-AMR-09 ::preferred
# ::snt FIGURE 9. TGF-beta1 induces snail-1 in hepatocytes in EMT state and lack of evidence for Akt/Erk1/2 activation
# ::save-date Sun Jan 17, 2016 ::file bel_pmid_1751_3865_31240.txt
(d / describe-01
      :ARG0 (f / figure :mod 9)
      :ARG1 (i / induce-01
            :ARG0 (p / protein :name (n / name :op1 "TGF-β1"))
            :ARG2 (p2 / protein :name (n2 / name :op1 "snail-1"))
            :location (c / cell :name (n3 / name :op1 "hepatocyte")
                  :condition (a / and
                        :op1 (e2 / event :name (n4 / name :op1 "epithelial−mesenchymal" :op2 "transition"))
                        :op2 (l / lack-01
                              :ARG1 (e / evidence-01
                                    :ARG1 (a2 / activate-01
                                          :ARG1 (p3 / pathway :name (n5 / name :op1 "Akt/Erk1/2")))))))))

# ::id bel_pmid_1751_3865.39040 ::date 2015-05-04T13:46:20 ::annotator SDL-AMR-09 ::preferred
# ::snt FIGURE 11. TGF-beta1 induces activation of Smad2/3 pathway in AML12 cell line
# ::save-date Sun Dec 20, 2015 ::file bel_pmid_1751_3865_39040.txt
(d / describe-01
      :ARG0 (f / figure :mod 11)
      :ARG1 (i / induce-01
            :ARG0 (p / protein :name (n / name :op1 "TGF-β1"))
            :ARG2 (a / activate-01
                  :ARG0 p
                  :ARG1 (p2 / pathway :name (n2 / name :op1 "Smad2/3"))
                  :location (c / cell-line :name (n3 / name :op1 "AML12")))))

# ::id bel_pmid_1764_3885.30204 ::date 2015-05-04T13:49:47 ::annotator SDL-AMR-09 ::preferred
# ::snt Aortas from COX-2?/? mice on atherogenic diet after 3 weeks had significantly larger areas of neutral lipid content as measured by Oil Red O staining (Fig. 1A).
# ::save-date Fri Feb 12, 2016 ::file bel_pmid_1764_3885_30204.txt
(h / have-03
      :ARG0 (a / aorta
            :source (m / mouse
                  :mod (e / enzyme :name (n / name :op1 "COX-2")
                        :ARG2-of (m2 / mutate-01 :mod "-/-"))
                  :condition (d / diet
                        :mod (a2 / atherogenic))))
      :ARG1 (a3 / area
            :quant (l / large
                  :degree (m3 / more)
                  :ARG1-of (s / significant-02))
            :ARG0-of (c / contain-01
                  :ARG1 (l2 / lipid
                        :ARG0-of (n2 / neutral-02)))
            :ARG1-of (m4 / measure-01
                  :ARG2 (s2 / stain-01
                        :ARG2 (s3 / small-molecule :name (n3 / name :op1 "Oil" :op2 "Red" :op3 "O")))))
      :time (a4 / after
            :op1 (t / temporal-quantity :quant 3
                  :unit (w / week)))
      :ARG1-of (d2 / describe-01
            :ARG0 (f / figure :mod "1A")))

# ::id bel_pmid_1764_3885.30206 ::date 2015-05-05T06:50:17 ::annotator SDL-AMR-09 ::preferred
# ::snt Serum TXB2 is significantly increased in COX-2?/? mice on chow compared to wild-type littermates (Fig. 4A).
# ::save-date Fri Feb 12, 2016 ::file bel_pmid_1764_3885_30206.txt
(i / increase-01
      :ARG1 (s3 / small-molecule :name (n / name :op1 "TXB2")
            :mod (s / serum))
      :ARG2 (s2 / significant-02)
      :location (m2 / mouse
            :mod (e / enzyme :name (n2 / name :op1 "COX-2")
                  :ARG2-of (m3 / mutate-01 :mod "-/-"))
            :mod (d / diet
                  :mod (c / chow)))
      :compared-to (l / littermate
            :mod (w / wild-type))
      :ARG1-of (d2 / describe-01
            :ARG0 (f / figure :mod "4A")))

# ::id bel_pmid_1764_3885.30216 ::date 2015-05-05T07:17:24 ::annotator SDL-AMR-09 ::preferred
# ::snt Interestingly, COX-2?/? mice on atherogenic diet showed more systemic inflammation with higher levels of TNF (Fig. 5B) and IL-6 (Fig. 5D) than wild-type controls. Furthermore, IL-12 was significantly increased by atherogenic diet in wild-type controls, while COX-2 depletion completely abolished this induction (Fig. 5E).
# ::save-date Fri Dec 18, 2015 ::file bel_pmid_1764_3885_30216.txt
(m / multi-sentence
      :snt1 (s / show-01
            :ARG0 (m2 / mouse
                  :mod (e / enzyme :name (n / name :op1 "COX-2")
                        :ARG2-of (m3 / mutate-01 :mod "-/-"))
                  :condition (d / diet
                        :mod (a / atherogenic)))
            :ARG1 (i / inflame-01
                  :mod (s2 / systemic
                        :degree (m4 / more))
                  :mod (l / level
                        :quant-of (a2 / and
                              :op1 (p / protein :name (n2 / name :op1 "TNF")
                                    :ARG1-of (d2 / describe-01
                                          :ARG0 (f / figure :mod "5B")))
                              :op2 (p2 / protein :name (n3 / name :op1 "IL-6")
                                    :ARG1-of (d3 / describe-01
                                          :ARG0 (f2 / figure :mod "5D"))))
                        :ARG1-of (h / high-02
                              :degree (m5 / more)
                              :compared-to (c / control-01
                                    :mod (w / wild-type)))))
            :manner (i2 / interesting))
      :snt2 (a3 / and
            :op2 (c2 / contrast-01
                  :ARG1 (i3 / increase-01
                        :ARG0 (d4 / diet
                              :mod (a4 / atherogenic))
                        :ARG1 (p3 / protein :name (n4 / name :op1 "IL-12"))
                        :ARG2 (s3 / significant-02)
                        :location (c3 / control-01
                              :mod (w2 / wild-type)))
                  :ARG2 (a5 / abolish-01
                        :ARG0 (d5 / deplete-01
                              :ARG1 (e2 / enzyme :name (n5 / name :op1 "COX-2")))
                        :ARG1 (i4 / induce-01
                              :mod (t / this))
                        :ARG1-of (c4 / complete-02)))
            :ARG1-of (d6 / describe-01
                  :ARG0 (f3 / figure :mod "5E"))))

# ::id bel_pmid_1769_2569.37970 ::date 2015-05-05T08:26:30 ::annotator SDL-AMR-09 ::preferred
# ::snt Table 1. Production of pro- and anti-angiogenic mediators by DCs Pro-angiogenic mediators: VEGF, FGF2, TNF-a, IL-6, TGF-b, CXCL8, CXCL5, CXCL1, 2, 3, CCL2, GM-CSF, ET-1, OPN,  Anti-angiogenic mediators: IL-12, IL-18, IL-10, TSP-1, PTX3, IFN-a/b, CXCL9, CXCL10, CXCL13, CCL21
# ::save-date Tue May 12, 2015 ::file bel_pmid_1769_2569_37970.txt
(d / describe-01
      :ARG0 (t / table :mod 1)
      :ARG1 (p / produce-01
            :ARG0 (c / cell :name (n / name :op1 "DC"))
            :ARG1 (a / and
                  :op1 (m / molecular-physical-entity
                        :ARG0-of (m2 / mediate-01)
                        :ARG0-of (f / favor-01
                              :ARG1 (a2 / angiogenesis))
                        :ARG1-of (m3 / mean-01
                              :ARG2 (a3 / and
                                    :op1 (p2 / protein :name (n2 / name :op1 "VEGF"))
                                    :op2 (p3 / protein :name (n3 / name :op1 "FGF2"))
                                    :op3 (p4 / protein :name (n4 / name :op1 "TNF-α"))
                                    :op4 (p5 / protein :name (n5 / name :op1 "IL-6"))
                                    :op5 (p6 / protein :name (n6 / name :op1 "TGF-β"))
                                    :op6 (p7 / protein :name (n7 / name :op1 "CXCL8"))
                                    :op7 (p8 / protein :name (n8 / name :op1 "CXCL5"))
                                    :op8 (p9 / protein :name (n9 / name :op1 "CXCL1"))
                                    :op9 (p10 / protein :name (n10 / name :op1 "CXCL2"))
                                    :op10 (p11 / protein :name (n11 / name :op1 "CXCL3"))
                                    :op11 (p12 / protein :name (n12 / name :op1 "CCL2"))
                                    :op12 (p13 / protein :name (n13 / name :op1 "GM-CSF"))
                                    :op13 (p14 / protein :name (n14 / name :op1 "ET-1"))
                                    :op14 (p15 / protein :name (n15 / name :op1 "OPN")))))
                  :op2 (m4 / molecular-physical-entity
                        :ARG0-of m2
                        :ARG0-of (c2 / counter-01
                              :ARG1 a2)
                        :ARG1-of (m5 / mean-01
                              :ARG2 (a4 / and
                                    :op1 (p16 / protein :name (n16 / name :op1 "IL-12"))
                                    :op2 (p17 / protein :name (n17 / name :op1 "IL-18"))
                                    :op3 (p18 / protein :name (n18 / name :op1 "IL-10"))
                                    :op4 (p19 / protein :name (n19 / name :op1 "TSP-1"))
                                    :op5 (p20 / protein :name (n20 / name :op1 "PTX3"))
                                    :op6 (p21 / protein :name (n21 / name :op1 "IFN-α/β"))
                                    :op7 (p22 / protein :name (n22 / name :op1 "CXCL9"))
                                    :op8 (p23 / protein :name (n23 / name :op1 "CXCL10"))
                                    :op9 (p24 / protein :name (n24 / name :op1 "CXCL13"))
                                    :op10 (p25 / protein :name (n25 / name :op1 "CCL21"))))))))

# ::id bel_pmid_1770_9751.28596 ::date 2015-05-05T09:44:50 ::annotator SDL-AMR-09 ::preferred
# ::snt Flow cytometry confirmed that follicular B cells present in Itpkb ?/? and Itpkb ?/? E?-2–22 BCL-2 mice expressed a higher level of Bim protein.
# ::save-date Mon Jan 4, 2016 ::file bel_pmid_1770_9751_28596.txt
(c / confirm-01
      :ARG0 (c3 / cytometry
            :mod (f2 / flow))
      :ARG1 (e / express-03
            :ARG2 (l / level
                  :quant-of (p / protein :name (n2 / name :op1 "Bim"))
                  :ARG1-of (h / high-02
                        :degree (m / more)))
            :ARG3 (c2 / cell :name (n3 / name :op1 "B")
                  :ARG1-of (p3 / present-02
                        :ARG2 (a / and
                              :op1 (m2 / mouse
                                    :mod (e2 / enzyme :name (n4 / name :op1 "Itpkb")
                                          :ARG2-of (m3 / mutate-01 :mod "-/-")))
                              :op2 (m4 / mouse
                                    :mod (p2 / protein :name (n5 / name :op1 "BCL-2")
                                          :mod (d / dna-sequence :name (n6 / name :op1 "Eμ-2–22")
                                                :mod e2)))))
                  :location (f / follicle))))

# ::id bel_pmid_1770_9751.28598 ::date 2015-05-05T10:24:02 ::annotator SDL-AMR-09 ::preferred
# ::snt Erk1 and Erk2 were found to be much less phosphorylated in Itpkb ?/? E?-2?22-BCL-2 B cells than in control B cells after BCR activation (Fig. 3 b).
# ::save-date Tue Jun 23, 2015 ::file bel_pmid_1770_9751_28598.txt
(f / find-01
      :ARG1 (p / phosphorylate-01
            :ARG1 (a / and
                  :op1 (e / enzyme :name (n / name :op1 "Erk1"))
                  :op2 (e2 / enzyme :name (n2 / name :op1 "Erk2")))
            :quant (l / less
                  :degree (m / much))
            :location (c / cell :name (n3 / name :op1 "B")
                  :mod (p2 / protein :name (n6 / name :op1 "BCL-2")
                        :mod (d / dna-sequence :name (n4 / name :op1 "Eμ-2–22")
                              :mod (e3 / enzyme :name (n5 / name :op1 "Itpkb")
                                    :ARG2-of (m2 / mutate-01 :mod "-/-"))))
                  :compared-to (c2 / cell :name (n7 / name :op1 "B")
                        :mod (c3 / control))))
      :time (a2 / after
            :op1 (a3 / activate-01
                  :ARG1 (p3 / protein :name (n8 / name :op1 "BCR"))))
      :ARG1-of (d2 / describe-01
            :ARG0 (f2 / figure :mod "3b")))

# ::id bel_pmid_1770_9751.28600 ::date 2015-05-05T10:38:48 ::annotator SDL-AMR-09 ::preferred
# ::snt Quantitative real-time RT-PCR analysis revealed a slight, but very significant, increase in Bim messenger RNA level in splenic resting follicular B cells persisting in Itpkb ?/? mice.
# ::save-date Tue May 12, 2015 ::file bel_pmid_1770_9751_28600.txt
(r / reveal-01
      :ARG0 (a / analyze-01
            :mod (t / thing :name (n / name :op1 "RT-PCR"))
            :mod (r2 / real-time)
            :mod (q / quantitative))
      :ARG1 (i / increase-01
            :ARG1 (l / level
                  :quant-of (n6 / nucleic-acid :name (n2 / name :op1 "messenger" :op2 "RNA")
                        :ARG1-of (e / express-03
                              :ARG2 (p / protein :name (n3 / name :op1 "Bim")))))
            :ARG2 (s / slight
                  :ARG1-of (c / contrast-01
                        :ARG2 (s2 / significant-02
                              :degree (v / very))))
            :location (c2 / cell :name (n4 / name :op1 "B")
                  :location (f / follicle)
                  :ARG1-of (r4 / rest-01
                        :location (s3 / spleen))
                  :ARG1-of (p2 / persist-01
                        :location (m / mouse
                              :mod (e2 / enzyme :name (n5 / name :op1 "Itpkb")
                                    :ARG2-of (m2 / mutate-01 :mod "-/-")))))))

# ::id bel_pmid_1780_4750.41494 ::date 2015-05-05T11:23:50 ::annotator SDL-AMR-09 ::preferred
# ::snt The forkhead transcription factor Foxp3 is highly expressed in CD4+CD25+ regulatory T cells (Treg) and was recently identified as a key player in mediating their inhibitory functions.
# ::save-date Mon Jan 4, 2016 ::file bel_pmid_1780_4750_41494.txt
(a / and
      :op1 (e / express-03
            :ARG2 (p / protein :name (n / name :op1 "forkhead" :op2 "transcription" :op3 "factor")
                  :ARG1-of (m / mean-01
                        :ARG2 (p2 / protein :name (n2 / name :op1 "Foxp3"))))
            :ARG3 (c / cell :name (n3 / name :op1 "T")
                  :mod (p3 / protein :name (n4 / name :op1 "CD4"))
                  :mod (p4 / protein :name (n5 / name :op1 "CD25"))
                  :ARG0-of (r / regulate-01))
            :ARG2-of (h / high-02))
      :op2 (i / identify-01
            :ARG1 p
            :ARG2 (m2 / molecular-physical-entity
                  :ARG0-of (p5 / play-08)
                  :ARG1-of (k / key-02
                        :ARG2 (m3 / mediate-01
                              :ARG0 p
                              :ARG1 (f / function-01
                                    :ARG0 c
                                    :ARG1 (i2 / inhibit-01)))))
            :time (r2 / recent)))

# ::id bel_pmid_1780_4750.41496 ::date 2015-05-05T11:47:26 ::annotator SDL-AMR-09 ::preferred
# ::snt Foxp3 expression was induced by transforming growth factor-(32 (TGF-(32), but not TGF-(31 stimulation in these cells, and was partially suppressed following antibody-mediated neutralization of TGF-(32.
# ::save-date Sun Dec 20, 2015 ::file bel_pmid_1780_4750_41496.txt
(a / and
      :op1 (c / contrast-01
            :ARG1 (i / induce-01
                  :ARG0 (s / stimulate-01
                        :ARG1 (p / protein :name (n / name :op1 "transforming" :op2 "growth" :op3 "factor-β2")))
                  :ARG2 (e / express-03
                        :ARG2 (p2 / protein :name (n2 / name :op1 "Foxp3"))))
            :ARG2 (i2 / induce-01 :polarity -
                  :ARG0 (s2 / stimulate-01
                        :ARG1 (p3 / protein :name (n3 / name :op1 "TGF-β1"))))
            :location (c2 / cell
                  :mod (t / this)))
      :op2 (s3 / suppress-01
            :ARG1 e
            :degree (p4 / part)
            :ARG1-of (f / follow-01
                  :ARG2 (n4 / neutralize-01
                        :ARG1 p
                        :ARG1-of (m / mediate-01
                              :ARG0 (a2 / antibody))))))

# ::id bel_pmid_1780_4750.41498 ::date 2015-05-05T11:58:56 ::annotator SDL-AMR-09 ::preferred
# ::snt Down-regulation of Foxp3 with small interfering RNA (siRNA) in pancreatic carcinoma cells resulted in the up-regulation of interleukin 6 (IL-6) and IL-8 expression, providing evidence for a negative transcriptional activity of Foxp3 also in these epithelial cells.
# ::save-date Thu Feb 4, 2016 ::file bel_pmid_1780_4750_41498.txt
(r / result-01
      :ARG1 (d / downregulate-01
            :ARG1 (p / protein :name (n / name :op1 "Foxp3"))
            :ARG2 (n6 / nucleic-acid :name (n2 / name :op1 "small" :op2 "interfering" :op3 "RNA"))
            :location (c / cell
                  :mod (m / medical-condition :name (n7 / name :op1 "carcinoma")
                        :mod (p2 / pancreas))))
      :ARG2 (u / upregulate-01
            :ARG1 (e / express-03
                  :ARG2 (a / and
                        :op1 (p3 / protein :name (n3 / name :op1 "interleukin" :op2 "6"))
                        :op2 (p4 / protein :name (n4 / name :op1 "IL-8")))))
      :ARG0-of (p5 / provide-01
            :ARG1 (e2 / evidence-01
                  :ARG0 u
                  :ARG1 (a2 / activity-06
                        :ARG0 p
                        :ARG1 (t / transcribe-01)
                        :ARG2-of (n5 / negative-01)
                        :location (c3 / cell
                              :mod (e3 / epithelium)
                              :mod (t2 / this)
                              :mod (a3 / also))))))

# ::id bel_pmid_1780_4750.41500 ::date 2015-05-05T12:29:41 ::annotator SDL-AMR-09 ::preferred
# ::snt Coculture of Foxp3-expressing tumor cells with naive T cells completely inhibited T-cell proliferation, but not activation, and this antiproliferative effect was partially abrogated following specific inhibition of Foxp3 expression.
# ::save-date Tue Feb 2, 2016 ::file bel_pmid_1780_4750_41500.txt
(a / and
      :op1 (c / contrast-01
            :ARG1 (i / inhibit-01
                  :ARG0 (c2 / coculture-01
                        :ARG1 (a5 / and
                              :op1 (c3 / cell
                                    :mod (t / tumor)
                                    :ARG3-of (e / express-03
                                          :ARG2 (p / protein :name (n / name :op1 "Foxp3"))))
                              :op2 (c4 / cell :name (n2 / name :op1 "T")
                                    :mod (n3 / naive))))
                  :ARG1 (p2 / proliferate-01
                        :ARG0 (c5 / cell :name (n4 / name :op1 "T")))
                  :ARG1-of (c6 / complete-02))
            :ARG2 (i2 / inhibit-01 :polarity -
                  :ARG0 c2
                  :ARG1 (a2 / activate-01
                        :ARG0 c5)))
      :op2 (a3 / abrogate-01
            :ARG1 (a4 / affect-01
                  :ARG2 i
                  :mod (t2 / this))
            :degree (p3 / part)
            :ARG1-of (f / follow-01
                  :ARG2 (i3 / inhibit-01
                        :ARG1 (e3 / express-03
                              :ARG2 p)
                        :ARG1-of (s / specific-02)))))

# ::id bel_pmid_1780_4750.41502 ::date 2015-05-05T12:45:44 ::annotator SDL-AMR-09 ::preferred
# ::snt In an initial analysis of microdissected pancreatic carcinoma tissue using Affymetrix chip technology, Foxp3 was among the up-regulated genes in some tumor samples (26); (Fig. 1A).
# ::save-date Mon Jan 4, 2016 ::file bel_pmid_1780_4750_41502.txt
(i / include-91
      :ARG1 (g / gene :name (n / name :op1 "Foxp3"))
      :ARG2 (g2 / gene
            :ARG1-of (u / upregulate-01))
      :location (t / tumor
            :ARG1-of (s / sample-01)
            :quant (s2 / some))
      :time (a / analyze-01
            :ARG1 (t2 / tissue
                  :ARG1-of (m / microdissect-00)
                  :mod (m2 / medical-condition :name (n3 / name :op1 "carcinoma")
                        :mod (p / pancreas)))
            :ARG0-of (u2 / use-01
                  :ARG1 (t3 / technology :name (n2 / name :op1 "Affymetrix" :op2 "chip")))
            :mod (i2 / initial))
      :ARG1-of (d / describe-01
            :ARG0 (p2 / publication
                  :ARG1-of (c2 / cite-01
                        :ARG2 26)))
      :ARG1-of (d2 / describe-01
            :ARG0 (f / figure :mod "1A")))

# ::id bel_pmid_1780_4750.41504 ::date 2015-05-05T13:02:17 ::annotator SDL-AMR-09 ::preferred
# ::snt In accordance with the immunohistochemistry data pointing to FoxP3 expression in tumor cells (see above), Foxp3 expression was clearly detectable in several pancreatic carcinoma cell lines at both mRNA (Fig. 2A) and protein levels (Fig. 2B).
# ::save-date Mon Jan 4, 2016 ::file bel_pmid_1780_4750_41504.txt
(p / possible-01
      :ARG1 (d / detect-01
            :ARG1 (e / express-03
                  :ARG2 (p2 / protein :name (n / name :op1 "Foxp3")))
            :ARG1-of (c / clear-06)
            :location (c2 / cell-line
                  :quant (s / several)
                  :location-of (a / and
                        :op1 (l / level
                              :mod (n3 / nucleic-acid :name (n2 / name :op1 "mRNA"))
                              :ARG1-of (d2 / describe-01
                                    :ARG0 (f / figure :mod "2A")))
                        :op2 (l2 / level
                              :mod (p4 / protein)
                              :ARG1-of (d3 / describe-01
                                    :ARG0 (f2 / figure :mod "2B"))))
                  :mod (m / medical-condition :name (n4 / name :op1 "carcinoma")
                        :mod (p3 / pancreas))))
      :ARG1-of (a3 / accord-02
            :ARG2 (d4 / data
                  :mod (i / immunohistochemistry)
                  :ARG0-of (p5 / point-01
                        :ARG2 (e2 / express-03
                              :ARG2 p2
                              :ARG3 (c5 / cell
                                    :mod (t / tumor)))))
            :ARG1-of (s2 / see-01 :mode imperative
                  :ARG0 (y / you)
                  :location (a2 / above))))

# ::id bel_pmid_1780_4750.41506 ::date 2015-05-05T13:22:54 ::annotator SDL-AMR-09 ::preferred
# ::snt Treatment of PANC-89, Capan1, and Panc1 cells with TGF-h2 led to an up-regulation of the Foxp3 protein, which was moderate for PANC-89 and Capan1 and strong for Panc1 (Fig. 3A and D).
# ::save-date Sat Jan 2, 2016 ::file bel_pmid_1780_4750_41506.txt
(l / lead-03
      :ARG0 (t / treat-04
            :ARG1 (a / and
                  :op1 (c / cell-line :name (n / name :op1 "PANC-89"))
                  :op2 (c2 / cell-line :name (n2 / name :op1 "Capan1"))
                  :op3 (c3 / cell-line :name (n3 / name :op1 "Panc1")))
            :ARG2 (p / protein :name (n4 / name :op1 "TGF-h2")))
      :ARG2 (a2 / and
            :op1 (u / upregulate-01
                  :ARG1 (p2 / protein :name (n5 / name :op1 "Foxp3"))
                  :ARG1-of (m / moderate-03
                        :beneficiary (a3 / and
                              :op1 c
                              :op2 c2)
                        :ARG1-of (d / describe-01
                              :ARG0 (f / figure :mod "3A"))))
            :op2 (u2 / upregulate-01
                  :ARG1 p2
                  :ARG1-of (s / strong-02
                        :beneficiary c3
                        :ARG1-of (d2 / describe-01
                              :ARG0 (f2 / figure :mod "3D"))))))

# ::id bel_pmid_1780_4750.41508 ::date 2015-05-05T13:35:38 ::annotator SDL-AMR-09 ::preferred
# ::snt RT-PCR analysis detected a 13-fold (mean value of four independent experiments) increase of Foxp3 mRNA expression in PANC-89 cells after a 48-h stimulation with TGF-h2, whereas no such effect was evident after stimulation with TGF-h1 (Fig. 3B).
# ::save-date Sun Jan 17, 2016 ::file bel_pmid_1780_4750_41508.txt
(c / contrast-01
      :ARG1 (d / detect-01
            :ARG0 (a / analyze-01
                  :instrument (t2 / thing :name (n3 / name :op1 "RT-PCR")))
            :ARG1 (i / increase-01
                  :ARG1 (e / express-03
                        :ARG1 (n7 / nucleic-acid :name (n2 / name :op1 "mRNA")
                              :part (p / protein :name (n / name :op1 "Foxp3")))
                        :ARG3 (c2 / cell-line :name (n4 / name :op1 "PANC-89")))
                  :ARG2 (p2 / product-of :op1 13
                        :ARG1-of (d2 / describe-01
                              :ARG0 (v / value
                                    :mod (m / mean)
                                    :quant-of (e2 / experiment-01 :quant 4
                                          :ARG0-of (d3 / depend-01 :polarity -)))))
                  :time (a2 / after
                        :op1 (s / stimulate-01
                              :ARG2 (p3 / protein :name (n5 / name :op1 "TGF-h2"))
                              :duration (t / temporal-quantity :quant 48
                                    :unit (h / hour))))))
      :ARG2 (e3 / evident :polarity -
            :domain (a4 / affect-01
                  :ARG2 (i2 / increase-01
                        :ARG1 e
                        :ARG2 p2))
            :time (a3 / after
                  :op1 (s3 / stimulate-01
                        :ARG2 (p4 / protein :name (n6 / name :op1 "TGF-h1")))))
      :ARG1-of (d4 / describe-01
            :ARG0 (f / figure :mod "3B")))

# ::id bel_pmid_1780_4750.41510 ::date 2015-05-05T13:54:53 ::annotator SDL-AMR-09 ::preferred
# ::snt Moreover, the incubation of PANC-89 and Capan1 cells with anti-TGF-h2 antibody for 48 h clearly suppressed the Foxp3 signal (Fig. 3A ), suggesting that endogenously produced TGF-h2 maintains Foxp3 expression in pancreatic cancer cell cultures.
# ::save-date Sun Jan 17, 2016 ::file bel_pmid_1780_4750_41510.txt
(a / and
      :op2 (s / suppress-01
            :ARG0 (i / incubate-01
                  :ARG1 (a2 / and
                        :op1 (c / cell-line :name (n / name :op1 "PANC-89"))
                        :op2 (c2 / cell-line :name (n2 / name :op1 "Capan1")))
                  :ARG2 (a3 / antibody
                        :ARG0-of (c6 / counter-01
                              :ARG1 (p4 / protein :name (n3 / name :op1 "TGF-h2"))))
                  :duration (t / temporal-quantity :quant 48
                        :unit (h / hour)))
            :ARG1 (s2 / signal-07
                  :ARG0 (p / protein :name (n4 / name :op1 "Foxp3")))
            :ARG1-of (c3 / clear-06)
            :ARG1-of (d / describe-01
                  :ARG0 (f / figure :mod "3A"))
            :ARG0-of (s3 / suggest-01
                  :ARG1 (m / maintain-01
                        :ARG0 (p2 / protein :name (n5 / name :op1 "TGF-h2")
                              :ARG1-of (p3 / produce-01
                                    :manner (e / endogenous)))
                        :ARG1 (e2 / express-03
                              :ARG2 p
                              :ARG3 (c4 / culture
                                    :mod (c5 / cell
                                          :mod (d2 / disease :wiki "Pancreatic_cancer" :name (n6 / name :op1 "pancreatic" :op2 "cancer")))))))))

# ::id bel_pmid_1780_4750.41512 ::date 2015-05-05T14:09:07 ::annotator SDL-AMR-09 ::preferred
# ::snt Specific down-regulation of Foxp3 in pancreatic carcinoma cells results in up-regulation of IL-6 and IL-8.
# ::save-date Mon Jan 4, 2016 ::file bel_pmid_1780_4750_41512.txt
(r / result-01
      :ARG1 (d / downregulate-01
            :ARG1 (p / protein :name (n / name :op1 "Foxp3"))
            :location (c / cell
                  :mod (m / medical-condition :name (n2 / name :op1 "carcinoma")
                        :mod (p2 / pancreas)))
            :ARG1-of (s / specific-02))
      :ARG2 (u / upregulate-01
            :ARG1 (a / and
                  :op1 (p3 / protein :name (n3 / name :op1 "IL-6"))
                  :op2 (p4 / protein :name (n4 / name :op1 "IL-8")))))

# ::id bel_pmid_1780_4750.41514 ::date 2015-05-05T14:12:53 ::annotator SDL-AMR-09 ::preferred
# ::snt A screen for changes in cytokine secretion in these cells using the Raybiotec Cytokine Array (Hoelzel Diagnostica) revealed an increase of IL-6 and IL-8 in the culture supernatant, whereas other cytokines remained unchanged (data not shown).
# ::save-date Tue May 12, 2015 ::file bel_pmid_1780_4750_41514.txt
(c / contrast-01
      :ARG1 (r / reveal-01
            :ARG0 (s / screen-01
                  :ARG2 (c2 / change-01
                        :ARG1 (s2 / secrete-01
                              :ARG1 (c3 / cytokine)
                              :location (c4 / cell
                                    :mod (t / this))))
                  :ARG2-of (u / use-01
                        :ARG1 (p / product :name (n / name :op1 "Raybiotech" :op2 "Cytokine" :op3 "Array")
                              :source (c5 / company :name (n2 / name :op1 "Hoelzel" :op2 "Diagnostika")))))
            :ARG1 (i / increase-01
                  :ARG1 (a / and
                        :op1 (p2 / protein :name (n3 / name :op1 "IL-6"))
                        :op2 (p3 / protein :name (n4 / name :op1 "IL-8")))
                  :location (s3 / supernatant
                        :ARG1-of (c6 / culture-01))))
      :ARG2 (r2 / remain-01
            :ARG1 (c7 / cytokine
                  :mod (o / other))
            :ARG3 (c8 / change-01 :polarity -)
            :ARG1-of (d / describe-01
                  :ARG0 (d2 / data
                        :ARG1-of (s4 / show-01 :polarity -)))))

# ::id bel_pmid_1780_4750.41518 ::date 2015-05-05T14:34:17 ::annotator SDL-AMR-09 ::preferred
# ::snt In the cocultures, Colo357, PANC-89, and PancTu1 tumor cells strongly inhibited the proliferation of anti-CD3/anti-CD28-stimulated T cells (Fig. 4D).
# ::save-date Tue Feb 2, 2016 ::file bel_pmid_1780_4750_41518.txt
(i / inhibit-01
      :ARG0 (a / and
            :op1 (c / cell-line :name (n / name :op1 "Colo357"))
            :op2 (c2 / cell-line :name (n2 / name :op1 "PANC-89"))
            :op3 (c3 / cell-line :name (n3 / name :op1 "PancTu1"))
            :mod (t / tumor))
      :ARG1 (p / proliferate-01
            :ARG0 (c4 / cell :name (n4 / name :op1 "T")
                  :ARG1-of (s / stimulate-01
                        :ARG0 (a2 / and
                              :op1 (m / molecular-physical-entity
                                    :ARG0-of (c5 / counter-01
                                          :ARG1 (p2 / protein :name (n5 / name :op1 "CD3"))))
                              :op2 (m2 / molecular-physical-entity
                                    :ARG0-of (c6 / counter-01
                                          :ARG1 (p3 / protein :name (n6 / name :op1 "CD28"))))))))
      :ARG1-of (s2 / strong-02)
      :location (c7 / cell
            :ARG1-of (c8 / coculture-01))
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod "4D")))

# ::id bel_pmid_1780_4750.41520 ::date 2015-05-05T14:43:23 ::annotator SDL-AMR-09 ::preferred
# ::snt As shown in Fig. 5B, CD25 GITR and CD69 were up-regulated after anti-CD3/anti-CD28 stimulation, irrespective of the presence or absence of tumor cells.
# ::save-date Thu Jan 7, 2016 ::file bel_pmid_1780_4750_41520.txt
(u / upregulate-01
      :ARG1 (a / and
            :op1 (p / protein :name (n / name :op1 "CD25"))
            :op2 (p2 / protein :name (n2 / name :op1 "GITR"))
            :op3 (p3 / protein :name (n3 / name :op1 "CD69")))
      :time (a2 / after
            :op1 (s / stimulate-01
                  :ARG0 (a3 / and
                        :op1 (m / molecular-physical-entity
                              :ARG0-of (c / counter-01
                                    :ARG1 (p4 / protein :name (n4 / name :op1 "CD3"))))
                        :op2 (m2 / molecular-physical-entity
                              :ARG0-of (c2 / counter-01
                                    :ARG1 (p5 / protein :name (n5 / name :op1 "CD28")))))))
      :ARG1-of (s2 / show-01
            :ARG0 (f / figure :mod "5B"))
      :ARG1-of (r / regardless-91
            :ARG2 (o / or
                  :op1 (p6 / present-02
                        :ARG1 (c3 / cell
                              :mod (t / tumor)))
                  :op2 (a4 / absent-01
                        :ARG1 c3))))

# ::id bel_pmid_1780_4750.41522 ::date 2015-05-05T14:54:55 ::annotator SDL-AMR-09 ::preferred
# ::snt When using these cells, we observed an ~ 45% recovery of T-cell proliferation in the coculture system (Fig. 5A).
# ::save-date Tue Feb 2, 2016 ::file bel_pmid_1780_4750_41522.txt
(o / observe-01
      :ARG0 (w / we)
      :ARG1 (r / recover-02
            :ARG1 (p / proliferate-01
                  :ARG0 (c / cell :name (n / name :op1 "T")))
            :quant (a / approximately
                  :op1 (p2 / percentage-entity :value 45)))
      :location (s / system
            :consist-of (c2 / coculture-01))
      :time (u / use-01
            :ARG0 w
            :ARG1 (c3 / cell
                  :mod (t / this)))
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod "5A")))

# ::id bel_pmid_1794_2936.40216 ::date 2015-05-09T23:23:27 ::annotator SDL-AMR-09 ::preferred
# ::snt Results Tumor-associated inflammation is reduced in IL-1R—/— mice.
# ::save-date Sat May 16, 2015 ::file bel_pmid_1794_2936_40216.txt
(r / reduce-01
      :ARG1 (i / inflame-01
            :ARG1-of (a / associate-01
                  :ARG2 (t / tumor)))
      :location (m2 / mouse
            :mod (p / protein :name (n2 / name :op1 "IL-1R")
                  :ARG2-of (m3 / mutate-01 :mod "-/-")))
      :ARG2-of (r2 / result-01))

# ::id bel_pmid_1794_2936.40218 ::date 2015-05-09T23:40:34 ::annotator SDL-AMR-09 ::preferred
# ::snt Canonical proinflammatory cytokines, such as IL-6, MCP-1, TGFh, and IL-1h were significantly elevated in 4T1 tumor tissue.
# ::save-date Thu Feb 4, 2016 ::file bel_pmid_1794_2936_40218.txt
(e / elevate-01
      :ARG1 (c7 / cytokine
            :mod (c2 / canonical)
            :ARG0-of (p / promote-01
                  :ARG1 (i / inflame-01))
            :example (a / and
                  :op1 (p2 / protein :name (n / name :op1 "IL-6"))
                  :op2 (p3 / protein :name (n2 / name :op1 "MCP-1"))
                  :op3 (p4 / protein :name (n3 / name :op1 "TGFh"))
                  :op4 (p5 / protein :name (n4 / name :op1 "IL-1h"))))
      :ARG1-of (s / significant-02)
      :location (t / tissue
            :mod (t2 / tumor
                  :mod (c / cell-line :name (n5 / name :op1 "4T1")))))

# ::id bel_pmid_1794_2936.40222 ::date 2015-05-09T23:48:40 ::annotator SDL-AMR-09 ::preferred
# ::snt Additionally, IL-1R—/— tumor tissue had less IL-12p70 and more TGFh and IFNg than tumor tissue from wild-type BALB/c mice.
# ::save-date Thu Jan 14, 2016 ::file bel_pmid_1794_2936_40222.txt
(a / and
      :op2 (h / have-03
            :ARG0 (t / tissue
                  :part-of (t2 / tumor)
                  :mod (p / protein :name (n / name :op1 "IL-1R")
                        :ARG2-of (m / mutate-01 :mod "-/-")))
            :ARG1 (a2 / and
                  :op1 (p2 / protein :name (n2 / name :op1 "IL-12p70")
                        :degree (l / less))
                  :op2 (p3 / protein :name (n3 / name :op1 "TGFh")
                        :degree (m3 / more))
                  :op3 (p4 / protein :name (n4 / name :op1 "IFNg")
                        :degree m3)
                  :compared-to (t3 / tissue
                        :mod (t4 / tumor)
                        :source (m4 / mouse
                              :mod (c / cell-line :name (n5 / name :op1 "BALB/c")
                                    :mod (w / wild-type)))))))

# ::id bel_pmid_1794_2936.40248 ::date 2015-05-10T00:06:13 ::annotator SDL-AMR-09 ::preferred
# ::snt A potential downstream candidate is the proinflammatory cytokine, IL-6, the production of which is reduced in IL-1R—/— tumor tissue (Fig. 1B).
# ::save-date Mon May 18, 2015 ::file bel_pmid_1794_2936_40248.txt
(c / cytokine :name (n / name :op1 "IL-6")
      :domain (c2 / candidate
            :mod (p3 / potential)
            :location (d / downstream))
      :ARG1-of (p / produce-01
            :ARG1-of (r / reduce-01
                  :location (t / tissue
                        :part-of (t2 / tumor)
                        :mod (p4 / protein :name (n2 / name :op1 "IL-1R")
                              :ARG2-of (m / mutate-01 :mod "-/-")))))
      :ARG0-of (p2 / promote-01
            :ARG1 (i / inflame-01))
      :ARG1-of (d2 / describe-01
            :ARG0 (f / figure :mod "1B")))

# ::id bel_pmid_1796_7787.34624 ::date 2015-05-10T00:24:28 ::annotator SDL-AMR-09 ::preferred
# ::snt These data demonstrate that it is the hemin-induced surge in cellular ROS levels, in particular the superoxide generated most likely from NADPH oxidase activity, and consequent oxidative stress which mediates Egr-1 upregulation via ERK-1/2 activation.
# ::save-date Sat Feb 13, 2016 ::file bel_pmid_1796_7787_34624.txt
(d3 / demonstrate-01
      :ARG0 (d2 / data
            :mod (t2 / this))
      :ARG1 (a / and
            :op1 (s / surge-01
                  :ARG1 (l2 / level
                        :quant-of (s4 / small-molecule :name (n / name :op1 "ROS")
                              :part-of (c / cell)))
                  :ARG2-of (i / induce-01
                        :ARG0 (s5 / small-molecule :name (n2 / name :op1 "hemin"))))
            :op2 (m4 / macro-molecular-complex :name (n3 / name :op1 "superoxide")
                  :mod (p / particular)
                  :ARG1-of (g / generate-01
                        :ARG2 (a2 / activity-06
                              :ARG0 (m5 / macro-molecular-complex
                                    :part (o / oxidase)
                                    :part (s6 / small-molecule :name (n4 / name :op1 "NADPH"))))
                        :ARG1-of (l / likely-01
                              :degree (m / most))))
            :op3 (s2 / stress-02
                  :ARG2-of (r / result-01
                        :ARG1 o))
            :ARG0-of (m2 / mediate-01
                  :ARG1 (u / upregulate-01
                        :ARG1 (p2 / protein :name (n5 / name :op1 "Egr-1"))
                        :ARG2 (a3 / activate-01
                              :ARG1 (s3 / slash
                                    :op1 (e / enzyme :name (n6 / name :op1 "ERK-1"))
                                    :op2 (e2 / enzyme :name (n7 / name :op1 "ERK-2"))))))))

# ::id bel_pmid_1798_2092.10006 ::date 2015-05-10T00:47:28 ::annotator SDL-AMR-09 ::preferred
# ::snt However, RELMbeta stimulated naive bone marrow-derived macrophages to secrete significant amounts of TNF-alpha, IL-6, and RANTES
# ::save-date Fri Dec 18, 2015 ::file bel_pmid_1798_2092_10006.txt
(h / have-concession-91
      :ARG1 (s / stimulate-01
            :ARG0 (s2 / small-molecule :name (n / name :op1 "RELMbeta"))
            :ARG1 (s3 / secrete-01
                  :ARG0 (m2 / macrophage
                        :ARG1-of (d / derive-01
                              :ARG2 (m / marrow
                                    :source (b / bone
                                          :mod (n3 / naive)))))
                  :ARG1 (a / amount
                        :quant-of (a2 / and
                              :op1 (p / protein :name (n4 / name :op1 "TNF-alpha"))
                              :op2 (p2 / protein :name (n5 / name :op1 "IL-6"))
                              :op3 (p3 / protein :name (n6 / name :op1 "RANTES")))
                        :ARG1-of (s4 / significant-02)))))

# ::id bel_pmid_1799_2263.15480 ::date 2015-05-10T01:11:41 ::annotator SDL-AMR-09 ::preferred
# ::snt MMP-2 (76 kDa) activity was elevated only at day 11 in C57BL/6 mice but not in MyD88–/– and IL-1R1–/– mice (Figure 4B).
# ::save-date Mon Jan 4, 2016 ::file bel_pmid_1799_2263_15480.txt
(c / contrast-01
      :ARG1 (e / elevate-01
            :ARG1 (a / activity-06
                  :ARG0 (e2 / enzyme :name (n / name :op1 "MMP-2")
                        :quant (m / mass-quantity :quant 76
                              :unit (k / kilodalton))))
            :time (a2 / after
                  :op1 (t / temporal-quantity :quant 11
                        :unit (d / day)))
            :mod (o / only)
            :location (m6 / mouse :name (n4 / name :op1 "C57BL/6")))
      :ARG2 (e3 / elevate-01 :polarity -
            :ARG1 (a3 / activity-06
                  :ARG0 e2)
            :time a2
            :location (a4 / and
                  :op1 (m2 / mouse
                        :mod (p / protein :name (n2 / name :op1 "MyD88")
                              :ARG2-of (m3 / mutate-01 :mod "-/-")))
                  :op2 (m4 / mouse
                        :mod (p2 / protein :name (n3 / name :op1 "IL-1R1")
                              :ARG2-of (m5 / mutate-01 :mod "-/-")))))
      :ARG1-of (d2 / describe-01
            :ARG0 (f / figure :mod "4B")))

# ::id bel_pmid_1799_2263.15482 ::date 2015-05-10T01:27:07 ::annotator SDL-AMR-09 ::preferred
# ::snt MMP-9 activity was significantly upregulated in BALF at day 1 in C57BL/6 mice but not in MyD88–/– mice, and only partially in IL-1R1–/– mice (Figure 4A).
# ::save-date Sat Feb 13, 2016 ::file bel_pmid_1799_2263_15482.txt
(c / contrast-01
      :ARG1 (a3 / and
            :op1 (u / upregulate-01
                  :ARG1 (a / activity-06
                        :ARG0 (e / enzyme :name (n / name :op1 "MMP-9")))
                  :ARG1-of (s / significant-02)
                  :location (f2 / fluid
                        :mod (l / lavage
                              :mod (a4 / alveolus
                                    :mod (b / bronchus))))
                  :time (a2 / after
                        :quant (u2 / up-to
                              :op1 (t2 / temporal-quantity :quant 1
                                    :unit (d / day))))
                  :location (m6 / mouse :name (n5 / name :op1 "C57BL/6")))
            :op2 (u3 / upregulate-01
                  :ARG1 a
                  :degree (p / part
                        :mod (o / only))
                  :location (m2 / mouse
                        :mod (p3 / protein :name (n3 / name :op1 "IL-1R1")
                              :ARG2-of (m3 / mutate-01 :mod "-/-")))))
      :ARG2 (u4 / upregulate-01 :polarity -
            :ARG1 a
            :location (m4 / mouse
                  :mod (p2 / protein :name (n4 / name :op1 "MyD88")
                        :ARG2-of (m5 / mutate-01 :mod "-/-"))))
      :ARG1-of (d2 / describe-01
            :ARG0 (f / figure :mod "4A")))

# ::id bel_pmid_1799_2263.15488 ::date 2015-05-10T01:51:51 ::annotator SDL-AMR-09 ::preferred
# ::snt Latent TGF-?1 was detected after activation in BALF from WT mice 7 days after BLM administration, but was not detected in BALF from MyD88- or IL-1R1–deficient mice (Figure 5G)
# ::save-date Sat Feb 13, 2016 ::file bel_pmid_1799_2263_15488.txt
(c / contrast-01
      :ARG1 (d2 / detect-01
            :ARG1 (p / protein :name (n / name :op1 "TGFβ-1")
                  :mod (l / latent))
            :time (a2 / after
                  :op1 (a3 / activate-01
                        :location (f2 / fluid
                              :source (m / mouse
                                    :mod (w / wild-type))
                              :mod (l2 / lavage
                                    :mod (a / alveolus
                                          :mod (b / bronchus))))))
            :time (a4 / after
                  :op1 (a5 / administer-01
                        :ARG1 (s / small-molecule :name (n3 / name :op1 "BLM")))
                  :quant (t3 / temporal-quantity :quant 7
                        :unit (d3 / day))))
      :ARG2 (d4 / detect-01 :polarity -
            :ARG1 p
            :location (o / or
                  :op1 (f3 / fluid
                        :source (m3 / mouse
                              :ARG0-of (l3 / lack-01
                                    :ARG1 (p3 / protein :name (n5 / name :op1 "MyD88"))))
                        :mod l2)
                  :op2 (f4 / fluid
                        :source (m4 / mouse
                              :ARG0-of (l4 / lack-01
                                    :ARG1 (p4 / protein :name (n9 / name :op1 "IL-1R1"))))
                        :mod l2)))
      :ARG1-of (d5 / describe-01
            :ARG0 (f / figure :mod "5G")))

# ::id bel_pmid_1799_2263.28110 ::date 2015-05-10T02:12:28 ::annotator SDL-AMR-09 ::preferred
# ::snt 7 days of administration IL-1? caused tissue injury with marked tissue destruction, disruption of alveolar architecture, inflammation, and fibrosis (although less pronounced than that obtained after BLM treatment; Figure 7, D and E) that was absent in saline controls (Figure 7C)
# ::save-date Sun Jan 17, 2016 ::file bel_pmid_1799_2263_28110.txt
(c / cause-01
      :ARG0 (a2 / administer-01
            :ARG1 (p / protein :name (n / name :op1 "IL-1β"))
            :duration (t2 / temporal-quantity :quant 7
                  :unit (d / day)))
      :ARG1 (i2 / injure-01
            :ARG1 (t3 / tissue)
            :accompanier (a / and
                  :op1 (d2 / destroy-01
                        :ARG1 t3
                        :ARG1-of (m / mark-01))
                  :op2 (d4 / disrupt-01
                        :ARG1 (a7 / architecture
                              :poss (a8 / alveolus)))
                  :op3 (i / inflame-01)
                  :op4 (f2 / fibrosis))
            :ARG2-of (h / have-concession-91)
            :ARG1-of (p2 / pronounced-02
                  :degree (l / less)
                  :compared-to (i4 / injure-01
                        :ARG1 (t4 / tissue)
                        :ARG1-of (o / obtain-01
                              :ARG2 (t5 / treat-04
                                    :ARG2 (s2 / small-molecule :name (n2 / name :op1 "BLM")))
                              :ARG1-of (d5 / describe-01
                                    :ARG0 (a9 / and
                                          :op1 (f3 / figure :mod "7D")
                                          :op2 (f4 / figure :mod "7E"))))))
            :ARG1-of (a10 / absent-01
                  :ARG2 (c2 / control-01
                        :ARG0 (s / saline))))
      :ARG1-of (d6 / describe-01
            :ARG0 (f5 / figure :mod "7C")))

# ::id bel_pmid_1799_2263.30264 ::date 2015-05-10T02:43:26 ::annotator SDL-AMR-09 ::preferred
# ::snt IL-1? production into the lung was attenuated in ASC–/– in comparison with ASC+/+ control littermates 24 hours after BLM administration (Figure 9D).
# ::save-date Mon May 18, 2015 ::file bel_pmid_1799_2263_30264.txt
(a2 / attenuate-01
      :ARG1 (p / produce-01
            :ARG1 (p2 / protein :wiki "IL1B"
                  :name (n / name :op1 "IL-1β"))
            :location (l / lung))
      :location (m / mouse
            :mod (l2 / littermate)
            :mod (p3 / protein :wiki -
                  :name (n2 / name :op1 "ASC")
                  :ARG2-of (m2 / mutate-01 :mod "-/-")
                  :ARG0-of (c / control-01)))
      :time (a4 / after
            :op1 (a5 / administer-01
                  :ARG1 (s / small-molecule :wiki "Bloom_syndrome_protein"
                        :name (n4 / name :op1 "BLM")))
            :quant (t3 / temporal-quantity :quant 24
                  :unit (h2 / hour)))
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod "9D"))
      :compared-to (p4 / produce-01
            :ARG1 p2
            :location (m3 / mouse
                  :mod (l3 / littermate)
                  :mod (p5 / protein :wiki -
                        :name (n3 / name :op1 "ASC")
                        :mod (w / wild-type)
                        :ARG0-of (c2 / control-01)))))

# ::id bel_pmid_1799_2263.30266 ::date 2015-05-10T02:58:29 ::annotator SDL-AMR-09 ::preferred
# ::snt IL-6 production into the lung 24 hours after BLM treatment was attenuated in ASC–/– in comparison with ASC+/+ control littermates (Figure 9E). Comparable reductions of IL-1? and IL-6 were obtained in the BALF
# ::save-date Sat Feb 13, 2016 ::file bel_pmid_1799_2263_30266.txt
(m4 / multi-sentence
      :snt1 (a / attenuate-01
            :ARG1 (p / produce-01
                  :ARG1 (p2 / protein :name (n / name :op1 "IL-6"))
                  :location (l / lung))
            :time (a2 / after
                  :op1 (t2 / treat-04
                        :ARG2 (s / small-molecule :name (n2 / name :op1 "BLM")))
                  :quant (t4 / temporal-quantity :quant 24
                        :unit (h / hour)))
            :location (m / mouse
                  :mod (l2 / littermate)
                  :mod (p3 / protein :name (n3 / name :op1 "ASC")
                        :ARG2-of (m2 / mutate-01 :mod "-/-")
                        :ARG0-of (c / control-01)))
            :compared-to (p4 / produce-01
                  :ARG1 p2
                  :location (m3 / mouse
                        :mod (l3 / littermate)
                        :mod (p5 / protein :name (n4 / name :op1 "ASC")
                              :mod (w / wild-type)
                              :ARG0-of (c2 / control-01))))
            :ARG1-of (d / describe-01
                  :ARG0 (f / figure :mod "9E")))
      :snt2 (o / obtain-01
            :ARG1 (r / reduce-01
                  :ARG1 (a3 / and
                        :op1 (p6 / protein :name (n5 / name :op1 "IL-1β"))
                        :op2 (p7 / protein :name (n6 / name :op1 "IL-6")))
                  :ARG1-of (c3 / comparable-03))
            :location (f2 / fluid
                  :mod (l4 / lavage
                        :mod (a4 / alveolus
                              :mod (b / bronchus))))))

# ::id bel_pmid_1803_2482.6302 ::date 2015-05-10T03:10:59 ::annotator SDL-AMR-09 ::preferred
# ::snt Studies using bone marrow-derived macrophages (BMDM) isolated from a spontaneous mouse model of Crohn's disease-like ileitis (SAMP1/YitFc strain) revealed significant inhibition by CGP57380 of the proinflammatory cytokines TNF, IL-6, and monocyte chemoattractant protein-1 at 4 and 24 h after LPS stimulation
# ::save-date Mon Jan 4, 2016 ::file bel_pmid_1803_2482_6302.txt
(r / reveal-01
      :ARG0 (s2 / study-01
            :ARG0-of (u / use-01
                  :ARG1 (m5 / macrophage
                        :ARG1-of (d / derive-01
                              :ARG2 (m / marrow
                                    :poss (b / bone)))
                        :ARG1-of (i / isolate-01
                              :ARG2 (m2 / model
                                    :mod (m3 / mouse)
                                    :mod (s / spontaneity)
                                    :topic (m7 / medical-condition :name (n2 / name :op1 "ileitis")
                                          :ARG1-of (r2 / resemble-01
                                                :ARG2 (d2 / disease :wiki "Crohn's_disease" :name (n / name :op1 "Crohn's"))))
                                    :ARG1-of (m6 / mean-01
                                          :ARG2 (s5 / strain :name (n3 / name :op1 "SAMP1/YitFc"))))))))
      :ARG1 (i2 / inhibit-01
            :ARG0 (s6 / small-molecule :name (n4 / name :op1 "CGP57380"))
            :ARG1 (a / and
                  :op1 (c2 / cytokine :name (n5 / name :op1 "TNF")
                        :ARG0-of (p2 / promote-01
                              :ARG1 (i3 / inflame-01)))
                  :op2 (c3 / cytokine :name (n6 / name :op1 "IL-6")
                        :ARG0-of p2)
                  :op3 (p / protein :name (n7 / name :op1 "monocyte-chemoattractant-protein-1"))
                  :op4 (p3 / protein :name (n8 / name :op1 "monocyte-chemoattractant-protein-4")))
            :ARG1-of (s3 / significant-02))
      :time (a2 / after
            :op1 (s4 / stimulate-01
                  :ARG0 (m4 / molecular-physical-entity :name (n9 / name :op1 "LPS")))
            :quant (t2 / temporal-quantity :quant 24
                  :unit (h / hour))))

# ::id bel_pmid_1804_8363.10226 ::date 2015-05-10T04:11:25 ::annotator SDL-AMR-09 ::preferred
# ::snt Co-immunoprecipitation studies with H-Ras-transformed cells revealed that Spry2 and H-Ras interact and that H-Ras interacts with Spry2-binding partners, c-Cbl and CIN85, in a Spry2-dependent manner.
# ::save-date Sun Dec 20, 2015 ::file bel_pmid_1804_8363_10226.txt
(r / reveal-01
      :ARG0 (s / study-01
            :ARG1 (c / coimmunoprecipitate-01)
            :instrument (c2 / cell
                  :ARG1-of (t / transform-01
                        :ARG0 (e / enzyme :name (n / name :op1 "H-Ras")))))
      :ARG1 (a / and
            :op1 (i / interact-01
                  :ARG0 (p / protein :name (n2 / name :op1 "Spry2"))
                  :ARG1 e)
            :op2 (i2 / interact-01
                  :ARG0 e
                  :ARG1 (a2 / and
                        :op1 (p2 / partner
                              :ARG2-of (b / bind-01
                                    :ARG1 p)
                              :ARG1-of (m / mean-01
                                    :ARG2 (a3 / and
                                          :op1 (p4 / protein :name (n3 / name :op1 "c-Cbl"))
                                          :op2 (p3 / protein :name (n4 / name :op1 "CIN85"))))))
                  :ARG0-of (d / depend-01
                        :ARG1 p))))

# ::id bel_pmid_1804_8363.20908 ::date 2015-05-10T04:23:06 ::annotator SDL-AMR-09 ::preferred
# ::snt We compared human fibroblasts malignantly transformed by overexpression of H-Ras(V12) oncogene to their nontransformed parental cells and found that the malignant cells express a high level of Spry2.
# ::save-date Sun Jan 17, 2016 ::file bel_pmid_1804_8363_20908.txt
(a / and
      :op1 (c / compare-01
            :ARG0 (w / we)
            :ARG1 (f / fibroblast
                  :mod (h2 / human)
                  :ARG1-of (t / transform-01
                        :ARG0 (o / overexpress-01
                              :ARG1 (g2 / gene :name (n / name :op1 "H-Ras")
                                    :ARG2-of (m2 / mutate-01 :value "V12")
                                    :ARG1-of (m / malignant-02)
                                    :ARG0-of (c4 / cause-01
                                          :ARG1 (d / disease :wiki "Cancer" :name (n3 / name :op1 "cancer")))))))
            :ARG2 (c2 / cell
                  :mod (p / parent)
                  :ARG1-of (t2 / transform-01 :polarity -)
                  :poss f))
      :op2 (f2 / find-01
            :ARG1 (e / express-03
                  :ARG1 (c3 / cell
                        :ARG1-of (m3 / malignant-02))
                  :ARG2 (l / level
                        :ARG1-of (h / high-02)
                        :quant-of (p2 / protein :name (n2 / name :op1 "Spry2"))))))

# ::id bel_pmid_1804_8363.30892 ::date 2015-05-10T04:32:34 ::annotator SDL-AMR-09 ::preferred
# ::snt When we decreased expression of Spry2, using a Spry2-specific shRNA, the H-Ras(V12)-transformed fibroblasts could no longer form large colonies in agarose, grow in reduced levels of serum, or form tumors in athymic mice. The level of active H-Ras in these cells remained unaltered.
# ::save-date Sun Jan 17, 2016 ::file bel_pmid_1804_8363_30892.txt
(m4 / multi-sentence
      :snt1 (o / or
            :op1 (p2 / possible-01
                  :ARG1 (f / form-01
                        :ARG0 (f2 / fibroblast
                              :ARG1-of (t / transform-01
                                    :ARG0 (e / enzyme :name (n2 / name :op1 "H-Ras")
                                          :ARG2-of (m / mutate-01 :value "V12"))))
                        :ARG1 (c / colony
                              :mod (l / large))
                        :location (a4 / agarose)))
            :op2 (p / possible-01
                  :ARG1 (g / grow-01
                        :ARG0 f2
                        :location (l2 / level
                              :quant-of (s / serum)
                              :ARG1-of (r / reduce-01))))
            :op3 (p3 / possible-01
                  :ARG1 (f3 / form-01
                        :ARG0 f2
                        :ARG1 (t2 / tumor)
                        :location (m3 / mouse
                              :mod (a / athymic))))
            :time (d / decrease-01
                  :ARG0 (w / we)
                  :ARG1 (e2 / express-03
                        :ARG2 (p4 / protein :name (n5 / name :op1 "Spry2")))
                  :instrument (n3 / nucleic-acid :name (n6 / name :op1 "shRNA")
                        :ARG1-of (s2 / specific-02
                              :ARG2 p4)))
            :time (n / no-longer))
      :snt2 (r3 / remain-01
            :ARG1 (l3 / level
                  :quant-of (e3 / enzyme :name (n7 / name :op1 "H-Ras")
                        :ARG0-of (a2 / activity-06)))
            :ARG3 (a3 / alter-01 :polarity -
                  :ARG1 l3)
            :location (c2 / cell
                  :mod (t3 / this))))

# ::id bel_pmid_1806_0032.38560 ::date 2015-05-10T04:49:29 ::annotator SDL-AMR-09 ::preferred
# ::snt We next determined whether the ?EGFR-expressing MCF-10A cells produced high levels of IL-6, leading to activation of STAT3, as was observed in lung adenocarcinoma–derived cell lines harboring mutant EGFR. The ?EGFR–MCF-10A cells were treated with P6, gp130, and IL-6 blocking antibodies, which inhibited STAT3 activation.
# ::save-date Thu Dec 10, 2015 ::file bel_pmid_1806_0032_38560.txt
(m2 / multi-sentence
      :snt1 (d / determine-01
            :ARG0 (w / we)
            :ARG1 (p / produce-01 :mode interrogative
                  :ARG0 (c2 / cell-line :name (n3 / name :op1 "MCF-10A")
                        :ARG1-of (e2 / express-03
                              :ARG2 (e / enzyme :name (n2 / name :op1 "ΔEGFR"))))
                  :ARG1 (l / level
                        :ARG1-of (h / high-02)
                        :quant-of (p2 / protein :name (n4 / name :op1 "IL-6")))
                  :ARG0-of (l2 / lead-03
                        :ARG1 (a / activate-01
                              :ARG1 (p3 / protein :name (n5 / name :op1 "STAT3")))))
            :ARG2-of (r / resemble-01
                  :ARG1 (o / observe-01
                        :location (c / cell-line
                              :ARG1-of (d2 / derive-01
                                    :ARG2 (m3 / medical-condition :name (n6 / name :op1 "adenocarcinoma")
                                          :mod (l3 / lung)))
                              :ARG0-of (h2 / harbor-01
                                    :ARG1 (e4 / enzyme :name (n7 / name :op1 "EGFR")
                                          :ARG2-of (m / mutate-01))))))
            :time (n / next))
      :snt2 (t / treat-04
            :ARG1 (c3 / cell-line :name (n8 / name :op1 "MCF-10A")
                  :ARG1-of (e5 / express-03
                        :ARG2 (e3 / enzyme :name (n9 / name :op1 "ΔEGFR"))))
            :ARG2 (a2 / and
                  :op1 (p4 / protein :name (n10 / name :op1 "P6"))
                  :op2 (p5 / protein :name (n11 / name :op1 "gp130"))
                  :op3 (a3 / antibody
                        :ARG0-of (b / block-01
                              :ARG1 (p7 / protein :name (n13 / name :op1 "IL-6"))))
                  :ARG0-of (i / inhibit-01
                        :ARG1 (a4 / activate-01
                              :ARG1 (p6 / protein :name (n12 / name :op1 "STAT3")))))))

# ::id bel_pmid_1806_0035.1688 ::date 2015-05-10T05:27:44 ::annotator SDL-AMR-09 ::preferred
# ::snt In contrast, enhanced thrombopoietin signaling, conferred by enforced expression of constitutively active JAK2 or c-MPL, induced phosphorylation of STAT3 and STAT5, but not STAT1, and failed to rescue megakaryocyte maturation.
# ::save-date Sun Jan 3, 2016 ::file bel_pmid_1806_0035_1688.txt
(c / contrast-01
      :ARG2 (a2 / and
            :op1 (i / induce-01
                  :ARG0 (s / signal-07
                        :ARG1 (p2 / protein :name (n / name :op1 "thrombopoietin"))
                        :ARG1-of (e / enhance-01)
                        :ARG1-of (c2 / confer-02
                              :ARG0 (e2 / express-03
                                    :ARG2 (o / or
                                          :op1 (e4 / enzyme :name (n2 / name :op1 "JAK2")
                                                :ARG0-of (a3 / activity-06
                                                      :mod (c5 / constitutive)))
                                          :op2 (p8 / protein :name (n3 / name :op1 "c-MPL")))
                                    :ARG1-of (e3 / enforce-01))))
                  :ARG2 (p / phosphorylate-01
                        :ARG1 (a / and
                              :op1 (p3 / protein :name (n4 / name :op1 "STAT3"))
                              :op2 (p4 / protein :name (n5 / name :op1 "STAT5")))
                        :ARG1-of (c3 / contrast-01
                              :ARG2 (i2 / induce-01 :polarity -
                                    :ARG0 s
                                    :ARG2 (p5 / phosphorylate-01
                                          :ARG1 (p6 / protein :name (n6 / name :op1 "STAT1")))))))
            :op2 (f / fail-01
                  :ARG0 s
                  :ARG1 (r / rescue-01
                        :ARG0 s
                        :ARG1 (m / maturate-03
                              :ARG1 (m2 / megakaryocyte))))))

# ::id bel_pmid_1806_0035.28492 ::date 2015-05-10T05:39:08 ::annotator SDL-AMR-09 ::preferred
# ::snt We show that ectopic expression of STAT1 or its downstream transcriptional target IRF-1 promotes features of megakaryocytic differentiation of G1ME cells, a Gata1-null erythromegakaryocytic cell line (25),
# ::save-date Sun Jan 17, 2016 ::file bel_pmid_1806_0035_28492.txt
(s2 / show-01
      :ARG0 (w / we)
      :ARG1 (p / promote-01
            :ARG0 (o / or
                  :op1 (e / express-03
                        :ARG2 (p2 / protein :name (n / name :op1 "STAT1"))
                        :mod (e2 / ectopic))
                  :op2 (p4 / protein :name (n2 / name :op1 "IRF-1")
                        :poss p2
                        :location (d / downstream)
                        :ARG0-of (t / transcribe-01)
                        :ARG1-of (t2 / target-01)))
            :ARG1 (f / feature
                  :topic (d2 / differentiate-01
                        :ARG0 (m5 / megakaryocyte)
                        :ARG1 (c / cell-line :name (n4 / name :op1 "G1ME")
                              :ARG1-of (m4 / mean-01
                                    :ARG2 (c3 / cell-line
                                          :ARG3-of (e3 / express-03
                                                :ARG2 (p5 / protein :name (n5 / name :op1 "Gata1")
                                                      :ARG2-of (m / mutate-01 :mod "-/-")))
                                          :mod (m2 / megakaryocyte)
                                          :mod (e4 / erythroid))))))
            :ARG1-of (d3 / describe-01
                  :ARG0 (p3 / publication
                        :ARG1-of (c5 / cite-01
                              :ARG2 25)))))

# ::id bel_pmid_1806_0035.31648 ::date 2015-05-10T05:53:48 ::annotator SDL-AMR-09 ::preferred
# ::snt In most cell types, STAT1 is primarily triggered by interferon signaling (21). However, TPO signaling phosphorylates STAT1 in WT megakaryocytes (10).
# ::save-date Mon Dec 21, 2015 ::file bel_pmid_1806_0035_31648.txt
(m2 / multi-sentence
      :snt1 (t / trigger-01
            :ARG0 (s / signal-07
                  :ARG1 (p3 / protein :name (n2 / name :op1 "interferon")))
            :ARG1 (p / protein :name (n / name :op1 "STAT1"))
            :manner (p2 / primary)
            :ARG1-of (d / describe-01
                  :ARG0 (p4 / publication
                        :ARG1-of (c2 / cite-01
                              :ARG2 21)))
            :location (c / cell
                  :ARG1-of (t2 / type-03
                        :mod (m / most))))
      :snt2 (h / have-concession-91
            :ARG1 (p5 / phosphorylate-01
                  :ARG1 (p6 / protein :name (n4 / name :op1 "STAT1"))
                  :ARG2 (s2 / signal-07
                        :ARG1 (p8 / protein :name (n3 / name :op1 "TPO")))
                  :location (m3 / megakaryocyte
                        :mod (w / wild-type))
                  :ARG1-of (d2 / describe-01
                        :ARG0 (p7 / publication
                              :ARG1-of (c4 / cite-01
                                    :ARG2 10))))))

# ::id bel_pmid_1806_0035.33056 ::date 2015-05-10T06:04:27 ::annotator SDL-AMR-09 ::preferred
# ::snt Moreover, GATA-1 transactivated the Stat1 promoter in luciferase reporter assays (Supplemental Figure 1). STAT1 and IRF-1 reciprocally activated each other’s transcription, as previously reported (Figure ?(Figure1D1D and Supplemental Table 1; also reviewed in ref. 26).
# ::save-date Mon Jan 4, 2016 ::file bel_pmid_1806_0035_33056.txt
(m / multi-sentence
      :snt1 (a / and
            :op2 (t / transactivate-01
                  :ARG1 (m2 / molecular-physical-entity
                        :ARG0-of (p2 / promote-01
                              :ARG1 (p3 / protein :name (n2 / name :op1 "Stat1"))))
                  :ARG2 (p / protein :name (n / name :op1 "GATA-1"))
                  :time (a2 / assay-01
                        :ARG0-of (r2 / report-01
                              :ARG1 (e / enzyme :name (n3 / name :op1 "luciferase"))))
                  :ARG1-of (d / describe-01
                        :ARG0 (f / figure :mod 1
                              :ARG2-of (s / supplement-01)))))
      :snt2 (a5 / and
            :op1 (a3 / activate-01
                  :ARG0 (p4 / protein :name (n4 / name :op1 "STAT1"))
                  :ARG1 (t3 / transcribe-01
                        :ARG1 (p7 / protein :name (n5 / name :op1 "IRF-1"))))
            :op2 (a4 / activate-01
                  :ARG0 p7
                  :ARG1 (t4 / transcribe-01
                        :ARG1 p4))
            :ARG1-of (r3 / report-01
                  :time (p5 / previous))
            :ARG1-of (d2 / describe-01
                  :ARG0 (a6 / and
                        :op1 (f2 / figure :mod "1D")
                        :op2 (t5 / table :mod 1
                              :ARG2-of (s2 / supplement-01))))
            :ARG1-of (r / review-02
                  :ARG2 (p6 / publication
                        :ARG1-of (c / cite-01
                              :ARG2 26))
                  :mod (a7 / also))))

# ::id bel_pmid_1806_0035.33182 ::date 2015-05-10T06:21:50 ::annotator SDL-AMR-09 ::preferred
# ::snt In addition, STAT1 or IRF-1 induced the expression of CD42, a late marker of megakaryocyte maturation, albeit to a much lesser extent than GATA-1 (Figure ?(Figure1C).1C).
# ::save-date Sun Dec 20, 2015 ::file bel_pmid_1806_0035_33182.txt
(a / and
      :op2 (i / induce-01
            :ARG0 (o / or
                  :op1 (p / protein :name (n / name :op1 "STAT1"))
                  :op2 (p3 / protein :name (n2 / name :op1 "IRF-1")))
            :ARG2 (e / express-03
                  :ARG2 (p2 / protein :name (n3 / name :op1 "CD42")
                        :ARG0-of (m / mark-02
                              :ARG1 (m2 / maturate-03
                                    :ARG1 (m4 / megakaryocyte)))
                        :mod (l3 / late))))
      :concession (i2 / induce-01
                  :ARG0 o
                  :ARG2 e
                  :extent (l / less
                        :degree (m3 / more
                              :degree (m5 / much)))
                  :compared-to (e2 / express-03
                        :ARG2 (p4 / protein :name (n5 / name :op1 "GATA-1"))))
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod "1C")))

# ::id bel_pmid_1806_0035.34122 ::date 2015-05-10T06:32:34 ::annotator SDL-AMR-09 ::preferred
# ::snt enforced STAT1 expression promoted several features of megakaryocytic differentiation of G1ME cells, as evidenced by increased cell size (forward scatter) and increased DNA content, reflecting polyploidization (Figure ?(Figure1,1, A and B). Similar effects were produced by enforced expression of IRF-1, a major STAT1 effector (reviewed in ref. 26).
# ::save-date Tue Feb 2, 2016 ::file bel_pmid_1806_0035_34122.txt
(m / multi-sentence
      :snt1 (p / promote-01
            :ARG0 (e / express-03
                  :ARG2 (p2 / protein :name (n / name :op1 "STAT1"))
                  :ARG1-of (e2 / enforce-01))
            :ARG1 (f / feature
                  :quant (s / several)
                  :topic (d / differentiate-01
                        :ARG0 (m3 / megakaryocyte)
                        :ARG1 (c2 / cell-line :name (n3 / name :op1 "G1ME"))))
            :ARG1-of (e3 / evidence-01
                  :ARG0 (a2 / and
                        :op1 (s2 / size
                              :poss (c3 / cell)
                              :ARG1-of (i / increase-01)
                              :ARG1-of (s3 / show-01
                                    :ARG0 (s4 / scatter-01
                                          :direction (f4 / forward))))
                        :op2 (c4 / contain-01
                              :ARG1 (n2 / nucleic-acid :wiki "DNA" :name (n6 / name :op1 "DNA")
                                    :ARG1-of (i2 / increase-01)))))
            :ARG1-of (r2 / reflect-01
                  :ARG2 (p3 / polyploidize-01))
            :ARG1-of (d3 / describe-01
                  :ARG0 (a / and
                        :op1 (f2 / figure :mod "1.1.A")
                        :op2 (f3 / figure :mod "1.1.B"))))
      :snt2 (p4 / produce-01
            :ARG0 (e5 / express-03
                  :ARG2 (p6 / protein :name (n4 / name :op1 "IRF-1")
                        :ARG0-of (a4 / affect-01
                              :ARG1 (p5 / protein :name (n5 / name :op1 "STAT1"))
                              :ARG1-of (m2 / major-02)))
                  :ARG1-of (e6 / enforce-01))
            :ARG1 (a3 / affect-01
                  :ARG1-of (r3 / resemble-01))
            :ARG1-of (d4 / describe-01
                  :ARG0 (p7 / publication
                        :ARG1-of (c / cite-01
                              :ARG2 26)))))

# ::id bel_pmid_1806_0035.34154 ::date 2015-05-10T06:49:57 ::annotator SDL-AMR-09 ::preferred
# ::snt Second, mice deficient for both STAT5A and STAT5B are thrombocytopenic, likely due to a reduction in functional hematopoietic progenitors (18).
# ::save-date Sun May 10, 2015 ::file bel_pmid_1806_0035_34154.txt
(t / thrombocytopenic
      :domain (m / mouse
            :ARG0-of (l / lack-01
                  :ARG1 (a / and
                        :op1 (g / gene :name (n / name :op1 "STAT1A"))
                        :op2 (g2 / gene :name (n2 / name :op1 "STAT1B")))))
      :ARG1-of (c / cause-01
            :ARG0 (r / reduce-01
                  :ARG1 (p / progenitor
                        :mod (h / hematopoietic)
                        :ARG0-of (f / function-01)))
            :ARG1-of (l2 / likely-01))
      :mod (o / ordinal-entity :value 2)
      :ARG1-of (d / describe-01
            :ARG0 (p2 / publication
                  :ARG1-of (c2 / cite-01
                        :ARG2 18))))

# ::id bel_pmid_1806_0035.39068 ::date 2015-05-10T07:07:40 ::annotator SDL-AMR-09 ::preferred
# ::snt TPO functions through binding its receptor, c-Mpl, to activate JAK2, STAT1, STAT3, and STAT5 in megakaryocytes and other hematopoietic cells (10–12).
# ::save-date Sun Jan 3, 2016 ::file bel_pmid_1806_0035_39068.txt
(f / function-01
      :ARG0 (p5 / protein :name (n / name :op1 "TPO"))
      :instrument (b / bind-01
            :ARG1 (p6 / protein :name (n7 / name :op1 "c-Mpl" :op2 "receptor")
                  :poss p5)
            :ARG2 p5
            :purpose (a / activate-01
                  :ARG0 p5
                  :ARG1 (a2 / and
                        :op1 (e / enzyme :name (n3 / name :op1 "JAK2"))
                        :op2 (p / protein :name (n4 / name :op1 "STAT1"))
                        :op3 (p2 / protein :name (n5 / name :op1 "STAT3"))
                        :op4 (p3 / protein :name (n6 / name :op1 "STAT5")))
                  :location (a3 / and
                        :op1 (m / megakaryocyte)
                        :op2 (c2 / cell
                              :mod (h / hematopoietic)
                              :mod (o / other)))))
      :ARG1-of (d / describe-01
            :ARG0 (p4 / publication
                  :ARG1-of (c3 / cite-01
                        :ARG2 (v / value-interval :op1 10 :op2 12)))))

# ::id bel_pmid_1806_0035.39758 ::date 2015-05-10T07:17:20 ::annotator SDL-AMR-09 ::preferred
# ::snt enforced STAT1 expression promoted several features of megakaryocytic differentiation of G1ME cells, as evidenced by increased cell size (forward scatter) and increased DNA content, reflecting polyploidization (Figure ?(Figure1,1, A and B). Similar effects were produced by enforced expression of IRF-1, a major STAT1 effector (reviewed in ref. 26).
# ::save-date Tue Feb 2, 2016 ::file bel_pmid_1806_0035_39758.txt
(m / multi-sentence
      :snt1 (p / promote-01
            :ARG0 (e / express-03
                  :ARG2 (p2 / protein :name (n / name :op1 "STAT1"))
                  :ARG1-of (e2 / enforce-01))
            :ARG1 (f / feature
                  :quant (s / several)
                  :topic (d / differentiate-01
                        :ARG0 (m3 / megakaryocyte)
                        :ARG1 (c2 / cell-line :name (n3 / name :op1 "G1ME"))))
            :ARG1-of (e3 / evidence-01
                  :ARG0 (a / and
                        :op1 (s2 / size
                              :poss (c3 / cell)
                              :ARG1-of (i / increase-01)
                              :ARG1-of (s3 / show-01
                                    :ARG0 (s4 / scatter-01
                                          :direction (f4 / forward))))
                        :op2 (c4 / contain-01
                              :ARG1 (n2 / nucleic-acid :wiki "DNA" :name (n6 / name :op1 "DNA")
                                    :ARG1-of (i2 / increase-01)))))
            :ARG1-of (r2 / reflect-01
                  :ARG2 (p3 / polyploidize-01))
            :ARG1-of (d3 / describe-01
                  :ARG0 (a2 / and
                        :op1 (f2 / figure :mod "1.1.A")
                        :op2 (f3 / figure :mod "1.1.B"))))
      :snt2 (p4 / produce-01
            :ARG0 (e4 / express-03
                  :ARG2 (p6 / protein :name (n4 / name :op1 "IRF-1")
                        :ARG0-of (a4 / affect-01
                              :ARG1 (p5 / protein :name (n5 / name :op1 "STAT1"))
                              :ARG1-of (m2 / major-02)))
                  :ARG1-of (e6 / enforce-01))
            :ARG1 (a3 / affect-01
                  :ARG1-of (r3 / resemble-01))
            :ARG1-of (d4 / describe-01
                  :ARG0 (p7 / publication
                        :ARG1-of (c / cite-01
                              :ARG2 26)))))

# ::id bel_pmid_1807_7438.4108 ::date 2015-05-08T07:50:45 ::annotator SDL-AMR-09 ::preferred
# ::snt Although inhibitors of PKC had no effect on this suppression, MAPK inhibitors completely prevented the TPA effect. RasGRP1 activates the MAPK pathway through activation of the small G protein H-Ras.
# ::save-date Tue Jul 28, 2015 ::file bel_pmid_1807_7438_4108.txt
(m / multi-sentence
      :snt1 (p / prevent-01
            :ARG0 (m2 / molecular-physical-entity
                  :ARG0-of (i / inhibit-01
                        :ARG1 (p2 / pathway :name (n / name :op1 "MAPK"))))
            :ARG1 (a / affect-01
                  :ARG0 (s / small-molecule :name (n2 / name :op1 "TPA")))
            :ARG1-of (c / complete-02)
            :concession (a2 / affect-01 :polarity -
                  :ARG0 (m3 / molecular-physical-entity
                        :ARG0-of (i2 / inhibit-01
                              :ARG1 (e2 / enzyme :name (n3 / name :op1 "PKC"))))
                  :ARG1 (s3 / suppress-01
                        :ARG1 a)))
      :snt2 (a3 / activate-01
            :ARG0 (p3 / protein :name (n4 / name :op1 "RasGRP1"))
            :ARG1 (p4 / pathway :name (n5 / name :op1 "MAPK"))
            :manner (a4 / activate-01
                  :ARG0 p3
                  :ARG1 (e3 / enzyme :name (n7 / name :op1 "H-Ras")
                        :mod (e4 / enzyme :name (n6 / name :op1 "small" :op2 "G" :op3 "protein"))))))

# ::id bel_pmid_1807_7438.32114 ::date 2015-05-08T08:04:50 ::annotator SDL-AMR-09 ::preferred
# ::snt Functional assessment of NCC by using thiazide-sensitive (22)Na(+) uptakes revealed that TPA completely suppresses NCC function. Biotinylation experiments demonstrated that this result was primarily because of decreased surface expression of NCC.
# ::save-date Tue Feb 2, 2016 ::file bel_pmid_1807_7438_32114.txt
(m / multi-sentence
      :snt1 (r / reveal-01
            :ARG0 (a / assess-01
                  :ARG1 p2
                  :mod (f2 / function-01)
                  :manner (u / use-01
                        :ARG1 (u2 / uptake
                              :mod (s5 / small-molecule :name (n3 / name :op1 "22Na+"))
                              :ARG1-of (s2 / sensitize-01
                                    :ARG2 (s3 / small-molecule :name (n4 / name :op1 "thiazide"))))))
            :ARG1 (s / suppress-01
                  :ARG0 (s6 / small-molecule :name (n / name :op1 "TPA"))
                  :ARG1 (f / function-01
                        :ARG0 (p2 / protein :name (n2 / name :op1 "NCC")))
                  :ARG1-of (c / complete-02)))
      :snt2 (d / demonstrate-01
            :ARG0 (e / experiment-01
                  :ARG1 (b / biotinylate-01))
            :ARG1 (c2 / cause-01
                  :ARG0 (d2 / decrease-01
                        :ARG1 (e2 / express-03
                              :ARG2 (p5 / protein :name (n5 / name :op1 "NCC"))
                              :ARG3 (s4 / surface)))
                  :ARG1 (t / thing
                        :ARG2-of (r2 / result-01)
                        :mod (t2 / this))
                  :mod (p4 / primary))))

# ::id bel_pmid_1820_0061.27886 ::date 2015-05-08T08:20:26 ::annotator SDL-AMR-09 ::preferred
# ::snt Expression of all proinflammatory/profibrotic mediators as assessed by reverse transcriptase-PCR and densitometry was less in Lenti-IL-10-injected wounds compared with Lenti-GFP-injected wounds, with the difference in the expression of IL-6, MCP-1, and HSP47 reaching statistical significance (Figure 5).
# ::save-date Mon Jan 4, 2016 ::file bel_pmid_1820_0061_27886.txt
(a6 / and
      :op1 (e / express-03
            :ARG2 (a / and
                  :op1 (m2 / molecular-physical-entity
                        :ARG0-of (f / favor-01
                              :ARG1 (i / inflame-01))
                        :ARG0-of (m / mediate-01))
                  :op2 (m3 / molecular-physical-entity
                        :ARG0-of m
                        :ARG0-of (f2 / favor-01
                              :ARG1 (f3 / fibrosis)))
                  :mod (a2 / all))
            :ARG3 (w / wound-01
                  :ARG2-of (i2 / inject-01
                        :ARG1 (p / protein :name (n / name :op1 "Lenti-IL-10"))))
            :mod (l / less)
            :compared-to (e5 / express-03
                  :ARG2 a
                  :ARG3 (w2 / wound-01
                        :ARG2-of (i3 / inject-01
                              :ARG1 (p2 / protein :name (n2 / name :op1 "Lenti-GFP")))))
            :ARG1-of (a4 / assess-01
                  :instrument (a5 / and
                        :op1 (r2 / react-01
                              :ARG0 (p6 / polymerase)
                              :ARG1-of (c / chain-01)
                              :mod (t2 / transcriptase
                                    :ARG1-of (r3 / reverse-01)))
                        :op2 (d3 / densitometry))))
      :op2 (r / reach-01
            :ARG0 (d / differ-02
                  :ARG1 (a3 / and
                        :op1 (e2 / express-03
                              :ARG2 (p3 / protein :name (n3 / name :op1 "IL-6")))
                        :op2 (e3 / express-03
                              :ARG2 (p4 / protein :name (n4 / name :op1 "MCP-1")))
                        :op3 (e4 / express-03
                              :ARG2 (p5 / protein :name (n5 / name :op1 "HSP47")))))
            :ARG1 (s3 / signify-01
                  :mod (s / statistics)))
      :ARG1-of (d2 / describe-01
            :ARG0 (f4 / figure :mod 5)))

# ::id bel_pmid_1826_8536.21638 ::date 2015-05-08T08:36:28 ::annotator SDL-AMR-09 ::preferred
# ::snt observations that inhibition of PI3K or EGF-R is sufficient to prevent terminal differentiation in keratinocytes in suspension (Rodeck et al., 1997; Nikolopoulos et al., 2005), and that function disrupting antibodies to E-cadherin abrogate Akt phosphorylation inducing growth arrest and terminal differentiation in conventional submerged mouse keratinocyte cultures at confluency (Calautti et al., 2005).
# ::save-date Sun Dec 20, 2015 ::file bel_pmid_1826_8536_21638.txt
(o / observe-02
      :ARG1 (a / and
            :op1 (s / suffice-01
                  :ARG0 (i / inhibit-01
                        :ARG1 (o2 / or
                              :op1 (e2 / enzyme :name (n2 / name :op1 "PI3K"))
                              :op2 (e / enzyme :name (n / name :op1 "EGF-R"))))
                  :ARG1 (p / prevent-01
                        :ARG0 i
                        :ARG1 (d / differentiate-01
                              :ARG1 (c / cell :name (n3 / name :op1 "keratinocyte")
                                    :ARG1-of (s2 / suspend-02))
                              :mod (t / terminal)))
                  :ARG1-of (d2 / describe-01
                        :ARG0 (a2 / and
                              :op1 (p2 / publication-91
                                    :ARG0 (a3 / and
                                          :op1 (p3 / person :name (n4 / name :op1 "Rodeck"))
                                          :op2 (p4 / person
                                                :mod (o3 / other)))
                                    :time (d7 / date-entity :year 1997))
                              :op2 (p5 / publication-91
                                    :ARG0 (a4 / and
                                          :op1 (p6 / person :name (n5 / name :op1 "Nikolopoulos"))
                                          :op2 (p7 / person
                                                :mod (o4 / other)))
                                    :time d6))))
            :op2 (a5 / abrogate-01
                  :ARG0 (a6 / antibody
                        :ARG0-of (d3 / disrupt-01
                              :ARG1 (f / function-01))
                        :ARG0-of (c2 / counter-01
                              :ARG1 (p8 / protein :name (n6 / name :op1 "E-cadherin"))))
                  :ARG1 (p9 / phosphorylate-01
                        :ARG1 (e3 / enzyme :name (n7 / name :op1 "Akt")))
                  :ARG0-of (i2 / induce-01
                        :ARG2 (a7 / and
                              :op1 (a8 / arrest-02
                                    :ARG1 (g / grow-01
                                          :ARG1 c3))
                              :op2 (d4 / differentiate-01
                                    :ARG1 (c3 / culture
                                          :source (m / mouse)
                                          :mod c
                                          :ARG1-of (s3 / submerge-01
                                                :manner (c4 / conventional)))
                                    :mod t))
                        :manner (c5 / confluency))
                  :ARG1-of (d5 / describe-01
                        :ARG0 (p10 / publication-91
                              :ARG0 (a9 / and
                                    :op1 (p11 / person :name (n8 / name :op1 "Calautti"))
                                    :op2 (p12 / person
                                          :mod (o5 / other)))
                              :time (d6 / date-entity :year 2005))))))

# ::id bel_pmid_1826_8536.21660 ::date 2015-05-08T08:55:37 ::annotator SDL-AMR-09 ::preferred
# ::snt In vivo, b4-integrin amplifies proproliferative signals in basal epidermal keratinocytes (Nikolopoulos et al., 2005), where STAT3 is expressed and can be activated by EGF/EGF-R (Nishio et al., 2001; Chan et al., 2004; Li et al., 2007)
# ::save-date Sun Jan 17, 2016 ::file bel_pmid_1826_8536_21660.txt
(a / amplify-01
      :ARG0 (p / protein :name (n / name :op1 "b4-integrin"))
      :ARG1 (s / signal-07
            :mod (p2 / proliferate-01))
      :location (c / cell :name (n2 / name :op1 "keratinocyte")
            :mod (b / basal)
            :part-of (e / epidermis)
            :ARG3-of (e2 / express-03
                  :ARG2 (p6 / protein :name (n4 / name :op1 "STAT3")))
            :location-of (p7 / possible-01
                  :ARG1 (a3 / activate-01
                        :ARG0 (s3 / slash
                              :op1 (p17 / protein :name (n5 / name :op1 "EGF"))
                              :op2 (e4 / enzyme :name (n6 / name :op1 "EGF-R")))
                        :ARG1 p6)
                  :ARG1-of (d2 / describe-01
                        :ARG0 (a5 / and
                              :op1 (p8 / publication-91
                                    :ARG0 (a6 / and
                                          :op1 (p9 / person :name (n7 / name :op1 "Nishio"))
                                          :op2 (p10 / person
                                                :mod (o2 / other)))
                                    :time (d3 / date-entity :year 2001))
                              :op2 (p11 / publication-91
                                    :ARG0 (a7 / and
                                          :op1 (p12 / person :name (n8 / name :op1 "Chan"))
                                          :op2 (p13 / person
                                                :mod (o3 / other)))
                                    :time (d4 / date-entity :year 2004))
                              :op3 (p14 / publication-91
                                    :ARG0 (a8 / and
                                          :op1 (p15 / person :name (n9 / name :op1 "Li"))
                                          :op2 (p16 / person
                                                :mod (o4 / other)))
                                    :time (d5 / date-entity :year 2007))))))
      :manner (i / in-vivo)
      :ARG1-of (d / describe-01
            :ARG0 (p3 / publication-91
                  :ARG0 (a2 / and
                        :op1 (p4 / person :name (n3 / name :op1 "Nikolopoulos"))
                        :op2 (p5 / person
                              :mod (o / other)))
                  :time (d6 / date-entity :year 2005))))

# ::id bel_pmid_1826_8536.22176 ::date 2015-05-08T09:08:29 ::annotator SDL-AMR-09 ::preferred
# ::snt Src-family kinases then phosphorylate the plaque proteins b-catenin, plakoglobin, p120cnt, and acatenin, which is required for their association with the E-cadherin tail (Calautti et al., 1998, 2005).
# ::save-date Mon Jan 4, 2016 ::file bel_pmid_1826_8536_22176.txt
(p / phosphorylate-01
      :ARG1 (a / and
            :op1 (p2 / protein :name (n2 / name :op1 "b-catenin"))
            :op2 (p3 / protein :name (n3 / name :op1 "plakoglobin"))
            :op3 (p4 / protein :name (n4 / name :op1 "p120cnt"))
            :op4 (p5 / protein :name (n5 / name :op1 "acatenin"))
            :part-of (p6 / plaque))
      :ARG2 (k / kinase
            :ARG1-of (i / include-91
                  :ARG2 (p13 / protein-family :name (n / name :op1 "Src"))))
      :time (t / then)
      :ARG1-of (d / describe-01
            :ARG0 (a4 / and
                  :op1 (p9 / publication-91
                        :ARG0 (a3 / and
                              :op1 (p10 / person :name (n7 / name :op1 "Calautti"))
                              :op2 (p11 / person
                                    :mod (o / other)))
                        :time (d2 / date-entity :year 1998))
                  :op2 (p12 / publication-91
                        :ARG0 a3
                        :time (d3 / date-entity :year 2005))))
      :ARG1-of (r / require-01
            :purpose (a2 / associate-01
                  :ARG1 a
                  :ARG2 (p7 / protein-segment
                        :part-of (p8 / protein :name (n6 / name :op1 "E-cadherin"))))))

# ::id bel_pmid_1826_8536.22182 ::date 2015-05-10T13:33:31 ::annotator SDL-AMR-09 ::preferred
# ::snt JNK2 might potentially be activated via Src kinasemediated phosphorylation of EGF-R on Tyr920 (Calautti et al., 2005),
# ::save-date Wed May 13, 2015 ::file bel_pmid_1826_8536_22182.txt
(p / possible-01
      :ARG1 (a / activate-01
            :ARG0 (p2 / phosphorylate-01
                  :ARG1 (a3 / amino-acid :mod 920 :name (n3 / name :op1 "tyrosine")
                        :part-of (e2 / enzyme :name (n4 / name :op1 "EGF-R")))
                  :ARG1-of (m / mediate-01
                        :ARG0 (k / kinase :name (n2 / name :op1 "Src"))))
            :ARG1 (e / enzyme :name (n / name :op1 "JNK2")))
      :manner (p3 / potential)
      :ARG1-of (d2 / describe-01
            :ARG0 (p5 / publication-91
                  :ARG0 (a2 / and
                        :op1 (p6 / person :name (n5 / name :op1 "Calautti"))
                        :op2 (p7 / person
                              :mod (o / other)))
                  :time (d / date-entity :year 2005))))

# ::id bel_pmid_1826_8536.22186 ::date 2015-05-10T13:43:09 ::annotator SDL-AMR-09 ::preferred
# ::snt b1-integrin phosphorylation by Src results in EGF-R activation (Miranti and Brugge, 2002), and b1-integrin expression is required for the initiation of mouse mammary tumors expressing the polyoma virus middle T antigen (White et al., 2004).
# ::save-date Wed May 13, 2015 ::file bel_pmid_1826_8536_22186.txt
(a / and
      :op1 (r / result-01
            :ARG1 (p / phosphorylate-01
                  :ARG1 (p2 / protein :name (n / name :op1 "b1-integrin"))
                  :ARG2 (p10 / protein :name (n2 / name :op1 "Src")))
            :ARG2 (a2 / activate-01
                  :ARG1 (e / enzyme :name (n3 / name :op1 "EGF-R")))
            :ARG1-of (d3 / describe-01
                  :ARG0 (p3 / publication-91
                        :ARG0 (a3 / and
                              :op1 (p4 / person :name (n4 / name :op1 "Miranti"))
                              :op2 (p5 / person :name (n5 / name :op1 "Brugge")))
                        :time (d / date-entity :year 2002))))
      :op2 (r2 / require-01
            :ARG0 (i / initiate-01
                  :ARG1 (t / tumor
                        :mod (m / mammary)
                        :location (m2 / mouse)
                        :ARG3-of (e3 / express-03
                              :ARG2 (p6 / protein :name (n6 / name :op1 "polyoma" :op2 "virus" :op3 "middle" :op4 "T" :op5 "antigen")))))
            :ARG1 (e2 / express-03
                  :ARG2 p2)
            :ARG1-of (d4 / describe-01
                  :ARG0 (p7 / publication-91
                        :ARG0 (a4 / and
                              :op1 (p8 / person :name (n7 / name :op1 "White"))
                              :op2 (p9 / person
                                    :mod (o / other)))
                        :time (d2 / date-entity :year 2004)))))

# ::id bel_pmid_1826_8536.25888 ::date 2015-05-10T13:50:50 ::annotator SDL-AMR-09 ::preferred
# ::snt E-cadherin gene deletion, which results in some hyperproliferation in the epidermis (Young et al., 2003; Tinkle et al., 2004; Tunggal et al., 2005).
# ::save-date Sun Jan 3, 2016 ::file bel_pmid_1826_8536_25888.txt
(d6 / delete-01
      :ARG1 (g / gene
            :ARG0-of (e / encode-01
                  :ARG1 (p / protein :name (n / name :op1 "E-cadherin"))))
      :ARG1-of (r / result-01
            :ARG2 (p11 / proliferate-01
                  :location (e2 / epidermis)
                  :mod (s / some)
                  :degree (h / hyper)))
      :ARG1-of (d5 / describe-01
            :ARG0 (a / and
                  :op1 (p2 / publication-91
                        :ARG0 (a2 / and
                              :op1 (p3 / person :name (n2 / name :op1 "Young"))
                              :op2 (p4 / person
                                    :mod (o / other)))
                        :time (d / date-entity :year 2003))
                  :op2 (p5 / publication-91
                        :ARG0 (a3 / and
                              :op1 (p6 / person :name (n3 / name :op1 "Tinkle"))
                              :op2 (p7 / person
                                    :mod (o2 / other)))
                        :time (d2 / date-entity :year 2004))
                  :op3 (p8 / publication-91
                        :ARG0 (a4 / and
                              :op1 (p9 / person :name (n4 / name :op1 "Tunggal"))
                              :op2 (p10 / person
                                    :mod (o3 / other)))
                        :time (d3 / date-entity :year 2005)))))

# ::id bel_pmid_1826_8536.25890 ::date 2015-05-10T13:56:10 ::annotator SDL-AMR-09 ::preferred
# ::snt E-cadherinknockout epidermis displays some hyperproliferation, which however appears to be limited due to compensatory upregulation of P-cadherin (Young et al., 2003; Tinkle et al., 2004; Tunggal et al., 2005)
# ::save-date Sun Jan 3, 2016 ::file bel_pmid_1826_8536_25890.txt
(c2 / contrast-01
      :ARG1 (d4 / display-01
            :ARG0 (e / epidermis
                  :mod (p / protein :wiki "CDH1_(gene)"
                        :name (n / name :op1 "E-cadherin")
                        :ARG2-of (m / mutate-01 :mod "-/-")))
            :ARG1 (p12 / proliferate-01
                  :mod (s / some)
                  :degree (h / hyper)))
      :ARG2 (a / appear-02
            :ARG1 (p13 / proliferate-01
                  :ARG1-of (l / limit-01
                        :ARG0 (u / upregulate-01
                              :ARG1 (p2 / protein :wiki "CDH3_(gene)"
                                    :name (n2 / name :op1 "P-cadherin"))
                              :ARG0-of (c / compensate-01)))
                  :degree h))
      :ARG1-of (d5 / describe-01
            :ARG0 (a2 / and
                  :op1 (p3 / publication-91
                        :ARG0 (a3 / and
                              :op1 (p4 / person :wiki -
                                    :name (n3 / name :op1 "Young"))
                              :op2 (p5 / person
                                    :mod (o / other)))
                        :time (d / date-entity :year 2003))
                  :op2 (p6 / publication-91
                        :ARG0 (a4 / and
                              :op1 (p7 / person :wiki -
                                    :name (n4 / name :op1 "Tinkle"))
                              :op2 (p8 / person
                                    :mod (o2 / other)))
                        :time (d2 / date-entity :year 2004))
                  :op3 (p9 / publication-91
                        :ARG0 (a5 / and
                              :op1 (p10 / person :wiki -
                                    :name (n5 / name :op1 "Tunggal"))
                              :op2 (p11 / person
                                    :mod (o3 / other)))
                        :time (d3 / date-entity :year 2005)))))

# ::id bel_pmid_1826_8536.25892 ::date 2015-05-10T14:08:54 ::annotator SDL-AMR-09 ::preferred
# ::snt Recently reported in A431 cells, this can occur through E-cadherin-mediated inhibition of transphosphorylation on Tyr845EGF-R (Perrais et al., 2007), the site, which catalyzes EGF-induced mitogenesis (Ishizawar and Parsons, 2004).
# ::save-date Tue Feb 2, 2016 ::file bel_pmid_1826_8536_25892.txt
(p / possible-01
      :ARG1 (t / this
            :ARG1-of (r / report-01
                  :time (r2 / recent)
                  :location (c2 / cell-line :name (n8 / name :op1 "A431"))))
      :manner (i / inhibit-01
            :ARG1 (t2 / transphosphorylate-01
                  :ARG1 (a3 / amino-acid :mod 845 :name (n3 / name :op1 "tyrosine")
                        :part-of (e / enzyme :name (n2 / name :op1 "EGF-R"))
                        :ARG0-of (c / catalyze-01
                              :ARG1 (m2 / mitogenesis
                                    :ARG2-of (i2 / induce-01
                                          :ARG0 (p3 / protein :name (n4 / name :op1 "EGF"))))
                              :ARG1-of (d3 / describe-01
                                    :ARG0 (p5 / publication-91
                                          :ARG0 (a / and
                                                :op1 (p6 / person :name (n5 / name :op1 "Ishizawar"))
                                                :op2 (p7 / person :name (n6 / name :op1 "Parsons")))
                                          :time (d2 / date-entity :year 2004))))))
            :ARG1-of (m / mediate-01
                  :ARG0 (p2 / protein :name (n / name :op1 "E-cadherin"))))
      :ARG1-of (d4 / describe-01
            :ARG0 (p8 / publication-91
                  :ARG0 (a2 / and
                        :op1 (p9 / person :name (n7 / name :op1 "Perrais"))
                        :op2 (p10 / person
                              :mod (o2 / other)))
                  :time (d / date-entity :year 2007))))

# ::id bel_pmid_1826_8536.26244 ::date 2015-05-10T21:25:06 ::annotator SDL-AMR-09 ::preferred
# ::snt In mouse keratinocytes, Src kinase-mediated phosphorylation was found to generate a docking site for PI3K (p85) on plakoglobin in an EGF-R-dependent manner, to a minor extent on p120cnt, but not on b-catenin, which apparently lacks a PI3K (p85)-docking motive (Calautti et al., 2005).
# ::save-date Wed May 13, 2015 ::file bel_pmid_1826_8536_26244.txt
(f / find-01
      :ARG1 (g / generate-01
            :ARG0 (p / phosphorylate-01
                  :ARG1-of (m2 / mediate-01
                        :ARG0 (k / kinase :name (n2 / name :op1 "Src"))))
            :ARG1 (s / site
                  :ARG2-of (d2 / dock-01
                        :ARG1 (p2 / protein-segment :name (n4 / name :op1 "p85")
                              :part-of (e / enzyme :name (n3 / name :op1 "PI3K"))))
                  :location (a / and
                        :op1 (p3 / protein :name (n5 / name :op1 "plakoglobin"))
                        :op2 (p5 / protein :name (n7 / name :op1 "p120cnt")
                              :extent (m3 / minor))
                        :ARG1-of (c2 / contrast-01
                              :ARG2 (p6 / protein :name (n8 / name :op1 "b-catenin")
                                    :ARG0-of (l / lack-01
                                          :ARG1 (m4 / motive
                                                :ARG2-of d2)
                                          :ARG1-of (a2 / appear-02))))))
            :manner (d3 / depend-01
                  :ARG1 (e2 / enzyme :name (n6 / name :op1 "EGF-R"))))
      :location (c / cell :name (n / name :op1 "keratinocyte")
            :source (m / mouse))
      :ARG1-of (d4 / describe-01
            :ARG0 (p7 / publication-91
                  :ARG0 (a3 / and
                        :op1 (p8 / person :name (n9 / name :op1 "Calautti"))
                        :op2 (p9 / person
                              :mod (o / other)))
                  :time (d / date-entity :year 2005))))

# ::id bel_pmid_1826_8536.28578 ::date 2015-05-10T21:44:21 ::annotator SDL-AMR-09 ::preferred
# ::snt Transgenic mice (both newborn and adult) expressing the signalingdefective b4-integrin mutant showed a twofold decrease in the epidermal proliferative index, confirming that b4-integrin actually contributes to proliferation (Nikolopoulos et al., 2005).
# ::save-date Mon Dec 21, 2015 ::file bel_pmid_1826_8536_28578.txt
(s / show-01
      :ARG0 (a4 / and
            :op1 (m / mouse
                  :mod (t / transgenic)
                  :ARG1-of (b / bear-02
                        :time (n / new-01))
                  :ARG3-of (e / express-03
                        :ARG2 (p / protein :name (n2 / name :op1 "b4-integrin")
                              :ARG2-of (m2 / mutate-01)
                              :ARG0-of (d2 / defect-01
                                    :ARG1 (s2 / signal-07)))))
            :op2 (m3 / mouse
                  :mod t
                  :mod (a / adult)
                  :ARG3-of e))
      :ARG1 (d3 / decrease-01
            :ARG1 (i / index
                  :mod (p3 / proliferate-01
                        :ARG0 (e2 / epidermis)))
            :ARG2 (p2 / product-of :op1 2))
      :ARG0-of (c / confirm-01
            :ARG1 (c2 / contribute-01
                  :ARG0 p
                  :ARG2 p3
                  :ARG1-of (a2 / actual-02)))
      :ARG1-of (d4 / describe-01
            :ARG0 (p4 / publication-91
                  :ARG0 (a3 / and
                        :op1 (p5 / person :name (n3 / name :op1 "Nikolopoulos"))
                        :op2 (p6 / person
                              :mod (o / other)))
                  :time (d / date-entity :year 2005))))

# ::id bel_pmid_1826_8536.28582 ::date 2015-05-10T21:51:36 ::annotator SDL-AMR-09 ::preferred
# ::snt b4-integrin mediates the phosphorylation of ErbB2 on Tyr877 by a Src-family kinase....(Ishizawar and Parsons, 2004).
# ::save-date Mon Jan 4, 2016 ::file bel_pmid_1826_8536_28582.txt
(m / mediate-01
      :ARG0 (p2 / protein :name (n / name :op1 "b4-integrin"))
      :ARG1 (p / phosphorylate-01
            :ARG1 (a2 / amino-acid :mod 877 :name (n2 / name :op1 "tyrosine")
                  :part-of (p4 / protein :name (n3 / name :op1 "ErbB2")))
            :ARG2 (k / kinase
                  :ARG1-of (i / include-91
                        :ARG2 (p3 / protein-family :name (n4 / name :op1 "Src")))))
      :ARG1-of (d2 / describe-01
            :ARG0 (p5 / publication-91
                  :ARG0 (a / and
                        :op1 (p6 / person :name (n5 / name :op1 "Ishizawar"))
                        :op2 (p7 / person :name (n6 / name :op1 "Parsons")))
                  :time (d / date-entity :year 2004))))

# ::id bel_pmid_1826_8536.28586 ::date 2015-05-10T21:54:53 ::annotator SDL-AMR-09 ::preferred
# ::snt In parallel to JNK, two other MAPKs, ERK1 and ERK2, were also found to be targeted to the nucleus in a b4-integrindependent manner in keratinocytes (Nikolopoulos et al., 2005).
# ::save-date Sun Jan 17, 2016 ::file bel_pmid_1826_8536_28586.txt
(f / find-01
      :ARG1 (t / target-01
            :ARG0 (n4 / nucleus)
            :ARG1 (a / and
                  :op1 (e / enzyme :name (n / name :op1 "ERK1"))
                  :op2 (e2 / enzyme :name (n2 / name :op1 "ERK2"))
                  :ARG1-of (i / include-91
                        :ARG2 (p6 / protein-family :name (n3 / name :op1 "MAPK")))
                  :ARG0-of (p2 / parallel-01
                        :ARG1 (e4 / enzyme :name (n7 / name :op1 "JNK"))))
            :manner (d2 / depend-01
                  :ARG1 (p / protein :name (n5 / name :op1 "b4-integrin")))
            :location (c / cell :name (n6 / name :op1 "keratinocyte")))
      :mod (a2 / also)
      :ARG1-of (d3 / describe-01
            :ARG0 (p3 / publication-91
                  :ARG0 (a3 / and
                        :op1 (p4 / person :name (n8 / name :op1 "Nikolopoulos"))
                        :op2 (p5 / person
                              :mod (o2 / other)))
                  :time (d / date-entity :year 2005))))

# ::id bel_pmid_1826_8536.28670 ::date 2015-05-10T22:01:58 ::annotator SDL-AMR-09 ::preferred
# ::snt plakoglobin-mediated suppression of the pro-proliferative proto-oncogene c-Myc, which is critical for growth inhibition in these cells (Arnold and Watt, 2001; Waikel et al., 2001; Kolly et al., 2005; Figure 2).
# ::save-date Sun Jan 3, 2016 ::file bel_pmid_1826_8536_28670.txt
(c / critical-02
      :ARG1 (s / suppress-01
            :ARG1 (g2 / gene :name (n2 / name :op1 "c-Myc")
                  :ARG0-of (f / favor-01
                        :ARG1 (p2 / proliferate-01))
                  :mod (p3 / proto)
                  :ARG0-of (c3 / cause-01
                        :ARG1 (d4 / disease :wiki "Cancer" :name (n7 / name :op1 "cancer"))))
            :ARG1-of (m / mediate-01
                  :ARG0 (p / protein :name (n / name :op1 "plakoglobin"))))
      :ARG3 (i / inhibit-01
            :ARG1 (g / grow-01)
            :location (c2 / cell
                  :mod (t / this)))
      :ARG1-of (d2 / describe-01
            :ARG0 (a / and
                  :op1 (p4 / publication-91
                        :ARG0 (a2 / and
                              :op1 (p7 / person :name (n3 / name :op1 "Arnold"))
                              :op2 (p8 / person :name (n4 / name :op1 "Watt")))
                        :time (d / date-entity :year 2001))
                  :op2 (p5 / publication-91
                        :ARG0 (a3 / and
                              :op1 (p9 / person :name (n5 / name :op1 "Waikel"))
                              :op2 (p10 / person
                                    :mod (o2 / other)))
                        :time d)
                  :op3 (p6 / publication-91
                        :ARG0 (a4 / and
                              :op1 (p11 / person :name (n6 / name :op1 "Kolly"))
                              :op2 (p12 / person
                                    :mod (o3 / other)))
                        :time (d3 / date-entity :year 2005))
                  :op4 (f2 / figure :mod 2))))

# ::id bel_pmid_1826_8536.29114 ::date 2015-05-10T22:08:43 ::annotator SDL-AMR-09 ::preferred
# ::snt JNK2 was found to be necessary for cell-cycle arrest in keratinocytes, as exemplified by hyperproliferation of JNK2-knockout epidermis (Sabapathy and Wagner, 2004; Weston et al., 2004).
# ::save-date Mon Jan 4, 2016 ::file bel_pmid_1826_8536_29114.txt
(f / find-01
      :ARG1 (n3 / need-01
            :ARG0 (a / arrest-02
                  :ARG1 (c / cycle-02
                        :ARG1 (c2 / cell))
                  :location (c3 / cell :name (n4 / name :op1 "keratinocyte")))
            :ARG1 (e / enzyme :name (n2 / name :op1 "JNK2")))
      :example (p7 / proliferate-01
                  :ARG0 (e3 / epidermis
                        :mod (e4 / enzyme :name (n5 / name :op1 "JNK2")
                              :ARG1-of (k / knock-out-03)))
                  :degree (h / hyper))
      :ARG1-of (d2 / describe-01
            :ARG0 (a2 / and
                  :op1 (p / publication-91
                        :ARG0 (a3 / and
                              :op1 (p2 / person :name (n / name :op1 "Sabapathy"))
                              :op2 (p3 / person :name (n6 / name :op1 "Wagner")))
                        :time (d / date-entity :year 2004))
                  :op2 (p4 / publication-91
                        :ARG0 (a4 / and
                              :op1 (p5 / person :name (n7 / name :op1 "Weston"))
                              :op2 (p6 / person
                                    :mod (o / other)))
                        :time d))))

# ::id bel_pmid_1826_8536.32064 ::date 2015-05-10T22:16:59 ::annotator SDL-AMR-09 ::preferred
# ::snt In mouse keratinocytes, it was however shown to result in Src kinase-mediated phosphorylation of EGF-R, presumably on Tyr920 (Calautti et al., 2005).
# ::save-date Wed May 13, 2015 ::file bel_pmid_1826_8536_32064.txt
(c / contrast-01
      :ARG2 (s / show-01
            :ARG1 (r / result-01
                  :ARG1 (i / it)
                  :ARG2 (p / phosphorylate-01
                        :ARG1 (a2 / amino-acid :mod 920 :name (n2 / name :op1 "tyrosine")
                              :ARG1-of (p3 / presume-01)
                              :part-of (e / enzyme :name (n3 / name :op1 "EGF-R")))
                        :ARG1-of (m / mediate-01
                              :ARG0 (k / kinase :name (n / name :op1 "Src")))))
            :location (c2 / cell :name (n5 / name :op1 "keratinocyte")
                  :source (m2 / mouse)))
      :ARG1-of (d2 / describe-01
            :ARG0 (p5 / publication-91
                  :ARG0 (a / and
                        :op1 (p6 / person :name (n4 / name :op1 "Calautti"))
                        :op2 (p7 / person
                              :mod (o / other)))
                  :time (d / date-entity :year 2005))))

# ::id bel_pmid_1826_8536.36030 ::date 2015-05-10T22:21:42 ::annotator SDL-AMR-09 ::preferred
# ::snt In human HaCaT keratinocytes for instance, ERK1/2 phosphorylation increases in dependence of EGF-R recruitment to transadhering E-cadherin, and E-cadherin-mediated activation of MAPK was also reported in intestinal epithelial cells (Pece and Gutkind, 2000; Laprise et al., 2004).
# ::save-date Sun Dec 13, 2015 ::file bel_pmid_1826_8536_36030.txt
(a / and
      :op1 (i / increase-01
            :ARG1 (p / phosphorylate-01
                  :ARG1 (s / slash
                        :op1 (e2 / enzyme :name (n2 / name :op1 "ERK1"))
                        :op2 (e3 / enzyme :name (n3 / name :op1 "ERK2"))))
            :ARG0-of (d3 / depend-01
                  :ARG1 (r / recruit-01
                        :ARG1 (e4 / enzyme :name (n4 / name :op1 "EGF-R"))
                        :ARG2 (p3 / protein :name (n5 / name :op1 "E-cadherin")
                              :ARG0-of (t / transadhere-00))))
            :location (c / cell-line :name (n6 / name :op1 "HaCaT")
                  :ARG0-of (e / exemplify-01)
                  :mod (h / human)
                  :part-of (c3 / cell :name (n10 / name :op1 "keratinocyte"))))
      :op2 (r2 / report-01
            :ARG1 (a4 / activate-01
                  :ARG1 (e6 / enzyme :name (n / name :op1 "MAPK"))
                  :ARG1-of (m / mediate-01
                        :ARG0 p3))
            :mod (a3 / also)
            :location (c2 / cell
                  :part-of (e5 / epithelium
                        :part-of (i2 / intestine))))
      :ARG1-of (d4 / describe-01
            :ARG0 (a5 / and
                  :op1 (p4 / publication-91
                        :ARG0 (a6 / and
                              :op1 (p5 / person :name (n7 / name :op1 "Pece"))
                              :op2 (p6 / person :name (n8 / name :op1 "Gutkind")))
                        :time (d / date-entity :year 2000))
                  :op2 (p7 / publication-91
                        :ARG0 (a7 / and
                              :op1 (p8 / person :name (n9 / name :op1 "Laprise"))
                              :op2 (p9 / person
                                    :mod (o / other)))
                        :time (d2 / date-entity :year 2004)))))

# ::id bel_pmid_1828_5820.25080 ::date 2015-05-10T22:29:47 ::annotator SDL-AMR-09 ::preferred
# ::snt Similar to AlkB, ABH2 and ABH3 have the ability to repair 1meA and 3meC residues. However, whereas ABH2 prefers double-stranded DNA, ABH3 and AlkB favour single-stranded DNA and RNA (Aas et al, 2003; Falnes et al, 2004).
# ::save-date Sun Jun 28, 2015 ::file bel_pmid_1828_5820_25080.txt
(m / multi-sentence
      :snt1 (c / capable-01
            :ARG1 (a / and
                  :op1 (p / protein :name (n / name :op1 "ABH2"))
                  :op2 (p2 / protein :name (n2 / name :op1 "ABH3"))
                  :ARG1-of (r3 / resemble-01
                        :ARG2 (p5 / protein :name (n5 / name :op1 "AlkB"))))
            :ARG2 (r2 / repair-01
                  :ARG0 a
                  :ARG1 (a2 / and
                        :op1 (p3 / protein-segment :name (n3 / name :op1 "1meA"))
                        :op2 (p4 / protein-segment :name (n4 / name :op1 "3meC")))))
      :snt2 (h / have-concession-91
            :ARG1 (c2 / contrast-01
                  :ARG1 (p6 / prefer-01
                        :ARG0 (p7 / protein :name (n6 / name :op1 "ABH2"))
                        :ARG1 (n12 / nucleic-acid :wiki "DNA" :name (n13 / name :op1 "DNA")
                              :mod (s3 / strand
                                    :mod (d4 / double))))
                  :ARG2 (f / favor-01
                        :ARG0 (a3 / and
                              :op1 (p8 / protein :name (n7 / name :op1 "ABH3"))
                              :op2 (p9 / protein :name (n8 / name :op1 "AlkB")))
                        :ARG1 (a4 / and
                              :op1 (n14 / nucleic-acid :wiki "DNA" :name (n15 / name :op1 "DNA")
                                    :mod (s / strand
                                          :ARG1-of (s2 / single-02)))
                              :op2 (n16 / nucleic-acid :name (n11 / name :op1 "RNA")
                                    :mod s)))
                  :ARG1-of (d6 / describe-01
                        :ARG0 (a5 / and
                              :op1 (p10 / publication-91
                                    :ARG0 (a6 / and
                                          :op1 (p11 / person :name (n9 / name :op1 "Aas"))
                                          :op2 (p12 / person
                                                :mod (o / other)))
                                    :time (d / date-entity :year 2003))
                              :op2 (p13 / publication-91
                                    :ARG0 (a7 / and
                                          :op1 (p14 / person :name (n10 / name :op1 "Falnes"))
                                          :op2 (p15 / person
                                                :mod (o2 / other)))
                                    :time (d2 / date-entity :year 2004)))))))

# ::id bel_pmid_1828_5820.25550 ::date 2015-05-10T22:41:07 ::annotator SDL-AMR-09 ::preferred
# ::snt A targeted Brca1-null mutation to the T-cell lineage resulted in increased genomic instability, apoptosis, cell-cycle arrest, and a drastic depletion of the T-cell lineage (Mak et al, 2000).
# ::save-date Sun Jan 17, 2016 ::file bel_pmid_1828_5820_25550.txt
(r / result-01
      :ARG1 (m / mutate-01 :mod "-/-"
            :ARG1 (p / protein :name (n / name :op1 "Brca1")
                  :part-of (c / cell :name (n2 / name :op1 "T-cell")))
            :ARG1-of (t / target-01))
      :ARG2 (a / and
            :op1 (i / increase-01
                  :ARG1 (i2 / instability
                        :mod (g / genome)))
            :op2 (a2 / apoptosis)
            :op3 (a3 / arrest-02
                  :ARG1 (c2 / cycle-02
                        :ARG1 (c3 / cell)))
            :op4 (d2 / deplete-01
                  :ARG2 c
                  :degree (d3 / drastic)))
      :ARG1-of (d4 / describe-01
            :ARG0 (p2 / publication-91
                  :ARG0 (a4 / and
                        :op1 (p3 / person :name (n3 / name :op1 "Mak"))
                        :op2 (p4 / person
                              :mod (o / other)))
                  :time (d / date-entity :year 2000))))

# ::id bel_pmid_1828_5820.25554 ::date 2015-05-10T22:48:13 ::annotator SDL-AMR-09 ::preferred
# ::snt null mutations for Brca2 result in early mouse embryonic lethality and impaired HR (Ludwig et al, 1997; Suzuki et al, 1997; Moynahan et al, 2001). Furthermore, loss of Brca2 in murine cells resulted in increased genomic instability and activation of p53.
# ::save-date Sun Dec 20, 2015 ::file bel_pmid_1828_5820_25554.txt
(m / multi-sentence
      :snt1 (r / result-01
            :ARG1 (m2 / mutate-01 :mod "-/-"
                  :ARG1 (p / protein :name (n / name :op1 "Brca2")))
            :ARG2 (a / and
                  :op1 (d2 / die-01
                        :ARG1 (e / embryo
                              :mod (m3 / mouse))
                        :time (e2 / early))
                  :op2 (i / impair-01
                        :ARG1 (t / thing :name (n2 / name :op1 "HR"))))
            :ARG1-of (d4 / describe-01
                  :ARG0 (a2 / and
                        :op1 (p2 / publication-91
                              :ARG0 (a3 / and
                                    :op1 (p3 / person :name (n3 / name :op1 "Ludwig"))
                                    :op2 (p4 / person
                                          :mod (o / other)))
                              :time (d / date-entity :year 1997))
                        :op2 (p5 / publication-91
                              :ARG0 (a4 / and
                                    :op1 (p6 / person :name (n4 / name :op1 "Suzuki"))
                                    :op2 (p7 / person
                                          :mod (o2 / other)))
                              :time d)
                        :op3 (p8 / publication-91
                              :ARG0 (a5 / and
                                    :op1 (p9 / person :name (n5 / name :op1 "Moynahan"))
                                    :op2 (p10 / person
                                          :mod (o3 / other)))
                              :time (d3 / date-entity :year 2001)))))
      :snt2 (a6 / and
            :op2 (r2 / result-01
                  :ARG1 (l / lose-02
                        :ARG1 (p11 / protein :name (n6 / name :op1 "Brca2"))
                        :location (c / cell
                              :part-of (o4 / organism :name (n8 / name :op1 "Murinae"))))
                  :ARG2 (a7 / and
                        :op1 (i2 / increase-01
                              :ARG1 (i3 / instability
                                    :mod (g / genome)))
                        :op2 (a8 / activate-01
                              :ARG1 (p12 / protein :name (n7 / name :op1 "p53")))))))

# ::id bel_pmid_1828_5820.25556 ::date 2015-05-10T22:58:30 ::annotator SDL-AMR-09 ::preferred
# ::snt BRCA2 functions in the loading of the HR protein RAD51 during filament formation. It directly binds to RAD51 and its phosphorylation on Ser3291 inhibits this binding (Esashi et al, 2005).
# ::save-date Fri Jul 24, 2015 ::file bel_pmid_1828_5820_25556.txt
(m / multi-sentence
      :snt1 (f / function-01
            :ARG0 (p2 / protein :name (n / name :op1 "BRCA2"))
            :ARG1 (l / load-01
                  :ARG2 (p3 / protein :name (n2 / name :op1 "RAD51")
                        :ARG0-of (c / cause-01
                              :ARG1 (t / thing :name (n3 / name :op1 "HR")))))
            :time (f2 / form-01
                  :ARG1 (f3 / filament)))
      :snt2 (a / and
            :op1 (b / bind-01
                  :ARG1 (i2 / it)
                  :ARG2 (p5 / protein :name (n5 / name :op1 "RAD51"))
                  :ARG1-of (d2 / direct-02))
            :op2 (i / inhibit-01
                  :ARG0 (p / phosphorylate-01
                        :ARG1 (a3 / amino-acid :mod 3291 :name (n6 / name :op1 "serine")
                              :part-of i2))
                  :ARG1 b)
            :ARG1-of (d3 / describe-01
                  :ARG0 (p7 / publication-91
                        :ARG0 (a2 / and
                              :op1 (p8 / person :name (n7 / name :op1 "Esashi"))
                              :op2 (p9 / person
                                    :mod (o / other)))
                        :time (d / date-entity :year 2005)))))

# ::id bel_pmid_1828_5820.28866 ::date 2015-05-10T23:11:39 ::annotator SDL-AMR-09 ::preferred
# ::snt The death of mutants such as Xrcc1/, LigIII/ and Polb/ was preceded by elevated levels of apoptosis (Gu et al, 1994; Tebbs et al, 1999; Sugo et al, 2000; Puebla-Osorio et al, 2006).
# ::save-date Wed May 13, 2015 ::file bel_pmid_1828_5820_28866.txt
(p / precede-01
      :ARG1 (l / level
            :ARG1-of (e / elevate-01)
            :degree-of (a2 / apoptosis))
      :ARG2 (d5 / die-01
            :ARG1 (p2 / protein
                  :ARG2-of (m / mutate-01)
                  :example (a / and
                        :op1 (p3 / protein :name (n / name :op1 "Xrcc1"))
                        :op2 (p4 / protein :name (n2 / name :op1 "LigIII"))
                        :op3 (p5 / protein :name (n3 / name :op1 "Polb")))))
      :ARG1-of (d6 / describe-01
            :ARG0 (a3 / and
                  :op1 (p6 / publication-91
                        :ARG0 (a4 / and
                              :op1 (p10 / person :name (n4 / name :op1 "Gu"))
                              :op2 (p11 / person
                                    :mod (o / other)))
                        :time (d / date-entity :year 1994))
                  :op2 (p7 / publication-91
                        :ARG0 (a5 / and
                              :op1 (p12 / person :name (n5 / name :op1 "Tebbs"))
                              :op2 (p13 / person
                                    :mod (o2 / other)))
                        :time (d2 / date-entity :year 1999))
                  :op3 (p8 / publication-91
                        :ARG0 (a6 / and
                              :op1 (p14 / person :name (n6 / name :op1 "Sugo"))
                              :op2 (p15 / person
                                    :mod (o3 / other)))
                        :time (d3 / date-entity :year 2000))
                  :op4 (p9 / publication-91
                        :ARG0 (a7 / and
                              :op1 (p16 / person :name (n7 / name :op1 "Puebla-Osorio"))
                              :op2 (p17 / person
                                    :mod (o4 / other)))
                        :time (d4 / date-entity :year 2006)))))

# ::id bel_pmid_1828_5820.29340 ::date 2015-05-10T23:19:38 ::annotator SDL-AMR-09 ::preferred
# ::snt (McPherson et al, 2004a). Heterozygous and homozygous Mus81 mutants show cancer predisposition, particularly to T- and B-cell lymphomas.
# ::save-date Sun Jan 3, 2016 ::file bel_pmid_1828_5820_29340.txt
(s / show-01
      :ARG0 (a / and
            :op1 (e / enzyme :name (n2 / name :op1 "Mus81")
                  :ARG2-of (m / mutate-01)
                  :mod (h / heterozygous))
            :op2 (e2 / enzyme :name (n3 / name :op1 "Mus81")
                  :ARG2-of m
                  :mod (h2 / homozygous)))
      :ARG1 (a2 / and
            :op1 (p / predispose-01
                  :ARG1 a
                  :ARG2 (d2 / disease :wiki "Cancer" :name (n / name :op1 "cancer")))
            :op2 (p2 / predispose-01
                  :ARG1 a
                  :ARG2 (a3 / and
                        :op1 (l / lymphoma
                              :mod (c2 / cell :name (n4 / name :op1 "T-cell")))
                        :op2 (l2 / lymphoma
                              :mod (c3 / cell :name (n5 / name :op1 "B-cell"))))
                  :mod (p6 / particular)))
      :ARG1-of (d3 / describe-01
            :ARG0 (p3 / publication-91 :li "a"
                  :ARG0 (a4 / and
                        :op1 (p4 / person :name (n6 / name :op1 "McPherson"))
                        :op2 (p5 / person
                              :mod (o / other)))
                  :time (d / date-entity :year 2004))))

# ::id bel_pmid_1828_5820.29342 ::date 2015-05-10T23:27:51 ::annotator SDL-AMR-09 ::preferred
# ::snt after a long latency, Ung/ and Mutyh/ mice developed B-cell lymphomas and intestinal tumors, respectively (Nilsen et al, 2003; Sakamoto et al, 2007).
# ::save-date Sun Dec 20, 2015 ::file bel_pmid_1828_5820_29342.txt
(a / and
      :op1 (d3 / develop-01
            :ARG1 (m / mouse
                  :mod (g / gene :name (n / name :op1 "Ung")))
            :ARG2 (l / lymphoma
                  :mod (c / cell :name (n3 / name :op1 "B-cell"))))
      :op2 (d4 / develop-01
            :ARG1 (m2 / mouse
                  :mod (g2 / gene :name (n2 / name :op1 "Mutyh")))
            :ARG2 (t / tumor
                  :mod (i / intestine)))
      :manner (r / respective)
      :time (a2 / after
            :op1 (l2 / latency
                  :ARG1-of (l3 / long-03)))
      :ARG1-of (d5 / describe-01
            :ARG0 (a3 / and
                  :op1 (p / publication-91
                        :ARG0 (a4 / and
                              :op1 (p3 / person :name (n4 / name :op1 "Nilsen"))
                              :op2 (p4 / person
                                    :mod (o / other)))
                        :time (d / date-entity :year 2003))
                  :op2 (p2 / publication-91
                        :ARG0 (a5 / and
                              :op1 (p5 / person :name (n5 / name :op1 "Sakamoto"))
                              :op2 (p6 / person
                                    :mod (o2 / other)))
                        :time (d2 / date-entity :year 2007)))))

# ::id bel_pmid_1828_5820.31706 ::date 2015-05-10T23:34:11 ::annotator SDL-AMR-09 ::preferred
# ::snt Increased apoptosis and proliferative arrest of pro-B cells in Ku80/ mice were rescued by a p53-null background (Difilippantonio et al, 2000).
# ::save-date Wed Oct 28, 2015 ::file bel_pmid_1828_5820_31706.txt
(r / rescue-01
      :ARG0 (b / background
            :mod (p3 / protein :name (n3 / name :op1 "p53")
                  :ARG2-of (m2 / mutate-01 :mod "-/-")))
      :ARG1 (a / and
            :op1 (a2 / apoptosis
                  :ARG1-of (i / increase-01))
            :op2 (a3 / arrest-02
                  :ARG1 (c / cell :name (n / name :op1 "B")
                        :part-of (m / mouse
                              :mod (p2 / protein :name (n2 / name :op1 "Ku80")))
                        :time (p7 / pro))
                  :ARG0-of (p / proliferate-01)))
      :ARG1-of (d2 / describe-01
            :ARG0 (p4 / publication-91
                  :ARG0 (a4 / and
                        :op1 (p5 / person :name (n4 / name :op1 "Difilippantonio"))
                        :op2 (p6 / person
                              :mod (o / other)))
                  :time (d / date-entity :year 2000))))

# ::id bel_pmid_1828_5820.36136 ::date 2015-05-10T23:43:36 ::annotator SDL-AMR-09 ::preferred
# ::snt The consequential loss of CDC25A results in G1/S arrest, due to the inefficient loading of CDC45 at the origin of replication. In addition, activated ATM, ATR, DNA–PK, Chk2, and Chk1 all aid in the phosphorylation and activation of p53, a key player in DNA-damage checkpoints. Activated p53 transactivates p21, which inhibits two G1/S-promoting cyclin-dependent kinases (CDKs), CDK2 and CDK4.
# ::save-date Sun Jan 17, 2016 ::file bel_pmid_1828_5820_36136.txt
(m / multi-sentence
      :snt1 (r / result-01
            :ARG1 (l / lose-02
                  :ARG1 (e11 / enzyme :name (n / name :op1 "CDC25A"))
                  :mod (c / consequential))
            :ARG2 (a / arrest-02
                  :ARG1 (e6 / event :name (n15 / name :op1 "G1/S"))
                  :ARG1-of (c2 / cause-01
                        :ARG0 (l2 / load-01
                              :ARG2 (e10 / enzyme :name (n2 / name :op1 "CDC45"))
                              :ARG1-of (e / efficient-01 :polarity -)
                              :time (o / origin
                                    :mod (r2 / replicate-01))))))
      :snt2 (a3 / and
            :op2 (a4 / aid-01
                  :ARG0 (a5 / and
                        :op1 (e2 / enzyme :name (n3 / name :op1 "ATM"))
                        :op2 (e12 / enzyme :name (n4 / name :op1 "ATR"))
                        :op3 (e3 / enzyme :name (n5 / name :op1 "DNA–PK"))
                        :op4 (e4 / enzyme :name (n6 / name :op1 "Chk2"))
                        :op5 (e5 / enzyme :name (n7 / name :op1 "Chk1"))
                        :mod (a6 / all)
                        :ARG1-of (a2 / activate-01))
                  :ARG1 (a7 / and
                        :op1 (p / phosphorylate-01
                              :ARG1 (p7 / protein :name (n8 / name :op1 "p53")
                                    :ARG0-of (p2 / play-08
                                          :ARG1-of (k / key-02
                                                :ARG2 (c3 / checkpoint
                                                      :mod (d / damage-01
                                                            :ARG1 (n12 / nucleic-acid :wiki "DNA" :name (n17 / name :op1 "DNA"))))))))
                        :op2 (a8 / activate-01
                              :ARG1 p7))))
      :snt3 (t / transactivate-01
            :ARG1 (p9 / protein :name (n10 / name :op1 "p21")
                  :ARG0-of (i / inhibit-01
                        :ARG1 (k2 / kinase :quant 2
                              :ARG0-of (p10 / promote-02
                                    :ARG1 (e7 / event :name (n16 / name :op1 "G1/S")))
                              :ARG1-of (m2 / mean-01
                                    :ARG2 (a11 / and
                                          :op1 (e8 / enzyme :name (n13 / name :op1 "CDK2"))
                                          :op2 (e9 / enzyme :name (n14 / name :op1 "CDK4"))))
                              :ARG0-of (d2 / depend-01
                                    :ARG1 (p3 / protein :name (n11 / name :op1 "cyclin"))))))
            :ARG2 (p8 / protein :name (n9 / name :op1 "p53")
                  :ARG1-of (a9 / activate-01))))

# ::id bel_pmid_1828_5820.36694 ::date 2015-05-11T00:00:54 ::annotator SDL-AMR-09 ::preferred
# ::snt Activated ATM and ATR mediate the phosphorylation and subsequent activation of Chk2 and Chk1, respectively; this process is necessary in the induction of phosphorylation of CDC25A, marking it for proteosomal degradation (Su, 2006).
# ::save-date Sun Jan 17, 2016 ::file bel_pmid_1828_5820_36694.txt
(m / multi-sentence
      :snt1 (a5 / and
            :op1 (m2 / mediate-01
                  :ARG0 (e / enzyme :name (n2 / name :op1 "ATM")
                        :ARG1-of (a / activate-01))
                  :ARG1 (a2 / and
                        :op1 (p / phosphorylate-01
                              :ARG1 (e2 / enzyme :name (n4 / name :op1 "Chk2")))
                        :op2 (a3 / activate-01
                              :ARG1 e2
                              :mod (s / subsequent))))
            :op2 (m3 / mediate-01
                  :ARG0 (e5 / enzyme :name (n3 / name :op1 "ATR")
                        :ARG1-of a)
                  :ARG1 (a6 / and
                        :op1 (p3 / phosphorylate-01
                              :ARG1 (e3 / enzyme :name (n5 / name :op1 "Chk1")))
                        :op2 (a7 / activate-01
                              :ARG1 e3
                              :mod s)))
            :manner (r / respective))
      :snt2 (n / need-01
            :ARG0 (i / induce-01
                  :ARG2 (p5 / phosphorylate-01
                        :ARG1 (e4 / enzyme :name (n6 / name :op1 "CDC25A"))
                        :ARG0-of (m4 / mark-02
                              :ARG1 e4
                              :purpose (d3 / degrade-01
                                    :ARG1 e4
                                    :ARG2 (p8 / protein :name (n8 / name :op1 "proteosome"))))))
            :ARG1 (p4 / process-02
                  :mod (t / this))
            :ARG1-of (d2 / describe-01
                  :ARG0 (p6 / publication-91
                        :ARG0 (p7 / person :name (n7 / name :op1 "Su"))
                        :time (d / date-entity :year 2006)))))

# ::id bel_pmid_1831_7950.3272 ::date 2015-05-11T00:16:14 ::annotator SDL-AMR-09 ::preferred
# ::snt Phosphorylation of 4E-BP1, S6k1(Thr(389)), and Erk 1/2 was reduced 2 h following IP injection of alcohol.
# ::save-date Wed Oct 28, 2015 ::file bel_pmid_1831_7950_3272.txt
(r / reduce-01
      :ARG1 (p / phosphorylate-01
            :ARG1 (a / and
                  :op1 (p2 / protein :name (n2 / name :op1 "4E-BP1"))
                  :op2 (a4 / amino-acid :mod 389 :name (n3 / name :op1 "tyrosine")
                        :part-of (e2 / enzyme :name (n4 / name :op1 "S6k1")))
                  :op3 (e3 / enzyme :name (n5 / name :op1 "Erk1"))
                  :op4 (e4 / enzyme :name (n6 / name :op1 "Erk2"))))
      :time (a2 / after
            :op1 (i / inject-01
                  :ARG1 (a3 / alcohol)
                  :ARG2 (p3 / peritoneum))
            :quant (t / temporal-quantity :quant 2
                  :unit (h / hour))))

# ::id bel_pmid_1836_8049.20310 ::date 2015-05-11T00:26:16 ::annotator SDL-AMR-09 ::preferred
# ::snt TGF-beta-induced Foxp3 expression is inhibited by IL-6 (ref. 17), IL-21 (ref. 10) and IL-23 (Supplementary Fig. 8).
# ::save-date Sun Dec 20, 2015 ::file bel_pmid_1836_8049_20310.txt
(i / inhibit-01
      :ARG0 (a / and
            :op1 (p3 / protein :name (n3 / name :op1 "IL-6")
                  :ARG1-of (d / describe-01
                        :ARG0 (p6 / publication
                              :ARG1-of (c / cite-01
                                    :ARG2 17))))
            :op2 (p4 / protein :name (n4 / name :op1 "IL-21")
                  :ARG1-of (d2 / describe-01
                        :ARG0 (p7 / publication
                              :ARG1-of (c2 / cite-01
                                    :ARG2 10))))
            :op3 (p5 / protein :name (n5 / name :op1 "IL-23")
                  :ARG1-of (d3 / describe-01
                        :ARG0 (f / figure :mod 8
                              :ARG2-of (s / supplement-01)))))
      :ARG1 (e / express-03
            :ARG2 (p / protein :name (n / name :op1 "Foxp3"))
            :ARG2-of (i2 / induce-01
                  :ARG0 (p2 / protein :name (n2 / name :op1 "TGF-beta")))))

# ::id bel_pmid_1836_8049.27060 ::date 2015-05-11T00:30:21 ::annotator SDL-AMR-09 ::preferred
# ::snt Forced expression of wild-type mouse Foxp3 inhibited IL-6/IL-21-induced Il23r expression, whereas Foxp3DeltaEx2 had less inhibitory activity (Fig. 4a)
# ::save-date Sun Dec 20, 2015 ::file bel_pmid_1836_8049_27060.txt
(c / contrast-01
      :ARG1 (i / inhibit-01
            :ARG0 (e / express-03
                  :ARG2 (p / protein :name (n / name :op1 "Foxp3"))
                  :ARG3 (m / mouse
                        :mod (w / wild-type))
                  :ARG1-of (f / force-02))
            :ARG1 (e2 / express-03
                  :ARG1 (p2 / protein :name (n2 / name :op1 "IL-23-R"))
                  :ARG2-of (i2 / induce-01
                        :ARG0 (s / slash
                              :op1 (p3 / protein :name (n3 / name :op1 "IL-6"))
                              :op2 (p4 / protein :name (n4 / name :op1 "IL-21"))))))
      :ARG2 (a / activity-06
            :ARG0 (p5 / protein :name (n5 / name :op1 "Foxp3ΔEx2"))
            :ARG1 (i3 / inhibit-01)
            :degree (l / less))
      :ARG1-of (d / describe-01
            :ARG0 (f2 / figure :mod "4a")))

# ::id bel_pmid_1836_8049.27066 ::date 2015-05-11T00:42:38 ::annotator SDL-AMR-09 ::preferred
# ::snt Both mouse and human Foxp3 blocked RORgammat-directed IL-17 expression, but full suppression required the presence of the exon 2-encoded sequence in Foxp3, suggesting that the interaction between Foxp3 and RORgammat is essential (Fig. 3c and Supplementary Fig. 5).
# ::save-date Mon Jan 4, 2016 ::file bel_pmid_1836_8049_27066.txt
(c / contrast-01
      :ARG1 (b / block-01
            :ARG0 (a / and
                  :op1 (p / protein :name (n / name :op1 "Foxp3")
                        :mod (m / mouse))
                  :op2 (p2 / protein :name (n2 / name :op1 "Foxp3")
                        :mod (h / human)))
            :ARG1 (e / express-03
                  :ARG2 (p3 / protein :name (n3 / name :op1 "IL-17"))
                  :ARG1-of (d / direct-01
                        :ARG0 (p4 / protein :name (n4 / name :op1 "RORgammat")))))
      :ARG2 (r / require-01
            :ARG0 (s / suppress-01
                  :ARG1 e
                  :ARG1-of (f / full-09))
            :ARG1 (p7 / present-02
                  :ARG1 (p5 / protein-segment :name (n5 / name :op1 "exon" :op2 "2")
                        :ARG1-of (e2 / encode-01)
                        :part-of (p6 / protein :name (n6 / name :op1 "Foxp3"))))
            :ARG0-of (s3 / suggest-01
                  :ARG1 (e3 / essential
                        :domain (i / interact-01
                              :ARG0 p6
                              :ARG1 p4))))
      :ARG1-of (d2 / describe-01
            :ARG0 (a2 / and
                  :op1 (f2 / figure :mod "3c")
                  :op2 (f3 / figure :mod 5
                        :ARG2-of (s4 / supplement-01)))))

# ::id bel_pmid_1836_8049.33032 ::date 2015-05-11T01:13:05 ::annotator SDL-AMR-09 ::preferred
# ::snt Examination of IL-17 expression in heterozygous RORgammat–GFP knock-in mice revealed that RORgammat+Foxp3+ lamina propria T cells produced much less IL-17 than RORgammat+Foxp3- cells, suggesting that Foxp3 may interfere with the ability of RORgammat to induce IL-17 (Fig. 1c).
# ::save-date Sun Dec 20, 2015 ::file bel_pmid_1836_8049_33032.txt
(r / reveal-01
      :ARG0 (e / examine-01
            :ARG1 (e2 / express-03
                  :ARG2 p
                  :ARG3 (m / mouse
                        :mod (h / heterozygous)
                        :ARG3-of (e3 / express-03
                              :ARG2 (a / and
                                    :op1 (p2 / protein :name (n2 / name :op1 "RORgammat"))
                                    :op2 (p3 / protein :name (n3 / name :op1 "GFP")))))))
      :ARG1 (p4 / produce-01
            :ARG0 (c / cell :name (n4 / name :op1 "T")
                  :part-of (l / lamina-propria)
                  :mod (p5 / protein :name (n5 / name :op1 "RORgammat+"))
                  :mod (p6 / protein :name (n6 / name :op1 "Foxp3+")))
            :ARG1 (p / protein :name (n / name :op1 "IL-17")
                  :quant (l2 / less
                        :degree (m2 / much)))
            :compared-to (c2 / cell
                  :mod (p7 / protein :name (n7 / name :op1 "Foxp3-"))
                  :mod p5))
      :ARG0-of (s / suggest-01
            :ARG1 (p8 / possible-01
                  :ARG1 (i / interfere-01
                        :ARG0 (p9 / protein :name (n8 / name :op1 "Foxp3"))
                        :ARG1 (c3 / capable-01
                              :ARG1 p2
                              :ARG2 (i2 / induce-01
                                    :ARG0 p2
                                    :ARG2 p)))))
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod "1c")))

# ::id bel_pmid_1842_3196.15956 ::date 2015-05-11T01:32:44 ::annotator SDL-AMR-09 ::preferred
# ::snt A) Increase in IL-6 production from baseline in WT, tlr4/, myd88/, and trif/ alveolar macrophages treated with LPS, BAL fluid from normal control, or BAL fluid from acid-treated WT mice. **p < 0.01. Data are from four separate experiments.
# ::save-date Sat Feb 13, 2016 ::file bel_pmid_1842_3196_15956.txt
(m / multi-sentence
      :snt1 (i / increase-01 :li "A"
            :ARG1 (p / produce-01
                  :ARG1 (p2 / protein :name (n / name :op1 "IL-6")))
            :location (a / and
                  :op1 (b / baseline
                        :source (m2 / macrophage
                              :mod (w / wild-type)
                              :mod (a2 / alveolus)))
                  :op2 (m3 / macrophage
                        :mod a2
                        :mod (p3 / protein :name (n2 / name :op1 "tlr4")
                              :ARG2-of (m4 / mutate-01 :mod "-/-")))
                  :op3 (m5 / macrophage
                        :mod a2
                        :mod (p4 / protein :name (n3 / name :op1 "myd88")
                              :ARG2-of m4))
                  :op4 (m6 / macrophage
                        :mod a2
                        :mod (p5 / protein :name (n4 / name :op1 "trif")
                              :ARG2-of m4))
                  :ARG1-of (t / treat-03
                        :ARG3 (o / or
                              :op1 (m7 / molecular-physical-entity :name (n5 / name :op1 "LPS"))
                              :op2 (f / fluid
                                    :source (c / control
                                          :ARG1-of (n7 / normal-02))
                                    :mod (l2 / lavage
                                          :mod (a4 / alveolus
                                                :mod (b2 / bronchus))))
                              :op3 (f2 / fluid
                                    :source (m10 / mouse
                                          :mod w
                                          :ARG1-of (t2 / treat-03
                                                :ARG3 (a3 / acid)))
                                    :mod l2))))
            :ARG1-of (s2 / statistical-test-91
                  :ARG2 (l / less-than :op1 0.01)))
      :snt2 (d / data
            :source (e / experiment :quant 4
                  :ARG1-of (s / separate-02))))

# ::id bel_pmid_1842_3196.15958 ::date 2015-05-11T01:33:03 ::annotator SDL-AMR-09 ::preferred
# ::snt By contrast, LPS-induced IL-6 production in alveolar macrophages was dependent on TLR4, MyD88, and TRIF (Figure 3A).
# ::save-date Sun Dec 20, 2015 ::file bel_pmid_1842_3196_15958.txt
(c / contrast-01
      :ARG2 (d / depend-01
            :ARG0 (p / produce-01
                  :ARG1 (p2 / protein :name (n / name :op1 "IL-6"))
                  :ARG2-of (i / induce-01
                        :ARG0 (m / molecular-physical-entity :name (n2 / name :op1 "LPS")))
                  :location (m2 / macrophage
                        :mod (a / alveolus)))
            :ARG1 (a2 / and
                  :op1 (p3 / protein :name (n3 / name :op1 "TLR4"))
                  :op2 (p4 / protein :name (n4 / name :op1 "MyD88"))
                  :op3 (p5 / protein :name (n5 / name :op1 "TRIF"))))
      :ARG1-of (d2 / describe-01
            :ARG0 (f / figure :mod "3A")))

# ::id bel_pmid_1843_4325.28378 ::date 2015-05-11T01:37:50 ::annotator SDL-AMR-09 ::preferred
# ::snt IL-6 reduced the expression levels of Foxp3 at 48–72 h. This is probably a direct effect of IL-6 on the Foxp3 promoter because IL-6 suppressed TGF-?1-mediated Foxp3 promoter activity in primary T cells (data not shown).
# ::save-date Mon Jan 4, 2016 ::file bel_pmid_1843_4325_28378.txt
(m / multi-sentence
      :snt1 (r / reduce-01
            :ARG0 (p / protein :name (n / name :op1 "IL-6"))
            :ARG1 (l / level
                  :degree-of (e / express-03
                        :ARG2 (p2 / protein :name (n2 / name :op1 "Foxp3"))))
            :time (b / between
                  :op1 (t / temporal-quantity :quant 48
                        :unit (h / hour))
                  :op2 (t2 / temporal-quantity :quant 72
                        :unit h)))
      :snt2 (p8 / probable
            :domain (a / affect-01
                  :ARG0 (p3 / protein :name (n3 / name :op1 "IL-6"))
                  :ARG1 (m3 / molecular-physical-entity
                        :ARG0-of (p9 / promote-01
                              :ARG1 (p5 / protein :name (n4 / name :op1 "Foxp3"))))
                  :ARG1-of (d / direct-02)
                  :domain (t3 / this)
                  :ARG1-of (c / cause-01
                        :ARG0 (s2 / suppress-01
                              :ARG0 p3
                              :ARG1 (a2 / activity-06
                                    :ARG0 m3
                                    :ARG1-of (m2 / mediate-01
                                          :ARG0 (p6 / protein :name (n5 / name :op1 "TGF-beta1"))))
                              :location (c2 / cell :name (n6 / name :op1 "T")
                                    :mod (p7 / primary))))
                  :ARG1-of (d2 / describe-01
                        :ARG0 (d3 / data
                              :ARG1-of (s3 / show-01 :polarity -))))))

# ::id bel_pmid_1843_4325.33034 ::date 2015-05-11T01:47:28 ::annotator SDL-AMR-09 ::preferred
# ::snt As shown in Fig. 4C, transient overexpression of WT Foxp3, but not {Delta}2 or {Delta}FKH, inhibited induction of IL-17A transcription (Fig. 4C). Taken together, these observations suggest that Foxp3 interacts with ROR{gamma}t in the exon 2 region and that the FKH domain plays a critical role in the suppression of ROR{gamma}t-mediated IL-17A transcription.
# ::save-date Sun Jan 3, 2016 ::file bel_pmid_1843_4325_33034.txt
(m / multi-sentence
      :snt1 (c / contrast-01
            :ARG1 (i / inhibit-01
                  :ARG0 (o / overexpress-01
                        :ARG1 (p / protein :name (n / name :op1 "Foxp3")
                              :mod (w / wild-type))
                        :ARG1-of (t / transient-02))
                  :ARG1 (i2 / induce-01
                        :ARG2 (t2 / transcribe-01
                              :ARG1 (p2 / protein :name (n2 / name :op1 "IL-17A")))))
            :ARG2 (i3 / inhibit-01 :polarity -
                  :ARG0 (o2 / overexpress-01
                        :ARG1 (o3 / or
                              :op1 (p3 / protein :name (n3 / name :op1 "Foxp3Δ2"))
                              :op2 (p4 / protein :name (n4 / name :op1 "Foxp3ΔFNK")))
                        :ARG2 t)
                  :ARG1 i2)
            :ARG1-of (s / show-01
                  :medium (f / figure :mod "4C"))
            :ARG1-of (d / describe-01
                  :ARG0 f))
      :snt2 (h / have-condition-91
            :ARG1 (s2 / suggest-01
                  :ARG0 (t3 / thing
                        :ARG1-of (o4 / observe-02)
                        :mod (t4 / this))
                  :ARG1 (a / and
                        :op1 (i4 / interact-01
                              :ARG0 (p7 / protein-segment :name (n7 / name :op1 "exon" :op2 "2")
                                    :part-of (p5 / protein :name (n5 / name :op1 "Foxp3")))
                              :ARG1 (p6 / protein :name (n6 / name :op1 "RORgammat")))
                        :op2 (p8 / play-08
                              :ARG0 (p9 / protein-segment :name (n8 / name :op1 "FKH")
                                    :part-of p5)
                              :ARG1 (s3 / suppress-01
                                    :ARG1 (t5 / transcribe-01
                                          :ARG1 (p10 / protein :name (n9 / name :op1 "IL-17A"))
                                          :ARG1-of (m2 / mediate-01
                                                :ARG0 p6)))
                              :ARG1-of (c2 / critical-02
                                    :ARG2 s3))))))

# ::id bel_pmid_1843_4325.33936 ::date 2015-05-11T05:13:56 ::annotator SDL-AMR-09 ::preferred
# ::snt Then, IL-17A promoter activity was examined with or without an ROR{gamma}t expression vector in the HEK 293T cells in which ROR{gamma}t was not expressed. In the presence of ROR{gamma}t, the promoter activity was significantly increased (Fig. 2A).
# ::save-date Wed Jan 13, 2016 ::file bel_pmid_1843_4325_33936.txt
(m / multi-sentence
      :snt1 (e / examine-01
            :ARG1 (a / activity-06
                  :ARG0 (m2 / molecular-physical-entity
                        :ARG0-of (p / promote-01
                              :ARG1 (p2 / protein :name (n / name :op1 "IL-17A")))))
            :manner (o / or
                  :op1 (v / vector
                        :mod (e2 / express-03
                              :ARG2 (p3 / protein :name (n2 / name :op1 "RORgammat"))))
                  :op2 (v2 / vector :polarity -
                        :mod e2))
            :location (c / cell-line :name (n3 / name :op1 "HEK" :op2 "293T")
                  :ARG3-of (e3 / express-03 :polarity -
                        :ARG2 p3))
            :time (t / then))
      :snt2 (i / increase-01
            :ARG1 (a2 / activity-06
                  :ARG0 (m3 / molecular-physical-entity
                        :ARG0-of (p4 / promote-01)))
            :ARG2 (s / significant-02)
            :condition (p6 / present-02
                  :ARG1 (p5 / protein :name (n4 / name :op1 "RORgammat")))
            :ARG1-of (d / describe-01
                  :ARG0 (f / figure :mod "2A"))))

# ::id bel_pmid_1848_3625.9006 ::date 2015-05-11T05:24:02 ::annotator SDL-AMR-09 ::preferred
# ::snt Germline expression of the endogenous H-RasG12V oncogene, even in homozygosis, resulted in hyperplasia of the mammary gland.
# ::save-date Sun Jan 17, 2016 ::file bel_pmid_1848_3625_9006.txt
(r / result-01
      :ARG1 (e / express-03
            :ARG1 (g3 / gene :name (n2 / name :op1 "H-Ras")
                  :ARG2-of (m / mutate-01 :value "G12V")
                  :mod (e2 / endogenous)
                  :ARG0-of (c / cause-01
                        :ARG1 (d / disease :wiki "Cancer" :name (n / name :op1 "cancer"))))
            :ARG3 (g2 / germline))
      :ARG2 (h / hyperplasia
            :mod (g / gland
                  :mod (m2 / mammary)))
      :location (h2 / homozygosis
            :mod (e3 / even)))

# ::id bel_pmid_1855_5587.7928 ::date 2015-05-11T05:34:36 ::annotator SDL-AMR-09 ::preferred
# ::snt We investigated whether globular adiponectin (gAd) affects the expression of inflammation-related genes in murine macrophages (RAW264 cells). DNA microarray analysis indicated that granulocyte colony-stimulating factor (G-CSF) showed the largest increase in expression in gAd-stimulated RAW264 cells. The gAd-induced secretion of G-CSF increased in a time- and dose-dependent manner.
# ::save-date Sun Jan 3, 2016 ::file bel_pmid_1855_5587_7928.txt
(m2 / multi-sentence
      :snt1 (i / investigate-01
            :ARG0 (w / we)
            :ARG1 (a / affect-01 :mode interrogative
                  :ARG0 (p / protein :name (n / name :op1 "globular" :op2 "adiponectin"))
                  :ARG1 (e / express-03
                        :ARG1 (g / gene
                              :ARG1-of (r / relate-01
                                    :ARG2 (i2 / inflame-01)))
                        :ARG3 (m3 / macrophage
                              :ARG1-of (m5 / mean-01
                                    :ARG2 (c / cell :name (n3 / name :op1 "RAW264")))
                              :part-of (o / organism :name (n2 / name :op1 "Murinae"))))))
      :snt2 (i3 / indicate-01
            :ARG0 (a3 / analyze-01
                  :instrument (m4 / microarray
                        :mod (n6 / nucleic-acid :wiki "DNA" :name (n11 / name :op1 "DNA"))))
            :ARG1 (s / show-01
                  :ARG0 (p3 / protein :name (n5 / name :op1 "granulocyte" :op2 "colony-stimulating" :op3 "factor"))
                  :ARG1 (i4 / increase-01
                        :ARG1 (e2 / express-03
                              :ARG3 (c2 / cell :name (n7 / name :op1 "RAW264")
                                    :ARG1-of (s2 / stimulate-01
                                          :ARG2 (p5 / protein :name (n8 / name :op1 "gAd")))))
                        :ARG2 (l / large
                              :degree (m / most)))))
      :snt3 (i5 / increase-01
            :ARG1 (s3 / secrete-01
                  :ARG1 (p7 / protein :name (n10 / name :op1 "G-CSF"))
                  :ARG2-of (i6 / induce-01
                        :ARG0 (p6 / protein :name (n9 / name :op1 "gAd"))))
            :manner (d3 / depend-01
                  :ARG1 (a2 / and
                        :op1 (t2 / time)
                        :op2 (d4 / dose)))))

# ::id bel_pmid_1855_5587.24926 ::date 2015-05-11T05:50:36 ::annotator SDL-AMR-09 ::preferred
# ::snt gAd induced the phosphorylation of MEK1/2 and ERK1/2 in RAW264 cells. In addition, the gAd-induced phosphorylation of MEK1/2 and ERK1/2 was dramatically reduced by PD98059 and U0126, respectively.
# ::save-date Sun Dec 20, 2015 ::file bel_pmid_1855_5587_24926.txt
(m / multi-sentence
      :snt1 (i / induce-01
            :ARG0 (p2 / protein :name (n2 / name :op1 "gAd"))
            :ARG2 (p / phosphorylate-01
                  :ARG1 (a / and
                        :op1 (e / enzyme :name (n3 / name :op1 "MEK1"))
                        :op2 (e2 / enzyme :name (n4 / name :op1 "MEK2"))
                        :op3 (e3 / enzyme :name (n5 / name :op1 "ERK1"))
                        :op4 (e4 / enzyme :name (n6 / name :op1 "ERK2"))))
            :location (c / cell :name (n7 / name :op1 "RAW264")))
      :snt2 (a2 / and
            :op2 (r / reduce-01
                  :ARG0 (a3 / and
                        :op1 (s2 / small-molecule :name (n8 / name :op1 "PD98059"))
                        :op2 (s / small-molecule :name (n / name :op1 "U0126"))
                        :manner (r2 / respective))
                  :ARG1 (p3 / phosphorylate-01
                        :ARG1 (a4 / and
                              :op1 (e5 / enzyme :name (n9 / name :op1 "MEK1"))
                              :op2 (e6 / enzyme :name (n10 / name :op1 "MEK2"))
                              :op3 (e7 / enzyme :name (n11 / name :op1 "ERK1"))
                              :op4 (e8 / enzyme :name (n12 / name :op1 "ERK2")))
                        :ARG2-of (i2 / induce-01
                              :ARG0 (p4 / protein :name (n13 / name :op1 "gAd"))))
                  :manner (d / dramatic))))

# ::id bel_pmid_1866_6314.27860 ::date 2015-05-11T02:58:25 ::annotator SDL-AMR-09 ::preferred
# ::snt from full text - An inactivation of IL-10 in mice results in an increased production of IL-12 and IFN-gamma [42,43]. Inflamed tissues and granulomas of CD show low IL-10[44]. Melgar et al[45] reported a highly significant increase in IL-10 mRNA levels in T lymphocytes and in IL-10-positive cells in the colons of UC patients.
# ::save-date Sun Jan 3, 2016 ::file bel_pmid_1866_6314_27860.txt
(m / multi-sentence
      :snt1 (r / result-01
            :ARG1 (a / activate-01 :polarity -
                  :ARG1 (p14 / protein :name (n / name :op1 "IL-10"))
                  :location (m2 / mouse))
            :ARG2 (p / produce-01
                  :ARG1 (a2 / and
                        :op1 (p2 / protein :name (n3 / name :op1 "IL-12"))
                        :op2 (p3 / protein :name (n4 / name :op1 "IFN-gamma"))))
            :ARG1-of (d / describe-01
                  :ARG0 (p4 / publication
                        :ARG1-of (c / cite-01
                              :ARG2 (a3 / and :op1 42 :op2 43))))
            :source (t2 / text
                  :ARG1-of (f / full-09)))
      :snt2 (s / show-01
            :ARG0 (a4 / and
                  :op1 (t / tissue)
                  :op2 (g2 / granuloma)
                  :part-of (d2 / disease :name (n5 / name :op1 "CD"))
                  :ARG1-of (i / inflame-01))
            :ARG1 (p11 / protein :name (n6 / name :op1 "IL-10")
                  :ARG1-of (l / low-04))
            :ARG1-of (d3 / describe-01
                  :ARG0 (p5 / publication
                        :ARG1-of (c2 / cite-01
                              :ARG2 44))))
      :snt3 (r2 / report-01
            :ARG0 (a5 / and
                  :op1 (p6 / person :name (n7 / name :op1 "Melgar"))
                  :op2 (p7 / person
                        :mod (o2 / other)))
            :ARG1 (i2 / increase-01
                  :ARG1 (l2 / level
                        :quant-of (n8 / nucleic-acid :name (n9 / name :op1 "mRNA")
                              :location (p13 / protein :name (n13 / name :op1 "IL-10"))))
                  :ARG2 (s2 / significant-02
                        :ARG1-of (h / high-02))
                  :location (a6 / and
                        :op1 (c3 / cell :name (n10 / name :op1 "T" :op2 "lymphocyte"))
                        :op2 (c4 / cell
                              :mod (p10 / positive
                                    :mod (p12 / protein :name (n12 / name :op1 "IL10"))))
                        :location (c5 / colon
                              :part-of (p8 / patient
                                    :mod (d4 / disease :name (n11 / name :op1 "UC"))))))
            :ARG1-of (d5 / describe-01
                  :ARG0 (p9 / publication
                        :ARG1-of (c6 / cite-01
                              :ARG2 45)))))

# ::id bel_pmid_1866_6314.28188 ::date 2015-05-11T03:12:06 ::annotator SDL-AMR-09 ::preferred
# ::snt from full text - in a murine model of UC, Sugimoto et al demonstrated a novel protective role for IL-22, in which IL-22 attenuates in the intestine inflammation
# ::save-date Mon Dec 21, 2015 ::file bel_pmid_1866_6314_28188.txt
(d / demonstrate-01
      :ARG0 (a / and
            :op1 (p / person :name (n / name :op1 "Sugimoto"))
            :op2 (p2 / person
                  :mod (o2 / other)))
      :ARG1 (p3 / protect-01
            :ARG0 (p4 / protein :name (n6 / name :op1 "IL-22"))
            :ARG0-of (m2 / mean-01
                  :ARG2 (a3 / attenuate-01
                        :ARG0 p4
                        :location (i / inflame-01
                              :ARG1 (i2 / intestine))))
            :mod (n3 / novel))
      :medium (m / model
            :mod (o / organism :name (n4 / name :op1 "Muridae"))
            :mod (d2 / disease :name (n2 / name :op1 "ulcerative" :op2 "colitis")))
      :source (t / text
            :ARG1-of (f / full-09)))

# ::id bel_pmid_1866_6314.28300 ::date 2015-05-11T03:12:39 ::annotator SDL-AMR-09 ::preferred
# ::snt from full text - T-cell receptor alpha chain-deficient mice (TCR -/-) treated with anti-IL-4 monoclonal antibody showed a decrease in Th2-type mRNA cytokine production and an increase in expression of IFN-gamma, suggesting that IL-4 plays a major role in inducing Th2-type CD4+ cells in the gut to shift towards a Th1 response[51].
# ::save-date Wed Mar 2, 2016 ::file bel_pmid_1866_6314_28300.txt
(a / and
      :op1 (s / show-01
            :ARG0 (m5 / mouse
                  :mod (d / deficient
                        :mod (c / chain
                              :mod (p / protein :name (n2 / name :op1 "T-cell" :op2 "receptor"))
                              :mod (a2 / alpha)))
                  :ARG1-of (t / treat-04
                        :ARG2 (a4 / antibody
                              :mod (m2 / monoclonal)
                              :ARG0-of (c4 / counter-01
                                    :ARG1 p7)))
                  :ARG1-of (m4 / mean-01
                        :ARG2 (p2 / protein :name (n3 / name :op1 "TCR")
                              :ARG2-of (m / mutate-01 :mod "−/−"))))
            :ARG1 (a3 / and
                  :op1 (d2 / decrease-01
                        :ARG1 (p4 / produce-01
                              :ARG1 (c5 / cytokine)
                              :ARG2 (n11 / nucleic-acid :name (n10 / name :op1 "mRNA")
                                    :mod (p11 / protein :name (n6 / name :op1 "Th2")))))
                  :op2 (i / increase-01
                        :ARG1 (e / express-03
                              :ARG2 (p5 / protein :name (n5 / name :op1 "IFN-gamma"))))))
      :op2 (s2 / suggest-01
            :ARG1 (p6 / play-08
                  :ARG0 (p7 / protein :name (n7 / name :op1 "IL-4"))
                  :ARG1 (i2 / induce-01
                        :ARG2 (s3 / shift-01
                              :ARG1 (p9 / protein :name (n8 / name :op1 "Th2")
                                    :location (g / gut)
                                    :mod (p3 / protein :name (n4 / name :op1 "CD4+")))
                              :ARG2 (r / respond-01
                                    :ARG0 (p8 / protein :name (n9 / name :op1 "Th1")))))
                  :ARG1-of (m3 / major-02)))
      :ARG1-of (d3 / describe-01
            :ARG0 (p10 / publication
                  :ARG1-of (c2 / cite-01
                        :ARG2 51)))
      :source (t2 / text
            :ARG1-of (f / full-09)))

# ::id bel_pmid_1866_6314.28380 ::date 2015-05-11T03:12:55 ::annotator SDL-AMR-09 ::preferred
# ::snt from full text - anti-IL-6 receptor monoclonal antibody to a murine colitis model and found that the treatment with this antibody reduced IFN-gamma, TNF-alpha, and IL-1beta mRNA, and suppressed expression of several intracellular adhesion molecules in the colonic vascular endothelium.
# ::save-date Mon Dec 21, 2015 ::file bel_pmid_1866_6314_28380.txt
(a / and
      :op1 (i / introduce-02
            :ARG0 (a5 / and
                  :op1 (p2 / person :name (n5 / name :op1 "Yamamoto"))
                  :op2 (p3 / person
                        :mod (o / other))
                  :ARG1-of (d2 / describe-01
                        :ARG0 (p4 / publication-91
                              :ARG0 (p5 / person :name (n9 / name :op1 "Kallen" :op2 "KJ"))
                              :ARG1-of (c2 / cite-01
                                    :ARG2 25))))
            :ARG1 (a6 / antibody
                  :mod (m / monoclonal)
                  :ARG0-of (c3 / counter-01
                        :ARG1 (r5 / receptor :name (n10 / name :op1 "IL-6"))))
            :ARG2 (m2 / model
                  :topic (d / disease :name (n8 / name :op1 "colitis")
                        :mod (o2 / organism :name (n7 / name :op1 "Muridae")))))
      :op2 (f / find-01
            :ARG1 (a3 / and
                  :op1 (r / reduce-01
                        :ARG0 (t / treat-04
                              :ARG2 (a2 / antibody
                                    :mod (t2 / this)))
                        :ARG1 (n / nucleic-acid :name (n6 / name :op1 "mRNA")
                              :ARG0-of (e3 / encode-01
                                    :ARG1 (a7 / and
                                          :op1 (p6 / protein :name (n11 / name :op1 "IFN-gamma"))
                                          :op2 (p7 / protein :name (n12 / name :op1 "TNF-alpha"))
                                          :op3 (p8 / protein :name (n13 / name :op1 "IL-1beta")))))
                        :location e2)
                  :op2 (s / suppress-01
                        :ARG0 t
                        :ARG1 (e / express-03
                              :ARG2 (p / protein :name (n4 / name :op1 "intracellular" :op2 "adhesion" :op3 "molecule")
                                    :quant (s2 / several)))
                        :location (e2 / endothelium
                              :part-of (v / vesel
                                    :part-of (c / colon))))))
      :source (t3 / text
            :ARG1-of (f2 / full-09)))

# ::id bel_pmid_1866_6314.35398 ::date 2015-05-11T03:15:41 ::annotator SDL-AMR-09 ::preferred
# ::snt from full text - STAT-3 itself induces the anti-apoptotic factors Bcl-2 and Bcl-xL
# ::save-date Mon Dec 21, 2015 ::file bel_pmid_1866_6314_35398.txt
(i / induce-01
      :ARG0 (p / protein :name (n / name :op1 "STAT-3")
            :mod (i2 / it))
      :ARG2 (f / factor
            :example (a / and
                  :op1 (p2 / protein :name (n2 / name :op1 "Bcl-2"))
                  :op2 (p3 / protein :name (n3 / name :op1 "Bcl-xL")))
            :ARG0-of (c / counter-01
                  :ARG1 (a2 / apoptosis)))
      :source (t / text
            :ARG1-of (f2 / full-09)))

# ::id bel_pmid_1866_6314.35432 ::date 2015-05-11T03:15:54 ::annotator SDL-AMR-09 ::preferred
# ::snt from full text - Increased levels of IL-1 in IBD may be result of stimulation of colonic macrophages that can activate interleukin (IL)-1 converting enzyme (ICE) and hence release mature IL-1beta into the colonic mucosa[20].
# ::save-date Mon Dec 21, 2015 ::file bel_pmid_1866_6314_35432.txt
(p / possible-01
      :ARG1 (r / result-01
            :ARG1 (s / stimulate-01
                  :ARG1 (c / cell :name (n / name :op1 "macrophage")
                        :mod (c2 / colon)
                        :ARG0-of (a3 / activate-01
                              :ARG1 (e / enzyme :name (n4 / name :op1 "interleukin-1" :op2 "converting" :op3 "enzyme"))
                              :ARG1-of (p3 / possible-01)
                              :ARG0-of (r2 / release-01
                                    :ARG1 (p4 / protein :name (n5 / name :op1 "IL-1" :op2 "beta")
                                          :ARG1-of (m / mature-02))
                                    :destination (m2 / mucosa
                                          :mod (c4 / colon))))))
            :ARG2 (l / level
                  :quant-of (p2 / protein :name (n2 / name :op1 "IL-1"))
                  :ARG1-of (i / increase-01)))
      :ARG1-of (d3 / describe-01
            :ARG0 (p5 / publication
                  :ARG1-of (c5 / cite-01
                        :ARG2 20)))
      :topic (d / disease :name (n3 / name :op1 "inflammatory" :op2 "bowel" :op3 "disease"))
      :source (t / text
            :ARG1-of (f / full-09)))

# ::id bel_pmid_1866_6314.36060 ::date 2015-05-11T03:16:10 ::annotator SDL-AMR-09 ::preferred
# ::snt from full text - Both cytokines (IL-12 and IL-23) activate TYK2 and JAK2 as well as STAT1, STAT3, STAT4, and STAT5 [60].
# ::save-date Mon Jan 4, 2016 ::file bel_pmid_1866_6314_36060.txt
(a / activate-01
      :ARG0 (p / protein :name (n / name :op1 "cytokine")
            :ARG1-of (m / mean-01
                  :ARG2 (a2 / and
                        :op1 (p2 / protein :name (n2 / name :op1 "IL-12"))
                        :op2 (p3 / protein :name (n3 / name :op1 "IL-23"))))
            :mod (b / both))
      :ARG1 (a3 / and
            :op1 (e / enzyme :name (n4 / name :op1 "TYK2"))
            :op2 (e2 / enzyme :name (n5 / name :op1 "JAK2"))
            :op3 (p5 / protein :name (n6 / name :op1 "STAT1"))
            :op4 (p6 / protein :name (n7 / name :op1 "STAT3"))
            :op5 (p7 / protein :name (n8 / name :op1 "STAT4"))
            :op6 (p8 / protein :name (n9 / name :op1 "STAT5")))
      :ARG1-of (d / describe-01
            :ARG0 (p4 / publication
                  :ARG1-of (c / cite-01
                        :ARG2 60)))
      :source (t / text
            :ARG1-of (f / full-09)))

# ::id bel_pmid_1866_6314.38544 ::date 2015-05-11T03:17:04 ::annotator SDL-AMR-09 ::preferred
# ::snt from full text - IL-6 signalling through signal transducer and activator of transcription- 3 (STAT3)
# ::save-date Mon Jan 4, 2016 ::file bel_pmid_1866_6314_38544.txt
(s / signal-07
      :ARG0 (p / protein :name (n / name :op1 "IL-6"))
      :path (p3 / protein :name (n3 / name :op1 "signal" :op2 "transducer" :op3 "and" :op4 "activator" :op5 "of" :op6 "transcription-3")
            :ARG1-of (m / mean-01
                  :ARG2 (p2 / protein :name (n2 / name :op1 "STAT3"))))
      :source (t / text
            :ARG1-of (f / full-09)))

# ::id bel_pmid_1866_6314.39148 ::date 2015-05-11T03:17:25 ::annotator SDL-AMR-09 ::preferred
# ::snt from full text - TNF-alpha exerts its pro-inflammatory effects through increased production of IL-1beta and IL-6, expression of adhesion molecules, proliferation of fibroblasts and procoagulant factors, as well as initiation of cytotoxic, apoptotic, acute-phase responses, and inhibition of apoptosis [8,9].
# ::save-date Wed Mar 2, 2016 ::file bel_pmid_1866_6314_39148.txt
(a9 / affect-01
      :ARG0 (p / protein :name (n / name :op1 "TNF-alpha"))
      :ARG0-of (f2 / favor-01
            :ARG1 (i / inflame-01))
      :manner (a / and
            :op1 (p3 / produce-01
                  :ARG1 (a2 / and
                        :op1 (p4 / protein :name (n2 / name :op1 "IL-1beta"))
                        :op2 (p5 / protein :name (n3 / name :op1 "IL-6")))
                  :ARG1-of (i2 / increase-01))
            :op2 (e3 / express-03
                  :ARG2 (m / molecule
                        :ARG0-of (a3 / adhere-01)))
            :op3 (p6 / proliferate-01
                  :ARG0 (a4 / and
                        :op1 (f / fibroblast)
                        :op2 (f4 / factor
                              :ARG0-of (f3 / favor-01
                                    :ARG1 (c / coagulate-01)))))
            :op4 (i3 / initiate-01
                  :ARG1 (a10 / and
                        :op1 (r / respond-01
                              :mod (c2 / cytotoxic))
                        :op2 (r2 / respond-01
                              :mod (a5 / apoptosis))
                        :op3 (r3 / respond-01
                              :mod (p2 / phase
                                    :mod (a6 / acute)))))
            :op5 (i4 / inhibit-01
                  :ARG1 a5))
      :ARG1-of (d / describe-01
            :ARG0 (p8 / publication
                  :ARG1-of (c3 / cite-01
                        :ARG2 (a8 / and :op1 8 :op2 9))))
      :source (t / text
            :ARG1-of (f5 / full-09)))

# ::id bel_pmid_1866_6314.39746 ::date 2015-05-11T03:18:26 ::annotator SDL-AMR-09 ::preferred
# ::snt from full text - Defective transforming growth factor TGF-beta1 signaling due to high levels of Smad7 is a feature of IBD[55]. UC patients have exhibited increased production of TGF-beta1 by LPMC as compared with both CD patients and controls
# ::save-date Sun Jan 17, 2016 ::file bel_pmid_1866_6314_39746.txt
(m / multi-sentence
      :snt1 (f / feature
            :domain (s2 / signal-07
                  :ARG0 (p6 / protein :name (n2 / name :op1 "transforming" :op2 "growth" :op3 "factor" :op4 "beta1"))
                  :mod (d / defective)
                  :ARG1-of (c4 / cause-01
                        :ARG0 (l / level
                              :ARG1-of (h / high-02)
                              :quant-of (p5 / protein :name (n / name :op1 "Smad7")))))
            :ARG1-of (d3 / describe-01
                  :ARG0 (p / publication
                        :ARG1-of (c / cite-01
                              :ARG2 55)))
            :poss (d2 / disease :name (n3 / name :op1 "IBD")))
      :snt2 (e / exhibit-01
            :ARG0 (p2 / patient
                  :mod (d5 / disease :name (n4 / name :op1 "ulcerative" :op2 "colitis")))
            :ARG1 (i / increase-01
                  :ARG1 (p3 / produce-01
                        :ARG0 (c2 / cell :name (n5 / name :op1 "LPMC"))
                        :ARG1 (p7 / protein :name (n6 / name :op1 "TGF-beta1")))
                  :compared-to (a / and
                        :op1 (p4 / patient
                              :mod (d4 / disease :name (n7 / name :op1 "coeliac" :op2 "disease")))
                        :op2 (c3 / control)))))

# ::id bel_pmid_1876_9721.19816 ::date 2015-05-11T03:19:41 ::annotator SDL-AMR-09 ::preferred
# ::snt To determine if XIAP enhanced proinflammatory gene expression in vivo, we performed qRT-PCR analysis on splenic RNA from WT and XIAP knockout mice. RNA was isolated from splenocytes harvested from uninfected animals or animals infected with L. monocytogenes for 48 h (Figure 6) {to activate XIAP}. The expression of il6 and ifng mRNAs were significantly enhanced in the presence of XIAP during infection.
# ::save-date Sat Feb 13, 2016 ::file bel_pmid_1876_9721_19816.txt
(m / multi-sentence
      :snt2 (i3 / isolate-01
            :ARG1 (n4 / nucleic-acid :name (n10 / name :op1 "RNA"))
            :source (c / cell :name (n7 / name :op1 "splenocyte")
                  :ARG1-of (h / harvest-01
                        :source (o3 / or
                              :op1 (a3 / animal
                                    :ARG1-of (i4 / infect-01 :polarity -))
                              :op2 (a4 / animal
                                    :ARG1-of (i5 / infect-01
                                          :ARG2 (o / organism :name (n8 / name :op1 "L." :op2 "monocytogene"))
                                          :duration (t2 / temporal-quantity :quant 48
                                                :unit (h2 / hour)))))))
            :purpose (a5 / activate-01
                  :ARG1 (p4 / protein :name (n9 / name :op1 "XIAP")))
            :ARG1-of (d2 / describe-01
                  :ARG0 (f2 / figure :mod 6)))
      :snt3 (e3 / enhance-01
            :ARG1 (e4 / express-03
                  :ARG1 (n3 / nucleic-acid :name (n2 / name :op1 "mRNA")
                        :ARG0-of (e6 / encode-01
                              :ARG1 (a7 / and
                                    :op1 (p / protein :name (n6 / name :op1 "IL6"))
                                    :op2 (p7 / protein :name (n13 / name :op1 "IFNG"))))))
            :ARG3 (s2 / significant-02)
            :condition (p2 / present-02
                  :ARG1 (p5 / protein :name (n12 / name :op1 "XIAP")))
            :time (i6 / infect-01))
      :snt1 (a / analyze-01
            :ARG0 (w / we)
            :ARG1 (n11 / nucleic-acid :name (n14 / name :op1 "RNA")
                  :mod (s / spleen)
                  :source (a2 / and
                        :op1 (m3 / mouse
                              :mod (w2 / wild-type))
                        :op2 (m4 / mouse
                              :ARG3-of (e5 / express-03
                                    :ARG2 (p3 / protein :name (n5 / name :op1 "XIAP")
                                          :ARG1-of (k / knock-out-03))))))
            :purpose (d / determine-01
                  :ARG0 w
                  :ARG1 (e / enhance-01
                        :ARG0 (p6 / protein :name (n / name :op1 "XIAP"))
                        :ARG1 (e2 / express-03
                              :ARG1 (g2 / gene)
                              :manner (i2 / in-vivo)
                              :ARG0-of (f / favor-01
                                    :ARG1 (i / inflame-01)))))
            :instrument (t / thing :name (n15 / name :op1 "qRT-PCR"))))

# ::id bel_pmid_1897_5310.25820 ::date 2015-05-11T03:20:15 ::annotator SDL-AMR-09 ::preferred
# ::snt Furthermore, the hydroxyproline content was significantly reduced in the anti-CD154 mAb–treated group compared with the control IgG– treated group (Figure 5c).
# ::save-date Sat Jan 2, 2016 ::file bel_pmid_1897_5310_25820.txt
(a / and
      :op2 (r / reduce-01
            :ARG1 (c / contain-01
                  :ARG1 (a2 / amino-acid :name (n / name :op1 "hydroxyproline")))
            :ARG2 (s / significant-02)
            :location (g / group
                  :ARG1-of (t / treat-03
                        :ARG3 (a3 / antibody
                              :ARG0-of (c2 / counter-01
                                    :ARG1 (p / protein :name (n2 / name :op1 "CD154")))
                              :mod (m / monoclone))))
            :compared-to (g2 / group
                  :ARG1-of (t2 / treat-03
                        :ARG3 (p2 / protein :name (n3 / name :op1 "IgG")))))
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod "5c")))

# ::id bel_pmid_1897_5310.25824 ::date 2015-05-11T03:21:00 ::annotator SDL-AMR-09 ::preferred
# ::snt In contrast, the number of BrdU-positive proliferating dermal fibroblasts at 1 week was significantly reduced in the anti-CD154 mAb–treated group compared with the control IgG–treated group
# ::save-date Sun Jan 17, 2016 ::file bel_pmid_1897_5310_25824.txt
(c / contrast-01
      :ARG2 (r / reduce-01
            :ARG1 (n / number
                  :quant-of (f / fibroblast
                        :mod (d / dermis)
                        :ARG0-of (p / proliferate-01)
                        :mod (p2 / positive
                              :mod (s2 / small-molecule :name (n2 / name :op1 "BrdU")))))
            :ARG2 (s / significant-02)
            :location (g / group
                  :ARG1-of (t2 / treat-03
                        :ARG3 (a / antibody
                              :mod (m / monoclonal)
                              :ARG0-of (c3 / counter-01
                                    :ARG1 (p4 / protein :name (n3 / name :op1 "CD154"))))))
            :compared-to (g2 / group
                  :mod (c2 / control)
                  :ARG1-of (t3 / treat-03
                        :ARG3 (p5 / protein :name (n4 / name :op1 "IgG"))))
            :time (a2 / after
                  :op1 (a3 / and
                        :op1 t2
                        :op2 t3)
                  :quant (t / temporal-quantity :quant 1
                        :unit (w / week)))))

# ::id bel_pmid_1897_5310.25836 ::date 2015-05-11T03:21:24 ::annotator SDL-AMR-09 ::preferred
# ::snt In addition, the anti-CD154 mAb treatment suppressed the up-regulated expression of COL1A1, RANTES, and MCP-1 mRNA (Figure 5g).
# ::save-date Tue Jun 16, 2015 ::file bel_pmid_1897_5310_25836.txt
(a / and
      :op2 (s / suppress-01
            :ARG0 (t / treat-04
                  :ARG2 (a3 / antibody
                        :mod (m / monoclonal)
                        :ARG0-of (c / counter-01
                              :ARG1 (p / protein :name (n / name :op1 "CD154")))))
            :ARG1 (e / express-03
                  :ARG1 (n2 / nucleic-acid :name (n5 / name :op1 "mRNA")
                        :ARG0-of (e2 / encode-01
                              :ARG1 (a5 / and
                                    :op1 (p2 / protein :name (n6 / name :op1 "COL1A1"))
                                    :op2 (p3 / protein :name (n7 / name :op1 "RANTES"))
                                    :op3 (p4 / protein :name (n8 / name :op1 "MCP-1")))))
                  :ARG1-of (u / upregulate-01))
            :ARG1-of (d / describe-01
                  :ARG0 (f / figure :mod "5g"))))

# ::id bel_pmid_1897_5310.36028 ::date 2015-05-11T03:21:37 ::annotator SDL-AMR-09 ::preferred
# ::snt Upon stimulation with soluble CD154, cultured fibroblasts induced to express CD40 by adenoviral gene transfer proliferated and showed up-regulation of the genes for intercellular adhesion molecule 1, interleukin-6 (IL-6), IL-8, monocyte chemoattractant protein 1 (MCP-1), and RANTES, as well as up-regulation of their proteins.
# ::save-date Tue Jun 16, 2015 ::file bel_pmid_1897_5310_36028.txt
(a / and
      :op1 (p / proliferate-01
            :ARG0 (f / fibroblast
                  :mod (c / cultured)
                  :ARG1-of (i / induce-01
                        :ARG2 (e / express-03
                              :ARG2 (p2 / protein :name (n / name :op1 "CD40"))
                              :ARG3 f
                              :manner (t / transfer-01
                                    :ARG1 (g / gene
                                          :mod (a2 / adenoviral)))))))
      :op2 (s3 / show-01
            :ARG0 f
            :ARG1 (a3 / and
                  :op1 (u / upregulate-01
                        :ARG1 (g2 / gene
                              :ARG0-of (e2 / encode-01
                                    :ARG1 (a4 / and
                                          :op1 (p4 / protein :name (n3 / name :op1 "intercellular" :op2 "adhesion" :op3 "molecule" :op4 "1"))
                                          :op2 (p5 / protein :name (n4 / name :op1 "interleukin-6"))
                                          :op3 (p6 / protein :name (n5 / name :op1 "monocyte" :op2 "chemoattractant" :op3 "protein"))
                                          :op4 (p7 / protein :name (n6 / name :op1 "RANTES"))))))
                  :op2 (u2 / upregulate-01
                        :ARG1 a4)))
      :condition (s / stimulate-01
            :ARG1 f
            :ARG2 (p3 / protein :name (n2 / name :op1 "CD154")
                  :mod (s2 / soluble))))

# ::id bel_pmid_1903_3457.27030 ::date 2015-05-11T03:22:00 ::annotator SDL-AMR-09 ::preferred
# ::snt Consistent with diminished numbers of squamous type I cells in epFoxm1-/- lungs, mRNA levels of T1-alpha and aquaporin 5 were significantly decreased as demonstrated by quantitative real-time (RT-PCR) (qRT-PCR) analysis (Fig. 3B).
# ::save-date Sat Jan 2, 2016 ::file bel_pmid_1903_3457_27030.txt
(d / decrease-01
      :ARG1 (l / level
            :quant-of (n4 / nucleic-acid :name (n / name :op1 "mRNA")
                  :ARG0-of (e / encode-01
                        :ARG1 (a / and
                              :op1 (p / protein :name (n2 / name :op1 "T1-alpha"))
                              :op2 (p2 / protein :name (n3 / name :op1 "aquaporin" :op2 "5"))))))
      :ARG2 (s / significant-02)
      :ARG1-of (d2 / demonstrate-01
            :ARG0 (a2 / analyze-01
                  :mod (q / quantity)
                  :mod (r2 / real-time)
                  :ARG1-of (m / mean-01
                        :ARG2 (t / thing :name (n5 / name :op1 "RT-PCR")))))
      :ARG1-of (c / consistent-01
            :ARG2 (n7 / number
                  :quant-of (c2 / cell :name (n6 / name :op1 "squamous" :op2 "type" :op3 "I" :op4 "cell")
                        :location (l2 / lung
                              :mod (p3 / protein :name (n8 / name :op1 "epFoxm1")
                                    :ARG2-of (m3 / mutate-01 :mod "−/−"))))
                  :ARG1-of (d4 / diminish-01)))
      :ARG1-of (d3 / describe-01
            :ARG0 (f / figure :mod "3B")))

# ::id bel_pmid_1903_3457.27038 ::date 2015-05-11T03:22:28 ::annotator SDL-AMR-09 ::preferred
# ::snt Significantly decreased mRNA levels of M-phase-promoting Cdc25B phosphatase (Fig. 3B), a known transcriptional target of Foxm1 (15), were observed in the lungs of epFoxm1-/- mice.
# ::save-date Sun Jan 3, 2016 ::file bel_pmid_1903_3457_27038.txt
(o / observe-01
      :ARG1 (d / decrease-01
            :ARG1 (l / level
                  :quant-of (n6 / nucleic-acid :name (n / name :op1 "mRNA")
                        :ARG0-of (e / encode-01
                              :ARG1 (e2 / enzyme :name (n4 / name :op1 "Cdc25B" :op2 "phosphatase")
                                    :ARG1-of (t / target-01
                                          :ARG0 (p2 / protein :name (n3 / name :op1 "Foxm1"))
                                          :ARG1-of (k / know-01)
                                          :purpose (t2 / transcribe-01)
                                          :ARG1-of (d3 / describe-01
                                                :ARG0 (p / publication
                                                      :ARG1-of (c / cite-01
                                                            :ARG2 15))))
                                    :ARG0-of (p4 / promote-01
                                          :ARG1 (e3 / event :name (n7 / name :op1 "M-phase")))))))
            :ARG2 (s / significant-02)
            :ARG1-of (d2 / describe-01
                  :ARG0 (f / figure :mod "3B")))
      :location (l2 / lung
            :part-of (m2 / mouse
                  :mod (p3 / protein :name (n5 / name :op1 "Foxm1")
                        :ARG2-of (m / mutate-01 :mod "−/−")))))

# ::id bel_pmid_1905_2556.19692 ::date 2015-05-11T03:23:42 ::annotator SDL-AMR-09 ::preferred
# ::snt The authors demonstrate that HMGB1 binds to TLR4 and that HMGB1, which is released by chemotherapy-induced cell death, can activate TLR4 and induce anti-tumour T-cell immunity79.
# ::save-date Sun Dec 20, 2015 ::file bel_pmid_1905_2556_19692.txt
(d / demonstrate-01
      :ARG0 (p5 / person
            :ARG0-of (a / author-01))
      :ARG1 (a2 / and
            :op1 (b / bind-01
                  :ARG1 (p / protein :name (n / name :op1 "HMGB1")
                        :ARG1-of (r / release-01
                              :ARG0 (d2 / die-01
                                    :ARG1 (c / cell)
                                    :ARG2-of (i2 / induce-01
                                          :ARG0 (c2 / chemotherapy)))))
                  :ARG2 (p3 / protein :name (n2 / name :op1 "TLR4")))
            :op2 (p2 / possible-01
                  :ARG1 (a3 / and
                        :op1 (a4 / activate-01
                              :ARG0 p
                              :ARG1 p3)
                        :op2 (i / induce-01
                              :ARG0 p
                              :ARG2 (i3 / immune-02
                                    :ARG1 (c3 / cell :name (n3 / name :op1 "T-cell"))
                                    :ARG0-of (c4 / counter-01
                                          :ARG1 (t / tumor)))))))
      :ARG1-of (d3 / describe-01
            :ARG0 (p4 / publication
                  :ARG1-of (c5 / cite-01
                        :ARG2 79))))

# ::id bel_pmid_1905_2556.29386 ::date 2015-05-11T03:23:53 ::annotator SDL-AMR-09 ::preferred
# ::snt In response to hepatocyte cell death, MyD88 signalling was responsible for the activation of NF-?B and for the production of factors such as IL-6 (ReF. 122).
# ::save-date Wed Jun 10, 2015 ::file bel_pmid_1905_2556_29386.txt
(r / responsible-01
      :ARG0 (s / signal-07
            :ARG0 (p / protein :name (n / name :op1 "MyD88")))
      :ARG1 (a / and
            :op1 (a2 / activate-01
                  :ARG1 (p2 / protein :name (n2 / name :op1 "NF-kB")))
            :op2 (p3 / produce-01
                  :ARG1 (f / factor
                        :example (p4 / protein :name (n3 / name :op1 "IL-6")))))
      :ARG2-of (r2 / respond-01
            :ARG1 (d / die-01
                  :ARG1 (c / cell :name (n4 / name :op1 "hepatocyte"))))
      :ARG1-of (d2 / describe-01
            :ARG0 (p5 / publication
                  :ARG1-of (c2 / cite-01
                        :ARG2 122))))

# ::id bel_pmid_1905_2556.35940 ::date 2015-05-11T03:24:04 ::annotator SDL-AMR-09 ::preferred
# ::snt All TLRs (except for TLR3) and IL-1 receptor family members signal through MyD88.
# ::save-date Mon Jan 4, 2016 ::file bel_pmid_1905_2556_35940.txt
(s / signal-07
      :ARG0 (a2 / and
            :op1 (p / protein :name (n5 / name :op1 "TLR")
                  :mod (a / all)
                  :ARG2-of (e / except-01
                        :ARG1 (p2 / protein :name (n2 / name :op1 "TLR3"))))
            :op2 (m / member
                  :ARG1-of (i2 / include-91
                        :ARG2 (p3 / protein-family :name (n3 / name :op1 "IL-1")))))
      :manner (p4 / protein :name (n4 / name :op1 "MyD88")))

# ::id bel_pmid_1905_3174.34990 ::date 2015-05-11T01:45:29 ::annotator SDL-AMR-09 ::preferred
# ::snt We veri?ed the secretion levels of several SASP proteins by ELISAs (Figure S1 and Text S1). Further, because secretion increased greater than 10-fold for some SASP factors, we could verify up-regulation by intracellular immunostaining. For example, IL-6 and IL-8 were barely visible in PRE cells but clearly detectable in SEN cells (Figure 1B, Figure S2, and Text S1).
# ::save-date Tue Jan 19, 2016 ::file bel_pmid_1905_3174_34990.txt
(m / multi-sentence
      :snt1 (v / verify-01
            :ARG0 (w / we)
            :ARG1 (l / level
                  :degree-of (s / secrete-01
                        :ARG1 (p / protein
                              :quant (s2 / several)
                              :mod (t5 / thing :name (n2 / name :op1 "SASP")))))
            :instrument (t / thing :name (n / name :op1 "ELISA"))
            :ARG1-of (d / describe-01
                  :ARG0 (a / and
                        :op1 (f / figure :mod "S1")
                        :op2 (t2 / text :mod "S1"))))
      :snt2 (p2 / possible-01
            :ARG1 (v2 / verify-01
                  :ARG0 (w2 / we)
                  :ARG1 (u / upregulate-01)
                  :ARG1-of (c / cause-01
                        :ARG0 (i / increase-01
                              :ARG1 (s3 / secrete-01
                                    :ARG1 (f2 / factor
                                          :mod (t3 / thing :name (n3 / name :op1 "SASP"))
                                          :mod (s4 / some)))
                              :ARG2 (m2 / more-than
                                    :mod (p4 / product-of :op1 10))))
                  :manner (i2 / immunostain-01
                        :manner (i3 / intracellular)))
            :mod (f5 / further))
      :snt3 (e / exemplify-01
            :ARG0 (c2 / contrast-01
                  :ARG1 (p5 / possible-01
                        :ARG1 (s5 / see-01
                              :ARG1 (a2 / and
                                    :op1 (p6 / protein :name (n5 / name :op1 "IL-6"))
                                    :op2 (p7 / protein :name (n6 / name :op1 "IL-8")))
                              :degree (b / bare)
                              :location (c3 / cell
                                    :mod (p8 / presenescent))))
                  :ARG2 (p9 / possible-01
                        :ARG1 (d2 / detect-01
                              :ARG1 a2
                              :ARG1-of (c4 / clear-06)
                              :location (c5 / cell
                                    :mod (s6 / senescent)))))
            :ARG1-of (d3 / describe-01
                  :ARG0 (a3 / and
                        :op1 (f3 / figure :mod "1B")
                        :op2 (f4 / figure :mod "S2")
                        :op3 (t4 / text :mod "S1")))))

# ::id bel_pmid_1905_3174.35034 ::date 2015-05-11T02:36:54 ::annotator SDL-AMR-09 ::preferred
# ::snt SASP components included inflammatory and immune-modulatory cytokines and chemokines (e.g., IL-6, ?7, and ?8, MCP-2, and MIP-3a). They also included growth factors (e.g., GRO, HGF, and IGFBPs), shed cell surface molecules (e.g., ICAMs, uPAR, and TNF receptors), and survival factors (Figure 1A and Table S2)
# ::save-date Wed Feb 24, 2016 ::file bel_pmid_1905_3174_35034.txt
(m / multi-sentence
      :snt1 (i / include-01
            :ARG1 (a / and
                  :op1 (c2 / cytokine)
                  :op2 (c3 / chemokine)
                  :ARG0-of (i4 / inflame-01)
                  :ARG0-of (m2 / modulate-01
                        :ARG1-of (i2 / immune-02))
                  :example (a2 / and
                        :op1 (c4 / cytokine :name (n2 / name :op1 "IL-6"))
                        :op2 (c5 / cytokine :name (n3 / name :op1 "IL-7"))
                        :op3 (c6 / chemokine :name (n4 / name :op1 "IL-8"))
                        :op4 (c7 / chemokine :name (n5 / name :op1 "MCP-2"))
                        :op5 (c8 / chemokine :name (n6 / name :op1 "MIP-3a"))))
            :ARG2 (c / component
                  :mod (t / thing :name (n / name :op1 "SASP"))))
      :snt2 (i3 / include-01
            :ARG1 (a3 / and
                  :op1 (g / growth-factor
                        :example (a4 / and
                              :op1 (g2 / growth-factor :name (n7 / name :op1 "GRO"))
                              :op2 (g3 / growth-factor :name (n8 / name :op1 "HGF"))
                              :op3 (g4 / growth-factor :name (n9 / name :op1 "IGFBP"))))
                  :op2 (m3 / molecule
                        :mod (s / surface)
                        :source (c9 / cell
                              :ARG1-of (s2 / shed-01))
                        :example (a5 / and
                              :op1 (p / protein :name (n10 / name :op1 "ICAM"))
                              :op2 (p3 / protein :name (n11 / name :op1 "uPAR"))
                              :op3 (p2 / protein :name (n12 / name :op1 "TNF" :op2 "receptor"))))
                  :op3 (f2 / factor
                        :mod (s3 / survive-01)))
            :ARG2 (t2 / they)
            :mod (a6 / also))
      :ARG1-of (d / describe-01
            :ARG0 (a7 / and
                  :op1 (f3 / figure :mod "1A")
                  :op2 (t3 / table :mod "S2"))))

# ::id bel_pmid_1917_3740.18146 ::date 2015-05-11T04:14:08 ::annotator SDL-AMR-09 ::preferred
# ::snt Hypoxia exposure of IL-6+/+ mice led to marked increases in IL-6 mRNA and protein levels within the first week, with positive IL-6 immunostaining in the pulmonary vessel walls ...In vitro studies of cultured human pulmonary-artery smooth-muscle-cells (PA-SMCs) and microvascular endothelial cells revealed prominent synthesis of IL-6 by PA-SMCs, with further stimulation by hypoxia.
# ::save-date Tue Jan 19, 2016 ::file bel_pmid_1917_3740_18146.txt
(m / multi-sentence
      :snt1 (l / lead-03
            :ARG0 (e / expose-01
                  :ARG1 (m2 / mouse
                        :mod (p / protein :name (n / name :op1 "IL-6")
                              :mod (w / wild-type)))
                  :ARG2 (h / hypoxia))
            :ARG2 (i / increase-01
                  :ARG1 (a / and
                        :op1 (l2 / level
                              :quant-of (n7 / nucleic-acid :name (n2 / name :op1 "mRNA")
                                    :ARG0-of (e2 / encode-01
                                          :ARG1 (p2 / protein :name (n3 / name :op1 "IL-6")))))
                        :op2 (l3 / level
                              :quant-of p2))
                  :ARG1-of (m3 / mark-01)
                  :time (w2 / week
                        :ord (o / ordinal-entity :value 1)))
            :accompanier (i2 / immunostain-01
                  :ARG1 (w3 / wall
                        :mod (v / vessel
                              :mod (p4 / pulmonary)))
                  :ARG3 p2
                  :mod (p3 / positive)))
      :snt2 (r2 / reveal-01
            :ARG0 (s / study-01
                  :ARG1 (a2 / and
                        :op1 (c4 / cell
                              :mod (m4 / mucle
                                    :ARG1-of (s4 / smooth-06))
                              :mod (a3 / artery
                                    :mod (l4 / lung))
                              :mod (h3 / human)
                              :ARG1-of (c2 / culture-01))
                        :op2 (c5 / cell
                              :mod (e3 / endothelium
                                    :mod (m5 / microvascular))))
                  :manner (i3 / in-vitro))
            :ARG1 (s2 / synthesize-01
                  :ARG0 c4
                  :ARG1 (p5 / protein :name (n6 / name :op1 "IL-6"))
                  :mod (p6 / prominent)
                  :ARG1-of (s3 / stimulate-01
                        :ARG0 (h2 / hypoxia)
                        :mod (f / further)))))

# ::id bel_pmid_1922_8664.9182 ::date 2015-05-11T04:32:36 ::annotator SDL-AMR-09 ::preferred
# ::snt In CIA synoviocytes, IL-17 increased the expression of TLR-2, 4, and 9, and this effect was significantly alleviated by neutralizing antibodies to IL-17, IL-1beta, and IL-6.
# ::save-date Sun Jan 3, 2016 ::file bel_pmid_1922_8664_9182.txt
(a / and
      :op1 (i / increase-01
            :ARG0 (p / protein :name (n / name :op1 "IL-17"))
            :ARG1 (e / express-03
                  :ARG2 (a2 / and
                        :op1 (p2 / protein :name (n2 / name :op1 "TLR-2"))
                        :op2 (p3 / protein :name (n3 / name :op1 "TLR-4"))
                        :op3 (p4 / protein :name (n4 / name :op1 "TLR-9"))))
            :location (c5 / cell :name (n9 / name :op1 "synoviocyte")
                  :mod (d / disease :name (n10 / name :op1 "collagen-induced" :op2 "arthritis"))))
      :op2 (a3 / alleviate-01
            :ARG0 (n6 / neutralize-01
                  :ARG0 (a4 / and
                        :op1 (a5 / antibody
                              :ARG0-of (c2 / counter-01
                                    :ARG1 p))
                        :op2 (a6 / antibody
                              :ARG0-of (c3 / counter-01
                                    :ARG1 (p5 / protein :name (n7 / name :op1 "IL-1beta"))))
                        :op3 (a7 / antibody
                              :ARG0-of (c4 / counter-01
                                    :ARG1 (p6 / protein :name (n8 / name :op1 "IL-6"))))))
            :ARG1 i
            :ARG1-of (s2 / significant-02)))

# ::id bel_pmid_1923_8385.18998 ::date 2015-05-11T04:45:30 ::annotator SDL-AMR-09 ::preferred
# ::snt CX3CR1 may also be of importance as it confers a survival signal, which prevents cell death of monocytes and foam cells [52].
# ::save-date Tue May 12, 2015 ::file bel_pmid_1923_8385_18998.txt
(p / possible-01
      :ARG1 (i / important
            :domain (p2 / protein :name (n / name :op1 "CX3CR1"))
            :mod (a2 / also))
      :ARG1-of (c / cause-01
            :ARG0 (c2 / confer-02
                  :ARG0 p2
                  :ARG1 (s / signal
                        :mod (s2 / survive-01)
                        :ARG0-of (p3 / prevent-01
                              :ARG1 (d / die-01
                                    :ARG1 (a / and
                                          :op1 (m / monocyte)
                                          :op2 (c3 / cell
                                                :mod (f / foam))))))))
      :ARG1-of (d2 / describe-01
            :ARG0 (p4 / publication
                  :ARG1-of (c4 / cite-01
                        :ARG2 52))))

# ::id bel_pmid_1923_8385.27652 ::date 2015-05-11T04:54:23 ::annotator SDL-AMR-09 ::preferred
# ::snt The same group demonstrated just recently that mast cells actively participate in the formation of aortic aneurysms by release of IL-6 and IFN?, which induced apoptosis of smooth muscle cells and protease expression [111].
# ::save-date Sun Dec 20, 2015 ::file bel_pmid_1923_8385_27652.txt
(d / demonstrate-01
      :ARG0 (g / group
            :ARG1-of (s / same-01))
      :ARG1 (p / participate-01
            :ARG0 (c / cell
                  :mod (m / mast))
            :ARG1 (f / form-01
                  :ARG1 (a2 / aneurysm
                        :mod (a3 / aorta)))
            :ARG1-of (a / activity-06
                  :ARG0 c)
            :manner (r / release-01
                  :ARG1 (a4 / and
                        :op1 (p2 / protein :name (n / name :op1 "IL-6"))
                        :op2 (p3 / protein :name (n2 / name :op1 "IFN-γ"))
                        :ARG0-of (i / induce-01
                              :ARG2 (a6 / and
                                    :op1 (a5 / apoptosis
                                          :mod (c2 / cell
                                                :part-of (m2 / muscle
                                                      :ARG1-of (s2 / smooth-06))))
                                    :op2 (e / express-03
                                          :ARG2 (e2 / enzyme :name (n3 / name :op1 "protease"))))))))
      :time (r2 / recent
            :mod (j / just))
      :ARG1-of (d2 / describe-01
            :ARG0 (p5 / publication
                  :ARG1-of (c3 / cite-01
                        :ARG2 111))))

# ::id bel_pmid_1927_3391.16158 ::date 2015-05-11T10:04:51 ::annotator SDL-AMR-09 ::preferred
# ::snt Several receptor tyrosine kinases exhibit stimulated activity upon peroxynitrite exposure, triggering downstream phosphotyrosine-dependent signalling, as shown for the platelet-derived growth factor receptor (PDGFR) and the receptor for brain-derived neurotrophic factor (TrkB) in murine fibroblasts (24,25), as well as the Epidermal Growth Factor Receptor (EGFR) in rat lung myofibroblasts (26).
# ::save-date Sun Jan 17, 2016 ::file bel_pmid_1927_3391_16158.txt
(e2 / exhibit-01
      :ARG0 (p / protein :name (n3 / name :op1 "receptor" :op2 "tyrosine" :op3 "kinase")
            :quant (s2 / several)
            :ARG0-of (t / trigger-01
                  :ARG1 (s / signal-07
                        :location (d / downstream)
                        :ARG0-of (d2 / depend-01
                              :ARG1 (a2 / amino-acid :name (n5 / name :op1 "tyrosine")
                                    :ARG3-of (p2 / phosphorylate-01))))
                  :ARG1-of (s6 / show-01
                        :topic (a3 / and
                              :op1 (p3 / protein :name (n6 / name :op1 "platelet-derived" :op2 "growth" :op3 "factor" :op4 "receptor"))
                              :op2 (p4 / protein :name (n7 / name :op1 "brain-derived" :op2 "neutrophic" :op3 "factor" :op4 "receptor")))
                        :location (f / fibroblast
                              :part-of (o / organism :name (n8 / name :op1 "Muridae")))
                        :ARG1-of (d3 / describe-01
                              :ARG0 (p6 / publication
                                    :ARG1-of (c / cite-01
                                          :ARG2 (a5 / and :op1 24 :op2 25)))))
                  :ARG1-of (s7 / show-01
                        :topic (e / enzyme :name (n9 / name :op1 "Epidermal" :op2 "Growth" :op3 "Factor" :op4 "Receptor"))
                        :location (m / myofibroblast
                              :source (l / lung
                                    :part-of (r / rat)))
                        :ARG1-of (d4 / describe-01
                              :ARG0 (p7 / publication
                                    :ARG1-of (c2 / cite-01
                                          :ARG2 26))))))
      :ARG1 (a / activity-06
            :ARG1-of (s3 / stimulate-01))
      :condition (e3 / expose-01
            :ARG2 (s4 / small-molecule :name (n4 / name :op1 "peroxynitrite"))))

# ::id bel_pmid_1927_3391.16160 ::date 2015-05-11T10:38:07 ::annotator SDL-AMR-09 ::preferred
# ::snt Peroxynitrite-mediated JNK activation has been associated with apoptotic cell death in murine alveolar C10 cells, in which JNK was activated upon the oxidation of the death receptor Fas.
# ::save-date Sun Jan 17, 2016 ::file bel_pmid_1927_3391_16160.txt
(a / associate-01
      :ARG1 (a2 / activate-01
            :ARG1 (e / enzyme :name (n / name :op1 "JNK"))
            :ARG1-of (m / mediate-01
                  :ARG0 (s / small-molecule :name (n2 / name :op1 "peroxynitrite"))))
      :ARG2 (d / die-01
            :ARG1 (c / cell)
            :mod (a3 / apoptosis))
      :location (c2 / cell-line :name (n3 / name :op1 "C10")
            :mod (a4 / alveolus)
            :part-of (o2 / organism :name (n4 / name :op1 "Muridae"))
            :location-of (a6 / activate-01
                  :ARG1 e
                  :condition (o / oxidize-01
                        :ARG1 (p / protein :name (n6 / name :op1 "death" :op2 "receptor" :op3 "Fas"))))))

# ::id bel_pmid_1927_3391.16162 ::date 2015-05-11T10:44:17 ::annotator SDL-AMR-09 ::preferred
# ::snt Nomiyama et al, who reported that peroxynitrite inhibited insulin-stimulated glucose uptake in preadipocyte-derived 3T3-L1 cells by reducing insulin receptor substrate-1 (IRS-1) protein levels and associated PI3K activity, upstream of Akt/PKB (122).
# ::save-date Mon Jan 4, 2016 ::file bel_pmid_1927_3391_16162.txt
(r / report-01
      :ARG0 (a / and
            :op1 (p2 / person :name (n2 / name :op1 "Nomiyama"))
            :op2 (p / person
                  :mod (o2 / other)))
      :ARG1 (i / inhibit-01
            :ARG0 (s / small-molecule :name (n3 / name :op1 "peroxynitrite"))
            :ARG1 (t / take-up-13
                  :ARG2 (s2 / small-molecule :name (n4 / name :op1 "glucose"))
                  :ARG1-of (s3 / stimulate-01
                        :ARG0 (p7 / protein :name (n5 / name :op1 "insulin"))))
            :location (c / cell-line :name (n6 / name :op1 "3T3-L1")
                  :ARG1-of (d / derive-01
                        :ARG2 (p3 / preadipocyte)))
            :manner (r2 / reduce-01
                  :ARG0 s
                  :ARG1 (a2 / and
                        :op1 (l / level
                              :quant-of (p4 / protein :name (n7 / name :op1 "insulin" :op2 "receptor" :op3 "substrate-1")))
                        :op2 (a3 / activity-06
                              :ARG0 (e / enzyme :name (n8 / name :op1 "PI3K"))
                              :ARG1-of (a4 / associate-01)))
                  :location (r3 / relative-position
                        :op1 (p5 / pathway :name (n9 / name :op1 "Akt/PKB"))
                        :direction (u2 / upstream))))
      :ARG1-of (d2 / describe-01
            :ARG0 (p6 / publication
                  :ARG1-of (c2 / cite-01
                        :ARG2 122))))

# ::id bel_pmid_1927_3391.30174 ::date 2015-05-11T10:59:41 ::annotator SDL-AMR-09 ::preferred
# ::snt Administration of PTEN-specific siRNA reversed PKB/Akt inhibition and mitigated apoptosis in diabetic mouse aortas. These findings therefore suggest that hyperglycaemia may promote apoptosis in endothelial cells through PKB/Akt downregulation, via a peroxynitrite-mediated, LKB1-dependent PTEN activation (46).
# ::save-date Fri Jul 24, 2015 ::file bel_pmid_1927_3391_30174.txt
(m / multi-sentence
      :snt1 (a2 / and
            :op1 (r / reverse-01
                  :ARG0 (a3 / administer-01
                        :ARG1 (n8 / nucleic-acid :name (n / name :op1 "siRNA")
                              :ARG1-of (s / specific-02
                                    :ARG2 (p / protein :name (n2 / name :op1 "PTEN")))))
                  :ARG1 (i / inhibit-01
                        :ARG1 (p2 / pathway :name (n3 / name :op1 "PKB/Akt"))))
            :op2 (m2 / mitigate-01
                  :ARG0 a3
                  :ARG1 (a4 / apoptosis))
            :location (a5 / aorta
                  :part-of (m3 / mouse
                        :mod (d2 / diabetes))))
      :snt2 (i2 / infer-01
            :ARG1 (s2 / suggest-01
                  :ARG0 (t2 / thing
                        :ARG1-of (f / find-01)
                        :mod (t / this))
                  :ARG1 (p3 / possible-01
                        :ARG1 (p4 / promote-01
                              :ARG0 (h / hyperglycaemia)
                              :ARG1 (a6 / apoptosis)
                              :location (c / cell
                                    :mod (e / endothelium))
                              :manner (d3 / downregulate-01
                                    :ARG1 (p5 / pathway :name (n4 / name :op1 "PKB/Akt"))
                                    :manner (a7 / activate-01
                                          :ARG1 (p6 / protein :name (n5 / name :op1 "PTEN"))
                                          :ARG1-of (m4 / mediate-01
                                                :ARG0 (s3 / small-molecule :name (n7 / name :op1 "peroxynitrite")))
                                          :ARG0-of (d4 / depend-01
                                                :ARG1 (e2 / enzyme :name (n6 / name :op1 "LKB1"))))))))
            :ARG1-of (d5 / describe-01
                  :ARG0 (p8 / publication
                        :ARG1-of (c2 / cite-01
                              :ARG2 46)))))

# ::id bel_pmid_1927_3391.36758 ::date 2015-05-11T11:14:45 ::annotator SDL-AMR-09 ::preferred
# ::snt activation of ERK depended on EGFR, Src tyrosine kinase and calcium calmodulin in PC12 cells (31), while requiring ras/Raf-1/MEK activation in human neutrophils (58).
# ::save-date Mon May 11, 2015 ::file bel_pmid_1927_3391_36758.txt
(c / contrast-01
      :ARG1 (d / depend-01
            :ARG0 (a / activate-01
                  :ARG1 (e / enzyme :name (n / name :op1 "ERK")))
            :ARG1 (a2 / and
                  :op1 (e2 / enzyme :name (n2 / name :op1 "EGFR"))
                  :op2 (t / tyrosine-kinase :name (n3 / name :op1 "Src"))
                  :op3 (p / protein :name (n4 / name :op1 "calcium" :op2 "calmodulin")))
            :location (c2 / cell-line :name (n5 / name :op1 "PC12"))
            :ARG1-of (d2 / describe-01
                  :ARG0 (p3 / publication
                        :ARG1-of (c3 / cite-01
                              :ARG2 31))))
      :ARG2 (r / require-01
            :ARG0 a
            :ARG1 (a3 / activate-01
                  :ARG1 (p2 / pathway :name (n6 / name :op1 "ras/Raf-1/MEK")))
            :location (n7 / neutrophil
                  :mod (h / human))
            :ARG1-of (d3 / describe-01
                  :ARG0 (p4 / publication
                        :ARG1-of (c4 / cite-01
                              :ARG2 58)))))

# ::id bel_pmid_1927_3391.37186 ::date 2015-05-11T12:31:33 ::annotator SDL-AMR-09 ::preferred
# ::snt we reported in H9C2 cardiomyocytes that peroxynitritemediated activation of ERK, although dependent on Raf-1 and MEK, was not due to upstream activation of p21ras (63).
# ::save-date Sun Jan 17, 2016 ::file bel_pmid_1927_3391_37186.txt
(r / report-01
      :ARG0 (w / we)
      :ARG1 (c3 / cause-01 :polarity -
            :ARG0 (a3 / activate-01
                  :ARG1 (p2 / protein :name (n7 / name :op1 "p21ras"))
                  :location (u / upstream))
            :ARG1 (a / activate-01
                  :ARG1 (e / enzyme :name (n / name :op1 "ERK"))
                  :ARG1-of (m / mediate-01
                        :ARG0 (s / small-molecule :name (n4 / name :op1 "peroxynitrite")))
                  :location (c / cardiomyocyte
                        :source (c2 / cell-line :name (n6 / name :op1 "H9C2"))))
            :concession (d / depend-01
                  :ARG0 a
                  :ARG1 (a2 / and
                        :op1 (e3 / enzyme :name (n5 / name :op1 "Raf-1"))
                        :op2 (e2 / enzyme :name (n2 / name :op1 "MEK")))))
      :ARG1-of (d2 / describe-01
            :ARG0 (p3 / publication
                  :ARG1-of (c4 / cite-01
                        :ARG2 63))))

# ::id bel_pmid_1934_2884.19318 ::date 2015-05-11T12:39:37 ::annotator SDL-AMR-09 ::preferred
# ::snt we found that IL6 effectively inhibited LIF signalling, repressing transcription of the LIF receptor gp190, and strongly inducing axotrophin/MARCH-7, a novel E3 ubitquitin ligase that we discovered to be active in degradation of gp190 protein.
# ::save-date Sun Jan 3, 2016 ::file bel_pmid_1934_2884_19318.txt
(f / find-01
      :ARG0 (w / we)
      :ARG1 (i / inhibit-01
            :ARG0 (p / protein :name (n / name :op1 "IL6"))
            :ARG1 (s / signal-07
                  :ARG0 (p2 / protein :name (n2 / name :op1 "LIF")))
            :manner (a2 / and
                  :op1 (r / repress-01
                        :ARG1 (t / transcribe-01
                              :ARG1 (p3 / protein :name (n3 / name :op1 "gp190")
                                    :mod p2)))
                  :op2 (i2 / induce-01
                        :ARG2 (p4 / protein :name (n6 / name :op1 "axotrophin/MARCH-7")
                              :ARG1-of (m / mean-01
                                    :ARG2 (p5 / protein :name (n7 / name :op1 "E3" :op2 "ubiquitin" :op3 "ligase")
                                          :mod (n4 / novel)))
                              :ARG0-of (a / activity-06
                                    :ARG1 (d / degrade-01
                                          :ARG1 p3)
                                    :ARG1-of (d2 / discover-01
                                          :ARG0 (w2 / we))))
                        :ARG1-of (s2 / strong-02)))
            :ARG1-of (e / effective-04)))

# ::id bel_pmid_1934_2884.27058 ::date 2015-05-11T12:56:34 ::annotator SDL-AMR-09 ::preferred
# ::snt Unlike IL6, LIF supported expression of Foxp3, the Treg lineage transcription factor, and LIF opposed IL6 by suppressing IL-6-induced IL-17A protein release.
# ::save-date Sun Dec 20, 2015 ::file bel_pmid_1934_2884_27058.txt
(a / and
      :op1 (s / support-01
            :ARG0 (p2 / protein :name (n3 / name :op1 "LIF"))
            :ARG1 (e / express-03
                  :ARG2 (p / protein :name (n / name :op1 "Foxp3")
                        :ARG1-of (m / mean-01
                              :ARG2 (f / factor
                                    :ARG0-of (t / transcribe-01
                                          :ARG1 (l / lineage
                                                :mod (c / cell :name (n2 / name :op1 "Treg"))))))))
            :ARG1-of (r / resemble-01 :polarity -
                  :ARG2 p3))
      :op2 (o / oppose-01
            :ARG0 p2
            :ARG1 (p3 / protein :name (n4 / name :op1 "IL-6"))
            :manner (s2 / suppress-01
                  :ARG1 (r2 / release-01
                        :ARG1 (p4 / protein :name (n5 / name :op1 "IL-17A"))
                        :ARG2-of (i / induce-01
                              :ARG0 p3)))))

# ::id bel_pmid_1935_9600.29984 ::date 2015-05-12T01:33:39 ::annotator SDL-AMR-09 ::preferred
# ::snt Macrophages from PC Tg mice can express high level of human PON2 besides intrinsic mouse PON2 and PON3 ... PC Tg macrophages maintained significantly lower levels of ROS for at least 2 hours than macrophages from Wt mice ... Inflammatory factors such as TNF-alpha and IL-6 are expressed at lower levels in PC Tg MPMs compared with Wt MPMs.
# ::save-date Sat Feb 13, 2016 ::file bel_pmid_1935_9600_29984.txt
(m2 / multi-sentence
      :snt1 (p / possible-01
            :ARG1 (e / express-03
                  :ARG2 (a3 / and
                        :op1 (l / level
                              :quant-of (p2 / protein :wiki "PON2" :name (n2 / name :op1 "PON2")
                                    :mod (h3 / human))
                              :ARG1-of (h2 / high-02))
                        :op2 (p3 / protein :wiki "PON2" :name (n3 / name :op1 "PON2")
                              :mod (i / intrinsic)
                              :mod (m7 / mouse))
                        :op3 (p4 / protein :wiki "PON3" :name (n4 / name :op1 "PON3")
                              :mod i
                              :mod m7))
                  :ARG3 (m3 / macrophage
                        :source (m4 / mouse
                              :mod (s3 / small-molecule :wiki "Phosphocholine" :name (n / name :op1 "phosphocholine")
                                    :mod (t2 / transgenic))))))
      :snt2 (m8 / maintain-01
            :ARG0 (m9 / macrophage
                  :mod (s4 / small-molecule :wiki "Phosphocholine" :name (n5 / name :op1 "phosphocholine")
                        :mod (t3 / transgenic)))
            :ARG1 (l3 / level
                  :quant-of (s / small-molecule :wiki "Reactive_oxygen_species" :name (n6 / name :op1 "ROS"))
                  :ARG1-of (l2 / low-04
                        :degree (m / more)
                        :ARG1-of (s2 / significant-02)
                        :compared-to (m5 / macrophage
                              :source (m10 / mouse
                                    :mod (w / wild-type)))))
            :duration (a / at-least
                  :op1 (t / temporal-quantity :quant 2
                        :unit (h / hour))))
      :snt3 (e2 / express-03
            :ARG2 (f / factor
                  :ARG0-of (i2 / inflame-01)
                  :example (a4 / and
                        :op1 (p5 / protein :wiki "Tumor_necrosis_factor_alpha" :name (n7 / name :op1 "TNF-alpha"))
                        :op2 (p6 / protein :wiki "Interleukin_6" :name (n8 / name :op1 "IL-6"))))
            :ARG3 (m14 / medical-condition :wiki - :name (n12 / name :op1 "malignant" :op2 "pleural" :op3 "mesothelioma")
                  :mod (s5 / small-molecule :wiki "Phosphocholine" :name (n10 / name :op1 "phosphocholine")
                        :mod (t4 / transgenic)))
            :degree (l4 / level
                  :ARG1-of (l5 / low-04
                        :degree (m11 / more)
                        :compared-to (m15 / medical-condition :wiki - :name (n9 / name :op1 "malignant" :op2 "pleural" :op3 "mesothelioma")
                              :mod (w2 / wild-type))))))

# ::id bel_pmid_1938_6603.36754 ::date 2015-05-12T02:10:55 ::annotator SDL-AMR-09 ::preferred
# ::snt ATP-mediated ADAM17 activation was also suppressed by the EGFR kinase inhibitor AG1478 and, to a lesser extent, by preincubation with ?-EGFR antibody (Fig. 6B), indicating a role for EGFR in ADAM17 activation.
# ::save-date Tue Feb 2, 2016 ::file bel_pmid_1938_6603_36754.txt
(a6 / and
      :op1 (s / suppress-01
            :ARG0 (s3 / small-molecule :name (n4 / name :op1 "AG1478")
                  :ARG0-of (i3 / inhibit-01
                        :ARG1 (k / kinase :name (n5 / name :op1 "EGFR"))))
            :ARG1 (a / activate-01
                  :ARG1 (p / protein :name (n2 / name :op1 "ADAM17"))
                  :ARG1-of (m / mediate-01
                        :ARG0 (s2 / small-molecule :name (n3 / name :op1 "ATP"))))
            :mod (a2 / also))
      :op2 (s4 / suppress-01
            :ARG0 (p2 / preincubate-01
                  :ARG2 (a4 / antibody
                        :ARG0-of (c / counter-01
                              :ARG1 k))
                  :degree (l / less
                        :mod (m2 / more)))
            :ARG1 a
            :degree (l2 / less
                  :degree (m3 / more)))
      :ARG0-of (i5 / indicate-01
            :ARG1 (r / role
                  :mod k
                  :prep-in (a5 / activate-01
                        :ARG1 p)))
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod "6B")))

# ::id bel_pmid_1938_6603.36760 ::date 2015-05-12T02:23:28 ::annotator SDL-AMR-09 ::preferred
# ::snt addition of AG1478 also suppressed ATP-mediated phosphorylation of ERK1/2 and I-?B? (Fig. 4A), indicating the involvement of EGFR activation in these signaling events.
# ::save-date Mon May 18, 2015 ::file bel_pmid_1938_6603_36760.txt
(s / suppress-01
      :ARG0 (a / add-02
            :ARG1 (s2 / small-molecule :name (n2 / name :op1 "AG1478")))
      :ARG1 (p2 / phosphorylate-01
            :ARG1 (a3 / and
                  :op1 (e3 / enzyme :name (n3 / name :op1 "ERK1/2"))
                  :op2 (p4 / protein :name (n4 / name :op1 "I-κBα")))
            :ARG1-of (m / mediate-01
                  :ARG0 (s3 / small-molecule :name (n5 / name :op1 "ATP"))))
      :mod (a2 / also)
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod "4A"))
      :ARG0-of (i / indicate-01
            :ARG1 (i2 / involve-01
                  :ARG1 (a4 / activate-01
                        :ARG1 (e / enzyme :name (n / name :op1 "EGFR")))
                  :ARG2 (e2 / event
                        :mod (t / this)
                        :mod (s4 / signal-07)))))

# ::id bel_pmid_1938_6603.38056 ::date 2015-05-12T02:28:36 ::annotator SDL-AMR-09 ::preferred
# ::snt As shown in Fig. 6A, both ATP and ?-ASGM1 indeed resulted in enhanced ADAM17 activity, measured by increased cleavage of a fluorogenic ADAM17 substrate, and this was attenuated after siRNA silencing of DUOX1 (Fig. 6A
# ::save-date Mon Jul 6, 2015 ::file bel_pmid_1938_6603_38056.txt
(a / and
      :op1 (r / result-01
            :ARG1 (a2 / and
                  :op1 (s2 / small-molecule :name (n / name :op1 "ATP"))
                  :op2 (a3 / antibody
                        :ARG0-of (c / counter-01
                              :ARG1 (p / protein :name (n2 / name :op1 "ASGM1")))))
            :ARG2 (a4 / activity-06
                  :ARG0 (p2 / protein :name (n3 / name :op1 "ADAM17"))
                  :ARG1-of (e / enhance-01)
                  :ARG1-of (m / measure-01
                        :ARG2 (c2 / cleave-01
                              :ARG1 (s3 / substrate
                                    :mod p2
                                    :mod (f2 / fluorogenic))
                              :ARG1-of (i / increase-01))))
            :mod (i2 / indeed))
      :op2 (a5 / attenuate-01
            :ARG1 a4
            :time (a6 / after
                  :op1 (s4 / silence-01
                        :ARG0 (n6 / nucleic-acid :name (n5 / name :op1 "siRNA"))
                        :ARG1 (e2 / enzyme :name (n4 / name :op1 "DUOX1")))))
      :ARG1-of (s / show-01
            :ARG0 (f / figure :mod "6A")))

# ::id bel_pmid_1938_6603.38058 ::date 2015-05-12T02:36:20 ::annotator SDL-AMR-09 ::preferred
# ::snt Silencing of DUOX1 attenuated the ATP- and ?-ASGM1-induced TGF-? production observed in the presence of EGFR mAb (Fig. 5B), indicating the involvement of DUOX1 activation in ATP-induced TGF-? production and EGFR activation.
# ::save-date Sun Dec 20, 2015 ::file bel_pmid_1938_6603_38058.txt
(a / attenuate-01
      :ARG0 (s / silence-01
            :ARG1 (e2 / enzyme :name (n2 / name :op1 "DUOX1")))
      :ARG1 (p2 / produce-01
            :ARG1 (p3 / protein :name (n4 / name :op1 "TGF-α"))
            :ARG1-of (i / induce-01
                  :ARG0 (a7 / and
                        :op1 (s2 / small-molecule :name (n5 / name :op1 "ATP"))
                        :op2 (a2 / antibody
                              :ARG0-of (c / counter-01
                                    :ARG1 (p / protein :name (n3 / name :op1 "ASGM1"))))))
            :ARG1-of (o / observe-01
                  :condition (p4 / present-02
                        :ARG1 (a3 / antibody
                              :mod (m / monoclonal)
                              :ARG0-of (c2 / counter-01
                                    :ARG1 (e / enzyme :name (n / name :op1 "EGFR")))))))
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod "5B"))
      :ARG0-of (i2 / indicate-01
            :ARG1 (i3 / involve-01
                  :ARG1 (a4 / activate-01
                        :ARG1 e2)
                  :ARG2 (a5 / and
                        :op1 (p5 / produce-01
                              :ARG1 p3
                              :ARG2-of (i4 / induce-01
                                    :ARG0 s2))
                        :op2 (a6 / activate-01
                              :ARG1 e)))))

# ::id bel_pmid_1943_9223.25342 ::date 2015-05-12T02:57:42 ::annotator SDL-AMR-09 ::preferred
# ::snt As shown in Fig. 1A, the HO-1 level in Bach1-/- mouse lungs was significantly higher than that of WT mice even before hyperoxic exposure, and the time-dependent increase in HO-1 expression in Bach1-/- mouse lungs was much greater than that ofWT mice during hyperoxic exposure.
# ::save-date Sun Jan 3, 2016 ::file bel_pmid_1943_9223_25342.txt
(s / show-01
      :ARG0 (f / figure :mod "1A")
      :ARG1 (a / and
            :op1 (h / high-02
                  :ARG1 (l / level
                        :quant-of (p / protein :name (n / name :op1 "HO-1"))
                        :location (l2 / lung
                              :part-of (m3 / mouse
                                    :ARG3-of (e / express-03
                                          :ARG1 (g3 / gene :name (n2 / name :op1 "Bach1")
                                                :ARG2-of (m4 / mutate-01 :mod "-/-"))))))
                  :degree (m / more)
                  :ARG1-of (s2 / significant-02)
                  :time (b / before
                        :op1 (e3 / expose-01
                              :ARG2 (h2 / hyperoxia))
                        :mod (e2 / even))
                  :compared-to (m5 / mouse
                        :mod (w / wild-type)))
            :op2 (g / great
                  :degree (m2 / more
                        :degree (m6 / much))
                  :domain (i / increase-01
                        :ARG1 (e4 / express-03
                              :ARG1 p
                              :ARG3 l2)
                        :ARG0-of (d / depend-01
                              :ARG1 (t / time)))
                  :compared-to (i2 / increase-01
                        :ARG1 (e5 / express-03
                              :ARG2 p
                              :ARG3 m5)
                        :time e3))))

# ::id bel_pmid_1943_9223.32684 ::date 2015-05-12T03:54:10 ::annotator SDL-AMR-09 ::preferred
# ::snt unexpectedly, however, the levels of IL-6 in bronchoalveolar lavage (BAL) fluid from Bach1(-/-) mice were significantly higher than those of WT mice. ..... In addition, a chromatin immunoprecipitation analysis revealed the binding of Bach1 to the IL-6 promoter and its detachment after oxidative stress.
# ::save-date Sat Feb 13, 2016 ::file bel_pmid_1943_9223_32684.txt
(m2 / multi-sentence
      :snt2 (a / and
            :op2 (r / reveal-01
                  :ARG0 (a2 / analyze-01
                        :manner (i / immunoprecipitate-01
                              :ARG3 (m8 / macro-molecular-complex :name (n7 / name :op1 "chromatin"))))
                  :ARG1 (a3 / and
                        :op1 (b / bind-01
                              :ARG1 (g2 / gene :name (n6 / name :op1 "Bach1"))
                              :ARG2 (m7 / molecular-physical-entity
                                    :ARG0-of (p2 / promote-01
                                          :ARG1 (p3 / protein :name (n5 / name :op1 "IL-6")))))
                        :op2 (d / detach-01
                              :ARG1 g2
                              :ARG2 m7
                              :time (a4 / after
                                    :op1 (s2 / stress-02
                                          :ARG3 (o / oxidize-01)))))))
      :snt1 (c / contrast-01
            :ARG2 (h / high-02
                  :ARG1 (l / level
                        :quant-of (p / protein :name (n / name :op1 "IL-6"))
                        :location (f / fluid
                              :source (m4 / mouse
                                    :ARG3-of (e / express-03
                                          :ARG1 (g / gene :name (n3 / name :op1 "Bach1")
                                                :ARG2-of (m5 / mutate-01 :mod "-/-"))))
                              :mod (l3 / lavage
                                    :mod (a5 / alveolus
                                          :mod (b2 / bronchus)))))
                  :degree (m / more)
                  :ARG1-of (s / significant-02)
                  :ARG1-of (e2 / expect-01 :polarity -)
                  :compared-to (l2 / level
                        :mod (m6 / mouse
                              :mod (w / wild-type))
                        :quant-of p))))

# ::id bel_pmid_1958_0863.2728 ::date 2015-05-12T04:05:31 ::annotator SDL-AMR-09 ::preferred
# ::snt Inhibition of COX2 markedly reduced both IL-1 beta and IL-6 release.
# ::save-date Tue May 12, 2015 ::file bel_pmid_1958_0863_2728.txt
(r / reduce-01
      :ARG0 (i / inhibit-01
            :ARG1 (e / enzyme :name (n / name :op1 "COX2")))
      :ARG1 (r2 / release-01
            :ARG1 (a / and
                  :op1 (p / protein :name (n2 / name :op1 "IL-1" :op2 "beta"))
                  :op2 (p2 / protein :name (n3 / name :op1 "IL-6"))))
      :manner (m / marked))

# ::id bel_pmid_1958_0863.38416 ::date 2015-05-12T04:08:54 ::annotator SDL-AMR-09 ::preferred
# ::snt The addition of IL-1b (100 pg/ml) alone significantly increased the levels of IL-6, and approximately to the same level as 160 lg/cm2 silica.
# ::save-date Mon Jan 4, 2016 ::file bel_pmid_1958_0863_38416.txt
(i / increase-01
      :ARG0 (a / add-02
            :ARG1 (p / protein :name (n / name :op1 "IL-1b")
                  :quant (c / concentration-quantity :quant 100
                        :unit (p2 / picogram-per-milliliter))
                  :mod (a2 / alone)))
      :ARG1 (l / level
            :quant-of (p3 / protein :name (n2 / name :op1 "IL-6"))
            :ARG1-of (s3 / same-01)
            :ARG0-of (a4 / approximate-01
                  :ARG1 (l2 / level
                        :ARG4-of (i2 / increase-01
                              :ARG0 (a3 / add-02
                                    :ARG1 (s2 / silica
                                          :quant (c2 / concentration-quantity :quant 160
                                                :unit (m / microgram-per-square-centimeter))))))))
      :ARG2 (s / significant-02))

# ::id bel_pmid_1969_3649.9324 ::date 2015-05-12T04:20:15 ::annotator SDL-AMR-09 ::preferred
# ::snt In TNBS colitis, no differences were found in interleukin (IL)-18 and tumor necrosis factor (TNF)-alpha expression between IRF4 knockout and wild-type mice. However, significant differences were detected in IL-6 and IL-17 production.
# ::save-date Fri Dec 18, 2015 ::file bel_pmid_1969_3649_9324.txt
(m / multi-sentence
      :snt1 (f / find-01
            :ARG1 (d5 / differ-02 :polarity -
                  :ARG1 (e / express-03
                        :ARG2 (a / and
                              :op1 (p / protein :name (n / name :op1 "interleukin" :op2 "18"))
                              :op2 (p2 / protein :name (n2 / name :op1 "tumor" :op2 "necrosis" :op3 "factor" :op4 "alpha")))
                        :ARG3 (m2 / mouse
                              :ARG3-of (e2 / express-03
                                    :ARG1 (g / gene :name (n3 / name :op1 "IRF4")
                                          :ARG1-of (k / knock-out-03)))))
                  :ARG2 (e3 / express-03
                        :ARG1 e
                        :ARG3 (m4 / mouse
                              :mod (w / wild-type)))
                  :prep-in (d / disease :name (n4 / name :op1 "TNBS" :op2 "colitis"))))
      :snt2 (h / have-concession-91
            :ARG2 (d3 / detect-01
                  :ARG1 (d4 / differ-02
                        :ARG1 (p3 / produce-01
                              :ARG1 (p4 / protein :name (n5 / name :op1 "IL-6")))
                        :ARG2 (p6 / produce-01
                              :ARG1 (p5 / protein :name (n6 / name :op1 "IL-17")))
                        :ARG1-of (s / significant-02)))))

# ::id bel_pmid_1970_6765.28338 ::date 2015-05-11T01:53:07 ::annotator SDL-AMR-09 ::preferred
# ::snt More importantly, persistent activation of IL-6 downstream Stat3 in AT II epithelial cellsdirec tly induced lung inflammation and bronchioalveolar adenocarcinoma (22).
# ::save-date Mon Jan 4, 2016 ::file bel_pmid_1970_6765_28338.txt
(i / induce-01
      :ARG0 (a / activate-01
            :ARG1 (p / protein :name (n / name :op1 "IL-6")
                  :location (r / relative-position
                        :op1 (p2 / protein :name (n2 / name :op1 "Stat3"))
                        :direction (d4 / downstream)))
            :ARG1-of (p3 / persist-01)
            :location (c / cell-line :name (n3 / name :op1 "AT" :op2 "II")
                  :mod (e / epithelium)))
      :ARG2 (a2 / and
            :op1 (i2 / inflame-01
                  :ARG1 (l / lung))
            :op2 (m2 / medical-condition :name (n4 / name :op1 "adenocarcinoma")
                  :mod (b / bronchioalveolar)))
      :ARG1-of (d / direct-02)
      :mod (i3 / important
            :degree (m / more))
      :ARG1-of (d3 / describe-01
            :ARG0 (p4 / publication
                  :ARG1-of (c2 / cite-01
                        :ARG2 22))))

# ::id bel_pmid_1970_6765.29240 ::date 2015-05-11T03:33:44 ::annotator SDL-AMR-09 ::preferred
# ::snt As shown in Fig. 3A, there was a steady increase of BrdUrd pulse-labeled AT II epithelial cells in the doxycycline-treated bitransgenic mice compared with untreated littermates. The increase of MMP12-induced cell proliferation wastime dependent.
# ::save-date Sun Jan 17, 2016 ::file bel_pmid_1970_6765_29240.txt
(m / multi-sentence
      :snt1 (i / increase-01
            :ARG1 (c / cell-line :name (n2 / name :op1 "AT" :op2 "II")
                  :mod (e / epithelium)
                  :ARG1-of (l / label-01
                        :ARG0 (p / pulse-01
                              :ARG1 (s4 / small-molecule :name (n / name :op1 "BrdUrd")))))
            :ARG1-of (s / steady-01)
            :ARG1-of (s2 / show-01
                  :ARG0 (f / figure :mod "3A"))
            :location (m3 / mouse
                  :mod (b / bitransgenic)
                  :ARG1-of (t2 / treat-04
                        :ARG2 (s3 / small-molecule :name (n3 / name :op1 "doxycycline"))))
            :compared-to (l2 / littermate
                  :ARG1-of (t3 / treat-04 :polarity -)))
      :snt2 (d / depend-01
            :ARG0 (i2 / increase-01
                  :ARG1 (p2 / proliferate-01
                        :ARG0 (c2 / cell)
                        :ARG2-of (i3 / induce-01
                              :ARG0 (e2 / enzyme :name (n4 / name :op1 "MMP12")))))
            :ARG1 (t4 / time)))

# ::id bel_pmid_1970_6765.29242 ::date 2015-05-11T07:20:56 ::annotator SDL-AMR-09 ::preferred
# ::snt MMP12 overexpression in lung epithelial cells, bitransgenic mice were treated with doxycycline for various time lengths. Histopathologic analyses revealed lung abnormalities in bitransgenic mice beginning at 6 weeks of doxycycline treatment. At this stage, marked inflammatory cell infiltration and emphysema were readily detectable (Fig. 2A, +Dox 6W).
# ::save-date Mon Dec 21, 2015 ::file bel_pmid_1970_6765_29242.txt
(m / multi-sentence
      :snt1 (a / and
            :op1 (o / overexpress-01
                  :ARG1 (e / enzyme :name (n / name :op1 "MMP12"))
                  :location (c / cell
                        :mod (e2 / epithelium)
                        :mod (l / lung)))
            :op2 (t2 / treat-04
                  :ARG1 (m2 / mouse
                        :mod (b / bitransgenic))
                  :ARG2 (s3 / small-molecule :name (n2 / name :op1 "doxycycline"))
                  :duration (t4 / temporal-quantity
                        :mod (v / various))))
      :snt2 (r / reveal-01
            :ARG0 (a2 / analyze-01
                  :mod (h / histopahtology))
            :ARG1 (a3 / abnormality
                  :mod (l3 / lung)
                  :location (m3 / mouse
                        :mod (b2 / bitransgenic))
                  :ARG1-of (b3 / begin-01
                        :time (a4 / after
                              :op1 (t5 / treat-04
                                    :ARG2 (s2 / small-molecule :name (n3 / name :op1 "doxycycline")))
                              :quant (t / temporal-quantity :quant 6
                                    :unit (w / week))))))
      :snt3 (d / detect-01
            :ARG1 (a5 / and
                  :op1 (i / infiltrate-01
                        :ARG0 (c2 / cell
                              :ARG0-of (i2 / inflame-01))
                        :ARG1-of (m4 / mark-01))
                  :op2 (e3 / emphysema))
            :ARG1-of (p / possible-01)
            :manner (r2 / ready)
            :time (s / stage
                  :mod (t7 / this))
            :ARG1-of (d2 / describe-01
                  :ARG0 (a6 / and
                        :op1 (f / figure :mod "2A")
                        :op2 (t3 / thing :name (n4 / name :op1 "+Dox" :op2 "6W"))))))

# ::id bel_pmid_1970_6765.29244 ::date 2015-05-11T07:43:53 ::annotator SDL-AMR-09 ::preferred
# ::snt FACS analysis showed a more than 5-fold decrease of Annexin V–labeled AT II epithelial cellsin 9-month doxycyclinetreated bitransgenic mice compared with untreated littermates (21.41% versus 4.91%).
# ::save-date Mon Jan 4, 2016 ::file bel_pmid_1970_6765_29244.txt
(s2 / show-01
      :ARG0 (a / analyze-01
            :mod (t4 / thing :name (n3 / name :op1 "FACS")))
      :ARG1 (d / decrease-01
            :ARG1 (c / cell-line :name (n2 / name :op1 "AT" :op2 "II")
                  :mod (e / epithelium)
                  :ARG1-of (l / label-01
                        :ARG0 (p3 / protein :name (n / name :op1 "Annexin" :op2 "V"))))
            :ARG2 (m2 / more-than
                  :op1 (p4 / product-of :value 5)
                  :ARG1-of (m4 / mean-01
                        :ARG2 (p / percentage-entity :value 21.41)))
            :location (m3 / mouse
                  :mod (b / bitransgenic)
                  :ARG1-of (t2 / treat-04
                        :ARG2 (s / small-molecule :name (n4 / name :op1 "doxycycline")))
                  :age (t / temporal-quantity :quant 9
                        :unit (m / month)))
            :compared-to (d3 / decrease-01
                  :ARG1 p3
                  :ARG2 (p2 / percentage-entity :value 4.91)
                  :location (l2 / littermate
                        :ARG1-of (t3 / treat-04 :polarity -)))))

# ::id bel_pmid_1970_6765.29246 ::date 2015-05-11T09:08:03 ::annotator SDL-AMR-09 ::preferred
# ::snt Bronchioalveolar adenocarcinomas were observed in the lungs of bitransgenic mice after doxycycline treatment asearly as16 weeks (Fig. 2A, +Dox 16W).
# ::save-date Mon Jan 4, 2016 ::file bel_pmid_1970_6765_29246.txt
(o / observe-01
      :ARG1 (m2 / medical-condition :name (n3 / name :op1 "adenocarcinoma")
            :mod (b / bronchioalveolar))
      :location (l / lung
            :part-of (m / mouse
                  :mod (b2 / bitransgenic)))
      :time (a2 / after
            :op1 (t / treat-04
                  :ARG2 (s / small-molecule :name (n / name :op1 "doxycycline"))
                  :quant (t2 / temporal-quantity :quant 16
                        :unit (w / week)
                        :mod (e / early))))
      :ARG1-of (d2 / describe-01
            :ARG0 (a4 / and
                  :op1 (f / figure :mod "2A")
                  :op2 (t3 / thing :name (n2 / name :op1 "+Dox" :op2 "16W")))))

# ::id bel_pmid_1970_6765.29248 ::date 2015-05-11T09:18:54 ::annotator SDL-AMR-09 ::preferred
# ::snt After 10 to 15 weeksof doxycycline treatment, the bitransgenic mice began to develop adenomatoid hyperplasia in both parenchyma and small conducting airways(F ig. 2A, +Dox 10W), which resembles to the histopathologic feature of dysplasia in clinical lesions.
# ::save-date Sat Jan 2, 2016 ::file bel_pmid_1970_6765_29248.txt
(b2 / begin-01
      :ARG0 (m / mouse
            :mod (b3 / bitransgenic))
      :ARG1 (d / develop-01
            :ARG1 (a2 / and
                  :op1 (p / parenchyma)
                  :op2 (a3 / airway
                        :mod (s / small)
                        :ARG1-of (c / conduct-03))
                  :part-of m)
            :ARG2 (h / hyperplasia
                  :mod (a / adenomatoid)
                  :ARG1-of (r / resemble-01
                        :ARG2 (f2 / feature
                              :poss (d5 / dysplasia)
                              :mod (h2 / histopathologic)
                              :location (l / lesion
                                    :mod (c2 / clinic))))))
      :ARG1-of (d2 / describe-01
            :ARG0 (a4 / and
                  :op1 (f / figure :mod "2A")
                  :op2 (t3 / thing :name (n2 / name :op1 "+Dox" :op2 "10W"))))
      :time (a5 / after
            :op1 (t / treat-04
                  :ARG1 m
                  :ARG2 (s2 / small-molecule :name (n / name :op1 "doxycycline"))
                  :duration (b4 / between
                        :op1 (t2 / temporal-quantity :quant 10
                              :unit (w2 / week))
                        :op2 (t4 / temporal-quantity :quant 15
                              :unit (w3 / week))))))

# ::id bel_pmid_1970_6765.29250 ::date 2015-05-11T09:38:46 ::annotator SDL-AMR-09 ::preferred
# ::snt In addition, Stat3-induced downstream developmental gene HNF4a wasup-regulated to 78.6-fold, Foxa3 to 9.3-fold, and SHH to 3.3-fold (Fig. 4D).
# ::save-date Sun Dec 20, 2015 ::file bel_pmid_1970_6765_29250.txt
(a / and
      :op2 (a3 / and
            :op1 (u / upregulate-01
                  :ARG1 (g / gene :name (n2 / name :op1 "HNF4a")
                        :mod (g2 / growth)
                        :location (d / downstream)
                        :ARG2-of (i / induce-01
                              :ARG0 (p / protein :name (n / name :op1 "Stat3"))))
                  :degree (p2 / product-of :value 78.6))
            :op2 (u2 / upregulate-01
                  :ARG1 (g3 / gene :name (n3 / name :op1 "Foxa3"))
                  :degree (p4 / product-of :value 9.3))
            :op3 (u3 / upregulate-01
                  :ARG1 (g4 / gene :name (n4 / name :op1 "SHH"))
                  :degree (p6 / product-of :value 3.3))
            :ARG1-of (d2 / describe-01
                  :ARG0 (f / figure :mod "4D"))))

# ::id bel_pmid_1970_6765.29252 ::date 2015-05-11T10:03:24 ::annotator SDL-AMR-09 ::preferred
# ::snt As shown in Fig. 4A, IL-6 concentration in BALF of doxycycline-treated mice was steadily increased compared with those in untreated bitransgenic mice in a time-dependent fashion,
# ::save-date Sat Feb 13, 2016 ::file bel_pmid_1970_6765_29252.txt
(i / increase-01
      :ARG1 (c / concentrate-02
            :ARG1 (p / protein :name (n / name :op1 "IL-6"))
            :location (f2 / fluid
                  :mod (m / mouse
                        :ARG1-of (t / treat-04
                              :ARG2 (s3 / small-molecule :name (n3 / name :op1 "doxycycline"))))
                  :mod (l / lavage
                        :mod (a / alveolus
                              :mod (b / bronchus)))))
      :manner (s / steady)
      :ARG1-of (s2 / show-01
            :ARG0 (f / figure :mod "4A"))
      :compared-to (c2 / concentrate-01
            :ARG1 p
            :location (m3 / mouse
                  :ARG1-of (t3 / treat-04 :polarity -)
                  :mod (b3 / bitransgenic)))
      :manner (d2 / depend-01
            :ARG0 i
            :ARG1 (t4 / time)))

# ::id bel_pmid_1970_6765.29260 ::date 2015-05-11T11:56:23 ::annotator SDL-AMR-09 ::preferred
# ::snt increased expression of several other MMPs was also observed in doxycycline-treated bitransgenic mice compared with untreated mice. (Fig 4D)
# ::save-date Tue May 26, 2015 ::file bel_pmid_1970_6765_29260.txt
(o2 / observe-01
      :ARG1 (i / increase-01
            :ARG1 (e / express-03
                  :ARG2 (e2 / enzyme :name (n / name :op1 "MMP")
                        :quant (s / several)
                        :mod (o / other)))
            :compared-to (m2 / mouse
                  :ARG1-of (t2 / treat-04 :polarity -)))
      :mod (a / also)
      :ARG1-of (d2 / describe-01
            :ARG0 (f / figure :mod "4D"))
      :location (m / mouse
            :mod (b / bitransgenic)
            :ARG1-of (t / treat-04
                  :ARG2 (s2 / small-molecule :name (n2 / name :op1 "doxycycline")))))

# ::id bel_pmid_1974_2316.9502 ::date 2015-05-11T12:12:13 ::annotator SDL-AMR-09 ::preferred
# ::snt In this study, we found disorganized actin in the form of membrane ruffling and enhanced cell migration in LRP1-deficient (LRP1-/-) SMCs.
# ::save-date Sun Jan 17, 2016 ::file bel_pmid_1974_2316_9502.txt
(f / find-01
      :ARG0 (w / we)
      :ARG1 (a / and
            :op1 (a2 / actin
                  :ARG1-of (d / disorganize-01
                        :manner (f2 / form
                              :mod (m / membrane
                                    :ARG1-of (r / ruffle-02)))))
            :op2 (m2 / migrate-01
                  :ARG0 (c / cell)
                  :ARG1 (c2 / cell :name (n / name :op1 "SMC")
                        :mod (p / protein :name (n2 / name :op1 "LRP1")
                              :ARG2-of (m3 / mutate-01 :mod "-/-")))
                  :ARG1-of (e / enhance-01)))
      :medium (s / study-01
            :mod (t / this)))

# ::id bel_pmid_1974_2316.22040 ::date 2015-05-11T12:21:29 ::annotator SDL-AMR-09 ::preferred
# ::snt Because PDGFRb activation, through transphosphorylation of tyrosine residues in its cytoplasmic domain, triggers a cascade of phosphorylation events which eventually lead to the activation of extracellular regulated-protein kinases (Erks), phosphorylated- Erk1/2 was used as an indicator of PDGFRb activation [7].
# ::save-date Tue Feb 2, 2016 ::file bel_pmid_1974_2316_22040.txt
(c / cause-01
      :ARG0 (t2 / trigger-01
            :ARG0 (a / activate-01
                  :ARG1 (p2 / protein :name (n / name :op1 "PDGFRb"))
                  :manner (t3 / transphosphorylate-01
                        :ARG1 (r / residue
                              :mod (a2 / amino-acid :name (n2 / name :op1 "tyrosine")
                                    :part-of (d / domain
                                          :mod (c2 / cytoplasm)
                                          :part-of p2)))))
            :ARG1 (c3 / cascade-01
                  :subevent (p / phosphorylate-01))
            :ARG0-of (l / lead-03
                  :ARG2 (a3 / activate-01
                        :ARG1 (e2 / enzyme :name (n3 / name :op1 "extracellular" :op2 "regulated-protein" :op3 "kinase")))
                  :time (e / eventual)))
      :ARG1 (u / use-01
            :ARG1 (e3 / enzyme :name (n4 / name :op1 "Erk1/2")
                  :ARG1-of (p3 / phosphorylate-01))
            :ARG2 (t / thing
                  :ARG0-of (i / indicate-01
                        :ARG1 a)))
      :ARG1-of (d2 / describe-01
            :ARG0 (p4 / publication
                  :ARG1-of (c4 / cite-01
                        :ARG2 7))))

# ::id bel_pmid_1974_2316.28806 ::date 2015-05-12T03:23:02 ::annotator SDL-AMR-09 ::preferred
# ::snt An approximately 2.5-fold increase of Smad2 phosphorylation at Ser 465/467 was also detected in LDLR expressing, LRP1-deficient SMCs (Figure 6B, C).
# ::save-date Tue May 19, 2015 ::file bel_pmid_1974_2316_28806.txt
(d / detect-01
      :ARG1 (i / increase-01
            :ARG1 (p / phosphorylate-01
                  :ARG1 (a5 / and
                        :op1 (a2 / amino-acid :mod 465 :name (n / name :op1 "serine")
                              :part-of (p2 / protein :name (n2 / name :op1 "Smad2")))
                        :op2 (a6 / amino-acid :mod 467 :name (n6 / name :op1 "serine")
                              :part-of p2)))
            :ARG2 (a3 / approximately
                  :op1 (p3 / product-of :value 2.5)))
      :mod (a / also)
      :ARG1-of (d2 / describe-01
            :ARG0 (a4 / and
                  :op1 (f / figure :mod "6B")
                  :op2 (f2 / figure :mod "6C")))
      :location (c / cell :name (n4 / name :op1 "SMC")
            :mod (p5 / protein :name (n5 / name :op1 "LRP1")
                  :ARG2-of (m / mutate-01 :mod "-/-"))
            :ARG3-of (e / express-03
                  :ARG2 (p4 / protein :name (n3 / name :op1 "LDLR")))))

# ::id bel_pmid_1974_2316.28914 ::date 2015-05-12T04:34:20 ::annotator SDL-AMR-09 ::preferred
# ::snt About a two-fold increase of PDGFRb expression was detected in smLRP1-/- mice regardless of LDLR genotype (Figure 2A, C). Increased Erk1/2 phosphorylation was also observed in these aortas (Figure 2A). These data suggest that the expression and activation of PDGFRb is only regulated by LRP1, not LDLR.
# ::save-date Thu Jan 7, 2016 ::file bel_pmid_1974_2316_28914.txt
(m / multi-sentence
      :snt1 (d / detect-01
            :ARG1 (i / increase-01
                  :ARG1 (e / express-03
                        :ARG2 (p2 / protein :name (n / name :op1 "PDGFRb")))
                  :ARG2 (a / about
                        :op1 (p3 / product-of :value 2)))
            :location (m2 / mouse
                  :mod (p4 / protein :name (n2 / name :op1 "smLRP1")
                        :ARG2-of (m3 / mutate-01 :mod "-/-")))
            :ARG1-of (r3 / regardless-91
                  :ARG2 (g / genotype
                        :mod (p5 / protein :name (n3 / name :op1 "LDLR"))))
            :ARG1-of (d2 / describe-01
                  :ARG0 (a2 / and
                        :op1 (f / figure :mod "2A")
                        :op2 (f2 / figure :mod "2C"))))
      :snt2 (o / observe-01
            :ARG1 (p / phosphorylate-01
                  :ARG1 (e2 / enzyme :name (n4 / name :op1 "Erk1/2"))
                  :ARG1-of (i2 / increase-01)
                  :location (a4 / aorta
                        :mod (t / this)))
            :mod (a3 / also)
            :ARG1-of (d3 / describe-01
                  :ARG0 (f3 / figure :mod "2A")))
      :snt3 (s / suggest-01
            :ARG0 (d4 / data
                  :mod (t2 / this))
            :ARG1 (c / contrast-01
                  :ARG1 (r / regulate-01
                        :ARG0 (p6 / protein :name (n5 / name :op1 "LRP1"))
                        :ARG1 (a5 / and
                              :op1 (e3 / express-03
                                    :ARG2 (p7 / protein :name (n6 / name :op1 "PDGFRb")))
                              :op2 (a6 / activate-01
                                    :ARG1 p7))
                        :mod (o2 / only))
                  :ARG2 (r2 / regulate-01 :polarity -
                        :ARG0 (p8 / protein :name (n7 / name :op1 "LDLR"))
                        :ARG1 a5))))

# ::id bel_pmid_1974_2316.28918 ::date 2015-05-12T05:00:16 ::annotator SDL-AMR-09 ::preferred
# ::snt Studies from our laboratory have shown that LRP1 suppresses PDGF receptor b (PDGFRb) activation and protects against atherosclerosis.
# ::save-date Tue May 12, 2015 ::file bel_pmid_1974_2316_28918.txt
(s / show-01
      :ARG0 (s2 / study-01
            :source (l / laboratory
                  :poss-of (w / we)))
      :ARG1 (a / and
            :op1 (s3 / suppress-01
                  :ARG0 (p / protein :name (n / name :op1 "LRP1"))
                  :ARG1 (a2 / activate-01
                        :ARG1 (p2 / protein :name (n2 / name :op1 "PDGF" :op2 "receptor" :op3 "b"))))
            :op2 (p3 / protect-01
                  :ARG0 p
                  :ARG2 (a3 / atherosclerosis))))

# ::id bel_pmid_1980_5133.8276 ::date 2015-05-12T05:06:15 ::annotator SDL-AMR-09 ::preferred
# ::snt Cebpb expression is therefore required in infiltrating macrophages for upregulation of M2-specific genes
# ::save-date Fri Jul 24, 2015 ::file bel_pmid_1980_5133_8276.txt
(c2 / cause-01
      :ARG1 (r / require-01
            :ARG0 (u / upregulate-01
                  :ARG1 (g2 / gene
                        :ARG1-of (s / specific-02
                              :ARG2 (c / cell :name (n2 / name :op1 "M2")))))
            :ARG1 (e2 / express-03
                  :ARG2 (p / protein :name (n / name :op1 "Cebpb")))
            :purpose (i / infiltrate-01)
            :location (m / macrophage)))

# ::id bel_pmid_1980_5133.25992 ::date 2015-05-12T05:24:27 ::annotator SDL-AMR-09 ::preferred
# ::snt deletion of two CREB-binding sites from the Cebpb promoter abrogates Cebpb induction upon macrophage activation. This blocks the downstream induction of M2-specific Msr1, Il10, II13ra, and Arg-1 genes, whereas the inflammatory (M1) genes Il1, Il6, Tnfa, and Il12 are not affected
# ::save-date Sun Dec 20, 2015 ::file bel_pmid_1980_5133_25992.txt
(m / multi-sentence
      :snt1 (a / abrogate-01
            :ARG0 (d / delete-01
                  :ARG1 (p / protein-segment :quant 2
                        :ARG1-of (b / bind-01
                              :ARG2 (p2 / protein :name (n / name :op1 "CREB")))
                        :part-of (m3 / molecular-physical-entity
                              :ARG0-of (p3 / promote-01
                                    :ARG1 (p4 / protein :name (n2 / name :op1 "Cebpb"))))))
            :ARG1 (i / induce-01
                  :ARG2 p4)
            :time (a2 / activate-01
                  :ARG1 (m2 / macrophage)))
      :snt2 (b2 / block-01
            :ARG0 (t2 / this)
            :ARG1 (i2 / induce-01
                  :ARG2 (g / gene
                        :ARG2-of (i3 / include-91
                              :ARG1 (a3 / and
                                    :op1 (g2 / gene :name (n5 / name :op1 "Msr1"))
                                    :op2 (g3 / gene :name (n6 / name :op1 "Il10"))
                                    :op3 (g4 / gene :name (n7 / name :op1 "II13ra"))
                                    :op4 (g5 / gene :name (n8 / name :op1 "Arg-1"))))
                        :ARG1-of (s / specific-02
                              :ARG2 (c2 / cell :name (n4 / name :op1 "M2"))))
                  :mod (d2 / downstream))
            :ARG1-of (c / contrast-01
                  :ARG2 (a4 / affect-01 :polarity -
                        :ARG1 (g11 / gene
                              :ARG2-of (i4 / include-91
                                    :ARG1 (a5 / and
                                          :op1 (g7 / gene :name (n10 / name :op1 "Il1"))
                                          :op2 (g8 / gene :name (n11 / name :op1 "Il6"))
                                          :op3 (g9 / gene :name (n12 / name :op1 "Tnfa"))
                                          :op4 (g10 / gene :name (n13 / name :op1 "Il12"))))
                              :ARG0-of (i5 / inflame-01))))))

# ::id bel_pmid_1984_2832.19720 ::date 2015-05-12T06:34:03 ::annotator SDL-AMR-09 ::preferred
# ::snt Studies using TLR-4 -/- mice have demonstrated that induction of MCP-1 in BAL fluid upon exposure of mice to subacute (exposed for a period of 5 weeks) levels of CS depends on the presence of wild-type TLR-4, whereas TLR-4 plays a minor role in MCP-1 induction in the presence of chronic smoke exposure (26 weeks) [45].
# ::save-date Sat Feb 13, 2016 ::file bel_pmid_1984_2832_19720.txt
(d / demonstrate-01
      :ARG0 (s / study-01
            :ARG0-of (u / use-01
                  :ARG1 (m / mouse
                        :mod (p / protein :name (n / name :op1 "TLR-4")
                              :ARG2-of (m2 / mutate-01 :mod "-/-")))))
      :ARG1 (d2 / depend-01
            :ARG0 (i / induce-01
                  :ARG2 (p2 / protein :name (n2 / name :op1 "MCP-1"))
                  :location (f / fluid
                        :mod (l2 / lavage
                              :mod (a / alveolus
                                    :mod (b / bronchus))))
                  :time (e / expose-01
                        :ARG1 (m3 / mouse)
                        :ARG2 (l / level
                              :quant-of (p4 / protein :name (n4 / name :op1 "CS"))
                              :mod (s2 / subacute))
                        :duration (t4 / temporal-quantity :quant 5
                              :unit (w / week))))
            :ARG1 (p5 / present-02
                  :ARG1 (p6 / protein :name (n5 / name :op1 "TLR-4")
                        :mod (w3 / wild-type)))
            :ARG1-of (c / contrast-01
                  :ARG2 (p7 / play-02
                        :ARG0 p6
                        :ARG1 (r / role
                              :ARG1-of (m4 / minor-01)
                              :domain (i2 / induce-01
                                    :ARG2 p2
                                    :condition (p8 / present-02
                                          :ARG1 (e2 / expose-01
                                                :ARG2 (s3 / smoke
                                                      :mod (c2 / chronic))
                                                :duration (t2 / temporal-quantity :quant 26
                                                      :unit (w2 / week)))))))))
      :ARG1-of (d3 / describe-01
            :ARG0 (p10 / publication
                  :ARG1-of (c3 / cite-01
                        :ARG2 45))))

# ::id bel_pmid_1984_2832.26184 ::date 2015-05-12T07:08:00 ::annotator SDL-AMR-09 ::preferred
# ::snt LPS stimulated pulmonary neutrophil recruitment, NF-kB promoter activity, and TNF-a secretion are found to be severely impaired in GM-CSF-/- mice.
# ::save-date Mon Jul 6, 2015 ::file bel_pmid_1984_2832_26184.txt
(f / find-01
      :ARG1 (i / impair-01
            :ARG1 (a / and
                  :op1 (r / recruit-01
                        :ARG1 (c / cell :name (n2 / name :op1 "neutrophil")
                              :mod (p / pulmonary))
                        :ARG1-of (s / stimulate-01
                              :ARG0 (m / molecular-physical-entity :name (n / name :op1 "LPS"))))
                  :op2 (a2 / activity-06
                        :ARG0 (t / thing
                              :ARG0-of (p2 / promote-01
                                    :ARG1 (p3 / protein :name (n3 / name :op1 "NF-kB")))))
                  :op3 (s2 / secrete-01
                        :ARG1 (p4 / protein :name (n4 / name :op1 "TNF-a"))))
            :manner (s3 / severe)
            :location (m2 / mouse
                  :mod (p5 / protein :name (n5 / name :op1 "GM-CSF")
                        :ARG2-of (m3 / mutate-01 :mod "-/-")))))

# ::id bel_pmid_1984_2832.28124 ::date 2015-05-12T07:25:09 ::annotator SDL-AMR-09 ::preferred
# ::snt IL-1b increased the production of neutrophil chemoattractants such as Gro-alpha (CXCL1) and MIP-2 (CXCL2) in lungs.
# ::save-date Tue May 19, 2015 ::file bel_pmid_1984_2832_28124.txt
(i / increase-01
      :ARG0 (p / protein :name (n / name :op1 "IL-1b"))
      :ARG1 (p2 / produce-01
            :ARG1 (c / chemoattractants
                  :mod (n2 / neutrophil)
                  :example (a / and
                        :op1 (p3 / protein :name (n3 / name :op1 "Gro-alpha")
                              :ARG1-of (m / mean-01
                                    :ARG2 (p5 / protein :name (n5 / name :op1 "CXCL1"))))
                        :op2 (p4 / protein :name (n4 / name :op1 "MIP-2")
                              :ARG1-of (m2 / mean-01
                                    :ARG2 (p6 / protein :name (n6 / name :op1 "CXCL2")))))
                  :location (l / lung))))

# ::id bel_pmid_1984_2832.31640 ::date 2015-05-12T07:34:40 ::annotator SDL-AMR-09 ::preferred
# ::snt Tollip has been shown to associate directly with TLR-4 and inhibit TLR-4-mediated activation of NF- kB luciferase reporter vectors in a mouse macrophage cell line (RAW-264.7).
# ::save-date Sun Jan 3, 2016 ::file bel_pmid_1984_2832_31640.txt
(s / show-01
      :ARG1 (a3 / and
            :op1 (a / associate-01
                  :ARG1 (p2 / protein :name (n / name :op1 "Tollip"))
                  :ARG2 (p3 / protein :name (n2 / name :op1 "TLR-4"))
                  :ARG1-of (d / direct-02))
            :op2 (i / inhibit-01
                  :ARG0 p2
                  :ARG1 (a2 / activate-01
                        :ARG1 (v / vector
                              :mod (p / protein :name (n3 / name :op1 "NF-" :op2 "kB" :op3 "luciferase" :op4 "reporter")))
                        :ARG1-of (m / mediate-01
                              :ARG0 p3))
                  :location (c / cell-line :name (n4 / name :op1 "RAW-264.7")
                        :mod (m2 / mouse)
                        :mod (m3 / macrophage)))))

# ::id bel_pmid_1984_2832.34344 ::date 2015-05-12T08:00:54 ::annotator SDL-AMR-09 ::preferred
# ::snt Treatment of sputum cells from COPD patients with acetylcholine produced increased amounts of LTB4, which was sensitive both to treatment with a muscarinic receptor antagonist and to the inhibition of ERK- 1/2 phosphorylation. This increased LTB4 synthesis also directly correlated with increased neutrophil chemotaxis.
# ::save-date Sat Feb 13, 2016 ::file bel_pmid_1984_2832_34344.txt
(m / multi-sentence
      :snt1 (p2 / produce-01
            :ARG0 (t / treat-04
                  :ARG1 (c / cell
                        :mod (s / sputum)
                        :source (p3 / patient
                              :mod (d / disease :name (n2 / name :op1 "COPD"))))
                  :ARG2 (s4 / small-molecule :name (n / name :op1 "acetylcholine")))
            :ARG1 (a / amount
                  :ARG1-of (i / increase-01)
                  :quant-of (p4 / protein :name (n3 / name :op1 "LTB4")
                        :ARG0-of (s2 / sensitive-03
                              :ARG1 (a3 / and
                                    :op1 (t2 / treat-04
                                          :ARG2 (p5 / protein :name (n4 / name :op1 "muscarinic" :op2 "receptor" :op3 "antagonist")))
                                    :op2 (i2 / inhibit-01
                                          :ARG1 (p / phosphorylate-01
                                                :ARG1 (e2 / enzyme :name (n5 / name :op1 "ERK-1/2")))))))))
      :snt2 (c2 / correlate-01
            :ARG1 (s3 / synthesize-01
                  :ARG1 (p6 / protein :name (n6 / name :op1 "LTB4"))
                  :ARG1-of (i3 / increase-01)
                  :mod (t3 / this))
            :ARG2 (c3 / chemotaxis
                  :mod (n7 / neutrophil)
                  :ARG1-of (i4 / increase-01))
            :mod (a4 / also)
            :ARG1-of (d2 / direct-02)))

# ::id bel_pmid_1984_2832.36854 ::date 2015-05-12T11:16:20 ::annotator SDL-AMR-09 ::preferred
# ::snt IRAK-1 activation and recruitment is essential for activation of TRAF6 (TNF-associated factor 6), which is an essential adaptor for MyD88-dependent NF-kB activation.
# ::save-date Tue May 12, 2015 ::file bel_pmid_1984_2832_36854.txt
(e / essential
      :domain (a / and
            :op1 (a2 / activate-01
                  :ARG1 (e2 / enzyme :name (n / name :op1 "IRAK-1")))
            :op2 (r / recruit-01
                  :ARG1 e2)
            :purpose (a3 / activate-01
                  :ARG1 (p / protein :name (n2 / name :op1 "TRAF6")
                        :ARG0-of (a4 / adapt-01
                              :ARG1 (a5 / activate-01
                                    :ARG1 (p2 / protein :name (n3 / name :op1 "NF-kB"))
                                    :ARG0-of (d / depend-01
                                          :ARG1 (p3 / protein :name (n4 / name :op1 "MyD88"))))
                              :mod (e3 / essential))))))

# ::id bel_pmid_1984_2832.38430 ::date 2015-05-12T11:32:17 ::annotator SDL-AMR-09 ::preferred
# ::snt It has also been shown that IL-1b stimulates the release and activity of MMP-9 (matrix metalloproteinase-9) from AM obtained from COPD smokers, which is significantly higher in comparison with those obtained from healthy smokers and non-smokers [155].
# ::save-date Sat Feb 13, 2016 ::file bel_pmid_1984_2832_38430.txt
(s2 / show-01
      :ARG1 (s3 / stimulate-01
            :ARG0 (p2 / protein :name (n / name :op1 "IL-1b"))
            :ARG1 (a2 / and
                  :op1 (r / release-01
                        :ARG1 (e / enzyme :name (n2 / name :op1 "MMP-9")))
                  :op2 (a3 / activity-06
                        :ARG0 e)
                  :source (s7 / small-molecule :name (n3 / name :op1 "AM")
                        :ARG1-of (o / obtain-01
                              :ARG2 (p / person
                                    :ARG0-of (s / smoke-02)
                                    :mod (d / disease :name (n4 / name :op1 "COPD")))))
                  :ARG1-of (h / high-02
                        :degree (m / more)
                        :ARG1-of (s4 / significant-02)
                        :compared-to (a5 / and
                              :op1 (r2 / release-01
                                    :ARG1 e)
                              :op2 (a6 / activity-06
                                    :ARG0 e)
                              :ARG1-of (o2 / obtain-01
                                    :ARG2 (a4 / and
                                          :op1 (p3 / person
                                                :ARG0-of (s5 / smoke-02)
                                                :mod (h2 / healthy))
                                          :op2 (p4 / person
                                                :ARG0-of (s6 / smoke-02 :polarity -)
                                                :mod h2)))))))
      :mod (a / also)
      :ARG1-of (d2 / describe-01
            :ARG0 (p5 / publication
                  :ARG1-of (c / cite-01
                        :ARG2 155))))

# ::id bel_pmid_1984_2832.38592 ::date 2015-05-12T23:39:44 ::annotator SDL-AMR-09 ::preferred
# ::snt Similarly, preincubation with F(ab')2 fragments of a monoclonal anti-human IL-8 antibody inhibited neutrophil chemotaxis to CB sputum supernatants by 75% [30].
# ::save-date Sat Feb 13, 2016 ::file bel_pmid_1984_2832_38592.txt
(i / inhibit-01
      :ARG0 (p2 / preincubate-01
            :ARG2 (f / fragment-01
                  :ARG1 (s3 / small-molecule :name (n3 / name :op1 "F(ab')2")
                        :part-of (a / antibody :name (n4 / name :op1 "monoclonal" :op2 "anti-human" :op3 "IL-8" :op4 "antibody")
                              :ARG0-of (c2 / counter-01
                                    :ARG1 (p4 / protein :name (n5 / name :op1 "IL-8")
                                          :mod (h / human)))
                              :mod (m / monoclone)))))
      :ARG1 (c / chemotaxis
            :mod (n2 / neutrophil))
      :location (s / supernatant
            :mod (s2 / sputum
                  :mod (d2 / disease :name (n / name :op1 "chronic" :op2 "bronchitis"))))
      :quant (p / percentage-entity :value 75)
      :ARG1-of (d / describe-01
            :ARG0 (p3 / publication
                  :ARG1-of (c3 / cite-01
                        :ARG2 30)))
      :ARG1-of (r / resemble-01))

# ::id bel_pmid_1984_6878.15410 ::date 2015-05-12T23:48:30 ::annotator SDL-AMR-09 ::preferred
# ::snt Including adenosine with IFN-gamma treatment delayed any measureable increase in STAT1 activation by >60 min, and led to significantly reduced STAT1 activity at 60, 120, and 240 min post-stimulation compared with cells treated with IFN-gamma alone ( p < 0.05; Fig. 4).
# ::save-date Sun Jan 17, 2016 ::file bel_pmid_1984_6878_15410.txt
(a / and
      :op1 (d / delay-01
            :ARG0 (i / include-01
                  :ARG1 (s4 / small-molecule :name (n4 / name :op1 "adenosine"))
                  :ARG2 (t / treat-04
                        :ARG2 (p / protein :name (n / name :op1 "IFN-gamma"))))
            :ARG1 (i2 / increase-01
                  :ARG1 (a3 / activate-01
                        :ARG1 (p2 / protein :name (n2 / name :op1 "STAT1")))
                  :ARG1-of (m / measure-01
                        :ARG1-of (p5 / possible-01)))
            :ARG2 (m2 / more-than
                  :op1 (t2 / temporal-quantity :quant 60
                        :unit (m3 / minute))))
      :op2 (l / lead-03
            :ARG0 i
            :ARG2 (r / reduce-01
                  :ARG1 (a4 / activity-06
                        :ARG0 p2)
                  :ARG2 (s / significant-02)
                  :time (a2 / after
                        :op1 (s2 / stimulate-01
                              :quant (a5 / and
                                    :op1 (t3 / temporal-quantity :quant 60
                                          :unit m3)
                                    :op2 (t4 / temporal-quantity :quant 120
                                          :unit m3)
                                    :op3 (t5 / temporal-quantity :quant 240
                                          :unit m3))))
                  :compared-to (c / cell
                        :ARG1-of (t6 / treat-04
                              :ARG2 p
                              :manner (a6 / alone)))))
      :ARG1-of (d2 / describe-01
            :ARG0 (f / figure :mod 4))
      :ARG1-of (s3 / statistical-test-91
            :ARG2 (l2 / less-than :op1 0.05)))

# ::id bel_pmid_1984_6878.18750 ::date 2015-05-13T00:12:19 ::annotator SDL-AMR-09 ::preferred
# ::snt Pretreatment with CCPA (A1 receptor agonist), NECA (non-specific A1 and A2 receptor agonist), and CGS21680 (A2A receptor agonist) all resulted in a 14- to 15-fold increase in STAT1 activity over control cells, levels comparable to what was observed in cells treated with IFN-gamma alone (Fig. 6, A?C)
# ::save-date Sat Feb 13, 2016 ::file bel_pmid_1984_6878_18750.txt
(a / and
      :op1 (r / result-01
            :ARG1 (p / pretreat-01
                  :ARG3 (a2 / and
                        :op1 (a3 / agonist :name (n / name :op1 "CCPA")
                              :ARG1-of (m / mean-01
                                    :ARG2 (a12 / agonist
                                          :mod (r3 / receptor :name (n8 / name :op1 "A1")))))
                        :op2 (a4 / agonist :name (n2 / name :op1 "NECA")
                              :ARG1-of (m2 / mean-01
                                    :ARG2 (a10 / and
                                          :op1 (a13 / agonist
                                                :mod r2)
                                          :op2 (a14 / agonist
                                                :mod r2)
                                          :ARG1-of (s / specific-02 :polarity -))))
                        :op3 (a5 / agonist :name (n3 / name :op1 "CGS21680")
                              :ARG1-of (m3 / mean-01
                                    :ARG2 (a9 / agonist
                                          :mod (r2 / receptor :name (n7 / name :op1 "A2A")))))))
            :ARG2 (i / increase-01
                  :ARG1 (a6 / activity-06
                        :ARG0 (p2 / protein :name (n4 / name :op1 "STAT1")))
                  :ARG2 (b / between
                        :op1 (p3 / product-of :value 14)
                        :op2 (p4 / product-of :value 15)
                        :ARG1-of (c3 / comparable-03
                              :ARG2 (l2 / level
                                    :ARG1-of (o / observe-01
                                          :location (c4 / cell
                                                :ARG1-of (t2 / treat-04
                                                      :ARG2 (p5 / protein :name (n5 / name :op1 "IFN-gamma")
                                                            :mod (a7 / alone))))))))
                  :location (c / cell
                        :mod (c2 / control-01))))
      :ARG1-of (d / describe-01
            :ARG0 (a8 / and
                  :op1 (f / figure :mod "6A")
                  :op2 (f2 / figure :mod "6C"))))

# ::id bel_pmid_1984_6878.27666 ::date 2015-05-13T00:22:13 ::annotator SDL-AMR-09 ::preferred
# ::snt As expected, we found that IFN-gamma led to a rapid rise in both JAK1 and JAK2 phosphorylation band density above baseline levels, and this IFN-gamma-induced JAK activation was not altered by adenosine treatment at any time point (data not shown).
# ::save-date Sun Jan 17, 2016 ::file bel_pmid_1984_6878_27666.txt
(a / and
      :op1 (f / find-01
            :ARG0 (w / we)
            :ARG1 (l / lead-03
                  :ARG1 (p2 / protein :name (n / name :op1 "IFN-gamma"))
                  :ARG2 (r / rise-01
                        :ARG1 (d / density
                              :poss (b / band
                                    :mod (p / phosphorylate-01
                                          :ARG1 (a2 / and
                                                :op1 (e3 / enzyme :name (n2 / name :op1 "JAK1"))
                                                :op2 (e2 / enzyme :name (n3 / name :op1 "JAK2"))))))
                        :ARG4 (a7 / above
                              :op1 (l2 / level
                                    :mod (b2 / baseline)))
                        :mod (r2 / rapid))))
      :op2 (a3 / alter-01 :polarity -
            :ARG0 (t / treat-04
                  :ARG1 (s2 / small-molecule :name (n5 / name :op1 "adenosine")))
            :ARG1 (a4 / activate-01
                  :ARG1 (e4 / enzyme :name (n4 / name :op1 "JAK"))
                  :ARG2-of (i / induce-01
                        :ARG0 p2))
            :time (p6 / point
                  :mod (a6 / any)))
      :ARG1-of (d2 / describe-01
            :ARG0 (d3 / data
                  :ARG1-of (s / show-01 :polarity -)))
      :ARG1-of (e / expect-01))

# ::id bel_pmid_1996_7723.42048 ::date 2015-05-11T12:38:04 ::annotator SDL-AMR-09 ::preferred
# ::snt Mechanistically, endothelial a6-integrin deficiency elevated significantly VEGF-mediated angiogenesis both in vivo and ex vivo.
# ::save-date Fri Dec 18, 2015 ::file bel_pmid_1996_7723_42048.txt
(e / elevate-01
      :ARG0 (l / lack-01
            :ARG1 (p / protein :name (n / name :op1 "a6-integrin")
                  :mod (e2 / endothelium)))
      :ARG1 (a / angiogenesis
            :ARG1-of (m2 / mediate-01
                  :ARG0 (p2 / protein :name (n2 / name :op1 "VEGF"))))
      :ARG1-of (s / significant-02)
      :manner (m / mechanistic)
      :manner (a2 / and
            :op2 (i / in-vivo)
            :op2 (e3 / ex-vivo)
            :mod (b / both)))

# ::id bel_pmid_1996_7723.42050 ::date 2015-05-11T12:39:11 ::annotator SDL-AMR-09 ::preferred
# ::snt In particular, a6-integrin-deficient endothelial cells displayed increased levels of VEGF-receptor 2 (VEGFR2) and VEGF-mediated downstream ERK1/2 activation.
# ::save-date Tue May 19, 2015 ::file bel_pmid_1996_7723_42050.txt
(d / display-01
      :ARG0 (c / cell
            :mod (e / endothelium)
            :ARG0-of (l / lack-01
                  :ARG1 (p / protein :name (n / name :op1 "a6-integrin"))))
      :ARG1 (a / and
            :op1 (l2 / level
                  :quant-of (p2 / protein :name (n2 / name :op1 "VEGF-receptor" :op2 "2"))
                  :ARG1-of (i / increase-01))
            :op2 (a2 / activate-01
                  :ARG1 (e2 / enzyme :name (n3 / name :op1 "ERK1/2"))
                  :location (d2 / downstream)
                  :ARG1-of (m / mediate-01
                        :ARG0 (p3 / protein :name (n4 / name :op1 "VEGF")))))
      :mod (p4 / particular))

# ::id bel_pmid_1996_7723.42052 ::date 2015-05-11T14:07:22 ::annotator SDL-AMR-09 ::preferred
# ::snt Blood vessels associated with IDC showed a significant reduction in mean a6-integrin pixel intensity when compared with blood vessels from normal breast tissue (**p < 0.0001, Figure 1b).
# ::save-date Sun Jan 3, 2016 ::file bel_pmid_1996_7723_42052.txt
(s / show-01
      :ARG0 (v / vessel
            :mod (b / blood)
            :ARG1-of (a / associate-01
                  :ARG2 (d / disease :name (n3 / name :op1 "IDC"))))
      :ARG1 (r / reduce-01
            :ARG1 (i2 / intensify-01
                  :ARG1 (p / pixel
                        :mod (p4 / protein :name (n / name :op1 "a6-integrin")))
                  :mod (m / mean))
            :ARG2 (s2 / significant-02)
            :compared-to (v2 / vessel
                  :mod (b2 / blood)
                  :location (t / tissue
                        :mod (b3 / breast)
                        :ARG1-of (n2 / normal-02)))
            :ARG1-of (s3 / statistical-test-91
                  :ARG2 (l / less-than :op1 0.0001)))
      :ARG1-of (d2 / describe-01
            :ARG0 (f / figure :mod "1b")))

# ::id bel_pmid_1996_7723.42058 ::date 2015-05-11T15:11:06 ::annotator SDL-AMR-09 ::preferred
# ::snt The results showed that there was a significant increase in tumour blood vessel density in a6fl/fl-Tie1Cre+ mice compared with a6fl/fl-Tie1Cre- controls (*p < 0.02, Figure 3b).
# ::save-date Sun Jan 3, 2016 ::file bel_pmid_1996_7723_42058.txt
(s / show-01
      :ARG0 (t2 / thing
            :ARG2-of (r / result-01))
      :ARG1 (i / increase-01
            :ARG1 (d / density
                  :poss (v / vessel
                        :mod (b / blood)
                        :mod (t / tumor)))
            :ARG2 (s2 / significant-02)
            :location (m / mouse
                  :mod (g / gene :name (n / name :op1 "a6fl/fl-Tie1Cre")
                        :mod (w / wild-type)))
            :ARG1-of (c / compare-01
                  :ARG2 (c2 / control
                        :mod (g2 / gene :name (n2 / name :op1 "a6fl/fl-Tie1Cre")
                              :ARG2-of (m2 / mutate-01 :mod "-/-"))))
            :ARG1-of (s3 / statistical-test-91
                  :ARG2 (l2 / less-than :op1 0.02)))
      :ARG1-of (d2 / describe-01
            :ARG0 (f / figure :mod "3b")))

# ::id bel_pmid_1996_7723.42064 ::date 2015-05-11T15:38:52 ::annotator SDL-AMR-09 ::preferred
# ::snt As predicted, the absence of a6-integrin reduced the ability of the a6-/— cells to adhere and migrate to Lm but did not affect the ability of these cells to adhere or migrate on Fn, Col or Vn (*p < 0.05, Figures 5c and 5d).
# ::save-date Sun Jan 3, 2016 ::file bel_pmid_1996_7723_42064.txt
(r / reduce-01
      :ARG0 (a / absent-01
            :ARG1 (p / protein :name (n / name :op1 "a6-integrin")))
      :ARG1 (c / capable-01
            :ARG1 (c2 / cell
                  :mod (p2 / protein :name (n2 / name :op1 "a6-integrin")
                        :ARG2-of (m / mutate-01 :mod "-/-")))
            :ARG2 (a2 / and
                  :op1 (a3 / adhere-01
                        :ARG1 c2
                        :ARG2 (p3 / protein :name (n3 / name :op1 "laminin")))
                  :op2 (m2 / migrate-01
                        :ARG0 c2
                        :ARG2 p3)))
      :ARG1-of (c3 / contrast-01
            :ARG2 (a4 / affect-01 :polarity -
                  :ARG0 a
                  :ARG1 (c4 / capable-01
                        :ARG1 c2
                        :ARG2 (a5 / and
                              :op1 (a6 / adhere-01
                                    :ARG1 c2
                                    :ARG2 (o / or
                                          :op1 (p4 / protein :name (n4 / name :op1 "fibronectin"))
                                          :op2 (p5 / protein :name (n5 / name :op1 "collagen"))
                                          :op3 (p6 / protein :name (n6 / name :op1 "vitronectin"))))
                              :op2 (m3 / migrate-01
                                    :ARG0 c2
                                    :ARG1 (o2 / or
                                          :op1 p4
                                          :op2 p5
                                          :op2 p6))))))
      :ARG1-of (d / describe-01
            :ARG0 (a7 / and
                  :op1 (f / figure :mod "5c")
                  :op2 (f2 / figure :mod "5d")))
      :ARG1-of (p9 / predict-01)
      :ARG1-of (s / statistical-test-91
            :ARG2 (l / less-than :op1 0.05)))

# ::id bel_pmid_1996_7723.42068 ::date 2015-05-12T10:25:19 ::annotator SDL-AMR-09 ::preferred
# ::snt Western blot analysis revealed that VEGF stimulated the phosphorylation of ERK1/2 in both a6fl/fl-Tie1Cre-and a6fl/fl-Tie1Cre+ endothelial cells and that the levels of phosphorylated ERK1/2 (pERK1/2) detected in a6fl/fl-Cre+ endothelial cells after a VEGF stimulus were dramatically higher than those detected in a6fl/flTie1Cre- endothelial cells (Figure 6b).
# ::save-date Sun Jan 17, 2016 ::file bel_pmid_1996_7723_42068.txt
(r / reveal-01
      :ARG0 (a5 / analyze-01
            :manner (i / immunoblot-01))
      :ARG1 (a2 / and
            :op1 (s / stimulate-01
                  :ARG0 (p / protein :name (n / name :op1 "VEGF"))
                  :ARG1 (p2 / phosphorylate-01
                        :ARG1 (e / enzyme :name (n2 / name :op1 "ERK1/2")))
                  :location (a3 / and
                        :op1 (c / cell
                              :mod (g2 / gene :name (n3 / name :op1 "a6fl/fl-Tie1Cre")
                                    :ARG2-of (m / mutate-01 :mod "-/-"))
                              :mod (e2 / endothelium))
                        :op2 (c2 / cell
                              :mod (g / gene :name (n4 / name :op1 "a6fl/fl-Tie1Cre")
                                    :mod (w2 / wild-type))
                              :mod e2)))
            :op2 (h / high-02
                  :ARG1 (l / level
                        :quant-of (e3 / enzyme :name (n5 / name :op1 "ERK1/2")
                              :ARG3-of (p5 / phosphorylate-01)
                              :ARG1-of (d2 / detect-01
                                    :location c)))
                  :mod (d / dramatic)
                  :time (a4 / after
                        :op1 (s2 / stimulus
                              :mod p))
                  :degree (m2 / more)
                  :ARG1-of (c3 / compare-01
                        :ARG2 (l2 / level
                              :ARG1-of (d3 / detect-01
                                    :location c2)))))
      :ARG1-of (d4 / describe-01
            :ARG0 (f / figure :mod "6b")))

# ::id bel_pmid_1996_7723.42070 ::date 2015-05-12T12:35:38 ::annotator SDL-AMR-09 ::preferred
# ::snt Furthermore, blockade of VEGFR2 using the function blocking monoclonal antibody to VEGFR2, DC101 [26], ablated these enhanced VEGF-mediated responses, demonstrating that the enhanced ERK1/2 phosphorylation was via VEGFR2 (Figure 6b).
# ::save-date Sun Jan 17, 2016 ::file bel_pmid_1996_7723_42070.txt
(a / and
      :op2 (a2 / ablate-01
            :ARG1 (t / thing
                  :ARG2-of (r / respond-01)
                  :mod (t2 / this)
                  :ARG1-of (e2 / enhance-01)
                  :ARG1-of (m2 / mediate-01
                        :ARG0 (p / protein :name (n5 / name :op1 "VEGF"))))
            :ARG3 (b / block-01
                  :ARG1 (p3 / protein :name (n / name :op1 "VEGFR2"))
                  :ARG1-of (d / describe-01
                        :ARG0 (p2 / publication
                              :ARG1-of (c2 / cite-01
                                    :ARG2 26)))
                  :ARG0-of (u / use-01
                        :ARG1 (s / small-molecule :name (n7 / name :op1 "DC101")
                              :ARG0-of (c3 / counter-01
                                    :ARG1 p3)
                              :ARG1-of (m / mean-01
                                    :ARG2 (a3 / antibody
                                          :mod (m3 / monoclonal)
                                          :ARG0-of (b2 / block-01
                                                :ARG1 (f2 / function-01)))))))
            :ARG0-of (d2 / demonstrate-01
                  :ARG1 (p4 / phosphorylate-01
                        :ARG1 (e3 / enzyme :name (n6 / name :op1 "ERK1/2"))
                        :ARG2 p3
                        :ARG1-of (e4 / enhance-01)))
            :ARG1-of (d3 / describe-01
                  :ARG0 (f / figure :mod "6b"))))

# ::id bel_pmid_2001_8915.2588 ::date 2015-05-12T13:30:19 ::annotator SDL-AMR-09 ::preferred
# ::snt The mouse tumors mimic molecular hallmarks of their human tumor counterparts, including elevated IL-6/Stat3/Bcl-X(L) signaling. The newly developed mouse strains may provide a good preclinical research tool for the design and testing of new approaches to target IL-6 in treatment and prevention of human PCNs.
# ::save-date Fri Feb 5, 2016 ::file bel_pmid_2001_8915_2588.txt
(m / multi-sentence
      :snt1 (m2 / mimic-01
            :ARG0 (t / tumor
                  :mod (m3 / mouse))
            :ARG1 (h / hallmark
                  :mod (m4 / molecule)
                  :poss (c / counterpart
                        :mod (t2 / tumor
                              :mod (h2 / human))
                        :poss m3)
                  :ARG2-of (i / include-01
                        :ARG1 (s / signal-07
                              :ARG1 (p / pathway :name (n / name :op1 "IL-6/Stat3/Bcl-X(L)"))
                              :ARG1-of (e / elevate-01)))))
      :snt2 (p2 / possible-01
            :ARG1 (p3 / provide-01
                  :ARG0 (s2 / strain
                        :mod (m5 / mouse)
                        :ARG1-of (d / develop-02
                              :ARG1-of (n2 / new-01)))
                  :ARG1 (t4 / tool
                        :mod (p4 / preclinical)
                        :mod (r / research-01)
                        :purpose (a / and
                              :op1 (d2 / design-01
                                    :ARG1 (a2 / approach-02
                                          :ARG1 (t6 / target-01
                                                :ARG1 (p5 / protein :name (n4 / name :op1 "IL-6"))
                                                :purpose (a3 / and
                                                      :op1 (t7 / treat-03
                                                            :ARG1 (d3 / disease :name (n5 / name :op1 "PCN")
                                                                  :mod (h3 / human)))
                                                      :op2 (p6 / prevent-01
                                                            :ARG1 d3)))
                                          :ARG1-of (n3 / new-01)))
                              :op2 (t5 / test-01
                                    :ARG1 a2))
                        :ARG1-of (g / good-02)))))

# ::id bel_pmid_2013_1264.5500 ::date 2015-05-12T14:13:47 ::annotator SDL-AMR-09 ::preferred
# ::snt In contrast to TGFbeta1/IL-6, IL-23 was critical for the induction of IL-22 in CD4+ T cells from both naive and CII-immunized DBA/1 mice.
# ::save-date Mon Dec 21, 2015 ::file bel_pmid_2013_1264_5500.txt
(c / critical-02
      :ARG1 (p / protein :name (n / name :op1 "IL-23")
            :ARG1-of (c3 / contrast-01
                  :ARG2 (m4 / macro-molecular-complex
                        :part (p5 / protein :name (n8 / name :op1 "TGFbeta1"))
                        :part (p6 / protein :name (n9 / name :op1 "IL-6")))))
      :ARG3 (i / induce-01
            :ARG2 (p2 / protein :name (n2 / name :op1 "IL-22"))
            :location (c2 / cell :name (n3 / name :op1 "T")
                  :mod (p3 / protein :name (n4 / name :op1 "CD4")
                        :mod (w / wild-type))
                  :source (a / and
                        :op1 (o / organism :name (n5 / name :op1 "DBA/1" :op2 "mouse")
                              :mod (n7 / naive))
                        :op2 (o2 / organism :name (n6 / name :op1 "DBA/1" :op2 "mouse")
                              :ARG1-of (i2 / immunize-01
                                    :ARG0 (p4 / protein :name (n10 / name :op1 "collagen" :op2 "II"))))
                        :mod (b / both)))))

# ::id bel_pmid_2013_1264.5504 ::date 2015-05-12T15:05:29 ::annotator SDL-AMR-09 ::preferred
# ::snt : In CD4+ T cells from naive DBA/1 mice, IL-23 alone hardly induced retinoic acid-related orphan receptor gammat (RORgammat), Th17 polarization, and Th17 cytokines, but it inhibited T-bet expression.
# ::save-date Sun Dec 20, 2015 ::file bel_pmid_2013_1264_5504.txt
(c / contrast-01
      :ARG1 (i / induce-01
            :ARG0 (p / protein :name (n / name :op1 "IL-23")
                  :mod (a / alone))
            :ARG2 (a2 / and
                  :op1 (p2 / protein :name (n2 / name :op1 "retinoic" :op2 "acid-related" :op3 "orphan" :op4 "receptor" :op5 "gammat"))
                  :op2 (p3 / polarize-01
                        :ARG1 (c2 / cell :name (n3 / name :op1 "Th17")))
                  :op3 (c3 / cytokine
                        :mod c2))
            :manner (h / hardly))
      :ARG2 (i2 / inhibit-01
            :ARG0 p
            :ARG1 (e / express-03
                  :ARG1 (p4 / protein :name (n4 / name :op1 "T-bet"))))
      :location (c4 / cell :name (n5 / name :op1 "T")
            :mod (p5 / protein :name (n6 / name :op1 "CD4")
                  :mod (w / wild-type))
            :source (o / organism :name (n8 / name :op1 "DBA/1" :op2 "mouse"))))

# ::id bel_pmid_2013_1264.20312 ::date 2015-05-12T15:27:48 ::annotator SDL-AMR-09 ::preferred
# ::snt However, in CD4+ T cells from naive mice, IL-23 significantly increased the TGFbeta1/IL-6-induced Th17 polarization, including elevated levels of IL-17A and IL-17F and decreased expression of T-bet and FoxP3. Of note, the IL-23-induced increase in IL-17A and IL-17F levels was prevented in T-bet-deficient mice.
# ::save-date Sun Dec 20, 2015 ::file bel_pmid_2013_1264_20312.txt
(m / multi-sentence
      :snt1 (c / contrast-01
            :ARG2 (i / increase-01
                  :ARG0 (p / protein :name (n / name :op1 "IL-23"))
                  :ARG1 (p2 / polarize-01
                        :ARG1 (c2 / cell :name (n2 / name :op1 "Th17"))
                        :ARG2-of (i2 / induce-01
                              :ARG0 (m2 / macro-molecular-complex
                                    :part (p3 / protein :name (n3 / name :op1 "TGFbeta1"))
                                    :part (p4 / protein :name (n4 / name :op1 "IL-6")))))
                  :ARG2 (s / significant-02)
                  :ARG2-of (i3 / include-01
                        :ARG1 (a / and
                              :op1 (l / level
                                    :quant-of (p5 / protein :name (n5 / name :op1 "IL-17A"))
                                    :ARG1-of (e / elevate-01))
                              :op2 (l2 / level
                                    :quant-of (p6 / protein :name (n6 / name :op1 "IL-17F"))
                                    :ARG1-of e)
                              :op3 (e2 / express-03
                                    :ARG2 (a2 / and
                                          :op1 (p7 / protein :name (n7 / name :op1 "T-bet"))
                                          :op2 (p8 / protein :name (n8 / name :op1 "FoxP3")))
                                    :ARG1-of (d / decrease-01)))))
            :location (c3 / cell :name (n9 / name :op1 "T")
                  :mod (p9 / protein :name (n10 / name :op1 "CD4")
                        :mod (w / wild-type))
                  :source (m4 / mouse
                        :mod (n11 / naive))))
      :snt2 (p10 / prevent-01
            :ARG1 (i4 / increase-01
                  :ARG1 (a3 / and
                        :op1 (l3 / level
                              :quant-of (p12 / protein :name (n13 / name :op1 "IL-17A")))
                        :op2 (l4 / level
                              :quant-of (p13 / protein :name (n14 / name :op1 "IL-17F"))))
                  :ARG2-of (i5 / induce-01
                        :ARG0 (p11 / protein :name (n12 / name :op1 "IL-23"))))
            :location (m5 / mouse
                  :ARG0-of (l5 / lack-01
                        :ARG1 (p14 / protein :name (n15 / name :op1 "T-bet"))))
            :ARG1-of (n16 / note-01)))

# ::id bel_pmid_2017_6957.28510 ::date 2015-05-12T15:52:31 ::annotator SDL-AMR-09 ::preferred
# ::snt However, on stimulation with R848 or CpG DNA, B cells from both young and old Irf5 -/- mice produced lower levels of IL-6 than the B cells from C57BL/6 mice.
# ::save-date Sun Jan 3, 2016 ::file bel_pmid_2017_6957_28510.txt
(c / contrast-01
      :ARG2 (p / produce-01
            :ARG0 (c2 / cell :name (n6 / name :op1 "B")
                  :source (a / and
                        :op1 (m / mouse
                              :mod (y / young)
                              :mod (p3 / protein :name (n2 / name :op1 "Irf5")
                                    :ARG2-of (m2 / mutate-01 :mod "-/-")))
                        :op2 (m3 / mouse
                              :mod (o / old)
                              :mod p3)
                        :mod (b / both)))
            :ARG1 (l / level
                  :quant-of (p2 / protein :name (n / name :op1 "IL-6"))
                  :ARG1-of (l2 / low-04
                        :degree (m4 / more))
                  :compared-to (c3 / cell :name (n5 / name :op1 "B")
                        :source (o3 / organism :name (n7 / name :op1 "C57BL/6" :op2 "mouse"))))
            :time (s / simulate-01
                  :ARG2 (o2 / or
                        :op1 (s2 / small-molecule :name (n3 / name :op1 "R848"))
                        :op2 (n8 / nucleic-acid :name (n4 / name :op1 "CpG" :op2 "DNA"))))))

# ::id bel_pmid_2017_6957.28512 ::date 2015-05-12T16:19:42 ::annotator SDL-AMR-09 ::preferred
# ::snt There was also a decrease in IRF-4 expression in Irf5 -/- B cells, seen both on RNA and protein levels (Fig. 4 A and B ).
# ::save-date Tue May 26, 2015 ::file bel_pmid_2017_6957_28512.txt
(d / decrease-01
      :ARG1 (e / express-03
            :ARG2 (p / protein :name (n / name :op1 "IRF-4"))
            :ARG3 (c2 / cell-line :name (n3 / name :op1 "B")
                  :mod (p2 / protein :name (n2 / name :op1 "Irf5")
                        :ARG2-of (m / mutate-01 :mod "-/-"))))
      :mod (a / also)
      :ARG1-of (s / see-01
            :location (a2 / and
                  :op1 (l2 / level
                        :quant-of (n4 / nucleic-acid :name (n5 / name :op1 "RNA")))
                  :op2 (l / level
                        :quant-of (p3 / protein))))
      :ARG1-of (d2 / describe-01
            :ARG0 (a3 / and
                  :op1 (f / figure :mod "4A")
                  :op2 (f2 / figure :mod "4B"))))

# ::id bel_pmid_2017_6957.28516 ::date 2015-05-12T16:25:55 ::annotator SDL-AMR-09 ::preferred
# ::snt Analysis of the expression of these factors by semiquantitative RT-PCR shows that purified B cells from both young and old Irf5 -/- mice exhibit significantly lower levels of Blimp-1 mRNA than B cells from the age-matched C57BL/6 mice (Fig. 4A ).
# ::save-date Sun Jan 3, 2016 ::file bel_pmid_2017_6957_28516.txt
(s / show-01
      :ARG0 (a / analyze-01
            :ARG1 (e / express-03
                  :ARG2 (f / factor
                        :mod (t / this)))
            :manner (t2 / thing :name (n4 / name :op1 "RT-PCR")
                  :mod (q / quantity
                        :degree (s2 / semi))))
      :ARG1 (e2 / exhibit-01
            :ARG0 (c / cell :name (n6 / name :op1 "B")
                  :ARG1-of (p / purify-01)
                  :source (a2 / and
                        :op1 (m / mouse
                              :mod (y / young)
                              :mod (p2 / protein :name (n / name :op1 "Irf5")
                                    :ARG2-of (m2 / mutate-01 :mod "-/-")))
                        :op2 (m3 / mouse
                              :mod (o / old)
                              :mod p2)
                        :mod (b / both)))
            :ARG1 (l / level
                  :quant-of (n8 / nucleic-acid :name (n2 / name :op1 "mRNA")
                        :ARG0-of (e3 / encode-01
                              :ARG1 (p3 / protein :name (n3 / name :op1 "Blimp-1"))))
                  :ARG1-of (l2 / low-04
                        :degree (m5 / more)
                        :compared-to (c2 / cell :name (n5 / name :op1 "B")
                              :source (o2 / organism :name (n7 / name :op1 "C57BL/6" :op2 "mouse")
                                    :ARG1-of (m6 / match-01
                                          :ARG2 (a3 / age))))
                        :ARG1-of (s3 / significant-02))))
      :ARG1-of (d / describe-01
            :ARG0 (f2 / figure :mod "A4")))

# ::id bel_pmid_2020_0353.35654 ::date 2015-05-12T16:54:25 ::annotator SDL-AMR-09 ::preferred
# ::snt we found that IL-33R signaling induced a time-dependent activation of Erk1/2, protein kinase B (PKB), JNK1/2, NF-kB, and p38, and degradation of IkB (supplemental Figure 1B).
# ::save-date Mon Jan 4, 2016 ::file bel_pmid_2020_0353_35654.txt
(f / find-01
      :ARG0 (w / we)
      :ARG1 (i2 / induce-01
            :ARG0 (s / signal-07
                  :ARG0 (p / protein :name (n / name :op1 "IL-33R")))
            :ARG2 (a3 / and
                  :op1 (a / activate-01
                        :ARG1 (a2 / and
                              :op1 (e / enzyme :name (n2 / name :op1 "Erk1/2"))
                              :op2 (e2 / enzyme :name (n3 / name :op1 "protein" :op2 "kinase" :op3 "B"))
                              :op3 (e3 / enzyme :name (n4 / name :op1 "JNK1/2"))
                              :op4 (p2 / protein :name (n5 / name :op1 "NF-kB"))
                              :op5 (e4 / enzyme :name (n6 / name :op1 "p38")))
                        :ARG0-of (d / depend-01
                              :ARG1 (t / time)))
                  :op2 (d2 / degrade-01
                        :ARG1 (p4 / protein :name (n7 / name :op1 "IkB")))))
      :ARG1-of (d3 / describe-01
            :ARG0 (f2 / figure :mod "1B"
                  :mod (s2 / supplement))))

# ::id bel_pmid_2020_0353.38622 ::date 2015-05-12T17:14:28 ::annotator SDL-AMR-09 ::preferred
# ::snt Y721-c-Kit is autophosphorylated in response to stem cell factor (SCF).
# ::save-date Sun Jan 17, 2016 ::file bel_pmid_2020_0353_38622.txt
(p / phosphorylate-01
      :ARG1 (a / amino-acid :mod 721 :name (n / name :op1 "tyrosine")
            :part-of (e / enzyme :name (n2 / name :op1 "c-Kit")))
      :ARG2 a
      :ARG2-of (r / respond-01
            :ARG1 (p3 / protein :name (n3 / name :op1 "stem" :op2 "cell" :op3 "factor"))))

# ::id bel_pmid_2022_6760.28942 ::date 2015-05-12T17:31:11 ::annotator SDL-AMR-09 ::preferred
# ::snt The supernatants from cultured LN cells were also collected and the production of various cytokines (TNF-alpha, IFN-gamma, IL-6, and IL-17) was measured (Fig. 3B). The cytokine levels in BLT1-/- cells were significantly lower than those in BLT1+/+ cells
# ::save-date Sun Jan 17, 2016 ::file bel_pmid_2022_6760_28942.txt
(m / multi-sentence
      :snt1 (a / and
            :op1 (c / collect-01
                  :ARG1 (s / supernatant
                        :source (c2 / cell
                              :ARG1-of (c3 / culture-01)
                              :mod (p8 / protein :name (n7 / name :op1 "laminin"))))
                  :mod (a3 / also))
            :op2 (m2 / measure-01
                  :ARG1 (p / produce-01
                        :ARG1 (c4 / cytokine
                              :mod (v / various)
                              :ARG2-of (i / include-91
                                    :ARG1 (a2 / and
                                          :op1 (c8 / cytokine :name (n / name :op1 "TNF-alpha"))
                                          :op2 (c9 / cytokine :name (n2 / name :op1 "IFN-gamma"))
                                          :op3 (c10 / cytokine :name (n3 / name :op1 "IL-6"))
                                          :op4 (c11 / cytokine :name (n4 / name :op1 "IL-17")))))))
            :ARG1-of (d / describe-01
                  :ARG0 (f / figure :mod "3B")))
      :snt2 (l / low-04
            :ARG1 (l3 / level
                  :quant-of (c5 / cytokine)
                  :location (c6 / cell
                        :mod (p6 / protein :name (n5 / name :op1 "BLT1")
                              :ARG2-of (m5 / mutate-01 :mod "-/-"))))
            :degree (m4 / more)
            :ARG1-of (s2 / significant-02)
            :compared-to (l4 / level
                  :location (c7 / cell
                        :mod (p7 / protein :name (n6 / name :op1 "BLT1")
                              :mod (w / wild-type))))))

# ::id bel_pmid_2033_8026.31778 ::date 2015-05-12T17:51:56 ::annotator SDL-AMR-09 ::preferred
# ::snt Table 2 Comparison of expression ratios between microarray and RT-qPCR, lipid and mixed annotated genes ## WT vs Tyk2-/- peritoneal macrophages ##
# ::save-date Sun Jan 3, 2016 ::file bel_pmid_2033_8026_31778.txt
(m / multi-sentence
      :snt1 (c / compare-01
            :ARG1 (r / ratio-of
                  :op1 (e / express-03
                        :ARG1 (a / and
                              :op1 (g / gene
                                    :mod (l / lipid))
                              :op2 (g2 / gene
                                    :mod (m3 / mixed))
                              :ARG1-of (a2 / annotate-01)))
                  :mod (m2 / microarray))
            :ARG2 (r2 / ratio-of
                  :op1 e
                  :mod (t / thing :name (n / name :op1 "RT-qPCR"))))
      :snt2 (c2 / contrast-01
            :ARG1 (m4 / macrophage
                  :mod (w / wild-type)
                  :mod (p / peritoneum))
            :ARG2 (e2 / enzyme :name (n2 / name :op1 "Tyk2")
                  :ARG2-of (m5 / mutate-01 :mod "-/-")
                  :mod p))
      :ARG1-of (d / describe-01
            :ARG0 (t2 / table :mod 2)))

# ::id bel_pmid_2049_7020.1770 ::date 2015-05-12T18:24:16 ::annotator SDL-AMR-09 ::preferred
# ::snt Leptin-induced MUC5B expression was blocked by the ERK1/2 and p38 pathway inhibitors, but not by the JAK2/STAT3 pathway inhibitor.
# ::save-date Sun Jan 17, 2016 ::file bel_pmid_2049_7020_1770.txt
(b / block-01
      :ARG0 (m / molecular-physical-entity
            :ARG0-of (i2 / inhibit-01
                  :ARG1 (a2 / and
                        :op1 (p5 / pathway :name (n3 / name :op1 "ERK1/2"))
                        :op2 (p3 / pathway :name (n4 / name :op1 "p38")))))
      :ARG1 (e / express-03
            :ARG1 (p / protein :name (n / name :op1 "MUC5B"))
            :ARG2-of (i / induce-01
                  :ARG0 (p2 / protein :name (n2 / name :op1 "leptin"))))
      :ARG1-of (c / contrast-01
            :ARG2 (b2 / block-01 :polarity -
                  :ARG0 (m3 / molecular-physical-entity
                        :ARG0-of (i3 / inhibit-01
                              :ARG1 (p4 / pathway :name (n5 / name :op1 "JAK2/STAT3"))))
                  :ARG1 e)))

# ::id bel_pmid_2060_5485.40420 ::date 2015-05-12T18:45:52 ::annotator SDL-AMR-09 ::preferred
# ::snt Both IL-6 and G-CSF treatment did not markedly change surface IL-4Ra amounts on BM cells; moreover, IL-6 had a detrimental effect on cell viability, thereby preventing any further functional characterization.
# ::save-date Mon Jun 22, 2015 ::file bel_pmid_2060_5485_40420.txt
(m / multi-sentence
      :snt1 (c / change-01 :polarity -
            :ARG0 (t / treat-04
                  :ARG2 (a / and
                        :op1 (p / protein :name (n / name :op1 "IL-6"))
                        :op2 (p2 / protein :name (n2 / name :op1 "G-CSF"))
                        :mod (b2 / both)))
            :ARG1 (a2 / amount
                  :quant-of (p3 / protein :name (n3 / name :op1 "IL-4Ra")
                        :mod (s / surface)))
            :manner (m2 / marked)
            :location (c2 / cell)
            :mod (m3 / marrow
                  :mod (b / bone)))
      :snt2 (a3 / and
            :op2 (a4 / affect-01
                  :ARG0 (p4 / protein :name (n4 / name :op1 "IL-6"))
                  :ARG1 (v / viability
                        :mod (c3 / cell))
                  :mod (d / detrimental)
                  :ARG0-of (p5 / prevent-01
                        :ARG1 (c4 / characterize-01
                              :ARG0-of (f / function-01)
                              :mod (f2 / further)
                              :mod (a5 / any))))))

# ::id bel_pmid_2060_5485.40422 ::date 2015-05-12T19:08:06 ::annotator SDL-AMR-09 ::preferred
# ::snt Despite the increased IL-4Ra expression following G-CSF treatment, this cytokine did not induce any appreciable imunosuppressive function in BM cells.
# ::save-date Sun Dec 20, 2015 ::file bel_pmid_2060_5485_40422.txt
(i / induce-01 :polarity -
      :ARG0 (c / cytokine
            :mod (t / this))
      :ARG2 (f / function
            :ARG1-of (a / appreciate-03
                  :ARG1-of (p / possible-01))
            :mod (i2 / imunosuppressive)
            :mod (a2 / any))
      :location (c2 / cell
            :mod (m / marrow
                  :mod (b / bone)))
      :concession (i3 / increase-01
            :ARG1 (e / express-03
                  :ARG2 (p2 / protein :name (n / name :op1 "IL-4Ra"))
                  :ARG1-of (f2 / follow-01
                        :ARG2 (t2 / treat-04
                              :ARG2 (p3 / protein :name (n2 / name :op1 "G-CSF")))))))

# ::id bel_pmid_2060_5485.40424 ::date 2015-05-12T19:17:25 ::annotator SDL-AMR-09 ::preferred
# ::snt GM-CSF induced a significant increase (p = 0.028 versus untreated BM) of IL-4Ra expression, and BM cells cultured with this cytokine inhibited CTL activity in a dose-dependent fashion (Figures 1A and 1B).
# ::save-date Sun Jan 3, 2016 ::file bel_pmid_2060_5485_40424.txt
(a / and
      :op1 (i / induce-01
            :ARG0 (p / protein :name (n / name :op1 "GM-CSF"))
            :ARG2 (i2 / increase-01
                  :ARG1 (e2 / express-03
                        :ARG2 (p4 / protein :name (n2 / name :op1 "IL-4Ra")))
                  :ARG2 (s / significant-02)
                  :ARG1-of (s2 / statistical-test-91
                        :ARG2 0.028
                        :ARG5 (c6 / cell-line
                              :mod m2
                              :ARG1-of (t / treat-04 :polarity -)))))
      :op2 (i3 / inhibit-01
            :ARG0 (c3 / cell-line
                  :mod (m2 / marrow
                        :mod (b / bone))
                  :ARG1-of (c4 / culture-01
                        :instrument (c5 / cytokine
                              :mod (t2 / this))))
            :ARG1 (a2 / activity-06
                  :ARG0 (c2 / cell :name (n3 / name :op1 "CTL")))
            :manner (d / depend-01
                  :ARG0 a2
                  :ARG1 (d2 / dose-01)))
      :ARG1-of (d3 / describe-01
            :ARG0 (a3 / and
                  :op1 (f / figure :mod "1A")
                  :op2 (f2 / figure :mod "1B"))))

# ::id bel_pmid_2060_5485.40432 ::date 2015-05-12T19:51:54 ::annotator SDL-AMR-09 ::preferred
# ::snt When we analyzed the percentage of the different subsets of CD11b+Gr-1+ cells, percentages of CD11bhiGr-1hi and CD11bhiGr-1- cells were decreased in both C/EBPp-deficient strains, but subsets characterized by low and intermediate expression of the Gr-1 marker were significantly decreased only in fully ablated mice (Figure 3D).
# ::save-date Mon Dec 21, 2015 ::file bel_pmid_2060_5485_40432.txt
(d / decrease-01
      :ARG1 (a / and
            :op1 (p / percentage
                  :quant-of (c / cell :name (n / name :op1 "CD11bhiGr-1hi")))
            :op2 (p2 / percentage
                  :quant-of (c2 / cell :name (n2 / name :op1 "CD11bhiGr-1-"))))
      :location (s / strain
            :ARG0-of (l / lack-01
                  :ARG1 (p3 / protein :name (n3 / name :op1 "C/EBPp")))
            :mod (b / both))
      :time (a2 / analyze-01
            :ARG0 (w / we)
            :ARG1 (p4 / percentage
                  :quant-of (s2 / subset
                        :poss (c3 / cell :name (n4 / name :op1 "CD11b+Gr-1+"))
                        :ARG1-of (d4 / differ-02))))
      :ARG1-of (c4 / contrast-01
            :ARG2 (d2 / decrease-01
                  :ARG1 (s3 / subset
                        :ARG1-of (c5 / characterize-01
                              :ARG2 (a3 / and
                                    :op1 (e / express-03
                                          :ARG2 (m / marker
                                                :mod (p5 / protein :name (n5 / name :op1 "Gr-1")))
                                          :ARG1-of (l2 / low-04))
                                    :op2 (e2 / express-03
                                          :ARG2 m
                                          :mod (i / intermediate)))))
                  :ARG2 (s4 / significant-02)
                  :location (m2 / mouse
                        :ARG1-of (a4 / ablate-01
                              :degree (f / full)))
                  :mod (o / only)))
      :ARG1-of (d3 / describe-01
            :ARG0 (f2 / figure :mod "3D")))

# ::id bel_pmid_2060_5485.40442 ::date 2015-05-12T20:17:25 ::annotator SDL-AMR-09 ::preferred
# ::snt Following separation of CD11b+ cells from MCA203 tumor infiltrate, we found that loss of C/EBPp caused a significant reduction in both arginase 1 (Arg1) and nitric oxide synthase 2 (Nos2) proteins (Figure 6A), two enzymes that were described as crucial components of MDSC inhibitory machinery (Bronte and Zanovello, 2005; Gabrilovich and Nagaraj, 2009).
# ::save-date Sun Jan 17, 2016 ::file bel_pmid_2060_5485_40442.txt
(f / find-01
      :ARG0 (w / we)
      :ARG1 (c / cause-01
            :ARG0 (l / lose-02
                  :ARG1 (p / protein :name (n / name :op1 "C/EBPp")))
            :ARG1 (r / reduce-01
                  :ARG1 (a / and
                        :op1 (e / enzyme :name (n2 / name :op1 "arginase" :op2 "1"))
                        :op2 (e2 / enzyme :name (n3 / name :op1 "nitric" :op2 "oxide" :op3 "synthase" :op4 "2"))
                        :mod (b / both)
                        :ARG1-of (d2 / describe-01
                              :ARG2 (c3 / component
                                    :mod (c4 / crucial)
                                    :part-of (m / machinery
                                          :ARG0-of (i2 / inhibit-01)
                                          :mod (c5 / cell :name (n6 / name :op1 "MDSC"))))
                              :ARG1-of (d3 / describe-01
                                    :ARG0 (a2 / and
                                          :op1 (p3 / publication-91
                                                :ARG0 (a3 / and
                                                      :op1 (p4 / person :name (n7 / name :op1 "Bronte"))
                                                      :op2 (p5 / person :name (n8 / name :op1 "Zanovello")))
                                                :time (d4 / date-entity :year 2015))
                                          :op2 (p6 / publication-91
                                                :ARG0 (a4 / and
                                                      :op1 (p7 / person :name (n9 / name :op1 "Gabrilovich"))
                                                      :op2 (p8 / person :name (n10 / name :op1 "Nagaraj")))
                                                :time (d5 / date-entity :year 2009))))))
                  :ARG2 (s2 / significant-02)
                  :ARG1-of (d / describe-01
                        :ARG0 (f2 / figure :mod "6A"))))
      :ARG1-of (f3 / follow-01
            :ARG2 (s / separate-01
                  :ARG1 (c2 / cell
                        :mod (p9 / protein :name (n4 / name :op1 "CD11b+")))
                  :ARG2 (i / infiltrate-01
                        :ARG0 (p2 / protein :name (n5 / name :op1 "MCA203"))
                        :mod (t / tumor)))))

# ::id bel_pmid_2060_5485.40446 ::date 2015-05-12T20:46:58 ::annotator SDL-AMR-09 ::preferred
# ::snt Cytokines were able to upregulate IL-4Ra expression, but a more pronounced effect was obtained by G-CSF+GM-CSF combination (Figure 7B and Figure S6B).
# ::save-date Mon Dec 21, 2015 ::file bel_pmid_2060_5485_40446.txt
(p / possible-01
      :ARG1 (u / upregulate-01
            :ARG0 (c / cytokine)
            :ARG1 (e / express-03
                  :ARG1 (p2 / protein :name (n / name :op1 "IL-4Ra"))))
      :ARG1-of (c2 / contrast-01
            :ARG2 (o / obtain-01
                  :ARG1 (a2 / affect-01
                        :ARG1-of (p5 / pronounced-02
                              :degree (m / more)))
                  :ARG2 (c3 / combine-01
                        :ARG1 (p3 / protein :name (n2 / name :op1 "G-CSF"))
                        :ARG2 (p4 / protein :name (n3 / name :op1 "GM-CSF")))))
      :ARG1-of (d / describe-01
            :ARG0 (a / and
                  :op1 (f / figure :mod "7B")
                  :op2 (f2 / figure :mod "S6B"))))

# ::id bel_pmid_2069_3421.19238 ::date 2015-05-12T05:50:33 ::annotator SDL-AMR-09 ::preferred
# ::snt These results indicate that the endogenous IL-33/ST2 signaling pathway enhances the expression of CCR3 on eosinophils.
# ::save-date Tue May 19, 2015 ::file bel_pmid_2069_3421_19238.txt
(i / indicate-01
      :ARG0 (t / thing
            :ARG2-of (r / result-01)
            :mod (t2 / this))
      :ARG1 (e / enhance-01
            :ARG0 (p / pathway :name (n / name :op1 "IL-33/ST2")
                  :ARG0-of (s / signal-07)
                  :mod (e2 / endogenous))
            :ARG1 (e3 / express-03
                  :ARG2 (p2 / protein :name (n2 / name :op1 "CCR3"))
                  :ARG3 (c / cell :name (n3 / name :op1 "eosinophil")))))

# ::id bel_pmid_2069_3421.19240 ::date 2015-05-12T06:44:55 ::annotator SDL-AMR-09 ::preferred
# ::snt IL-33 triggered the production of IL-13 and IL-6 and strongly increased the production of CCL17 and TGF-b from WT eosinophils, but not ST2-/- eosinophils, in a dosedependent manner (Fig. 5A).
# ::save-date Sun Jan 3, 2016 ::file bel_pmid_2069_3421_19240.txt
(a / and
      :op1 (t / trigger-01
            :ARG0 (p3 / protein :name (n / name :op1 "IL-33"))
            :ARG1 (p4 / produce-01
                  :ARG1 (a2 / and
                        :op1 (p5 / protein :name (n2 / name :op1 "IL-13"))
                        :op2 (p6 / protein :name (n3 / name :op1 "IL-6")))))
      :op2 (c / contrast-01
            :ARG1 (i / increase-01
                  :ARG0 p3
                  :ARG1 (p / produce-01
                        :ARG1 (a3 / and
                              :op1 (p7 / protein :name (n4 / name :op1 "CCL17"))
                              :op2 (p8 / protein :name (n5 / name :op1 "TGF-b"))
                              :source (c2 / cell :name (n6 / name :op1 "eosinophil")
                                    :mod (w / wild-type))))
                  :ARG1-of (s / strong-02)
                  :manner (d / depend-01
                        :ARG1 (d2 / dose-01)))
            :ARG2 (i2 / increase-01 :polarity -
                  :ARG0 p3
                  :ARG1 (p2 / produce-01
                        :ARG1 (a4 / and
                              :op1 p7
                              :op2 p8
                              :source (c3 / cell :name (n7 / name :op1 "eosinophil")
                                    :mod (g / gene :name (n8 / name :op1 "ST2")
                                          :ARG2-of (m / mutate-01 :mod "-/-")))))))
      :ARG1-of (d3 / describe-01
            :ARG0 (f / figure :mod "5A")))

# ::id bel_pmid_2092_1519.3016 ::date 2015-05-12T07:12:05 ::annotator SDL-AMR-09 ::preferred
# ::snt Pharmacological intervention with a VEGFR-2-neutralizing Ab (anti-Flk1 mAb) abolished the production of IL-6 (but not IL-12p70) and the subsequent development of allergen-specific Th17 cell response.
# ::save-date Wed Jan 13, 2016 ::file bel_pmid_2092_1519_3016.txt
(c3 / contrast-01
      :ARG1 (a / abolish-01
            :ARG0 (i / intervene-01
                  :mod (p2 / pharmacology)
                  :instrument (a3 / antibody
                        :ARG0-of (n / neutralize-01
                              :ARG1 (p6 / protein :name (n2 / name :op1 "VEGFR-2")))))
            :ARG1 (a2 / and
                  :op2 (d / develop-01
                        :ARG1 (r / respond-01
                              :ARG0 (c2 / cell :name (n5 / name :op1 "Th17"))
                              :ARG1-of (s2 / specific-02
                                    :ARG2 (a5 / allergen)))
                        :mod (s / subsequent))
                  :op2 (p / produce-01
                        :ARG1 (p3 / protein :name (n3 / name :op1 "IL-6")))))
      :ARG2 (a6 / abolish-01 :polarity -
            :ARG1 (p4 / produce-01
                  :ARG1 (p5 / protein :name (n4 / name :op1 "IL-12p70")))))

# ::id bel_pmid_2092_1519.3466 ::date 2015-05-12T07:27:41 ::annotator SDL-AMR-09 ::preferred
# ::snt In vivo production of VEGF and Th1- and Th17-polarizing cytokines (IL-12p70 and IL-6, respectively) were upregulated by airway exposure to LPS.
# ::save-date Sun Jan 17, 2016 ::file bel_pmid_2092_1519_3466.txt
(u / upregulate-01
      :ARG0 (e / expose-01
            :ARG2 (m2 / molecular-physical-entity :name (n6 / name :op1 "LPS"))
            :mod (a3 / airway))
      :ARG1 (p / produce-01
            :ARG1 (a / and
                  :op1 (p3 / protein :name (n3 / name :op1 "VEGF"))
                  :op2 (c / cytokine :name (n / name :op1 "IL-12p70")
                        :ARG0-of (p2 / polarize-01
                              :ARG1 (p5 / protein :name (n4 / name :op1 "Th1"))))
                  :op3 (c2 / cytokine :name (n2 / name :op1 "IL-6")
                        :ARG0-of (p4 / polarize-01
                              :ARG1 (c4 / cell :name (n5 / name :op1 "Th17")))))
            :manner (i / in-vivo)))

# ::id bel_pmid_2094_4008.19124 ::date 2015-05-12T07:42:49 ::annotator SDL-AMR-09 ::preferred
# ::snt Both Fyn and Hck phosphorylate the adaptor protein Gab2 to activate PI3K signaling and promote microtubule formation that is important for granule translocation to the plasma membrane (9, 11).
# ::save-date Sat Feb 13, 2016 ::file bel_pmid_2094_4008_19124.txt
(p4 / phosphorylate-01
      :ARG1 (p3 / protein :name (n3 / name :op1 "Gab2")
            :mod (a3 / adaptor))
      :ARG2 (a2 / and
            :op1 (e2 / enzyme :name (n / name :op1 "Fyn"))
            :op2 (e3 / enzyme :name (n2 / name :op1 "Hck"))
            :mod (b / both))
      :purpose (a4 / and
            :op1 (a5 / activate-01
                  :ARG0 a2
                  :ARG1 (s / signal-07
                        :ARG0 (p6 / pathway :name (n4 / name :op1 "PI3K"))))
            :op2 (p2 / promote-01
                  :ARG0 a2
                  :ARG1 (f / form-01
                        :ARG1 (m / microtubule)
                        :mod (i / important
                              :purpose (t / translocate-01
                                    :ARG2 (m2 / membrane
                                          :poss (p / plasma))
                                    :path (g3 / granule))))))
      :ARG1-of (d / describe-01
            :ARG0 (p5 / publication
                  :ARG1-of (c2 / cite-01
                        :ARG2 (v / value-interval :op1 9 :op2 11)))))

# ::id bel_pmid_2094_4008.19126 ::date 2015-05-12T08:00:51 ::annotator SDL-AMR-09 ::preferred
# ::snt PTP? is required for SCF-induced c-Kit and Fyn activation, and in this way regulates a Fyn-based c-Kit signaling axis (Fyn/Gab2/Shp2/Vav/PAK/Rac/JNK) that mediates mast cell migration.
# ::save-date Wed Jan 13, 2016 ::file bel_pmid_2094_4008_19126.txt
(a3 / and
      :op1 (r / require-01
            :ARG1 (e / enzyme :name (n / name :op1 "PTPβ"))
            :purpose (a / activate-01
                  :ARG1 (a2 / and
                        :op1 (e2 / enzyme :name (n2 / name :op1 "c-Kit"))
                        :op2 (e3 / enzyme :name (n3 / name :op1 "Fyn")))
                  :ARG2-of (i / induce-01
                        :ARG0 (p3 / protein :name (n4 / name :op1 "SCF")))))
      :op2 (r2 / regulate-01
            :ARG0 e
            :ARG1 (a4 / axis
                  :ARG0-of (s / signal-07
                        :ARG1 e2)
                  :ARG1-of (b / base-02
                        :ARG2 e3)
                  :ARG0-of (m / mediate-01
                        :ARG1 (m2 / migrate-01
                              :ARG0 (c / cell
                                    :mod (m3 / mast))))
                  :consist-of (a5 / and
                        :op1 e2
                        :op2 (p / protein :name (n6 / name :op1 "Gab2"))
                        :op3 (e6 / enzyme :name (n7 / name :op1 "Shp2"))
                        :op4 (p2 / protein :name (n8 / name :op1 "Vav"))
                        :op5 (e7 / enzyme :name (n9 / name :op1 "PAK"))
                        :op6 (e8 / enzyme :name (n10 / name :op1 "Rac"))
                        :op7 (e9 / enzyme :name (n11 / name :op1 "JNK"))))
            :manner (w / way
                  :mod (t / this))))

# ::id bel_pmid_2108_5614.26518 ::date 2015-05-12T09:02:20 ::annotator SDL-AMR-09 ::preferred
# ::snt Furthermore, we find that basal arginase 1 expression and associated arginase activity is markedly increased in MKP-2 deletion mice, a response which would also mediate a reduction in NO formation, this is again different to the findings in MKP-1?/? macrophages .
# ::save-date Fri Jan 15, 2016 ::file bel_pmid_2108_5614_26518.txt
(a / and
      :op2 (f / find-01
            :ARG0 (w / we)
            :ARG1 (i / increase-01
                  :ARG1 (a2 / and
                        :op1 (e / express-03
                              :ARG2 (e2 / enzyme :name (n / name :op1 "arginase-1")
                                    :mod (b / basal)))
                        :op2 (a3 / activity-06
                              :ARG0 (e3 / enzyme :name (n2 / name :op1 "arginase"))
                              :ARG1-of (a4 / associate-01)))
                  :ARG1-of (m / mark-01)
                  :location (m2 / mouse
                        :ARG2-of (d / delete-01
                              :ARG1 (e4 / enzyme :name (n3 / name :op1 "MKP-2"))))
                  :ARG2-of (r / respond-01
                        :ARG0-of (m3 / mediate-01
                              :ARG1 (r2 / reduce-01
                                    :ARG1 (f2 / form-01
                                          :ARG1 (s / small-molecule :name (n4 / name :op1 "NO"))))
                              :mod (a5 / also)))
                  :ARG0-of (d2 / differ-01
                        :ARG1 (t / thing
                              :ARG1-of (f3 / find-01
                                    :location (c / cell :name (n5 / name :op1 "macrophage")
                                          :part (g / gene :mode interrogative :name (n6 / name :op1 "MKP-1")
                                                :ARG2-of (m4 / mutate-01 :mod "-/-")))))
                        :mod (a6 / again)))))

# ::id bel_pmid_2108_5614.26520 ::date 2015-05-12T09:26:19 ::annotator SDL-AMR-09 ::preferred
# ::snt MKP-2 negatively regulated IL-12, IL-6 and TNF-a expression and positively regulates IL-10 confirming this hypothesis.
# ::save-date Sat Jun 13, 2015 ::file bel_pmid_2108_5614_26520.txt
(a / and
      :op1 (d / downregulate-01
            :ARG0 (e2 / enzyme :name (n / name :op1 "MKP-2"))
            :ARG1 (e / express-03
                  :ARG2 (a2 / and
                        :op1 (p / protein :name (n2 / name :op1 "IL-12"))
                        :op2 (p2 / protein :name (n3 / name :op1 "IL-6"))
                        :op3 (p3 / protein :name (n4 / name :op1 "TNF")))))
      :op2 (u / upregulate-01
            :ARG0 e2
            :ARG1 (p4 / protein :name (n5 / name :op1 "IL-10")))
      :ARG0-of (c / confirm-01
            :ARG1 (t2 / thing
                  :ARG1-of (h / hypothesize-01)
                  :mod (t / this))))

# ::id bel_pmid_2111_5688.4192 ::date 2015-05-12T09:35:06 ::annotator SDL-AMR-09 ::preferred
# ::snt pDCs were found to rapidly infiltrate both murine and human skin wounds and to transiently produce type I IFNs via TLR7- and TLR9-dependent recognition of nucleic acids.
# ::save-date Mon Jan 4, 2016 ::file bel_pmid_2111_5688_4192.txt
(a / and
      :op1 (i / infiltrate-01
            :ARG0 (e / enzyme :name (n / name :op1 "pDC"))
            :ARG1 (a2 / and
                  :op1 (w / wound
                        :mod (s / skin
                              :mod (h / human)))
                  :op2 (w2 / wound
                        :location (s2 / skin
                              :mod (m / murine))))
            :manner (r / rapid))
      :op2 (p / produce-01
            :ARG0 e
            :ARG1 (p5 / protein :name (n6 / name :op1 "type" :op2 "I" :op3 "IFN"))
            :ARG1-of (t / transient-02)
            :instrument (r2 / recognize-02
                  :ARG1 (n2 / nucleic-acid)
                  :ARG0-of (d / depend-01
                        :ARG1 (a3 / and
                              :op1 (p3 / protein :name (n3 / name :op1 "TLR-7"))
                              :op2 (p4 / protein :name (n4 / name :op1 "TLR-9"))))))
      :ARG1-of (f / find-01))

# ::id bel_pmid_2111_5688.27614 ::date 2015-05-12T09:50:30 ::annotator SDL-AMR-09 ::preferred
# ::snt Like pDC-depleted mice, IFN-alpha/beta receptor-deficient mice showed a significant delay in wound reepithelization (Fig. 5 E) and displayed a profound deficiency in IL-6, IL-17, and IL-22 expression levels in injured skin, without affecting the expression of IFN-gamma (Fig. 5 F).
# ::save-date Wed May 20, 2015 ::file bel_pmid_2111_5688_27614.txt
(a / and
      :op1 (s / show-01
            :ARG0 (m2 / mouse
                  :consist-of (d6 / deficit
                        :consist-of (r2 / receptor :name (n2 / name :op1 "IFN-alpha/beta"))))
            :ARG1 (d3 / delay-01
                  :ARG1 (r3 / reepithelize-00
                        :ARG1 (w / wound))
                  :ARG1-of (s3 / significant-02))
            :ARG1-of (r / resemble-01
                  :ARG2 (m / mouse
                        :ARG2-of (d2 / deplete-01
                              :ARG1 (e / enzyme :name (n / name :op1 "pDC")))))
            :ARG1-of (d4 / describe-01
                  :ARG0 (f / figure :mod "5E")))
      :op2 (d / display-01
            :ARG0 m2
            :ARG1 (l2 / lack-01
                  :ARG1 (l3 / level
                        :degree-of (e2 / express-03
                              :ARG2 (a2 / and
                                    :op1 (p / protein :name (n3 / name :op1 "IL-6"))
                                    :op2 (p2 / protein :name (n4 / name :op1 "IL-17"))
                                    :op3 (p3 / protein :name (n5 / name :op1 "IL-22"))))
                        :location (s2 / skin
                              :ARG1-of (i / injure-01)))
                  :mod (p5 / profound))
            :ARG0-of (a3 / affect-01 :polarity -
                  :ARG1 (e3 / express-03
                        :ARG2 (p4 / protein :name (n6 / name :op1 "IFN-gamma"))))
            :ARG1-of (d5 / describe-01
                  :ARG0 (f2 / figure :mod "5F"))))

# ::id bel_pmid_2111_5688.31368 ::date 2015-05-12T22:47:22 ::annotator SDL-AMR-09 ::preferred
# ::snt Expression of both IFN-a2 and IFN-b mRNA was found to be profoundly abrogated in TLR7-deficient mice
# ::save-date Sun Jan 3, 2016 ::file bel_pmid_2111_5688_31368.txt
(a / abrogate-01
      :ARG1 (e / express-03
            :ARG2 (a3 / and
                  :op1 (n2 / nucleic-acid :name (n5 / name :op1 "mRNA")
                        :ARG0-of (e2 / encode-01
                              :ARG1 (p / protein :name (n / name :op1 "IFN-a2"))))
                  :op2 (n7 / nucleic-acid :name (n6 / name :op1 "mRNA")
                        :ARG0-of (e3 / encode-01
                              :ARG1 (p2 / protein :name (n3 / name :op1 "IFN-b"))))))
      :manner (p3 / profound)
      :location (m / mouse
            :ARG0-of (d / delete-01
                  :ARG1 (p4 / protein :name (n4 / name :op1 "TLR7"))))
      :ARG1-of (f / find-01))

# ::id bel_pmid_2123_9520.35054 ::date 2015-05-12T23:12:42 ::annotator SDL-AMR-09 ::preferred
# ::snt In the present study, we found that when RSK4 is inhibited in vitro using short hairpin RNA technology, cells can bypass stress-induced senescence and oncogene-induced senescence: normal human fibroblasts grew following oxidative stress, induction of DNA damage and KRAS(V12) or BRAF(E600) overexpression.
# ::save-date Sat Jan 16, 2016 ::file bel_pmid_2123_9520_35054.txt
(p / possible-01
      :ARG1 (b / bypass-01
            :ARG0 (c / cell)
            :ARG1 (a / and
                  :op1 (s / senescence
                        :ARG2-of (i / induce-01
                              :ARG0 (s2 / stress-02)))
                  :op2 (s3 / senescence
                        :ARG2-of (i2 / induce-01
                              :ARG0 (o / oncogene))))
            :manner (g / grow-01
                  :ARG1 (f2 / fibroblast
                        :mod (h / human)
                        :ARG1-of (n2 / normal-02))
                  :time (a2 / after
                        :op1 (s4 / stress-02
                              :ARG3 (o2 / oxidize-01))
                        :op2 (i5 / induce-01
                              :ARG2 (d / damage-01
                                    :ARG1 (n4 / nucleic-acid :wiki "DNA" :name (n7 / name :op1 "DNA"))))
                        :op3 (o3 / overexpress-01
                              :ARG1 (a3 / and
                                    :op1 (e2 / enzyme :name (n5 / name :op1 "KRAS")
                                          :ARG2-of (m2 / mutate-01 :value "V12"))
                                    :op2 (e3 / enzyme :name (n6 / name :op1 "BRAF")
                                          :ARG2-of (m3 / mutate-01 :value "E600")))))))
      :time (i3 / inhibit-01
            :ARG1 (e / enzyme :name (n / name :op1 "RSK4"))
            :instrument (t / technology
                  :mod (n8 / nucleic-acid :name (n3 / name :op1 "short" :op2 "hairpin" :op3 "RNA")))
            :manner (i4 / in-vitro))
      :ARG1-of (f / find-01
            :ARG0 (w / we)
            :medium (s5 / study-01
                  :time (p2 / present))))

# ::id bel_pmid_2123_9520.37214 ::date 2015-05-12T23:35:57 ::annotator SDL-AMR-09 ::preferred
# ::snt Two days after BRAFE600 selection, we seeded cells at low density and performed growth curves. RSK4 inhibition partially rescued BRAFE600-induced senescence in both TIG3 and TIG3 p16-null (Figure 4A).
# ::save-date Thu Feb 4, 2016 ::file bel_pmid_2123_9520_37214.txt
(m / multi-sentence
      :snt1 (a / and
            :op1 (s / seed-02
                  :ARG0 (w / we)
                  :ARG2 (c / cell)
                  :mod (d2 / dense
                        :ARG1-of (l / low-04)))
            :op2 (p / perform-02
                  :ARG0 w
                  :ARG1 (c2 / curve
                        :topic (g / grow-01)))
            :time (a2 / after
                  :op1 (s2 / select-01
                        :ARG1 (e2 / enzyme :name (n / name :op1 "BRAF")
                              :ARG2-of (m2 / mutate-01 :value "E600")))
                  :quant (t2 / temporal-quantity :quant 2
                        :unit (d3 / day))))
      :snt2 (r / rescue-01
            :ARG0 (i / inhibit-01
                  :ARG1 (e / enzyme :name (n2 / name :op1 "RSK4"))
                  :degree (p2 / part))
            :ARG1 (s3 / senescence
                  :ARG2-of (i2 / induce-01
                        :ARG0 (e3 / enzyme :name (n3 / name :op1 "BRAF")
                              :ARG2-of (m3 / mutate-01 :value "E600"))))
            :location (a3 / and
                  :op1 (c3 / cell
                        :mod (p3 / protein :name (n4 / name :op1 "TIG3")))
                  :op2 (c4 / cell
                        :mod (p4 / protein :name (n5 / name :op1 "TIG3"))
                        :mod (p5 / protein :name (n6 / name :op1 "p16")
                              :mod (n7 / null))))
            :ARG1-of (d4 / describe-01
                  :ARG0 (f / figure :mod "4A"))))

# ::id bel_pmid_2123_9533.1678 ::date 2015-05-12T23:49:08 ::annotator SDL-AMR-09 ::preferred
# ::snt This IFNg-stimulated expression of T-bet is dependent on signaling through JAK2 and signal transducers and activators of transcription 1 (STAT1) and activates T-bet-dependent DNA binding activity
# ::save-date Mon Jul 6, 2015 ::file bel_pmid_2123_9533_1678.txt
(a3 / and
      :op1 (d / depend-01
            :ARG0 (e / express-03
                  :ARG2 (p3 / protein
                        :name (n2 / name :op1 "T-bet"))
                  :ARG1-of (s / stimulate-01
                        :ARG0 (p / protein
                              :name (n / name :op1 "IFNg")))
                  :mod (t4 / this))
            :ARG1 (a2 / and
                  :op1 (s2 / signal-07
                        :instrument (e2 / enzyme
                              :name (n3 / name :op1 "JAK2")))
                  :op2 (p4 / protein
                        :name (n5 / name :op1 "signal" :op2 "transducers" :op3 "and" :op4 "activators" :op5 "of" :op6 "transcription" :op7 1))))
      :op2 (a4 / activate-01
            :ARG0 e
            :ARG1 (a / activity-06
                  :ARG1 (b / bind-01
                        :ARG1 (n4 / nucleic-acid :wiki "DNA"
                              :name (n6 / name :op1 "DNA")))
                  :ARG0-of (d3 / depend-01
                        :ARG1 p3))))

# ::id bel_pmid_2137_8275.40580 ::date 2015-05-13T00:04:57 ::annotator SDL-AMR-09 ::preferred
# ::snt In the lung, the concentration of IL-6 was increased, which aberrantly activated oncogenic Stat3 and increased expression of Stat3 downstream genes in epithelial tumor progenitor cells.
# ::save-date Mon Jan 4, 2016 ::file bel_pmid_2137_8275_40580.txt
(i / increase-01
      :ARG1 (c / concentrate-02
            :ARG1 (p / protein :name (n / name :op1 "IL-6")))
      :location (l / lung)
      :ARG0-of (a / activate-01
            :ARG1 (p2 / protein :name (n2 / name :op1 "Stat3")
                  :ARG0-of (c3 / cause-01
                        :ARG1 (d2 / disease :wiki "Cancer" :name (n4 / name :op1 "cancer"))))
            :manner (a2 / aberrant))
      :ARG0-of (i2 / increase-01
            :ARG1 (e / express-03
                  :ARG1 (g / gene :name (n3 / name :op1 "Stat3")
                        :location (d / downstream)))
            :location (c2 / cell
                  :ARG0-of (b / bear-02
                        :ARG1 (t / tumor
                              :mod (e2 / epithelium))))))

# ::id bel_pmid_2137_8275.40582 ::date 2015-05-13T00:20:13 ::annotator SDL-AMR-09 ::preferred
# ::snt Spontaneous emphysema and lung adenocarcinoma were sequentially developed after MMP12 overexpression.
# ::save-date Thu Dec 10, 2015 ::file bel_pmid_2137_8275_40582.txt
(d / develop-01
      :ARG2 (a / and
            :op1 (d2 / disease :name (n / name :op1 "emphysema")
                  :mod (s2 / spontaneous))
            :op2 (m / medical-condition :name (n2 / name :op1 "adenocarcinoma")
                  :mod (l / lung)))
      :manner (s / sequential)
      :time (a2 / after
            :op1 (o / overexpress-01
                  :ARG1 (e / enzyme :name (n3 / name :op1 "MMP12")))))

# ::id bel_pmid_2137_8275.40590 ::date 2015-05-13T00:25:34 ::annotator SDL-AMR-09 ::preferred
# ::snt MMP12 suppresses T-cell proliferation and function in vivo The CD4+ T-lymphocyte population was significantly decreased in the spleen of doxycycline-treated bitransgenic mice (5.58%) compared with that in untreated ones (21.14%), while the CD8+ T-lymphocyte population was less affected (Figure 2A).
# ::save-date Sun Jan 17, 2016 ::file bel_pmid_2137_8275_40590.txt
(m2 / multi-sentence
      :snt1 (s / suppress-01
            :ARG0 (e / enzyme :name (n / name :op1 "MMP12"))
            :ARG1 (a / and
                  :op1 (p3 / proliferate-01
                        :ARG0 (c / cell :name (n2 / name :op1 "T-cell")))
                  :op2 (f / function-01
                        :ARG0 c))
            :manner (i / in-vivo))
      :snt2 (d / decrease-01
            :ARG1 (p4 / population
                  :quant-of (c2 / cell :name (n3 / name :op1 "T-lymphocyte")
                        :ARG3-of (e2 / express-03
                              :ARG2 (e3 / enzyme :name (n4 / name :op1 "CD4+")))))
            :ARG2 (p5 / percentage-entity :value 5.58)
            :ARG1-of (s2 / significant-02)
            :location (s3 / spleen
                  :part-of (m3 / mouse
                        :ARG1-of (t / treat-03
                              :ARG3 (d2 / doxycycline))
                        :mod (b / bitransgenic)))
            :compared-to (d3 / decrease-01
                  :ARG1 (p6 / population
                        :quant-of c2)
                  :ARG2 (p7 / percentage-entity :value 21.14)
                  :location (m4 / mouse
                        :ARG1-of (t2 / treat-04 :polarity -)))
            :ARG1-of (d4 / describe-01
                  :ARG0 (f2 / figure :mod "2A"))
            :ARG1-of (c5 / contrast-01
                  :ARG2 (a3 / affect-01
                        :ARG1 (p8 / population
                              :quant-of (c4 / cell :name (n7 / name :op1 "T-lymphocyte")
                                    :ARG1-of (e6 / express-03
                                          :ARG2 e3)
                                    :mod (p / protein :name (n6 / name :op1 "CD8+"))))
                        :degree (l / less)))))

# ::id bel_pmid_2137_8275.40594 ::date 2015-05-13T01:00:47 ::annotator SDL-AMR-09 ::preferred
# ::snt The culture medium showed decreased secretion of IL-2, IL-4, and IFN7 in the activated MMP12-treated samples (Figure 2F).
# ::save-date Sun Dec 20, 2015 ::file bel_pmid_2137_8275_40594.txt
(s / show-01
      :ARG0 (m / medium
            :mod (c / culture))
      :ARG1 (s2 / secrete-01
            :ARG1 (a / and
                  :op1 (p / protein :name (n / name :op1 "IL-2"))
                  :op2 (p2 / protein :name (n2 / name :op1 "IL-4"))
                  :op3 (p3 / protein :name (n3 / name :op1 "IFN7")))
            :ARG1-of (d2 / decrease-01))
      :location (t2 / thing
            :ARG1-of (t / treat-04
                  :ARG2 (e / enzyme :name (n4 / name :op1 "MMP12")
                        :ARG1-of (a2 / activate-01)))
            :ARG1-of (s3 / sample-01))
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod "2F")))

# ::id bel_pmid_2137_8275.40598 ::date 2015-05-13T01:09:14 ::annotator SDL-AMR-09 ::preferred
# ::snt CD11b+/Gr-1+ cells from doxcycline-treated bitransgenic mice showed the strongest inhibition on proliferation of wild-type CD4+ T cells (Figure 3C).
# ::save-date Sun Jan 17, 2016 ::file bel_pmid_2137_8275_40598.txt
(s / show-01
      :ARG0 (c / cell
            :mod (s2 / slash
                  :op1 (p2 / protein :name (n / name :op1 "CD11b+"))
                  :op2 (p3 / protein :name (n2 / name :op1 "Gr-1+")))
            :source (m / mouse
                  :mod (b / bitransgenic)
                  :ARG1-of (t / treat-04
                        :ARG2 (s4 / small-molecule :name (n5 / name :op1 "doxycycline")))))
      :ARG1 (i / inhibit-01
            :ARG1 (p / proliferate-01
                  :ARG0 (c2 / cell :name (n3 / name :op1 "T-cell")
                        :ARG3-of (e / express-03
                              :ARG2 (p4 / protein :name (n4 / name :op1 "CD4+")))
                        :mod (w / wild-type)))
            :ARG1-of (s3 / strong-02
                  :degree (m2 / most)))
      :ARG1-of (d2 / describe-01
            :ARG0 (f / figure :mod "3C")))

# ::id bel_pmid_2137_8275.40600 ::date 2015-05-13T01:15:58 ::annotator SDL-AMR-09 ::preferred
# ::snt This inhibition was further confirmed by a significant reduction of IL-2 and IL-4 secretion, implicating a functional impairment of CD4+ T cells by CD11b+/Gr-1+ cells from doxcycline-treated bitransgenic mice (Figure 3D).
# ::save-date Sun Jan 17, 2016 ::file bel_pmid_2137_8275_40600.txt
(c / confirm-01
      :ARG0 (r / reduce-01
            :ARG1 (s / secrete-01
                  :ARG1 (a / and
                        :op1 (p / protein :name (n / name :op1 "IL-2"))
                        :op2 (p2 / protein :name (n2 / name :op1 "IL-4"))))
            :ARG2 (s3 / significant-02))
      :ARG1 (i / inhibit-01
            :mod (t / this))
      :degree (f / further)
      :ARG0-of (i2 / implicate-01
            :ARG1 (i3 / impair-01
                  :ARG0 (c3 / cell
                        :part (s2 / slash
                              :op1 (p3 / protein :name (n5 / name :op1 "CD11b+"))
                              :op2 (p4 / protein :name (n6 / name :op1 "Gr-1+")))
                        :source (m / mouse
                              :mod (b / bitransgenic)
                              :ARG1-of (t2 / treat-04
                                    :ARG2 (s4 / small-molecule :name (n7 / name :op1 "doxycycline")))))
                  :ARG1 (f2 / function-01
                        :ARG0 (c2 / cell :name (n3 / name :op1 "T-cell")
                              :ARG3-of (e / express-03
                                    :ARG2 (p5 / protein :name (n4 / name :op1 "CD4+")))))))
      :ARG1-of (d2 / describe-01
            :ARG0 (f3 / figure :mod "3D")))

# ::id bel_pmid_2137_8275.40608 ::date 2015-05-13T10:03:59 ::annotator SDL-AMR-09 ::preferred
# ::snt Compared with doxycycline-untreated bitransgenic mice, the expression levels of IL-1p, IL-6, MIP-2, and TNF-a were abnormally increased in the plasma of doxycycline-treated bitransgenic mice (Figure 4A).
# ::save-date Mon Jan 4, 2016 ::file bel_pmid_2137_8275_40608.txt
(i / increase-01
      :ARG1 (l / level
            :degree-of (e / express-03
                  :ARG2 (a2 / and
                        :op1 (p / protein :name (n / name :op1 "IL-1p"))
                        :op2 (p2 / protein :name (n2 / name :op1 "IL-6"))
                        :op3 (p3 / protein :name (n3 / name :op1 "MIP-2"))
                        :op4 (p4 / protein :name (n4 / name :op1 "TNF-a")))))
      :ARG1-of (n5 / normal-02 :polarity -)
      :location (p5 / plasma
            :part-of (m / mouse
                  :mod (b / bitransgenic)
                  :ARG1-of (t / treat-04
                        :ARG2 (s / small-molecule :name (n6 / name :op1 "doxycycline")))))
      :compared-to (m2 / mouse
            :mod (b2 / bitransgenic)
            :ARG1-of (t2 / treat-04 :polarity -
                  :ARG2 s))
      :ARG1-of (d3 / describe-01
            :ARG0 (f / figure :mod "4A")))

# ::id bel_pmid_2145_4454.35882 ::date 2015-05-13T10:13:00 ::annotator SDL-AMR-09 ::preferred
# ::snt To determine if the ERK-MAPK pathway was also activated by TLR2 in megakaryocytes, lysates of Meg-01 cells were treated with 1 ?g/mL Pam3CSK4 for up to 1 hour and were immunoblotted for phosphorylated ERK1/2. As shown in Figure 1A, there was an increase in the phosphorylation of ERK beginning at 5 minutes that peaks at 30 minutes (105.8% ±3.9).
# ::save-date Mon Jan 4, 2016 ::file bel_pmid_2145_4454_35882.txt
(m4 / multi-sentence
      :snt1 (a / and
            :op1 (t4 / treat-04
                  :ARG1 (l / lysate
                        :source (c / cell-line :name (n2 / name :op1 "Meg-01")))
                  :ARG2 (p3 / protein :name (n3 / name :op1 "Pam3CSK4")
                        :quant (c3 / concentration-quantity :quant 1
                              :unit (g / gram-per-milliliter)))
                  :duration (u / up-to
                        :op1 (t6 / temporal-quantity :quant 1
                              :unit (h2 / hour))))
            :op2 (i / immunoblot-01
                  :ARG1 (s / slash
                        :op1 (e2 / enzyme :name (n4 / name :op1 "ERK-1"))
                        :op2 (e3 / enzyme :name (n5 / name :op1 "ERK-2"))
                        :ARG1-of (p4 / phosphorylate-01))
                  :ARG2 l)
            :purpose (d / determine-01
                  :ARG1 (a2 / activate-01 :mode interrogative
                        :ARG0 (p6 / protein :name (n7 / name :op1 "TLR2"))
                        :ARG1 (p5 / pathway :name (n6 / name :op1 "ERK-MAPK"))
                        :location (c2 / cell :name (n8 / name :op1 "megakaryocyte"))
                        :mod (a5 / also))))
      :snt2 (i2 / increase-01
            :ARG1 (p7 / phosphorylate-01
                  :ARG1 (e4 / enzyme :name (n9 / name :op1 "ERK")))
            :ARG0-of (b / begin-01
                  :time (a6 / after
                        :op1 (t3 / temporal-quantity :quant 5
                              :unit (m3 / minute))))
            :ARG1-of (p8 / peak-01
                  :ARG2 (p9 / percentage-entity :value 105.8
                        :ARG2-of (a4 / add-02
                              :ARG1 (p / percentage-entity :value 3.9))
                        :ARG2-of (s3 / subtract-01
                              :ARG1 (p2 / percentage-entity :value 3.9)))
                  :time (a3 / after
                        :op1 (t / temporal-quantity :quant 30
                              :unit (m2 / minute))))
            :ARG1-of (s2 / show-01
                  :location (f2 / figure :mod "1A"))))

# ::id bel_pmid_2145_4454.35884 ::date 2015-05-13T10:52:59 ::annotator SDL-AMR-09 ::preferred
# ::snt GP1b is part of the GPIb-IX-V complex that binds vWF and thrombin. Its expression level was significantly increased by 162% and cell surface expression, as determined by flow cytometry, was also increased by 114% with Pam3CSK4 treatment (Figure 5A and Supplemental Figure 4C).
# ::save-date Sat Jan 2, 2016 ::file bel_pmid_2145_4454_35884.txt
(m / multi-sentence
      :snt2 (a / and
            :op1 (i / increase-01
                  :ARG1 (l / level
                        :degree-of (e2 / express-03
                              :ARG2 (p6 / protein :name (n6 / name :op1 "GP1b"))))
                  :ARG2 (p / percentage-entity :value 162)
                  :ARG1-of (s / significant-02))
            :op2 (i2 / increase-01
                  :ARG1 (e3 / express-03
                        :ARG2 p6
                        :location (s2 / surface
                              :poss (c2 / cell))
                        :ARG1-of (d / determine-01
                              :ARG0 (c3 / cytometry
                                    :mod (f / flow))))
                  :ARG2 (p2 / percentage-entity :value 114)
                  :mod (a2 / also)
                  :instrument (t / treat-04
                        :ARG2 (p5 / protein :name (n5 / name :op1 "Pam3CSK4"))))
            :ARG1-of (d2 / describe-01
                  :ARG0 (a3 / and
                        :op1 (f2 / figure :mod "5A")
                        :op2 (f3 / figure :mod "4C"
                              :ARG2-of (s3 / supplement-01)))))
      :snt1 (h / have-part-91
            :ARG1 (c / complex :name (n2 / name :op1 "GPIb-IX-V")
                  :ARG1-of (b / bind-01
                        :ARG2 (a4 / and
                              :op1 (p4 / protein :name (n3 / name :op1 "vWF"))
                              :op2 (e / enzyme :name (n4 / name :op1 "thrombin")))))
            :ARG2 (p3 / protein :name (n / name :op1 "GP1b"))))

# ::id bel_pmid_2145_4454.35890 ::date 2015-05-13T11:35:14 ::annotator SDL-AMR-09 ::preferred
# ::snt CD41, also known as integrin ?IIb, part of the ?IIb?III receptor that binds fibrinogen, was also significantly increased in the presence of Pam3CSK4 by 123% (Figure 5B). Surface expression of CD41 was increased by 125% as shown by flow cytometry (Supplemental Figure 4D).
# ::save-date Sat Jan 2, 2016 ::file bel_pmid_2145_4454_35890.txt
(m / multi-sentence
      :snt1 (i / increase-01
            :ARG1 (p3 / protein :name (n / name :op1 "CD41")
                  :ARG1-of (k / know-02
                        :ARG2 (p4 / protein :mode interrogative :name (n2 / name :op1 "integrin-IIb"))
                        :mod (a / also))
                  :part-of (r / receptor :name (n3 / name :op1 "IIb/IIIa")
                        :ARG0-of (b / bind-01
                              :ARG1 (p5 / protein :name (n4 / name :op1 "fibrinogen")
                                    :ARG1-of (i2 / increase-01
                                          :ARG2 (p / percentage-entity :value 123)
                                          :ARG1-of (s2 / significant-02)
                                          :mod (a2 / also)
                                          :condition (p6 / present-02
                                                :ARG1 (p7 / protein :name (n5 / name :op1 "Pam3CSK4"))))))))
            :ARG2 s2
            :ARG1-of (d / describe-01
                  :ARG0 (f / figure :mod "5B")))
      :snt2 (i3 / increase-01
            :ARG1 (e / express-03
                  :ARG2 (p8 / protein :name (n6 / name :op1 "CD41"))
                  :location (s3 / surface))
            :ARG2 (p2 / percentage-entity :value 125)
            :ARG1-of (s4 / show-01
                  :ARG0 (c / cytometry
                        :mod (f2 / flow)))
            :ARG1-of (d2 / describe-01
                  :ARG0 (f3 / figure :mod "4D"
                        :ARG2-of (s5 / supplement-01)))))

# ::id bel_pmid_2151_8970.1890 ::date 2015-05-14T00:31:11 ::annotator SDL-AMR-09 ::preferred
# ::snt Unexpectedly, TGF-beta treatment also induced increased IL-6 production by pDC.
# ::save-date Sun Dec 20, 2015 ::file bel_pmid_2151_8970_1890.txt
(i / induce-01
      :ARG0 (t / treat-04
            :ARG2 (p / protein :name (n / name :op1 "TGF-beta")))
      :ARG2 (p2 / produce-01
            :ARG0 (e / enzyme :name (n3 / name :op1 "pDC"))
            :ARG1 (p3 / protein :name (n2 / name :op1 "IL-6"))
            :ARG1-of (i2 / increase-01))
      :ARG1-of (e2 / expect-01 :polarity -)
      :mod (a / also))

# ::id bel_pmid_2169_7282.25874 ::date 2015-05-14T00:37:49 ::annotator SDL-AMR-09 ::preferred
# ::snt Api6 overexpression in lung epithelial cells only caused regional inflammation, not systemic inflammation.
# ::save-date Wed Jun 24, 2015 ::file bel_pmid_2169_7282_25874.txt
(c3 / contrast-01
      :ARG1 (c / cause-01
            :ARG0 (o / overexpress-01
                  :ARG1 (p / protein :name (n / name :op1 "Api6"))
                  :location (c2 / cell
                        :part-of (e / epithelium
                              :mod (l / lung))))
            :ARG1 (i / inflame-01
                  :mod (r / region))
            :mod (o2 / only))
      :ARG2 (c4 / cause-01 :polarity -
            :ARG0 o
            :ARG1 (i2 / inflame-01
                  :ARG1 (s / system))))

# ::id bel_pmid_2169_7282.25878 ::date 2015-05-14T00:42:54 ::annotator SDL-AMR-09 ::preferred
# ::snt At the gene transcriptional level, Api6 overexpression stimulated mRNA expression of Stat3 and its upstream stimuli IL-6 in whole lung cells, AT II epithelial cells, and alveolar macrophages (Fig. 4A).
# ::save-date Mon Dec 14, 2015 ::file bel_pmid_2169_7282_25878.txt
(s / stimulate-01
      :ARG0 (o / overexpress-01
            :ARG1 (p / protein :name (n / name :op1 "Api6")))
      :ARG1 (a / and
            :op1 (e / express-03
                  :ARG1 (n7 / nucleic-acid :name (n3 / name :op1 "mRNA"))
                  :ARG2 (p2 / protein :name (n2 / name :op1 "Stat3")))
            :op2 (e2 / express-03
                  :ARG1 n7
                  :ARG2 (p3 / protein :name (n4 / name :op1 "IL-6")
                        :ARG0-of (s2 / stimulate-01
                              :ARG1 p2)
                        :location (u / upstream))))
      :location (l / level
            :mod (t / transcribe-01
                  :ARG1 (g / gene)))
      :location (a2 / and
            :op1 (c / cell
                  :mod (l2 / lung)
                  :mod (w / whole))
            :op2 (c2 / cell
                  :part-of (e3 / epithelium
                        :part (p4 / protein :name (n5 / name :op1 "AT-II"))))
            :op3 (c3 / cell :name (n6 / name :op1 "macrophage")
                  :mod (a3 / alveolus)))
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod "4A")))

# ::id bel_pmid_2193_6896.27282 ::date 2015-05-13T04:44:00 ::annotator SDL-AMR-09 ::preferred
# ::snt Significant reductions in brain levels of early cytokines, including IL-1beta and IL-6 mRNA expression, and late cytokine high mobility group box-1 protein (HMGB1), were found in the gelsolin-treated group compared to the placebo group at all time points (Figure 4).
# ::save-date Mon May 25, 2015 ::file bel_pmid_2193_6896_27282.txt
(f / find-01
      :ARG1 (r / reduce-01
            :ARG1 (a / and
                  :op1 (c / cytokine
                        :ARG2-of (i / include-91
                              :ARG1 (e / express-03
                                    :ARG2 (a2 / and
                                          :op1 (n7 / nucleic-acid :name (n / name :op1 "mRNA")
                                                :ARG0-of (e2 / encode-01
                                                      :ARG1 (p / protein :name (n2 / name :op1 "IL-1β"))))
                                          :op2 (n8 / nucleic-acid :name (n3 / name :op1 "mRNA")
                                                :ARG0-of (e3 / encode-01
                                                      :ARG1 (p2 / protein :name (n4 / name :op1 "IL-6")))))))
                        :mod (e4 / early))
                  :op2 (c2 / cytokine
                        :domain (p3 / protein :name (n5 / name :op1 "high" :op2 "mobility" :op3 "group" :op4 "box-1"))
                        :mod (l / late)))
            :ARG2 (s / significant-02)
            :location (l2 / level
                  :mod (b / brain))
            :compared-to (g / group
                  :mod (p4 / placebo)))
      :location (g2 / group
            :ARG1-of (t / treat-04
                  :ARG2 (p5 / protein :name (n6 / name :op1 "gelsolin"))))
      :time (p6 / point
            :mod (t2 / time
                  :mod (a3 / all)))
      :ARG1-of (d / describe-01
            :ARG0 (f2 / figure :mod 4)))

# ::id bel_pmid_2213_2131.40908 ::date 2015-05-13T05:49:39 ::annotator SDL-AMR-09 ::preferred
# ::snt Factors from murine pancreatic cancer cells cause the down-regulation of SHIP-1 expression, which may potentially contribute to MDSC expansion, and the suppression of CD8+ T cell immune responses.
# ::save-date Wed Dec 9, 2015 ::file bel_pmid_2213_2131_40908.txt
(c / cause-01
      :ARG0 (f / factor
            :source (c2 / cell
                  :part-of (o / organism :name (n2 / name :op1 "Muridae"))
                  :mod (d3 / disease :wiki "Pancreatic_cancer" :name (n7 / name :op1 "pancreatic" :op2 "cancer"))))
      :ARG1 (d2 / downregulate-01
            :ARG0 f
            :ARG1 (e / express-03
                  :ARG2 (p2 / protein :name (n3 / name :op1 "SHIP-1")))
            :ARG0-of (c3 / contribute-01
                  :ARG2 (a / and
                        :op1 (e2 / expand-01
                              :ARG0 d2
                              :ARG1 (c4 / cell :name (n4 / name :op1 "MDSC")))
                        :op2 (s / suppress-01
                              :ARG0 d2
                              :ARG1 (t / thing
                                    :ARG2-of (r / respond-01
                                          :ARG0 (c5 / cell :name (n5 / name :op1 "T")
                                                :mod (p3 / protein :name (n6 / name :op1 "CD8"))))
                                    :ARG1-of (i / immune-02))))
                  :mod (p4 / potential)
                  :ARG1-of (p5 / possible-01))))

# ::id bel_pmid_2213_2131.40910 ::date 2015-05-13T06:35:06 ::annotator SDL-AMR-09 ::preferred
# ::snt qRT-PCR and Western blot analyses revealed the in vivo down-regulation of SHIP-1 expression in splenocytes from TB mice.
# ::save-date Sun Jan 3, 2016 ::file bel_pmid_2213_2131_40910.txt
(r / reveal-01
      :ARG0 (a / and
            :op1 (a2 / analyze-01
                  :instrument (t2 / thing :name (n / name :op1 "qRT-PCR")))
            :op2 (a3 / analyze-01
                  :manner (i2 / immunoblot-01)))
      :ARG1 (d / downregulate-01
            :ARG1 (e / express-03
                  :ARG2 (p / protein :name (n3 / name :op1 "SHIP-1")))
            :manner (i / in-vivo)
            :location (s / splenocyte
                  :source (m / mouse
                        :ARG0-of (b / bear-01
                              :ARG1 (t / tumor))))))

# ::id bel_pmid_2213_2131.40912 ::date 2015-05-13T06:58:11 ::annotator SDL-AMR-09 ::preferred
# ::snt Western blot analyses also detected reduced SHIP-1 activity, increased AKT-1 and BAD hyper-phosphorylation and up-regulation of BCL-2 expression in splenocytes from TB mice.
# ::save-date Sun Jan 17, 2016 ::file bel_pmid_2213_2131_40912.txt
(d / detect-01
      :ARG0 (a / analyze-01
            :manner (i2 / immunoblot-01))
      :ARG1 (a2 / and
            :op1 (a3 / activity-06
                  :ARG0 (p3 / protein :name (n2 / name :op1 "SHIP-1"))
                  :ARG1-of (r / reduce-01))
            :op2 (a4 / and
                  :op1 (h / hyperphosphorylate-01
                        :ARG1 (a5 / and
                              :op1 (e2 / enzyme :name (n3 / name :op1 "AKT-1"))
                              :op2 (p / protein :name (n4 / name :op1 "BAD")))
                        :ARG1-of (i / increase-01)))
            :op3 (u / upregulate-01
                  :ARG1 (e3 / express-03
                        :ARG2 (p2 / protein :name (n5 / name :op1 "BCL-2")))))
      :mod (a6 / also)
      :location (s / splenocyte
            :source (m / mouse
                  :ARG0-of (b / bear-01
                        :ARG1 (t / tumor)))))

# ::id bel_pmid_2213_2131.40914 ::date 2015-05-13T07:37:55 ::annotator SDL-AMR-09 ::preferred
# ::snt In vitro, qRT-PCR and Western blot analyses detected reduced SHIP-1 mRNA and protein expression in control splenocytes co-cultured with Panc 02.03 cells.
# ::save-date Sun Jan 3, 2016 ::file bel_pmid_2213_2131_40914.txt
(d / detect-01
      :ARG0 (a / and
            :op1 (a2 / analyze-01
                  :instrument (t / thing :name (n / name :op1 "qRT-PCR")))
            :op2 (a3 / analyze-01
                  :manner (i2 / immunoblot-01)))
      :ARG1 (a4 / and
            :op1 (e / express-03
                  :ARG1 (n6 / nucleic-acid :name (n3 / name :op1 "mRNA")
                        :ARG0-of (e2 / encode-01
                              :ARG1 (p / protein :name (n4 / name :op1 "SHIP-1")))))
            :op2 (e3 / express-03
                  :ARG2 p)
            :ARG1-of (r2 / reduce-01))
      :location (s / splenocyte
            :ARG2-of (c / control-01)
            :op1-of (a5 / and
                  :op2 (c3 / cell :name (n5 / name :op1 "Panc" :op2 "02.03"))
                  :ARG1-of (c2 / culture-01)))
      :manner (i / in-vitro))

# ::id bel_pmid_2213_2131.40918 ::date 2015-05-13T08:19:13 ::annotator SDL-AMR-09 ::preferred
# ::snt Results from the Inflammatory Cytometric Bead Analysis (CBA) Kit detected pro-inflammatory factors Interleukin-6 (IL-6), Interleukin-10 (IL-10) and Monocyte Chemoattractant Protein-1 (MCP-1) to a greater extent than Tumor Necrosis Factor (TNF), Interferon gamma (IFN-y and Interleukin-12p 70 (IL-12p70) in the supernatants of cultured murine Panc 02.03 cells (Figure 1a).
# ::save-date Sun Jan 3, 2016 ::file bel_pmid_2213_2131_40918.txt
(d / detect-01
      :ARG0 (t / thing
            :ARG2-of (r / result-01)
            :source (k / kit :name (n / name :op1 "Inflammatory" :op2 "Cytometric" :op3 "Bead" :op4 "Analysis")))
      :ARG1 (e / extent
            :mod (g / great
                  :degree (m / more))
            :domain (a / and
                  :op1 (p / protein :name (n2 / name :op1 "Interleukin-6"))
                  :op2 (p2 / protein :name (n3 / name :op1 "Interleukin-10"))
                  :op3 (p3 / protein :name (n4 / name :op1 "Monocyte" :op2 "Chemoattractant" :op3 "Protein-1"))
                  :ARG0-of (f8 / favor-01
                        :ARG1 (i2 / inflame-01)))
            :compared-to (a2 / and
                  :op1 (p4 / protein :name (n5 / name :op1 "Tumor" :op2 "Necrosis" :op3 "Factor"))
                  :op2 (p5 / protein :name (n6 / name :op1 "Interferon" :op2 "gamma"))
                  :op3 (p6 / protein :name (n7 / name :op1 "Interleukin-12p-70"))))
      :location (s / supernatant
            :part-of (c / cell :name (n8 / name :op1 "Panc" :op2 "02.03")
                  :part-of (o / organism :name (n9 / name :op1 "Muridae"))
                  :ARG1-of (c2 / culture-01)))
      :ARG1-of (d2 / describe-01
            :ARG0 (f7 / figure :mod "1a")))

# ::id bel_pmid_2213_2131.40920 ::date 2015-05-13T09:12:36 ::annotator SDL-AMR-09 ::preferred
# ::snt TB splenocytes have a reduction in SHIP-1 expression.
# ::save-date Fri May 22, 2015 ::file bel_pmid_2213_2131_40920.txt
(h / have-03
      :ARG0 (s / splenocyte
            :ARG0-of (b / bear-01
                  :ARG1 (t / tumor)))
      :ARG1 (r / reduce-01
            :ARG1 (e / express-03
                  :ARG2 (p / protein :name (n / name :op1 "SHIP-1")))))

# ::id bel_pmid_2213_2131.40922 ::date 2015-05-13T09:16:08 ::annotator SDL-AMR-09 ::preferred
# ::snt Quantitative Reverse Transcription Polymerase Chain Reaction (qRT-PCR) results detected a decrease in SHIP-1 mRNA expression in TB compared to control splenocytes (Figure 3b).
# ::save-date Fri May 22, 2015 ::file bel_pmid_2213_2131_40922.txt
(d / detect-01
      :ARG0 (t / thing
            :ARG2-of (r / result-01)
            :source (t2 / thing :name (n / name :op1 "Quantitative" :op2 "Reverse" :op3 "Transcription" :op4 "Polymerase" :op5 "Chain" :op6 "Reaction")))
      :ARG1 (d2 / decrease-01
            :ARG1 (e / express-03
                  :ARG1 (n4 / nucleic-acid :name (n2 / name :op1 "mRNA")
                        :ARG0-of (e2 / encode-01
                              :ARG1 (p / protein :name (n3 / name :op1 "SHIP-1")))))
            :location (s / splenocyte
                  :ARG0-of (b / bear-01
                        :ARG1 (t3 / tumor)))
            :compared-to (s2 / splenocyte
                  :ARG2-of (c / control-01)))
      :ARG1-of (d3 / describe-01
            :ARG0 (f / figure :mod "3b")))

# ::id bel_pmid_2213_2131.40924 ::date 2015-05-13T09:34:54 ::annotator SDL-AMR-09 ::preferred
# ::snt TB splenocytes have reduced SHIP-1 activity.
# ::save-date Sun Jan 17, 2016 ::file bel_pmid_2213_2131_40924.txt
(h / have-03
      :ARG0 (s / splenocyte
            :ARG0-of (b / bear-01
                  :ARG1 (t / tumor)))
      :ARG1 (a / activity-06
            :ARG1 (p / protein :name (n / name :op1 "SHIP-1"))
            :ARG1-of (r / reduce-01)))

# ::id bel_pmid_2213_2131.40926 ::date 2015-05-13T09:43:28 ::annotator SDL-AMR-09 ::preferred
# ::snt Western blot analyses did not detect phosphorylation of tyrosine 1020 on SHIP-1, in splenocytes from TB compared to control mice (Figure 4a).
# ::save-date Sun Dec 13, 2015 ::file bel_pmid_2213_2131_40926.txt
(d / detect-01 :polarity -
      :ARG0 (a / analyze-01
            :manner (i / immunoblot-01))
      :ARG1 (p / phosphorylate-01
            :ARG1 (a2 / amino-acid :mod 1020 :name (n2 / name :op1 "tyrosine")
                  :part-of (p2 / protein :name (n3 / name :op1 "SHIP-1")))
            :location (s / splenocyte
                  :source (m / mouse
                        :ARG0-of (b / bear-01
                              :ARG1 (t / tumor)))
                  :compared-to (s2 / splenocyte
                        :source (m2 / mouse
                              :ARG2-of (c / control-01)))))
      :ARG1-of (d2 / describe-01
            :ARG0 (f / figure :mod "4a")))

# ::id bel_pmid_2213_2131.40928 ::date 2015-05-13T11:01:25 ::annotator SDL-AMR-09 ::preferred
# ::snt TB splenocytes have increased AKT activity.
# ::save-date Mon Jul 6, 2015 ::file bel_pmid_2213_2131_40928.txt
(h / have-03
      :ARG0 (s / splenocyte
            :ARG0-of (b / bear-01
                  :ARG1 (t / tumor)))
      :ARG1 (a / activity-06
            :ARG1 (e / enzyme :name (n / name :op1 "AKT"))
            :ARG1-of (i / increase-01)))

# ::id bel_pmid_2213_2131.40930 ::date 2015-05-13T11:07:01 ::annotator SDL-AMR-09 ::preferred
# ::snt Western Blot results revealed hyper-phosphorylation of AKT-1 at Ser473 in whole splenocytes from TB compared to control mice (Figure 4b).
# ::save-date Thu Dec 17, 2015 ::file bel_pmid_2213_2131_40930.txt
(r / reveal-01
      :ARG0 (t / thing
            :ARG2-of (r2 / result-01
                  :ARG1 (i / immunoblot-01)))
      :ARG1 (h / hyperphosphorylate-01
            :ARG1 (e / enzyme :name (n3 / name :op1 "AKT-1")
                  :part (a / amino-acid :mod 473 :name (n2 / name :op1 "serine")))
            :location (s / splenocyte
                  :mod (w / whole)
                  :source (m / mouse
                        :ARG0-of (b / bear-01
                              :ARG1 (t3 / tumor))))
            :compared-to (s2 / splenocyte
                  :source (m2 / mouse
                        :ARG2-of (c / control-01))))
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod "4b")))

# ::id bel_pmid_2213_2131.40932 ::date 2015-05-13T12:50:40 ::annotator SDL-AMR-09 ::preferred
# ::snt TB splenocytes have increased BCL-2 expression.
# ::save-date Fri May 22, 2015 ::file bel_pmid_2213_2131_40932.txt
(h / have-03
      :ARG0 (s / splenocyte
            :ARG0-of (b / bear-01
                  :ARG1 (t / tumor)))
      :ARG1 (e / express-03
            :ARG2 (p / protein :name (n / name :op1 "BCL-2"))
            :ARG1-of (i / increase-01)))

# ::id bel_pmid_2213_2131.40934 ::date 2015-05-13T12:59:13 ::annotator SDL-AMR-09 ::preferred
# ::snt Western Blot results showed hyperphosphorylation of BAD at Ser112 in splenocytes from TB mice compared to control mice (Figure 4c).
# ::save-date Thu Dec 17, 2015 ::file bel_pmid_2213_2131_40934.txt
(s / show-01
      :ARG0 (t / thing
            :ARG2-of (r / result-01
                  :ARG1 (i / immunoblot-01)))
      :ARG1 (h / hyperphosphorylate-01
            :ARG1 (p / protein :name (n / name :op1 "BAD")
                  :part (a / amino-acid :mod 112 :name (n2 / name :op1 "serine")))
            :location (s2 / splenocyte
                  :source (m / mouse
                        :ARG0-of (b / bear-01
                              :ARG1 (t3 / tumor))))
            :compared-to (s3 / splenocyte
                  :source (m2 / mouse
                        :ARG2-of (c / control-01))))
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod "4c")))

# ::id bel_pmid_2213_2131.40936 ::date 2015-05-13T14:10:14 ::annotator SDL-AMR-09 ::preferred
# ::snt Western blot results revealed an up-regulation in BCL-2 expression in splenocytes from TB mice (Figure 4d) compared to control.
# ::save-date Sun Dec 13, 2015 ::file bel_pmid_2213_2131_40936.txt
(r / reveal-01
      :ARG0 (t / thing
            :ARG2-of (r2 / result-01
                  :ARG1 (i / immunoblot-01)))
      :ARG1 (u / upregulate-01
            :ARG1 (e / express-03
                  :ARG2 (p / protein :name (n2 / name :op1 "BCL-2")))
            :location (s / splenocyte
                  :source (m / mouse
                        :ARG0-of (b / bear-01
                              :ARG1 (t3 / tumor)))
                  :ARG1-of (d / describe-01
                        :ARG0 (f / figure :mod "4d")))
            :compared-to (s2 / splenocyte
                  :source (m2 / mouse
                        :ARG2-of (c / control-01)))))

# ::id bel_pmid_2213_2131.40938 ::date 2015-05-13T14:25:37 ::annotator SDL-AMR-09 ::preferred
# ::snt Murine Panc 02.03 cells down-regulate SHIP-1 expression in vitro.
# ::save-date Wed May 13, 2015 ::file bel_pmid_2213_2131_40938.txt
(d / downregulate-01
      :ARG0 (c / cell :name (n / name :op1 "Panc" :op2 "02.03")
            :part-of (o / organism :name (n2 / name :op1 "Muridae")))
      :ARG1 (e / express-03
            :ARG2 (p / protein :name (n3 / name :op1 "SHIP-1")))
      :manner (i / in-vitro))

# ::id bel_pmid_2213_2131.40940 ::date 2015-05-13T14:30:13 ::annotator SDL-AMR-09 ::preferred
# ::snt qRT-PCR analysis revealed a significant decrease in SHIP-1 mRNA expression in control splenocytes co-cultured with Panc 02.03 cells compared to control splenocytes cultured alone (Figure 5a).
# ::save-date Sun Jan 3, 2016 ::file bel_pmid_2213_2131_40940.txt
(r / reveal-01
      :ARG0 (a / analyze-01
            :instrument (t / thing :name (n6 / name :op1 "qRT-PCR")))
      :ARG1 (d / decrease-01
            :ARG1 (e / express-03
                  :ARG1 (n5 / nucleic-acid :name (n2 / name :op1 "mRNA")
                        :ARG0-of (e2 / encode-01
                              :ARG1 (p / protein :name (n3 / name :op1 "SHIP-1")))))
            :ARG2 (s / significant-02)
            :location (s2 / splenocyte
                  :ARG2-of (c / control-01)
                  :op1-of (a3 / and
                        :op2 (c3 / cell :name (n4 / name :op1 "Panc" :op2 "02.03"))
                        :ARG1-of (c2 / culture-01)))
            :compared-to (s3 / splenocyte
                  :ARG2-of c
                  :ARG1-of (c4 / culture-01
                        :manner (a2 / alone))))
      :ARG1-of (d2 / describe-01
            :ARG0 (f / figure :mod "5a")))

# ::id bel_pmid_2213_2131.40942 ::date 2015-05-13T14:48:28 ::annotator SDL-AMR-09 ::preferred
# ::snt In addition, western blot results revealed greater than a a 2-fold reduction in SHIP-1 protein expression in control splenocytes cocultured with Panc 02.03 cells compared to control splenocytes cultured alone (Figure 5b).
# ::save-date Sun Jan 3, 2016 ::file bel_pmid_2213_2131_40942.txt
(a / and
      :op2 (r / reveal-01
            :ARG0 (t / thing
                  :ARG2-of (r2 / result-01
                        :ARG1 (i / immunoblot-01)))
            :ARG1 (r3 / reduce-01
                  :ARG1 (e / express-03
                        :ARG2 (p / protein :name (n2 / name :op1 "SHIP-1")))
                  :ARG2 (g / great
                        :degree (m / more)
                        :compared-to (p2 / product-of :op1 2))
                  :location (s / splenocyte
                        :ARG2-of (c / control-01)
                        :compared-to (s2 / splenocyte
                              :ARG1-of (c4 / culture-01
                                    :manner (a2 / alone)))
                        :op1-of (a3 / and
                              :op2 (c3 / cell :name (n3 / name :op1 "Panc" :op2 "02.03"))
                              :ARG1-of (c2 / culture-01)))))
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod "5b")))

# ::id bel_pmid_2213_2131.40944 ::date 2015-05-14T10:57:24 ::annotator SDL-AMR-09 ::preferred
# ::snt These results correlate with our in vivo data and show that Panc 02.03 cells are able to suppress SHIP-1 mRNA and protein expression in vitro.
# ::save-date Fri May 22, 2015 ::file bel_pmid_2213_2131_40944.txt
(a / and
      :op1 (c / correlate-01
            :ARG1 (t / thing
                  :ARG2-of (r / result-01)
                  :mod (t2 / this))
            :ARG2 (d / data
                  :manner (i / in-vivo)
                  :poss (w / we)))
      :op2 (s / show-01
            :ARG0 t
            :ARG1 (p / possible-01
                  :ARG1 (s2 / suppress-01
                        :ARG0 (c2 / cell :name (n / name :op1 "Panc" :op2 "02.03"))
                        :ARG1 (a2 / and
                              :op1 (e / express-03
                                    :ARG2 (n4 / nucleic-acid :name (n2 / name :op1 "mRNA")
                                          :ARG0-of (e2 / encode-01
                                                :ARG1 (p2 / protein :name (n3 / name :op1 "SHIP-1")))))
                              :op2 (e3 / express-03
                                    :ARG2 p2))
                        :manner (i2 / in-vitro)))))

# ::id bel_pmid_2219_4859.25580 ::date 2015-05-14T11:06:14 ::annotator SDL-AMR-09 ::preferred
# ::snt In WT mice CH induced an approximate 2-fold increase in IL-6 mRNA at three weeks that was abrogated in C3 -/- mice... We observed increases in lung intracellular adhesion molecule 1 (ICAM-1)...the increase in ICAM-1 was abrogated in C3 -/- mice (Fig. 7).
# ::save-date Sun Dec 20, 2015 ::file bel_pmid_2219_4859_25580.txt
(m / multi-sentence
      :snt1 (i / induce-01
            :ARG0 (m7 / medical-condition :name (n / name :op1 "chronic" :op2 "hypoxia"))
            :ARG2 (a / approximately
                  :op1 (p / product-of :op1 2)
                  :op2 (i2 / increase-01
                        :ARG1 (n8 / nucleic-acid :name (n2 / name :op1 "mRNA")
                              :ARG0-of (e / encode-01
                                    :ARG1 (p2 / protein :name (n3 / name :op1 "IL-6"))))
                        :ARG1-of (a2 / abrogate-01
                              :location (m2 / mouse
                                    :mod (p3 / protein :name (n4 / name :op1 "C3")
                                          :ARG2-of (m3 / mutate-01 :mod "-/-"))))
                        :time (a4 / after
                              :op1 (t / temporal-quantity :quant 3
                                    :unit (w / week)))))
            :location (m4 / mouse
                  :mod (w2 / wild-type)))
      :snt2 (o / observe-01
            :ARG0 (w3 / we)
            :ARG1 (i3 / increase-01
                  :ARG1 (p4 / protein :name (n5 / name :op1 "intracellular" :op2 "adhesion" :op3 "molecule-1")
                        :part-of (l / lung))))
      :snt3 (a3 / abrogate-01
            :ARG1 (i4 / increase-01
                  :ARG1 (p5 / protein :name (n6 / name :op1 "ICAM-1")))
            :location (m5 / mouse
                  :mod (p6 / protein :name (n7 / name :op1 "C3")
                        :ARG2-of (m6 / mutate-01 :mod "-/-"))))
      :ARG1-of (d2 / describe-01
            :ARG0 (f / figure :mod 7)))

# ::id bel_pmid_2220_9329.1840 ::date 2015-05-14T12:41:37 ::annotator SDL-AMR-09 ::preferred
# ::snt This Raf-1-mediated fine tuning of Rok-a signaling allows the activation of junctional myosin and the timely maturation of AJ essential for maintaining cell cohesion during sprouting angiogenesis
# ::save-date Mon Dec 21, 2015 ::file bel_pmid_2220_9329_1840.txt
(a / allow-01
      :ARG0 (f2 / finetune-01
            :ARG1 (s / signal-07
                  :ARG0 (e / enzyme :name (n / name :op1 "Rok-α")))
            :ARG1-of (m / mediate-01
                  :ARG0 (e2 / enzyme :name (n2 / name :op1 "Raf-1")))
            :mod (t2 / this))
      :ARG1 (a2 / and
            :op1 (a3 / activate-01
                  :ARG1 (p / protein :name (n3 / name :op1 "myosin")
                        :mod (j / junctional)))
            :op2 (m2 / maturate-03
                  :ARG1 (p2 / protein :name (n4 / name :op1 "AJ"))
                  :ARG1-of (t3 / timely-03))
            :mod (e3 / essential
                  :purpose (m3 / maintain-01
                        :ARG1 (c / cohere-01
                              :ARG1 (c2 / cell))
                        :time (a4 / angiogenesis
                              :ARG1-of (s2 / sprout-01))))))

# ::id bel_pmid_2226_7479.1138 ::date 2015-05-14T13:15:36 ::annotator SDL-AMR-09 ::preferred
# ::snt In TLR2 agonist, heat-killed Listeria monocytogenes-activated human monocytes, NA reduced secretion of TNF-? (by 48.6±7.1%), interleukin-6 (by 60.9±1.6%), and monocyte chemoattractant protein-1 (by 59.3±5.3%)
# ::save-date Sat Feb 13, 2016 ::file bel_pmid_2226_7479_1138.txt
(a / and
      :op1 (r / reduce-01
            :ARG0 (s7 / small-molecule :name (n / name :op1 "NA"))
            :ARG1 (s / secrete-01
                  :ARG1 (p / protein :name (n2 / name :op1 "TNF-α")))
            :ARG2 (o / or
                  :op1 (p4 / percentage-entity :value 48.6
                        :ARG2-of (a3 / add-02
                              :ARG1 (p5 / percentage-entity :value 7.1)))
                  :op2 (p6 / percentage-entity :value 48.6
                        :ARG2-of (s2 / subtract-01
                              :ARG1 p5))))
      :op2 (r2 / reduce-01
            :ARG0 s7
            :ARG1 (s5 / secrete-01
                  :ARG1 (p2 / protein :name (n3 / name :op1 "interleukin-6")))
            :ARG2 (o3 / or
                  :op1 (p7 / percentage-entity :value 60.9
                        :ARG2-of (a4 / add-02
                              :ARG1 (p8 / percentage-entity :value 1.6)))
                  :op2 (p9 / percentage-entity :value 60.9
                        :ARG2-of (s3 / subtract-01
                              :ARG1 p8))))
      :op3 (r3 / reduce-01
            :ARG0 s7
            :ARG1 (s6 / secrete-01
                  :ARG1 (p3 / protein :name (n4 / name :op1 "monocyte" :op2 "chemoattractant" :op3 "protein-1")))
            :ARG2 (o4 / or
                  :op1 (p10 / percentage-entity :value 59.3
                        :ARG2-of (a5 / add-02
                              :ARG1 (p11 / percentage-entity :value 5.3)))
                  :op2 (p12 / percentage-entity :value 59.3
                        :ARG2-of (s4 / subtract-01
                              :ARG1 p11))))
      :location (a6 / agonist :name (n5 / name :op1 "TLR2")
            :mod (c / cell :name (n6 / name :op1 "monocyte")
                  :part-of (h / human)
                  :ARG1-of (a7 / activate-01
                        :ARG0 (o2 / organism :name (n7 / name :op1 "Listeria" :op2 "monocytogene")
                              :ARG1-of (k / kill-01
                                    :ARG0 (h2 / heat-01)))))))

# ::id bel_pmid_2236_7719.24892 ::date 2015-05-14T13:46:39 ::annotator SDL-AMR-09 ::preferred
# ::snt Cytokine determination within BAL fluid revealed that LPS challenged Tie2-adam17 -/- mice showed reduced release of IL-6 (Fig 7A, 3.9-fold) and TNF-a (Fig 7B, 1.6-fold), whereas no effect was observed in PBS-challenged mice.
# ::save-date Sat Feb 13, 2016 ::file bel_pmid_2236_7719_24892.txt
(r / reveal-01
      :ARG0 (d / determine-01
            :ARG1 (c / cytokine)
            :location (f / fluid
                  :mod (l / lavage
                        :mod (a3 / alveolus
                              :mod (b / bronchus)))))
      :ARG1 (c2 / contrast-01
            :ARG1 (s / show-01
                  :ARG0 (m / mouse
                        :mod (e / enzyme :name (n2 / name :op1 "Tie2-adam17")
                              :ARG2-of (m2 / mutate-01 :mod "-/-"))
                        :ARG1-of (c3 / challenge-01
                              :ARG0 (m3 / molecular-physical-entity :name (n3 / name :op1 "LPS"))))
                  :ARG1 (r2 / release-01
                        :ARG1 (a / and
                              :op1 (p / protein :name (n4 / name :op1 "IL-6")
                                    :ARG1-of (r3 / reduce-01
                                          :ARG2 (p2 / product-of :op1 3.9))
                                    :ARG1-of (d2 / describe-01
                                          :ARG0 (f2 / figure :mod "7A")))
                              :op2 (p3 / protein :name (n5 / name :op1 "TNF-α")
                                    :ARG1-of (r4 / reduce-01
                                          :ARG2 (p4 / product-of :op1 1.6))
                                    :ARG1-of (d3 / describe-01
                                          :ARG0 (f3 / figure :mod "7B"))))))
            :ARG2 (o / observe-01 :polarity -
                  :ARG1 (a2 / affect-01)
                  :location (m4 / mouse
                        :ARG1-of (c4 / challenge-01
                              :ARG0 (s2 / small-molecule :name (n6 / name :op1 "PBS")))))))

# ::id bel_pmid_2243_8032.25776 ::date 2015-05-14T21:27:36 ::annotator SDL-AMR-09 ::preferred
# ::snt . The concentration of IL-6, IL-13 and IL-17 was significantly higher in KO mice relative to wild-type mice, while that of IL-12 was significantly higher in wild-type mice relative to KO mice.
# ::save-date Fri Dec 18, 2015 ::file bel_pmid_2243_8032_25776.txt
(c / contrast-01
      :ARG1 (h / high-02
            :ARG1 (c2 / concentrate-02
                  :ARG1 (a / and
                        :op1 (p / protein :name (n / name :op1 "IL-6"))
                        :op2 (p2 / protein :name (n2 / name :op1 "IL-13"))
                        :op3 (p3 / protein :name (n3 / name :op1 "IL-17"))))
            :degree (m / more)
            :location (m2 / mouse
                  :location-of (k / knock-out-03))
            :ARG2-of (r / relative-05
                  :ARG3 (m3 / mouse
                        :mod (w / wild-type)))
            :ARG1-of (s / significant-02))
      :ARG2 (h2 / high-02
            :ARG1 (c3 / concentrate-02
                  :ARG1 (p4 / protein :name (n4 / name :op1 "IL-12")))
            :degree m
            :location m3
            :ARG2-of (r2 / relative-05
                  :ARG3 m2)))

# ::id bel_pmid_2243_8032.25784 ::date 2015-05-14T21:44:37 ::annotator SDL-AMR-09 ::preferred
# ::snt the expression of tissue damage-related proteins, TGF-? and mesothelin was more markedly increased in the lungs of KO mice relative to wild-type mice.
# ::save-date Mon Jan 4, 2016 ::file bel_pmid_2243_8032_25784.txt
(i / increase-01
      :ARG1 (e / express-03
            :ARG2 (a / and
                  :op1 (p / protein :name (n / name :op1 "TGF-βl"))
                  :op2 (p2 / protein :name (n2 / name :op1 "mesothelin"))
                  :ARG1-of (r / relate-01
                        :ARG2 (d / damage-01
                              :ARG1 (t / tissue)))))
      :ARG2 (m / marked
            :degree (m2 / more))
      :location (l / lung
            :part-of (m3 / mouse
                  :ARG1-of (k / knock-out-03)))
      :ARG2-of (r2 / relative-05
            :ARG3 (m4 / mouse
                  :mod (w / wild-type))))

# ::id bel_pmid_2254_4933.40994 ::date 2015-05-12T11:37:40 ::annotator SDL-AMR-09 ::preferred
# ::snt In this study, we identified microRNA-494 (miR-494), whose expression was dramatically induced by tumor-derived factors, as an essential player in regulating the accumulation and activity of MDSCs by targeting of phosphatase and tensin homolog (PTEN) and activation of the Akt pathway.
# ::save-date Mon Jan 4, 2016 ::file bel_pmid_2254_4933_40994.txt
(i / identify-01
      :ARG0 (w / we)
      :ARG1 (n4 / nucleic-acid :name (n / name :op1 "RNA-494")
            :mod (m / micro)
            :ARG2-of (e / express-03
                  :ARG2-of (i2 / induce-01
                        :ARG0 (f / factor
                              :ARG1-of (d2 / derive-01
                                    :ARG2 (t3 / tumor)))
                        :manner (d / dramatic)
                        :manner (p / play-08
                              :ARG0 e
                              :ARG1 (r2 / regulate-01
                                    :ARG1 (a / and
                                          :op1 (a2 / accumulate-01
                                                :ARG1 (c / cell :name (n3 / name :op1 "MDSC")))
                                          :op2 (a3 / activity-06
                                                :ARG0 c))
                                    :manner (a5 / and
                                          :op1 (t2 / target-01
                                                :ARG0 e
                                                :ARG1 (p3 / protein :name (n2 / name :op1 "phosphatase" :op2 "and" :op3 "tensin" :op4 "homolog")
                                                      :ARG1-of (m2 / mean-01
                                                            :ARG2 (p5 / protein :name (n7 / name :op1 "PTEN")))))
                                          :op2 (a6 / activate-01
                                                :ARG0 e
                                                :ARG1 (p2 / pathway :name (n6 / name :op1 "Akt")))))
                              :mod (e3 / essential)))))
      :medium (s / study-01
            :mod (t / this)))

# ::id bel_pmid_2254_4933.41002 ::date 2015-05-13T11:51:56 ::annotator SDL-AMR-09 ::preferred
# ::snt miR-494 is highly expressed in tumor-expanded MDSCs.
# ::save-date Mon Dec 21, 2015 ::file bel_pmid_2254_4933_41002.txt
(e / express-03
      :ARG2 (n3 / nucleic-acid :name (n / name :op1 "miR-494"))
      :ARG3 (c / cell :name (n2 / name :op1 "MDSC")
            :ARG1-of (e2 / expand-01
                  :ARG0 (t / tumor)))
      :ARG1-of (h / high-02))

# ::id bel_pmid_2254_4933.41006 ::date 2015-05-13T11:57:58 ::annotator SDL-AMR-09 ::preferred
# ::snt As shown in Fig. 1C, significantly increased expression of miR-494 was detected in both subpopulations compared with their counterpart from tumor-free mice (granulocytic MDSCs, p < 0.01; monocytic MDSCs, p < 0.001).
# ::save-date Sat Jan 2, 2016 ::file bel_pmid_2254_4933_41006.txt
(a2 / and
      :op1 (d / detect-01
            :ARG1 (e / express-03
                  :ARG2 (n4 / nucleic-acid :name (n / name :op1 "miR-494"))
                  :ARG1-of (i / increase-01
                        :ARG2 (s2 / significant-02)))
            :location (c2 / cell :name (n2 / name :op1 "MDSC")
                  :mod (g / granulocytic))
            :ARG1-of (s4 / statistical-test-91
                  :ARG2 (l / less-than :op1 0.01)))
      :op2 (d2 / detect-01
            :ARG1 e
            :location (c3 / cell :name (n3 / name :op1 "MDSC")
                  :mod (m3 / monocytic))
            :ARG1-of (s5 / statistical-test-91
                  :ARG2 (l2 / less-than :op1 0.001)))
      :ARG1-of (s / show-01
            :ARG0 (f / figure :mod "1C"))
      :compared-to (c / counterpart
            :location (m / mouse
                  :ARG1-of (f2 / free-04
                        :ARG2 (t / tumor)))
            :poss (a / and
                  :op1 c2
                  :op2 c3)))

# ::id bel_pmid_2254_4933.41010 ::date 2015-05-14T00:28:57 ::annotator SDL-AMR-09 ::preferred
# ::snt Tumor-derived factors, especially TG'F-fH, markedly induce the upregulation of miR-494 in MDSCs.
# ::save-date Sun Dec 20, 2015 ::file bel_pmid_2254_4933_41010.txt
(i / induce-01
      :ARG0 (f / factor
            :example (p2 / protein :name (n2 / name :op1 "TG'F-fH")
                  :manner (e / especially))
            :ARG1-of (d / derive-01
                  :ARG2 (t / tumor)))
      :ARG2 (u / upregulate-01
            :ARG1 (n / nucleic-acid :name (n3 / name :op1 "miR-494"))
            :location (c / cell :name (n4 / name :op1 "MDSC")))
      :manner (m / marked))

# ::id bel_pmid_2254_4933.41012 ::date 2015-05-14T00:36:33 ::annotator SDL-AMR-09 ::preferred
# ::snt As expected, we found that miR-494 expression was significantly induced by TCCM in a dose-dependent manner (Fig. 2A).
# ::save-date Sat Jan 2, 2016 ::file bel_pmid_2254_4933_41012.txt
(f / find-01
      :ARG0 (w / we)
      :ARG1 (i / induce-01
            :ARG2 (e2 / express-03
                  :ARG1 (t / thing :name (n2 / name :op1 "TCCM"))
                  :ARG2 (n3 / nucleic-acid :name (n / name :op1 "miR-494")))
            :ARG0-of (d / depend-01
                  :ARG1 (d2 / dose-01))
            :manner (s / significant-02))
      :ARG1-of (e / expect-01)
      :ARG1-of (d3 / describe-01
            :ARG0 (f2 / figure :mod "2A")))

# ::id bel_pmid_2254_4933.41014 ::date 2015-05-13T13:24:22 ::annotator SDL-AMR-09 ::preferred
# ::snt As shown in Fig. 2B, we found that the expression of miR-494 in Gr-1+ CD11b+ cells was not affected by GM-CSF and IL-6, but interestingly, miR-494 expression was significantly induced by TGF-b1 treatment (p < 0.001).
# ::save-date Sun Dec 20, 2015 ::file bel_pmid_2254_4933_41014.txt
(f / find-01
      :ARG0 (w / we)
      :ARG1 (c / contrast-01
            :ARG1 (a / affect-01 :polarity -
                  :ARG0 (a2 / and
                        :op1 (p3 / protein :name (n4 / name :op1 "GM-CSF"))
                        :op2 (p4 / protein :name (n5 / name :op1 "IL-6")))
                  :ARG1 (e / express-03
                        :ARG2 (n7 / nucleic-acid :name (n / name :op1 "miR-494"))
                        :ARG3 (c2 / cell
                              :mod (p / protein :name (n2 / name :op1 "Gr-1+"))
                              :mod (p2 / protein :name (n3 / name :op1 "CD11b+"))))
                  :ARG1-of (s3 / statistical-test-91
                        :ARG2 (l / less-than :op1 0.001)))
            :ARG2 (i / induce-01
                  :ARG0 (t / treat-04
                        :ARG2 (p5 / protein :name (n6 / name :op1 "TGF-b1")))
                  :ARG2 e
                  :ARG2-of (i2 / interest-01)
                  :ARG1-of (s2 / significant-02)))
      :ARG1-of (s / show-01
            :ARG0 (f2 / figure :mod "2B")))

# ::id bel_pmid_2254_4933.41016 ::date 2015-05-13T13:45:05 ::annotator SDL-AMR-09 ::preferred
# ::snt Moreover, the induction of miR-494 was partially blocked by anti-TGF-p1 mAb in cells stimulated with 4T1 TCCM (Fig. 2C), and the upregulation of miR-494 was impaired in Smad 3-deficient Gr-1+ CD11b+ cells isolated from the spleen of Smad 3_/_ mice (Fig. 2D).
# ::save-date Wed Jan 13, 2016 ::file bel_pmid_2254_4933_41016.txt
(a / and
      :op2 (a2 / and
            :op1 (b / block-01
                  :ARG0 (p2 / protein :name (n2 / name :op1 "TGF-p1")
                        :ARG1-of (c / counter-01
                              :ARG0 (a4 / antidoby)))
                  :ARG1 (i2 / induct-02
                        :ARG1 (n9 / nucleic-acid :name (n / name :op1 "miR-494")))
                  :degree (p / part)
                  :location (c2 / cell
                        :ARG1-of (s / stimulate-01
                              :ARG2 (c5 / cell-line :name (n8 / name :op1 "4T1")
                                    :part-of (t / thing :name (n4 / name :op1 "TCCM")))))
                  :ARG1-of (d / describe-01
                        :ARG0 (f / figure :mod "2C")))
            :op2 (i / impair-01
                  :ARG1 (u / upregulate-01
                        :ARG1 n9)
                  :location (c3 / cell
                        :ARG1-of (i3 / isolate-01
                              :ARG2 (s2 / spleen
                                    :part-of (m2 / mouse
                                          :mod (p6 / protein :name (n5 / name :op1 "Smad" :op2 "3")
                                                :ARG2-of (m3 / mutate-01 :mod "-/-"))))))
                  :ARG1-of (d2 / describe-01
                        :ARG0 (f2 / figure :mod "2D"))
                  :location (a3 / and
                        :op1 (c6 / cell
                              :mod (p4 / protein :name (n6 / name :op1 "Gr-1+")))
                        :op2 (c7 / cell
                              :mod (p3 / protein :name (n3 / name :op1 "CD11b+")))
                        :ARG0-of (l / lack-01
                              :ARG1 p6)))))

# ::id bel_pmid_2254_4933.41022 ::date 2015-05-13T14:14:49 ::annotator SDL-AMR-09 ::preferred
# ::snt As expected, the expression levels of ARG1, MMP2, MMP13, and MMP14 were significantly upregulated in lv-494-infected MDSCs compared with those in lv-ctrl-infected MDSCs (Fig. 4B); moreover, lv-sponge overtly blocked the induction in the expression of these molecules.
# ::save-date Sat Feb 13, 2016 ::file bel_pmid_2254_4933_41022.txt
(a / and
      :op1 (u / upregulate-01
            :ARG1 (l2 / level
                  :degree-of (e3 / express-03
                        :ARG2 (a3 / and
                              :op1 (e4 / enzyme :name (n / name :op1 "ARG1"))
                              :op2 (e5 / enzyme :name (n2 / name :op1 "MMP2"))
                              :op3 (e6 / enzyme :name (n3 / name :op1 "MMP13"))
                              :op4 (e7 / enzyme :name (n4 / name :op1 "MMP14")))))
            :ARG1-of (e2 / expect-01)
            :ARG1-of (s / significant-02)
            :location (c / cell :name (n5 / name :op1 "MDSC")
                  :ARG1-of (i2 / infect-01
                        :ARG0 (s2 / small-molecule :name (n6 / name :op1 "lv-494"))))
            :compared-to (l4 / level
                  :location (c2 / cell :name (n7 / name :op1 "MDSC")
                        :ARG1-of (i3 / infect-01
                              :ARG0 (s4 / small-molecule :name (n8 / name :op1 "lv-ctrl"))))
                  :degree-of e3)
            :ARG1-of (d3 / describe-01
                  :ARG0 (f / figure :mod "4B")))
      :op2 (a2 / and
            :op2 (b / block-01
                  :ARG0 (s3 / small-molecule :name (n9 / name :op1 "lv-sponge"))
                  :ARG1 (i / induce-01
                        :ARG2 (e / express-03
                              :ARG1 a3))
                  :manner (o / overt))))

# ::id bel_pmid_2254_4933.41028 ::date 2015-05-13T13:35:27 ::annotator SDL-AMR-09 ::preferred
# ::snt As shown in Fig. 4G, OT-1 CD8+ T cell proliferation was significantly suppressed by lv-494-infected MDSCs in comparison with lv-ctrl-infected MDSCs, and this suppressive activity could be partially blocked by an ARG1 inhibitor nor-NOHA.
# ::save-date Sat Feb 13, 2016 ::file bel_pmid_2254_4933_41028.txt
(a / and
      :op1 (s / suppress-01
            :ARG0 (c4 / cell :name (n6 / name :op1 "MDSC")
                  :ARG1-of (i2 / infect-01
                        :ARG0 (s5 / small-molecule :name (n7 / name :op1 "lv-494"))))
            :ARG1 (p2 / proliferate-01
                  :ARG0 (c / cell :name (n3 / name :op1 "T" :op2 "cell")
                        :source (o / organism :name (n4 / name :op1 "OT-1"))
                        :mod (p4 / protein :name (n5 / name :op1 "CD8")
                              :mod (p5 / positive))))
            :ARG1-of (s2 / significant-02)
            :compared-to (c5 / cell :name (n8 / name :op1 "MDSC")
                  :ARG1-of (i3 / infect-01
                        :ARG0 (s4 / small-molecule :name (n9 / name :op1 "lv-ctrl")))))
      :op2 (p3 / possible-01
            :ARG1 (b / block-01
                  :ARG0 (s6 / small-molecule :name (n / name :op1 "Nor-NOHA")
                        :ARG0-of (i / inhibit-01
                              :ARG1 (e / enzyme :name (n2 / name :op1 "ARG1"))))
                  :ARG1 s
                  :degree (p / part)))
      :ARG1-of (s3 / show-01
            :ARG0 (f / figure :mod "4G")))

# ::id bel_pmid_2254_4933.41038 ::date 2015-05-13T14:41:06 ::annotator SDL-AMR-09 ::preferred
# ::snt Notably, the PTEN protein level was significantly downregulated in tumor-expanded MDSCs compared with that in Gr-1+ CD11b+ cells from tumor-free mice, whereas PTEN mRNA expression showed no difference (Fig. 6A).
# ::save-date Fri Dec 18, 2015 ::file bel_pmid_2254_4933_41038.txt
(c / contrast-01
      :ARG1 (d2 / downregulate-01
            :ARG1 (l / level
                  :quant-of (p / protein :name (n / name :op1 "PTEN")))
            :ARG1-of (s / significant-02)
            :location (c2 / cell :name (n2 / name :op1 "MDSC")
                  :ARG1-of (e / expand-01
                        :ARG0 (t / tumor)))
            :compared-to (l2 / level
                  :location (c3 / cell
                        :source (m / mouse
                              :ARG1-of (f2 / free-04
                                    :ARG2 t))
                        :ARG1-of (m2 / mutate-01
                              :ARG2 (a / and
                                    :op1 (p2 / protein :name (n3 / name :op1 "Gr-1+"))
                                    :op2 (p3 / protein :name (n4 / name :op1 "CD11b+")))))
                  :degree-of p))
      :ARG2 (s2 / show-01 :polarity -
            :ARG0 (e2 / express-03
                  :ARG2 (n7 / nucleic-acid :name (n5 / name :op1 "mRNA")
                        :mod p))
            :ARG1 (d3 / differ-02))
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod "6A"))
      :ARG1-of (n6 / notable-04))

# ::id bel_pmid_2254_4933.41040 ::date 2015-05-14T00:09:54 ::annotator SDL-AMR-09 ::preferred
# ::snt When the reporter plasmids with miR-494 mimics or the scrambled oligonucleotide were cotransfected to HEK-293 cells, we observed that the miR-494 mimics markedly decreased the luciferase activity (Fig. 6B).
# ::save-date Thu Dec 17, 2015 ::file bel_pmid_2254_4933_41040.txt
(o / observe-01
      :ARG0 (w / we)
      :ARG1 (d / decrease-01
            :ARG0 (m2 / mimic-01
                  :ARG1 (n3 / nucleic-acid :name (n / name :op1 "miR-494")))
            :ARG1 (a / activity-06
                  :ARG0 (l / luciferase))
            :manner (m / marked))
      :ARG1-of (d2 / describe-01
            :ARG0 (f / figure :mod "6B"))
      :time (c / cotransfect-01
            :ARG1 (c2 / cell :name (n2 / name :op1 "HEK-293"))
            :ARG2 (o2 / or
                  :op1 (p / plasmid
                        :instrument m2
                        :ARG0-of (r2 / report-01))
                  :op2 (o3 / oligonucleotide
                        :ARG1-of (s / scramble-02)))))

# ::id bel_pmid_2254_4933.41042 ::date 2015-05-14T00:16:11 ::annotator SDL-AMR-09 ::preferred
# ::snt Furthermore, transfection of lv-494 significantly decreased PTEN expression in MDSCs, thus suggesting that endogenous PTEN is targeted and regulated by miR-494 (Fig. 6C).. To confirm whether miR-494-induced activation of MDSCs was mediated by targeting of PTEN expression, we designed a lentiviral vector encoding 39-UTR-depleted PTEN to enforce the expression of PTEN in MDSCs.
# ::save-date Sat Feb 13, 2016 ::file bel_pmid_2254_4933_41042.txt
(m / multi-sentence
      :snt1 (a / and
            :op2 (d2 / decrease-01
                  :ARG0 (t / transfect-01
                        :ARG2 (s3 / small-molecule :name (n / name :op1 "lv-494")))
                  :ARG1 (e / express-03
                        :ARG2 p2
                        :ARG3 (c / cell :name (n3 / name :op1 "MDSC")))
                  :ARG1-of (s / significant-02)
                  :ARG0-of (s2 / suggest-01
                        :ARG1 (a2 / and
                              :op1 (t2 / target-01
                                    :ARG0 (n9 / nucleic-acid :name (n4 / name :op1 "miR-494"))
                                    :ARG1 (p2 / protein :name (n5 / name :op1 "PTEN")
                                          :mod (m2 / monocot)))
                              :op2 (r / regulate-01
                                    :ARG0 n9
                                    :ARG1 p2))))
            :ARG1-of (d4 / describe-01
                  :ARG0 (f / figure :mod "6C")))
      :snt2 (d / design-01
            :ARG0 (w / we)
            :ARG1 (v / vector
                  :mod (l2 / lentiviral)
                  :ARG0-of (e2 / encode-01
                        :ARG1 (p / protein :name (n2 / name :op1 "PTEN")
                              :ARG1-of (d5 / deplete-01
                                    :ARG2 (d3 / dna-sequence :name (n6 / name :op1 "39-UTR"))))))
            :purpose (e4 / enforce-01
                  :ARG0 v
                  :ARG1 (e5 / express-03
                        :ARG2 p
                        :ARG3 (c2 / cell :name (n7 / name :op1 "MDSC"))))
            :purpose (c3 / confirm-01
                  :ARG0 w
                  :ARG1 (m4 / mediate-01
                        :ARG0 (a3 / activate-01
                              :ARG1 c2
                              :ARG2-of (i / induce-01
                                    :ARG0 (n10 / nucleic-acid :name (n8 / name :op1 "miR-494"))))
                        :ARG1 (t3 / target-01
                              :ARG1 (e6 / express-03))))))

# ::id bel_pmid_2254_4933.41044 ::date 2015-05-14T02:04:39 ::annotator SDL-AMR-09 ::preferred
# ::snt Overexpression of PTEN in Gr-1+ CD11b+ cells did not affect the TDF-induced miR-494 up-regulation, whereas the increased expression of MMPs induced by TCCM were significantly blocked (Fig. 6D), and SDF-1/CXCL12-mediated MDSC migration was abrogated (Fig. 6E).
# ::save-date Sun Jan 17, 2016 ::file bel_pmid_2254_4933_41044.txt
(c / contrast-01
      :ARG1 (a / affect-01 :polarity -
            :ARG0 (o / overexpress-01
                  :ARG1 (p3 / protein :name (n3 / name :op1 "PTEN"))
                  :location (c2 / cell
                        :ARG1-of (m / mutate-01
                              :ARG0 (a3 / and
                                    :op1 (p / protein :name (n / name :op1 "Gr-1+"))
                                    :op2 (p2 / protein :name (n2 / name :op1 "CD11b+"))))))
            :ARG1 (u / upregulate-01
                  :ARG1 (n11 / nucleic-acid :name (n5 / name :op1 "miR-494"))
                  :ARG2-of (i / induce-01
                        :ARG0 (e2 / enzyme :name (n4 / name :op1 "TDF")))))
      :ARG2 (a4 / and
            :op1 (b / block-01
                  :ARG1 (e / express-03
                        :ARG2 (p5 / protein :name (n6 / name :op1 "MMP"))
                        :ARG1-of (i2 / increase-01)
                        :ARG2-of (i3 / induce-01
                              :ARG0 (t / thing :name (n7 / name :op1 "TCCM"))))
                  :ARG1-of (s / significant-02)
                  :ARG1-of (d2 / describe-01
                        :ARG0 (f2 / figure :mod "6D")))
            :op2 (a5 / abrogate-01
                  :ARG1 (m2 / migrate-01
                        :ARG0 (c3 / cell :name (n8 / name :op1 "MDSC"))
                        :ARG1-of (m3 / mediate-01
                              :ARG0 (a6 / and
                                    :op1 (p7 / protein :name (n9 / name :op1 "SDF-1"))
                                    :op2 (p8 / protein :name (n10 / name :op1 "CXCL12")))))))
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod "6E")))

# ::id bel_pmid_2254_4933.41046 ::date 2015-05-14T02:16:51 ::annotator SDL-AMR-09 ::preferred
# ::snt Significantly reduced PTEN expression was also detected in Gr-1+ CD11b+ cells after TCCM stimulation (Fig. 6G); this was inversely correlated with the phosphorylation levels of mTOR and NF-kB.
# ::save-date Fri Dec 18, 2015 ::file bel_pmid_2254_4933_41046.txt
(m / multi-sentence
      :snt1 (d / detect-01
            :ARG1 (e / express-03
                  :ARG2 (p / protein :name (n / name :op1 "PTEN"))
                  :ARG1-of (r / reduce-01
                        :ARG2 (s / significant-02)))
            :mod (a / also)
            :location (c / cell
                  :ARG1-of (m2 / mutate-01
                        :ARG0 (a2 / and
                              :op1 (p2 / protein :name (n2 / name :op1 "Gr-1+"))
                              :op2 (p3 / protein :name (n3 / name :op1 "CD11b+")))))
            :time (a3 / after
                  :op1 (s2 / stimulate-01
                        :ARG0 (t2 / thing :name (n4 / name :op1 "TCCM"))))
            :ARG1-of (d2 / describe-01
                  :ARG0 (f / figure :mod "6G")))
      :snt2 (c2 / correlate-01
            :ARG1 (t / this)
            :ARG2 (l2 / level
                  :degree-of (p5 / phosphorylate-01
                        :ARG1 (l / level
                              :quant-of (a4 / and
                                    :op1 (p6 / protein :name (n5 / name :op1 "mTOR"))
                                    :op2 (p7 / protein :name (n6 / name :op1 "NF-kB"))))))
            :manner (i / inverse)))

# ::id bel_pmid_2254_4933.41048 ::date 2015-05-14T01:42:51 ::annotator SDL-AMR-09 ::preferred
# ::snt As shown in Fig. 6H, the increased levels of MMPs induced by TCCM were completely abolished by LY294002, suggesting that the Akt activity is indispensable for the activation of MDSCs.
# ::save-date Sun Jan 17, 2016 ::file bel_pmid_2254_4933_41048.txt
(a / abolish-01
      :ARG0 (s3 / small-molecule :name (n / name :op1 "LY294002"))
      :ARG1 (l / level
            :ARG1-of (i / increase-01)
            :quant-of (e / enzyme :name (n2 / name :op1 "MMP"))
            :ARG2-of (i2 / induce-01
                  :ARG0 (t / thing :name (n3 / name :op1 "TCCM"))))
      :ARG1-of (s2 / show-01
            :ARG0 (f / figure :mod "6H"))
      :ARG1-of (c / complete-02)
      :ARG0-of (s / suggest-01
            :ARG1 (p2 / possible-01
                  :ARG1 (i3 / indispensable-01
                        :ARG1 (a2 / activity-06
                              :ARG0 (p3 / pathway :name (n5 / name :op1 "Akt")))
                        :ARG2 (a3 / activate-01
                              :ARG1 (c2 / cell :name (n6 / name :op1 "MDSC")))))))

# ::id bel_pmid_2254_4933.41050 ::date 2015-05-14T01:55:00 ::annotator SDL-AMR-09 ::preferred
# ::snt BAY-117802 significantly blocked MMP13 expression but had a limited effect on the upregulation of MMP2 and MMP14, whereas rapamycin eliminated the expression of all MMPs.
# ::save-date Sat Feb 13, 2016 ::file bel_pmid_2254_4933_41050.txt
(c / contrast-01
      :ARG1 (c2 / contrast-01
            :ARG1 (b / block-01
                  :ARG0 (s2 / small-molecule :name (n3 / name :op1 "BAY-117802"))
                  :ARG1 (e4 / express-03
                        :ARG2 (e3 / enzyme :name (n2 / name :op1 "MMP13")))
                  :ARG1-of (s / significant-02))
            :ARG2 (a3 / affect-01
                  :ARG0 s2
                  :ARG1 (u / upregulate-01
                        :ARG1 (a2 / and
                              :op1 (e5 / enzyme :name (n4 / name :op1 "MMP2"))
                              :op2 (e6 / enzyme :name (n5 / name :op1 "MMP14"))))
                  :ARG1-of (l / limit-01)))
      :ARG2 (e / eliminate-01
            :ARG0 (r / rapamycin)
            :ARG1 (e2 / express-03
                  :ARG2 (p / protein-family :name (n / name :op1 "MMP")
                        :mod (a / all)))))

# ::id bel_pmid_2254_4933.41052 ::date 2015-05-14T01:05:48 ::annotator SDL-AMR-09 ::preferred
# ::snt TGF-p1-induced miR-494 was involved in the negative regulation of PTEN expression.
# ::save-date Sun Dec 20, 2015 ::file bel_pmid_2254_4933_41052.txt
(i / involve-01
      :ARG1 (n4 / nucleic-acid :name (n / name :op1 "miR-494")
            :ARG2-of (i2 / induce-01
                  :ARG0 (p / protein :name (n2 / name :op1 "TGF-p1"))))
      :ARG2 (d / downregulate-01
            :ARG1 (e / express-03
                  :ARG2 (p2 / protein :name (n3 / name :op1 "PTEN")))))

# ::id bel_pmid_2295_2847.42202 ::date 2015-05-14T01:08:22 ::annotator SDL-AMR-09 ::preferred
# ::snt Transcriptional reprogramming of tumors via DmiR-580, 588 or 190 over-expression resulted in downregulation of pro-angiogenic factors such as TIMP-3, bFGF and TGFalpha.
# ::save-date Mon Jan 4, 2016 ::file bel_pmid_2295_2847_42202.txt
(r / result-01
      :ARG1 (r2 / reprogram-00
            :ARG1 (t2 / tumor)
            :mod (t / transcribe-01)
            :path (o / overexpress-01
                  :ARG1 (o2 / or
                        :op1 (n7 / nucleic-acid :name (n4 / name :op1 "DmiR-580"))
                        :op2 (n8 / nucleic-acid :name (n5 / name :op1 "DmiR-588"))
                        :op3 (n9 / nucleic-acid :name (n6 / name :op1 "DmiR-190")))))
      :ARG2 (d / downregulate-01
            :ARG1 (f / factor
                  :ARG0-of (f2 / favor-01
                        :ARG1 (a3 / angiogenesis))
                  :example (a / and
                        :op1 (p / protein :name (n / name :op1 "TIMP-3"))
                        :op2 (p3 / protein :name (n2 / name :op1 "bFGF"))
                        :op3 (p4 / protein :name (n3 / name :op1 "TGFalpha"))))))

# ::id bel_pmid_2295_2847.42206 ::date 2015-05-14T01:18:50 ::annotator SDL-AMR-09 ::preferred
# ::snt Figure 2D shows the high rate of proliferative Ki67+ cells in a representative dormant miR-588 expressing A-GBM tumor at day 113 post injection.
# ::save-date Mon Jan 4, 2016 ::file bel_pmid_2295_2847_42206.txt
(s / show-01
      :ARG0 (f / figure :mod "2D")
      :ARG1 (r / rate
            :ARG1-of (h / high-02)
            :degree-of (c / cell :name (n / name :op1 "Ki67+")
                  :ARG0-of (p / proliferate-01)))
      :location (n4 / nucleic-acid :name (n3 / name :op1 "miR-588")
            :ARG1-of (e / express-03
                  :ARG2 (t / tumor
                        :mod (c2 / cell :name (n2 / name :op1 "A-GBM")))
                  :time (a / after
                        :op1 (i / inject-01)
                        :quant (t2 / temporal-quantity :quant 113
                              :unit (d2 / day))))
            :mod (d / dormant)
            :ARG0-of (r3 / represent-01)))

# ::id bel_pmid_2295_2847.42214 ::date 2015-05-13T11:58:43 ::annotator SDL-AMR-09 ::preferred
# ::snt We found that antiangiogenic and dormancy promoting genes, Angiomotin (AMOT-1) and Eph receptor A5 (EphA5), were both upregulated in all DmiR expressing A-GBM tumors as compared to the GFP-vector- control A-GBM cells (Figure 4).
# ::save-date Mon Jan 4, 2016 ::file bel_pmid_2295_2847_42214.txt
(f / find-01
      :ARG0 (w / we)
      :ARG1 (u / upregulate-01
            :ARG1 (a / and
                  :op1 (g / gene :name (n / name :op1 "Angiomotin"))
                  :op2 (g3 / gene :name (n3 / name :op1 "Eph" :op2 "receptor" :op3 "A5"))
                  :ARG0-of (p2 / promote-02
                        :ARG1 (d3 / dormancy))
                  :ARG0-of (c3 / counter-01
                        :ARG1 (a2 / angiogenesis)))
            :compared-to (c / cell :name (n6 / name :op1 "GFP-vector-control" :op2 "A-GBM"))
            :location (t / tumor
                  :mod (c2 / cell :name (n4 / name :op1 "A-GBM")
                        :ARG3-of (e / express-03
                              :ARG1 (n2 / nucleic-acid :name (n5 / name :op1 "Dmir"))))
                  :mod (a3 / all)))
      :ARG1-of (d / describe-01
            :ARG0 (f2 / figure :mod 4)))

# ::id bel_pmid_2295_2847.42216 ::date 2015-05-14T01:42:09 ::annotator SDL-AMR-09 ::preferred
# ::snt In contrast, genes involved in pro-angiogenic signaling, including tissue inhibitor of metalloprotei-nases 3 (TIMP-3), hypoxia-induced factor 1 alpha (HIF-1-alpha), basic fibroblast growth factor (bFGF, FGF2), and the K-ras tumor oncogene, were consistently downregulated in DmiR expressing A-GBM.
# ::save-date Mon Feb 1, 2016 ::file bel_pmid_2295_2847_42216.txt
(c / contrast-01
      :ARG2 (d / downregulate-01
            :ARG1 (g2 / gene
                  :ARG1-of (i / involve-01
                        :ARG2 (s / signal-07
                              :ARG0-of (f / favor-01
                                    :ARG1 (a2 / angiogenesis))))
                  :ARG2-of (i2 / include-91
                        :ARG1 (a / and
                              :op1 (p / protein :name (n / name :op1 "tissue" :op2 "inhibitor" :op3 "of" :op4 "metalloprotei-nase" :op5 "3"))
                              :op2 (p3 / protein :name (n2 / name :op1 "hypoxia-induced" :op2 "factor" :op3 "1"))
                              :op3 (p4 / protein :name (n5 / name :op1 "basic" :op2 "fibroblast" :op3 "growth" :op4 "factor"))
                              :op4 (o / oncogene
                                    :mod (e / enzyme :name (n6 / name :op1 "K-ras"))
                                    :mod (t / tumor)))))
            :ARG2 (c3 / cell :name (n3 / name :op1 "A-GBM")
                  :ARG3-of (e2 / express-03
                        :ARG1 (n7 / nucleic-acid :name (n4 / name :op1 "DmiR"))))
            :manner (c2 / consistent-02)))

# ::id bel_pmid_2295_2847.42218 ::date 2015-05-13T13:12:09 ::annotator SDL-AMR-09 ::preferred
# ::snt Importantly, we found Bv8 also known as prokineticin 2 (Prok2) to be markedly downregulated in all three DmiR expressing A-GBM (Figure 5A).
# ::save-date Tue May 26, 2015 ::file bel_pmid_2295_2847_42218.txt
(f / find-01
      :ARG0 (w / we)
      :ARG1 (d2 / downregulate-01
            :ARG1 (p / protein :name (n / name :op1 "Bv8")
                  :ARG1-of (k / know-02
                        :ARG2 (p2 / protein :name (n5 / name :op1 "prokineticin" :op2 "2")
                              :ARG1-of (m / mean-01
                                    :ARG2 (p3 / protein :name (n2 / name :op1 "Prok2"))))
                        :mod (a2 / also)))
            :manner (m2 / marked)
            :location (n6 / nucleic-acid :quant 3 :name (n3 / name :op1 "DmiR")
                  :mod (a / all)
                  :ARG1-of (e / express-03
                        :ARG2 (c / cell :name (n4 / name :op1 "A-GBM")))))
      :ARG1-of (d / describe-01
            :ARG0 (f2 / figure :mod "5A"))
      :manner (i / important))

# ::id bel_pmid_2295_2847.42226 ::date 2015-05-13T11:58:53 ::annotator SDL-AMR-09 ::preferred
# ::snt Over-expression of miR-580, miR-588 and miR-190 in fast-growing angiogenic glioblastoma.
# ::save-date Wed Jan 20, 2016 ::file bel_pmid_2295_2847_42226.txt
(o / overexpress-01
      :ARG1 (a / and
            :op1 (n4 / nucleic-acid :name (n / name :op1 "miR-580"))
            :op2 (n5 / nucleic-acid :name (n2 / name :op1 "miR-588"))
            :op3 (n6 / nucleic-acid :name (n3 / name :op1 "miR-190")))
      :location (g / glioblastoma
            :mod (a2 / angiogenic)
            :ARG1-of (g2 / grow-01
                  :ARG1-of (f / fast-02))))

# ::id bel_pmid_2313_1846.42236 ::date 2015-05-13T12:08:45 ::annotator SDL-AMR-09 ::preferred
# ::snt In contrast, VEGF plugs in Pld1~-~ mice exhibited almost no vascularization (Fig. 2, A and B).
# ::save-date Tue Feb 2, 2016 ::file bel_pmid_2313_1846_42236.txt
(c / contrast-01
      :ARG2 (e / exhibit-01
            :ARG0 (p / plug
                  :poss (p2 / protein :name (n / name :op1 "VEGF"))
                  :location (m / mouse
                        :mod (g / gene :name (n2 / name :op1 "Pld1")
                              :ARG2-of (m2 / mutate-01 :mod "-/-"))))
            :ARG1 (v / vascularize-01
                  :ARG1 p
                  :mod (a2 / almost :polarity -)))
      :ARG1-of (d / describe-01
            :ARG0 (a / and
                  :op1 (f / figure :mod "2A")
                  :op2 (f2 / figure :mod "2B"))))

# ::id bel_pmid_2313_1846.42240 ::date 2015-05-13T12:23:58 ::annotator SDL-AMR-09 ::preferred
# ::snt PLD1 deficiency reduced basal phosphorylation of Ser473 in Akt and prevented VEGF-induced phosphorylation of Akt at Ser473 (Fig. 3, C and D).
# ::save-date Sun Dec 20, 2015 ::file bel_pmid_2313_1846_42240.txt
(a / and
      :op1 (r / reduce-01
            :ARG0 (l / lack-01
                  :ARG1 (p / protein :name (n / name :op1 "PLD1")))
            :ARG1 (p3 / phosphorylate-01
                  :ARG1 (a3 / amino-acid :name (n2 / name :op1 "Ser473")
                        :part-of (e / enzyme :name (n4 / name :op1 "Akt")))
                  :mod (b / basal)))
      :op2 (p2 / prevent-01
            :ARG0 l
            :ARG1 (p5 / phosphorylate-01
                  :ARG1 e
                  :ARG2-of (i / induce-01
                        :ARG0 (p6 / protein :name (n3 / name :op1 "VEGF")))))
      :ARG1-of (d / describe-01
            :ARG0 (a2 / and
                  :op1 (f / figure :mod "3C")
                  :op2 (f2 / figure :mod "3D"))))

# ::id bel_pmid_2313_1846.42242 ::date 2015-05-14T01:33:18 ::annotator SDL-AMR-09 ::preferred
# ::snt Pldl-- endothelial cells similarly exhibited a 50% reduction in basal phosphorylation of ERK1/2 but otherwise exhibited similar kinetics to wild-type cells for VEGF-induced phosphorylation of ERK1/2.
# ::save-date Sun Dec 20, 2015 ::file bel_pmid_2313_1846_42242.txt
(c / contrast-01
      :ARG1 (e / exhibit-01
            :ARG0 (c2 / cell
                  :mod (e2 / endothelium)
                  :mod (p3 / protein :name (n / name :op1 "Pldl")
                        :ARG2-of (m / mutate-01 :mod "-/-")))
            :ARG1 (r2 / reduce-01
                  :ARG1 (p2 / phosphorylate-01
                        :ARG1 (e4 / enzyme :name (n2 / name :op1 "ERK1/2"))
                        :mod (b / basal))
                  :ARG2 (p / percentage-entity :value 50))
            :manner (r / resemble-01))
      :ARG2 (e3 / exhibit-01
            :ARG1 (a / and
                  :op1 (k / kinetics
                        :mod (r3 / resemble-01))
                  :op2 (c3 / cell
                        :mod (w / wild-type))
                  :purpose (p5 / phosphorylate-01
                        :ARG1 e4
                        :ARG2-of (i / induce-01
                              :ARG0 (p6 / protein :name (n3 / name :op1 "VEGF")))))))

# ::id bel_pmid_2313_1846.42248 ::date 2015-05-14T02:36:10 ::annotator SDL-AMR-09 ::preferred
# ::snt Histological and quantitative analyses of the tumors revealed a 79% decrease in microvessels in the tumors that formed in FIPI-treated mice (Fig. 4C).
# ::save-date Tue May 26, 2015 ::file bel_pmid_2313_1846_42248.txt
(r / reveal-01
      :ARG0 (a / and
            :op1 (a2 / analyze-01
                  :ARG1 (t / tumor)
                  :mod (h / histology))
            :op2 (a3 / analyze-01
                  :ARG1 t
                  :mod (q / quantitative)))
      :ARG1 (d2 / decrease-01
            :ARG1 (m / microvessel
                  :part-of (t2 / tumor
                        :ARG0-of (f2 / form-01
                              :location (m2 / mouse
                                    :ARG1-of (t3 / treat-04
                                          :ARG2 (s / small-molecule :name (n / name :op1 "FIPI")))))))
            :ARG2 (p / percentage-entity :value 79))
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod "4C")))

# ::id bel_pmid_2334_3326.26540 ::date 2015-05-14T08:28:31 ::annotator SDL-AMR-09 ::preferred
# ::snt Engagement of Gi- and Gq-protein-coupled ETB receptors by ET-1 led to phosphorylation of ERK1/2, p38 MAPK, and JNK1/2 and then activated transcription factor NF-?B.
# ::save-date Tue May 26, 2015 ::file bel_pmid_2334_3326_26540.txt
(a4 / and
      :op1 (l / lead-03
            :ARG0 (e / engage-01
                  :ARG0 (p / protein :name (n / name :op1 "ET-1"))
                  :ARG1 (r / receptor :name (n2 / name :op1 "ETB")
                        :ARG1-of (c / couple-01
                              :ARG2 (a / and
                                    :op1 (p2 / protein :name (n3 / name :op1 "Gi"))
                                    :op2 (p3 / protein :name (n4 / name :op1 "Gq"))))))
            :ARG2 (p4 / phosphorylate-01
                  :ARG1 (a2 / and
                        :op1 (e2 / enzyme :name (n5 / name :op1 "ERK1"))
                        :op2 (e3 / enzyme :name (n6 / name :op1 "ERK2"))
                        :op3 (e4 / enzyme :name (n8 / name :op1 "p38" :op2 "MAPK"))
                        :op4 (e6 / enzyme :name (n9 / name :op1 "JNK1"))
                        :op5 (e7 / enzyme :name (n10 / name :op1 "JNK2")))))
      :op2 (a3 / activate-01
            :ARG0 e
            :ARG1 (m / macro-molecular-complex :name (n11 / name :op1 "NF-kappaB")
                  :mod (f / factor
                        :ARG0-of (t2 / transcribe-01)))
            :time (t / then)))

# ::id bel_pmid_2334_3326.38068 ::date 2015-05-14T08:40:42 ::annotator SDL-AMR-09 ::preferred
# ::snt Engagement of Gi- and Gq-protein-coupled ETB receptors by ET-1 led to phosphorylation of ERK1/2, p38 MAPK, and JNK1/2 and then activated transcription factor NF-?B.
# ::save-date Tue May 26, 2015 ::file bel_pmid_2334_3326_38068.txt
(a4 / and
      :op1 (l / lead-03
            :ARG0 (e / engage-01
                  :ARG0 (p / protein :name (n / name :op1 "ET-1"))
                  :ARG1 (r / receptor :name (n2 / name :op1 "ETB"))
                  :ARG1-of (c / couple-01
                        :ARG2 (a / and
                              :op1 (p2 / protein :name (n3 / name :op1 "Gi"))
                              :op2 (p3 / protein :name (n4 / name :op1 "Gq")))))
            :ARG2 (p4 / phosphorylate-01
                  :ARG1 (a2 / and
                        :op1 (e2 / enzyme :name (n5 / name :op1 "ERK1"))
                        :op2 (e3 / enzyme :name (n6 / name :op1 "ERK2"))
                        :op3 (e4 / enzyme :name (n7 / name :op1 "p38" :op2 "MAPK"))
                        :op4 (e5 / enzyme :name (n8 / name :op1 "JNK1"))
                        :op5 (e6 / enzyme :name (n9 / name :op1 "JNK2")))))
      :op2 (a3 / activate-01
            :ARG0 e
            :ARG1 (m / macro-molecular-complex :name (n10 / name :op1 "NF-kappaB")
                  :mod (f / factor
                        :ARG0-of (t2 / transcribe-01)))
            :time (t / then)))

# ::id bel_pmid_2364_0055.42272 ::date 2015-05-14T08:41:05 ::annotator SDL-AMR-09 ::preferred
# ::snt Against this background, we conducted in vitro phosphorylation studies of the phosphorylation of in-tegrin avp3 dimer with activated ERK1 and found phosphorylation of the dimer (Fig. 3A) that was inhibited by the ERK inhibitor, FR180204.
# ::save-date Sat Feb 13, 2016 ::file bel_pmid_2364_0055_42272.txt
(c2 / contrast-01
      :ARG1 (b / background
            :mod (t / this))
      :ARG2 (a / and
            :op1 (c / conduct-01
                  :ARG0 (w / we)
                  :ARG1 (s / study-01
                        :ARG1 (p / phosphorylate-01
                              :ARG1 (d / dimer :name (n / name :op1 "integrin" :op2 "αVβ3"))
                              :ARG2 (e / enzyme :name (n3 / name :op1 "ERK1")
                                    :ARG1-of (a2 / activate-01))))
                  :manner (i / in-vitro))
            :op2 (f / find-01
                  :ARG0 w
                  :ARG1 (i2 / inhibit-01
                        :ARG0 (s2 / small-molecule :name (n4 / name :op1 "FR180204")
                              :ARG0-of (i3 / inhibit-01
                                    :ARG1 (p2 / protein-family :name (n2 / name :op1 "ERK"))))
                        :ARG1 p)
                  :ARG1-of (d2 / describe-01
                        :ARG0 (f2 / figure :mod "3A")))))

# ::id bel_pmid_2364_0055.42278 ::date 2015-05-14T08:53:20 ::annotator SDL-AMR-09 ::preferred
# ::snt Integrin av bound to the COX-2 promoter in both OVCAR-3 and H522 cells in response to T4 (Fig. 4A)
# ::save-date Tue May 26, 2015 ::file bel_pmid_2364_0055_42278.txt
(b / bind-01
      :ARG1 (p / protein :name (n / name :op1 "integrin" :op2 "av"))
      :ARG2 (m / molecular-physical-entity
            :ARG0-of (p2 / promote-02
                  :ARG1 (e / enzyme :name (n2 / name :op1 "COX-2"))))
      :location (a / and
            :op1 (c / cell-line :name (n3 / name :op1 "OVCAR-3"))
            :op2 (c2 / cell-line :name (n4 / name :op1 "H522")))
      :ARG2-of (r / respond-01
            :ARG1 (s / small-molecule :name (n5 / name :op1 "T4")))
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod "4A")))

# ::id bel_pmid_2364_0055.42282 ::date 2015-05-14T09:03:34 ::annotator SDL-AMR-09 ::preferred
# ::snt These results suggest that although T4 increased complex formation between integrin av and NCoR/SMRT, the association between NCoR/SMRT and DNA was unchanged.
# ::save-date Tue May 26, 2015 ::file bel_pmid_2364_0055_42282.txt
(s / suggest-01
      :ARG0 (t / thing
            :ARG2-of (r / result-01)
            :mod (t2 / this))
      :ARG1 (h / have-concession-91
            :ARG1 (c / change-01 :polarity -
                  :ARG1 (a / associate-01
                        :ARG1 m
                        :ARG2 (n4 / nucleic-acid :wiki "DNA" :name (n5 / name :op1 "DNA"))))
            :ARG2 (i / increase-01
                  :ARG0 (s2 / small-molecule :name (n / name :op1 "T4"))
                  :ARG1 (f / form-01
                        :ARG1 (m2 / macro-molecular-complex
                              :part (p / protein :name (n2 / name :op1 "integrin" :op2 "av"))
                              :part (m / macro-molecular-complex :name (n3 / name :op1 "NCoR/SMRT")))))))

# ::id bel_pmid_2364_0055.42284 ::date 2015-05-14T09:10:31 ::annotator SDL-AMR-09 ::preferred
# ::snt The transcription of COX-2, ERa, HIF-la, and TR$1 was increased in thyroid hormone-treated cells (Fig. 4B).
# ::save-date Tue May 26, 2015 ::file bel_pmid_2364_0055_42284.txt
(i / increase-01
      :ARG1 (t / transcribe-01
            :ARG1 (a / and
                  :op1 (e / enzyme :name (n / name :op1 "COX-2"))
                  :op2 (p / protein :name (n2 / name :op1 "ERalpha"))
                  :op3 (p2 / protein :name (n3 / name :op1 "HIF-1alpha"))
                  :op4 (p3 / protein :name (n4 / name :op1 "TRbeta1"))))
      :location (c / cell
            :ARG1-of (t2 / treat-04
                  :ARG2 (h / hormone
                        :source (t3 / thyroid))))
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod "4B")))

# ::id bel_pmid_2382_4538.18804 ::date 2015-05-14T09:18:36 ::annotator SDL-AMR-09 ::preferred
# ::snt Abundant autophagosomes in K-rasG12D/+;atg7+/+ but not in K-rasG12D/+;atg7 -/- tumors were confirmed by electron microscopy (Fig. 2B).
# ::save-date Tue Jun 23, 2015 ::file bel_pmid_2382_4538_18804.txt
(c3 / contrast-01
      :ARG1 (c / confirm-01
            :ARG0 (m4 / microscopy
                  :mod (e2 / electron))
            :ARG1 (s / small-molecule :name (n / name :op1 "autophagosome")
                  :mod (a / abundant))
            :location (t / tumor
                  :mod (s2 / slash
                        :op1 (e / enzyme :name (n2 / name :op1 "K-ras")
                              :ARG2-of (m / mutate-01 :value "G12D"))
                        :op2 (p2 / protein :name (n3 / name :op1 "atg7")
                              :mod (w / wild-type)))))
      :ARG2 (c4 / confirm-01 :polarity -
            :ARG0 m4
            :ARG1 s
            :location (t2 / tumor
                  :mod (s3 / slash
                        :op1 e
                        :op2 (p3 / protein :name (n4 / name :op1 "atg7")
                              :ARG2-of (m3 / mutate-01 :mod "-/-")))))
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod "2B")))

# ::id bel_pmid_2382_4538.18808 ::date 2015-05-14T23:57:27 ::annotator SDL-AMR-09 ::preferred
# ::snt Reduction of atg7-deficient tumor burden was coincident with reduced proliferation (Ki67) and decreased levels of phospho-MEK1/2 (P-MEK1/2) and P-ERK1/2 and p53 and p21 induction, compared with wild-type tumors (Fig. 1I; Supplemental Figs. S4A–C, S5A–C), suggesting that inhibition of tumor cell proliferation upon atg7 deletion is the main cause of reduced tumor burden.
# ::save-date Sat Jan 2, 2016 ::file bel_pmid_2382_4538_18808.txt
(c / coincide-01
      :ARG1 (r / reduce-01
            :ARG1 (b / burden-01
                  :ARG2 (t / tumor
                        :mod (p / protein :name (n / name :op1 "atg7")
                              :ARG1-of (d4 / delete-01)))))
      :ARG2 (a / and
            :op1 (p2 / proliferate-01
                  :ARG1-of (r2 / reduce-01)
                  :ARG1-of (m2 / measure-01
                        :ARG2 (p3 / protein :name (n2 / name :op1 "Ki67"))))
            :op2 (l2 / level
                  :ARG1-of (d / decrease-01)
                  :quant-of (a2 / and
                        :op1 (e / enzyme :name (n3 / name :op1 "MEK1"))
                        :op2 (e2 / enzyme :name (n4 / name :op1 "MEK2"))
                        :op3 (e3 / enzyme :name (n5 / name :op1 "ERK1"))
                        :op4 (e4 / enzyme :name (n6 / name :op1 "ERK2"))
                        :ARG1-of (p4 / phosphorylate-01)))
            :op3 (i / induce-01
                  :ARG2 (a3 / and
                        :op1 (p5 / protein :name (n7 / name :op1 "p53"))
                        :op2 (p6 / protein :name (n8 / name :op1 "p21"))))
            :compared-to (t2 / tumor
                  :mod (w / wild-type)))
      :ARG1-of (d2 / describe-01
            :ARG0 (a4 / and
                  :op1 (f / figure :mod "1I")
                  :op2 (a5 / and
                        :op1 (f4 / figure :mod "S4A")
                        :op2 (f5 / figure :mod "S4B")
                        :op3 (f6 / figure :mod "S4C")
                        :ARG2-of (s / supplement-01))
                  :op3 (a6 / and
                        :op1 (f2 / figure :mod "S5A")
                        :op2 (f7 / figure :mod "S5B")
                        :op3 (f8 / figure :mod "S5C")
                        :ARG2-of s)))
      :ARG0-of (s2 / suggest-01
            :ARG1 (c2 / cause-01
                  :ARG0 (i2 / inhibit-01
                        :ARG0 (d3 / delete-01
                              :ARG1 p)
                        :ARG1 (p7 / proliferate-01
                              :ARG0 (c3 / cell
                                    :mod t3)))
                  :ARG1 (b2 / burden-01
                        :ARG2 (t3 / tumor)
                        :ARG1-of (r3 / reduce-01))
                  :mod (m / main))))

# ::id bel_pmid_2382_4538.18812 ::date 2015-05-15T00:26:52 ::annotator SDL-AMR-09 ::preferred
# ::snt atg7 deficiency in tumors prevented LC3-I processing to LC3-II and caused accumulation of LC3-I and autophagy substrate p62 in large aggregates apparent at 6 wk that increased throughout tumorigenesis
# ::save-date Sun Jan 17, 2016 ::file bel_pmid_2382_4538_18812.txt
(a / and
      :op1 (p2 / prevent-01
            :ARG0 (d / delete-01
                  :ARG1 (p / protein :name (n / name :op1 "atg7"))
                  :ARG2 (t / tumor))
            :ARG1 (p3 / process-01
                  :ARG1 (p4 / protein :name (n2 / name :op1 "LC3-I"))
                  :ARG2 (p5 / protein :name (n3 / name :op1 "LC3-II"))))
      :op2 (c / cause-01
            :ARG0 d
            :ARG1 (a3 / accumulate-01
                  :ARG1 (a2 / and
                        :op1 p4
                        :op2 (s / substrate
                              :consist-of (p6 / protein :name (n4 / name :op1 "p62"))
                              :mod (a4 / autophagy)))
                  :ARG1-of (a5 / aggregate-01
                        :mod (l2 / large)
                        :ARG1-of (a6 / appear-01
                              :time (a7 / after
                                    :op1 a3
                                    :quant (t2 / temporal-quantity :quant 6
                                          :unit (w / week))))
                        :ARG1-of (i / increase-01
                              :time (t3 / throughout
                                    :op1 (c2 / create-01
                                          :ARG1 t)))))))

# ::id bel_pmid_2465_2403.41226 ::date 2015-05-15T00:41:37 ::annotator SDL-AMR-09 ::preferred
# ::snt e ALDH1 activity in human PC (N = 11); representative flow cytometry plot of human PC tumor gated on live EpCAM+ cells using Aldefluor assay.
# ::save-date Thu Feb 11, 2016 ::file bel_pmid_2465_2403_41226.txt
(m / multi-sentence
      :snt1 (a / activity-06
            :ARG0 (e / enzyme :name (n / name :op1 "ALDH1"))
            :ARG1 (d2 / disease :wiki "Pancreatic_cancer" :name (n3 / name :op1 "pancreatic" :op2 "cancer")
                  :mod h2
                  :ARG1-of (s / sample-01
                        :ARG2 (t2 / thing :quant 11))))
      :snt2 (p2 / plot
            :mod (c2 / cytometry
                  :mod (f / flow)
                  :ARG0-of (r / represent-01))
            :mod (t3 / tumor
                  :mod (d4 / disease :wiki "Pancreatic_cancer" :name (n6 / name :op1 "pancreatic" :op2 "cancer")
                        :mod (h2 / human)
                        :ARG1-of (g / gate-01
                              :ARG0 (u / use-01
                                    :ARG1 (a2 / assay-01
                                          :instrument (t / thing :name (n5 / name :op1 "Aldefluor"))))
                              :location (c / cell
                                    :mod (p3 / protein :name (n4 / name :op1 "EpCAM+"))
                                    :ARG0-of (l / live-01))))))
      :ARG1-of (d3 / describe-01
            :ARG0 (f2 / figure :mod "E")))

# ::id bel_pmid_2465_2403.41228 ::date 2015-05-15T00:53:15 ::annotator SDL-AMR-09 ::preferred
# ::snt Furthermore, GCSFR-/- mice exhibit a shift in the immune profile of PC tumors from a TH-2 to TH-1 immune response, characterized by increased expression of IFN-y, TNF-a and IL-12 with decreased expression of arginase-1, IL-6, TGF-P, IL-10 compared to WT mice (Fig. 2d).
# ::save-date Wed Jan 13, 2016 ::file bel_pmid_2465_2403_41228.txt
(a / and
      :op2 (e / exhibit-01
            :ARG0 (m / mouse
                  :mod (p / protein :name (n / name :op1 "GCSFR")
                        :ARG2-of (m2 / mutate-01 :mod "-/-")))
            :ARG1 (s / shift-01
                  :ARG1 (p2 / profile
                        :ARG1-of (i / immune-02)
                        :ARG1-of (c3 / characterize-01
                              :ARG2 (a2 / and
                                    :op1 (e2 / express-03
                                          :ARG2 (a3 / and
                                                :op1 (p3 / protein :name (n4 / name :op1 "IFN-y"))
                                                :op2 (p4 / protein :name (n5 / name :op1 "TNF-a"))
                                                :op3 (p5 / protein :name (n6 / name :op1 "IL-12")))
                                          :ARG1-of (i2 / increase-01))
                                    :op2 (e3 / express-03
                                          :ARG2 (a4 / and
                                                :op1 (e4 / enzyme :name (n7 / name :op1 "arginase-1"))
                                                :op2 (p6 / protein :name (n8 / name :op1 "IL-6"))
                                                :op3 (p7 / protein :name (n9 / name :op1 "TGF-P"))
                                                :op4 (p8 / protein :name (n10 / name :op1 "IL-10")))
                                          :ARG1-of (d / decrease-01
                                                :compared-to (e5 / express-03
                                                      :ARG2 a4
                                                      :ARG3 (m3 / mouse
                                                            :mod (w / wild-type)))))))
                        :mod (t / tumor
                              :mod (d4 / disease :wiki "Pancreatic_cancer" :name (n12 / name :op1 "pancreatic" :op2 "cancer"))))
                  :ARG2 (r2 / respond-01
                        :ARG2 (i4 / immune-02
                              :ARG1 (c2 / cell :name (n3 / name :op1 "TH-1"))))
                  :ARG3 (r / respond-01
                        :ARG2 (i3 / immune-02
                              :ARG1 (c / cell :name (n2 / name :op1 "TH-2"))))))
      :ARG1-of (d2 / describe-01
            :ARG0 (f / figure :mod "2d")))

# ::id bel_pmid_2465_2403.41236 ::date 2015-05-15T01:15:47 ::annotator SDL-AMR-09 ::preferred
# ::snt These monocytes acquired a Mo-MDSC phenotype characterized by a significantly decreased expression of HLA-DR and increased expression of arginase-1 as well as the ability to suppress CD8+ T cell proliferation in vitro [29-32] (Fig. 4a-c).
# ::save-date Sat Jan 2, 2016 ::file bel_pmid_2465_2403_41236.txt
(a / acquire-01
      :ARG0 (c / cell :name (n / name :op1 "monocyte")
            :mod (t / this))
      :ARG1 (p / phenotype
            :mod (c2 / cell :name (n2 / name :op1 "Mo-MDSC"))
            :ARG1-of (c3 / characterize-01
                  :ARG0 (a2 / and
                        :op1 (e / express-03
                              :ARG2 (p2 / protein :name (n3 / name :op1 "HLA-DR"))
                              :ARG1-of (d / decrease-01
                                    :ARG2 (s / significant-02)))
                        :op2 (e2 / express-03
                              :ARG2 (e3 / enzyme :name (n4 / name :op1 "arginase-1"))
                              :ARG1-of (i / increase-01))
                        :op3 (c4 / capable-01
                              :ARG1 c
                              :ARG2 (s2 / suppress-01
                                    :ARG0 c
                                    :ARG1 (p3 / proliferate-01
                                          :ARG0 (c5 / cell :name (n5 / name :op1 "CD8+" :op2 "T")))
                                    :manner (i2 / in-vitro))))))
      :ARG1-of (d2 / describe-01
            :ARG0 (a3 / and
                  :op1 (p4 / publication
                        :ARG1-of (c6 / cite-01
                              :ARG2 (v2 / value-interval :op1 29 :op2 32)))
                  :op2 (a4 / and
                        :op1 (f / figure :mod "1a")
                        :op2 (f2 / figure :mod "1b")
                        :op3 (f3 / figure :mod "1c")))))

# ::id bel_pmid_2465_2403.41248 ::date 2015-05-15T01:29:17 ::annotator SDL-AMR-09 ::preferred
# ::snt While we found that IL-6 mRNA gene expression was significantly downregulated by STAT3 inhibition (Supplementary figure 11), IL-6 blockade using anti-IL-6 antibodies decreased but did not fully reverse the effect of Mo-MDSC on increasing the prevalence of ALDH1Bright CSCs.
# ::save-date Fri Dec 18, 2015 ::file bel_pmid_2465_2403_41248.txt
(c / contrast-01
      :ARG1 (f / find-01
            :ARG0 (w / we)
            :ARG1 (d / downregulate-01
                  :ARG1 (e / express-03
                        :ARG1 (g / gene)
                        :ARG2 (n6 / nucleic-acid :name (n / name :op1 "mRNA")
                              :ARG0-of (e2 / encode-01
                                    :ARG1 (p / protein :name (n2 / name :op1 "IL-6")))))
                  :ARG2 (i / inhibit-01
                        :ARG1 (p2 / protein :name (n3 / name :op1 "STAT-3")))
                  :ARG1-of (s / significant-02))
            :ARG1-of (d2 / describe-01
                  :ARG0 (f2 / figure :mod 11
                        :ARG2-of (s2 / supplement-01))))
      :ARG2 (c2 / contrast-01
            :ARG1 (d3 / decrease-01
                  :ARG0 (b / block-01
                        :ARG1 p
                        :ARG3 (a / antibody
                              :ARG0-of (c3 / counter-01
                                    :ARG1 p)))
                  :ARG1 (a2 / affect-01
                        :ARG0 (c4 / cell :name (n4 / name :op1 "Mo-MDSC"))
                        :ARG1 (i2 / increase-01
                              :ARG1 (p4 / prevail-01
                                    :ARG0 (c5 / cell :name (n5 / name :op1 "ALDH1" :op2 "Bright" :op3 "CSC"))))))
            :ARG2 (r2 / reverse-01 :polarity -
                  :ARG0 b
                  :ARG1 a2
                  :degree (f3 / full))))

# ::id bel_pmid_247_2096.38400 ::date 2015-05-15T01:43:28 ::annotator SDL-AMR-09 ::preferred
# ::snt the 2 cytokines most intensively involved in eliciting the acute phase response are IL6 and IL1
# ::save-date Tue May 26, 2015 ::file bel_pmid_247_2096_38400.txt
(c4 / cytokine :quant 2
      :domain (a3 / and
            :op1 (c / cytokine :name (n / name :op1 "IL-6"))
            :op2 (c2 / cytokine :name (n2 / name :op1 "IL-1")))
      :ARG1-of (i2 / involve-01
            :ARG2 (e / elicit-01
                  :ARG1 (t / thing
                        :ARG2-of (r / respond-01
                              :ARG1 (p / phase
                                    :mod (a2 / acute)))))
            :manner (i / intensive
                  :degree (m / most))))

# ::id bel_pmid_248_3767.28356 ::date 2015-05-15T01:52:57 ::annotator SDL-AMR-09 ::preferred
# ::snt alpha 2-macroglobulin, alpha 1-antichymotrypsin ( = contrapsin), cysteine protease inhibitor ( = thiostatin), alpha 1-antitrypsin, ceruloplasmin and fibrinogens are predominantly regulated by the keratinocyte-derived HSF-III/-II or IL-6
# ::save-date Sun May 17, 2015 ::file bel_pmid_248_3767_28356.txt
(r / regulate-01
      :ARG0 (o / or
            :op1 (s / slash
                  :op1 (p3 / protein :name (n2 / name :op1 "HSF-III"))
                  :op2 (p4 / protein :name (n3 / name :op1 "HSF-II")))
            :op2 (p2 / protein :name (n / name :op1 "IL-6"))
            :ARG1-of (d / derive-01
                  :ARG2 (c / cell :name (n4 / name :op1 "keratinocyte"))))
      :ARG1 (a / and
            :op1 (p5 / protein :name (n5 / name :op1 "alpha-2-macroglobulin"))
            :op2 (p6 / protein :name (n6 / name :op1 "alpha" :op2 "1-antichymotrypsin")
                  :ARG1-of (m2 / mean-01
                        :ARG2 (p9 / protein :name (n11 / name :op1 "contrapsin"))))
            :op3 (p10 / protein :name (n12 / name :op1 "thiostatin")
                  :ARG0-of (i / inhibit-01
                        :ARG1 (e / enzyme :name (n7 / name :op1 "cysteine" :op2 "protease"))))
            :op4 (p7 / protein :name (n8 / name :op1 "alpha" :op2 "1-antitrypsin"))
            :op5 (e2 / enzyme :name (n9 / name :op1 "ceruloplasmin"))
            :op6 (p8 / protein :name (n10 / name :op1 "fibrinogen")))
      :manner (p / predominant))

# ::id bel_pmid_2494_9077.41642 ::date 2015-05-15T02:04:03 ::annotator SDL-AMR-09 ::preferred
# ::snt The mRNA expression of Foxp3 and RORyt in the spleen was very low in the normal control group but significantly higher in the model control group (P < 0.05).
# ::save-date Fri Dec 18, 2015 ::file bel_pmid_2494_9077_41642.txt
(c / contrast-01
      :ARG1 (l / low-04
            :ARG1 (e / express-03
                  :ARG2 (n5 / nucleic-acid :name (n / name :op1 "mRNA")
                        :ARG0-of (e2 / encode-01
                              :ARG1 (a / and
                                    :op1 (p / protein :name (n2 / name :op1 "Foxp3"))
                                    :op2 (p2 / protein :name (n3 / name :op1 "RORyt")))))
                  :ARG3 (s / spleen))
            :degree (v / very)
            :location (g / group
                  :mod (c2 / control-01
                        :ARG1-of (n4 / normal-02))))
      :ARG2 (h / high-02
            :ARG1 e
            :degree (m / more)
            :ARG1-of (s2 / significant-02)
            :location (g2 / group
                  :mod (c3 / control-01
                        :mod (m2 / model))))
      :ARG1-of (s3 / statistical-test-91
            :ARG2 (l2 / less-than :op1 0.05)))

# ::id bel_pmid_2494_9077.41646 ::date 2015-05-15T02:10:38 ::annotator SDL-AMR-09 ::preferred
# ::snt SOCS3 protein expression was significantly downregulated in all groups except for the normal control group (P < 0.05).
# ::save-date Fri Dec 18, 2015 ::file bel_pmid_2494_9077_41646.txt
(d / downregulate-01
      :ARG1 (e / express-03
            :ARG2 (p / protein :name (n / name :op1 "SOCS3")))
      :ARG1-of (s / significant-02)
      :location (g / group
            :mod (a / all)
            :ARG2-of (e2 / except-01
                  :ARG1 (g2 / group
                        :mod (c / control-01
                              :ARG1-of (n2 / normal-02)))))
      :ARG1-of (s2 / statistical-test-91
            :ARG2 (l / less-than :op1 0.05)))

# ::id bel_pmid_2494_9077.41648 ::date 2015-05-15T02:14:26 ::annotator SDL-AMR-09 ::preferred
# ::snt Jak2 and STAT3 protein expression was significantly higher in the model control group than in all other groups (P < 0.05).
# ::save-date Fri Dec 18, 2015 ::file bel_pmid_2494_9077_41648.txt
(h2 / high-02
      :ARG1 (e / express-03
            :ARG2 (a / and
                  :op1 (e2 / enzyme :name (n / name :op1 "Jak2"))
                  :op2 (p2 / protein :name (n2 / name :op1 "STAT3"))))
      :degree (m / more)
      :ARG1-of (s / significant-02)
      :location (g / group
            :mod (c / control-01
                  :mod (m3 / model)))
      :compared-to (g2 / group
            :mod (a2 / all)
            :mod (o / other))
      :ARG1-of (s2 / statistical-test-91
            :ARG2 (l / less-than :op1 0.05)))

# ::id bel_pmid_2506_3873.41328 ::date 2015-05-15T02:18:13 ::annotator SDL-AMR-09 ::preferred
# ::snt Blocking STAT3 activation with the small molecule inhibitor JSI-124 significantly inhibited the accumulation of NIK and IDO expression in MDSCs.
# ::save-date Fri Dec 18, 2015 ::file bel_pmid_2506_3873_41328.txt
(i2 / inhibit-01
      :ARG0 (b / block-01
            :ARG1 (a / activate-01
                  :ARG1 (p / protein :name (n / name :op1 "STAT3")))
            :ARG3 (s / small-molecule :name (n2 / name :op1 "JSI-124")
                  :ARG0-of (i / inhibit-01)))
      :ARG1 (a2 / and
            :op1 (a3 / accumulate-01
                  :ARG0 c
                  :ARG1 (e / enzyme :name (n3 / name :op1 "NIK")))
            :op2 (e2 / express-03
                  :ARG2 (e3 / enzyme :name (n4 / name :op1 "IDO"))
                  :ARG3 (c / cell :name (n5 / name :op1 "MDSC"))))
      :ARG1-of (s2 / significant-02))

# ::id bel_pmid_2506_3873.41330 ::date 2015-05-15T02:23:49 ::annotator SDL-AMR-09 ::preferred
# ::snt Knockdown of NIK in MDSCs suppressed IDO expression but not STAT3 activation.
# ::save-date Mon Jun 22, 2015 ::file bel_pmid_2506_3873_41330.txt
(c / contrast-01
      :ARG1 (s / suppress-01
            :ARG0 (k / knock-down-02
                  :ARG1 (e / enzyme :name (n / name :op1 "NIK"))
                  :location (c2 / cell :name (n2 / name :op1 "MDSC")))
            :ARG1 (e2 / express-03
                  :ARG2 (e3 / enzyme :name (n3 / name :op1 "IDO"))))
      :ARG2 (s2 / suppress-01 :polarity -
            :ARG0 k
            :ARG1 (a / activate-01
                  :ARG1 (p / protein :name (n4 / name :op1 "STAT3")))))

# ::id bel_pmid_2506_3873.41332 ::date 2015-05-15T02:26:54 ::annotator SDL-AMR-09 ::preferred
# ::snt RelB-p52 dimers were found to directly bind to the IDO promoter, leading to IDO expression in MDSCs.
# ::save-date Fri Jul 24, 2015 ::file bel_pmid_2506_3873_41332.txt
(f / find-01
      :ARG1 (b / bind-01
            :ARG1 (d2 / dimer
                  :part (p3 / protein :name (n / name :op1 "p52"))
                  :part (p / protein :name (n2 / name :op1 "RelB")))
            :ARG2 (m / molecular-physical-entity
                  :ARG0-of (p2 / promote-01
                        :ARG1 (e / enzyme :name (n3 / name :op1 "IDO"))))
            :ARG1-of (d / direct-02)
            :ARG0-of (l / lead-03
                  :ARG2 (e2 / express-03
                        :ARG2 e
                        :ARG3 (c / cell :name (n4 / name :op1 "MDSC"))))))

# ::id bel_pmid_2506_3873.41334 ::date 2015-05-15T02:32:18 ::annotator SDL-AMR-09 ::preferred
# ::snt STAT3 activation-induced IDO expression is independent of direct binding of STAT3 to the promoter region of IDO gene.
# ::save-date Sun Dec 20, 2015 ::file bel_pmid_2506_3873_41334.txt
(d / depend-01 :polarity -
      :ARG0 (e / express-03
            :ARG2 (e2 / enzyme :name (n / name :op1 "IDO"))
            :ARG2-of (i / induce-01
                  :ARG0 (a / activate-01
                        :ARG1 (p / protein :name (n2 / name :op1 "STAT3")))))
      :ARG1 (b / bind-01
            :ARG1 p
            :ARG2 (r / region
                  :ARG0-of (p2 / promote-01)
                  :part-of (g / gene
                        :ARG0-of (e3 / encode-01
                              :ARG1 e2)))
            :ARG1-of (d2 / direct-02)))

# ::id bel_pmid_2506_3873.41344 ::date 2015-05-15T02:36:40 ::annotator SDL-AMR-09 ::preferred
# ::snt Blocking STAT3 activation by JSI-124 dramatically decreased the levels of p52 and RelB in nuclei (Fig. 2C, p < 0.05).
# ::save-date Tue Dec 15, 2015 ::file bel_pmid_2506_3873_41344.txt
(d / decrease-01
      :ARG0 (b / block-01
            :ARG1 (a / activate-01
                  :ARG1 (p / protein :name (n / name :op1 "STAT3")))
            :ARG3 (s / small-molecule :name (n2 / name :op1 "JSI-124")))
      :ARG1 (l / level
            :quant-of (a2 / and
                  :op1 (p2 / protein :name (n3 / name :op1 "p52"))
                  :op2 (p3 / protein :name (n4 / name :op1 "RelB"))))
      :degree (d2 / dramatic)
      :location (n5 / nucleus)
      :ARG1-of (d3 / describe-01
            :ARG0 (f / figure :mod "2C"))
      :ARG1-of (s2 / statistical-test-91
            :ARG2 (l2 / less-than :op1 0.05)))

# ::id bel_pmid_2506_3873.41346 ::date 2015-05-15T02:41:17 ::annotator SDL-AMR-09 ::preferred
# ::snt The level of STAT3 phosphorylation in MDSCs was reduced at 30 min and completely suppressed at 4 h after treatment with JSI-124.
# ::save-date Tue Jul 28, 2015 ::file bel_pmid_2506_3873_41346.txt
(a / and
      :op1 (r / reduce-01
            :ARG1 (l / level
                  :degree-of (p / phosphorylate-01
                        :ARG1 (p2 / protein :name (n / name :op1 "STAT3")))
                  :location (c / cell :name (n2 / name :op1 "MDSC")))
            :time (a2 / after
                  :op1 (t / treat-04
                        :ARG2 (s / small-molecule :name (n3 / name :op1 "JSI-124")))
                  :quant (t2 / temporal-quantity :quant 30
                        :unit (m / minute))))
      :op2 (s2 / suppress-01
            :ARG1 l
            :ARG1-of (c2 / complete-02)
            :time (a3 / after
                  :op1 t
                  :quant (t3 / temporal-quantity :quant 4
                        :unit (h / hour)))))

# ::id bel_pmid_2506_3873.41348 ::date 2015-05-15T02:46:15 ::annotator SDL-AMR-09 ::preferred
# ::snt Consistently, the level of NIK in MDSCs started to decline at 1 h and was completely blocked at 8 h after JSI-124 treatment.
# ::save-date Mon Feb 1, 2016 ::file bel_pmid_2506_3873_41348.txt
(a / and
      :op1 (s / start-01
            :ARG0 (l / level
                  :quant-of (e / enzyme :name (n / name :op1 "NIK"))
                  :location (c / cell :name (n2 / name :op1 "MDSC")))
            :ARG1 (d / decline-01
                  :ARG1 l)
            :time (a2 / after
                  :op1 (t / treat-04
                        :ARG2 (s2 / small-molecule :name (n3 / name :op1 "JSI-124")))
                  :quant (t2 / temporal-quantity :quant 1
                        :unit (h / hour))))
      :op2 (b / block-01
            :ARG1 l
            :ARG1-of (c2 / complete-02)
            :time (a3 / after
                  :op1 t
                  :quant (t3 / temporal-quantity :quant 8
                        :unit h)))
      :manner (c3 / consistent-02))

# ::id bel_pmid_2506_3873.41350 ::date 2015-05-15T02:51:11 ::annotator SDL-AMR-09 ::preferred
# ::snt The level of IDO significantly decreased at 4 h after JSI-124 treatment (Fig. 3A).
# ::save-date Fri Dec 18, 2015 ::file bel_pmid_2506_3873_41350.txt
(d / decrease-01
      :ARG1 (l / level
            :quant-of (e / enzyme :name (n / name :op1 "IDO")))
      :ARG2 (s / significant-02)
      :time (a / after
            :op1 (t / treat-04
                  :ARG2 (s2 / small-molecule :name (n2 / name :op1 "JSI-124")))
            :quant (t2 / temporal-quantity :quant 4
                  :unit (h / hour)))
      :ARG1-of (d2 / describe-01
            :ARG0 (f / figure :mod "3A")))

# ::id bel_pmid_2506_3873.41352 ::date 2015-05-15T02:53:36 ::annotator SDL-AMR-09 ::preferred
# ::snt In NIK knockdown MDSCs, the level of IDO protein was reduced significantly, but the level of pSTAT3 protein was not affected (Fig. 3B, 3C).
# ::save-date Fri Dec 18, 2015 ::file bel_pmid_2506_3873_41352.txt
(c / contrast-01
      :ARG1 (r / reduce-01
            :ARG1 (l / level
                  :quant-of (e2 / enzyme :name (n3 / name :op1 "IDO")))
            :ARG2 (s / significant-02))
      :ARG2 (a / affect-01 :polarity -
            :ARG1 (l2 / level
                  :quant-of (p2 / protein :name (n4 / name :op1 "STAT3"))))
      :location (c2 / cell :name (n / name :op1 "MDSC")
            :mod (k / knock-down-02
                  :ARG1 (e / enzyme :name (n2 / name :op1 "NIK"))))
      :ARG1-of (d / describe-01
            :ARG0 (a2 / and
                  :op1 (f / figure :mod "3B")
                  :op2 (f2 / figure :mod "3C"))))

# ::id bel_pmid_2506_3873.41354 ::date 2015-05-15T02:57:03 ::annotator SDL-AMR-09 ::preferred
# ::snt In contrast, both IDO and NIK expression were reduced by JSI-124 treatment in MDSCs (Fig. 3A).
# ::save-date Tue May 26, 2015 ::file bel_pmid_2506_3873_41354.txt
(c / contrast-01
      :ARG2 (r / reduce-01
            :ARG0 (t / treat-04
                  :ARG2 (s / small-molecule :name (n3 / name :op1 "JSI-124")))
            :ARG1 (a / and
                  :op1 (e / express-03
                        :ARG2 (e4 / enzyme :name (n / name :op1 "IDO"))
                        :ARG3 (c2 / cell :name (n4 / name :op1 "MDSC")))
                  :op2 (e2 / express-03
                        :ARG2 (e3 / enzyme :name (n2 / name :op1 "NIK"))
                        :ARG3 c2)))
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod "3A")))

# ::id bel_pmid_2506_3873.41356 ::date 2015-05-15T03:00:28 ::annotator SDL-AMR-09 ::preferred
# ::snt RelB/p52 dimers directly bind to the IDO promoter to regulate IDO expression in MDSCs.
# ::save-date Fri Jul 24, 2015 ::file bel_pmid_2506_3873_41356.txt
(b / bind-01
      :ARG1 (d3 / dimer
            :part (p4 / protein :name (n / name :op1 "p52"))
            :part (p / protein :name (n2 / name :op1 "RelB")))
      :ARG2 (m / molecular-physical-entity
            :ARG0-of (p2 / promote-01
                  :ARG1 (e2 / enzyme :name (n3 / name :op1 "IDO"))))
      :ARG1-of (d / direct-02)
      :purpose (r / regulate-01
            :ARG0 d3
            :ARG1 (e / express-03
                  :ARG2 e2
                  :ARG3 (c / cell :name (n4 / name :op1 "MDSC")))))

# ::id bel_pmid_2506_3873.41366 ::date 2015-05-15T03:02:40 ::annotator SDL-AMR-09 ::preferred
# ::snt We isolated CD11b+ MDSCs from the spleen of JSI-124-treated mice and found decreased expression of p-STAT3, NIK, and IDO protein in CD11b+ MDSCs compared with those isolated from the controls (Fig. 6D).
# ::save-date Sun Jan 3, 2016 ::file bel_pmid_2506_3873_41366.txt
(a / and
      :op1 (i / isolate-01
            :ARG0 (w / we)
            :ARG1 (c / cell :name (n / name :op1 "MDSC")
                  :mod (p / protein :name (n2 / name :op1 "CD11b+")))
            :ARG2 (s / spleen
                  :poss (m / mouse
                        :ARG1-of (t / treat-04
                              :ARG2 (s2 / small-molecule :name (n3 / name :op1 "JSI-124"))))))
      :op2 (f / find-01
            :ARG0 w
            :ARG1 (e / express-03
                  :ARG2 (a2 / and
                        :op1 (p2 / protein :name (n4 / name :op1 "STAT3")
                              :ARG3-of (p3 / phosphorylate-01))
                        :op2 (e3 / enzyme :name (n5 / name :op1 "NIK"))
                        :op3 (e4 / enzyme :name (n6 / name :op1 "IDO")))
                  :ARG3 c
                  :ARG1-of (d / decrease-01)
                  :compared-to (e2 / express-03
                        :ARG2 a2
                        :ARG3 (c2 / cell :name (n7 / name :op1 "MDSC")
                              :mod p
                              :ARG1-of (i2 / isolate-01
                                    :ARG2 (c3 / control))))))
      :ARG1-of (d2 / describe-01
            :ARG0 (f2 / figure :mod "6D")))

# ::id bel_pmid_2506_3873.41374 ::date 2015-05-15T03:12:17 ::annotator SDL-AMR-09 ::preferred
# ::snt Furthermore, a specific IL-6-neutralizing Ab significantly decreased the levels of p-STAT3, NIK, and IDO in MDSCs (Fig. 7E, p < 0.05).
# ::save-date Mon Jan 4, 2016 ::file bel_pmid_2506_3873_41374.txt
(a / and
      :op2 (d / decrease-01
            :ARG0 (a2 / antibody
                  :ARG0-of (n / neutralize-01
                        :ARG1 (p / protein :name (n2 / name :op1 "IL-6")))
                  :ARG1-of (s2 / specific-02))
            :ARG1 (l / level
                  :quant-of (a3 / and
                        :op1 (p2 / protein :name (n3 / name :op1 "STAT-3")
                              :ARG3-of (p3 / phosphorylate-01))
                        :op2 (e / enzyme :name (n4 / name :op1 "NIK"))
                        :op3 (e2 / enzyme :name (n5 / name :op1 "IDO"))))
            :ARG2 (s / significant-02)
            :location (c / cell :name (n6 / name :op1 "MDSC"))
            :ARG1-of (s3 / statistical-test-91
                  :ARG2 (l2 / less-than :op1 0.05)))
      :ARG1-of (d2 / describe-01
            :ARG0 (f / figure :mod "7E")))

# ::id bel_pmid_778_0739.6222 ::date 2015-03-31T11:22:41 ::annotator SDL-AMR-09 ::preferred
# ::snt Mitogen-activated protein (MAP) kinase is central to a signal transduction pathway that triggers cell proliferation or differentiation. Activation of the p42mapk isoform requires its phosphorylation at two residues, Thr 183 and Tyr 185, and this phosphorylation is catalysed by MAP kinase kinase (MAPKK).
# ::save-date Tue Jan 19, 2016 ::file bel_pmid_778_0739_6222.txt
(m / multi-sentence
      :snt1 (c / central
            :purpose (p2 / pathway
                  :ARG0-of (t2 / trigger-01
                        :ARG1 (o / or
                              :op1 (p / proliferate-01
                                    :ARG0 (c2 / cell))
                              :op2 (d / differentiate-01
                                    :ARG1 c2)))
                  :ARG2-of (t / transduce-01
                        :ARG1 (s / signal-07)))
            :domain (e4 / enzyme :name (n / name :op1 "Mitogen-activated" :op2 "protein" :op3 "kinase")))
      :snt2 (r / require-01
            :ARG0 (a2 / activate-01
                  :ARG0 (e3 / enzyme :name (n7 / name :op1 "p42" :op2 "MAPK")
                        :mod (i2 / isoform)))
            :ARG1 (p4 / phosphorylate-01
                  :ARG1 (r2 / residue :quant 2
                        :part-of (i / isoform)
                        :mod (a4 / amino-acid :mod 183 :name (n4 / name :op1 "threonine"))
                        :mod (a5 / amino-acid :mod 185 :name (n5 / name :op1 "tyrosine")))
                  :ARG1-of (c3 / catalyze-01
                        :ARG0 (e / enzyme :name (n2 / name :op1 "MAP" :op2 "kinase" :op3 "kinase"))))))

# ::id bel_pmid_812_5955.5778 ::date 2015-04-01T22:26:06 ::annotator SDL-AMR-09 ::preferred
# ::snt Stable transfection of activated Ha-ras into a number of murine cells correlated with a down-regulation of the expression of the NF1 genes NF1/CTF and NF1/X.
# ::save-date Sat Jan 16, 2016 ::file bel_pmid_812_5955_5778.txt
(c / correlate-01
      :ARG1 (t / transfect-01
            :ARG1 (c2 / cell
                  :quant (n4 / number)
                  :mod (m / murine))
            :ARG2 (e2 / enzyme :name (n3 / name :op1 "Ha-ras")
                  :ARG1-of (a2 / activate-01))
            :ARG1-of (s / stable-03))
      :ARG2 (d / downregulate-01
            :ARG1 (e / express-03
                  :ARG1 (a / and
                        :op1 (g / gene :name (n / name :op1 "NF1/CTF"))
                        :op2 (g2 / gene :name (n2 / name :op1 "NF1/X"))))))

# ::id bel_pmid_812_5955.9008 ::date 2015-04-02T03:35:27 ::annotator SDL-AMR-09 ::preferred
# ::snt The level of the DNA binding activity of the NF1 proteins was also reduced in Ha-v-ras-transformed cells, and the expression of a gene that depends on this family of transcription factors was specifically repressed.
# ::save-date Mon Dec 21, 2015 ::file bel_pmid_812_5955_9008.txt
(a / and
      :op1 (r / reduce-01
            :ARG1 (l / level
                  :degree-of (a3 / activity-06
                        :ARG0 (p / protein :name (n / name :op1 "NF1"))
                        :ARG1 (b / bind-01
                              :ARG0 p
                              :ARG1 (n3 / nucleic-acid :wiki "DNA" :name (n4 / name :op1 "DNA")))))
            :location (c / cell
                  :ARG2-of (t / transform-01
                        :ARG0 (g / gene :name (n2 / name :op1 "Ha-v-ras"))))
            :mod (a2 / also))
      :op2 (r2 / repress-01
            :ARG1 (e / express-03
                  :ARG1 (g2 / gene
                        :ARG0-of (d2 / depend-01
                              :ARG1 (f / family
                                    :consist-of (f2 / factor
                                          :ARG0-of (t3 / transcribe-01))
                                    :mod p))))
            :ARG1-of (s / specific-02)))

# ::id bel_pmid_822_6933.9532 ::date 2015-04-03T09:17:44 ::annotator SDL-AMR-09 ::preferred
# ::snt MEK1 and MEK2 can also be activated by autophosphorylation. Autophosphorylation of MEKs correlates with their ability to phosphorylate and activate ERKs.
# ::save-date Sat Jan 16, 2016 ::file bel_pmid_822_6933_9532.txt
(m / multi-sentence
      :snt1 (p / possible-01
            :ARG1 (a / activate-01
                  :ARG0 (p2 / phosphorylate-01
                        :ARG1 a2
                        :ARG2 a2)
                  :ARG1 (a2 / and
                        :op1 (e / enzyme :name (n / name :op1 "MEK1"))
                        :op2 (e2 / enzyme :name (n2 / name :op1 "MEK2")))
                  :mod (a5 / also)))
      :snt2 (c / correlate-01
            :ARG1 (p3 / phosphorylate-01
                  :ARG1 (e3 / enzyme :name (n3 / name :op1 "MEK"))
                  :ARG2 e3)
            :ARG2 (c2 / capable-01
                  :ARG1 e3
                  :ARG2 (a3 / and
                        :op1 (p4 / phosphorylate-01
                              :ARG2 (p5 / protein-family :name (n4 / name :op1 "ERK")))
                        :op2 (a4 / activate-01
                              :ARG1 p5)))))

# ::id bel_pmid_854_8291.16558 ::date 2015-04-03T10:20:36 ::annotator SDL-AMR-09 ::preferred
# ::snt The two SAPK isoforms are 46 and 54 kDa. A 46 kDa kinase activity was induced in response to anisomycin but not in response to TPA.
# ::save-date Sun Jan 17, 2016 ::file bel_pmid_854_8291_16558.txt
(m / multi-sentence
      :snt1 (a / and
            :op1 (i4 / isoform
                  :mod (e3 / enzyme :name (n5 / name :op1 "SAPK"))
                  :quant (m2 / mass-quantity :quant 46
                        :unit (k / kilodalton)))
            :op2 (i5 / isoform
                  :mod e3
                  :quant (m3 / mass-quantity :quant 54
                        :unit (k3 / kilodalton)))
            :domain (i3 / isoform :quant 2
                  :mod e3))
      :snt2 (i / induce-01
            :ARG2 (a2 / activity-06
                  :ARG0 (k2 / kinase
                        :quant (m4 / mass-quantity :quant 46
                              :unit (k4 / kilodalton))))
            :ARG2-of (r / respond-01
                  :ARG1 (s / small-molecule :name (n6 / name :op1 "anisomycin")))
            :ARG1-of (c / contrast-01
                  :ARG2 (i2 / induce-01 :polarity -
                        :ARG2 a2
                        :ARG2-of (r2 / respond-01
                              :ARG1 (s2 / small-molecule :name (n4 / name :op1 "TPA")))))))

# ::id bel_pmid_854_8291.16560 ::date 2015-04-12T13:47:52 ::annotator SDL-AMR-09 ::preferred
# ::snt In NIH3T3 cells, co-transfection of an expression vector for Gal-Elk mediates expression from a transfected GAL-CAT reporter gene, which, as shown in Figure 6a,b, is potentiated upon treatment of serum-starved cells with anisomycin. Replacement of the major SAPK phosphorylation site in Gal-Elk, Ser383, with alanine (Gal-Elks 383 A) abrogates induction of reporter gene expression.
# ::save-date Sun Jan 17, 2016 ::file bel_pmid_854_8291_16560.txt
(m2 / multi-sentence
      :snt1 (m / mediate-01
            :ARG0 (c2 / cotransfect-01
                  :ARG2 (v / vector
                        :ARG1-of (e / express-03
                              :ARG2 (p / protein :name (n2 / name :op1 "Gal-Elk")))))
            :ARG1 (e2 / express-03
                  :ARG1 (g / gene :name (n3 / name :op1 "GAL-CAT")
                        :ARG0-of (r / report-01)
                        :ARG2-of (t / transfect-01))
                  :ARG1-of (p2 / potentiate-01
                        :ARG2 (t2 / treat-04
                              :ARG1 (c3 / cell
                                    :ARG1-of (s / starve-01
                                          :ARG2 (s2 / serum)))
                              :ARG2 (s4 / small-molecule :name (n7 / name :op1 "anisomycin")))
                        :ARG1-of (s3 / show-01
                              :ARG0 (a2 / and
                                    :op1 (f / figure :mod "6a")
                                    :op2 (f2 / figure :mod "6b")))))
            :location (c / cell-line :name (n / name :op1 "NIH3T3")))
      :snt2 (a3 / abrogate-01
            :ARG0 (r2 / replace-01
                  :ARG1 (p5 / protein-segment
                        :mod (a / amino-acid :mod 383 :name (n5 / name :op1 "serine")
                              :part-of (p4 / protein :name (n6 / name :op1 "Gal-Elk"))
                              :ARG1-of (p3 / phosphorylate-01
                                    :ARG2 (e4 / enzyme :name (n8 / name :op1 "SAPK"))))
                        :ARG1-of (m3 / major-02))
                  :ARG2 (a5 / amino-acid :mod 383 :name (n4 / name :op1 "alanine")
                        :part-of p4))
            :ARG1 (i / induce-01
                  :ARG0 r2
                  :ARG2 (e3 / express-03
                        :ARG1 (g2 / gene
                              :ARG0-of (r3 / report-01))))))

# ::id bel_pmid_854_8291.18250 ::date 2015-04-04T01:28:36 ::annotator SDL-AMR-09 ::preferred
# ::snt Elk-1 is phosphorylated by both kinases (MAPK8 and MAPK9) , each of which is strongly stimulated by pre-treatment of cells with ultraviolet light.
# ::save-date Mon Jul 13, 2015 ::file bel_pmid_854_8291_18250.txt
(p / phosphorylate-01
      :ARG1 (p2 / protein :name (n / name :op1 "Elk-1"))
      :ARG2 (a / and
            :op1 (k / kinase :name (n2 / name :op1 "MAPK8"))
            :op2 (k2 / kinase :name (n3 / name :op1 "MAPK9"))
            :ARG1-of (s / stimulate-01
                  :ARG0 (t / treat-04
                        :ARG1 (c / cell)
                        :ARG2 (l / light
                              :mod (u / ultraviolet))
                        :time (b / before))
                  :ARG1-of (s2 / strong-02))
            :mod (b2 / both)))

# ::id bel_pmid_854_8291.21982 ::date 2015-04-04T02:11:20 ::annotator SDL-AMR-09 ::preferred
# ::snt Figure 3b shows that activated SAPKs isolated from cells stimulate the formation of a ternary complex by Elk-1 (Fig. 3b, lanes 8 and 10).
# ::save-date Mon Apr 6, 2015 ::file bel_pmid_854_8291_21982.txt
(s / show-01
      :ARG0 (f / figure :mod "3b")
      :ARG1 (e / enzyme :name (n / name :op1 "SAPK")
            :ARG1-of (a / activate-01)
            :ARG1-of (i / isolate-01
                  :ARG2 (c / cell))
            :ARG0-of (s2 / stimulate-01
                  :ARG1 (f2 / form-01
                        :ARG0 (p / protein :name (n2 / name :op1 "Elk-1"))
                        :ARG1 (c2 / complex
                              :mod (t / ternary)))))
      :ARG1-of (d / describe-01
            :ARG0 (l / lane
                  :ARG1-of (l2 / label-01
                        :ARG2 (a2 / and :op1 8 :op2 10))
                  :part-of f)))

# ::id bel_pmid_854_8291.22000 ::date 2015-04-06T00:43:58 ::annotator SDL-AMR-09 ::preferred
# ::snt As shown in Figure 6e, expression of MEKK1 fails to activate either ERK1 or ERK2, whereas both p46 SAPK and p54SAPK are activated at expression levels that result in reporter gene expression.
# ::save-date Fri Apr 24, 2015 ::file bel_pmid_854_8291_22000.txt
(f2 / fail-01
      :ARG1 (e / express-03
            :ARG2 (e2 / enzyme :name (n / name :op1 "MEKK1")))
      :ARG2 (a / activate-01
            :ARG0 e
            :ARG1 (o / or
                  :op1 (e3 / enzyme :name (n2 / name :op1 "ERK1"))
                  :op2 (e4 / enzyme :name (n3 / name :op1 "ERK2"))))
      :ARG1-of (c / contrast-01
            :ARG2 (a2 / activate-01
                  :ARG0 (l / level
                        :ARG1-of (r / result-01
                              :ARG2 (e8 / express-03
                                    :ARG1 (g / gene
                                          :ARG0-of (r2 / report-01))))
                        :degree-of e)
                  :ARG1 (a3 / and
                        :op1 (e5 / enzyme :name (n4 / name :op1 "p46" :op2 "SAPK"))
                        :op2 (e6 / enzyme :name (n5 / name :op1 "p54" :op2 "SAPK"))
                        :mod (b / both))))
      :ARG1-of (s / show-01
            :ARG0 (f / figure :mod "6e")))

# ::id bel_pmid_854_8291.29024 ::date 2015-04-07T22:51:45 ::annotator SDL-AMR-09 ::preferred
# ::snt Co-transfection of 1.25 ug MEKK1 expression vector elicited a 24-fold activation of Gal-Elk-dependent reporter expression in serum-starved NIH3T3 cells (Fig. 6c,d).
# ::save-date Sun Jan 17, 2016 ::file bel_pmid_854_8291_29024.txt
(e / elicit-01
      :ARG0 (c / cotransfect-01
            :ARG2 (v / vector
                  :ARG1-of (e2 / express-03
                        :ARG2 (e3 / enzyme :name (n / name :op1 "MEKK1")
                              :quant (m / mass-quantity :quant 1.25
                                    :unit (m2 / microgram))))))
      :ARG1 (a / activate-01
            :ARG0 c
            :ARG1 (e4 / express-03
                  :ARG1 (g / gene
                        :ARG0-of (r / report-01)
                        :ARG0-of (d / depend-01
                              :ARG1 (p2 / protein :name (n2 / name :op1 "Gal-Elk"))))
                  :ARG3 (c2 / cell-line :name (n3 / name :op1 "NIH3T3")
                        :ARG1-of (s / starve-01
                              :ARG2 (s2 / serum))))
            :quant (p / product-of :op1 24))
      :ARG1-of (d2 / describe-01
            :ARG0 (a2 / and
                  :op1 (f / figure :mod "6c")
                  :op2 (f2 / figure :mod "6d"))))

# ::id bel_pmid_854_8291.32900 ::date 2015-04-06T09:17:27 ::annotator SDL-AMR-09 ::preferred
# ::snt The observation that Elk-1 is phosphorylated directly and activated by p46SAPK and p54SAPK further implicates it in the stress-response induction of the c-fos gene.
# ::save-date Sun Jan 3, 2016 ::file bel_pmid_854_8291_32900.txt
(i / implicate-01
      :ARG0 (o / observe-01
            :ARG1 (a / and
                  :op1 (p / phosphorylate-01
                        :ARG1 (p2 / protein :name (n / name :op1 "Elk-1"))
                        :ARG2 (a3 / and
                              :op1 (e / enzyme :name (n2 / name :op1 "p46SAPK"))
                              :op2 (e2 / enzyme :name (n3 / name :op1 "p54SAPK")))
                        :ARG1-of (d / direct-02))
                  :op2 (a2 / activate-01
                        :ARG0 a3
                        :ARG1 p2)))
      :ARG1 p2
      :ARG2 (i2 / induce-01
            :ARG2 (g / gene :name (n4 / name :op1 "c-fos"))
            :ARG2-of (r / respond-01
                  :ARG1 (s / stress-02)))
      :degree (f / further))

# ::id bel_pmid_854_8291.36930 ::date 2015-04-07T00:33:38 ::annotator SDL-AMR-09 ::preferred
# ::snt For comparison, ElkC was also phosphorylated using recombinant ERK1 that had been activated by phosphorylation with a constitutively active mutant of the MAPK/ERK kinase MKK1 [23].
# ::save-date Wed Jan 13, 2016 ::file bel_pmid_854_8291_36930.txt
(p / phosphorylate-01
      :ARG1 (p2 / protein :name (n / name :op1 "ElkC"))
      :ARG2 (u / use-01
            :ARG1 (e / enzyme :name (n2 / name :op1 "ERK1")
                  :ARG0-of (r / recombine-01)
                  :ARG1-of (a2 / activate-01
                        :ARG0 (p3 / phosphorylate-01
                              :ARG1 e
                              :ARG2 (e2 / enzyme :name (n3 / name :op1 "MKK1")
                                    :ARG0-of (a3 / activity-06
                                          :mod (c2 / constitutive))
                                    :ARG1-of (i / include-91
                                          :ARG2 (p5 / protein-family :name (n5 / name :op1 "MAPK/ERK"))))))))
      :purpose (c / compare-01)
      :mod (a / also)
      :ARG1-of (d / describe-01
            :ARG0 (p4 / publication-91
                  :ARG1-of (c3 / cite-01
                        :ARG2 23))))

# ::id bel_pmid_859_8496.27892 ::date 2015-04-09T21:25:46 ::annotator SDL-AMR-09 ::preferred
# ::snt In the case of Th2-type cytokines, enhanced production of IL-4 and IL-6 was reduced by treatment with anti-TGF-/3 or anti-IL- IO (Fig. 5B).
# ::save-date Mon Dec 21, 2015 ::file bel_pmid_859_8496_27892.txt
(r / reduce-01
      :ARG0 (t / treat-04
            :ARG1 (c4 / cytokine :name (n4 / name :op1 "Th2")
                  :ARG1-of (t2 / type-03))
            :ARG2 (o / or
                  :op1 (a2 / antibody
                        :ARG0-of (c3 / counter-01
                              :ARG1 (p4 / protein :name (n3 / name :op1 "TGF-/3"))))
                  :op2 (a3 / antibody
                        :ARG0-of (c / counter-01
                              :ARG1 (p7 / protein :name (n5 / name :op1 "IL-IO"))))))
      :ARG1 (p / produce-01
            :ARG1 (a / and
                  :op1 (p2 / protein :name (n / name :op1 "IL-4"))
                  :op2 (p3 / protein :name (n2 / name :op1 "IL-6")))
            :ARG1-of (e / enhance-01))
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod "5B")))

# ::id bel_pmid_859_8496.31126 ::date 2015-04-15T21:52:07 ::annotator SDL-AMR-09 ::preferred
# ::snt As shown in Figure 5A, reduced production of Th I -type cytokines (IFN-y, not detected; IL-2, 38.0 -t 10.0%) by EL4-T was significantly rcstored by treatmcnt with anti-TGF-P (IFN-y, 191.0 i 21.9%; IL-2, 8 I . 1 i 17.5%), while anti-IL- IO treatment had little etfect
# ::save-date Thu Feb 4, 2016 ::file bel_pmid_859_8496_31126.txt
(r / restore-01
      :ARG1 (p / produce-01
            :ARG1 (c3 / cytokine :name (n8 / name :op1 "Th1")
                  :ARG1-of (t3 / type-03)
                  :example (a / and
                        :op1 (p2 / protein :name (n2 / name :op1 "IFN-y")
                              :ARG1-of (d / detect-01 :polarity -))
                        :op2 (p6 / protein :name (n5 / name :op1 "IL-2," :op2 "38.0" :op3 "-t")
                              :quant (p7 / percentage-entity :value 10.0))))
            :ARG1-of (r2 / reduce-01
                  :ARG0 (c2 / cell :name (n / name :op1 "EL4-T"))))
      :ARG1-of (s2 / significant-02)
      :manner (t / treat-04
            :ARG1 c2
            :ARG2 (a4 / antibody
                  :ARG0-of (c6 / counter-01
                        :ARG1 (p5 / protein :name (n4 / name :op1 "TGF-P")
                              :example (a3 / and
                                    :op1 (p8 / protein :name (n6 / name :op1 "IFN-y," :op2 "191.0" :op3 "i")
                                          :quant (p9 / percentage-entity :value 21.9))
                                    :op2 (p10 / protein :name (n7 / name :op1 "IL-2," :op2 "8" :op3 "I" :op4 "." :op5 "1" :op6 "i")
                                          :quant (p11 / percentage-entity :value 17.5)))))))
      :ARG1-of (c4 / contrast-01
            :ARG2 (a2 / affect-01
                  :ARG0 (t2 / treat-04
                        :ARG1 c2
                        :ARG2 (a5 / antibody
                              :ARG0-of (c5 / counter-01
                                    :ARG1 (p4 / protein :name (n3 / name :op1 "IL-IO")))))
                  :ARG1 c2
                  :degree (l / little)))
      :ARG1-of (s / show-01
            :ARG0 (f / figure :mod "5A")))

# ::id bel_pmid_862_1729.21570 ::date 2015-04-07T04:29:41 ::annotator SDL-AMR-09 ::preferred
# ::snt Similar observation that immunoprecipitated B-Raf from EGF-stimulated Swiss3T3 cells could activate both MEK1 and MEK2 was also obtained (data not shown).
# ::save-date Sun Jan 3, 2016 ::file bel_pmid_862_1729_21570.txt
(o / obtain-01
      :ARG1 (o2 / observe-01
            :ARG1 (p / possible-01
                  :ARG1 (a / activate-01
                        :ARG0 (e / enzyme :name (n / name :op1 "B-Raf")
                              :ARG1-of (i / immunoprecipitate-01
                                    :ARG2 (c / cell-line :name (n2 / name :op1 "Swiss3T3")
                                          :ARG1-of (s / stimulate-01
                                                :ARG0 (p2 / protein :name (n3 / name :op1 "EGF"))))))
                        :ARG1 (a2 / and
                              :op1 (e2 / enzyme :name (n4 / name :op1 "MEK1"))
                              :op2 (e3 / enzyme :name (n5 / name :op1 "MEK2"))
                              :mod (b / both))))
            :ARG1-of (r / resemble-01))
      :mod (a3 / also)
      :ARG1-of (d / describe-01
            :ARG0 (d2 / data
                  :ARG1-of (s2 / show-01 :polarity -))))

# ::id bel_pmid_862_1729.36932 ::date 2015-04-15T08:57:17 ::annotator SDL-AMR-09 ::preferred
# ::snt The activated GST-MEK1 was then used to activate the purified recombinant extracellular signal-regulated kinase 1, whose activity was measured by the [32P-g]ATP incorporation into MBP, an extracellular signal-regulated kinase 1 substrate.
# ::save-date Sun Jan 17, 2016 ::file bel_pmid_862_1729_36932.txt
(u / use-01
      :ARG1 (e / enzyme :name (n / name :op1 "GST-MEK1")
            :ARG1-of (a / activate-01))
      :ARG2 (a2 / activate-01
            :ARG0 e
            :ARG1 (e2 / enzyme :name (n2 / name :op1 "extracellular" :op2 "signal-regulated" :op3 "kinase" :op4 "1")
                  :ARG0-of (r / recombine-01)
                  :ARG1-of (p / purify-01)
                  :ARG0-of (a3 / activity-06
                        :ARG1-of (m / measure-01
                              :manner (i / incorporate-02
                                    :ARG1 (s / small-molecule :name (n3 / name :op1 "ATP")
                                          :part (p3 / phosphate
                                                :quant (m2 / molecular-mass :value 32)
                                                :mod (g / gamma)))
                                    :ARG2 (p2 / protein :name (n4 / name :op1 "MBP")
                                          :ARG1-of (m4 / mean-01
                                                :ARG2 (s2 / substrate
                                                      :poss e2))))))))
      :time (t / then))

# ::id bel_pmid_862_1729.37176 ::date 2015-04-04T03:10:14 ::annotator SDL-AMR-09 ::preferred
# ::snt c-Raf activates MEK1 by phosphorylating at serine residues 218 and 222 (30–32).
# ::save-date Sun Jan 3, 2016 ::file bel_pmid_862_1729_37176.txt
(a / activate-01
      :ARG0 (e / enzyme :name (n / name :op1 "c-Raf"))
      :ARG1 e3
      :manner (p / phosphorylate-01
            :ARG1 (r / residue :mod 218 :mod 222
                  :mod (a2 / amino-acid :name (n3 / name :op1 "serine")
                        :part-of (e3 / enzyme :name (n4 / name :op1 "MEK1"))
                        :mod (b / between
                              :op1 (a3 / amino-acid :mod 30)
                              :op2 (a4 / amino-acid :mod 32))))))

# ::id bel_pmid_862_2669.21840 ::date 2015-04-04T13:31:38 ::annotator SDL-AMR-09 ::preferred
# ::snt activated MEK1 increased Elk-1- and c-Jun-dependent gene expression but not ATF2-dependent gene expression (Fig. 4).
# ::save-date Wed Apr 22, 2015 ::file bel_pmid_862_2669_21840.txt
(i / increase-01
      :ARG0 (e / enzyme :name (n / name :op1 "MEK1")
            :ARG1-of (a / activate-01))
      :ARG1 (e2 / express-03
            :ARG1 (g / gene
                  :ARG0-of (d / depend-01
                        :ARG1 (a2 / and
                              :op1 (p / protein :name (n2 / name :op1 "Elk-1"))
                              :op2 (p2 / protein :name (n3 / name :op1 "c-Jun"))))))
      :ARG1-of (c / contrast-01
            :ARG2 (i2 / increase-01 :polarity -
                  :ARG0 e
                  :ARG1 (e3 / express-03
                        :ARG1 (g2 / gene
                              :ARG0-of (d2 / depend-01
                                    :ARG1 (p3 / protein :name (n4 / name :op1 "ATF2")))))))
      :ARG1-of (d3 / describe-01
            :ARG0 (f / figure :mod 4)))

# ::id bel_pmid_862_2669.21852 ::date 2015-04-05T22:27:26 ::annotator SDL-AMR-09 ::preferred
# ::snt MKK3(Glu) increased ATF2- and Elk-1-dependent reporter gene expression but caused only a small increase in Jun-dependent gene expression (Fig. 4).
# ::save-date Wed Apr 22, 2015 ::file bel_pmid_862_2669_21852.txt
(c / contrast-01
      :ARG1 (i / increase-01
            :ARG0 (e / enzyme :name (n / name :op1 "MKK3(Glu)"))
            :ARG1 (e2 / express-03
                  :ARG1 (g / gene
                        :ARG0-of (r / report-01)
                        :ARG0-of (d / depend-01
                              :ARG1 (a / and
                                    :op1 (p2 / protein :name (n2 / name :op1 "ATF2"))
                                    :op2 (p / protein :name (n3 / name :op1 "Elk-1")))))))
      :ARG2 (c2 / cause-01
            :ARG0 e
            :ARG1 (i2 / increase-01
                  :ARG1 (e4 / express-03
                        :ARG1 (g2 / gene
                              :ARG0-of (d2 / depend-01
                                    :ARG1 (p3 / protein :name (n4 / name :op1 "Jun")))))
                  :degree (s / small
                        :mod (o / only))))
      :ARG1-of (d3 / describe-01
            :ARG0 (f / figure :mod 4)))

# ::id bel_pmid_862_2669.21858 ::date 2015-04-05T23:27:41 ::annotator SDL-AMR-09 ::preferred
# ::snt In contrast, the effect of MKK6(Glu) was markedly reduced in experiments using phosphorylation-defective (Ala-69, Ala-71) ATF2.
# ::save-date Tue Jun 16, 2015 ::file bel_pmid_862_2669_21858.txt
(c / contrast-01
      :ARG2 (r / reduce-01
            :ARG1 (a / affect-01
                  :ARG0 (e2 / enzyme :name (n / name :op1 "MKK6(Glu)")))
            :manner (m / marked)
            :topic (e3 / experiment-01
                  :ARG2 (u / use-01
                        :ARG1 (p2 / protein :name (n2 / name :op1 "ATF2")
                              :ARG2-of (p / phosphorylate-01
                                    :mod (d / defective))
                              :part (a4 / amino-acid :mod 69 :mod 71 :name (n5 / name :op1 "alanine")))))))

# ::id bel_pmid_862_2669.21860 ::date 2015-04-14T04:16:44 ::annotator SDL-AMR-09 ::preferred
# ::snt Increased ATF2-dependent gene expression was observed in cells transfected with MKK6(Glu). In contrast, MKK3(Glu) did not increase ATF2-dependent gene expression in the absence of overexpression of p38 MAP kinase (Fig. 8A).
# ::save-date Fri Jan 15, 2016 ::file bel_pmid_862_2669_21860.txt
(m / multi-sentence
      :snt1 (o / observe-01
            :ARG1 (e / express-03
                  :ARG1 (g / gene
                        :ARG0-of (d / depend-01
                              :ARG1 (p / protein :name (n / name :op1 "ATF2"))))
                  :ARG3 (c / cell
                        :ARG1-of (t / transfect-01
                              :ARG2 (e3 / enzyme :name (n2 / name :op1 "MKK6(Glu)"))))
                  :ARG1-of (i / increase-01)))
      :snt2 (i2 / increase-01 :polarity -
            :ARG0 (e4 / enzyme :name (n3 / name :op1 "MKK3(Glu)"))
            :ARG1 (e5 / express-03
                  :ARG1 (g2 / gene
                        :ARG0-of (d2 / depend-01
                              :ARG1 (p2 / protein :name (n4 / name :op1 "ATF2")))))
            :ARG2-of (c2 / contrast-01)
            :condition (a / absent-01
                  :ARG1 (o2 / overexpress-01
                        :ARG1 (k / kinase :name (n5 / name :op1 "p38" :op2 "MAP" :op3 "kinase"))))
            :ARG1-of (d3 / describe-01
                  :ARG0 (f / figure :mod "8A"))))

# ::id bel_pmid_872_5172.30236 ::date 2015-04-09T09:13:49 ::annotator SDL-AMR-09 ::preferred
# ::snt Specifically, PTH and PTHrP rapidly and transiently induce expression of the mRNAs encoding IL-6 and LIF.
# ::save-date Sun Jan 3, 2016 ::file bel_pmid_872_5172_30236.txt
(i / induce-01
      :ARG0 (a / and
            :op1 (e / enzyme :name (n / name :op1 "PTH"))
            :op2 (e2 / enzyme :name (n2 / name :op1 "PTHrP")))
      :ARG2 (e3 / express-03
            :ARG1 (n5 / nucleic-acid :name (n6 / name :op1 "mRNA")
                  :ARG0-of (e4 / encode-01
                        :ARG1 (a2 / and
                              :op1 (p / protein :name (n3 / name :op1 "IL-6"))
                              :op2 (p2 / protein :name (n4 / name :op1 "LIF"))))))
      :ARG1-of (s / specific-02)
      :manner (r / rapid)
      :ARG1-of (t / transient-02))

# ::id bel_pmid_879_8479.3974 ::date 2015-04-11T22:16:31 ::annotator SDL-AMR-09 ::preferred
# ::snt endogenous GMF is rapidly phosphorylated upon stimulation of astrocytes by phorbol 12-myristate 13-acetate We further observed that protein kinase A (PKA)-phosphorylated GMF is a potent inhibitor (IC50 = 3 nM) of the ERK1/ERK2 (p44/p42) subfamily of mitogen-activated protein (MAP) kinase.
# ::save-date Mon Jan 4, 2016 ::file bel_pmid_879_8479_3974.txt
(m / multi-sentence
      :snt1 (p / phosphorylate-01
            :ARG1 (p2 / protein :name (n / name :op1 "GMF")
                  :mod (e / endogenous))
            :ARG2 (e3 / enzyme :name (n6 / name :op1 "PKA"))
            :manner (r / rapid)
            :condition (s / stimulate-01
                  :ARG0 (s3 / small-molecule :name (n2 / name :op1 "phorbol" :op2 "12-myristate" :op3 "13-acetate"))
                  :ARG1 (a / astrocyte)))
      :snt2 (o / observe-01
            :ARG0 (w / we)
            :ARG1 (i / inhibit-01
                  :ARG0 (p3 / protein :name (n3 / name :op1 "GMF")
                        :ARG1-of (p4 / phosphorylate-01
                              :ARG2 (e2 / enzyme :name (n10 / name :op1 "protein" :op2 "kinase" :op3 "A"))))
                  :ARG1 (s2 / slash
                        :op1 (e6 / enzyme :name (n4 / name :op1 "p44" :op2 "ERK1"))
                        :op2 (e7 / enzyme :name (n11 / name :op1 "p42" :op2 "ERK2"))
                        :ARG1-of (i2 / include-91
                              :ARG2 (p5 / protein-family :name (n9 / name :op1 "mitogen-activated" :op2 "protein" :op3 "kinase"))))
                  :mod (p6 / potent)
                  :ARG3-of (h / have-percentage-maximal-inhibitory-concentration-01
                        :ARG2 50
                        :ARG4 (c / concentration-quantity :quant 3
                              :unit (n5 / nanomolar))))
            :degree (f / further)))

# ::id bel_pmid_879_8479.8862 ::date 2015-04-08T00:14:46 ::annotator SDL-AMR-09 ::preferred
# ::snt PKA-phosphorylated GMF strongly enhances the activity of a related but distinct subfamily of MAP kinase, the p38 MAP kinase, showing an increase of 60-fold over baseline and an EC50 of 7 nM.
# ::save-date Sun Jan 3, 2016 ::file bel_pmid_879_8479_8862.txt
(a / and
      :op1 (e / enhance-01
            :ARG0 (p / protein :name (n / name :op1 "GMF")
                  :ARG1-of (p2 / phosphorylate-01
                        :ARG2 (e2 / enzyme :name (n2 / name :op1 "PKA"))))
            :ARG1 (a2 / activity-06
                  :ARG0 (k / kinase :name (n4 / name :op1 "p38" :op2 "MAP")
                        :ARG1-of (r / relate-01
                              :ARG2 p5
                              :concession-of (d / distinct
                                    :compared-to p5))
                        :ARG1-of (i2 / include-91
                              :ARG2 (p5 / protein-family :name (n6 / name :op1 "MAP" :op2 "kinase")))))
            :ARG1-of (s2 / strong-02))
      :op2 (s / show-01
            :ARG0 p
            :ARG1 (a3 / and
                  :op1 (i / increase-01
                        :ARG1 k
                        :ARG2 (p3 / product-of :op1 60)
                        :manner (o / over
                              :op1 (b / baseline)))
                  :op2 (h / have-percentage-maximal-effective-concentration-01
                        :ARG1 p
                        :ARG2 50
                        :ARG4 (c3 / concentration-quantity :quant 7
                              :unit (n5 / nanomolar))))))

# ::id bel_pmid_879_8479.16716 ::date 2015-04-09T09:12:44 ::annotator SDL-AMR-09 ::preferred
# ::snt intracellular interaction of PKA, GMF, and p38 is supported by the phosphorylation of GMF upon cellular stimulation by forskolin (blocked by PKA inhibitor) and by the co-immunoprecipitation of p38 with GMF from cell lysates. Withdrawal of nerve growth factor from PC12 leads to increased GMF phosphorylation with a time course similar to that reported for p38 activation.
# ::save-date Wed Feb 24, 2016 ::file bel_pmid_879_8479_16716.txt
(m / multi-sentence
      :snt1 (s / support-01
            :ARG0 (a2 / and
                  :op1 (p / phosphorylate-01
                        :ARG1 p5
                        :ARG2 (s2 / stimulate-01
                              :ARG0 (s3 / small-molecule :name (n8 / name :op1 "forskolin")
                                    :ARG1-of (b / block-01
                                          :ARG0 (m2 / molecular-physical-entity
                                                :ARG0-of (i4 / inhibit-01
                                                      :ARG1 (e4 / enzyme :name (n9 / name :op1 "PKA"))))))
                              :ARG1 (c / cell)))
                  :op2 (c2 / coimmunoprecipitate-01
                        :ARG1 (e / enzyme :name (n / name :op1 "p38"))
                        :ARG2 (p5 / protein :name (n3 / name :op1 "GMF")
                              :source (l / lysate
                                    :part-of (c3 / cell
                                          :ARG0-of (c4 / contain-01
                                                :ARG1 (p3 / protein)))))))
            :ARG1 (i / interact-01
                  :ARG0 (a / and
                        :op1 (e3 / enzyme)
                        :op2 p3)
                  :ARG1 e))
      :snt2 (l2 / lead-03
            :ARG1 (w / withdraw-01
                  :ARG1 (g / growth-factor
                        :mod (n2 / nerve))
                  :ARG2 (c5 / cell-line :name (n4 / name :op1 "PC12")))
            :ARG2 (p2 / phosphorylate-01
                  :ARG1 (p4 / protein :name (n6 / name :op1 "GMF")
                        :ARG1-of (i3 / increase-01))
                  :ARG0-of (h / have-03
                        :ARG1 (c6 / course
                              :mod (t / time)
                              :ARG1-of (r / resemble-01
                                    :ARG2 (c7 / course
                                          :mod (t2 / time)
                                          :ARG1-of (r2 / report-01
                                                :topic (a3 / activate-01
                                                      :ARG1 (e2 / enzyme :name (n7 / name :op1 "p38")))))))))))

# ::id bel_pmid_894_3354.24786 ::date 2015-04-01T06:03:05 ::annotator SDL-AMR-09 ::preferred
# ::snt In addition, SHP-1 and its mutants showed similar association and dephosphorylation of the other Jak family members (JAK1, Tyk2, and JAK3) but not c-fes when coexpressed in Cos-7 cells (data not shown).
# ::save-date Tue Feb 2, 2016 ::file bel_pmid_894_3354_24786.txt
(a / and
      :op2 (s / show-01
            :ARG0 (a2 / and
                  :op1 (e / enzyme :name (n / name :op1 "SHP-1"))
                  :op2 (e2 / enzyme :name (n8 / name :op1 "SHP-1")
                        :ARG2-of (m / mutate-01)))
            :ARG1 (a3 / and
                  :op1 (a4 / associate-01
                        :ARG1 a2
                        :ARG2 (m2 / member
                              :mod (o / other)
                              :ARG1-of (m3 / mean-01
                                    :ARG2 (a5 / and
                                          :op1 (e3 / enzyme :name (n3 / name :op1 "JAK1"))
                                          :op2 (e4 / enzyme :name (n4 / name :op1 "Tyk2"))
                                          :op3 (e5 / enzyme :name (n5 / name :op1 "JAK3"))))
                              :ARG1-of (c / contrast-01
                                    :ARG2 (e8 / enzyme :name (n2 / name :op1 "c-fes")))
                              :ARG1-of (i2 / include-91
                                    :ARG2 (p / protein-family :name (n6 / name :op1 "Jak")))))
                  :op2 (d / dephosphorylate-01
                        :ARG1 m2
                        :ARG2 a2)
                  :ARG1-of (r / resemble-01))
            :time (c2 / coexpress-01
                  :ARG2 a2
                  :ARG3 (c3 / cell-line :name (n7 / name :op1 "Cos-7"))))
      :ARG1-of (d2 / describe-01
            :ARG0 (d3 / data
                  :ARG1-of (s2 / show-01 :polarity -))))

# ::id bel_pmid_902_3347.41730 ::date 2015-04-01T06:22:17 ::annotator SDL-AMR-09 ::preferred
# ::snt Hypoxia was capable of inducing VEGF mRNA in both immortalized and transformed endothelial cells (4.5-fold in cells expressing SV40 large T antigen alone or in combination with H-ras), but both baseline and induced VEGF mRNA expression was increased in cells containing activated ras (Fig. 4).
# ::save-date Thu Jan 28, 2016 ::file bel_pmid_902_3347_41730.txt
(c8 / contrast-01
      :ARG1 (c / capable-01
            :ARG1 (h / hypoxia)
            :ARG2 (i2 / induce-01
                  :ARG2 (n3 / nucleic-acid :name (n6 / name :op1 "mRNA")
                        :ARG0-of (e3 / encode-01
                              :ARG1 (p / protein :name (n4 / name :op1 "VEGF"))))
                  :location (a / and
                        :op1 (c2 / cell
                              :ARG1-of (i / immortalize-03))
                        :op2 (c3 / cell
                              :ARG1-of (t / transform-01))
                        :part-of (e4 / endothelium)
                        :mod (b3 / both))
                  :ARG1-of (m2 / mean-01
                        :ARG2 (p2 / product-of :op1 4.5)
                        :location (c6 / cell
                              :ARG3-of (e7 / express-03
                                    :ARG1 (o / or
                                          :op1 (p3 / protein :name (n5 / name :op1 "SV40" :op2 "large" :op3 "T" :op4 "antigen")
                                                :mod (a4 / alone))
                                          :op2 (c7 / combine-01
                                                :ARG1 p3
                                                :ARG2 (e / enzyme :name (n / name :op1 "H-Ras")))))))))
      :ARG2 (i4 / increase-01
            :ARG1 (a3 / and
                  :op1 (e5 / express-03
                        :ARG2 n3
                        :mod (b / baseline))
                  :op2 (e6 / express-03
                        :ARG2 n3
                        :ARG1-of i2)
                  :mod (b2 / both))
            :location (c4 / cell
                  :ARG0-of (c5 / contain-01
                        :ARG1 (e2 / enzyme :name (n2 / name :op1 "Ras")
                              :ARG1-of (a2 / activate-01)))))
      :ARG1-of (d2 / describe-01
            :ARG0 (f / figure :mod 4)))

# ::id bel_pmid_902_3347.41732 ::date 2015-04-01T06:49:52 ::annotator SDL-AMR-09 ::preferred
# ::snt Treatment of cells with wortmannin, a steroidal inhibitor of phosphatidylinositol-3-kinase (15), resulted in a decreased level of VEGF under hypoxic conditions but the fold stimulation of VEGF mRNA was not changed (Fig. 5).
# ::save-date Wed Apr 8, 2015 ::file bel_pmid_902_3347_41732.txt
(c3 / contrast-01
      :ARG1 (r / result-01
            :ARG1 (t / treat-04
                  :ARG1 (c / cell)
                  :ARG2 (s3 / small-molecule :name (n / name :op1 "wortmannin")
                        :ARG0-of (i3 / inhibit-01
                              :ARG1 (e / enzyme :name (n2 / name :op1 "phosphatidylinositol-3-kinase")))
                        :mod (s / steroid)
                        :ARG1-of (d / describe-01
                              :ARG0 (p / publication
                                    :ARG1-of (c2 / cite-01
                                          :ARG2 15)))))
            :ARG2 (l / level
                  :quant-of (p2 / protein :name (n3 / name :op1 "VEGF"))
                  :ARG1-of (d2 / decrease-01))
            :condition (h / hypoxia))
      :ARG2 (c4 / change-01 :polarity -
            :ARG1 (s2 / stimulate-01
                  :ARG1 (n4 / nucleic-acid :name (n5 / name :op1 "mRNA")
                        :ARG0-of (e2 / encode-01
                              :ARG1 p2))
                  :extent (f / fold)))
      :ARG1-of (d4 / describe-01
            :ARG0 (f2 / figure :mod 5)))

# ::id bel_pmid_902_3347.41734 ::date 2015-04-01T07:04:28 ::annotator SDL-AMR-09 ::preferred
# ::snt Cells with activated ras demonstrated high level of expression of 72-kDa metalloproteinase (MMP-2, gelatinase A), and 92-kDa metalloproteinase (MMP-9, gelatinase B) compared with cells containing SV40 large T antigen alone.
# ::save-date Sun Jan 3, 2016 ::file bel_pmid_902_3347_41734.txt
(d / demonstrate-01
      :ARG0 (c / cell
            :ARG0-of (c2 / contain-01
                  :ARG1 (e / enzyme :name (n / name :op1 "Ras")
                        :ARG1-of (a / activate-01))))
      :ARG1 (l / level
            :ARG1-of (h / high-02
                  :compared-to (c3 / cell
                        :ARG0-of (c4 / contain-01
                              :ARG1 (p / protein :name (n8 / name :op1 "SV40" :op2 "large" :op3 "T" :op4 "antigen")
                                    :mod (a5 / alone)))))
            :degree-of (e2 / express-03
                  :ARG2 (a2 / and
                        :op1 (e3 / enzyme :name (n2 / name :op1 "metalloproteinase")
                              :ARG1-of (m / mean-01
                                    :ARG2 (a3 / and
                                          :op1 (e5 / enzyme :name (n4 / name :op1 "MMP-2"))
                                          :op2 (e6 / enzyme :name (n5 / name :op1 "gelatinase" :op2 "A"))))
                              :quant (m3 / mass-quantity :quant 72
                                    :unit (k / kilodalton)))
                        :op2 (e4 / enzyme :name (n3 / name :op1 "metalloproteinase")
                              :ARG1-of (m2 / mean-01
                                    :ARG2 (a4 / and
                                          :op1 (e7 / enzyme :name (n6 / name :op1 "MMP-9"))
                                          :op2 (e8 / enzyme :name (n7 / name :op1 "gelatinase" :op2 "B"))))
                              :quant (m4 / mass-quantity :quant 92
                                    :unit (k2 / kilodalton)))))))

# ::id bel_pmid_902_3347.41736 ::date 2015-04-01T07:16:48 ::annotator SDL-AMR-09 ::preferred
# ::snt Treatment of ras-containing cells with wortmannin resulted in a decrease in MMP expression (Fig. 6).
# ::save-date Wed Apr 8, 2015 ::file bel_pmid_902_3347_41736.txt
(r / result-01
      :ARG1 (t / treat-04
            :ARG1 (c / cell
                  :ARG0-of (c2 / contain-01
                        :ARG1 (e / enzyme :name (n / name :op1 "Ras"))))
            :ARG2 (s / small-molecule :name (n2 / name :op1 "wortmannin")))
      :ARG2 (d / decrease-01
            :ARG1 (e2 / express-03
                  :ARG2 (e3 / enzyme :name (n3 / name :op1 "MMP"))))
      :ARG1-of (d2 / describe-01
            :ARG0 (f / figure :mod 6)))

# ::id bel_pmid_902_3347.41744 ::date 2015-04-01T07:21:26 ::annotator SDL-AMR-09 ::preferred
# ::snt Since wortmannin inhibits VEGF and MMP activity, but does not restore TIMP activity, tumor-igenesis is not expected to be fully suppressed.
# ::save-date Mon Jul 6, 2015 ::file bel_pmid_902_3347_41744.txt
(e / expect-01 :polarity -
      :ARG1 (s / suppress-01
            :ARG1 (c3 / create-01
                  :ARG1 (t / tumor))
            :degree (f / full))
      :ARG1-of (c / cause-01
            :ARG0 (c2 / contrast-01
                  :ARG1 (i / inhibit-01
                        :ARG0 (s2 / small-molecule :name (n / name :op1 "wortmannin"))
                        :ARG1 (a / activity-06
                              :ARG0 (a2 / and
                                    :op1 (p / protein :name (n2 / name :op1 "VEGF"))
                                    :op2 (e2 / enzyme :name (n3 / name :op1 "MMP")))))
                  :ARG2 (r / restore-01 :polarity -
                        :ARG0 s2
                        :ARG1 (a3 / activity-06
                              :ARG0 (p2 / protein :name (n4 / name :op1 "TIMP")))))))

# ::id bel_pmid_902_3347.41748 ::date 2015-04-01T07:30:11 ::annotator SDL-AMR-09 ::preferred
# ::snt Wortmannin could inhibit ras-mediated induction of VEGF, but it did not inhibit the hypoxic regulation of VEGF.
# ::save-date Sun Dec 20, 2015 ::file bel_pmid_902_3347_41748.txt
(c / contrast-01
      :ARG1 (p / possible-01
            :ARG1 (i / inhibit-01
                  :ARG0 (s / small-molecule :name (n / name :op1 "wortmannin"))
                  :ARG1 (i2 / induce-01
                        :ARG2 (p2 / protein :name (n2 / name :op1 "VEGF"))
                        :ARG1-of (m2 / mediate-01
                              :ARG0 (e / enzyme :name (n3 / name :op1 "Ras"))))))
      :ARG2 (i3 / inhibit-01 :polarity -
            :ARG0 s
            :ARG1 (r / regulate-01
                  :ARG1 p2
                  :mod (h / hypoxia))))

# ::id bel_pmid_902_3347.41750 ::date 2015-04-01T07:33:57 ::annotator SDL-AMR-09 ::preferred
# ::snt This suggests that the hypoxic regulation of VEGF is independent of phosphatidylinositol-3-kinase.
# ::save-date Wed Apr 8, 2015 ::file bel_pmid_902_3347_41750.txt
(s / suggest-01
      :ARG0 (t / this)
      :ARG1 (d / depend-01 :polarity -
            :ARG0 (r / regulate-01
                  :ARG1 (p / protein :name (n / name :op1 "VEGF"))
                  :mod (h / hypoxia))
            :ARG1 (e / enzyme :name (n2 / name :op1 "phosphatidylinositol-3-kinase"))))

# ::id bel_pmid_911_5219.31418 ::date 2015-04-01T07:36:46 ::annotator SDL-AMR-09 ::preferred
# ::snt PITSLRE kinases are a superfamily of Cdc2-like kinases that have been implicated in apoptotic signaling and tumorigenesis. In this paper we report that tumor necrosis factor (TNF)-mediated apoptosis is associated with a CrmA- and Bcl-2-inhibitable cleavage of PITSLRE kinases, indicating a role for CASPs.
# ::save-date Sun Jan 3, 2016 ::file bel_pmid_911_5219_31418.txt
(m / multi-sentence
      :snt1 (s / superfamily
            :domain (k2 / kinase :name (n / name :op1 "PITSLRE"))
            :ARG1-of (i / implicate-01
                  :ARG2 (a / and
                        :op1 (s2 / signal-07
                              :ARG1 (a2 / apoptosis))
                        :op2 (c2 / create-01
                              :ARG1 (t / tumor))))
            :ARG2-of (i4 / include-91
                  :ARG1 (k / kinase
                        :ARG1-of (r / resemble-01
                              :ARG2 (e3 / enzyme :name (n2 / name :op1 "Cdc2"))))))
      :snt2 (r2 / report-01
            :ARG0 (w / we)
            :ARG1 (a3 / associate-01
                  :ARG1 (a4 / apoptosis
                        :ARG1-of (m2 / mediate-01
                              :ARG0 (p4 / protein :name (n3 / name :op1 "TNF"))))
                  :ARG2 (c / cleave-01
                        :ARG1 (k3 / kinase :name (n6 / name :op1 "PITSLRE"))
                        :ARG1-of (i2 / inhibit-01
                              :ARG0 (a5 / and
                                    :op1 (p6 / protein :name (n4 / name :op1 "CrmA"))
                                    :op1 (p7 / protein :name (n5 / name :op1 "Bcl-2")))
                              :ARG1-of (p5 / possible-01))))
            :medium (p3 / paper
                  :mod (t2 / this))
            :ARG0-of (i3 / indicate-01
                  :ARG1 (r3 / role
                        :poss (e / enzyme :name (n7 / name :op1 "CASP"))))))

# ::id bel_pmid_930_0710.10502 ::date 2015-04-01T07:39:08 ::annotator SDL-AMR-09 ::preferred
# ::snt Elevated levels of human TNF-alpha were accompanied by increases in synovial cell expression of murine IL-1beta and IL-6
# ::save-date Wed Apr 1, 2015 ::file bel_pmid_930_0710_10502.txt
(a / accompany-01
      :ARG0 (i / increase-01
            :ARG1 (e2 / express-03
                  :ARG2 (a2 / and
                        :op1 (p / protein :name (n / name :op1 "IL-1beta"))
                        :op2 (p3 / protein :name (n3 / name :op1 "IL-6"))
                        :mod (m / murine))
                  :ARG3 (c / cell
                        :mod (s / synovial))))
      :ARG1 (l / level
            :mod (e / elevated)
            :quant-of (p2 / protein :name (n2 / name :op1 "TNF-alpha")
                  :mod (h / human))))

# ::id bel_pmid_930_5854.5780 ::date 2015-04-01T07:43:56 ::annotator SDL-AMR-09 ::preferred
# ::snt e show here that oncogenic forms of Ha-Ras activate NF-kappaB, not through induced nuclear translocation, but rather through the activation of the transcriptional function of the NF-kappaB RelA/p65 subunit.
# ::save-date Sun Jan 17, 2016 ::file bel_pmid_930_5854_5780.txt
(s / show-01
      :ARG0 (w / we)
      :ARG1 (a / activate-01
            :ARG0 (e / enzyme :name (n / name :op1 "Ha-Ras")
                  :ARG0-of (c / cause-01
                        :ARG1 (d / disease :wiki "Cancer" :name (n4 / name :op1 "cancer"))))
            :ARG1 (p / protein :name (n2 / name :op1 "NF-kB"))
            :manner (i / instead-of-91
                  :ARG1 (a2 / activate-01
                        :ARG1 (f2 / function-01
                              :ARG0 (p2 / protein :name (n5 / name :op1 "RelA/p65" :op2 "subunit")
                                    :part-of p)
                              :ARG1 (t2 / transcribe-01))
                        :mod (r / rather))
                  :ARG2 (t / translocate-01
                        :ARG2 (n3 / nucleus)
                        :ARG2-of (i2 / induce-01))))
      :medium (h / here))

# ::id bel_pmid_930_5939.36880 ::date 2015-04-01T07:56:08 ::annotator SDL-AMR-09 ::preferred
# ::snt 1) STAT proteins play an essential role in angiotensin II-induced vascular smooth muscle cell proliferation, 2) JAK2 plays an essential role in the tyrosine phosphorylation of Raf-1, and 3) convergent mitogenic signaling cascades involving the cytosolic kinases JAK2, MEK1, and ERK1 mediate vascular smooth muscle cell proliferation
# ::save-date Sun Dec 20, 2015 ::file bel_pmid_930_5939_36880.txt
(a / and
      :op1 (p2 / play-08 :li 1
            :ARG0 (p3 / protein :name (n / name :op1 "STAT"))
            :ARG1 (p4 / proliferate-01
                  :ARG0 (c / cell
                        :part-of (m / muscle
                              :ARG1-of (s / smooth-06)
                              :mod (v / vascular)))
                  :ARG2-of (i / induce-01
                        :ARG0 (s2 / small-molecule :name (n2 / name :op1 "angiotensin" :op2 "II"))))
            :mod (e / essential))
      :op2 (p5 / play-08 :li 2
            :ARG0 (e2 / enzyme :name (n3 / name :op1 "JAK2"))
            :ARG1 (p / phosphorylate-01
                  :ARG1 (a2 / amino-acid :name (n4 / name :op1 "tyrosine")
                        :part-of (e4 / enzyme :name (n5 / name :op1 "Raf-1"))))
            :mod e)
      :op3 (m2 / mediate-01 :li 3
            :ARG0 (c2 / cascade
                  :mod (m3 / mitogenic)
                  :ARG0-of (c3 / converge-01)
                  :ARG0-of (s3 / signal-07)
                  :ARG2-of (i2 / involve-01
                        :ARG1 (k / kinase
                              :part-of (c4 / cytosol)
                              :ARG1-of (m4 / mean-01
                                    :ARG2 (a3 / and
                                          :op1 e2
                                          :op2 (e3 / enzyme :name (n6 / name :op1 "MEK1"))
                                          :op3 (e5 / enzyme :name (n7 / name :op1 "ERK1")))))))
            :ARG1 p4))

# ::id bel_pmid_934_4843.8622 ::date 2015-04-02T00:56:22 ::annotator SDL-AMR-09 ::preferred
# ::snt The present study demonstrates that erythropoietin (Epo) and IL-3 induce tyrosine phosphorylation of the SH2/SH3-containing adapter protein CrkL and its transient association with tyrosine-phosphorylated SHP-2, Shc, and Cbl in a murine IL-3-dependent cell line, 32D, expressing the Epo receptor (EpoR).
# ::save-date Sun Jan 17, 2016 ::file bel_pmid_934_4843_8622.txt
(d / demonstrate-01
      :ARG0 (s / study-01
            :time (p3 / present))
      :ARG1 (i / induce-01
            :ARG0 (a / and
                  :op1 (s2 / small-molecule :name (n2 / name :op1 "erythropoietin")
                        :ARG1-of (d2 / describe-01
                              :ARG2 (s3 / small-molecule :name (n3 / name :op1 "Epo"))))
                  :op2 (p4 / protein :name (n4 / name :op1 "IL-3")))
            :ARG2 (a5 / and
                  :op1 (p2 / phosphorylate-01
                        :ARG1 (a2 / amino-acid :name (n / name :op1 "tyrosine")
                              :part-of (p / protein :name (n5 / name :op1 "CrkL")
                                    :ARG0-of (a3 / adapt-01)
                                    :ARG0-of (c / contain-01
                                          :ARG1 (a4 / and
                                                :op1 (p5 / protein-segment :name (n6 / name :op1 "SH2"))
                                                :op2 (p6 / protein-segment :name (n7 / name :op1 "SH3")))))))
                  :op2 (a6 / associate-01
                        :ARG1 p
                        :ARG2 (a7 / and
                              :op1 (a8 / amino-acid :name (n14 / name :op1 "tyrosine")
                                    :part-of (p11 / protein :name (n8 / name :op1 "SHP-2"))
                                    :ARG1-of (p8 / phosphorylate-01))
                              :op2 (a9 / amino-acid :name (n15 / name :op1 "tyrosine")
                                    :part-of (p10 / protein :name (n9 / name :op1 "Shc"))
                                    :ARG1-of p8)
                              :op3 (a10 / amino-acid :name (n16 / name :op1 "tyrosine")
                                    :part-of (p12 / protein :name (n10 / name :op1 "Cbl"))
                                    :ARG1-of p8))
                        :ARG1-of (t / transient-02)))
            :location (c3 / cell-line :name (n12 / name :op1 "32D")
                  :mod (m / murine)
                  :ARG0-of (d3 / depend-01
                        :ARG1 p4)
                  :ARG3-of (e2 / express-03
                        :ARG2 (p7 / protein :name (n11 / name :op1 "Epo" :op2 "receptor")
                              :ARG1-of (d4 / describe-01
                                    :ARG2 (p9 / protein :name (n13 / name :op1 "EpoR"))))))))

# ::id bel_pmid_946_1509.18046 ::date 2015-04-02T01:18:51 ::annotator SDL-AMR-09 ::preferred
# ::snt The hsp90beta gene promoter contains binding sites for the transcription factors nuclear factor IL-6 (\"NF-IL6\") and signal transducer and activator of transcription 3 (STAT-3), which are activated respectively by the mitogen-activated-protein-kinase and Jak-kinase pathways following IL-6 treatment.
# ::save-date Sun Jan 3, 2016 ::file bel_pmid_946_1509_18046.txt
(c / contain-01
      :ARG0 (p8 / protein :name (n / name :op1 "hsp90beta")
            :ARG0-of (p / promote-01
                  :ARG1 (g / gene)))
      :ARG1 (p2 / protein-segment
            :ARG2-of (b / bind-01
                  :ARG1 (f4 / factor
                        :ARG0-of (t2 / transcribe-01)
                        :ARG1-of (m2 / mean-01
                              :ARG2 (a2 / and
                                    :op1 (p5 / protein :name (n2 / name :op1 "nuclear" :op2 "factor" :op3 "IL-6")
                                          :ARG1-of (d / describe-01
                                                :ARG2 (p9 / protein :name (n7 / name :op1 "NF-IL6"))))
                                    :op2 (p6 / protein :name (n3 / name :op1 "signal" :op2 "transducer" :op3 "and" :op4 "activator" :op5 "of" :op6 "transcription" :op7 "3")
                                          :ARG1-of (d2 / describe-01
                                                :ARG2 (p10 / protein :name (n8 / name :op1 "STAT-3"))))))
                        :ARG1-of (a3 / activate-01
                              :ARG0 (a4 / and
                                    :op1 (p3 / pathway :name (n4 / name :op1 "mitogen-activated-protein-kinase"))
                                    :op2 (p4 / pathway :name (n5 / name :op1 "Jak-kinase")))
                              :manner (r / respective)
                              :ARG1-of (f / follow-01
                                    :ARG2 (t / treat-04
                                          :ARG2 (p7 / protein :name (n6 / name :op1 "IL-6")))))))))

# ::id bel_pmid_946_1509.22508 ::date 2015-04-02T01:29:36 ::annotator SDL-AMR-09 ::preferred
# ::snt In contrast, IL-1, which activates only the \"NF-IL6\" pathway, synergizes with heat shock to produce strong activation of hsp90.
# ::save-date Tue Feb 2, 2016 ::file bel_pmid_946_1509_22508.txt
(c / contrast-01
      :ARG2 (s / synergize-01
            :ARG0 (p / protein :name (n / name :op1 "IL-1")
                  :ARG0-of (a / activate-01
                        :ARG1 (p2 / pathway :name (n2 / name :op1 "NF-IL6"))
                        :mod (o / only)))
            :ARG1 (s2 / shock
                  :mod (h / heat))
            :ARG2 (p3 / produce-01
                  :ARG0 p
                  :ARG1 (a2 / activate-01
                        :ARG1 (p4 / protein :name (n3 / name :op1 "hsp90"))
                        :mod (s3 / strong)))))

# ::id bel_pmid_982_0826.5420 ::date 2015-04-02T01:46:19 ::annotator SDL-AMR-09 ::preferred
# ::snt formation of the hCAF-1/BTG1 complex is driven by phosphorylation at BTG1 (Ser-159) and implicates this complex in the signalling events of cell division that lead to changes in cellular proliferation associated with cell-cell contact.
# ::save-date Mon Jun 22, 2015 ::file bel_pmid_982_0826_5420.txt
(a2 / and
      :op1 (d / drive-02
            :ARG0 (p / phosphorylate-01
                  :ARG1 (a / amino-acid :mod 159 :name (n3 / name :op1 "serine")
                        :part-of p3))
            :ARG1 (f / form-01
                  :ARG1 (m / macro-molecular-complex
                        :part (p2 / protein :name (n / name :op1 "hCAF-1"))
                        :part (p3 / protein :name (n2 / name :op1 "BTG1")))))
      :op2 (i / implicate-01
            :ARG0 f
            :ARG1 m
            :ARG2 (e / event
                  :ARG0-of (s / signal-07)
                  :subevent-of (d2 / divide-02
                        :ARG1 (c / cell))
                  :ARG0-of (l / lead-03
                        :ARG2 (c2 / change-01
                              :ARG1 (p4 / proliferate-01
                                    :ARG0 c
                                    :ARG1-of (a3 / associate-01
                                          :ARG2 (c3 / contact-01
                                                :ARG0 (c4 / cell)
                                                :ARG1 c))))))))

# ::id bel_pmid_982_0826.5840 ::date 2015-04-02T02:00:34 ::annotator SDL-AMR-09 ::preferred
# ::snt in vitro the hCAF-1/BTG1 complex formation was dependent on the phosphorylation of a putative p34cdc2 kinase site on BTG1 (Ser-159).
# ::save-date Tue Apr 21, 2015 ::file bel_pmid_982_0826_5840.txt
(d / depend-01
      :ARG0 (f / form-01
            :ARG1 (m / macro-molecular-complex
                  :part (p2 / protein :name (n / name :op1 "hCAF-1"))
                  :part (p3 / protein :name (n2 / name :op1 "BTG1"))))
      :ARG1 (p / phosphorylate-01
            :ARG1 (p4 / protein-segment
                  :ARG1-of (t / think-01)
                  :part-of p3
                  :mod (k / kinase :name (n5 / name :op1 "p34cdc2"))
                  :ARG1-of (m2 / mean-01
                        :ARG2 (a / amino-acid :mod 159 :name (n4 / name :op1 "serine")))))
      :manner (i / in-vitro))

# ::id bel_pmid_982_0826.8154 ::date 2015-04-02T02:08:54 ::annotator SDL-AMR-09 ::preferred
# ::snt The human BTG1 protein is thought to be a potential tumour suppressor because its overexpression inhibits NIH 3T3 cell proliferation.
# ::save-date Wed Jun 24, 2015 ::file bel_pmid_982_0826_8154.txt
(t / think-01
      :ARG1 (s / suppress-01
            :ARG0 (p / protein :name (n / name :op1 "BTG1")
                  :mod (h / human))
            :ARG1 (t2 / tumor)
            :mod (p2 / potential))
      :ARG1-of (c / cause-01
            :ARG0 (i / inhibit-01
                  :ARG0 (o / overexpress-01
                        :ARG1 p)
                  :ARG1 (p3 / proliferate-01
                        :ARG0 (c2 / cell-line :name (n2 / name :op1 "NIH" :op2 "3T3"))))))

# ::id bel_pmid_982_3899.2738 ::date 2015-04-02T02:13:22 ::annotator SDL-AMR-09 ::preferred
# ::snt Pak3 phosphorylates Raf-1 on serine 338 in vitro and in vivo. The p21-activated protein kinases are regulated by the Rho-family GTPases Rac and Cdc42.
# ::save-date Sun Jan 17, 2016 ::file bel_pmid_982_3899_2738.txt
(m / multi-sentence
      :snt1 (p / phosphorylate-01
            :ARG1 (e2 / enzyme :name (n3 / name :op1 "Raf-1"))
            :ARG2 (e / enzyme :name (n2 / name :op1 "Pak3"))
            :location (a / amino-acid :mod 338 :name (n / name :op1 "serine")
                  :part-of e2)
            :manner (a2 / and
                  :op1 (i / in-vitro)
                  :op2 (i2 / in-vivo)))
      :snt2 (r / regulate-01
            :ARG0 (a4 / and
                  :op1 (e5 / enzyme :name (n7 / name :op1 "Rac"))
                  :op2 (p5 / protein :name (n8 / name :op1 "Cdc42"))
                  :ARG1-of (i3 / include-91
                        :ARG2 (p4 / protein-family :name (n4 / name :op1 "Rho" :op2 "GTPase"))))
            :ARG1 (k / kinase
                  :ARG1-of (a3 / activate-01
                        :ARG0 (p2 / protein :name (n5 / name :op1 "p21")))
                  :mod (p3 / protein))))

# ::id bio.chicago_2015.9828 ::date 2015-10-22T07:21:22 ::annotator SDL-AMR-09 ::preferred
# ::snt The amino acids altered in mutation DECM2 (YEG  G), which have a strong effect on  DEC binding to  beta-cateninArm in our assays, are bold and underlined.
# ::save-date Mon Jan 4, 2016 ::file bio_chicago_2015_9828.txt
(a / and
      :op1 (b / bold-03
            :ARG1 (a6 / amino-acid
                  :ARG1-of (a3 / alter-01
                        :time (m / mutate-01
                              :ARG2 (p3 / protein :name (n2 / name :op1 "DECM2"))))
                  :ARG0-of (a4 / affect-01
                        :ARG1 (b2 / bind-01
                              :ARG1 (p / protein :name (n3 / name :op1 "DEC"))
                              :ARG2 (p2 / protein :name (n4 / name :op1 "beta-cateninArm"))
                              :location (a5 / assay-01
                                    :ARG0 (w / we)))
                        :ARG1-of (s / strong-02))
                  :ARG1-of (l / label-01
                        :ARG2 (s2 / string-entity :value "YEG-G"))))
      :op2 (u / underline-01
            :ARG1 a6))

# ::id bio.chicago_2015.19528 ::date 2015-10-21T18:07:43 ::annotator SDL-AMR-09 ::preferred
# ::snt The less efficient phosphorylation of  MLC by  Rho-kinase may become sufficient when the  myosin phosphatase activity is inhibited by  Rho-kinase.
# ::save-date Mon Oct 26, 2015 ::file bio_chicago_2015_19528.txt
(p / possible-01
      :ARG1 (s / suffice-01
            :ARG0 (p2 / phosphorylate-01
                  :ARG1 (p3 / protein :name (n / name :op1 "MLC"))
                  :ARG2 (e2 / enzyme :name (n2 / name :op1 "Rho-kinase"))
                  :ARG1-of (e / efficient-01
                        :degree (l / less))))
      :condition (i / inhibit-01
            :ARG0 e2
            :ARG1 (a / activity-06
                  :ARG0 (p4 / phosphatase :name (n3 / name :op1 "myosin")))))

# ::id bio.chicago_2015.19534 ::date 2015-10-21T18:29:58 ::annotator SDL-AMR-09 ::preferred
# ::snt In support of these findings, it has also been found that displacement of  Rb-E2F complexes from promoters with a  dominant-negative E2F (DN-E2F) containing a  DNA binding domain but lacking an  Rb binding site, or titration of  Rb-E2F complexes away from promoters by transfection of a  plasmid containing  multiple E2F binding site repeats, prevents  Rb-mediated repression of  cyclin E and A expression and growth arrest by  p16   (Zhang et al., 1999  ;
# ::save-date Fri Feb 5, 2016 ::file bio_chicago_2015_19534.txt
(f / find-01
      :ARG1 (p7 / prevent-01
            :ARG0 (o / or
                  :op1 (d / displace-01
                        :ARG1 (m5 / macro-molecular-complex
                              :part p3
                              :part p6)
                        :ARG2 (m / molecular-physical-entity
                              :ARG0-of (p / promote-02)
                              :ARG0-of (h / have-03
                                    :ARG1 (p14 / protein :name (n2 / name :op1 "E2F")
                                          :ARG0-of (c2 / contain-01
                                                :ARG1 (d3 / domain
                                                      :ARG1-of (b / bind-01
                                                            :ARG2 (n3 / nucleic-acid :name (n4 / name :op1 "DNA"))))
                                                :ARG1-of (c3 / contrast-01
                                                      :ARG2 (l / lack-01
                                                            :ARG0 p14
                                                            :ARG1 (s / site
                                                                  :ARG2-of (b2 / bind-01
                                                                        :ARG1 (p3 / protein :name (n5 / name :op1 "Rb")))))))
                                          :ARG2-of (m2 / mutate-01 :mod "-/-")
                                          :ARG0-of (d2 / dominate-01)))))
                  :op2 (t / titrate-01
                        :ARG1 m5
                        :location (a2 / away
                              :op1 (m3 / molecular-physical-entity
                                    :ARG0-of (p2 / promote-02)))
                        :manner (t2 / transfect-01
                              :ARG1 (p5 / plasmid
                                    :ARG0-of (c4 / contain-01
                                          :ARG1 (r / repeat-01
                                                :ARG1 (s2 / site
                                                      :ARG2-of (b3 / bind-01
                                                            :ARG1 (p6 / protein :name (n6 / name :op1 "E2F"))))))))))
            :ARG1 (a4 / and
                  :op1 (r2 / repress-01
                        :ARG1 (e / express-03
                              :ARG2 (a3 / and
                                    :op1 (p8 / protein :name (n7 / name :op1 "cyclin" :op2 "E"))
                                    :op2 (p9 / protein :name (n8 / name :op1 "cyclin" :op2 "A"))))
                        :ARG1-of (m4 / mediate-01
                              :ARG0 p3))
                  :op2 (a5 / arrest-02
                        :ARG0 (p10 / protein :name (n9 / name :op1 "p16"))
                        :ARG1 (g3 / grow-01))))
      :mod (a / also)
      :ARG0-of (s3 / support-01
            :ARG1 (t3 / thing
                  :ARG1-of (f2 / find-01)
                  :mod (t4 / this)))
      :ARG1-of (d5 / describe-01
            :ARG0 (p11 / publication-91
                  :ARG0 (a6 / and
                        :op1 (p12 / person :name (n10 / name :op1 "Zhang"))
                        :op2 (p13 / person
                              :mod (o2 / other)))
                  :time (d6 / date-entity :year 1999))))

# ::id bio.chicago_2015.19551 ::date 2015-10-21T19:15:29 ::annotator SDL-AMR-09 ::preferred
# ::snt More recently,  PSQ was found to colocalize and coimmunoprecipitate with  TRL/ GAF, an interaction that was shown to depend on the  BTB/ POZ domains of the two proteins ( 64).
# ::save-date Tue Feb 2, 2016 ::file bio_chicago_2015_19551.txt
(f / find-01
      :ARG1 (a / and
            :op1 (c / colocalize-01
                  :ARG1 (a2 / and
                        :op1 (p / protein :name (n / name :op1 "PSQ"))
                        :op2 (s / slash
                              :op1 (p2 / protein :name (n2 / name :op1 "TRL"))
                              :op2 (p3 / protein :name (n3 / name :op1 "GAF")))))
            :op2 (c2 / coimmunoprecipitate-01
                  :ARG1 p
                  :ARG2 s)
            :ARG1-of (m2 / mean-01
                  :ARG2 (i / interact-01
                        :ARG0-of (d / depend-01
                              :ARG1 (s2 / slash
                                    :op1 (p5 / protein-segment :name (n4 / name :op1 "BTB"))
                                    :op2 (p6 / protein-segment :name (n5 / name :op1 "POZ"))
                                    :part-of s)
                              :ARG1-of (s3 / show-01)))))
      :time (r / recent
            :degree (m / more))
      :ARG1-of (d4 / describe-01
            :ARG0 (p4 / publication
                  :ARG1-of (c3 / cite-01
                        :ARG2 64))))

# ::id bio.chicago_2015.19555 ::date 2015-10-21T19:59:16 ::annotator SDL-AMR-09 ::preferred
# ::snt The  PI3K inhibitory domain inhibits  p110 , but not  p110
# ::save-date Mon Oct 26, 2015 ::file bio_chicago_2015_19555.txt
(c / contrast-01
      :ARG1 (i / inhibit-01
            :ARG0 (d / domain
                  :ARG0-of (i2 / inhibit-01
                        :ARG1 (e / enzyme :name (n2 / name :op1 "PI3K"))))
            :ARG1 (p / protein :name (n / name :op1 "p110")))
      :ARG2 (i3 / inhibit-01 :polarity -
            :ARG0 d
            :ARG1 p))

# ::id bio.chicago_2015.19589 ::date 2015-10-21T20:06:47 ::annotator SDL-AMR-09 ::preferred
# ::snt The spatial expression and sequence of   ppa suggest that  Ppa might negatively regulate  Prd, either by transcriptional co-repression or degradation of the  Prd protein.
# ::save-date Mon Dec 21, 2015 ::file bio_chicago_2015_19589.txt
(s / suggest-01
      :ARG0 (a / and
            :op1 (e / express-03
                  :ARG2 (p / protein :name (n / name :op1 "ppa"))
                  :mod (s2 / space))
            :op2 (s3 / sequence
                  :poss p
                  :mod s2))
      :ARG1 (p2 / possible-01
            :ARG1 (d2 / downregulate-01
                  :ARG0 p
                  :ARG1 (p3 / protein :name (n3 / name :op1 "Prd"))
                  :manner (o / or
                        :op1 (c / corepress-00
                              :ARG1 (t / transcribe-01))
                        :op2 (d / degrade-01
                              :ARG1 p3)))))

# ::id bio.chicago_2015.19651 ::date 2015-10-21T20:15:42 ::annotator SDL-AMR-09 ::preferred
# ::snt Within this complex,  NDPK interacts with  dynamin I through a  proline-rich domain, whereas its interaction with  phocein is ill defined.
# ::save-date Thu Jan 28, 2016 ::file bio_chicago_2015_19651.txt
(c / contrast-01
      :ARG1 (i / interact-01
            :ARG0 (e / enzyme :name (n / name :op1 "NDPK"))
            :ARG1 (p / protein :name (n2 / name :op1 "dynamin" :op2 "I"))
            :ARG2 (d / domain
                  :mod (r / rich
                        :mod (a / amino-acid :name (n3 / name :op1 "proline")))))
      :ARG2 (i2 / interact-01
            :ARG0 e
            :ARG1 (p2 / protein :name (n4 / name :op1 "phocein"))
            :ARG1-of (d2 / define-01
                  :ARG1-of (i3 / ill-02)))
      :location (c2 / complex
            :mod (t / this)))

# ::id bio.chicago_2015.19673 ::date 2015-10-21T20:23:04 ::annotator SDL-AMR-09 ::preferred
# ::snt However, although  Rb has been shown to bind at least 10 distinct proteins including the transcription factors  ATF-2 ( 44) and  E2F ( 45), direct interaction of  Rb with  Sp proteins has not been reported.
# ::save-date Mon Oct 26, 2015 ::file bio_chicago_2015_19673.txt
(c3 / contrast-01
      :ARG2 (h / have-concession-91
            :ARG1 (r / report-01 :polarity -
                  :ARG1 (i / interact-01
                        :ARG0 (p / protein :name (n / name :op1 "Rb"))
                        :ARG1 (p2 / protein :name (n2 / name :op1 "Sp"))
                        :ARG1-of (d / direct-02)))
            :ARG2 (s / show-01
                  :ARG1 (b / bind-01
                        :ARG1 p
                        :ARG2 (p3 / protein
                              :mod (d2 / distinct)
                              :ARG2-of (i2 / include-01
                                    :ARG1 (a2 / and
                                          :op1 (p4 / protein :name (n3 / name :op1 "ATF-2")
                                                :ARG1-of (d3 / describe-01
                                                      :ARG0 (p6 / publication
                                                            :ARG1-of (c / cite-01
                                                                  :ARG2 44))))
                                          :op2 (p5 / protein :name (n4 / name :op1 "E2F")
                                                :ARG1-of (d4 / describe-01
                                                      :ARG0 (p7 / publication
                                                            :ARG1-of (c2 / cite-01
                                                                  :ARG2 45))))
                                          :mod (f / factor
                                                :ARG0-of (t / transcribe-01))))
                              :quant (a / at-least :op1 10))))))

# ::id bio.chicago_2015.19721 ::date 2015-10-21T20:41:15 ::annotator SDL-AMR-09 ::preferred
# ::snt In addition, the amino-terminal  PTB domain can directly interact with  EGFR and  Syk/Zap-70 (  Lupher and   Thien).
# ::save-date Tue Jan 12, 2016 ::file bio_chicago_2015_19721.txt
(a / and
      :op2 (p / possible-01
            :ARG1 (i / interact-01
                  :ARG0 (p2 / protein-segment :wiki "N-terminus"
                        :name (n7 / name :op1 "amino-terminus")
                        :part-of (p8 / protein :wiki "Polypyrimidine_tract-binding_protein"
                              :name (n8 / name :op1 "PTB")))
                  :ARG1 (a3 / and
                        :op1 (e / enzyme :wiki "Epidermal_growth_factor_receptor"
                              :name (n2 / name :op1 "EGFR"))
                        :op2 (s / slash
                              :op1 (e2 / enzyme :wiki "Syk"
                                    :name (n3 / name :op1 "Syk"))
                              :op2 (e3 / enzyme :wiki "ZAP70"
                                    :name (n4 / name :op1 "Zap-70"))))
                  :ARG1-of (d / direct-02))
            :ARG1-of (d3 / describe-01
                  :ARG0 (p5 / publication-91
                        :ARG0 (a4 / and
                              :op1 (p6 / person :wiki -
                                    :name (n5 / name :op1 "Lupher"))
                              :op2 (p7 / person :wiki -
                                    :name (n6 / name :op1 "Thien")))))))

# ::id bio.chicago_2015.19785 ::date 2015-10-21T20:49:13 ::annotator SDL-AMR-09 ::preferred
# ::snt Here, we demonstrate that  V-ATPase binds directly to  actin filaments.
# ::save-date Sun Nov 8, 2015 ::file bio_chicago_2015_19785.txt
(d / demonstrate-01
      :ARG0 (w / we)
      :ARG1 (b / bind-01
            :ARG1 (e / enzyme :name (n / name :op1 "V-ATPase"))
            :ARG2 (f / filament
                  :part-of (p / protein :name (n2 / name :op1 "actin")))
            :ARG1-of (d2 / direct-02))
      :medium (h / here))

# ::id bio.chicago_2015.19847 ::date 2015-10-21T20:55:30 ::annotator SDL-AMR-09 ::preferred
# ::snt Rho-kinase phosphorylates  MBS and consequently inactivates  myosin phosphatase ( 12).
# ::save-date Sun Nov 8, 2015 ::file bio_chicago_2015_19847.txt
(c / cause-01
      :ARG0 (p / phosphorylate-01
            :ARG1 (p2 / protein-segment :name (n2 / name :op1 "MBS"))
            :ARG2 (e2 / enzyme :name (n / name :op1 "Rho-kinase")))
      :ARG1 (a / activate-01 :polarity -
            :ARG0 e2
            :ARG1 (p3 / phosphatase :name (n3 / name :op1 "myosin")))
      :ARG1-of (d / describe-01
            :ARG0 (p4 / publication
                  :ARG1-of (c2 / cite-01
                        :ARG2 12))))

# ::id bio.chicago_2015.19850 ::date 2015-10-21T21:06:52 ::annotator SDL-AMR-09 ::preferred
# ::snt Some  E2F may remain bound to a  partially phosphorylated  Rb throughout the normal cell cycle.
# ::save-date Thu Dec 10, 2015 ::file bio_chicago_2015_19850.txt
(p / possible-01
      :ARG1 (r / remain-01
            :ARG1 (p2 / protein :name (n / name :op1 "E2F")
                  :quant (s / some))
            :ARG3 (b / bind-01
                  :ARG1 p2
                  :ARG2 (p3 / protein :name (n2 / name :op1 "Rb")
                        :ARG2-of (p4 / phosphorylate-01
                              :degree (p5 / part))))
            :duration (c / cycle-02
                  :ARG1 (c2 / cell)
                  :ARG1-of (n3 / normal-02))))

# ::id bio.chicago_2015.19878 ::date 2015-10-20T14:31:08 ::annotator SDL-AMR-09 ::preferred
# ::snt ( B) A model on how the proneural complex encompassing  Pnr, Chip, and the (Ac/Sc)- Da heterodimer is regulated by  Osa.
# ::save-date Sat Oct 31, 2015 ::file bio_chicago_2015_19878.txt
(m5 / model-01 :li "b"
      :ARG1 (t / thing
            :manner-of (r / regulate-01
                  :ARG0 (p2 / protein :name (n5 / name :op1 "Osa"))
                  :ARG1 (c / complex
                        :mod (p / proneuron)
                        :ARG0-of (e / encompass-01
                              :ARG1 (a / and
                                    :op1 (p3 / protein :name (n2 / name :op1 "pnr"))
                                    :op2 (p4 / protein :name (n3 / name :op1 "chip"))
                                    :op3 (h / heterodimer
                                          :part (p5 / protein :name (n / name :op1 "Ac/Sc"))
                                          :part (p6 / protein :name (n6 / name :op1 "Da")))))))))

# ::id bio.chicago_2015.19893 ::date 2015-10-20T14:46:56 ::annotator SDL-AMR-09 ::preferred
# ::snt This possibility is supported by the demonstration that phosphorylation of  Thr-654 in the proximal  membrane domain of the  EGF receptor by protein kinase C decreases  EGF-dependent activation of the  EGF receptor  [ 6.
# ::save-date Sun Jan 17, 2016 ::file bio_chicago_2015_19893.txt
(s / support-01 :li 6
      :ARG0 (d / demonstrate-01
            :ARG1 (d2 / decrease-01
                  :ARG0 (p / phosphorylate-01
                        :ARG1 (a2 / amino-acid :mod 654 :name (n4 / name :op1 "threonine"))
                        :ARG2 (e2 / enzyme :name (n2 / name :op1 "protein" :op2 "kinase" :op3 "C"))
                        :location (d3 / domain
                              :mod (p4 / proximal
                                    :mod (m / membrane))
                              :part-of (e / enzyme :name (n / name :op1 "EGF" :op2 "receptor"))))
                  :ARG1 (a / activate-01
                        :ARG1 e
                        :ARG0-of (d4 / depend-01
                              :ARG1 e))))
      :ARG1 (p2 / possible-01
            :ARG1 (t / this)))

# ::id bio.chicago_2015.19949 ::date 2015-10-20T14:48:42 ::annotator SDL-AMR-09 ::preferred
# ::snt In contrast,  EGF failed to promote the spreading of  MDCK cells and  Paxillin  displayed a diffuse distribution within the cytoplasm  ( Figure 1A), similar to  unstimulated  MDCK cells ( Figure  1A).
# ::save-date Sun Jan 17, 2016 ::file bio_chicago_2015_19949.txt
(c / contrast-01
      :ARG2 (a2 / and
            :op1 (f / fail-01
                  :ARG1 (p3 / protein :name (n / name :op1 "EGF"))
                  :ARG2 (p / promote-01
                        :ARG0 p3
                        :ARG1 (s2 / spread-03
                              :ARG1 (c2 / cell :name (n2 / name :op1 "MDCK")))))
            :op2 (d / display-01
                  :ARG0 (p2 / protein :name (n3 / name :op1 "Paxillin"))
                  :ARG1 (d2 / distribute-01
                        :ARG1-of (d3 / diffuse-01)
                        :location (c3 / cytoplasm)
                        :ARG1-of (r / resemble-01
                              :ARG2 (c5 / cell :name (n4 / name :op1 "MDCK")
                                    :ARG1-of (s3 / stimulate-01 :polarity -))
                              :ARG1-of d4))
                  :ARG1-of (d4 / describe-01
                        :ARG0 (f2 / figure :mod "1A")))))

# ::id bio.chicago_2015.19979 ::date 2015-10-20T21:01:08 ::annotator SDL-AMR-09 ::preferred
# ::snt The lack of  PKA activity in the purified  I  B/PKAc fractions (  Figure 1A and data not shown) and in purified  NF- B - I B - PKAc complexes (  Figure 1D) suggested  that the binding of I B to  PKAc inhibits the enzymatic activity of   PKA.
# ::save-date Thu Nov 12, 2015 ::file bio_chicago_2015_19979.txt
(s / suggest-01
      :ARG0 (l / lack-01
            :ARG1 (a / activity-06
                  :ARG0 (e / enzyme :name (n / name :op1 "PKA"))
                  :ARG1 (a2 / and
                        :op1 (f / fraction-01
                              :ARG1 (s3 / slash
                                    :op1 (e2 / enzyme :name (n2 / name :op1 "IB"))
                                    :op2 e)
                              :ARG1-of (p / purify-01)
                              :ARG1-of (d / describe-01
                                    :ARG0 (a3 / and
                                          :op1 (f2 / figure :mod "1A")
                                          :op2 (d2 / data
                                                :ARG1-of (s2 / show-01 :polarity -)))))
                        :op2 (m3 / macro-molecular-complex
                              :part (p3 / protein :name (n3 / name :op1 "NF-B"))
                              :part e2
                              :part e
                              :ARG1-of (d3 / describe-01
                                    :ARG0 (f3 / figure :mod "1D"))
                              :ARG1-of p))))
      :ARG1 (i / inhibit-01
            :ARG0 (b / bind-01
                  :ARG1 e2
                  :ARG2 e)
            :ARG1 (a4 / activity-06
                  :ARG0 e
                  :mod (e4 / enzyme))))

# ::id bio.chicago_2015.20002 ::date 2015-10-20T21:10:55 ::annotator SDL-AMR-09 ::preferred
# ::snt E, concentration-dependent inhibitory effect of AG1478 on  EGF-induced phosphorylation of the  EGF-R at Tyr1173.
# ::save-date Sun Nov 1, 2015 ::file bio_chicago_2015_20002.txt
(a / affect-01 :li "e"
      :ARG0 (s / small-molecule :name (n5 / name :op1 "AG1478"))
      :ARG1 (p / phosphorylate-01
            :ARG1 (a2 / amino-acid :mod 1173 :name (n3 / name :op1 "tyrosine")
                  :part-of (e2 / enzyme :name (n2 / name :op1 "EGF-R")))
            :ARG2-of (i2 / induce-01
                  :ARG0 (p3 / protein :name (n4 / name :op1 "EGF"))))
      :ARG2 (i / inhibit-01)
      :ARG0-of (d / depend-01
            :ARG1 (c / concentrate-02)))

# ::id bio.chicago_2015.20021 ::date 2015-10-20T21:19:57 ::annotator SDL-AMR-09 ::preferred
# ::snt Importantly, this peptide also blocked  EGF activation of endogenous  Ral.
# ::save-date Tue Oct 20, 2015 ::file bio_chicago_2015_20021.txt
(b / block-01
      :ARG0 (p / peptide
            :mod (t / this))
      :ARG1 (a2 / activate-01
            :ARG0 (p2 / protein :name (n / name :op1 "EGF"))
            :ARG1 (p3 / protein :name (n2 / name :op1 "Ral")
                  :mod (e / endogenous)))
      :mod (a / also)
      :mod (i / important))

# ::id bio.chicago_2015.20023 ::date 2015-10-20T21:26:03 ::annotator SDL-AMR-09 ::preferred
# ::snt Kek1 inhibits ligand binding   To examine the mechanistic details underlying  Kek1 suppression of  EGFR activity, we used the  baculovirus/ Sf9 insect cell expression system.
# ::save-date Thu Nov 12, 2015 ::file bio_chicago_2015_20023.txt
(m / multi-sentence
      :snt1 (i / inhibit-01
            :ARG0 (p2 / protein :name (n / name :op1 "Kek1"))
            :ARG1 (b / bind-01
                  :ARG1 (l / ligand)))
      :snt2 (u2 / use-01
            :ARG0 (w / we)
            :ARG1 (s2 / system
                  :mod (e3 / express-03
                        :ARG2 (o / organism :name (n4 / name :op1 "baculovirus"))
                        :ARG3 (c2 / cell-line :name (n5 / name :op1 "Sf9")
                              :mod (i2 / insect))))
            :ARG2 (e2 / examine-01
                  :ARG0 w
                  :ARG1 (d / detail
                        :mod (m2 / mechanistic)
                        :ARG0-of (u / underlie-01
                              :ARG1 (s / suppress-01
                                    :ARG0 (p / protein :name (n2 / name :op1 "Kek1"))
                                    :ARG1 (a / activity-06
                                          :ARG0 (e4 / enzyme :name (n3 / name :op1 "EGFR")))))))))

# ::id bio.chicago_2015.20029 ::date 2015-10-20T21:41:14 ::annotator SDL-AMR-09 ::preferred
# ::snt To test whether the extracellular domain of  Kek1, which contains five  LRR and  one  Ig motif (Musacchio and Perrimon, 1996   ), is required for the inhibition  of the  EGFR activity by  Kek1, we generated transgenic lines that contain either   UAS-kek1extra or   UAS-kek1intra.
# ::save-date Sat Feb 13, 2016 ::file bio_chicago_2015_20029.txt
(g / generate-01
      :ARG0 (w / we)
      :ARG1 (l / line
            :mod (t / transgenic)
            :ARG0-of (c / contain-01
                  :ARG1 (o / or
                        :op1 (s / small-molecule :name (n2 / name :op1 "UAS-kek1")
                              :mod (e2 / extra))
                        :op2 (s2 / small-molecule :name (n3 / name :op1 "UAS-kek1")
                              :mod (i / intra)))))
      :purpose (t2 / test-01
            :ARG0 w
            :ARG1 (r / require-01 :mode interrogative
                  :ARG0 (i2 / inhibit-01
                        :ARG0 p5
                        :ARG1 (a / activity-06
                              :ARG0 (e / enzyme :name (n / name :op1 "EGFR"))))
                  :ARG1 (d2 / domain
                        :mod (e4 / extracellular)
                        :mod (p5 / protein :name (n4 / name :op1 "Kek1"))
                        :ARG0-of (c2 / contain-01
                              :ARG1 (a2 / and
                                    :op1 (s3 / small-molecule :quant 5 :name (n5 / name :op1 "LRR"))
                                    :op2 (m4 / motif :quant 1
                                          :mod (p3 / protein :name (n8 / name :op1 "immunoglobulin"))))
                              :ARG1-of (d3 / describe-01
                                    :ARG0 (p4 / publication-91
                                          :ARG0 (a3 / and
                                                :op1 (p / person :name (n6 / name :op1 "Musacchio"))
                                                :op2 (p2 / person :name (n7 / name :op1 "Perrimon")))
                                          :time (d / date-entity :year 1996))))))))

# ::id bio.chicago_2015.20072 ::date 2015-10-20T21:41:26 ::annotator SDL-AMR-09 ::preferred
# ::snt Pharmacological disruption of  actin affects  MT organization, and vice versa   ( Lin and Forscher, 1993  ; Rochlin et al., 1999  ).
# ::save-date Thu Nov 12, 2015 ::file bio_chicago_2015_20072.txt
(a / and
      :op1 (a2 / affect-01
            :ARG0 (d3 / disrupt-01
                  :ARG1 (p5 / protein :name (n4 / name :op1 "actin"))
                  :mod (p / pharmacology))
            :ARG1 (o / organize-01
                  :ARG1 (p6 / protein :name (n5 / name :op1 "MT"))))
      :op2 (a3 / affect-01
            :ARG0 o
            :ARG1 d3)
      :ARG1-of (d4 / describe-01
            :ARG0 (a8 / and
                  :op1 (p7 / publication-91
                        :ARG0 (a5 / and
                              :op1 (p2 / person :name (n / name :op1 "Lin"))
                              :op2 (p3 / person :name (n2 / name :op1 "Forscher")))
                        :time (d / date-entity :year 1993))
                  :op2 (p8 / publication-91
                        :ARG0 (a6 / and
                              :op1 (p4 / person :name (n3 / name :op1 "Rochlin"))
                              :op2 (p9 / person
                                    :mod (o2 / other)))
                        :time (d2 / date-entity :year 1999)))))

# ::id bio.chicago_2015.20206 ::date 2015-10-20T21:46:28 ::annotator SDL-AMR-09 ::preferred
# ::snt An N-terminal peptide of  Ral-GDS prevents  EGF-induced complex formation between  PDK1 and  Ral-GDS and suppresses  EGF-induced activation of  Ral   If this hypothesis is correct, then expression of just the N-terminus of  Ral-GDS (N-Ral-GDS) should bind to  PDK1 in cells, block binding of  PDK1 to  Ral-GDS and interfere with  Ral activation by  EGF.
# ::save-date Sun Jan 17, 2016 ::file bio_chicago_2015_20206.txt
(m / multi-sentence
      :snt1 (a / and
            :op1 (p2 / prevent-01
                  :ARG0 (p13 / peptide
                        :part-of (p9 / protein-segment :name (n9 / name :op1 "N-terminus")
                              :part-of (p10 / protein :name (n10 / name :op1 "Ral-GDS"))))
                  :ARG1 (f / form-02
                        :ARG1 (m4 / macro-molecular-complex
                              :part (e3 / enzyme :name (n11 / name :op1 "PDK1"))
                              :part p10)))
            :op2 (s / suppress-01
                  :ARG0 p9
                  :ARG1 (a3 / activate-01
                        :ARG1 (p5 / protein :name (n4 / name :op1 "Ral"))
                        :ARG2-of (i2 / induce-01
                              :ARG0 (p3 / protein :name (n3 / name :op1 "EGF"))))))
      :snt2 (h2 / have-condition-91
            :ARG1 (r / recommend-01
                  :ARG1 (a4 / and
                        :op1 (b / bind-01
                              :ARG1 (e / express-03
                                    :ARG2 (p / protein-segment :name (n / name :op1 "N-terminus")
                                          :mod (j / just)
                                          :part-of p10)
                                    :ARG3 (c3 / cell))
                              :ARG2 (e2 / enzyme :name (n2 / name :op1 "PDK1")))
                        :op2 (b2 / block-01
                              :ARG0 e
                              :ARG1 (b3 / bind-01
                                    :ARG1 e2
                                    :ARG2 (p6 / peptide)))
                        :op3 (i3 / interfere-01
                              :ARG0 e
                              :ARG1 (a5 / activate-01
                                    :ARG0 (p8 / protein :name (n8 / name :op1 "EGF"))
                                    :ARG1 (p7 / protein :name (n7 / name :op1 "Ral"))))))
            :ARG2 (c2 / correct-02
                  :ARG1 (t / thing
                        :ARG1-of (h / hypothesize-01)
                        :mod (t3 / this)))))

# ::id bio.chicago_2015.20220 ::date 2015-10-20T21:46:41 ::annotator SDL-AMR-09 ::preferred
# ::snt Surprisingly, we observed that  KSR specifically blocks  EGF and  Ras-induced phosphorylation and activation of ternary complex  factors (TCF), physiological substrates of  MAP kinases, without affecting the activation of  MAP kinase itself.
# ::save-date Sun Jan 17, 2016 ::file bio_chicago_2015_20220.txt
(o / observe-01
      :ARG0 (w / we)
      :ARG1 (b / block-01
            :ARG0 (e2 / enzyme :name (n / name :op1 "KSR"))
            :ARG1 (a / and
                  :op1 (p2 / protein :name (n2 / name :op1 "EGF"))
                  :op2 (a5 / and
                        :op1 (p / phosphorylate-01
                              :ARG1 p5)
                        :op2 (a2 / activate-01
                              :ARG1 (p5 / protein :name (n5 / name :op1 "ternary" :op2 "complex" :op3 "factor")))
                        :ARG2-of (i / induce-01
                              :ARG1 (e / enzyme :name (n3 / name :op1 "Ras"))))
                  :op4 (s2 / substrate
                        :mod (p3 / physiologic)
                        :poss (p6 / protein-family :name (n6 / name :op1 "MAP" :op2 "kinase"))))
            :ARG1-of (s / specific-02)
            :manner (a3 / affect-01 :polarity -
                  :ARG1 (a4 / activate-01
                        :ARG1 (k / kinase))))
      :ARG0-of (s3 / surprise-01))

# ::id bio.chicago_2015.20225 ::date 2015-10-20T21:56:14 ::annotator SDL-AMR-09 ::preferred
# ::snt The activation of  DER by  EGF leads to the stimulation of the  Ras/mitogen-activated  protein (MAP) kinase pathway ( 7).
# ::save-date Thu Nov 12, 2015 ::file bio_chicago_2015_20225.txt
(l / lead-03
      :ARG0 (a / activate-01
            :ARG0 (p / protein :name (n / name :op1 "EGF"))
            :ARG1 (e / enzyme :name (n2 / name :op1 "DER")))
      :ARG2 (s / stimulate-01
            :ARG1 (p3 / pathway :name (n5 / name :op1 "Ras/MAPK")))
      :ARG1-of (d / describe-01
            :ARG0 (p2 / publication
                  :ARG1-of (c / cite-01
                        :ARG2 7))))

# ::id bio.chicago_2015.20250 ::date 2015-10-20T22:04:21 ::annotator SDL-AMR-09 ::preferred
# ::snt Ser1 expression is regulated positively by  Notch activity; Dl1 and  Ser2 are regulated negatively ( 7).
# ::save-date Thu Feb 4, 2016 ::file bio_chicago_2015_20250.txt
(a5 / and
      :op1 (r / regulate-01
            :ARG0 (a / activity-06
                  :ARG0 (p / protein :name (n / name :op1 "Notch")))
            :ARG1 (e / express-03
                  :ARG2 (a2 / amino-acid :mod 1 :name (n2 / name :op1 "serine")))
            :manner (p2 / positive))
      :op2 (d2 / downregulate-01
            :ARG1 (a3 / and
                  :op1 (a4 / amino-acid :mod 11 :name (n3 / name :op1 "aspartate"))
                  :op2 (a6 / amino-acid :mod 2 :name (n5 / name :op1 "serine"))))
      :ARG1-of (d / describe-01
            :ARG0 (p3 / publication
                  :ARG1-of (c / cite-01
                        :ARG2 7))))

# ::id bio.chicago_2015.20268 ::date 2015-10-21T11:18:09 ::annotator SDL-AMR-09 ::preferred
# ::snt However, in cell  lines expressing the dominant  negative mutants S222A and  K97A, which  showed inhibition of  RSK activation by  EGF, the decrease in  GSK-3beta   activity was partially blocked.
# ::save-date Sat Feb 13, 2016 ::file bio_chicago_2015_20268.txt
(c2 / contrast-01
      :ARG2 (b / block-01
            :ARG1 (d / decrease-01
                  :ARG1 (a / activity-06
                        :ARG0 (e4 / enzyme :name (n2 / name :op1 "GSK-3beta"))))
            :degree (p / part)
            :location (c / cell-line
                  :ARG3-of (e2 / express-03
                        :ARG2 (a2 / and
                              :op1 (m2 / mutate-01 :value "S222A")
                              :op2 (m3 / mutate-01 :value "K97A")
                              :ARG0-of (d2 / dominate-01
                                    :mod (n / negative))
                              :ARG0-of (s / show-01
                                    :ARG1 (i / inhibit-01
                                          :ARG0 (p2 / protein :name (n6 / name :op1 "EGF"))
                                          :ARG1 (a3 / activate-01
                                                :ARG0 (e3 / enzyme :name (n5 / name :op1 "RSK"))))))))))

# ::id bio.chicago_2015.20273 ::date 2015-10-21T12:46:30 ::annotator SDL-AMR-09 ::preferred
# ::snt The antibody binds equally well to both the wt  EGFR and deltaEGFR and does not affect the binding of  EGF to the wt  EGFR.
# ::save-date Thu Nov 12, 2015 ::file bio_chicago_2015_20273.txt
(a / and
      :op1 (b / bind-01
            :ARG1 (a2 / antibody)
            :ARG2 (a3 / and
                  :op1 (e / enzyme :name (n / name :op1 "EGFR")
                        :mod (w2 / wild-type))
                  :op2 (e5 / enzyme :name (n4 / name :op1 "delta-EGFR")))
            :ARG1-of (w / well-09
                  :ARG1-of (e2 / equal-01)))
      :op2 (a4 / affect-01 :polarity -
            :ARG0 a2
            :ARG1 (b3 / bind-01
                  :ARG1 (p / protein :name (n3 / name :op1 "EGF"))
                  :ARG2 e)))

# ::id bio.chicago_2015.20290 ::date 2015-10-21T12:52:32 ::annotator SDL-AMR-09 ::preferred
# ::snt Instead,  PtdIns(4,5)- P2 binding was found to inhibit  alpha-actinin binding  to  actin filaments and did not appear to be required for localization to focal  adhesions.
# ::save-date Wed Mar 2, 2016 ::file bio_chicago_2015_20290.txt
(a / and
      :op1 (f / find-01
            :ARG1 (b / bind-01
                  :ARG1 (s / small-molecule :name (n2 / name :op1 "PtdIns(4,5)-" :op2 "P2"))
                  :ARG0-of (i / inhibit-01
                        :ARG1 (b2 / bind-01
                              :ARG1 (p / protein :name (n / name :op1 "alpha-actinin"))
                              :ARG2 (f2 / filament
                                    :mod (p2 / protein :name (n3 / name :op1 "actin")))))))
      :op2 (a2 / appear-02 :polarity -
            :ARG1 (r / require-01
                  :ARG0 (l / localize-01
                        :location (a3 / adhere-01
                              :mod (f3 / focal)))
                  :ARG1 b))
      :ARG1-of (i2 / instead-of-91))

# ::id bio.chicago_2015.20303 ::date 2015-10-21T13:02:48 ::annotator SDL-AMR-09 ::preferred
# ::snt Our study establishes  Rac/ Cdc42/Pak as an upstream module for  Raf-1 activation in association with the integrity of microtubules, but not for  EGF activation of  Raf.
# ::save-date Sun Jan 17, 2016 ::file bio_chicago_2015_20303.txt
(e / establish-01
      :ARG0 (s / study-01
            :ARG0 (w / we))
      :ARG1 (p3 / pathway :name (n3 / name :op1 "Rac/Cdc42/Pak"))
      :ARG2 (m / module
            :direction (u / upstream)
            :beneficiary (a / activate-01
                  :ARG1 (e3 / enzyme :name (n2 / name :op1 "Raf-1"))
                  :ARG1-of (a3 / associate-01
                        :ARG2 (i / integrity
                              :poss (m2 / microtubule))
                        :ARG1-of (c / contrast-01
                              :ARG2 (a4 / activate-01 :polarity -
                                    :ARG0 (p / protein :name (n / name :op1 "EGF"))
                                    :ARG1 (e2 / enzyme :name (n4 / name :op1 "Raf"))))))))

# ::id bio.chicago_2015.20312 ::date 2015-10-21T13:11:19 ::annotator SDL-AMR-09 ::preferred
# ::snt Enhancement of  EGF-induced   EGF  receptor autophosphorylation and   MAPK  phosphorylation by  GD1a.
# ::save-date Sat Feb 13, 2016 ::file bio_chicago_2015_20312.txt
(a / and
      :op1 (e / enhance-01
            :ARG1 (p2 / phosphorylate-01
                  :ARG1 (e3 / enzyme :name (n2 / name :op1 "EGF" :op2 "receptor"))
                  :ARG2 e3
                  :ARG2-of (i / induce-01
                        :ARG0 e3)))
      :op2 (p4 / phosphorylate-01
            :ARG1 (e2 / enzyme :name (n / name :op1 "MAPK"))
            :ARG2 (s / small-molecule :name (n3 / name :op1 "GD1a"))))

# ::id bio.chicago_2015.20319 ::date 2015-10-21T13:16:56 ::annotator SDL-AMR-09 ::preferred
# ::snt EGF receptor levels were significantly decreased following  EGF stimulation of  cells co-expressing ACK2 and  SH3PX1, thus highlighting a novel role for  ACK2, working together with  SH3PX1 to promote the degradation of the  EGF receptor.
# ::save-date Sat Feb 13, 2016 ::file bio_chicago_2015_20319.txt
(c2 / cause-01
      :ARG0 (d / decrease-01
            :ARG1 (l / level
                  :quant-of (e2 / enzyme :name (n3 / name :op1 "EGF" :op2 "receptor")))
            :ARG1-of (s / significant-02)
            :ARG1-of (f / follow-01
                  :ARG2 (s2 / stimulate-01
                        :ARG0 e2
                        :ARG1 (c / cell
                              :ARG3-of (e / express-03
                                    :ARG2 (a / and
                                          :op1 (p / protein :name (n / name :op1 "ACK2"))
                                          :op2 (p3 / protein :name (n5 / name :op1 "SH3PX1")))
                                    :mod (t2 / together))))))
      :ARG1 (a4 / and
            :op1 (h / highlight-01
                  :ARG0 l
                  :ARG1 (r2 / role
                        :mod (n4 / novel)
                        :beneficiary p))
            :op2 (w / work-01
                  :ARG0 l
                  :ARG1 (p2 / promote-01
                        :ARG0 (a2 / and
                              :op1 l
                              :op2 p3)
                        :ARG1 (d2 / degrade-01
                              :ARG1 e2))
                  :ARG3 p3)))

# ::id bio.chicago_2015.20334 ::date 2015-10-21T13:29:58 ::annotator SDL-AMR-09 ::preferred
# ::snt At the Z line,  titin may determine the  minimum extent and  tropomyosin the maximum extent of thin  filament overlap by regulating  alpha-actinin binding to  actin,  while a unique Z filament may bind to  capZ and regulate barbed  end capping.
# ::save-date Sat Feb 13, 2016 ::file bio_chicago_2015_20334.txt
(p / possible-01
      :ARG1 (a / and
            :op1 (d2 / determine-01
                  :ARG0 (p3 / protein :name (n2 / name :op1 "titin"))
                  :ARG1 (e / extent
                        :degree (m / minimum)
                        :poss (f / filament
                              :mod (t / thin)
                              :ARG1-of (o / overlap-01
                                    :ARG0 (b / bind-01
                                          :ARG1 (p4 / protein :name (n3 / name :op1 "alpha-actinin")
                                                :ARG0-of (r / regulate-01))
                                          :ARG2 (p5 / protein :name (n4 / name :op1 "actin")))))))
            :op2 (d3 / determine-01
                  :ARG0 (p2 / protein :name (n / name :op1 "tropomyosin"))
                  :ARG1 (e2 / extent
                        :degree (m2 / maximum)
                        :poss f)))
      :time (p6 / possible-01
            :ARG1 (a2 / and
                  :op1 (b2 / bind-01
                        :ARG1 (f2 / filament :name (n7 / name :op1 "Z")
                              :mod (u / unique))
                        :ARG2 (p7 / protein :name (n5 / name :op1 "capZ")))
                  :op2 (r2 / regulate-01
                        :ARG0 f2
                        :ARG1 (e3 / end
                              :ARG1-of (b3 / barb-01)
                              :ARG0-of (c / cap-02)))))
      :location (l / line :mod "Z"))

# ::id bio.chicago_2015.20374 ::date 2015-10-21T13:48:45 ::annotator SDL-AMR-09 ::preferred
# ::snt Binding of  Tubulin to  Synaptotagmin I-- To identify soluble proteins that specifically interact with  synaptotagmin I, the soluble fraction from the  rat brain was incubated with  GST fusion protein of the cytoplasmic portion of  synaptotagmin I immobilized on  glutathione-Sepharose.
# ::save-date Sat Feb 13, 2016 ::file bio_chicago_2015_20374.txt
(m / multi-sentence
      :snt1 (b / bind-01
            :ARG1 (p / protein :name (n / name :op1 "tubulin"))
            :ARG2 (p5 / protein :name (n2 / name :op1 "Synaptotagmin" :op2 "I-")))
      :snt2 (i / incubate-01
            :ARG1 (f / fraction
                  :mod (s / soluble)
                  :part-of (b2 / brain
                        :part-of (r / rat)))
            :ARG2 (e / enzyme :name (n3 / name :op1 "GST")
                  :ARG1-of (f2 / fuse-01)
                  :source (p3 / portion-01
                        :ARG1 (p6 / protein :name (n4 / name :op1 "synaptotagmin" :op2 "I")
                              :ARG1-of (i2 / immobilize-01
                                    :location (s4 / small-molecule :name (n5 / name :op1 "glutathione-Sepharose"))))
                        :mod (c / cytoplasm)))
            :purpose (i3 / identify-01
                  :ARG1 (p4 / protein
                        :mod (s2 / soluble)
                        :ARG0-of (i4 / interact-01
                              :ARG1 (p7 / protein :name (n6 / name :op1 "Synaptotagmin" :op2 "I"))
                              :ARG1-of (s3 / specific-02))))))

# ::id bio.chicago_2015.20674 ::date 2015-10-21T13:48:56 ::annotator SDL-AMR-09 ::preferred
# ::snt As previously reported,  CSP also binds to  Hsc70 (right diagram, col.
# ::save-date Fri Dec 18, 2015 ::file bio_chicago_2015_20674.txt
(b / bind-01
      :ARG1 (p / protein :name (n / name :op1 "CSP"))
      :ARG2 (p2 / protein :name (n2 / name :op1 "Hsc70"))
      :ARG1-of (r / report-01
            :time (p3 / previous))
      :ARG1-of (d / describe-01
            :ARG0 (a / and
                  :op1 (d2 / diagram
                        :ARG1-of (r2 / right-04))
                  :op2 (c / col)))
      :mod (a2 / also))

# ::id bio.chicago_2015.20679 ::date 2015-10-21T14:00:25 ::annotator SDL-AMR-09 ::preferred
# ::snt Furthermore, we provide the first evidence of interaction of  NK-4 with the  p300 coactivator and the  Groucho corepressor.
# ::save-date Sun Jan 17, 2016 ::file bio_chicago_2015_20679.txt
(a / and
      :op2 (p / provide-01
            :ARG0 (w / we)
            :ARG1 (e / evidence-01
                  :ARG1 (i / interact-01
                        :ARG0 (p3 / protein :name (n4 / name :op1 "NK-4"))
                        :ARG1 (a3 / and
                              :op1 (p2 / protein :name (n2 / name :op1 "p300")
                                    :ARG0-of (a2 / activate-01
                                          :mod t))
                              :op2 (p4 / protein :name (n / name :op1 "Groucho"))
                              :ARG0-of (r / repress-01
                                    :mod (t / together))))
                  :mod (o / ordinal-entity :value 1))))

# ::id bio.chicago_2015.20700 ::date 2015-10-21T14:07:32 ::annotator SDL-AMR-09 ::preferred
# ::snt Note that despite the extensive cell-cell rearrangements occurring after  Raf activation,  E-cadherin still colocalizes with cortical  actin at areas of cell-cell contact (in yellow-orange).
# ::save-date Tue Feb 2, 2016 ::file bio_chicago_2015_20700.txt
(n2 / note-01
      :ARG0 (y / you)
      :ARG1 (h / have-concession-91
            :ARG1 (c / colocalize-01
                  :ARG1 (a5 / and
                        :op1 (p2 / protein :name (n3 / name :op1 "E-cadherin"))
                        :op2 (p / protein :name (n / name :op1 "actin")
                              :mod (c4 / cortical)))
                  :ARG2 (a2 / area
                        :mod (c5 / contact-01
                              :ARG0 c3
                              :ARG1 c3))
                  :mod (s / still))
            :ARG2 (r / rearrange-01
                  :ARG0 c3
                  :ARG1 (c3 / cell)
                  :ARG1-of (e / extensive-03)
                  :time (a4 / after
                        :op1 (a / activate-01
                              :ARG1 (e2 / enzyme :name (n6 / name :op1 "Raf"))))))
      :ARG1-of (d / describe-01
            :ARG0 (a3 / and
                  :op1 (y2 / yellow)
                  :op2 (o / orange))))

# ::id bio.chicago_2015.20701 ::date 2015-10-21T20:31:36 ::annotator SDL-AMR-09 ::preferred
# ::snt In fact, an earlier report ( 31) suggests that  Src, which can up-regulate  NMDA receptor activity, binds to the  NMDA receptor complex.
# ::save-date Thu Nov 12, 2015 ::file bio_chicago_2015_20701.txt
(s / suggest-01
      :ARG0 (r / report-01
            :mod (e2 / early
                  :degree (m2 / more))
            :ARG1-of (d / describe-01
                  :ARG0 (p / publication
                        :ARG1-of (c / cite-01
                              :ARG2 31))))
      :ARG1 (b / bind-01
            :ARG1 (p2 / protein :name (n / name :op1 "Src")
                  :ARG0-of (u2 / upregulate-01
                        :ARG1 (a / activity-06
                              :ARG0 r3)
                        :ARG1-of (p3 / possible-01)))
            :ARG2 (c2 / complex
                  :mod (r3 / receptor :name (n2 / name :op1 "NMDA"))))
      :mod (i / in-fact))

# ::id bio.chicago_2015.20736 ::date 2015-10-21T20:53:26 ::annotator SDL-AMR-09 ::preferred
# ::snt In  SW 48 the  beta-catenin protein coprecipitated with  E-cadherin and  APC but not with  alpha-catenin.
# ::save-date Tue Feb 2, 2016 ::file bio_chicago_2015_20736.txt
(c3 / contrast-01
      :ARG1 (c / coprecipitate-01
            :ARG1 (a2 / and
                  :op1 (p / protein :name (n2 / name :op1 "beta-catenin"))
                  :op2 (a / and
                        :op1 (p2 / protein :name (n3 / name :op1 "E-cadherin"))
                        :op2 (p4 / protein :name (n5 / name :op1 "APC"))))
            :location (c2 / cell-line :name (n / name :op1 "SW48")))
      :ARG2 (c4 / coprecipitate-01 :polarity -
            :ARG1 (a3 / and
                  :op1 p
                  :op2 (p3 / protein :name (n4 / name :op1 "alpha-catenin")))
            :location c2))

# ::id bio.chicago_2015.20797 ::date 2015-10-21T21:01:42 ::annotator SDL-AMR-09 ::preferred
# ::snt To study the significance of  TFIID interactions with the  Inr and downstream regions in greater detail, we performed  DNase I footprinting, EMSA, and in vitro transcription experiments with the natural AdML promoter.
# ::save-date Sat Feb 13, 2016 ::file bio_chicago_2015_20797.txt
(p / perform-01
      :ARG0 (w / we)
      :ARG1 (a / and
            :op1 (f / footprint
                  :mod (e3 / enzyme :name (n6 / name :op1 "DNase" :op2 "I")))
            :op2 (t / thing :name (n / name :op1 "EMSA"))
            :op3 (e / experiment-01
                  :ARG1 (t3 / transcribe-01)
                  :ARG2 (m3 / molecular-physical-entity
                        :ARG1-of (n3 / natural-03)
                        :ARG0-of (p2 / promote-01)
                        :mod (l / late
                              :mod (m4 / major))
                        :mod (a3 / adenovirus))
                  :manner (i / in-vitro)))
      :purpose (s / study-01
            :ARG0 (w2 / we)
            :ARG1 (s2 / signify-01
                  :ARG0 (i2 / interact-01
                        :ARG0 (p3 / protein :name (n4 / name :op1 "TFIID"))
                        :ARG1 (a2 / and
                              :op1 (m / molecular-physical-entity
                                    :ARG0-of (i3 / initiate-01))
                              :op2 (r / region
                                    :direction (d / downstream))))
                  :manner (d2 / detail-01
                        :mod (g / great
                              :degree (m2 / most))))))

# ::id bio.chicago_2015.20835 ::date 2015-10-21T21:09:04 ::annotator SDL-AMR-09 ::preferred
# ::snt In addition, overexpression of a  FAK mutant that is incapable of binding to  Src fails to induce  paxillin phosphorylation, and expression of the  COOH-terminal domain of  FAK inhibits both  FAK activation and   paxillin tyrosine phosphorylation (Schaller and Parsons,  1995  ; Richardson and Parsons, 1996  ).
# ::save-date Sun Jan 17, 2016 ::file bio_chicago_2015_20835.txt
(a / and
      :op2 (a2 / and
            :op1 (f / fail-01
                  :ARG1 (o / overexpress-01
                        :ARG1 (e2 / enzyme :name (n5 / name :op1 "FAK")
                              :ARG2-of (m2 / mutate-01)
                              :ARG1-of (c / capable-01 :polarity -
                                    :ARG2 (b / bind-01
                                          :ARG1 e2
                                          :ARG2 (p2 / protein :name (n2 / name :op1 "Src"))))))
                  :ARG2 (i / induce-01
                        :ARG0 e2
                        :ARG2 (p3 / phosphorylate-01
                              :ARG1 (p4 / protein :name (n3 / name :op1 "paxillin")))))
            :op2 (i2 / inhibit-01
                  :ARG0 (e / express-03
                        :ARG3 (p5 / protein-segment :name (n / name :op1 "COOH-terminus")
                              :part-of (p12 / protein :name (n6 / name :op1 "FAK"))))
                  :ARG1 (a3 / and
                        :op1 (a4 / activate-01
                              :ARG1 p12)
                        :op2 (p / phosphorylate-01
                              :ARG1 (a8 / amino-acid :name (n4 / name :op1 "tyrosine")
                                    :part-of p4)))))
      :ARG1-of (d3 / describe-01
            :ARG0 (a5 / and
                  :op1 (p6 / publication-91
                        :ARG0 (a6 / and
                              :op1 (p8 / person :name (n7 / name :op1 "Schaller"))
                              :op2 (p9 / person :name (n8 / name :op1 "Parsons")))
                        :time (d / date-entity :year 1995))
                  :op2 (p7 / publication-91
                        :ARG0 (a7 / and
                              :op1 (p10 / person :name (n9 / name :op1 "Richardson"))
                              :op2 p9)
                        :time (d2 / date-entity :year 1996)))))

# ::id bio.chicago_2015.20957 ::date 2015-10-21T21:21:30 ::annotator SDL-AMR-09 ::preferred
# ::snt SRC can be activated by  EGFR engagement in various cell types ( 51-53) and potentiates the ability of the  EGFR to transform  murine fibroblasts ( 54).
# ::save-date Thu Nov 12, 2015 ::file bio_chicago_2015_20957.txt
(a / and
      :op1 (p / possible-01
            :ARG1 (a2 / activate-01
                  :ARG0 (e2 / engage-01
                        :ARG1 (e3 / enzyme :name (n3 / name :op1 "EGFR"))
                        :ARG2 (t / type
                              :mod (v / various)
                              :mod (c / cell)))
                  :ARG1 (p2 / protein :name (n2 / name :op1 "SRC")))
            :ARG1-of (d2 / describe-01
                  :ARG0 (p5 / publication
                        :ARG1-of (c4 / cite-01
                              :ARG2 (v2 / value-interval :op1 51 :op2 53)))))
      :op2 (p4 / potentiate-01
            :ARG0 p2
            :ARG1 (c2 / capable-01
                  :ARG1 e3
                  :ARG2 (t2 / transform-01
                        :ARG0 e3
                        :ARG1 (f / fibroblast
                              :mod (m / murine)))))
      :ARG1-of (d / describe-01
            :ARG0 (p3 / publication
                  :ARG1-of (c3 / cite-01
                        :ARG2 54))))

# ::id bio.chicago_2015.20967 ::date 2015-10-21T21:27:26 ::annotator SDL-AMR-09 ::preferred
# ::snt Anterior cells that receive high doses of  Hh (the  AP wing organiser) activate Col, which, in turn, upregulates expression of  BS,   vn,   emc and   mtv, and represses expression of   EGFR (aMohler et al., 2000  ).
# ::save-date Wed Mar 2, 2016 ::file bio_chicago_2015_20967.txt
(a / activate-01
      :ARG0 (c / cell
            :mod (a2 / anterior)
            :ARG0-of (r / receive-01
                  :ARG1 (d2 / dose-01
                        :ARG1 (p2 / protein :name (n3 / name :op1 "Hh")
                              :ARG0-of (o2 / organize-01
                                    :ARG1 (w / wing
                                          :mod (a5 / anterior)
                                          :mod (p9 / posterior))))
                        :ARG1-of (h / high-02))))
      :ARG1 (e2 / enzyme :name (n / name :op1 "Col")
            :ARG0-of (u / upregulate-01
                  :ARG1 (e3 / express-03
                        :ARG2 (a3 / and
                              :op1 (p4 / protein :name (n4 / name :op1 "BS"))
                              :op2 (p5 / protein :name (n5 / name :op1 "vn"))
                              :op3 (p6 / protein :name (n6 / name :op1 "emc"))
                              :op4 (p7 / protein :name (n7 / name :op1 "mtv"))))
                  :mod (i / in-turn))
            :ARG0-of (r3 / repress-01
                  :ARG1 (e4 / express-03
                        :ARG2 (e / enzyme :name (n2 / name :op1 "EGFR")))))
      :ARG1-of (d3 / describe-01
            :ARG0 (p3 / publication-91
                  :ARG0 (a4 / and
                        :op1 (p / person :name (n8 / name :op1 "Mohler"))
                        :op2 (p8 / person
                              :mod (o / other)))
                  :time (d / date-entity :year 2000))))

# ::id bio.chicago_2015.21011 ::date 2015-10-21T21:40:26 ::annotator SDL-AMR-09 ::preferred
# ::snt If this was the case, we would predict that increased levels of   Dl expression would enhance the   spl mutant phenotype.
# ::save-date Sat Jan 30, 2016 ::file bio_chicago_2015_21011.txt
(h / have-condition-91
      :ARG1 (p / predict-01
            :ARG0 (w / we)
            :ARG1 (e2 / enhance-01
                  :ARG0 (l / level
                        :ARG1-of (i / increase-01)
                        :degree-of (e / express-03
                              :ARG1 (g / gene :name (n / name :op1 "D1"))))
                  :ARG1 (p2 / phenotype
                        :mod (g2 / gene :name (n2 / name :op1 "sp1")
                              :ARG2-of (m / mutate-01)))))
      :ARG2 (c / case-04
            :ARG1 (t / this)))

# ::id bio.chicago_2015.21196 ::date 2015-10-21T21:45:37 ::annotator SDL-AMR-09 ::preferred
# ::snt Myosin phosphatase interacts with both  ERM family proteins and  adducin through  MBS, and dephosphorylates the phosphorylated  ERM family proteins and  adducin ( Fukata et al. 1998   ;   Kimura et al. 1998   ).
# ::save-date Fri Jan 15, 2016 ::file bio_chicago_2015_21196.txt
(a / and
      :op1 (i / interact-01
            :ARG0 (e2 / enzyme :name (n7 / name :op1 "Myosin" :op2 "phosphatase"))
            :ARG1 (a2 / and
                  :op1 (p3 / protein-family :name (n2 / name :op1 "ERM"))
                  :op2 (p4 / protein-family :name (n3 / name :op1 "adducin")))
            :manner (p / protein-segment :name (n4 / name :op1 "MBS")))
      :op2 (d2 / dephosphorylate-01
            :ARG1 (a3 / and
                  :op1 p3
                  :op2 p4
                  :ARG3-of (p2 / phosphorylate-01))
            :ARG2 e2)
      :ARG1-of (d3 / describe-01
            :ARG0 (a4 / and
                  :op1 (p7 / publication-91
                        :ARG0 (a5 / and
                              :op1 (p5 / person :name (n5 / name :op1 "Fukata"))
                              :op2 (p9 / person
                                    :mod (o / other)))
                        :time (d / date-entity :year 1998))
                  :op2 (p8 / publication-91
                        :ARG0 (a7 / and
                              :op1 (p6 / person :name (n6 / name :op1 "Kimura"))
                              :op2 p9)
                        :time d))))

# ::id bio.chicago_2015.22716 ::date 2015-10-21T21:56:34 ::annotator SDL-AMR-09 ::preferred
# ::snt In   Drosophila, it was reported that ceramide functions downstream of caspases during  Rpr-induced apoptosis on the basis  of the effects of the  tripeptide caspase inhibitor  N-benzyloxycarbonyl-VAD-fluoromethylketone (zVAD.
# ::save-date Sat Feb 13, 2016 ::file bio_chicago_2015_22716.txt
(r / report-01
      :ARG1 (f / function-01
            :ARG0 (s / small-molecule :name (n / name :op1 "ceramide"))
            :location (r2 / relative-position
                  :op1 (p / protein :name (n6 / name :op1 "caspase"))
                  :direction (d / downstream))
            :time (a / apostosis
                  :ARG2-of (i3 / induce-01
                        :ARG0 (e / enzyme :name (n2 / name :op1 "Rpr"))))
            :ARG1-of (b / base-02
                  :ARG2 (a2 / affect-01
                        :ARG0 (s2 / small-molecule :name (n4 / name :op1 "N-benzyloxycarbonyl-VAD-fluoromethylketone")
                              :mod (t / tripeptide)
                              :ARG0-of (i / inhibit-01
                                    :ARG1 p)))))
      :location (o / organism :name (n5 / name :op1 "Drosophila")))

# ::id bio.chicago_2015.22780 ::date 2015-10-21T02:55:53 ::annotator SDL-AMR-09 ::preferred
# ::snt After 5 min of incubation, the reaction was stopped by the addition of 5  mul of 5xLaemmli's  SDS-sample buffer.
# ::save-date Sat Feb 13, 2016 ::file bio_chicago_2015_22780.txt
(s / stop-01
      :ARG0 (a / add-02
            :ARG1 (p / product :name (n / name :op1 "5x" :op2 "Laemmli" :op3 "SDS" :op4 "sample" :op5 "buffer")
                  :quant (v / volume-quantity :quant 5
                        :unit (m2 / milliliter))))
      :ARG1 (r / react-01)
      :time (a2 / after
            :op1 (i / incubate-01
                  :duration (t / temporal-quantity :quant 5
                        :unit (m4 / minute)))))

# ::id bio.chicago_2015.22788 ::date 2015-10-21T03:08:24 ::annotator SDL-AMR-09 ::preferred
# ::snt We show that  E2F1 has a clear role in the induction of  p53-dependent apoptosis and, surprisingly, is also required for the  tumor cell division cycle.
# ::save-date Wed Oct 28, 2015 ::file bio_chicago_2015_22788.txt
(s / show-01
      :ARG0 (w / we)
      :ARG1 (a / and
            :op1 (h / have-03
                  :ARG0 (p / protein :name (n / name :op1 "E2F1"))
                  :ARG1 (r / role
                        :ARG1-of (c / clear-06)
                        :prep-in (i / induce-01
                              :ARG1 (a2 / apoptosis
                                    :ARG0-of (d / depend-01
                                          :ARG1 (p2 / protein :name (n2 / name :op1 "p53")))))))
            :op1 (r2 / require-01
                  :ARG0 (c2 / cycle-02
                        :ARG1 (d2 / divide-02
                              :ARG1 (c3 / cell
                                    :mod (t / tumor))))
                  :ARG1 p
                  :ARG0-of (s2 / surprise-01)
                  :mod (a3 / also))))

# ::id bio.chicago_2015.22808 ::date 2015-10-21T03:18:23 ::annotator SDL-AMR-09 ::preferred
# ::snt SV-SOD1 wt, but not  SV-SOD1 M or  SV-SOD1 R, potentiates  SV-induced apoptosis.
# ::save-date Sat Feb 13, 2016 ::file bio_chicago_2015_22808.txt
(c / contrast-01
      :ARG1 (p / potentiate-01
            :ARG0 (v / virus :name (n / name :op1 "sindbis")
                  :ARG3-of (e / express-03
                        :ARG2 (e2 / enzyme :name (n2 / name :op1 "superoxide" :op2 "dismutase")
                              :mod (w / wild-type))))
            :ARG1 (a / apoptosis
                  :ARG1-of (i / induce-01
                        :ARG0 v)))
      :ARG2 (p2 / potentiate-01 :polarity -
            :ARG0 (o / or
                  :op1 (v3 / virus :name (n3 / name :op1 "sindbis")
                        :ARG3-of (e3 / express-03
                              :ARG2 (e4 / enzyme :name (n4 / name :op1 "superoxide" :op2 "dismutase")
                                    :ARG2-of (m / mutate-01))))
                  :op2 (v2 / virus :name (n5 / name :op1 "sindbis")
                        :ARG3-of (e5 / express-03
                              :ARG2 (e6 / enzyme :name (n6 / name :op1 "superoxide" :op2 "dismutase")
                                    :ARG1-of (r / reverse-01)))))
            :ARG1 a))

# ::id bio.chicago_2015.22836 ::date 2015-10-21T03:43:58 ::annotator SDL-AMR-09 ::preferred
# ::snt Together, these studies provide substantial evidence that  E2F1 has a key role in  p53-dependent apoptosis associated with aberrant cell cycle activity in vivo.
# ::save-date Wed Oct 28, 2015 ::file bio_chicago_2015_22836.txt
(p / provide-01
      :ARG0 (s / study-01
            :mod (t2 / this))
      :ARG1 (e / evidence-01
            :ARG1 (h / have-03
                  :ARG0 (p2 / protein :name (n / name :op1 "E2F1"))
                  :ARG1 (r / role
                        :ARG1-of (k / key-02
                              :ARG2 (a / apoptosis
                                    :ARG0-of (d / depend-01
                                          :ARG1 (p3 / protein :name (n2 / name :op1 "p53")))
                                    :ARG1-of (a2 / associate-01
                                          :ARG2 (a3 / activity-06
                                                :ARG0 (c / cell)
                                                :ARG1 (c2 / cycle-02
                                                      :ARG1 c)
                                                :mod (a4 / aberrant))
                                          :manner (i / in-vivo))))))
            :mod (s2 / substantial))
      :manner (t / together))

# ::id bio.chicago_2015.22874 ::date 2015-10-21T03:53:36 ::annotator SDL-AMR-09 ::preferred
# ::snt PAK is involved in  Agrin-induced  AChR clustering.
# ::save-date Wed Oct 28, 2015 ::file bio_chicago_2015_22874.txt
(i / involve-01
      :ARG1 (e / enzyme :name (n / name :op1 "PAK"))
      :ARG2 (c / cluster-01
            :ARG1 (p2 / protein :name (n2 / name :op1 "AChR"))
            :ARG2-of (i2 / induce-01
                  :ARG0 (p / protein :name (n3 / name :op1 "Agrin")))))

# ::id bio.chicago_2015.22906 ::date 2015-10-21T04:33:11 ::annotator SDL-AMR-09 ::preferred
# ::snt However,  Sina has also been implicated in  ubiquitin-dependent proteolysis ( 21,  29,  46).
# ::save-date Wed Oct 21, 2015 ::file bio_chicago_2015_22906.txt
(c / contrast-01
      :ARG2 (i / implicate-01
            :ARG1 (p / protein :name (n / name :op1 "Sina"))
            :ARG2 (p2 / proteolysis
                  :ARG0-of (d / depend-01
                        :ARG1 (p3 / protein :name (n2 / name :op1 "ubiquitin"))))
            :mod (a / also))
      :ARG1-of (d2 / describe-01
            :ARG0 (p4 / publication
                  :ARG1-of (c2 / cite-01
                        :ARG2 (a2 / and :op1 21 :op2 29 :op3 46)))))

# ::id bio.chicago_2015.22931 ::date 2015-10-21T06:59:12 ::annotator SDL-AMR-09 ::preferred
# ::snt Induction of apoptosis by  p53 is critical for  the  tumor suppressor function of  p53.
# ::save-date Wed Oct 28, 2015 ::file bio_chicago_2015_22931.txt
(c / critical-02
      :ARG1 (i / induce-01
            :ARG0 (p / protein :name (n / name :op1 "p53"))
            :ARG2 (a / apoptosis))
      :ARG2 (f / function-01
            :ARG0 p
            :ARG1 (s / suppress-01
                  :ARG0 p
                  :ARG1 (t / tumor))))

# ::id bio.chicago_2015.23115 ::date 2015-10-21T07:01:58 ::annotator SDL-AMR-09 ::preferred
# ::snt We conclude that  TFIIE contamination is not responsible for the enhanced  CTD phosphorylation by  TFIIH relative to free  CAK.
# ::save-date Sun Jan 17, 2016 ::file bio_chicago_2015_23115.txt
(c / conclude-01
      :ARG0 (w / we)
      :ARG1 (r / responsible-01 :polarity -
            :ARG0 (c2 / contaminate-01
                  :ARG2 (p2 / protein :name (n / name :op1 "TFIIE")))
            :ARG1 (p / phosphorylate-01
                  :ARG1 (p4 / protein-segment :name (n3 / name :op1 "C-terminus"))
                  :ARG2 (p5 / protein :name (n4 / name :op1 "TFIIH"))
                  :ARG1-of (e / enhance-01)
                  :ARG1-of (r2 / relative-05
                        :ARG2 (e2 / enzyme :name (n2 / name :op1 "CAK")
                              :ARG1-of (f / free-04))))))

# ::id bio.chicago_2015.23123 ::date 2015-10-21T07:13:50 ::annotator SDL-AMR-09 ::preferred
# ::snt U1 snRNP bound to the 5' splice site,  U2AF65 bound to the  Py tract, and bridging activities, for which members of the  SR family of factors are strong candidates.
# ::save-date Sun Jan 17, 2016 ::file bio_chicago_2015_23123.txt
(a / and
      :op1 (b / bind-01
            :ARG1 (p3 / protein :name (n / name :op1 "U1" :op2 "snRNP"))
            :ARG2 (d2 / dna-sequence :name (n5 / name :op1 "5'" :op2 "site")
                  :ARG1-of (s2 / splice-01)))
      :op2 (b2 / bind-01
            :ARG1 (p / protein :name (n2 / name :op1 "U2AF65"))
            :ARG2 (d / dna-sequence :name (n3 / name :op1 "Py" :op2 "tract")))
      :op3 (c / candidate
            :purpose (a2 / activity-06
                  :ARG1 (b3 / bridge-01))
            :domain (m / member
                  :ARG1-of (i / include-91
                        :ARG2 (p2 / protein-family :name (n4 / name :op1 "SR")
                              :mod (f2 / factor))))
            :ARG1-of (s3 / strong-02)))

# ::id bio.chicago_2015.23189 ::date 2015-10-21T07:14:40 ::annotator SDL-AMR-09 ::preferred
# ::snt The observation that  BDNF does not elicit calcium transients, but induces  CREB phosphorylation also in acute slices of visual cortex strengthens the transferability  in vivo of these results.
# ::save-date Sat Oct 31, 2015 ::file bio_chicago_2015_23189.txt
(s / strengthen-01
      :ARG0 (o / observe-01
            :ARG1 (c / contrast-01
                  :ARG1 (e / elicit-01 :polarity -
                        :ARG0 (p2 / protein :name (n / name :op1 "BDNF"))
                        :ARG1 (e2 / event :name (n2 / name :op1 "calcium" :op2 "transient")))
                  :ARG2 (i / induce-01
                        :ARG0 p2
                        :ARG2 (p / phosphorylate-01
                              :ARG2 (p3 / protein :name (n3 / name :op1 "CREB"))
                              :location (s2 / slice
                                    :mod (a / acute)
                                    :part-of (c2 / cortex
                                          :mod (v / visual))
                                    :mod (a2 / also))))))
      :ARG1 (p4 / possible-01
            :ARG1 (t / transfer-01
                  :ARG1 (t3 / thing
                        :ARG2-of (r / result-01)
                        :mod (t2 / this))
                  :ARG2 (i2 / in-vivo))))

# ::id bio.chicago_2015.23275 ::date 2015-10-21T07:22:58 ::annotator SDL-AMR-09 ::preferred
# ::snt It has been proposed that enhancers function by promoting binding of  U2AF65 to weak  Py tracts (Wang et al. 1995  ; Zuo and Maniatis 1996  ; Bouck et al. 1998  ).
# ::save-date Sun Jan 17, 2016 ::file bio_chicago_2015_23275.txt
(p / propose-01
      :ARG1 (f / function-01
            :ARG0 (m / molecular-physical-entity
                  :ARG0-of (e / enhance-01))
            :manner (p2 / promote-01
                  :ARG0 m
                  :ARG1 (b / bind-01
                        :ARG1 (p3 / protein :name (n / name :op1 "U2AF65"))
                        :ARG2 (d4 / dna-sequence :name (n2 / name :op1 "Py" :op2 "tract")
                              :ARG1-of (w / weak-02)))))
      :ARG1-of (d5 / describe-01
            :ARG0 (a / and
                  :op1 (p4 / publication-91
                        :ARG0 (a2 / and
                              :op1 (p5 / person :name (n3 / name :op1 "Wang"))
                              :op2 (p6 / person
                                    :mod (o / other)))
                        :time (d / date-entity :year 1995))
                  :op2 (p7 / publication-91
                        :ARG0 (a3 / and
                              :op1 (p8 / person :name (n4 / name :op1 "Zuo"))
                              :op2 (p9 / person :name (n5 / name :op1 "Maniatis")))
                        :time (d2 / date-entity :year 1996))
                  :op3 (p10 / publication-91
                        :ARG0 (a4 / and
                              :op1 (p11 / person :name (n6 / name :op1 "Bouck"))
                              :op2 p6)
                        :time (d3 / date-entity :year 1998)))))

# ::id bio.chicago_2015.23324 ::date 2015-10-21T07:31:09 ::annotator SDL-AMR-09 ::preferred
# ::snt Because the  GTP-bound form of  Ras is a key transducer in the mitogen signaling pathway ( 18), we decided to examine  Ras GTP loading in anchored or suspended 3T3 cells treated with either  PDGF or  EGF.
# ::save-date Tue Jan 19, 2016 ::file bio_chicago_2015_23324.txt
(d / decide-01
      :ARG0 (w / we)
      :ARG1 (e / examine-01
            :ARG0 w
            :ARG1 (l / load-01
                  :ARG1 (o / or
                        :op1 (c / cell-line :name (n3 / name :op1 "3T3")
                              :ARG1-of (a / anchor-01))
                        :op2 (c2 / cell-line :name (n4 / name :op1 "3T3")
                              :ARG1-of (s2 / suspend-01))
                        :ARG1-of (t / treat-04
                              :ARG2 (o2 / or
                                    :op1 (p2 / protein :name (n5 / name :op1 "PDGF"))
                                    :op2 (p3 / protein :name (n6 / name :op1 "EGF")))))
                  :ARG2 (s / small-molecule :name (n2 / name :op1 "GTP"))
                  :ARG3 (e2 / enzyme :name (n / name :op1 "Ras"))))
      :ARG1-of (c3 / cause-01
            :ARG0 (m / molecular-physical-entity
                  :ARG2-of (t2 / transduce-01)
                  :ARG1-of (k / key-02)
                  :prep-in (p5 / pathway :name (n8 / name :op1 "mitogen" :op2 "signaling" :op3 "pathway"))
                  :domain (e3 / enzyme :name (n7 / name :op1 "Ras")
                        :ARG1-of (b / bind-01
                              :ARG2 s)))
            :ARG1-of (d2 / describe-01
                  :ARG0 (p6 / publication
                        :ARG1-of (c4 / cite-01
                              :ARG2 18)))))

# ::id bio.chicago_2015.23329 ::date 2015-10-22T10:11:53 ::annotator SDL-AMR-09 ::preferred
# ::snt We also found that the  CaMK antagonist KN93, but not the inactive congener KN92, blocked  BDNF-induced  CREB phosphorylation, further suggesting that KN62 is acting specifically (data not shown).
# ::save-date Wed Oct 28, 2015 ::file bio_chicago_2015_23329.txt
(f / find-01
      :ARG0 (w / we)
      :ARG1 (c / contrast-01
            :ARG1 (b / block-01
                  :ARG0 (s / small-molecule :name (n / name :op1 "KN93")
                        :ARG0-of (a2 / antagonize-01
                              :ARG1 (e / enzyme :name (n2 / name :op1 "CaMK"))))
                  :ARG1 (p / phosphorylate-01
                        :ARG1 (p2 / protein :name (n3 / name :op1 "CREB"))
                        :ARG2-of (i / induce-01
                              :ARG0 (p3 / protein :name (n4 / name :op1 "BDNF")))))
            :ARG2 (b2 / block-01 :polarity -
                  :ARG0 (s2 / small-molecule :name (n5 / name :op1 "KN92")
                        :mod (c2 / congener
                              :ARG0-of (a3 / act-02 :polarity -)))
                  :ARG1 p)
            :ARG0-of (s3 / suggest-01
                  :ARG1 (a4 / act-02
                        :ARG0 (s4 / small-molecule :name (n6 / name :op1 "KN62"))
                        :ARG1-of (s5 / specific-02))
                  :degree (f2 / further)))
      :mod (a / also)
      :ARG1-of (d / describe-01
            :ARG0 (d2 / data
                  :ARG1-of (s6 / show-01 :polarity -))))

# ::id bio.chicago_2015.23353 ::date 2015-10-22T10:40:16 ::annotator SDL-AMR-09 ::preferred
# ::snt However, the mechanism by which c-  myc induces apoptosis is unknown.
# ::save-date Wed Oct 28, 2015 ::file bio_chicago_2015_23353.txt
(c / contrast-01
      :ARG2 (k / know-01 :polarity -
            :ARG1 (m / mechanism
                  :manner-of (i / induce-01
                        :ARG0 (p / protein :name (n / name :op1 "c-myc"))
                        :ARG2 (a / apoptosis)))))

# ::id bio.chicago_2015.23361 ::date 2015-10-22T10:41:55 ::annotator SDL-AMR-09 ::preferred
# ::snt These data show that activation of  PKA by addition of cAMP or by depletion of the  Bcy1p subunit stimulates phosphorylation of  pyruvate kinase.
# ::save-date Thu Oct 22, 2015 ::file bio_chicago_2015_23361.txt
(s / show-01
      :ARG0 (d / data
            :mod (t / this))
      :ARG1 (s2 / stimulate-01
            :ARG0 (a / activate-01
                  :ARG0 (o / or
                        :op1 (a2 / add-02
                              :ARG1 (s3 / small-molecule :name (n / name :op1 "cAMP")))
                        :op2 (d2 / deplete-01
                              :ARG1 (s4 / subunit
                                    :mod (g / gene :name (n2 / name :op1 "Bcy1p")))))
                  :ARG1 (e / enzyme :name (n3 / name :op1 "PKA")))
            :ARG1 (p / phosphorylate-01
                  :ARG1 (e2 / enzyme :name (n4 / name :op1 "pyruvate" :op2 "kinase")))))

# ::id bio.chicago_2015.23365 ::date 2015-10-22T10:48:47 ::annotator SDL-AMR-09 ::preferred
# ::snt Ub exists in a dynamic equilibrium between free and conjugated forms that is determined by the relative rates of conjugation, deubiquitinylation by  Ub-specific isopeptidases and  Ub-dependent proteolysis, which releases free  Ub.
# ::save-date Tue Feb 2, 2016 ::file bio_chicago_2015_23365.txt
(e / exist-01
      :ARG1 (p / protein :name (n / name :op1 "ubiquitin"))
      :ARG2 (e2 / equilibrate-01
            :ARG1 (a / and
                  :op1 (f / form
                        :ARG1-of (f2 / free-04))
                  :op2 (f3 / form
                        :ARG1-of (c / conjugate-02)))
            :mod (d / dynamic)
            :ARG1-of (d2 / determine-01
                  :ARG0 (a2 / and
                        :op1 (r / rate
                              :ARG1-of (r2 / relative-05)
                              :mod c)
                        :op2 (d3 / deubiquitinylate-00
                              :ARG0 (e3 / enzyme :name (n2 / name :op1 "isopeptidase")
                                    :ARG1-of (s / specific-02
                                          :ARG2 p)))
                        :op3 (p2 / proteolysis
                              :ARG0-of (d4 / depend-01
                                    :ARG1 p)
                              :ARG0-of (r3 / release-01
                                    :ARG1 (p3 / protein :name (n3 / name :op1 "ubiquitin")
                                          :ARG1-of f2)))))))

# ::id bio.chicago_2015.23430 ::date 2015-10-22T10:56:01 ::annotator SDL-AMR-09 ::preferred
# ::snt In order to determine which sugars on  Notch are required for  Notch signaling and/or for fringe to function,  Jagged1-induced  Notch signaling was measured in a series of  CHO glycosylation mutants [ 2 and  50].
# ::save-date Wed Jan 13, 2016 ::file bio_chicago_2015_23430.txt
(m / measure-01
      :ARG1 (s / signal-07
            :ARG0 (p / pathway :name (n / name :op1 "Notch"))
            :ARG1-of (i / induce-01
                  :ARG0 (p2 / protein :name (n2 / name :op1 "Jagged1"))))
      :location (c / cell-line :name (n3 / name :op1 "CHO")
            :quant (s4 / series)
            :ARG2-of (m2 / mutate-01
                  :ARG0 (g / glycosylate-01)))
      :purpose (d / determine-01
            :ARG1 (a / amr-unknown
                  :mod (s2 / sugar)
                  :ARG1-of (r / require-01
                        :ARG0 (a4 / and-or
                              :op1 (s3 / signal-07
                                    :ARG0 p)
                              :op2 (f / function-01
                                    :ARG0 (f2 / fringe))))
                  :part-of p))
      :ARG1-of (d2 / describe-01
            :ARG0 (p3 / publication
                  :ARG1-of (c2 / cite-01
                        :ARG2 (a3 / and :op1 2 :op2 50)))))

# ::id bio.chicago_2015.23434 ::date 2015-10-22T11:05:05 ::annotator SDL-AMR-09 ::preferred
# ::snt Unlike Mad2 or  Mad2B,  Emi1 can inhibit  APC already activated by  Cdc20 or  Cdh1.
# ::save-date Fri Oct 23, 2015 ::file bio_chicago_2015_23434.txt
(r / resemble-01 :polarity -
      :ARG1 (p / possible-01
            :ARG1 (i / inhibit-01
                  :ARG0 (s / small-molecule :name (n / name :op1 "Emi1"))
                  :ARG1 (p2 / protein :name (n2 / name :op1 "APC")
                        :ARG1-of (a / activate-01
                              :ARG0 (o / or
                                    :op1 (p3 / protein :name (n3 / name :op1 "Cdc20"))
                                    :op2 (p4 / protein :name (n4 / name :op1 "Cdh1")))
                              :time (a2 / already)))))
      :ARG2 (o2 / or
            :op1 (p5 / protein :name (n5 / name :op1 "Mad2"))
            :op2 (p6 / protein :name (n6 / name :op1 "Mad2B"))))

# ::id bio.chicago_2015.23439 ::date 2015-10-23T01:33:06 ::annotator SDL-AMR-09 ::preferred
# ::snt Upregulation of the  p53 protein, mediated either by   irradiation [ 81] or by a temperature-sensitive  p53 transgene [ 80], together with  E2F1 overexpression induced apoptosis even in the presence of  serum growth factors.
# ::save-date Sun Nov 1, 2015 ::file bio_chicago_2015_23439.txt
(i / induce-01
      :ARG0 (a2 / and
            :op1 (u / upregulate-01
                  :ARG1 (p2 / protein :name (n2 / name :op1 "p53"))
                  :ARG1-of (m / mediate-01
                        :ARG0 (o / or
                              :op1 (i2 / irradiate-01
                                    :ARG1-of (d / describe-01
                                          :ARG0 (p4 / publication
                                                :ARG1-of (c / cite-01
                                                      :ARG2 81))))
                              :op2 (t / transgene
                                    :mod p2
                                    :ARG0-of (s2 / sensitive-03
                                          :ARG1 (t2 / temperature))
                                    :ARG1-of (d2 / describe-01
                                          :ARG0 (p5 / publication
                                                :ARG1-of (c2 / cite-01
                                                      :ARG2 80)))))))
            :op2 (o2 / overexpress-01
                  :ARG1 (p3 / protein :name (n3 / name :op1 "E2F1"))))
      :ARG2 (a / apoptosis)
      :concession (p / present-02
            :ARG1 (s / small-molecule :name (n / name :op1 "serum" :op2 "growth" :op3 "factor"))))

# ::id bio.chicago_2015.23524 ::date 2015-10-23T01:39:36 ::annotator SDL-AMR-09 ::preferred
# ::snt (B)  TRAF6 failed to activate  IKK in  Uev1A-depleted extracts.
# ::save-date Fri Oct 23, 2015 ::file bio_chicago_2015_23524.txt
(f / fail-01
      :ARG1 (p / protein :name (n / name :op1 "TRAF6"))
      :ARG2 (a / activate-01
            :ARG0 p
            :ARG1 (e / enzyme :name (n2 / name :op1 "IKK"))
            :location (e2 / extract
                  :ARG1-of (d / deplete-01
                        :ARG2 (p2 / protein :name (n3 / name :op1 "Uev1A")))))
      :ARG1-of (d2 / describe-01
            :ARG0 (f2 / figure :mod "B")))

# ::id bio.chicago_2015.23580 ::date 2015-10-23T01:44:02 ::annotator SDL-AMR-09 ::preferred
# ::snt Thus,  Ptc inhibits  the activity of  Smo and  HH binding  to  Ptc releases Smo from this inhibitory  process.
# ::save-date Sun Nov 1, 2015 ::file bio_chicago_2015_23580.txt
(i / infer-01
      :ARG1 (a / and
            :op1 (i2 / inhibit-01
                  :ARG0 (p / protein :name (n / name :op1 "Ptc"))
                  :ARG1 (a2 / activity-06
                        :ARG0 (p2 / protein :name (n2 / name :op1 "Smo"))))
            :op2 (r / release-01
                  :ARG0 (b / bind-01
                        :ARG1 (p3 / pathway :name (n3 / name :op1 "HH"))
                        :ARG2 p)
                  :ARG1 p2
                  :ARG2 (p4 / process-02
                        :ARG1 (i3 / inhibit-01
                              :ARG0 p2)))))

# ::id bio.chicago_2015.23632 ::date 2015-10-23T01:49:13 ::annotator SDL-AMR-09 ::preferred
# ::snt These data demonstrated that  Tyr phosphorylation was not required for  JNK activation by  MKK7.
# ::save-date Fri Oct 23, 2015 ::file bio_chicago_2015_23632.txt
(d / demonstrate-01
      :ARG0 (d2 / data
            :mod (t / this))
      :ARG1 (r / require-01 :polarity -
            :ARG0 (a / activate-01
                  :ARG0 (e2 / enzyme :name (n2 / name :op1 "MKK7"))
                  :ARG1 (e / enzyme :name (n / name :op1 "JNK")))
            :ARG1 (p / phosphorylate-01
                  :ARG1 (a2 / amino-acid :name (n3 / name :op1 "tyrosine")))))

# ::id bio.chicago_2015.23691 ::date 2015-10-23T02:08:43 ::annotator SDL-AMR-09 ::preferred
# ::snt Whereas the highly  conserved cysteine-rich domain is able to inhibit  EGF-induced  MAP kinase activation, the amino-terminal domain potentiates  EGF-induced MAP kinase activation by interfering with  EGFR ubiquitination and down-regulation.
# ::save-date Wed Oct 28, 2015 ::file bio_chicago_2015_23691.txt
(c / contrast-01
      :ARG1 (p2 / potentiate-01
            :ARG0 (p3 / protein-segment :name (n2 / name :op1 "amino-terminal" :op2 "domain"))
            :ARG1 (a / activate-01
                  :ARG1 (k / kinase :name (n3 / name :op1 "MAP"))
                  :ARG2-of (i / induce-01
                        :ARG0 (p4 / protein :name (n4 / name :op1 "EGF"))))
            :manner (i2 / interfere-01
                  :ARG0 p3
                  :ARG1 (a2 / and
                        :op1 (u / ubiquitinate-01
                              :ARG1 (e / enzyme :name (n / name :op1 "EGFR")))
                        :op2 (d / downregulate-01
                              :ARG1 e))))
      :ARG2 (c3 / capable-01
            :ARG1 p5
            :ARG2 (i3 / inhibit-01
                  :ARG0 (p5 / protein-segment :name (n5 / name :op1 "cysteine-rich" :op2 "domain")
                        :ARG1-of (c2 / conserve-01
                              :degree (h / high-02)))
                  :ARG1 a)))

# ::id bio.chicago_2015.23692 ::date 2015-10-23T02:19:19 ::annotator SDL-AMR-09 ::preferred
# ::snt Reduction of  profilin suppresses the disorganized  actin phenotype caused by reduction of  capping protein function, suggesting that  profilin promotes  actin assembly in the elongating bristle.
# ::save-date Wed Oct 28, 2015 ::file bio_chicago_2015_23692.txt
(s / suggest-01
      :ARG0 (s2 / suppress-01
            :ARG0 (r / reduce-01
                  :ARG1 (p / protein :name (n / name :op1 "profilin")))
            :ARG1 (p2 / phenotype
                  :mod (p3 / protein :name (n2 / name :op1 "actin"))
                  :ARG1-of (d / disorganize-01)
                  :ARG1-of (c / cause-01
                        :ARG0 (r2 / reduce-01
                              :ARG1 (f / function-01
                                    :ARG0 (p4 / protein :name (n3 / name :op1 "capping" :op2 "protein")))))))
      :ARG1 (p5 / promote-01
            :ARG0 p
            :ARG1 (a / assemble-01
                  :ARG1 p3
                  :location (b / bristle
                        :ARG0-of (e / elongate-01)))))

# ::id bio.chicago_2015.23746 ::date 2015-10-23T02:25:10 ::annotator SDL-AMR-09 ::preferred
# ::snt Significantly, it is shown that Zap-70 plays an adaptor role in  Cbl-induced  Ub conjugation to  TCRzeta chain.
# ::save-date Tue Feb 2, 2016 ::file bio_chicago_2015_23746.txt
(s / show-01
      :ARG1 (p / play-02
            :ARG0 (e / enzyme :name (n / name :op1 "Zap-70"))
            :ARG1 (c / conjugate-02
                  :ARG1 (p3 / protein :name (n3 / name :op1 "ubiquitin"))
                  :ARG2 (p4 / protein :name (n4 / name :op1 "TCRzeta" :op2 "chain"))
                  :mod (m / molecular-physical-entity
                        :ARG0-of (a / adapt-01))
                  :ARG2-of (i / induce-01
                        :ARG0 (p2 / protein :name (n2 / name :op1 "Cbl")))))
      :ARG1-of (s2 / significant-02))

# ::id bio.chicago_2015.23757 ::date 2015-10-23T02:38:58 ::annotator SDL-AMR-09 ::preferred
# ::snt Thus,  Eya-induced apoptosis involves both caspase-dependent and caspase-independent pathways.
# ::save-date Sun Jan 17, 2016 ::file bio_chicago_2015_23757.txt
(c / cause-01
      :ARG1 (i2 / involve-01
            :ARG1 (a2 / and
                  :op1 (p2 / pathway
                        :ARG0-of (d / depend-01
                              :ARG1 (p4 / protein :name (n2 / name :op1 "caspase"))))
                  :op2 (p3 / pathway
                        :ARG0-of (d2 / depend-01 :polarity -
                              :ARG1 p4)))
            :ARG2 (a / apoptosis
                  :ARG2-of (i3 / induce-01
                        :ARG0 (p / protein :name (n / name :op1 "Eya"))))))

# ::id bio.chicago_2015.23765 ::date 2015-10-23T04:31:30 ::annotator SDL-AMR-09 ::preferred
# ::snt A number of proteins have recently been identified that specifically interact with the  GTP-bound form of  Rho (reviewed in  [30]  ).
# ::save-date Sun Jan 17, 2016 ::file bio_chicago_2015_23765.txt
(i / identify-01
      :ARG1 (p / protein
            :quant (n / number)
            :ARG0-of (i2 / interact-01
                  :ARG1 (p3 / protein :name (n3 / name :op1 "Rho")
                        :ARG1-of (b / bind-01
                              :ARG2 (s2 / small-molecule :name (n2 / name :op1 "GTP"))))
                  :ARG1-of (s / specific-02))
            :ARG1-of (r2 / review-01
                  :ARG0 (p2 / publication
                        :ARG1-of (c / cite-01
                              :ARG2 30))))
      :time (r / recent))

# ::id bio.chicago_2015.23795 ::date 2015-10-23T04:37:52 ::annotator SDL-AMR-09 ::preferred
# ::snt However, this reduction in tension could contribute to checkpoint activation by other mechanisms, such as those that regulate  BubR1 inhibition of  Cdc20 activation of the  APC/C ( Skoufias et al., 2001;  Sudakin et al., 2001;  Tang et al., 2001).
# ::save-date Wed Oct 28, 2015 ::file bio_chicago_2015_23795.txt
(c / contrast-01
      :ARG2 (p2 / possible-01
            :ARG1 (c2 / contribute-01
                  :ARG0 (r / reduce-01
                        :ARG1 (t / tension)
                        :mod (t2 / this))
                  :ARG2 (a / activate-01
                        :ARG0 (m / mechanism
                              :mod (o / other)
                              :example (m2 / mechanism
                                    :ARG0-of (r2 / regulate-01
                                          :ARG1 (i / inhibit-01
                                                :ARG0 (e / enzyme :name (n / name :op1 "BubR1"))
                                                :ARG1 (a2 / activate-01
                                                      :ARG0 (p3 / protein :name (n2 / name :op1 "Cdc20"))
                                                      :ARG1 (p4 / protein :name (n3 / name :op1 "APC/C")))))))
                        :ARG1 (c3 / checkpoint))))
      :ARG1-of (d2 / describe-01
            :ARG0 (a3 / and
                  :op1 (p5 / publication-91
                        :ARG0 (a4 / and
                              :op1 (p8 / person :name (n4 / name :op1 "Skoufias"))
                              :op2 (p9 / person
                                    :mod (o2 / other)))
                        :time (d / date-entity :year 2001))
                  :op2 (p6 / publication-91
                        :ARG0 (a5 / and
                              :op1 (p10 / person :name (n5 / name :op1 "Sudakin"))
                              :op2 p9)
                        :time d)
                  :op3 (p7 / publication-91
                        :ARG0 (a6 / and
                              :op1 (p12 / person :name (n6 / name :op1 "Tang"))
                              :op2 p9)
                        :time d))))

# ::id bio.chicago_2015.23851 ::date 2015-10-23T04:47:16 ::annotator SDL-AMR-09 ::preferred
# ::snt Axin binds directly to  GSK-3beta,  beta-catenin, and  APC, whereas  APC also directly binds to  GSK-3beta and  beta-catenin.
# ::save-date Fri Oct 23, 2015 ::file bio_chicago_2015_23851.txt
(c / contrast-01
      :ARG1 (b / bind-01
            :ARG1 (p / protein :name (n / name :op1 "axin"))
            :ARG2 (a / and
                  :op1 (e / enzyme :name (n2 / name :op1 "GSK-3beta"))
                  :op2 (p2 / protein :name (n3 / name :op1 "beta-catenin"))
                  :op3 (p3 / protein :name (n4 / name :op1 "APC")))
            :ARG1-of (d / direct-02))
      :ARG2 (b2 / bind-01
            :ARG1 p3
            :ARG2 (a3 / and
                  :op1 e
                  :op2 p2)
            :ARG1-of d
            :mod (a2 / also)))

# ::id bio.chicago_2015.23862 ::date 2015-10-23T05:18:06 ::annotator SDL-AMR-09 ::preferred
# ::snt Thus, prolonged or  transient activation of  ERK induced by  nerve growth factor or  EGF  stimulation of PC12 cells, respectively( 28 ) , may involve  different  VH-1-like PTPases.
# ::save-date Sun Jan 17, 2016 ::file bio_chicago_2015_23862.txt
(c3 / cause-01
      :ARG1 (p2 / possible-01
            :ARG1 (i2 / involve-01
                  :ARG1 (e / enzyme :name (n5 / name :op1 "PTPase")
                        :ARG1-of (d2 / differ-02)
                        :ARG1-of (r / resemble-01
                              :ARG2 (e2 / enzyme :name (n6 / name :op1 "VH-1"))))
                  :ARG2 (o / or
                        :op1 (a / activate-01
                              :ARG1 (e3 / enzyme :name (n / name :op1 "ERK"))
                              :ARG1-of (p3 / prolong-01)
                              :ARG2-of (i3 / induce-01
                                    :ARG0 (s2 / stimulate-01
                                          :ARG0 (p / protein :name (n2 / name :op1 "nerve" :op2 "growth" :op3 "factor"))
                                          :ARG1 (c / cell-line :name (n3 / name :op1 "PC12")))
                                    :ARG1-of (d3 / describe-01
                                          :ARG0 (p5 / publication
                                                :ARG1-of (c2 / cite-01
                                                      :ARG2 28)))))
                        :op2 (a2 / activate-01
                              :ARG1 e3
                              :ARG1-of (t / transient-02)
                              :ARG2-of (i4 / induce-01
                                    :ARG0 (s3 / stimulate-01
                                          :ARG0 (p4 / protein :name (n4 / name :op1 "EGF"))
                                          :ARG1 c)
                                    :ARG1-of d3))))))

# ::id bio.chicago_2015.23867 ::date 2015-10-23T05:28:12 ::annotator SDL-AMR-09 ::preferred
# ::snt Conversely,  Ubc4/5 cannot substitute for  Ubc13/Uev1A in the activation of  IKK by   TRAF6 (  Figure 4D).
# ::save-date Sun Jan 17, 2016 ::file bio_chicago_2015_23867.txt
(c / contrast-01
      :ARG1 (p / possible-01 :polarity -
            :ARG1 (s / substitute-01
                  :ARG1 (e / enzyme :name (n / name :op1 "Ubc4/5"))
                  :ARG2 (p2 / protein :name (n2 / name :op1 "Ubc13/Uev1A"))
                  :ARG3 (a / activate-01
                        :ARG0 (p3 / protein :name (n3 / name :op1 "TRAF6"))
                        :ARG1 (e3 / enzyme :name (n4 / name :op1 "IKK")))))
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod "4D")))

# ::id bio.chicago_2015.23926 ::date 2015-10-23T05:34:53 ::annotator SDL-AMR-09 ::preferred
# ::snt A, lysates of biosynthetically labeled MOLT16  cells were first cleared with protein A-Sepharose ( lane 1) or  with  GST coupled to  glutathione-Sepharose 4B beads ( lane 6)  and then precipitated (  PP) with  mAb 6G4 coupled to protein  A-Sepharose ( lane 2) or  GST-DI ( lane 3),  GST-DII ( lane 4), or  GST-DIII ( lane 5) coupled to   glutathione-Sepharose 4B beads, as described under
# ::save-date Sat Feb 13, 2016 ::file bio_chicago_2015_23926.txt
(a / and
      :op1 (c / clear-01
            :ARG0 (o2 / or
                  :op1 (p3 / protein :name (n2 / name :op1 "A-sepharose")
                        :ARG1-of (d / describe-01
                              :ARG0 (l3 / lane :mod 1)))
                  :op2 (e / enzyme :name (n3 / name :op1 "GST")
                        :ARG1-of (c3 / couple-01
                              :ARG2 (b2 / bead
                                    :consist-of (s / small-molecule :name (n4 / name :op1 "gluthatione-Sepharose" :op2 "4b"))))
                        :ARG1-of (d2 / describe-01
                              :ARG0 (l4 / lane :mod 6))))
            :ARG1 (c2 / cell-line :name (n / name :op1 "MOLT16")
                  :ARG1-of (l / lysate-00)
                  :ARG1-of (l2 / label-01
                        :ARG2 (b / biosynthetic)))
            :time (f / first))
      :op2 (p / precipitate-00
            :ARG1 c2
            :instrument (o3 / or
                  :op1 (a2 / antibody
                        :ARG1-of (c4 / couple-01
                              :ARG2 p3)
                        :ARG1-of (d5 / describe-01
                              :ARG0 (l5 / lane :mod 2))
                        :ARG0-of (c7 / counter-01
                              :ARG1 (p2 / protein :name (n5 / name :op1 "6G5")))
                        :mod (m3 / monoclone))
                  :op2 (a3 / antibody
                        :ARG1-of (c5 / couple-01
                              :ARG2 (e2 / enzyme :name (n7 / name :op1 "GST-DI")))
                        :ARG1-of (d6 / describe-01
                              :ARG0 (l6 / lane :mod 3))
                        :ARG0-of c7
                        :mod m3)
                  :op3 (e3 / enzyme :name (n9 / name :op1 "GST-DII")
                        :ARG1-of (d7 / describe-01
                              :ARG0 (l7 / lane :mod 4)))
                  :op4 (e4 / enzyme :name (n8 / name :op1 "GST-DIII")
                        :ARG1-of (c6 / couple-01
                              :ARG2 s)
                        :ARG1-of (d8 / describe-01
                              :ARG0 (l8 / lane :mod 5))))
            :time (t / then))
      :ARG1-of (d3 / describe-01
            :ARG0 (f2 / figure :mod "A")))

# ::id bio.chicago_2015.23937 ::date 2015-10-23T05:52:03 ::annotator SDL-AMR-09 ::preferred
# ::snt Several proteins have been isolated as putative  Rho effectors on the basis of their selective interaction with the  GTP-bound form of  Rho.
# ::save-date Sun Nov 1, 2015 ::file bio_chicago_2015_23937.txt
(i / isolate-01
      :ARG1 (p / protein
            :mod (e / effector
                  :mod (p2 / protein :name (n / name :op1 "Rho"))
                  :ARG1-of (t / think-01))
            :quant (s / several))
      :ARG1-of (b2 / base-02
            :ARG2 (i2 / interact-01
                  :ARG0 p
                  :ARG1 (p3 / protein :name (n3 / name :op1 "Rho")
                        :ARG1-of (b / bind-01
                              :ARG2 (s3 / small-molecule :name (n2 / name :op1 "GTP"))))
                  :manner (s2 / selective))))

# ::id bio.chicago_2015.23977 ::date 2015-10-23T06:02:06 ::annotator SDL-AMR-09 ::preferred
# ::snt These results demonstrate that  Sp1 and  Sp3 can both bind to the  Sp1 consensus sequence in the  IGF-II promoter.
# ::save-date Wed Oct 28, 2015 ::file bio_chicago_2015_23977.txt
(d / demonstrate-01
      :ARG0 (t2 / thing
            :mod (t / this)
            :ARG2-of (r / result-01))
      :ARG1 (p / possible-01
            :ARG1 (b / bind-01
                  :ARG1 (a / and
                        :op1 (p2 / protein :name (n / name :op1 "Sp1"))
                        :op2 (p3 / protein :name (n2 / name :op1 "Sp3")))
                  :ARG2 (s / sequence
                        :mod (c / consensus)
                        :part-of (m / molecular-physical-entity
                              :ARG0-of (p4 / promote-01
                                    :ARG1 (p5 / protein :name (n3 / name :op1 "IGF-II"))))
                        :mod p2))))

# ::id bio.chicago_2015.24061 ::date 2015-10-23T06:08:52 ::annotator SDL-AMR-09 ::preferred
# ::snt Alternatively, the absence of an   Xbra band in the  ActRIIBdn cells would suggest that  activin induces   Xbra directly.
# ::save-date Fri Oct 23, 2015 ::file bio_chicago_2015_24061.txt
(s / suggest-01
      :ARG0 (a2 / absent-01
            :ARG1 (b / band
                  :mod (g / gene :name (n / name :op1 "Xbra")))
            :ARG2 (c / cell-line :name (n2 / name :op1 "ActRIIBdn")))
      :ARG1 (i / induce-01
            :ARG0 (p / protein :name (n3 / name :op1 "activin"))
            :ARG1 g
            :ARG1-of (d / direct-02))
      :manner (a / alternative))

# ::id bio.chicago_2015.24105 ::date 2015-10-23T06:12:52 ::annotator SDL-AMR-09 ::preferred
# ::snt In contrast, as previously described ( 13), co-expression of  kinase-inactive MEKK1 markedly reduced  NIK activation of  JNK (Fig.  7 B).
# ::save-date Tue Feb 2, 2016 ::file bio_chicago_2015_24105.txt
(c / contrast-01
      :ARG2 (r / reduce-01
            :ARG0 (c2 / coexpress-01
                  :ARG2 (e / enzyme :name (n / name :op1 "MEKK1")
                        :ARG0-of (a / activity-06 :polarity -
                              :mod (k / kinase))))
            :ARG1 (a2 / activate-01
                  :ARG0 (e2 / enzyme :name (n2 / name :op1 "NIK"))
                  :ARG1 (e3 / enzyme :name (n3 / name :op1 "JNK")))
            :manner (m / marked)
            :ARG1-of (d2 / describe-01
                  :ARG0 (f / figure :mod "7B")))
      :ARG1-of (d / describe-01
            :ARG0 (p / publication
                  :ARG1-of (c3 / cite-01
                        :ARG2 13))
            :time (p2 / previous)))

# ::id bio.chicago_2015.24115 ::date 2015-10-23T06:17:39 ::annotator SDL-AMR-09 ::preferred
# ::snt Additionally, we recently showed that  kinase subdomain VIII of  PAK1 could be phosphorylated  in vitro by  PDK1, suggesting phosphorylation events within the catalytic domain may regulate  PAK1 activity ( 26).
# ::save-date Sat Feb 13, 2016 ::file bio_chicago_2015_24115.txt
(a / and
      :op2 (s / show-01
            :ARG0 (w / we)
            :ARG1 (p / possible-01
                  :ARG1 (p2 / phosphorylate-01
                        :ARG1 (p3 / protein-segment :mod 8
                              :part-of (e / enzyme :name (n2 / name :op1 "PAK1")))
                        :ARG2 (e2 / enzyme :name (n3 / name :op1 "PDK1"))
                        :manner (i / in-vitro))
                  :ARG0-of (s2 / suggest-01
                        :ARG1 (p4 / possible-01
                              :ARG1 (r2 / regulate-01
                                    :ARG0 (p5 / phosphorylate-01
                                          :location (d2 / domain
                                                :mod (c / catalytic)))
                                    :ARG1 (a2 / activity-06
                                          :ARG0 e)))))
            :time (r / recent)
            :ARG1-of (d3 / describe-01
                  :ARG0 (p6 / publication
                        :ARG1-of (c2 / cite-01
                              :ARG2 26)))))

# ::id bio.chicago_2015.24118 ::date 2015-10-23T06:26:09 ::annotator SDL-AMR-09 ::preferred
# ::snt Direct Phosphorylation and Inhibition of  Cdc25 by  Cds1 and  Chk1 In Vitro
# ::save-date Fri Oct 23, 2015 ::file bio_chicago_2015_24118.txt
(a / and
      :op1 (p / phosphorylate-01
            :ARG1 (e / enzyme :name (n / name :op1 "Cdc25"))
            :ARG2 (a2 / and
                  :op1 (e3 / enzyme :name (n2 / name :op1 "Cds1"))
                  :op2 (e2 / enzyme :name (n3 / name :op1 "Chk1"))))
      :op2 (i / inhibit-01
            :ARG0 a2
            :ARG1 e)
      :ARG1-of (d / direct-02)
      :manner (i2 / in-vitro))

# ::id bio.chicago_2015.24126 ::date 2015-10-23T06:29:37 ::annotator SDL-AMR-09 ::preferred
# ::snt It is unclear why activation of endogenous  PKC by  TPA, which strongly inhibits the DNA-binding activity of endogenous HES-1 protein, does not also induce neurite outgrowth although it greatly potentiates the response to  NGF.
# ::save-date Sun Nov 1, 2015 ::file bio_chicago_2015_24126.txt
(c / clear-06 :polarity -
      :ARG1 (c2 / cause-01
            :ARG0 (a / amr-unknown)
            :ARG1 (i / induce-01 :polarity -
                  :ARG0 (a3 / activate-01
                        :ARG0 (s / small-molecule :name (n / name :op1 "TPA")
                              :ARG0-of (i2 / inhibit-01
                                    :ARG1 (a4 / activity-06
                                          :ARG0 (p / protein :name (n3 / name :op1 "HES-1"))
                                          :ARG1 (b / bind-01
                                                :ARG1 (n6 / nucleic-acid :name (n7 / name :op1 "DNA"))))
                                    :ARG1-of (s2 / strong-02)))
                        :ARG1 (e / enzyme :name (n2 / name :op1 "PKC")
                              :mod (e2 / endogenous))
                        :ARG1-of (c3 / contrast-01
                              :ARG2 (p2 / potentiate-01
                                    :ARG1 (r / respond-01
                                          :ARG1 (p3 / protein :name (n5 / name :op1 "NGF")))
                                    :manner (g2 / great))))
                  :ARG2 (o / outgrow-01
                        :ARG0 (n4 / neurite))
                  :mod (a2 / also))))

# ::id bio.chicago_2015.24129 ::date 2015-10-23T06:35:12 ::annotator SDL-AMR-09 ::preferred
# ::snt C-Daam1 activation  of  RhoA is not affected by deltaPDZ-Dvl    (Figure 3A), which inhibits  RhoA activation by  Fz or   Dvl     (Figure 1F), further demonstrating that  Daam1 functions downstream  of  Dvl in  Rho activation.
# ::save-date Wed Oct 28, 2015 ::file bio_chicago_2015_24129.txt
(a / affect-01 :polarity -
      :ARG0 (p / protein-segment :name (n / name :op1 "deltaPDZ-Dvl")
            :ARG0-of (i / inhibit-01
                  :ARG1 (a3 / activate-01
                        :ARG0 (o / or
                              :op1 (p4 / protein :name (n4 / name :op1 "Fz"))
                              :op2 (p5 / protein :name (n5 / name :op1 "Dvl")))
                        :ARG1 p3)
                  :ARG0-of (d2 / demonstrate-01
                        :ARG1 (f3 / function-01
                              :ARG0 (p6 / protein :name (n6 / name :op1 "Daam1"))
                              :ARG1 (a4 / activate-01
                                    :ARG1 (p7 / protein :name (n7 / name :op1 "Rho")))
                              :location (r / relative-position
                                    :op1 p5
                                    :direction (d3 / downstream)))
                        :manner (f2 / further))
                  :ARG1-of (d4 / describe-01
                        :ARG0 (f4 / figure :mod "1F"))))
      :ARG1 (a2 / activate-01
            :ARG0 (p2 / protein :name (n2 / name :op1 "C-Daam1"))
            :ARG1 (p3 / protein :name (n3 / name :op1 "RhoA")))
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod "3A")))

# ::id bio.chicago_2015.24156 ::date 2015-10-31T09:54:47 ::annotator SDL-AMR-09 ::preferred
# ::snt Furthermore, manipulation of other   wingless signaling molecules downstream from  shaggy demonstrated that components of the  Wnt signaling pathway modulate neurodegeneration induced by  tau pathology in vivo but suggested that  tau phosphorylation by  GSK-3  differs from canonical  Wnt effects on  - catenin stability and  TCF activity.
# ::save-date Mon Jan 4, 2016 ::file bio_chicago_2015_24156.txt
(a / and
      :op2 (c / contrast-01
            :ARG1 (d / demonstrate-01
                  :ARG0 (m2 / manipulate-01
                        :ARG1 (m3 / molecule
                              :ARG0-of (s3 / signal-07
                                    :ARG1 (g / gene :name (n4 / name :op1 "wingless")))
                              :mod (o / other)
                              :location (r / relative-position
                                    :op1 (e / enzyme :name (n5 / name :op1 "shaggy"))
                                    :direction (d3 / downstream))))
                  :ARG1 (m / modulate-01
                        :ARG0 (c2 / component
                              :ARG1-of (i / include-91
                                    :ARG2 (p2 / pathway :name (n / name :op1 "Wnt")
                                          :ARG0-of (s2 / signal-07))))
                        :ARG1 (n2 / neurodegeneration
                              :ARG2-of (i2 / induce-01
                                    :ARG0 (p3 / pathology
                                          :mod (p4 / protein :name (n3 / name :op1 "tau"))))
                              :manner (i3 / in-vivo))))
            :ARG2 (s / suggest-01
                  :ARG0 m2
                  :ARG1 (d2 / differ-02
                        :ARG1 (p / phosphorylate-01
                              :ARG1 p4
                              :ARG2 (e2 / enzyme :name (n7 / name :op1 "GSK-3")))
                        :ARG2 (a2 / affect-01
                              :ARG0 (p6 / pathway :name (n8 / name :op1 "Wnt"))
                              :ARG1 (a3 / and
                                    :op1 (s4 / stability
                                          :mod (p7 / protein :name (n10 / name :op1 "β-catenin")))
                                    :op2 (a4 / activity-06
                                          :ARG0 (p5 / protein :name (n9 / name :op1 "TCF"))))
                              :mod (c3 / canon))))))

# ::id bio.chicago_2015.24160 ::date 2015-10-31T10:32:26 ::annotator SDL-AMR-09 ::preferred
# ::snt The cell surface expression of  glypican-1 in these cells was analyzed by quantitative immunofluorescence flow cytometry (data not shown), and the effects of cells expressing one-chain ( SAA), two-chain ( SSA), or wild-type ( SSS) forms of  glypican-1 on  FGF2-induced  FGFR1 autophosphorylation were compared.
# ::save-date Tue Feb 2, 2016 ::file bio_chicago_2015_24160.txt
(a / and
      :op1 (a2 / analyze-01
            :ARG1 (e / express-03
                  :ARG2 (p2 / protein)
                  :ARG3 (c / cell
                        :ARG1-of (s / surface-02))
                  :location (c2 / cell
                        :mod (t / this)))
            :manner (c3 / cytometry
                  :mod (i / immunofluoresce-01
                        :mod (q / quantitative))
                  :mod (f / flow))
            :ARG1-of (d2 / describe-01
                  :ARG0 (d / data
                        :ARG1-of (s2 / show-01 :polarity -))))
      :op2 (c4 / compare-01
            :ARG1 (a3 / affect-01
                  :ARG0 (c5 / cell
                        :ARG2-of (e2 / express-03
                              :ARG1 (o / or
                                    :op1 (p / protein :name (n7 / name :op1 "glypican-1")
                                          :mod (f3 / form)
                                          :mod (c11 / chain :quant 1)
                                          :ARG1-of (m / mean-01
                                                :ARG2 (n / name :op1 "SAA")))
                                    :op2 (p6 / protein :name (n8 / name :op1 "glypican-1")
                                          :mod (f4 / form)
                                          :mod (c12 / chain :quant 2)
                                          :ARG1-of (m2 / mean-01
                                                :ARG2 (n5 / name :op1 "SSA")))
                                    :op3 (p7 / protein :name (n9 / name :op1 "glypican-1")
                                          :mod (w2 / wild-type)
                                          :ARG1-of (m3 / mean-01
                                                :ARG2 (n6 / name :op1 "SSS"))))))
                  :ARG1 (p3 / phosphorylate-01
                        :ARG1 (e4 / enzyme :name (n3 / name :op1 "FGFR1"))
                        :ARG2 e4
                        :ARG2-of (i2 / induce-01
                              :ARG0 (p4 / protein :name (n4 / name :op1 "FGF2")))))))

# ::id bio.chicago_2015.24247 ::date 2015-10-31T11:01:24 ::annotator SDL-AMR-09 ::preferred
# ::snt Moreover, the  Raf-1 bound to  Ras membranes undergoes activation, whereas  Raf-1 bound to control membranes does not (Fig.  5A and C).
# ::save-date Thu Nov 19, 2015 ::file bio_chicago_2015_24247.txt
(a / and
      :op2 (c / contrast-01
            :ARG1 (u / undergo-28
                  :ARG1 (a2 / activate-01
                        :ARG1 e)
                  :ARG2 (e / enzyme :name (n2 / name :op1 "Raf-1")
                        :ARG1-of (b / bind-01
                              :ARG2 (m / membrane
                                    :mod (e2 / enzyme :name (n3 / name :op1 "Ras"))))))
            :ARG2 (u2 / undergo-28 :polarity -
                  :ARG1 (a3 / activate-01
                        :ARG1 e3)
                  :ARG2 (e3 / enzyme :name (n / name :op1 "Raf-1")
                        :ARG1-of (b2 / bind-01
                              :ARG2 (m2 / membrane
                                    :ARG0-of (c2 / control-01))))))
      :ARG1-of (d / describe-01
            :ARG0 (a4 / and
                  :op1 (f / figure :mod "5A")
                  :op2 (f2 / figure :mod "5C"))))

# ::id bio.chicago_2015.24257 ::date 2015-10-31T11:15:07 ::annotator SDL-AMR-09 ::preferred
# ::snt DAG activates  PKC directly.
# ::save-date Thu Nov 12, 2015 ::file bio_chicago_2015_24257.txt
(a / activate-01
      :ARG0 (s / small-molecule :name (n / name :op1 "DAG"))
      :ARG1 (e / enzyme :name (n2 / name :op1 "PKC"))
      :ARG1-of (d / direct-02))

# ::id bio.chicago_2015.24353 ::date 2015-10-31T11:19:00 ::annotator SDL-AMR-09 ::preferred
# ::snt On the other hand, PD98059 (50  muM) reduced  Cr(VI)-activated  ERK to endogenous levels and decreased  Cr(VI)-activated  p38 by ~60%, but did not significantly alter  Cr(VI)-activated  JNK (Figure 9  ).
# ::save-date Sun Jan 17, 2016 ::file bio_chicago_2015_24353.txt
(c / contrast-01
      :ARG2 (c2 / contrast-01
            :ARG1 (a / and
                  :op1 (r / reduce-01
                        :ARG0 (s3 / small-molecule :name (n2 / name :op1 "PD98059")
                              :mod (c3 / concentration-quantity :quant 50
                                    :unit (m / micromolar)))
                        :ARG1 (e / enzyme :name (n3 / name :op1 "ERK")
                              :ARG1-of (a3 / activate-01
                                    :ARG0 (s / small-molecule :name (n4 / name :op1 "Cr(VI)"))))
                        :ARG4 (l / level
                              :mod (e2 / endogene)))
                  :op2 (d / decrease-01
                        :ARG0 s3
                        :ARG1 (e4 / enzyme :name (n5 / name :op1 "p38")
                              :ARG1-of a3)
                        :ARG2 (a6 / about
                              :op1 (p / percentage-entity :value 60))))
            :ARG2 (a2 / alter-01 :polarity -
                  :ARG0 s3
                  :ARG1 (e3 / enzyme :name (n / name :op1 "JNK")
                        :ARG1-of (a5 / activate-01
                              :ARG0 s))
                  :ARG1-of (s2 / significant-02)))
      :ARG1-of (d2 / describe-01
            :ARG0 (f / figure :mod 9)))

# ::id bio.chicago_2015.24368 ::date 2015-10-31T11:38:15 ::annotator SDL-AMR-09 ::preferred
# ::snt However, we do not believe that our findings exclude the possibility that  MDM2 may also inhibit  p53-dependent transcription by  masking its  activation domain from important basal factor contacts.
# ::save-date Thu Nov 12, 2015 ::file bio_chicago_2015_24368.txt
(c / contrast-01
      :ARG2 (b / believe-01 :polarity -
            :ARG0 (w / we)
            :ARG1 (e / exclude-01
                  :ARG0 (t2 / thing
                        :ARG1-of (f / find-01
                              :ARG0 w))
                  :ARG1 (p / possible-01
                        :ARG1 (i / inhibit-01
                              :ARG0 (p3 / protein :name (n / name :op1 "MDM2"))
                              :ARG1 (t / transcribe-01
                                    :ARG0-of (d2 / depend-01
                                          :ARG1 (p4 / protein :name (n2 / name :op1 "p53"))))
                              :mod (a / also)
                              :ARG1-of (p2 / possible-01)
                              :manner (m / mask-01
                                    :ARG0 p3
                                    :ARG1 (d3 / domain
                                          :location-of (a2 / activate-01)
                                          :poss p3
                                          :source (c3 / contact
                                                :mod (f3 / factor)
                                                :mod (b3 / basal)
                                                :mod (i2 / important)))))))))

# ::id bio.chicago_2015.24456 ::date 2015-11-01T01:06:38 ::annotator SDL-AMR-09 ::preferred
# ::snt Stoichiometry of Binding of  eIF4A with  eIF4G(613-1560)-- The forgoing result indicated that one molecule of  eIF4A could bind to either the central or  COOH-terminal sites of  eIF4G.
# ::save-date Thu Nov 19, 2015 ::file bio_chicago_2015_24456.txt
(m / multi-sentence
      :snt1 (s / stoichiometry
            :mod (b2 / bind-01
                  :ARG1 (p / protein :name (n / name :op1 "eIF4A"))
                  :ARG3 (p3 / protein :name (n2 / name :op1 "eIF4G")
                        :mod (v / value-interval :op1 613 :op2 1560))))
      :snt2 (i / indicate-01
            :ARG0 (t / thing
                  :ARG1-of (r / result-01)
                  :ARG1-of (f / forgo-02))
            :ARG1 (p2 / possible-01
                  :ARG1 (b4 / bind-01
                        :ARG1 (m4 / molecule :quant 1
                              :mod (p5 / protein :name (n3 / name :op1 "eIF4A")))
                        :ARG2 (o2 / or
                              :op1 (s4 / site
                                    :mod (c2 / central))
                              :op2 (p4 / protein-segment :name (n4 / name :op1 "COOH-terminus"))
                              :part-of (p6 / protein :name (n5 / name :op1 "eIF4G")))))))

# ::id bio.chicago_2015.24491 ::date 2015-11-01T01:28:47 ::annotator SDL-AMR-09 ::preferred
# ::snt (B)  Rho-N19, but neither  Rac-N17  nor  Cdc42-N17, blocks  RhoA activation by  Wnt,  Fz,  Dvl, or  C-Daam1.
# ::save-date Sun Jan 17, 2016 ::file bio_chicago_2015_24491.txt
(c / contrast-01 :li "B"
      :ARG1 (b / block-01
            :ARG0 (p5 / protein :name (n / name :op1 "Rho-N19"))
            :ARG1 (a / activate-01
                  :ARG0 (o / or
                        :op1 (p / protein :name (n3 / name :op1 "Wnt"))
                        :op2 (p2 / protein :name (n4 / name :op1 "Fz"))
                        :op3 (p3 / protein :name (n5 / name :op1 "Dvl"))
                        :op4 (p4 / protein :name (n6 / name :op1 "C-Daam1")))
                  :ARG1 (p6 / protein :name (n2 / name :op1 "RhoA"))))
      :ARG2 (b2 / block-01 :polarity -
            :ARG0 (a2 / and
                  :op1 (e3 / enzyme :name (n7 / name :op1 "Rac-N17"))
                  :op2 (e4 / enzyme :name (n8 / name :op1 "Cdc42-N17")))
            :ARG1 o))

# ::id bio.chicago_2015.24497 ::date 2015-11-01T01:36:16 ::annotator SDL-AMR-09 ::preferred
# ::snt Although we could not evaluate the effect of  PI3K inhibition on  mutant huntingtin-induced cell death due to the high  toxicity of the  PI3K inhibitor LY in striatal neurons, we found an increase in the percentage of striatal neurons containing intranuclear inclusions when treated with subtoxic doses of  LY (100 nM; data not shown).
# ::save-date Thu Jan 14, 2016 ::file bio_chicago_2015_24497.txt
(f / find-01
      :ARG0 (w / we)
      :ARG1 (i2 / increase-01
            :ARG1 (p2 / percentage
                  :quant-of (n / neuron
                        :mod (s / striatum)
                        :ARG0-of (c / contain-01
                              :ARG1 (t / thing
                                    :ARG1-of (i3 / include-01
                                          :location (i4 / intranuclear))))))
            :time (t2 / treat-04
                  :ARG1 n
                  :ARG2 (d / dose-01
                        :ARG2 (s3 / small-molecule :name (n2 / name :op1 "LY")
                              :quant (c2 / concentration-quantity :quant 100
                                    :unit (n3 / nanomolar)))
                        :mod (s2 / subtoxic))))
      :concession (p3 / possible-01 :polarity -
            :ARG1 (e / evaluate-01
                  :ARG0 w
                  :ARG1 (a / affect-01
                        :ARG0 (i / inhibit-01
                              :ARG1 (e2 / enzyme :name (n4 / name :op1 "PI3K")))
                        :ARG1 (d3 / die-01
                              :ARG1 (c3 / cell)
                              :ARG1-of (c4 / cause-01
                                    :ARG0 (t3 / toxicity
                                          :ARG1-of (h / high-02)
                                          :location n
                                          :poss (s5 / small-molecule :name (n7 / name :op1 "LY")
                                                :ARG0-of (i5 / inhibit-01
                                                      :ARG1 e2))))
                              :ARG2-of (i6 / induce-01
                                    :ARG0 (p5 / protein :name (n5 / name :op1 "huntingtin")
                                          :ARG2-of (m / mutate-01)))))))
      :ARG2-of (d4 / describe-01
            :ARG0 (d5 / data
                  :ARG1-of (s7 / show-01 :polarity -))))

# ::id bio.chicago_2015.24503 ::date 2015-11-01T01:04:26 ::annotator SDL-AMR-09 ::preferred
# ::snt The morphologic features of apoptosis induced by  Diva, including rounding and membrane blebbing (Fig.  5 B) as well as nuclear fragmentation (Fig.  5 C) were inhibited by  vBcl-2.
# ::save-date Thu Nov 19, 2015 ::file bio_chicago_2015_24503.txt
(i / inhibit-01
      :ARG0 (p / protein :name (n / name :op1 "vBcl-2"))
      :ARG1 (f / feature-01
            :ARG1 (a / apoptosis
                  :ARG2-of (i2 / induce-01
                        :ARG0 (p2 / protein :name (n2 / name :op1 "Diva"))))
            :mod (m / morphology)
            :ARG2-of (i3 / include-91
                  :ARG1 (a2 / and
                        :op1 (r / round-04)
                        :op2 (b / bleb-00
                              :ARG1 (m3 / membrane)
                              :ARG1-of (d / describe-01
                                    :ARG0 (f2 / figure :mod "5B")))
                        :op3 (f5 / fragment-01
                              :ARG1 (n3 / nucleus)
                              :ARG1-of (d2 / describe-01
                                    :ARG0 (f3 / figure :mod "5C")))))))

# ::id bio.chicago_2015.24508 ::date 2015-11-01T01:13:31 ::annotator SDL-AMR-09 ::preferred
# ::snt Mist1 efficiently inhibits  MyoD from activating the  TnI-Luc gene whereas  Mist1mutbasic has no effect.
# ::save-date Sun Nov 1, 2015 ::file bio_chicago_2015_24508.txt
(c / contrast-01
      :ARG1 (i / inhibit-01
            :ARG0 (p / protein :name (n / name :op1 "Mist1"))
            :ARG1 (p2 / protein :name (n2 / name :op1 "MyoD")
                  :ARG0-of (a / activate-01
                        :ARG1 (g / gene :name (n3 / name :op1 "TnI-Luc"))))
            :ARG2-of (e / efficient-01))
      :ARG2 (a2 / affect-01 :polarity -
            :ARG0 (p3 / protein :name (n4 / name :op1 "Mist1mutbasic"))))

# ::id bio.chicago_2015.24550 ::date 2015-11-01T01:18:29 ::annotator SDL-AMR-09 ::preferred
# ::snt It is also well established that  JNK and  IKK are activated by  LPS or the proinflammatory cytokines.
# ::save-date Thu Nov 19, 2015 ::file bio_chicago_2015_24550.txt
(e / establish-01
      :ARG1 (a / activate-01
            :ARG0 (o / or
                  :op1 (m / molecular-physical-entity :name (n3 / name :op1 "LPS"))
                  :op2 (c / cytokine
                        :ARG0-of (f / favor-01
                              :ARG1 (i / inflame-01))))
            :ARG1 (a2 / and
                  :op1 (e2 / enzyme :name (n / name :op1 "JNK"))
                  :op2 (e3 / enzyme :name (n2 / name :op1 "IKK"))))
      :mod (a3 / also)
      :mod (w / well))

# ::id bio.chicago_2015.24562 ::date 2015-11-01T01:23:04 ::annotator SDL-AMR-09 ::preferred
# ::snt The formation of a functional signaling complex of active ligand dimer and type I and  II receptor dimer heterotetramer, results in the phosphorylation of  type I receptor by the constitutively active  type II receptor (for review, see  Massague 1998).
# ::save-date Wed Mar 2, 2016 ::file bio_chicago_2015_24562.txt
(a3 / and
      :op1 (r / result-01
            :ARG1 (f / form-01
                  :ARG1 (m / macro-molecular-complex
                        :ARG0-of (s / signal-07
                              :ARG1-of (f2 / function-01))
                        :part (d / dimer
                              :mod (l / ligand
                                    :ARG0-of (a2 / activity-06)))
                        :part (h / heterotetramer
                              :part (d3 / dimer :name (n4 / name :op1 "type" :op2 "II" :op3 "receptor"))
                              :part (d2 / dimer :name (n3 / name :op1 "type" :op2 "I" :op3 "receptor")))))
            :ARG2 (p2 / phosphorylate-01
                  :ARG1 d2
                  :ARG3 (d5 / dimer :name (n / name :op1 "type" :op2 "I" :op3 "receptor")
                        :ARG1-of (a / activate-01
                              :mod (c / constitutive)))))
      :op2 (s2 / see-01 :mode imperative
            :ARG0 (y / you)
            :ARG1 (p / publication-91
                  :ARG0 (p5 / person :wiki - :name (n5 / name :op1 "Massague"))
                  :time (d4 / date-entity :year 1998))
            :purpose (r2 / review-01)))

# ::id bio.chicago_2015.24596 ::date 2015-11-01T01:38:40 ::annotator SDL-AMR-09 ::preferred
# ::snt Moreover, association is accompanied by reciprocal phosphorylation of  Dlar and  Ena by  Abl and dephosphorylation of phosphorylated  Abl and  Ena by  Dlar.
# ::save-date Thu Nov 19, 2015 ::file bio_chicago_2015_24596.txt
(a / and
      :op2 (a2 / accompany-01
            :ARG0 (a3 / associate-01)
            :ARG1 (a4 / and
                  :op1 (p2 / phosphorylate-01
                        :ARG1 (a5 / and
                              :op1 (p3 / protein :name (n / name :op1 "Dlar"))
                              :op2 (p4 / protein :name (n2 / name :op1 "Ena")))
                        :ARG2 (p5 / protein :name (n3 / name :op1 "Abl"))
                        :manner (r / reciprocal))
                  :op2 (d / dephosphorylate-01
                        :ARG1 (a6 / and
                              :op1 p5
                              :op2 p4
                              :ARG3-of (p / phosphorylate-01))
                        :ARG2 p3))))

# ::id bio.chicago_2015.24600 ::date 2015-11-01T01:45:02 ::annotator SDL-AMR-09 ::preferred
# ::snt Mad2 binds  Cdc20 to inhibit  APC  activity (Alexandru et al., 1999   ; Fang et al., 1998b   ; Hwang et al., 1998   ; Kallio et al., 1998   ; Kim et al., 1998   ;  Li et al., 1997   ; Wassmann and Benezra, 1998   ), although how  Mad2 inhibits APCCdc20 is  not clear.
# ::save-date Thu Nov 19, 2015 ::file bio_chicago_2015_24600.txt
(b / bind-01
      :ARG0 (p2 / protein
            :name (n / name :op1 "Mad2"))
      :ARG1 (p3 / protein
            :name (n2 / name :op1 "Cdc20"))
      :purpose (i / inhibit-01
            :ARG0 p2
            :ARG1 (a2 / activity-06
                  :ARG0 (p25 / protein
                        :name (n3 / name :op1 "APC"))))
      :ARG1-of (d / describe-01
            :ARG0 (a / and
                  :op1 (p / publication-91
                        :ARG0 (a4 / and
                              :op1 (p5 / person :wiki -
                                    :name (n5 / name :op1 "Alexandru"))
                              :op2 (p6 / person
                                    :mod (o / other)))
                        :time (d2 / date-entity :year 1999))
                  :op2 (p7 / publication-91
                        :ARG0 (a5 / and
                              :op1 (p8 / person :wiki -
                                    :name (n6 / name :op1 "Fang"))
                              :op2 (p9 / person
                                    :mod (o2 / other)))
                        :time (d3 / date-entity :year 1998 :li "b"))
                  :op3 (p10 / publication-91
                        :ARG0 (a6 / and
                              :op1 (p11 / person :wiki -
                                    :name (n7 / name :op1 "Hwang"))
                              :op2 (p12 / person
                                    :mod (o3 / other)))
                        :time (d4 / date-entity :year 1998))
                  :op4 (p13 / publication-91
                        :ARG0 (a7 / and
                              :op1 (p14 / person :wiki -
                                    :name (n8 / name :op1 "Kallio"))
                              :op2 (p15 / person
                                    :mod (o4 / other)))
                        :time (d5 / date-entity :year 1998))
                  :op5 (p16 / publication-91
                        :ARG0 (a8 / and
                              :op1 (p17 / person :wiki -
                                    :name (n9 / name :op1 "Kim"))
                              :op2 (p18 / person
                                    :mod (o5 / other)))
                        :time (d6 / date-entity :year 1998))
                  :op6 (p19 / publication-91
                        :ARG0 (a9 / and
                              :op1 (p20 / person :wiki -
                                    :name (n10 / name :op1 "Li"))
                              :op2 (p21 / person
                                    :mod (o6 / other)))
                        :time (d7 / date-entity :year 1997))
                  :op7 (p22 / publication-91
                        :ARG0 (a10 / and
                              :op1 (p23 / person :wiki -
                                    :name (n11 / name :op1 "Wassmann"))
                              :op2 (p24 / person :wiki -
                                    :name (n12 / name :op1 "Benezra")))
                        :time (d8 / date-entity :year 1998))))
      :concession (c / clear-06 :polarity -
            :ARG1 (t / thing
                  :manner-of (i3 / inhibit-01
                        :ARG0 p2
                        :ARG1 (p4 / protein
                              :name (n4 / name :op1 "APCCdc20"))))))

# ::id bio.chicago_2015.24623 ::date 2015-11-01T03:38:35 ::annotator SDL-AMR-09 ::preferred
# ::snt Aliquots of filtrate (10  mul) were separated by  SDS-PAGE and processed for Western blotting using an  anti-cytochrome  c monoclonal antibody.
# ::save-date Sun Dec 13, 2015 ::file bio_chicago_2015_24623.txt
(a / and
      :op1 (s / separate-01
            :ARG1 (a2 / aliquot
                  :mod (f / filtrate
                        :quant (c / concentration-quantity :quant 10
                              :unit (m / micromolar))))
            :manner (a3 / analyze-01
                  :mod (t / thing :name (n2 / name :op1 "SDS-PAGE"))))
      :op2 (p / process-01
            :ARG1 a2
            :purpose (i / immunoblot-01
                  :ARG3 (a5 / antibody
                        :mod (m2 / monoclone)
                        :ARG0-of (c2 / counter-01
                              :ARG1 (p3 / protein :name (n4 / name :op1 "cytochrome" :op2 "c")))))))

# ::id bio.chicago_2015.24629 ::date 2015-11-01T04:06:56 ::annotator SDL-AMR-09 ::preferred
# ::snt The early, broad   snail pattern might create a broad domain of potential  Notch signaling by repressing components of the  Notch pathway, such as Delta and  T3.
# ::save-date Thu Nov 19, 2015 ::file bio_chicago_2015_24629.txt
(p2 / possible-01
      :ARG1 (c2 / create-01
            :ARG0 (p3 / pattern-01
                  :ARG1 (p7 / protein :name (n4 / name :op1 "snail"))
                  :ARG1-of (b / broad-02)
                  :time (e / early))
            :ARG1 (d / domain
                  :ARG1-of (b2 / broad-02)
                  :mod (p / potential)
                  :poss (s2 / signal-07
                        :ARG0 (p4 / pathway :name (n / name :op1 "Notch"))))
            :manner (r / repress-01
                  :ARG1 (c3 / component
                        :ARG1-of (i / include-91
                              :ARG2 p4)
                        :example (a / and
                              :op1 (p5 / protein :name (n2 / name :op1 "Delta"))
                              :op2 (p6 / protein :name (n3 / name :op1 "T3")))))))

# ::id bio.chicago_2015.24662 ::date 2015-11-01T04:20:12 ::annotator SDL-AMR-09 ::preferred
# ::snt The simplest mechanism by which  Mck1p might inhibit  PKA activity is by phosphorylating  PKA.
# ::save-date Fri Nov 27, 2015 ::file bio_chicago_2015_24662.txt
(m2 / mechanism
      :ARG1-of (s / simple-02
            :degree (m / most))
      :instrument-of (i / inhibit-01
            :ARG0 (p3 / protein :name (n / name :op1 "Mck1p"))
            :ARG1 (a / activity-06
                  :ARG0 (e2 / enzyme :name (n2 / name :op1 "PKA")))
            :ARG1-of (p2 / possible-01))
      :domain (p / phosphorylate-01
            :ARG1 e2))

# ::id bio.chicago_2015.24678 ::date 2015-11-01T04:28:01 ::annotator SDL-AMR-09 ::preferred
# ::snt PTEN controls  p53 transcriptional activity
# ::save-date Thu Nov 19, 2015 ::file bio_chicago_2015_24678.txt
(c / control-01
      :ARG0 (p2 / protein :name (n / name :op1 "PTEN"))
      :ARG1 (a / activity-06
            :ARG0 (t / transcribe-01
                  :ARG0 (p / protein :name (n2 / name :op1 "p53")))))

# ::id bio.chicago_2015.24683 ::date 2015-11-01T04:30:10 ::annotator SDL-AMR-09 ::preferred
# ::snt (A)  Histone H1 inhibits  ERalpha-mediated transcription in the presence of added  p300.
# ::save-date Fri Nov 13, 2015 ::file bio_chicago_2015_24683.txt
(i / inhibit-01 :li "A"
      :ARG0 (p / protein :name (n / name :op1 "Histone" :op2 "H1"))
      :ARG1 (t / transcribe-01
            :ARG1-of (m / mediate-01
                  :ARG0 (p4 / protein :name (n2 / name :op1 "ERalpha"))))
      :condition (p2 / present-02
            :ARG1 (p3 / protein :name (n3 / name :op1 "p300")
                  :ARG1-of (a / add-02))))

# ::id bio.chicago_2015.24739 ::date 2015-11-01T04:33:27 ::annotator SDL-AMR-09 ::preferred
# ::snt At higher concentrations, inhibition of certain  JNK isoforms may occur; however, these kinases are not activated by  LPS in the neutrophil under our experimental conditions ( 13).
# ::save-date Thu Nov 19, 2015 ::file bio_chicago_2015_24739.txt
(c / contrast-01
      :ARG1 (p / possible-01
            :ARG1 (i / inhibit-01
                  :ARG1 (i2 / isoform
                        :mod (e2 / enzyme :name (n / name :op1 "JNK"))
                        :mod (c2 / certain)))
            :condition (c3 / concentrate-02
                  :ARG1-of (h2 / high-02
                        :degree (m3 / more))))
      :ARG2 (a / activate-01 :polarity -
            :ARG0 (m2 / molecular-physical-entity :name (n2 / name :op1 "LPS"))
            :ARG1 i2
            :condition (e / experiment-01
                  :ARG0 (w / we))
            :location (c4 / cell :name (n4 / name :op1 "neutrophil")))
      :ARG1-of (d / describe-01
            :ARG0 (p2 / publication
                  :ARG1-of (c5 / cite-01
                        :ARG2 13))))

# ::id bio.chicago_2015.24746 ::date 2015-11-01T04:41:47 ::annotator SDL-AMR-09 ::preferred
# ::snt In addition, the back-phosphorylation experiments demonstrated an increase in a  PKC-specific phosphorylation of  AC7 within  HEK 293 cells after  exposure of the intact cells to  ethanol.
# ::save-date Thu Nov 19, 2015 ::file bio_chicago_2015_24746.txt
(a / and
      :op2 (d / demonstrate-01
            :ARG0 (e / experiment-01
                  :ARG2 (p2 / phosphorylate-01
                        :ARG1-of (b / back-02)))
            :ARG1 (i / increase-01
                  :ARG1 (p3 / phosphorylate-01
                        :ARG1 (p / protein :name (n2 / name :op1 "AC7"))
                        :ARG2 (e2 / enzyme :name (n3 / name :op1 "PKC"))
                        :ARG1-of (s / specific-02)
                        :location (c / cell :name (n / name :op1 "HEK" :op2 "293")))
                  :time (a2 / after
                        :op1 (e3 / expose-01
                              :ARG1 (c2 / cell
                                    :mod (i2 / intact))
                              :ARG2 (e4 / ethanol))))))

# ::id bio.chicago_2015.24858 ::date 2015-11-01T04:48:48 ::annotator SDL-AMR-09 ::preferred
# ::snt More recent study demonstrated  Akt also phosphorylates  FKHRL1, one of the  Forkhead transcription factor family members, and transcriptionally regulates  Fas-dependent apoptosis in cerebellar granule neurons.
# ::save-date Thu Nov 19, 2015 ::file bio_chicago_2015_24858.txt
(d / demonstrate-01
      :ARG0 (s / study-01
            :time (r2 / recent
                  :degree (m / more)))
      :ARG1 (a2 / and
            :op1 (p / phosphorylate-01
                  :ARG1 (p4 / protein :name (n2 / name :op1 "FKHRL1")
                        :ARG1-of (i / include-91
                              :ARG2 (p5 / protein-family :name (n6 / name :op1 "Forkhead")
                                    :ARG0-of (t / transcribe-01))))
                  :ARG2 (e / enzyme :name (n / name :op1 "Akt"))
                  :mod (a / also))
            :op2 (r / regulate-01
                  :ARG0 e
                  :ARG1 (a3 / apoptosis
                        :ARG0-of (d2 / depend-01
                              :ARG1 (p3 / protein :name (n4 / name :op1 "Fas"))))
                  :manner t)
            :location (n5 / neuron
                  :mod (g / granule)
                  :mod (c / cerebellar))))

# ::id bio.chicago_2015.24920 ::date 2015-11-01T05:05:07 ::annotator SDL-AMR-09 ::preferred
# ::snt These results suggest that  p38 and  JNK activation by  Cr(VI) is mediated differently through oxidative stress in  CL3 cells, while  ERK is less sensitive.
# ::save-date Sun Jan 17, 2016 ::file bio_chicago_2015_24920.txt
(s / suggest-01
      :ARG0 (t / thing
            :ARG1-of (r / result-01)
            :mod (t2 / this))
      :ARG1 (c / contrast-01
            :ARG1 (m / mediate-01
                  :ARG1 (a / activate-01
                        :ARG0 (s4 / small-molecule :name (n3 / name :op1 "Cr(VI)"))
                        :ARG1 (a2 / and
                              :op1 (e3 / enzyme :name (n4 / name :op1 "p38"))
                              :op2 (e / enzyme :name (n5 / name :op1 "JNK"))))
                  :ARG1-of (d / differ-02
                        :manner (s2 / stress-02
                              :mod (o / oxidize-01)
                              :location (c2 / cell-line :name (n2 / name :op1 "CL3")))))
            :ARG2 (s3 / sensitive-03
                  :ARG0 (e2 / enzyme :name (n6 / name :op1 "ERK"))
                  :degree (l / less))))

# ::id bio.chicago_2015.24932 ::date 2015-11-01T05:13:29 ::annotator SDL-AMR-09 ::preferred
# ::snt We have identified a new SH3-containing  Rac target, POSH, which activates  JNK when transfected into Cos-1 cells and induces nuclear translocation of  NF-kappaB.
# ::save-date Fri Feb 5, 2016 ::file bio_chicago_2015_24932.txt
(i / identify-01
      :ARG0 (w2 / we)
      :ARG1 (p / protein :name (n7 / name :op1 "POSH")
            :ARG0-of (t4 / target-01
                  :ARG1 (e / enzyme :name (n / name :op1 "Rac"))
                  :ARG0-of (a / activate-01
                        :ARG1 (e2 / enzyme :name (n3 / name :op1 "JNK"))
                        :condition (t2 / transfect-01
                              :ARG1 (c2 / cell-line :name (n4 / name :op1 "Cos-1"))))
                  :ARG0-of (i2 / induce-01
                        :ARG2-of (t3 / translocate-01
                              :ARG1 (p2 / protein :name (n6 / name :op1 "NF-kappaB"))
                              :ARG3 (n5 / nucleus))))
            :ARG0-of (c / contain-01
                  :ARG1 (p4 / protein-segment :name (n2 / name :op1 "SH3")))
            :ARG1-of (n8 / new-02)))

# ::id bio.chicago_2015.24982 ::date 2015-11-01T05:26:59 ::annotator SDL-AMR-09 ::preferred
# ::snt Recent reports on  Cdc42 and  Rac1  activation of  JNK also failed to establish a clear hierarchal action of  these  Rho-related GTPases( 38,  39) .
# ::save-date Wed Jan 13, 2016 ::file bio_chicago_2015_24982.txt
(f / fail-01
      :ARG1 (r / report-01
            :ARG1 (a2 / activate-01
                  :ARG0 (a3 / and
                        :op1 (p / protein :name (n / name :op1 "Cdc42"))
                        :op2 (p2 / protein :name (n2 / name :op1 "Rac1")))
                  :ARG1 (e3 / enzyme :name (n3 / name :op1 "JNK")))
            :time (r3 / recent))
      :ARG2 (e / establish-01
            :ARG0 r
            :ARG1 (a4 / act-02
                  :ARG0 (e2 / enzyme :name (n4 / name :op1 "GTPase")
                        :ARG1-of (r2 / relate-01
                              :ARG2 (p4 / protein-family :name (n5 / name :op1 "Rho"))))
                  :mod (h / hierarchy
                        :ARG1-of (c / clear-06))))
      :mod (a / also)
      :ARG1-of (d / describe-01
            :ARG0 (p3 / publication
                  :ARG1-of (c2 / cite-01
                        :ARG2 (a6 / and :op1 38 :op2 39)))))

# ::id bio.chicago_2015.25001 ::date 2015-11-01T05:32:38 ::annotator SDL-AMR-09 ::preferred
# ::snt A dominant negative form of RHAMMv4 inhibits mutant active  Ras activation of  ERK and coimmunoprecipitates with both mitogen-activated protein kinase kinase and  ERK, suggesting that the intracellular RHAMMv4 acts downstream of  Ras, possibly at the level of mitogen-activated protein kinase  kinase-ERK interactions.
# ::save-date Fri Feb 5, 2016 ::file bio_chicago_2015_25001.txt
(a5 / and
      :op1 (i / inhibit-01
            :ARG0 (p2 / protein :name (n3 / name :op1 "RHAMMv4")
                  :mod (f / form
                        :ARG0-of (d / dominate-01)
                        :ARG2-of (m / mutate-01 :mod "-/-")))
            :ARG1 (a2 / activate-01
                  :ARG0 (e / enzyme :name (n5 / name :op1 "Ras")
                        :ARG2-of (m2 / mutate-01)
                        :ARG1-of (a / activate-01))
                  :ARG1 (e3 / enzyme :name (n6 / name :op1 "ERK"))))
      :op2 (c / coimmunoprecipitate-01
            :ARG1 p2
            :ARG2 (a3 / and
                  :op1 (e4 / enzyme :name (n7 / name :op1 "mitogen-activated" :op2 "protein" :op3 "kinase"))
                  :op2 e3))
      :ARG0-of (s2 / suggest-01
            :ARG1 (a4 / act-02
                  :ARG0 (p / protein :name (n / name :op1 "RHAMMv4")
                        :mod (i4 / intracellular))
                  :location (r / relative-position
                        :op1 (e2 / enzyme :name (n2 / name :op1 "Ras"))
                        :direction (d2 / downstream))
                  :condition (l2 / level
                        :location-of (i3 / interact-01
                              :ARG0 e4
                              :ARG1 e3)
                        :ARG1-of (p3 / possible-01)))))

# ::id bio.chicago_2015.25013 ::date 2015-11-01T05:49:30 ::annotator SDL-AMR-09 ::preferred
# ::snt Dishevelled decreases  GSK-3beta phosphorylation of  tau.
# ::save-date Fri Nov 13, 2015 ::file bio_chicago_2015_25013.txt
(d / decrease-01
      :ARG0 (p2 / protein :name (n / name :op1 "Dishevelled"))
      :ARG1 (p3 / phosphorylate-01
            :ARG1 (p / protein :name (n2 / name :op1 "tau"))
            :ARG2 (e2 / enzyme :name (n3 / name :op1 "GSK-3beta"))))

# ::id bio.chicago_2015.25044 ::date 2015-11-01T05:52:00 ::annotator SDL-AMR-09 ::preferred
# ::snt Isolated  S.cerevisiae mitochondria released  cytochrome  c, but did not induce apoptosis when incubated in   Xenopus extracts (R.M.Kluck, D.R.Green, M.Yaffe, E.Margoliash and D.D.Newmeyer, in preparation).
# ::save-date Thu Nov 19, 2015 ::file bio_chicago_2015_25044.txt
(c / contrast-01
      :ARG1 (r / release-01
            :ARG0 (m / mitochondria
                  :part-of (o2 / organism :name (n8 / name :op1 "S.cerevisiae")
                        :ARG1-of (i3 / isolate-01)))
            :ARG1 (p8 / protein :name (n7 / name :op1 "cytochrome" :op2 "c")))
      :ARG2 (i / induce-01 :polarity -
            :ARG0 m
            :ARG2 (a2 / apoptosis))
      :ARG1-of (d / describe-01
            :ARG0 (p / publication-91
                  :ARG0 (a / and
                        :op1 (p3 / person :name (n2 / name :op1 "R.M.Kluck"))
                        :op2 (p2 / person :name (n / name :op1 "D.R.Green"))
                        :op3 (p4 / person :name (n3 / name :op1 "M.Yaffe"))
                        :op4 (p5 / person :name (n4 / name :op1 "E.Margoliash"))
                        :op5 (p6 / person :name (n5 / name :op1 "D.D.Newmeyer")))
                  :ARG1-of (p7 / prepare-01)))
      :condition (i2 / incubate-01
            :ARG1 m
            :location (e / extract-01
                  :mod (o / organism :name (n6 / name :op1 "Xenopus")))))

# ::id bio.chicago_2015.25064 ::date 2015-11-01T06:01:32 ::annotator SDL-AMR-09 ::preferred
# ::snt ( A)  Functional Rho is required for efficient  VASP-induced  SRF activation.
# ::save-date Thu Nov 19, 2015 ::file bio_chicago_2015_25064.txt
(r / require-01 :li "A"
      :ARG0 (a / activate-01
            :ARG1 (p2 / protein :name (n2 / name :op1 "SRF"))
            :ARG1-of (e2 / efficient-01)
            :ARG2-of (i / induce-01
                  :ARG0 (p / protein :name (n3 / name :op1 "VASP"))))
      :ARG1 (e / enzyme :name (n / name :op1 "Rho")
            :ARG0-of (f / function-01)))

# ::id bio.chicago_2015.25079 ::date 2015-11-01T06:05:02 ::annotator SDL-AMR-09 ::preferred
# ::snt Phosphorylation of   AC7  by   PKC.
# ::save-date Fri Nov 13, 2015 ::file bio_chicago_2015_25079.txt
(p2 / phosphorylate-01
      :ARG1 (p3 / protein :name (n2 / name :op1 "AC7"))
      :ARG2 (e / enzyme :name (n / name :op1 "PKC")))

# ::id bio.chicago_2015.25123 ::date 2015-11-01T06:42:14 ::annotator SDL-AMR-09 ::preferred
# ::snt PDK1 phosphorylation of  PAK1 was not blocked by pretreatment with wortmannin or when  PDK1 was mutated to prevent phosphatidylinositol binding, indicating this process is independent of  phosphatidylinositol 3-kinase activity.
# ::save-date Sat Feb 13, 2016 ::file bio_chicago_2015_25123.txt
(b / block-01 :polarity -
      :ARG1 (p2 / phosphorylate-01
            :ARG1 (e3 / enzyme :name (n2 / name :op1 "PAK1"))
            :ARG2 (e / enzyme :name (n / name :op1 "PDK1")))
      :ARG3 (o / or
            :op1 (p3 / pretreat-01
                  :ARG3 (s / small-molecule :name (n3 / name :op1 "wortmannin")))
            :op1 (m / mutate-01
                  :ARG1 e
                  :purpose (p / prevent-01
                        :ARG1 (b2 / bind-01
                              :ARG1 (s2 / small-molecule :name (n4 / name :op1 "phosphatidylinositol"))))))
      :ARG0-of (i / indicate-01
            :ARG1 (d / depend-01 :polarity -
                  :ARG0 (p5 / process-02
                        :mod (t / this))
                  :ARG1 (a / activity-06
                        :ARG0 (e2 / enzyme :name (n5 / name :op1 "phosphatidylinositol" :op2 "3-kinase"))))))

# ::id bio.chicago_2015.25144 ::date 2015-11-01T07:53:24 ::annotator SDL-AMR-09 ::preferred
# ::snt Requirements for  Presenilin-Dependent Cleavage of  Notch and  Other Transmembrane Proteins.
# ::save-date Fri Nov 13, 2015 ::file bio_chicago_2015_25144.txt
(r / require-01
      :ARG0 (c / cleave-01
            :ARG1 (a / and
                  :op1 (p / protein :name (n2 / name :op1 "Notch"))
                  :op2 (p2 / protein
                        :mod (t / transmembrane)
                        :mod (o / other)))
            :ARG0-of (d / depend-01
                  :ARG1 (p3 / protein :name (n / name :op1 "Presenilin")))))

# ::id bio.chicago_2015.25172 ::date 2015-11-01T08:04:51 ::annotator SDL-AMR-09 ::preferred
# ::snt In contrast,  intersectin activated  Elk-1 to levels 2- to 3-fold higher than the level obtained with maximal  EGF stimulation (see Fig.  2).
# ::save-date Sun Jan 17, 2016 ::file bio_chicago_2015_25172.txt
(c / contrast-01
      :ARG2 (a / activate-01
            :ARG0 (p4 / protein :name (n / name :op1 "intersectin"))
            :ARG1 (p / protein :name (n2 / name :op1 "Elk-1"))
            :degree (l / level
                  :quant-of p
                  :degree (p2 / product-of
                        :op1 (b / between :op1 2 :op2 3))
                  :ARG1-of (h2 / high-02
                        :compared-to (l2 / level
                              :ARG1-of (o / obtain-01
                                    :condition (s2 / stimulate-01
                                          :ARG1 (p3 / protein :name (n3 / name :op1 "EGF"))
                                          :degree (m2 / maximum))))
                        :degree (m3 / more))))
      :ARG1-of (s3 / see-01 :mode imperative
            :ARG0 (y / you)
            :medium (f / figure :mod 2)))

# ::id bio.chicago_2015.25207 ::date 2015-11-01T08:18:44 ::annotator SDL-AMR-09 ::preferred
# ::snt In contrast,  MEFs deficient in downstream   Apaf-1 once again displayed only early protection from  BIM- or  BAD-induced death   (Figures 3B and 3C).
# ::save-date Thu Nov 19, 2015 ::file bio_chicago_2015_25207.txt
(c / contrast-01
      :ARG2 (d / display-01
            :ARG0 (c2 / cell :name (n / name :op1 "MEF")
                  :ARG0-of (l / lack-01
                        :ARG1 (p / protein :name (n2 / name :op1 "Apaf-1")
                              :location (d3 / downstream))))
            :ARG1 (p2 / protect-01
                  :ARG2 (d4 / die-01
                        :ARG2-of (i / induce-01
                              :ARG0 (o3 / or
                                    :op1 (p3 / protein :name (n3 / name :op1 "BIM"))
                                    :op2 (p4 / protein :name (n4 / name :op1 "BAD")))))
                  :time (e / early))
            :mod (o4 / only)
            :mod (a3 / again
                  :mod (o2 / once)))
      :ARG1-of (d2 / describe-01
            :ARG0 (a2 / and
                  :op1 (f / figure :mod "3B")
                  :op2 (f2 / figure :mod "3C"))))

# ::id bio.chicago_2015.25236 ::date 2015-11-01T08:31:20 ::annotator SDL-AMR-09 ::preferred
# ::snt Taken together, the data indicate that  PTEN can control  p53 stability by both  phosphatase and  MDM2-dependent and -independent mechanisms.
# ::save-date Fri Nov 13, 2015 ::file bio_chicago_2015_25236.txt
(i / indicate-01
      :ARG0 (d / data)
      :ARG1 (p / possible-01
            :ARG1 (c / control-01
                  :ARG0 (p2 / protein :name (n / name :op1 "PTEN"))
                  :ARG1 (s / stability
                        :poss (p3 / protein :name (n2 / name :op1 "p53")))
                  :instrument (a / and
                        :op1 (m / mechanism
                              :mod (p4 / phosphatase))
                        :op2 (m2 / mechanism
                              :ARG0-of (d2 / depend-01
                                    :ARG1 (p5 / protein :name (n3 / name :op1 "MDM2")))
                              :ARG0-of (d3 / depend-01 :polarity -
                                    :ARG1 p5)))))
      :condition (t / take-01
            :ARG1 d
            :mod (t2 / together)))

# ::id bio.chicago_2015.25358 ::date 2015-11-01T08:39:25 ::annotator SDL-AMR-09 ::preferred
# ::snt p300 acetylates histones  H3 and  H4 within nucleosomes located in the promoter and 5' proximal regions of the template.
# ::save-date Mon Jan 4, 2016 ::file bio_chicago_2015_25358.txt
(a / acetylate-01
      :ARG1 (a2 / and
            :op1 (p2 / protein :name (n2 / name :op1 "histone" :op2 "H3"))
            :op2 (p3 / protein :name (n3 / name :op1 "histone" :op2 "H4"))
            :location (n4 / nucleosome
                  :location (a3 / and
                              :op1 (r2 / region
                                    :mod (m / molecular-physical-entity
                                          :ARG0-of (p4 / promote-01)))
                              :op2 (r3 / region
                                    :mod (p5 / proximal :mod 5))
                              :part-of (t / template))))
      :ARG2 (p / protein :name (n / name :op1 "p300")))

# ::id bio.chicago_2015.25362 ::date 2015-11-01T08:44:02 ::annotator SDL-AMR-09 ::preferred
# ::snt The proposed cooperativity between sites may also explain why  eIF4F complexes purified from plant ( 31,  47,  48),  yeast ( 33), and   Drosophila ( 35) do not contain  eIF4A, despite the fact that direct binding of  eIF4A to  eIF4G can be demonstrated in  wheat germ ( 49,  50) and  yeast ( 51,  52) and that the affinity of  yeast eIF4G for  eIF4A ( K d  30 nM; Ref.  52) is comparable with that of the central site of  human eIF4G ( K d = 17 nM; Fig.  6).
# ::save-date Thu Nov 19, 2015 ::file bio_chicago_2015_25362.txt
(p / possible-01
      :ARG1 (e / explain-01
            :ARG0 (c / cooperate-01
                  :ARG0 (s / site)
                  :ARG1-of (p2 / propose-01))
            :ARG1 (t / thing
                  :ARG0-of (c2 / cause-01
                        :ARG1 (c3 / contain-01 :polarity -
                              :ARG0 (m / macro-molecular-complex
                                    :ARG1-of (p3 / purify-01
                                          :ARG2 (a2 / and
                                                :op1 (p4 / plant
                                                      :ARG1-of (d2 / describe-01
                                                            :ARG0 (p7 / publication
                                                                  :ARG1-of (c8 / cite-01
                                                                        :ARG2 (a10 / and :op1 31 :op2 47 :op3 48)))))
                                                :op2 (y / yeast
                                                      :ARG1-of (d6 / describe-01
                                                            :ARG0 (p8 / publication
                                                                  :ARG1-of (c9 / cite-01
                                                                        :ARG2 33))))
                                                :op3 (o / organism :name (n2 / name :op1 "Drosophila")
                                                      :ARG1-of (d8 / describe-01
                                                            :ARG0 (p9 / publication
                                                                  :ARG1-of (c10 / cite-01
                                                                        :ARG2 35))))))
                                    :mod (p12 / protein :name (n / name :op1 "eIF4F")))
                              :ARG1 (p6 / protein :name (n3 / name :op1 "eIF4A")))))
            :concession (p5 / possible-01
                  :ARG1 (d10 / demonstrate-01
                        :ARG1 (a7 / and
                              :op1 (b / bind-01
                                    :ARG1 p6
                                    :ARG2 p12
                                    :ARG1-of (d / direct-02)
                                    :location (a4 / and
                                          :op1 (g / germ
                                                :mod (w / wheat)
                                                :ARG1-of (d12 / describe-01
                                                      :ARG0 (p10 / publication
                                                            :ARG1-of (c11 / cite-01
                                                                  :ARG2 (a3 / and :op1 49 :op2 50)))))
                                          :op2 (y2 / yeast
                                                :ARG1-of (d15 / describe-01
                                                      :ARG0 (p11 / publication
                                                            :ARG1-of (c12 / cite-01
                                                                  :ARG2 (a5 / and :op1 51 :op2 52)))))))
                              :op2 (c4 / comparable-03
                                    :ARG1 (a8 / affinity
                                          :poss (y3 / yeast
                                                :mod (p13 / protein :name (n4 / name :op1 "eIF4G")
                                                      :quant (c5 / concentration-quantity :quant 30
                                                            :unit (n6 / nanomolar))))
                                          :ARG1-of (d18 / describe-01
                                                :ARG0 (r / reference :mod 52))
                                          :topic p6)
                                    :ARG2 (a9 / affinity
                                          :poss (s2 / site
                                                :mod (c6 / central)
                                                :mod (h / human)
                                                :part-of p13)
                                          :quant (c7 / concentration-quantity :quant 17
                                                :unit (n5 / nanomolar))
                                          :ARG1-of (d19 / describe-01
                                                :ARG0 (f / figure :mod 6)))))))
            :mod (a6 / also)))

# ::id bio.chicago_2015.25364 ::date 2015-11-01T08:44:36 ::annotator SDL-AMR-09 ::preferred
# ::snt In somatic cells,  Cdc20 and   Cdh1 binding to the  APC is differentially  regulated, resulting in a peak of APCCdc20 activity  in mitosis and APCCdh1 activity in G1  (Kramer et al., 2000   ; Shirayama et al., 1998   ; Zachariae et al., 1998   ).
# ::save-date Fri Jan 15, 2016 ::file bio_chicago_2015_25364.txt
(r3 / regulate-01
      :ARG1 (b / bind-01
            :ARG1 (a2 / and
                  :op1 (p2 / protein :name (n / name :op1 "Cdc20"))
                  :op2 (p3 / protein :name (n2 / name :op1 "Cdh1")))
            :ARG2 (p4 / protein :name (n3 / name :op1 "APC")))
      :ARG1-of (r4 / result-01
            :ARG2 (p5 / peak-01
                  :ARG1 (a3 / and
                        :op1 (a4 / activity-06
                              :ARG0 (p14 / protein :name (n4 / name :op1 "APCCdc20"))
                              :ARG1 (m / mitosis))
                        :op2 (a5 / activity-06
                              :ARG0 (p15 / protein :name (n5 / name :op1 "APCCdh1"))
                              :ARG1 (e / event :name (n6 / name :op1 "G1")))))
            :ARG1-of (d / describe-01
                  :ARG0 (a / and
                        :op1 (p6 / publication-91
                              :ARG0 (a6 / and
                                    :op1 (p7 / person :wiki - :name (n7 / name :op1 "Kramer"))
                                    :op2 (p / person
                                          :mod (o / other)))
                              :time (d2 / date-entity :year 2000))
                        :op2 (p8 / publication-91
                              :ARG0 (a7 / and
                                    :op1 (p9 / person :wiki - :name (n8 / name :op1 "Shirayama"))
                                    :op2 (p10 / person
                                          :mod (o2 / other)))
                              :time (d4 / date-entity :year 1998))
                        :op3 (p11 / publication-91
                              :ARG0 (a8 / and
                                    :op1 (p12 / person :wiki - :name (n9 / name :op1 "Zachariae"))
                                    :op2 (p13 / person
                                          :mod (o3 / other)))
                              :time d4)))
            :location (c / cell
                  :mod (s / somatic)))
      :ARG1-of (d3 / differ-02))

# ::id bio.chicago_2015.25419 ::date 2015-11-01T08:57:55 ::annotator SDL-AMR-09 ::preferred
# ::snt Inhibition of  NESK-induced  JNK Activation by the Dominant Negative Mutants of  MKK4 and  MEKK1--  MKK4 is an upstream activator of  JNK, which phosphorylates and activates  JNK.
# ::save-date Fri Feb 5, 2016 ::file bio_chicago_2015_25419.txt
(m / multi-sentence
      :snt1 (i / inhibit-01
            :ARG0 (a3 / and
                  :op1 (e / enzyme :name (n4 / name :op1 "MKK4"))
                  :op2 (e2 / enzyme :name (n5 / name :op1 "MEKK1"))
                  :ARG2-of (m2 / mutate-01 :mod "-/-")
                  :ARG0-of (d / dominate-01))
            :ARG1 (a2 / activate-01
                  :ARG1 (e3 / enzyme :name (n2 / name :op1 "JNK"))
                  :ARG2-of (i2 / induce-01
                        :ARG0 (e4 / enzyme :name (n / name :op1 "NESK")))))
      :snt2 (a4 / and
            :op1 (a6 / activate-01
                  :ARG0 (e7 / enzyme :name (n8 / name :op1 "MKK4"))
                  :ARG1 (e8 / enzyme :name (n9 / name :op1 "JNK"))
                  :location (u2 / upstream))
            :op2 (p / phosphorylate-01
                  :ARG1 e8
                  :ARG2 e7)
            :op3 (a5 / activate-01
                  :ARG0 e7
                  :ARG1 e8)))

# ::id bio.chicago_2015.25430 ::date 2015-11-01T09:06:15 ::annotator SDL-AMR-09 ::preferred
# ::snt The convex shape of the Scatchard plot indicated that  Arg binds to  F-actin with positive cooperativity (Fig.  1 G; ref.  19).
# ::save-date Thu Nov 19, 2015 ::file bio_chicago_2015_25430.txt
(i / indicate-01
      :ARG0 (s / shape-01
            :ARG1 (t / thing :name (n / name :op1 "Scatchard" :op2 "plot"))
            :ARG2 (c / convex))
      :ARG1 (b / bind-01
            :ARG1 (p / protein :name (n2 / name :op1 "Arg"))
            :ARG2 (p2 / protein :name (n3 / name :op1 "F-actin"))
            :manner (c2 / cooperate-01
                  :ARG0 p
                  :ARG1 p2
                  :mod (p3 / positive)))
      :ARG1-of (d / describe-01
            :ARG0 (a / and
                  :op1 (f / figure :mod "1G")
                  :op2 (p4 / publication
                        :ARG1-of (c3 / cite-01
                              :ARG2 19)))))

# ::id bio.chicago_2015.25436 ::date 2015-11-01T09:13:24 ::annotator SDL-AMR-09 ::preferred
# ::snt Related chromosome binding sites for  zeste, suppressors of  zeste and  Polycomb group proteins in   Drosophila and their dependence on  Enhancer of zeste function.
# ::save-date Thu Nov 19, 2015 ::file bio_chicago_2015_25436.txt
(a / and
      :op1 (a2 / and
            :op1 (s3 / site
                  :ARG2-of (b2 / bind-01
                        :ARG0 (c / chromosome
                              :ARG1-of (r / relate-01))
                        :ARG1 (p2 / protein :name (n3 / name :op1 "zeste"))))
            :op2 (m / molecular-physical-entity
                  :ARG0-of (s4 / suppress-01
                        :ARG1 (a3 / and
                              :op1 p2
                              :op2 (p3 / protein-family :name (n4 / name :op1 "Polycomb"))))
                  :location (o / organism :name (n5 / name :op1 "Drosophila"))))
      :op2 (d / depend-01
            :ARG0 a2
            :ARG1 (m2 / molecular-physical-entity
                  :ARG0-of (e2 / enhance-01
                        :ARG1 (f2 / function-01
                              :ARG1 p2)))))

# ::id bio.chicago_2015.25466 ::date 2015-11-01T09:38:28 ::annotator SDL-AMR-09 ::preferred
# ::snt The reason for the difference between this result in COS-7 cells and that in the  yeast assay (Fig.  1 B) is not known, but the difference in mammalian cells and in  yeast was also observed in the interaction of  FKBP12 with  TbetaR-I ( 11).
# ::save-date Wed Jan 13, 2016 ::file bio_chicago_2015_25466.txt
(c / contrast-01
      :ARG1 (k2 / know-01 :polarity -
            :ARG1 (t3 / thing
                  :ARG0-of (c5 / cause-01
                        :ARG1 (d / differ-02
                              :ARG1 (t / thing
                                    :ARG1-of (r / result-01
                                          :mod (t4 / this))
                                    :location (c3 / cell-line :name (n / name :op1 "COS-7")))
                              :ARG2 (t2 / thing
                                    :ARG1-of (r2 / result-01)
                                    :time (a / assay-01
                                          :instrument (y / yeast))))))
            :ARG1-of (d2 / describe-01
                  :ARG0 (f / figure :mod "1B")))
      :ARG2 (o / observe-01
            :ARG1 (d3 / differ-02
                  :location (a2 / and
                        :op1 (c4 / cell
                              :mod (m / mammalian))
                        :op2 (y2 / yeast)))
            :time (i / interact-01
                  :ARG0 (p2 / protein :name (n3 / name :op1 "FKBP12"))
                  :ARG1 (p / protein :name (n2 / name :op1 "TbetaR-I")))
            :ARG1-of (d4 / describe-01
                  :ARG0 (p3 / publication
                        :ARG1-of (c2 / cite-01
                              :ARG2 11)))
            :mod (a3 / also)))

# ::id bio.chicago_2015.25467 ::date 2015-11-01T09:46:31 ::annotator SDL-AMR-09 ::preferred
# ::snt (C) A  TSC syndrome-related GAP mutant of  TSC2 fails to inhibit  Rheb-induced  S6K1 phosphorylation.
# ::save-date Sun Jan 17, 2016 ::file bio_chicago_2015_25467.txt
(f / fail-01 :li "C"
      :ARG1 (m / mutate-01
            :ARG1 (p / protein :name (n3 / name :op1 "GAP"))
            :ARG3 (p5 / protein :name (n4 / name :op1 "TSC2"))
            :ARG1-of (r / relate-01
                  :ARG2 (s / syndrome :name (n5 / name :op1 "TSC"))))
      :ARG2 (i / inhibit-01
            :ARG0 m
            :ARG1 (p2 / phosphorylate-01
                  :ARG3 (e / enzyme :name (n / name :op1 "S6K1"))
                  :ARG2-of (i2 / induce-01
                        :ARG0 (p4 / protein :name (n2 / name :op1 "Rheb"))))))

# ::id bio.chicago_2015.25525 ::date 2015-11-01T09:51:36 ::annotator SDL-AMR-09 ::preferred
# ::snt Tyr phosphorylation of  PLSCR1 was detected by Western blotting with  anti-Tyr(P)  mAb PY99 ( upper panel, A) and abundance of  immunoprecipitated PLSCR1 protein was detected with  anti-PLSCR1 mAb 4D2 ( lower panel, A).
# ::save-date Wed Jan 13, 2016 ::file bio_chicago_2015_25525.txt
(a / and
      :op1 (d / detect-01
            :ARG1 (p2 / phosphorylate-01
                  :ARG1 (a3 / amino-acid :name (n2 / name :op1 "Tyrosine")
                        :part-of (p4 / protein :name (n3 / name :op1 "PLSCR1"))))
            :ARG2 (i2 / immunoblot-01
                  :ARG3 (a4 / antibody
                        :ARG0-of (c3 / counter-01
                              :ARG1 (p3 / protein :name (n8 / name :op1 "PY99")))))
            :ARG1-of (d3 / describe-01
                  :ARG0 (p6 / panel
                        :mod (u / upper)
                        :mod (s2 / string-entity :value "A"))))
      :op2 (d2 / detect-01
            :ARG1 (a2 / abound-01
                  :ARG2 (p7 / protein :name (n6 / name :op1 "PLSCR1")
                        :ARG1-of (i / immunoprecipitate-01)))
            :ARG2 (a5 / antibody
                  :ARG0-of (c / counter-01
                        :ARG1 (p8 / protein :name (n7 / name :op1 "PLSCR1")))
                  :ARG1-of (l2 / label-01
                        :ARG2 (s / string-entity :value "4D2"))
                  :mod (m / monoclone))
            :ARG1-of (d4 / describe-01
                  :ARG0 (p9 / panel
                        :ARG1-of (l / low-04
                              :degree (m3 / more))
                        :mod s2))))

# ::id bio.chicago_2015.25541 ::date 2015-11-01T13:13:33 ::annotator SDL-AMR-09 ::preferred
# ::snt In transient transfection assays, we  demonstrate that  TLD cleaves  SOG and that cleavage is stimulated by  DPP.
# ::save-date Thu Nov 19, 2015 ::file bio_chicago_2015_25541.txt
(d / demonstrate-01
      :ARG0 (w / we)
      :ARG1 (a / and
            :op1 (c / cleave-01
                  :ARG0 (p / protein :name (n / name :op1 "TLD"))
                  :ARG1 (p2 / protein :name (n2 / name :op1 "SOG")))
            :op2 (s / stimulate-01
                  :ARG0 (p3 / protein :name (n3 / name :op1 "DPP"))
                  :ARG1 c))
      :time (a2 / assay-01
            :ARG1 (t4 / transfect-01
                  :ARG1-of (t5 / transient-02))))

# ::id bio.chicago_2015.25564 ::date 2015-11-01T13:17:50 ::annotator SDL-AMR-09 ::preferred
# ::snt In vitro transcription and translation of full-length wild-type  Sgk (Wt Sgk),  kinase dead Sgk (K127 M Sgk), N- and C -terminal deleted  Sgk (deltaN Sgk,  deltaC Sgk), catalytic domain of  Sgk (Cat 60-355 Sgk), and  truncated fragments of the  Sgk central catalytic domain (60-157 Sgk) and (66-122  Sgk) subcloned into pCDNA3  vectors or  pCite vectors were performed using the  TNT coupled  rabbit reticulocyte kit (Promega Corporation) according to manufacturer's instructions.
# ::save-date Sat Feb 13, 2016 ::file bio_chicago_2015_25564.txt
(p / perform-01
      :ARG1 (a2 / and
            :op1 (t2 / transcribe-01
                  :ARG1 (a3 / and
                        :op1 (e / enzyme :name (n3 / name :op1 "Sgk")
                              :mod (w / wild-type)
                              :ARG1-of (l / long-03
                                    :ARG2 (f / full)))
                        :op2 (e2 / enzyme :name (n4 / name :op1 "Sgk"))
                        :op3 (e3 / enzyme :name (n9 / name :op1 "Sgk")
                              :ARG1-of (m6 / mean-01
                                    :ARG2 (a5 / and
                                          :op1 (e4 / enzyme :name (n10 / name :op1 "deltaN" :op2 "Sgk"))
                                          :op2 (e5 / enzyme :name (n11 / name :op1 "deltaC" :op2 "Sgk"))))
                              :ARG0-of (h / have-03
                                    :ARG1 (a4 / and
                                          :op1 (p5 / protein-segment :name (n12 / name :op1 "N-terminus"))
                                          :op2 (p6 / protein-segment :name (n13 / name :op1 "C-terminus"))
                                          :ARG1-of (d2 / delete-01)))
                              :ARG1-of (d / die-01))
                        :op4 (d3 / domain
                              :mod (c4 / catalytic)
                              :mod (e6 / enzyme :name (n14 / name :op1 "Sgk"))
                              :ARG1-of (m11 / mean-01
                                    :ARG2 (e7 / enzyme :name (n15 / name :op1 "Cat" :op2 "Sgk")
                                          :extent (v / value
                                                :quant (b4 / between :op1 60 :op2 355)))))
                        :op5 (f2 / fragment-01
                              :ARG1 d3
                              :ARG1-of (t5 / truncate-01
                                    :ARG4 (a6 / and
                                          :op1 (e8 / enzyme :name (n18 / name :op1 "Sgk")
                                                :value (b5 / between :op1 60 :op2 157))
                                          :op2 (e9 / enzyme :name (n19 / name :op1 "Sgk")
                                                :value (b6 / between :op1 66 :op2 122))))
                              :ARG1-of (s / subclone-01
                                    :ARG3 (o2 / or
                                          :op1 (v3 / vector :name (n17 / name :op1 "pCDNA3"))
                                          :op2 (v2 / vector :name (n16 / name :op1 "pCite")))))))
            :op2 (t / translate-02
                  :ARG1 a3)
            :manner (i2 / in-vitro))
      :ARG2 (u / use-01
            :ARG1 (k / kit
                  :consist-of (r / reticulocyte
                        :part-of (r2 / rabbit)
                        :mod (s2 / small-molecule :name (n / name :op1 "TNT")
                              :ARG1-of (c2 / couple-01)))
                  :mod (o / organization :wiki - :name (n2 / name :op1 "Promega" :op2 "Corporation")))
            :ARG3-of (i / instruct-01
                  :ARG0 o)))

# ::id bio.chicago_2015.25584 ::date 2015-10-23T08:37:21 ::annotator SDL-AMR-09 ::preferred
# ::snt These results suggest that multiple positive-feedback loops exist  among these genes during normal eye development and raised the possibility that   ey may be required for  ectopic retinal induction by   eya and   dac.
# ::save-date Fri Jan 15, 2016 ::file bio_chicago_2015_25584.txt
(a / and
      :op1 (s / suggest-01
            :ARG0 (t / thing
                  :ARG1-of (r / result-01)
                  :mod (t2 / this))
            :ARG1 (e / exist-01
                  :ARG1 (l / loop
                        :mod (f / feedback)
                        :mod (p / positive)
                        :quant (m / multiple))
                  :location (g / gene
                        :ARG1-of (i / include-91
                              :ARG2 (g2 / gene
                                    :mod (t3 / this))))
                  :time (d2 / develop-02
                        :ARG1 (e2 / eye)
                        :ARG1-of (n / normal-02))))
      :op1 (r2 / raise-01
            :ARG0 t
            :ARG1 (p2 / possible-01
                  :ARG1 (p3 / possible-01
                        :ARG1 (r3 / require-01
                              :ARG0 (i2 / induce-01
                                    :ARG0 (a2 / and
                                          :op1 (g5 / gene :name (n3 / name :op1 "eya"))
                                          :op2 (g4 / gene :name (n4 / name :op1 "dac")))
                                    :ARG2 (r4 / retinal
                                          :mod (e3 / ectopic)))
                              :ARG1 (p4 / protein :name (n2 / name :op1 "ey")))))))

# ::id bio.chicago_2015.25656 ::date 2015-10-23T08:54:22 ::annotator SDL-AMR-09 ::preferred
# ::snt PKG phosphorylation of  SF1 blocked its ability to bind to  U2AF65 and inhibited  pre-spliceosome assembly.
# ::save-date Sat Feb 13, 2016 ::file bio_chicago_2015_25656.txt
(a / and
      :op1 (b / block-01
            :ARG0 (p / phosphorylate-01
                  :ARG1 (p2 / protein :name (n / name :op1 "SF1"))
                  :ARG2 (e / enzyme :name (n2 / name :op1 "PKG")))
            :ARG1 (c / capable-01
                  :ARG1 e
                  :ARG2 (b2 / bind-01
                        :ARG1 e
                        :ARG2 (p3 / protein :name (n3 / name :op1 "U2AF65")))))
      :op2 (i / inhibit-01
            :ARG0 p
            :ARG1 (a2 / assemble-01
                  :time (b3 / before
                        :op1 (s / small-molecule :name (n4 / name :op1 "spliceosome"))))))

# ::id bio.chicago_2015.25659 ::date 2015-10-23T09:53:45 ::annotator SDL-AMR-09 ::preferred
# ::snt The possibility that caffeine inhibits  ATM directly was therefore tested.
# ::save-date Mon Nov 9, 2015 ::file bio_chicago_2015_25659.txt
(t / test-01
      :ARG1 (p2 / possible-01
            :ARG1 (i / inhibit-01
                  :ARG0 (c / caffeine)
                  :ARG1 (e / enzyme :name (n / name :op1 "ATM"))
                  :ARG1-of (d / direct-02))
            :ARG0-of (c2 / cause-01)))

# ::id bio.chicago_2015.25663 ::date 2015-10-23T09:59:58 ::annotator SDL-AMR-09 ::preferred
# ::snt In quiescent Swiss 3T3 fibroblasts, the activation of  Rho induces the assembly of  actin into bundles and stress fibers, while the activation of  Rac and  Cdc42 induces  actin polymerization leading to ruffles and filopodia, respectively (reviewed by  Hall and Nobes, 2000  ).
# ::save-date Thu Oct 29, 2015 ::file bio_chicago_2015_25663.txt
(c2 / contrast-01
      :ARG1 (i / induce-01
            :ARG0 (a / activate-01
                  :ARG1 (p / protein :name (n2 / name :op1 "Rho")))
            :ARG2 (a2 / assemble-01
                  :ARG1 (f / fiber
                        :ARG1-of (s / stress-02)
                        :ARG1-of (b / bundle-01))
                  :ARG2 (p2 / protein :name (n3 / name :op1 "actin"))))
      :ARG2 (i2 / induce-01
            :ARG0 (a3 / activate-01
                  :ARG1 (a4 / and
                        :op1 (e / enzyme :name (n4 / name :op1 "Rac"))
                        :op2 (p3 / protein :name (n5 / name :op1 "Cdc-42"))))
            :ARG2 (p4 / polymerize-01
                  :ARG1 p2)
            :ARG0-of (l / lead-03
                  :ARG2 (a5 / and
                        :op1 (t / thing
                              :ARG1-of (r / ruffle-02))
                        :op2 (f2 / filopodia)
                        :mod (r2 / respective))))
      :location (f3 / fibroblast
            :mod (q / quiescent)
            :mod (c4 / cell-line :name (n9 / name :op1 "Swiss" :op2 "3T3")))
      :ARG1-of (r3 / review-01
            :ARG0 (a6 / and
                  :op1 (p5 / person :name (n7 / name :op1 "Hall"))
                  :op2 (p6 / person :name (n8 / name :op1 "Nobes")))
            :time (d / date-entity :year 2000)))

# ::id bio.chicago_2015.25683 ::date 2015-10-23T10:14:51 ::annotator SDL-AMR-09 ::preferred
# ::snt firstly, the isolated  SH3 domain binds tightly to dynamin  in vitro; and secondly, coexpression of both  dynamin and the  amphiphysin SH3 domain rescues the  transferrin uptake.
# ::save-date Tue Feb 2, 2016 ::file bio_chicago_2015_25683.txt
(a / and
      :op1 (b / bind-01
            :ARG1 (p / protein-segment :name (n / name :op1 "SH3" :op2 "domain")
                  :ARG1-of (i / isolate-01))
            :ARG2 (p5 / protein :name (n2 / name :op1 "dynamin"))
            :ARG1-of (t / tight-05)
            :manner (i2 / in-vitro)
            :ord (o / ordinal-entity :value 1))
      :op2 (r / rescue-01
            :ARG0 (c / coexpress-01
                  :ARG2 (a2 / and
                        :op1 p5
                        :op2 (p2 / protein-segment :name n
                              :part-of (p3 / protein :name (n4 / name :op1 "amphiphysin")))))
            :ARG1 (t2 / take-up-13
                  :ARG2 (p4 / protein :name (n5 / name :op1 "transferrin")))
            :ord (o2 / ordinal-entity :value 2)))

# ::id bio.chicago_2015.25696 ::date 2015-10-23T10:28:29 ::annotator SDL-AMR-09 ::preferred
# ::snt RACK1 also interacted with the  IGF-1R in fibroblasts and  MCF-7 cells and with endogenous  insulin receptor in  COS cells.
# ::save-date Thu Oct 29, 2015 ::file bio_chicago_2015_25696.txt
(a / and
      :op1 (i / interact-01
            :ARG0 (p / protein :name (n / name :op1 "RACK1"))
            :ARG1 (p2 / protein :name (n2 / name :op1 "IGF-1R"))
            :mod (a2 / also)
            :location (a3 / and
                  :op1 (f / fibroblast)
                  :op2 (c / cell-line :name (n3 / name :op1 "MCF-7"))))
      :op2 (i2 / interact-01
            :ARG0 p
            :ARG1 (r2 / receptor
                  :mod (i3 / insulin)
                  :mod (e / endogenous))
            :location (c2 / cell-line :name (n5 / name :op1 "COS"))))

# ::id bio.chicago_2015.25712 ::date 2015-10-23T10:39:05 ::annotator SDL-AMR-09 ::preferred
# ::snt Given that  DLAK has the most extensive sequence similarity with  IKK and that  DLAK exists in the form of a complex with  Cactus and  LPS-induced  Cactus degradation is specifically blocked by dominant-negative  DLAK, we could speculate that the dominant-negative form of  DLAK fails to transmit the  Cactus degradation signal, essential for  Rel/ NF-kappaB activation and subsequently prevents  LPS inducibility of at least certain kappaB-dependent antimicrobial  peptide genes.
# ::save-date Sun Jan 17, 2016 ::file bio_chicago_2015_25712.txt
(c / cause-01
      :ARG0 (a2 / and
            :op1 (h / have-03
                  :ARG0 (e / enzyme :name (n / name :op1 "DLAK"))
                  :ARG1 (r / resemble-01
                        :ARG1 e
                        :ARG2 (e2 / enzyme :name (n2 / name :op1 "IKK"))
                        :mod (s / sequence)
                        :ARG1-of (e3 / extensive-03
                              :ARG2 (m / most))))
            :op2 (e4 / exist-01
                  :ARG1 e
                  :ARG2 (f / form-02
                        :ARG0 (a5 / and
                              :op1 e
                              :op2 (p2 / protein :name (n3 / name :op1 "Cactus")))
                        :ARG1 (c2 / complex)))
            :op3 (b / block-01
                  :ARG0 (e5 / enzyme :name (n6 / name :op1 "DLAK")
                        :ARG2-of (m2 / mutate-01 :mod "-/-")
                        :ARG0-of (d2 / dominate-01))
                  :ARG1 (d / degrade-01
                        :ARG1 p2
                        :ARG2-of (i / induce-01
                              :ARG0 (m3 / molecular-physical-entity :name (n5 / name :op1 "LPS"))))
                  :ARG1-of (s3 / specific-02)))
      :ARG1 (p / possible-01
            :ARG1 (s4 / speculate-01
                  :ARG0 (w / we)
                  :ARG1 (a4 / and
                        :op1 (f2 / fail-01
                              :ARG0 e5
                              :ARG1 (t / transmit-01
                                    :ARG0 (f3 / form-02)
                                    :ARG1 (s5 / signal-07
                                          :ARG1 d
                                          :mod (e6 / essential)
                                          :condition-of (a3 / activate-01
                                                      :ARG1 (s7 / slash
                                                            :op1 (p4 / protein :name (n7 / name :op1 "Rel"))
                                                            :op2 (p3 / protein :name (n10 / name :op1 "NF-kappaB")))))))
                        :op2 (p6 / prevent-01
                              :ARG0 f3
                              :ARG1 (i2 / induce-01
                                    :ARG0 m3
                                    :ARG1 (g / gene
                                          :mod (p8 / peptide)
                                          :ARG0-of (o / oppose-01
                                                :ARG1 (m4 / microbe))
                                          :ARG0-of (d3 / depend-01
                                                :ARG1 (p5 / protein :name (n8 / name :op1 "kappaB")))
                                          :mod (a / at-least)
                                          :mod (c3 / certain))
                                    :ARG1-of (p7 / possible-01))
                              :time (s6 / subsequent))))))

# ::id bio.chicago_2015.25761 ::date 2015-10-23T12:05:09 ::annotator SDL-AMR-09 ::preferred
# ::snt However, only the  JNK cascade can activate  c-Jun ( 16,  65,  66,  67).
# ::save-date Mon Nov 9, 2015 ::file bio_chicago_2015_25761.txt
(h / have-concession-91
      :ARG1 (p4 / possible-01
            :ARG1 (a / activate-01
                  :ARG0 (p / pathway :name (n3 / name :op1 "JNK"))
                  :ARG1 (p2 / protein :name (n2 / name :op1 "c-Jun"))
                  :mod (o / only)))
      :ARG1-of (d / describe-01
            :ARG0 (p3 / publication
                  :ARG1-of (c / cite-01
                        :ARG2 (a2 / and :op1 16 :op2 65 :op3 66 :op4 67)))))

# ::id bio.chicago_2015.25828 ::date 2015-10-23T12:12:43 ::annotator SDL-AMR-09 ::preferred
# ::snt Under conditions where  Rac induced strong  actin polymerization and lamellipodia, POSH induced no detectable assembly of  actin filaments (data not shown).
# ::save-date Fri Jan 15, 2016 ::file bio_chicago_2015_25828.txt
(c / condition-01
      :ARG1 (i2 / induce-01
            :ARG0 (p5 / protein :name (n4 / name :op1 "POSH"))
            :ARG2 (a2 / assemble-02
                  :ARG2 (f / filament
                        :mod p2)
                  :ARG1-of (d / detect-01
                        :ARG1-of (p4 / possible-01 :polarity -))))
      :ARG2 (i / induce-01
            :ARG0 (e / enzyme :name (n / name :op1 "Rac"))
            :ARG2 (a / and
                  :op1 (p / polymerize-01
                        :ARG1 (p2 / protein :name (n2 / name :op1 "actin"))
                        :ARG1-of (s / strong-02))
                  :op2 (p3 / protein :name (n3 / name :op1 "lamellipodia"))))
      :ARG1-of (d2 / describe-01
            :ARG0 (d3 / data
                  :ARG1-of (s2 / show-01 :polarity -))))

# ::id bio.chicago_2015.25847 ::date 2015-10-23T13:06:00 ::annotator SDL-AMR-09 ::preferred
# ::snt Dvl2 Activation of  JNK Does  Not Require MEKK1 and Binding of  Dvl2 to  Axin Is Independent of the  Axin-MEKK1 Interaction--  We have previously demonstrated that  MEKK1 binds  Axin and is critical for  Axin activation of  JNK ( 22).
# ::save-date Mon Oct 26, 2015 ::file bio_chicago_2015_25847.txt
(m / multi-sentence
      :snt1 (a / and
            :op1 (r / require-01 :polarity -
                  :ARG0 (a2 / activate-01
                        :ARG0 (p / protein :name (n / name :op1 "Dvl2"))
                        :ARG1 (e / enzyme :name (n2 / name :op1 "JNK")))
                  :ARG1 (e2 / enzyme :name (n3 / name :op1 "MEKK1")))
            :op2 (d / depend-01 :polarity -
                  :ARG0 (b / bind-01
                        :ARG1 p
                        :ARG2 (p2 / protein :name (n4 / name :op1 "Axin")))
                  :ARG1 (i / interact-01
                        :ARG0 p2
                        :ARG1 e2)))
      :snt2 (d2 / demonstrate-01
            :ARG0 (w2 / we)
            :ARG1 (b2 / bind-01
                  :ARG1 (e3 / enzyme :name (n5 / name :op1 "MEKK1"))
                  :ARG2 (p3 / protein :name (n6 / name :op1 "Axin"))
                  :ARG1-of (c / critical-02
                        :ARG2 (a3 / activate-01
                              :ARG0 p3
                              :ARG1 (e4 / enzyme :name (n7 / name :op1 "JNK")))))
            :time (p4 / previous)
            :ARG1-of (d3 / describe-01
                  :ARG0 (p5 / publication
                        :ARG1-of (c2 / cite-01
                              :ARG2 22)))))

# ::id bio.chicago_2015.25875 ::date 2015-10-23T13:15:12 ::annotator SDL-AMR-09 ::preferred
# ::snt We show that the  Tuberin-Hamartin heterodimer inhibits  Rheb-induced  S6K1 activation during conditions of amino acid withdrawal   (Figure 5A).
# ::save-date Thu Oct 29, 2015 ::file bio_chicago_2015_25875.txt
(s / show-01
      :ARG0 (w / we)
      :ARG1 (i / inhibit-01
            :ARG0 (h / heterodimer
                  :part (p / protein :name (n / name :op1 "Tuberin"))
                  :part (p2 / protein :name (n2 / name :op1 "Hamartin")))
            :ARG1 (a / activate-01
                  :ARG1 (e / enzyme :name (n3 / name :op1 "S6K1"))
                  :ARG2-of (i2 / induce-01
                        :ARG0 (p3 / protein :name (n4 / name :op1 "Rheb"))))
            :ARG1-of (c / condition-01
                  :ARG2 (w2 / withdraw-01
                        :ARG1 (a2 / amino-acid))))
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod "5A")))

# ::id bio.chicago_2015.25880 ::date 2015-10-23T13:27:32 ::annotator SDL-AMR-09 ::preferred
# ::snt Therefore, downregulation of  Rho activity by  Cdc42 may either involve activation of  Rac or occur independently of  Rac, possibly by a downstream signaling pathway shared by  Cdc42 and  Rac.
# ::save-date Thu Oct 29, 2015 ::file bio_chicago_2015_25880.txt
(c / cause-01
      :ARG1 (p3 / possible-01
            :ARG1 (o / or
                  :op1 (i / involve-01
                        :ARG1 (a2 / activate-01
                              :ARG1 (e / enzyme :name (n3 / name :op1 "Rac")))
                        :ARG2 (d / downregulate-01
                              :ARG1 (a / activity-06
                                    :ARG0 (p / protein :name (n / name :op1 "Rho")))
                              :ARG2 (p2 / protein :name (n2 / name :op1 "Cdc42"))))
                  :op2 (d3 / depend-01 :polarity -
                        :ARG0 d
                        :ARG1 e
                        :ARG1-of (c2 / cause-01
                              :ARG0 (s / share-01
                                    :ARG0 (a3 / and
                                          :op1 p2
                                          :op2 e)
                                    :ARG1 (p5 / pathway
                                          :ARG0-of (s2 / signal-07
                                                :direction (d4 / downstream))))
                              :ARG1-of (p4 / possible-01))))))

# ::id bio.chicago_2015.25882 ::date 2015-10-23T13:55:36 ::annotator SDL-AMR-09 ::preferred
# ::snt Ethanol-induced  Cbl tyrosine phosphorylation in  rat cerebellum
# ::save-date Fri Oct 23, 2015 ::file bio_chicago_2015_25882.txt
(p2 / phosphorylate-01
      :ARG1 (a / amino-acid :name (n / name :op1 "tyrosine")
            :part-of (p3 / protein :name (n2 / name :op1 "Cbl")))
      :ARG2-of (i / induce-01
            :ARG0 (e / ethanol))
      :location (c / cerebellum
            :mod (r / rat)))

# ::id bio.chicago_2015.25952 ::date 2015-10-23T13:59:03 ::annotator SDL-AMR-09 ::preferred
# ::snt Importantly, the  RNAi oligo inhibits  RhoA activation by   Wnt-1,  Fz, or  Dvl, but not by  Ephexin     (Figure 3C).
# ::save-date Sun Jan 17, 2016 ::file bio_chicago_2015_25952.txt
(c / contrast-01
      :ARG1 (i / inhibit-01
            :ARG0 (n / nucleic-acid :name (n8 / name :op1 "RNAi" :op2 "oligo"))
            :ARG1 (a / activate-01
                  :ARG0 (o / or
                        :op1 (p2 / protein :name (n3 / name :op1 "Wnt-1"))
                        :op2 (p3 / protein :name (n4 / name :op1 "Fz"))
                        :op3 (p4 / protein :name (n5 / name :op1 "Dvl")))
                  :ARG1 (p / protein :name (n6 / name :op1 "RhoA"))))
      :ARG2 (i3 / inhibit-01 :polarity -
            :ARG0 (n2 / nucleic-acid :name (n9 / name :op1 "RNA"))
            :ARG1 (a2 / activate-01
                  :ARG0 (p5 / protein :name (n7 / name :op1 "Ephexin"))
                  :ARG1 p))
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod "3C"))
      :mod (i2 / important))

# ::id bio.chicago_2015.26022 ::date 2015-10-23T14:09:48 ::annotator SDL-AMR-09 ::preferred
# ::snt Regulation of  GSK-3beta by  PKA and  PP1 in the  AKAP220 Complex-- Finally we examined the physiological significance of the binding of  GSK-3beta to  AKAP220.
# ::save-date Thu Oct 29, 2015 ::file bio_chicago_2015_26022.txt
(m / multi-sentence
      :snt1 (r / regulate-01
            :ARG0 (a / and
                  :op1 (e2 / enzyme :name (n2 / name :op1 "PKA"))
                  :op2 (p / protein :name (n3 / name :op1 "PP1")))
            :ARG1 (e / enzyme :name (n / name :op1 "GSK-3beta"))
            :location (c / complex
                  :mod (p2 / protein :name (n4 / name :op1 "AKAP220"))))
      :snt2 (e3 / examine-01
            :ARG0 (w / we)
            :ARG1 (s / signify-01
                  :ARG0 (b / bind-01
                        :ARG1 (e4 / enzyme :name (n5 / name :op1 "GSK-3beta"))
                        :ARG2 (p4 / protein :name (n6 / name :op1 "AKAP220")))
                  :mod (p3 / physiology)
                  :time (f / final))))

# ::id bio.chicago_2015.26080 ::date 2015-10-23T14:14:08 ::annotator SDL-AMR-09 ::preferred
# ::snt In accordance with our previous results in  32D/EpoR-Wt cells ( 4),  Epo stimulation induced activation of  ERK1 and  ERK2, which was detected by their phosphorylation on tyrosines, in 32DE/Tet- CrkL cells (Fig.  3).
# ::save-date Sun Jan 17, 2016 ::file bio_chicago_2015_26080.txt
(i / induce-01
      :ARG0 (s / stimulate-01
            :ARG1 (s2 / small-molecule :name (n2 / name :op1 "Epo")))
      :ARG2 (a2 / activate-01
            :ARG1 (a3 / and
                  :op1 (e / enzyme :name (n3 / name :op1 "ERK1"))
                  :op2 (e2 / enzyme :name (n4 / name :op1 "ERK2")))
            :ARG1-of (d / detect-01
                  :ARG0 (p2 / phosphorylate-01
                        :ARG1 (a4 / amino-acid :name (n5 / name :op1 "tyrosine")
                              :part-of a3)
                        :location (c / cell-line :name (n6 / name :op1 "32DE")
                              :mod (p / protein :name (n / name :op1 "Tet-CrkL"))))))
      :ARG1-of (d2 / describe-01
            :ARG0 (f / figure :mod 3))
      :ARG1-of (a / accord-02
            :ARG2 (t / thing
                  :ARG2-of (r / result-01
                        :ARG1 (c2 / cell-line :name (n7 / name :op1 "32D")
                              :mod (p6 / protein :name (n8 / name :op1 "EpoR")
                                    :mod (w / wild-type)))
                        :time (p4 / previous))
                  :ARG1-of (d3 / describe-01
                        :ARG0 (p5 / publication
                              :ARG1-of (c3 / cite-01
                                    :ARG2 4))))))

# ::id bio.chicago_2015.26085 ::date 2015-10-23T14:23:59 ::annotator SDL-AMR-09 ::preferred
# ::snt Cross Talk between  ERK and  PKA Is Required for Ca2+ Stimulation of  CREB-Dependent Transcription and  ERK Nuclear Translocation
# ::save-date Sat Jan 16, 2016 ::file bio_chicago_2015_26085.txt
(r / require-01
      :ARG0 (a / and
            :op1 (s / stimulate-01
                  :ARG0 (c2 / calcium
                        :ARG1-of (i / ionize-01 :value "2+"))
                  :ARG1 (t2 / transcribe-01
                        :ARG0-of (d / depend-01
                              :ARG1 (p2 / protein :name (n3 / name :op1 "CREB")))))
            :op2 (t3 / translocate-01
                  :ARG1 e2
                  :mod (n5 / nucleus)))
      :ARG1 (t / talk-01
            :ARG0 (e2 / enzyme :name (n / name :op1 "ERK"))
            :ARG2 (e / enzyme :name (n2 / name :op1 "PKA"))
            :ARG1-of (c / cross-01)))

# ::id bio.chicago_2015.26119 ::date 2015-10-23T14:31:59 ::annotator SDL-AMR-09 ::preferred
# ::snt Acetylation of  MyoD Directed by  PCAF Is Necessary for the Execution of the Muscle Program.
# ::save-date Sun Jan 17, 2016 ::file bio_chicago_2015_26119.txt
(n2 / need-01
      :ARG0 (e / execute-02
            :ARG1 (p2 / program
                  :mod (m / muscle)))
      :ARG1 (a / acetylate-01
            :ARG1 (p / protein :name (n3 / name :op1 "MyoD"))
            :ARG1-of (d / direct-01
                  :ARG0 (p3 / protein :name (n4 / name :op1 "PCAF")))))

# ::id bio.chicago_2015.26145 ::date 2015-10-23T14:34:15 ::annotator SDL-AMR-09 ::preferred
# ::snt Binding of  Cdc20 and  Cdh1 to the  APC is differentially regulated.
# ::save-date Fri Oct 23, 2015 ::file bio_chicago_2015_26145.txt
(r / regulate-01
      :ARG1 (b / bind-01
            :ARG1 (a / and
                  :op1 (p / protein :name (n / name :op1 "Cdc20"))
                  :op2 (p2 / protein :name (n2 / name :op1 "Cdh1")))
            :ARG2 (p3 / protein :name (n3 / name :op1 "APC")))
      :manner (d / differential))

# ::id bio.chicago_2015.26161 ::date 2015-10-23T14:38:04 ::annotator SDL-AMR-09 ::preferred
# ::snt As shown in    Figure 3, neither of these fractions alone supported   dATP-dependent activation of  CPP32 (lanes 3 - 6).
# ::save-date Tue Jan 12, 2016 ::file bio_chicago_2015_26161.txt
(s / support-01 :polarity -
      :ARG0 (f / fraction-01
            :mod (t / this)
            :mod (a / alone))
      :ARG1 (a2 / activate-01
            :ARG1 (p / protein :wiki "Caspase_3"
                  :name (n / name :op1 "CPP32"))
            :ARG0-of (d / depend-01
                  :ARG1 (s3 / small-molecule :wiki "Deoxyadenosine_triphosphate"
                        :name (n2 / name :op1 "dATP"))))
      :ARG1-of (s2 / show-01
            :ARG0 (f2 / figure :mod 3))
      :ARG1-of (d2 / describe-01
            :ARG0 (v / value-interval
                  :op1 (l / lane :mod 3)
                  :op2 (l2 / lane :mod 6))))

# ::id bio.chicago_2015.26163 ::date 2015-10-25T06:06:51 ::annotator SDL-AMR-09 ::preferred
# ::snt We do not know at present how  Bni1p and  Bnr1p are involved in this  profilin-actin interaction, but the genetic results that the phenotypes of the   bni1 bnr1 mutant are similar to those of the   pfy1 mutant indicate that the interactions of  Bni1p and  Bnr1p with  profilin are important for the proper functions of  profilin.
# ::save-date Thu Oct 29, 2015 ::file bio_chicago_2015_26163.txt
(c / contrast-01
      :ARG1 (k / know-01 :polarity -
            :ARG0 (w / we)
            :ARG1 (t2 / thing
                  :manner-of (i / involve-01
                        :ARG1 (a / and
                              :op1 (p2 / protein :name (n / name :op1 "Bni1p"))
                              :op2 (p3 / protein :name (n2 / name :op1 "Bnr1p")))
                        :ARG2 (i2 / interact-01
                              :ARG0 (p4 / protein :name (n3 / name :op1 "profilin"))
                              :ARG1 (p5 / protein :name (n4 / name :op1 "actin"))
                              :mod (t / this))))
            :time (p / present))
      :ARG2 (i3 / indicate-01
            :ARG0 (r2 / result-01
                  :ARG2 (r / resemble-01
                        :ARG1 (a2 / and
                              :op1 (p6 / phenotype
                                    :mod (p8 / protein :name (n5 / name :op1 "bni1")
                                          :ARG2-of (m / mutate-01)))
                              :op2 (p7 / phenotype
                                    :mod (p9 / protein :name (n6 / name :op1 "bnr1")
                                          :ARG2-of m)))
                        :ARG2 (p10 / phenotype
                              :mod (p11 / protein :name (n7 / name :op1 "pfy1")
                                    :ARG2-of m)))
                  :mod (g / genetic))
            :ARG1 (i4 / important
                  :domain (i5 / interact-01
                        :ARG0 (a3 / and
                              :op1 p2
                              :op2 p3)
                        :ARG1 p4)
                  :purpose (f / function-01
                        :ARG0 p4
                        :mod (p12 / proper)))))

# ::id bio.chicago_2015.26193 ::date 2015-10-25T06:25:50 ::annotator SDL-AMR-09 ::preferred
# ::snt Moreover,  CBP/ p300 directly acetylates  transcription factors such as  GATA-1 ( 6) and  p53 ( 21).
# ::save-date Sun Oct 25, 2015 ::file bio_chicago_2015_26193.txt
(a / and
      :op2 (a2 / acetylate-01
            :ARG0 (s / slash
                  :op1 (p / protein :name (n / name :op1 "CBP"))
                  :op2 (p2 / protein :name (n2 / name :op1 "p300")))
            :ARG1 (f / factor
                  :ARG0-of (t / transcribe-01)
                  :example (a3 / and
                              :op1 (p3 / protein :name (n3 / name :op1 "GATA-1")
                                    :ARG1-of (d2 / describe-01
                                          :ARG0 (p5 / publication
                                                :ARG1-of (c / cite-01
                                                      :ARG2 6))))
                              :op2 (p4 / protein :name (n4 / name :op1 "p53")
                                    :ARG1-of (d3 / describe-01
                                          :ARG0 (p6 / publication
                                                :ARG1-of (c2 / cite-01
                                                      :ARG2 21))))))
            :ARG1-of (d / direct-02)))

# ::id bio.chicago_2015.26198 ::date 2015-10-25T09:04:24 ::annotator SDL-AMR-09 ::preferred
# ::snt To identify a  direct target molecule of  Ras, we have established a cell-free  assay system using   Xenopus  oocyte extract in which  Ras  activates  ERK through  MEK( 39 ) .
# ::save-date Sat Jan 16, 2016 ::file bio_chicago_2015_26198.txt
(e / establish-01
      :ARG0 (w2 / we)
      :ARG1 (s / system
            :mod (a / assay-01
                  :ARG1-of (f / free-04
                        :ARG2 (c / cell))))
      :instrument (e2 / extract-01
            :ARG1 (c2 / cell :name (n3 / name :op1 "Xenopus" :op2 "oocyte")
                  :location-of (a2 / activate-01
                        :ARG0 (e3 / enzyme :name (n / name :op1 "Ras"))
                        :ARG1 (e4 / enzyme :name (n2 / name :op1 "ERK"))
                        :path (e5 / enzyme :name (n4 / name :op1 "MEK")))))
      :purpose (i / identify-01
            :ARG0 w2
            :ARG1 (m / molecule
                  :ARG1-of (t / target-01
                        :ARG0 e3)
                  :ARG1-of (d / direct-02)))
      :ARG1-of (d2 / describe-01
            :ARG0 (p4 / publication
                  :ARG1-of (c3 / cite-01
                        :ARG2 39))))

# ::id bio.chicago_2015.26222 ::date 2015-10-25T09:13:50 ::annotator SDL-AMR-09 ::preferred
# ::snt Chain Valence Mutants of  Glypican-1 in  FGF2-induced  FGFR1 Phosphorylation--  All syndecans and  glypicans carry multiple  HS chains, which are clustered in one small domain of the protein.
# ::save-date Sat Feb 13, 2016 ::file bio_chicago_2015_26222.txt
(m / multi-sentence
      :snt1 (m2 / mutate-01
            :ARG2 (p / protein :name (n / name :op1 "Glypican-1"))
            :mod (v / valence)
            :mod (c / chain)
            :location (p2 / phosphorylate-01
                  :ARG1 (e / enzyme :name (n2 / name :op1 "FGFR1"))
                  :ARG2-of (i / induce-01
                        :ARG0 (e2 / enzyme :name (n3 / name :op1 "FGF2")))))
      :snt2 (c2 / carry-01
            :ARG0 (a / and
                  :op1 (p3 / protein :name (n4 / name :op1 "syndecan"))
                  :op2 (p4 / protein :name (n5 / name :op1 "glypican"))
                  :mod (a2 / all))
            :ARG1 (c3 / chain
                  :mod (s2 / small-molecule :name (n6 / name :op1 "HS"))
                  :ARG1-of (c4 / cluster-01
                        :ARG2 (p5 / protein-segment :quant 1
                              :mod (s / small)
                              :part-of (p6 / protein)))
                  :quant (m4 / multiple))))

# ::id bio.chicago_2015.26233 ::date 2015-10-25T09:26:19 ::annotator SDL-AMR-09 ::preferred
# ::snt For the case of  PKC activation by  PMA, we also tested the possibility of an increased Ca2+ sensitivity of the vesicle supply process without a change of the maximal activity.
# ::save-date Sat Jan 30, 2016 ::file bio_chicago_2015_26233.txt
(t / test-01
      :ARG0 (w / we)
      :ARG1 (p / possible-01
            :ARG1 (i / increase-01
                  :ARG1 (s / sensitive-03
                        :ARG0 (p2 / process-02
                              :ARG1 (s2 / supply-01
                                    :ARG1 (v / vesicle)))
                        :ARG1 (c3 / calcium
                              :ARG1-of (i2 / ionize-01 :value "2+")))
                  :manner (c / change-01 :polarity -
                        :ARG1 (a2 / activity-06
                              :mod (m2 / maximal)))))
      :mod (a / also)
      :purpose (c2 / case-04
            :ARG1 (a3 / activate-01
                  :ARG0 (s3 / small-molecule :name (n3 / name :op1 "PMA"))
                  :ARG1 (e / enzyme :name (n2 / name :op1 "PKC")))))

# ::id bio.chicago_2015.26279 ::date 2015-10-25T09:33:38 ::annotator SDL-AMR-09 ::preferred
# ::snt Using co-immunoprecipitation approaches, we showed that  dSlo binds only to free  PKAc but not to the  PKA holoenzyme, and that both  PKA regulatory subunit and  PKI inhibit the association between  dSlo and  PKAc.
# ::save-date Mon Nov 9, 2015 ::file bio_chicago_2015_26279.txt
(s / show-01
      :ARG0 (w / we)
      :ARG1 (a / and
            :op1 (c / contrast-01
                  :ARG1 (b / bind-01
                        :ARG1 (p / protein :name (n / name :op1 "dSlo"))
                        :ARG2 (e / enzyme :name (n2 / name :op1 "PKAc")
                              :ARG1-of (f / free-04))
                        :mod (o / only))
                  :ARG2 (b2 / bind-01 :polarity -
                        :ARG1 p
                        :ARG2 (e2 / enzyme :name (n3 / name :op1 "PKA")
                              :mod (h / holoenzyme))))
            :op2 (i / inhibit-01
                  :ARG0 (a2 / and
                        :op1 (s2 / subunit
                              :ARG0-of (r / regulate-01)
                              :mod e2)
                        :op2 (e3 / enzyme :name (n4 / name :op1 "PKI")))
                  :ARG1 (a3 / associate-01
                        :ARG1 p
                        :ARG2 (e4 / enzyme :name n2))))
      :manner (u / use-01
            :ARG0 w
            :ARG1 (a4 / approach-02
                  :mod (c2 / coimmunoprecipitate-01))))

# ::id bio.chicago_2015.26283 ::date 2015-10-25T09:44:24 ::annotator SDL-AMR-09 ::preferred
# ::snt Therefore,  RBP interaction with  TFIID and  TFIIA alters optimal interaction between these two coactivators, not to dislodge them from the promoter, but instead to subvert activated transcription.
# ::save-date Tue Feb 2, 2016 ::file bio_chicago_2015_26283.txt
(c / cause-01
      :ARG1 (a / alter-01
            :ARG0 (i / interact-01
                  :ARG0 (p / protein-family :name (n / name :op1 "RBP"))
                  :ARG1 (a4 / and
                        :op1 (p2 / protein :name (n2 / name :op1 "TFIID"))
                        :op2 (p3 / protein :name (n3 / name :op1 "TFIIA"))
                        :ARG0-of (c2 / coactivate-01)))
            :ARG1 (i2 / interact-01
                  :ARG0 p2
                  :ARG1 p3
                  :mod (o / optimal))
            :purpose (i3 / instead-of-91
                  :ARG1 (s / subvert-01
                        :ARG0 i
                        :ARG1 (t2 / transcribe-01
                              :ARG1-of (a3 / activate-01)))
                  :ARG2 (d / dislodge-01 :polarity -
                        :ARG0 i
                        :ARG1 a4
                        :ARG2 (t / thing
                              :ARG1-of (p4 / promote-02))))))

# ::id bio.chicago_2015.26335 ::date 2015-10-25T09:50:57 ::annotator SDL-AMR-09 ::preferred
# ::snt Currently it is unclear whether within the centromere chromatin  CENP-A replaces all  histone H3 subunits   (Choo, 2000  ; Lo et al., 2001a  ).
# ::save-date Mon Oct 26, 2015 ::file bio_chicago_2015_26335.txt
(c / clear-06 :polarity -
      :ARG1 (r / replace-01 :mode interrogative
            :ARG0 (p / protein :name (n / name :op1 "CENP-A"))
            :ARG1 (s / subunit
                  :part-of (p2 / protein :name (n2 / name :op1 "histone" :op2 "H3"))
                  :mod (a / all))
            :location (c2 / chromatin
                  :mod (c3 / centromere)))
      :time (c4 / current)
      :ARG1-of (d3 / describe-01
            :ARG0 (a2 / and
                  :op1 (p3 / publication-91
                        :ARG0 (p4 / person :name (n3 / name :op1 "Choo"))
                        :time (d / date-entity :year 2000))
                  :op2 (p5 / publication-91
                        :ARG0 (a3 / and
                              :op1 (p6 / person :name (n4 / name :op1 "Lo"))
                              :op2 (p7 / person
                                    :mod (o / other)))
                        :time (d2 / date-entity :year 2001)))))

# ::id bio.chicago_2015.26340 ::date 2015-10-25T09:57:55 ::annotator SDL-AMR-09 ::preferred
# ::snt d,  in vitro reconstitution of  SUMO-1 modification of the indicated  HDAC1 mutants with (+) or without ( ) addition of the assay mix (as in Fig.  1 b).
# ::save-date Thu Feb 4, 2016 ::file bio_chicago_2015_26340.txt
(r / reconstitute-01 :li "d"
      :ARG2 (m / modify-01
            :ARG0 (p / protein :name (n / name :op1 "SUMO-1"))
            :ARG1 (m2 / mutate-01
                  :ARG2 (e / enzyme :name (n2 / name :op1 "HDAC1"))
                  :ARG1-of (i2 / indicate-01))
            :manner (o2 / or
                  :op1 (a / add-02
                        :ARG1 (m3 / mix-01
                              :ARG1 (a2 / assay-01))
                        :mod (p2 / positive))
                  :op2 (a3 / add-02 :polarity -
                        :ARG1 m3
                        :ARG2-of (n3 / negative-01))))
      :manner (i / in-vitro)
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod "1b")))

# ::id bio.chicago_2015.26346 ::date 2015-10-25T12:35:46 ::annotator SDL-AMR-09 ::preferred
# ::snt We therefore examined whether  GSK-3beta,  PKA, and  PP1 bind simultaneously to  AKAP220.
# ::save-date Sun Oct 25, 2015 ::file bio_chicago_2015_26346.txt
(c / cause-01
      :ARG1 (e / examine-01
            :ARG0 (w / we)
            :ARG1 (b / bind-01 :mode interrogative
                  :ARG1 (a / and
                        :op1 (e2 / enzyme :name (n / name :op1 "GSK-3beta"))
                        :op2 (e3 / enzyme :name (n2 / name :op1 "PKA"))
                        :op3 (p / protein :name (n3 / name :op1 "PP1")))
                  :ARG2 (p2 / protein :name (n4 / name :op1 "AKAP220"))
                  :manner (s / simultaneous))))

# ::id bio.chicago_2015.26365 ::date 2015-10-25T12:37:53 ::annotator SDL-AMR-09 ::preferred
# ::snt Activin and TGFbeta also lead to the specific association of  Smad2 and  Smad4 as assessed by co-immunoprecipitation from cultured cells following ligand binding ( 9).
# ::save-date Sun Oct 25, 2015 ::file bio_chicago_2015_26365.txt
(l / lead-03
      :ARG0 (a / and
            :op1 (p / protein :name (n / name :op1 "activin"))
            :op2 (p2 / protein :name (n2 / name :op1 "TGFbeta")))
      :ARG1 (a3 / associate-01
            :ARG1 (p3 / protein :name (n3 / name :op1 "Smad2"))
            :ARG2 (p4 / protein :name (n4 / name :op1 "Smad4"))
            :ARG1-of (s / specific-02))
      :mod (a2 / also)
      :ARG1-of (a4 / assess-01
            :ARG0 (c / coimmunoprecipitate-01
                  :ARG4 (c2 / cell
                        :ARG1-of (c3 / culture-01)))
            :ARG1-of (f / follow-01
                  :ARG2 (b / bind-01
                        :ARG1 (l2 / ligand))))
      :ARG1-of (d / describe-01
            :ARG0 (p5 / publication
                  :ARG1-of (c4 / cite-01
                        :ARG2 9))))

# ::id bio.chicago_2015.26400 ::date 2015-10-25T12:44:46 ::annotator SDL-AMR-09 ::preferred
# ::snt PTB is known to bind to the  CU elements within the 3  splice site upstream of  N1 ( Chan and Black 1995  ).
# ::save-date Mon Nov 9, 2015 ::file bio_chicago_2015_26400.txt
(k / know-01
      :ARG1 (b / bind-01
            :ARG1 (p / protein :name (n / name :op1 "PTB"))
            :ARG2 (e / element
                  :mod (p2 / protein-family :name (n2 / name :op1 "CU")))
            :location (s / site
                  :mod (d2 / distance-quantity :quant 3
                        :unit (s2 / splice))
                  :location (r / relative-position
                        :op1 (e2 / enzyme :name (n3 / name :op1 "N1"))
                        :direction (u / upstream))))
      :ARG1-of (d3 / describe-01
            :ARG0 (p3 / publication-91
                  :ARG0 (a / and
                        :op1 (p4 / person :name (n4 / name :op1 "Chan"))
                        :op2 (p5 / person :name (n5 / name :op1 "Black")))
                  :time (d / date-entity :year 1995))))

# ::id bio.chicago_2015.26414 ::date 2015-10-25T12:50:25 ::annotator SDL-AMR-09 ::preferred
# ::snt However,  PKA-induced  PKB translocation is abolished after pretreatment of the cells with high concentrations (300 nM) of wortmannin, implying that translocation to the cell surface may require the generation of phospholipids.
# ::save-date Tue Jan 19, 2016 ::file bio_chicago_2015_26414.txt
(h / have-concession-91
      :ARG1 (a / abolish-01
            :ARG1 (t / translocate-01
                  :ARG1 (e / enzyme :name (n / name :op1 "PKB"))
                  :ARG2-of (i / induce-01
                        :ARG0 (e2 / enzyme :name (n2 / name :op1 "PKA"))))
            :time (a2 / after
                  :op1 (p / pretreat-01
                        :ARG1 (c / cell)
                        :ARG3 (c2 / concentrate-02
                              :ARG1 (s / small-molecule :name (n3 / name :op1 "wortmannin"))
                              :quant (c3 / concentration-quantity :quant 300
                                    :unit (n4 / nanomolar))
                              :ARG1-of (h2 / high-02))))
            :ARG0-of (i2 / imply-01
                  :ARG1 (p2 / possible-01
                        :ARG1 (r / require-01
                              :ARG0 (t2 / translocate-01
                                    :ARG2 (s2 / surface
                                          :mod (c4 / cell)))
                              :ARG1 (g / generate-01
                                    :ARG1 (p3 / phospholipid)))))))

# ::id bio.chicago_2015.26430 ::date 2015-10-25T12:56:35 ::annotator SDL-AMR-09 ::preferred
# ::snt We have thus examined whether  actin binding of  fascin can be regulated in a calcium-dependent way by controlling  actin binding of  caldesmon with  Ca2+/calmodulin.
# ::save-date Mon Nov 9, 2015 ::file bio_chicago_2015_26430.txt
(c / cause-01
      :ARG1 (e / examine-01
            :ARG0 (w2 / we)
            :ARG1 (p / possible-01
                  :ARG1 (r / regulate-01 :mode interrogative
                        :ARG0 (c3 / control-01
                              :ARG1 (b2 / bind-01
                                    :ARG1 p2
                                    :ARG2 (p4 / protein :name (n3 / name :op1 "caldesmon"))
                                    :ARG3 (s / slash
                                          :op1 (c4 / calcium
                                                :ARG1-of (i / ionize-01 :value "2+"))
                                          :op2 (p5 / protein :name (n4 / name :op1 "calmodulin")))))
                        :ARG1 (b / bind-01
                              :ARG1 (p2 / protein :name (n / name :op1 "actin"))
                              :ARG2 (p3 / protein :name (n2 / name :op1 "fascin")))
                        :manner (w3 / way
                              :ARG0-of (d / depend-01
                                    :ARG1 (c2 / calcium)))))))

# ::id bio.chicago_2015.26440 ::date 2015-10-25T13:07:12 ::annotator SDL-AMR-09 ::preferred
# ::snt Affinity chromatography demonstrates a direct binding between  cytoplasmic dynein and the  dynactin complex.
# ::save-date Sun Oct 25, 2015 ::file bio_chicago_2015_26440.txt
(d / demonstrate-01
      :ARG0 (c / chromatography
            :mod (a / affinity))
      :ARG1 (b / bind-01
            :ARG1 (p / protein :name (n / name :op1 "dynein")
                  :mod (c2 / cytoplasmic))
            :ARG2 (c3 / complex
                  :mod (p2 / protein :name (n2 / name :op1 "dynactin")))
            :ARG1-of (d2 / direct-02)))

# ::id bio.chicago_2015.26449 ::date 2015-10-25T13:09:55 ::annotator SDL-AMR-09 ::preferred
# ::snt In mink lung epithelial  (Mv1Lu) cells,  TNF-alpha-induced  JNK activation and apoptosis were dependent on another upstream kinase,  ASK1, which displayed sequence similarities to upstream kinases in the   S. cerevisiae HOG pathway ( 230).
# ::save-date Sun Oct 25, 2015 ::file bio_chicago_2015_26449.txt
(d / depend-01
      :ARG0 (a / and
            :op1 (a2 / activate-01
                  :ARG1 (e / enzyme :name (n / name :op1 "JNK"))
                  :ARG2-of (i / induce-01
                        :ARG0 (p / protein :name (n2 / name :op1 "TNF-alpha-"))))
            :op2 (a3 / apoptosis))
      :ARG1 (e2 / enzyme :name (n3 / name :op1 "ASK1")
            :mod (k / kinase
                  :mod (a4 / another)
                  :direction (u / upstream)))
      :ARG0-of (d2 / display-01
            :ARG1 (r / resemble-01
                  :ARG1 (s / sequence)
                  :ARG2 (k2 / kinase
                        :direction u))
            :ARG2 (p2 / pathway :name (n4 / name :op1 "S." :op2 "cerevisiae" :op3 "HOG")))
      :ARG1-of (d3 / describe-01
            :ARG0 (p3 / publication
                  :ARG1-of (c / cite-01
                        :ARG2 230)))
      :location (c2 / cell
            :mod (e3 / epithelium)
            :mod (l / lung)
            :mod (m / mink)))

# ::id bio.chicago_2015.26503 ::date 2015-10-25T13:42:56 ::annotator SDL-AMR-09 ::preferred
# ::snt However, the kinetics of their activation were different, i.e.  Cr(VI) activated  p38 faster than  JNK (Figure 3  ).
# ::save-date Wed Jan 20, 2016 ::file bio_chicago_2015_26503.txt
(h / have-concession-91
      :ARG1 (d / differ-02
            :ARG1 (k / kinetic
                  :topic (a / activate-01
                        :ARG1 (t / they)))
            :ARG3 (a2 / activate-01
                  :ARG0 (s / small-molecule :name (n / name :op1 "Cr(VI)"))
                  :ARG1 (e2 / enzyme :name (n2 / name :op1 "p38"))
                  :ARG1-of (f / fast-02
                        :degree (m / more))
                  :compared-to (a3 / activate-01
                        :ARG0 s
                        :ARG1 (e / enzyme :name (n3 / name :op1 "JNK")))))
      :ARG1-of (d2 / describe-01
            :ARG0 (f3 / figure :mod 3)))

# ::id bio.chicago_2015.26513 ::date 2015-10-25T14:04:17 ::annotator SDL-AMR-09 ::preferred
# ::snt Taken together with the finding that mutation of   CREB Ser133 to alanine  blocks PKA stimulation of  CREB-dependent  transcription, it demonstrates that  PKA phosphorylation is required  for  CREB activity.
# ::save-date Thu Nov 26, 2015 ::file bio_chicago_2015_26513.txt
(d / demonstrate-01
      :ARG0 (f / find-01
            :ARG1 (b / block-01
                  :ARG0 (a4 / and
                        :op1 (m / mutate-01
                              :ARG1 (a / amino-acid :mod 133 :name (n4 / name :op1 "serine")
                                    :part-of p2)
                              :ARG2 (a5 / amino-acid :name (n5 / name :op1 "alanine"))))
                  :ARG1 (s / stimulate-01
                        :ARG0 e
                        :ARG1 (t2 / transcribe-01
                              :ARG0-of (d2 / depend-01
                                    :ARG1 p2))))
            :ARG1-of (t / take-01
                  :manner (t3 / together)))
      :ARG1 (r / require-01
            :ARG1 (p / phosphorylate-01
                  :ARG1 (e / enzyme :name (n2 / name :op1 "PKA")))
            :purpose (a2 / activity-06
                  :ARG0 (p2 / protein :name (n3 / name :op1 "CREB")))))

# ::id bio.chicago_2015.26539 ::date 2015-10-25T14:11:35 ::annotator SDL-AMR-09 ::preferred
# ::snt Activation of  JNK,  p38 and  ERK by  Cr(VI)    CL3 cells were treated with 10 - 80  muM Cr(VI) in serum-free medium for 3 h and a whole cell extract prepared to examine activation of  JNK,  p38 and  ERK.
# ::save-date Sun Jan 17, 2016 ::file bio_chicago_2015_26539.txt
(a / and
      :op1 (t / treat-04
            :ARG1 (a2 / activate-01
                  :ARG0 (c / cell-line :name (n5 / name :op1 "CL3")
                        :mod (s / small-molecule :name (n6 / name :op1 "Cr(VI)")))
                  :ARG1 (a3 / and
                        :op1 (e / enzyme :name (n2 / name :op1 "JNK"))
                        :op2 (e5 / enzyme :name (n3 / name :op1 "p38"))
                        :op3 (e2 / enzyme :name (n4 / name :op1 "ERK"))))
            :ARG2 (s2 / small-molecule :name n6
                  :quant (c2 / concentration-quantity
                        :quant (v / value-interval :op1 10 :op2 80)
                        :unit (m / millimolar)))
            :location (m2 / medium
                  :ARG1-of (f / free-04
                        :ARG2 (s3 / serum)))
            :duration (t2 / temporal-quantity :quant 3
                  :unit (h / hour)))
      :op2 (p3 / prepare-02
            :ARG1 (e3 / extract-01
                  :ARG1 (c3 / cell)
                  :mod (w / whole))
            :ARG2 (e4 / examine-01
                  :ARG1 (a4 / activate-01
                        :ARG1 a3))))

# ::id bio.chicago_2015.26566 ::date 2015-10-25T14:22:34 ::annotator SDL-AMR-09 ::preferred
# ::snt Nor is it known whether the amyloid-induced  tau hyperphosphorylation and NFT formation observed recently in  mutant tau transgenic mice   (Gotz et al., 2001  ; Lewis et al., 2001  ) occurs via  tau phosphorylation by  GSK-3  or an alternate pathway.
# ::save-date Sat Feb 13, 2016 ::file bio_chicago_2015_26566.txt
(k / know-01 :polarity -
      :ARG1 (a / and
            :op1 (h / hyperphosphorylate-01
                  :ARG1 (p2 / protein :name (n / name :op1 "tau"))
                  :ARG2-of (i / induce-01
                        :ARG0 (s / small-molecule :name (n2 / name :op1 "amyloid"))))
            :op2 (f / form-01
                  :ARG1 (p10 / protein :name (n3 / name :op1 "NFT")))
            :ARG1-of (o / observe-01
                  :time (r / recent)
                  :location (m3 / mouse
                        :mod (t / transgenic)
                        :mod (p3 / protein :name n
                              :ARG2-of (m4 / mutate-01))))
            :manner (o2 / or
                  :op1 (p / phosphorylate-01
                        :ARG1 p2
                        :ARG2 (e / enzyme :name (n5 / name :op1 "GSK-3")))
                  :op2 (p4 / pathway
                        :ARG1-of (a2 / alternate-01)))
            :ARG1-of (d2 / describe-01
                  :ARG0 (a3 / and
                        :op1 (p5 / publication-91
                              :ARG0 (a4 / and
                                    :op1 (p6 / person :name (n6 / name :op1 "Gotz"))
                                    :op2 (p7 / person
                                          :mod (o3 / other)))
                              :time (d / date-entity :year 2001))
                        :op2 (p8 / publication-91
                              :ARG0 (a5 / and
                                    :op1 (p9 / person :name (n7 / name :op1 "Lewis"))
                                    :op2 p7)
                              :time d)))))

# ::id bio.chicago_2015.34132 ::date 2015-10-25T14:56:00 ::annotator SDL-AMR-09 ::preferred
# ::snt Without Ca2+,  Rho-kinase but not  MLCK can phosphorylate  MLC, and this phosphorylation was completely inhibited by 10 mug/ml HA1077 (lane 3).
# ::save-date Wed Mar 2, 2016 ::file bio_chicago_2015_34132.txt
(p2 / possible-01
      :ARG1 (c / contrast-01
            :ARG1 (p / phosphorylate-01
                  :ARG0 (e / enzyme :name (n / name :op1 "Rho-kinase"))
                  :ARG1 (p3 / protein :name (n2 / name :op1 "MLC"))
                  :manner (c4 / calcium :polarity -
                        :ARG1-of (i2 / ionize-01 :value "2+"))
                  :ARG1-of (i / inhibit-01
                        :ARG0 (s / small-molecule :name (n5 / name :op1 "HA1077")
                              :quant (c3 / concentration-quantity :quant 10
                                    :unit (m / microgram-per-milliliter)))
                        :ARG1-of (c2 / complete-02)))
            :ARG2 (p4 / phosphorylate-01 :polarity -
                  :ARG0 (e2 / enzyme :name (n3 / name :op1 "MLCK"))
                  :ARG1 p3))
      :ARG1-of (d / describe-01
            :ARG0 (l / lane :mod 3)))

# ::id bio.chicago_2015.34134 ::date 2015-10-25T23:54:27 ::annotator SDL-AMR-09 ::preferred
# ::snt The fact that  Rb preferentially associates with specific  E2F target promoters during senescence suggests that it may play a particularly important role in SAHF formation and the silencing of  E2F target promoters.
# ::save-date Sat Feb 13, 2016 ::file bio_chicago_2015_34134.txt
(s / suggest-01
      :ARG0 (f / fact
            :domain (a / associate-01
                  :ARG1 (p / protein :name (n / name :op1 "Rb"))
                  :ARG2 (m2 / molecular-physical-entity
                        :ARG0-of (p3 / promote-01
                              :ARG1 (t2 / target-01
                                    :ARG1 (p7 / protein :name (n2 / name :op1 "E2F"))))
                        :ARG1-of (s4 / specific-02))
                  :ARG1-of (p2 / prefer-01)
                  :time (s2 / senescence)))
      :ARG1 (p4 / possible-01
            :ARG1 (p5 / play-01
                  :ARG0 f
                  :ARG1 (r / role
                        :mod (i / important
                              :mod (p6 / particular))
                        :topic (a2 / and
                              :op1 (f2 / form-01
                                    :ARG1 (f3 / focus
                                          :mod (h / heterochromatin)
                                          :ARG1-of (a3 / associate-01
                                                :ARG2 (s5 / senescence))))
                              :op2 (s3 / silence-01
                                    :ARG1 m2))))))

# ::id bio.chicago_2015.34138 ::date 2015-10-26T00:09:50 ::annotator SDL-AMR-09 ::preferred
# ::snt We report that  arsenite induces rapid phosphorylation and acetylation of  histone H3, events that precede the induction of both c-  fos and c-  jun in normal  human diploid fibroblasts.
# ::save-date Sun Jan 17, 2016 ::file bio_chicago_2015_34138.txt
(r / report-01
      :ARG0 (w / we)
      :ARG1 (i / induce-01
            :ARG0 (s / small-molecule :name (n / name :op1 "arsenite"))
            :ARG2 (a / and
                  :op1 (p / phosphorylate-01
                        :ARG1 (p2 / protein :name (n2 / name :op1 "histone" :op2 "H3"))
                        :mod (r2 / rapid))
                  :op2 (a2 / acetylate-01
                        :ARG1 p2)
                  :ARG1-of (p3 / precede-01
                        :ARG2 (i2 / induce-01
                              :ARG1 (a3 / and
                                    :op1 (p5 / protein :name (n3 / name :op1 "c-fos"))
                                    :op2 (p4 / protein :name (n4 / name :op1 "c-jun")))
                              :location (f / fibroblast
                                    :mod (d2 / diploid)
                                    :ARG1-of (n5 / normal-02)))))))

# ::id bio.chicago_2015.34199 ::date 2015-10-27T04:33:35 ::annotator SDL-AMR-09 ::preferred
# ::snt EGF stimulated the phosphorylation of Ser369 and Ser386 in the  linker of  RSK2, apparently via activation of  ERK and the  CTK, respectively, and both sites contributed to the activation of  RSK2 by  EGF, as evidenced by mutational analysis.
# ::save-date Sun Jan 17, 2016 ::file bio_chicago_2015_34199.txt
(a / and
      :op1 (a5 / and
            :op1 (s / stimulate-01
                  :ARG0 (p2 / protein :name (n2 / name :op1 "EGF"))
                  :ARG1 (p3 / phosphorylate-01
                        :ARG1 (a3 / amino-acid :mod 369 :name (n3 / name :op1 "serine")
                              :part-of (p / protein-segment
                                    :part-of (e / enzyme :name (n5 / name :op1 "RSK2"))
                                    :ARG0-of (l / link-01))))
                  :manner (a2 / activate-01
                        :ARG0 p2
                        :ARG1 (e2 / enzyme :name (n / name :op1 "ERK"))))
            :op2 (s3 / stimulate-01
                  :ARG0 p2
                  :ARG1 (p4 / phosphorylate-01
                        :ARG1 (a4 / amino-acid :mod 386 :name (n4 / name :op1 "serine")
                              :part-of p))
                  :manner (a6 / activate-01
                        :ARG0 p2
                        :ARG1 (e3 / enzyme :name (n6 / name :op1 "CTK"))))
            :ARG1-of (a7 / appear-02)
            :manner (r / respective))
      :op2 (c / contribute-01
            :ARG0 (a8 / and
                  :op1 a3
                  :op2 a4)
            :ARG2 (a9 / activate-01
                  :ARG0 p2
                  :ARG1 e)
            :ARG1-of (e4 / evidence-01
                  :ARG0 (a10 / analyze-01
                        :mod (m / mutate-01)))))

# ::id bio.chicago_2015.34201 ::date 2015-10-27T04:54:30 ::annotator SDL-AMR-09 ::preferred
# ::snt There appear to be multiple mechanisms through  which  p53 promotes apoptosis.
# ::save-date Fri Oct 30, 2015 ::file bio_chicago_2015_34201.txt
(a / appear-02
      :ARG1 (m / mechanism
            :quant (m2 / multiple)
            :manner-of (p / promote-02
                  :ARG0 (p2 / protein :name (n / name :op1 "p53"))
                  :ARG1 (a2 / apoptosis))))

# ::id bio.chicago_2015.34258 ::date 2015-10-27T04:57:08 ::annotator SDL-AMR-09 ::preferred
# ::snt Moreover, we found that  paxillin alpha associates with both the kinase-inactive and the  Cdc42-activated forms of  PAK3  in vivo; and that the  paxillin alpha binding to  PAK3 could be competitive with the betaPIX binding to  PAK3  in vivo and  in vitro.
# ::save-date Sun Jan 17, 2016 ::file bio_chicago_2015_34258.txt
(a / and
      :op2 (f / find-01
            :ARG0 (w / we)
            :ARG1 (a2 / and
                  :op1 (a3 / associate-01
                        :ARG1 (p2 / protein :name (n / name :op1 "paxillin" :op2 "alpha"))
                        :ARG2 (a4 / and
                              :op1 (e / enzyme :name (n2 / name :op1 "PAK3")
                                    :ARG1-of (a5 / activate-01 :polarity -
                                          :mod (k / kinase)))
                              :op2 (e2 / enzyme :name (n3 / name :op1 "PAK3")
                                    :ARG1-of (a6 / activate-01
                                          :ARG0 (p4 / protein :name (n4 / name :op1 "Cdc42")))))
                        :manner (i / in-vivo))
                  :op2 (p / possible-01
                        :ARG1 (c / compete-01
                              :ARG0 (b / bind-01
                                    :ARG1 p2
                                    :ARG2 (e4 / enzyme :name (n6 / name :op1 "PAK3")))
                              :ARG1 (b2 / bind-01
                                    :ARG1 (p3 / protein :name (n5 / name :op1 "betaPIX"))
                                    :ARG2 e4))
                        :manner (a7 / and
                              :op1 i
                              :op2 (i2 / in-vitro))))))

# ::id bio.chicago_2015.34262 ::date 2015-10-27T05:08:30 ::annotator SDL-AMR-09 ::preferred
# ::snt However, our preliminary results indicate that when  paxillin alpha was highly phosphorylated by  PAK3  in vitro, these two phosphorylated proteins could no longer stay bound to each other.
# ::save-date Fri Oct 30, 2015 ::file bio_chicago_2015_34262.txt
(c / contrast-01
      :ARG2 (i / indicate-01
            :ARG0 (t / thing
                  :ARG2-of (r / result-01)
                  :poss (w / we)
                  :mod (p2 / preliminary))
            :ARG1 (p / possible-01
                  :ARG1 (s / stay-01
                        :ARG1 (b / bind-01
                              :ARG1 (p5 / protein :quant 2
                                    :ARG1-of (p6 / phosphorylate-01)
                                    :mod (t2 / this))
                              :ARG2 p5)
                        :time (n / no-longer))
                  :time (p3 / phosphorylate-01
                        :ARG1 (p4 / protein :name (n2 / name :op1 "paxillin" :op2 "alpha"))
                        :ARG2 (e / enzyme :name (n3 / name :op1 "PAK3"))
                        :ARG1-of (h / high-02)
                        :manner (i2 / in-vitro)))))

# ::id bio.chicago_2015.34268 ::date 2015-10-27T05:15:43 ::annotator SDL-AMR-09 ::preferred
# ::snt While it is still unclear how  Rac  downregulates  Rho and to what extent the influence of oncogenic  Ras on  the relative activities of  Rac and  Rho is common to epithelial cells  other than  MDCK cells, it is reasonable to assume that cross-talk between  Ras,  Rac, and   Rho contributes to the morphologic phenotype of  Ras-transformed cells.
# ::save-date Mon Dec 21, 2015 ::file bio_chicago_2015_34268.txt
(c4 / contrast-01
      :ARG1 (c5 / clear-06 :polarity -
            :ARG1 (a3 / and
                  :op1 (t2 / thing
                        :manner-of (d / downregulate-01
                              :ARG1 p2
                              :ARG2 e2))
                  :op2 (t3 / thing
                        :extent-of (c6 / common
                              :domain (i / influence-01
                                    :ARG0 (e / enzyme :name (n2 / name :op1 "Ras")
                                          :ARG0-of (c7 / cause-01
                                                :ARG1 (d2 / disease :wiki "Cancer" :name (n6 / name :op1 "cancer"))))
                                    :ARG1 (a5 / and
                                          :op1 (a6 / act-02
                                                :ARG0 e)
                                          :op2 (a7 / act-02
                                                :ARG0 p2)
                                          :ARG1-of (r2 / relative-05)))
                              :prep-to (c9 / cell
                                    :part-of (e3 / epithelium)
                                    :ARG2-of (e4 / except-01
                                          :ARG1 (c10 / cell :name (n / name :op1 "MDCK")))))))
            :mod (s / still))
      :ARG2 (r / reasonable-02
            :ARG1 (a / assume-02
                  :ARG1 (c / contribute-01
                        :ARG0 (c2 / crosstalk-00
                              :ARG0 (a2 / and
                                    :op1 (e5 / enzyme :name (n5 / name :op1 "Ras"))
                                    :op2 (e2 / enzyme :name (n3 / name :op1 "Rac"))
                                    :op3 (p2 / protein :name (n4 / name :op1 "Rho"))))
                        :ARG2 (p3 / phenotype
                              :mod (m / morphology)
                              :poss (c3 / cell
                                    :ARG1-of (t / transform-01
                                          :ARG0 e5)))))))

# ::id bio.chicago_2015.34272 ::date 2015-10-27T05:34:03 ::annotator SDL-AMR-09 ::preferred
# ::snt Recently, using  GST-binding assays, we demonstrated that  Sox10 can directly interact with  Sp1 and  Sp3 in vitro ( Melnikova et al., 2000).
# ::save-date Fri Oct 30, 2015 ::file bio_chicago_2015_34272.txt
(d2 / demonstrate-01
      :ARG0 (w / we)
      :ARG1 (p / possible-01
            :ARG1 (i / interact-01
                  :ARG0 (p2 / protein :name (n / name :op1 "Sox10"))
                  :ARG1 (a / and
                        :op1 (p3 / protein :name (n2 / name :op1 "Sp1"))
                        :op2 (p4 / protein :name (n3 / name :op1 "Sp3")))
                  :ARG1-of (d3 / direct-02)
                  :manner (i2 / in-vitro)))
      :time (r / recent)
      :manner (u / use-01
            :ARG0 w
            :ARG1 (a2 / assay-01
                  :ARG1 (b / bind-01
                        :ARG1 (e / enzyme :name (n4 / name :op1 "GST")))))
      :ARG1-of (d4 / describe-01
            :ARG0 (p6 / publication-91
                  :ARG0 (a3 / and
                        :op1 (p7 / person :name (n5 / name :op1 "Melnikova"))
                        :op2 (p8 / person
                              :mod (o / other)))
                  :time (d / date-entity :year 2000))))

# ::id bio.chicago_2015.34275 ::date 2015-10-27T05:43:22 ::annotator SDL-AMR-09 ::preferred
# ::snt duplicate  Shc IPs were resolved by 15%  SDS-PAGE and  Grb2 associated with  Shc was visualized by  anti-Grb2 blotting (lanes 5-8).
# ::save-date Thu Dec 17, 2015 ::file bio_chicago_2015_34275.txt
(a / and
      :op1 (r / resolve-01
            :ARG0 (t / thing :name (n2 / name :op1 "SDS-PAGE")
                  :mod (p / percentage-entity :value 15))
            :ARG1 (i / immunoprecipitate-01
                  :ARG1 (p2 / protein :name (n / name :op1 "Shc"))
                  :ARG1-of (d / duplicate-01)))
      :op2 (v / visualize-01
            :ARG1 (a2 / associate-01
                  :ARG1 (p3 / protein :name (n3 / name :op1 "Grb2"))
                  :ARG2 p2)
            :manner (i2 / immunoblot-01
                  :ARG0-of (c / counter-01
                        :ARG1 p3)))
      :ARG1-of (d2 / describe-01
            :ARG0 (l / lane
                  :mod (v2 / value-interval :op1 5 :op2 8))))

# ::id bio.chicago_2015.34279 ::date 2015-10-27T05:51:56 ::annotator SDL-AMR-09 ::preferred
# ::snt Moreover,  c-Src inhibition of  hSlo is enhanced by its  beta1 subunit and switched on by micromolar Ca2+ (>1.5  muM).
# ::save-date Fri Jan 15, 2016 ::file bio_chicago_2015_34279.txt
(a / and
      :op2 (a2 / and
            :op1 (e / enhance-01
                  :ARG0 (p3 / protein-segment :name (n3 / name :op1 "beta1")
                        :part-of e2)
                  :ARG1 (i / inhibit-01
                        :ARG0 (e2 / enzyme :name (n / name :op1 "c-Src"))
                        :ARG1 (p2 / protein :name (n2 / name :op1 "hSlo"))))
            :op2 (s / switch-01
                  :ARG0 (c2 / calcium
                        :quant (m2 / more-than
                              :op1 (c / concentration-quantity :quant 1.5
                                    :unit (m / micromolar)))
                        :mod m
                        :ARG1-of (i2 / ionize-01 :value "2+"))
                  :ARG1 i
                  :ARG2 (o / on))))

# ::id bio.chicago_2015.34309 ::date 2015-10-27T06:01:57 ::annotator SDL-AMR-09 ::preferred
# ::snt Treatment of cells with  IL-1 activates endogenous  TAK1 activity and consequently stimulates the  MAPK cascade and  IKK, leading to the activation of  JNK/ p38 MAPKs and  NF-kappaB, respectively.
# ::save-date Sun Dec 13, 2015 ::file bio_chicago_2015_34309.txt
(a / and
      :op1 (a2 / activate-01
            :ARG0 (t / treat-04
                  :ARG1 (c / cell)
                  :ARG2 (p2 / protein :name (n2 / name :op1 "IL-1")))
            :ARG1 (a3 / act-02
                  :ARG0 (e / enzyme :name (n3 / name :op1 "TAK1")
                        :mod (e2 / endogenous))))
      :op2 (s / stimulate-01
            :ARG0 t
            :ARG1 (a4 / and
                  :op1 (c2 / cascade
                        :mod (p / pathway :name (n / name :op1 "MAPK")))
                  :op2 (e5 / enzyme :name (n4 / name :op1 "IKK")))
            :ARG1-of (c3 / cause-01
                  :ARG0 a2))
      :ARG0-of (l / lead-03
            :ARG2 (a5 / activate-01
                  :ARG1 (a6 / and
                        :op1 (p3 / pathway :name (n5 / name :op1 "JNK/" :op2 "p38" :op3 "MAPK"))
                        :op2 (m / macro-molecular-complex :name (n7 / name :op1 "NF-kappaB"))
                        :manner (r / respective)))))

# ::id bio.chicago_2015.34324 ::date 2015-10-27T06:14:03 ::annotator SDL-AMR-09 ::preferred
# ::snt Using  P19 cells, we show that  BMP7 and  activin bind to the common  type II receptors,  ActRII and  IIB, but recruit different  type I receptors into the  ligand-receptor complex and activate distinct Smad signaling pathways.
# ::save-date Sun Jan 17, 2016 ::file bio_chicago_2015_34324.txt
(s / show-01
      :ARG0 (w / we)
      :ARG1 (c2 / contrast-01
            :ARG1 (b / bind-01
                  :ARG1 (a / and
                        :op1 (p / protein :name (n2 / name :op1 "BMP7"))
                        :op2 (p2 / protein :name (n3 / name :op1 "activin")))
                  :ARG2 (r / receptor
                        :mod (t / type
                              :ord (o / ordinal-entity :value 2))
                        :mod (c3 / common)
                        :ARG1-of (m / mean-01
                              :ARG2 (a2 / and
                                    :op1 (r2 / receptor :name (n4 / name :op1 "ActRII"))
                                    :op2 (r3 / receptor :name (n5 / name :op1 "IIB"))))))
            :ARG2 (a3 / and
                  :op1 (r4 / recruit-01
                        :ARG0 a
                        :ARG1 (r5 / receptor
                              :mod (t2 / type
                                    :ord (o2 / ordinal-entity :value 1))
                              :ARG1-of (d / differ-02))
                        :ARG2 (c4 / complex
                              :part (l2 / ligand)
                              :part (r6 / receptor)))
                  :op2 (a4 / activate-01
                        :ARG0 a
                        :ARG1 (p3 / pathway :name (n6 / name :op1 "Smad")
                              :ARG0-of (s2 / signal-07)
                              :mod (d2 / distinct)))))
      :manner (u / use-01
            :ARG0 w
            :ARG1 (c / cell :name (n / name :op1 "P19"))))

# ::id bio.chicago_2015.34338 ::date 2015-10-27T06:26:33 ::annotator SDL-AMR-09 ::preferred
# ::snt Using  COS cells we demonstrate that, in the absence of ectopically  overexpressed proteins, endogenous  PKB can be activated by cAMP-elevating drugs.
# ::save-date Fri Jan 15, 2016 ::file bio_chicago_2015_34338.txt
(d / demonstrate-01
      :ARG0 (w / we)
      :ARG1 (p / possible-01
            :ARG1 (a / activate-01
                  :ARG0 (d2 / drug
                        :ARG0-of (e3 / elevate-01
                              :ARG1 (s / small-molecule :name (n3 / name :op1 "cAMP"))))
                  :ARG1 (e / enzyme :name (n2 / name :op1 "PKB")
                        :mod (e2 / endogenous)))
            :condition (a2 / absent-01
                  :ARG1 (p2 / protein
                        :ARG1-of (o / overexpress-01
                              :manner (e4 / ectopic)))))
      :manner (u / use-01
            :ARG0 w
            :ARG1 (c / cell-line :name (n / name :op1 "COS"))))

# ::id bio.chicago_2015.34339 ::date 2015-10-27T06:32:51 ::annotator SDL-AMR-09 ::preferred
# ::snt In contrast to a preferential binding to  GTP S-bound Rac,  PlexB  binds to the  GTP S and  GDP-bound forms of  RhoA equally well (  Figure 3B, lanes 3 and 4).
# ::save-date Tue Oct 27, 2015 ::file bio_chicago_2015_34339.txt
(c / contrast-01
      :ARG1 (b2 / bind-01
            :ARG2 (e / enzyme :name (n2 / name :op1 "Rac")
                  :ARG1-of (b3 / bind-01
                        :ARG2 (s2 / small-molecule :name (n3 / name :op1 "GTP" :op2 "S"))))
            :ARG1-of (p / prefer-01))
      :ARG2 (b / bind-01
            :ARG1 (p2 / protein :name (n4 / name :op1 "PlexB"))
            :ARG2 (a / and
                  :op1 (p3 / protein :name (n5 / name :op1 "RhoA")
                        :ARG1-of b3)
                  :op2 (p4 / protein :name (n6 / name :op1 "RhoA")
                        :ARG1-of (b4 / bind-01
                              :ARG2 (s3 / small-molecule :name (n7 / name :op1 "GDP")))))
            :ARG1-of (w / well-09
                  :ARG1-of (e2 / equal-01)))
      :ARG1-of (d / describe-01
            :ARG0 (a2 / and
                  :op1 (l / lane :mod 3)
                  :op2 (l2 / lane :mod 4)
                  :part-of (f / figure :mod "3B"))))

# ::id bio.chicago_2015.34385 ::date 2015-10-27T06:34:53 ::annotator SDL-AMR-09 ::preferred
# ::snt ( B)  Heat shock induction of one  GAL4 - HP1 transgene results in variegation.
# ::save-date Fri Oct 30, 2015 ::file bio_chicago_2015_34385.txt
(r / result-01 :li "B"
      :ARG1 (i / induce-01
            :ARG0 (s / shock-01
                  :ARG0 (h / heat))
            :ARG2 (t / transgene :quant 1 :name (n / name :op1 "GAL4-HP1")))
      :ARG2 (v / variegation))

# ::id bio.chicago_2015.34424 ::date 2015-10-27T06:57:22 ::annotator SDL-AMR-09 ::preferred
# ::snt The binding sites on  EVL for  profilin,  WW domains, and  SH3 domains overlap, and several of these interactions are selectively modulated by  PKA phosphorylation of  EVL.
# ::save-date Tue Oct 27, 2015 ::file bio_chicago_2015_34424.txt
(a / and
      :op1 (o / overlap-01
            :ARG0 (a2 / and
                  :op1 (s / site
                        :location-of (b / bind-01
                              :ARG2 (p2 / protein :name (n / name :op1 "profilin"))))
                  :op2 (s2 / site
                        :location-of (b2 / bind-01
                              :ARG2 (p4 / protein-segment :name (n3 / name :op1 "WW"))))
                  :op3 (s3 / site
                        :location-of (b3 / bind-01
                              :ARG2 (p5 / protein-segment :name (n4 / name :op1 "SH3"))))
                  :part-of (p3 / protein :name (n2 / name :op1 "EVL"))))
      :op2 (m / modulate-01
            :ARG0 (p / phosphorylate-01
                  :ARG1 p3
                  :ARG2 (e / enzyme :name (n5 / name :op1 "PKA")))
            :ARG1 (i / interact-01
                  :quant (s5 / several)
                  :mod (t / this))
            :manner (s4 / selective)))

# ::id bio.chicago_2015.34435 ::date 2015-10-27T07:08:06 ::annotator SDL-AMR-09 ::preferred
# ::snt Those studies also suggested that we could create competition between the binding of  HSF and a  histone H2A-H2B dimer by rotating the  HSF binding determinants so that they face into the  histone octamer.
# ::save-date Fri Oct 30, 2015 ::file bio_chicago_2015_34435.txt
(s / suggest-01
      :ARG0 (s2 / study-01
            :mod (t / that))
      :ARG1 (p2 / possible-01
            :ARG1 (c / create-01
                  :ARG0 (w / we)
                  :ARG1 (c2 / compete-01
                        :ARG0 (b / bind-01
                              :ARG1 (p / protein :name (n / name :op1 "HSF")))
                        :ARG1 (d2 / dimer
                              :part (p3 / protein :name (n2 / name :op1 "histone" :op2 "H2A"))
                              :part (p4 / protein :name (n3 / name :op1 "histone" :op2 "H2B"))))
                  :manner (r / rotate-01
                        :ARG0 w
                        :ARG1 (m3 / molecular-physical-entity
                              :ARG0-of (d / determine-01
                                    :ARG1 (b2 / bind-01
                                          :ARG1 p)))
                        :purpose (f / face-01
                              :ARG0 m3
                              :ARG1 (m2 / macro-molecular-complex :name (n4 / name :op1 "histone" :op2 "octamer"))))))
      :mod (a / also))

# ::id bio.chicago_2015.34462 ::date 2015-10-27T07:18:44 ::annotator SDL-AMR-09 ::preferred
# ::snt Inhibition of  calcineurin activity by  CsA suppresses biochemical markers of differentiation, as well as  p21 WAF1/CIP1 and  p27KIP1 expression.
# ::save-date Wed Jan 13, 2016 ::file bio_chicago_2015_34462.txt
(s / suppress-01
      :ARG0 (i / inhibit-01
            :ARG0 (s2 / small-molecule :name (n2 / name :op1 "CsA"))
            :ARG1 (a / activity-06
                  :ARG0 (e2 / enzyme :name (n / name :op1 "calcineurin"))))
      :ARG1 (a2 / and
            :op1 (m / marker
                  :mod (b / biochemistry)
                  :mod (d / differentiate-01))
            :op2 (e / express-03
                  :ARG2 (a3 / and
                        :op1 (p2 / protein :name (n3 / name :op1 "p21" :op2 "WAF1/CIP1"))
                        :op2 (p3 / protein :name (n4 / name :op1 "p27KIP1"))))))

# ::id bio.chicago_2015.34464 ::date 2015-10-27T07:24:53 ::annotator SDL-AMR-09 ::preferred
# ::snt Our finding that  arsenite induces  histone H3 phosphorylation-acetylation may provide additional insight into the mechanisms for both the carcinogenic properties and the therapeutic effects of  arsenite.
# ::save-date Tue Oct 27, 2015 ::file bio_chicago_2015_34464.txt
(p / possible-01
      :ARG1 (p2 / provide-01
            :ARG0 (t / thing
                  :poss (w / we)
                  :ARG1-of (f / find-01)
                  :topic (i / induce-01
                        :ARG0 (s / small-molecule :name (n / name :op1 "arsenite"))
                        :ARG2 (a / and
                              :op1 (p3 / phosphorylate-01
                                    :ARG1 (p4 / protein :name (n2 / name :op1 "histone" :op2 "H3")))
                              :op2 (a2 / acetylate-01
                                    :ARG1 p4))))
            :ARG1 (i2 / insight
                  :mod (a3 / additional)
                  :topic (a4 / and
                        :op1 (m2 / mechanism
                              :mod (p5 / property
                                    :ARG0-of (c / cause-01
                                          :ARG1 (c2 / carcinoma))
                                    :poss s))
                        :op2 (m3 / mechanism
                              :mod (a5 / affect-01
                                    :ARG0 s
                                    :mod (t2 / therapy)))))))

# ::id bio.chicago_2015.34540 ::date 2015-10-27T07:31:44 ::annotator SDL-AMR-09 ::preferred
# ::snt However, it should be noted that the amounts of  vinculin as well as  talin that bound to  paxillin were quite low, compared with  Fak binding to  paxillin (see Fig.  3).
# ::save-date Sun Jan 17, 2016 ::file bio_chicago_2015_34540.txt
(h / have-concession-91
      :ARG1 (r / recommend-01
            :ARG1 (n / note-01
                  :ARG1 (l / low-04
                        :ARG1 (a / and
                              :op1 (a2 / amount
                                    :quant-of (p / protein :name (n2 / name :op1 "vinculin")))
                              :op2 (a3 / amount
                                    :quant-of (p2 / protein :name (n3 / name :op1 "talin")))
                              :ARG1-of (b / bind-01
                                    :ARG2 (p3 / protein :name (n4 / name :op1 "paxillin"))))
                        :mod (q / quite)
                        :compared-to (b2 / bind-01
                              :ARG1 (e / enzyme :name (n5 / name :op1 "Fak"))
                              :ARG2 p3))))
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod 3
                  :ARG1-of (s / see-01 :mode imperative
                        :ARG0 (y / you)))))

# ::id bio.chicago_2015.34551 ::date 2015-10-27T07:37:18 ::annotator SDL-AMR-09 ::preferred
# ::snt Mitochondrially targeted expression of  ActA largely simulates the initial phase of  actin recruitment, namely the formation of  actin clouds, which normally occurs around intracytoplasmic   Listeria.
# ::save-date Fri Oct 30, 2015 ::file bio_chicago_2015_34551.txt
(s / simulate-01
      :ARG0 (e / express-03
            :ARG2 (p / protein :name (n / name :op1 "ActA"))
            :ARG3 (m / mitochondrion)
            :ARG1-of (t / target-01))
      :ARG1 (p2 / phase
            :mod (i / initial)
            :subevent-of (r / recruit-01
                  :ARG1 (p3 / protein :name (n2 / name :op1 "actin")))
            :ARG1-of (m2 / mean-01
                  :ARG2 (f / form-01
                        :ARG1 (c / cloud
                              :consist-of p3)
                        :location (a / around
                              :op1 (o2 / organism :name (n4 / name :op1 "Listeria")
                                    :mod (i2 / intracytoplasmic))
                              :ARG1-of (n3 / normal-02)))))
      :degree (l / large))

# ::id bio.chicago_2015.34559 ::date 2015-10-27T07:44:33 ::annotator SDL-AMR-09 ::preferred
# ::snt We also analyzed functions of the specific phosphorylation  of  GFAP by  Rho-kinase during cytokinesis.
# ::save-date Sun Jan 17, 2016 ::file bio_chicago_2015_34559.txt
(a / analyze-01
      :ARG0 (w / we)
      :ARG1 (f / function-01
            :ARG0 (p / phosphorylate-01
                  :ARG1 (p2 / protein :name (n / name :op1 "GFAP"))
                  :ARG2 (e / enzyme :name (n2 / name :op1 "Rho-kinase"))
                  :ARG1-of (s / specific-02))
            :time (c / cytokinesis))
      :mod (a2 / also))

# ::id bio.chicago_2015.34560 ::date 2015-10-27T07:47:04 ::annotator SDL-AMR-09 ::preferred
# ::snt Thus, the association of  TFIIA with  TBP is an excellent candidate for regulation by posttranslational modification.
# ::save-date Thu Mar 3, 2016 ::file bio_chicago_2015_34560.txt
(i / infer-01
      :ARG1 (c / candidate
            :ARG0-of (e / excel-01
                  :ARG1 (r / regulate-01
                        :ARG0 (m / modify-01
                              :time (a2 / after
                                    :op1 (t / translate-02)))))
            :domain (a / associate-01
                  :ARG1 (p / protein :name (n / name :op1 "TFIIA"))
                  :ARG2 (p2 / protein :name (n2 / name :op1 "TBP")))))

# ::id bio.chicago_2015.34581 ::date 2015-10-27T07:50:31 ::annotator SDL-AMR-09 ::preferred
# ::snt Snail represses   sim in the mesoderm, and thereby restricts expression to lateral regions that form the mesectoderm (Kasai et al., 1992  ; Kasai et al., 1998  ; Nibu et al., 1998  ).
# ::save-date Thu Jan 14, 2016 ::file bio_chicago_2015_34581.txt
(a / and
      :op1 (r / repress-01
            :ARG0 (p7 / protein :name (n / name :op1 "Snail"))
            :ARG1 (g / gene :name (n2 / name :op1 "sim"))
            :location (m / mesoderm))
      :op2 (r2 / restrict-01
            :ARG0 p7
            :ARG1 (e2 / express-03
                  :ARG1 g)
            :ARG2 (r3 / region
                  :mod (l / lateral)
                  :ARG0-of (f / form-01
                        :ARG1 (m2 / mesectoderm)))
            :manner (t / thereby))
      :ARG1-of (d3 / describe-01
            :ARG0 (a2 / and
                  :op1 (p / publication-91
                        :ARG0 (a3 / and
                              :op1 (p2 / person :name (n3 / name :op1 "Kasai"))
                              :op2 (p3 / person
                                    :mod (o / other)))
                        :time (d / date-entity :year 1992))
                  :op2 (p4 / publication-91
                        :ARG0 a3
                        :time (d2 / date-entity :year 1998))
                  :op3 (p5 / publication-91
                        :ARG0 (a4 / and
                              :op1 (p6 / person :name (n4 / name :op1 "Nibu"))
                              :op2 p3)
                        :time d2))))

# ::id bio.chicago_2015.34679 ::date 2015-10-27T07:57:53 ::annotator SDL-AMR-09 ::preferred
# ::snt GRB2 Becomes Associated with  RasGAP and  Shc, in Lateral Amygdala, following Fear Conditioning
# ::save-date Tue Oct 27, 2015 ::file bio_chicago_2015_34679.txt
(b / become-01
      :ARG1 (p / protein :name (n / name :op1 "GRB2"))
      :ARG2 (a / associate-01
            :ARG1 p
            :ARG2 (a2 / and
                  :op1 (p2 / protein :name (n2 / name :op1 "RasGAP"))
                  :op2 (p3 / protein :name (n3 / name :op1 "Shc"))))
      :location (a3 / amygdala
            :mod (l / lateral))
      :ARG1-of (f / follow-01
            :ARG2 (c / condition-01
                  :ARG0 (f2 / fear))))

# ::id bio.chicago_2015.34680 ::date 2015-10-27T08:01:42 ::annotator SDL-AMR-09 ::preferred
# ::snt We use signal  transduction inhibitors and  ES cells lacking  p90RSK activity and  ES cells deficient in  MSK1 to demonstrate that phosphorylation of  LKB1 induced by  EGF and  TPA is likely to be mediated by  p90RSK rather than by  MSK1 or  S6K1 and that phosphorylation of  LKB1 induced by forskolin is mediated by  PKA.
# ::save-date Sun Jan 17, 2016 ::file bio_chicago_2015_34680.txt
(u / use-01
      :ARG0 (w / we)
      :ARG1 (a / and
            :op1 (s / small-molecule :name (n / name :op1 "signal" :op2 "transduction" :op3 "inhibitor"))
            :op2 (c / cell :name (n2 / name :op1 "ES")
                  :ARG0-of (l / lack-01
                        :ARG1 (a2 / act-02
                              :ARG0 (e / enzyme :name (n3 / name :op1 "p90RSK")))))
            :op3 (c2 / cell :name (n4 / name :op1 "ES")
                  :ARG0-of (l2 / lack-01
                        :ARG1 (e2 / enzyme :name (n5 / name :op1 "MSK1")))))
      :ARG2 (d2 / demonstrate-01
            :ARG0 w
            :ARG1 (a4 / and
                  :op1 (l3 / likely-01
                        :ARG1 (m / mediate-01
                              :ARG0 e
                              :ARG1 (p / phosphorylate-01
                                    :ARG1 (e3 / enzyme :name (n6 / name :op1 "LKB1"))
                                    :ARG2-of (i2 / induce-01
                                          :ARG0 (a3 / and
                                                :op1 (p3 / protein :name (n7 / name :op1 "EGF"))
                                                :op2 (s3 / small-molecule :name (n8 / name :op1 "TPA")))))
                              :ARG1-of (i3 / instead-of-91
                                    :ARG2 (m2 / mediate-01
                                          :ARG0 (o / or
                                                :op1 e2
                                                :op2 (e4 / enzyme :name (n9 / name :op1 "S6K1")))
                                          :ARG1 p))))
                  :op2 (m3 / mediate-01
                        :ARG0 (e5 / enzyme :name (n11 / name :op1 "PKA"))
                        :ARG1 (p2 / phosphorylate-01
                              :ARG1 e3
                              :ARG2-of (i4 / induce-01
                                    :ARG0 (s4 / small-molecule :name (n10 / name :op1 "forskolin"))))))))

# ::id bio.chicago_2015.34743 ::date 2015-10-27T08:13:58 ::annotator SDL-AMR-09 ::preferred
# ::snt (C) EMSAs of the  SMA promoter show that  CRP2 and  GATA4 recruited by  SRF vastly increased cooperative  SRF DNA binding affinity.
# ::save-date Fri Jan 15, 2016 ::file bio_chicago_2015_34743.txt
(s / show-01 :li "C"
      :ARG0 (t / thing :name (n / name :op1 "EMSA")
            :mod (p / protein :name (n2 / name :op1 "SMA")
                  :ARG0-of (p2 / promote-01)))
      :ARG1 (i / increase-01
            :ARG0 (a / and
                  :op1 (p3 / protein :name (n3 / name :op1 "CRP2"))
                  :op2 (p4 / protein :name (n4 / name :op1 "GATA4"))
                  :ARG1-of (r / recruit-01
                        :ARG0 (p5 / protein :name (n5 / name :op1 "SRF"))))
            :ARG1 (a2 / affinity
                  :mod (b / bind-01
                        :ARG1 p5
                        :ARG2 (n6 / nucleic-acid :name (n7 / name :op1 "DNA"))
                        :mod (c / cooperate-01)))
            :ARG2 (v / vast)))

# ::id bio.chicago_2015.34745 ::date 2015-10-27T08:24:22 ::annotator SDL-AMR-09 ::preferred
# ::snt Because  CsA inhibits  calcineurin, this finding implicated the calcium-calmodulin dependent  phosphatase as an essential regulator of chondrogenesis, even in  the absence of the calcium ionophore.
# ::save-date Tue Oct 27, 2015 ::file bio_chicago_2015_34745.txt
(i / implicate-01
      :ARG0 (t / thing
            :ARG1-of (f / find-01)
            :mod (t2 / this))
      :ARG1 (e / enzyme :name (n / name :op1 "calcium-calmodulin" :op2 "dependent" :op3 "phosphatase"))
      :ARG2 (r2 / regulate-01
            :ARG0 e
            :ARG1 (c / chondrogenesis)
            :mod (e2 / essential))
      :concession (a / absent-01
            :ARG1 (s / small-molecule :name (n2 / name :op1 "calcium" :op2 "ionophore")))
      :ARG1-of (c2 / cause-01
            :ARG0 (i2 / inhibit-01
                  :ARG0 (s2 / small-molecule :name (n3 / name :op1 "CsA"))
                  :ARG1 (e3 / enzyme :name (n4 / name :op1 "calcineurin")))))

# ::id bio.chicago_2015.34748 ::date 2015-10-27T08:34:15 ::annotator SDL-AMR-09 ::preferred
# ::snt In the absence of stimulation, basal  Tyr phosphorylation of  Fus3 is governed by the balance between autophosphorylation by the kinase and dephosphorylation by  Ptp3 phosphatase.
# ::save-date Fri Oct 30, 2015 ::file bio_chicago_2015_34748.txt
(g / govern-01
      :ARG0 (b2 / balance-01
            :ARG1 (p3 / phosphorylate-01
                  :ARG1 k
                  :ARG2 (k / kinase))
            :ARG2 (d / dephosphorylate-01
                  :ARG2 (e / enzyme :name (n3 / name :op1 "Ptp3" :op2 "phosphatase"))))
      :ARG1 (p / phosphorylate-01
            :ARG1 (a / amino-acid :name (n / name :op1 "tyrosine")
                  :part-of (p2 / protein :name (n2 / name :op1 "Fus3")))
            :mod (b / basal))
      :condition (a3 / absent-01
            :ARG1 (s / stimulate-01)))

# ::id bio.chicago_2015.34764 ::date 2015-10-27T08:42:08 ::annotator SDL-AMR-09 ::preferred
# ::snt R62C Defines a  Novel Rab Mutation   utations that have previously been studied for  rab6 are those engineered based on the  GTP- and  GDP-bound forms of  ras-like molecules.
# ::save-date Fri Nov 27, 2015 ::file bio_chicago_2015_34764.txt
(m / multi-sentence
      :snt1 (d / define-01
            :ARG0 (m6 / mutate-01
                  :ARG1 (a2 / amino-acid :mod 62 :name (n7 / name :op1 "arginine"))
                  :ARG2 (a3 / amino-acid :name (n8 / name :op1 "cysteine")))
            :ARG1 (m2 / mutate-01
                  :ARG1 (p / protein :name (n2 / name :op1 "Rab"))
                  :mod (n3 / novel)))
      :snt2 (m3 / mutate-01
            :ARG1 (p4 / protein :name (n6 / name :op1 "Rab6"))
            :ARG1-of (s2 / study-01
                  :time (p2 / previous))
            :domain (m7 / mutate-01
                  :ARG1-of (e / engineer-01
                        :ARG1-of (b / base-02
                              :ARG2 (a / and
                                    :op1 (m4 / molecule
                                          :ARG1-of (r2 / resemble-01
                                                :ARG2 (e2 / enzyme :name (n4 / name :op1 "Ras")))
                                          :ARG1-of (b2 / bind-01
                                                :ARG2 (s / small-molecule :name (n / name :op1 "GTP"))))
                                    :op2 (m5 / molecule
                                          :ARG1-of r2
                                          :ARG1-of (b3 / bind-01
                                                :ARG2 (s3 / small-molecule :name (n5 / name :op1 "GDP"))))))))))

# ::id bio.chicago_2015.34874 ::date 2015-10-27T10:01:42 ::annotator SDL-AMR-09 ::preferred
# ::snt Indeed, our results demonstrate that  YY1 was acetylated by both  p300 and  PCAF and was deacetylated by  HDAC1 and  HDAC2.
# ::save-date Tue Oct 27, 2015 ::file bio_chicago_2015_34874.txt
(d / demonstrate-01
      :ARG0 (t / thing
            :poss (w / we)
            :ARG2-of (r / result-01))
      :ARG1 (a / and
            :op1 (a2 / acetylate-01
                  :ARG1 (p / protein :name (n / name :op1 "YY1"))
                  :ARG2 (a3 / and
                        :op1 (p2 / protein :name (n2 / name :op1 "p300"))
                        :op2 (p3 / protein :name (n3 / name :op1 "PCAF"))))
            :op2 (d2 / deacetylate-01
                  :ARG1 p
                  :ARG2 (a4 / and
                        :op1 (e / enzyme :name (n4 / name :op1 "HDAC1"))
                        :op2 (e2 / enzyme :name (n5 / name :op1 "HDAC2")))))
      :mod (i / indeed))

# ::id bio.chicago_2015.34888 ::date 2015-10-27T10:05:39 ::annotator SDL-AMR-09 ::preferred
# ::snt Oxidative stress differentially modulates phosphorylation of  ERK,  p38 and  CREB induced by  NGF or  EGF in PC12 cells.
# ::save-date Sun Jan 17, 2016 ::file bio_chicago_2015_34888.txt
(m / modulate-01
      :ARG0 (s / stress-02
            :ARG0 (o / oxidize-01))
      :ARG1 (a / and
            :op1 (p / phosphorylate-01
                  :ARG1 (e / enzyme :name (n / name :op1 "ERK")))
            :op2 (p2 / phosphorylate-01
                  :ARG1 (e2 / enzyme :name (n2 / name :op1 "p38")))
            :op3 (p3 / phosphorylate-01
                  :ARG1 (p5 / protein :name (n3 / name :op1 "CREB")))
            :ARG2-of (i / induce-01
                  :ARG0 (o2 / or
                        :op1 (p6 / protein :name (n4 / name :op1 "NGF"))
                        :op2 (p4 / protein :name (n5 / name :op1 "EGF")))))
      :manner (d / differential)
      :location (c / cell-line :name (n6 / name :op1 "PC12")))

# ::id bio.chicago_2015.34920 ::date 2015-10-27T10:10:51 ::annotator SDL-AMR-09 ::preferred
# ::snt Cross Talk between  ERK and  PKA Is Required for Ca2+ Stimulation of  CREB-Dependent Transcription and  ERK Nuclear Translocation.
# ::save-date Sun Jan 17, 2016 ::file bio_chicago_2015_34920.txt
(r / require-01
      :ARG0 (s / stimulate-01
            :ARG0 (c2 / calcium
                  :ARG1-of (i / ionize-01 :value "2+"))
            :ARG1 (a3 / and
                  :op1 (t / transcribe-01
                        :ARG0-of (d / depend-01
                              :ARG1 (p / protein :name (n5 / name :op1 "CREB"))))
                  :op2 (t2 / translocate-01
                        :ARG1 e
                        :ARG2 (n6 / nucleus))))
      :ARG1 (c / crosstalk-00
            :ARG1 (a / and
                  :op1 (e / enzyme :name (n2 / name :op1 "ERK"))
                  :op2 (e2 / enzyme :name (n3 / name :op1 "PKA")))))

# ::id bio.chicago_2015.34944 ::date 2015-10-27T10:15:31 ::annotator SDL-AMR-09 ::preferred
# ::snt It is conceivable  that  alpha-adducin phosphorylated by  PKC dissociates from  a  spectrin-F-actin meshwork during membrane ruffling.
# ::save-date Tue Oct 27, 2015 ::file bio_chicago_2015_34944.txt
(p / possible-01
      :ARG1 (c / conceive-01
            :ARG1 (d / dissociate-01
                  :ARG1 (p2 / protein :name (n / name :op1 "alpha-adducin")
                        :ARG1-of (p3 / phosphorylate-01
                              :ARG2 (e / enzyme :name (n2 / name :op1 "PKC"))))
                  :ARG2 (m / meshwork
                        :consist-of (a / and
                              :op1 (p4 / protein :name (n3 / name :op1 "spectrin"))
                              :op2 (p5 / protein :name (n4 / name :op1 "F-actin"))))
                  :time (r / ruffle-02
                        :ARG1 (m2 / membrane)))))

# ::id bio.chicago_2015.34963 ::date 2015-10-27T10:21:01 ::annotator SDL-AMR-09 ::preferred
# ::snt Since many of the inflammatory cytokines are produced by macrophages upon activation by  LPS, a potent activator of the  p38 MAPK pathway,  LPS-activated  p38 MAPK activity in  MKK3-deficient macrophages was studied.
# ::save-date Sun Jan 17, 2016 ::file bio_chicago_2015_34963.txt
(s / study-01
      :ARG1 (a2 / act-02
            :ARG0 (p2 / pathway :name (n2 / name :op1 "p38" :op2 "MAPK"))
            :ARG1-of (a3 / activate-01
                  :ARG0 m4)
            :location (m / macrophage
                  :ARG0-of (l / lack-01
                        :ARG1 (e / enzyme :name (n4 / name :op1 "MKK3")))))
      :ARG1-of (c / cause-01
            :ARG0 (p3 / produce-01
                  :ARG0 (m3 / macrophage)
                  :ARG1 (p4 / protein :name (n5 / name :op1 "cytokines")
                        :quant (m2 / many)
                        :ARG0-of (i / inflame-01))
                  :time (a4 / activate-01
                        :ARG0 (m4 / molecular-physical-entity :name (n3 / name :op1 "LPS")
                              :mod (p5 / potent)
                              :ARG0-of (a5 / activate-01
                                    :ARG1 p2))
                        :ARG1 m3))))

# ::id bio.chicago_2015.34991 ::date 2015-10-27T10:31:37 ::annotator SDL-AMR-09 ::preferred
# ::snt Stimulation of  PKC by  phorbol esters or  Gq-coupled receptors results in activation of  Pyk2 ( 35,  38,  39,  46).
# ::save-date Sun Jan 17, 2016 ::file bio_chicago_2015_34991.txt
(r / result-01
      :ARG1 (s / stimulate-01
            :ARG0 (o / or
                  :op1 (e3 / ester
                        :mod (s3 / small-molecule :name (n5 / name :op1 "phorbol")))
                  :op2 (p2 / protein :name (n3 / name :op1 "Gq-coupled" :op2 "receptor")))
            :ARG1 (e / enzyme :name (n / name :op1 "PKC")))
      :ARG2 (a / activate-01
            :ARG1 (e2 / enzyme :name (n4 / name :op1 "Pyk2")))
      :ARG1-of (d / describe-01
            :ARG0 (a2 / and
                  :op1 (p3 / publication
                        :ARG1-of (c / cite-01
                              :ARG2 35))
                  :op2 (p4 / publication
                        :ARG1-of (c2 / cite-01
                              :ARG2 38))
                  :op3 (p5 / publication
                        :ARG1-of (c3 / cite-01
                              :ARG2 39))
                  :op4 (p6 / publication
                        :ARG1-of (c4 / cite-01
                              :ARG2 46)))))

# ::id bio.chicago_2015.34994 ::date 2015-10-27T10:36:43 ::annotator SDL-AMR-09 ::preferred
# ::snt These data indicate that the interactions of  Gab1 with  SHP-2 and PI-3 kinase are not simply mediated by interactions between phosphotyrosines and  SH2 domains.
# ::save-date Tue Oct 27, 2015 ::file bio_chicago_2015_34994.txt
(i / indicate-01
      :ARG0 (d / data
            :mod (t / this))
      :ARG1 (m / mediate-01 :polarity -
            :ARG0 (i3 / interact-01
                  :ARG0 (a2 / amino-acid :name (n4 / name :op1 "tyrosine")
                        :ARG1-of (p2 / phosphorylate-01))
                  :ARG1 (p5 / protein-segment :name (n7 / name :op1 "SH2" :op2 "domain")))
            :ARG1 (i2 / interact-01
                  :ARG0 (p / protein :name (n / name :op1 "Gab1"))
                  :ARG1 (a / and
                        :op1 (k / kinase :name (n2 / name :op1 "SHP-2"))
                        :op2 (k2 / kinase :name (n3 / name :op1 "PI-3"))))
            :ARG1-of (s / simple-02)))

# ::id bio.chicago_2015.34997 ::date 2015-10-27T10:40:48 ::annotator SDL-AMR-09 ::preferred
# ::snt First,  Rabaptin-5 binds directly to the  GTP-bound form of  Rab5 and is recruited to early endosomes by  Rab5 in a  GTP-dependent manner (Stenmark  et al., 1995b).
# ::save-date Fri Jan 15, 2016 ::file bio_chicago_2015_34997.txt
(a / and
      :op1 (b / bind-01
            :ARG1 (p4 / protein :name (n / name :op1 "Rabaptin-5"))
            :ARG2 (p5 / protein :name (n2 / name :op1 "Rab5")
                  :ARG1-of (b2 / bind-01
                        :ARG2 (s / small-molecule :name (n3 / name :op1 "GTP"))))
            :ARG1-of (d2 / direct-02))
      :op2 (r / recruit-01
            :ARG0 p5
            :ARG1 p4
            :ARG2 (e3 / endosome
                  :mod (e4 / early))
            :manner (d3 / depend-01
                  :ARG0 r
                  :ARG1 s))
      :time (f / first)
      :ARG1-of (d4 / describe-01
            :ARG0 (p / publication-91
                  :ARG0 (a2 / and
                        :op1 (p2 / person :name (n4 / name :op1 "Stenmark"))
                        :op2 (p3 / person
                              :mod (o2 / other)))
                  :time (d / date-entity :year 1995))))

# ::id bio.chicago_2015.35041 ::date 2015-10-27T10:47:30 ::annotator SDL-AMR-09 ::preferred
# ::snt Since  alpha-catenin binds to  actin, ARM (or  beta-catenin) establishes a bridge between  cadherins and the  actin cytoskeleton, a bridge that is needed for proper cell adhesion ( K EMLER 1993   ;   C OX et al. 1996   ).
# ::save-date Sun Jan 17, 2016 ::file bio_chicago_2015_35041.txt
(e / establish-01
      :ARG0 (o / or
            :op1 (p / protein-segment :name (n / name :op1 "ARM"))
            :op2 (p2 / protein :name (n2 / name :op1 "beta-catenin")))
      :ARG1 (b / bridge
            :location (b2 / between
                  :op1 (p3 / protein-family :name (n3 / name :op1 "cadherin"))
                  :op2 (c / cytoskeleton
                        :mod (p4 / protein :name (n4 / name :op1 "actin"))))
            :ARG1-of (n5 / need-01
                  :ARG0 (a / adhere-01
                        :ARG1 (c2 / cell)
                        :mod (p5 / proper))))
      :ARG1-of (c3 / cause-01
            :ARG0 (b3 / bind-01
                  :ARG1 (p6 / protein :name (n6 / name :op1 "alpha-catenin"))
                  :ARG2 p4))
      :ARG1-of (d3 / describe-01
            :ARG0 (a2 / and
                  :op1 (p7 / publication-91
                        :ARG0 (p8 / person :name (n7 / name :op1 "Kemler"))
                        :time (d / date-entity :year 1993))
                  :op2 (p9 / publication-91
                        :ARG0 (a3 / and
                              :op1 (p10 / person :name (n8 / name :op1 "Cox"))
                              :op2 (p11 / person
                                    :mod (o2 / other)))
                        :time (d2 / date-entity :year 1996)))))

# ::id bio.chicago_2015.35048 ::date 2015-10-27T11:07:57 ::annotator SDL-AMR-09 ::preferred
# ::snt It previously has been shown that  GSK3beta can phosphorylate  APC in vitro (Rubinfeld et al., 1996  ), that  Axin promotes  this event (Hart et al., 1998  ), and that this phosphorylation  enhances the ability of  APC to bind to  beta-catenin (Rubinfeld et al., 1996  ).
# ::save-date Wed Oct 28, 2015 ::file bio_chicago_2015_35048.txt
(s / show-01
      :ARG1 (a / and
            :op1 (p3 / possible-01
                  :ARG1 (p / phosphorylate-01
                        :ARG1 (p4 / protein :name (n2 / name :op1 "APC"))
                        :ARG2 (e / enzyme :name (n / name :op1 "GSK3" :op2 "beta"))
                        :manner (i / in-vitro))
                  :ARG1-of (d3 / describe-01
                        :ARG0 (p5 / publication-91
                              :ARG0 (a2 / and
                                    :op1 (p6 / person :name (n3 / name :op1 "Rubinfeld"))
                                    :op2 (p7 / person
                                          :mod (o / other)))
                              :time (d / date-entity :year 1996))))
            :op2 (p8 / promote-02
                  :ARG0 (p9 / protein :name (n4 / name :op1 "Axin"))
                  :ARG1 p
                  :ARG1-of (d4 / describe-01
                        :ARG0 (p10 / publication-91
                              :ARG0 (a3 / and
                                    :op1 (p11 / person :name (n5 / name :op1 "Hart"))
                                    :op2 p7)
                              :time (d2 / date-entity :year 1998))))
            :op3 (e3 / enhance-01
                  :ARG0 p
                  :ARG1 (c / capable-01
                        :ARG1 p4
                        :ARG2 (b / bind-01
                              :ARG1 p4
                              :ARG2 (p13 / protein :name (n6 / name :op1 "beta-catenin"))))
                  :ARG1-of d3))
      :time (p2 / previous))

# ::id bio.chicago_2015.35049 ::date 2015-10-27T02:43:41 ::annotator SDL-AMR-09 ::preferred
# ::snt Activation of N-WASP by  Cdc42 is required for initiating  actin-based motility of intracellular   Shigella            In vitro studies have indicated that activation of N-WASP in cells requires  Cdc42 bound to the  GBD of N-WASP ( 47,  62,  66,  67).
# ::save-date Sun Nov 8, 2015 ::file bio_chicago_2015_35049.txt
(m2 / multi-sentence
      :snt1 (r / require-01
            :ARG0 (i / initiate-01
                  :ARG1 (m / motility
                        :ARG1-of (b / base-02
                              :ARG2 (p2 / protein :name (n3 / name :op1 "actin")))
                        :poss (o / organism :name (n4 / name :op1 "Shigella")
                              :mod (i2 / intracellular))))
            :ARG1 (a / activate-01
                  :ARG0 (p / protein :name (n2 / name :op1 "Cdc42"))
                  :ARG1 (p4 / protein :name (n / name :op1 "N-WASP"))))
      :snt2 (i3 / indicate-01
            :ARG0 (s / study-01
                  :manner (i4 / in-vitro))
            :ARG1 (r2 / require-01
                  :ARG0 (a2 / activate-01
                        :ARG1 (p5 / protein :name (n6 / name :op1 "N-WASP"))
                        :location (c / cell))
                  :ARG1 (b2 / bind-01
                        :ARG1 (p6 / protein :name (n7 / name :op1 "Cdc42"))
                        :ARG2 (p7 / protein-segment :name (n5 / name :op1 "GBD")
                              :part-of p5)))
            :ARG1-of (d2 / describe-01
                  :ARG0 (p3 / publication
                        :ARG1-of (c2 / cite-01
                              :ARG2 (a3 / and :op1 47 :op2 62 :op3 66 :op4 67))))))

# ::id bio.chicago_2015.35062 ::date 2015-10-27T02:56:42 ::annotator SDL-AMR-09 ::preferred
# ::snt In oocytes from one-third of   Xenopus donors, the activation of  CFTR by  cGMP averaged 87 % of the level achieved by cAMP.
# ::save-date Sat Feb 13, 2016 ::file bio_chicago_2015_35062.txt
(a / average-01
      :ARG1 (a2 / activate-01
            :ARG0 (s2 / small-molecule :name (n2 / name :op1 "cGMP"))
            :ARG1 (p3 / protein :name (n / name :op1 "CFTR")))
      :ARG2 (p4 / percentage-entity :value 87
            :ARG3-of (i / include-91
                  :ARG2 (l / level
                        :ARG1-of (a3 / achieve-01
                              :ARG0 (s / small-molecule :name (n3 / name :op1 "cAMP"))))))
      :location (c / cell :name (n4 / name :op1 "oocyte")
            :source (o / organism :quant "1/3" :name (n5 / name :op1 "Xenopus")
                  :ARG0-of (d2 / donate-01))))

# ::id bio.chicago_2015.35082 ::date 2015-10-27T03:22:45 ::annotator SDL-AMR-09 ::preferred
# ::snt After washing with  GST binding buffer, proteins associated with  GST-agarose beads were analyzed with 4% - 20%  SDS-PAGE and visualized by autoradiography.
# ::save-date Sat Feb 13, 2016 ::file bio_chicago_2015_35082.txt
(a3 / and
      :op1 (a / analyze-01
            :ARG1 (p3 / protein
                  :ARG1-of (a2 / associate-01
                        :ARG2 (b2 / bead
                              :consist-of (a6 / and
                                    :op1 e
                                    :op2 (a7 / agarose)))))
            :instrument (t / thing :name (n2 / name :op1 "SDS-PAGE")
                  :quant (v / value-interval
                        :op1 (p / percentage-entity :value 4)
                        :op2 (p2 / percentage-entity :value 20))))
      :op2 (v2 / visualize-01
            :ARG1 p3
            :instrument (a4 / autoradiography))
      :time (a5 / after
            :op1 (w / wash-01
                  :ARG1 p3
                  :ARG2 (b3 / buffer
                        :ARG1-of (b4 / bind-01
                              :ARG2 (e / enzyme :name (n3 / name :op1 "GST")))))))

# ::id bio.chicago_2015.35109 ::date 2015-10-27T03:30:02 ::annotator SDL-AMR-09 ::preferred
# ::snt As shown in Fig.  5 E, both the  GTP-  and the  GDP-bound forms of  RhoA are able to bind   p116Rip.
# ::save-date Tue Nov 3, 2015 ::file bio_chicago_2015_35109.txt
(c / capable-01
      :ARG1 (a / and
            :op1 (f / form
                  :mod (p2 / protein :name (n2 / name :op1 "RhoA"))
                  :ARG1-of (b2 / bind-01
                        :ARG2 (s3 / small-molecule :name (n3 / name :op1 "GTP"))))
            :op2 (f2 / form
                  :mod p2
                  :ARG1-of (b / bind-01
                        :ARG2 (s4 / small-molecule :name (n4 / name :op1 "GDP")))))
      :ARG2 (b3 / bind-01
            :ARG1 a
            :ARG2 (p3 / protein :name (n5 / name :op1 "p116Rip")))
      :ARG1-of (s / show-01
            :ARG0 (f3 / figure :mod "5E")))

# ::id bio.chicago_2015.35124 ::date 2015-10-27T03:38:27 ::annotator SDL-AMR-09 ::preferred
# ::snt beta-Adrenergic receptor-induced apoptosis requires  tyrosine kinase Lck.
# ::save-date Tue Nov 3, 2015 ::file bio_chicago_2015_35124.txt
(r / require-01
      :ARG0 (a / apoptosis
            :ARG2-of (i / induce-01
                  :ARG0 (r2 / receptor :name (n3 / name :op1 "beta-Adrenergic"))))
      :ARG1 (t / tyrosine-kinase :name (n2 / name :op1 "Lck")))

# ::id bio.chicago_2015.35127 ::date 2015-10-27T03:42:04 ::annotator SDL-AMR-09 ::preferred
# ::snt Like  PKB, PKBR-1 kinase activity is stimulated in response to cAMP; however, unlike the activation of  PKB the activation of PKBR-1 is not inhibited by the  PI3K inhibitor LY294002 ( Meili et al. 2000   ).
# ::save-date Sun Jan 17, 2016 ::file bio_chicago_2015_35127.txt
(s / stimulate-01
      :ARG1 (a / activity-06
            :ARG0 (k / kinase :name (n / name :op1 "PKBR-1")))
      :ARG2-of (r2 / respond-01
            :ARG1 (s3 / small-molecule :name (n2 / name :op1 "cAMP")))
      :concession-of (i2 / inhibit-01 :polarity -
                  :ARG0 (s2 / small-molecule :name (n4 / name :op1 "LY294002")
                        :ARG0-of (i3 / inhibit-01
                              :ARG1 (e2 / enzyme :name (n5 / name :op1 "PI3K"))))
                  :ARG1 (a2 / activate-01
                        :ARG1 k)
                  :ARG1-of (r4 / resemble-01 :polarity -
                        :ARG2 (a3 / activate-01
                              :ARG1 e)))
      :ARG1-of (r3 / resemble-01
            :ARG2 (e / enzyme :name (n3 / name :op1 "PKB")))
      :ARG1-of (d2 / describe-01
            :ARG0 (p / publication-91
                  :ARG0 (a4 / and
                        :op1 (p2 / person :name (n6 / name :op1 "Meili"))
                        :op2 (p3 / person
                              :mod (o / other)))
                  :time (d3 / date-entity :year 2000))))

# ::id bio.chicago_2015.35185 ::date 2015-10-27T03:53:11 ::annotator SDL-AMR-09 ::preferred
# ::snt Rb association with  E2F not only blocks transcriptional activation by  E2F but also forms an active  transcriptional repressor complex at promoters that can block transcription by recruiting  histone deacetylase (HDAC) and remodeling chromatin [  98,   99,   100 and   101].
# ::save-date Sun Jan 17, 2016 ::file bio_chicago_2015_35185.txt
(a3 / and
      :op1 (b / block-01
            :ARG0 (a / associate-01
                  :ARG1 (p2 / protein :name (n / name :op1 "Rb"))
                  :ARG2 (p / protein :name (n2 / name :op1 "E2F")))
            :ARG1 (a2 / activate-01
                  :ARG0 p
                  :ARG1 (t / transcribe-01)))
      :op2 (f / form-01
            :ARG0 a
            :ARG1 (m / macro-molecular-complex
                  :ARG0-of (r2 / repress-01
                        :ARG1 t)
                  :ARG0-of (a5 / activity-06)
                  :ARG0-of (b2 / block-01
                        :ARG1 t
                        :ARG3 (a7 / and
                              :op1 (r3 / recruit-01
                                    :ARG1 (e / enzyme :name (n4 / name :op1 "histone" :op2 "deacetylase")))
                              :op2 (r4 / remodel-01
                                    :ARG1 (m3 / macro-molecular-complex :name (n5 / name :op1 "chromatin"))))
                        :ARG1-of (p4 / possible-01)))
            :mod (a4 / also)
            :location (m2 / molecular-physical-entity
                  :ARG0-of (p3 / promote-02)))
      :ARG1-of (d / describe-01
            :ARG0 (p6 / publication
                  :ARG1-of (c2 / cite-01
                        :ARG2 (a6 / and :op1 98 :op2 99 :op3 100 :op4 101)))))

# ::id bio.chicago_2015.35239 ::date 2015-10-27T05:08:56 ::annotator SDL-AMR-09 ::preferred
# ::snt Reactions were allowed to elongate for the indicated amounts of time at room temperature and were stopped by the addition of 200  mul of Sarkosyl Stop Solution (100  mM Tris, 100 mM NaCl, 10  mM EDTA, 1% Sarkosyl, 200 mug/ml  tRNA).
# ::save-date Sat Feb 13, 2016 ::file bio_chicago_2015_35239.txt
(a3 / and
      :op1 (a / allow-01
            :ARG1 (e / elongate-01
                  :ARG0 (t / thing
                        :ARG2-of (r / react-01))
                  :duration (a2 / amount
                        :quant-of (t2 / time)
                        :ARG1-of (i / indicate-01))
                  :condition (t3 / temperature
                        :mod (r2 / room))))
      :op2 (s / stop-01
            :ARG1 t
            :ARG2 (a4 / add-02
                  :ARG1 (p2 / product :name (n / name :op1 "Sarkosyl" :op2 "Stop" :op3 "Solution")
                        :quant (v / volume-quantity :quant 200
                              :unit (m / microlitre))
                        :ARG1-of (e2 / equal-01
                              :ARG2 (a5 / and
                                    :op1 (s2 / small-molecule :name (n2 / name :op1 "Tris")
                                          :quant (c2 / concentration-quantity :quant 100
                                                :unit (m3 / millimolar)))
                                    :op2 (s3 / small-molecule :name (n3 / name :op1 "NaCl")
                                          :quant (c3 / concentration-quantity :quant 100
                                                :unit (m4 / millimolar)))
                                    :op3 (s4 / small-molecule :name (n4 / name :op1 "EDTA")
                                          :quant (c4 / concentration-quantity :quant 10
                                                :unit (m5 / millimolar)))
                                    :op4 (s5 / small-molecule :name (n5 / name :op1 "Sarkosyl")
                                          :quant (p / percentage-entity :value 1))
                                    :op5 (n7 / nucleic-acid :name (n6 / name :op1 "tRNA")
                                          :quant (c5 / concentration-quantity :quant 200
                                                :unit (m7 / microgram-per-milliliter)))))))))

# ::id bio.chicago_2015.35250 ::date 2015-10-27T05:22:23 ::annotator SDL-AMR-09 ::preferred
# ::snt Binding to the membrane is mediated by its  PH domain, which binds PI(4,5) P2 ( 14,  15), and by a region upstream of this domain that can directly penetrate into the lipid bilayer ( 16).
# ::save-date Sat Feb 13, 2016 ::file bio_chicago_2015_35250.txt
(m2 / mediate-01
      :ARG0 (a4 / and
            :op1 (p7 / protein-segment :name (n / name :op1 "PH")
                  :poss m
                  :ARG2-of (b2 / bind-01
                        :ARG1 (a / and
                              :op1 (s / small-molecule :name (n2 / name :op1 "PI(4,5)P2")
                                    :ARG1-of (d3 / describe-01
                                          :ARG0 (p4 / publication
                                                :ARG1-of (c2 / cite-01
                                                      :ARG2 (a3 / and :op1 14 :op2 15))))))))
            :op2 (r / region
                  :part-of p7
                  :ARG1-of (d4 / describe-01
                        :ARG0 (p6 / publication
                              :ARG1-of (c4 / cite-01
                                    :ARG2 16)))
                  :location (r3 / relative-position
                        :op1 p7
                        :direction (u / upstream))
                  :ARG1-of (c3 / capable-01
                        :ARG2 (p5 / penetrate-01
                              :ARG0 p7
                              :ARG1 (b3 / bilayer
                                    :mod (l / lipid))
                              :ARG1-of (d / direct-02)))))
      :ARG1 (b / bind-01
            :ARG2 (m / membrane)))

# ::id bio.chicago_2015.35259 ::date 2015-10-27T05:29:32 ::annotator SDL-AMR-09 ::preferred
# ::snt PKA phosphorylation of  adducin reduced activity of  adducin in association with  spectrin-actin complexes and in promoting binding of  spectrin to  F-actin.
# ::save-date Sun Nov 8, 2015 ::file bio_chicago_2015_35259.txt
(r / reduce-01
      :ARG0 (p / phosphorylate-01
            :ARG1 (p2 / protein :name (n / name :op1 "adducin"))
            :ARG2 (e / enzyme :name (n2 / name :op1 "PKA"))
            :ARG1-of (a2 / associate-01
                  :ARG2 (m / macro-molecular-complex
                        :part (p4 / protein :name (n4 / name :op1 "spectrin"))
                        :part (p5 / protein :name (n5 / name :op1 "actin"))))
            :purpose (p3 / promote-02
                  :ARG1 (b / bind-01
                        :ARG1 p4
                        :ARG2 (p6 / protein :name (n3 / name :op1 "F-actin")))))
      :ARG1 (a / activity-06
            :ARG0 p2))

# ::id bio.chicago_2015.35282 ::date 2015-10-27T05:36:28 ::annotator SDL-AMR-09 ::preferred
# ::snt This domain mediates the association of  NIK with  MEKK1 and is critical for  NIK activation of the  SAPK pathway, suggesting that the C-terminal domain of these proteins encodes a new protein domain family that couples these kinases to the  SAPK pathway, possibly by interacting with  MEKK1.
# ::save-date Fri Feb 5, 2016 ::file bio_chicago_2015_35282.txt
(a2 / and
      :op1 (m / mediate-01
            :ARG0 (d / domain
                  :mod (t / this))
            :ARG1 (a / associate-01
                  :ARG1 (e / enzyme :name (n / name :op1 "NIK"))
                  :ARG2 (e2 / enzyme :name (n2 / name :op1 "MEKK1"))))
      :op2 (c / critical-02
            :ARG1 d
            :ARG3 (a3 / activate-01
                  :ARG0 e
                  :ARG1 (p / pathway :name (n3 / name :op1 "SAPK"))))
      :ARG0-of (s / suggest-01
            :ARG1 (e3 / encode-01
                  :ARG0 (p4 / protein-segment :name (n4 / name :op1 "C-terminus")
                        :part-of (a4 / and
                              :op1 e
                              :op2 e2))
                  :ARG1 (p2 / protein-family
                        :mod (d3 / domain)
                        :ARG0-of (c2 / couple-01
                              :ARG1 (a5 / and
                                    :op1 e
                                    :op2 e2)
                              :ARG2 p
                              :manner (i / interact-01
                                    :ARG1 e2
                                    :ARG1-of (p3 / possible-01)))
                        :ARG1-of (n5 / new-02)))))

# ::id bio.chicago_2015.35301 ::date 2015-10-27T22:08:34 ::annotator SDL-AMR-09 ::preferred
# ::snt We conclude that   ind represses   msh and   achaete gene expression directly or indirectly, and that   ind is necessary for establishing proper intermediate-column identity within the neuroectoderm.
# ::save-date Wed Jan 13, 2016 ::file bio_chicago_2015_35301.txt
(c / conclude-01
      :ARG0 (w / we)
      :ARG1 (a / and
            :op1 (r / repress-01
                  :ARG0 (p2 / protein :name (n2 / name :op1 "ind"))
                  :ARG1 (e2 / express-03
                        :ARG1 (a2 / and
                              :op1 (g / gene :name (n3 / name :op1 "msh"))
                              :op2 (g2 / gene :name (n4 / name :op1 "achaete"))))
                  :manner (o / or
                        :op1 (d / direct-02)
                        :op2 (d2 / direct-02 :polarity -)))
            :op2 (n / need-01
                  :ARG0 (e3 / establish-01
                        :ARG1 (i / identity
                              :mod (c2 / column
                                    :mod (i2 / intermediate))
                              :mod (p / proper))
                        :location (n5 / neuroectoderm))
                  :ARG1 p2)))

# ::id bio.chicago_2015.35359 ::date 2015-10-27T22:18:18 ::annotator SDL-AMR-09 ::preferred
# ::snt In vivo analysis of the association of  PML and  Sp1.
# ::save-date Tue Nov 3, 2015 ::file bio_chicago_2015_35359.txt
(a / analyze-01
      :ARG1 (a2 / associate-01
            :ARG1 (p2 / protein :name (n / name :op1 "PML"))
            :ARG2 (p / protein :name (n2 / name :op1 "Sp1")))
      :manner (i / in-vivo))

# ::id bio.chicago_2015.35392 ::date 2015-10-27T22:23:23 ::annotator SDL-AMR-09 ::preferred
# ::snt A gain-of-function mutation in  Drosophila MAP kinase activates multiple  receptor tyrosine kinase signaling pathways.
# ::save-date Sun Nov 8, 2015 ::file bio_chicago_2015_35392.txt
(a / activate-01
      :ARG0 (m / mutate-01
            :ARG1 (k / kinase :name (n / name :op1 "MAP")
                  :part-of (o / organism :name (n2 / name :op1 "Drosophila")))
            :mod (g2 / gain-02
                  :mod (f / function-01)))
      :ARG1 (p / pathway
            :ARG0-of (s / signal-07
                  :ARG1 (e / enzyme :name (n3 / name :op1 "receptor" :op2 "tyrosine" :op3 "kinase")
                        :mod (m2 / multiple)))))

# ::id bio.chicago_2015.35414 ::date 2015-10-27T22:27:28 ::annotator SDL-AMR-09 ::preferred
# ::snt Since  DEDD was found to associate with  FADD and  caspase-8  in vitro, we tested whether under conditions with significant amounts of  DEDD in the cytoplasm an association with  endogenous FADD and/or  caspase-8 could be found  in vivo.
# ::save-date Tue Nov 3, 2015 ::file bio_chicago_2015_35414.txt
(t / test-01
      :ARG0 (w / we)
      :ARG1 (p / possible-01 :mode interrogative
            :ARG1 (f / find-01
                  :ARG1 (a / associate-01
                        :ARG1 (p4 / protein :name (n / name :op1 "DEDD"))
                        :ARG2 (a2 / and-or
                              :op1 (p2 / protein :name (n2 / name :op1 "FADD")
                                    :mod (e / endogenous))
                              :op2 (p3 / protein :name (n3 / name :op1 "caspase-8"))))
                  :manner (i / in-vivo)
                  :condition (a4 / amount
                        :ARG1-of (s / significant-02)
                        :quant-of p4
                        :location (c2 / cytoplasm))))
      :ARG1-of (c / cause-01
            :ARG0 (f2 / find-01
                  :ARG0 w
                  :ARG1 (a5 / associate-01
                        :ARG1 p4
                        :ARG2 (a6 / and
                              :op1 p2
                              :op2 p3)
                        :manner (i2 / in-vitro)))))

# ::id bio.chicago_2015.35423 ::date 2015-10-27T22:37:22 ::annotator SDL-AMR-09 ::preferred
# ::snt Further, we also demonstrated that  Dermo-1 represses the transactivation of  MyoD and  MEF2 through different mechanisms.
# ::save-date Tue Nov 3, 2015 ::file bio_chicago_2015_35423.txt
(d / demonstrate-01
      :ARG0 (w / we)
      :ARG1 (r / repress-01
            :ARG0 (p / protein :name (n / name :op1 "Dermo-1"))
            :ARG1 (t / transactivate-01
                  :ARG1 (a3 / and
                        :op1 (p2 / protein :name (n2 / name :op1 "MyoD"))
                        :op2 (p3 / protein :name (n3 / name :op1 "MEF2"))))
            :instrument (m / mechanism
                  :ARG1-of (d2 / differ-02)))
      :mod (a / also)
      :mod (f / further))

# ::id bio.chicago_2015.35431 ::date 2015-10-27T23:58:06 ::annotator SDL-AMR-09 ::preferred
# ::snt A novel group of   pumilio mutations affects the asymmetric division of  germline stem cells in the  Drosophila ovary.
# ::save-date Tue Nov 3, 2015 ::file bio_chicago_2015_35431.txt
(a / affect-01
      :ARG0 (g2 / group
            :mod (n3 / novel)
            :consist-of (m / mutate-01
                  :ARG1 (g / gene :name (n / name :op1 "pumilio"))))
      :ARG1 (d / divide-02
            :ARG1 (c / cell
                  :mod (s / stem)
                  :mod (g3 / germline))
            :mod (s2 / symmetric :polarity -)
            :location (o / ovary
                  :part-of (o2 / organism :name (n2 / name :op1 "Drosophila")))))

# ::id bio.chicago_2015.35452 ::date 2015-10-28T00:09:03 ::annotator SDL-AMR-09 ::preferred
# ::snt Moreover,  PAK activation by  Agrin is dependent on  Cdc42 and  Rac, suggesting that  PAK may be downstream of the small GTPases.
# ::save-date Sun Nov 8, 2015 ::file bio_chicago_2015_35452.txt
(a3 / and
      :op2 (d2 / depend-01
            :ARG0 (a / activate-01
                  :ARG0 (p / protein :name (n2 / name :op1 "Agrin"))
                  :ARG1 (e / enzyme :name (n / name :op1 "PAK")))
            :ARG1 (a2 / and
                  :op1 (p3 / protein :name (n3 / name :op1 "Cdc42"))
                  :op2 (e3 / enzyme :name (n4 / name :op1 "Rac")))
            :ARG0-of (s / suggest-01
                  :ARG1 (p2 / possible-01
                        :ARG1 (b / be-located-at-91
                              :ARG1 e
                              :ARG2 (r / relative-position
                                    :op1 (e4 / enzyme :name (n5 / name :op1 "GTPase")
                                          :mod (s2 / small))
                                    :direction (d / downstream)))))))

# ::id bio.chicago_2015.35459 ::date 2015-10-28T00:15:01 ::annotator SDL-AMR-09 ::preferred
# ::snt B,  IKAP significantly potentiates  MEKK1-induced  JNK activation.
# ::save-date Sun Nov 8, 2015 ::file bio_chicago_2015_35459.txt
(p / potentiate-01 :li "b"
      :ARG0 (p3 / protein :name (n2 / name :op1 "IKAP"))
      :ARG1 (a2 / activate-01
            :ARG1 (e / enzyme :name (n3 / name :op1 "JNK"))
            :ARG2-of (i / induce-01
                  :ARG0 (e2 / enzyme :name (n4 / name :op1 "MEKK1"))))
      :ARG1-of (s / significant-02))

# ::id bio.chicago_2015.35483 ::date 2015-10-28T00:19:51 ::annotator SDL-AMR-09 ::preferred
# ::snt It has been found that  KSR is bound directly to  MEK in the cytoplasm of quiescent cells; upon activation of the  MAPK pathway by  growth factors or activated  RAS,  KSR is relocalized to the plasma membrane in a complex containing  RAF,  MEK, and  MAPK ( M ICHAUD et al. 1997   ;   D ENOUEL-GALY et al. 1998   ;
# ::save-date Wed Feb 24, 2016 ::file bio_chicago_2015_35483.txt
(a / and
      :op1 (f / find-01
            :ARG1 (b / bind-01
                  :ARG1 (e5 / enzyme :name (n5 / name :op1 "KSR"))
                  :ARG2 (e / enzyme :name (n / name :op1 "MEK"))
                  :ARG1-of (d3 / direct-02)
                  :location (c / cytoplasm
                        :part-of (c2 / cell
                              :mod (q / quiescent)))))
      :op2 (r / relocalize-00
            :ARG1 e5
            :destination (m / membrane
                  :mod (p6 / plasma)
                  :location (m2 / macro-molecular-complex
                        :ARG0-of (c4 / contain-01
                              :ARG1 (a3 / and
                                    :op1 (e3 / enzyme :name (n4 / name :op1 "Raf"))
                                    :op2 e
                                    :op3 (e4 / enzyme :name (n2 / name :op1 "MAPK"))))))
            :condition (a4 / activate-01
                  :ARG0 (o / or
                        :op1 (g / growth-factor)
                        :op2 (e2 / enzyme :name (n3 / name :op1 "Ras")
                              :ARG1-of (a2 / activate-01)))
                  :ARG1 (p / pathway :name (n9 / name :op1 "MAPK"))))
      :ARG1-of (d4 / describe-01
            :ARG0 (a5 / and
                  :op1 (p7 / publication-91
                        :ARG0 (a6 / and
                              :op1 (p8 / person :name (n6 / name :op1 "Michaud"))
                              :op2 (p9 / person
                                    :mod (o2 / other)))
                        :time (d / date-entity :year 1997))
                  :op2 (p10 / publication-91
                        :ARG0 (a7 / and
                              :op1 (p11 / person :name (n7 / name :op1 "Denouel-Galy"))
                              :op2 (p12 / person
                                    :mod (o3 / other)))
                        :time (d2 / date-entity :year 1998)))))

# ::id bio.chicago_2015.35489 ::date 2015-10-28T00:50:05 ::annotator SDL-AMR-09 ::preferred
# ::snt SXL associates with the  U1 snRNP particle in embryonic extracts.
# ::save-date Tue Nov 3, 2015 ::file bio_chicago_2015_35489.txt
(a / associate-01
      :ARG1 (p3 / protein :name (n / name :op1 "SXL"))
      :ARG2 (p / particle :name (n2 / name :op1 "U1")
            :part-of (p2 / protein :name (n3 / name :op1 "snRNP")))
      :location (m / molecular-physical-entity
            :ARG1-of (e / extract-01
                  :ARG2 (e2 / embryo))))

# ::id bio.chicago_2015.35547 ::date 2015-10-28T00:54:01 ::annotator SDL-AMR-09 ::preferred
# ::snt Ubc9 Binding to  Mdm2 Is Decreased after UV Irradiation-- Since UV irradiation has been shown to reduce the degree of  Mdm2 sumoylation, we have monitored possible changes in the association of  Ubc9 with  Mdm2 in UV-treated cells.
# ::save-date Sun Nov 8, 2015 ::file bio_chicago_2015_35547.txt
(m / multi-sentence
      :snt1 (d / decrease-01
            :ARG1 (b / bind-01
                  :ARG1 (e / enzyme :name (n / name :op1 "Ubc9"))
                  :ARG2 (p2 / protein :name (n2 / name :op1 "Mdm2")))
            :time (a / after
                  :op1 (i / irradiate-01
                        :ARG2 (u / ultraviolet))))
      :snt2 (m2 / monitor-01
            :ARG0 (w2 / we)
            :ARG1 (c / change-01
                  :ARG1 (a2 / associate-01
                        :ARG1 (e2 / enzyme :name (n3 / name :op1 "Ubc9"))
                        :ARG2 (p3 / protein :name (n4 / name :op1 "Mdm2"))
                        :location (c2 / cell
                              :ARG1-of (t / treat-04
                                    :ARG2 u2)))
                  :ARG1-of (p / possible-01))
            :ARG1-of (c3 / cause-01
                  :ARG0 (s / show-01
                        :ARG1 (r / reduce-01
                              :ARG0 (i2 / irradiate-01
                                    :ARG2 (u2 / ultraviolet))
                              :ARG1 (d2 / degree
                                    :degree-of (s2 / sumoylate-00
                                          :ARG0 p2)))))))

# ::id bio.chicago_2015.35599 ::date 2015-10-28T01:09:32 ::annotator SDL-AMR-09 ::preferred
# ::snt From previous experiments it is known that a single application of  5HT induces  STF, which declines to baseline levels within ~15 min, whereas five applications of  5HT induce  LTF that lasts at least up to 24 hr after its induction (Walters et al., 1983  ; Emptage and Carew, 1993  ;
# ::save-date Sun Nov 8, 2015 ::file bio_chicago_2015_35599.txt
(k / know-01
      :ARG1 (c / contrast-01
            :ARG1 (i / induce-01
                  :ARG0 (a2 / apply-03
                        :ARG1 (e / enzyme :name (n / name :op1 "5HT"))
                        :ARG1-of (s / single-02))
                  :ARG2 (f / facilitate-01
                        :ARG1-of (d3 / decline-01
                              :ARG4 (l3 / level
                                    :mod (b / baseline))
                              :time (u / up-to
                                    :op1 (t2 / temporal-quantity :quant 15
                                          :unit (m / minute))))
                        :ARG1-of (s2 / short-07)))
            :ARG2 (i2 / induce-01
                  :ARG0 (a3 / apply-03
                        :ARG1 e
                        :mod (p / product-of :op1 5))
                  :ARG2 (f2 / facilitate-01
                        :ARG1-of (l / last-01
                              :ARG2 (a4 / after
                                    :op1 i2)
                              :quant (a8 / at-least
                                    :op1 (u2 / up-to
                                          :op1 (t4 / temporal-quantity :quant 24
                                                :unit (h / hour)))))
                        :ARG1-of (l2 / long-03))))
      :source (e2 / experiment-01
            :time (p2 / previous))
      :ARG1-of (d4 / describe-01
            :ARG0 (a5 / and
                  :op1 (p3 / publication-91
                        :ARG0 (a6 / and
                              :op1 (p4 / person :name (n4 / name :op1 "Walters"))
                              :op1 (p5 / person
                                    :mod (o / other)))
                        :time (d / date-entity :year 1983))
                  :op2 (p6 / publication-91
                        :ARG0 (a7 / and
                              :op1 (p7 / person :name (n5 / name :op1 "Emptage"))
                              :op2 (p8 / person :name (n6 / name :op1 "Carew")))
                        :time (d2 / date-entity :year 1993)))))

# ::id bio.chicago_2015.35619 ::date 2015-10-28T01:24:06 ::annotator SDL-AMR-09 ::preferred
# ::snt To examine whether  AES interacts with  p65 in cultured cells, we performed the co-immunoprecipitation experiment.
# ::save-date Tue Nov 3, 2015 ::file bio_chicago_2015_35619.txt
(p / perform-02
      :ARG0 (w / we)
      :ARG1 (e / experiment-01
            :ARG2 (c / coimmunoprecipitate-01))
      :purpose (e2 / examine-01
            :ARG0 w
            :ARG1 (i / interact-01 :mode interrogative
                  :ARG0 (p3 / protein :name (n / name :op1 "AES"))
                  :ARG1 (p2 / protein :name (n2 / name :op1 "p65"))
                  :location (c2 / cell
                        :ARG1-of (c3 / culture-01)))))

# ::id bio.chicago_2015.35635 ::date 2015-10-28T01:28:05 ::annotator SDL-AMR-09 ::preferred
# ::snt Our results show that the C-terminal domains of the xCRYs are necessary for nuclear localization, but it is still unclear if this is achieved via  importin binding to an authentic  NLS within the C-terminal domain or via a more indirect mechanism.
# ::save-date Sun Nov 8, 2015 ::file bio_chicago_2015_35635.txt
(c / contrast-01
      :ARG1 (s / show-01
            :ARG0 (t / thing
                  :ARG2-of (r / result-01)
                  :poss (w / we))
            :ARG1 (n / need-01
                  :ARG0 (l / localize-01
                        :ARG1 (n4 / nucleus))
                  :ARG1 (p2 / protein-segment :name (n2 / name :op1 "C-terminus")
                        :part-of (p3 / protein :name (n3 / name :op1 "xCRY")))))
      :ARG2 (c2 / clear-06 :polarity -
            :ARG1 (a / achieve-01 :mode interrogative
                  :ARG1 n
                  :instrument (o / or
                        :op1 (b / bind-01
                              :ARG1 (p / protein :name (n5 / name :op1 "importin"))
                              :ARG2 (p4 / protein-segment :name (n6 / name :op1 "NLS")
                                    :ARG1-of (a3 / authentic-02))
                              :location p2)
                        :op2 (m / mechanism
                              :ARG1-of (d2 / direct-02 :polarity -
                                    :degree (m2 / more)))))
            :time (s2 / still)))

# ::id bio.chicago_2015.35638 ::date 2015-10-28T04:31:56 ::annotator SDL-AMR-09 ::preferred
# ::snt The   Drosophila melanogaster suppressor of  Hairy-wing protein binds to specific sequences of the gypsy retrotransposon.
# ::save-date Mon Jan 4, 2016 ::file bio_chicago_2015_35638.txt
(b / bind-01
      :ARG1 (m / molecular-physical-entity
            :ARG0-of (s / suppress-01
                  :ARG1 (p2 / protein :name (n5 / name :op1 "Harry-wing")))
            :mod (o / organism :name (n / name :op1 "Drosophila" :op2 "melanogaster")))
      :ARG2 (s2 / sequence
            :ARG1-of (s3 / specific-02)
            :part-of (d / dna-sequence :name (n4 / name :op1 "retrotransposon")
                  :mod (g / gypsy))))

# ::id bio.chicago_2015.35639 ::date 2015-10-28T04:37:44 ::annotator SDL-AMR-09 ::preferred
# ::snt The   fat facets gene is required for  Drosophila eye and embryo development.
# ::save-date Sun Nov 8, 2015 ::file bio_chicago_2015_35639.txt
(r / require-01
      :ARG0 (d / develop-01
            :ARG2 (a / and
                  :op1 (e / eye)
                  :op2 (e2 / embryo)
                  :part-of (o / organism :name (n / name :op1 "Drosophila"))))
      :ARG1 (g / gene :name (n2 / name :op1 "fat" :op2 "facet")))

# ::id bio.chicago_2015.35656 ::date 2015-10-28T04:50:06 ::annotator SDL-AMR-09 ::preferred
# ::snt Our data showing that full-length  TAF130p tightly binds  TBP and prevents subsequent  TBP-TATA DNA interactions, as well as the published work of others (see above), illustrates an intriguing conundrum.
# ::save-date Wed Mar 2, 2016 ::file bio_chicago_2015_35656.txt
(i / illustrate-01
      :ARG0 (a2 / and
            :op1 (d / data
                  :poss (w / we)
                  :ARG0-of (s / show-01
                        :ARG1 (a / and
                              :op1 (b / bind-01
                                    :ARG1 (p6 / protein-segment :name (n / name :op1 "TAF130p")
                                          :ARG1-of (l / long-03
                                                :mod (f / full)))
                                    :ARG2 (p2 / protein :name (n2 / name :op1 "TBP"))
                                    :ARG1-of (t2 / tight-05))
                              :op2 (p / prevent-01
                                    :ARG0 p2
                                    :ARG1 (i2 / interact-01
                                          :ARG0 p2
                                          :ARG1 (n3 / nucleic-acid :name (n4 / name :op1 "DNA")
                                                :part-of (d2 / dna-sequence :name (n5 / name :op1 "TATA")))
                                          :time (s3 / subsequent))))))
            :op2 (w2 / work-01
                  :ARG0 (p5 / person
                        :mod (o / other))
                  :ARG1-of (p4 / publish-01)
                  :ARG1-of (s2 / see-01 :mode imperative
                        :ARG0 (y / you)
                        :location (a3 / above))))
      :ARG1 (c / conundrum
            :ARG0-of (i3 / intrigue-01)))

# ::id bio.chicago_2015.35670 ::date 2015-10-28T04:58:51 ::annotator SDL-AMR-09 ::preferred
# ::snt Furthermore, we show that high  Dpp signalling antagonizes  Wg-mediated repression.
# ::save-date Sun Jan 17, 2016 ::file bio_chicago_2015_35670.txt
(a / and
      :op2 (s / show-01
            :ARG0 (w / we)
            :ARG1 (a2 / antagonize-02
                  :ARG1 (s2 / signal-07
                        :ARG0 (p / pathway :name (n / name :op1 "Dpp"))
                        :ARG1-of (h / high-02))
                  :ARG2 (r / repress-01
                        :ARG1-of (m / mediate-01
                              :ARG0 (p2 / protein :name (n2 / name :op1 "Wg")))))))

# ::id bio.chicago_2015.35685 ::date 2015-10-28T05:02:54 ::annotator SDL-AMR-09 ::preferred
# ::snt The interaction of  rAxin with  beta-catenin was confirmed by the  yeast two-hybrid method
# ::save-date Tue Nov 3, 2015 ::file bio_chicago_2015_35685.txt
(c / confirm-01
      :ARG0 (m / method :name (n3 / name :op1 "yeast" :op2 "two-hybrid"))
      :ARG1 (i / interact-01
            :ARG0 (p2 / protein :name (n / name :op1 "rAxin"))
            :ARG1 (p / protein :name (n2 / name :op1 "beta-catenin"))))

# ::id bio.chicago_2015.35692 ::date 2015-10-28T05:05:47 ::annotator SDL-AMR-09 ::preferred
# ::snt Consistent with data shown in  Fig. 1, tyrosine phosphorylation of either  cortactin or  EC MLCK 1 by  p60src resulted in enhanced affinity with measured  Kd's of 0.2  M ( Fig. 2B) and 0.1  M ( Fig. 2C), respectively.
# ::save-date Sun Nov 8, 2015 ::file bio_chicago_2015_35692.txt
(r / result-01
      :ARG1 (p / phosphorylate-01
            :ARG1 (o / or
                  :op1 (a / amino-acid :name (n / name :op1 "tyrosine")
                        :part-of (p2 / protein :name (n2 / name :op1 "cortactin")))
                  :op2 (a4 / amino-acid :name (n4 / name :op1 "tyrosine")
                        :part-of (p3 / protein :name (n3 / name :op1 "EC" :op2 "MLCK" :op3 "1"))))
            :ARG2 (e5 / enzyme :name (n5 / name :op1 "p60" :op2 "src")))
      :ARG2 (a2 / affinity
            :ARG1-of (e / enhance-01)
            :ARG0-of (h / have-03
                  :ARG1 (a3 / and
                        :op1 (d6 / dissociate-01
                              :ARG1 (e3 / equilibrium
                                    :quant (d / distance-quantity :quant 0.2
                                          :unit (m / molar)))
                              :ARG1-of (m3 / measure-01)
                              :ARG1-of (d3 / describe-01
                                    :ARG0 (f / figure :mod "2B")))
                        :op2 (d2 / dissociate-01
                              :ARG1 (e4 / equilibrium
                                    :quant (c2 / concentration-quantity :quant 0.1
                                          :unit m))
                              :ARG1-of m3
                              :ARG1-of (d4 / describe-01
                                    :ARG0 (f2 / figure :mod "2C"))))))
      :ARG1-of (c / consistent-01
            :ARG2 (d5 / data
                  :ARG1-of (s2 / show-01
                        :medium (f3 / figure :mod 1)))))

# ::id bio.chicago_2015.35756 ::date 2015-10-28T05:13:05 ::annotator SDL-AMR-09 ::preferred
# ::snt Comparable to the interactions of  GATA4 and FOG-2,  Pnr and  Ush heterodimerize through the amino-terminal  zinc finger of  Pnr ( 24), and genetic studies have shown that  Ush antagonizes the function of  Pnr in the establishment of the thoracic bristle pattern in the adult ( 24,  25).
# ::save-date Sun Nov 8, 2015 ::file bio_chicago_2015_35756.txt
(a2 / and
      :op1 (h / heterodimerize-01
            :ARG0 (p9 / protein-segment :name (n5 / name :op1 "amino-terminal" :op2 "zinc" :op3 "finger"))
            :ARG1 (p7 / protein :name (n / name :op1 "Pnr"))
            :ARG2 (p8 / protein :name (n2 / name :op1 "Ush"))
            :ARG1-of (d / describe-01
                  :ARG0 (p / publication
                        :ARG1-of (c / cite-01
                              :ARG2 24)))
            :ARG1-of (c2 / comparable-03
                  :ARG2 (i / interact-01
                        :ARG0 (p5 / protein :name (n3 / name :op1 "GATA4"))
                        :ARG1 (p6 / protein :name (n4 / name :op1 "FOG-2")))))
      :op2 (s / show-01
            :ARG0 (s2 / study-01
                  :mod (g / genetics))
            :ARG1 (a3 / antagonize-02
                  :ARG1 p8
                  :ARG2 (f2 / function-01
                        :ARG0 p7
                        :ARG1 (e3 / establish-01
                              :ARG0 p7
                              :ARG1 (p2 / pattern
                                    :mod (b / bristle)
                                    :mod (t3 / thoracic))
                              :location (a / adult))))
            :ARG1-of (d2 / describe-01
                  :ARG0 (p4 / publication
                        :ARG1-of (c3 / cite-01
                              :ARG2 (a5 / and :op1 24 :op2 25))))))

# ::id bio.chicago_2015.35779 ::date 2015-10-28T05:20:59 ::annotator SDL-AMR-09 ::preferred
# ::snt To test for functional association of  DEDD with  FADD or  caspase-8, suboptimal non-cytotoxic concentrations of  FADD or  caspase-8 were co-transfected with suboptimal concentrations of the  DEDD deletion mutants (Figure  4C).
# ::save-date Tue Nov 3, 2015 ::file bio_chicago_2015_35779.txt
(c / cotransfect-01
      :ARG1 (o / or
            :op1 (c2 / concentrate-02
                  :ARG1 (p2 / protein :wiki "FADD"
                        :name (n / name :op1 "FADD")))
            :op2 (c3 / concentrate-02
                  :ARG1 (p / protein :wiki "Caspase_8"
                        :name (n2 / name :op1 "caspase-8")))
            :mod (s / suboptimal)
            :mod (c4 / cytotoxic :polarity -))
      :instrument (c5 / concentrate-02
            :ARG1 (m / mutate-01
                  :ARG1-of (c6 / cause-01
                        :ARG0 (d / delete-01
                              :ARG1 (p3 / protein :wiki "DEDD"
                                    :name (n3 / name :op1 "DEDD")))))
            :mod s)
      :purpose (t3 / test-01
            :ARG2 (a / associate-01
                  :ARG0 p3
                  :ARG1 (o2 / or
                        :op1 p2
                        :op2 p)
                  :ARG0-of (f / function-01)))
      :ARG1-of (d2 / describe-01
            :ARG0 (f2 / figure :mod "4C")))

# ::id bio.chicago_2015.35797 ::date 2015-10-28T05:27:34 ::annotator SDL-AMR-09 ::preferred
# ::snt However,  Dox-induced expression of  Axin during the first 4 days (aggregation), followed by withdrawal of  Dox for the next 6 days (differentiation), had no effect on betaIII-tubulin expression (Fig.  6, compare  lanes 2 and  6).
# ::save-date Sun Nov 8, 2015 ::file bio_chicago_2015_35797.txt
(h / have-concession-91
      :ARG1 (a / affect-01 :polarity -
            :ARG0 (e2 / express-03
                  :ARG2 (p2 / protein :name (n2 / name :op1 "Axin"))
                  :ARG2-of (i / induce-01
                        :ARG0 (s / small-molecule :name (n3 / name :op1 "Dox")))
                  :duration (t / temporal-quantity :quant 4
                        :unit (d / day)
                        :ord (o2 / ordinal-entity :value 1))
                  :ARG1-of (m / mean-01
                        :ARG2 (a2 / aggregate-01))
                  :ARG2-of (f / follow-01
                        :ARG1 (w / withdraw-01
                              :ARG1 s
                              :duration (t2 / temporal-quantity :quant 6
                                    :unit (d2 / day)
                                    :mod (n4 / next))
                              :ARG1-of (m2 / mean-01
                                    :ARG2 (d3 / differentiate-01)))))
            :ARG1 (e / express-03
                  :ARG2 (p / protein :name (n / name :op1 "betaIII-tubulin"))))
      :ARG1-of (d4 / describe-01
            :ARG0 (f2 / figure :mod 6
                  :location-of (c / compare-01 :mode imperative
                        :ARG0 (y / you)
                        :ARG1 (l / lane :mod 2)
                        :ARG2 (l2 / lane :mod 6)))))

# ::id bio.chicago_2015.35826 ::date 2015-10-28T05:37:55 ::annotator SDL-AMR-09 ::preferred
# ::snt Thus,  Robo2 does not control  midline crossing of retinal axons, but rather shapes their pathway, by both preventing and correcting pathfinding errors.
# ::save-date Fri Nov 6, 2015 ::file bio_chicago_2015_35826.txt
(c6 / cause-01
      :ARG1 (c4 / contrast-01
            :ARG1 (c2 / control-01 :polarity -
                  :ARG0 (p4 / protein :name (n / name :op1 "Robo2"))
                  :ARG1 (c3 / cross-01
                        :ARG1 (a2 / axon
                              :mod (r / retina))
                        :mod (m / midline)))
            :ARG2 (s / shape-01
                  :ARG0 p4
                  :ARG1 (p / pathway
                        :poss a2)
                  :mod (r2 / rather)
                  :manner (a3 / and
                        :op1 (p2 / prevent-01
                              :ARG0 p4
                              :ARG1 (t / thing
                                    :ARG1-of (e / err-01)
                                    :ARG0-of (f / find-01
                                          :ARG1 (p3 / path))))
                        :op2 (c5 / correct-01
                              :ARG0 p4
                              :ARG1 t)))))

# ::id bio.chicago_2015.35827 ::date 2015-10-27T02:07:41 ::annotator SDL-AMR-09 ::preferred
# ::snt ( A)  PIASy represses  LEF1 activity from a  multimerized LEF1 reporter.
# ::save-date Fri Nov 6, 2015 ::file bio_chicago_2015_35827.txt
(r2 / repress-01 :li "A"
      :ARG0 (e / enzyme :name (n / name :op1 "PIASy"))
      :ARG1 (a / activity-06
            :ARG0 (p2 / protein :name (n2 / name :op1 "LEF1")))
      :ARG2 (m / molecular-physical-entity
            :ARG0-of (r / report-01
                  :ARG1 p2)
            :ARG1-of (m2 / multimerize-00)))

# ::id bio.chicago_2015.35949 ::date 2015-10-27T06:40:33 ::annotator SDL-AMR-09 ::preferred
# ::snt Furthermore,  gamma-tubulin can interact with  beta-tubulin (Leguy  et al., 2000  ), the subunit exposed at the plus ends of microtubules (Nogales  et al., 1999  ).
# ::save-date Sun Nov 8, 2015 ::file bio_chicago_2015_35949.txt
(a / and
      :op2 (p / possible-01
            :ARG1 (i / interact-01
                  :ARG0 (p7 / protein-family :name (n / name :op1 "gamma-tubulin"))
                  :ARG1 (p8 / protein-family :name (n2 / name :op1 "beta-tubulin")
                        :ARG1-of (d3 / describe-01
                              :ARG0 (p9 / publication-91
                                    :ARG0 (a3 / and
                                          :op1 (p6 / person :name (n3 / name :op1 "Leguy"))
                                          :op2 (p5 / person
                                                :mod (o / other)))
                                    :time (d / date-entity :year 2000))))
                  :manner (e / expose-01
                        :ARG1 (s / subunit)
                        :location (e2 / end-02
                              :ARG1 (m4 / microtubule)
                              :mod (p2 / plus))
                        :ARG1-of (d4 / describe-01
                              :ARG0 (p10 / publication-91
                                    :ARG0 (a2 / and
                                          :op1 (p3 / person :name (n4 / name :op1 "Nogales"))
                                          :op2 (p4 / person
                                                :mod (o2 / other))
                                          :time (d2 / date-entity :year 1999))))))))

# ::id bio.chicago_2015.35955 ::date 2015-10-27T06:40:39 ::annotator SDL-AMR-09 ::preferred
# ::snt Interestingly,  PDK1 phosphorylates and activates another  pleckstrin homology domain containing protein kinase,  Akt, as well ( 16,  17).
# ::save-date Sun Nov 8, 2015 ::file bio_chicago_2015_35955.txt
(a / and
      :op1 (p / phosphorylate-01
            :ARG1 (p3 / protein-segment :name (n2 / name :op1 "pleckstrin" :op2 "homology")
                  :ARG0-of (c2 / contain-01
                        :ARG1 (e / enzyme :name (n3 / name :op1 "protein" :op2 "kinase" :op3 "Akt"))
                        :mod (a4 / as-well))
                  :mod (a5 / another))
            :ARG2 (e2 / enzyme :name (n / name :op1 "PDK1")))
      :op2 (a2 / activate-01
            :ARG0 e2
            :ARG1 p3)
      :ARG2-of (i / interest-01)
      :ARG1-of (d / describe-01
            :ARG0 (p2 / publication
                  :ARG1-of (c / cite-01
                        :ARG2 (a3 / and :op1 16 :op2 17)))))

# ::id bio.chicago_2015.36045 ::date 2015-10-27T06:40:49 ::annotator SDL-AMR-09 ::preferred
# ::snt The  Torso receptor tyrosine kinase can activate  Raf in a  Ras-independent pathway.
# ::save-date Wed Jan 13, 2016 ::file bio_chicago_2015_36045.txt
(p / possible-01
      :ARG1 (a / activate-01
            :ARG0 (e3 / enzyme :name (n3 / name :op1 "Torso" :op2 "receptor" :op3 "tyrosine" :op4 "kinase"))
            :ARG1 (e / enzyme :name (n / name :op1 "Raf"))
            :location (p2 / pathway
                  :ARG0-of (d / depend-01 :polarity -
                        :ARG1 (e2 / enzyme :name (n2 / name :op1 "Ras"))))))

# ::id bio.chicago_2015.36075 ::date 2015-10-27T06:52:10 ::annotator SDL-AMR-09 ::preferred
# ::snt Arabidopsis SGS2 and  SGS3 Genes Are Required for  Posttranscriptional Gene Silencing and  Natural Virus Resistance.
# ::save-date Sun Nov 8, 2015 ::file bio_chicago_2015_36075.txt
(r / require-01
      :ARG0 (a2 / and
            :op1 (s / silence-01
                  :ARG1 (g3 / gene)
                  :time (a3 / after
                        :op1 (t / transcribe-01)))
            :op1 (r2 / resist-01
                  :ARG1 (v / virus)
                  :ARG1-of (n4 / natural-03)))
      :ARG1 (a / and
            :op1 (g / gene :name (n2 / name :op1 "SGS2"))
            :op2 (g2 / gene :name (n3 / name :op1 "SGS3"))
            :source (o / organism :name (n / name :op1 "Arabidopsis"))))

# ::id bio.chicago_2015.36082 ::date 2015-10-27T07:29:32 ::annotator SDL-AMR-09 ::preferred
# ::snt Spatially Restricted Activation of the  SAX Receptor by  SCW Modulates DPP/ TKV Signaling in  Drosophila Dorsal - Ventral Patterning.
# ::save-date Wed Mar 2, 2016 ::file bio_chicago_2015_36082.txt
(m / modulate-01
      :ARG0 (a / activate-01
            :ARG0 (p2 / protein :name (n2 / name :op1 "SCW"))
            :ARG1 (p / protein :name (n / name :op1 "SAX" :op2 "Receptor"))
            :ARG1-of (r / restrict-01
                  :manner (s / space)))
      :ARG1 (s4 / signal-07
            :ARG0 (p3 / pathway :name (n3 / name :op1 "DPP/TKV"))
            :time (p4 / pattern-01
                  :ARG1 (o / organism :name (n5 / name :op1 "Drosophila"))
                  :mod (d / dorsal)
                  :mod (v / ventral))))

# ::id bio.chicago_2015.36092 ::date 2015-10-27T10:55:27 ::annotator SDL-AMR-09 ::preferred
# ::snt Supernatants were diluted  in 40  mM Tris-HCl (pH 8), 0.1 M NaCl, 0.4  mg/ml bovine serum albumin, 1  mM dithiothreitol, 0.45 mM okadaic acid (Buffer 1) and incubated at 30 degrees C for 1  min in buffer 1 containing 1 mM of the peptide [ 32]- RII subunit  of cyclic AMP-dependent  protein kinase (PKA) and either 0.1  mM calmodulin (Sigma) and 0.66  mM Ca2+ or 0.33 mM EGTA (pH 7.5).
# ::save-date Sat Feb 13, 2016 ::file bio_chicago_2015_36092.txt
(a / and
      :op1 (d / dilute-01
            :ARG1 (s / supernatant)
            :ARG3 (a2 / and
                  :op1 (m12 / macro-molecular-complex :name (n / name :op1 "Tris-HCl")
                        :quant (c / concentration-quantity :quant 40
                              :unit (m / micromolar)))
                  :op2 (s6 / small-molecule :name (n2 / name :op1 "NaCl")
                        :quant (c2 / concentration-quantity :quant 0.1
                              :unit (m2 / molar)))
                  :op3 (p4 / protein :name (n9 / name :op1 "albumin")
                        :mod (s2 / serum
                              :source (b / bovine))
                        :quant (c3 / concentration-quantity :quant 0.4
                              :unit (m3 / milligram-per-milliliter)))
                  :op4 (s7 / small-molecule :name (n3 / name :op1 "dithiothreitol")
                        :quant (c5 / concentration-quantity :quant 1
                              :unit (m4 / micromolar)))
                  :op5 (s3 / small-molecule :name (n4 / name :op1 "okadaic" :op2 "acid")
                        :quant (c4 / concentration-quantity :quant 0.45
                              :unit (m5 / micromolar)))))
      :op2 (i / incubate-01
            :ARG1 s
            :ARG2 (b2 / buffer :mod 1
                  :ARG0-of (c6 / contain-01
                        :ARG1 (a5 / and
                              :op1 (p5 / peptide :name (n10 / name :op1 "[32]-RII" :op2 "subunit")
                                    :quant (c7 / concentration-quantity :quant 1
                                          :unit (m7 / micromolar))
                                    :poss (e / enzyme :name (n5 / name :op1 "AMP-dependent" :op2 "protein" :op3 "kinase")
                                          :mod (c8 / cyclic)))
                              :op2 (o2 / or
                                    :op1 (p3 / protein :name (n6 / name :op1 "calmodulin")
                                          :quant (c9 / concentration-quantity :quant 0.1
                                                :unit (m8 / micromolar)))
                                    :op2 (s4 / small-molecule :name (n8 / name :op1 "calcium")
                                          :quant (c11 / concentration-quantity :quant 0.66
                                                :unit (m11 / micromolar))
                                          :ARG1-of (i2 / ionize-01 :value "2+")))
                              :op3 (s5 / small-molecule :name (n7 / name :op1 "EGTA")
                                    :quant (c10 / concentration-quantity :quant 0.33
                                          :unit (m9 / micromolar))))))
            :mod (t4 / temperature-quantity :quant 30
                  :scale (c12 / celsius))
            :duration (t5 / temporal-quantity :quant 1
                  :unit (m6 / minute))))

# ::id bio.chicago_2015.36117 ::date 2015-10-27T07:30:25 ::annotator SDL-AMR-09 ::preferred
# ::snt These results indicate that the inhibition of  EGF-induced  Erk2 activation by  Abi-1 is specific to the  Erk pathway.
# ::save-date Sun Jan 17, 2016 ::file bio_chicago_2015_36117.txt
(i / indicate-01
      :ARG0 (t / thing
            :ARG2-of (r / result-01)
            :mod (t2 / this))
      :ARG1 (s / specific-02
            :ARG1 (i2 / inhibit-01
                  :ARG1 (a / activate-01
                        :ARG0 (p2 / protein :name (n2 / name :op1 "Abi-1"))
                        :ARG1 (e / enzyme :name (n3 / name :op1 "Erk2"))
                        :ARG2-of (i3 / induce-01
                              :ARG0 (p3 / protein :name (n4 / name :op1 "EGF")))))
            :ARG2 (p / pathway :name (n / name :op1 "Erk"))))

# ::id bio.chicago_2015.36125 ::date 2015-10-27T07:37:09 ::annotator SDL-AMR-09 ::preferred
# ::snt The 60 kDa subunit of  importin,  importin  , recognizes and directly  binds the  NLS (reviewed in Gorlich and Mattaj, 1996   ).
# ::save-date Fri Jan 15, 2016 ::file bio_chicago_2015_36125.txt
(a / and
      :op1 (r / recognize-02
            :ARG0 (p / protein-family :name (n / name :op1 "subunit" :op2 "of" :op3 "importin")
                  :quant (m / mass-quantity :quant 60
                        :unit (k / kilodalton)))
            :ARG1 p5)
      :op2 (b / bind-01
            :ARG0 p
            :ARG1 (p5 / protein-segment :name (n2 / name :op1 "NLS"))
            :ARG1-of (d2 / direct-02))
      :ARG1-of (r2 / review-01
            :ARG0 (p4 / publication-91
                  :ARG0 (a2 / and
                        :op1 (p2 / person :name (n3 / name :op1 "Gorlich"))
                        :op2 (p3 / person :name (n4 / name :op1 "Mattaj")))
                  :time (d / date-entity :year 1996))))

# ::id bio.chicago_2015.36130 ::date 2015-10-27T10:13:22 ::annotator SDL-AMR-09 ::preferred
# ::snt Previous studies showed that both  Smad6 and  Smurf1 inhibit  BMP signals in  vivo (Tsuneizumi  et al.,  1997  ;  Hata  et al.,  1998  ; Nakayama  et  al., 1998  ; Zhang  et  al., 2001  ).
# ::save-date Sun Nov 8, 2015 ::file bio_chicago_2015_36130.txt
(s / show-01
      :ARG0 (s2 / study-01
            :time (p / previous))
      :ARG1 (i / inhibit-01
            :ARG0 (a / and
                  :op1 (p11 / protein :name (n / name :op1 "Smad6"))
                  :op2 (p12 / protein :name (n2 / name :op1 "Smurf1")))
            :ARG1 (s3 / signal-07
                  :ARG0 (p2 / protein :name (n3 / name :op1 "BMP")))
            :manner (i2 / in-vivo))
      :ARG1-of (d6 / describe-01
            :ARG0 (a6 / and
                  :op1 (p16 / publication-91
                        :ARG0 (a2 / and
                              :op1 (p3 / person :name (n4 / name :op1 "Tsuneizumi"))
                              :op2 (p4 / person
                                    :mod (o / other)))
                        :time (d / date-entity :year 1997))
                  :op2 (p13 / publication-91
                        :ARG0 (a3 / and
                              :op1 (p5 / person :name (n5 / name :op1 "Hata"))
                              :op2 (p6 / person
                                    :mod o))
                        :time (d2 / date-entity :year 1998))
                  :op3 (p14 / publication-91
                        :ARG0 (a4 / and
                              :op1 (p8 / person :name (n6 / name :op1 "Nakayama"))
                              :op2 (p7 / person
                                    :mod o))
                        :time d2)
                  :op4 (p15 / publication-91
                        :ARG0 (a5 / and
                              :op1 (p9 / person :name (n7 / name :op1 "Zhang"))
                              :op2 (p10 / person
                                    :mod o))
                        :time (d4 / date-entity :year 2001)))))

# ::id bio.chicago_2015.36162 ::date 2015-10-27T10:22:50 ::annotator SDL-AMR-09 ::preferred
# ::snt One prediction of these studies is that an overlap in   MLL-and  CREB-dependent target genes exists such that the cooperative interaction of  MLL and  CREB with  CBP would play a role in regulating these genes (Fig.  7).
# ::save-date Sun Nov 8, 2015 ::file bio_chicago_2015_36162.txt
(p / predict-01 :quant 1
      :ARG0 (s / study-01
            :mod (t / this))
      :ARG1 (e / exist-01
            :ARG1 (o / overlap-01
                  :ARG0 (a2 / and
                        :op1 (g / gene
                              :ARG1-of (t2 / target-01
                                    :ARG0 p3))
                        :op2 (g2 / gene
                              :ARG1-of (t3 / target-01
                                    :ARG0 p5))))
            :purpose (p2 / play-02
                  :ARG0 (i / interact-01
                        :ARG0 (a / and
                              :op1 (p3 / protein :name (n / name :op1 "MLL"))
                              :op2 (p4 / protein :name (n2 / name :op1 "CREB")))
                        :ARG1 (p5 / protein :name (n3 / name :op1 "CBP"))
                        :ARG2-of (c / cooperate-01))
                  :ARG1 (r / regulate-01
                        :ARG0 i
                        :ARG1 a2)))
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod 7)))

# ::id bio.chicago_2015.36163 ::date 2015-10-27T08:31:09 ::annotator SDL-AMR-09 ::preferred
# ::snt Together, these results showed that the coiled-coil domain of  PML was required for the association of  PML with  Sp1 in vitro.
# ::save-date Sun Nov 8, 2015 ::file bio_chicago_2015_36163.txt
(s / show-01
      :ARG0 (t2 / thing
            :mod (t3 / this)
            :ARG2-of (r / result-01))
      :ARG1 (r2 / require-01
            :ARG0 (a / associate-01
                  :ARG1 p
                  :ARG2 (p2 / protein :name (n2 / name :op1 "Sp1"))
                  :manner (i / in-vitro))
            :ARG1 (p3 / protein-segment :name (n3 / name :op1 "coiled-coil")
                  :part-of (p / protein :name (n / name :op1 "PML"))))
      :mod (t / together))

# ::id bio.chicago_2015.36212 ::date 2015-10-27T08:39:36 ::annotator SDL-AMR-09 ::preferred
# ::snt Receptor serine/ threonine kinase implicated in the control of  Drosophila body pattern by   decapentaplegic..
# ::save-date Sun Nov 8, 2015 ::file bio_chicago_2015_36212.txt
(e / enzyme :name (n / name :op1 "receptor" :op2 "serine/threonine" :op3 "kinase")
      :ARG1-of (i / implicate-01
            :ARG2 (c / control-01
                  :ARG0 (p2 / protein :name (n4 / name :op1 "decapentaplegic"))
                  :ARG1 (p / pattern-01
                        :ARG2 (b / body
                              :mod (o / organism :name (n3 / name :op1 "Drosophila")))))))

# ::id bio.chicago_2015.36218 ::date 2015-10-27T09:42:36 ::annotator SDL-AMR-09 ::preferred
# ::snt In contrast to many soluble cytokines,  UPD is associated with  ECM (extracellular matrix), which may help it bind to the receptor and limit the range of activity of the ligand.
# ::save-date Sat Feb 13, 2016 ::file bio_chicago_2015_36218.txt
(c / contrast-01
      :ARG1 (a / associate-01
            :ARG1 (p / protein :name (n / name :op1 "UPD"))
            :ARG2 (m2 / matrix
                  :ARG0-of (h / help-01
                        :ARG1 p
                        :ARG2 (a2 / and
                              :op1 (b / bind-01
                                    :ARG1 p
                                    :ARG2 (r / receptor))
                              :op2 (l / limit-01
                                    :ARG1 (r2 / range-01
                                          :ARG1 (a3 / activity-06
                                                :ARG0 (l2 / ligand)))))
                        :ARG1-of (p2 / possible-01))
                  :mod (e / extracellular)))
      :ARG2 (c2 / cytokine
            :mod (s / soluble)
            :quant (m / many)))

# ::id bio.chicago_2015.36244 ::date 2015-10-27T08:20:02 ::annotator SDL-AMR-09 ::preferred
# ::snt Overexpression of  ARC Inhibits Apoptosis Induced by Caspases in 293T Cells.
# ::save-date Wed Jan 13, 2016 ::file bio_chicago_2015_36244.txt
(i / inhibit-01
      :ARG0 (o / overexpress-01
            :ARG1 (p / protein :name (n2 / name :op1 "ARC")))
      :ARG1 (a / apoptosis
            :ARG2-of (i2 / induce-01
                  :ARG0 (p2 / protein-family :name (n3 / name :op1 "caspase"))
                  :location (c / cell-line :name (n / name :op1 "293T")))))

# ::id bio.chicago_2015.36265 ::date 2015-10-27T08:23:31 ::annotator SDL-AMR-09 ::preferred
# ::snt activator interaction (through  Ada2,  Gcn5, and  Ada3),  histone acetylation (by  Gcn5), and  TBP interaction (through  Spt8 and  Spt3).
# ::save-date Sun Nov 8, 2015 ::file bio_chicago_2015_36265.txt
(a2 / and
      :op1 (i / interact-01
            :ARG1 (m / molecular-physical-entity
                  :ARG0-of (a3 / activate-01))
            :instrument (a5 / and
                  :op1 (p3 / protein :name (n6 / name :op1 "Ada2"))
                  :op2 p5
                  :op3 (p4 / protein :name (n7 / name :op1 "Ada3"))))
      :op2 (a / acetylate-01
            :ARG1 (p / protein :name (n / name :op1 "histone"))
            :ARG2 (p5 / protein :name (n5 / name :op1 "Gcn5")))
      :op3 (i2 / interact-01
            :ARG1 (p2 / protein :name (n2 / name :op1 "TBP"))
            :instrument (a4 / and
                  :op1 (p7 / protein :name (n3 / name :op1 "Spt8"))
                  :op2 (p6 / protein :name (n4 / name :op1 "Spt3")))))

# ::id bio.chicago_2015.36278 ::date 2015-10-27T06:52:46 ::annotator SDL-AMR-09 ::preferred
# ::snt The molecular mechanisms of   tinman induction by  Dpp have largely been clarified.
# ::save-date Sun Nov 8, 2015 ::file bio_chicago_2015_36278.txt
(c / clarify-10
      :ARG1 (m / mechanism
            :mod (m2 / molecule)
            :instrument-of (i / induce-01
                  :ARG0 (p / protein :name (n2 / name :op1 "Dpp"))
                  :ARG2 (p2 / protein :name (n / name :op1 "tinman"))))
      :degree (l / large))

# ::id bio.chicago_2015.36299 ::date 2015-10-27T06:56:59 ::annotator SDL-AMR-09 ::preferred
# ::snt The interaction of   p110C with  PAK1 occurred within the residues 210 - 332 of  PAK1.
# ::save-date Sun Nov 8, 2015 ::file bio_chicago_2015_36299.txt
(i / interact-01
      :ARG0 (e / enzyme :name (n / name :op1 "p110C"))
      :ARG1 (e2 / enzyme :name (n2 / name :op1 "PAK1"))
      :location (b / between
            :op1 (r / residue :mod 210)
            :op2 (r2 / residue :mod 332)
            :part-of e2))

# ::id bio.chicago_2015.36305 ::date 2015-10-27T07:04:05 ::annotator SDL-AMR-09 ::preferred
# ::snt The  protein phosphatase activity is involved in  PTEN downregulation of  IGF-II signaling
# ::save-date Sun Nov 1, 2015 ::file bio_chicago_2015_36305.txt
(i / involve-01
      :ARG1 (a / activity-06
            :ARG1 (e / enzyme :name (n / name :op1 "protein" :op2 "phosphatase")))
      :ARG2 (d / downregulate-01
            :ARG1 (s / signal-07
                  :ARG0 (p2 / protein :name (n3 / name :op1 "IGF-II")))
            :ARG2 (p / protein :name (n2 / name :op1 "PTEN"))))

# ::id bio.chicago_2015.36312 ::date 2015-10-27T07:21:08 ::annotator SDL-AMR-09 ::preferred
# ::snt ( D) Direct interaction of  rAxin with  beta-catenin.
# ::save-date Sun Nov 8, 2015 ::file bio_chicago_2015_36312.txt
(i / interact-01 :li "D"
      :ARG0 (p / protein :name (n2 / name :op1 "rAxin"))
      :ARG1 (p2 / protein :name (n / name :op1 "beta-catenin"))
      :ARG1-of (d / direct-02))

# ::id bio.chicago_2015.36320 ::date 2015-10-27T07:24:35 ::annotator SDL-AMR-09 ::preferred
# ::snt JIP1 and  JIP2 selectively bind components of the  JNK signaling cascade such as  JNK (MAP kinase),  MKK7 (MAP kinase kinase), and mixed  lineage kinase family proteins (MAP kinase kinase kinase) ( 23,  24).
# ::save-date Sun Nov 8, 2015 ::file bio_chicago_2015_36320.txt
(b / bind-01
      :ARG1 (a2 / and
            :op1 (p2 / protein :name (n / name :op1 "JIP1"))
            :op2 (p3 / protein :name (n2 / name :op1 "JIP2")))
      :ARG2 (c2 / component
            :part-of (p4 / pathway :name (n3 / name :op1 "JNK")
                  :ARG0-of (s2 / signal-07))
            :example (a3 / and
                  :op1 (e / enzyme :name (n4 / name :op1 "JNK"))
                  :op2 (e3 / enzyme :name (n6 / name :op1 "MKK7"))
                  :op3 (e4 / enzyme :name (n5 / name :op1 "MAP" :op2 "kinase" :op3 "kinase" :op4 "kinase"))))
      :manner (s / selective)
      :ARG1-of (d / describe-01
            :ARG0 (p / publication
                  :ARG1-of (c / cite-01
                        :ARG2 (a / and :op1 23 :op2 24)))))

# ::id bio.chicago_2015.36321 ::date 2015-10-27T08:56:44 ::annotator SDL-AMR-09 ::preferred
# ::snt Similarly, treatment of cells with okadaic acid inhibited  DLK association with  JIP and resulted in  DLK dimerization in the presence of  JIP.
# ::save-date Fri Jan 15, 2016 ::file bio_chicago_2015_36321.txt
(a / and
      :op1 (i / inhibit-01
            :ARG0 (t / treat-04
                  :ARG1 (c / cell)
                  :ARG2 (s / small-molecule :name (n3 / name :op1 "okadaic" :op2 "acid")))
            :ARG1 (a3 / associate-01
                  :ARG1 (p / protein :name (n / name :op1 "DLK"))
                  :ARG2 (p2 / protein :name (n2 / name :op1 "JIP"))))
      :op2 (r / result-01
            :ARG1 t
            :ARG2 (d / dimerize-01
                  :ARG1 p
                  :condition (p3 / present-02
                        :ARG1 p2)))
      :ARG1-of (r2 / resemble-01))

# ::id bio.chicago_2015.36328 ::date 2015-10-27T09:00:44 ::annotator SDL-AMR-09 ::preferred
# ::snt Concomitant with the insulin-stimulated decrease in association between  Rap1 and  Raf1, there was a reciprocal increase in the amount of  Raf1 that was associated with  Ras (Figure  1B).
# ::save-date Sun Jan 17, 2016 ::file bio_chicago_2015_36328.txt
(i / increase-01
      :ARG1 (a / amount
            :quant-of (e / enzyme :name (n / name :op1 "Raf1"))
            :ARG1-of (a2 / associate-01
                  :ARG2 (e2 / enzyme :name (n2 / name :op1 "Ras"))))
      :time (d / decrease-01
            :ARG1 (a3 / associate-01
                  :ARG1 (e3 / enzyme :name (n3 / name :op1 "Rap1"))
                  :ARG2 e)
            :ARG1-of (s / stimulate-01
                  :ARG0 (p / protein :name (n4 / name :op1 "insulin"))))
      :mod (r / reciprocal)
      :ARG1-of (d2 / describe-01
            :ARG0 (f / figure :mod "1B")))

# ::id bio.chicago_2015.36331 ::date 2015-10-27T09:02:44 ::annotator SDL-AMR-09 ::preferred
# ::snt Colocalization of   ASIP with  aPKC and  ZO-1  at cell junctions in  rat intestinal epithelium and hepatic  bile capillaries.
# ::save-date Tue Feb 2, 2016 ::file bio_chicago_2015_36331.txt
(c / colocalize-01
      :ARG1 (a3 / and
            :op1 (p3 / protein :name (n3 / name :op1 "ASIP"))
            :op2 (a2 / and
                  :op1 (e2 / enzyme :name (n / name :op1 "aPKC"))
                  :op2 (p2 / protein :name (n2 / name :op1 "ZO-1"))))
      :ARG2 (j / junction
            :mod (c2 / cell)
            :location (a / and
                  :op1 (e / epithelium
                        :source (i / intestine
                              :mod (r / rat)))
                  :op2 (c3 / capillary
                        :source (b / bile
                              :mod (h / hepatic))))))

# ::id bio.chicago_2015.36349 ::date 2015-10-27T08:40:17 ::annotator SDL-AMR-09 ::preferred
# ::snt Compartment boundaries and the control of  Drosophila limb pattern by  hedgehog protein.
# ::save-date Sun Nov 8, 2015 ::file bio_chicago_2015_36349.txt
(a / and
      :op1 (b / boundary
            :mod (c2 / compartment))
      :op2 (c / control-01
            :ARG0 (p / protein-family :name (n / name :op1 "hedgehog" :op2 "protein"))
            :ARG1 (p2 / pattern-01
                  :ARG2 (l / limb
                        :mod (o / organism :name (n2 / name :op1 "Drosophila"))))))

# ::id bio.chicago_2015.36384 ::date 2015-10-27T07:39:02 ::annotator SDL-AMR-09 ::preferred
# ::snt To address the issue, we determined the molecular interaction of  QRS with  ASK1 in 293 cells.
# ::save-date Sun Nov 8, 2015 ::file bio_chicago_2015_36384.txt
(d / determine-01
      :ARG0 w
      :ARG1 (i2 / interact-01
            :ARG0 (m2 / macro-molecular-complex :name (n / name :op1 "QRS"))
            :ARG1 (e / enzyme :name (n2 / name :op1 "ASK1"))
            :ARG2 (m / molecule)
            :location (c / cell :quant 293))
      :purpose (a / address-02
            :ARG0 (w / we)
            :ARG1 (i / issue-02)))

# ::id bio.chicago_2015.36390 ::date 2015-10-27T07:43:18 ::annotator SDL-AMR-09 ::preferred
# ::snt Figure  7C shows that in contrast to  Irak,  Irak D358N did not activate  p38 in COS-1 cells, although both proteins were expressed at a comparable level.
# ::save-date Fri Jan 15, 2016 ::file bio_chicago_2015_36390.txt
(h / have-concession-91
      :ARG1 (c / contrast-01
            :ARG1 (p / protein :name (n / name :op1 "Irak"))
            :ARG2 (a / activate-01 :polarity -
                  :ARG0 (p2 / protein :name (n2 / name :op1 "Irak" :op2 "D358N"))
                  :ARG1 (e2 / enzyme :name (n4 / name :op1 "p38"))
                  :location (c2 / cell-line :name (n3 / name :op1 "COS-1"))))
      :ARG2 (e / express-03
            :ARG2 (a2 / and
                  :op1 p
                  :op2 p2)
            :mod (l / level
                  :ARG1-of (c3 / comparable-03)))
      :ARG1-of (s / show-01
            :ARG0 (f / figure :mod "7C")))

# ::id bio.chicago_2015.36404 ::date 2015-10-27T06:33:44 ::annotator SDL-AMR-09 ::preferred
# ::snt The   fat facets gene is required for   Drosophila eye and embryo development.
# ::save-date Sun Nov 8, 2015 ::file bio_chicago_2015_36404.txt
(r / require-01
      :ARG0 (d / develop-01
            :ARG1 (o / organism :name (n / name :op1 "Drosophila"))
            :ARG2 (a / and
                  :op1 (e / eye)
                  :op2 (e2 / embryo)))
      :ARG1 (g / gene :name (n2 / name :op1 "fat" :op2 "facets")))

# ::id bio.chicago_2015.36407 ::date 2015-10-27T06:43:47 ::annotator SDL-AMR-09 ::preferred
# ::snt B,  HEL cells were exposed to increasing concentrations of chelerythrine for 30 min prior to the potentiation of  PGE1-stimulated  AC activity by the addition of  ethanol (200 mM EtOH) or PDBu (100 nM).
# ::save-date Sat Feb 13, 2016 ::file bio_chicago_2015_36407.txt
(e / expose-01 :li "B"
      :ARG1 (c2 / cell :name (n2 / name :op1 "HEL"))
      :ARG2 (c3 / concentrate-02
            :ARG1 (s3 / small-molecule :name (n / name :op1 "chelerythrine"))
            :ARG1-of (i / increase-01))
      :duration (t / temporal-quantity :quant 30
            :unit (m2 / minute))
      :time (p / prior
            :op1 (p2 / potentiate-01
                  :ARG1 (a2 / activity-06
                        :ARG0 (e2 / enzyme :name (n3 / name :op1 "AC"))
                        :ARG1-of (s / stimulate-01
                              :ARG0 (s2 / small-molecule :name (n4 / name :op1 "PGE1"))
                              :ARG2 (a3 / add-02
                                    :ARG1 (o / or
                                          :op1 (e4 / ethanol
                                                :quant (c6 / concentration-quantity :quant 200
                                                      :unit (m / micromolar)))
                                          :op2 (s4 / small-molecule :name (n5 / name :op1 "PDBu")
                                                :quant (c5 / concentration-quantity :quant 100
                                                      :unit (n6 / nanomolar))))))))))

# ::id bio.chicago_2015.36416 ::date 2015-10-27T10:34:16 ::annotator SDL-AMR-09 ::preferred
# ::snt The results showed that the 306-amino acid region between amino acids 827 and 1132 in the C-terminal half of  GLI3 bound to  CBP with almost the same efficiency as full-length  GLI3.
# ::save-date Wed Mar 2, 2016 ::file bio_chicago_2015_36416.txt
(s / show-01
      :ARG0 (t / thing
            :ARG2-of (r / result-01))
      :ARG1 (b / bind-01
            :ARG1 (r2 / region :quant 306
                  :mod (a2 / amino-acid)
                  :location (b2 / between
                        :op1 (a3 / amino-acid :mod 827)
                        :op2 (a4 / amino-acid :mod 1132)
                        :location (h / half
                              :part-of (p2 / protein-segment :name (n3 / name :op1 "C-terminus")
                                    :part-of p3))))
            :ARG2 (p / protein :name (n / name :op1 "CBP"))
            :manner (e / efficient-01
                  :ARG1 p
                  :ARG1-of (s2 / same-01
                        :ARG2 (p3 / protein :name (n2 / name :op1 "GLI3")
                              :ARG1-of (l / long-03
                                    :mod (f / full))))
                  :degree (a / almost))))

# ::id bio.chicago_2015.36428 ::date 2015-10-27T10:24:58 ::annotator SDL-AMR-09 ::preferred
# ::snt It appears that  Su(fu) binds directly to  Fu and  Ci, but not to  Cos2, and that the bulk of these interactions are stable in both the presence and absence of Hh.
# ::save-date Sun Nov 8, 2015 ::file bio_chicago_2015_36428.txt
(a / appear-01
      :ARG1 (a2 / and
            :op1 (c / contrast-01
                  :ARG1 (b2 / bind-01
                        :ARG1 (p3 / protein :name (n2 / name :op1 "Su(fu)"))
                        :ARG2 (a4 / and
                              :op1 (p4 / protein :name (n3 / name :op1 "Fu"))
                              :op2 (p5 / protein :name (n4 / name :op1 "Ci")))
                        :ARG1-of (d / direct-02))
                  :ARG2 (b3 / bind-01 :polarity -
                        :ARG1 p3
                        :ARG2 (p6 / protein :name (n5 / name :op1 "Cos2"))))
            :op2 (s / stable-03
                  :ARG1 (b / bulk-01
                        :ARG1 (i / interact-01
                              :mod (t / this)))
                  :condition (a5 / and
                        :op1 (p / present-02
                              :ARG2 (p2 / protein :name (n / name :op1 "Hh")))
                        :op3 (a3 / absent-01
                              :ARG1 p2)))))

# ::id bio.chicago_2015.36448 ::date 2015-10-27T10:32:51 ::annotator SDL-AMR-09 ::preferred
# ::snt Phosphorylation of the  alpha-subunit of  eIF2, catalysed by any of several  eIF2 kinases, leads to inhibition of  eIF2B since  eIF2(alphaP) is a potent competitive inhibitor of  eIF2B (reviewed in  Clemens, 1996;  Hinnebusch, 2000).
# ::save-date Sun Nov 8, 2015 ::file bio_chicago_2015_36448.txt
(l / lead-03
      :ARG0 (p2 / phosphorylate-01
            :ARG1 (p / protein-segment :name (n3 / name :op1 "alpha-subunit")
                  :ARG1-of (c3 / catalyze-01
                        :ARG0 (k / kinase
                              :ARG1-of (i4 / include-91
                                    :ARG2 (k2 / kinase :name (n6 / name :op1 "eIF2")
                                          :quant (s / several)))
                              :mod (a / any)))
                  :part-of p3))
      :ARG2 (i2 / inhibit-01
            :ARG1 p4)
      :ARG1-of (c / cause-01
            :ARG0 (p3 / protein :name (n / name :op1 "eIF2(alphaP)")
                  :ARG0-of (i3 / inhibit-01
                        :ARG1 (p4 / protein :name (n2 / name :op1 "eIF2B"))
                        :ARG0-of (c2 / compete-01))
                  :mod (p5 / potent)))
      :ARG1-of (r / review-01
            :ARG0 (a3 / and
                  :op1 (p8 / publication-91
                        :ARG0 (p6 / person :name (n4 / name :op1 "Clemens"))
                        :time (d / date-entity :year 1996))
                  :op2 (p9 / publication-91
                        :ARG0 (p7 / person :name (n5 / name :op1 "Hinnebusch"))
                        :time (d2 / date-entity :year 2000)))))

# ::id bio.chicago_2015.36507 ::date 2015-10-27T09:51:43 ::annotator SDL-AMR-09 ::preferred
# ::snt Overexpression of  CrkL did not significantly change the time course of  Epo-induced  JNK activation, although the activation level at the peak was moderately enhanced (Fig.  5 B).
# ::save-date Sun Jan 17, 2016 ::file bio_chicago_2015_36507.txt
(h / have-concession-91
      :ARG1 (c / change-01 :polarity -
            :ARG0 (o / overexpress-01
                  :ARG2 (p2 / protein :name (n / name :op1 "CrkL")))
            :ARG1 (c2 / course-01
                  :ARG0 (a2 / activate-01
                        :ARG1 (e2 / enzyme :name (n2 / name :op1 "JNK"))
                        :ARG2-of (i / induce-01
                              :ARG0 (s2 / small-molecule :name (n3 / name :op1 "Epo"))))
                  :mod (t / time))
            :ARG1-of (s / significant-02))
      :ARG2 (e / enhance-01
            :ARG1 (l / level
                  :degree-of (a / activate-01)
                  :location (p / peak))
            :ARG1-of (m / moderate-01))
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod "5B")))

# ::id bio.chicago_2015.36510 ::date 2015-10-27T09:15:12 ::annotator SDL-AMR-09 ::preferred
# ::snt APP and  FE65 colocalize with  actin and  Mena, an  Abl-associated signaling protein thought to regulate  actin dynamics, in lamellipodia.
# ::save-date Tue Feb 2, 2016 ::file bio_chicago_2015_36510.txt
(c / colocalize-01
      :ARG1 (a4 / and
            :op1 (a / and
                  :op1 (p / protein :name (n / name :op1 "APP"))
                  :op2 (p2 / protein :name (n2 / name :op1 "FE65")))
            :op2 (a2 / and
                  :op1 (p3 / protein :name (n3 / name :op1 "actin"))
                  :op2 (p4 / protein :name (n4 / name :op1 "Mena")
                        :ARG1-of (m / mean-01
                              :ARG2 (p5 / protein
                                    :ARG0-of (s / signal-07)
                                    :ARG1-of (a3 / associate-01
                                          :ARG2 (p7 / protein :name (n5 / name :op1 "Abl")))
                                    :ARG1-of (t / think-01
                                          :ARG2 (r / regulate-01
                                                :ARG0 p4
                                                :ARG1 (d / dynamic
                                                      :mod p3)
                                                :location (p6 / protein :name (n6 / name :op1 "lamellipodia"))))))))))

# ::id bio.chicago_2015.36540 ::date 2015-10-27T09:03:33 ::annotator SDL-AMR-09 ::preferred
# ::snt CRIPT, a  Novel Postsynaptic Protein that Binds to the  Third PDZ Domain of  PSD-95/SAP90.
# ::save-date Sun Nov 8, 2015 ::file bio_chicago_2015_36540.txt
(p / protein :name (n / name :op1 "CRIPT")
      :ARG1-of (m / mean-01
            :ARG2 (p2 / protein
                  :mod (p3 / postsynaptic)
                  :mod (n2 / novel)
                  :ARG1-of (b / bind-01
                        :ARG2 (p4 / protein-segment :name (n3 / name :op1 "PDZ")
                              :part-of (p5 / protein-family :name (n4 / name :op1 "PSD-95/SAP90"))
                              :ord (o / ordinal-entity :value 3))))))

# ::id bio.chicago_2015.36582 ::date 2015-10-27T09:11:31 ::annotator SDL-AMR-09 ::preferred
# ::snt We previously demonstrated that  Wnt-11 and  Wnt-1 activate  RhoA via  Fz/Dvl signaling, and we identified  Daam1, a  Formin-homology protein, as being required for Wnt/ Fz/Dvl activation of  RhoA,  Wnt-induced Dvl-RhoA complex formation, and  CE movements during   Xenopus gastrulation (Habas et al. 2001  ).
# ::save-date Sun Nov 8, 2015 ::file bio_chicago_2015_36582.txt
(a / and
      :op1 (d3 / demonstrate-01
            :ARG0 (w / we)
            :ARG1 (a3 / activate-01
                  :ARG0 (a4 / and
                        :op1 (p11 / protein :name (n2 / name :op1 "Wnt-11"))
                        :op2 (p12 / protein :name (n3 / name :op1 "Wnt-1")))
                  :ARG1 (p4 / protein :name (n4 / name :op1 "RhoA"))
                  :manner (s / signal-07
                        :ARG0 (s2 / slash
                              :op1 (p5 / protein :name (n5 / name :op1 "Fz"))
                              :op2 (p6 / protein :name (n6 / name :op1 "Dvl")))))
            :time (p3 / previous))
      :op2 (i / identify-01
            :ARG0 w
            :ARG1 (r / require-01
                  :ARG0 (a6 / and
                        :op1 (a5 / activate-01
                              :ARG0 (s3 / slash
                                    :op1 (p9 / protein :name (n9 / name :op1 "Wnt"))
                                    :op2 p5
                                    :op3 p6)
                              :ARG1 p4)
                        :op2 (f / form-01
                              :ARG1 (m2 / macro-molecular-complex
                                    :part p6
                                    :part p4)
                              :ARG2-of (i2 / induce-01
                                    :ARG0 p9))
                        :op3 (m3 / move-01
                              :time (g3 / gastrulate-00
                                    :ARG0 (o2 / organism :name (n11 / name :op1 "Xenopus")))
                              :mod (e / extension
                                    :mod (c / convergent))))
                  :ARG1 (p7 / protein :name (n7 / name :op1 "Daam1")
                        :ARG1-of (m / mean-01
                              :ARG2 (p8 / protein :name (n8 / name :op1 "Formin-homology"))))))
      :ARG1-of (d2 / describe-01
            :ARG0 (p10 / publication-91
                  :ARG0 (a2 / and
                        :op1 (p / person :name (n / name :op1 "Habas"))
                        :op2 (p2 / person
                              :mod (o / other)))
                  :time (d / date-entity :year 2001))))

# ::id bio.chicago_2015.36590 ::date 2015-10-27T11:06:21 ::annotator SDL-AMR-09 ::preferred
# ::snt To verify that both the  AHR and  ARNT interact with  TFIIB, similar coaffinity precipitation experiments were performed, except that we used either  immobilized AHR or  ARNT and 35S-TFIIB (Fig.  1B).
# ::save-date Fri Nov 27, 2015 ::file bio_chicago_2015_36590.txt
(p / perform-02
      :ARG0 w
      :ARG1 (e / experiment-01
            :ARG1 (p2 / precipitate-01
                  :ARG1 (c / coaffinity))
            :ARG1-of (r / resemble-01))
      :purpose (v / verify-01
            :ARG0 w
            :ARG1 (i / interact-01
                  :ARG0 (a / and
                        :op1 (p3 / protein :name (n / name :op1 "AHR"))
                        :op2 (p4 / protein :name (n2 / name :op1 "ARNT")))
                  :ARG1 (p5 / protein :name (n3 / name :op1 "TFIIB"))))
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod "1B"))
      :ARG2-of (e2 / except-01
            :ARG1 (u / use-01
                  :ARG0 (w / we)
                  :ARG1 (a2 / and
                        :op1 (o / or
                              :op1 p3
                              :op2 p4
                              :ARG1-of (i2 / immobilize-01))
                        :op2 (p6 / protein :name (n4 / name :op1 "35S-TFIIB"))))))

# ::id bio.chicago_2015.36667 ::date 2015-10-27T08:13:57 ::annotator SDL-AMR-09 ::preferred
# ::snt E1A, an adenoviral oncoprotein, interacts with  p300 or  CBP and directly inhibits the  histone acetyltransferase activity ( 29).
# ::save-date Wed Dec 9, 2015 ::file bio_chicago_2015_36667.txt
(a / and
      :op1 (i / interact-01
            :ARG0 (p2 / protein :name (n / name :op1 "E1A")
                  :ARG0-of (c2 / cause-01
                        :ARG1 (d3 / disease :wiki "Cancer" :name (n5 / name :op1 "cancer")))
                  :mod (a3 / adenoviral))
            :ARG1 (o / or
                  :op1 (p3 / protein :name (n2 / name :op1 "p300"))
                  :op2 (p4 / protein :name (n3 / name :op1 "CBP"))))
      :op2 (i2 / inhibit-01
            :ARG1 (a2 / activity-06
                  :ARG0 (e / enzyme :name (n4 / name :op1 "histone" :op2 "acetyltransferase")))
            :ARG1-of (d2 / direct-02))
      :ARG1-of (d / describe-01
            :ARG0 (p / publication
                  :ARG1-of (c / cite-01
                        :ARG2 29))))

# ::id bio.chicago_2015.36670 ::date 2015-10-27T07:54:38 ::annotator SDL-AMR-09 ::preferred
# ::snt Binding of the  4E-BPs to  eIF4E is regulated by phosphorylation ( Lin et al. 1994  ; Pause et al. 1994  ).
# ::save-date Fri Nov 27, 2015 ::file bio_chicago_2015_36670.txt
(r / regulate-01
      :ARG0 (p / phosphorylate-01)
      :ARG1 (b / bind-01
            :ARG1 (p2 / protein :name (n / name :op1 "4E-BP"))
            :ARG2 (p3 / protein :name (n2 / name :op1 "eIF4E")))
      :ARG1-of (d / describe-01
            :ARG0 (a4 / and
                  :op1 (p8 / publication-91
                        :ARG0 (a2 / and
                              :op1 (p4 / person :name (n3 / name :op1 "Lin"))
                              :op2 (p5 / person
                                    :mod (o / other)))
                        :time (d2 / date-entity :year 1994))
                  :op2 (p9 / publication-91
                        :ARG0 (a3 / and
                              :op1 (p7 / person :name (n4 / name :op1 "Pause"))
                              :op2 (p6 / person
                                    :mod (o2 / other)))
                        :time d2))))

# ::id bio.chicago_2015.36675 ::date 2015-10-27T10:45:31 ::annotator SDL-AMR-09 ::preferred
# ::snt To test if oxidative stress modulates the activation of  ERK1/2,  p38 or  CREB induced by  NGF and  EGF, PC12 cells were briefly (10 min) exposed to 200  M H2O2 before treatment with  NGF or  EGF.
# ::save-date Sun Jan 17, 2016 ::file bio_chicago_2015_36675.txt
(e / expose-01
      :ARG1 (c / cell-line :name (n / name :op1 "PC12"))
      :ARG2 (s2 / small-molecule :name (n2 / name :op1 "H2O2")
            :mod (c2 / concentration-quantity :quant 200
                  :unit (m4 / molar)))
      :duration (t / temporal-quantity :quant 10
            :unit (m2 / minute))
      :manner (b / brief)
      :time (b2 / before
            :op1 (t2 / treat-04
                  :ARG1 c
                  :ARG2 (o / or
                        :op1 (p3 / protein :name (n3 / name :op1 "NGF"))
                        :op2 (p2 / protein :name (n4 / name :op1 "EGF")))))
      :purpose (t3 / test-01
            :ARG2 (m / modulate-01 :mode interrogative
                  :ARG0 (s3 / stress-02
                        :ARG0 (o4 / oxidize-01))
                  :ARG1 (a / activate-01
                        :ARG1 (o3 / or
                              :op1 (e2 / enzyme :name (n5 / name :op1 "ERK1/2"))
                              :op2 (e3 / enzyme :name (n6 / name :op1 "p38"))
                              :op3 (p / protein :name (n7 / name :op1 "CREB")))
                        :ARG2-of (i / induce-01
                              :ARG0 (a2 / and
                                    :op1 p3
                                    :op2 p2))))))

# ::id bio.chicago_2015.36678 ::date 2015-10-27T11:05:28 ::annotator SDL-AMR-09 ::preferred
# ::snt Together with cell culture experiments showing binding and phosphorylation of  mPER1 and  mPER2 by  CKI  and research in   Drosophila showing the importance of the  CKI  homolog DOUBLE-TIME for destabilizing  dPER, the genetic data in both  rodents and  humans strongly suggest that  CKI -dependent phosphorylation of  PER proteins is an essential and ancient part of the circadian clock mechanism (references in  Toh et al., 2001  ).
# ::save-date Thu Nov 12, 2015 ::file bio_chicago_2015_36678.txt
(s / suggest-01
      :ARG0 (d2 / data
            :topic (g / gene)
            :source (a / and
                  :op1 (r / rodent)
                  :op2 (h / human)))
      :ARG1 (p2 / part
            :mod (e / essential)
            :mod (a2 / ancient)
            :domain (p3 / phosphorylate-01
                  :ARG1 (p4 / protein :name (n2 / name :op1 "PER"))
                  :ARG0-of (d3 / depend-01
                        :ARG1 (e2 / enzyme :name (n / name :op1 "CKI"))))
            :part-of (m / mechanism
                  :mod (c / clock
                        :mod (c2 / circadian))))
      :ARG1-of (s2 / strong-02)
      :accompanier (a3 / and
            :op1 (e3 / experiment-01
                  :ARG1 (c3 / culture
                        :mod (c4 / cell))
                  :ARG0-of (s3 / show-01
                        :ARG1 (a4 / and
                              :op1 (b / bind-01
                                    :ARG0 e2
                                    :ARG1 (a5 / and
                                          :op1 (p8 / protein :name (n3 / name :op1 "mPER1"))
                                          :op2 (p9 / protein :name (n4 / name :op1 "mPER2"))))
                              :op2 (p / phosphorylate-01
                                    :ARG1 a5
                                    :ARG2 e2))))
            :op2 (r2 / research-01
                  :ARG1 (o / organism :name (n5 / name :op1 "Drosophila"))
                  :ARG0-of (s4 / show-01
                        :ARG1 (i / importance
                              :purpose (d4 / destabilize-01
                                    :ARG1 (p11 / protein :name (n7 / name :op1 "dPER")))
                              :mod (p10 / protein :name (n9 / name :op1 "CKI" :op2 "homolog" :op3 "DOUBLE-TIME"))))))
      :ARG1-of (r3 / reference-04
            :location (p5 / publication-91
                  :ARG0 (a6 / and
                        :op1 (p6 / person :name (n8 / name :op1 "Toh"))
                        :op2 (p7 / person
                              :mod (o2 / other)))
                  :time (d / date-entity :year 2001))))

# ::id bio.chicago_2015.36682 ::date 2015-10-28T09:06:49 ::annotator SDL-AMR-09 ::preferred
# ::snt In response to cAMP,  CREB bound to the  CRE enhancer is phosphorylated, which results in recruitment of  CBP/ p300 and eventually transcriptional activation of cAMP-responsive genes.
# ::save-date Sun Jan 17, 2016 ::file bio_chicago_2015_36682.txt
(p / phosphorylate-01
      :ARG1 (p2 / protein :wiki "CREB"
            :name (n / name :op1 "CREB")
            :ARG1-of (b / bind-01
                  :ARG2 (e3 / enzyme :wiki "Cre_recombinase"
                        :name (n2 / name :op1 "CRE")
                        :mod (e / enhancer))))
      :ARG2-of (r / respond-01
            :ARG1 (s / small-molecule :wiki "Cyclic_adenosine_monophosphate"
                  :name (n3 / name :op1 "cAMP")))
      :ARG1-of (r2 / result-01
            :ARG2 (a / and
                  :op1 (r3 / recruit-01
                        :ARG1 (o / or
                              :op1 (p3 / protein :wiki "CREB-binding_protein"
                                    :name (n4 / name :op1 "CBP"))
                              :op2 (p4 / protein :wiki "EP300"
                                    :name (n5 / name :op1 "p300"))))
                  :op2 (a2 / activate-01
                        :ARG1 (g / gene
                              :ARG0-of (r4 / respond-01
                                    :ARG1 s))
                        :mod (t / transcribe-01)
                        :time (e2 / eventual)))))

# ::id bio.chicago_2015.36695 ::date 2015-10-28T09:19:24 ::annotator SDL-AMR-09 ::preferred
# ::snt Association of  DLC with  nNOS in differentiated PC12 cells reduced  nNOS activity.
# ::save-date Wed Nov 4, 2015 ::file bio_chicago_2015_36695.txt
(r / reduce-01
      :ARG0 (a / associate-01
            :ARG1 (p / protein :name (n / name :op1 "DLC"))
            :ARG2 (e / enzyme :name (n2 / name :op1 "nNOS"))
            :location (c / cell-line :name (n3 / name :op1 "PC12")
                  :ARG1-of (d / differentiate-01)))
      :ARG1 (a2 / activity-06
            :ARG0 e))

# ::id bio.chicago_2015.36696 ::date 2015-10-28T09:24:48 ::annotator SDL-AMR-09 ::preferred
# ::snt The time courses of  p38,  ERK1/2 and  CREB phosphorylation induced by  NGF and  EGF.
# ::save-date Sun Jan 17, 2016 ::file bio_chicago_2015_36696.txt
(i / induce-01
      :ARG0 (a2 / and
            :op1 (p4 / protein :name (n4 / name :op1 "NGF"))
            :op2 (p / protein :name (n5 / name :op1 "EGF")))
      :ARG2 (p2 / phosphorylate-01
            :ARG1 (a / and
                  :op1 (e2 / enzyme :name (n / name :op1 "p38"))
                  :op2 (e / enzyme :name (n2 / name :op1 "ERK1/2"))
                  :op3 (p3 / protein :name (n3 / name :op1 "CREB")))
            :duration (c / course
                  :mod (t / time))))

# ::id bio.chicago_2015.36704 ::date 2015-10-28T09:28:27 ::annotator SDL-AMR-09 ::preferred
# ::snt Regulation of  Armadillo by a  Drosophila APC Inhibits Neuronal Apoptosis during Retinal Development.
# ::save-date Wed Nov 4, 2015 ::file bio_chicago_2015_36704.txt
(i / inhibit-01
      :ARG0 (r / regulate-01
            :ARG0 (p / protein :name (n / name :op1 "APC")
                  :source (o / organism :name (n2 / name :op1 "Drosophila")))
            :ARG1 (p2 / protein :name (n3 / name :op1 "Armadillo")))
      :ARG1 (a / apoptosis
            :mod (n4 / neuronal))
      :time (d2 / develop-01
            :ARG2 (r2 / retina)))

# ::id bio.chicago_2015.36735 ::date 2015-10-28T09:33:10 ::annotator SDL-AMR-09 ::preferred
# ::snt NGF  induced co-association of   IRAK  with  TRAF6 and atypical   PKC  binding protein/ p62.
# ::save-date Sun Jan 17, 2016 ::file bio_chicago_2015_36735.txt
(i / induce-01
      :ARG0 (p3 / protein :name (n / name :op1 "NGF"))
      :ARG2 (a3 / associate-01
            :ARG1 (e2 / enzyme :name (n2 / name :op1 "IRAK"))
            :ARG2 (a / and
                  :op1 (p / protein :name (n3 / name :op1 "TRAF6"))
                  :op2 (p2 / protein :name (n4 / name :op1 "p62")
                        :mod (a2 / atypical)
                        :ARG0-of (b / bind-01
                              :ARG1 (e / enzyme :name (n5 / name :op1 "PKC")))))))

# ::id bio.chicago_2015.36749 ::date 2015-10-28T09:39:15 ::annotator SDL-AMR-09 ::preferred
# ::snt PI3K induction of  cyclin D1 was inhibited by a dominant  negative Tcf, and a single  Tcf site in the  cyclin D1 promoter was required for its induction by  IKKalpha and  PI3K.
# ::save-date Fri Feb 5, 2016 ::file bio_chicago_2015_36749.txt
(a / and
      :op1 (i / inhibit-01
            :ARG0 (p2 / protein :name (n3 / name :op1 "Tcf")
                  :ARG2-of (m2 / mutate-01 :mod "-/-")
                  :ARG0-of (d / dominate-01))
            :ARG1 (i2 / induce-01
                  :ARG0 (e / enzyme :name (n / name :op1 "PI3K"))
                  :ARG1 (p / protein :name (n2 / name :op1 "cyclin" :op2 "D1"))))
      :op2 (r / require-01
            :ARG0 (i3 / induce-01
                  :ARG0 (a2 / and
                        :op1 (e2 / enzyme :name (n5 / name :op1 "IKKalpha"))
                        :op2 e)
                  :ARG1 p)
            :ARG1 (s / site
                  :mod p2
                  :ARG1-of (s2 / single-02)
                  :location (m / molecular-physical-entity
                        :ARG0-of (p3 / promote-01
                              :ARG1 p)))))

# ::id bio.chicago_2015.36758 ::date 2015-10-28T09:50:52 ::annotator SDL-AMR-09 ::preferred
# ::snt However,  Zw5 does not bind to   scs``; instead,   scs`` has multiple target sites for the  BEAF ( boundary  element  associated  factor) proteins,  BEAF 32A and  BEAF 32B.
# ::save-date Fri Nov 27, 2015 ::file bio_chicago_2015_36758.txt
(c / contrast-01
      :ARG1 (b / bind-01 :polarity -
            :ARG1 (p / protein :name (n / name :op1 "Zw5"))
            :ARG2 (p5 / protein :name (n2 / name :op1 "scs``")))
      :ARG2-of (i / instead-of-91
            :ARG1 (h / have-03
                  :ARG0 p5
                  :ARG1 (s / site
                        :mod (t2 / target)
                        :quant (m / multiple)
                        :beneficiary (a / and
                              :op1 (p2 / protein :name (n3 / name :op1 "BEAF" :op2 "32A"))
                              :op2 (p3 / protein :name (n4 / name :op1 "BEAF" :op2 "32B"))
                              :ARG1-of (i2 / include-01
                                    :ARG2 (p4 / protein-family :name (n6 / name :op1 "boundary" :op2 "element" :op3 "associated" :op4 "factor"))))))))

# ::id bio.chicago_2015.36797 ::date 2015-10-28T10:03:01 ::annotator SDL-AMR-09 ::preferred
# ::snt More specifically,  cortactin binds and activates the  Arp2/3 complex of  actin polymerizing proteins at sites of peripheral cytoskeletal rearrangement while cross-linking and stabilizing  actin filaments against depolymerization [ 23,  24 and  25].
# ::save-date Wed Nov 4, 2015 ::file bio_chicago_2015_36797.txt
(a / and
      :op1 (b / bind-01
            :ARG0 (p / protein :name (n / name :op1 "cortactin"))
            :ARG1 (m / macro-molecular-complex :name (n2 / name :op1 "Arp2/3")
                  :part (p2 / protein
                        :ARG0-of (p3 / polymerize-01
                              :ARG1 (p4 / protein :name (n3 / name :op1 "actin")))))
            :location (s2 / site
                  :mod (r / rearrange-01
                        :mod (c2 / cytoskeletal)
                        :mod (p5 / peripheral))))
      :op2 (a2 / activate-01
            :ARG0 p
            :ARG1 m)
      :ARG1-of (s3 / specific-02
            :degree (m2 / more))
      :ARG1-of (d2 / describe-01
            :ARG0 (p7 / publication
                  :ARG1-of (c3 / cite-01
                        :ARG2 (a3 / and :op1 23 :op2 24 :op3 25))))
      :time (a4 / and
            :op1 (l / link-01
                  :ARG0 p
                  :ARG1 f
                  :manner (c / cross))
            :op2 (s / stabilize-01
                  :ARG0 p
                  :ARG1 (f / filament
                        :mod p4)
                  :prep-against (d / depolymerize-00))))

# ::id bio.chicago_2015.36801 ::date 2015-10-28T10:15:21 ::annotator SDL-AMR-09 ::preferred
# ::snt TGIF Recruits CtBP To Activated Smad Complexes-- To investigate the possibility that  TGIF can recruit  CtBP to a  TGF-beta-activated Smad complex, COS-1 cells were transfected with  FLAG-tagged CtBP,  HA-tagged TGIF, and  Smad2.
# ::save-date Fri Nov 27, 2015 ::file bio_chicago_2015_36801.txt
(m / multi-sentence
      :snt1 (r / recruit-01
            :ARG0 (p8 / protein :name (n / name :op1 "TGIF"))
            :ARG1 (p / protein :name (n2 / name :op1 "CtBP"))
            :ARG2 (c / complex
                  :mod (p2 / protein :name (n3 / name :op1 "Smad"))
                  :ARG1-of (a / activate-01)))
      :snt2 (t / transfect-01
            :ARG1 (c2 / cell-line :name (n4 / name :op1 "COS-1"))
            :ARG2 (a2 / and
                  :op1 (p3 / protein :name (n5 / name :op1 "CtBP")
                        :ARG1-of (t2 / tag-01
                              :ARG2 (p4 / protein :name (n6 / name :op1 "FLAG"))))
                  :op2 (p10 / protein :name (n7 / name :op1 "TGIF")
                        :ARG1-of (t3 / tag-01
                              :ARG2 (p5 / protein :name (n8 / name :op1 "HA"))))
                  :op3 (p6 / protein :name (n9 / name :op1 "Smad2")))
            :purpose (i / investigate-01
                  :ARG1 (p7 / possible-01
                        :ARG1 (r2 / recruit-01
                              :ARG0 p10
                              :ARG1 p3
                              :ARG2 (c3 / complex
                                    :mod p6
                                    :ARG1-of (a3 / activate-01
                                          :ARG0 (p9 / protein :name (n10 / name :op1 "TGF" :op2 "beta")))))))))

# ::id bio.chicago_2015.36813 ::date 2015-10-28T12:13:02 ::annotator SDL-AMR-09 ::preferred
# ::snt Expression of the RasN17 dominant-negative mutant (deVries-Smits  et al., 1992; Wood  et al., 1992) blocked  EGF-induced  Elk-1 phosphorylation (Figure  5D).
# ::save-date Fri Feb 5, 2016 ::file bio_chicago_2015_36813.txt
(b / block-01
      :ARG0 (e / express-03
            :ARG2 (e2 / enzyme :name (n / name :op1 "Ras")
                  :ARG2-of (m / mutate-01 :value "N17" :mod "-/-")
                  :ARG0-of (d2 / dominate-01))
            :ARG1-of (d3 / describe-01
                  :ARG0 (a3 / and
                        :op1 (p / publication-91
                              :ARG0 (a2 / and
                                    :op1 (p5 / person :name (n5 / name :op1 "deVries-Smits"))
                                    :op2 (p6 / person
                                          :mod (o / other)))
                              :time (d / date-entity :year 1992))
                        :op2 (p7 / publication-91
                              :ARG0 (a / and
                                    :op1 (p8 / person :name (n6 / name :op1 "Wood"))
                                    :op2 p6)
                              :time d))))
      :ARG1 (p3 / phosphorylate-01
            :ARG1 (p4 / protein :name (n3 / name :op1 "Elk-1"))
            :ARG2-of (i / induce-01
                  :ARG0 (p2 / protein :name (n4 / name :op1 "EGF"))))
      :ARG1-of (d5 / describe-01
            :ARG0 (f / figure :mod "5D")))

# ::id bio.chicago_2015.36817 ::date 2015-10-28T12:24:53 ::annotator SDL-AMR-09 ::preferred
# ::snt Rb Interacts with  Histone Deacetylase to Repress Transcription.
# ::save-date Wed Oct 28, 2015 ::file bio_chicago_2015_36817.txt
(i / interact-01
      :ARG0 (p / protein :name (n / name :op1 "Rb"))
      :ARG1 (e / enzyme :name (n2 / name :op1 "Histone" :op2 "Deacetylase"))
      :ARG2 (r / repress-01
            :ARG0 (a / and
                  :op1 p
                  :op2 e)
            :ARG1 (t / transcribe-01)))

# ::id bio.chicago_2015.36902 ::date 2015-10-28T12:27:04 ::annotator SDL-AMR-09 ::preferred
# ::snt However, inhibition of  PKA by  H89 did not inhibit process formation (Figure  7e), contrary to inhibition of MARK by  HD and did not inhibit the phosphorylation of KXGS motifs (Figure  8b, lane 2, staining with 12E8).
# ::save-date Thu Nov 12, 2015 ::file bio_chicago_2015_36902.txt
(c / contrast-01
      :ARG2 (a / and
            :op1 (i / inhibit-01 :polarity -
                  :ARG0 (i2 / inhibit-01
                        :ARG0 (s / small-molecule :name (n / name :op1 "H89"))
                        :ARG1 (e / enzyme :name (n2 / name :op1 "PKA")))
                  :ARG1 (f / form-01
                        :ARG1 (p2 / process-02))
                  :ARG1-of (d / describe-01
                        :ARG0 (f2 / figure :mod "7e"))
                  :ARG1-of (c2 / contrary-01
                        :ARG2 (i3 / inhibit-01
                              :ARG0 (s2 / small-molecule :name (n4 / name :op1 "HD"))
                              :ARG1 (e2 / enzyme :name (n3 / name :op1 "MARK")))))
            :op2 (i4 / inhibit-01 :polarity -
                  :ARG1 (p / phosphorylate-01
                        :ARG1 (p4 / protein-segment :name (n5 / name :op1 "KXGS" :op2 "motif")))
                  :ARG1-of (d2 / describe-01
                        :ARG0 (s3 / stain-01
                              :ARG2 (p3 / protein :name (n6 / name :op1 "12E8"))
                              :location (l / lane :mod 2
                                          :part-of (f3 / figure :mod "8b")))))))

# ::id bio.chicago_2015.36940 ::date 2015-10-28T12:49:41 ::annotator SDL-AMR-09 ::preferred
# ::snt Induction of  LTP by  tetanic stimulation (at Time = 0; see Experimental Procedures) is observed in hippocampal slices from wt ( n = 5) and   - Syn /  (n = 5) mice.
# ::save-date Fri Jan 15, 2016 ::file bio_chicago_2015_36940.txt
(o / observe-01
      :ARG1 (i / induce-01
            :ARG0 (s / simulate-01
                  :mod (t2 / tetanic)
                  :time (t3 / time
                        :ARG1-of (e2 / equal-01
                              :ARG2 0))
                  :mod (s2 / see-01
                        :ARG1 (p / procedure
                              :mod (e / experiment-01))))
            :ARG2 (p2 / potentiate-01
                  :ARG1-of (l / long-03)))
      :location (s3 / slice
            :mod (h / hippocampus)
            :source (a2 / and
                  :op1 (m / mouse :quant 5
                        :mod (w / wild-type))
                  :op2 (m2 / mouse :quant 5
                        :mod (e3 / enzyme :name (n2 / name :op1 "Syn")
                              :ARG2-of (m3 / mutate-01 :mod "-/+"))))))

# ::id bio.chicago_2015.36945 ::date 2015-10-28T12:59:53 ::annotator SDL-AMR-09 ::preferred
# ::snt About 10  min after synthesis, a maximal amount of  gp160 was bound to  calnexin  and  calreticulin and about half remained bound after 25-35 min.
# ::save-date Wed Mar 2, 2016 ::file bio_chicago_2015_36945.txt
(a2 / and
      :op1 (b2 / bind-01
            :ARG1 (a3 / amount
                  :quant-of (p / protein :name (n / name :op1 "gp160"))
                  :quant (m / maximum))
            :ARG2 (a4 / and
                  :op1 (p2 / protein :name (n2 / name :op1 "calnexin"))
                  :op2 (p3 / protein :name (n3 / name :op1 "calreticulin")))
            :time (a7 / after
                  :op1 s
                  :duration (a / about
                        :op1 (t2 / temporal-quantity :quant 10
                              :unit (m3 / minute)))))
      :op2 (r / remain-01
            :ARG1 (a5 / amount
                  :quant (h / half)
                  :quant-of p)
            :ARG3 (b3 / bind-01
                  :ARG1 a5
                  :ARG2 a4)
            :time (a6 / after
                  :op1 (s / synthesize-01)
                  :duration (t / temporal-quantity
                        :quant (v / value-interval :op1 25 :op2 35)
                        :unit (m2 / minute)))))

# ::id bio.chicago_2015.36967 ::date 2015-10-28T13:12:00 ::annotator SDL-AMR-09 ::preferred
# ::snt Phosphorylation of  GST-FKBP46 and  FKBP46 by endogenous Sf9  CKII and  human recombinant casein kinase II.
# ::save-date Wed Nov 4, 2015 ::file bio_chicago_2015_36967.txt
(p2 / phosphorylate-01
      :ARG1 (a / and
            :op1 (p / protein :name (n / name :op1 "GST-FKBP46"))
            :op2 (p3 / protein :name (n2 / name :op1 "FKBP46")))
      :ARG2 (a2 / and
            :op1 (e / enzyme :name (n3 / name :op1 "CKII"))
            :op2 (e2 / enzyme :name (n5 / name :op1 "human" :op2 "recombinant" :op3 "casein" :op4 "kinase" :op5 "II"))
            :mod (e3 / endogenous)
            :source (c / cell-line :name (n4 / name :op1 "Sf9"))))

# ::id bio.chicago_2015.37004 ::date 2015-10-28T13:24:01 ::annotator SDL-AMR-09 ::preferred
# ::snt Furthermore,  LTP induced by either  theta burst or  tetanic stimulation is blocked by pretreating slices with the  TrkB-IgG fusion protein, a protein that  removes BDNF from extracellular fluids (Figurov et al. 1996  ; Kang et al. 1997  ), suggesting that endogenous  BDNF is involved in the induction of  LTP.
# ::save-date Tue Jan 19, 2016 ::file bio_chicago_2015_37004.txt
(a / and
      :op2 (b / block-01
            :ARG0 (p10 / pretreat-01
                  :ARG1 (s2 / slice)
                  :ARG3 (p / protein :name (n2 / name :op1 "TrkB-IgG")
                        :mod (f / fuse-01)
                        :ARG0-of (r / remove-01
                              :ARG1 (p2 / protein :name (n3 / name :op1 "BDNF"))
                              :ARG2 (f2 / fluid
                                    :mod (e / extracellular))
                              :ARG1-of (d3 / describe-01
                                    :ARG0 (a2 / and
                                          :op1 (p4 / publication-91
                                                :ARG0 (a3 / and
                                                      :op1 (p5 / person :name (n5 / name :op1 "Figurov"))
                                                      :op2 (p6 / person
                                                            :mod (o2 / other)))
                                                :time (d / date-entity :year 1996))
                                          :op2 (p7 / publication-91
                                                :ARG0 (a4 / and
                                                      :op1 (p8 / person :name (n6 / name :op1 "Kang"))
                                                      :op2 p6)
                                                :time (d2 / date-entity :year 1997)))))))
            :ARG1 (p11 / potentiate-01
                  :ARG1-of (l / long-03)
                  :ARG2-of (i / induce-01
                        :ARG0 (o / or
                              :op1 (t / theta-burst)
                              :op2 (s / stimulate-01
                                    :mod (t3 / tetanic)))))
            :ARG0-of (s3 / suggest-01
                  :ARG1 (i2 / involve-01
                        :ARG1 (p3 / protein :name (n4 / name :op1 "BDNF")
                              :mod (e2 / endogenous))
                        :ARG2 (i3 / induce-01
                              :ARG2 (p9 / protein))))))

# ::id bio.chicago_2015.37047 ::date 2015-10-28T13:39:32 ::annotator SDL-AMR-09 ::preferred
# ::snt TFIIA interaction with  TBP.
# ::save-date Wed Oct 28, 2015 ::file bio_chicago_2015_37047.txt
(i / interact-01
      :ARG0 (p / protein :name (n / name :op1 "TFIIA"))
      :ARG1 (p2 / protein :name (n2 / name :op1 "TBP")))

# ::id bio.chicago_2015.37055 ::date 2015-10-28T13:40:33 ::annotator SDL-AMR-09 ::preferred
# ::snt Second, misexpression of   ey can strongly induce   dac.
# ::save-date Thu Nov 12, 2015 ::file bio_chicago_2015_37055.txt
(p4 / possible-01
      :ARG1 (i / induce-01
            :ARG0 (e / express-03
                  :ARG2 (p / protein :name (n / name :op1 "ey"))
                  :ARG1-of (w / wrong-04))
            :ARG1 (p2 / protein :name (n2 / name :op1 "dac"))
            :ARG1-of (s / strong-02))
      :mod (o / ordinal-entity :value 2))

# ::id bio.chicago_2015.37068 ::date 2015-10-28T13:44:45 ::annotator SDL-AMR-09 ::preferred
# ::snt The  PTB domains of  scaffolding proteins such as  Shc,  FRS2 or  IRS-1 bind autophosphorylated receptors, positioning these proteins for multisite phosphorylation and subsequent binding of  SH2 domain targets such as  Grb2 (for  Shc and  FRS2) or PI 3''-kinase (for  IRS-1) [  98,   99 and   100].
# ::save-date Thu Nov 12, 2015 ::file bio_chicago_2015_37068.txt
(a / and
      :op1 (b / bind-01
            :ARG0 (p12 / protein-segment :name (n8 / name :op1 "PTB" :op2 "domain")
                  :part-of (p3 / protein
                        :mod (s / scaffold)
                        :example (a2 / and
                              :op1 (p4 / protein :name (n2 / name :op1 "Shc"))
                              :op2 (p5 / protein :name (n3 / name :op1 "FRS2"))
                              :op3 (p6 / protein :name (n4 / name :op1 "IRS-1")))))
            :ARG1 (r / receptor
                  :ARG1-of (p2 / phosphorylate-01
                        :ARG2 r)))
      :op2 (p7 / position-01
            :ARG0 p12
            :ARG1 (p8 / protein
                  :mod (t / this))
            :ARG2 (a4 / and
                  :op1 (p9 / phosphorylate-01
                        :mod (m / multisite))
                  :op2 (b2 / bind-01
                        :ARG1 (m2 / molecular-physical-entity
                              :ARG1-of (t2 / target-01
                                    :ARG0 (p10 / protein-segment :name (n5 / name :op1 "SH2" :op2 "domain")))
                              :example (o / or
                                    :op1 (p11 / protein :name (n6 / name :op1 "Grb2")
                                          :prep-for (a5 / and
                                                :op1 p4
                                                :op2 p5))
                                    :op2 (e / enzyme :name (n7 / name :op1 "PI" :op2 "3``-kinase")
                                          :prep-for p6)))
                        :time (s2 / subsequent))))
      :ARG1-of (d3 / describe-01
            :ARG0 (p / publication
                  :ARG1-of (c / cite-01
                        :ARG2 (a6 / and :op1 98 :op2 99 :op3 100)))))

# ::id bio.chicago_2015.37115 ::date 2015-10-29T04:35:51 ::annotator SDL-AMR-09 ::preferred
# ::snt Like  TAK1, two other  MAP kinase kinase kinases,  MEKK1 and  MLK3, act downstream of  HPK1 and upstream of  MAPK kinase 4/SEK. However, we found that the dominant-negative mutants of  MEKK1 and  MLK3 did not inhibit  TAK1-induced  JNK activity, indicating that the activation of  JNK1 by  TAK1 is independent of  MEKK1 and  MLK3.
# ::save-date Fri Feb 5, 2016 ::file bio_chicago_2015_37115.txt
(h / have-concession-91
      :ARG1 (f / find-01
            :ARG0 (w / we)
            :ARG1 (i / inhibit-01 :polarity -
                  :ARG0 (a4 / and
                        :op1 e9
                        :op2 e8
                        :ARG0-of (d2 / dominate-01)
                        :ARG2-of (m2 / mutate-01 :mod "-/-"))
                  :ARG1 (a5 / activity-06
                        :ARG0 (e4 / enzyme :wiki "C-Jun_N-terminal_kinases" :name (n9 / name :op1 "JNK"))
                        :ARG2-of (i2 / induce-01
                              :ARG0 e5))
                  :ARG0-of (i3 / indicate-01
                        :ARG1 (d3 / depend-01 :polarity -
                              :ARG0 (a6 / activate-01
                                    :ARG0 e5
                                    :ARG1 (e3 / enzyme :wiki "C-Jun_N-terminal_kinases" :name (n10 / name :op1 "JNK1")))
                              :ARG1 (a7 / and
                                    :op1 e9
                                    :op2 e8)))))
      :ARG2 (a / act-02
            :ARG0 (k / kinase :quant 2 :wiki "MAP_kinase_kinase_kinase" :name (n2 / name :op1 "MAP" :op2 "kinase" :op3 "kinase")
                  :mod (o / other)
                  :ARG1-of (m / mean-01
                        :ARG2 (a2 / and
                              :op1 (e9 / enzyme :wiki "MAP3K1" :name (n3 / name :op1 "MEKK1"))
                              :op2 (e8 / enzyme :wiki "MAP3K11" :name (n4 / name :op1 "MLK3")))))
            :location (a3 / and
                  :op1 (r / relative-position
                        :op1 (e7 / enzyme :wiki "MAP4K1" :name (n5 / name :op1 "HPK1"))
                        :direction (d / downstream))
                  :op2 (r2 / relative-position
                        :op1 (p / pathway :wiki - :name (n / name :op1 "MAPK" :op2 "kinase" :op3 "4/SEK"))
                        :direction (u / upstream)))
            :ARG1-of (s / same-01
                  :ARG2 (e5 / enzyme :wiki "MAP3K7" :name (n7 / name :op1 "TAK1")))))

# ::id bio.chicago_2015.37124 ::date 2015-10-29T05:05:14 ::annotator SDL-AMR-09 ::preferred
# ::snt Together, the modest activation of  JNK exerted by  Rac1 and  Cdc42, and the observation that the Rac1L61C40 mutant still inhibits differentiation, raise questions about the involvement of the  JNK pathway with respect to the block of differentiation by expression of these proteins.
# ::save-date Wed Nov 4, 2015 ::file bio_chicago_2015_37124.txt
(r / raise-01
      :ARG0 (a / and
            :op1 (a2 / activate-01
                  :ARG1 (e3 / enzyme :name (n / name :op1 "JNK"))
                  :ARG1-of (e / exert-01
                        :ARG0 (a3 / and
                              :op1 (p / protein :name (n2 / name :op1 "Rac1"))
                              :op2 (p2 / protein :name (n3 / name :op1 "Cdc42"))))
                  :mod (m2 / modest))
            :op2 (o / observe-01
                  :ARG1 (i / inhibit-01
                        :ARG0 (p3 / protein :name (n4 / name :op1 "Rac1L61C40")
                              :ARG2-of (m / mutate-01))
                        :ARG1 (d / differentiate-01)
                        :mod (s / still)))
            :mod (t / together))
      :ARG1 (q / question-01
            :ARG1 (i2 / involve-01
                  :ARG1 (p4 / pathway :name (n5 / name :op1 "JNK"))
                  :topic (b / block-01
                        :ARG0 (e2 / express-03
                              :ARG2 (p5 / protein
                                    :mod (t2 / this)))
                        :ARG1 d))))

# ::id bio.chicago_2015.37139 ::date 2015-10-29T05:15:24 ::annotator SDL-AMR-09 ::preferred
# ::snt Recently, controversial results have been reported by our group indicating that cellular  Cdc42 is certainly required for the  actin-based motility of   Shigella in infected cells ( 83).
# ::save-date Wed Nov 4, 2015 ::file bio_chicago_2015_37139.txt
(r / report-01
      :ARG0 (g / group
            :poss (w / we))
      :ARG1 (t / thing
            :ARG2-of (r2 / result-01)
            :mod (c / controversy)
            :ARG0-of (i / indicate-01
                  :ARG1 (r4 / require-01
                        :ARG0 (m / motility
                              :ARG1-of (b / base-02
                                    :ARG2 (p2 / protein :name (n2 / name :op1 "actin")))
                              :mod (o / organism :name (n3 / name :op1 "Shigella"))
                              :location (c4 / cell
                                    :ARG1-of (i2 / infect-01)))
                        :ARG1 (p / protein :name (n / name :op1 "Cdc42")
                              :mod (c2 / cellular))
                        :manner (c3 / certain))))
      :time (r3 / recent)
      :ARG1-of (d / describe-01
            :ARG0 (p3 / publication
                  :ARG1-of (c5 / cite-01
                        :ARG2 83))))

# ::id bio.chicago_2015.37195 ::date 2015-10-29T05:21:27 ::annotator SDL-AMR-09 ::preferred
# ::snt On the other hand,  ADP significantly inhibited the  actin-activated ATPase activity of  myosin VIIA.
# ::save-date Thu Oct 29, 2015 ::file bio_chicago_2015_37195.txt
(c / contrast-01
      :ARG2 (i / inhibit-01
            :ARG0 (s / small-molecule :name (n / name :op1 "ADP"))
            :ARG1 (a / activity-06
                  :ARG0 (p / protein :name (n2 / name :op1 "myosin" :op2 "VIIA"))
                  :ARG1 (e / enzyme :name (n3 / name :op1 "ATPase")
                        :ARG1-of (a2 / activate-01
                              :ARG0 (p2 / protein :name (n4 / name :op1 "actin")))))
            :ARG1-of (s2 / significant-02)))

# ::id bio.chicago_2015.37242 ::date 2015-10-29T05:26:45 ::annotator SDL-AMR-09 ::preferred
# ::snt Ethanol inhibited  D2L receptor coupling to  adenylyl cyclase as a function of increasing  ethanol concentration (Fig.  2A).
# ::save-date Thu Nov 12, 2015 ::file bio_chicago_2015_37242.txt
(i / inhibit-01
      :ARG0 (e / ethanol)
      :ARG1 (c / couple-01
            :ARG1 (r / receptor :name (n / name :op1 "D2L"))
            :ARG2 (e2 / enzyme :name (n2 / name :op1 "adenylyl" :op2 "cyclase")))
      :ARG1-of (f / function-01
            :ARG0 (i2 / increase-01
                  :ARG1 (c2 / concentrate-02
                        :ARG1 e)))
      :ARG1-of (d / describe-01
            :ARG0 (f2 / figure :mod "2A")))

# ::id bio.chicago_2015.37257 ::date 2015-10-29T05:32:06 ::annotator SDL-AMR-09 ::preferred
# ::snt In the   Clk loop,  CLK-CYC heterodimers activate   vri transcription via E boxes in the   vri promoter.
# ::save-date Mon Jan 4, 2016 ::file bio_chicago_2015_37257.txt
(a / activate-01
      :ARG0 (h / heterodimer
            :part (p / protein :name (n / name :op1 "CLK"))
            :part (p2 / protein :name (n2 / name :op1 "CYC")))
      :ARG1 (t / transcribe-01
            :ARG1 (g / gene :name (n3 / name :op1 "vri"))
            :instrument (d / dna-sequence :name (n4 / name :op1 "E" :op2 "box")
                  :location (m / molecular-physical-entity
                        :ARG0-of (p3 / promote-01
                              :ARG1 g))))
      :location (l / loop
            :mod p))

# ::id bio.chicago_2015.37286 ::date 2015-10-29T05:43:23 ::annotator SDL-AMR-09 ::preferred
# ::snt The   Caenorhabditis elegans unc-64 locus encodes a  syntaxin that interacts genetically with  synaptobrevin.
# ::save-date Thu Oct 29, 2015 ::file bio_chicago_2015_37286.txt
(e / encode-01
      :ARG0 (g / gene :name (n / name :op1 "unc-64" :op2 "locus")
            :source (o / organism :name (n2 / name :op1 "Caenorhabditis" :op2 "elegans")))
      :ARG1 (p / protein :name (n3 / name :op1 "syntaxin")
            :ARG0-of (i / interact-01
                  :ARG1 (p2 / protein :name (n4 / name :op1 "synaptobrevin"))
                  :manner (g2 / genetic))))

# ::id bio.chicago_2015.37333 ::date 2015-10-29T05:49:00 ::annotator SDL-AMR-09 ::preferred
# ::snt One of the modes by which interaction of  E1A with  p300 modulates transcription appears to involve disruption of a complex of  p300 with a cellular  acetyl transferase,  P/CAF, which regulates transcription by chromatin remodeling ( 4).
# ::save-date Wed Nov 4, 2015 ::file bio_chicago_2015_37333.txt
(a / appear-02
      :ARG1 (m / mode
            :ARG1-of (i / include-91
                  :ARG2 (m2 / mode
                        :instrument-of (m3 / modulate-01
                              :ARG0 (i2 / interact-01
                                    :ARG0 (p / protein :name (n / name :op1 "E1A"))
                                    :ARG1 (p2 / protein :name (n2 / name :op1 "p300")))
                              :ARG1 (t / transcribe-01))))
            :ARG2-of (i3 / involve-01
                  :ARG1 (d / disrupt-01
                        :ARG1 (c / complex
                              :mod p2)
                        :instrument (e / enzyme :name (n3 / name :op1 "P/CAF")
                              :ARG1-of (m4 / mean-01
                                    :ARG2 (e2 / enzyme :name (n4 / name :op1 "acetyltransferase")
                                          :mod (c2 / cell)))
                              :ARG0-of (r / regulate-01
                                    :ARG1 (t3 / transcribe-01)
                                    :instrument (r2 / remodel-01
                                          :ARG1 (c3 / chromatin)))))))
      :ARG1-of (d2 / describe-01
            :ARG0 (p3 / publication
                  :ARG1-of (c4 / cite-01
                        :ARG2 4))))

# ::id bio.chicago_2015.37349 ::date 2015-10-29T06:19:38 ::annotator SDL-AMR-09 ::preferred
# ::snt Alternative splicing removes repeat six ( cortactin B) or  repeats 5 and 6 (cortactin C); all of these isoforms bind  F-actin.
# ::save-date Mon Jan 4, 2016 ::file bio_chicago_2015_37349.txt
(m / multi-sentence
      :snt1 (r / remove-01
            :ARG0 (s / splice-01
                  :mod (a / alternative))
            :ARG1 (o / or
                  :op1 (d4 / dna-sequence :name (n7 / name :op1 "repeat" :op2 "6")
                        :part-of (p / protein :name (n / name :op1 "cortactin" :op2 "B")))
                  :op2 (a2 / and
                        :op1 (d / dna-sequence :name (n4 / name :op1 "repeat" :op2 "5")
                              :part-of (p2 / protein :name (n2 / name :op1 "cortactin" :op2 "C")))
                        :op2 (d5 / dna-sequence :name (n8 / name :op1 "repeat" :op2 "6")
                              :part-of p2))
                  :ARG0-of (b / bind-01
                        :ARG1 (p3 / protein :name (n3 / name :op1 "F-actin")))
                  :mod (a3 / all))))

# ::id bio.chicago_2015.37392 ::date 2015-10-29T06:23:47 ::annotator SDL-AMR-09 ::preferred
# ::snt ( iv) Upon amino acid  starvation, uncharged  tRNA binds to the  HisRS domain of  Gcn2 and induces a conformational change that results in the release of  Hsp90.
# ::save-date Mon Dec 14, 2015 ::file bio_chicago_2015_37392.txt
(a / and :li "iv"
      :op1 (b / bind-01
            :ARG0 (n5 / nucleic-acid :name (n / name :op1 "tRNA")
                  :ARG1-of (c / charge-03 :polarity -))
            :ARG2 (p / protein-segment :name (n2 / name :op1 "HisRS" :op2 "domain")
                  :part-of (e / enzyme :name (n3 / name :op1 "Gcn2"))))
      :op2 (i / induce-01
            :ARG0 n5
            :ARG2 (c2 / change-01
                  :mod (c3 / conformational)
                  :ARG1-of (r2 / result-01
                        :ARG2 (r3 / release-01
                              :ARG1 (p2 / protein :name (n4 / name :op1 "Hsp90"))))))
      :condition (s / starve-01
            :ARG1 n5
            :ARG2 (a2 / amino-acid)))

# ::id bio.chicago_2015.37393 ::date 2015-10-29T06:31:07 ::annotator SDL-AMR-09 ::preferred
# ::snt All four  TnI-derived sequences bound  TnC, with hcTnI, dTnIA, and dTnIV exhibiting the most robust binding signals.
# ::save-date Wed Nov 4, 2015 ::file bio_chicago_2015_37393.txt
(a / and
      :op1 (b / bind-01
            :ARG0 (s / sequence :quant 4
                  :mod (a2 / all)
                  :ARG1-of (d / derive-01
                        :ARG2 (p / protein :name (n / name :op1 "TnI"))))
            :ARG1 (p2 / protein :name (n2 / name :op1 "TnC")))
      :op2 (e / exhibit-01
            :ARG0 (a3 / and
                  :op1 (p3 / protein-segment :name (n3 / name :op1 "hcTnI"))
                  :op2 (p4 / protein-segment :name (n4 / name :op1 "dTnIA"))
                  :op3 (p5 / protein-segment :name (n5 / name :op1 "dTnIV")))
            :ARG1 (s2 / signal-07
                  :ARG3 (b2 / bind-01)
                  :mod (r / robust
                        :degree (m / most)))))

# ::id bio.chicago_2015.37409 ::date 2015-10-29T11:47:14 ::annotator SDL-AMR-09 ::preferred
# ::snt N-Wasp and  cortactin can bind simultaneously to the  Arp2/3 complex and activate  actin assembly ( Weaver et al., 2002).
# ::save-date Thu Oct 29, 2015 ::file bio_chicago_2015_37409.txt
(a / and
      :op1 (p7 / possible-01
            :ARG1 (b / bind-01
                  :ARG0 (a2 / and
                        :op1 (p / protein :name (n / name :op1 "N-Wasp"))
                        :op2 (p2 / protein :name (n2 / name :op1 "cortactin")))
                  :ARG2 (m / macro-molecular-complex :name (n3 / name :op1 "Arp2/3"))
                  :manner (s / simultaneous)))
      :op2 (a3 / activate-01
            :ARG0 a2
            :ARG1 (a4 / assemble-01
                  :ARG2 (p3 / protein :name (n4 / name :op1 "actin"))))
      :ARG1-of (d2 / describe-01
            :ARG0 (p4 / publication-91
                  :ARG0 (a5 / and
                        :op1 (p5 / person :name (n5 / name :op1 "Weaver"))
                        :op2 (p6 / person
                              :mod (o / other)))
                  :time (d / date-entity :year 2002))))

# ::id bio.chicago_2015.37426 ::date 2015-10-29T11:51:56 ::annotator SDL-AMR-09 ::preferred
# ::snt Rb interacts with  histone deacetylase to repress transcription.
# ::save-date Wed Nov 4, 2015 ::file bio_chicago_2015_37426.txt
(i / interact-01
      :ARG0 (p / protein :name (n / name :op1 "Rb"))
      :ARG1 (e / enzyme :name (n2 / name :op1 "histone" :op2 "deacetylase"))
      :ARG2 (r / repress-01
            :ARG0 (a / and
                  :op1 p
                  :op2 e)
            :ARG1 (t / transcribe-01)))

# ::id bio.chicago_2015.37451 ::date 2015-10-27T08:53:32 ::annotator SDL-AMR-09 ::preferred
# ::snt Although  TIM can interact with  dCLOCK in the absence of PER (  Figure 4),  dCLOCK appears to have a higher affinity for the PER-TIM complex compared to a version of  TIM that does not associate with PER (  Figure 5).
# ::save-date Mon Nov 2, 2015 ::file bio_chicago_2015_37451.txt
(h3 / have-concession-91
      :ARG1 (a2 / appear-02
            :ARG1 (h / have-03
                  :ARG0 p3
                  :ARG1 (a3 / affinity
                        :ARG1-of (h2 / high-02
                              :degree (m / more))
                        :topic (m2 / macro-molecular-complex
                              :part p4
                              :part p2)
                        :compared-to (v / version
                              :poss p2
                              :ARG1-of (a4 / associate-01 :polarity -
                                    :ARG2 p4))))
            :ARG1-of (d2 / describe-01
                  :ARG0 (f2 / figure :mod 5)))
      :ARG2 (p / possible-01
            :ARG1 (i / interact-01
                  :ARG0 (p2 / protein :name (n / name :op1 "TIM"))
                  :ARG2 (p3 / protein :name (n2 / name :op1 "dCLOCK"))
                  :condition (a / absent-01
                        :ARG1 (p4 / protein :name (n3 / name :op1 "PER")))
                  :ARG1-of (d / describe-01
                        :ARG0 (f / figure :mod 4)))))

# ::id bio.chicago_2015.37483 ::date 2015-10-27T09:36:25 ::annotator SDL-AMR-09 ::preferred
# ::snt In an  ATP-consuming reaction, the C terminus of  ubiquitin is first activated by an enzyme called  E1, to which it becomes attached by a thiolester bond.
# ::save-date Sat Feb 13, 2016 ::file bio_chicago_2015_37483.txt
(a / activate-01
      :ARG0 (e / enzyme :name (n / name :op1 "E1"))
      :ARG1 (p / protein-segment :name (n2 / name :op1 "C" :op2 "terminus")
            :part-of (p2 / protein :name (n3 / name :op1 "ubiquitin"))
            :ARG1-of (a2 / attach-01
                  :ARG2 e
                  :ARG3 (s2 / small-molecule :name (n6 / name :op1 "thiolester")
                        :ARG3-of (b2 / bond-01))
                  :ARG1-of (b / become-01)))
      :time (f / first)
      :condition (r / react-01
            :ARG0-of (c / consume-01
                  :ARG1 (s / small-molecule :name (n4 / name :op1 "ATP")))))

# ::id bio.chicago_2015.37518 ::date 2015-10-27T09:55:50 ::annotator SDL-AMR-09 ::preferred
# ::snt Moreover,  HGF also increases the amount of newly synthesized  E-cadherin molecules found in  beta-catenin complexes.
# ::save-date Mon Nov 2, 2015 ::file bio_chicago_2015_37518.txt
(a3 / and
      :op2 (i / increase-01
            :ARG0 (p / protein :name (n / name :op1 "HGF"))
            :ARG1 (a2 / amount
                  :quant-of (m / molecule
                        :mod (p2 / protein :name (n2 / name :op1 "E-cadherin"))
                        :ARG1-of (s / synthesize-01
                              :ARG1-of (n3 / new-01))
                        :ARG1-of (f / find-01
                              :location (m2 / macro-molecular-complex
                                    :part (p3 / protein :name (n4 / name :op1 "beta-catenin"))))))
            :mod (a / also)))

# ::id bio.chicago_2015.37572 ::date 2015-10-27T10:10:10 ::annotator SDL-AMR-09 ::preferred
# ::snt Evidence suggests that  DREF is required for DNA replication in both the  endo and mitotic cell cycles.
# ::save-date Mon Nov 2, 2015 ::file bio_chicago_2015_37572.txt
(s / suggest-01
      :ARG0 (e / evidence-01)
      :ARG1 (r / require-01
            :ARG0 (r2 / replicate-01
                  :ARG1 (n2 / nucleic-acid :wiki "DNA" :name (n3 / name :op1 "DNA"))
                  :time (a / and
                        :op1 (c / cycle
                              :mod (c2 / cell
                                    :mod (e2 / endo)))
                        :op2 (c3 / cycle
                              :mod (c4 / cell
                                    :mod (m / mitosis)))))
            :ARG1 (p / protein :name (n / name :op1 "DREF"))))

# ::id bio.chicago_2015.37588 ::date 2015-10-27T10:21:16 ::annotator SDL-AMR-09 ::preferred
# ::snt Induction of  p21 by  p16.
# ::save-date Tue Oct 27, 2015 ::file bio_chicago_2015_37588.txt
(i / induce-01
      :ARG0 (p / protein :name (n / name :op1 "p16"))
      :ARG1 (p2 / protein :name (n2 / name :op1 "p21")))

# ::id bio.chicago_2015.37589 ::date 2015-10-27T10:22:18 ::annotator SDL-AMR-09 ::preferred
# ::snt In vitro,  OTK associates with  Plexins.
# ::save-date Tue Oct 27, 2015 ::file bio_chicago_2015_37589.txt
(a / associate-01
      :ARG1 (p / protein :name (n / name :op1 "OTK"))
      :ARG2 (p2 / protein :name (n2 / name :op1 "Plexin"))
      :manner (i / in-vitro))

# ::id bio.chicago_2015.37606 ::date 2015-10-27T10:56:02 ::annotator SDL-AMR-09 ::preferred
# ::snt It remains to be determined how the interaction of either the  AHR or  ARNT with  TFIIB may influence the ability of either of these proteins to activate genes.
# ::save-date Mon Nov 2, 2015 ::file bio_chicago_2015_37606.txt
(r / remain-01
      :ARG1 (d / determine-01
            :ARG1 (t / thing
                  :manner-of (i / influence-01
                        :ARG0 (i2 / interact-01
                              :ARG0 (o / or
                                    :op1 (p / protein :name (n / name :op1 "AHR"))
                                    :op2 (p2 / protein :name (n2 / name :op1 "ARNT")))
                              :ARG1 (p3 / protein :name (n3 / name :op1 "TFIIB")))
                        :ARG1 (c / capable-01
                              :ARG1 o
                              :ARG2 (a / activate-01
                                    :ARG0 o
                                    :ARG1 (g / gene)))
                        :ARG1-of (p4 / possible-01)))))

# ::id bio.chicago_2015.37655 ::date 2015-10-27T11:08:58 ::annotator SDL-AMR-09 ::preferred
# ::snt Hypoxia also induces  VEGF ( 76-84), and there are also several cellular conditions or factors that down-regulate expression of this gene product, including the  tumor suppressor gene p53 and the  von Hippel-Lindau tumor suppressor gene product ( 85-89).
# ::save-date Mon Nov 2, 2015 ::file bio_chicago_2015_37655.txt
(a / and
      :op1 (i / induce-01
            :ARG0 (h / hypoxia)
            :ARG1 (p / protein :name (n / name :op1 "VEGF")
                  :ARG1-of (p2 / produce-01
                        :ARG0 (g / gene)))
            :ARG1-of (d3 / describe-01
                  :ARG0 (p6 / publication
                        :ARG1-of (c4 / cite-01
                              :ARG2 (b / between :op1 76 :op2 84))))
            :mod a3)
      :op2 (d / downregulate-01
            :ARG0 (o / or
                  :op1 (c / condition
                        :mod (c2 / cell)
                        :quant (s / several))
                  :op2 (f / factor
                        :mod c2
                        :quant s)
                  :ARG2-of (i2 / include-01
                        :ARG1 (a2 / and
                              :op1 (p3 / protein :name (n2 / name :op1 "p53")
                                    :ARG1-of (p4 / produce-01
                                          :ARG0 (g2 / gene
                                                :ARG0-of (s3 / suppress-01
                                                      :ARG1 (t / tumor)))))
                              :op2 (p5 / product
                                    :poss (g3 / gene
                                          :ARG0-of (s4 / suppress-01
                                                :ARG1 (d2 / disease :name (n3 / name :op1 "Hippel-Lindau"))))))))
            :ARG1 (e / express-03
                  :ARG2 p)
            :mod (a3 / also)
            :ARG1-of (d4 / describe-01
                  :ARG0 (p7 / publication
                        :ARG1-of (c5 / cite-01
                              :ARG2 (b2 / between :op1 85 :op2 89))))))

# ::id bio.chicago_2015.37678 ::date 2015-10-27T11:58:37 ::annotator SDL-AMR-09 ::preferred
# ::snt Extracellular death pathway   Experiments using the   egfrts1a allele confirmed that  EGFR was required for survival of pupal retinal cells, as suggested by prior misexpression experiments (Miller and Cagan, 1998  ; Sawamoto et al., 1998  ).
# ::save-date Mon Nov 2, 2015 ::file bio_chicago_2015_37678.txt
(c / confirm-01
      :ARG0 (e / experiment-01
            :ARG1 (p / pathway :name (n / name :op1 "Extracellular" :op2 "death" :op3 "pathway"))
            :ARG2 (a / allele :name (n2 / name :op1 "egfrts1a")))
      :ARG1 (r / require-01
            :ARG0 (s / survive-01
                  :ARG0 (c2 / cell
                        :source (r2 / retina)
                        :mod (p2 / pupa)))
            :ARG1 (e2 / enzyme :name (n3 / name :op1 "EGFR"))
            :ARG1-of (s2 / suggest-01
                  :ARG0 (e3 / experiment-01
                        :ARG1 (e4 / express-03
                              :ARG1-of (w / wrong-04))
                        :time (p3 / prior))))
      :ARG1-of (d / describe-01
            :ARG0 (a3 / and
                  :op1 (p4 / publication-91
                        :ARG0 (a2 / and
                              :op1 (p5 / person :name (n4 / name :op1 "Miller"))
                              :op2 (p6 / person :name (n5 / name :op1 "Cagan")))
                        :time (d2 / date-entity :year 1998))
                  :op2 (p7 / publication-91
                        :ARG0 (a4 / and
                              :op1 (p8 / person :name (n6 / name :op1 "Sawamoto"))
                              :op2 (p9 / person
                                    :mod (o / other)))
                        :time d2))))

# ::id bio.chicago_2015.37682 ::date 2015-10-27T12:46:09 ::annotator SDL-AMR-09 ::preferred
# ::snt Using Biacore and  yeast two-hybrid analyses, they found that  Hrs interacts with  Tsg101, although the  PSAP-containing peptide from  Hrs bound with lower affinity than that from  HIV p6 to the  UEV domain of  Tsg101 ( Pornillos et al., 2003).
# ::save-date Mon Jan 4, 2016 ::file bio_chicago_2015_37682.txt
(f / find-01
      :ARG0 (t / they)
      :ARG1 (h2 / have-concession-91
            :ARG1 (i / interact-01
                  :ARG0 (p9 / protein :name (n2 / name :op1 "Hrs"))
                  :ARG1 (p10 / protein :name (n4 / name :op1 "Tsg101")))
            :ARG2 (b / bind-01
                  :ARG1 (p / peptide
                        :ARG0-of (c3 / contain-01
                              :ARG1 (p2 / protein :name (n3 / name :op1 "PSAP")))
                        :source p9)
                  :manner (a4 / affinity
                        :ARG1-of (l / low-04
                              :degree (m / more)
                              :compared-to (p3 / peptide
                                    :source (p11 / protein :name (n9 / name :op1 "HIV" :op2 "p6")
                                          :ARG1-of (b2 / bind-01
                                                :ARG2 (p5 / protein-segment :name (n6 / name :op1 "UEV")
                                                      :part-of p10))))))))
      :instrument (a / and
            :op1 (a2 / analyze-01
                  :mod (c / company :name (n / name :op1 "Biacore")))
            :op2 (a3 / analyze-01 :name (n5 / name :op1 "yeast" :op2 "two-hybrid")))
      :ARG1-of (d2 / describe-01
            :ARG0 (p6 / publication-91
                  :ARG0 (a5 / and
                        :op1 (p7 / person :name (n7 / name :op1 "Pornillos"))
                        :op2 (p8 / person
                              :mod (o / other)))
                  :time (d3 / date-entity :year 2003))))

# ::id bio.chicago_2015.37689 ::date 2015-10-27T14:05:17 ::annotator SDL-AMR-09 ::preferred
# ::snt Parallel experiments in which the effects of PD098059 on  IL-2 activation of  E2F were monitored (  Figure 4C) showed that  IL-2 can potently induce  E2F activity in the presence of levels of PD098059 that completely block  IL-2 activation of  Elk-1.
# ::save-date Tue Oct 27, 2015 ::file bio_chicago_2015_37689.txt
(s / show-01
      :ARG0 (e / experiment-01
            :ARG1 (m / monitor-01
                  :ARG1 (a / affect-01
                        :ARG0 (s2 / small-molecule :name (n / name :op1 "PD098059"))
                        :ARG1 (a2 / activate-01
                              :ARG0 (p3 / protein :name (n3 / name :op1 "IL-2"))
                              :ARG1 (p2 / protein :name (n2 / name :op1 "E2F"))))
                  :ARG1-of (d / describe-01
                        :ARG0 (f / figure :mod "4C")))
            :ARG0-of (p / parallel-01))
      :ARG1 (p4 / possible-01
            :ARG1 (i / induce-01
                  :ARG0 p3
                  :ARG2 (a3 / activity-06
                        :ARG0 p2)
                  :manner (p5 / potent)
                  :condition (p6 / present-02
                        :ARG1 (l / level
                              :quant-of s2
                              :ARG0-of (b / block-01
                                    :ARG1 (a4 / activate-01
                                          :ARG0 p3
                                          :ARG1 (p7 / protein :name (n4 / name :op1 "Elk-1")))
                                    :ARG1-of (c / complete-02)))))))

# ::id bio.chicago_2015.37690 ::date 2015-10-27T15:10:55 ::annotator SDL-AMR-09 ::preferred
# ::snt Phosphorylation of  rAxin by  GSK-3beta.
# ::save-date Wed Oct 28, 2015 ::file bio_chicago_2015_37690.txt
(p / phosphorylate-01
      :ARG1 (p2 / protein :name (n2 / name :op1 "rAxin"))
      :ARG2 (e / enzyme :name (n / name :op1 "GSK-3beta")))

# ::id bio.chicago_2015.37704 ::date 2015-10-28T02:01:04 ::annotator SDL-AMR-09 ::preferred
# ::snt Phosphorylation of   Munc-18 by  PKC.
# ::save-date Wed Oct 28, 2015 ::file bio_chicago_2015_37704.txt
(p / phosphorylate-01
      :ARG1 (p2 / protein :name (n2 / name :op1 "Munc-18"))
      :ARG2 (e / enzyme :name (n / name :op1 "PKC")))

# ::id bio.chicago_2015.37713 ::date 2015-10-28T02:02:36 ::annotator SDL-AMR-09 ::preferred
# ::snt The  GCKH domain of  NIK interacted with  MEKK1, and the dominant negative mutant of  MEKK1 inhibited  NIK-induced  JNK activation ( 12).
# ::save-date Sun Jan 17, 2016 ::file bio_chicago_2015_37713.txt
(a / and
      :op1 (i / interact-01
            :ARG0 (p / protein-segment :name (n / name :op1 "GCKH")
                  :part-of (e4 / enzyme :name (n2 / name :op1 "NIK")))
            :ARG1 (e / enzyme :name (n3 / name :op1 "MEKK1")))
      :op2 (i2 / inhibit-01
            :ARG0 (e2 / enzyme :name (n4 / name :op1 "MEKK1")
                  :ARG2-of (m / mutate-01 :mod "-/-")
                  :ARG0-of (d / dominate-01))
            :ARG1 (a2 / activate-01
                  :ARG1 (e3 / enzyme :name (n5 / name :op1 "JNK"))
                  :ARG2-of (i3 / induce-01
                        :ARG0 e4)))
      :ARG1-of (d2 / describe-01
            :ARG0 (p3 / publication
                  :ARG1-of (c / cite-01
                        :ARG2 12))))

# ::id bio.chicago_2015.37728 ::date 2015-10-28T02:28:45 ::annotator SDL-AMR-09 ::preferred
# ::snt Interestingly,  CKI  binds to  mPER1 in a region that has no obvious sequence similarity to the suggested  DBT-binding region of  dPER ( 27).
# ::save-date Mon Nov 2, 2015 ::file bio_chicago_2015_37728.txt
(b / bind-01
      :ARG1 (e / enzyme :name (n / name :op1 "CKI"))
      :ARG2 (p3 / protein :name (n2 / name :op1 "mPER1"))
      :location (r / region
            :ARG0-of (h / have-03
                  :ARG1 (r2 / resemble-01
                        :ARG1 (s / sequence)
                        :ARG2 (r3 / region
                              :ARG1-of (s2 / suggest-01)
                              :ARG1-of (b2 / bind-01
                                    :ARG2 (p / protein :name (n3 / name :op1 "DBT")))
                              :part-of (p2 / protein :name (n4 / name :op1 "dPER")))
                        :ARG1-of (o / obvious-01 :polarity -))))
      :ARG2-of (i / interest-01)
      :ARG1-of (d / describe-01
            :ARG0 (p4 / publication
                  :ARG1-of (c / cite-01
                        :ARG2 27))))

# ::id bio.chicago_2015.37742 ::date 2015-10-28T02:50:42 ::annotator SDL-AMR-09 ::preferred
# ::snt The binding of  Sp1 to the  EBS and to the downstream canonical  Sp1 site occurred with comparable affinities.
# ::save-date Wed Oct 28, 2015 ::file bio_chicago_2015_37742.txt
(a / affinity
      :ARG1-of (c / comparable-03)
      :topic (b / bind-01
            :ARG1 (p / protein :name (n / name :op1 "Sp1"))
            :ARG2 (a2 / and
                  :op1 (p2 / protein :name (n2 / name :op1 "EBS"))
                  :op2 (s / site
                        :mod (p3 / protein :name (n3 / name :op1 "Sp1")
                              :mod (c2 / canonical)
                              :mod (d / downstream))))))

# ::id bio.chicago_2015.37761 ::date 2015-10-28T03:12:29 ::annotator SDL-AMR-09 ::preferred
# ::snt Perhaps  intersectin plays a role in  EGF-stimulated  Ras activation specifically at  clathrin-coated pits.
# ::save-date Mon Nov 2, 2015 ::file bio_chicago_2015_37761.txt
(p / possible-01
      :ARG1 (p2 / play-02
            :ARG0 (p3 / protein :name (n / name :op1 "intersectin"))
            :ARG1 (r / role)
            :topic (a / activate-01
                  :ARG1 (e / enzyme :name (n2 / name :op1 "Ras"))
                  :ARG1-of (s / stimulate-01
                        :ARG0 (p4 / protein :name (n3 / name :op1 "EGF"))))
            :location (p5 / pit
                  :ARG1-of (c / coat-01
                        :ARG2 (p6 / protein :name (n4 / name :op1 "clathrin")))
                  :ARG1-of (s2 / specific-02))))

# ::id bio.chicago_2015.37797 ::date 2015-10-28T04:19:15 ::annotator SDL-AMR-09 ::preferred
# ::snt The substance has been shown previously not only to prevent phosphorylation-dependent activation of  MEK by  Raf-1 but also to interfere with signaling from activated  MEK1 ( 1,  22).
# ::save-date Mon Nov 2, 2015 ::file bio_chicago_2015_37797.txt
(s / show-01
      :ARG1 (a / and
            :op1 (p / prevent-01
                  :ARG0 (s2 / substance)
                  :ARG1 (a2 / activate-01
                        :ARG0 (e2 / enzyme :name (n2 / name :op1 "Raf-1"))
                        :ARG1 (e / enzyme :name (n / name :op1 "MEK"))
                        :ARG0-of (d / depend-01
                              :ARG1 (p3 / phosphorylate-01))))
            :op2 (i / interfere-01
                  :ARG0 s2
                  :ARG1 (s3 / signal-07
                        :ARG0 (e3 / enzyme :name (n3 / name :op1 "MEK1")
                              :ARG1-of (a3 / activate-01)))
                  :mod (a5 / also)))
      :time (p2 / previous)
      :ARG1-of (d2 / describe-01
            :ARG0 (p4 / publication
                  :ARG1-of (c / cite-01
                        :ARG2 (a4 / and :op1 1 :op2 22)))))

# ::id bio.chicago_2015.37803 ::date 2015-10-28T04:34:50 ::annotator SDL-AMR-09 ::preferred
# ::snt Repression of   hsp70 heat shock gene transcription by the suppressor of  Hairy-wing protein of   Drosophila melanogaster..
# ::save-date Wed Oct 28, 2015 ::file bio_chicago_2015_37803.txt
(r / repress-01
      :ARG0 (m / molecular-physical-entity
            :ARG0-of (s / suppress-01
                  :ARG1 (p2 / protein :name (n2 / name :op1 "Hairy-wing")
                        :source (o / organism :name (n3 / name :op1 "Drosophila" :op2 "melanogaster")))))
      :ARG1 (t / transcribe-01
            :ARG1 (g / gene
                  :ARG0-of (e / encode-01
                        :ARG1 (p / protein :name (n / name :op1 "hsp70" :op2 "heat" :op3 "shock"))))))

# ::id bio.chicago_2015.37835 ::date 2015-10-28T05:11:17 ::annotator SDL-AMR-09 ::preferred
# ::snt To investigate whether the binding of  E1A to  p300 correlates with a loss of  p300 transcriptional activity, we examined the binding of full-length  E1A to the series of  mutant p300 proteins.
# ::save-date Thu Nov 12, 2015 ::file bio_chicago_2015_37835.txt
(e / examine-01
      :ARG0 (w / we)
      :ARG1 (b / bind-01
            :ARG1 (p / protein :name (n / name :op1 "E1A")
                  :ARG1-of (l2 / long-03
                        :ARG1-of (f / full-09)))
            :ARG2 (s / series
                  :consist-of (p3 / protein :name (n2 / name :op1 "p300")
                        :ARG2-of (m / mutate-01))))
      :purpose (i / investigate-01
            :ARG0 w
            :ARG1 (c / correlate-01 :mode interrogative
                  :ARG1 (b2 / bind-01
                        :ARG1 p
                        :ARG2 (p2 / protein :name (n3 / name :op1 "p300")))
                  :ARG2 (l / lose-02
                        :ARG1 (a / activity-06
                              :ARG0 p2
                              :ARG1 (t / transcribe-01
                                    :ARG0 p2))))))

# ::id bio.chicago_2015.37883 ::date 2015-10-28T05:25:30 ::annotator SDL-AMR-09 ::preferred
# ::snt We recently presented evidence that the rate of dephosphorylation of  Cdc2 on  tyrosine-15 is decreased in cells arrested in early S with  HU, which indicates that  Cdc25 might be inhibited by the  S-M replication checkpoint (Rhind and Russell, 1998a  ).
# ::save-date Fri Mar 4, 2016 ::file bio_chicago_2015_37883.txt
(p / present-01
      :ARG0 (w / we)
      :ARG1 (e / evidence-01
            :ARG1 (d / decrease-01
                  :ARG1 (r / rate
                        :degree-of (d2 / dephosphorylate-01
                              :ARG1 (a / amino-acid :mod 15 :name (n2 / name :op1 "tyrosine")
                                    :part-of (e2 / enzyme :name (n / name :op1 "Cdc2")))))
                  :location (c / cell
                        :ARG1-of (a2 / arrest-02
                              :instrument (s / small-molecule :name (n8 / name :op1 "HU"))
                              :time (e3 / early
                                    :op1 (p2 / phase :name (n3 / name :op1 "S")))))
                  :ARG0-of (i / indicate-01
                        :ARG1 (p3 / possible-01
                              :ARG1 (i2 / inhibit-01
                                    :ARG0 (c2 / checkpoint
                                          :mod (r2 / replicate-01
                                                :ARG1 (p4 / phase :name (n5 / name :op1 "S-M"))))
                                    :ARG1 (e4 / enzyme :name (n4 / name :op1 "Cdc25"))))
                        :ARG1-of (d3 / describe-01
                              :ARG0 (p5 / publication-91
                                    :ARG0 (a3 / and
                                          :op1 (p6 / person :name (n6 / name :op1 "Rhind"))
                                          :op2 (p7 / person :name (n7 / name :op1 "Russell")))
                                    :time (d4 / date-entity :year 1998))))))
      :time (r3 / recent))

# ::id bio.chicago_2015.37893 ::date 2015-10-28T06:00:01 ::annotator SDL-AMR-09 ::preferred
# ::snt MSL2 and  MSL3 interact with  MSL1 in a  yeast two-hybrid system (Copps  et al., 1998)  .
# ::save-date Wed Oct 28, 2015 ::file bio_chicago_2015_37893.txt
(i / interact-01
      :ARG0 (a / and
            :op1 (p4 / protein :name (n / name :op1 "MSL2"))
            :op2 (p5 / protein :name (n2 / name :op1 "MSL3")))
      :ARG1 (p6 / protein :name (n3 / name :op1 "MSL1"))
      :condition (s / system :name (n4 / name :op1 "yeast" :op2 "two-hybrid"))
      :ARG1-of (d / describe-01
            :ARG0 (p / publication-91
                  :ARG0 (a2 / and
                        :op1 (p2 / person :name (n5 / name :op1 "Copps"))
                        :op2 (p3 / person
                              :mod (o / other)))
                  :time (d2 / date-entity :year 1998))))

# ::id bio.chicago_2015.37903 ::date 2015-10-28T06:11:28 ::annotator SDL-AMR-09 ::preferred
# ::snt Phosphorylation of  eIF2alpha by  Hri1p and  Hri2p is induced by  heat shock or arsenic.
# ::save-date Mon Nov 2, 2015 ::file bio_chicago_2015_37903.txt
(i / induce-01
      :ARG0 (a2 / and
            :op1 (p3 / protein :name (n4 / name :op1 "heat" :op2 "shock"))
            :op2 (a3 / arsenic))
      :ARG2 (p / phosphorylate-01
            :ARG1 (p2 / protein :name (n / name :op1 "eIF2alpha"))
            :ARG2 (a / and
                  :op1 (e / enzyme :name (n2 / name :op1 "Hri1p"))
                  :op2 (e2 / enzyme :name (n3 / name :op1 "Hri2p")))))

# ::id bio.chicago_2015.37947 ::date 2015-10-28T06:20:33 ::annotator SDL-AMR-09 ::preferred
# ::snt Polyglutamine-Expanded Human Huntingtin Transgenes Induce Degeneration of  Drosophila Photoreceptor Neurons.
# ::save-date Mon Nov 2, 2015 ::file bio_chicago_2015_37947.txt
(i / induce-01
      :ARG0 (t / transgene :name (n / name :op1 "Polyglutamine-Expanded" :op2 "Human" :op3 "Huntingtin"))
      :ARG2 (d / degenerate-01
            :ARG1 (n2 / neuron
                  :mod (p2 / photoreceptor)
                  :source (o / organism :name (n3 / name :op1 "Drosophila")))))

# ::id bio.chicago_2015.37956 ::date 2015-10-28T06:30:50 ::annotator SDL-AMR-09 ::preferred
# ::snt Scattering measurements have suggested that the rate of activation of  transducin by photoexcited  rhodopsin could proceed as rapidly as 700 - 1000  s-1 ( Vuong et al 1984,  Kahlert & Hofmann 1991,  Bruckert et al 1992) under conditions of saturating  guanosine triphosphate (GTP).
# ::save-date Wed Jan 13, 2016 ::file bio_chicago_2015_37956.txt
(s / suggest-01
      :ARG0 (m / measure-01
            :ARG0-of (s2 / scatter-01))
      :ARG1 (p / possible-01
            :ARG1 (p2 / proceed-01
                  :ARG1 (r / rate-entity-91
                        :ARG1 (b / between :op1 700 :op2 1000
                              :mod (r2 / rapid))
                        :ARG2 (t / temporal-quantity :quant "-1"
                              :unit (s3 / second))
                        :degree-of (a / activate-01
                              :ARG0 (p4 / protein :name (n2 / name :op1 "rhodopsin")
                                    :ARG1-of (p5 / photoexcite-00))
                              :ARG1 (p3 / protein :name (n / name :op1 "transducin"))))
                  :condition (s5 / small-molecule :name (n3 / name :op1 "guanosine" :op2 "triphosphate")
                        :ARG2-of (s4 / saturate-01))
                  :ARG1-of (d / describe-01
                        :ARG0 (a2 / and
                              :op1 (p6 / publication-91
                                    :ARG0 (a3 / and
                                          :op1 (p7 / person :name (n4 / name :op1 "Vuong"))
                                          :op2 (p8 / person
                                                :mod (o / other)))
                                    :time (d2 / date-entity :year 1984))
                              :op2 (p9 / publication-91
                                    :ARG0 (a4 / and
                                          :op1 (p10 / person :name (n5 / name :op1 "Kahlert"))
                                          :op2 (p11 / person :name (n6 / name :op1 "Hofmann")))
                                    :time (d3 / date-entity :year 1991))
                              :op3 (p12 / publication-91
                                    :ARG0 (a5 / and
                                          :op1 (p13 / person :name (n7 / name :op1 "Bruckert"))
                                          :op2 p8)
                                    :time (d4 / date-entity :year 1992)))))))

# ::id bio.chicago_2015.38037 ::date 2015-10-28T07:41:26 ::annotator SDL-AMR-09 ::preferred
# ::snt It was also shown that the  GST-A box of  HMG-1 was able to pull down  TFIID in crude HeLa extract, suggesting that  HMG-1 binds to  TBP and/or other  TFIID components ( 41).
# ::save-date Sun Jan 17, 2016 ::file bio_chicago_2015_38037.txt
(s / show-01
      :ARG1 (c / capable-01
            :ARG1 (d / dna-sequence :name (n / name :op1 "GST-A" :op2 "box")
                  :part-of (g / gene :name (n2 / name :op1 "HMG-1")))
            :ARG2 (p / pull-down-08
                  :ARG1 (p2 / protein :name (n3 / name :op1 "TFIID"))
                  :ARG2 (e / extract-01
                        :ARG2 (c2 / cell-line :name (n4 / name :op1 "HeLa"))
                        :mod (c3 / crude))
                  :ARG3 d)
            :ARG0-of (s2 / suggest-01
                  :ARG1 (b / bind-01
                        :ARG1 g
                        :ARG2 (a3 / and-or
                              :op1 (a2 / and
                                    :op1 (p3 / protein :name (n5 / name :op1 "TBP"))
                                    :op2 (c4 / component
                                          :part-of p2
                                          :mod (o / other)))
                              :op2 (o2 / or
                                    :op1 p3
                                    :op2 c4)))))
      :mod (a / also)
      :ARG1-of (d2 / describe-01
            :ARG0 (p4 / publication
                  :ARG1-of (c5 / cite-01
                        :ARG2 41))))

# ::id bio.chicago_2015.38040 ::date 2015-10-28T08:02:07 ::annotator SDL-AMR-09 ::preferred
# ::snt If a similar structure mediates the formation of the  MSL1-MSL2 heterodimer, then part of the region of  MSL2 that interacts with  MSL1 should form a coiled-coil structure.
# ::save-date Mon Nov 2, 2015 ::file bio_chicago_2015_38040.txt
(h / have-condition-91
      :ARG1 (r2 / recommend-01
            :ARG1 (f2 / form-01
                  :ARG0 (p3 / part
                        :part-of (r3 / region
                              :part-of (p4 / protein :name (n3 / name :op1 "MSL2")
                                    :ARG0-of (i / interact-01
                                          :ARG1 p))))
                  :ARG1 (s3 / structure
                        :mod (c / coil
                              :ARG1-of (c2 / coil-01)))))
      :ARG2 (m / mediate-01
            :ARG0 (s / structure
                  :ARG1-of (r / resemble-01))
            :ARG1 (f / form-01
                  :ARG1 (h2 / heterodimer
                        :part (p / protein :name (n / name :op1 "MSL1"))
                        :part (p2 / protein :name (n2 / name :op1 "MSL2"))))))

# ::id bio.chicago_2015.38085 ::date 2015-10-28T08:26:49 ::annotator SDL-AMR-09 ::preferred
# ::snt Anaphase initiation in  Saccharomyces cerevisiae is controlled by the  APC-dependent degradation of the  anaphase inhibitor Pds1p.
# ::save-date Sun Jan 17, 2016 ::file bio_chicago_2015_38085.txt
(c / control-01
      :ARG1 (i / initiate-01
            :ARG1 (a / anaphase)
            :location (o / organism :name (n / name :op1 "Saccharomyces" :op2 "cerevisiae")))
      :ARG2 (d / degrade-01
            :ARG1 (p / protein :name (n2 / name :op1 "Pds1p")
                  :ARG0-of (i2 / inhibit-01
                        :ARG1 a))
            :ARG0-of (d2 / depend-01
                  :ARG1 (p2 / protein :name (n3 / name :op1 "APC")))))

# ::id bio.chicago_2015.38107 ::date 2015-10-28T08:43:29 ::annotator SDL-AMR-09 ::preferred
# ::snt The role of these  virus-like particles, if any, in neuronal cell death induced by  huntingtin transgenes requires further analysis.
# ::save-date Mon Nov 2, 2015 ::file bio_chicago_2015_38107.txt
(r / role
      :poss (p / particle
            :ARG1-of (r2 / resemble-01
                  :ARG2 (v / virus))
            :mod (t2 / this))
      :condition (a / any)
      :ARG0-of (r3 / require-01
            :ARG1 (a2 / analyze-01
                  :mod (f / further)))
      :topic (d / die-01
            :ARG1 (c / cell
                  :mod (n / neuron))
            :ARG2-of (i / induce-01
                  :ARG0 (t / transgene :name (n2 / name :op1 "huntingtin")))))

# ::id bio.chicago_2015.38113 ::date 2015-10-28T09:22:03 ::annotator SDL-AMR-09 ::preferred
# ::snt These date indicate that  MEK plays a crucial role in  Epo-induced activation of  Elk-1 and is also involved in  CrkL-enhanced activation of  Elk-1.
# ::save-date Sun Jan 17, 2016 ::file bio_chicago_2015_38113.txt
(i / indicate-01
      :ARG0 (d / data
            :mod (t / this))
      :ARG1 (a / and
            :op1 (p / play-02
                  :ARG0 (e / enzyme :name (n / name :op1 "MEK"))
                  :ARG1 (r / role
                        :mod (c / crucial)
                        :topic (a2 / activate-01
                              :ARG1 (p2 / protein :name (n2 / name :op1 "Elk-1"))
                              :ARG2-of (i2 / induce-01
                                    :ARG0 (s / small-molecule :name (n3 / name :op1 "Epo"))))))
            :op2 (i3 / involve-01
                  :ARG1 e
                  :ARG2 (a3 / activate-01
                        :ARG1 p2
                        :ARG1-of (e2 / enhance-01
                              :ARG0 (p3 / protein :name (n4 / name :op1 "CrkL"))))
                  :mod (a4 / also))))

# ::id bio.chicago_2015.38119 ::date 2015-10-28T12:07:07 ::annotator SDL-AMR-09 ::preferred
# ::snt Because   APC inhibition by  Mad2 or  proteasome inhibition  by addition of  MG132 (J.D.R.R. and P.J., unpublished data), rescued  mitosis in  Emi1-depleted extracts,  Emi1 most likely affects   cyclin B ubiquitylation and destruction, rather than, for example, its  translation.
# ::save-date Sun Jan 17, 2016 ::file bio_chicago_2015_38119.txt
(c / cause-01
      :ARG0 (r / rescue-01
            :ARG0 (o / or
                  :op1 (i / inhibit-01
                        :ARG0 (p / protein :name (n / name :op1 "Mad2"))
                        :ARG1 (p9 / protein :name (n2 / name :op1 "APC")))
                  :op2 (i2 / inhibit-01
                        :ARG0 (a / add-02
                              :ARG1 (s / small-molecule :name (n4 / name :op1 "MG132")))
                        :ARG1 (m2 / macro-molecular-complex :name (n3 / name :op1 "proteasome")))
                  :ARG1-of (d2 / describe-01
                        :ARG0 (a2 / and
                              :op1 (p4 / publication-91
                                    :ARG0 (a3 / and
                                          :op1 (p5 / person :name (n6 / name :op1 "J.D.R.R."))
                                          :op2 (p6 / person :name (n7 / name :op1 "P.J."))))
                              :op2 (d3 / data
                                    :ARG1-of (p7 / publish-01 :polarity -)))))
            :ARG1 (m3 / mitosis)
            :condition (e / extract-01
                  :ARG1-of (d / deplete-01
                        :ARG2 (s2 / small-molecule :name (n5 / name :op1 "Emi1")))))
      :ARG1 (a4 / affect-01
            :ARG0 s2
            :ARG1 (a5 / and
                  :op1 (u / ubiquitylate-00
                        :ARG1 (p8 / protein :name (n8 / name :op1 "cyclin" :op2 "B")))
                  :op2 (d4 / destroy-01
                        :ARG1 p8)
                  :ARG1-of (i3 / instead-of-91
                        :ARG2 (t / translate-02
                              :ARG1 p8
                              :ARG0-of (e2 / exemplify-01))))
            :ARG1-of (l / likely-01
                  :degree (m4 / most))))

# ::id bio.chicago_2015.38154 ::date 2015-10-28T12:47:17 ::annotator SDL-AMR-09 ::preferred
# ::snt In vivo, we observed that overexpression of the cytoplasmic domain of  plexin-B1 inhibited the activation of  PAK by  Rac.
# ::save-date Mon Nov 2, 2015 ::file bio_chicago_2015_38154.txt
(o / observe-01
      :ARG0 (w / we)
      :ARG1 (i2 / inhibit-01
            :ARG0 (o2 / overexpress-01
                  :ARG1 (d / domain
                        :mod (c / cytoplasm)
                        :part-of (p / protein :name (n / name :op1 "plexin-B1"))))
            :ARG1 (a / activate-01
                  :ARG0 (e2 / enzyme :name (n3 / name :op1 "Rac"))
                  :ARG1 (e / enzyme :name (n2 / name :op1 "PAK"))))
      :manner (i / in-vivo))

# ::id bio.chicago_2015.38179 ::date 2015-10-28T12:54:02 ::annotator SDL-AMR-09 ::preferred
# ::snt The transcriptional and genetic relationships we have identified between   sens and   ro imply that the process of  R8 differentiation involves a hierarchical interaction where   sens normally represses   ro to prevent both   ro repression of  R8 and   ro induction of  R2/R5.
# ::save-date Fri Nov 27, 2015 ::file bio_chicago_2015_38179.txt
(i / imply-01
      :ARG0 (a / and
            :op1 (r / relation-03
                  :ARG0 (p / protein :name (n / name :op1 "sens"))
                  :ARG1 (t / transcribe-01)
                  :ARG2 (p2 / protein :name (n2 / name :op1 "ro")))
            :op2 (r2 / relation-03
                  :ARG0 p
                  :ARG1 (g / genetic)
                  :ARG2 p2)
            :ARG1-of (i2 / identify-01
                  :ARG0 (w / we)))
      :ARG1 (i3 / involve-01
            :ARG0 (p3 / process-02
                  :ARG1 (d / differentiate-01
                        :ARG1 (p4 / protein :name (n3 / name :op1 "R8"))))
            :ARG1 (i4 / interact-01
                  :ARG2 (h / hierarchy)
                  :time (r3 / repress-01
                        :ARG0 p
                        :ARG1 p2
                        :ARG1-of (n4 / normal-02)
                        :purpose (p5 / prevent-01
                              :ARG0 p
                              :ARG1 (a2 / and
                                    :op1 (r4 / repress-01
                                          :ARG0 p2
                                          :ARG1 p4)
                                    :op2 (i5 / induce-01
                                          :ARG0 p2
                                          :ARG1 (s / slash
                                                :op1 (p6 / protein :name (n5 / name :op1 "R2"))
                                                :op2 (p7 / protein :name (n6 / name :op1 "R5"))))))))))

# ::id bio.chicago_2015.38213 ::date 2015-10-28T13:26:23 ::annotator SDL-AMR-09 ::preferred
# ::snt Detection of bound probe employed  anti-digoxigenin Fab conjugated to  alkaline phosphatase, which catalyzed the degradation of the chemiluminescent  substrate CDP-Star (Tropix, Bedford, MA), following the protocol of Engler-Blum  et al. ( 26).
# ::save-date Tue Feb 2, 2016 ::file bio_chicago_2015_38213.txt
(e / employ-02
      :ARG0 (d / detect-01
            :ARG1 (p / probe
                  :ARG1-of (b / bind-01)))
      :ARG1 (p2 / protein :name (n / name :op1 "anti-digoxigenin" :op2 "Fab")
            :ARG1-of (c / conjugate-02
                  :ARG2 (e2 / enzyme :name (n2 / name :op1 "alkaline" :op2 "phosphatase"))))
      :ARG0-of (c2 / catalyze-01
            :ARG1 (d2 / degrade-01
                  :ARG1 (s / substrate :name (n3 / name :op1 "CDP-Star")
                        :mod (c3 / chemiluminescent)
                        :source (c4 / company :name (n4 / name :op1 "Tropix")
                              :location (s2 / street-address-91
                                    :ARG2 (s3 / state :name (n6 / name :op1 "MA"))
                                    :ARG4 (c5 / city :name (n5 / name :op1 "Bedford")))))))
      :ARG0-of (f / follow-02
            :ARG1 (p8 / protocol
                  :ARG1-of (d3 / describe-01
                        :ARG0 (a2 / and
                              :op1 (p3 / publication-91
                                    :ARG0 (a / and
                                          :op1 (p4 / person :name (n7 / name :op1 "Engler"))
                                          :op2 (p5 / person :name (n8 / name :op1 "Blum"))
                                          :op3 (p6 / person
                                                :mod (o / other))))
                              :op2 (p7 / publication
                                    :ARG1-of (c6 / cite-01
                                          :ARG2 26)))))))

# ::id bio.chicago_2015.38247 ::date 2015-10-28T13:51:21 ::annotator SDL-AMR-09 ::preferred
# ::snt The  Ou group showed that  Nedd8 acts genetically downstream of  Hh signaling components Smoothened ( Smo) and  PKA to regulate  Ci processing in cells anterior to the  MF.
# ::save-date Mon Nov 2, 2015 ::file bio_chicago_2015_38247.txt
(s / show-01
      :ARG0 (g / group :name (n / name :op1 "Ou"))
      :ARG1 (a / act-02
            :ARG0 (p / protein :name (n2 / name :op1 "Nedd8"))
            :location (r / relative-position
                  :op1 (a2 / and
                        :op1 (p3 / protein :name (n4 / name :op1 "Smoothened"))
                        :op2 (p4 / protein :name (n5 / name :op1 "PKA"))
                        :ARG0-of (s2 / signal-07
                              :ARG1 (p2 / protein :name (n3 / name :op1 "Hh"))))
                  :direction (d / downstream))
            :mod (g2 / genetic)
            :purpose (r2 / regulate-01
                  :ARG0 p
                  :ARG1 (p5 / process-01
                        :ARG1 (p6 / protein :name (n6 / name :op1 "Ci"))
                        :location (c / cell)
                        :time (a3 / anterior
                              :op1 (p7 / protein :name (n7 / name :op1 "MF")))))))

# ::id bio.chicago_2015.38248 ::date 2015-10-28T14:21:52 ::annotator SDL-AMR-09 ::preferred
# ::snt Association of  CIZ with  Cas.
# ::save-date Wed Oct 28, 2015 ::file bio_chicago_2015_38248.txt
(a / associate-01
      :ARG1 (p / protein :name (n / name :op1 "CIZ"))
      :ARG2 (p2 / protein :name (n2 / name :op1 "Cas")))

# ::id bio.chicago_2015.38266 ::date 2015-10-28T14:23:36 ::annotator SDL-AMR-09 ::preferred
# ::snt Repression activity of MM-1 toward  c-Myc was sensitive to  TSA, a specific inhibitor of  HDAC, indicating that  HDAC is involved in the N-terminal transrepression pathway of  c-Myc.
# ::save-date Mon Nov 2, 2015 ::file bio_chicago_2015_38266.txt
(s / sensitive-03
      :ARG0 (a / activity-06
            :ARG0 (p / protein :name (n / name :op1 "MM-1"))
            :ARG1 (r / repress-01)
            :direction (p2 / protein :name (n2 / name :op1 "c-Myc")))
      :ARG1 (s2 / small-molecule :name (n3 / name :op1 "TSA")
            :ARG0-of (i / inhibit-01
                  :ARG1 (e / enzyme :name (n4 / name :op1 "HDAC")))
            :ARG1-of (s3 / specific-02))
      :ARG0-of (i2 / indicate-01
            :ARG1 (i3 / involve-01
                  :ARG1 e
                  :ARG2 (p3 / pathway
                        :ARG0-of (t / transrepress-00
                              :ARG1 (p4 / protein-segment :name (n5 / name :op1 "N-terminus")))
                        :poss p2))))

# ::id bio.chicago_2015.38278 ::date 2015-10-28T14:44:55 ::annotator SDL-AMR-09 ::preferred
# ::snt Cells were washed with phosphate-buffered saline and fed with 3 ml of either phosphate-free or  methionine-free Dulbecco's modified  Eagle's medium containing 10% dialyzed fetal  bovine serum.
# ::save-date Wed Mar 2, 2016 ::file bio_chicago_2015_38278.txt
(a / and
      :op1 (w / wash-01
            :ARG1 (c / cell)
            :ARG2 (s2 / small-molecule :wiki "Phosphate-buffered_saline" :name (n3 / name :op1 "phosphate-buffered" :op2 "saline")))
      :op2 (f / feed-01
            :ARG1 (o / or
                  :op1 (t / thing :wiki "Eagle's_minimal_essential_medium" :name (n / name :op1 "Dulbecco's" :op2 "Modified" :op3 "Eagle's" :op4 "Medium")
                        :quant (c2 / concentration-quantity :quant 3
                              :unit (m / milliliter))
                        :ARG1-of (f2 / free-04
                              :ARG2 (p2 / phosphate))
                        :ARG0-of (c3 / contain-01
                              :ARG1 (s / serum
                                    :source (f4 / fetus
                                          :mod (b / bovine))
                                    :ARG1-of (d2 / dialyze-00)
                                    :quant (p3 / percentage-entity :value 10))))
                  :op2 (t2 / thing :wiki "Eagle's_minimal_essential_medium" :name (n2 / name :op1 "Dulbecco's" :op2 "Modified" :op3 "Eagle's" :op4 "Medium")
                        :quant c2
                        :ARG1-of (f3 / free-04
                              :ARG2 (a2 / amino-acid :wiki "Methionine" :name (n4 / name :op1 "methionine")))
                        :ARG0-of c3))
            :ARG2 c))

# ::id bio.chicago_2015.38344 ::date 2015-10-28T15:03:11 ::annotator SDL-AMR-09 ::preferred
# ::snt (a)  Plexin-B1 interacts with  Rac in a  GTP-dependent manner.
# ::save-date Wed Oct 28, 2015 ::file bio_chicago_2015_38344.txt
(i / interact-01
      :ARG0 (p / protein :name (n / name :op1 "Plexin-B1"))
      :ARG1 (e / enzyme :name (n2 / name :op1 "Rac"))
      :manner (d / depend-01
            :ARG1 (s / small-molecule :name (n3 / name :op1 "GTP")))
      :ARG1-of (d2 / describe-01
            :ARG0 (f / figure :mod "A")))

# ::id bio.chicago_2015.38348 ::date 2015-10-28T15:11:49 ::annotator SDL-AMR-09 ::preferred
# ::snt Recovery of  IKK was determined by immunoblotting ( IB).
# ::save-date Wed Jan 13, 2016 ::file bio_chicago_2015_38348.txt
(d / determine-01
      :ARG0 (i / immunoblot-01)
      :ARG1 (r / recover-02
            :ARG1 (e / enzyme :name (n / name :op1 "IKK"))))

# ::id bio.chicago_2015.38364 ::date 2015-10-28T15:14:14 ::annotator SDL-AMR-09 ::preferred
# ::snt Sprouty, an intracellular inhibitor of  Ras signaling.
# ::save-date Sat Jan 16, 2016 ::file bio_chicago_2015_38364.txt
(i / inhibit-01
      :ARG0 (p / protein :name (n / name :op1 "Sprouty")
            :mod (i2 / intracellular))
      :ARG1 (s / signal-07
            :ARG0 (e / enzyme :name (n2 / name :op1 "Ras"))))

# ::id bio.chicago_2015.38368 ::date 2015-10-28T15:17:52 ::annotator SDL-AMR-09 ::preferred
# ::snt Interaction of  RGL with  Ras Effector Loop Mutants
# ::save-date Thu Nov 12, 2015 ::file bio_chicago_2015_38368.txt
(i / interact-01
      :ARG0 (p / protein :name (n / name :op1 "RGL"))
      :ARG1 (l / loop
            :ARG2-of (m / mutate-01)
            :mod (e / effector)
            :mod (p2 / protein-family :name (n2 / name :op1 "Ras"))))

# ::id bio.chicago_2015.38377 ::date 2015-10-28T15:25:37 ::annotator SDL-AMR-09 ::preferred
# ::snt Actin Binding Assay--  Actin binding of cultured  cell TMs,  caldesmon, and  human fascin was assayed in the following four conditions.
# ::save-date Wed Oct 28, 2015 ::file bio_chicago_2015_38377.txt
(a2 / assay-01
      :ARG1 (b / bind-01
            :ARG1 (p / protein :name (n / name :op1 "Actin"))
            :ARG2 (a / and
                  :op1 (c2 / cell :name (n2 / name :op1 "TMs")
                        :ARG1-of (c3 / culture-01))
                  :op2 (p2 / protein :name (n3 / name :op1 "caldesmon"))
                  :op3 (p3 / protein :name (n4 / name :op1 "fascin")
                        :mod (h / human))))
      :manner (c / condition :quant 4
            :ARG1-of (f / follow-04)))

# ::id bio.chicago_2015.38397 ::date 2015-10-28T15:58:05 ::annotator SDL-AMR-09 ::preferred
# ::snt These results suggest that  CIZ binds  Cas at focal adhesions, at least when they are formed.
# ::save-date Wed Mar 2, 2016 ::file bio_chicago_2015_38397.txt
(s / suggest-01
      :ARG0 (t2 / thing
            :mod (t / this)
            :ARG2-of (r2 / result-01))
      :ARG1 (b / bind-01
            :ARG1 (p / protein :name (n / name :op1 "CIZ"))
            :ARG2 (p2 / protein :name (n2 / name :op1 "Cas"))
            :location (a2 / adhere-01
                  :mod (f2 / focal))
            :time (f / form-01
                  :ARG1 a2
                  :mod (a / at-least))))

# ::id bio.chicago_2015.38411 ::date 2015-10-28T16:05:55 ::annotator SDL-AMR-09 ::preferred
# ::snt However, when the full-length  Dlx3 protein was phosphorylated by  PKC, a decreased DNA binding activity was observed.
# ::save-date Mon Nov 2, 2015 ::file bio_chicago_2015_38411.txt
(h / have-concession-91
      :ARG2 (o / observe-01
            :ARG1 (a / activity-06
                  :ARG1 (b / bind-01
                        :ARG1 (n / nucleic-acid :wiki "DNA" :name (n2 / name :op1 "DNA")))
                  :ARG1-of (d / decrease-01))
            :time (p / phosphorylate-01
                  :ARG1 (p2 / protein :name (n3 / name :op1 "Dlx3")
                        :ARG1-of (l / long-03
                              :ARG1-of (f / full-09)))
                  :ARG2 (e / enzyme :name (n4 / name :op1 "PKC")))))

# ::id bio.chicago_2015.38447 ::date 2015-10-28T16:13:29 ::annotator SDL-AMR-09 ::preferred
# ::snt Regardless of the extent of  TRP binding to  INAD in the   InaD P215 mutant, however, the results of this study suggest that the presence of  TRPL stabilizes the  TRP channel and allows the latter to contribute to the photoreceptor response in   InaD P215, implying physical interactions between these two proteins.
# ::save-date Thu Jan 7, 2016 ::file bio_chicago_2015_38447.txt
(c / contrast-01
      :ARG2 (s / suggest-01
            :ARG0 (t / thing
                  :ARG2-of (r3 / result-01
                        :ARG1 (s2 / study
                              :mod (t2 / this))))
            :ARG1 (a / and
                  :op1 (s3 / stabilize-01
                        :ARG0 (p / present-02
                              :ARG1 (p2 / protein :name (n / name :op1 "TRPL")))
                        :ARG1 (p8 / protein :name (n5 / name :op1 "TRP" :op2 "channel")))
                  :op2 (a2 / allow-01
                        :ARG0 p2
                        :ARG1 (c2 / contribute-01
                              :ARG0 (p5 / protein)
                              :ARG2 (r2 / respond-01
                                    :ARG0 (p3 / photoreceptor)
                                    :location (p4 / protein :name (n3 / name :op1 "INAD")
                                          :ARG2-of (m / mutate-01 :value "P215")))))
                  :ARG0-of (i / imply-01
                        :ARG1 (i2 / interact-01
                              :ARG1 p2
                              :ARG2 p5
                              :manner (p6 / physical))))
            :ARG1-of (r / regardless-91
                  :ARG2 (e / extent
                        :degree-of (b / bind-01
                              :ARG1 p5
                              :ARG2 (p7 / protein :name (n4 / name :op1 "INAD"))
                              :location p4)))))

# ::id bio.chicago_2015.38490 ::date 2015-10-28T16:46:32 ::annotator SDL-AMR-09 ::preferred
# ::snt We investigated the association of  CIZ with  Cas by overexpressing  CIZ-FLAG and  Cas in COS-7 cells.
# ::save-date Wed Jan 13, 2016 ::file bio_chicago_2015_38490.txt
(i / investigate-01
      :ARG0 (w / we)
      :ARG1 (a / associate-01
            :ARG1 (p / protein :name (n / name :op1 "CIZ"))
            :ARG2 (p2 / protein :name (n2 / name :op1 "Cas")))
      :manner (o / overexpress-01
            :ARG1 (a2 / and
                  :op1 (p3 / protein :name (n3 / name :op1 "CIZ-FLAG"))
                  :op2 p2)
            :location (c / cell-line :name (n4 / name :op1 "COS-7"))))

# ::id bio.chicago_2015.38505 ::date 2015-10-27T12:11:08 ::annotator SDL-AMR-09 ::preferred
# ::snt Sexual orientation in   Drosophila is altered by the   satori mutation in the sex-determination gene  fruitless that encodes a  zinc finger protein with a  BTB domain.
# ::save-date Mon Dec 7, 2015 ::file bio_chicago_2015_38505.txt
(a / alter-01
      :ARG0 (m / mutate-01
            :ARG1 (g2 / gene :name (n3 / name :op1 "fruitless")
                  :ARG0-of (d / determine-01
                        :ARG1 (s4 / sex))
                  :ARG0-of (e / encode-01
                        :ARG1 (p3 / protein :name (n4 / name :op1 "zinc" :op2 "finger")
                              :part (p4 / protein-segment :name (n5 / name :op1 "BTB" :op2 "domain")))))
            :ARG2 (s3 / satori))
      :ARG1 (o / orient-01
            :ARG1 (o2 / organism :name (n / name :op1 "Drosophila"))
            :ARG3 (s / sex)))

# ::id bio.chicago_2015.38519 ::date 2015-10-27T12:51:00 ::annotator SDL-AMR-09 ::preferred
# ::snt Treatment of HeLa cells with leptomycin B ( LMB), a specific inhibitor of the  NES-dependent transport, resulted in nuclear accumulation of  cyclin B1 in G2 phase.
# ::save-date Wed Jan 13, 2016 ::file bio_chicago_2015_38519.txt
(r / result-01
      :ARG1 (t2 / treat-04
            :ARG1 (c / cell-line :name (n / name :op1 "hela"))
            :ARG2 (s2 / small-molecule :name (n6 / name :op1 "leptomicin" :op2 "B")
                  :ARG0-of (i / inhibit-01
                        :ARG1 (t3 / transport-01
                              :ARG0-of (d / depend-01
                                    :ARG1 (p4 / protein-segment :name (n2 / name :op1 "NES"))))
                        :ARG1-of (s / specific-02))))
      :ARG2 (a / accumulate-01
            :ARG1 (p / protein :name (n4 / name :op1 "cyclin" :op2 "B1")
                  :mod (e / event :name (n7 / name :op1 "phase" :op2 "G2")))
            :mod (n3 / nucleus)))

# ::id bio.chicago_2015.38552 ::date 2015-10-27T13:02:10 ::annotator SDL-AMR-09 ::preferred
# ::snt The  Raf/ MEK/ ERK Signaling Pathway Is Involved in the  CrkL-enhanced Activation of  Elk-1-- To define the downstream signal transduction pathway leading to the  Elk-1 activation, we next examined the possible involvement of the  Raf/ MEK/ ERK cascade.
# ::save-date Tue Jan 19, 2016 ::file bio_chicago_2015_38552.txt
(m / multi-sentence
      :snt1 (i / involve-01
            :ARG1 (p2 / pathway :name (n2 / name :op1 "Raf/MEK/ERK")
                  :ARG0-of (s / signal-07))
            :ARG2 (a / activate-01
                  :ARG1 (p / protein :name (n / name :op1 "Elk-1"))
                  :ARG1-of (e / enhance-01
                        :ARG0 (p3 / protein :name (n3 / name :op1 "CrkL")))))
      :snt2 (e2 / examine-01
            :ARG0 (w / we)
            :ARG1 (i2 / involve-01
                  :ARG1 (c / cascade-01
                        :ARG1 (p4 / pathway :name (n4 / name :op1 "Raf/MEK/ERK")))
                  :ARG1-of (p5 / possible-01))
            :time (n5 / next)
            :purpose (d / define-01
                  :ARG0 w
                  :ARG1 (p9 / pathway
                        :ARG0-of (l / lead-01
                              :ARG4 (a2 / activate-01
                                    :ARG1 (p10 / protein :name (n9 / name :op1 "Elk-1"))))
                        :ARG2-of (t / transduce-01
                              :ARG1 (s3 / signal-07
                                    :direction (d2 / downstream)))))))

# ::id bio.chicago_2015.38555 ::date 2015-10-27T13:18:23 ::annotator SDL-AMR-09 ::preferred
# ::snt We show that precocious induction of   Hoxb1 and   Hoxb2 by  RA is operational at E6.0 already, before primitive streak formation and long before the gene is transcriptionally initiated.
# ::save-date Sat Feb 13, 2016 ::file bio_chicago_2015_38555.txt
(s / show-01
      :ARG0 (w / we)
      :ARG1 (p4 / possible-01
            :ARG1 (o2 / operate-01
                  :ARG0 (i / induce-01
                        :ARG0 (s3 / small-molecule :name (n3 / name :op1 "RA"))
                        :ARG1 (a / and
                              :op1 (p2 / protein :name (n / name :op1 "Hoxb1"))
                              :op2 (p3 / protein :name (n2 / name :op1 "Hoxb2")))
                        :mod (p / precocious))
                  :time (a3 / and
                        :op1 (b / before
                              :op1 (f / form-01
                                    :ARG1 (s2 / streak
                                          :mod (p5 / primitive))))
                        :op2 (b2 / before
                              :op1 (i2 / initiate-01
                                    :ARG1 (g / gene)
                                    :manner (t / transcribe-01))
                              :ARG1-of (l / long-03)))
                  :time (a2 / already)
                  :time (a4 / age-01
                        :ARG1 (e / embryo)
                        :ARG2 (t2 / temporal-quantity :quant 6
                              :unit (d / day))))))

# ::id bio.chicago_2015.38557 ::date 2015-10-27T20:42:40 ::annotator SDL-AMR-09 ::preferred
# ::snt Because half-maximal binding of  syntaxin 1A to the  C2A domain of  synaptotagmin 1 occurs at calcium levels required for vesicle fusion ( 200  muM calcium) (Heidelberger et al., 1994  ), this interaction may be particularly important for regulating neurotransmitter release by providing a direct means for calcium to regulate vesicle-plasma membrane fusion.
# ::save-date Thu Feb 4, 2016 ::file bio_chicago_2015_38557.txt
(c4 / cause-01
      :ARG0 (b / bind-01
            :ARG1 (p9 / protein :name (n6 / name :op1 "syntaxin" :op2 "A1"))
            :ARG2 (p5 / protein-segment :name (n4 / name :op1 "C2A")
                  :part-of (p7 / protein :name (n2 / name :op1 "synaptotagmin" :op2 "1")))
            :mod (m2 / maximal
                  :degree (h2 / half))
            :condition (l / level
                  :ARG1-of (r4 / require-01
                        :ARG0 (f2 / fuse-01
                              :ARG1 v))
                  :quant-of c
                  :ARG1-of (m3 / mean-01
                        :ARG2 (c3 / calcium :quant 200
                              :unit (m6 / millimolar))))
            :ARG1-of (d4 / describe-01
                  :ARG0 (a / and
                        :op1 (p6 / person :name (n3 / name :op1 "Heidelberger"))
                        :op2 (p8 / person
                              :mod (o / other)))
                  :time (d / date-entity :year 1994)))
      :ARG1 (p / possible-01
            :ARG1 (i / important
                  :domain (i2 / interact-01
                        :mod (t / this))
                  :manner (p2 / particular)
                  :topic (r / regulate-01
                        :ARG0 i2
                        :ARG1 (r2 / release-01
                              :ARG1 (n / neurotransmitter))
                        :manner (p3 / provide-01
                              :ARG0 i2
                              :ARG1 (m / mean
                                    :ARG1-of (d3 / direct-01))
                              :ARG2 (c / calcium)
                              :purpose (r3 / regulate-01
                                    :ARG0 c
                                    :ARG1 (f / fuse-01
                                          :ARG1 (v / vesicle)
                                          :ARG2 (m5 / membrane
                                                :mod (p4 / plasma)))))))))

# ::id bio.chicago_2015.38559 ::date 2015-10-27T21:08:06 ::annotator SDL-AMR-09 ::preferred
# ::snt Second,  DRB potently inhibits  phosphorylation of the  CTD by  P-TEFb, and  DRB inhibition of  P-TEFb  kinase correlates well with  DRB-induced inhibition of elongation by   RNA polymerase II.
# ::save-date Sun Jan 17, 2016 ::file bio_chicago_2015_38559.txt
(a / and
      :op1 (i / inhibit-01
            :ARG0 (s / small-molecule :name (n / name :op1 "DRB"))
            :ARG1 (p3 / phosphorylate-01
                  :ARG1 (p / protein-segment :name (n2 / name :op1 "C-terminus"))
                  :ARG2 (k / kinase :name (n3 / name :op1 "P-TEFb")))
            :manner (p2 / potent))
      :op2 (c / correlate-01
            :ARG1 (i2 / inhibit-01
                  :ARG0 s
                  :ARG1 k)
            :ARG2 (i3 / inhibit-01
                  :ARG1 (e2 / elongate-01
                        :ARG0 (n4 / nucleic-acid :name (n6 / name :op1 "RNA")
                              :ARG0-of (e3 / encode-01
                                    :ARG1 (e4 / enzyme :name (n5 / name :op1 "polymerase" :op2 "II")))))
                  :ARG2-of (i4 / induce-01
                        :ARG0 s))
            :ARG1-of (w / well-09))
      :mod (o / ordinal-entity :value 2))

# ::id bio.chicago_2015.38566 ::date 2015-10-27T21:20:00 ::annotator SDL-AMR-09 ::preferred
# ::snt NIK can interact  in vivo with  MEKK1.
# ::save-date Mon Nov 2, 2015 ::file bio_chicago_2015_38566.txt
(p / possible-01
      :ARG1 (i / interact-01
            :ARG0 (e2 / enzyme :name (n / name :op1 "NIK"))
            :ARG1 (e / enzyme :name (n2 / name :op1 "MEKK1"))
            :manner (i2 / in-vivo)))

# ::id bio.chicago_2015.38569 ::date 2015-10-27T21:22:21 ::annotator SDL-AMR-09 ::preferred
# ::snt P120ctn is colocalized with  Vav2 within growth cones and a subset of dendritic spines
# ::save-date Tue Feb 2, 2016 ::file bio_chicago_2015_38569.txt
(c / colocalize-01
      :ARG1 (a2 / and
            :op1 (p / protein :name (n / name :op1 "P120ctn"))
            :op2 (p2 / protein :name (n2 / name :op1 "Vav2")))
      :ARG2 (a / and
            :op1 (c2 / cone
                  :mod (g / grow-01))
            :op2 (s / subset
                  :mod (s2 / spine
                        :mod (d / dendrite)))))

# ::id bio.chicago_2015.38579 ::date 2015-10-27T21:26:31 ::annotator SDL-AMR-09 ::preferred
# ::snt In the present study, we have shown that  TFIIB interacts with the  AHR at a site (the region bordered by amino acids 81 and 183) that lies slightly adjacent to its  ARNT dimerization motif as well as interacting with its carboxyl terminus.
# ::save-date Thu Nov 12, 2015 ::file bio_chicago_2015_38579.txt
(s / show-01
      :ARG0 (w / we)
      :ARG1 (i / interact-01
            :ARG0 (p3 / protein :name (n / name :op1 "TFIIB"))
            :ARG1 (a5 / and
                  :op1 (p / protein :name (n2 / name :op1 "AHR"))
                  :op2 (p4 / protein-segment :name (n4 / name :op1 "carboxyl" :op2 "terminus")
                        :part-of p3))
            :location (s2 / site
                  :ARG1-of (m2 / mean-01
                        :ARG2 (r / region
                              :ARG2-of (b / border-01
                                    :ARG1 (a / and
                                          :op1 (a2 / amino-acid :mod 81)
                                          :op2 (a3 / amino-acid :mod 183)))))
                  :ARG1-of (l / lay-01
                        :ARG2 (r2 / relative-position
                              :op1 (m3 / motif
                                    :ARG0-of (d / dimerize-01
                                          :ARG1 (p5 / protein :name (n3 / name :op1 "ARNT")))
                                    :part-of p3)
                              :mod (a4 / adjacent
                                    :degree (s3 / slight))))))
      :medium (s4 / study-01
            :mod (p2 / present)))

# ::id bio.chicago_2015.38598 ::date 2015-10-27T21:42:45 ::annotator SDL-AMR-09 ::preferred
# ::snt Whereas removal of  Ci activity from clones of cells was shown to result in the loss of expression of some  Hh target genes, notably   ptc (Dominguez et al. 1996  ), consistent with  Hh activation of   ptc transcription being mediated by  Ci (Alexandre et al. 1996  ), other  Hh targets, such as   dpp, were found to be activated in the absence of  Ci, albeit at a lower level than in their normal domain close to the compartment border.
# ::save-date Sun Jan 17, 2016 ::file bio_chicago_2015_38598.txt
(c / contrast-01
      :ARG1 (s / show-01
            :ARG1 (r / remove-01
                  :ARG1 (a / activity-06
                        :ARG0 (p3 / protein :name (n / name :op1 "Ci")))
                  :ARG2 (c2 / clone-01
                        :ARG1 (c3 / cell)))
            :ARG1-of (r2 / result-01
                  :ARG2 (l / lose-02
                        :ARG1 (e / express-03
                              :ARG1 (g / gene
                                    :mod (s2 / some)
                                    :ARG1-of (t / target-01
                                          :ARG0 (p5 / protein :name (n3 / name :op1 "Hh")))
                                    :ARG2-of (n8 / notable-04
                                          :ARG1 (g4 / gene :name (n9 / name :op1 "ptc")
                                                :ARG1-of (c4 / consistent-01
                                                      :ARG2 (a4 / activate-01
                                                            :ARG0 p5
                                                            :ARG1 (t2 / transcribe-01
                                                                  :ARG1 g4
                                                                  :ARG1-of (m3 / mediate-01
                                                                        :ARG0 p3)))
                                                      :ARG1-of (d3 / describe-01
                                                            :ARG0 (a5 / and
                                                                  :op1 (p / person :name (n4 / name :op1 "Alexandre"))
                                                                  :op2 (p4 / person
                                                                        :mod (o2 / other))
                                                                  :time d)))))))))
            :ARG1-of (d2 / describe-01
                  :ARG0 (a2 / and
                        :op1 (p2 / person :name (n7 / name :op1 "Dominguez"))
                        :op2 p4
                        :time (d / date-entity :year 1996))))
      :ARG2 (f / find-01
            :ARG1 (g2 / gene
                  :mod (o / other)
                  :example (g3 / gene :name (n5 / name :op1 "dpp"))
                  :ARG1-of (a7 / activate-01
                        :condition (a8 / absent-01
                              :ARG1 p3)
                        :concession (a3 / activate-01
                                    :ARG1 g2
                                    :degree (l3 / level
                                          :ARG1-of (l4 / low-04
                                                :degree (m4 / more))
                                          :compared-to (d5 / domain
                                                :ARG1-of (n6 / normal-02)
                                                :part-of p3)
                                          :location (c5 / close-06
                                                :ARG2 (b / border-01
                                                      :ARG2 (c6 / compartment))))))
                  :ARG1-of (t3 / target-01
                        :ARG0 p5))))

# ::id bio.chicago_2015.38602 ::date 2015-10-27T21:44:02 ::annotator SDL-AMR-09 ::preferred
# ::snt The mutation in the APPKPPR sequence (mPR) abolished the binding of  CIZ to  Cas SH3 (Fig.  3B, lanes 1, 2), strongly suggesting that this sequence was the binding site for  Cas SH3.
# ::save-date Thu Nov 12, 2015 ::file bio_chicago_2015_38602.txt
(a / abolish-01
      :ARG0 (m / mutate-01
            :ARG1 (d / dna-sequence :name (n / name :op1 "APPKPPR")
                  :mod (t / this)))
      :ARG1 (b / bind-01
            :ARG1 (p / protein :name (n2 / name :op1 "CIZ"))
            :ARG2 (p4 / protein-segment :name (n4 / name :op1 "SH3")
                  :part-of (p3 / protein :name (n3 / name :op1 "Cas"))
                  :ARG1-of (d2 / describe-01
                        :ARG0 (a2 / and
                              :op1 (f / figure :mod "3B")
                              :op2 (l / lane :mod 1)
                              :op3 (l2 / lane :mod 2)))))
      :ARG0-of (s / suggest-01
            :ARG1 (s3 / site
                  :ARG1-of (b2 / bind-01
                        :ARG2 p4)
                  :domain d)
            :ARG1-of (s2 / strong-02)))

# ::id bio.chicago_2015.38616 ::date 2015-10-27T21:54:46 ::annotator SDL-AMR-09 ::preferred
# ::snt The conclusion that   spen is partially required for  Wg-dependent bristle inhibition is complicated by the fact that loss of   spen causes an increase in  Ac expression in wild-type eyes as well ( Fig. 3E,F).
# ::save-date Sun Jan 17, 2016 ::file bio_chicago_2015_38616.txt
(c / complicate-01
      :ARG0 (f / fact
            :mod (c3 / cause-01
                  :ARG0 (l / lose-02
                        :ARG1 p2)
                  :ARG1 (i2 / increase-01
                        :ARG1 (e / express-03
                              :ARG2 (e3 / enzyme :name (n2 / name :op1 "Ac"))
                              :ARG3 (e2 / eye
                                    :mod (w / wild-type))))
                  :mod (a / as-well)))
      :ARG1 (c2 / conclude-01
            :ARG1 (r / require-01
                  :ARG0 (i / inhibit-01
                        :ARG1 (b / bristle-01)
                        :ARG0-of (d / depend-01
                              :ARG1 (p3 / protein :name (n / name :op1 "Wg"))))
                  :ARG1 (p2 / protein :name (n3 / name :op1 "spen"))
                  :degree (p / part)))
      :ARG1-of (d2 / describe-01
            :ARG0 (a2 / and
                  :op1 (f2 / figure :mod "3E")
                  :op2 (f3 / figure :mod "3F"))))

# ::id bio.chicago_2015.38618 ::date 2015-10-27T22:08:35 ::annotator SDL-AMR-09 ::preferred
# ::snt These findings indicate that  DTRAF1 activates  JNK, but -- in contrast to the activation of  JNK by mammalian  TRAFs 2,  5 and 6 -- this activation does not require either the Ring-finger or  zinc-finger domains   [10,11]  .
# ::save-date Thu Nov 12, 2015 ::file bio_chicago_2015_38618.txt
(i / indicate-01
      :ARG0 (t2 / thing
            :ARG1-of (f / find-01)
            :mod (t / this))
      :ARG1 (c / contrast-01
            :ARG1 (a / activate-01
                  :ARG0 (p3 / protein :name (n / name :op1 "DTRAF1"))
                  :ARG1 (e2 / enzyme :name (n2 / name :op1 "JNK")))
            :ARG2 (r / require-01 :polarity -
                  :ARG0 a
                  :ARG1 (o / or
                        :op1 (p4 / protein-segment :name (n4 / name :op1 "ring-finger" :op2 "domain"))
                        :op2 (p5 / protein-segment :name (n5 / name :op1 "zinc-finger" :op2 "domain")))
                  :ARG1-of (c2 / contrast-01
                        :ARG2 (a2 / activate-01
                              :ARG0 (a4 / and
                                    :op1 (p / protein :name (n3 / name :op1 "TRAF2"))
                                    :op2 (p6 / protein :name (n6 / name :op1 "TRAF5"))
                                    :op3 (p7 / protein :name (n7 / name :op1 "TRAF6"))
                                    :mod (m / mammal))
                              :ARG1 e2))
                  :mod (e / either)))
      :ARG1-of (d3 / describe-01
            :ARG0 (p2 / publication
                  :ARG1-of (c3 / cite-01
                        :ARG2 (a3 / and :op1 10 :op2 11)))))

# ::id bio.chicago_2015.38621 ::date 2015-10-27T22:23:01 ::annotator SDL-AMR-09 ::preferred
# ::snt If the binding of  c-Myb to  S2 is important for silencer function, we could predict that the site-specific mutation of the  c-Myb recognition site in  S2 in the appropriate context would lead to abrogation of silencer function.
# ::save-date Thu Nov 12, 2015 ::file bio_chicago_2015_38621.txt
(h / have-condition-91
      :ARG1 (p4 / possible-01
            :ARG1 (p3 / predict-01
                  :ARG0 (w / we)
                  :ARG1 (l / lead-03
                        :ARG0 (m / mutate-01
                              :ARG1 (s4 / site
                                    :ARG0-of (r / recognize-02
                                          :ARG1 p
                                          :location p2
                                          :location (c / context
                                                :ARG1-of (a / appropriate-02))))
                              :ARG1-of (s2 / specific-02
                                    :ARG2 (s3 / site)))
                        :ARG2 (a2 / abrogate-01
                              :ARG1 f))))
      :ARG2 (i / important
            :domain (b / bind-01
                  :ARG1 (p / protein :name (n / name :op1 "c-Myb"))
                  :ARG2 (p2 / protein :name (n2 / name :op1 "S2")))
            :purpose (f / function-01
                  :ARG0 (s / silencer))))

# ::id bio.chicago_2015.38629 ::date 2015-10-27T22:32:42 ::annotator SDL-AMR-09 ::preferred
# ::snt Mammalian isopeptidase T, similar in its functional properties to  yeast Ubp14   ( 351), stimulates the degradation of ubiquitinated   proteins specifically by   deconjugating free  Lys-48 - linked  Ub chains   after the degradation of the target   protein ( 281,  350,  375).
# ::save-date Tue Feb 2, 2016 ::file bio_chicago_2015_38629.txt
(s / stimulate-01
      :ARG0 (e / enzyme :name (n4 / name :op1 "isopeptidase" :op2 "t")
            :mod (m / mammal)
            :ARG1-of (r2 / resemble-01
                  :ARG2 (e2 / enzyme :name (n / name :op1 "Ubp14")
                        :mod (y2 / yeast))
                  :topic (p / property
                        :mod (f / function-01))
                  :ARG1-of (d4 / describe-01
                        :ARG0 (p6 / publication
                              :ARG1-of (c4 / cite-01
                                    :ARG2 351)))))
      :ARG1 (d / degrade-01
            :ARG1 (p2 / protein
                  :ARG1-of (u / ubiquitinate-01))
            :manner (c2 / conjugate-02 :polarity -
                  :ARG1 (c / chain
                        :mod (p5 / protein :name (n2 / name :op1 "Ub")
                              :ARG1-of (l / link-01
                                    :ARG2 (a3 / amino-acid :mod 48 :name (n3 / name :op1 "lysine")))
                              :ARG1-of (f2 / free-04)))))
      :time (a / after
            :op1 (d3 / degrade-01
                  :ARG1 (p4 / protein
                        :ARG1-of (t / target-01))))
      :ARG1-of (s3 / specific-02)
      :ARG1-of (d2 / describe-01
            :ARG0 (p3 / publication
                  :ARG1-of (c3 / cite-01
                        :ARG2 (a2 / and :op1 281 :op2 350 :op3 375)))))

# ::id bio.chicago_2015.38647 ::date 2015-10-28T12:46:45 ::annotator SDL-AMR-09 ::preferred
# ::snt One such mutation,  R89L, is located in the  RBD and prevents the binding and activation of  Raf-1 by  Ras ( 17,  28,  29).
# ::save-date Sat Jan 16, 2016 ::file bio_chicago_2015_38647.txt
(a / and
      :op1 (b2 / be-located-at-91
            :ARG1 (m / mutate-01 :value "R89L"
                  :mod (o / one)
                  :mod (s / such))
            :ARG2 (p / protein-segment :name (n2 / name :op1 "RBD")))
      :op2 (p2 / prevent-01
            :ARG0 m
            :ARG1 (a2 / and
                  :op1 (b / bind-01
                        :ARG0 (e2 / enzyme :name (n4 / name :op1 "Ras"))
                        :ARG1 (e / enzyme :name (n3 / name :op1 "Raf-1")))
                  :op2 (a3 / activate-01
                        :ARG0 e2
                        :ARG1 e)))
      :ARG1-of (d / describe-01
            :ARG0 (p3 / publication
                  :ARG1-of (c / cite-01
                        :ARG2 (a4 / and :op1 17 :op2 28 :op3 29)))))

# ::id bio.chicago_2015.38657 ::date 2015-10-28T12:59:00 ::annotator SDL-AMR-09 ::preferred
# ::snt In three experiments, the binding of  Ras to  Raf-1 peptide increased upon antigen stimulation and showed similar maximal increases at 1-2 min in both control (2.0  plus-or-minus  0.5-fold, mean  plus-or-minus  S.E.) and dexamethasone-treated (1.9  plus-or-minus  0.3-fold) cells.
# ::save-date Thu Feb 4, 2016 ::file bio_chicago_2015_38657.txt
(a / and
      :op1 (i / increase-01
            :ARG1 (b2 / bind-01
                  :ARG1 (e3 / enzyme :name (n / name :op1 "Ras"))
                  :ARG2 (p / peptide :name (n2 / name :op1 "Raf-1")))
            :time (s2 / stimulate-01
                  :ARG0 (a2 / antigen)))
      :op2 (s / show-01
            :ARG0 b2
            :ARG1 (i2 / increase-01
                  :ARG1-of (r / resemble-01
                        :ARG2 i)
                  :mod (m / maximal)
                  :time (a4 / after
                        :op1 (t2 / temporal-quantity
                              :quant (v4 / value-interval :op1 1 :op2 2)
                              :unit (m2 / minute))))
            :location (a3 / and
                  :op1 (c / cell
                        :ARG0-of (c2 / control-01)
                        :ARG1-of (m3 / mean-01
                              :ARG2 (a5 / and
                                    :op1 (v2 / value-interval
                                          :op1 (a6 / add-02
                                                :ARG1 (p4 / product-of :op1 0.5)
                                                :ARG2 2)
                                          :op2 (s3 / subtract-01
                                                :ARG1 p4
                                                :ARG2 2))
                                    :op2 (v3 / value-interval
                                          :op1 (a7 / add-02
                                                :ARG1 (e / err-01
                                                      :ARG1-of (s5 / standard-02))
                                                :ARG2 (m4 / mean))
                                          :op2 (s6 / subtract-01
                                                :ARG1 e
                                                :ARG2 m4)))))
                  :op2 (c3 / cell
                        :ARG1-of (t / treat-04
                              :ARG2 (s4 / small-molecule :name (n7 / name :op1 "dexamethasone")))
                        :ARG1-of (m5 / mean-01
                              :ARG2 (v / value-interval
                                    :op1 (a8 / add-02
                                          :ARG1 1.9
                                          :ARG2 (p2 / product-of :op1 0.3))
                                    :op2 (s7 / subtract-01
                                          :ARG1 p2
                                          :ARG2 1.9))))))
      :location (e2 / experiment-01 :quant 3))

# ::id bio.chicago_2015.38673 ::date 2015-10-28T13:29:07 ::annotator SDL-AMR-09 ::preferred
# ::snt Data in Figure  5A show that  Elk-1 phosphorylation was acutely stimulated by  EGF with maximum phosphorylation occurring at 5  min. Co-transfection of  KSR completely blocked  EGF-stimulated  Elk-1 phosphorylation (Figure  5B,  panel pElk-1).
# ::save-date Tue Nov 3, 2015 ::file bio_chicago_2015_38673.txt
(m3 / multi-sentence
      :snt1 (s / show-01
            :ARG0 (d / data
                  :location (f / figure :mod "5A"))
            :ARG1 (s2 / stimulate-01
                  :ARG0 (p4 / protein :name (n2 / name :op1 "EGF"))
                  :ARG1 (p2 / phosphorylate-01
                        :ARG1 (p3 / protein :name (n / name :op1 "Elk-1"))
                        :mod (m / maximum)
                        :time (a3 / after
                              :op1 (t2 / temporal-quantity :quant 5
                                    :unit (m4 / minute))))
                  :manner (a2 / acute)))
      :snt2 (b / block-01
            :ARG0 (c2 / cotransfect-01
                  :ARG2 (e / enzyme :name (n3 / name :op1 "KSR")))
            :ARG1 (p / phosphorylate-01
                  :ARG1 (p5 / protein :name (n4 / name :op1 "Elk-1"))
                  :ARG1-of (s3 / stimulate-01
                        :ARG0 (p6 / protein :name (n5 / name :op1 "EGF"))))
            :ARG1-of (c / complete-02))
      :ARG1-of (d2 / describe-01
            :ARG0 (a / and
                  :op1 (f2 / figure :mod "5b")
                  :op2 (p7 / panel :name (n6 / name :op1 "pElka-1")))))

# ::id bio.chicago_2015.38676 ::date 2015-10-28T13:46:29 ::annotator SDL-AMR-09 ::preferred
# ::snt Binding features of  DSL proteins to  Notch2.
# ::save-date Tue Nov 3, 2015 ::file bio_chicago_2015_38676.txt
(f / feature
      :mod (b / bind-01
            :ARG1 (p / protein :name (n / name :op1 "DSL"))
            :ARG2 (p2 / protein :name (n2 / name :op1 "Notch2"))))

# ::id bio.chicago_2015.38704 ::date 2015-10-28T13:56:09 ::annotator SDL-AMR-09 ::preferred
# ::snt To confirm the specific binding of  magoh to  Y14, we carried out  in vitro binding assays using recombinant  GST - magoh.
# ::save-date Tue Nov 3, 2015 ::file bio_chicago_2015_38704.txt
(h / have-purpose-91
      :ARG1 (c2 / carry-out-03
            :ARG0 (w / we)
            :ARG1 (a / assay-01
                  :ARG1 (b2 / bind-01))
            :mod (i / in-vitro)
            :manner (u / use-01
                  :ARG0 w
                  :ARG1 (p / protein :name (n3 / name :op1 "GST" :op2 "magoh")
                        :ARG3-of (r2 / recombine-01))))
      :ARG2 (c / confirm-01
            :ARG0 w
            :ARG1 (b / bind-01
                  :ARG1 (p2 / protein :name (n2 / name :op1 "magoh"))
                  :ARG2 (a2 / amino-acid :mod 14 :name (n / name :op1 "tyrosine"))
                  :ARG1-of (s / specific-02))))

# ::id bio.chicago_2015.38710 ::date 2015-10-28T14:04:18 ::annotator SDL-AMR-09 ::preferred
# ::snt Although  PKB can phosphorylate  GSK-3 at this site and inhibit its activity, our results also implicate a direct role for ILK in the regulation of  GSK-3 activity.
# ::save-date Tue Nov 3, 2015 ::file bio_chicago_2015_38710.txt
(h / have-concession-91
      :ARG1 (i2 / implicate-01
            :ARG0 (t2 / thing
                  :ARG2-of (r / result-01
                        :ARG1 (w / we)))
            :ARG1 (r2 / role
                  :topic (r3 / regulate-01
                        :ARG0 e2
                        :ARG1 (a4 / activity-06
                              :ARG0 e3))
                  :ARG1-of (d / direct-02)
                  :poss (e2 / enzyme :name (n3 / name :op1 "ILK")))
            :mod (a3 / also))
      :ARG2 (p / possible-01
            :ARG1 (a / and
                  :op1 (p2 / phosphorylate-01
                        :ARG1 (e3 / enzyme :name (n2 / name :op1 "GSK-3"))
                        :ARG2 (e / enzyme :name (n / name :op1 "PKB"))
                        :location (s / site
                              :mod (t / this)))
                  :op2 (i / inhibit-01
                        :ARG0 e
                        :ARG1 (a2 / activity-06
                              :ARG0 e3)))))

# ::id bio.chicago_2015.38763 ::date 2015-10-28T20:37:39 ::annotator SDL-AMR-09 ::preferred
# ::snt Phosphorylation of  K Protein by  JNK and  ERK in Vivo-- To confirm phosphorylation of the  K protein by  JNK or  ERK  in vivo, we performed orthophosphate labeling of cells that had been transfected with the  K protein and the respective upstream kinases for  ERK,  p38, or  JNK.
# ::save-date Sat Jan 16, 2016 ::file bio_chicago_2015_38763.txt
(m / multi-sentence
      :snt1 (p / phosphorylate-01
            :ARG1 (p3 / protein :name (n2 / name :op1 "K"))
            :ARG2 (a / and
                  :op1 (e / enzyme :name (n3 / name :op1 "JNK"))
                  :op2 (e2 / enzyme :name (n4 / name :op1 "ERK")))
            :manner (i / in-vivo))
      :snt2 (p4 / perform-02
            :ARG0 (w / we)
            :ARG1 (l / label-01
                  :ARG1 (c / cell
                        :ARG1-of (t / transfect-01
                              :ARG2 (a2 / and
                                    :op1 p5
                                    :op2 (k / kinase
                                          :beneficiary (a3 / and
                                                :op1 e5
                                                :op2 (e3 / enzyme :name (n / name :op1 "p38"))
                                                :op3 e4)
                                          :direction (u / upstream)
                                          :mod (r / respective)))))
                  :ARG2 (s / small-molecule :name (n8 / name :op1 "orthophosphate")))
            :purpose (c2 / confirm-01
                  :ARG0 w
                  :ARG1 (p2 / phosphorylate-01
                        :ARG1 (p5 / protein :name (n5 / name :op1 "K"))
                        :ARG2 (a4 / and
                              :op1 (e4 / enzyme :name (n6 / name :op1 "JNK"))
                              :op2 (e5 / enzyme :name (n7 / name :op1 "ERK"))
                              :manner (i2 / in-vivo))))))

# ::id bio.chicago_2015.38801 ::date 2015-10-28T20:48:23 ::annotator SDL-AMR-09 ::preferred
# ::snt Insulin and  PMA Induce Dissociation of the  Grb2-SOS Complex-- Previous studies have observed that agents that activate the  Ras/ Raf/ MEK/ ERK pathway can also induce the  serine/ threonine phosphorylation of  SOS and dissociation of the  Grb2-SOS complex ( 29,  35,  36).
# ::save-date Thu Nov 12, 2015 ::file bio_chicago_2015_38801.txt
(m / multi-sentence
      :snt1 (i / induce-01
            :ARG0 (a2 / and
                  :op1 (i2 / insulin)
                  :op2 (s / small-molecule :name (n3 / name :op1 "PMA")))
            :ARG2 (d / dissociate-01
                  :ARG1 (m2 / macro-molecular-complex
                        :part (p7 / protein :name (n / name :op1 "Grb2"))
                        :part (p8 / protein :name (n8 / name :op1 "SOS")))))
      :snt2 (o / observe-01
            :ARG0 (s2 / study-01
                  :mod (p3 / previous))
            :ARG1 (p4 / possible-01
                  :ARG1 (i3 / induce-01
                        :ARG0 (a3 / agent
                              :ARG0-of (a4 / activate-01
                                    :ARG1 (p6 / pathway :name (n4 / name :op1 "Ras/Raf/MEK/ERK"))))
                        :ARG2 (a6 / and
                              :op1 (p2 / phosphorylate-01
                                    :ARG1 (s3 / slash
                                          :op1 (a5 / amino-acid :name (n5 / name :op1 "serine"))
                                          :op2 (a / amino-acid :name (n2 / name :op1 "threonine"))
                                          :part-of (p5 / protein :name (n6 / name :op1 "SOS"))))
                              :op2 (d2 / dissociate-01
                                    :ARG1 (m3 / macro-molecular-complex
                                          :part (p9 / protein :name (n9 / name :op1 "Grb2"))
                                          :part p5)))
                        :mod (a8 / also)))
            :ARG1-of (d3 / describe-01
                  :ARG0 (p / publication
                        :ARG1-of (c3 / cite-01
                              :ARG2 (a7 / and :op1 29 :op2 35 :op3 36))))))

# ::id bio.chicago_2015.38881 ::date 2015-10-28T21:02:09 ::annotator SDL-AMR-09 ::preferred
# ::snt These data suggest that   sens normally represses  Ro in the differentiating  R8 photoreceptor.
# ::save-date Thu Nov 12, 2015 ::file bio_chicago_2015_38881.txt
(s / suggest-01
      :ARG0 (d / data
            :mod (t / this))
      :ARG1 (r / repress-01
            :ARG0 (p4 / protein :name (n4 / name :op1 "sens"))
            :ARG1 (p2 / protein :name (n2 / name :op1 "Ro"))
            :ARG2 (d2 / differentiate-01
                  :ARG1 (p3 / photoreceptor
                        :part-of (p / protein :name (n3 / name :op1 "R8"))))
            :ARG1-of (n / normal-02)))

# ::id bio.chicago_2015.38884 ::date 2015-10-28T21:07:02 ::annotator SDL-AMR-09 ::preferred
# ::snt Rather surprisingly, however, experiments with the deltaGP5 mutant indicate this did not require  profilin binding to  VASP.
# ::save-date Thu Nov 12, 2015 ::file bio_chicago_2015_38884.txt
(c / contrast-01
      :ARG2 (i / indicate-01
            :ARG0 (e / experiment-01
                  :ARG1 (e2 / enzyme :name (n / name :op1 "deltaGP5")
                        :ARG2-of (m2 / mutate-01)))
            :ARG1 (r / require-01 :polarity -
                  :ARG0 (t / this)
                  :ARG1 (b / bind-01
                        :ARG1 (p / protein :name (n2 / name :op1 "profilin"))
                        :ARG2 (p2 / protein :name (n3 / name :op1 "VASP")))))
      :ARG0-of (s / surprise-01
            :degree (r2 / rather)))

# ::id bio.chicago_2015.38908 ::date 2015-10-28T21:13:33 ::annotator SDL-AMR-09 ::preferred
# ::snt One report shows that, in addition to activating  Rho,  Wnt signaling can also activate  Rac but not  Cdc42  (Habas et al., 2003  ).
# ::save-date Sun Jan 17, 2016 ::file bio_chicago_2015_38908.txt
(s / show-01
      :ARG0 (r / report
            :mod (o / one))
      :ARG1 (a4 / and
            :op1 (a5 / activate-01
                  :ARG0 p2
                  :ARG1 (p3 / protein :name (n4 / name :op1 "Rho")))
            :op2 (p / possible-01
                  :ARG1 (c / contrast-01
                        :ARG1 (a / activate-01
                              :ARG0 (p2 / protein :name (n / name :op1 "Wnt")
                                    :ARG0-of (s2 / signal-07))
                              :ARG1 (e / enzyme :name (n2 / name :op1 "Rac")))
                        :ARG2 (a3 / activate-01 :polarity -
                              :ARG0 p2
                              :ARG1 (p6 / protein :name (n3 / name :op1 "Cdc42"))))
                  :mod (a2 / also)))
      :ARG1-of (d2 / describe-01
            :ARG0 (a6 / and
                  :op1 (p4 / person :name (n5 / name :op1 "Habas"))
                  :op2 (p5 / person
                        :mod (o2 / other))
                  :time (d / date-entity :year 2003))))

# ::id bio.chicago_2015.38917 ::date 2015-10-28T21:26:04 ::annotator SDL-AMR-09 ::preferred
# ::snt Shank, a  Novel Family of  Postsynaptic Density Proteins that Binds to the  NMDA Receptor/ PSD-95/GKAP Complex and  Cortactin
# ::save-date Thu Nov 12, 2015 ::file bio_chicago_2015_38917.txt
(p8 / protein-family :name (n2 / name :op1 "Shank")
      :mod (n / novel)
      :consist-of (p / protein
            :mod (d / density
                  :mod (p2 / postsynaptic))
            :ARG1-of (b / bind-01
                  :ARG2 (a / and
                        :op1 (m / macro-molecular-complex
                              :part (p4 / protein :name (n4 / name :op1 "NMDA" :op2 "Receptor"))
                              :part (p5 / protein :name (n5 / name :op1 "PSD-95"))
                              :part (p6 / protein :name (n6 / name :op1 "GKAP")))
                        :op2 (p3 / protein :name (n3 / name :op1 "cortactin"))))))

# ::id bio.chicago_2015.38985 ::date 2015-10-28T21:32:37 ::annotator SDL-AMR-09 ::preferred
# ::snt (D) Association between  CIZ and  Cas expressed in COS-7 cells.
# ::save-date Wed Jan 13, 2016 ::file bio_chicago_2015_38985.txt
(e / express-03 :li "D"
      :ARG2 (a2 / associate-01
            :ARG1 (p / protein :name (n2 / name :op1 "CIZ"))
            :ARG2 (p2 / protein :name (n3 / name :op1 "Cas")))
      :ARG3 (c / cell-line :name (n / name :op1 "COS-7")))

# ::id bio.chicago_2015.39001 ::date 2015-10-31T00:57:48 ::annotator SDL-AMR-09 ::preferred
# ::snt ORC and regulation of the  metazoan cell cycle   In  yeast, where  ORC remains stably bound to chromatin throughout the cell cycle (see Introduction), conversion of  ORCs into  pre-RCs is delayed until mitosis is completed, because  Cdk1/cyclin B simultaneously promotes mitosis and inhibits binding of  Cdc6 to  ORC ( Dahmann  et al., 1995;  Piatti  et al., 1996), apparently by phosphorylation of  Cdc6 protein ( Jallepalli  et al., 1997).
# ::save-date Wed Jan 13, 2016 ::file bio_chicago_2015_39001.txt
(m / multi-sentence
      :snt1 (a / and
            :op1 (m6 / macro-molecular-complex :name (n / name :op1 "ORC"))
            :op2 (r / regulate-01
                  :ARG1 (c / cycle
                        :mod (c2 / cell
                              :mod (m2 / metazoan)))))
      :snt2 (d4 / delay-01
            :ARG1 (c3 / convert-01
                  :ARG1 (m4 / macro-molecular-complex :name (n2 / name :op1 "ORC"))
                  :ARG2 (m5 / macro-molecular-complex :name (n3 / name :op1 "pre-RCs")))
            :ARG2 (u / until
                  :op1 (c4 / complete-01
                        :ARG1 (m3 / mitosis)))
            :location (y / yeast
                  :location-of (r2 / remain-01
                        :ARG1 m4
                        :ARG3 (b / bind-01
                              :ARG1 m4
                              :ARG2 (m7 / macro-molecular-complex :name (n4 / name :op1 "chromatin"))
                              :ARG1-of (s / stable-03))
                        :duration (c5 / cycle
                              :mod (c6 / cell))
                        :ARG1-of (d7 / describe-01
                              :ARG0 (i2 / introduce-01
                                    :ARG1-of (s2 / see-01
                                          :ARG0 (y2 / you))))))
            :ARG1-of (c7 / cause-01
                  :ARG0 (a2 / and
                        :op1 (p2 / promote-01
                              :ARG0 (m8 / macro-molecular-complex
                                    :part (e / enzyme :name (n5 / name :op1 "Cdk1"))
                                    :part (p12 / protein :name (n6 / name :op1 "cyclin" :op2 "B")))
                              :ARG1 m3)
                        :op2 (i / inhibit-01
                              :ARG0 m8
                              :ARG1 (b2 / bind-01
                                    :ARG1 (p4 / protein :name (n7 / name :op1 "Cdc6"))
                                    :ARG2 m4))
                        :manner (p / phosphorylate-01
                              :ARG1 p4
                              :ARG1-of (a3 / appear-02)
                              :ARG1-of (d6 / describe-01
                                    :ARG0 (p10 / publication-91
                                          :ARG0 (a7 / and
                                                :op1 (p11 / person :name (n10 / name :op1 "Jallepalli"))
                                                :op2 p7)
                                          :time (d3 / date-entity :year 1997))))
                        :ARG1-of (d5 / describe-01
                              :ARG0 (a5 / and
                                    :op1 (p5 / publication-91
                                          :ARG0 (a4 / and
                                                :op1 (p6 / person :name (n8 / name :op1 "Dahmann"))
                                                :op2 (p7 / person
                                                      :mod (o / other)))
                                          :time (d / date-entity :year 1995))
                                    :op2 (p8 / publication-91
                                          :ARG0 (a6 / and
                                                :op1 (p9 / person :name (n9 / name :op1 "Piatti"))
                                                :op2 p7)
                                          :time (d2 / date-entity :year 1996))))
                        :manner (s3 / simultaneous)))))

# ::id bio.chicago_2015.39049 ::date 2015-10-31T01:01:57 ::annotator SDL-AMR-09 ::preferred
# ::snt The association of  alpha-catenin with  beta-catenin was also markedly increased in  ApcMin/   adenoma cells (Fig.  8 B).
# ::save-date Thu Dec 10, 2015 ::file bio_chicago_2015_39049.txt
(i / increase-01
      :ARG1 (a / associate-01
            :ARG1 (p / protein :name (n / name :op1 "alpha-catenin"))
            :ARG2 (p2 / protein :name (n2 / name :op1 "beta-catenin")))
      :ARG2 (m / mark-01)
      :mod (a2 / also)
      :location (c / cell
            :mod (g / gene :name (n3 / name :op1 "ApcMin"))
            :mod (m2 / medical-condition :name (n4 / name :op1 "adenoma")))
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod "8B")))

# ::id bio.chicago_2015.39066 ::date 2015-10-31T01:07:32 ::annotator SDL-AMR-09 ::preferred
# ::snt The   disassembly of a  Lys-48 - linked  Ub   chain by PA700 isopeptidase proceeds by   sequentially removing the distal  Ub moiety [ 346;    Figure 6 b   ( right)].
# ::save-date Mon Nov 9, 2015 ::file bio_chicago_2015_39066.txt
(p / proceed-01
      :ARG0 (r / remove-01
            :ARG1 (m / moiety
                  :mod (p3 / protein :name (n4 / name :op1 "ubiquitin")
                        :mod (d / distal)))
            :manner (s / sequence))
      :ARG1 (a / assemble-01 :polarity -
            :ARG0 (i / isopeptidase :name (n / name :op1 "PA700"))
            :ARG1 (c / chain
                  :mod (p2 / protein :name (n2 / name :op1 "ubiquitin"))
                  :ARG1-of (l / link-01
                        :ARG2 (a2 / amino-acid :mod 48 :name (n3 / name :op1 "lysine")))))
      :ARG1-of (d2 / describe-01
            :ARG0 (f / figure :mod "6b"
                  :ARG1-of (r2 / right-04)))
      :ARG1-of (d3 / describe-01
            :ARG0 (p4 / publication
                  :ARG1-of (c2 / cite-01
                        :ARG2 346))))

# ::id bio.chicago_2015.39083 ::date 2015-10-31T01:26:13 ::annotator SDL-AMR-09 ::preferred
# ::snt Amphiphysin 1 can bind simultaneously to  dynamin and either  clathrin or  AP-2.
# ::save-date Sun Nov 1, 2015 ::file bio_chicago_2015_39083.txt
(p4 / possible-01
      :ARG1 (b / bind-01
            :ARG1 (p / protein :name (n / name :op1 "Amphiphysin" :op2 "1"))
            :ARG2 (a / and
                  :op1 (p5 / protein :name (n2 / name :op1 "dynamin"))
                  :op2 (o / or
                        :op1 (p2 / protein :name (n3 / name :op1 "clathrin"))
                        :op2 (p3 / protein :name (n4 / name :op1 "AP-2"))))
            :manner (s / simultaneous)))

# ::id bio.chicago_2015.39129 ::date 2015-10-31T06:23:24 ::annotator SDL-AMR-09 ::preferred
# ::snt MEKK1 Can Phosphorylate the N Terminus of  p300 in Vitro-- Given the fact that  JNK1 is not involved in the response of  p300 to  MEKK1, nor are the other potential downstream kinases such as  p38 and  IkappaBalpha, we considered the possibility that  MEKK1delta may be able to directly phosphorylate  p300.
# ::save-date Sat Oct 31, 2015 ::file bio_chicago_2015_39129.txt
(m / multi-sentence
      :snt1 (p / possible-01
            :ARG1 (p2 / phosphorylate-01
                  :ARG1 (p3 / protein-segment :name (n2 / name :op1 "N-Terminus")
                        :part-of (p4 / protein :name (n3 / name :op1 "p300")))
                  :ARG2 (e / enzyme :name (n / name :op1 "MEKK1"))
                  :manner (i / in-vitro)))
      :snt2 (c / consider-01
            :ARG0 (w / we)
            :ARG1 (p5 / possible-01
                  :ARG1 (c2 / capable-01
                        :ARG1 (p6 / phosphorylate-01
                              :ARG1 p4
                              :ARG2 (e2 / enzyme :name (n4 / name :op1 "MEKK1delta"))
                              :ARG1-of (d2 / direct-02))))
            :ARG1-of (c3 / cause-01
                  :ARG0 (i2 / involve-01 :polarity -
                        :ARG1 (o / or
                              :op1 (e3 / enzyme :name (n5 / name :op1 "JNK1"))
                              :op2 (k / kinase
                                    :mod (o2 / other)
                                    :direction (d3 / downstream)
                                    :mod (p7 / potential)
                                    :ARG2-of (i3 / include-91
                                          :ARG1 (a / and
                                                :op1 (k2 / kinase :name (n6 / name :op1 "p38"))
                                                :op2 (k3 / kinase :name (n7 / name :op1 "IkappaBalpha"))))))
                        :ARG2 (r / respond-01
                              :ARG0 p4
                              :ARG1 e)))))

# ::id bio.chicago_2015.39166 ::date 2015-10-31T06:40:34 ::annotator SDL-AMR-09 ::preferred
# ::snt Cdk1/cyclin B simultaneously promotes mitosis and inhibits binding of  Cdc6 to  ORC by  phosphorylating Cdc6.
# ::save-date Sun Jan 17, 2016 ::file bio_chicago_2015_39166.txt
(a / and
      :op1 (p / promote-01
            :ARG0 (m2 / macro-molecular-complex
                  :part (e / enzyme :name (n / name :op1 "Cdk1"))
                  :part (p6 / protein :name (n2 / name :op1 "cyclin" :op2 "B")))
            :ARG1 (m / mitosis))
      :op2 (i / inhibit-01
            :ARG0 m2
            :ARG1 (b / bind-01
                  :ARG1 (p3 / protein :name (n3 / name :op1 "Cdc6"))
                  :ARG2 (m3 / macro-molecular-complex :name (n4 / name :op1 "ORC"))))
      :manner (s2 / simultaneous)
      :manner (p5 / phosphorylate-01
            :ARG1 p3
            :ARG2 m2))

# ::id bio.chicago_2015.39206 ::date 2015-10-31T06:52:26 ::annotator SDL-AMR-09 ::preferred
# ::snt Our genetic analyses suggest that the vein phenotype and wing shape alterations are due to an effect on the balance between  TGF  and  Wnt signaling and the subsequent activation of  JNK signaling that ensues.
# ::save-date Sat Oct 31, 2015 ::file bio_chicago_2015_39206.txt
(s / suggest-01
      :ARG0 (a / analyze-01
            :ARG0 (w / we)
            :ARG1 (g / genetics))
      :ARG1 (c / cause-01
            :ARG0 (a2 / affect-01
                  :ARG1 (b / balance-01
                        :ARG1 (s2 / signal-07
                              :ARG0 (a3 / and
                                    :op1 (p / protein :name (n / name :op1 "TGF"))
                                    :op2 (p2 / protein :name (n2 / name :op1 "Wnt"))))
                        :ARG2 (a4 / activate-01
                              :ARG1 (s4 / signal-07
                                    :ARG0 (e / enzyme :name (n3 / name :op1 "JNK")))
                              :mod (s3 / subsequent)
                              :ARG1-of (e2 / ensue-01))))
            :ARG1 (a5 / alter-01
                  :ARG1 (a6 / and
                        :op1 (p3 / phenotype
                              :mod (v / vein))
                        :op2 (s5 / shape
                              :mod (w2 / wing))))))

# ::id bio.chicago_2015.39226 ::date 2015-10-31T07:29:05 ::annotator SDL-AMR-09 ::preferred
# ::snt IKK recovery was determined by  immunoblotting ( IB) with antibody to  IKKgamma.
# ::save-date Wed Jan 13, 2016 ::file bio_chicago_2015_39226.txt
(d / determine-01
      :ARG1 (r / recover-02
            :ARG1 (e / enzyme :name (n / name :op1 "IKK")))
      :ARG2 (i / immunoblot-01
            :ARG1 e
            :ARG3 (a / antibody
                  :ARG0-of (o / oppose-01
                        :ARG1 (e2 / enzyme :name (n2 / name :op1 "IKKgamma"))))))

# ::id bio.chicago_2015.39236 ::date 2015-10-31T07:35:58 ::annotator SDL-AMR-09 ::preferred
# ::snt Other studies showed that  PI3K is also activated by  small GTPase molecules such as  Ras and  Rac1   (Nishida et al., 1999  ; Rodriguez-Viciana et al., 1994  ).
# ::save-date Sun Jan 17, 2016 ::file bio_chicago_2015_39236.txt
(s / show-01
      :ARG0 (s2 / study-01
            :mod (o / other))
      :ARG1 (a / activate-01
            :ARG0 (m / molecule
                  :mod (p / protein-family :name (n / name :op1 "GTPase"))
                  :mod (s3 / small)
                  :ARG2-of (i / include-91
                        :ARG1 (a2 / and
                              :op1 (e2 / enzyme :name (n2 / name :op1 "Ras"))
                              :op2 (p2 / protein :name (n5 / name :op1 "Rac1")))))
            :ARG1 (e / enzyme :name (n3 / name :op1 "PI3K"))
            :mod (a3 / also))
      :ARG1-of (d3 / describe-01
            :ARG0 (a4 / and
                  :op1 (p3 / publication-91
                        :ARG0 (a5 / and
                              :op1 (p4 / person :name (n6 / name :op1 "Nishida"))
                              :op2 (p6 / person
                                    :mod (o2 / other)))
                        :time (d / date-entity :year 1999))
                  :op2 (p7 / publication-91
                        :ARG0 (a6 / and
                              :op1 (p8 / person :name (n4 / name :op1 "Rodriguez-Viciana"))
                              :op2 p6)
                        :time (d2 / date-entity :year 1994)))))

# ::id bio.chicago_2015.39239 ::date 2015-10-31T07:51:51 ::annotator SDL-AMR-09 ::preferred
# ::snt The PI bound to PI-TPalpha is delivered as a substrate for  phospholipase A2 ( PLA2).
# ::save-date Fri Jan 15, 2016 ::file bio_chicago_2015_39239.txt
(d / deliver-01
      :ARG1 (b / bind-01
            :ARG1 (s2 / small-molecule :name (n / name :op1 "PI"))
            :ARG2 (p2 / protein :name (n2 / name :op1 "PI-TPalpha"))
            :purpose (s / substrate
                  :beneficiary (e / enzyme :name (n3 / name :op1 "phospholipase" :op2 "A2")))))

# ::id bio.chicago_2015.39287 ::date 2015-11-01T01:30:58 ::annotator SDL-AMR-09 ::preferred
# ::snt sepA Is Required for  Actin Ring Formation
# ::save-date Mon Nov 9, 2015 ::file bio_chicago_2015_39287.txt
(r / require-01
      :ARG0 (f / form-01
            :ARG1 (r2 / ring
                  :mod (p2 / protein :name (n2 / name :op1 "actin"))))
      :ARG1 (p / protein :name (n / name :op1 "sepA")))

# ::id bio.chicago_2015.39301 ::date 2015-11-01T01:35:15 ::annotator SDL-AMR-09 ::preferred
# ::snt In this study, we show that  Cos2 inhibits  Ci activity by tethering it in the cytoplasm via a 125 amino acid domain in the C-terminal region of  Ci, whereas  Su(fu) inhibits  Ci nuclear import through the N-terminal region of  Ci.
# ::save-date Mon Nov 9, 2015 ::file bio_chicago_2015_39301.txt
(s / show-01
      :ARG0 (w / we)
      :ARG1 (c3 / contrast-01
            :ARG1 (i3 / inhibit-01
                  :ARG0 (p / protein :name (n / name :op1 "Cos2"))
                  :ARG1 (a / activity-06
                        :ARG0 (p2 / protein :name (n2 / name :op1 "Ci")))
                  :manner (t / tether-01
                        :ARG0 p
                        :ARG1 p2
                        :location (c4 / cytoplasm)
                        :manner (d / domain
                              :mod (a2 / amino-acid :mod 125
                                    :location (r / region
                                          :mod (p3 / protein-segment :name (n3 / name :op1 "C-terminus")
                                                :part-of p2))))))
            :ARG2 (i4 / inhibit-01
                  :ARG0 (p4 / protein :name (n4 / name :op1 "Su(fu)"))
                  :ARG1 (i5 / import-01
                        :ARG1 (n5 / nucleus
                              :part-of p2)
                        :location (r2 / region
                              :mod (p5 / protein-segment :name (n6 / name :op1 "N-terminus")
                                    :part-of p2)))))
      :location (s2 / study-01
            :mod (t2 / this)))

# ::id bio.chicago_2015.39321 ::date 2015-11-01T01:51:59 ::annotator SDL-AMR-09 ::preferred
# ::snt Therefore we analyzed the role of  p38MAPK in  TNF-induced inhibition of conventional  kinesin and  KLC hyperphosphorylation.
# ::save-date Mon Nov 9, 2015 ::file bio_chicago_2015_39321.txt
(c / cause-01
      :ARG1 (a / analyze-01
            :ARG0 (w / we)
            :ARG1 (r / role
                  :poss (e / enzyme :name (n / name :op1 "p38MAPK"))
                  :topic (i / inhibit-01
                        :ARG1 (a2 / and
                              :op1 (p3 / protein :name (n3 / name :op1 "kinesin")
                                    :mod (c2 / conventional))
                              :op2 (h / hyperphosphorylate-01
                                    :ARG1 (p4 / protein :name (n4 / name :op1 "KLC"))))
                        :ARG2-of (i2 / induce-01
                              :ARG0 (p2 / protein :name (n2 / name :op1 "TNF")))))))

# ::id bio.chicago_2015.39324 ::date 2015-11-01T01:59:48 ::annotator SDL-AMR-09 ::preferred
# ::snt The semiquantification in  Fig. 2C and F shows that the ME significantly decreased the  CRE-DNA binding activity of  CREB to 77 and 63% of the control in the ipsilateral cerebral cortex on the third and seventh days, respectively, after the operation (  Fig. 2C), and to 74 and 59%, respectively, in the ipsilateral  hippocampus (  Fig. 2F).
# ::save-date Fri Nov 27, 2015 ::file bio_chicago_2015_39324.txt
(s / show-01
      :ARG0 (q / quantify-01
            :degree (s2 / semi)
            :location (a / and
                  :op1 (f / figure :mod "2C")
                  :op2 (f2 / figure :mod "F")))
      :ARG1 (a3 / and
            :op1 (d / decrease-01
                  :ARG0 (m / medical-condition :name (n / name :op1 "microsphere" :op2 "embolism"))
                  :ARG1 (a2 / activity-06
                        :ARG0 (p3 / protein :name (n2 / name :op1 "CREB"))
                        :ARG1 (b / bind-01
                              :ARG1 p3
                              :ARG2 (e / enzyme :name (n3 / name :op1 "CRE-DNA"))))
                  :ARG2 (s3 / significant-02)
                  :ARG4 (a4 / and
                        :op1 (p4 / percentage-entity :value 77)
                        :op2 (p / percentage-entity :value 63)
                        :quant-of (c / control-01
                              :ARG1 (c2 / cortex
                                    :mod (c3 / cerebral)
                                    :mod (i / ipsilateral))))
                  :time (a5 / and
                        :op1 (d2 / day
                              :ord (o2 / ordinal-entity :value 3))
                        :op2 (d3 / day
                              :ord (o3 / ordinal-entity :value 7))
                        :manner (r / respective))
                  :time (a6 / after
                        :op1 (o4 / operate-02))
                  :ARG1-of (d4 / describe-01
                        :ARG0 (f3 / figure :mod "2C")))
            :op2 (d5 / decrease-01
                  :ARG0 m
                  :ARG1 a2
                  :ARG2 s3
                  :ARG4 (a7 / and
                        :op1 (p5 / percentage-entity :value 74)
                        :op2 (p2 / percentage-entity :value 59)
                        :manner r)
                  :location (h / hippocampus
                        :mod (i2 / ipsilateral))
                  :ARG1-of (d6 / describe-01
                        :ARG0 (f4 / figure :mod "2F")))))

# ::id bio.chicago_2015.39367 ::date 2015-11-01T01:29:58 ::annotator SDL-AMR-09 ::preferred
# ::snt (d)  NAK is activated by recombinant  Nef and  CDC42  in vitro.
# ::save-date Sun Nov 1, 2015 ::file bio_chicago_2015_39367.txt
(a / activate-01 :li "d"
      :ARG0 (a2 / and
            :op1 (p2 / protein :name (n2 / name :op1 "Nef"))
            :op2 (p3 / protein :name (n3 / name :op1 "CDC42"))
            :ARG3-of (r / recombine-01))
      :ARG1 (p / protein :name (n / name :op1 "NAK"))
      :manner (i / in-vitro))

# ::id bio.chicago_2015.39416 ::date 2015-11-01T01:35:07 ::annotator SDL-AMR-09 ::preferred
# ::snt Furthermore, it has been shown that  GSK-3beta phosphorylates  APC and that the phosphorylation enhances the binding of  APC to  beta-catenin (Rubinfeld  et al., 1996  ).
# ::save-date Sun Nov 1, 2015 ::file bio_chicago_2015_39416.txt
(a / and
      :op2 (s / show-01
            :ARG1 (a2 / and
                  :op1 (p3 / phosphorylate-01
                        :ARG1 (p4 / protein :name (n / name :op1 "APC"))
                        :ARG2 (e / enzyme :name (n2 / name :op1 "GSK-3beta")))
                  :op2 (e2 / enhance-01
                        :ARG0 p3
                        :ARG1 (b / bind-01
                              :ARG1 p4
                              :ARG2 (p5 / protein :name (n3 / name :op1 "beta-catenin")))))
            :ARG1-of (d2 / describe-01
                  :ARG0 (p6 / publication-91
                        :ARG0 (a3 / and
                              :op1 (p7 / person :name (n4 / name :op1 "Rubinfeld"))
                              :op2 (p8 / person
                                    :mod (o / other)))
                        :time (d / date-entity :year 1996)))))

# ::id bio.chicago_2015.39423 ::date 2015-11-01T01:41:18 ::annotator SDL-AMR-09 ::preferred
# ::snt All the results indicate that the activation of  MAPK through  Ras inhibits  Fas-mediated apoptosis in Balb3T3 cells, which may play a role in oncogenesis.
# ::save-date Sat Jan 16, 2016 ::file bio_chicago_2015_39423.txt
(i / indicate-01
      :ARG0 (t / thing
            :ARG2-of (r / result-01)
            :mod (a / all))
      :ARG1 (i2 / inhibit-01
            :ARG0 (a2 / activate-01
                  :ARG0 (e / enzyme :name (n2 / name :op1 "Ras"))
                  :ARG1 (p / pathway :name (n / name :op1 "MAPK")))
            :ARG1 (a3 / apoptosis
                  :location (c / cell :name (n3 / name :op1 "Balb3T3"))
                  :ARG1-of (m / mediate-01
                        :ARG0 (p3 / protein :name (n4 / name :op1 "Fas"))))
            :ARG0-of (p4 / play-08
                  :ARG1 (c3 / cause-01
                        :ARG1 (d / disease :wiki "Cancer" :name (n5 / name :op1 "cancer")))
                  :ARG1-of (p5 / possible-01))))

# ::id bio.chicago_2015.39438 ::date 2015-11-01T01:49:03 ::annotator SDL-AMR-09 ::preferred
# ::snt Mapping the region of   HBO1  that interacts with  MCM2 and  ORC1.
# ::save-date Sun Nov 1, 2015 ::file bio_chicago_2015_39438.txt
(m / map-01
      :ARG1 (r / region
            :poss (e / enzyme :name (n / name :op1 "HBO1"))
            :ARG0-of (i / interact-01
                  :ARG1 (a / and
                        :op1 (p / protein :name (n2 / name :op1 "MCM2"))
                        :op2 (p2 / protein :name (n3 / name :op1 "ORC1"))))))

# ::id bio.chicago_2015.39496 ::date 2015-11-01T01:52:30 ::annotator SDL-AMR-09 ::preferred
# ::snt To illustrate, elevated levels of cAMP that induce the activation of  PKA can determine which  Raf isoform will be engaged in a cell to stimulate  MEKs.
# ::save-date Sun Jan 17, 2016 ::file bio_chicago_2015_39496.txt
(p2 / possible-01
      :ARG1 (d / determine-01
            :ARG0 (l / level
                  :ARG1-of (e / elevate-01)
                  :quant-of (s2 / small-molecule :name (n2 / name :op1 "cAMP")
                        :ARG0-of (i / induce-01
                              :ARG2 (a / activate-01
                                    :ARG1 (e2 / enzyme :name (n3 / name :op1 "PKA"))))))
            :ARG1 (e3 / engage-01
                  :ARG1 (a2 / amr-unknown
                        :ARG1-of (i2 / include-91
                              :ARG2 (i3 / isoform
                                    :mod (e4 / enzyme :name (n / name :op1 "Raf")))))
                  :ARG2 (c / cell)
                  :purpose (s / stimulate-01
                        :ARG0 a2
                        :ARG1 (p4 / protein-family :name (n4 / name :op1 "MEK"))))
            :purpose (i4 / illustrate-01)))

# ::id bio.chicago_2015.39508 ::date 2015-11-01T02:00:19 ::annotator SDL-AMR-09 ::preferred
# ::snt Phosphorylation of  SR Proteins by  SRPK1 and  Clk/ty
# ::save-date Sun Nov 1, 2015 ::file bio_chicago_2015_39508.txt
(p / phosphorylate-01
      :ARG1 (p2 / protein-family :name (n / name :op1 "SR"))
      :ARG2 (a / and
            :op1 (e / enzyme :name (n2 / name :op1 "SRPK1"))
            :op2 (e2 / enzyme :name (n3 / name :op1 "Clk/ty"))))

# ::id bio.chicago_2015.39510 ::date 2015-11-01T02:02:43 ::annotator SDL-AMR-09 ::preferred
# ::snt Fzr can not activate the  APC/C in these cells because  cdk1 - cyclin B1 phosphorylates  fzr and prevents its binding to the  APC/C ( Zachariae  et al., 1998;  Lukas  et al., 1999;  Listovsky  et al., 2000).
# ::save-date Wed Jan 13, 2016 ::file bio_chicago_2015_39510.txt
(c / cause-01
      :ARG0 (a2 / and
            :op1 (p4 / phosphorylate-01
                  :ARG1 p2
                  :ARG2 (m / macro-molecular-complex
                        :part (e / enzyme :name (n3 / name :op1 "cdk1"))
                        :part (p14 / protein :name (n7 / name :op1 "cyclin" :op2 "B1"))))
            :op2 (p5 / prevent-01
                  :ARG0 m
                  :ARG1 (b / bind-01
                        :ARG1 p2
                        :ARG2 p3)))
      :ARG1 (p / possible-01 :polarity -
            :ARG1 (a / activate-01
                  :ARG0 (p2 / protein :name (n / name :op1 "Fzr"))
                  :ARG1 (p3 / protein :name (n2 / name :op1 "APC/C"))
                  :location (c2 / cell
                        :mod (t / this))))
      :ARG1-of (d4 / describe-01
            :ARG0 (a3 / and
                  :op1 (p7 / publication-91
                        :ARG0 (a4 / and
                              :op1 (p8 / person :name (n4 / name :op1 "Zachariae"))
                              :op2 (p9 / person
                                    :mod (o / other)))
                        :time (d / date-entity :year 1998))
                  :op2 (p10 / publication-91
                        :ARG0 (a5 / and
                              :op1 (p11 / person :name (n5 / name :op1 "Lukas"))
                              :op2 p9)
                        :time (d2 / date-entity :year 1999))
                  :op3 (p12 / publication-91
                        :ARG0 (a6 / and
                              :op1 (p13 / person :name (n6 / name :op1 "Listovsky"))
                              :op2 p9)
                        :time (d3 / date-entity :year 2000)))))

# ::id bio.chicago_2015.39521 ::date 2015-11-01T02:11:05 ::annotator SDL-AMR-09 ::preferred
# ::snt SRF Activation by  LIMK-1 Is Largely  Dependent on  RhoA
# ::save-date Sun Nov 1, 2015 ::file bio_chicago_2015_39521.txt
(d / depend-01
      :ARG0 (a / activate-01
            :ARG0 (e / enzyme :name (n / name :op1 "LIMK-1"))
            :ARG1 (p / protein :name (n2 / name :op1 "SRF")))
      :ARG1 (p2 / protein :name (n3 / name :op1 "RhoA"))
      :degree (l / large))

# ::id bio.chicago_2015.39527 ::date 2015-11-01T02:21:05 ::annotator SDL-AMR-09 ::preferred
# ::snt APC appears to be critical  for the rapid turnover of  beta-catenin (Munemitsu et al., 1995   ), and phosphorylation  of  APC by  GSK-3 appears to enhance the interaction of  APC and  beta-catenin (Rubinfeld et al., 1996   ).
# ::save-date Sun Nov 1, 2015 ::file bio_chicago_2015_39527.txt
(a2 / and
      :op1 (a3 / appear-02
            :ARG1 (c2 / critical-02
                  :ARG1 (p3 / protein :name (n / name :op1 "APC"))
                  :ARG2 (t / turn-over-12
                        :ARG1 (p4 / protein :name (n2 / name :op1 "beta-catenin"))
                        :mod (r / rapid)))
            :ARG1-of (d3 / describe-01
                  :ARG0 (p7 / publication-91
                        :ARG0 (a4 / and
                              :op1 (p5 / person :name (n3 / name :op1 "Munemitsu"))
                              :op2 (p6 / person
                                    :mod (o / other)))
                        :time (d / date-entity :year 1995))))
      :op2 (a5 / appear-02
            :ARG1 (e / enhance-01
                  :ARG0 (p8 / phosphorylate-01
                        :ARG1 p3
                        :ARG2 (e2 / enzyme :name (n4 / name :op1 "GSK-3")))
                  :ARG1 (i / interact-01
                        :ARG0 p3
                        :ARG1 p4))
            :ARG1-of (d4 / describe-01
                  :ARG0 (p10 / publication-91
                        :ARG0 (a6 / and
                              :op1 (p11 / person :name (n6 / name :op1 "Rubinfeld"))
                              :op2 p6)
                        :time (d2 / date-entity :year 1996)))))

# ::id bio.chicago_2015.39535 ::date 2015-11-01T02:31:14 ::annotator SDL-AMR-09 ::preferred
# ::snt It is interesting to note that the results we obtained by assaying  BDNF-induced  c- fos expression in transient gene reporter assays were qualitatively similar to those we obtained by assaying  BDNF-induced expression of endogenous  Fos (compare   Figure 1 and   Figure 2).
# ::save-date Mon Jan 4, 2016 ::file bio_chicago_2015_39535.txt
(i / interest-01
      :ARG0 (n / note-01
            :ARG1 (r2 / resemble-01
                  :ARG1 (t / thing
                        :ARG2-of (r3 / result-01)
                        :ARG1-of (o / obtain-01
                              :ARG0 (w / we)
                              :ARG2 (a / assay-01
                                    :ARG0 w
                                    :ARG1 (e / express-03
                                          :ARG2 (p2 / protein :name (n2 / name :op1 "c-fos"))
                                          :ARG2-of (i2 / induce-01
                                                :ARG0 (p3 / protein :name (n3 / name :op1 "BDNF")))
                                          :location (a2 / assay-01
                                                :ARG1 (g2 / gene
                                                      :ARG1-of (t2 / transient-02)
                                                      :ARG0-of (r / report-01)))))))
                  :ARG2 (t3 / thing
                        :ARG2-of (r5 / result-01
                              :ARG1-of (o2 / obtain-01
                                    :ARG0 w
                                    :ARG2 (a3 / assay-01
                                          :ARG0 w
                                          :ARG1 (e2 / express-03
                                                :ARG2 (p4 / protein :name (n4 / name :op1 "Fos")
                                                      :mod (e3 / endogenous))
                                                :ARG2-of i2)))))
                  :mod (q / qualitative)))
      :ARG1-of (d / describe-01
            :ARG0 (c / compare-01
                  :ARG1 (f / figure :mod 1)
                  :ARG2 (f2 / figure :mod 2))))

# ::id bio.chicago_2015.39542 ::date 2015-11-01T02:45:22 ::annotator SDL-AMR-09 ::preferred
# ::snt amphiphysin binds to  clathrin,  AP2,  synaptojanin, and  dynamin, while  epsin binds to  AP2 and  clathrin (reviewed by   [34, 38]  ).
# ::save-date Sun Nov 1, 2015 ::file bio_chicago_2015_39542.txt
(c / contrast-01
      :ARG1 (b / bind-01
            :ARG1 (p / protein :name (n / name :op1 "amphiphysin"))
            :ARG2 (a / and
                  :op1 (p2 / protein :name (n2 / name :op1 "clathrin"))
                  :op2 (p3 / protein :name (n3 / name :op1 "AP2"))
                  :op3 (p4 / protein :name (n4 / name :op1 "synaptojanin"))
                  :op4 (p8 / protein :name (n5 / name :op1 "dynamin"))))
      :ARG2 (b2 / bind-01
            :ARG1 (p5 / protein :name (n6 / name :op1 "epsin"))
            :ARG2 (a2 / and
                  :op1 p3
                  :op2 p2))
      :ARG1-of (d / describe-01
            :ARG0 (p7 / publication
                  :ARG1-of (c2 / cite-01
                        :ARG2 (a3 / and :op1 34 :op2 38))
                  :ARG0-of (r / review-01))))

# ::id bio.chicago_2015.39546 ::date 2015-11-01T02:51:34 ::annotator SDL-AMR-09 ::preferred
# ::snt Indeed, FynKD is able to inhibit  Cbl phosphorylation by  Abl (unpublished result).
# ::save-date Mon Nov 9, 2015 ::file bio_chicago_2015_39546.txt
(c / capable-01
      :ARG1 p
      :ARG2 (i / inhibit-01
            :ARG0 (p / protein :name (n / name :op1 "FynKD"))
            :ARG1 (p2 / phosphorylate-01
                  :ARG1 (p3 / protein :name (n2 / name :op1 "Cbl"))
                  :ARG2 (p4 / protein :name (n3 / name :op1 "Abl"))))
      :mod (i2 / indeed)
      :ARG1-of (d / describe-01
            :ARG0 (t / thing
                  :ARG2-of (r / result-01)
                  :ARG1-of (p5 / publish-01 :polarity -))))

# ::id bio.chicago_2015.39559 ::date 2015-11-01T02:56:18 ::annotator SDL-AMR-09 ::preferred
# ::snt Because binding of  p53 by  mdm2 is required for  mdm2-mediated  p53 degradation ( 15,  16), these results suggest that  TAFII31 either  out-competes mdm2 for binding to  p53 or excludes  mdm2 from the  p53 complex, thus preventing  mdm2-mediated  p53 degradation.
# ::save-date Mon Dec 21, 2015 ::file bio_chicago_2015_39559.txt
(s / suggest-01
      :ARG0 (t / thing
            :ARG2-of (r / result-01)
            :mod (t2 / this))
      :ARG1 (o / or
            :op1 (o2 / outcompete-00
                  :ARG0 (p / protein :name (n / name :op1 "TAFII31"))
                  :ARG1 (p2 / protein :name (n2 / name :op1 "mdm2"))
                  :ARG3 (b / bind-01
                        :ARG1 p
                        :ARG2 (p3 / protein :name (n3 / name :op1 "p53"))))
            :op1 (e / exclude-01
                  :ARG0 p
                  :ARG1 p2
                  :ARG2 (c / complex
                        :mod p3)
                  :ARG0-of (p4 / prevent-01
                        :ARG1 (d / degrade-01
                              :ARG1 p3
                              :ARG1-of (m / mediate-01
                                    :ARG0 p2)))))
      :ARG1-of (c2 / cause-01
            :ARG0 (r2 / require-01
                  :ARG0 d
                  :ARG1 b)
            :ARG1-of (d2 / describe-01
                  :ARG0 (p5 / publication
                        :ARG1-of (c3 / cite-01
                              :ARG2 (a / and :op1 15 :op2 16))))))

# ::id bio.chicago_2015.39560 ::date 2015-11-01T06:30:52 ::annotator SDL-AMR-09 ::preferred
# ::snt Cytochrome c and  dATP-dependent formation of  Apaf-1/caspase-9 complex initiates an apoptotic protease cascade.
# ::save-date Sun Jan 17, 2016 ::file bio_chicago_2015_39560.txt
(i / initiate-01
      :ARG0 (f / form-01
            :ARG1 (m / macro-molecular-complex
                  :part (p / protein :name (n / name :op1 "Apaf-1"))
                  :part (e / enzyme :name (n2 / name :op1 "caspase-9")))
            :ARG0-of (d / depend-01
                  :ARG1 (a2 / and
                        :op1 (p3 / protein :name (n3 / name :op1 "Cytochrome" :op2 "c"))
                        :op2 (s / small-molecule :name (n4 / name :op1 "dATP")))))
      :ARG1 (c / cascade
            :mod (p2 / protease)
            :mod (a / apoptotic)))

# ::id bio.chicago_2015.39589 ::date 2015-11-01T06:39:30 ::annotator SDL-AMR-09 ::preferred
# ::snt kuz Is Required for the Proteolytic Processing of   Notch
# ::save-date Mon Nov 9, 2015 ::file bio_chicago_2015_39589.txt
(r / require-01
      :ARG0 (p2 / process-01
            :ARG1 (p3 / protein :name (n2 / name :op1 "Notch"))
            :mod (p4 / proteolysis))
      :ARG1 (p / protein :name (n / name :op1 "kuz")))

# ::id bio.chicago_2015.39645 ::date 2015-11-01T09:33:50 ::annotator SDL-AMR-09 ::preferred
# ::snt Because  CI is caused by the presence of  Wolbachia in male reproductive cells, this 10-fold difference alone would seem sufficient to explain the very  low CI phenotype exhibited by Wien 5 males in contrast with the high  CI exhibited by transinfected ME males.
# ::save-date Fri Nov 27, 2015 ::file bio_chicago_2015_39645.txt
(c3 / cause-01
      :ARG0 (c4 / cause-01
            :ARG0 (p / present-02
                  :ARG1 (o / organism :name (n2 / name :op1 "Wolbachia"))
                  :ARG2 (c5 / cell
                        :ARG0-of (c6 / cause-01
                              :ARG1 (r / reproduce-01))
                        :mod (m2 / male)))
            :ARG1 c)
      :ARG1 (s / seem-01
            :ARG1 (s2 / suffice-01
                  :ARG0 (d / differ-02
                        :mod (a / alone)
                        :mod (p2 / product-of :op1 10))
                  :ARG1 (e / explain-01
                        :ARG0 d
                        :ARG1 (l / low-04
                              :ARG1 (p3 / phenotype
                                    :ARG1-of (e2 / exhibit-01
                                          :ARG0 (m3 / male
                                                :mod (o3 / organism :name (n4 / name :op1 "Wien" :op2 "5"))))
                                    :mod (c / compatible :polarity -
                                          :mod (c2 / cytoplasm)))
                              :degree (v / very)
                              :ARG1-of (c7 / contrast-01
                                    :ARG2 (h / high-02
                                          :ARG1 (c8 / compatible :polarity -
                                                :ARG1-of (e3 / exhibit-01
                                                      :ARG0 (m4 / male
                                                            :mod (o2 / organism :name (n6 / name :op1 "ME")))
                                                      :ARG1-of (t2 / transinfect-00))
                                                :mod c2))))))))

# ::id bio.chicago_2015.39663 ::date 2015-11-01T10:06:57 ::annotator SDL-AMR-09 ::preferred
# ::snt These results suggest that, although it strongly stimulates caspase activation, the cell death induced by the down-regulation of  DIAP1 can be executed through a caspase-independent pathway.
# ::save-date Sun Jan 17, 2016 ::file bio_chicago_2015_39663.txt
(s / suggest-01
      :ARG0 (t / thing
            :ARG2-of (r / result-01)
            :mod (t2 / this))
      :ARG1 (p / possible-01
            :ARG1 (e / execute-02
                  :ARG1 (d / die-01
                        :ARG1 (c / cell)
                        :ARG2-of (i / induce-01
                              :ARG0 (d2 / downregulate-01
                                    :ARG1 (p2 / protein :name (n / name :op1 "DIAP1")))))
                  :ARG3 (p3 / pathway
                        :ARG0-of (d3 / depend-01 :polarity -
                              :ARG1 (p4 / protein :name (n2 / name :op1 "caspase"))))
                  :concession (s2 / stimulate-01
                              :ARG0 d
                              :ARG1 (a / activate-01
                                    :ARG1 p4)
                              :ARG1-of (s3 / strong-02)))))

# ::id bio.chicago_2015.39706 ::date 2015-11-01T10:18:44 ::annotator SDL-AMR-09 ::preferred
# ::snt TSH rapidly activated  Rap1, an effect that was reproduced by cAMP elevating agents, but  PKA independent.
# ::save-date Sun Jan 17, 2016 ::file bio_chicago_2015_39706.txt
(a / activate-01
      :ARG0 (s2 / small-molecule :name (n / name :op1 "TSH"))
      :ARG1 (e3 / enzyme :name (n2 / name :op1 "Rap1"))
      :manner (r / rapid)
      :ARG2-of (a2 / affect-01
            :ARG1-of (r2 / reproduce-01
                  :ARG0 (a3 / agent
                        :ARG0-of (e / elevate-01)
                        :mod (s / small-molecule :name (n3 / name :op1 "cAMP")))
                  :ARG1-of (c / contrast-01
                        :ARG2 (d / depend-01 :polarity -
                              :ARG0 a2
                              :ARG1 (e2 / enzyme :name (n4 / name :op1 "PKA")))))))

# ::id bio.chicago_2015.39736 ::date 2015-11-01T10:29:47 ::annotator SDL-AMR-09 ::preferred
# ::snt Phosphorylation of  Cdc25 by  Cds1 and/or  Chk1 inhibits its activity and thereby prevents dephosphorylation and activation of  Cdc2-Cyclin B.
# ::save-date Sun Jan 17, 2016 ::file bio_chicago_2015_39736.txt
(i / inhibit-01
      :ARG0 (p / phosphorylate-01
            :ARG1 (e4 / enzyme :name (n / name :op1 "Cdc25"))
            :ARG2 (a / and-or
                  :op1 (e / enzyme :name (n2 / name :op1 "Cds1"))
                  :op2 (e2 / enzyme :name (n3 / name :op1 "Chk1"))))
      :ARG1 (a2 / activity-06
            :ARG0 e4)
      :ARG0-of (c / cause-01
            :ARG1 (p3 / prevent-01
                  :ARG0 p
                  :ARG1 (a3 / and
                        :op1 (d / dephosphorylate-01
                              :ARG1 (m / macro-molecular-complex
                                    :part (e3 / enzyme :name (n4 / name :op1 "Cdc2"))
                                    :part (p5 / protein :name (n5 / name :op1 "Cyclin" :op2 "B"))))
                        :op2 (a4 / activate-01
                              :ARG1 m)))))

# ::id bio.chicago_2015.39738 ::date 2015-11-01T10:44:19 ::annotator SDL-AMR-09 ::preferred
# ::snt GBP might sterically block access of protein substrates to the active site of  GSK-3, and we are currently attempting to map the residues of  Xgsk-3 that are important for  GBP binding to  Xgsk-3 to determine if  GBP might bind in the region of  Xgsk-3's active site.
# ::save-date Sun Jan 17, 2016 ::file bio_chicago_2015_39738.txt
(a3 / and
      :op1 (p / possible-01
            :ARG1 (b / block-01
                  :ARG0 (p4 / protein :name (n2 / name :op1 "GBP"))
                  :ARG1 (a / access-01
                        :ARG0 (s / substrate
                              :mod (p2 / protein))
                        :ARG1 (s2 / site
                              :part-of (e / enzyme :name (n / name :op1 "GSK-3"))
                              :ARG1-of (a2 / activity-06)))
                  :manner (s3 / steric)))
      :op2 (a4 / attempt-01
            :ARG0 (w / we)
            :ARG1 (m / map-02
                  :ARG0 w
                  :ARG1 (r / residue
                        :poss (p5 / protein :name (n3 / name :op1 "Xgsk-3"))
                        :mod (i / important
                              :topic (b2 / bind-01
                                    :ARG1 p4
                                    :ARG2 p5)
                              :purpose (d / determine-01
                                    :ARG0 w
                                    :ARG1 (p6 / possible-01 :mode interrogative
                                          :ARG1 (b3 / bind-01
                                                :ARG1 p4
                                                :ARG2 (r2 / region
                                                      :poss (s4 / site
                                                            :ARG1-of a2
                                                            :mod p5))))))))
            :time (c / current)))

# ::id bio.chicago_2015.39759 ::date 2015-11-01T11:09:51 ::annotator SDL-AMR-09 ::preferred
# ::snt The defect appears to be caused by the lack of  filamin, as reintroduction of  filamin restores  NF-kappaB activation by  TNF and constitutively active  TLR4 or  TRAF6.
# ::save-date Thu Nov 19, 2015 ::file bio_chicago_2015_39759.txt
(a / appear-02
      :ARG1 (c / cause-01
            :ARG0 (l / lack-01
                  :ARG1 (p / protein :name (n / name :op1 "filamin")))
            :ARG1 (d / defect))
      :ARG1-of (c2 / cause-01
            :ARG0 (r / restore-01
                  :ARG0 (r2 / reintroduce-02
                        :ARG1 p)
                  :ARG1 (a2 / activate-01
                        :ARG0 (a3 / and
                              :op1 (p3 / protein :name (n3 / name :op1 "TNF"))
                              :op2 (o / or
                                    :op1 (p4 / protein :name (n4 / name :op1 "TLR4"))
                                    :op2 (p5 / protein :name (n5 / name :op1 "TRAF6"))
                                    :ARG0-of (a4 / activity-06
                                          :mod (c3 / constitutive))))
                        :ARG1 (p2 / protein :name (n2 / name :op1 "NF-kappaB"))))))

# ::id bio.chicago_2015.39792 ::date 2015-11-01T11:31:27 ::annotator SDL-AMR-09 ::preferred
# ::snt Residues 170 to 200 of  YY1 are acetylated by  p300 and  PCAF, while the C-terminal  zinc finger domain is acetylated only by  PCAF (Fig.  9A).
# ::save-date Mon Nov 9, 2015 ::file bio_chicago_2015_39792.txt
(c / contrast-01
      :ARG1 (a / acetylate-01
            :ARG0 (a2 / and
                  :op1 (p2 / protein :name (n2 / name :op1 "p300"))
                  :op2 (p3 / protein :name (n3 / name :op1 "PCAF")))
            :ARG1 (r / residue
                  :part-of (p / protein :name (n / name :op1 "YY1"))
                  :mod (v / value-interval :op1 170 :op2 200)))
      :ARG2 (a3 / acetylate-01
            :ARG0 p3
            :ARG1 (p4 / protein-segment :name (n4 / name :op1 "C-terminal" :op2 "zinc" :op3 "finger" :op4 "domain"))
            :mod (o / only))
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod "9A")))

# ::id bio.chicago_2015.39808 ::date 2015-11-01T11:45:25 ::annotator SDL-AMR-09 ::preferred
# ::snt Indeed, mutant analysis indicates that   msh is repressed ventrally by  DER (D'Alessio and Frasch 1996  ; Skeath 1998  ), by   ind (Weiss et al. 1998  ), and by   vnd (this work);   ind is repressed by   vnd (McDonald et al. 1998  ), and   vnd and   rho are repressed by   snail (Ip et al. 1992  ; Mellerick and Nirenberg 1995  ), a mesoderm  master gene that is expressed in the ventral-most region of the blastoderm.
# ::save-date Fri Jan 15, 2016 ::file bio_chicago_2015_39808.txt
(a12 / and
      :op1 (i4 / indicate-01
            :ARG0 (a / analyze-01
                  :ARG1 (m / mutate-01))
            :ARG1 (a2 / and
                  :op1 (r / repress-01
                        :ARG0 (e2 / enzyme :name (n2 / name :op1 "DER"))
                        :ARG1 (g2 / gene :name (n / name :op1 "msh"))
                        :ARG1-of (d3 / describe-01
                              :ARG0 (a4 / and
                                    :op1 (p5 / publication-91
                                          :ARG0 (a3 / and
                                                :op1 (p6 / person :name (n3 / name :op1 "D'Alessio"))
                                                :op2 (p7 / person :name (n4 / name :op1 "Frasch")))
                                          :time (d / date-entity :year 1996))
                                    :op2 (p8 / publication-91
                                          :ARG0 (p9 / person :name (n5 / name :op1 "Skeath"))
                                          :time (d2 / date-entity :year 1998))))
                        :manner (v2 / ventral))
                  :op2 (r2 / repress-01
                        :ARG0 (p10 / protein :name (n6 / name :op1 "ind"))
                        :ARG1 g2
                        :ARG1-of (d4 / describe-01
                              :ARG0 (p11 / publication-91
                                    :ARG0 (a5 / and
                                          :op1 (p12 / person :name (n7 / name :op1 "Weiss"))
                                          :op2 (p13 / person
                                                :mod (o2 / other)))
                                    :time d2)))
                  :op3 (r3 / repress-01
                        :ARG0 (p14 / protein :name (n8 / name :op1 "vdn"))
                        :ARG1 g2
                        :ARG1-of (d7 / describe-01
                              :ARG0 (w / work
                                    :mod (t / this)))))
            :mod (i / indeed))
      :op2 (a6 / and
            :op1 (r4 / repress-01
                  :ARG0 p14
                  :ARG1 p10
                  :ARG1-of (d8 / describe-01
                        :ARG0 (p15 / publication-91
                              :ARG0 (a7 / and
                                    :op1 (p16 / person :name (n9 / name :op1 "McDonald"))
                                    :op2 p13)
                              :time d2)))
            :op2 (r5 / repress-01
                  :ARG0 (g / gene :name (n10 / name :op1 "snail")
                        :ARG1-of (e / express-03
                              :ARG3 (r6 / region
                                    :mod (v / ventral
                                          :degree (m5 / most))
                                    :poss (b / blastoderm)))
                        :mod (m3 / mesoderm)
                        :mod (m4 / master))
                  :ARG1 (a8 / and
                        :op1 p14
                        :op2 (p18 / protein :name (n11 / name :op1 "rho")))
                  :ARG1-of (d9 / describe-01
                        :ARG0 (a9 / and
                              :op1 (p19 / publication-91
                                    :ARG0 (a10 / and
                                          :op1 (p20 / person :name (n12 / name :op1 "Ip"))
                                          :op2 p13)
                                    :time (d5 / date-entity :year 1992))
                              :op2 (p21 / publication-91
                                    :ARG0 (a11 / and
                                          :op1 (p22 / person :name (n13 / name :op1 "Mellerick"))
                                          :op2 (p23 / person :name (n14 / name :op1 "Nirenberg")))
                                    :time (d6 / date-entity :year 1995)))))))

# ::id bio.chicago_2015.39809 ::date 2015-11-01T12:21:53 ::annotator SDL-AMR-09 ::preferred
# ::snt the  Ras-binding domain (RBD) of  Raf-1, which specifically binds the active,  GTP-bound form of  Ras, and the  Rap1-binding domain of  Ral-GDS, which binds the  GTP-bound form of  Rap1.
# ::save-date Sat Jan 16, 2016 ::file bio_chicago_2015_39809.txt
(a / and
      :op1 (p5 / protein-segment :name (n6 / name :op1 "RBD")
            :part-of (e / enzyme :name (n2 / name :op1 "Raf-1"))
            :ARG0-of (b2 / bind-01
                  :ARG1 (e2 / enzyme :name (n7 / name :op1 "Ras")
                        :ARG0-of (a2 / activity-06)
                        :ARG2-of (b3 / bind-01
                              :ARG1 (s / small-molecule :name (n3 / name :op1 "GTP"))))
                  :ARG1-of (s2 / specific-02)))
      :op2 (d2 / domain
            :part-of (p3 / protein :name (n4 / name :op1 "Ral-GDS"))
            :ARG0-of (b5 / bind-01
                  :ARG1 (p4 / protein :name (n5 / name :op1 "Rap1")
                        :ARG1-of b3))))

# ::id bio.chicago_2015.39838 ::date 2015-11-01T12:42:17 ::annotator SDL-AMR-09 ::preferred
# ::snt Amphiphysin, a cytosolic protein that can simultaneously bind the  AP2 alpha ear and  dynamin through different domains ( 39), has been implicated in  dynamin recruitment.
# ::save-date Mon Nov 9, 2015 ::file bio_chicago_2015_39838.txt
(i / implicate-01
      :ARG1 (p / protein :name (n / name :op1 "amphiphysin")
            :mod (c / cytosolic)
            :ARG0-of (b / bind-01
                  :ARG1 (a / and
                        :op1 (p6 / protein-segment :name (n2 / name :op1 "ear")
                              :part-of (p3 / protein :name (n3 / name :op1 "AP2" :op2 "alpha")))
                        :op2 (p4 / protein :name (n4 / name :op1 "dynamin")))
                  :ARG1-of (p2 / possible-01)
                  :manner (s / simultaneous)
                  :manner (d / domain
                        :ARG1-of (d2 / differ-02))
                  :ARG1-of (d3 / describe-01
                        :ARG0 (p5 / publication
                              :ARG1-of (c2 / cite-01
                                    :ARG2 39)))))
      :ARG2 (r / recruit-01
            :ARG1 p4))

# ::id bio.chicago_2015.39840 ::date 2015-11-01T12:53:22 ::annotator SDL-AMR-09 ::preferred
# ::snt Cos2 inhibits  Ci activity independent of  Ci processing
# ::save-date Sun Nov 1, 2015 ::file bio_chicago_2015_39840.txt
(i / inhibit-01
      :ARG0 (p / protein :name (n / name :op1 "Cos2"))
      :ARG1 (a / activity-06
            :ARG1 (p2 / protein :name (n2 / name :op1 "Ci")))
      :ARG0-of (d / depend-01 :polarity -
            :ARG1 (p3 / process-01
                  :ARG1 p2)))

# ::id bio.chicago_2015.39843 ::date 2015-11-01T12:57:05 ::annotator SDL-AMR-09 ::preferred
# ::snt Anaphase initiation in   Saccharomyces cerevisiae is controlled by the  APC-dependent degradation of the  anaphase inhibitor Pds1p.
# ::save-date Mon Nov 9, 2015 ::file bio_chicago_2015_39843.txt
(c / control-01
      :ARG0 (d / degrade-01
            :ARG1 (p2 / protein :name (n2 / name :op1 "Pds1p")
                  :ARG0-of (i / inhibit-01
                        :ARG1 (a / anaphase)))
            :ARG0-of (d2 / depend-01
                  :ARG1 (p / protein :name (n / name :op1 "APC"))))
      :ARG1 (i2 / initiate-01
            :ARG1 a
            :location (o / organism :name (n3 / name :op1 "Saccharomyces" :op2 "cerevisiae"))))

# ::id bio.chicago_2015.39899 ::date 2015-11-01T13:12:05 ::annotator SDL-AMR-09 ::preferred
# ::snt A reverse-function mutant of  Nkx3.2 can block the induction of  Sox9 and  cartilage gene expression by  Shh/ BMP signals
# ::save-date Fri Jan 15, 2016 ::file bio_chicago_2015_39899.txt
(p / possible-01
      :ARG1 (b / block-01
            :ARG0 (m2 / mutate-01
                  :ARG1 (p4 / protein :name (n4 / name :op1 "Nkx3.2"))
                  :ARG0-of (r / reverse-01
                        :ARG1 (f / function-01)))
            :ARG1 (i / induce-01
                  :ARG0 (s / signal-07
                        :ARG0 (m / macro-molecular-complex
                              :part (p2 / protein :name (n2 / name :op1 "Shh"))
                              :part (p3 / protein :name (n3 / name :op1 "BMP"))))
                  :ARG2 (e / express-03
                        :ARG1 (a / and
                              :op1 (g / gene :name (n / name :op1 "Sox9"))
                              :op2 (g2 / gene
                                    :mod (c / cartilage)))))))

# ::id bio.chicago_2015.39944 ::date 2015-11-01T13:27:04 ::annotator SDL-AMR-09 ::preferred
# ::snt Thus, activation of  TAK1 induces phosphorylation of  TCF-4 through  NLK.
# ::save-date Sun Nov 1, 2015 ::file bio_chicago_2015_39944.txt
(c / cause-01
      :ARG1 (i / induce-01
            :ARG0 (a / activate-01
                  :ARG1 (e / enzyme :name (n3 / name :op1 "TAK1")))
            :ARG2 (p2 / phosphorylate-01
                  :ARG1 (p3 / protein :name (n / name :op1 "TCF-4"))
                  :ARG2 (e2 / enzyme :name (n2 / name :op1 "NLK")))))

# ::id bio.chicago_2015.39948 ::date 2015-11-01T13:31:43 ::annotator SDL-AMR-09 ::preferred
# ::snt Indeed, phosphorylation of  APC by  GSK-3beta stimulates its ability to bind  beta-catenin and overexpression of  APC following transfection substantially reduces  beta-catenin levels (Munemitsu et al. 1995  ).
# ::save-date Mon Nov 9, 2015 ::file bio_chicago_2015_39948.txt
(a2 / and
      :op1 (s / stimulate-01
            :ARG0 (p3 / phosphorylate-01
                  :ARG1 (p4 / protein :name (n / name :op1 "APC"))
                  :ARG2 (e / enzyme :name (n2 / name :op1 "GSK-3beta")))
            :ARG1 (c2 / capable-01
                  :ARG1 p4
                  :ARG2 (b / bind-01
                        :ARG0 p4
                        :ARG1 (p5 / protein :name (n3 / name :op1 "beta-catenin")))))
      :op2 (r / reduce-01
            :ARG0 (o / overexpress-01
                  :ARG1 p4
                  :ARG1-of (f / follow-01
                        :ARG2 (t / transfect-01)))
            :ARG1 (l / level
                  :quant-of p5)
            :ARG2 (s2 / substantial))
      :mod (i / indeed)
      :ARG1-of (d2 / describe-01
            :ARG0 (p6 / publication-91
                  :ARG0 (a3 / and
                        :op1 (p7 / person :name (n4 / name :op1 "Munemitsu"))
                        :op2 (p8 / person
                              :mod (o2 / other)))
                  :time (d / date-entity :year 1995))))

# ::id bio.chicago_2015.39970 ::date 2015-11-01T13:47:59 ::annotator SDL-AMR-09 ::preferred
# ::snt At low levels of expression,  dynamin-2 specifically induces cell death.
# ::save-date Mon Nov 9, 2015 ::file bio_chicago_2015_39970.txt
(i / induce-01
      :ARG0 (p / protein :name (n / name :op1 "dynamin-2"))
      :ARG2 (d / die-01
            :ARG1 (c / cell))
      :ARG1-of (s / specific-02)
      :condition (l / low-04
            :ARG1 (l2 / level
                  :quant-of (e / express-03
                        :ARG2 p))))

# ::id bio.chicago_2015.40024 ::date 2015-11-01T13:50:51 ::annotator SDL-AMR-09 ::preferred
# ::snt Like  TAK1, both  MEKK1 and  MLK3 also activate  JNK through  SEK1.
# ::save-date Sun Jan 17, 2016 ::file bio_chicago_2015_40024.txt
(a / activate-01
      :ARG0 (a2 / and
            :op1 (e / enzyme :name (n / name :op1 "MEKK1"))
            :op2 (e3 / enzyme :name (n2 / name :op1 "MLK3")))
      :ARG1 (e2 / enzyme :name (n3 / name :op1 "JNK"))
      :mod (a3 / also)
      :instrument (e5 / enzyme :name (n4 / name :op1 "SEK1"))
      :ARG1-of (r / resemble-01
            :ARG2 (e4 / enzyme :name (n5 / name :op1 "TAK1"))))

# ::id bio.chicago_2015.40045 ::date 2015-10-31T02:44:49 ::annotator SDL-AMR-09 ::preferred
# ::snt A,  LEF1 represses  Runx2-mediated activation of a mOG2-luc reporter lacking the  LEF1 DNA binding site.
# ::save-date Thu Nov 5, 2015 ::file bio_chicago_2015_40045.txt
(r2 / repress-01 :li "a"
      :ARG0 (p2 / protein :name (n3 / name :op1 "LEF1"))
      :ARG1 (a / activate-01
            :ARG1 (m2 / molecular-physical-entity
                  :ARG0-of (r / report-01
                        :ARG1 (e / enzyme :name (n4 / name :op1 "mOG2-luc")))
                  :ARG0-of (l / lack-01
                        :ARG1 (s / site
                              :ARG1-of (b / bind-01
                                    :ARG2 (n6 / nucleic-acid :name (n7 / name :op1 "DNA")
                                          :ARG0-of (e2 / encode-01
                                                :ARG1 p2))))))
            :ARG1-of (m / mediate-01
                  :ARG0 (p3 / protein :name (n5 / name :op1 "Runx2")))))

# ::id bio.chicago_2015.40110 ::date 2015-10-31T03:42:12 ::annotator SDL-AMR-09 ::preferred
# ::snt Furthermore, we showed that  CED-12 physically interacts with  CED-5 and forms a ternary complex with  CED-2 in vitro, with  CED-5 bridging  CED-2 and  CED-12.
# ::save-date Sat Oct 31, 2015 ::file bio_chicago_2015_40110.txt
(a / and
      :op2 (s / show-01
            :ARG0 (w / we)
            :ARG1 (a2 / and
                  :op1 (i / interact-01
                        :ARG0 (p / protein :name (n / name :op1 "CED-12"))
                        :ARG1 (p3 / protein :name (n2 / name :op1 "CED-5"))
                        :manner (p2 / physical))
                  :op2 (f / form-01
                        :ARG0 p
                        :ARG1 (c / complex
                              :mod (t / ternary))
                        :accompanier (p4 / protein :name (n3 / name :op1 "CED-2"))
                        :manner (i2 / in-vitro)
                        :manner (b / bridge-01
                              :ARG0 p3
                              :ARG1 p4
                              :ARG2 p)))))

# ::id bio.chicago_2015.40137 ::date 2015-10-31T04:25:09 ::annotator SDL-AMR-09 ::preferred
# ::snt The  Drosophila endocycle is controlled by  cyclin E and lacks a checkpoint ensuring  S-phase completion.
# ::save-date Sun Jan 17, 2016 ::file bio_chicago_2015_40137.txt
(a / and
      :op1 (c / control-01
            :ARG0 (p / protein :name (n2 / name :op1 "cyclin" :op2 "E"))
            :ARG1 (e / endocycle
                  :mod (o / organism :name (n / name :op1 "Drosophila"))))
      :op2 (l / lack-01
            :ARG0 e
            :ARG1 (c2 / checkpoint
                  :ARG0-of (e2 / ensure-01
                        :ARG1 (c3 / complete-01
                              :ARG1 (e3 / event :name (n3 / name :op1 "S-phase")))))))

# ::id bio.chicago_2015.40191 ::date 2015-10-31T04:32:40 ::annotator SDL-AMR-09 ::preferred
# ::snt Because  HC-Pro suppression of  PTGS is accompanied by the loss of smRNAs   [5, 6]  , this  viral protein can potentially provide a tool to study RNA requirements for RdDM.
# ::save-date Sat Oct 31, 2015 ::file bio_chicago_2015_40191.txt
(c / cause-01
      :ARG0 (a / accompany-01
            :ARG0 (l / lose-02
                  :ARG1 (n5 / nucleic-acid :name (n6 / name :op1 "smRNA")))
            :ARG1 (s / suppress-01
                  :ARG0 (p / protein :name (n3 / name :op1 "HC-Pro"))
                  :ARG1 (p2 / protein-family :name (n4 / name :op1 "PTGS")))
            :ARG1-of (d / describe-01
                  :ARG0 (p3 / publication
                        :ARG1-of (c2 / cite-01
                              :ARG2 (a2 / and :op1 5 :op2 6)))))
      :ARG1 (p4 / possible-01
            :ARG1 (p5 / provide-01
                  :ARG0 (p6 / protein
                        :mod (v / viral)
                        :mod (t / this))
                  :ARG1 (t3 / thing
                        :ARG3-of (t2 / tool-03)
                        :instrument-of (s2 / study-01
                              :ARG1 (r / require-01
                                    :ARG0 (t4 / thing :name (n7 / name :op1 "RdDM"))
                                    :ARG1 (n / nucleic-acid :wiki "RNA" :name (n2 / name :op1 "RNA")))))
                  :mod (p7 / potential))))

# ::id bio.chicago_2015.40291 ::date 2015-10-31T04:42:40 ::annotator SDL-AMR-09 ::preferred
# ::snt Consistent with this localization, we have previously shown that in HeLa cells overexpression of  GTP-bound forms of  rab6 (wt rab6 and  rab6 Q72L) affects transport of both membrane and secretory proteins between an  alpha-mannosidase II-positive and a  sialyl-transferase-positive Golgi compartment ( 15).
# ::save-date Sun Jan 17, 2016 ::file bio_chicago_2015_40291.txt
(s / show-01
      :ARG0 (w2 / we)
      :ARG1 (a / affect-01
            :ARG0 (o / overexpress-01
                  :ARG1 (p2 / protein-family :name (n2 / name :op1 "Rab6")
                        :ARG2-of (i / include-91
                              :ARG1 (a2 / and
                                    :op1 (p9 / protein :name (n4 / name :op1 "Rab6")
                                          :mod (w3 / wild-type))
                                    :op2 (p3 / protein :name (n5 / name :op1 "Rab6")
                                          :ARG2-of (m / mutate-01 :value "Q72L"))))
                        :ARG1-of (b / bind-01
                              :ARG2 (s2 / small-molecule :name (n3 / name :op1 "GTP"))))
                  :location (c / cell-line :name (n / name :op1 "HeLa")))
            :ARG1 (t / transport-01
                  :ARG1 (a3 / and
                        :op1 (p4 / protein
                              :mod (m2 / membrane))
                        :op2 (p5 / protein
                              :ARG0-of (s4 / secrete-01)))
                  :ARG2 (c2 / compartment
                        :mod (t3 / thing :name (n6 / name :op1 "Golgi"))
                        :mod (p6 / positive)
                        :mod (e2 / enzyme :name (n8 / name :op1 "alpha-mannosidase" :op2 "II")))
                  :ARG3 (c3 / compartment
                        :mod t3
                        :mod (p7 / positive)
                        :mod (e / enzyme :name (n7 / name :op1 "sialyl-transferase")))))
      :time (p / previous)
      :ARG1-of (c4 / consistent-01
            :ARG2 (b2 / be-located-at-91
                  :mod (t2 / this)))
      :ARG1-of (d / describe-01
            :ARG0 (p8 / publication
                  :ARG1-of (c5 / cite-01
                        :ARG2 15))))

# ::id bio.chicago_2015.40308 ::date 2015-10-31T05:13:01 ::annotator SDL-AMR-09 ::preferred
# ::snt Furthermore, simultaneous overexpression of both  Hsp90 and  Flag-p50Cdc37 did not increase the association of  Hsp90 with   tsHck499F above that seen upon overexpression of  Flag-p50Cdc37 alone (Fig.  7A).
# ::save-date Thu Nov 26, 2015 ::file bio_chicago_2015_40308.txt
(a / and
      :op2 (i / increase-01 :polarity -
            :ARG0 (o / overexpress-01
                  :ARG1 (a2 / and
                        :op1 (p / protein :name (n / name :op1 "Hsp90"))
                        :op2 (p2 / protein :name (n2 / name :op1 "p50Cdc37")
                              :ARG1-of t2))
                  :mod (s / simultaneous))
            :ARG1 (a3 / associate-01
                  :ARG1 p
                  :ARG2 (e / enzyme :name (n3 / name :op1 "tsHck499F")
                        :ARG2-of (m / mutate-01)))
            :ARG2 (a4 / above
                  :op1 (i2 / increase-01
                        :ARG1-of (s2 / see-01
                              :location (o2 / overexpress-01
                                    :ARG1 (p3 / protein :name (n4 / name :op1 "p50Cdc37")
                                          :mod (a5 / alone)
                                          :ARG1-of (t2 / tag-01
                                                :ARG2 (p4 / protein-segment :name (n5 / name :op1 "Flag"))))))
                        :mod (t / that))))
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod "7A")))

# ::id bio.chicago_2015.40323 ::date 2015-10-31T05:27:05 ::annotator SDL-AMR-09 ::preferred
# ::snt Together, these data suggest that  intersectin regulates  MAPK activation through regulation of  EGFR endocytosis as well as  Ras activation.
# ::save-date Sat Jan 16, 2016 ::file bio_chicago_2015_40323.txt
(s / suggest-01
      :ARG0 (d / data
            :mod (t / this)
            :mod (t2 / together))
      :ARG1 (r / regulate-01
            :ARG0 (p3 / protein :name (n4 / name :op1 "intersectin"))
            :ARG1 (a / activate-01
                  :ARG1 (p / pathway :name (n5 / name :op1 "MAPK")))
            :manner (r2 / regulate-01
                  :ARG1 (a2 / and
                        :op1 (e3 / endocytosis
                              :mod (e / enzyme :name (n2 / name :op1 "EGFR")))
                        :op2 (a3 / activate-01
                              :ARG1 (e2 / enzyme :name (n3 / name :op1 "Ras")))))))

# ::id bio.chicago_2015.40343 ::date 2015-10-31T05:32:42 ::annotator SDL-AMR-09 ::preferred
# ::snt Moreover, a wide variety of studies using both dominant negative mutants and  SHP-2 mutant fibroblasts have shown that  SHP-2 function is required for full activation of  MAPK in response to  growth factors, cytokines, antigen receptors, and integrin engagement.
# ::save-date Wed Feb 24, 2016 ::file bio_chicago_2015_40343.txt
(a / and
      :op2 (s / show-01
            :ARG0 (s2 / study-01
                  :mod (v / variety)
                  :ARG1-of (w / wide-02)
                  :ARG0-of (u / use-01
                        :ARG1 (a2 / and
                              :op1 (m / mutate-01 :mod "-/-"
                                    :ARG0-of (d / dominate-01))
                              :op2 (f / fibroblasts
                                    :mod (p2 / protein :name (n3 / name :op1 "SHP-2")
                                          :ARG2-of (m2 / mutate-01))))))
            :ARG1 (r / require-01
                  :ARG0 (a3 / activate-01
                        :ARG1 (p / pathway :name (n5 / name :op1 "MAPK"))
                        :ARG1-of (f3 / full-09))
                  :ARG1 (f2 / function-01
                        :ARG0 (p3 / protein :name (n4 / name :op1 "SHP-2")))
                  :ARG2-of (r2 / respond-01
                        :ARG1 (a4 / and
                              :op1 (g / growth-factor)
                              :op2 (c / cytokine)
                              :op3 (r3 / receptor
                                    :mod (a5 / antigen))
                              :op4 (e2 / engage-01
                                    :ARG1 (p4 / protein :name (n7 / name :op1 "integrin"))))))))

# ::id bio.chicago_2015.40381 ::date 2015-10-31T05:56:49 ::annotator SDL-AMR-09 ::preferred
# ::snt Phosphorylation site mapping studies performed in vitro also support the hypothesis that  Cds1 and  Chk1 inhibit  Cdc25.
# ::save-date Thu Nov 19, 2015 ::file bio_chicago_2015_40381.txt
(s / support-01
      :ARG0 (s2 / site
            :mod (p / phosphorylate-01)
            :ARG0-of (m / map-01
                  :ARG1 (s3 / study-01
                        :ARG1-of (p2 / perform-01
                              :manner (i / in-vitro)))))
      :ARG1 (h / hypothesize-01
            :ARG1 (i2 / inhibit-01
                  :ARG0 (a2 / and
                        :op1 (e / enzyme :name (n / name :op1 "Cds1"))
                        :op2 (e2 / enzyme :name (n2 / name :op1 "Chk1")))
                  :ARG1 (e3 / enzyme :name (n3 / name :op1 "Cdc25"))))
      :mod (a / also))

# ::id bio.chicago_2015.40436 ::date 2015-10-31T06:00:42 ::annotator SDL-AMR-09 ::preferred
# ::snt To examine the interaction of  Duplin with  beta-catenin using the purified proteins  in vitro,  GST-beta-catenin and its deletion mutants (0.5  muM) were incubated with  MBP-Duplin-(482-749) (30 pmol) immobilized on amylose resin in 100  mul of reaction mixture (20 mM Tris/ Cl, pH 7.5, 1 mM DTT) for 1 h at 4   degrees C. MBP-Duplin was precipitated by centrifugation, and then the precipitates were probed with the  anti-GST antibody.
# ::save-date Tue Jan 12, 2016 ::file bio_chicago_2015_40436.txt
(m2 / multi-sentence
      :snt1 (i / incubate-01
            :ARG1 (a / and
                  :op1 (m3 / macro-molecular-complex
                        :part (e / enzyme :wiki "Glutathione_S-transferase"
                              :name (n / name :op1 "GST"))
                        :part (p / protein :wiki "Beta-catenin"
                              :name (n2 / name :op1 "beta-catenin")))
                  :op2 (m4 / mutate-01
                        :ARG0-of (d2 / delete-01)
                        :quant (c / concentration-quantity :quant 0.5
                              :unit m7)))
            :ARG2 (m / macro-molecular-complex
                  :part (p6 / protein :wiki "Maltose-binding_protein"
                        :name (n9 / name :op1 "MBP"))
                  :part (p9 / protein :wiki -
                        :name (n10 / name :op1 "Duplin"))
                  :quant (c2 / concentration-quantity :quant 30
                        :unit (p2 / picomol))
                  :ARG1-of (i2 / immobilize-01
                        :ARG0 (s2 / small-molecule :wiki -
                              :name (n4 / name :op1 "amylose" :op2 "resin"))
                        :duration (t / temporal-quantity :quant 1
                              :unit (h / hour))
                        :condition (t2 / temperature-quantity :quant 4
                              :scale (c5 / celsius))
                        :location (m5 / mul :value 100
                              :consist-of (m6 / mixture
                                    :ARG0-of (r / react-01)
                                    :consist-of (a2 / and
                                          :op1 (s3 / small-molecule :wiki "Tris"
                                                :name (n5 / name :op1 "Tris/Cl")
                                                :quant (c3 / concentration-quantity :quant 20
                                                      :unit (m7 / millimolar)))
                                          :op2 (s4 / small-molecule :wiki "Dithiothreitol"
                                                :name (n6 / name :op1 "DTT")
                                                :quant (c4 / concentration-quantity :quant 1
                                                      :unit m7)))
                                    :mod (a3 / acidity-quantity :quant 7.5
                                          :scale (p3 / ph)))))
                  :mod (v / value-interval :op1 482 :op2 749))
            :purpose (e3 / examine-01
                  :ARG1 (i3 / interact-01
                        :ARG1 m
                        :ARG2 p)
                  :manner (u / use-01
                        :ARG1 (p7 / protein
                              :ARG1-of (p8 / purify-01
                                    :manner (i4 / in-vitro))))))
      :snt2 (a4 / and
            :op1 (p4 / precipitate-01
                  :ARG0 (c6 / centrifugation)
                  :ARG1 (m8 / macro-molecular-complex
                        :part (p10 / protein :wiki "Maltose-binding_protein"
                              :name (n3 / name :op1 "MBP"))
                        :part (p11 / protein :wiki -
                              :name (n11 / name :op1 "Duplin"))))
            :op2 (p5 / probe-01
                  :ARG1 p4
                  :instrument (a5 / antibody
                        :ARG0-of (o / oppose-01
                              :ARG1 (e2 / enzyme :wiki "Glutathione_S-transferase"
                                    :name (n8 / name :op1 "GST"))))
                  :time (t3 / then))))

# ::id bio.chicago_2015.40510 ::date 2015-10-31T06:36:45 ::annotator SDL-AMR-09 ::preferred
# ::snt Thus, both  Sox9 and  Nkx3.2 are induced by  Shh, prior to the expression of cartilage differentiation markers.
# ::save-date Sat Oct 31, 2015 ::file bio_chicago_2015_40510.txt
(c / cause-01
      :ARG1 (i / induce-01
            :ARG0 (p3 / protein :name (n3 / name :op1 "Shh"))
            :ARG1 (a / and
                  :op1 (p / protein :name (n / name :op1 "Sox9"))
                  :op2 (p2 / protein :name (n2 / name :op1 "Nkx3.2")))
            :time (p4 / prior
                  :op1 (e / express-03
                        :ARG1 (m / marker
                              :mod (d / differentiate-01
                                    :ARG1 (c2 / cartilage)))))))

# ::id bio.chicago_2015.40538 ::date 2015-10-31T06:48:19 ::annotator SDL-AMR-09 ::preferred
# ::snt Resistance of  RNA-mediated TGS to  HC-Pro, a viral suppressor of  PTGS, suggests alternative pathways for dsRNA processing.
# ::save-date Sat Oct 31, 2015 ::file bio_chicago_2015_40538.txt
(s / suggest-01
      :ARG0 (r / resist-01
            :ARG0 (p / protein :name (n / name :op1 "TGS")
                  :ARG1-of (m / mediate-01
                        :ARG0 (n2 / nucleic-acid :name (n3 / name :op1 "RNA"))))
            :ARG1 (p2 / protein :name (n4 / name :op1 "HC-Pro")
                  :ARG0-of (s2 / suppress-01
                        :ARG1 (p3 / protein-family :name (n5 / name :op1 "PTGS")))
                  :mod (v / viral)))
      :ARG1 (p4 / pathway
            :mod (a / alternative)
            :beneficiary (p5 / process-01
                  :ARG1 (n6 / nucleic-acid :name (n7 / name :op1 "dsRNA")))))

# ::id bio.chicago_2015.40555 ::date 2015-10-31T07:14:45 ::annotator SDL-AMR-09 ::preferred
# ::snt Cytochrome c and  dATP-Dependent Formation of  Apaf-1/Caspase-9 Complex Initiates an  Apoptotic Protease Cascade.
# ::save-date Sun Jan 17, 2016 ::file bio_chicago_2015_40555.txt
(i / initiate-01
      :ARG0 (a / and
            :op1 (p / protein :name (n / name :op1 "Cytochrome" :op2 "c"))
            :op2 (f / form-01
                  :ARG1 (m2 / macro-molecular-complex
                        :part (p2 / protein :name (n2 / name :op1 "Apaf-1"))
                        :part (e / enzyme :name (n3 / name :op1 "Caspase-9")))
                  :ARG0-of (d / depend-01
                        :ARG1 (s / small-molecule :name (n4 / name :op1 "dATP")))))
      :ARG1 (c2 / cascade
            :mod (p3 / protease
                  :mod (a3 / apoptotic))))

# ::id bio.chicago_2015.40576 ::date 2015-10-31T07:19:28 ::annotator SDL-AMR-09 ::preferred
# ::snt It remains possible, however, that the phosphorylation of  Dsh by  CK2 and by perhaps other  unidentified kinases is required but not sufficient for the transduction of the  Wg signal.
# ::save-date Tue Jan 19, 2016 ::file bio_chicago_2015_40576.txt
(h / have-concession-91
      :ARG1 (r / remain-01
            :ARG1 (p3 / possible-01
                  :ARG1 (c / contrast-01
                        :ARG1 (r2 / require-01
                              :ARG0 t
                              :ARG1 (a2 / and
                                    :op1 (p / phosphorylate-01
                                          :ARG0 (e / enzyme :name (n2 / name :op1 "CK2"))
                                          :ARG1 (p4 / protein-family :name (n / name :op1 "Dsh")))
                                    :op2 (p5 / phosphorylate-01
                                          :ARG0 (k / kinase
                                                :ARG1-of (i / identify-01 :polarity -)
                                                :mod (o / other))
                                          :ARG1 p4
                                          :ARG1-of (p6 / possible-01))))
                        :ARG2 (s / suffice-01 :polarity -
                              :ARG0 a2
                              :ARG1 (t / transduce-01
                                    :ARG1 (s2 / signal-07
                                          :ARG1 (p7 / protein :name (n3 / name :op1 "Wg")))
                                    :ARG2 a2))))))

# ::id bio.chicago_2015.53561 ::date 2015-10-31T07:30:09 ::annotator SDL-AMR-09 ::preferred
# ::snt In control experiments,  ERK2 was strongly activated by an activated  Raf mutant, RafBxB, to phosphorylate  MBP ( Fig. 4B), and  p38 was activated by ultraviolet irradiation and cotransfection of a  MKK6 expression vector ( Fig. 4C).
# ::save-date Sun Jan 17, 2016 ::file bio_chicago_2015_53561.txt
(a / and
      :op1 (a2 / activate-01
            :ARG0 (m / mutate-01
                  :ARG2 (e2 / enzyme :name (n3 / name :op1 "RafBxB"))
                  :ARG1-of (a3 / activate-01)
                  :mod (e6 / enzyme :name (n / name :op1 "Raf")))
            :ARG1 (e / enzyme :name (n2 / name :op1 "ERK2"))
            :purpose (p2 / phosphorylate-01
                  :ARG1 (p3 / protein :name (n4 / name :op1 "MBP"))
                  :ARG2 e)
            :ARG1-of (d / describe-01
                  :ARG0 (f / figure :mod "4B"))
            :ARG1-of (s / strong-02))
      :op2 (a4 / activate-01
            :ARG0 (a5 / and
                  :op1 (i / irradiate-01
                        :ARG2 (u / ultraviolet))
                  :op2 (c / cotransfect-01
                        :ARG1 (e3 / express-03
                              :ARG1 (v / vector)
                              :ARG2 (e4 / enzyme :name (n6 / name :op1 "MKK6")))))
            :ARG1 (e7 / enzyme :name (n5 / name :op1 "p38"))
            :ARG1-of (d2 / describe-01
                  :ARG0 (f2 / figure :mod "4C")))
      :location (t / thing
            :ARG1-of (e5 / experiment-01)
            :mod (c2 / control)))

# ::id bio.chicago_2015.53577 ::date 2015-10-31T08:39:44 ::annotator SDL-AMR-09 ::preferred
# ::snt To determine whether  NIK mediates  JNK activation by  EphB1, we used the RevTet-On system to inducibly express  NIK(KD) in  P19 cells.
# ::save-date Sun Jan 17, 2016 ::file bio_chicago_2015_53577.txt
(u / use-01
      :ARG0 (w / we)
      :ARG1 (s / system :name (n / name :op1 "RevTet-On"))
      :ARG2 (e / express-03
            :ARG2 (e2 / enzyme :name (n2 / name :op1 "NIK(KD)"))
            :ARG3 (c / cell :name (n3 / name :op1 "P19"))
            :manner (i / induce-01
                  :ARG1-of (p / possible-01)))
      :purpose (d / determine-01
            :ARG0 w
            :ARG1 (m / mediate-01 :mode interrogative
                  :ARG0 e2
                  :ARG1 (a / activate-01
                        :ARG0 (p2 / protein :name (n4 / name :op1 "EphB1"))
                        :ARG1 (e3 / enzyme :name (n5 / name :op1 "JNK"))))))

# ::id bio.chicago_2015.53583 ::date 2015-10-31T08:43:49 ::annotator SDL-AMR-09 ::preferred
# ::snt Regardless of the receptor-coupling mechanism involved,  TGF-beta activation of  JNK or  p38 in some cell lines and conditions can be rapid and mediate transcriptional responses by activating  AP-1 complexes via phosphorylation of  c-Jun transcription factor (Hocevar et al. 1999  ) or  CRE-regulatory complexes via phosphorylation of  ATF2 transcription factor (Sano et al. 1999  ).
# ::save-date Sun Jan 17, 2016 ::file bio_chicago_2015_53583.txt
(r5 / regardless-91
      :ARG1 (a / and
            :op1 (p2 / possible-01
                  :ARG1 (r2 / rapid
                        :domain (a2 / and
                              :op1 (a3 / activate-01
                                    :ARG0 (p14 / protein :name (n / name :op1 "TGF-beta"))
                                    :ARG1 (o / or
                                          :op1 (e2 / enzyme :name (n2 / name :op1 "JNK"))
                                          :op2 (e / enzyme :name (n3 / name :op1 "p38")))
                                    :location (c2 / cell-line
                                          :quant (s / some)))
                              :op2 (t / thing
                                    :ARG2-of (c3 / condition-01)))))
            :op2 (m2 / mediate-01
                  :ARG0 a2
                  :ARG1 (r3 / respond-01
                        :ARG2 (t2 / transcribe-01))
                  :manner (o3 / or
                        :op1 (a4 / activate-01
                              :ARG0 (p / phosphorylate-01
                                    :ARG1 (f / factor
                                          :ARG0-of (t3 / transcribe-01
                                                :ARG1 (p5 / protein :name (n5 / name :op1 "c-Jun")))))
                              :ARG1 (c4 / complex
                                    :mod (p4 / protein :name (n4 / name :op1 "AP-1")))
                              :ARG1-of (d2 / describe-01
                                    :ARG0 (p6 / publication-91
                                          :ARG0 (a5 / and
                                                :op1 (p7 / person :name (n6 / name :op1 "Hocevar"))
                                                :op2 (p8 / person
                                                      :mod (o2 / other)))
                                          :time (d / date-entity :year 1999))))
                        :op2 (a6 / activate-01
                              :ARG0 (p9 / phosphorylate-01
                                    :ARG1 (p10 / protein :name (n8 / name :op1 "ATF2")))
                              :ARG1 (c5 / complex
                                    :ARG0-of (r4 / regulate-01
                                          :ARG1 (e3 / enzyme :name (n7 / name :op1 "CRE"))))
                              :ARG1-of (d3 / describe-01
                                    :ARG0 (p11 / publication-91
                                          :ARG0 (a7 / and
                                                :op1 (p12 / person :name (n9 / name :op1 "Sano"))
                                                :op2 (p13 / person
                                                      :mod (o4 / other)))
                                          :time d))))))
      :ARG2 (i / involve-01
            :ARG1 (m / mechanism
                  :ARG0-of (c / couple-01
                        :ARG1 (r / receptor)))))

# ::id bio.chicago_2015.53648 ::date 2015-11-01T01:36:57 ::annotator SDL-AMR-09 ::preferred
# ::snt Activation of  PKC with  TPA leads to inactivation of  GSK3  in the absence of a  wnt signal and downregulation of  PKC by prolonged treatment with  TPA prevents  wnt-mediated inactivation of  GSK3  [  113].
# ::save-date Sun Jan 17, 2016 ::file bio_chicago_2015_53648.txt
(a / and
      :op1 (l / lead-03
            :ARG0 (a2 / activate-01
                  :ARG0 (s2 / small-molecule :name (n2 / name :op1 "TPA"))
                  :ARG1 (e / enzyme :name (n / name :op1 "PKC")))
            :ARG2 (a3 / activate-01 :polarity -
                  :ARG1 (e2 / enzyme :name (n3 / name :op1 "GSK3")))
            :condition (a4 / absent-01
                        :ARG1 (s / signal-07
                              :ARG0 (p2 / pathway :name (n4 / name :op1 "wnt")))))
      :op2 (p3 / prevent-01
            :ARG0 (d / downregulate-01
                  :ARG1 e
                  :ARG2 (t / treat-04
                        :ARG2 s2
                        :ARG1-of (p4 / prolong-01)))
            :ARG1 (a5 / activate-01 :polarity -
                  :ARG1 e2
                  :ARG1-of (m / mediate-01
                        :ARG0 p2)))
      :ARG1-of (d2 / describe-01
            :ARG0 (p5 / publication
                  :ARG1-of (c / cite-01
                        :ARG2 113))))

# ::id bio.chicago_2015.53659 ::date 2015-11-01T01:52:03 ::annotator SDL-AMR-09 ::preferred
# ::snt To confirm that  p65 activates  PI3K  in vivo, 3-phosphorylated inositol lipid levels were measured in different cells expressing  p65 or  p85alpha.
# ::save-date Wed Jan 13, 2016 ::file bio_chicago_2015_53659.txt
(m / measure-01
      :ARG1 (l / level :quant 3
            :ARG1-of (p / phosphorylate-01)
            :quant-of (l3 / lipid :name (n5 / name :op1 "3-phosphorylated" :op2 "inositol")))
      :location (c / cell
            :ARG1-of (d / differ-02)
            :ARG3-of (e / express-03
                  :ARG2 (o / or
                        :op1 (p2 / protein :name (n2 / name :op1 "p65"))
                        :op2 (p3 / protein-segment :name (n3 / name :op1 "p85alpha")))))
      :purpose (c2 / confirm-01
            :ARG1 (a / activate-01
                  :ARG0 p2
                  :ARG1 (e2 / enzyme :name (n4 / name :op1 "PI3K"))
                  :manner (i / in-vivo))))

# ::id bio.chicago_2015.53662 ::date 2015-11-01T01:59:05 ::annotator SDL-AMR-09 ::preferred
# ::snt However, in   slp mutants, in contrast to the   slp+ situation,  VP16En activates   hh expression (compare  Fig. 6D with  Fig. 4B) and also that of  en (not shown).
# ::save-date Thu Nov 26, 2015 ::file bio_chicago_2015_53662.txt
(h / have-concession-91
      :ARG1 (a2 / and
            :op1 (a / activate-01
                  :ARG0 (p / protein :name (n / name :op1 "VP16En"))
                  :ARG1 (e / express-03
                        :ARG2 (p2 / protein :name (n2 / name :op1 "Hh")))
                  :ARG1-of (d / describe-01
                        :ARG0 (c / compare-01
                              :ARG1 (f / figure :mod "6D")
                              :ARG2 (f2 / figure :mod "4B"))))
            :op2 (a3 / activate-01
                  :ARG0 p
                  :ARG1 (e2 / express-03
                        :ARG2 (p3 / protein :name (n3 / name :op1 "En")))
                  :ARG1-of (s / show-01 :polarity -)
                  :mod (a4 / also))
            :location (g / gene :name (n4 / name :op1 "SLP")
                  :ARG2-of (m / mutate-01)
                  :ARG1-of (c2 / contrast-01
                        :ARG2 (s2 / situation
                              :mod (g2 / gene :name (n5 / name :op1 "SLP")
                                    :mod (w / wild-type)))))))

# ::id bio.chicago_2015.53694 ::date 2015-11-01T03:20:52 ::annotator SDL-AMR-09 ::preferred
# ::snt A, Responses to 10 msec flashes recorded in WT photoreceptors in controls and in the presence of 8-Br- cGMP (5 mM), 8-Br-cAMP (5 mM), IBMX (100  muM), and photoreceptors from  flies expressing activated  Gsalpha (Gsalpha*).
# ::save-date Thu Feb 4, 2016 ::file bio_chicago_2015_53694.txt
(a2 / and :li "a"
      :op1 (t / thing
            :ARG2-of (r / respond-01
                  :ARG1 (f / flash-01
                        :duration (t2 / temporal-quantity :quant 10
                              :unit (m2 / millisecond))
                        :ARG1-of (r2 / record-01
                              :location (p / photoreceptor
                                    :mod (w / wild-type)
                                    :location (c / control)
                                    :ARG2-of (p2 / present-02
                                          :ARG1 (a / and
                                                :op1 (s / small-molecule :name (n / name :op1 "8-Br-cGMP")
                                                      :quant (c2 / concentration-quantity :quant 5
                                                            :unit (m3 / millmolar)))
                                                :op2 (s2 / small-molecule :name (n2 / name :op1 "8-Br-cAMP")
                                                      :quant c2)
                                                :op3 (s3 / small-molecule :name (n3 / name :op1 "IBMX")
                                                      :quant (c3 / concentration-quantity :quant 100
                                                            :unit (m4 / millimolar))))))))))
      :op2 (p3 / photoreceptor
            :source (f2 / fly
                  :ARG3-of (e / express-03
                        :ARG2 (p4 / protein :name (n4 / name :op1 "Gsalpha")
                              :ARG1-of (a3 / activate-01))))))

# ::id bio.chicago_2015.53701 ::date 2015-11-01T03:31:33 ::annotator SDL-AMR-09 ::preferred
# ::snt Consistent with the findings in   Drosophila,  Habas et al. (2001)   recently demonstrated biochemically in mammalian cells that  Fz/Dvl (mouse Disheveled) signaling activates  Rho and weakly  Rac, but not  Cdc42.
# ::save-date Thu Nov 19, 2015 ::file bio_chicago_2015_53701.txt
(d2 / demonstrate-01
      :ARG1 (c / contrast-01
            :ARG1 (a3 / and
                  :op1 (a2 / activate-01
                        :ARG0 (s / signal-07
                              :ARG0 (p3 / pathway :name (n2 / name :op1 "Fz/Dvl"))
                              :location (m / mouse :name (n3 / name :op1 "Disheveled")))
                        :ARG1 (p4 / protein :name (n4 / name :op1 "Rho"))
                        :manner (b / biochemical))
                  :op2 (a4 / activate-01
                        :ARG0 s
                        :ARG1 (e / enzyme :name (n5 / name :op1 "Rac"))
                        :ARG1-of (w / weak-02))
                  :location (c2 / cell
                        :mod (m2 / mammal)))
            :ARG2 (a5 / activate-01 :polarity -
                  :ARG0 s
                  :ARG1 (p5 / protein :name (n6 / name :op1 "Cdc42"))
                  :location c2))
      :time (r / recent)
      :ARG1-of (c3 / consistent-01
            :ARG2 (t / thing
                  :ARG1-of (f / find-01)
                  :location (o2 / organism :name (n7 / name :op1 "Drosophila"))))
      :ARG1-of (d3 / describe-01
            :ARG0 (p6 / publication-91
                  :ARG0 (a / and
                        :op1 (p / person :name (n / name :op1 "Habas"))
                        :op2 (p2 / person
                              :mod (o / other)))
                  :time (d / date-entity :year 2001))))

# ::id bio.chicago_2015.53712 ::date 2015-11-01T03:40:44 ::annotator SDL-AMR-09 ::preferred
# ::snt NPAT activates  histone gene transcription
# ::save-date Thu Nov 5, 2015 ::file bio_chicago_2015_53712.txt
(a / activate-01
      :ARG0 (p / protein :name (n / name :op1 "NPAT"))
      :ARG1 (t / transcribe-01
            :ARG1 (g2 / gene :name (n2 / name :op1 "histone"))))

# ::id bio.chicago_2015.53750 ::date 2015-11-01T03:42:58 ::annotator SDL-AMR-09 ::preferred
# ::snt KN-CKI  inhibited the activation of  Lef-1 reporter by  Wnt-1 (Fig.  3 c), suggesting the involvement of endogenous  CKI  during the  Wnt signal.
# ::save-date Sun Nov 1, 2015 ::file bio_chicago_2015_53750.txt
(i / inhibit-01
      :ARG0 (e / enzyme :name (n / name :op1 "KN-CKI"))
      :ARG1 (a / activate-01
            :ARG0 (p2 / protein :name (n2 / name :op1 "Wnt-1"))
            :ARG1 (m / molecular-physical-entity
                  :ARG0-of (r / report-01
                        :ARG1 (p3 / protein :name (n3 / name :op1 "Lef-1")))))
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod "3C"))
      :ARG0-of (s / suggest-01
            :ARG1 (i2 / involve-01
                  :ARG1 (e2 / enzyme :name (n4 / name :op1 "CKI")
                        :mod (e3 / endogenous))
                  :time (s2 / signal-07
                        :ARG0 (p4 / pathway :name (n5 / name :op1 "Wnt"))))))

# ::id bio.chicago_2015.53769 ::date 2015-11-01T03:53:22 ::annotator SDL-AMR-09 ::preferred
# ::snt Initial integrin clustering results in rapid activation of  Rac and  Cdc42, and this activation of  Rac and  Cdc42 induces formation of lamellipodia and filopodia, leading to cell spreading and subsequent activation of  Rho.
# ::save-date Thu Nov 5, 2015 ::file bio_chicago_2015_53769.txt
(i / induce-01
      :ARG0 (r / result-01
            :ARG1 (p / protein :name (n / name :op1 "integrin")
                  :ARG0-of (c / cluster-01)
                  :mod (i2 / initial))
            :ARG2 (a2 / activate-01
                  :ARG1 (a3 / and
                        :op1 (e / enzyme :name (n2 / name :op1 "Rac"))
                        :op2 (p2 / protein :name (n3 / name :op1 "Cdc42")))
                  :mod (r2 / rapid)))
      :ARG2 (f / form-01
            :ARG1 (a4 / and
                  :op1 (l / lamellipodia)
                  :op2 (f2 / filopodia)))
      :ARG0-of (l2 / lead-01
            :ARG2 (a5 / and
                  :op1 (s / spread-03
                        :ARG1 (c2 / cell))
                  :op2 (a6 / activate-01
                        :ARG1 (p3 / protein :name (n4 / name :op1 "Rho"))
                        :mod (s2 / subsequent)))))

# ::id bio.chicago_2015.53781 ::date 2015-11-01T03:59:14 ::annotator SDL-AMR-09 ::preferred
# ::snt It is, therefore, possible that  Ad2 activation of  PKA involves both integrins and functional  F-actin.
# ::save-date Thu Nov 5, 2015 ::file bio_chicago_2015_53781.txt
(c / cause-01
      :ARG1 (p / possible-01
            :ARG1 (i / involve-01
                  :ARG1 (a2 / and
                        :op1 (p3 / protein :name (n3 / name :op1 "integrin"))
                        :op2 (p4 / protein :name (n4 / name :op1 "F-actin")
                              :ARG0-of (f / function-01)))
                  :ARG2 (a / activate-01
                        :ARG0 (p2 / protein :name (n / name :op1 "Ad2"))
                        :ARG1 (e / enzyme :name (n2 / name :op1 "PKA"))))))

# ::id bio.chicago_2015.53810 ::date 2015-11-01T07:47:29 ::annotator SDL-AMR-09 ::preferred
# ::snt One answer to how  PYK2 might activate  Ras comes from analysis of a structurally homologous protein, the  focal adhesion kinase (p125FAK or  FAK).
# ::save-date Sun Jan 17, 2016 ::file bio_chicago_2015_53810.txt
(c / come-03
      :ARG1 (a / answer-01 :quant 1
            :ARG1 (t / thing
                  :manner-of (a2 / activate-01
                        :ARG0 (e / enzyme :name (n2 / name :op1 "PYK2"))
                        :ARG1 (e2 / enzyme :name (n / name :op1 "Ras"))
                        :ARG1-of (p / possible-01))))
      :ARG2 (a3 / analyze-01
            :ARG1 (p3 / protein
                  :mod (h / homologous)
                  :mod (s / structural)
                  :ARG1-of (m / mean-01
                        :ARG2 (e5 / enzyme :name (n3 / name :op1 "focal" :op2 "adhesion" :op3 "kinase")
                              :ARG1-of (m2 / mean-01
                                    :ARG2 (a4 / and
                                          :op1 (e4 / enzyme :name (n4 / name :op1 "p125FAK"))
                                          :op1 (e3 / enzyme :name (n5 / name :op1 "FAK")))))))))

# ::id bio.chicago_2015.53850 ::date 2015-11-01T08:09:05 ::annotator SDL-AMR-09 ::preferred
# ::snt To test whether  GSK-3 activity is required for this response, we tested the effect of LiCl in the `collapse assay` since it is an established inhibitor of both  GSK-3alpha and  GSK-3beta ( Stambolic et al., 1996) and can prevent the  Sema 3A activation of  GSK-3 ( Fig. 4).
# ::save-date Thu Nov 5, 2015 ::file bio_chicago_2015_53850.txt
(t2 / test-01
      :ARG0 (w / we)
      :ARG1 (a / affect-01
            :ARG0 (s / small-molecule :name (n / name :op1 "LiCl"))
            :location (a2 / assay-01
                  :mod (c / collapse-01)))
      :ARG1-of (c2 / cause-01
            :ARG0 (a3 / and
                  :op1 (e / establish-01
                        :ARG1 s
                        :ARG2 (i2 / inhibit-01
                              :ARG0 s
                              :ARG1 (a4 / and
                                    :op1 (e2 / enzyme :name (n2 / name :op1 "GSK-3alpha"))
                                    :op2 (e3 / enzyme :name (n3 / name :op1 "GSK-3beta"))))
                        :ARG1-of (d2 / describe-01
                              :ARG0 (p / publication-91
                                    :ARG0 (a5 / and
                                          :op1 (p2 / person :name (n4 / name :op1 "Stambolic"))
                                          :op2 (p3 / person
                                                :mod (o / other)))
                                    :time (d / date-entity :year 1996))))
                  :op2 (p4 / possible-01
                        :ARG1 (p5 / prevent-01
                              :ARG0 s
                              :ARG1 (a6 / activate-01
                                    :ARG0 (p6 / protein :name (n6 / name :op1 "Sema" :op2 "3A"))
                                    :ARG1 (e4 / enzyme :name (n5 / name :op1 "GSK-3"))))
                        :ARG1-of (d3 / describe-01
                              :ARG0 (f / figure :mod 4)))))
      :purpose (t3 / test-01
            :ARG0 w
            :ARG1 (r / require-01 :mode interrogative
                  :ARG0 (t4 / thing
                        :ARG2-of (r2 / respond-01)
                        :mod (t5 / this))
                  :ARG1 (a7 / activity-06
                        :ARG0 e4))))

# ::id bio.chicago_2015.53852 ::date 2015-11-01T08:18:04 ::annotator SDL-AMR-09 ::preferred
# ::snt In support of this observation, when  oligonucleotide C3-3PmA was used as 32P-labeled probe in the presence of a nuclear extract from  PMA/ PHA activated fresh  human T lymphocytes, no binding activity was observed ( lane 9).
# ::save-date Thu Nov 5, 2015 ::file bio_chicago_2015_53852.txt
(o / observe-01
      :ARG1 (a2 / activity-06 :polarity -
            :ARG1 (b / bind-01))
      :time (u / use-01
            :ARG1 (o3 / oligonucleotide :name (n / name :op1 "C3-3PmA"))
            :ARG2 (p3 / probe-01
                  :ARG1-of (l / label-01
                        :ARG2 (p4 / phosphorus
                              :mod (m / molecular-mass :value 32))))
            :manner (p / present-02
                  :ARG1 (e / extract-01
                        :ARG2 (c / cell :name (n4 / name :op1 "T" :op2 "lymphocytes")
                              :mod (h / human)
                              :ARG1-of (f / fresh-04)
                              :ARG1-of (a / activate-01
                                    :ARG0 (s / slash
                                          :op1 (s2 / small-molecule :name (n5 / name :op1 "PMA"))
                                          :op2 (p2 / protein :name (n6 / name :op1 "PHA")))))
                        :mod (n3 / nucleus))))
      :ARG1-of (d / describe-01
            :ARG0 (l2 / lane :mod 9))
      :ARG0-of (s3 / support-01
            :ARG1 (t / thing
                  :ARG1-of (o2 / observe-01)
                  :mod (t2 / this))))

# ::id bio.chicago_2015.53861 ::date 2015-11-01T08:35:19 ::annotator SDL-AMR-09 ::preferred
# ::snt Cooperative activation of  muscle gene expression by  MEF2 and myogenic  bHLH proteins.
# ::save-date Thu Nov 5, 2015 ::file bio_chicago_2015_53861.txt
(a / activate-01
      :ARG0 (a2 / and
            :op1 (p / protein :name (n / name :op1 "MEF2"))
            :op2 (p2 / protein :name (n2 / name :op1 "bHLH")
                  :mod (m2 / myogenic)))
      :ARG1 (e / express-03
            :ARG1 (g / gene
                  :mod (m / muscle)))
      :ARG0-of (c / cooperate-01))

# ::id bio.chicago_2015.53933 ::date 2015-11-01T08:39:31 ::annotator SDL-AMR-09 ::preferred
# ::snt Because the single channel conductances of  GABAA receptors activated by  GABA and  pentobarbital are similar (Jackson et al., 1982  ; Akk and Steinbach, 2000  ), it is likely that the open states of receptors activated by either of these compounds have similar conformations.
# ::save-date Sun Nov 1, 2015 ::file bio_chicago_2015_53933.txt
(c / cause-01
      :ARG0 (r / resemble-01
            :ARG1 (c2 / conduct-03
                  :ARG2 (r3 / receptor :name (n2 / name :op1 "GABAA")
                        :ARG1-of (a / activate-01
                              :ARG0 (s2 / small-molecule :name (n3 / name :op1 "GABA"))))
                  :mod (c3 / channel)
                  :ARG1-of (s / single-02))
            :ARG2 (p2 / pentobarbital)
            :ARG1-of (d3 / describe-01
                  :ARG0 (a2 / and
                        :op1 (p3 / publication-91
                              :ARG0 (a3 / and
                                    :op1 (p4 / person :name (n4 / name :op1 "Jackson"))
                                    :op2 (p5 / person
                                          :mod (o / other)))
                              :time (d / date-entity :year 1982))
                        :op2 (p6 / publication-91
                              :ARG0 (a4 / and
                                    :op1 (p7 / person :name (n5 / name :op1 "Akk"))
                                    :op2 (p8 / person :name (n6 / name :op1 "Steinbach")))
                              :time (d2 / date-entity :year 2000)))))
      :ARG1 (l / likely-01
            :ARG1 (h / have-03
                  :ARG0 (s3 / state
                        :ARG1-of (o2 / open-01)
                        :mod (r2 / receptor
                              :ARG1-of (a5 / activate-01
                                    :ARG0 (c4 / compound
                                          :mod (e / either)
                                          :mod (t / this)))))
                  :ARG1 (r4 / resemble-01
                        :ARG1 (c5 / conformation)))))

# ::id bio.chicago_2015.53950 ::date 2015-11-01T08:49:21 ::annotator SDL-AMR-09 ::preferred
# ::snt Activation of  GCN2 by various  starvation or stress conditions requires the  tRNA binding activity of its  HisRS-like domain (for review, see Hinnebusch and Natarajan 2002  ).
# ::save-date Thu Nov 5, 2015 ::file bio_chicago_2015_53950.txt
(r / require-01
      :ARG0 (a / activate-01
            :ARG0 (c / condition-02
                  :ARG1 (o / or
                        :op1 (s / starve-01)
                        :op2 (s2 / stress-02))
                  :quant (v / various))
            :ARG1 (e / enzyme :name (n / name :op1 "GCN2")))
      :ARG1 (a2 / activity-06
            :ARG0 (p4 / protein-segment :name (n7 / name :op1 "HisRS-like" :op2 "domain"))
            :ARG1 (b / bind-01
                  :ARG1 (d2 / domain)
                  :ARG2 (n3 / nucleic-acid :name (n4 / name :op1 "tRNA"))))
      :ARG1-of (r2 / review-01
            :purpose-of (s4 / see-01
                  :ARG1 (p / publication-91
                        :ARG0 (a3 / and
                              :op1 (p2 / person :name (n5 / name :op1 "Hinnebusch"))
                              :op2 (p3 / person :name (n6 / name :op1 "Natarajan")))
                        :time (d / date-entity :year 2002)))))

# ::id bio.chicago_2015.53994 ::date 2015-11-01T08:58:35 ::annotator SDL-AMR-09 ::preferred
# ::snt Ubiquitination is a multi-step process that begins with the activation of a  Ub molecule by an  E1 or  Ub-activating enzyme.
# ::save-date Wed Mar 2, 2016 ::file bio_chicago_2015_53994.txt
(p / process-02
      :ARG1 (u / ubiquitinate-01)
      :mod (m / multistep)
      :ARG1-of (b / begin-01
            :ARG2 (a / activate-01
                  :ARG0 (o / or
                        :op1 (e / enzyme :name (n2 / name :op1 "E1"))
                        :op2 (e2 / enzyme
                              :ARG1-of (a2 / activate-01
                                    :ARG0 m2)))
                  :ARG1 (m2 / molecule
                        :mod (p2 / protein :name (n / name :op1 "Ub"))))))

# ::id bio.chicago_2015.54023 ::date 2015-11-01T09:14:53 ::annotator SDL-AMR-09 ::preferred
# ::snt At this concentration forskolin slightly enhanced  Rap1 activation by  PDGF (e.g. 1.9- to 2.6-fold in Figure  4C).
# ::save-date Sun Jan 17, 2016 ::file bio_chicago_2015_54023.txt
(h / have-condition-91
      :ARG1 (e / enhance-01
            :ARG0 (s / small-molecule :name (n / name :op1 "forskolin"))
            :ARG1 (a / activate-01
                  :ARG0 (p3 / protein :name (n2 / name :op1 "PDGF"))
                  :ARG1 (e3 / enzyme :name (n3 / name :op1 "Rap1")))
            :ARG3 (v / value-interval
                  :op1 (p / product-of :op1 1.9)
                  :op2 (p2 / product-of :op2 2.6))
            :degree (s2 / slight))
      :ARG2 (c / concentrate-01
            :mod (t / this))
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod "4C")))

# ::id bio.chicago_2015.54073 ::date 2015-11-01T09:19:07 ::annotator SDL-AMR-09 ::preferred
# ::snt For example, compared to native channels,  -only channels have decreased Ca2+ permeability, less voltage dependence, a lack of  Ca2+/calmodulin modulation, less  flickery  single-channel records, lower apparent affinity for  cGMP, and minimal activation by cAMP.
# ::save-date Sun Jan 17, 2016 ::file bio_chicago_2015_54073.txt
(c2 / compare-01
      :ARG1 (c3 / channel
            :mod (n / native)
            :mod (o / only)
            :ARG0-of (h / have-03
                  :ARG1 (a / and
                        :op1 (p / permeability
                              :ARG1-of (d / decrease-01)
                              :mod (c / calcium
                                    :ARG1-of (i / ionize-01 :value "2+")))
                        :op2 (d2 / depend-01
                              :ARG0 c3
                              :ARG1 (v / voltage)
                              :mod (l2 / less))
                        :op3 (l3 / lack-01
                              :ARG0 c3
                              :ARG1 (m3 / modulate-01
                                    :ARG1 (p2 / protein :name (n3 / name :op1 "calmodulin"))
                                    :mod c))
                        :op4 (r / record
                              :mod (c4 / channel
                                    :ARG1-of (s / single-02)
                                    :mod (f / flickery))
                              :mod l2)
                        :op5 (a2 / affinity
                              :beneficiary (s2 / small-molecule :name (n4 / name :op1 "cGMP"))
                              :ARG1-of (a3 / appear-02)
                              :ARG1-of (l4 / low-04
                                    :degree (m5 / more)))
                        :op6 (a4 / activate-01
                              :ARG0 (s3 / small-molecule :name (n5 / name :op1 "cAMP"))
                              :ARG1 c3
                              :ARG1-of (m6 / minimal-02)))))
      :ARG0-of (e2 / exemplify-01))

# ::id bio.chicago_2015.54091 ::date 2015-11-01T09:31:28 ::annotator SDL-AMR-09 ::preferred
# ::snt Upon stimulation of the bombesin receptors,  KUZ increases the docking and activation of  adaptors Src homology 2 domain - containing protein and  Gab1 on the  EGFR, and activation of  Ras and  Erk.
# ::save-date Sat Feb 13, 2016 ::file bio_chicago_2015_54091.txt
(i / increase-01
      :ARG0 (p3 / protein :name (n4 / name :op1 "KUZ"))
      :ARG1 (a / and
            :op1 (d / dock-01
                  :ARG1 (a5 / and
                        :op1 (a3 / adaptor
                              :mod (p4 / protein
                                    :ARG0-of (c / contain-01
                                          :ARG1 (p5 / protein-segment :name (n5 / name :op1 "Src" :op2 "homology" :op3 "2" :op4 "domain")))))
                        :op2 (p6 / protein :name (n6 / name :op1 "GAb1")))
                  :ARG2 (e / enzyme :name (n / name :op1 "EGFR")))
            :op2 (a2 / activate-01
                  :ARG0 e
                  :ARG1 a5)
            :op3 (a4 / activate-01
                  :ARG1 (a6 / and
                        :op1 (e2 / enzyme :name (n2 / name :op1 "Ras"))
                        :op2 (e3 / enzyme :name (n3 / name :op1 "ERK")))))
      :time (s / stimulate-01
            :ARG1 (r / receptor
                  :mod (s2 / small-molecule :name (n7 / name :op1 "bombesin")))))

# ::id bio.chicago_2015.54241 ::date 2015-11-01T10:43:45 ::annotator SDL-AMR-09 ::preferred
# ::snt Tinman is a direct activator of   D-mef2 in  heart precursor cells and this regulation probably requires a  Tinman co-activator protein, since  Tinman expression in the dorsal mesoderm is much broader than   D-mef2, and  ectopic Tinman expression can activate the   D-mef2 cardiac enhancer in some but not all regions of the embryo.
# ::save-date Tue Feb 2, 2016 ::file bio_chicago_2015_54241.txt
(a2 / and
      :op1 (a3 / activate-01
            :ARG0 (p / protein :name (n / name :op1 "Tinman"))
            :ARG1 (p2 / protein :name (n2 / name :op1 "D-mef2"))
            :ARG1-of (d / direct-02)
            :location (c / cell
                  :mod (p3 / precursor)
                  :mod (h / heart)))
      :op2 (r / require-01
            :ARG0 (r2 / regulate-01
                  :mod (t2 / this))
            :ARG1 (p4 / protein
                  :ARG0-of (c2 / coactivate-01
                        :ARG1 p))
            :mod (p5 / probable))
      :ARG1-of (c5 / cause-01
            :ARG0 (a4 / and
                  :op1 (b / broad-02
                        :ARG1 (e / express-03
                              :ARG2 p
                              :ARG3 (m / mesoderm
                                    :mod (d2 / dorsal)))
                        :degree (m2 / more)
                        :compared-to (b2 / broad-02
                              :ARG1 (e2 / express-03
                                    :ARG2 p2)))
                  :op2 (p6 / possible-01
                        :ARG1 (a5 / activate-01
                              :ARG0 (e4 / express-03
                                    :ARG2 p
                                    :mod (e3 / ectopic))
                              :ARG1 (m3 / molecular-physical-entity
                                    :ARG0-of (e5 / enhance-01
                                          :ARG1 p2
                                          :mod (c3 / cardiac)))
                              :location (r3 / region
                                    :quant (s / some)
                                    :location (e6 / embryo))
                              :ARG1-of (c4 / contrast-01
                                    :ARG2 (a6 / activate-01 :polarity -
                                          :ARG0 e4
                                          :ARG1 m3
                                          :location (r4 / region
                                                :mod (a7 / all)
                                                :location e6))))))))

# ::id bio.chicago_2015.54249 ::date 2015-11-01T12:25:08 ::annotator SDL-AMR-09 ::preferred
# ::snt TAK1 activates  p38-MAPK activity through  MAPK kinase 4/SEK1 by a coupled kinase assay ( 16).
# ::save-date Sun Jan 17, 2016 ::file bio_chicago_2015_54249.txt
(a / activate-01
      :ARG0 (e / enzyme :name (n2 / name :op1 "TAK1"))
      :ARG1 (a2 / activity-06
            :ARG0 (e2 / enzyme :name (n / name :op1 "p38-MAPK")))
      :ARG1-of (d / describe-01
            :ARG0 (p3 / publication
                  :ARG1-of (c2 / cite-01
                        :ARG2 16)))
      :ARG1-of (s / say-01
            :ARG0 (a3 / assay-01
                  :ARG1 (k / kinase)
                  :ARG1-of (c / couple-01)))
      :path (p2 / pathway :name (n3 / name :op1 "MAPK" :op2 "kinase" :op3 "4/SEK1")))

# ::id bio.chicago_2015.54262 ::date 2015-11-01T12:30:13 ::annotator SDL-AMR-09 ::preferred
# ::snt While only 4 deficiencies were identified as specifically inducing  ectopic activation of the   ems HRE, 11 were found to severely reduce [  Df(2L)al,   Df(2L)dp-79b,   Df(2L)TW84,   Df(3L)lxd6, and   Df(3R)B81] or abolish [  Df(2L)H20,   Df(2R)H3E1,   Df(2R)Jp1,   Df(2R)AA21,   Df(3L)h-i22, and   Df(3R)e-R1] its activity [  Table 2; shown in   Fig 5E and  Fig F, and   Fig 4C for   Df(2L)dp-79b,   Df(3R)e-F1, and   Df(3R)B81].
# ::save-date Sun Jan 17, 2016 ::file bio_chicago_2015_54262.txt
(c / contrast-01
      :ARG1 (i / identify-01
            :ARG1 (m / molecular-physical-entity :quant 4
                  :ARG1-of (l / lack-01)
                  :mod (o / only))
            :ARG2 (i2 / induce-01
                  :ARG0 m
                  :ARG2 (a / activate-01
                        :ARG1 (d2 / dna-sequence :name (n2 / name :op1 "HRE")
                              :ARG0-of (e2 / encode-01
                                    :ARG1 (p / protein :name (n3 / name :op1 "ems"))))
                        :mod (e / ectopic))
                  :ARG1-of (s5 / specific-02)))
      :ARG2 (f / find-01
            :ARG1 (m2 / molecular-physical-entity :quant 11
                  :ARG1-of (l2 / lack-01))
            :ARG2 (o2 / or
                  :op1 (r / reduce-01
                        :ARG0 (m3 / molecular-physical-entity
                              :ARG1-of (i4 / include-91
                                    :ARG2 m2)
                              :ARG1-of (m4 / mean-01
                                    :ARG2 (a4 / and
                                          :op1 (m5 / molecular-physical-entity :name (n4 / name :op1 "Df(2L)al"))
                                          :op2 (m6 / molecular-physical-entity :name (n5 / name :op1 "Df(2L)dp-79b")
                                                :ARG1-of (s2 / show-01
                                                      :ARG0 (f2 / figure :mod "5E")))
                                          :op3 (m7 / molecular-physical-entity :name (n6 / name :op1 "Df(2L)TW84"))
                                          :op4 (m8 / molecular-physical-entity :name (n7 / name :op1 "Df(3L)lxd6"))
                                          :op5 (m9 / molecular-physical-entity :name (n8 / name :op1 "Df(3R)B81")
                                                :ARG1-of (s4 / show-01
                                                      :ARG0 (f4 / figure :mod "4C"))))))
                        :ARG1 (a3 / activity-06
                              :ARG0 d2)
                        :manner (s / severe))
                  :op2 (a2 / abolish-01
                        :ARG0 (m10 / molecular-physical-entity
                              :ARG1-of (i3 / include-91
                                    :ARG2 m2)
                              :ARG1-of (m11 / mean-01
                                    :ARG2 (a5 / and
                                          :op1 (m12 / molecular-physical-entity :name (n9 / name :op1 "Df(2L)H20"))
                                          :op2 (m13 / molecular-physical-entity :name (n10 / name :op1 "Df(2R)H3E1"))
                                          :op3 (m14 / molecular-physical-entity :name (n11 / name :op1 "Df(2R)Jp1"))
                                          :op4 (m15 / molecular-physical-entity :name (n12 / name :op1 "Df(2R)AA21"))
                                          :op5 (m16 / molecular-physical-entity :name (n13 / name :op1 "Df(3L)h-i22"))
                                          :op6 (m17 / molecular-physical-entity :name (n14 / name :op1 "Df(3R)e-R1")
                                                :ARG1-of (s3 / show-01
                                                      :ARG0 (f3 / figure :mod "5F"))))))
                        :ARG1 a3)))
      :ARG1-of (d / describe-01
            :ARG0 (t / table :mod 1)))

# ::id bio.chicago_2015.54288 ::date 2015-11-01T13:02:46 ::annotator SDL-AMR-09 ::preferred
# ::snt Initially,  ubiquitin is activated by the  ATP-dependent formation of a high-energy thioester intermediate between the  ubiquitin-activating enzyme (E1) and the C terminus of  ubiquitin.
# ::save-date Sat Feb 13, 2016 ::file bio_chicago_2015_54288.txt
(a / activate-01
      :ARG0 (f / form-02
            :ARG0 (a2 / and
                  :op1 (e2 / enzyme :name (n5 / name :op1 "ubiquitin-activating" :op2 "enzyme"))
                  :op2 (p3 / protein-segment :name (n6 / name :op1 "C" :op2 "terminus")
                        :part-of p2))
            :ARG1 (i / intermediate
                  :mod (s2 / small-molecule :name (n4 / name :op1 "thioester")
                        :mod (e / energy
                              :ARG1-of (h / high-02))))
            :ARG0-of (d / depend-01
                  :ARG1 (s / small-molecule :name (n3 / name :op1 "ATP"))))
      :ARG1 (p2 / protein :name (n2 / name :op1 "ubiquitin"))
      :time (i2 / initial))

# ::id bio.chicago_2015.54303 ::date 2015-11-01T13:10:11 ::annotator SDL-AMR-09 ::preferred
# ::snt To determine wether activation of  JNK by  SLK occurs through a known  MEKK, transfections were performed in the presence of dominant negative versions of  MEKK or  SEK1, both upstream activators of  JNK ( 13).
# ::save-date Fri Feb 5, 2016 ::file bio_chicago_2015_54303.txt
(p / perform-01
      :ARG1 (t2 / transfect-01)
      :condition (p2 / present-02
                  :ARG1 (o / or
                        :op1 (v / version
                              :ARG0-of (d / dominate-01)
                              :mod (e / enzyme :name (n2 / name :op1 "MEKK"))
                              :ARG2-of (m / mutate-01 :mod "-/-"))
                        :op2 (v2 / version
                              :ARG0-of d
                              :mod (e2 / enzyme :name (n3 / name :op1 "SEK1"))
                              :ARG2-of m)
                        :ARG0-of (a2 / activate-01
                              :ARG1 (e3 / enzyme :name (n4 / name :op1 "JNK"))
                              :direction (u / upstream))))
      :purpose (d2 / determine-01
            :ARG1 (a3 / activate-01 :mode interrogative
                  :ARG0 (e4 / enzyme :name (n5 / name :op1 "SLK"))
                  :ARG1 e3
                  :manner (e5 / enzyme :name (n6 / name :op1 "MEKK")
                        :ARG1-of (k / know-01)))))

# ::id bio.chicago_2015.54322 ::date 2015-11-01T13:18:24 ::annotator SDL-AMR-09 ::preferred
# ::snt In PC12 cells,  NGF activates  CREB phosphorylation through sequential activation of  Ras,  Raf,  MEK,  ERK, and  RSK ( Xing et al. 1996  ).
# ::save-date Sun Jan 17, 2016 ::file bio_chicago_2015_54322.txt
(a / activate-01
      :ARG0 (p6 / protein :name (n5 / name :op1 "NGF"))
      :ARG1 (p / phosphorylate-01
            :ARG1 (p7 / protein :name (n6 / name :op1 "CREB")))
      :manner (a2 / activate-01
            :ARG1 (a3 / and
                  :op1 (e / enzyme :name (n / name :op1 "Ras"))
                  :op2 (e2 / enzyme :name (n2 / name :op1 "Raf"))
                  :op3 (e3 / enzyme :name (n3 / name :op1 "MEK"))
                  :op4 (e4 / enzyme :name (n4 / name :op1 "ERK"))
                  :op5 (e5 / enzyme :name (n9 / name :op1 "RSK")))
            :mod (s / sequential))
      :location (c / cell-line :name (n7 / name :op1 "PC12"))
      :ARG1-of (d2 / describe-01
            :ARG0 (p8 / publication-91
                  :ARG0 (a4 / and
                        :op1 (p9 / person :name (n8 / name :op1 "Xing"))
                        :op2 (p10 / person
                              :mod (o / other)))
                  :time (d / date-entity :year 1996))))

# ::id bio.chicago_2015.54328 ::date 2015-11-01T13:23:05 ::annotator SDL-AMR-09 ::preferred
# ::snt GTP-dependent adenylyl cyclase activity in control (  cn,  ry) flies and  flies expressing the activated  Gsalpha subunit
# ::save-date Sat Jan 30, 2016 ::file bio_chicago_2015_54328.txt
(a / and
      :op1 (a2 / activity-06
            :ARG0 (e / enzyme :name (n / name :op1 "adenylyl" :op2 "cyclase")
                  :ARG0-of (d / depend-01
                        :ARG1 (s / small-molecule :name (n2 / name :op1 "GTP"))))
            :location (a4 / and
                  :op1 (f / fly
                        :mod (c / control)
                        :mod (o / organism :name (n4 / name :op1 "cn")))
                  :op2 (f3 / fly
                        :mod c
                        :mod (o2 / organism :name (n5 / name :op1 "ry")))))
      :op2 (e2 / express-03
            :ARG2 (s2 / subunit
                  :part-of (p / protein :name (n3 / name :op1 "Gsalpha"))
                  :ARG1-of (a3 / activate-01))
            :ARG3 (f2 / fly)))

# ::id bio.chicago_2015.54349 ::date 2015-11-01T13:30:45 ::annotator SDL-AMR-09 ::preferred
# ::snt (c) That  Ephexin can  also activate  Cdc42 raises the possibility that  it may function to control cytoskeletal dynamics  downstream from attractant receptors through  Pak activation
# ::save-date Fri Nov 27, 2015 ::file bio_chicago_2015_54349.txt
(p2 / possible-01 :li "c"
      :ARG1 (a / activate-01
            :ARG0 (p / protein :name (n / name :op1 "Ephexin"))
            :ARG1 (p3 / protein :name (n2 / name :op1 "Cdc42"))
            :mod (a2 / also))
      :ARG0-of (c / cause-01
            :ARG1 (r / raise-01
                  :ARG1 (p4 / possible-01
                        :ARG1 (p5 / possible-01
                              :ARG1 (f / function-01
                                    :ARG0 a
                                    :ARG1 (c2 / control-01
                                          :ARG0 a
                                          :ARG1 (d2 / dynamic
                                                :mod (c3 / cytoskeletal))
                                          :direction (d3 / downstream
                                                :op1 (r2 / receptor
                                                      :ARG0-of (a3 / attract-01
                                                            :manner (a4 / activate-01
                                                                  :ARG1 (e / enzyme :name (n3 / name :op1 "Pak")))))))))))))

# ::id bio.chicago_2015.54352 ::date 2015-10-30T08:44:59 ::annotator SDL-AMR-09 ::preferred
# ::snt Since the expression of either active  Rit or  RGL3 is sufficient to induce  Ral GDP/ GTP exchange, the amount of individual  expression vectors was adjusted to limit endogenous  Ral activation by either  RitQ79L or  RGL3 expression alone.
# ::save-date Mon Nov 9, 2015 ::file bio_chicago_2015_54352.txt
(a / adjust-01
      :ARG1 (a2 / amount
            :quant-of (v / vector
                  :ARG3-of (e / express-03)
                  :mod (i / individual)))
      :ARG4 (l / limit-01
            :ARG0 (o / or
                  :op1 (e4 / express-03
                        :ARG2 (p3 / protein :name (n3 / name :op1 "RitQ79L")))
                  :op2 (e5 / express-03
                        :ARG2 (p2 / protein :name (n4 / name :op1 "RGL3")))
                  :mod (a4 / alone))
            :ARG1 (a3 / activate-01
                  :ARG1 (p / protein :name (n2 / name :op1 "Ral")
                        :mod (e2 / endogenous))))
      :ARG1-of (c / cause-01
            :ARG0 (s2 / suffice-01
                  :ARG0 (e3 / express-03
                        :ARG2 (o2 / or
                              :op1 (p4 / protein :name (n5 / name :op1 "Rit"))
                              :op2 p2
                              :ARG1-of (a5 / activate-01)))
                  :ARG1 (i2 / induce-01
                        :ARG0 e3
                        :ARG2 (e7 / exchange-01
                              :ARG0 p
                              :ARG1 (s4 / small-molecule :name (n6 / name :op1 "GDP"))
                              :ARG3 (s / small-molecule :name (n / name :op1 "GTP")))))))

# ::id bio.chicago_2015.54392 ::date 2015-10-30T09:00:06 ::annotator SDL-AMR-09 ::preferred
# ::snt However, activation of  Rap1 by both  thrombin and  TCR stimulation in platelets and  T cells, respectively, displayed similar calcium dependences.
# ::save-date Sun Jan 17, 2016 ::file bio_chicago_2015_54392.txt
(h / have-concession-91
      :ARG1 (d / display-01
            :ARG0 (a / and
                  :op1 (a2 / activate-01
                        :ARG0 (s2 / stimulate-01
                              :ARG1 (e2 / enzyme :name (n3 / name :op1 "thrombin")))
                        :ARG1 (e / enzyme :name (n2 / name :op1 "Rap1"))
                        :location (c / cell
                              :part-of (p / platelet)))
                  :op2 (a3 / activate-01
                        :ARG0 (s3 / stimulate-01
                              :ARG1 (p2 / protein :name (n4 / name :op1 "TCR")))
                        :ARG1 e
                        :location (c2 / cell :name (n5 / name :op1 "T")))
                  :mod (r / respective))
            :ARG1 (d2 / depend-01
                  :ARG0 a
                  :ARG1 (s / small-molecule :name (n / name :op1 "calcium"))
                  :ARG1-of (r2 / resemble-01))))

# ::id bio.chicago_2015.54403 ::date 2015-10-30T09:07:00 ::annotator SDL-AMR-09 ::preferred
# ::snt We demonstrate that inhibition of  dMLK using gene silencing with  RNAi specifically blocked  JNK activation without inhibiting activation of  p38 or  ERK by ceramide   (Figure 1E).
# ::save-date Sat Jan 16, 2016 ::file bio_chicago_2015_54403.txt
(d / demonstrate-01
      :ARG0 (w / we)
      :ARG1 (b / block-01
            :ARG0 (i / inhibit-01
                  :ARG0 (u / use-01
                        :ARG1 (s / silence-01
                              :ARG0 (i2 / interfere-01
                                    :ARG0 (n / nucleic-acid :name (n7 / name :op1 "RNA")))
                              :ARG1 (g / gene)))
                  :ARG1 (e / enzyme :name (n2 / name :op1 "dMLK")))
            :ARG1 (a / activate-01
                  :ARG1 (e2 / enzyme :name (n3 / name :op1 "JNK")))
            :ARG1-of (s2 / specific-02)
            :manner (i3 / inhibit-01 :polarity -
                  :ARG0 i
                  :ARG1 (o / or
                        :op1 (a2 / activate-01
                              :ARG0 (s3 / small-molecule :name (n6 / name :op1 "ceramide"))
                              :ARG1 (e3 / enzyme :name (n4 / name :op1 "p38")))
                        :op2 (a3 / activate-01
                              :ARG0 s3
                              :ARG1 (e4 / enzyme :name (n5 / name :op1 "ERK"))))))
      :ARG1-of (d2 / describe-01
            :ARG0 (f / figure :mod "1E")))

# ::id bio.chicago_2015.54425 ::date 2015-10-30T09:16:10 ::annotator SDL-AMR-09 ::preferred
# ::snt Activation of intracellular  CaM-KII by  GD3,  GD1b,  GT1b and its oligosaccharide.
# ::save-date Sat Feb 13, 2016 ::file bio_chicago_2015_54425.txt
(a / activate-01
      :ARG0 (a2 / and
            :op1 (s / small-molecule :name (n2 / name :op1 "GD3"))
            :op2 (s2 / small-molecule :name (n3 / name :op1 "GD1b"))
            :op3 (s3 / small-molecule :name (n4 / name :op1 "GT1b"))
            :op4 (o / oligosaccharide
                  :poss s3))
      :ARG1 (e / enzyme :name (n / name :op1 "CaM-KII")
            :mod (i / intracellular)))

# ::id bio.chicago_2015.54432 ::date 2015-10-30T09:21:50 ::annotator SDL-AMR-09 ::preferred
# ::snt All three  RTKs are known to activate an overlapping set of intracellular  signaling proteins, such as  Ras,  MAP kinase,  PLC-gamma, and  Src family kinases.
# ::save-date Mon Nov 9, 2015 ::file bio_chicago_2015_54432.txt
(k / know-01
      :ARG1 (a / activate-01
            :ARG0 (e / enzyme :quant 3 :name (n2 / name :op1 "RTK")
                  :mod (a2 / all))
            :ARG1 (s / set
                  :ARG0-of (o / overlap-01)
                  :consist-of (p2 / protein
                        :mod (i / intracellular)
                        :ARG0-of (s2 / signal-07)
                        :example (a3 / and
                              :op1 (p / protein-family :name (n / name :op1 "Ras"))
                              :op2 (p3 / protein-family :name (n3 / name :op1 "MAP" :op2 "kinase"))
                              :op3 (p4 / protein-family :name (n4 / name :op1 "PLC-gamma"))
                              :op4 (p5 / protein-family :name (n5 / name :op1 "Src")))))))

# ::id bio.chicago_2015.54450 ::date 2015-10-30T09:27:09 ::annotator SDL-AMR-09 ::preferred
# ::snt Because most extracellular stimuli that activate  MKK7 also activate  MKK4 in parallel, it is difficult to assess the function of  MKK7 independently from  MKK4.
# ::save-date Mon Nov 2, 2015 ::file bio_chicago_2015_54450.txt
(d / difficult
      :domain (a / assess-01
            :ARG1 (f / function-01
                  :ARG0 (e / enzyme :name (n / name :op1 "MKK7"))
                  :manner (d2 / depend-01 :polarity -
                        :ARG0 f
                        :ARG1 (e2 / enzyme :name (n2 / name :op1 "MKK4")))))
      :ARG1-of (c / cause-01
            :ARG0 (a2 / activate-01
                  :ARG0 (s / stimulus
                        :quant (m / most)
                        :mod (e3 / extracellular)
                        :ARG0-of (a3 / activate-01
                              :ARG1 e))
                  :ARG1 e2
                  :mod (a4 / also)
                  :manner (p / parallel))))

# ::id bio.chicago_2015.54455 ::date 2015-10-30T09:32:05 ::annotator SDL-AMR-09 ::preferred
# ::snt induction of  cyclin D1 is required for  S-phase entry in  Rb-expressing cells.
# ::save-date Sun Jan 17, 2016 ::file bio_chicago_2015_54455.txt
(r / require-01
      :ARG0 (e / enter-01
            :ARG0 (c / cell
                  :ARG3-of (e2 / express-03
                        :ARG2 (p3 / protein :name (n2 / name :op1 "Rb"))))
            :ARG1 (e3 / event :name (n3 / name :op1 "S-phase")))
      :ARG1 (i / induce-01
            :ARG2 (p / protein :name (n / name :op1 "cyclin" :op2 "D1"))))

# ::id bio.chicago_2015.54458 ::date 2015-10-30T09:35:21 ::annotator SDL-AMR-09 ::preferred
# ::snt Phosphoinositides, particularly  PIP2, formed secondarily to  ARF activation of  phospholipase D, have been implicated in the recruitment of  COPI coat proteins onto the membranes of the Golgi stacks ( Donaldson et al. 1992   ;   Palmer et al. 1993   ;   Ktistakis et al. 1996   ).
# ::save-date Sun Jan 17, 2016 ::file bio_chicago_2015_54458.txt
(i / implicate-01
      :ARG1 (a / and
            :op1 (s / small-molecule :name (n / name :op1 "phosphoinositide"))
            :op2 (s2 / small-molecule :name (n2 / name :op1 "PIP2")
                  :manner (p / particular))
            :ARG1-of (f / form-01
                  :ARG2 (a2 / activate-01
                        :ARG0 (p2 / protein :name (n3 / name :op1 "ARF"))
                        :ARG1 (e / enzyme :name (n4 / name :op1 "phospholipase" :op2 "D")))
                  :manner (s3 / secondary)))
      :ARG2 (r / recruit-01
            :ARG1 (p10 / protein :name (n5 / name :op1 "COPI" :op2 "coat" :op3 "protein"))
            :ARG2 (m2 / membrane
                  :part-of (s4 / stack
                        :mod (t / thing :name (n9 / name :op1 "Golgi")))))
      :ARG1-of (d4 / describe-01
            :ARG0 (a3 / and
                  :op1 (p3 / publication-91
                        :ARG0 (a4 / and
                              :op1 (p4 / person :name (n6 / name :op1 "Donaldson"))
                              :op2 (p5 / person
                                    :mod (o / other)))
                        :time (d / date-entity :year 1992))
                  :op2 (p6 / publication-91
                        :ARG0 (a5 / and
                              :op1 (p7 / person :name (n7 / name :op1 "Palmer"))
                              :op2 p5)
                        :time (d2 / date-entity :year 1993))
                  :op3 (p8 / publication-91
                        :ARG0 (a6 / and
                              :op1 (p9 / person :name (n8 / name :op1 "Ktistakis"))
                              :op2 p5)
                        :time (d3 / date-entity :year 1996)))))

# ::id bio.chicago_2015.54513 ::date 2015-10-30T09:44:08 ::annotator SDL-AMR-09 ::preferred
# ::snt For example, in most  pheochromocytoma 12 (PC12) cell lines, transient  Erk activation [evoked by  epidermal growth factor (EGF)] results in cell proliferation, whereas sustained  Erk activation (evoked by  NGF) causes these cells to leave the cell cycle and differentiate toward a neuronal phenotype (Traverse et al., 1992  ;  Yaka et al., 1998  ;  York et al., 1998  ).
# ::save-date Sun Jan 17, 2016 ::file bio_chicago_2015_54513.txt
(c / contrast-01
      :ARG1 (r / result-01
            :ARG1 (a / activate-01
                  :ARG1 (e / enzyme :name (n / name :op1 "Erk"))
                  :ARG1-of (t / transient-02)
                  :ARG1-of (e3 / evoke-01
                        :ARG0 (p10 / protein :name (n3 / name :op1 "epidermal" :op2 "growth" :op3 "factor"))))
            :ARG2 (p2 / proliferate-01
                  :ARG0 c7))
      :ARG2 (c3 / cause-01
            :ARG0 (a2 / activate-01
                  :ARG1 e
                  :ARG1-of (s2 / sustain-01)
                  :ARG1-of (e4 / evoke-01
                        :ARG0 (p11 / protein :name (n4 / name :op1 "NGF"))))
            :ARG1 (a3 / and
                  :op1 (l / leave-11
                        :ARG0 c7
                        :ARG1 (c2 / cycle-02
                              :ARG1 (c6 / cell)))
                  :op2 (d3 / differentiate-101
                        :ARG1 c7
                        :ARG3 (p / phenotype
                              :mod (n5 / neuron)))))
      :ARG0-of (e5 / exemplify-01)
      :location (c7 / cell-line :name (n6 / name :op1 "pheochromocytoma" :op2 "12")
            :quant (m / most))
      :ARG1-of (d4 / describe-01
            :ARG0 (a4 / and
                  :op1 (p3 / publication-91
                        :ARG0 (a5 / and
                              :op1 (p4 / person :name (n7 / name :op1 "Traverse"))
                              :op2 (p5 / person
                                    :mod (o / other)))
                        :time (d / date-entity :year 1992))
                  :op2 (p6 / publication-91
                        :ARG0 (a6 / and
                              :op1 (p7 / person :name (n8 / name :op1 "Yaka"))
                              :op2 p5)
                        :time (d2 / date-entity :year 1998))
                  :op3 (p8 / publication-91
                        :ARG0 (a7 / and
                              :op1 (p9 / person :name (n9 / name :op1 "York"))
                              :op2 p5)
                        :time d2))))

# ::id bio.chicago_2015.54546 ::date 2015-10-30T09:56:15 ::annotator SDL-AMR-09 ::preferred
# ::snt Exchange of T145, Q156, K157, Q166, T167, K171, or H175 for  alanine enhanced transactivation by  Raf basal activity 1.5- to 2.5-fold and increased  Ras(G12V)-induced  Raf activation accordingly, to 1.5- to 2-fold over the activity achieved by activation of  Raf(wt) by  Ras(G12V) (Fig.  2A).
# ::save-date Mon Nov 9, 2015 ::file bio_chicago_2015_54546.txt
(a / and
      :op1 (e / enhance-01
            :ARG0 (e2 / exchange-01
                  :ARG1 (o / or
                        :op1 (a2 / amino-acid :mod 145 :name (n / name :op1 "threonine"))
                        :op2 (a3 / amino-acid :mod 156 :name (n2 / name :op1 "glutamine"))
                        :op3 (a4 / amino-acid :mod 157 :name (n3 / name :op1 "lysine"))
                        :op4 (a5 / amino-acid :mod 166 :name (n4 / name :op1 "threonine"))
                        :op5 (a6 / amino-acid :mod 167 :name (n5 / name :op1 "glutamine"))
                        :op7 (a7 / amino-acid :mod 171 :name (n6 / name :op1 "lysine"))
                        :op8 (a8 / amino-acid :mod 175 :name (n7 / name :op1 "histidine")))
                  :ARG3 (a9 / amino-acid :name (n8 / name :op1 "alanine")))
            :ARG1 (t / transactivate-01
                  :ARG2 (a10 / activity-06
                        :ARG0 (e3 / enzyme :name (n9 / name :op1 "Raf")
                              :mod (w / wild-type))
                        :mod (b / basal)))
            :ARG3 (v / value-interval
                  :op1 (p / product-of :op1 1.5)
                  :op2 (p2 / product-of :op1 2.5)))
      :op2 (i / increase-01
            :ARG0 e2
            :ARG1 (a11 / activate-01
                  :ARG1 e3
                  :ARG2-of (i2 / induce-01
                        :ARG0 (e4 / enzyme :name (n10 / name :op1 "Ras")
                              :ARG2-of (m / mutate-01 :value "G12V"))))
            :ARG2 v
            :ARG4 (m2 / more-than
                  :op1 (a13 / activity-06
                        :ARG1-of (a14 / achieve-01
                              :ARG0 (a15 / activate-01
                                    :ARG0 e4
                                    :ARG1 e3))))
            :manner (a12 / accordingly))
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod "2A")))

# ::id bio.chicago_2015.54584 ::date 2015-10-30T10:21:30 ::annotator SDL-AMR-09 ::preferred
# ::snt Previous studies have shown that  rRNA transcription is up-regulated in both mammalian ( 1,  51) and   Drosophila ( 54,  64) cells by the  phorbol ester tetradecanoyl  phorbol acetate ( TPA), a potent activator of  protein kinase C (PKC).
# ::save-date Sun Jan 17, 2016 ::file bio_chicago_2015_54584.txt
(s / show-01
      :ARG0 (s2 / study-01
            :time (p / previous))
      :ARG1 (u / upregulate-01
            :ARG1 (t2 / transcribe-01
                  :ARG1 (n5 / nucleic-acid :name (n / name :op1 "rRNA")))
            :ARG2 (e / ester :name (n2 / name :op1 "tetradecanoyl" :op2 "phorbol" :op3 "acetate")
                  :mod (s3 / small-molecule :name (n3 / name :op1 "phorbol"))
                  :ARG0-of (a5 / activate-01
                        :ARG1 (e2 / enzyme :name (n4 / name :op1 "protein" :op2 "kinase" :op3 "C"))
                        :mod (p6 / potent)))
            :location (a2 / and
                  :op1 (c / cell
                        :mod (m / mammal)
                        :ARG1-of (d2 / describe-01
                              :ARG0 (a3 / and
                                    :op1 (p2 / publication
                                          :ARG1-of (c3 / cite-01
                                                :ARG2 1))
                                    :op2 (p3 / publication
                                          :ARG1-of (c4 / cite-01
                                                :ARG2 51)))))
                  :op2 (c2 / cell
                        :ARG1-of (d3 / describe-01
                              :ARG0 (a4 / and
                                    :op1 (p4 / publication
                                          :ARG1-of (c5 / cite-01
                                                :ARG2 54))
                                    :op2 (p5 / publication
                                          :ARG1-of (c6 / cite-01
                                                :ARG2 64))))
                        :mod (o / organism :name (n6 / name :op1 "Drosophila"))))))

# ::id bio.chicago_2015.54586 ::date 2015-10-31T09:37:26 ::annotator SDL-AMR-09 ::preferred
# ::snt S6k1 is one of the major cellular targets for the immunosuppressant rapamycin and it was recognised several years ago that  IL-2 activation of  p70S6k was blocked by rapamycin [  28].
# ::save-date Mon Nov 2, 2015 ::file bio_chicago_2015_54586.txt
(a / and
      :op1 (t3 / thing :quant 1
            :ARG1-of (t2 / target-01
                  :ARG0 (s2 / small-molecule :name (n4 / name :op1 "rapamycin")
                        :ARG0-of (s3 / suppress-01
                              :ARG1 (i / immunity)))
                  :mod (c / cell))
            :domain (e / enzyme :name (n3 / name :op1 "S6k1"))
            :ARG1-of (m / major-02))
      :op2 (r / recognize-02
            :ARG1 (b3 / block-01
                  :ARG0 s2
                  :ARG1 (a2 / activate-01
                        :ARG0 (p / protein :name (n5 / name :op1 "IL-2"))
                        :ARG1 (p2 / protein :name (n6 / name :op1 "p70S6k"))))
            :time (b / before
                  :op1 (n / now)
                  :quant (s / several
                        :op1 (t / temporal-quantity :quant 1
                              :unit (y / year)))))
      :ARG1-of (d / describe-01
            :ARG0 (p3 / publication
                  :ARG1-of (c2 / cite-01
                        :ARG2 28))))

# ::id bio.chicago_2015.54598 ::date 2015-10-31T09:50:46 ::annotator SDL-AMR-09 ::preferred
# ::snt We initially utilized the dsRNAi-mediated gene silencing method  (Clemens et al., 2000  ) to identify an agonist that induces  JNK activation through  dMLK.
# ::save-date Mon Nov 9, 2015 ::file bio_chicago_2015_54598.txt
(u / utilize-01
      :ARG0 (w / we)
      :ARG1 (m / method
            :ARG0-of (s / silence-01
                  :ARG1 (g / gene))
            :ARG1-of (m2 / mediate-01
                  :ARG0 (i2 / interfere-01
                        :ARG0 (n5 / nucleic-acid :name (n / name :op1 "dsRNA"))))
            :ARG1-of (d2 / describe-01
                  :ARG0 (p / publication-91
                        :ARG0 (a / and
                              :op1 (p2 / person :name (n2 / name :op1 "Clemens"))
                              :op2 (p3 / person
                                    :mod (o / other))
                              :time (d / date-entity :year 2000)))))
      :time (i / initial)
      :purpose (i3 / identify-01
            :ARG0 w
            :ARG1 (a2 / agonist
                  :ARG0-of (i4 / induce-01
                        :ARG2 (a3 / activate-01
                              :ARG0 (e2 / enzyme :name (n4 / name :op1 "dMLK"))
                              :ARG1 (e / enzyme :name (n3 / name :op1 "JNK")))))))

# ::id bio.chicago_2015.54639 ::date 2015-10-31T09:56:07 ::annotator SDL-AMR-09 ::preferred
# ::snt This finding was unexpected, since in vitro  aMKII, when compared to  CaMKIV, is a more potent activator of  CREB  Ser133 phosphorylation.
# ::save-date Mon Nov 9, 2015 ::file bio_chicago_2015_54639.txt
(e / expect-01 :polarity -
      :ARG1 (t2 / thing
            :mod (t3 / this)
            :ARG1-of (f / find-01))
      :ARG1-of (c / cause-01
            :ARG0 (e3 / enzyme :name (n / name :op1 "CaMKII")
                  :ARG0-of (a2 / activate-01
                        :ARG1 (p3 / phosphorylate-01
                              :ARG1 (a3 / amino-acid :mod 133 :name (n2 / name :op1 "serine")
                                    :part-of (p / protein :name (n3 / name :op1 "CREB"))))
                        :mod (p2 / potent
                              :degree (m2 / more)
                              :compared-to (e4 / enzyme :name (n4 / name :op1 "CaMKIV")))
                        :manner (i / in-vitro)))))

# ::id bio.chicago_2015.54645 ::date 2015-10-31T10:03:06 ::annotator SDL-AMR-09 ::preferred
# ::snt Whereas  MKK4 also activates  p38 MAPK, experiments with ectopically expressed or recombinant  MKK7 revealed that it activates  JNK but not  ERK or  p38 MAPKs  in vivo and  in vitro ( 3-6).
# ::save-date Mon Jan 4, 2016 ::file bio_chicago_2015_54645.txt
(c2 / contrast-01
      :ARG1 (r / reveal-01
            :ARG0 (e / experiment-01
                  :ARG2 (o / or
                        :op1 (e2 / enzyme :name (n3 / name :op1 "MKK7")
                              :ARG2-of (e3 / express-03
                                    :manner (e4 / ectopic)))
                        :op2 (e5 / enzyme :name (n4 / name :op1 "MKK7")
                              :ARG1-of (r2 / recombine-01))))
            :ARG1 (c / contrast-01
                  :ARG1 (a / activate-01
                        :ARG0 o
                        :ARG1 (e6 / enzyme :name (n5 / name :op1 "JNK")))
                  :ARG2 (a2 / activate-01 :polarity -
                        :ARG0 o
                        :ARG1 (o2 / or
                              :op1 (p3 / protein-family :name (n6 / name :op1 "ERK"))
                              :op2 (p2 / protein-family :name (n7 / name :op1 "p38" :op2 "MAPK"))))
                  :manner (a3 / and
                        :op1 (i / in-vivo)
                        :op2 (i2 / in-vitro))))
      :ARG2 (a4 / activate-01
            :ARG0 (e9 / enzyme :name (n8 / name :op1 "MKK4"))
            :ARG1 p2
            :mod (a5 / also))
      :ARG1-of (d / describe-01
            :ARG0 (p / publication
                  :ARG1-of (c3 / cite-01
                        :ARG2 (v / value-interval :op1 3 :op2 6)))))

# ::id bio.chicago_2015.54654 ::date 2015-10-31T10:09:50 ::annotator SDL-AMR-09 ::preferred
# ::snt Phototransduction in   Drosophila is mediated by a phosphoinositide (PI) cascade, whereby absorption of light by  rhodopsin activates sequentially a heterotrimeric  Gq protein and  phospholipase C (PLC) (reviewed by    Hardie and Minke 1995  ; Minke and Selinger 1996  ; Scott and Zuker 1998a  ).
# ::save-date Tue Jan 19, 2016 ::file bio_chicago_2015_54654.txt
(c / contrast-01
      :ARG1 (m / mediate-01
            :ARG0 (c2 / cascade
                  :mod (s / small-molecule :name (n / name :op1 "phosphoinositide")))
            :ARG1 (t / transduce-01
                  :ARG1 l)
            :location (o / organism :name (n10 / name :op1 "Drosophila")))
      :ARG2 (a / activate-01
            :ARG0 (a2 / absorb-01
                  :ARG0 (p2 / protein :name (n2 / name :op1 "rhodopsin"))
                  :ARG1 (l / light))
            :ARG1 (a3 / and
                  :op1 (p / protein :name (n3 / name :op1 "Gq")
                        :mod (h / heterotrimeric))
                  :op2 (e / enzyme :name (n4 / name :op1 "phospholipase" :op2 "C")))
            :manner (s2 / sequence))
      :ARG1-of (d5 / describe-01
            :ARG0 (a4 / and
                  :op1 (p3 / publication-91
                        :ARG1-of (r / review-01
                              :ARG0 (a5 / and
                                    :op1 (p4 / person :name (n5 / name :op1 "Hardie"))
                                    :op2 (p5 / person :name (n6 / name :op1 "Minke"))))
                        :time (d / date-entity :year 1995))
                  :op2 (p6 / publication-91
                        :ARG0 (a6 / and
                              :op1 p5
                              :op2 (p7 / person :name (n7 / name :op1 "Selinger")))
                        :time (d2 / date-entity :year 1996))
                  :op3 (p8 / publication-91
                        :ARG0 (a7 / and
                              :op1 (p9 / person :name (n8 / name :op1 "Scott"))
                              :op2 (p10 / person :name (n9 / name :op1 "Zuker")))
                        :time (d3 / date-entity :year 1998)))))

# ::id bio.chicago_2015.54672 ::date 2015-10-31T10:18:04 ::annotator SDL-AMR-09 ::preferred
# ::snt KSR inhibits  ERK MAP kinase activation by activated forms of  Ras,  Raf, and  MEK.
# ::save-date Sat Oct 31, 2015 ::file bio_chicago_2015_54672.txt
(i / inhibit-01
      :ARG0 (e / enzyme :name (n5 / name :op1 "KSR"))
      :ARG1 (a / activate-01
            :ARG0 (a2 / and
                  :op1 (e2 / enzyme :name (n7 / name :op1 "Ras"))
                  :op2 (e3 / enzyme :name (n8 / name :op1 "Raf"))
                  :op3 (e4 / enzyme :name (n9 / name :op1 "MEK"))
                  :ARG1-of (a3 / activate-01))
            :ARG1 (k / kinase :name (n6 / name :op1 "ERK" :op2 "MAP"))))

# ::id bio.chicago_2015.54723 ::date 2015-10-31T10:20:18 ::annotator SDL-AMR-09 ::preferred
# ::snt From in vitro experiments using cultured cells and biochemical assays,  Dbl is known to activate mainly  Rho and  Cdc42.
# ::save-date Mon Nov 9, 2015 ::file bio_chicago_2015_54723.txt
(k / know-01
      :ARG1 (a / activate-01
            :ARG0 (p / protein :name (n / name :op1 "Dbl"))
            :ARG1 (a2 / and
                  :op1 (p2 / protein :name (n2 / name :op1 "Rho"))
                  :op2 (p3 / protein :name (n3 / name :op1 "Cdc42")))
            :manner (m / main))
      :ARG1-of (c / cause-01
            :ARG0 (e2 / experiment-01
                  :manner (i / in-vitro)
                  :ARG0-of (u / use-01
                        :ARG1 (a3 / and
                              :op1 (c2 / cell
                                    :ARG1-of (c3 / culture-01))
                              :op2 (a4 / assay-01
                                    :mod (b / biochemistry)))))))

# ::id bio.chicago_2015.54732 ::date 2015-10-31T10:25:08 ::annotator SDL-AMR-09 ::preferred
# ::snt At concentrations substantially greater than those required to modulate the  GABA-evoked response, 5 3  (300  nM-10  M) directly (i.e. in the absence of  GABA) activated all the recombinant  GABAA receptors investigated.
# ::save-date Wed Jan 13, 2016 ::file bio_chicago_2015_54732.txt
(a / activate-01
      :ARG0 (a4 / amr-unintelligible :value 53)
      :ARG1 (p / protein :name (n / name :op1 "GABAA" :op2 "receptor")
            :ARG0-of (r / recombine-01)
            :mod (a2 / all)
            :ARG1-of (i / investigate-01))
      :ARG1-of (d / direct-02
            :ARG1-of (m2 / mean-01
                  :ARG2 (a3 / absent-01
                        :ARG1 (s2 / small-molecule :name (n2 / name :op1 "GABA")))))
      :condition (c / concentrate-02
            :ARG1 a4
            :mod (g / great
                  :degree (m / more)
                  :manner (s / substantial)
                  :compared-to (c2 / concentrate-01
                        :ARG1-of (r2 / require-01
                              :ARG0 (m3 / modulate-01
                                    :ARG1 (r3 / respond-01
                                          :ARG1-of (e / evoke-01
                                                :ARG0 s2))))))
            :ARG1-of (m4 / mean-01
                  :ARG2 (v / value-interval
                        :op1 (c4 / concentration-quantity :quant 300
                              :unit (n3 / nanomolar))
                        :op2 (c5 / concentration-quantity :quant 10
                              :unit (m5 / molar))))))

# ::id bio.chicago_2015.54762 ::date 2015-10-31T10:35:16 ::annotator SDL-AMR-09 ::preferred
# ::snt However,  TNF ,  IL-1, and  LPS are potent activators of the  IKK and  JNK pathways, which lead to stimulation of  NF- B and  AP-1 activities.
# ::save-date Tue Jan 12, 2016 ::file bio_chicago_2015_54762.txt
(h / have-concession-91
      :ARG1 (a2 / and
            :op1 (p / protein :wiki "Tumor_necrosis_factors"
                  :name (n / name :op1 "TNF"))
            :op2 (p2 / protein :wiki "Interleukin_1_family"
                  :name (n2 / name :op1 "IL-1"))
            :op3 (m / molecular-physical-entity :wiki "Lipopolysaccharide"
                  :name (n3 / name :op1 "LPS"))
            :ARG0-of (a3 / activate-01
                  :ARG1 (a4 / and
                        :op1 (p4 / pathway :wiki -
                              :name (n4 / name :op1 "IKK"))
                        :op2 (p5 / pathway :wiki -
                              :name (n5 / name :op1 "JNK"))
                        :ARG0-of (l / lead-03
                              :ARG2 (s / stimulate-01
                                    :ARG1 (a / and
                                          :op1 (a5 / activity-06
                                                :ARG0 (p7 / protein :wiki "NF-κB"
                                                      :name (n6 / name :op1 "NF-B")))
                                          :op2 (a6 / activity-06
                                                :ARG0 (p6 / protein :wiki "AP-1_transcription_factor"
                                                      :name (n7 / name :op1 "AP-1")))))))
                  :mod (p3 / potent))))

# ::id bio.chicago_2015.54870 ::date 2015-10-31T10:39:43 ::annotator SDL-AMR-09 ::preferred
# ::snt Note that  importin beta, the  importin alpha/ beta heterodimer,  transportin,  RanBP5 and  RanBP7 all bound specifically to  rpL23a.
# ::save-date Mon Nov 9, 2015 ::file bio_chicago_2015_54870.txt
(n / note-01 :mode imperative
      :ARG0 (y / you)
      :ARG1 (b / bind-01
            :ARG1 (a / and
                  :op1 (p / protein :name (n2 / name :op1 "importin" :op2 "beta"))
                  :op2 (h / heterodimer
                        :part (p2 / protein :name (n3 / name :op1 "importin" :op2 "alpha"))
                        :part p)
                  :op3 (p3 / protein :name (n4 / name :op1 "transportin"))
                  :op4 (p4 / protein :name (n5 / name :op1 "RanBP5"))
                  :op5 (p5 / protein :name (n6 / name :op1 "RanBP7"))
                  :mod (a2 / all))
            :ARG2 (p6 / protein :name (n7 / name :op1 "rpL23a"))
            :ARG1-of (s / specific-02)))

# ::id bio.chicago_2015.54875 ::date 2015-10-31T10:44:33 ::annotator SDL-AMR-09 ::preferred
# ::snt Indeed, transcriptional repression by  Gal4 fusions to  PHO polypeptides that could bind  PC [PHO(1-356) and  PHO(118-172)] was markedly enhanced by overexpression of  PC (Fig.  7B).
# ::save-date Wed Jan 13, 2016 ::file bio_chicago_2015_54875.txt
(e / enhance-01
      :ARG0 (o2 / overexpress-01
            :ARG1 p2)
      :ARG1 (r / repress-01
            :ARG0 (f / fuse-01
                  :ARG1 (g / gene :name (n2 / name :op1 "Gal4"))
                  :ARG2 (p / polypeptide :name (n4 / name :op1 "PHO")
                        :ARG1-of (b3 / bind-01
                              :ARG2 (p2 / protein :name (n5 / name :op1 "PC"))
                              :ARG1-of (p5 / possible-01))
                        :ARG1-of (m / mean-01
                              :ARG2 (a3 / and
                                    :op1 (p6 / protein-segment
                                          :quant (b / between :op1 1 :op2 356))
                                    :op2 (p7 / protein-segment
                                          :quant (b2 / between :op1 118 :op2 172))
                                    :part-of p))))
            :ARG1 (t / transcribe-01))
      :ARG1-of (m2 / mark-01)
      :mod (i / indeed)
      :ARG1-of (d / describe-01
            :ARG0 (f2 / figure :mod "7B")))

# ::id bio.chicago_2015.54886 ::date 2015-10-31T10:56:11 ::annotator SDL-AMR-09 ::preferred
# ::snt Binding of  ERM Proteins to  CD43 and  ICAM-2 As Well As CD44 through Their Juxta-Membrane  Positively Charged Amino Acid Clusters
# ::save-date Sat Oct 31, 2015 ::file bio_chicago_2015_54886.txt
(c / charge-03
      :ARG0 (b / bind-01
            :ARG1 (p / protein-family :name (n / name :op1 "ERM"))
            :ARG2 (a / and
                  :op1 (p2 / protein :name (n2 / name :op1 "CD43"))
                  :op2 (p3 / protein :name (n3 / name :op1 "ICAM-2"))
                  :op3 (p4 / protein :name (n4 / name :op1 "CD44")))
            :ARG3 (m / membrane
                  :mod (j / juxtra)
                  :poss p))
      :ARG1 (c2 / cluster-01
            :ARG1 (a2 / amino-acid))
      :manner (p5 / positive))

# ::id bio.chicago_2015.54932 ::date 2015-10-31T11:00:12 ::annotator SDL-AMR-09 ::preferred
# ::snt Significant binding of  Arp1 to the  DI and  DIII constructs was observed.
# ::save-date Mon Nov 2, 2015 ::file bio_chicago_2015_54932.txt
(o / observe-01
      :ARG1 (b / bind-01
            :ARG1 (p / protein :name (n / name :op1 "Arp1"))
            :ARG2 (a / and
                  :op1 (c / construct-01
                        :ARG2 (p2 / protein :name (n2 / name :op1 "DI")))
                  :op2 (c2 / construct-01
                        :ARG1 (p3 / protein :name (n3 / name :op1 "DIII"))))
            :ARG1-of (s / significant-02)))

# ::id bio.chicago_2015.54956 ::date 2015-10-31T11:03:18 ::annotator SDL-AMR-09 ::preferred
# ::snt The above data support the idea that  eIF4G just binds a single  eIF4A molecule, either  eIF4AI or  eIF4AII.
# ::save-date Sat Oct 31, 2015 ::file bio_chicago_2015_54956.txt
(s / support-01
      :ARG0 (d / data
            :location (a / above))
      :ARG1 (i / idea
            :topic (b / bind-01
                  :ARG1 (p / protein :name (n / name :op1 "eIF4G"))
                  :ARG2 (m / molecule
                        :part-of (p2 / protein-family :name (n2 / name :op1 "eIF4A"))
                        :ARG1-of (s2 / single-02)
                        :ARG1-of (m2 / mean-01
                              :ARG2 (o / or
                                    :op1 (p3 / protein :name (n3 / name :op1 "eIF4AI"))
                                    :op2 (p4 / protein :name (n4 / name :op1 "eIF4AII")))))
                  :mod (j / just))))

# ::id bio.chicago_2015.54971 ::date 2015-10-31T11:07:27 ::annotator SDL-AMR-09 ::preferred
# ::snt We have hypothesized that the binding of  PP2A to  the  Axin complex might counteract the phosphorylation  of  beta-catenin by  GSK3beta (Hsu et al., 1999  ) that could account for the increased ventralization activity in the absence of this domain.
# ::save-date Mon Nov 9, 2015 ::file bio_chicago_2015_54971.txt
(h2 / hypothesize-01
      :ARG0 (w2 / we)
      :ARG1 (p / possible-01
            :ARG1 (c / counteract-01
                  :ARG0 (b / bind-01
                        :ARG1 (e2 / enzyme :name (n2 / name :op1 "PP2A"))
                        :ARG2 (m / macro-molecular-complex
                              :part (p3 / protein :name (n3 / name :op1 "Axin"))))
                  :ARG1 (p2 / phosphorylate-01
                        :ARG1 (p4 / protein :name (n4 / name :op1 "beta-catenin"))
                        :ARG2 (e3 / enzyme :name (n5 / name :op1 "GSK3" :op2 "beta"))
                        :ARG0-of (a / account-01
                              :ARG1 (a2 / activity-06
                                    :ARG1 (v / ventralization)
                                    :ARG1-of (i / increase-01))
                              :ARG1-of (p5 / possible-01)
                              :condition (a3 / absent-01
                                    :ARG1 (d2 / domain
                                          :mod (t / this))))))
            :ARG1-of (d3 / describe-01
                  :ARG0 (p6 / publication-91
                        :ARG0 (a4 / and
                              :op1 (p7 / person :name (n6 / name :op1 "Hsu"))
                              :op2 (p8 / person
                                    :mod (o / other)))
                        :time (d / date-entity :year 1999)))))

# ::id bio.chicago_2015.54984 ::date 2015-10-31T11:14:39 ::annotator SDL-AMR-09 ::preferred
# ::snt CEP2 and  CEP5 bind to  Cdc42.
# ::save-date Sun Jan 17, 2016 ::file bio_chicago_2015_54984.txt
(b / bind-01
      :ARG1 (a / and
            :op1 (p / protein :name (n / name :op1 "CEP2"))
            :op2 (p2 / protein :name (n2 / name :op1 "CEP5")))
      :ARG2 (p3 / protein :name (n3 / name :op1 "Cdc42")))

# ::id bio.chicago_2015.55013 ::date 2015-10-31T11:15:58 ::annotator SDL-AMR-09 ::preferred
# ::snt We also introduced two amino acid substitutions into the  JNK-binding motif of  JIP3 ( Kelkar  et al., 2000).
# ::save-date Sat Oct 31, 2015 ::file bio_chicago_2015_55013.txt
(i / introduce-02
      :ARG0 (w / we)
      :ARG1 (s / substitute-01 :quant 2
            :ARG1 (a2 / amino-acid)
            :location (p / protein-segment
                  :ARG1-of (b / bind-01
                        :ARG2 (e / enzyme :name (n / name :op1 "JNK")))
                  :part-of (p2 / protein :name (n2 / name :op1 "JIP3"))))
      :mod (a / also)
      :ARG1-of (d2 / describe-01
            :ARG0 (p3 / publication-91
                  :ARG0 (a3 / and
                        :op1 (p4 / person :name (n3 / name :op1 "Kelkar"))
                        :op2 (p5 / person
                              :mod (o / other)))
                  :time (d / date-entity :year 2000))))

# ::id bio.chicago_2015.55022 ::date 2015-10-31T11:19:21 ::annotator SDL-AMR-09 ::preferred
# ::snt NF-1 was detected as described for panel B. (D)  GR and hSwi/ nf facilitation of binding of  NF-1 to  MMTV chromatin.
# ::save-date Mon Jan 4, 2016 ::file bio_chicago_2015_55022.txt
(m / multi-sentence
      :snt1 (d / detect-01
            :ARG1 (p / protein :name (n / name :op1 "NF-1"))
            :ARG2-of (d2 / describe-01
                  :ARG1 (p2 / panel
                        :ARG1-of (l / label-01
                              :ARG2 (s / string-entity :value "B")))))
      :snt2 (f / facilitate-01 :li "D"
            :ARG0 (a / and
                  :op1 (p3 / protein :name (n2 / name :op1 "GR"))
                  :op2 (m2 / macro-molecular-complex
                        :part (p4 / protein :name (n3 / name :op1 "hSwi"))
                        :part (p5 / protein :name (n4 / name :op1 "hSnf"))))
            :ARG1 (b / bind-01
                  :ARG1 (p6 / protein :name (n5 / name :op1 "NF-1"))
                  :ARG2 (m3 / macro-molecular-complex :name (n7 / name :op1 "chromatin")
                        :part-of (o / organism :name (n6 / name :op1 "MMTV"))))))

# ::id bio.chicago_2015.55025 ::date 2015-10-31T11:31:36 ::annotator SDL-AMR-09 ::preferred
# ::snt Effects of  Tcf3 phosphorylation on its activity   These experiments establish that both  GSK3 and  CK1epsilon can bind and phosphorylate  Tcf3 and suggest a possible role for both  GSK3 and  CK1epsilon in modulating  Tcf3 activity.
# ::save-date Mon Nov 9, 2015 ::file bio_chicago_2015_55025.txt
(m / multi-sentence
      :snt1 (a / affect-01
            :ARG0 (p / phosphorylate-01
                  :ARG1 (p2 / protein :wiki "TCF3"
                        :name (n / name :op1 "Tcf3")))
            :ARG1 (a2 / activity-06
                  :ARG0 p2))
      :snt2 (a3 / and
            :op1 (e / establish-01
                  :ARG0 (e2 / experiment-01
                        :mod (t / this))
                  :ARG1 (p3 / possible-01
                        :ARG1 (a5 / and
                              :op1 (b / bind-01
                                    :ARG1 (a4 / and
                                          :op1 (e3 / enzyme :wiki "GSK-3"
                                                :name (n2 / name :op1 "GSK3"))
                                          :op2 (p4 / protein :wiki "Casein_kinase_1_isoform_epsilon"
                                                :name (n3 / name :op1 "CK1epsilon")))
                                    :ARG2 p6)
                              :op2 (p5 / phosphorylate-01
                                    :ARG1 (p6 / protein :wiki "TCF3"
                                          :name (n4 / name :op1 "Tcf3"))
                                    :ARG2 a4))))
            :op2 (s / suggest-01
                  :ARG0 e2
                  :ARG1 (r / role
                        :ARG1-of (p7 / possible-01)
                        :poss a4
                        :topic (m2 / modulate-01
                              :ARG0 a4
                              :ARG1 (a6 / activity-06
                                    :ARG0 p6))))))

# ::id bio.chicago_2015.55068 ::date 2015-10-31T11:42:23 ::annotator SDL-AMR-09 ::preferred
# ::snt As shown in Table  I,  RitS35N, which corresponds to the  RasS17N dominant negative mutant and would be expected to be predominantly  GDP-bound, showed no detectable interaction with  RGL3-RBD, suggesting that  RGL3 showed preferential binding to the active  GTP-bound form of  Rit.
# ::save-date Fri Feb 5, 2016 ::file bio_chicago_2015_55068.txt
(s / show-01
      :ARG0 (p / protein :name (n / name :op1 "RitS35N")
            :ARG0-of (c / correspond-01
                  :ARG1 (p2 / protein :name (n2 / name :op1 "RasS17N")
                        :ARG2-of (m / mutate-01 :mod "-/-")
                        :ARG1-of (d / dominate-01)))
            :ARG1-of (b / bind-01
                  :ARG2 (s2 / small-molecule :name (n4 / name :op1 "GDP"))
                  :ARG1-of (p3 / predominate-01
                        :ARG1-of (e / expect-01))))
      :ARG1 (i / interact-01 :polarity -
            :ARG0 p
            :ARG1 (p5 / protein :name (n5 / name :op1 "RGL3-RBD"))
            :ARG1-of (d2 / detect-01
                  :ARG1-of (p4 / possible-01)))
      :ARG0-of (s3 / suggest-01
            :ARG1 (s4 / show-01
                  :ARG0 (p6 / protein :name (n6 / name :op1 "RGL3"))
                  :ARG1 (b2 / bind-01
                        :ARG1 p6
                        :ARG2 (p8 / protein :name (n7 / name :op1 "Rit")
                              :ARG1-of (a / activate-01)
                              :ARG1-of (b3 / bind-01
                                    :ARG2 (s5 / small-molecule :name (n8 / name :op1 "GTP"))))
                        :ARG1-of (p7 / prefer-01
                              :ARG0 p6))))
      :ARG1-of (s6 / show-01
            :medium (t / table :mod "I")))

# ::id bio.chicago_2015.55070 ::date 2015-11-01T11:26:56 ::annotator SDL-AMR-09 ::preferred
# ::snt ( A)   p120ctn isoforms bind to both   GST-Prox and  GST-FL.
# ::save-date Sun Nov 1, 2015 ::file bio_chicago_2015_55070.txt
(b / bind-01 :li "A"
      :ARG1 (i / isoform
            :mod (p / protein :name (n / name :op1 "p120ctn")))
      :ARG2 (a / and
            :op1 (p2 / protein :name (n2 / name :op1 "GST-Prox"))
            :op2 (p3 / protein :name (n3 / name :op1 "GST-FL"))))

# ::id bio.chicago_2015.55128 ::date 2015-11-01T11:28:46 ::annotator SDL-AMR-09 ::preferred
# ::snt In stark contrast to the  Sly1p/Sed5p-complex,  Munc18a binds  syntaxin in the central cleft via interactions that involve both the Habc domain and the SNARE motif  (Misura et al., 2000  ).
# ::save-date Sun Nov 1, 2015 ::file bio_chicago_2015_55128.txt
(b / bind-01
      :ARG1 (p3 / protein :name (n3 / name :op1 "Munc18a"))
      :ARG2 (c2 / cleft
            :mod (c3 / center)
            :part-of (p4 / protein :name (n4 / name :op1 "syntaxin")))
      :ARG3 (i / interact-01
            :ARG0-of (i2 / involve-01
                  :ARG1 (a / and
                        :op1 (p5 / protein-segment :name (n5 / name :op1 "Habc"))
                        :op2 (p6 / protein-segment :name (n6 / name :op1 "SNARE"))
                        :part-of p4)))
      :ARG1-of (c / contrast-01
            :ARG2 (m / macro-molecular-complex
                  :part (p / protein :name (n / name :op1 "Sly1p"))
                  :part (p2 / protein :name (n2 / name :op1 "Sed5p")))
            :mod (s / stark))
      :ARG1-of (d2 / describe-01
            :ARG0 (p7 / publication-91
                  :ARG0 (a2 / and
                        :op1 (p8 / person :name (n7 / name :op1 "Misura"))
                        :op2 (p9 / person
                              :mod (o / other)))
                  :time (d / date-entity :year 2000))))

# ::id bio.chicago_2015.55187 ::date 2015-11-01T11:35:51 ::annotator SDL-AMR-09 ::preferred
# ::snt (A)  Gab1 mutants were expressed as  LexA-tpr-met fusion proteins and tested for  yeast two-hybrid interactions with substrates as in   Fig 3  A. CBR represents the  CRKL-binding region of  Gab1.
# ::save-date Fri Nov 27, 2015 ::file bio_chicago_2015_55187.txt
(m / multi-sentence
      :snt1 (a / and :li "A"
            :op1 (e / express-03
                  :ARG2 (p / protein :name (n / name :op1 "Gab1")
                        :ARG2-of (m2 / mutate-01))
                  :manner (p2 / protein :name (n2 / name :op1 "LexA-tpr-met")
                        :ARG1-of (f2 / fuse-01)))
            :op2 (t / test-01
                  :ARG1 p
                  :ARG2 (i / interact-01
                        :ARG0 (h / hybrid :quant 2)
                        :ARG1 (s / substrate)
                        :location (y / yeast)))
            :ARG1-of (d / describe-01
                  :ARG0 (f / figure :mod "3A")))
      :snt2 (r / represent-01
            :ARG0 (p3 / protein-segment :name (n4 / name :op1 "CBR"))
            :ARG1 (r2 / region
                  :ARG1-of (b / bind-01
                        :ARG2 (p4 / protein :name (n5 / name :op1 "CRKL")))
                  :part-of (p5 / protein :name (n6 / name :op1 "Gab1")))))

# ::id bio.chicago_2015.55208 ::date 2015-11-01T11:43:40 ::annotator SDL-AMR-09 ::preferred
# ::snt Binding of  Sp1 and  Smad2,  Smad3,  Smad4 and  Sp1 to the wild-type oligonucleotide, as was also done in (E), was compared with their binding to the corresponding mutant oligonucleotides, in which the  SBEs and  Sp1 binding sequences were mutated, as shown in Figure  3A.
# ::save-date Sun Jan 17, 2016 ::file bio_chicago_2015_55208.txt
(c / compare-01
      :ARG1 (b / bind-01
            :ARG1 (a / and
                  :op1 (p / protein :name (n / name :op1 "Sp1"))
                  :op2 (p2 / protein :name (n2 / name :op1 "Smad2"))
                  :op3 (p3 / protein :name (n3 / name :op1 "Smad3"))
                  :op4 (p4 / protein :name (n4 / name :op1 "Smad4"))
                  :op5 p)
            :ARG2 (o / oligonucleotide
                  :mod (w / wild-type))
            :ARG1-of (d / do-02
                  :mod (a2 / also)
                  :medium (f2 / figure :mod "E")))
      :ARG2 (b2 / bind-01
            :ARG1 a
            :ARG2 (o2 / oligonucleotide
                  :ARG2-of (m / mutate-01)
                  :ARG1-of (c2 / correspond-02)
                  :location-of (m2 / mutate-01
                        :ARG1 (a3 / and
                              :op1 (s / sequence
                                    :ARG1-of (b3 / bind-01
                                          :ARG2 (p5 / protein-segment :name (n5 / name :op1 "SBE"))))
                              :op2 (s2 / sequence
                                    :ARG1-of (b4 / bind-01
                                          :ARG2 p)))
                        :ARG1-of (s3 / show-01
                              :medium (f / figure :mod "3A"))))))

# ::id bio.chicago_2015.55244 ::date 2015-11-01T11:54:43 ::annotator SDL-AMR-09 ::preferred
# ::snt The finding that  LARFN5C binds to  LAR and  the absence of the LARFN5C N-terminal sequence in  LAR make the possibility of N-terminal to N-terminal isologous homophilic binding unlikely.
# ::save-date Sun Jan 17, 2016 ::file bio_chicago_2015_55244.txt
(m / make-02
      :ARG0 (a / and
            :op1 (f / find-01
                  :ARG1 (b / bind-01
                        :ARG1 (p / protein-segment :name (n / name :op1 "LARFN5C"))
                        :ARG2 (e / enzyme :name (n2 / name :op1 "LAR"))))
            :op2 (a2 / absent-01
                  :ARG1 (p3 / protein-segment :name (n3 / name :op1 "N-terminus")
                        :part-of p)
                  :ARG2 e))
      :ARG1 (l / likely-01 :polarity -
            :ARG1 (p4 / possible-01
                  :ARG1 (b2 / bind-01
                        :ARG1 (p5 / protein-segment :name (n4 / name :op1 "N-terminus"))
                        :ARG2 (i / isologus
                              :mod p5)
                        :mod (h / homophilic)))))

# ::id bio.chicago_2015.55261 ::date 2015-11-01T12:01:56 ::annotator SDL-AMR-09 ::preferred
# ::snt Dystroglycan, which binds to  laminins,  agrin, and  perlecan through its   subunit, has been another candidate for mediation of basement membrane assembly  (Henry and Campbell, 1998  ).
# ::save-date Sun Nov 1, 2015 ::file bio_chicago_2015_55261.txt
(c / candidate
      :mod (a / another)
      :domain (p / protein :name (n / name :op1 "dystroglycan")
            :ARG1-of (b / bind-01
                  :ARG2 (a2 / and
                        :op1 (p2 / protein :name (n2 / name :op1 "laminin"))
                        :op2 (p3 / protein :name (n3 / name :op1 "agrin"))
                        :op3 (p4 / protein :name (n4 / name :op1 "perlecan")))
                  :ARG3 (p5 / protein-segment
                        :part-of p)))
      :ARG0-of (m / mediate-01
            :ARG1 (a3 / assemble-01
                  :ARG1 (m2 / membrane
                        :mod (b2 / basement))))
      :ARG1-of (d2 / describe-01
            :ARG0 (p6 / publication-91
                  :ARG0 (a4 / and
                        :op1 (p7 / person :name (n5 / name :op1 "Henry"))
                        :op2 (p8 / person :name (n6 / name :op1 "Campbell")))
                  :time (d / date-entity :year 1998))))

# ::id bio.chicago_2015.55278 ::date 2015-11-01T12:06:59 ::annotator SDL-AMR-09 ::preferred
# ::snt Binding of the  VHL protein and  Elongin A  to the  Elongin BC complex is mutually exclusive in vitro ( 101).
# ::save-date Mon Nov 2, 2015 ::file bio_chicago_2015_55278.txt
(e / exclude-01
      :ARG1 (a / and
            :op1 (b / bind-01
                  :ARG1 (p / protein :name (n / name :op1 "VHL"))
                  :ARG2 m)
            :op2 (b2 / bind-01
                  :ARG1 (p2 / protein :name (n2 / name :op1 "Elongin" :op2 "A"))
                  :ARG2 (m / macro-molecular-complex
                        :part (p3 / protein :name (n3 / name :op1 "Elongin" :op2 "B"))
                        :part (p4 / protein :name (n4 / name :op1 "Elongin" :op2 "C")))))
      :manner (m2 / mutual)
      :manner (i / in-vitro)
      :ARG1-of (d / describe-01
            :ARG0 (p5 / publication
                  :ARG1-of (c / cite-01
                        :ARG2 101))))

# ::id bio.chicago_2015.55289 ::date 2015-11-01T12:13:13 ::annotator SDL-AMR-09 ::preferred
# ::snt Here, we have demonstrated that intact  p140mDia can bind to  profilin  in vitro, and its distribution  in vivo largely overlaps with that of  profilin in cells.
# ::save-date Mon Nov 2, 2015 ::file bio_chicago_2015_55289.txt
(d / demonstrate-01
      :ARG0 (w2 / we)
      :ARG1 (a / and
            :op1 (p / possible-01
                  :ARG1 (b / bind-01
                        :ARG1 (p2 / protein :name (n / name :op1 "p140mDia")
                              :mod (i / intact))
                        :ARG2 (p3 / protein :name (n2 / name :op1 "profilin"))
                        :manner (i2 / in-vitro)))
            :op2 (o / overlap-01
                  :ARG0 (d2 / distribute-01
                        :ARG1 p2
                        :manner (i3 / in-vivo))
                  :ARG1 (d3 / distribute-01
                        :ARG0 p3
                        :location (c / cell))
                  :ARG2 (l / large)))
      :medium (h2 / here))

# ::id bio.chicago_2015.55319 ::date 2015-11-01T12:17:55 ::annotator SDL-AMR-09 ::preferred
# ::snt The finding that  p115 binding to  GM130 is inhibited by phosphorylation of  GM130 on  serine 25 suggests that this residue must be dephosphorylated for Golgi reassembly to occur.
# ::save-date Mon Nov 9, 2015 ::file bio_chicago_2015_55319.txt
(s / suggest-01
      :ARG0 (f / find-01
            :ARG1 (i / inhibit-01
                  :ARG0 (p / phosphorylate-01
                        :ARG1 (a2 / amino-acid :mod 25 :name (n4 / name :op1 "serine")
                              :part-of p3))
                  :ARG1 (b / bind-01
                        :ARG1 (p2 / protein :name (n2 / name :op1 "p115"))
                        :ARG2 (p3 / protein :name (n3 / name :op1 "GM130")))))
      :ARG1 (o / obligate-01
            :ARG2 (d / dephosphorylate-01
                  :ARG1 a2
                  :purpose (a3 / assemble-01
                        :ARG1 (t / thing :name (n / name :op1 "Golgi"))
                        :mod (a4 / again)))))

# ::id bio.chicago_2015.55330 ::date 2015-11-01T12:21:57 ::annotator SDL-AMR-09 ::preferred
# ::snt Treatment with   C3 exoenzyme (C3) may block  m1 mAChR - mediated suppression of  Kv1.2 or may disrupt  the binding between  RhoA and  Kv1.2.
# ::save-date Sun Nov 1, 2015 ::file bio_chicago_2015_55330.txt
(o / or
      :op1 (p / possible-01
            :ARG1 (b / block-01
                  :ARG0 (t / treat-04
                        :ARG2 (e / enzyme :name (n / name :op1 "C3" :op2 "exoenzyme")))
                  :ARG1 (s / suppress-01
                        :ARG1 (p3 / protein :name (n3 / name :op1 "Kv1.2"))
                        :ARG1-of (m / mediate-01
                              :ARG0 (p2 / protein :name (n2 / name :op1 "m1" :op2 "mAChR"))))))
      :op2 (p4 / possible-01
            :ARG1 (d2 / disrupt-01
                  :ARG0 t
                  :ARG1 (b2 / bind-01
                        :ARG1 (p5 / protein :name (n4 / name :op1 "RhoA"))
                        :ARG2 p3))))

# ::id bio.chicago_2015.55334 ::date 2015-11-01T12:30:10 ::annotator SDL-AMR-09 ::preferred
# ::snt Reconstitution of the binding of  alpha-actinin to  VPMs in the presence of  actin stress fibers.
# ::save-date Mon Nov 9, 2015 ::file bio_chicago_2015_55334.txt
(r / reconstitute-01
      :ARG1 (b / bind-01
            :ARG1 (p / protein :wiki "Actinin,_alpha_1"
                  :name (n / name :op1 "alpha-actinin"))
            :ARG2 (m / membrane
                  :mod (p5 / plasma
                        :mod (v / ventral))))
      :condition (p3 / present-02
            :ARG1 (f / fiber
                  :mod (s / stress)
                  :consist-of (p4 / protein :wiki "Actin"
                        :name (n3 / name :op1 "actin")))))

# ::id bio.chicago_2015.55368 ::date 2015-11-01T12:35:08 ::annotator SDL-AMR-09 ::preferred
# ::snt The binding of the native  CaMKII to  projectin (maximally bound  CaMKII (native)/projectin=1.38 plus-or-minus 0.02 mol  mol-1) had a higher stoichiometry than the in vitro autophosphorylated  CaMKII (maximally bound  CaMKII (autophosphorylated)/projectin=0.86 plus-or-minus 0.04 mol  mol-1).
# ::save-date Mon Nov 9, 2015 ::file bio_chicago_2015_55368.txt
(h / have-03
      :ARG0 (b / bind-01
            :ARG1 (e / enzyme :name (n / name :op1 "CaMKII")
                  :mod (n3 / native))
            :ARG2 (p / protein :name (n2 / name :op1 "projectin"))
            :ARG1-of (m2 / mean-01
                  :ARG2 (b2 / bind-01
                        :ARG1 e
                        :ARG2 p
                        :degree (m3 / maximum)
                        :quant (v / value-interval
                              :op1 (a / add-02
                                    :ARG1 0.02
                                    :ARG2 1.38)
                              :op2 (s2 / subtract-01
                                    :ARG1 0.02
                                    :ARG2 1.38)
                              :unit (m5 / molar)))))
      :ARG1 (s / stoichiometry
            :ARG1-of (h2 / high-02
                  :degree (m / more)
                  :compared-to (e2 / enzyme :name (n4 / name :op1 "CaMKII")
                        :ARG1-of (p2 / phosphorylate-01
                              :ARG2 e2
                              :manner (i / in-vitro)))
                  :ARG1-of (m4 / mean-01
                        :ARG2 (b3 / bind-01
                              :ARG1 e2
                              :ARG2 p
                              :degree m3
                              :quant (v2 / value-interval
                                    :op1 (a2 / add-02
                                          :ARG1 0.04
                                          :ARG2 0.86)
                                    :op2 (s3 / subtract-01
                                          :ARG1 0.04
                                          :ARG2 0.86)
                                    :unit (m6 / molar)))))))

# ::id bio.chicago_2015.55380 ::date 2015-11-01T12:39:29 ::annotator SDL-AMR-09 ::preferred
# ::snt Oct-1 binds to the  PRL3 element.
# ::save-date Sun Nov 1, 2015 ::file bio_chicago_2015_55380.txt
(b / bind-01
      :ARG1 (p / protein :name (n / name :op1 "Oct-1"))
      :ARG2 (e / element
            :mod (e2 / enzyme :name (n2 / name :op1 "PRL3"))))

# ::id bio.chicago_2015.55448 ::date 2015-11-01T12:41:08 ::annotator SDL-AMR-09 ::preferred
# ::snt However, the interaction between the mutated  CtIP and  GST-BRCT was unaffected (Fig.  4 A, compare  lanes 3 and  7), suggesting that  CtIP binds to  CtBP and the  BRCT repeats of  BRCA1 using different motifs.
# ::save-date Mon Nov 9, 2015 ::file bio_chicago_2015_55448.txt
(h / have-concession-91
      :ARG1 (a / affect-01 :polarity -
            :ARG1 (i / interact-01
                  :ARG0 (p / protein :name (n / name :op1 "CtIP")
                        :ARG2-of (m / mutate-01))
                  :ARG2 (p2 / protein :name (n2 / name :op1 "GST-BRCT")))
            :ARG1-of (d / describe-01
                  :ARG0 (f / figure :mod "4A"
                        :location-of (c2 / compare-01 :mode imperative
                              :ARG0 (y / you)
                              :ARG1 (l / lane :mod 3)
                              :ARG2 (l2 / lane :mod 7))))
            :ARG0-of (s / suggest-01
                  :ARG1 (b / bind-01
                        :ARG1 p
                        :ARG2 (a2 / and
                              :op1 (p3 / protein :name (n3 / name :op1 "CtBP"))
                              :op2 (r / repeat-01
                                    :ARG1 (p5 / protein :name (n5 / name :op1 "BRCA1"))
                                    :mod (p4 / protein :name (n4 / name :op1 "BRCT"))))
                        :ARG3 (u / use-01
                              :ARG0 p
                              :ARG1 (p6 / protein-segment
                                    :ARG1-of (d2 / differ-02)))))))

# ::id bio.chicago_2015.55495 ::date 2015-11-01T12:48:21 ::annotator SDL-AMR-09 ::preferred
# ::snt In contrast, although the  HDL binding activities of the COS[ mSR-BI] and COS[hCD36] cells differed by only ~50% in this experiment (see legend), there were essentially only control (background) levels of  DiI uptake mediated by hCD36 in the COS[hCD36] cells.
# ::save-date Fri Jan 15, 2016 ::file bio_chicago_2015_55495.txt
(c5 / contrast-01
      :ARG2 (p / present-02
            :ARG1 (l / level
                  :mod (c / control
                        :ARG1-of (m / mean-01
                              :ARG2 (b / background)))
                  :mod (o / only)
                  :quant-of (u / uptake
                        :mod (p2 / protein :name (n / name :op1 "DiI"))
                        :ARG1-of (m2 / mediate-01
                              :ARG0 (p3 / protein :name (n2 / name :op1 "hCD36")))))
            :manner (e / essential)
            :location (c2 / cell-line :name (n3 / name :op1 "COS[hCD36]"))
            :concession (d / differ-02
                  :ARG1 (a / activity-06
                        :ARG0 (c3 / cell-line :name (n5 / name :op1 "COS[mSR-BI]"))
                        :ARG1 (b2 / bind-01
                              :ARG1 (p4 / protein :name (n4 / name :op1 "HDL"))))
                  :ARG2 (a2 / activity-06
                        :ARG0 c2
                        :ARG1 b2)
                  :condition (e2 / experiment-01
                        :mod (t / this)
                        :ARG1-of (s / see-01 :mode imperative
                              :ARG0 (y / you)
                              :medium (l2 / legend)))
                  :extent (a3 / approximately
                        :op1 (p5 / percentage-entity :value 50
                              :mod o)))))

# ::id bio.chicago_2015.55503 ::date 2015-11-01T12:53:45 ::annotator SDL-AMR-09 ::preferred
# ::snt Second, noggin and  follistatin bind  BMPs with greater affinity than  BMP receptors (Holley et al., 1996  ; Zimmerman et al., 1996  ; Fainsod et al., 1997  ; Iemura et al., 1998), so it is unlikely that the extracellular compartment contains significant levels of antagonist not complexed to BMPs.
# ::save-date Mon Nov 9, 2015 ::file bio_chicago_2015_55503.txt
(a4 / and
      :op2 (b / bind-01
            :ARG1 (a / and
                  :op1 (p / protein :name (n / name :op1 "noggin"))
                  :op2 (p2 / protein :name (n2 / name :op1 "follistatin")))
            :ARG2 (p3 / protein :name (n3 / name :op1 "BMP"))
            :manner (a2 / affinity
                  :mod (g / great
                        :degree (m / more)
                        :compared-to (r / receptor
                              :mod p3)))
            :ARG0-of (c / cause-01
                  :ARG1 (l / likely-01 :polarity -
                        :ARG1 (c2 / contain-01
                              :ARG0 (c3 / compartment
                                    :mod (e / extracellular))
                              :ARG1 (l2 / level
                                    :ARG1-of (s / significant-02)
                                    :quant-of (a3 / antagonist
                                          :ARG2-of (h / have-part-91 :polarity -
                                                :ARG1 (m2 / macro-molecular-complex
                                                      :part p3)))))))
            :ARG1-of (d2 / describe-01
                  :ARG0 (a5 / and
                        :op1 (p4 / publication-91
                              :ARG0 (a6 / and
                                    :op1 (p5 / person :name (n4 / name :op1 "Holley"))
                                    :op2 (p6 / person
                                          :mod (o2 / other)))
                              :time (d / date-entity :year 1996))
                        :op2 (p7 / publication-91
                              :ARG0 (a8 / and
                                    :op1 (p8 / person :name (n5 / name :op1 "Zimmerman"))
                                    :op2 p6)
                              :time d)
                        :op3 (p9 / publication-91
                              :ARG0 (a7 / and
                                    :op1 (p10 / person :name (n6 / name :op1 "Fainsod"))
                                    :op2 p6)
                              :time (d3 / date-entity :year 1997))
                        :op4 (p11 / publication-91
                              :ARG0 (a9 / and
                                    :op1 (p12 / person :name (n7 / name :op1 "Iemura"))
                                    :op2 p6)
                              :time (d4 / date-entity :year 1998))))))

# ::id bio.chicago_2015.55550 ::date 2015-11-02T05:59:53 ::annotator SDL-AMR-09 ::preferred
# ::snt The lack of observed binding between  Sog and  alphaPS3 could result from a difficulty in detecting an alternatively processed form of  Sog bound to  alphaPS3, or may reflect an indirect mode of action of   scb (e.g. by altering the abundance of interacting integrins such as  alphaPS1betaPS or by binding to a different  Bmp inhibitor).
# ::save-date Mon Nov 9, 2015 ::file bio_chicago_2015_55550.txt
(o / or
      :op1 (p2 / possible-01
            :ARG1 (r / result-01
                  :ARG1 (d / difficult
                        :domain (d3 / detect-01
                              :ARG1 (p6 / protein :name (n3 / name :op1 "Sog")
                                    :ARG1-of (b2 / bind-01
                                          :ARG2 (p7 / protein :name (n4 / name :op1 "alphaPS3"))
                                          :ARG1-of (o3 / observe-01))
                                    :ARG1-of (p5 / process-01
                                          :ARG1-of (a / alternate-01)))))
                  :ARG2 (l / lack-01
                        :ARG1 (b / bind-01
                              :ARG1 (p3 / protein :name (n / name :op1 "Sog"))
                              :ARG2 p7))))
      :op2 (p / possible-01
            :ARG1 (r2 / reflect-01
                  :ARG1 l
                  :ARG2 (m / mode
                        :manner-of (a2 / act-01
                              :ARG0 (p8 / protein :name (n5 / name :op1 "scb"))
                              :ARG1-of (d4 / direct-02 :polarity -
                                    :example (o2 / or
                                                :op1 (a3 / alter-01
                                                      :ARG0 p8
                                                      :ARG1 (a4 / abound-01
                                                            :ARG1 (p4 / protein-family :name (n2 / name :op1 "integrin")
                                                                  :ARG0-of (i3 / interact-01)
                                                                  :example (p9 / protein :name (n6 / name :op1 "alphaPS1betaPS")))))
                                                :op2 (b3 / bind-01
                                                      :ARG1 p8
                                                      :ARG2 (m4 / molecular-physical-entity
                                                            :ARG0-of (i4 / inhibit-01
                                                                  :ARG1 (p10 / protein :name (n7 / name :op1 "Bmp")))
                                                            :ARG1-of (d2 / differ-02))))))))))

# ::id bio.chicago_2015.55555 ::date 2015-11-03T08:01:54 ::annotator SDL-AMR-09 ::preferred
# ::snt Screening a brain library demonstrates that the  PDZ-containing  domain of  nNOS binds to  PDZ repeats in postsynaptic density 95 (PSD-95) ( Cho  et al., 1992   ) and a novel related protein,  PSD-93.
# ::save-date Thu Nov 19, 2015 ::file bio_chicago_2015_55555.txt
(d2 / demonstrate-01
      :ARG0 (s / screen-01
            :ARG1 (l / library
                  :mod (b / brain)))
      :ARG1 (b2 / bind-01
            :ARG1 (p / protein-segment
                  :part-of (e / enzyme :name (n2 / name :op1 "nNOS"))
                  :ARG0-of (c / contain-01
                        :ARG1 (p2 / protein-segment :name (n / name :op1 "PZD"))))
            :ARG2 (p8 / protein-segment :name (n8 / name :op1 "PDZ" :op2 "repeat"))
            :location (a / and
                  :op1 (p3 / protein :name (n4 / name :op1 "postsynaptic" :op2 "density" :op3 "95")
                        :ARG1-of (d3 / describe-01
                              :ARG0 (p5 / publication-91
                                    :ARG0 (a2 / and
                                          :op1 (p6 / person :name (n7 / name :op1 "Cho"))
                                          :op2 (p7 / person
                                                :mod (o / other)))
                                    :time (d / date-entity :year 1992))))
                  :op2 (p4 / protein :name (n5 / name :op1 "PSD-93")
                        :mod (n6 / novel)
                        :ARG1-of (r2 / relate-01
                              :ARG2 p3)))))

# ::id bio.chicago_2015.55576 ::date 2015-11-03T08:13:11 ::annotator SDL-AMR-09 ::preferred
# ::snt Panel A, mutations introduced in the  AP-2 and  clathrin binding regions of  amphiphysin 1.
# ::save-date Thu Nov 19, 2015 ::file bio_chicago_2015_55576.txt
(i / introduce-02
      :ARG1 (m / mutate-01)
      :ARG2 (r / region
            :ARG2-of (b / bind-01
                  :ARG1 (a / and
                        :op1 (p / protein :name (n / name :op1 "AP-2"))
                        :op2 (p2 / protein :name (n2 / name :op1 "clathrin"))))
            :part-of (p3 / protein :name (n3 / name :op1 "amphiphysin" :op2 "1")))
      :ARG1-of (d / describe-01
            :ARG0 (p4 / panel
                  :mod (s / string-entity :value "A"))))

# ::id bio.chicago_2015.55580 ::date 2015-11-03T08:18:37 ::annotator SDL-AMR-09 ::preferred
# ::snt These results argue that a factor that binds to poly-U Sepharose and that is eluted from the resin at 2 M KCl is necessary for efficient recruitment of  U1 snRNP to   msl-2 5  ss, but not for  U1 snRNP binding to a consensus 5   ss lacking downstream U-rich sequences.
# ::save-date Sat Feb 13, 2016 ::file bio_chicago_2015_55580.txt
(a / argue-01
      :ARG0 (t / thing
            :ARG2-of (r / result-01)
            :mod (t2 / this))
      :ARG1 (f / factor
            :ARG1-of (b / bind-01
                  :ARG2 (s2 / small-molecule :name (n2 / name :op1 "poly-U" :op2 "Sepharose")))
            :ARG1-of (e / elute-01
                  :ARG2 (r5 / resin)
                  :condition (s3 / small-molecule :name (n3 / name :op1 "KCl")
                        :quant (c / concentration-quantity :quant 2
                              :unit (m2 / molar))))
            :ARG1-of (n4 / need-01
                  :ARG0 (r2 / recruit-01
                        :ARG1 (p / protein :name (n5 / name :op1 "U1" :op2 "snRNP"))
                        :ARG2 (p4 / protein-segment :name (n6 / name :op1 "5'" :op2 "ss")
                              :part-of (p2 / protein :name (n8 / name :op1 "msl-2")))
                        :ARG2-of (e2 / efficient-01))
                  :ARG1-of (c2 / contrast-01
                        :ARG2 (n7 / need-01 :polarity -
                              :ARG0 (r3 / recruit-01
                                    :ARG1 p
                                    :ARG2 (d / dna-sequence :name (n / name :op1 "5'ss")
                                          :mod (c3 / consensus)
                                          :ARG0-of (l / lack-01
                                                :ARG1 (s / sequence :name (n10 / name :op1 "U-rich")
                                                      :direction (d2 / downstream)))))
                              :ARG1 f)))))

# ::id bio.chicago_2015.55595 ::date 2015-11-03T08:32:06 ::annotator SDL-AMR-09 ::preferred
# ::snt Degradation of any endogenous  ATP present in retinal extracts resulted in no change of binding activity of  P112 to  CLD (Fig.  2).
# ::save-date Sun Jan 17, 2016 ::file bio_chicago_2015_55595.txt
(r / result-01
      :ARG1 (d / degrade-01
            :ARG1 (s / small-molecule :name (n / name :op1 "ATP")
                  :mod (e2 / endogenous)
                  :ARG1-of (p / present-02
                        :ARG2 (m / molecular-physical-entity
                              :ARG1-of (e3 / extract-01
                                    :ARG2 (r2 / retina))))
                  :mod (a2 / any)))
      :ARG2 (c / change-01 :polarity -
            :ARG1 (a / activity-06
                  :ARG1 (b / bind-01
                        :ARG1 (p2 / protein :name (n2 / name :op1 "P112"))
                        :ARG2 (p3 / protein :name (n3 / name :op1 "CLD")))))
      :ARG1-of (d2 / describe-01
            :ARG0 (f / figure :mod 2)))

# ::id bio.chicago_2015.55666 ::date 2015-11-03T09:03:35 ::annotator SDL-AMR-09 ::preferred
# ::snt We next tested the contribution of the  IAP binding activity of  Omi to its killing activity.
# ::save-date Thu Jan 14, 2016 ::file bio_chicago_2015_55666.txt
(t / test-01
      :ARG0 (w / we)
      :ARG1 (c / contribute-01
            :ARG0 (a / activity-06
                  :ARG0 p2
                  :ARG1 (b / bind-01
                        :ARG1 (p2 / protein :name (n3 / name :op1 "Omi"))
                        :ARG2 (p / protein :name (n2 / name :op1 "IAP"))))
            :ARG2 (a2 / activity-06
                  :ARG0 p2
                  :ARG1 (k / kill-01
                        :ARG0 p2)))
      :time (n / next))

# ::id bio.chicago_2015.55671 ::date 2015-11-03T09:17:02 ::annotator SDL-AMR-09 ::preferred
# ::snt Although the binding experiments described above demonstrated that the C-terminal 378 residues of  E6TP1, which lack the  PDZ domain, were sufficient for  E6 binding, it remained possible that the  PDZ domain of  E6TP1 could also bind to  E6, either independently or cooperatively with the C-terminal region.
# ::save-date Fri Nov 27, 2015 ::file bio_chicago_2015_55671.txt
(h / have-concession-91
      :ARG1 (r3 / remain-01
            :ARG1 (p4 / possible-01
                  :ARG1 (b3 / bind-01
                        :ARG1 (p8 / protein-segment :name (n7 / name :op1 "PDZ" :op2 "domain")
                              :part-of p2)
                        :ARG2 p6
                        :manner (o / or
                              :op1 (d3 / depend-01 :polarity -
                                    :ARG0 p8)
                              :op2 (c / cooperate-01
                                    :ARG0 p8
                                    :ARG1 (p3 / protein-segment :name (n6 / name :op1 "C-terminus"))))
                        :mod (a3 / also))))
      :ARG2 (d / demonstrate-01
            :ARG0 (e / experiment-01
                  :ARG1 (b / bind-01)
                  :ARG1-of (d2 / describe-01
                        :location (a / above)))
            :ARG1 (s / suffice-01
                  :ARG0 (r2 / residue
                        :ARG0-of (l / lack-01
                              :ARG1 p8)
                        :mod (a2 / amino-acid :mod 378
                              :part-of (p / protein-segment :name (n / name :op1 "C-terminus")
                                    :part-of (p2 / protein :name (n2 / name :op1 "E6TP1")))))
                  :ARG1 (b2 / bind-01
                        :ARG2 (p6 / protein :name (n5 / name :op1 "E6"))))))

# ::id bio.chicago_2015.55702 ::date 2015-11-03T09:28:14 ::annotator SDL-AMR-09 ::preferred
# ::snt C, summary of the  Rab binding specificity of the  mouse or  human Slp family (Slp1-5), the Slac2  family (Slac2-a/b/c),  Rim1,  Rim2,  Noc2, and  rabphilin (see also Fig.  5).
# ::save-date Fri Nov 20, 2015 ::file bio_chicago_2015_55702.txt
(s2 / summarize-01 :li "c"
      :ARG1 (s3 / specific-02
            :ARG1 (b / bind-01
                  :ARG1 (a / and
                        :op1 (p2 / protein-family :name (n2 / name :op1 "Slp")
                              :mod (m / mouse
                                    :op1-of (o / or
                                          :op2 (h / human)))
                              :ARG1-of (m3 / mean-01
                                    :ARG2 (v / value-interval
                                          :op1 (p10 / protein :name (n10 / name :op1 "Slp1"))
                                          :op2 (p11 / protein :name (n11 / name :op1 "Slp5")))))
                        :op2 (p3 / protein-family :name (n3 / name :op1 "Slac2")
                              :ARG1-of (m2 / mean-01
                                    :ARG2 (a2 / and
                                          :op1 (p7 / protein :name (n7 / name :op1 "Slac2-a"))
                                          :op2 (p8 / protein :name (n8 / name :op1 "Slac2-b"))
                                          :op3 (p9 / protein :name (n9 / name :op1 "Slac2-c")))))
                        :op3 (p4 / protein :name (n4 / name :op1 "Rim1"))
                        :op4 (p5 / protein :name (n5 / name :op1 "Rim2"))
                        :op5 (p6 / protein :name (n6 / name :op1 "Noc2"))
                        :op6 (r / rabphilin))
                  :ARG2 (p / protein-family :name (n / name :op1 "Rab"))))
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod 5
                  :ARG1-of (s4 / see-01 :mode imperative
                        :ARG0 (y / you)
                        :mod (a3 / also)))))

# ::id bio.chicago_2015.55713 ::date 2015-11-03T09:39:32 ::annotator SDL-AMR-09 ::preferred
# ::snt Exchange of the  GDP bound to  eIF2 with  GTP is catalyzed by  eIF2B.
# ::save-date Tue Nov 3, 2015 ::file bio_chicago_2015_55713.txt
(c / catalyze-01
      :ARG0 (p3 / protein :name (n4 / name :op1 "eIF2B"))
      :ARG1 (e / exchange-01
            :ARG1 (s / small-molecule :wiki "Guanosine_diphosphate" :name (n / name :op1 "GDP")
                  :ARG1-of (b / bind-01
                        :ARG2 (p2 / protein :name (n3 / name :op1 "eIF2"))))
            :ARG3 (s2 / small-molecule :name (n2 / name :op1 "GTP"))))

# ::id bio.chicago_2015.55730 ::date 2015-11-03T09:58:21 ::annotator SDL-AMR-09 ::preferred
# ::snt Binding of  PTB or  PTB  to uniformly labeled  MSE1-4 RNA was assayed by UV crosslinking followed by immunoprecipitation using the  AntiXpress antibody.
# ::save-date Fri Nov 20, 2015 ::file bio_chicago_2015_55730.txt
(a / assay-01
      :ARG1 (b / bind-01
            :ARG1 (o / or
                  :op1 (p / protein :name (n3 / name :op1 "PTB"))
                  :op2 p)
            :ARG2 (n4 / nucleic-acid :name (n5 / name :op1 "RNA")
                  :ARG1-of (l / label-01
                        :ARG1-of (u / uniform-02))
                  :ARG0-of (e / encode-01
                        :ARG1 (p2 / protein :name (n / name :op1 "MSE1-4")))))
      :manner (c / crosslink-00
            :ARG0 (l2 / light
                  :mod (u2 / ultraviolet))
            :ARG2-of (f / follow-01
                  :ARG1 (i / immunoprecipitate-01
                        :ARG3 (a2 / antibody :name (n7 / name :op1 "AntiXpressdd"))))))

# ::id bio.chicago_2015.55746 ::date 2015-11-03T10:05:15 ::annotator SDL-AMR-09 ::preferred
# ::snt The N-terminal boundary for  PABP binding resides between amino acids 132 and 139, because  eIF4GI(132-329) bound  PABP, but  eIF4GI(139-329) did not (Figure  3B, compare lanes 3 and 4).
# ::save-date Fri Nov 27, 2015 ::file bio_chicago_2015_55746.txt
(c / cause-01
      :ARG0 (c2 / contrast-01
            :ARG1 (b6 / bind-01
                  :ARG1 p2
                  :ARG2 (p3 / protein :name (n5 / name :op1 "eIF4GI")
                        :part (a3 / amino-acid
                              :mod (v / value-interval :op1 132 :op2 329))))
            :ARG2 (b7 / bind-01 :polarity -
                  :ARG1 p2
                  :ARG2 (p4 / protein :name (n6 / name :op1 "eIF4GI")
                        :part (a4 / amino-acid
                              :mod (v2 / value-interval :op1 139 :op2 329)))))
      :ARG1 (r / reside-01
            :ARG0 (b3 / boundary
                  :mod (p / protein-segment :name (n / name :op1 "N-terminus"))
                  :purpose (b4 / bind-01
                        :ARG2 (p2 / protein :name (n2 / name :op1 "PABP"))))
            :ARG1 (b5 / between
                  :op1 (a / amino-acid :mod 139)
                  :op2 (a2 / amino-acid :mod 329)))
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod "3B"
                  :location-of (c3 / compare-01 :mode imperative
                        :ARG0 (y / you)
                        :ARG1 (l / lane :mod 3)
                        :ARG2 (l2 / lane :mod 4)))))

# ::id bio.chicago_2015.55796 ::date 2015-11-03T21:38:43 ::annotator SDL-AMR-09 ::preferred
# ::snt This sequence shows marked homology to the amino-terminal sequence determined here for  processed Smac/ DIABLO bound to  XIAP, AVPIAQ;  Smac/ DIABLO has been processed here to remove the first 55 amino acids.
# ::save-date Fri Feb 5, 2016 ::file bio_chicago_2015_55796.txt
(a3 / and
      :op1 (s / show-01
            :ARG0 (s2 / sequence
                  :mod (t / this))
            :ARG1 (h / homologous
                  :compared-to (s3 / sequence
                        :ARG1-of (d / determine-01
                              :ARG2 (p / protein :name (n / name :op1 "Smac/DIABLO")
                                    :ARG1-of (p2 / process-01)
                                    :ARG1-of (b / bind-01
                                          :ARG2 (a2 / and
                                                :op1 (p3 / protein :name (n2 / name :op1 "XIAP"))
                                                :op2 (p4 / protein :name (n3 / name :op1 "AVPIAQ")))))
                              :location (h3 / here))
                        :mod (p6 / protein-segment :name (n4 / name :op1 "amino-terminus")))
                  :ARG1-of (m / mark-01)))
      :op2 (p5 / process-01
            :ARG1 (p7 / protein :name (n5 / name :op1 "Smac/DIABLO"))
            :purpose (r / remove-01
                  :ARG0 p7
                  :ARG1 (a4 / amino-acid :quant 55
                        :ord (o / ordinal-entity :value 1)))
            :location h3))

# ::id bio.chicago_2015.55877 ::date 2015-11-03T22:10:46 ::annotator SDL-AMR-09 ::preferred
# ::snt Rab binding properties of the   Slp  family, the  Slac2  family,  Rim1,  Rim2,  Noc2, and  rabphilin.
# ::save-date Wed Nov 11, 2015 ::file bio_chicago_2015_55877.txt
(p / property
      :mod (b / bind-01
            :ARG1 (a / and
                  :op1 (p3 / protein-family :name (n2 / name :op1 "Slp"))
                  :op2 (p4 / protein-family :name (n3 / name :op1 "Slac2"))
                  :op3 (p5 / protein :name (n4 / name :op1 "Rim1"))
                  :op4 (p6 / protein :name (n5 / name :op1 "Rim2"))
                  :op5 (p7 / protein :name (n6 / name :op1 "Noc2"))
                  :op6 (p8 / protein :name (n7 / name :op1 "rabphilin")))
            :ARG2 (p2 / protein-family :name (n / name :op1 "Rab"))))

# ::id bio.chicago_2015.55886 ::date 2015-11-03T22:16:41 ::annotator SDL-AMR-09 ::preferred
# ::snt Raf did not inhibit the binding of  RGL to  RasG12V/E37G under the condition that  Raf inhibited that of  RGL to  RasG12V.
# ::save-date Thu Jan 14, 2016 ::file bio_chicago_2015_55886.txt
(i / inhibit-01 :polarity -
      :ARG0 (e4 / enzyme :name (n2 / name :op1 "Raf"))
      :ARG1 (b / bind-01
            :ARG1 (p / protein :name (n3 / name :op1 "RGL"))
            :ARG2 (e3 / enzyme :name (n4 / name :op1 "Ras")
                  :ARG1-of (m / mutate-01 :value "G12V")
                  :ARG1-of (m2 / mutate-01 :value "E37G")))
      :condition (i2 / inhibit-01
            :ARG0 e4
            :ARG1 (b2 / bind-01
                  :ARG1 p
                  :ARG2 (e / enzyme :name (n5 / name :op1 "Ras")
                        :ARG1-of (m3 / mutate-01 :value "G12V")))))

# ::id bio.chicago_2015.55914 ::date 2015-11-03T22:22:53 ::annotator SDL-AMR-09 ::preferred
# ::snt Because  Src does not bind to  Abl (not shown), its binding to  Cbl in the presence of  Abl could be explained by a modification of  Cbl conformation induced by its binding to  Abl.
# ::save-date Wed Nov 11, 2015 ::file bio_chicago_2015_55914.txt
(c / cause-01
      :ARG0 (b / bind-01 :polarity -
            :ARG1 (p2 / protein :name (n / name :op1 "Src"))
            :ARG2 (p4 / protein :name (n2 / name :op1 "Abl"))
            :ARG1-of (s / show-01 :polarity -))
      :ARG1 (p / possible-01
            :ARG1 (e / explain-01
                  :ARG1 (b2 / bind-01
                        :ARG1 p2
                        :ARG2 (p5 / protein :name (n3 / name :op1 "Cbl"))
                        :condition (p3 / present-02
                              :ARG1 p4))
                  :manner (m / modify-01
                        :ARG1 (c2 / conform-01
                              :ARG1 p5)
                        :ARG2-of (i / induce-01
                              :ARG0 (b3 / bind-01
                                    :ARG1 p2
                                    :ARG2 p4))))))

# ::id bio.chicago_2015.55915 ::date 2015-11-03T22:28:39 ::annotator SDL-AMR-09 ::preferred
# ::snt In agreement with the published data   [7,19]  , we readily demonstrated that a  PAK CRIB peptide can bind directly to both  Cdc42 and  Rac1, whereas an N-WASP CRIB peptide bound only to  Cdc42.
# ::save-date Sun Jan 17, 2016 ::file bio_chicago_2015_55915.txt
(c / contrast-01
      :ARG1 (d / demonstrate-01
            :ARG0 (w / we)
            :ARG1 (p / possible-01
                  :ARG1 (b / bind-01
                        :ARG1 (p2 / peptide :name (n / name :op1 "PAK" :op2 "CRIB"))
                        :ARG2 (a / and
                              :op1 (p3 / protein :name (n2 / name :op1 "Cdc42"))
                              :op2 (p7 / protein :name (n3 / name :op1 "Rac1")))
                        :ARG1-of (d2 / direct-02)))
            :ARG2-of (r / ready-02))
      :ARG2 (b2 / bind-01
            :ARG1 (p4 / peptide :name (n4 / name :op1 "N-WASP" :op2 "CRIB"))
            :ARG2 p3
            :mod (o / only))
      :ARG1-of (a2 / agree-01
            :ARG2 (d3 / data
                  :ARG1-of (p5 / publish-01)
                  :ARG1-of (d4 / describe-01
                        :ARG0 (p6 / publication
                              :ARG1-of (c2 / cite-01
                                    :ARG2 (a3 / and :op1 7 :op2 19)))))))

# ::id bio.chicago_2015.55927 ::date 2015-11-03T22:34:52 ::annotator SDL-AMR-09 ::preferred
# ::snt TLP can bind  TFIIA and  TFIIB,  like TBP, but does not bind to the TATA sequence ( 40,  42,  48,  57).
# ::save-date Sun Jan 17, 2016 ::file bio_chicago_2015_55927.txt
(c / contrast-01
      :ARG1 (p / possible-01
            :ARG1 (b / bind-01
                  :ARG1 (a / and
                        :op1 (p3 / protein :name (n2 / name :op1 "TFIIA"))
                        :op2 (p4 / protein :name (n3 / name :op1 "TFIIB")))
                  :ARG2 (p2 / protein :name (n / name :op1 "TLP")
                        :ARG1-of (r / resemble-01
                              :ARG2 (p5 / protein :name (n4 / name :op1 "TBP"))))))
      :ARG2 (b2 / bind-01 :polarity -
            :ARG1 (p7 / protein :name (n6 / name :op1 "TLP"))
            :ARG2 (d2 / dna-sequence :name (n5 / name :op1 "TATA")))
      :ARG1-of (d / describe-01
            :ARG0 (p6 / publication
                  :ARG1-of (c2 / cite-01
                        :ARG2 (a2 / and :op1 40 :op2 42 :op3 48 :op4 57)))))

# ::id bio.chicago_2015.55934 ::date 2015-11-03T22:59:14 ::annotator SDL-AMR-09 ::preferred
# ::snt For this, nonspecific binding of the  PTN radioligand to 32D/control cells was subtracted from the total binding to  32D/ALK cells to obtain the amount of  PTN bound to  ALK at different concentrations of  PTN.
# ::save-date Sun Jan 17, 2016 ::file bio_chicago_2015_55934.txt
(s / subtract-01
      :ARG1 (b / bind-01
            :ARG1 (r / radioligand
                  :mod (p2 / protein :name (n3 / name :op1 "PTN")))
            :ARG2 (s3 / slash
                  :op1 (c / cell-line :name (n2 / name :op1 "32D"))
                  :op2 (c6 / cell
                        :ARG0-of (c2 / control-01)))
            :ARG1-of (s2 / specific-02 :polarity -))
      :ARG2 (b2 / bind-01
            :ARG2 (s4 / slash
                  :op1 c
                  :op2 (c4 / cell
                        :mod e))
            :mod (t / total))
      :purpose (o / obtain-01
            :ARG1 (a / amount
                  :quant-of (p / protein :name (n5 / name :op1 "PTN")
                        :ARG1-of (b3 / bind-01
                              :ARG2 (e / enzyme :name (n6 / name :op1 "ALK"))
                              :condition (c5 / concentrate-02
                                    :ARG1-of (d / differ-02))))))
      :purpose (t2 / this))

# ::id bio.chicago_2015.55945 ::date 2015-11-03T23:15:26 ::annotator SDL-AMR-09 ::preferred
# ::snt The crystal structures of both the  GDP- and  GTP-bound forms of  ARF1 have been solved ( 1,  20,  21).
# ::save-date Wed Nov 11, 2015 ::file bio_chicago_2015_55945.txt
(s2 / solve-01
      :ARG1 (s3 / structure-01
            :ARG1 (a3 / and
                  :op1 (p / protein :name (n / name :op1 "ARF1")
                        :ARG1-of (b2 / bind-01
                              :ARG2 (a / and
                                    :op1 (s4 / small-molecule :name (n2 / name :op1 "GDP")))))
                  :op2 (p3 / protein :name (n5 / name :op1 "ARF1")
                        :ARG1-of (b3 / bind-01
                              :ARG2 (s5 / small-molecule :name (n3 / name :op1 "GTP")))))
            :ARG2 (c / crystal))
      :ARG1-of (d2 / describe-01
            :ARG0 (p2 / publication
                  :ARG1-of (c2 / cite-01
                        :ARG2 (a2 / and :op1 1 :op2 20 :op3 21)))))

# ::id bio.chicago_2015.55950 ::date 2015-11-03T23:21:22 ::annotator SDL-AMR-09 ::preferred
# ::snt Pins nearly completely  abolishes the binding between  Galphai and  Gbeta13F.
# ::save-date Wed Nov 11, 2015 ::file bio_chicago_2015_55950.txt
(a / abolish-01
      :ARG0 (p3 / protein :name (n2 / name :op1 "Pins"))
      :ARG1 (b / bind-01
            :ARG1 (p / protein :name (n3 / name :op1 "Galphai"))
            :ARG2 (p2 / protein :name (n4 / name :op1 "Gbeta13F")))
      :ARG1-of (c / complete-02
            :degree (n / near)))

# ::id bio.chicago_2015.55988 ::date 2015-11-03T23:25:06 ::annotator SDL-AMR-09 ::preferred
# ::snt Crk Binding to  CAS Is Required for the Induction of  Cell Migration
# ::save-date Wed Nov 11, 2015 ::file bio_chicago_2015_55988.txt
(r / require-01
      :ARG0 (i / induce-01
            :ARG1 (c / cell)
            :ARG2 (m / migrate-01
                  :ARG0 c))
      :ARG1 (b / bind-01
            :ARG1 (p2 / protein :name (n / name :op1 "Crk"))
            :ARG2 (p / protein :name (n2 / name :op1 "CAS"))))

# ::id bio.chicago_2015.56033 ::date 2015-11-03T23:33:53 ::annotator SDL-AMR-09 ::preferred
# ::snt These results indicate that  FAST2 constitutively binds the   gsc promoter and that  Smad2 and  Smad4 expressed in mammalian cells cannot interact directly with the element.
# ::save-date Fri Nov 20, 2015 ::file bio_chicago_2015_56033.txt
(i / indicate-01
      :ARG0 (t / thing
            :ARG2-of (r / result-01)
            :mod (t2 / this))
      :ARG1 (a / and
            :op1 (b / bind-01
                  :ARG1 (p2 / protein :name (n / name :op1 "FAST2"))
                  :ARG2 (m / molecular-physical-entity
                        :ARG0-of (p3 / promote-01
                              :ARG1 (p4 / protein :name (n2 / name :op1 "gsc"))))
                  :manner (c / constitutive))
            :op2 (p / possible-01 :polarity -
                  :ARG1 (i2 / interact-01
                        :ARG0 (a2 / and
                              :op1 (p5 / protein :name (n3 / name :op1 "Smad2"))
                              :op2 (p6 / protein :name (n4 / name :op1 "Smad4"))
                              :ARG2-of (e / express-03
                                    :ARG3 (c2 / cell
                                          :mod (m2 / mammal))))
                        :ARG1 m
                        :ARG1-of (d / direct-02)))))

# ::id bio.chicago_2015.56052 ::date 2015-11-03T23:41:20 ::annotator SDL-AMR-09 ::preferred
# ::snt This observation suggests that  APP may play an important role in  neurotransmitter release at nerve terminals or that  Mint-2 may regulate the binding ability of  X11L to  APP.
# ::save-date Wed Nov 11, 2015 ::file bio_chicago_2015_56052.txt
(s / suggest-01
      :ARG0 (o / observe-01
            :mod (t2 / this))
      :ARG1 (o2 / or
            :op1 (p / possible-01
                  :ARG1 (p2 / play-02
                        :ARG0 (p3 / protein :name (n / name :op1 "APP"))
                        :ARG1 (r / role
                              :mod (i / important)
                              :purpose (r2 / release-01
                                    :ARG1 (n2 / neurotransmitter)
                                    :location (t / terminal
                                          :part-of (n3 / nerve))))))
            :op2 (p4 / possible-01
                  :ARG1 (r3 / regulate-01
                        :ARG0 (p6 / protein :name (n4 / name :op1 "Mint-2"))
                        :ARG1 (c / capable-01
                              :ARG1 (p5 / protein :name (n5 / name :op1 "X11L"))
                              :ARG2 (b / bind-01
                                    :ARG1 p5
                                    :ARG2 p3))))))

# ::id bio.chicago_2015.56121 ::date 2015-11-03T23:49:26 ::annotator SDL-AMR-09 ::preferred
# ::snt SLBP associated with the  pre-mRNA stabilizes the binding of  U7 snRNP, suggesting that  SLBP bound to the  pre-mRNA might interact with one of the  U7 snRNP specific proteins (Dominski et al. 1999  ).
# ::save-date Wed Nov 11, 2015 ::file bio_chicago_2015_56121.txt
(s / stabilize-01
      :ARG0 (p7 / protein :name (n / name :op1 "SLBP")
            :ARG1-of (a / associate-01
                  :ARG2 (n2 / nucleic-acid :name (n3 / name :op1 "pre-mRNA"))))
      :ARG1 (b / bind-01
            :ARG1 (p2 / protein :name (n4 / name :op1 "U7" :op2 "snRNP")))
      :ARG0-of (s2 / suggest-01
            :ARG1 (p / possible-01
                  :ARG1 (i / interact-01
                        :ARG0 (p8 / protein :name (n5 / name :op1 "SLBP")
                              :ARG1-of (b2 / bind-01
                                    :ARG2 n2))
                        :ARG1 (p3 / protein
                              :ARG1-of (s3 / specific-02
                                    :ARG2 p2)))))
      :ARG1-of (d2 / describe-01
            :ARG0 (p4 / publication-91
                  :ARG0 (a2 / and
                        :op1 (p5 / person :name (n6 / name :op1 "Dominski"))
                        :op2 (p6 / person
                              :mod (o / other)))
                  :time (d / date-entity :year 1999))))

# ::id bio.chicago_2015.56140 ::date 2015-11-04T00:00:36 ::annotator SDL-AMR-09 ::preferred
# ::snt We have shown that the region downstream of the DNA -binding domain in  D-Myb binds to  dCBP.
# ::save-date Wed Nov 11, 2015 ::file bio_chicago_2015_56140.txt
(s / show-01
      :ARG0 (w2 / we)
      :ARG1 (b / bind-01
            :ARG1 (r / region
                  :location (r2 / relative-position
                        :op1 (d2 / domain
                              :ARG2-of (b2 / bind-01
                                    :ARG1 (n3 / nucleic-acid :name (n4 / name :op1 "DNA")))
                              :location (p2 / protein :name (n5 / name :op1 "D-Myb")))
                        :direction (d / downstream)))
            :ARG2 (p / protein :name (n6 / name :op1 "dCBP"))))

# ::id bio.chicago_2015.56172 ::date 2015-11-04T00:06:06 ::annotator SDL-AMR-09 ::preferred
# ::snt The inhibition of  Sp1 binding by  EDTA was not abrogated by the addition of ZnCl2.
# ::save-date Sat Feb 13, 2016 ::file bio_chicago_2015_56172.txt
(a / abrogate-01 :polarity -
      :ARG0 (a3 / add-02
            :ARG1 (s / small-molecule :name (n3 / name :op1 "ZnCl2")))
      :ARG1 (i / inhibit-01
            :ARG1 (b / bind-01
                  :ARG1 (p / protein :name (n / name :op1 "Sp1"))
                  :ARG2 (s2 / small-molecule :name (n2 / name :op1 "EDTA")))))

# ::id bio.chicago_2015.56218 ::date 2015-11-04T00:12:24 ::annotator SDL-AMR-09 ::preferred
# ::snt ( B) Binding of  Dfd and  Dfd-VP16 to the 2xD site (see Figure  4 for sequence) in EMSAs.
# ::save-date Sun Jan 17, 2016 ::file bio_chicago_2015_56218.txt
(b / bind-01
      :ARG1 (a / and
            :op1 (p / protein :name (n / name :op1 "Dfd"))
            :op2 (p2 / protein :name (n2 / name :op1 "Dfd-VP16")))
      :ARG2 (p3 / protein-segment :name (n5 / name :op1 "2xD" :op2 "site")
            :ARG1-of (d / describe-01
                  :ARG0 (f / figure :mod 4
                        :ARG1-of (s2 / see-01 :mode imperative
                              :ARG0 (y / you)
                              :purpose (s3 / sequence)))))
      :location (a2 / assay-01
            :instrument (t / thing :name (n3 / name :op1 "EMSA")))
      :ARG1-of (d2 / describe-01
            :ARG0 (f2 / figure :mod "B")))

# ::id bio.chicago_2015.56261 ::date 2015-11-04T00:16:40 ::annotator SDL-AMR-09 ::preferred
# ::snt Actin binds so tightly to  Brg1 that only denaturing conditions will separate them, and it has not been established that  Brg is active as an ATPase in the absence of  actin.
# ::save-date Fri Nov 20, 2015 ::file bio_chicago_2015_56261.txt
(a / and
      :op1 (c / cause-01
            :ARG0 (b / bind-01
                  :ARG1 (p / protein :name (n / name :op1 "Actin"))
                  :ARG2 (p2 / protein :name (n2 / name :op1 "Brg1"))
                  :ARG1-of (t / tight-05
                        :degree (s2 / so)))
            :ARG1 (s / separate-01
                  :ARG0 (c2 / condition
                        :ARG0-of (d / denaturate-00)
                        :mod (o / only))
                  :ARG1 (a2 / and
                        :op1 p
                        :op2 p2)))
      :op2 (e / establish-01 :polarity -
            :ARG1 (a3 / activity-06
                  :ARG0 (p3 / protein :name (n3 / name :op1 "Brg"))
                  :ARG1 (e2 / enzyme :name (n4 / name :op1 "ATPase"))
                  :condition (a4 / absent-01
                        :ARG1 p))))

# ::id bio.chicago_2015.56319 ::date 2015-11-04T00:23:55 ::annotator SDL-AMR-09 ::preferred
# ::snt Transcription factor IIE binds preferentially to  RNA polymerase IIA and  recruits TFIIH a model for promoter clearance.
# ::save-date Fri Nov 20, 2015 ::file bio_chicago_2015_56319.txt
(a / and
      :op1 (b / bind-01
            :ARG1 (f / factor :name (n3 / name :op1 "IIE")
                  :ARG0-of (t / transcribe-01))
            :ARG2 (e2 / enzyme :name (n6 / name :op1 "RNA" :op2 "polymerase" :op3 "IIA"))
            :ARG1-of (p / prefer-01))
      :op2 (r / recruit-01
            :ARG0 f
            :ARG1 (p2 / protein :name (n5 / name :op1 "TFIIH")
                  :ARG1-of (m / mean-01
                        :ARG2 (m2 / model-01
                              :ARG2 (c / clear-02
                                    :ARG1 (m3 / molecular-physical-entity
                                          :ARG0-of (p3 / promote-01))))))))

# ::id bio.chicago_2015.56329 ::date 2015-11-04T00:28:48 ::annotator SDL-AMR-09 ::preferred
# ::snt Binding of both  SLBP and  U7 snRNP to the  pre-mRNA results in formation of a stable complex due to interaction between these two factors and their mutual stabilization on the substrate.
# ::save-date Fri Nov 20, 2015 ::file bio_chicago_2015_56329.txt
(c / cause-01
      :ARG0 (a2 / and
            :op1 (i / interact-01
                  :ARG0 p2
                  :ARG1 p)
            :op2 (s2 / stabilize-01
                  :ARG1 (a4 / and
                        :op1 p
                        :op2 p2)
                  :location (s3 / substrate)
                  :mod (m2 / mutual)))
      :ARG1 (r / result-01
            :ARG1 (b / bind-01
                  :ARG1 (a / and
                        :op1 (p2 / protein :name (n / name :op1 "SLBP"))
                        :op2 (p / protein :name (n2 / name :op1 "U7" :op2 "snRNP")))
                  :ARG2 (n3 / nucleic-acid :name (n4 / name :op1 "pre-mRNA")))
            :ARG2 (f / form-01
                  :ARG1 (m / macro-molecular-complex
                        :ARG1-of (s / stable-03)))))

# ::id bio.chicago_2015.56330 ::date 2015-11-04T00:34:48 ::annotator SDL-AMR-09 ::preferred
# ::snt Yeast two-hybrid liquid assays, affinity chromatography, and coimmunoprecipitation experiments confirm  binding between  PS2 and  calmyrin.
# ::save-date Wed Nov 11, 2015 ::file bio_chicago_2015_56330.txt
(c / confirm-01
      :ARG0 (a / and
            :op1 (a2 / assay-01
                  :mod (l / liquid)
                  :mod (h / hybrid :quant 2)
                  :mod (y / yeast))
            :op2 (c2 / chromatography
                  :mod (a3 / affinity))
            :op3 (e / experiment-01
                  :ARG2 (c3 / coimmunoprecipitate-01)))
      :ARG1 (b / bind-01
            :ARG1 (p2 / protein :name (n / name :op1 "PS2"))
            :ARG2 (p / protein :name (n2 / name :op1 "calmyrin"))))

# ::id bio.chicago_2015.56367 ::date 2015-11-04T00:39:23 ::annotator SDL-AMR-09 ::preferred
# ::snt It is not clear whether  PS1 binds directly to  E-cadherin; their interaction might be mediated by other components of the  cadherin/ catenin system.
# ::save-date Wed Nov 11, 2015 ::file bio_chicago_2015_56367.txt
(a / and
      :op1 (c / clear-06 :polarity -
            :ARG1 (b / bind-01 :mode interrogative
                  :ARG1 (p3 / protein :name (n / name :op1 "PS1"))
                  :ARG2 (p2 / protein :name (n2 / name :op1 "E-cadherin"))
                  :ARG1-of (d / direct-02)))
      :op2 (p / possible-01
            :ARG1 (m / mediate-01
                  :ARG0 (c2 / component
                        :part-of (s / system
                              :part (p4 / protein :name (n3 / name :op1 "cadherin"))
                              :part (p5 / protein :name (n4 / name :op1 "catenin")))
                        :mod (o / other))
                  :ARG1 (i / interact-01
                        :ARG0 p3
                        :ARG1 p2))))

# ::id bio.chicago_2015.56383 ::date 2015-11-04T00:44:25 ::annotator SDL-AMR-09 ::preferred
# ::snt While a highly purified preparation of  TFII-I bound to an intact  Inr element (Fig.  2B, lane 2), the binding of  TFII-I to the  mutant Inr probe is nearly abrogated (about fivefold less as revealed by densitometric measurements) (Fig.  2B, lane 5).
# ::save-date Sat Feb 13, 2016 ::file bio_chicago_2015_56383.txt
(c / contrast-01
      :ARG1 (b / bind-01
            :ARG1 (t / thing
                  :ARG1-of (p / prepare-01
                        :ARG2 (p2 / protein :name (n / name :op1 "TFII-I")))
                  :ARG1-of (p3 / purify-01
                        :ARG1-of (h / high-02)))
            :ARG2 (m5 / molecular-physical-entity
                  :mod (i / intact)
                  :mod (e / element)
                  :ARG0-of (i2 / initiate-01))
            :ARG1-of (d / describe-01
                  :ARG0 (a / and
                        :op1 (f / figure :mod "2B")
                        :op2 (l / lane :mod 2))))
      :ARG2 (a2 / abrogate-01
            :ARG1 (b2 / bind-01
                  :ARG1 p2
                  :ARG2 (m4 / molecular-physical-entity
                        :ARG2-of (m / mutate-01)
                        :ARG1-of (p4 / probe-01)
                        :ARG1-of i2))
            :degree (n3 / near)
            :ARG1-of (m2 / mean-01
                  :ARG2 (l2 / less
                        :quant (p5 / product-of :op1 5)
                        :ARG1-of (r / reveal-01
                              :ARG0 (m3 / measure-01
                                    :mod (d2 / densitometric)))))
            :ARG1-of (d3 / describe-01
                  :ARG0 (a3 / and
                        :op1 (f2 / figure :mod "2B")
                        :op2 (l3 / lane :mod 5)))))

# ::id bio.chicago_2015.56386 ::date 2015-11-04T00:52:47 ::annotator SDL-AMR-09 ::preferred
# ::snt In contrast, a specific binding of  GST-HP1  to the  linker histone H1, isolated from either  calf thymus (  Figure 4D, lane 5) or  P19 nuclei (  Figure 4D, lane 6), was observed, indicating that  HP1 , but neither  HP1  nor  HP1  (  Figures 4E and 4F, lane 5), can bind to both  H3 and  H1.
# ::save-date Sun Jan 17, 2016 ::file bio_chicago_2015_56386.txt
(c / contrast-01
      :ARG2 (o / observe-01
            :ARG1 (b / bind-01
                  :ARG1 (p4 / protein :name (n / name :op1 "GST-HP1"))
                  :ARG2 (p5 / protein :name (n2 / name :op1 "histone" :op2 "H1")
                        :ARG0-of (l / link-01))
                  :ARG1-of (s / specific-02)
                  :ARG1-of (i / isolate-01
                        :ARG2 (o2 / or
                              :op1 (d / dna-sequence :name (n3 / name :op1 "calf" :op2 "thymus")
                                    :ARG1-of (d2 / describe-01
                                          :ARG0 (a / and
                                                :op1 (f / figure :mod "4D")
                                                :op2 (l2 / lane :mod 5))))
                              :op2 (n4 / nucleus
                                    :ARG1-of (d3 / describe-01
                                          :ARG0 (a2 / and
                                                :op1 f
                                                :op2 (l3 / lane :mod 6)))
                                    :part-of (c3 / cell :name (n5 / name :op1 "P19"))))))
            :ARG0-of (i2 / indicate-01
                  :ARG1 (c2 / contrast-01
                        :ARG1 (b2 / bind-01
                              :ARG1 (p / protein :name (n6 / name :op1 "HP1"))
                              :ARG2 (a3 / and
                                    :op1 (p2 / protein :name (n7 / name :op1 "H3"))
                                    :op2 (p3 / protein :name (n8 / name :op1 "H1"))))
                        :ARG2 (b3 / bind-01 :polarity -
                              :ARG1 (o3 / or
                                    :op1 p
                                    :op2 p)
                              :ARG2 a3
                              :ARG1-of (d4 / describe-01
                                    :ARG0 (a4 / and
                                          :op1 (a5 / and
                                                :op1 (f2 / figure :mod "4E")
                                                :op2 (f3 / figure :mod "4F"))
                                          :op2 (l4 / lane :mod 5))))))))

# ::id bio.chicago_2015.56388 ::date 2015-11-04T01:02:50 ::annotator SDL-AMR-09 ::preferred
# ::snt Our data further suggest that this element might be an  NES because its activity is inhibited by the antibiotic  LMB, which specifically binds to the  NES receptor,  CRM1.
# ::save-date Wed Nov 11, 2015 ::file bio_chicago_2015_56388.txt
(c / cause-01
      :ARG0 (i / inhibit-01
            :ARG0 (a3 / antibiotic :name (n2 / name :op1 "LMB")
                  :ARG1-of (b / bind-01
                        :ARG2 (r / receptor :name (n3 / name :op1 "CRM1")
                              :mod p2)
                        :ARG1-of (s2 / specific-02)))
            :ARG1 (a2 / activity-06
                  :ARG0 e))
      :ARG1 (s / suggest-01
            :ARG0 (d / data
                  :poss (w / we))
            :ARG1 (p / possible-01
                  :ARG1 (e / element
                        :mod (t / this)
                        :mod (p2 / protein-segment :name (n / name :op1 "NES"))))
            :mod (f / further)))

# ::id bio.chicago_2015.56477 ::date 2015-11-04T01:08:08 ::annotator SDL-AMR-09 ::preferred
# ::snt In the  presence of the  anti-STII-C2B antibody, the  IP   binding  activity of both  GST-STII-C2B and purified  synaptotagmin II was  completely inhibited dose dependently ( Fig. 1,  B  and  C).
# ::save-date Wed Nov 11, 2015 ::file bio_chicago_2015_56477.txt
(i4 / inhibit-01
      :ARG1 (a / activity-06
            :ARG0 (a3 / and
                  :op1 (p / protein :name (n / name :op1 "GST-STII-C2B"))
                  :op2 (p2 / protein :name (n2 / name :op1 "synaptotagmin" :op2 "II")
                        :ARG1-of (p3 / purify-01)))
            :ARG1 (b / bind-01)
            :mod (i3 / immunoprecipitate-01))
      :ARG1-of (c / complete-01)
      :ARG0-of (d / depend-01
            :ARG1 (d2 / dose))
      :condition (p4 / present-02
            :ARG1 (a4 / antibody
                  :ARG0-of (o2 / oppose-01
                        :ARG1 (p5 / protein :name (n3 / name :op1 "STII-C2B")))))
      :ARG1-of (d3 / describe-01
            :ARG0 (a6 / and
                  :op1 (f / figure :mod 1)
                  :op2 (f2 / figure :mod "B")
                  :op3 (f3 / figure :mod "C"))))

# ::id bio.chicago_2015.56492 ::date 2015-11-02T07:53:20 ::annotator SDL-AMR-09 ::preferred
# ::snt Because the  proline-rich core of  Mena binds to the  profilin,  WW, and  SH3 domains, it will be important to determine which of these interactions are compatible and which are competitive.
# ::save-date Sun Jan 17, 2016 ::file bio_chicago_2015_56492.txt
(c / cause-01
      :ARG0 (b / bind-01
            :ARG1 (c2 / core
                  :part-of (p / protein :name (n / name :op1 "Mena"))
                  :mod (r / rich
                        :mod (a / amino-acid :name (n2 / name :op1 "proline"))))
            :ARG2 (a2 / and
                  :op1 (p2 / protein-segment
                        :part-of (p5 / protein :name (n3 / name :op1 "profilin")))
                  :op2 (p3 / protein-segment :name (n4 / name :op1 "WW"))
                  :op2 (p4 / protein-segment :name (n5 / name :op1 "SH3"))))
      :ARG1 (i / important
            :domain (d / determine-01
                  :ARG1 (a3 / and
                        :op1 (c3 / compatible
                              :domain (i2 / interact-01
                                    :mod (t / this)))
                        :op2 (c4 / compete-01
                              :ARG0 i2)))))

# ::id bio.chicago_2015.56510 ::date 2015-11-02T08:24:39 ::annotator SDL-AMR-09 ::preferred
# ::snt The checkpoint-resistant  Cdc20 mutants greatly diminished the binding of  Mad2 and  Mad3 to  Cdc20 (Fig.  3C) but had no effect on the overall level of  Mad1,  Mad2, or  Mad3 in the cell ( 21).
# ::save-date Sun Nov 8, 2015 ::file bio_chicago_2015_56510.txt
(c / contrast-01
      :ARG1 (d / diminish-01
            :ARG0 (p6 / protein :name (n / name :op1 "Cdc20")
                  :ARG2-of (m / mutate-01)
                  :ARG0-of (r / resist-01
                        :ARG1 (c2 / checkpoint)))
            :ARG1 (b / bind-01
                  :ARG1 (a / and
                        :op1 (p / protein :name (n2 / name :op1 "Mad2"))
                        :op2 (p2 / protein :name (n3 / name :op1 "Mad3")))
                  :ARG2 (p5 / protein :name (n4 / name :op1 "Cdc20")))
            :degree (g2 / great)
            :ARG1-of (d2 / describe-01
                  :ARG0 (f / figure :mod "3C")))
      :ARG2 (a2 / affect-01 :polarity -
            :ARG0 p6
            :ARG1 (o2 / or
                  :op1 (l2 / level
                        :mod (o / overall)
                        :location (c3 / cell)
                        :quant-of (p3 / protein :name (n5 / name :op1 "Mad1")))
                  :op2 (l3 / level
                        :mod o
                        :location c3
                        :quant-of p)
                  :op3 (l4 / level
                        :mod o
                        :location c3
                        :quant-of p2))
            :ARG1-of (d3 / describe-01
                  :ARG0 (p4 / publication
                        :ARG1-of (c4 / cite-01
                              :ARG2 21)))))

# ::id bio.chicago_2015.56529 ::date 2015-11-02T08:58:42 ::annotator SDL-AMR-09 ::preferred
# ::snt Corto binds to  ESC and E(Z), two members of the  PcG initiation complex   We first performed  GST pull-down assays to check the interactions between  Corto and  ESC and between  Corto and E(Z).
# ::save-date Sun Jan 17, 2016 ::file bio_chicago_2015_56529.txt
(m / multi-sentence
      :snt1 (b / bind-01
            :ARG1 (p / protein :name (n / name :op1 "Corto"))
            :ARG2 (a / and
                  :op1 (p2 / protein :name (n2 / name :op1 "ESC"))
                  :op2 (p3 / protein :name (n3 / name :op1 "E(Z)"))
                  :ARG1-of (i / include-91
                        :ARG2 (m2 / macro-molecular-complex
                              :ARG0-of (i2 / initiate-01
                                    :ARG1 (p7 / protein :name (n4 / name :op1 "PcG")))))))
      :snt2 (p4 / perform-02
            :ARG0 (w / we)
            :ARG1 (a2 / assay-01
                  :ARG1 (p5 / pull-down-08
                        :ARG1 (e / enzyme :name (n5 / name :op1 "GST"))))
            :purpose (c / check-01
                  :ARG0 w
                  :ARG1 (a4 / and
                        :op1 (i3 / interact-01
                              :ARG0 p
                              :ARG1 p2)
                        :op2 (i4 / interact-01
                              :ARG0 p
                              :ARG1 p3)))
            :time (f / first)))

# ::id bio.chicago_2015.56563 ::date 2015-11-02T09:23:06 ::annotator SDL-AMR-09 ::preferred
# ::snt Moreover, it has been shown that mutations in the N-terminal region of  actin, which yielded a change of charge, affect  myosin S1 binding to  actin and thereby reduce in vitro motility (Aspenstrom and Karlsson, 1991  ; Aspenstrom  et al., 1992  ; Sutoh  et al., 1991  ; Miller  et al., 1996  ).
# ::save-date Sun Nov 8, 2015 ::file bio_chicago_2015_56563.txt
(a / and
      :op2 (s / show-01
            :ARG1 (a2 / affect-01
                  :ARG0 (m / mutate-01
                        :ARG1 (p / protein-segment :name (n / name :op1 "N-terminus")
                              :part-of (p2 / protein :name (n2 / name :op1 "actin")))
                        :ARG0-of (y / yield-01
                              :ARG1 (c / change-01
                                    :ARG1 (c2 / charge-03))))
                  :ARG1 (b / bind-01
                        :ARG1 (p3 / protein-segment :name (n3 / name :op1 "S1")
                              :part-of (p4 / protein :name (n4 / name :op1 "myosin")))
                        :ARG2 p2)
                  :ARG0-of (c3 / cause-01
                        :ARG1 (r / reduce-01
                              :ARG0 m
                              :ARG1 (m2 / motility
                                    :mod (i / in-vitro)))))
            :ARG1-of (d / describe-01
                  :ARG0 (a3 / and
                        :op1 (p6 / publication-91
                              :ARG0 (a4 / and
                                    :op1 (p7 / person :name (n6 / name :op1 "Aspenstrom"))
                                    :op2 (p8 / person :name (n7 / name :op1 "Karlsson")))
                              :time (d2 / date-entity :year 1991))
                        :op2 (p9 / publication-91
                              :ARG0 (a5 / and
                                    :op1 p7
                                    :op2 (p11 / person
                                          :mod (o / other)))
                              :time (d3 / date-entity :year 1992))
                        :op3 (p12 / publication-91
                              :ARG0 (a6 / and
                                    :op1 (p13 / person :name (n9 / name :op1 "Sutoh"))
                                    :op2 (p14 / person
                                          :mod (o2 / other)))
                              :time d2)
                        :op4 (p15 / publication-91
                              :ARG0 (a7 / and
                                    :op1 (p16 / person :name (n10 / name :op1 "Miller"))
                                    :op2 (p17 / person
                                          :mod (o3 / other)))
                              :time (d5 / date-entity :year 1996))))))

# ::id bio.chicago_2015.56580 ::date 2015-11-02T10:03:21 ::annotator SDL-AMR-09 ::preferred
# ::snt Dimerization of  Rabaptin-5 could also form a divalent  Rab5-binding site, since single  Rabaptin-5 chains can bind  Rab5 (Horiuchi  et al., 1997).
# ::save-date Fri Jan 15, 2016 ::file bio_chicago_2015_56580.txt
(c / cause-01
      :ARG0 (p / possible-01
            :ARG1 (b / bind-01
                  :ARG1 (c2 / chain-01
                        :ARG0 (p2 / protein :name (n / name :op1 "Rabaptin-5"))
                        :ARG1-of (s / single-02))
                  :ARG2 (p3 / protein :name (n2 / name :op1 "Rab5"))))
      :ARG1 (p4 / possible-01
            :ARG1 (f / form-01
                  :ARG0 (d / dimerize-01
                        :ARG1 p2)
                  :ARG1 (s2 / site
                        :ARG1-of (b2 / bind-01
                              :ARG2 p3)
                        :mod (d2 / divalent)))
            :mod (a / also))
      :ARG1-of (d3 / describe-01
            :ARG0 (p5 / publication-91
                  :ARG0 (a2 / and
                        :op1 (p6 / person :name (n3 / name :op1 "Horiuchi"))
                        :op2 (p7 / person
                              :mod (o / other)))
                  :time (d4 / date-entity :year 1997))))

# ::id bio.chicago_2015.56582 ::date 2015-11-02T10:23:34 ::annotator SDL-AMR-09 ::preferred
# ::snt Originally identified by virtue of its physical binding to  Src, the  mDab1 protein also binds other  nonreceptor tyrosine kinases such as  Fyn and  Abl (Howell et al., 1997a  ).
# ::save-date Wed Jan 13, 2016 ::file bio_chicago_2015_56582.txt
(b / bind-01
      :ARG1 (p / protein :name (n / name :op1 "mDab1"))
      :ARG2 (e / enzyme :name (n2 / name :op1 "nonreceptor" :op2 "tyrosine" :op3 "kinase")
            :example (a2 / and
                  :op1 (k2 / kinase :name (n3 / name :op1 "Fyn"))
                  :op2 (k / kinase :name (n4 / name :op1 "Abl"))))
      :mod (a / also)
      :ARG1-of (i / identify-01
            :ARG1-of (c / cause-01
                  :ARG0 (b2 / bind-01
                        :ARG1 p
                        :ARG2 (p2 / protein :name (n5 / name :op1 "Src"))
                        :mod (p3 / physical)))
            :mod (o / original))
      :ARG1-of (d / describe-01
            :ARG0 (p4 / publication-91
                  :ARG0 (a3 / and
                        :op1 (p5 / person :name (n6 / name :op1 "Howell"))
                        :op2 (p6 / person
                              :mod (o2 / other)))
                  :time (d2 / date-entity :year 1997 :li "a"))))

# ::id bio.chicago_2015.56594 ::date 2015-11-02T10:36:00 ::annotator SDL-AMR-09 ::preferred
# ::snt Evidently, the peptide only slightly affected binding of  c-Cbl to  EGFR, but it almost completely abolished the interaction with the shorter viral form of Cbl.
# ::save-date Sat Nov 7, 2015 ::file bio_chicago_2015_56594.txt
(c / contrast-01
      :ARG1 (a / affect-01
            :ARG0 (p / peptide)
            :ARG1 (b / bind-01
                  :ARG1 (p2 / protein :name (n / name :op1 "c-Cbl"))
                  :ARG2 (e / enzyme :name (n2 / name :op1 "EGFR")))
            :degree (s / slight
                  :mod (o / only)))
      :ARG2 (a2 / abolish-01
            :ARG0 p
            :ARG1 (i / interact-01
                  :ARG1 (f / form
                        :mod (v / viral)
                        :ARG1-of (s2 / short-07
                              :degree (m / more))
                        :mod (p3 / protein :name (n3 / name :op1 "Cbl"))))
            :ARG1-of (c2 / complete-02
                  :degree (a3 / almost)))
      :ARG1-of (e2 / evidence-01))

# ::id bio.chicago_2015.56667 ::date 2015-11-02T10:47:06 ::annotator SDL-AMR-09 ::preferred
# ::snt These data prompted us to test for a disruption of  TFIID binding to various  DCE mutations (Fig.  6).
# ::save-date Sun Nov 8, 2015 ::file bio_chicago_2015_56667.txt
(p / prompt-02
      :ARG0 (d / data
            :mod (t / this))
      :ARG1 (w / we)
      :ARG2 (t2 / test-01
            :ARG0 w
            :ARG2 (d2 / disrupt-01
                  :ARG1 (b / bind-01
                        :ARG1 (p2 / protein :name (n / name :op1 "TFIID"))
                        :ARG2 (m / mutate-01
                              :ARG2 (p3 / protein :name (n2 / name :op1 "DCE"))
                              :mod (v / various)))))
      :ARG1-of (d3 / describe-01
            :ARG0 (f / figure :mod 6)))

# ::id bio.chicago_2015.56680 ::date 2015-11-02T10:59:30 ::annotator SDL-AMR-09 ::preferred
# ::snt Hence, it can be predicted that  BAG4 binds  Hsc70 in a manner analogous to  BAG1 ( 3,  15).
# ::save-date Sun Nov 8, 2015 ::file bio_chicago_2015_56680.txt
(c2 / cause-01
      :ARG1 (p4 / possible-01
            :ARG1 (p / predict-01
                  :ARG1 (b / bind-01
                        :ARG1 (p5 / protein :name (n / name :op1 "BAG4"))
                        :ARG2 (p2 / protein :name (n2 / name :op1 "Hsc70"))
                        :ARG1-of (r / resemble-01
                              :ARG2 (b2 / bind-01
                                    :ARG1 (p7 / protein :name (n3 / name :op1 "BAG1")))))))
      :ARG1-of (d / describe-01
            :ARG0 (p3 / publication
                  :ARG1-of (c / cite-01
                        :ARG2 (a2 / and :op1 3 :op2 15)))))

# ::id bio.chicago_2015.56736 ::date 2015-11-02T11:25:56 ::annotator SDL-AMR-09 ::preferred
# ::snt Western blotting confirmed that the  Cdc11 septin binds to the  Gin4 affinity column (Fig.  2 B).
# ::save-date Sun Nov 8, 2015 ::file bio_chicago_2015_56736.txt
(c / confirm-01
      :ARG0 (t / thing :name (n / name :op1 "Western" :op2 "blotting"))
      :ARG1 (b / bind-01
            :ARG1 (s / septin :name (n2 / name :op1 "Cdc11"))
            :ARG2 (c2 / column
                  :mod (a2 / affinity)
                  :mod (p / protein :name (n3 / name :op1 "Gin4"))))
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod "2B")))

# ::id bio.chicago_2015.56738 ::date 2015-11-02T11:33:41 ::annotator SDL-AMR-09 ::preferred
# ::snt HMG-I(Y) and  NF-kappaB subunit p50 bind to the  iNOS promoter/enhancer and form a ternary DNA-protein complex.
# ::save-date Sun Jan 17, 2016 ::file bio_chicago_2015_56738.txt
(a / and
      :op1 (b / bind-01
            :ARG1 (a2 / and
                  :op1 (p6 / protein :name (n / name :op1 "p50")
                        :part-of (m2 / macro-molecular-complex :name (n2 / name :op1 "HMG-I(Y)")))
                  :op2 (p7 / protein :name (n3 / name :op1 "p50")
                        :part-of (m5 / macro-molecular-complex :name (n4 / name :op1 "NF-kappaB"))))
            :ARG2 (s3 / slash
                  :op1 (m3 / molecular-physical-entity
                        :ARG0-of (p4 / promote-02
                              :ARG1 (e2 / enzyme :name (n5 / name :op1 "iNOS"))))
                  :op2 (m4 / molecular-physical-entity
                        :ARG0-of (e / enhance-01
                              :ARG1 e2))))
      :op2 (f / form-01
            :ARG0 a2
            :ARG1 (m / macro-molecular-complex
                  :part (p5 / protein)
                  :part (n6 / nucleic-acid :wiki "DNA" :name (n7 / name :op1 "DNA"))
                  :mod (t / ternary))))

# ::id bio.chicago_2015.56780 ::date 2015-11-02T11:47:34 ::annotator SDL-AMR-09 ::preferred
# ::snt Despite the fact that  myo-D and  P/CAF bind to distinct  CBP/ p300 sites, both interactions are disrupted by  E1A.
# ::save-date Wed Jan 13, 2016 ::file bio_chicago_2015_56780.txt
(h / have-concession-91
      :ARG1 (d2 / disrupt-01
            :ARG0 (p5 / protein :name (n5 / name :op1 "E1A"))
            :ARG1 b)
      :ARG2 (b / bind-01
            :ARG1 (a / and
                  :op1 (p / protein :name (n / name :op1 "myo-D"))
                  :op2 (e / enzyme :name (n2 / name :op1 "P/CAF")))
            :ARG2 (a2 / and
                  :op1 (s / site
                        :mod (p3 / protein :name (n3 / name :op1 "CBP"))
                        :mod (d / distinct))
                  :op2 (s2 / site
                        :mod (p4 / protein :name (n4 / name :op1 "p300"))
                        :mod d))))

# ::id bio.chicago_2015.56853 ::date 2015-11-02T12:07:42 ::annotator SDL-AMR-09 ::preferred
# ::snt In  mammals, however, there has been no evidence that  eIF4G binds  PABP.
# ::save-date Mon Nov 2, 2015 ::file bio_chicago_2015_56853.txt
(h / have-concession-91
      :ARG1 (e / evidence-01 :polarity -
            :ARG1 (b / bind-01
                  :ARG1 (p / protein :name (n / name :op1 "eIF4G"))
                  :ARG2 (p2 / protein :name (n2 / name :op1 "PABP")))
            :location (m / mammal)))

# ::id bio.chicago_2015.56858 ::date 2015-11-02T13:05:52 ::annotator SDL-AMR-09 ::preferred
# ::snt A mutation within the 6-aa motif that mediates the binding between  CtBP and  HPC2 results in a significant but only small decrease in the repressing abilities of  HPC2 (Fig.  9).
# ::save-date Mon Jan 4, 2016 ::file bio_chicago_2015_56858.txt
(r / result-01
      :ARG1 (m / mutate-01
            :ARG1 (d3 / dna-sequence :name (n / name :op1 "6-aa" :op2 "motif")
                  :ARG0-of (m2 / mediate-01
                        :ARG1 (b / bind-01
                              :ARG1 (p / protein :name (n2 / name :op1 "CtBP"))
                              :ARG2 (p2 / protein :name (n3 / name :op1 "HPC2"))))))
      :ARG2 (d / decrease-01
            :ARG1 (c2 / capable-01
                  :ARG1 p2
                  :ARG2 (r2 / repress-01
                        :ARG0 p2))
            :ARG1-of (s / significant-02
                  :ARG1-of (c / contrast-01
                        :ARG2 (s2 / small
                              :mod (o / only)))))
      :ARG1-of (d2 / describe-01
            :ARG0 (f / figure :mod 9)))

# ::id bio.chicago_2015.56861 ::date 2015-11-02T13:37:31 ::annotator SDL-AMR-09 ::preferred
# ::snt Each binding site in  eIF4G can bind either  eIF4AI or  eIF4AII.
# ::save-date Mon Nov 2, 2015 ::file bio_chicago_2015_56861.txt
(p / possible-01
      :ARG1 (b / bind-01
            :ARG1 (s / site
                  :mod (e / each)
                  :ARG2-of (b2 / bind-01)
                  :location (p2 / protein :name (n / name :op1 "eIF4G")))
            :ARG2 (o / or
                  :op1 (p3 / protein :name (n2 / name :op1 "eIF4AI"))
                  :op2 (p4 / protein :name (n3 / name :op1 "eIF4AII")))))

# ::id bio.chicago_2015.56879 ::date 2015-11-02T13:51:27 ::annotator SDL-AMR-09 ::preferred
# ::snt ura4+ at 30 and 32  degrees C, where  the effects of the  mts3-1 mutation will be greater than at 25  degrees C, is due to the lack of  polyubiquitin binding by Pus1N5 to bind conjugates.
# ::save-date Tue Feb 2, 2016 ::file bio_chicago_2015_56879.txt
(c / cause-01
      :ARG0 (l / lack-01
            :ARG1 (b / bind-01
                  :ARG1 (p2 / protein :name (n3 / name :op1 "Pus1N5"))
                  :ARG2 (p / protein :name (n2 / name :op1 "polyubiquitin"))
                  :ARG1-of (b2 / bind-01
                        :ARG2 (m / molecular-physical-entity
                              :ARG3-of (c3 / conjugate-02)))))
      :ARG1 (g / gene :name (n / name :op1 "ura4+")
            :ARG0-of (c4 / cause-01
                  :ARG1 (a2 / affect-01
                        :ARG0 (m2 / mutate-01
                              :ARG1 (p3 / protein :name (n4 / name :op1 "mts3-1")))
                        :mod (g3 / great
                              :degree (m3 / more)
                              :compared-to (t3 / temperature-quantity :quant 25
                                    :scale (c5 / celsius)))))
            :mod (t / temperature-quantity :quant 30
                  :scale (c2 / celsius))
            :mod (t2 / temperature-quantity :quant 32
                  :scale c2)))

# ::id bio.chicago_2015.56963 ::date 2015-11-03T00:38:39 ::annotator SDL-AMR-09 ::preferred
# ::snt We also find that three  lysine-rich boxes in the N-terminal segment of  eIF2beta mediate the binding of  eIF2 to both  eIF5 and  eIF2B.
# ::save-date Tue Nov 3, 2015 ::file bio_chicago_2015_56963.txt
(f / find-01
      :ARG0 (w / we)
      :ARG1 (m / mediate-01
            :ARG0 (b / box :quant 3
                  :mod (r / rich
                        :mod (a / amino-acid :name (n / name :op1 "lysine")))
                  :location (p / protein-segment :name (n2 / name :op1 "N-terminus")
                        :part-of (p2 / protein :name (n3 / name :op1 "eIF2beta"))))
            :ARG1 (b2 / bind-01
                  :ARG1 (p3 / protein :name (n4 / name :op1 "eIF2"))
                  :ARG2 (a3 / and
                        :op1 (p4 / protein :name (n5 / name :op1 "eIF5"))
                        :op2 (p5 / protein :name (n6 / name :op1 "eIF2B")))))
      :mod (a2 / also))

# ::id bio.chicago_2015.56965 ::date 2015-11-03T00:46:28 ::annotator SDL-AMR-09 ::preferred
# ::snt DAG binding to  UNC-13 is required to stimulate  acetylcholine release.
# ::save-date Sat Feb 13, 2016 ::file bio_chicago_2015_56965.txt
(r / require-01
      :ARG0 (s / stimulate-01
            :ARG1 (r2 / release-01
                  :ARG1 (s3 / small-molecule :name (n3 / name :op1 "acetylcholine"))))
      :ARG1 (b / bind-01
            :ARG1 (s2 / small-molecule :name (n / name :op1 "DAG"))
            :ARG2 (p2 / protein :name (n2 / name :op1 "UNC-13"))))

# ::id bio.chicago_2015.56989 ::date 2015-11-03T00:51:55 ::annotator SDL-AMR-09 ::preferred
# ::snt In contrast, minimal binding of  Arp1 to the  DII and  GST columns was observed.
# ::save-date Sun Jan 17, 2016 ::file bio_chicago_2015_56989.txt
(c / contrast-01
      :ARG2 (o / observe-01
            :ARG1 (b / bind-01
                  :ARG1 (p / protein :name (n / name :op1 "Arp1"))
                  :ARG2 (a / and
                        :op1 (c2 / column
                              :mod (p2 / protein :name (n2 / name :op1 "DII")))
                        :op2 (c3 / column
                              :mod (e / enzyme :name (n3 / name :op1 "GST"))))
                  :ARG1-of (m / minimal-02))))

# ::id bio.chicago_2015.56998 ::date 2015-11-03T00:57:35 ::annotator SDL-AMR-09 ::preferred
# ::snt Ena is phosphorylated on multiple tyrosine residues, most of which are found near  proline-rich sequences that mediate  Ena's binding to the  Abl and  Src SH3 domains.
# ::save-date Sun Jan 17, 2016 ::file bio_chicago_2015_56998.txt
(p / phosphorylate-01
      :ARG1 (r / residue
            :mod (a / amino-acid :name (n / name :op1 "tyrosine")
                  :part-of (p2 / protein :name (n2 / name :op1 "Ena")))
            :quant (m / multiple)
            :ARG2-of (i / include-91
                  :ARG1 (r2 / residue
                        :ARG1-of (f / find-01
                              :ARG1-of (n3 / near-02
                                    :ARG2 (s / sequence
                                          :mod (r3 / rich
                                                :mod (a3 / amino-acid :name (n4 / name :op1 "proline")))
                                          :ARG0-of (m3 / mediate-01
                                                :ARG1 (b / bind-01
                                                      :ARG1 p2
                                                      :ARG2 (a2 / and
                                                            :op1 (p4 / protein-segment :name (n5 / name :op1 "SH3")
                                                                  :part-of (p6 / protein :name (n7 / name :op1 "Abl")))
                                                            :op1 (p7 / protein-segment :name (n8 / name :op1 "SH3")
                                                                  :part-of (p5 / protein :name (n6 / name :op1 "Src"))))))))))
                  :mod (m2 / most))))

# ::id bio.chicago_2015.57043 ::date 2015-11-03T01:34:44 ::annotator SDL-AMR-09 ::preferred
# ::snt Complex Formation of  GSK-3beta,  AKAP220,  PKA, and  PP1--  It has been shown that  AKAP220 binds to  PP1 in addition to  PKA ( 29).
# ::save-date Sat Nov 7, 2015 ::file bio_chicago_2015_57043.txt
(m / multi-sentence
      :snt1 (f / form-01
            :ARG1 (m2 / macro-molecular-complex
                  :part (e / enzyme :name (n / name :op1 "GSK-3beta"))
                  :part (p / protein :name (n2 / name :op1 "AKAP220"))
                  :part (e2 / enzyme :name (n3 / name :op1 "PKA"))
                  :part (p2 / protein :name (n4 / name :op1 "PP1"))))
      :snt2 (s / show-01
            :ARG1 (b / bind-01
                  :ARG1 (p4 / protein :name (n5 / name :op1 "AKAP220"))
                  :ARG2 (a / and
                        :op1 (p5 / protein :name (n6 / name :op1 "PP1"))
                        :op2 (e3 / enzyme :name (n7 / name :op1 "PKA"))))
            :ARG1-of (d / describe-01
                  :ARG0 (p3 / publication
                        :ARG1-of (c / cite-01
                              :ARG2 29)))))

# ::id bio.chicago_2015.57105 ::date 2015-11-03T03:39:24 ::annotator SDL-AMR-09 ::preferred
# ::snt The  GTP-bound form of  ARF1 recruits protein coats, including the  clathrin-associated adaptor proteins AP-1 and  AP-3 and the nonclathrin  coatomer, to membranes and initiates budding of the membrane vesicles (Lenhard  et al., 1992  ; Donaldson and Klausner, 1994  ; Boman and Kahn, 1995  ; Dittie  et al., 1996  ; Ooi  et al., 1998  ;  Springer  et al., 1999  ).
# ::save-date Sat Nov 7, 2015 ::file bio_chicago_2015_57105.txt
(a4 / and
      :op1 (r / recruit-01
            :ARG0 (p / protein :name (n2 / name :op1 "ARF1")
                  :ARG2-of (b / bind-01
                        :ARG1 (s / small-molecule :name (n / name :op1 "GTP"))))
            :ARG1 (c / coat-01
                  :ARG2 (p2 / protein)
                  :ARG2-of (i / include-01
                        :ARG1 (a / and
                              :op1 (p3 / protein :name (n3 / name :op1 "AP-1")
                                    :mod (a2 / adaptor)
                                    :ARG1-of (a3 / associate-01
                                          :ARG2 (p5 / protein :name (n5 / name :op1 "clathrin"))))
                              :op2 (p4 / protein :name (n4 / name :op1 "AP-3")
                                    :mod a2
                                    :ARG1-of a3)
                              :op3 (p6 / protein :name (n6 / name :op1 "nonclathrin" :op2 "coatomer")))))
            :purpose (m / membrane))
      :op2 (i2 / initiate-01
            :ARG0 p
            :ARG1 (b2 / bud-01
                  :ARG1 (v / vesicle
                        :mod m)))
      :ARG1-of (d / describe-01
            :ARG0 (a5 / and
                  :op1 (p7 / publication-91
                        :ARG0 (a6 / and
                              :op1 (p8 / person :name (n7 / name :op1 "Lenhard"))
                              :op2 (p9 / person
                                    :mod (o / other)))
                        :time (d2 / date-entity :year 1992))
                  :op2 (p10 / publication-91
                        :ARG0 (a7 / and
                              :op1 (p11 / person :name (n8 / name :op1 "Donaldson"))
                              :op2 (p12 / person :name (n9 / name :op1 "Klausner")))
                        :time (d3 / date-entity :year 1994))
                  :op3 (p13 / publication-91
                        :ARG0 (a8 / and
                              :op1 (p14 / person :name (n10 / name :op1 "Boman"))
                              :op2 (p15 / person :name (n11 / name :op1 "Kahn")))
                        :time (d4 / date-entity :year 1995))
                  :op4 (p16 / publication-91
                        :ARG0 (a9 / and
                              :op1 (p17 / person :name (n12 / name :op1 "Dittie"))
                              :op2 (p18 / person
                                    :mod (o2 / other)))
                        :time (d5 / date-entity :year 1996))
                  :op5 (p19 / publication-91
                        :ARG0 (a10 / and
                              :op1 (p20 / person :name (n13 / name :op1 "Ooi"))
                              :op2 (p21 / person
                                    :mod (o3 / other)))
                        :time (d6 / date-entity :year 1998))
                  :op6 (p22 / publication-91
                        :ARG0 (a11 / and
                              :op1 (p23 / person :name (n14 / name :op1 "Springer"))
                              :op2 (p24 / person
                                    :mod (o4 / other)))
                        :time (d7 / date-entity :year 1999)))))

# ::id bio.chicago_2015.57113 ::date 2015-11-03T04:23:18 ::annotator SDL-AMR-09 ::preferred
# ::snt This analysis revealed specific in vivo binding of  NFAT5 to the   TNF  proximal promoter and the  aldose reductase enhancer in response to hypertonic stimulation, either alone or in combination with  PMA (  Figure 6D, right, top and middle panels,  lanes 5 and 6).
# ::save-date Sun Nov 8, 2015 ::file bio_chicago_2015_57113.txt
(r / reveal-01
      :ARG0 (a / analyze-01
            :mod (t / this))
      :ARG1 (b / bind-01
            :ARG1 (p / protein :name (n / name :op1 "NFAT5"))
            :ARG2 (a2 / and
                  :op1 (m / molecular-physical-entity
                        :ARG0-of (p2 / promote-01
                              :ARG1 (p3 / protein :name (n2 / name :op1 "TNF")))
                        :mod (p4 / proximal))
                  :op2 (m2 / molecular-physical-entity
                        :ARG0-of (e / enhance-01
                              :ARG1 (e2 / enzyme :name (n3 / name :op1 "aldose" :op2 "reductase")))))
            :ARG1-of (s / specific-02)
            :manner (i / in-vivo)
            :ARG2-of (r2 / respond-01
                  :ARG1 (o / or
                        :op1 (s2 / stimulate-01
                              :ARG0 (h / hypertonic)
                              :mod (a3 / alone))
                        :op2 (c / combine-01
                              :ARG1 s2
                              :ARG2 (s3 / small-molecule :name (n4 / name :op1 "PMA"))))))
      :ARG1-of (d / describe-01
            :ARG0 (a4 / and
                  :op1 (a5 / and
                        :op1 (l / lane :mod 5)
                        :op2 (l2 / lane :mod 6))
                  :op2 (a6 / and
                        :op1 (p5 / panel
                              :ARG1-of (r3 / right-04))
                        :op2 (p6 / panel
                              :location (t2 / top))
                        :op3 (p7 / panel
                              :location (m3 / middle)))
                  :part-of (f / figure :mod "6D"))))

# ::id bio.chicago_2015.57142 ::date 2015-11-03T07:33:46 ::annotator SDL-AMR-09 ::preferred
# ::snt C, DNA binding of  Smad5 and  Smad4 to the  GC-rich sequence is shown.
# ::save-date Sat Feb 13, 2016 ::file bio_chicago_2015_57142.txt
(s / show-01
      :ARG1 (b / bind-01
            :ARG0 (n2 / nucleic-acid :wiki "DNA" :name (n3 / name :op1 "DNA"))
            :ARG1 (a / and
                  :op1 (p2 / protein :name (n4 / name :op1 "Smad5"))
                  :op2 (p3 / protein :name (n5 / name :op1 "Smad4")))
            :ARG2 (s2 / sequence
                  :mod (r / rich
                        :op1 (s3 / small-molecule :name (n / name :op1 "guanine"))
                        :op2 (s4 / small-molecule :name (n6 / name :op1 "cytosine")))))
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod "4C")))

# ::id bio.chicago_2015.57166 ::date 2015-11-03T07:45:15 ::annotator SDL-AMR-09 ::preferred
# ::snt Because  Sec15p also binds to activated  Sec4p, the exocyst might be an effector for this  Rab-like GTPase that is necessary for the targeting or tethering of secretory vesicles to sites of secretion.
# ::save-date Sat Nov 7, 2015 ::file bio_chicago_2015_57166.txt
(c / cause-01
      :ARG0 (b / bind-01
            :ARG1 (p / protein :name (n / name :op1 "Sec15p"))
            :ARG2 (p2 / protein :name (n2 / name :op1 "Sec4p")
                  :ARG1-of (a / activate-01))
            :mod (a3 / also))
      :ARG1 (p3 / possible-01
            :ARG1 (e / effector
                  :domain (p4 / protein :name (n3 / name :op1 "exocyst"))
                  :beneficiary (e2 / enzyme :name (n4 / name :op1 "GTPase")
                        :ARG1-of (r / resemble-01
                              :ARG2 (p5 / protein :name (n5 / name :op1 "Rab")))
                        :ARG1-of (n6 / need-01
                              :ARG0 (o / or
                                    :op1 (t / target-01
                                          :ARG0 (v / vesicle
                                                :ARG0-of (s / secrete-01))
                                          :ARG1 (s2 / site
                                                :location-of (s3 / secrete-01)))
                                    :op2 (t2 / tether-01
                                          :ARG0 v
                                          :ARG1 s2)))
                        :mod (t3 / this)))))

# ::id bio.chicago_2015.57186 ::date 2015-11-03T08:22:51 ::annotator SDL-AMR-09 ::preferred
# ::snt Calmodulin binding activities of the  adducin recombinant polypeptides and the  MARCKS-related domain peptide were inhibited by  PKA and  PKC phosphorylation.
# ::save-date Sun Jan 17, 2016 ::file bio_chicago_2015_57186.txt
(i / inhibit-01
      :ARG0 (p / phosphorylate-01
            :ARG1 (a / and
                  :op1 (e / enzyme :name (n / name :op1 "PKA"))
                  :op2 (e2 / enzyme :name (n2 / name :op1 "PKC"))))
      :ARG1 (a2 / and
            :op1 (a3 / activity-06
                  :ARG0 (p5 / polypeptide :name (n4 / name :op1 "adducin" :op2 "recombinant"))
                  :ARG1-of (b / bind-01
                        :ARG2 (p4 / protein :name (n3 / name :op1 "calmodulin"))))
            :op2 (p6 / peptide
                  :part-of (d / domain
                        :ARG1-of (r / relate-01
                              :ARG2 (p7 / protein :name (n5 / name :op1 "MARCKS")))))))

# ::id bio.chicago_2015.57199 ::date 2015-11-03T08:48:31 ::annotator SDL-AMR-09 ::preferred
# ::snt All of these results indicate that the binding of  Axin to  Dvl is probably mediated by two interactions; one between DvlN and AxinC and the other between DvlPDZ and an N-terminal sequence of  Axin.
# ::save-date Sun Nov 8, 2015 ::file bio_chicago_2015_57199.txt
(i / indicate-01
      :ARG0 (t / thing
            :ARG2-of (r / result-01)
            :mod (t2 / this)
            :mod (a / all))
      :ARG1 (m / mediate-01
            :ARG0 (a2 / and
                  :op1 (i2 / interact-01
                        :ARG0 (p3 / protein :name (n3 / name :op1 "DvlN"))
                        :ARG1 (p5 / protein :name (n4 / name :op1 "AxinC")))
                  :op2 (i3 / interact-01
                        :ARG0 (p4 / protein :name (n5 / name :op1 "DvlPDZ"))
                        :ARG1 (p7 / protein-segment :name (n7 / name :op1 "N-terminus")
                              :part-of p6)))
            :ARG1 (b / bind-01
                  :ARG1 (p6 / protein :name (n / name :op1 "Axin"))
                  :ARG2 (p / protein :name (n2 / name :op1 "Dvl")))
            :mod (p2 / probable)))

# ::id bio.chicago_2015.57217 ::date 2015-11-03T09:04:37 ::annotator SDL-AMR-09 ::preferred
# ::snt TIF1alpha and  TIF1beta bind directly to  HP1alpha, - beta and -gamma in vitro
# ::save-date Sun Nov 8, 2015 ::file bio_chicago_2015_57217.txt
(b / bind-01
      :ARG1 (a / and
            :op1 (p / protein :name (n / name :op1 "TIF1" :op2 "alpha"))
            :op2 (p2 / protein :name (n2 / name :op1 "TIF1" :op2 "beta")))
      :ARG2 (a2 / and
            :op1 (p3 / protein :name (n3 / name :op1 "HP1" :op2 "alpha"))
            :op2 (p4 / protein :name (n4 / name :op1 "HP1" :op2 "beta"))
            :op3 (p5 / protein :name (n5 / name :op1 "HP1" :op2 "gamma")))
      :ARG1-of (d / direct-02)
      :manner (i / in-vitro))

# ::id bio.chicago_2015.57274 ::date 2015-11-03T09:25:42 ::annotator SDL-AMR-09 ::preferred
# ::snt The mechanism of indirect binding of  ERM proteins to  integral membrane proteins has also been reported.
# ::save-date Sat Nov 7, 2015 ::file bio_chicago_2015_57274.txt
(r / report-01
      :ARG1 (m / mechanism
            :instrument-of (b / bind-01
                  :ARG1 (p / protein-family :name (n / name :op1 "ERM"))
                  :ARG2 (p2 / protein :name (n2 / name :op1 "integral" :op2 "membrane" :op3 "protein"))
                  :ARG1-of (d / direct-02 :polarity -)))
      :mod (a / also))

# ::id bio.chicago_2015.57316 ::date 2015-11-03T09:32:12 ::annotator SDL-AMR-09 ::preferred
# ::snt The Tyr43/Asp49 conformational switch is the most probable explanation for the  GTP-dependent binding of  Sec5 to  RalA.
# ::save-date Sat Nov 7, 2015 ::file bio_chicago_2015_57316.txt
(e / explain-01
      :ARG0 (s / switch-01
            :ARG1-of (c / conform-01
                  :ARG2 (s2 / slash
                        :op1 (a / amino-acid :mod 43 :name (n6 / name :op1 "tyrosine"))
                        :op2 (a2 / amino-acid :mod 49 :name (n / name :op1 "aspartic" :op2 "acid")))))
      :ARG1 (b / bind-01
            :ARG1 (p3 / protein :name (n3 / name :op1 "Sec5"))
            :ARG2 (p4 / protein :name (n4 / name :op1 "RalA"))
            :ARG0-of (d / depend-01
                  :ARG1 (s3 / small-molecule :name (n5 / name :op1 "GTP"))))
      :mod (p5 / probable
            :degree (m / most)))

# ::id bio.chicago_2015.57334 ::date 2015-11-03T09:50:51 ::annotator SDL-AMR-09 ::preferred
# ::snt In our studies no increase in endogenous  plakoglobin levels was detected in response to the expression of  E-cadherin in  L cells, despite the fact that  plakoglobin can effectively bind to  E-cadherin in other cell types ( 24,  25).
# ::save-date Sun Nov 8, 2015 ::file bio_chicago_2015_57334.txt
(h / have-concession-91
      :ARG1 (d / detect-01 :polarity -
            :ARG1 (i / increase-01
                  :ARG1 (l / level
                        :quant-of (p / protein :name (n / name :op1 "plakoglobin")
                              :mod (e / endogenous)))
                  :ARG2-of (r / respond-01
                        :ARG1 (e2 / express-03
                              :ARG2 (p2 / protein :name (n2 / name :op1 "E-cadherin"))
                              :ARG3 (c / cell :name (n3 / name :op1 "L")))))
            :ARG2 (s / study-01
                  :ARG0 (w / we)))
      :ARG2 (p3 / possible-01
            :ARG1 (b / bind-01
                  :ARG1 p
                  :ARG2 p2
                  :ARG1-of (e3 / effective-04)
                  :location (c4 / cell
                        :mod (t / type)
                        :mod (o / other))))
      :ARG1-of (d2 / describe-01
            :ARG0 (p5 / publication
                  :ARG1-of (c3 / cite-01
                        :ARG2 (a / and :op1 24 :op2 25)))))

# ::id bio.chicago_2015.57387 ::date 2015-11-03T10:39:45 ::annotator SDL-AMR-09 ::preferred
# ::snt Binding of  Smad3 and  Sp1 was demonstrated upon immunodetection with specific antibodies.
# ::save-date Sat Nov 7, 2015 ::file bio_chicago_2015_57387.txt
(d / demonstrate-01
      :ARG1 (b / bind-01
            :ARG1 (a / and
                  :op1 (p / protein :name (n / name :op1 "Smad3"))
                  :op2 (p2 / protein :name (n2 / name :op1 "Sp1"))))
      :time (i / immunodetect-01
            :ARG3 (a2 / antibody
                  :ARG1-of (s / specific-02))))

# ::id bio.chicago_2015.57447 ::date 2015-11-03T10:43:43 ::annotator SDL-AMR-09 ::preferred
# ::snt While the homeodomain alone of  Pbx1 or  exd  binds DNA cooperatively with  Hox proteins, studies with  Pbx1 have shown that a  16-residue C-terminal tail, which is conserved in  exd, is required for maximal cooperative interactions  with  Hox partners (Chang et al., 1995   ;   Lu and Kamps,  1996   ;  Green et al., 1998   ) and for maximal binding of  monomeric  Pbx1 homeodomain to  DNA (Lu and Kamps, 1996   ;  Green  et al., 1998   ).
# ::save-date Sun Jan 17, 2016 ::file bio_chicago_2015_57447.txt
(c3 / contrast-01
      :ARG1 (s / show-01
            :ARG0 (s2 / study-01
                  :ARG1 (p / protein :name (n / name :op1 "Pbx1")))
            :ARG1 (r / require-01
                  :ARG0 (a / and
                        :op1 (i / interact-01
                              :ARG1 (p3 / partner-01
                                    :ARG1 (p2 / protein-family :name (n3 / name :op1 "Hox")))
                              :degree (m / maximal)
                              :manner (c2 / cooperate-01)
                              :ARG1-of (d / describe-01
                                    :ARG0 (a2 / and
                                          :op1 (p7 / publication-91
                                                :ARG0 (a4 / and
                                                      :op1 (p10 / person :name (n8 / name :op1 "Chang"))
                                                      :op2 (p11 / person
                                                            :mod (o2 / other)))
                                                :time (d2 / date-entity :year 1995))
                                          :op2 (p8 / publication-91
                                                :ARG0 (a5 / and
                                                      :op1 (p12 / person :name (n9 / name :op1 "Lu"))
                                                      :op2 (p13 / person :name (n10 / name :op1 "Kamps")))
                                                :time (d3 / date-entity :year 1996))
                                          :op3 (p9 / publication-91
                                                :ARG0 (a6 / and
                                                      :op1 (p14 / person :name (n11 / name :op1 "Green"))
                                                      :op2 (p15 / person
                                                            :mod (o3 / other)))
                                                :time (d4 / date-entity :year 1998)))))
                        :op2 (b / bind-01
                              :ARG1 (h4 / homeodomain
                                    :part-of (p5 / protein :name (n4 / name :op1 "Pbx1")
                                          :mod (m3 / monomeric)))
                              :ARG2 (n5 / nucleic-acid :wiki "DNA" :name (n6 / name :op1 "DNA"))
                              :degree m
                              :ARG1-of (d5 / describe-01
                                    :ARG0 (a7 / and
                                          :op1 p8
                                          :op2 p9))))
                  :ARG1 (t / tail
                        :mod (r2 / residue :mod 16)
                        :ARG1-of (c / conserve-01
                              :location (p6 / protein :name (n7 / name :op1 "edx")))
                        :part-of (p16 / protein-segment :name (n12 / name :op1 "C-terminus")))))
      :ARG2 (b2 / bind-01
            :ARG1 (o / or
                  :op1 (h2 / homeodomain
                        :part-of p
                        :mod (a3 / alone))
                  :op2 (h3 / homeodomain
                        :part-of p6
                        :mod a3))
            :ARG2 n5
            :ARG3 p2
            :ARG2-of c2))

# ::id bio.chicago_2015.57503 ::date 2015-11-03T11:40:02 ::annotator SDL-AMR-09 ::preferred
# ::snt Incubation of wild-type  Tsg protein with  Chordin and  BMP4 generated a ternary complex corresponding to a  Tsg dimer bound to a  BMP4 dimer and  Chordin ( Fig. 4D, lane 3).
# ::save-date Fri Jan 15, 2016 ::file bio_chicago_2015_57503.txt
(g / generate-01
      :ARG0 (i / incubate-01
            :ARG1 (p / protein :name (n / name :op1 "Tsg")
                  :mod (w / wild-type))
            :ARG2 (a / and
                  :op1 (p2 / protein :name (n2 / name :op1 "Chordin"))
                  :op2 (p3 / protein :name (n3 / name :op1 "BMP4"))))
      :ARG1 (m / macro-molecular-complex
            :mod (t / ternary)
            :ARG1-of (c / correspond-02
                  :ARG2 (p5 / protein :name (n4 / name :op1 "Tsg")
                        :ARG1-of (b / bind-01
                              :ARG2 (a2 / and
                                    :op1 (p4 / protein :name (n5 / name :op1 "BMP4")
                                          :ARG3-of (d2 / dimerize-01))
                                    :op2 p2))
                        :ARG3-of (d / dimerize-01))))
      :ARG1-of (d4 / describe-01
            :ARG0 (f / figure :mod "4D"
                  :location (l / lane :mod 3))))

# ::id bio.chicago_2015.57541 ::date 2015-11-03T12:01:08 ::annotator SDL-AMR-09 ::preferred
# ::snt (C) Differential binding of recombinant  s-synaphin constructs to  syntaxin.
# ::save-date Sat Nov 7, 2015 ::file bio_chicago_2015_57541.txt
(b / bind-01
      :ARG1 (c / construct
            :mod (p / protein :name (n / name :op1 "s-synaphin")
                  :ARG3-of (r / recombine-01)))
      :ARG2 (p2 / protein :name (n2 / name :op1 "syntaxin"))
      :ARG1-of (d2 / differ-02)
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod "C")))

# ::id bio.chicago_2015.57550 ::date 2015-11-03T12:23:40 ::annotator SDL-AMR-09 ::preferred
# ::snt Binding of   actin    to  tropomyosin is directly demonstrated by  cosedimentation and  SDS-gel electrophoresis ( Fig. 1 ).
# ::save-date Sat Nov 7, 2015 ::file bio_chicago_2015_57550.txt
(d / demonstrate-01
      :ARG0 (a / and
            :op1 (c / cosedimentation)
            :op2 (e / electrophoresis
                  :instrument (t / thing :name (n3 / name :op1 "SDS" :op2 "gel"))))
      :ARG1 (b / bind-01
            :ARG1 (p / protein :name (n / name :op1 "actin"))
            :ARG2 (p2 / protein :name (n2 / name :op1 "tropomyosin")))
      :ARG1-of (d2 / direct-02)
      :ARG1-of (d3 / describe-01
            :ARG0 (f / figure :mod 1)))

# ::id bio.chicago_2015.57613 ::date 2015-11-03T12:35:28 ::annotator SDL-AMR-09 ::preferred
# ::snt As Fig.  4 b shows, the amount of  MYPT bound  to phosphorylated  myosin was two to three times higherR  using  MYPT phosphorylated with mitotic extracts compared to the  MYPT phosphorylated by  interphase extracts.
# ::save-date Sun Nov 8, 2015 ::file bio_chicago_2015_57613.txt
(h2 / high-02
      :ARG1 (a / amount
            :quant-of (p / protein :name (n / name :op1 "MYPT")
                  :ARG1-of (b / bind-01
                        :ARG2 (p2 / protein :name (n2 / name :op1 "myosin")
                              :ARG3-of (p3 / phosphorylate-01)))))
      :degree (m / more)
      :degree (b2 / between
            :op1 (p4 / product-of :op1 2)
            :op2 (p5 / product-of :op2 3))
      :condition (u / use-01
            :ARG1 (p6 / protein :name (n3 / name :op1 "MYPT")
                  :ARG3-of (p7 / phosphorylate-01
                        :ARG2 (m3 / molecular-physical-entity
                              :ARG1-of (e / extract-01
                                    :time (m2 / mitosis)))))
            :compared-to (p8 / protein :name (n4 / name :op1 "MYPT")
                  :ARG3-of (p9 / phosphorylate-01
                        :ARG2 (m4 / molecular-physical-entity
                              :ARG1-of (e2 / extract-01
                                    :time (i / interphase))))))
      :ARG1-of (s / show-01
            :ARG0 (f / figure :mod "4b")))

# ::id bio.chicago_2015.57633 ::date 2015-11-03T13:08:47 ::annotator SDL-AMR-09 ::preferred
# ::snt Finally,  NIMA can phosphorylate  histone H3 at   Ser-10 in vitro.
# ::save-date Sat Nov 7, 2015 ::file bio_chicago_2015_57633.txt
(p / possible-01 :li "-1"
      :ARG1 (p2 / phosphorylate-01
            :ARG1 (a / amino-acid :mod 10 :name (n / name :op1 "serine")
                  :part-of (p3 / protein :name (n2 / name :op1 "histone" :op2 "H3")))
            :ARG2 (e / enzyme :name (n3 / name :op1 "NIMA"))
            :manner (i / in-vitro)))

# ::id bio.chicago_2015.57664 ::date 2015-11-03T13:17:12 ::annotator SDL-AMR-09 ::preferred
# ::snt Although  Pax6 is phosphorylated by two members of the  MAPK family (ERK and  p38), it is not phosphorylated by  JNK (Mikkola et al. 1999  );  JNK-dependent Pax6 regulation may therefore be indirect.
# ::save-date Mon Jan 4, 2016 ::file bio_chicago_2015_57664.txt
(i / infer-01
      :ARG1 (p7 / possible-01
            :ARG1 (d3 / direct-02 :polarity -
                  :ARG1 (r / regulate-01
                        :ARG1 p2
                        :ARG0-of (d4 / depend-01
                              :ARG1 e4))))
      :ARG2 (h / have-concession-91
            :ARG1 (p3 / phosphorylate-01 :polarity -
                  :ARG1 p2
                  :ARG2 (e4 / enzyme :name (n5 / name :op1 "JNK"))
                  :ARG1-of (d / describe-01
                        :ARG0 (p6 / publication-91
                              :ARG0 (a2 / and
                                    :op1 (p4 / person :name (n6 / name :op1 "Mikkola"))
                                    :op2 (p5 / person
                                          :mod (o / other)))
                              :time (d2 / date-entity :year 1999))))
            :ARG2 (p / phosphorylate-01
                  :ARG1 (p2 / protein :name (n / name :op1 "Pax6"))
                  :ARG2 (a / and
                        :op1 (e / enzyme :name (n2 / name :op1 "ERK"))
                        :op2 (e2 / enzyme :name (n3 / name :op1 "p38"))
                        :ARG1-of (i2 / include-91
                              :ARG2 (p8 / protein-family :name (n4 / name :op1 "MAPK")))))))

# ::id bio.chicago_2015.57688 ::date 2015-11-03T13:41:50 ::annotator SDL-AMR-09 ::preferred
# ::snt Importantly, we found a weak but direct interaction between  Pelle and  dTRAF2  in vitro, and showed that  dTRAF2 can be phosphorylated by  Pelle.
# ::save-date Sat Nov 7, 2015 ::file bio_chicago_2015_57688.txt
(a / and
      :op1 (f / find-01
            :ARG0 (w / we)
            :ARG1 (i / interact-01
                  :ARG0 (e / enzyme :name (n / name :op1 "Pelle"))
                  :ARG1 (p2 / protein :name (n2 / name :op1 "dTRAF2"))
                  :manner (i2 / in-vitro)
                  :ARG1-of (w2 / weak-02
                        :ARG1-of (c / contrast-01
                              :ARG2 (d / direct-02
                                    :ARG1 i)))))
      :op2 (s / show-01
            :ARG0 w
            :ARG1 (p3 / possible-01
                  :ARG1 (p4 / phosphorylate-01
                        :ARG1 p2
                        :ARG2 e)))
      :mod (i3 / important))

# ::id bio.chicago_2015.57709 ::date 2015-11-04T05:36:45 ::annotator SDL-AMR-09 ::preferred
# ::snt This view is consistent with previous data that suggest  ATM phosphorylates  Nbs1 when it is bound to DNA damage ( 37) (Fig.  8).
# ::save-date Wed Nov 11, 2015 ::file bio_chicago_2015_57709.txt
(c / consistent-01
      :ARG1 (v / view-02
            :mod (t / this))
      :ARG2 (d3 / data
            :ARG0-of (s / suggest-01
                  :ARG1 (p2 / phosphorylate-01
                        :ARG1 (p3 / protein :name (n4 / name :op1 "Nbs1"))
                        :ARG2 (e / enzyme :name (n / name :op1 "ATM"))
                        :time (b2 / bind-01
                              :ARG1 p3
                              :ARG2 (d4 / damage-01
                                    :ARG1 (n2 / nucleic-acid :name (n3 / name :op1 "DNA"))))))
            :time (p4 / previous))
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod 8))
      :ARG1-of (d2 / describe-01
            :ARG0 (p / publication
                  :ARG1-of (c2 / cite-01
                        :ARG2 37))))

# ::id bio.chicago_2015.57767 ::date 2015-11-04T06:51:20 ::annotator SDL-AMR-09 ::preferred
# ::snt The data presented in Fig.  1 suggest that  KSR is phosphorylated by  MAPK in response to  Ras activation.
# ::save-date Sat Jan 16, 2016 ::file bio_chicago_2015_57767.txt
(s / suggest-01
      :ARG0 (d / data
            :ARG1-of (p / present-01
                  :location (f / figure :op1 1)))
      :ARG1 (p4 / phosphorylate-01
            :ARG1 (e2 / enzyme :name (n3 / name :op1 "KSR"))
            :ARG2 (e / enzyme :name (n4 / name :op1 "MAPK"))
            :ARG2-of (r / respond-01
                  :ARG1 (a / activate-01
                        :ARG1 (e3 / enzyme :name (n5 / name :op1 "Ras"))))))

# ::id bio.chicago_2015.57774 ::date 2015-11-04T07:08:10 ::annotator SDL-AMR-09 ::preferred
# ::snt PTP2C inhibits  PLC  tyrosine phosphorylation by  c-Src.
# ::save-date Wed Nov 11, 2015 ::file bio_chicago_2015_57774.txt
(i / inhibit-01
      :ARG0 (e / enzyme :name (n / name :op1 "PTP2C"))
      :ARG1 (p2 / phosphorylate-01
            :ARG1 (a / amino-acid :name (n4 / name :op1 "tyrosine")
                  :part-of (e3 / enzyme :name (n2 / name :op1 "PLC")))
            :ARG2 (e2 / enzyme :name (n3 / name :op1 "c-Src"))))

# ::id bio.chicago_2015.57802 ::date 2015-11-04T07:13:02 ::annotator SDL-AMR-09 ::preferred
# ::snt Previous data from Wahba and colleagues ( Dholakia and Wahba, 1988) suggested that phosphorylation of  eIF2Bepsilon by  CK2 increased its activity in nucleotide exchange, and our findings thus provide an explanation of this effect.
# ::save-date Fri Nov 20, 2015 ::file bio_chicago_2015_57802.txt
(a / and
      :op1 (s / suggest-01
            :ARG0 (d2 / data
                  :time (p3 / previous)
                  :source (a3 / and
                        :op1 (p4 / person :name (n2 / name :op1 "Wahba"))
                        :op2 (c / colleagues))
                  :ARG1-of (d3 / describe-01
                        :ARG0 (p5 / publication-91
                              :ARG0 (a4 / and
                                    :op1 (p6 / person :name (n / name :op1 "Dholakia"))
                                    :op2 p4)
                              :time (d / date-entity :year 1988))))
            :ARG1 (i / increase-01
                  :ARG0 (p / phosphorylate-01
                        :ARG1 (p7 / protein :name (n3 / name :op1 "eIF2Bepsilon"))
                        :ARG2 (e3 / enzyme :name (n4 / name :op1 "CK2")))
                  :ARG1 (a5 / activity-06
                        :ARG0 p7
                        :ARG1 (e2 / exchange-01
                              :ARG1 (n5 / nucleotide)))))
      :op2 (p2 / provide-01
            :ARG0 (t2 / thing
                  :ARG1-of (f / find-01
                        :ARG0 (w / we)))
            :ARG1 (e / explain-01
                  :ARG1-of (a2 / affect-01
                        :mod (t / this)))
            :ARG1-of (c2 / cause-01)))

# ::id bio.chicago_2015.57826 ::date 2015-11-05T08:00:56 ::annotator SDL-AMR-09 ::preferred
# ::snt The regulation of  Chk1 is perhaps best characterized in   Xenopus, where it has been demonstrated that  Chk1 is phosphorylated and activated by  ATR and that the  ATR-Chk1 pathway responds to  unreplicated DNA and UV-damaged DNA ( 26).
# ::save-date Wed Nov 11, 2015 ::file bio_chicago_2015_57826.txt
(c / characterize-01
      :ARG1 (r / regulate-01
            :ARG1 (e / enzyme :name (n3 / name :op1 "Chk1")))
      :ARG1-of (p3 / possible-01)
      :ARG1-of (g / good-02
            :degree (m / most))
      :location (o / organism :name (n4 / name :op1 "Xenopus")
            :location-of (a / and
                  :op1 (d / demonstrate-01
                        :ARG1 (a3 / and
                              :op1 (p / phosphorylate-01
                                    :ARG1 e
                                    :ARG2 (e2 / enzyme :name (n9 / name :op1 "ATR")))
                              :op1 (a4 / activate-01
                                    :ARG0 e2
                                    :ARG1 e)))
                  :op2 (r2 / respond-01
                        :ARG0 (p4 / pathway :name (n5 / name :op1 "ATR-Chk1"))
                        :ARG1 (a2 / and
                              :op1 (n / nucleic-acid :name (n2 / name :op1 "DNA")
                                    :ARG1-of (r3 / replicate-01 :polarity -))
                              :op2 (n6 / nucleic-acid :name (n7 / name :op1 "DNA")
                                    :ARG1-of (d2 / damage-01 :polarity -
                                          :ARG0 (l / light
                                                :mod (u / ultraviolet))))))))
      :ARG1-of (d3 / describe-01
            :ARG0 (p5 / publication
                  :ARG1-of (c2 / cite-01
                        :ARG2 26))))

# ::id bio.chicago_2015.57852 ::date 2015-11-05T06:03:46 ::annotator SDL-AMR-09 ::preferred
# ::snt In addition to  JNK,  JNKK1 also phosphorylates  p38 in in-vitro kinase assay and activates  p38 in cotransfection assay ( Derijard et al., 1995;   Lin et al., 1995).
# ::save-date Wed Nov 11, 2015 ::file bio_chicago_2015_57852.txt
(a5 / and
      :op1 (p / phosphorylate-01
            :ARG1 (a3 / and
                  :op1 (e / enzyme :name (n / name :op1 "p38"))
                  :location (a4 / assay-01
                        :ARG1 (k / kinase)
                        :manner (i / in-vitro)))
            :ARG2 (e2 / enzyme :name (n2 / name :op1 "JNKK1"))
            :mod (a / also)
            :ARG1-of (a2 / add-02
                  :ARG2 (p2 / phosphorylate-01
                        :ARG1 (e3 / enzyme :name (n3 / name :op1 "JNK"))
                        :ARG2 e2)))
      :op2 (a6 / activate-01
            :ARG0 e2
            :ARG1 e
            :location (a7 / assay-01
                  :ARG1 (c / cotransfect-01)))
      :ARG1-of (d2 / describe-01
            :ARG0 (a8 / and
                  :op1 (p3 / publication-91
                        :ARG0 (a9 / and
                              :op1 (p5 / person :name (n4 / name :op1 "Derijard"))
                              :op2 (p8 / person
                                    :mod (o / other))))
                  :op2 (p4 / publication-91
                        :ARG0 (a10 / and
                              :op1 (p7 / person :name (n5 / name :op1 "Lin"))
                              :op2 p8))
                  :time (d / date-entity :year 1995))))

# ::id bio.chicago_2015.57855 ::date 2015-11-04T06:30:38 ::annotator SDL-AMR-09 ::preferred
# ::snt Hsc70 Is Not Phosphorylated by  p16
# ::save-date Wed Nov 11, 2015 ::file bio_chicago_2015_57855.txt
(p / phosphorylate-01 :polarity -
      :ARG1 (p2 / protein :name (n / name :op1 "Hsc70"))
      :ARG2 (p3 / protein :name (n2 / name :op1 "p16")))

# ::id bio.chicago_2015.57886 ::date 2015-11-04T06:33:15 ::annotator SDL-AMR-09 ::preferred
# ::snt ( B) Tryptic peptide map of  MBP phosphorylated by  GST - LKB1 and  GST - LKB1/flag-STRAD (left panel), and the corresponding Edman degradation diagram (right panel) and  PAA analysis (insert).
# ::save-date Sat Jan 30, 2016 ::file bio_chicago_2015_57886.txt
(a / and :li "B"
      :op1 (m / map-01
            :ARG1 (p2 / protein :name (n6 / name :op1 "MBP")
                  :ARG1-of (p3 / phosphorylate-01
                        :ARG2 (a2 / and
                              :op1 (p4 / protein :name (n2 / name :op1 "GST-LKB1"))
                              :op2 (s / slash
                                    :op1 p4
                                    :op2 (p6 / protein :name (n4 / name :op1 "Flag-STRAD")
                                          :ARG1-of (d / describe-01
                                                :ARG0 (p5 / panel
                                                      :ARG1-of (l / left-20))))))))
            :mod (p / peptide :name (n / name :op1 "trypsin")))
      :op2 (a3 / and
            :op1 (d2 / diagram-01
                  :ARG1 (d3 / degrade-01
                        :mod (p7 / person :name (n3 / name :op1 "Edman")))
                  :ARG1-of (d4 / describe-01
                        :ARG0 (p9 / panel
                              :ARG1-of (r / right-04)))
                  :ARG1-of (c / correspond-01))
            :op2 (a4 / analyze-01 :name (n5 / name :op1 "PAA")
                  :ARG1-of (d5 / describe-01
                        :ARG0 (i / insert)))))

# ::id bio.chicago_2015.57908 ::date 2015-11-04T21:37:37 ::annotator SDL-AMR-09 ::preferred
# ::snt Src family kinases phosphorylate  c-Abl
# ::save-date Wed Nov 11, 2015 ::file bio_chicago_2015_57908.txt
(p / phosphorylate-01
      :ARG1 (p3 / protein :name (n2 / name :op1 "c-Abl"))
      :ARG2 (p2 / protein-family :name (n / name :op1 "Src" :op2 "kinase")))

# ::id bio.chicago_2015.57910 ::date 2015-11-04T05:47:42 ::annotator SDL-AMR-09 ::preferred
# ::snt Overexpression of   PTC1 did not inhibit  Tyr phosphorylation of  Hog1, suggesting it does not act on  Pbs2 (Fig.  4A).
# ::save-date Tue Jan 12, 2016 ::file bio_chicago_2015_57910.txt
(i / inhibit-01 :polarity -
      :ARG0 (o / overexpress-01
            :ARG1 (e / enzyme :wiki "Ptc1"
                  :name (n / name :op1 "PTC1")))
      :ARG1 (p / phosphorylate-01
            :ARG1 (a / amino-acid :wiki "Tyrosine"
                  :name (n2 / name :op1 "tyrosine")
                  :part-of (p2 / protein :wiki -
                        :name (n3 / name :op1 "Hog1"))))
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod "4A"))
      :ARG0-of (s / suggest-01
            :ARG1 (a2 / act-02 :polarity -
                  :ARG0 o
                  :ARG1 (e2 / enzyme :wiki -
                        :name (n4 / name :op1 "Pbs2")))))

# ::id bio.chicago_2015.57934 ::date 2015-11-04T06:29:36 ::annotator SDL-AMR-09 ::preferred
# ::snt The  plus sign (+) indicates the  serine residue potentially phosphorylated by  casein kinase II.
# ::save-date Fri Nov 20, 2015 ::file bio_chicago_2015_57934.txt
(i / indicate-01
      :ARG0 (s / sign
            :mod (s2 / string-entity :value +))
      :ARG1 (p2 / phosphorylate-01
            :ARG1 (r / residue
                  :mod (a / amino-acid :name (n / name :op1 "serine")))
            :ARG2 (e / enzyme :name (n2 / name :op1 "casein" :op2 "kinase" :op3 "II"))
            :mod (p3 / potential)))

# ::id bio.chicago_2015.57958 ::date 2015-11-04T22:52:13 ::annotator SDL-AMR-09 ::preferred
# ::snt TFIIH phosphorylates  CDC2,  CDK2,  TFIIF,  TFIIE, TATA-binding  protein (TBP) and the  CTD (Lu  et al., 1992; Serizawa  et al., 1992; Ohkuma and Roeder, 1994; Serizawa  et al.,  1995; Shiekhattar  et al., 1995).
# ::save-date Sun Jan 17, 2016 ::file bio_chicago_2015_57958.txt
(p / phosphorylate-01
      :ARG1 (a / and
            :op1 (e / enzyme :name (n2 / name :op1 "CDC2"))
            :op2 (e2 / enzyme :name (n3 / name :op1 "CDK2"))
            :op3 (p4 / protein :name (n4 / name :op1 "TFIIF"))
            :op4 (p5 / protein :name (n5 / name :op1 "TFIIE"))
            :op5 (p6 / protein :name (n6 / name :op1 "TATA-binding" :op2 "protein"))
            :op6 (p3 / protein-segment :name (n7 / name :op1 "C-terminus")))
      :ARG2 (p2 / protein :name (n / name :op1 "TFIIH"))
      :ARG1-of (d2 / describe-01
            :ARG0 (a2 / and
                  :op1 (p8 / publication-91
                        :ARG0 (a3 / and
                              :op1 (p13 / person :name (n8 / name :op1 "Lu"))
                              :op2 (p18 / person
                                    :mod (o / other)))
                        :time d)
                  :op2 (p9 / publication-91
                        :ARG0 (a4 / and
                              :op1 (p14 / person :name (n9 / name :op1 "Serizawa"))
                              :op2 p18)
                        :time (d / date-entity :year 1992))
                  :op3 (p10 / publication-91
                        :ARG0 (a5 / and
                              :op1 (a8 / and
                                    :op1 (p15 / person :name (n10 / name :op1 "Ohkuma"))
                                    :op2 (p23 / person :name (n13 / name :op1 "Roeder"))
                                    :time (d3 / date-entity :year 1994))
                              :op2 p18))
                  :op4 (p11 / publication-91
                        :ARG0 (a6 / and
                              :op1 p14
                              :op2 p18
                              :time d4))
                  :op5 (p12 / publication-91
                        :ARG0 (a7 / and
                              :op1 (p17 / person :name (n12 / name :op1 "Shiekhattar"))
                              :op2 p18)
                        :time (d4 / date-entity :year 1995)))))

# ::id bio.chicago_2015.57959 ::date 2015-11-04T22:04:03 ::annotator SDL-AMR-09 ::preferred
# ::snt Tyrosine phosphorylation of the  Kv1.3 potassium channel.
# ::save-date Wed Nov 11, 2015 ::file bio_chicago_2015_57959.txt
(p / phosphorylate-01
      :ARG1 (a / amino-acid :name (n2 / name :op1 "Tyrosine")
            :part-of (p2 / protein :name (n / name :op1 "Kv1.3" :op2 "potassium" :op3 "channel"))))

# ::id bio.chicago_2015.57964 ::date 2015-11-04T22:14:23 ::annotator SDL-AMR-09 ::preferred
# ::snt Experiments with  transgenic mice also support a crucial role of  CaM-KII phosphorylation of  GluR1 as an important component of  CA1 LTP in mature animals.
# ::save-date Fri Nov 20, 2015 ::file bio_chicago_2015_57964.txt
(s / support-01
      :ARG0 (e / experiment-01
            :ARG1 (m / mouse
                  :mod (t / transgenic)))
      :ARG1 (r / role
            :mod (c / crucial)
            :poss (p / phosphorylate-01
                  :ARG1 (p2 / protein :name (n2 / name :op1 "GluR1"))
                  :ARG2 (e2 / enzyme :name (n / name :op1 "CaM-KII")))
            :domain (c2 / component
                  :mod (i / important)
                  :purpose (p3 / potentiate-01
                        :ARG1 (g / gene :name (n3 / name :op1 "CA1"))
                        :location (a2 / animal
                              :ARG1-of (m2 / mature-01))
                        :ARG1-of (l / long-03))))
      :mod (a / also))

# ::id bio.chicago_2015.58014 ::date 2015-11-04T22:21:51 ::annotator SDL-AMR-09 ::preferred
# ::snt Phosphorylation of  Myosin VI by  PAK In Vitro
# ::save-date Wed Nov 4, 2015 ::file bio_chicago_2015_58014.txt
(p / phosphorylate-01
      :ARG1 (p2 / protein :name (n / name :op1 "Myosin" :op2 "VI"))
      :ARG2 (e / enzyme :name (n2 / name :op1 "PAK"))
      :manner (i / in-vitro))

# ::id bio.chicago_2015.58026 ::date 2015-11-04T06:52:30 ::annotator SDL-AMR-09 ::preferred
# ::snt dTRAF2 Is Phosphorylated by  Pelle.
# ::save-date Wed Nov 11, 2015 ::file bio_chicago_2015_58026.txt
(p / phosphorylate-01
      :ARG1 (p2 / protein :name (n / name :op1 "dTRAF2"))
      :ARG2 (e / enzyme :name (n2 / name :op1 "Pelle")))

# ::id bio.chicago_2015.58031 ::date 2015-11-04T06:55:02 ::annotator SDL-AMR-09 ::preferred
# ::snt Thus, the phosphorylation of  MEF2 by  p38 MAP kinase and  ERK5/BMK1 may precede or stabilise the Smad -  MEF2 interaction.
# ::save-date Fri Jan 15, 2016 ::file bio_chicago_2015_58031.txt
(c / cause-01
      :ARG1 (o / or
            :op1 (p2 / precede-01
                  :ARG1 (p3 / phosphorylate-01
                        :ARG1 p
                        :ARG2 (a / and
                              :op1 (k / kinase :name (n / name :op1 "p38" :op2 "MAP" :op3 "kinase"))
                              :op2 (p5 / pathway :name (n2 / name :op1 "ERK5/BMK1"))))
                  :ARG2 (i / interact-01
                        :ARG0 (p6 / protein :name (n4 / name :op1 "Smad"))
                        :ARG1 (p / protein :name (n5 / name :op1 "MEF2"))))
            :op2 (s / stabilize-01
                  :ARG0 p3
                  :ARG1 i)
            :ARG1-of (p4 / possible-01)))

# ::id bio.chicago_2015.58034 ::date 2015-11-04T08:51:50 ::annotator SDL-AMR-09 ::preferred
# ::snt A number of  transcription factors are phosphorylated in response to  SAPK activation; for example, the  c-Jun factor is regulated by  JNK (Hibi  et al., 1993  ; Derijard  et al., 1994  ; Kyriakis  et al., 1994  ) but not by  p38, whereas  ATF2 is phosphorylated and regulated by both  JNK (Gupta  et al., 1995  ; Livingstone  et al., 1995  ; van Dam  et al., 1995  ) and  p38 (Raingeaud  et al., 1995  ).
# ::save-date Fri Nov 20, 2015 ::file bio_chicago_2015_58034.txt
(m / multi-sentence
      :snt1 (p / phosphorylate-01
            :ARG1 (f / factor
                  :ARG0-of (t / transcribe-01)
                  :quant (n13 / number))
            :ARG2-of (r / respond-01
                  :ARG1 (a / activate-01
                        :ARG1 (e2 / enzyme :name (n2 / name :op1 "SAPK")))))
      :snt2 (c / contrast-01
            :ARG1 (e3 / exemplify-01
                  :ARG0 (r2 / regulate-01
                        :ARG0 (e / enzyme :name (n4 / name :op1 "JNK"))
                        :ARG1 (p2 / protein :name (n3 / name :op1 "c-Jun")))
                  :ARG1-of (d3 / describe-01
                        :ARG0 (a4 / and
                              :op1 (p5 / publication-91
                                    :ARG0 (a5 / and
                                          :op1 (p8 / person :name (n6 / name :op1 "Hibi"))
                                          :op2 (p9 / person
                                                :mod (o / other)))
                                    :time (d / date-entity :year 1993))
                              :op2 (p6 / publication-91
                                    :ARG0 (a6 / and
                                          :op1 (p10 / person :name (n7 / name :op1 "Derijard"))
                                          :op2 p9)
                                    :time (d2 / date-entity :year 1994))
                              :op3 (p7 / publication-91
                                    :ARG0 (a7 / and
                                          :op1 (p12 / person :name (n8 / name :op1 "Kyriakis"))
                                          :op2 p9)
                                    :time d2))))
            :ARG2 (r3 / regulate-01 :polarity -
                  :ARG0 (e4 / enzyme :name (n5 / name :op1 "p38"))
                  :ARG1 p2)
            :ARG1-of (c2 / contrast-01
                  :ARG2 (a2 / and
                        :op1 (p4 / phosphorylate-01
                              :ARG1 (p3 / protein :name (n14 / name :op1 "ATF2"))
                              :ARG2 (a3 / and
                                    :op1 e
                                    :op2 e4)
                              :ARG1-of (d5 / describe-01
                                    :ARG0 (a8 / and
                                          :op1 (p14 / publication-91
                                                :ARG0 (a9 / and
                                                      :op1 (p17 / person :name (n9 / name :op1 "Gupta"))
                                                      :op2 p9)
                                                :time (d4 / date-entity :year 1995))
                                          :op2 (p15 / publication-91
                                                :ARG0 (a10 / and
                                                      :op1 (p19 / person :name (n10 / name :op1 "Livingstone"))
                                                      :op2 p9)
                                                :time d4)
                                          :op3 (p16 / publication-91
                                                :ARG0 (a11 / and
                                                      :op1 (p21 / person :name (n11 / name :op1 "Van" :op2 "Dam"))
                                                      :op2 p9)
                                                :time d4))))
                        :op2 (r4 / regulate-01
                              :ARG0 a3
                              :ARG1 p3
                              :ARG1-of (d6 / describe-01
                                    :ARG0 (p23 / publication-91
                                          :ARG0 (a12 / and
                                                :op1 (p24 / person :name (n12 / name :op1 "Raingeaud")
                                                      :op2 p9))
                                          :time d4)))))))

# ::id bio.chicago_2015.58063 ::date 2015-11-05T06:58:31 ::annotator SDL-AMR-09 ::preferred
# ::snt To determine whether  Src family kinases could directly phosphorylate  c-Abl, we produced  Src and  Fyn in  baculovirus-infected Sf9 insect cells, and incubated  Src or  Fyn immunoprecipitates with various  GST-Abl fragments.
# ::save-date Sun Jan 17, 2016 ::file bio_chicago_2015_58063.txt
(a2 / and
      :op1 (p2 / produce-01
            :ARG0 (w / we)
            :ARG1 (a / and
                  :op1 (p / protein-family :name (n3 / name :op1 "Src"))
                  :op2 (e / enzyme :name (n4 / name :op1 "Fyn")))
            :location (c / cell-line :name (n / name :op1 "Sf9")
                  :part-of (i / insect
                        :ARG1-of (i2 / infect-01
                              :ARG2 (o2 / organism :name (n6 / name :op1 "baculovirus"))))))
      :op2 (i3 / incubate-01
            :ARG0 w
            :ARG1 (o / or
                  :op1 (i4 / immunoprecipitate-01
                        :ARG1 p)
                  :op2 (i5 / immunoprecipitate-01
                        :ARG1 e))
            :ARG2 (f / fragment-01
                  :ARG1 (p8 / protein :name (n5 / name :op1 "GST-Abl"))
                  :ARG1-of (v / vary-01)))
      :purpose (d / determine-01
            :ARG0 w
            :ARG1 (p5 / possible-01 :mode interrogative
                  :ARG1 (p3 / phosphorylate-01
                        :ARG1 (p6 / protein :name (n2 / name :op1 "c-Abl"))
                        :ARG2 (k / kinase
                              :mod p)
                        :ARG1-of (d2 / direct-02)))))

# ::id bio.chicago_2015.58067 ::date 2015-11-04T08:06:09 ::annotator SDL-AMR-09 ::preferred
# ::snt Our lab and others have recently identified  S6K2, a homolog of  S6K1 that phosphorylates  S6  in vitro ( 4-7).
# ::save-date Sun Jan 17, 2016 ::file bio_chicago_2015_58067.txt
(i / identify-01
      :ARG0 (a / and
            :op1 (l / lab
                  :poss (w / we))
            :op2 (l2 / lab
                  :mod (o / other)))
      :ARG1 (e / enzyme :name (n / name :op1 "S6K2")
            :domain (h / homolog
                  :poss (e2 / enzyme :name (n2 / name :op1 "S6K1")
                        :ARG2-of (p / phosphorylate-01
                              :ARG1 (e3 / enzyme :name (n3 / name :op1 "S6"))
                              :manner (i2 / in-vitro)))))
      :time (r / recent)
      :ARG1-of (d / describe-01
            :ARG0 (p3 / publication)
            :ARG1-of (c / cite-01
                  :ARG2 (v / value-interval :op1 4 :op2 7))))

# ::id bio.chicago_2015.58101 ::date 2015-11-04T08:15:12 ::annotator SDL-AMR-09 ::preferred
# ::snt Myosin II was phosphorylated by  MLCK in the presence of various concentrations of isolated  RLC-GFP.
# ::save-date Sat Feb 13, 2016 ::file bio_chicago_2015_58101.txt
(p / phosphorylate-01
      :ARG1 (p2 / protein :name (n / name :op1 "Myosin" :op2 "II"))
      :ARG2 (e / enzyme :name (n2 / name :op1 "MLCK"))
      :ARG2-of (p3 / present-02
            :ARG1 (c / concentrate-02
                  :ARG1 (m / macro-molecular-complex :name (n3 / name :op1 "RLC-GFP")
                        :ARG1-of (i / isolate-01))
                  :ARG1-of (v / vary-01))))

# ::id bio.chicago_2015.58172 ::date 2015-11-04T08:27:38 ::annotator SDL-AMR-09 ::preferred
# ::snt This initial phosphorylation of  Rb by  cyclin D/Cdk4 also disrupts its interaction with  HDAC, thereby relieving the repression of the  cyclin E gene and allowing further progression into  S phase (  Zhang et al., 2000).
# ::save-date Sun Jan 17, 2016 ::file bio_chicago_2015_58172.txt
(c / cause-01
      :ARG0 (d2 / disrupt-01
            :ARG0 (p2 / phosphorylate-01
                  :ARG1 (p3 / protein :name (n / name :op1 "Rb"))
                  :ARG2 (m / macro-molecular-complex
                        :part (p4 / protein :name (n2 / name :op1 "Cyclin" :op2 "D"))
                        :part (e2 / enzyme :name (n7 / name :op1 "Cdk4")))
                  :mod (i / initial)
                  :mod (t / this))
            :ARG1 (i2 / interact-01
                  :ARG0 p2
                  :ARG1 (e / enzyme :name (n3 / name :op1 "HDAC")))
            :mod (a / also))
      :ARG1 (a2 / and
            :op1 (r / relieve-01
                  :ARG0 p2
                  :ARG1 (r2 / repress-01
                        :ARG0 (g / gene :name (n4 / name :op1 "cyclin" :op2 "E"))))
            :op2 (a3 / allow-01
                  :ARG0 p2
                  :ARG1 (p5 / progress-01
                        :ARG3 (p6 / phase :name (n6 / name :op1 "S"))
                        :degree (f / further))))
      :ARG1-of (d3 / describe-01
            :ARG0 (p7 / publication-91
                  :ARG0 (a4 / and
                        :op1 (p / person :name (n5 / name :op1 "Zhang"))
                        :op2 (p8 / person
                              :mod (o / other)))
                  :time (d / date-entity :year 2000))))

# ::id bio.chicago_2015.58176 ::date 2015-11-04T21:57:56 ::annotator SDL-AMR-09 ::preferred
# ::snt Phosphorylation and activation of  myosin by  Rho-associated kinase (Rho-kinase).
# ::save-date Wed Nov 11, 2015 ::file bio_chicago_2015_58176.txt
(a / and
      :op1 (p / phosphorylate-01
            :ARG1 (p2 / protein :name (n / name :op1 "myosin"))
            :ARG2 (e / enzyme :name (n2 / name :op1 "Rho-associated" :op2 "kinase")))
      :op2 (a2 / activate-01
            :ARG0 e
            :ARG1 p2))

# ::id bio.chicago_2015.58200 ::date 2015-11-04T22:03:06 ::annotator SDL-AMR-09 ::preferred
# ::snt p34 cdc2 phosphorylated the  threonine residue located in the  tail domain that is conserved within the   bimC family of  kinesin-related protein.
# ::save-date Wed Nov 11, 2015 ::file bio_chicago_2015_58200.txt
(p / phosphorylate-01
      :ARG1 (r / residue
            :mod (a2 / amino-acid :name (n3 / name :op1 "threonine"))
            :location (d / domain
                        :mod (t / tail)
                        :ARG1-of (c / conserve-01
                              :location (p2 / protein-family :name (n4 / name :op1 "BimC")
                                    :ARG1-of (r2 / relate-01
                                          :ARG2 (p3 / protein :name (n / name :op1 "kinesin")))))))
      :ARG2 (e / enzyme :name (n2 / name :op1 "p34" :op2 "cdc2")))

# ::id bio.chicago_2015.58215 ::date 2015-11-04T08:30:12 ::annotator SDL-AMR-09 ::preferred
# ::snt It is possible, however, that  Myt1 can phosphorylate  Cdk2 that has been initially phosphorylated on Tyr15, as has been previously suggested ( 11).
# ::save-date Wed Nov 11, 2015 ::file bio_chicago_2015_58215.txt
(p / possible-01
      :ARG1 (p2 / possible-01
            :ARG1 (p3 / phosphorylate-01
                  :ARG1 (e / enzyme :name (n2 / name :op1 "Cdk2")
                        :part-of (a / amino-acid :mod 15 :name (n3 / name :op1 "Tyrosine"))
                        :ARG3-of (p6 / phosphorylate-01
                              :time (i / initial)
                              :ARG1-of (s / suggest-01
                                    :time (p7 / previous))))
                  :ARG2 (p4 / protein :name (n / name :op1 "Myt1"))))
      :ARG2-of (c2 / contrast-01)
      :ARG1-of (d / describe-01
            :ARG0 (p8 / publication
                  :ARG1-of (c / cite-01
                        :ARG2 11))))

# ::id bio.chicago_2015.58274 ::date 2015-11-04T08:38:57 ::annotator SDL-AMR-09 ::preferred
# ::snt ( B) Similar amounts of  Cdc2 can be precipitated from either wild-type or mutant embryos using  anti-Cyclin B antibodies but the fast migrating ( Thr-161 phosphorylated) isoform of  Cdc2 (Edgar et al. 1994  ) is reduced in the   cdk7ts embryos as compared to wild type.
# ::save-date Wed Jan 20, 2016 ::file bio_chicago_2015_58274.txt
(c / contrast-01 :li "B"
      :ARG1 (p / possible-01
            :ARG1 (p2 / precipitate-01
                  :ARG1 (a / amount-01
                        :ARG1 (e5 / enzyme :name (n / name :op1 "Cdc2"))
                        :ARG1-of (r / resemble-01))
                  :source (o / or
                        :op1 (e / embryo
                              :mod (w / wild-type))
                        :op2 (e2 / embryo
                              :ARG2-of (m / mutate-01)))
                  :instrument (a2 / antibody
                        :ARG0-of (c2 / counter-01
                              :ARG1 (p4 / protein :name (n2 / name :op1 "Cyclin" :op2 "B"))))))
      :ARG2 (r2 / reduce-01
            :ARG1 (i / isoform
                  :ARG0-of (m2 / migrate-01
                        :ARG1-of (f / fast-02))
                  :mod e5
                  :ARG1-of (d2 / describe-01
                        :ARG0 (p5 / publication-91
                              :ARG0 (a3 / and
                                    :op1 (p6 / person :name (n3 / name :op1 "Edgar"))
                                    :op2 (p7 / person
                                          :mod (o2 / other)))
                              :time (d / date-entity :year 1994)))
                  :part (a4 / amino-acid :mod 161 :name (n5 / name :op1 "Threonine")
                        :ARG3-of (p3 / phosphorylate-01)))
            :location (e3 / embryo
                  :mod (p8 / protein :name (n4 / name :op1 "cdk7ts")))
            :ARG1-of (c3 / compare-01
                  :ARG2 e)))

# ::id bio.chicago_2015.58292 ::date 2015-11-05T06:37:58 ::annotator SDL-AMR-09 ::preferred
# ::snt To confirm further the specific phosphorylation of  MARCKS by  PKC, we included the  PKC inhibitor peptide (19-31) in the phosphorylation assay.
# ::save-date Sun Jan 17, 2016 ::file bio_chicago_2015_58292.txt
(i2 / include-01
      :ARG0 (w / we)
      :ARG1 (p2 / peptide
            :ARG0-of (i3 / inhibit-01
                  :ARG1 (e / enzyme :name (n / name :op1 "PKC")))
            :ARG1-of (d / describe-01
                  :ARG0 (p4 / publication
                        :ARG1-of (c2 / cite-01
                              :ARG2 (v / value-interval :op1 19 :op2 31)))))
      :ARG2 (a / assay-01
            :ARG1 (p / phosphorylate-01))
      :purpose (c / confirm-01
            :ARG0 w
            :ARG1 (p3 / phosphorylate-01
                  :ARG1 (p5 / protein :name (n2 / name :op1 "MARCKS"))
                  :ARG2 e
                  :ARG1-of (s / specific-02))
            :degree (f / further)))

# ::id bio.chicago_2015.58296 ::date 2015-11-05T06:41:32 ::annotator SDL-AMR-09 ::preferred
# ::snt N-terminal KSR was phosphorylated by  Nm23-H1 only under the specific conditions of transfection with Pyo-tagged  N-terminal KSR, immunoprecipitation with anti-Pyo, and incubation with wild type autophosphorylated  Nm23-H1 ( upper panel).
# ::save-date Thu Nov 26, 2015 ::file bio_chicago_2015_58296.txt
(p / phosphorylate-01
      :ARG1 (e / enzyme :name (n / name :op1 "N-terminal" :op2 "KSR"))
      :ARG2 (p4 / protein :name (n2 / name :op1 "Nm23-H1"))
      :condition (a / and
            :op1 (t / transfect-01
                  :ARG1 e
                  :ARG2 (e2 / enzyme :name (n3 / name :op1 "N-terminal" :op2 "KSR")
                        :ARG1-of (t2 / tag-01
                              :ARG2 s)))
            :op2 (i / immunoprecipitate-01
                  :ARG1 e
                  :ARG3 (m / molecular-physical-entity
                        :ARG0-of (c / counter-01
                              :ARG1 (s / small-molecule :name (n4 / name :op1 "Pyo")))))
            :op3 (i2 / incubate-01
                  :ARG1 e
                  :ARG2 (p5 / protein :name (n5 / name :op1 "Nm23-H1")
                        :mod (w / wild-type)
                        :ARG1-of (p3 / phosphorylate-01
                              :ARG2 p4)))
            :ARG1-of (s2 / specific-02))
      :ARG1-of (d / describe-01
            :ARG0 (p2 / panel
                  :mod (u / upper)))
      :mod (o / only))

# ::id bio.chicago_2015.58306 ::date 2015-11-04T22:53:25 ::annotator SDL-AMR-09 ::preferred
# ::snt PKC directly phosphorylates  GluR2 but not GluR2S880A  mutant fusion proteins.
# ::save-date Thu Nov 5, 2015 ::file bio_chicago_2015_58306.txt
(c / contrast-01
      :ARG1 (p / phosphorylate-01
            :ARG1 (p4 / protein :name (n2 / name :op1 "GluR2"))
            :ARG2 (e / enzyme :name (n / name :op1 "PKC"))
            :ARG1-of (d / direct-02))
      :ARG2 (p2 / phosphorylate-01 :polarity -
            :ARG1 (p3 / protein :name (n3 / name :op1 "GluR2S880A")
                  :ARG1-of (f / fuse-01)
                  :ARG2-of (m / mutate-01))
            :ARG2 e))

# ::id bio.chicago_2015.58325 ::date 2015-11-04T07:25:49 ::annotator SDL-AMR-09 ::preferred
# ::snt It did, however, inhibit the phosphorylation and binding of endogenous  Shc to  MT and  Grb2.
# ::save-date Sun Jan 17, 2016 ::file bio_chicago_2015_58325.txt
(c / contrast-01
      :ARG2 (i / inhibit-01
            :ARG1 (a / and
                  :op1 (p2 / phosphorylate-01
                        :ARG1 (p / protein :name (n / name :op1 "Sch")
                              :mod (e / endogenous)))
                  :op2 (b / bind-01
                        :ARG1 p
                        :ARG2 (a2 / and
                              :op1 (p3 / protein :name (n2 / name :op1 "MT"))
                              :op2 (p4 / protein :name (n3 / name :op1 "Grb2")))))))

# ::id bio.chicago_2015.58328 ::date 2015-11-04T07:49:30 ::annotator SDL-AMR-09 ::preferred
# ::snt Taken together, Frat-1 prefers  Dvl-1 phosphorylated by  CKIepsilon, and the amino acid region 228-250 of  Dvl-1 is necessary for the direct binding of  Dvl-1 to Frat-1.
# ::save-date Wed Nov 11, 2015 ::file bio_chicago_2015_58328.txt
(a / and
      :op1 (p / prefer-01
            :ARG0 (p2 / protein :name (n3 / name :op1 "Frat-1"))
            :ARG1 (p4 / phosphorylate-01
                  :ARG1 (p5 / protein :name (n5 / name :op1 "Dvl-1"))
                  :ARG2 (e / enzyme :name (n4 / name :op1 "CKIepsilon"))))
      :op2 (n2 / need-01
            :ARG0 (b2 / bind-01
                  :ARG1 p5
                  :ARG2 p2
                  :ARG1-of (d / direct-02))
            :ARG1 (r / region
                  :mod (a2 / amino-acid)
                  :part-of p5
                  :mod (v / value-interval :op1 228 :op2 250)))
      :ARG1-of (t2 / take-01
            :manner (t / together)))

# ::id bio.chicago_2015.58338 ::date 2015-11-04T06:56:09 ::annotator SDL-AMR-09 ::preferred
# ::snt In contrast,  PKG phosphorylation of  SF1-C4 completely inhibited spliceosome assembly (Figure  7B, lanes 7-9).
# ::save-date Wed Nov 11, 2015 ::file bio_chicago_2015_58338.txt
(c / contrast-01
      :ARG2 (i / inhibit-01
            :ARG0 (p2 / phosphorylate-01
                  :ARG1 (p3 / protein :name (n / name :op1 "SF1-C4"))
                  :ARG2 (e / enzyme :name (n2 / name :op1 "PKG")))
            :ARG1 (a / assembly
                  :mod (s / spliceosome))
            :ARG1-of (c2 / complete-02))
      :ARG1-of (d / describe-01
            :ARG0 (a2 / and
                  :op1 (f / figure :mod "7B")
                  :op2 (l / lane
                        :mod (v / value-interval :op1 7 :op2 9)))))

# ::id bio.chicago_2015.62138 ::date 2015-11-04T07:00:05 ::annotator SDL-AMR-09 ::preferred
# ::snt ( A)  Emi1 can bind  Cdc20 and  Cdh1 already associated with the  APC.
# ::save-date Sun Jan 17, 2016 ::file bio_chicago_2015_62138.txt
(p2 / possible-01 :li "A"
      :ARG1 (b / bind-01
            :ARG1 (s / small-molecule :name (n4 / name :op1 "Emi1"))
            :ARG2 (a2 / and
                  :op1 (p4 / protein :name (n2 / name :op1 "Cdc20"))
                  :op2 (p5 / protein :name (n3 / name :op1 "Cdh1"))
                  :ARG1-of (a / associate-01
                        :ARG2 (p / protein :name (n / name :op1 "APC"))
                        :time (a3 / already)))))

# ::id bio.chicago_2015.68191 ::date 2015-11-04T22:45:52 ::annotator SDL-AMR-09 ::preferred
# ::snt As shown in Fig.  2D,   M. tuberculosis stimulation of J774 cells results in the inducible binding of  ATF-2,  c-jun,  Ets-1/2,  Egr-1, and  Sp1 to the  TNF-alpha promoter in vivo.
# ::save-date Wed Nov 11, 2015 ::file bio_chicago_2015_68191.txt
(s / show-01
      :ARG0 (f / figure :mod "2D")
      :ARG1 (r / result-01
            :ARG1 (s2 / stimulate-01
                  :ARG0 (o / organism :name (n / name :op1 "M." :op2 "tuberculosis"))
                  :ARG1 (c / cell-line :name (n2 / name :op1 "J774")))
            :ARG2 (b / bind-01
                  :ARG1 (a / and
                        :op1 (p / protein :name (n3 / name :op1 "ATF-2"))
                        :op2 (p2 / protein :name (n4 / name :op1 "c-jun"))
                        :op3 (p3 / protein :name (n5 / name :op1 "Ets-1/2"))
                        :op4 (p4 / protein :name (n6 / name :op1 "Egr-1"))
                        :op5 (p5 / protein :name (n7 / name :op1 "Sp1")))
                  :ARG2 (m / molecular-physical-entity
                        :ARG0-of (p6 / promote-02
                              :ARG1 (p7 / protein :name (n8 / name :op1 "TNF-alpha"))))
                  :ARG2-of (i2 / induce-01
                        :ARG1-of (p8 / possible-01))
                  :manner (i / in-vivo))))

# ::id bio.chicago_2015.68528 ::date 2015-11-05T06:42:18 ::annotator SDL-AMR-09 ::preferred
# ::snt This result again supports the notion that binding of the  GATA family factors to the  GATA motif is important for   E4bp4 expression in  IL-3-dependent Ba/F3 cells.
# ::save-date Sun Jan 17, 2016 ::file bio_chicago_2015_68528.txt
(s / support-01
      :ARG0 (t / thing
            :mod (t2 / this)
            :ARG2-of (r / result-01))
      :ARG1 (n / notion
            :topic (i / important
                  :domain (b / bind-01
                        :ARG1 (f / factor
                              :mod (p / protein-family :name (n2 / name :op1 "GATA")))
                        :ARG2 (m / motif
                              :part-of p))
                  :purpose (e / express-03
                        :ARG2 (p3 / protein :name (n4 / name :op1 "E4bp4"))
                        :ARG3 (c / cell-line :name (n6 / name :op1 "Ba/F3")
                              :ARG0-of (d / depend-01
                                    :ARG1 (p4 / protein :name (n5 / name :op1 "IL-3")))))))
      :mod (a / again))

# ::id bio.chicago_2015.68624 ::date 2015-11-04T05:39:52 ::annotator SDL-AMR-09 ::preferred
# ::snt We tested cells growing in low and high serum for  mDia1 and  mDia2 associated  Src activity (shown in pairs).
# ::save-date Wed Mar 2, 2016 ::file bio_chicago_2015_68624.txt
(t / test-01
      :ARG0 (w / we)
      :ARG1 (c / cell
            :ARG1-of (g / grow-01
                  :location (a / and
                        :op1 (s / serum
                              :ARG1-of (l / low-04))
                        :op2 (s2 / serum
                              :ARG1-of (h / high-02)))))
      :ARG2 (a2 / and
            :op1 (p / protein :name (n / name :op1 "mDia1"))
            :op2 (p2 / protein :name (n3 / name :op1 "mDia2"))
            :ARG1-of (a3 / associate-01
                  :ARG2 (a4 / activity-06
                        :ARG0 (p3 / protein :name (n2 / name :op1 "Src")))))
      :ARG1-of (s3 / show-01
            :manner (p4 / pair)))

# ::id bio.chicago_2015.69904 ::date 2015-11-04T05:47:11 ::annotator SDL-AMR-09 ::preferred
# ::snt The  oxysterol binding protein and  beta-spectrin PH domains bound  PtdIns-3,4,5-P3 and  PtdIns-4,5-P2 with similar affinities.
# ::save-date Fri Nov 20, 2015 ::file bio_chicago_2015_69904.txt
(b / bind-01
      :ARG1 (a / and
            :op1 (p / protein
                  :ARG1-of (b2 / bind-01
                        :ARG2 (o / oxysterol)))
            :op2 (d / domain :name (n / name :op1 "beta-spectrin" :op2 "PH")))
      :ARG2 (a2 / and
            :op1 (e / enzyme :name (n2 / name :op1 "PtdIns-3,4,5-P3"))
            :op2 (e2 / enzyme :name (n3 / name :op1 "PtdIns-4,5-P2")))
      :ARG3 (a3 / affinity
            :ARG1-of (r / resemble-01)))

# ::id bio.chicago_2015.70184 ::date 2015-11-04T22:59:58 ::annotator SDL-AMR-09 ::preferred
# ::snt Effect of okadaic acid on  apoB and  apoA-I secretion by  CaCo-2 cells.
# ::save-date Fri Jan 15, 2016 ::file bio_chicago_2015_70184.txt
(a / affect-01
      :ARG0 (s2 / small-molecule :name (n4 / name :op1 "okadaic" :op2 "acid"))
      :ARG1 (s / secrete-01
            :ARG0 (c2 / cell-line :name (n3 / name :op1 "CaCo-2"))
            :ARG1 (a3 / and
                  :op1 (p2 / protein :name (n / name :op1 "apoB"))
                  :op2 (p / protein :name (n2 / name :op1 "apoA-I")))))

# ::id bio.chicago_2015.70354 ::date 2015-11-04T23:05:52 ::annotator SDL-AMR-09 ::preferred
# ::snt A simple  alfalfa seedling  infection model for  Pseudomonas aeruginosa strains associated with  cystic fibrosis shows  AlgT (sigma-22) and  RhlR contribute to pathogenesis.
# ::save-date Thu Dec 10, 2015 ::file bio_chicago_2015_70354.txt
(s / show-01
      :ARG0 (m / model-01
            :ARG1 (s2 / strain-01
                  :ARG0 (o / organism :name (n / name :op1 "Pseudomonas" :op2 "aeruginosa"))
                  :ARG1-of (a2 / associate-01
                        :ARG2 (d / disease :name (n5 / name :op1 "cystic" :op2 "fibrosis"))))
            :topic (i / infect-01
                  :ARG1 (s3 / seedling
                        :mod (o2 / organism :name (n3 / name :op1 "Alfalfa"))))
            :ARG1-of (s4 / simple-02))
      :ARG1 (c / contribute-01
            :ARG0 (a / and
                  :op1 (p4 / protein :name (n6 / name :op1 "AlgT" :op2 "sigma-22"))
                  :op2 (p3 / protein :name (n4 / name :op1 "RhlR")))
            :ARG2 (p / pathogenesis)))

# ::id bio.chicago_2015.70864 ::date 2015-11-05T00:13:01 ::annotator SDL-AMR-09 ::preferred
# ::snt Concurrently,  gp41 dissociates from  gp120, associates with the target membrane and mediates fusion of the viral and the cellular membranes by a process that involves the N-terminal hydrophobic region of  gp41, termed the fusion peptide (Gallaher, 1987  ).
# ::save-date Wed Nov 11, 2015 ::file bio_chicago_2015_70864.txt
(a / and
      :op1 (d3 / dissociate-01
            :ARG1 (p3 / protein :name (n2 / name :op1 "gp41"))
            :ARG2 (p4 / protein :name (n3 / name :op1 "gp120")))
      :op2 (a2 / associate-01
            :ARG1 p3
            :ARG2 (m2 / membrane
                  :ARG1-of (t / target-01)))
      :op3 (m / mediate-01
            :ARG0 p3
            :ARG1 (f / fuse-01
                  :ARG1 (a3 / and
                        :op1 (m3 / membrane
                              :mod (v / viral))
                        :op2 (m4 / membrane
                              :mod (c2 / cell))))
            :manner (p5 / process-02
                  :ARG2-of (i / involve-01
                        :ARG1 (r / region
                              :mod (h / hydrophobic)
                              :part-of p3
                              :mod (p7 / protein-segment :name (n4 / name :op1 "N-terminus"))))
                  :ARG1-of (t2 / term-01
                        :ARG0 (p6 / peptide
                              :ARG0-of (f2 / fuse-01)))))
      :ARG1-of (d2 / describe-01
            :ARG0 (p / publication-91
                  :ARG0 (p2 / person :name (n / name :op1 "Gallaher"))
                  :time (d / date-entity :year 1987)))
      :ARG1-of (c / concurrent-02))

# ::id bio.chicago_2015.70878 ::date 2015-11-04T22:35:05 ::annotator SDL-AMR-09 ::preferred
# ::snt AAK1 localizes to regions active in endocytosis    AAK1 binds directly to  AP2.
# ::save-date Fri Nov 20, 2015 ::file bio_chicago_2015_70878.txt
(m / multi-sentence
      :snt1 (l / localize-01
            :ARG1 (p2 / protein :name (n / name :op1 "AAK1"))
            :location (r / region
                  :ARG0-of (a / activity-06
                        :ARG1 (e / endocytosis))))
      :snt2 (b / bind-01
            :ARG1 (p3 / protein :name (n3 / name :op1 "AAK1"))
            :ARG2 (p / protein :name (n2 / name :op1 "AP2"))
            :ARG1-of (d / direct-02)))

# ::id bio.chicago_2015.70927 ::date 2015-11-04T08:53:46 ::annotator SDL-AMR-09 ::preferred
# ::snt Characterization of a novel member of the  DOK family that binds and modulates  Abl signaling.
# ::save-date Wed Jan 13, 2016 ::file bio_chicago_2015_70927.txt
(c / characterize-01
      :ARG1 (m / member
            :mod (n / novel)
            :poss (p / protein-family :name (n2 / name :op1 "DOK"))
            :ARG0-of (b / bind-01
                  :ARG1 (s / signal-07
                        :ARG0 (p2 / protein :name (n3 / name :op1 "Abl"))))
            :ARG0-of (m2 / modulate-01
                  :ARG1 s)))

# ::id bio.chicago_2015.71093 ::date 2015-11-04T14:02:00 ::annotator SDL-AMR-09 ::preferred
# ::snt The  tyrosine phosphatase PTP1C associates with  Vav,  Grb2, and mSos1 in hematopoietic cells.
# ::save-date Fri Nov 20, 2015 ::file bio_chicago_2015_71093.txt
(a / associate-01
      :ARG1 (e / enzyme :name (n / name :op1 "tyrosine" :op2 "phosphatase" :op3 "PTP1C"))
      :ARG2 (a2 / and
            :op1 (p2 / protein :name (n2 / name :op1 "Vav"))
            :op2 (p3 / protein :name (n3 / name :op1 "Grb2"))
            :op2 (p4 / protein :name (n4 / name :op1 "Sos1")
                  :part-of (m / mouse)))
      :location (c / cell
            :mod (h / hematopoietic)))

# ::id bio.chicago_2015.71185 ::date 2015-11-04T14:14:30 ::annotator SDL-AMR-09 ::preferred
# ::snt S phase induction and   c-MYC RNA and  c-JUN protein in quiescent  MCF10A cells infected  at 20 pfu/cell with dl1500 (wild-type  E1A) and dl2-36 ( mutant E1A that does not bind to  p300).
# ::save-date Sat Feb 13, 2016 ::file bio_chicago_2015_71185.txt
(a / and
      :op1 (i / induce-01
            :ARG2 (p / phase :name (n / name :op1 "S")))
      :op2 (a2 / and
            :op1 (n3 / nucleic-acid :name (n4 / name :op1 "RNA")
                  :ARG0-of (e3 / encode-01
                        :ARG1 (p7 / protein :name (n2 / name :op1 "c-MYC"))))
            :op2 (p2 / protein :name (n5 / name :op1 "c-JUN")))
      :location (c / cell-line :name (n6 / name :op1 "MCF10A")
            :mod (q / quiescent)
            :ARG1-of (i2 / infect-01
                  :ARG2 (a3 / and
                        :op1 (v / virus :name (n7 / name :op1 "dl1500")
                              :ARG1-of (e / express-03
                                    :ARG2 (p3 / protein :name (n8 / name :op1 "E1A")
                                          :mod (w / wild-type))))
                        :op2 (v2 / virus :name (n9 / name :op1 "dl2-36")
                              :ARG1-of (e2 / express-03
                                    :ARG2 (p4 / protein :name (n10 / name :op1 "E1A")
                                          :ARG2-of (m3 / mutate-01)
                                          :ARG1-of (b / bind-01 :polarity -
                                                :ARG2 (p5 / protein :name (n11 / name :op1 "p300")))))))
                  :mod (r / rate-entity-91
                        :ARG1 (u / unit :quant 20
                              :ARG0-of (f / form-01
                                    :ARG1 (p6 / plaque)))
                        :ARG2 (c2 / cell :quant 1)))))

# ::id bio.chicago_2015.71284 ::date 2015-11-05T05:58:33 ::annotator SDL-AMR-09 ::preferred
# ::snt Characterization of a representative  U2OS clone conditionally coexpressing Rbdeltacdk with  cyclin E (clone B3B4).
# ::save-date Tue Feb 2, 2016 ::file bio_chicago_2015_71284.txt
(c / characterize-01
      :ARG1 (c2 / clone-01
            :ARG1 (c3 / cell :name (n / name :op1 "U2OS"))
            :ARG0-of (r / represent-01)
            :ARG3-of (c4 / coexpress-01
                  :ARG2 (a / and
                        :op1 (p / protein :name (n2 / name :op1 "RbΔcdk"))
                        :op2 (p2 / protein :name (n3 / name :op1 "cyclin" :op2 "E")
                              :ARG1-of (m / mean-01
                                    :ARG2 (c5 / clone-01
                                          :ARG1 (a2 / and
                                                :op1 (p3 / protein :name (n4 / name :op1 "cyclin" :op2 "B3"))
                                                :op2 (p4 / protein :name (n5 / name :op1 "cyclin" :op2 "B4")))))))
                  :ARG1-of (c6 / condition-01))))

# ::id bio.chicago_2015.71299 ::date 2015-11-05T06:48:51 ::annotator SDL-AMR-09 ::preferred
# ::snt In summary, the results of these experiments are consistent with previous studies in the  Hepa-1 cell line (Gassmann et al., 1997  ) and support the hypothesis that the formation of  AHR/ ARNT complexes capable of binding DNA is not affected by conditions in which up to 15% of the  ARNT protein pool has been recruited to the  hypoxia signaling pathway.
# ::save-date Wed Nov 11, 2015 ::file bio_chicago_2015_71299.txt
(a / and
      :op1 (c / consistent-01
            :ARG1 (t / thing
                  :ARG2-of (r / result-01
                        :ARG1 (e / experiment-01
                              :mod (t2 / this))))
            :ARG2 (s / study-01
                  :ARG1 (c2 / cell-line :name (n / name :op1 "Hepa-1"))
                  :time (p / previous))
            :ARG1-of (d / describe-01
                  :ARG0 (p2 / publication-91
                        :ARG0 (a2 / and
                              :op1 (p3 / person :name (n2 / name :op1 "Gassmann"))
                              :op2 (p4 / person
                                    :mod (o / other)))
                        :time (d2 / date-entity :year 1997))))
      :op2 (s2 / support-01
            :ARG0 t
            :ARG1 (h / hypothesize-01
                  :ARG1 (a3 / affect-01 :polarity -
                        :ARG0 (c3 / condition-01
                              :ARG2 (r2 / recruit-01
                                    :ARG1 (p5 / pool-01
                                          :ARG1 (p6 / protein :name (n3 / name :op1 "ARNT"))
                                          :quant (u / up-to
                                                :op1 (p7 / percentage-entity :value 15)))
                                    :ARG2 (p8 / pathway :name (n4 / name :op1 "hypoxia")
                                          :ARG0-of (s3 / signal-07))))
                        :ARG1 (f / form-01
                              :ARG1 (m / macro-molecular-complex
                                    :part (p9 / protein :name (n5 / name :op1 "AHR"))
                                    :part p6
                                    :ARG1-of (c4 / capable-01
                                          :ARG2 (b / bind-01
                                                :ARG0 m
                                                :ARG1 (n6 / nucleic-acid :name (n7 / name :op1 "DNA")))))))))
      :ARG2-of (s4 / summarize-01))

# ::id bio.chicago_2015.71300 ::date 2015-11-05T07:23:14 ::annotator SDL-AMR-09 ::preferred
# ::snt To independently prove that  IkappaBalpha  is linked to   ubiquitin, cells were treated with  TNFalpha  and  Z-LLL-H, and extracts  were immunoprecipitated with antibodies to  IkappaBalpha,  NF-kappaB p50,   NF-kappaB p65, or nonimmune serum prior to detection of  bound ubiquitin  by Western blotting with a monoclonal antibody directed against   ubiquitin( 59) .
# ::save-date Sat Feb 13, 2016 ::file bio_chicago_2015_71300.txt
(a / and
      :op1 (t / treat-04
            :ARG1 (c / cell)
            :ARG2 (a2 / and
                  :op1 (p / protein :name (n / name :op1 "TNFα"))
                  :op2 (s2 / small-molecule :name (n2 / name :op1 "Z-LLL-H"))))
      :op2 (i / immunoprecipitate-01
            :ARG2 (m2 / molecular-physical-entity
                  :ARG1-of (e / extract-01))
            :ARG3 (o / or
                  :op1 (a3 / and
                        :op1 (a4 / antibody
                              :ARG0-of (c2 / counter-01
                                    :ARG1 (p2 / protein :name (n3 / name :op1 "IκBα"))))
                        :op2 (a5 / antibody
                              :ARG0-of (c3 / counter-01
                                    :ARG1 (p3 / protein :name (n4 / name :op1 "p50")
                                          :part-of (m3 / macro-molecular-complex :name (n5 / name :op1 "NF-κB")))))
                        :op3 (a6 / antibody
                              :ARG0-of (c4 / counter-01
                                    :ARG1 (p4 / protein :name (n6 / name :op1 "p65")
                                          :part-of m3))))
                  :op2 (s / serum
                        :ARG1-of (i2 / immune-02 :polarity -))))
      :time (p5 / prior
            :op1 (d / detect-01
                  :ARG1 (p6 / protein :name (n8 / name :op1 "ubiquitin")
                        :ARG1-of (b / bind-01))
                  :ARG2 (i3 / immunoblot-01
                        :ARG3 (a7 / antibody
                              :mod (m4 / monoclonal)
                              :ARG1-of (d2 / direct-01
                                    :ARG2 (a8 / against
                                          :op1 (p7 / protein :name (n9 / name :op1 "ubiquitin"))))))))
      :purpose (p8 / prove-01
            :ARG1 (l / link-01
                  :ARG1 p2
                  :ARG2 p7)
            :ARG0-of (d3 / depend-01 :polarity -))
      :ARG1-of (d4 / describe-01
            :ARG0 (p9 / publication
                  :ARG1-of (c5 / cite-01
                        :ARG2 59))))

# ::id bio.chicago_2015.71532 ::date 2015-11-10T02:27:42 ::annotator SDL-AMR-09 ::preferred
# ::snt Skb1 and  Shk1 Associate with  Cdc2 in   S. pombe.
# ::save-date Fri Nov 20, 2015 ::file bio_chicago_2015_71532.txt
(a / associate-01
      :ARG1 (a2 / and
            :op1 (p / protein :name (n / name :op1 "Skb1"))
            :op2 (p2 / protein :name (n2 / name :op1 "Shk1")))
      :ARG2 (e2 / enzyme :name (n3 / name :op1 "Cdc2"))
      :location (o / organism :name (n4 / name :op1 "Schizosaccharomyces" :op2 "pombe")))

# ::id bio.chicago_2015.71733 ::date 2015-11-10T02:41:43 ::annotator SDL-AMR-09 ::preferred
# ::snt The  labels  RNAP IIO and   IIA represent hyperphosphorylated and hypophosphorylated forms of the  RNAP II larger subunit, respectively.
# ::save-date Tue Nov 17, 2015 ::file bio_chicago_2015_71733.txt
(a / and
      :op1 (r / represent-01
            :ARG0 (e / enzyme :name (n / name :op1 "RNAP" :op2 "IIO")
                  :ARG2-of (l / label-01))
            :ARG1 (s / subunit
                  :ARG1-of (h / hyperphosphorylate-01)
                  :mod (e2 / enzyme :name (n2 / name :op1 "RNAP" :op2 "II"))
                  :mod (l2 / large
                        :degree (m / more))))
      :op2 (r2 / represent-01
            :ARG0 (e3 / enzyme :name (n3 / name :op1 "RNAP" :op2 "IIA")
                  :ARG2-of l)
            :ARG1 (s2 / subunit
                  :ARG1-of (h2 / hypophosphorylate-00)
                  :mod e2
                  :mod l2)))

# ::id bio.chicago_2015.71734 ::date 2015-11-10T02:53:49 ::annotator SDL-AMR-09 ::preferred
# ::snt The fluorescent microscopy method has allowed us to examine how quickly caldesmon coupled with  TM can disassemble preformed  fascin-actin bundles.
# ::save-date Tue Jan 12, 2016 ::file bio_chicago_2015_71734.txt
(a / allow-01
      :ARG0 (m / method
            :mod (m2 / microscopy
                  :mod (f / fluoresce-01)))
      :ARG1 (e / examine-01
            :ARG0 (w / we)
            :ARG1 (q / quick-02
                  :ARG1 (p / possible-01
                        :ARG1 (d / disassemble-01
                              :ARG0 (p2 / protein :wiki "Caldesmon"
                                    :name (n2 / name :op1 "caldesmon")
                                    :ARG1-of (c / couple-01
                                          :ARG2 (p3 / protein :wiki "Tropomyosin"
                                                :name (n3 / name :op1 "tropomyosin"))))
                              :ARG1 (b / bundle-01
                                    :ARG2 (a2 / and
                                          :op1 (p4 / protein :wiki "Fascin"
                                                :name (n4 / name :op1 "fascin"))
                                          :op2 (p5 / protein :wiki "Actin"
                                                :name (n5 / name :op1 "actin")))
                                    :ARG1-of (p6 / preform-01))))
                  :degree (a3 / amr-unknown))))

# ::id bio.chicago_2015.71778 ::date 2015-11-10T03:28:07 ::annotator SDL-AMR-09 ::preferred
# ::snt As determined by immunoprecipitation, these affinity-purified antisera detected a single protein band of ~43 kDa in an  SDS-PAGE using  in vitro translated  Spy1 (Figure  3A, lane 4).
# ::save-date Tue Nov 10, 2015 ::file bio_chicago_2015_71778.txt
(d / detect-01
      :ARG0 (a / antiserum
            :ARG1-of (p / purify-01
                  :ARG2 (a2 / affinity))
            :mod (t / this))
      :ARG1 (b / band
            :mod (p2 / protein
                  :quant (a3 / approximately
                        :op1 (m / mass-quantity :quant 43
                              :unit (k / kilodalton))))
            :ARG1-of (s / single-02))
      :ARG2 (t2 / thing :name (n / name :op1 "SDS-PAGE"))
      :ARG2-of (u / use-01
            :ARG1 (p3 / protein :name (n2 / name :op1 "Spy1")
                  :ARG2-of (t3 / translate-02
                        :manner (i / in-vitro))))
      :ARG1-of (d2 / determine-01
            :ARG0 (i2 / immunoprecipitate-01))
      :ARG1-of (d3 / describe-01
            :ARG0 (l / lane :mod 4
                  :part-of (f / figure :mod "3A"))))

# ::id bio.chicago_2015.71791 ::date 2015-11-10T04:28:36 ::annotator SDL-AMR-09 ::preferred
# ::snt Actin depolymerization with latrunculin delocalized  myosin II and  anillin, as expected, and had little effect on the organization of cytokinesis-associated microtubules.
# ::save-date Sat Feb 13, 2016 ::file bio_chicago_2015_71791.txt
(a / and
      :op1 (d / delocalize-01
            :ARG0 (d2 / depolymerize-00
                  :ARG1 (p / protein :name (n / name :op1 "actin"))
                  :instrument (s / small-molecule :name (n4 / name :op1 "latrunculin")))
            :ARG1 (a2 / and
                  :op1 (p2 / protein :name (n2 / name :op1 "myosin" :op2 "II"))
                  :op2 (p3 / protein :name (n3 / name :op1 "anillin")))
            :ARG1-of (e / expect-01))
      :op2 (a3 / affect-01
            :ARG0 d2
            :ARG1 (o / organize-01
                  :ARG1 (m2 / microtubule
                        :ARG1-of (a4 / associate-01
                              :ARG2 (c / cytokinesis))))
            :degree (l2 / little)))

# ::id bio.chicago_2015.71819 ::date 2015-11-10T04:41:34 ::annotator SDL-AMR-09 ::preferred
# ::snt The synergistic interaction between  cofilin and  Arp2/3, where  Arp2/3 caps and stabilizes short filaments produced by  cofilin severing activity, may resolve the inconsistencies inherent in the above two mechanisms ( Bailly et al. 1999   ).
# ::save-date Fri Feb 5, 2016 ::file bio_chicago_2015_71819.txt
(p / possible-01
      :ARG1 (r / resolve-01
            :ARG0 (i / interact-01
                  :ARG0 (p2 / protein :name (n / name :op1 "cofilin"))
                  :ARG1 (m / macro-molecular-complex
                        :part (p3 / protein :name (n2 / name :op1 "Arp2"))
                        :part (p4 / protein :name (n3 / name :op1 "Arp3")))
                  :ARG0-of (s / synergize-01)
                  :location-of (a / and
                        :op1 (c / cap-02
                              :ARG0 m
                              :ARG1 (f / filament
                                    :ARG1-of (s2 / short-07)
                                    :ARG1-of (p5 / produce-01
                                          :ARG0 (a2 / activity-06
                                                :ARG0 p2
                                                :ARG1 (s3 / sever-01
                                                      :ARG0 p2)))))
                        :op2 (s4 / stabilize-01
                              :ARG0 m
                              :ARG1 f)))
            :ARG1 (c2 / consistent-01 :polarity -
                  :ARG1 c
                  :ARG2 s4
                  :mod (i2 / inherent)))
      :ARG1-of (d / describe-01
            :ARG0 (p6 / publication-91
                  :ARG0 (a3 / and
                        :op1 (p7 / person :name (n4 / name :op1 "Bailly"))
                        :op2 (p8 / person
                              :mod (o / other)))
                  :time (d2 / date-entity :year 1999))))

# ::id bio.chicago_2015.72000 ::date 2015-11-10T05:23:18 ::annotator SDL-AMR-09 ::preferred
# ::snt In the  MSI( ) tumors, 11 of 37 (30%) displayed methylation of   p16, and, in contrast, in sporadic  MSI(+) tumors hypermethylation of   p16 was observed in 14 of 20 (70%) ( P < 0.05 versus  MSI-negative).
# ::save-date Tue Jan 19, 2016 ::file bio_chicago_2015_72000.txt
(c / contrast-01
      :ARG1 (d / display-01
            :ARG0 (t / tumor :quant 11
                  :ARG1-of (s3 / stable-03
                        :mod (m2 / microsatellite))
                  :ARG1-of (i / include-91
                        :ARG2 (t3 / tumor :quant 37
                              :ARG1-of s3)
                        :ARG3 (p / percentage-entity :value 30)))
            :ARG1 (m / methylate-01
                  :ARG1 (p2 / protein :name (n2 / name :op1 "p16"))))
      :ARG2 (o / observe-01
            :ARG1 (h / hypermethylate-01
                  :ARG2 p2)
            :location (t4 / tumor :quant 14
                  :ARG1-of (s2 / stable-03 :polarity -
                        :mod m2)
                  :mod (s / sporadic)
                  :ARG1-of (i2 / include-91
                        :ARG2 (t6 / tumor :quant 20
                              :ARG1-of s2
                              :mod s)
                        :ARG3 (p3 / percentage-entity :value 70)))
            :ARG1-of (s4 / statistical-test-91
                  :ARG2 (l / less-than :op1 0.05)
                  :ARG5 t)))

# ::id bio.chicago_2015.72003 ::date 2015-11-10T06:20:45 ::annotator SDL-AMR-09 ::preferred
# ::snt This is true for intraphylum splits in many animal groups (  19,  33), the origin and divergences of major  insect clades (  34), early (Paleozoic) splits among basal  vertebrates (  35) and  tetrapods (  12,  32), and most intraordinal splits among birds (  28,  29) and  mammals (  32,  36,  37).
# ::save-date Tue Nov 17, 2015 ::file bio_chicago_2015_72003.txt
(t / true-01
      :ARG1 (t2 / this)
      :ARG2 (a / and
            :op1 (s / split-01
                  :mod (i / intraphylum)
                  :location (g / group-01
                        :ARG2 (a2 / animal)
                        :quant (m / many))
                  :ARG1-of (d / describe-01
                        :ARG0 (p / publication
                              :ARG1-of (c / cite-01
                                    :ARG2 (a3 / and :op1 19 :op2 33)))))
            :op2 (a4 / and
                  :op1 (o / originate-01
                        :ARG1 (c2 / clade
                              :mod (i2 / insect)
                              :ARG1-of (m2 / major-02)))
                  :op2 (d2 / diverge-01
                        :ARG0 c2)
                  :ARG1-of (d3 / describe-01
                        :ARG0 (p2 / publication
                              :ARG1-of (c3 / cite-01
                                    :ARG2 34))))
            :op3 (s2 / split-01
                  :ARG2 (a5 / and
                        :op1 (v / vertebrate
                              :mod (b / basal)
                              :ARG1-of (d4 / describe-01
                                    :ARG0 (p3 / publication
                                          :ARG1-of (c4 / cite-01
                                                :ARG2 35))))
                        :op2 (t3 / tetrapod
                              :ARG1-of (d5 / describe-01
                                    :ARG0 (p4 / publication
                                          :ARG1-of (c5 / cite-01
                                                :ARG2 (a6 / and :op1 12 :op2 32))))))
                  :time (e / early
                        :ARG1-of (m3 / mean-01
                              :ARG2 (e2 / era :name (n / name :op1 "Paleozoic")))))
            :op4 (s3 / split-01
                  :ARG2 (a7 / and
                        :op1 (b2 / bird
                              :ARG1-of (d6 / describe-01
                                    :ARG0 (p5 / publication
                                          :ARG1-of (c6 / cite-01
                                                :ARG2 (a8 / and :op1 28 :op2 29)))))
                        :op2 (m4 / mammal
                              :ARG1-of (d7 / describe-01
                                    :ARG0 (p6 / publication
                                          :ARG1-of (c7 / cite-01
                                                :ARG2 (a9 / and :op1 32 :op2 36 :op3 37))))))
                  :mod (i3 / intraordinal)
                  :quant (m5 / most))))

# ::id bio.chicago_2015.72086 ::date 2015-11-10T06:55:23 ::annotator SDL-AMR-09 ::preferred
# ::snt A membrane location for this   a-factor NH2-terminal  protease is consistent with our previous observation that  all  COOH-terminally prenylated   a-factor intermediates,  including  P1, are membrane associated ( Chen, 1993  ;  Chen  et al., 1997  ).
# ::save-date Sat Feb 13, 2016 ::file bio_chicago_2015_72086.txt
(c / consistent-01
      :ARG1 (b / be-located-at-91
            :ARG1 (e / enzyme :name (n / name :op1 "protease")
                  :part (p / protein-segment :name (n2 / name :op1 "NH2-terminus"))
                  :mod (g / gene :name (n3 / name :op1 "a-factor"))
                  :mod (t / this))
            :ARG2 (m2 / membrane))
      :ARG2 (o / observe-01
            :ARG0 (w / we)
            :ARG1 (a / associate-01
                  :ARG1 (i / intermediate
                        :mod g
                        :ARG1-of (p2 / prenylate-00
                              :location (p3 / protein-segment :name (n4 / name :op1 "COOH-terminus")))
                        :mod (a2 / all)
                        :ARG2-of (i2 / include-91
                              :ARG1 (i3 / intermediate :name (n5 / name :op1 "P1"))))
                  :ARG2 m2)
            :time (p4 / previous))
      :ARG1-of (d / describe-01
            :ARG0 (a3 / and
                  :op1 (p5 / publication-91
                        :ARG0 (p6 / person :name (n6 / name :op1 "Chen"))
                        :time (d2 / date-entity :year 1993))
                  :op2 (p7 / publication-91
                        :ARG0 (a4 / and
                              :op1 p6
                              :op2 (p8 / person
                                    :mod (o2 / other)))
                        :time (d3 / date-entity :year 1997)))))

# ::id bio.chicago_2015.72090 ::date 2015-11-10T15:06:55 ::annotator SDL-AMR-09 ::preferred
# ::snt If  Ste5 constrains  Ste11 and  Ste7 to within, say, 10 nm of each other, then the effective concentration of the scaffold-bound  Ste7 in the eyes of the scaffold-bound  Ste11 will be 250,000 molecules per  fl, an increase of more than 104-fold.
# ::save-date Wed Mar 2, 2016 ::file bio_chicago_2015_72090.txt
(c / concentrate-01
      :ARG2 (e / enzyme :name (n / name :op1 "Ste7")
            :ARG1-of (b / bind-01
                  :ARG2 (s / scaffold))
            :quant (c2 / concentration-quantity :quant 250000
                  :unit (m / molecule-per-femtoliter)
                  :ARG1-of (i / increase-01
                        :ARG2 (m2 / more-than
                              :op1 (p / product-of :op1 104)))))
      :ARG0-of (e2 / effective-04)
      :compared-to (c3 / concentrate-01
            :ARG2 (e3 / enzyme :name (n2 / name :op1 "Ste11")
                  :ARG1-of b))
      :condition (c4 / constrain-01
            :ARG0 (e4 / enzyme :name (n3 / name :op1 "Ste5"))
            :ARG1 (a / and
                  :op1 e3
                  :op2 e)
            :degree (w / within
                  :example (r / relative-position
                        :op1 a
                        :quant (d / distance-quantity :quant 10
                              :unit (n4 / nanometer))))))

# ::id bio.chicago_2015.72096 ::date 2015-11-10T16:04:22 ::annotator SDL-AMR-09 ::preferred
# ::snt Figure 2 shows that all  Gcn4 genes tested here, i.e.,   TRP3,   ARG1,   HIS3,   CPA1, and   CPA2,  displayed H3 hyperacetylation similar to   HIS3.
# ::save-date Fri Nov 20, 2015 ::file bio_chicago_2015_72096.txt
(s / show-01
      :ARG0 (f / figure :mod 2)
      :ARG1 (d / display-01
            :ARG0 (g / gene
                  :ARG0-of (e / encode-01
                        :ARG1 (p / protein :name (n2 / name :op1 "Gcn4")))
                  :mod (a / all)
                  :ARG1-of (t / test-01
                        :location (h / here))
                  :example (a2 / and
                        :op1 (g2 / gene :name (n3 / name :op1 "TRP3"))
                        :op2 (g3 / gene :name (n4 / name :op1 "ARG1"))
                        :op3 (g4 / gene :name (n5 / name :op1 "HIS3"))
                        :op4 (g5 / gene :name (n6 / name :op1 "CPA1"))
                        :op5 (g6 / gene :name (n7 / name :op1 "CPA2"))))
            :ARG1 (h2 / hyperacetylate-00
                  :ARG1 (p2 / protein :name (n8 / name :op1 "H3"))
                  :ARG1-of (r / resemble-01
                        :ARG2 (h3 / hyperacetylate-00
                              :ARG1 g4)))))

# ::id bio.chicago_2015.72107 ::date 2015-11-10T16:20:21 ::annotator SDL-AMR-09 ::preferred
# ::snt AD designated as the  sole or principal cause and no contributing  cerebrovascular disease; AD with contributing  cerebrovascular disease (CVD); VaD as the  sole or principal cause without any apparent AD component; and other  dementias attributed to  Parkinson s disease,  progressive supranuclear palsy,  subdural hematoma,  trauma, and  vitamin B12 deficiency.
# ::save-date Wed Dec 9, 2015 ::file bio_chicago_2015_72107.txt
(m / multi-sentence
      :snt1 (a / and
            :op1 (d / designate-01
                  :ARG1 (d2 / disease :wiki "Alzheimer's_disease" :name (n / name :op1 "Alzheimer's"))
                  :ARG2 (c / cause-01
                        :mod (o / or
                              :op1 (s / sole)
                              :op2 (p / principal))))
            :op2 (d3 / disease
                  :mod (c2 / cerebrovascular)
                  :ARG0-of (c3 / contribute-01 :polarity -)))
      :snt2 (d4 / disease :wiki "Alzheimer's_disease" :name (n2 / name :op1 "Alzheimer's")
            :accompanier (d5 / disease
                  :mod (c4 / cerebrovascular)
                  :ARG0-of (c5 / contribute-01)))
      :snt3 (m2 / medical-condition :name (n3 / name :op1 "vascular" :op2 "dementia")
            :ARG0-of (c6 / cause-01
                  :mod (o2 / or
                        :op1 (s2 / sole)
                        :op2 (p2 / principal)))
            :accompanier (c7 / component :polarity -
                  :mod (d7 / disease :wiki "Alzheimer's_disease" :name (n4 / name :op1 "Alzheimer's"))
                  :ARG1-of (a2 / appear-01)
                  :mod (a3 / any)))
      :snt4 (a4 / and
            :op2 (d8 / dementia
                  :mod (o3 / other)
                  :ARG1-of (a5 / attribute-01
                        :ARG2 (a6 / and
                              :op1 (d9 / disease :wiki "Parkinson's_disease" :name (n5 / name :op1 "Parkinson's"))
                              :op2 (d10 / disease :name (n6 / name :op1 "progressive" :op2 "supranuclear" :op3 "palsy"))
                              :op3 (h / hematoma
                                    :mod (s3 / subdural))
                              :op4 (t / trauma)
                              :op5 (d11 / deficiency
                                    :mod (v / vitamin :name (n7 / name :op1 "B12"))))))))

# ::id bio.chicago_2015.72190 ::date 2015-11-11T01:40:26 ::annotator SDL-AMR-09 ::preferred
# ::snt Of 22   omp-1 paralogs examined by  RT-PCR,   omp-1B was the only   omp-1 transcript detected in all 16 groups of  tick tissues (Fig.  2).
# ::save-date Wed Nov 11, 2015 ::file bio_chicago_2015_72190.txt
(t / transcript
      :mod (p / protein :name (n / name :op1 "omp-1"))
      :domain (p2 / protein :name (n2 / name :op1 "omp-1B")
            :mod (o / only)
            :ARG1-of (d / detect-01
                  :location (g / group-01 :quant 16
                        :ARG2 (t2 / tissue
                              :mod (t3 / tick))
                        :mod (a / all)))
            :ARG1-of (i / include-91
                  :ARG2 (p3 / paralog :quant 22
                        :mod p
                        :ARG1-of (e / examine-01
                              :instrument (t4 / thing :name (n3 / name :op1 "RT-PCR"))))))
      :ARG1-of (d2 / describe-01
            :ARG0 (f / figure :mod 2)))

# ::id bio.chicago_2015.72229 ::date 2015-11-11T01:53:39 ::annotator SDL-AMR-09 ::preferred
# ::snt However, Southern analysis following 5-azaC treatment ruled out the demethylation of  RI and  RII genes as  a contributor to  RI and  RII expression ( 14,  16).
# ::save-date Sat Feb 13, 2016 ::file bio_chicago_2015_72229.txt
(h / have-concession-91
      :ARG2 (r / rule-out-02
            :ARG0 (t / thing :name (n / name :op1 "Southern" :op2 "analysis")
                  :ARG1-of (f / follow-01
                        :ARG2 (t2 / treat-04
                              :ARG2 (s / small-molecule :name (n2 / name :op1 "5-azaC")))))
            :ARG1 (c / contribute-01
                  :ARG0 (d / demethylate-01
                        :ARG1 (a / and
                              :op1 (g / gene :name (n3 / name :op1 "RI"))
                              :op2 (g2 / gene :name (n4 / name :op1 "RII"))))
                  :ARG2 (e / express-03
                        :ARG1 a)))
      :ARG1-of (d2 / describe-01
            :ARG0 (p / publication
                  :ARG1-of (c2 / cite-01
                        :ARG2 (a2 / and :op1 14 :op2 16)))))

# ::id bio.chicago_2015.72242 ::date 2015-11-11T02:14:46 ::annotator SDL-AMR-09 ::preferred
# ::snt Other less exquisitely specific proteases produced by some  bacteria (e.g.,   Pseudomonas aeruginosa,   Porphyromonas gingivalis, or   Proteus mirabilis) can completely break down  IgA and other Igs ( 9,  14,  24) but do not achieve this effect.
# ::save-date Fri Nov 20, 2015 ::file bio_chicago_2015_72242.txt
(c / contrast-01
      :ARG1 (p / possible-01
            :ARG1 (b / break-down-12
                  :ARG0 (e / enzyme :name (n / name :op1 "protease")
                        :ARG1-of (s / specific-02
                              :degree (e2 / exquisite
                                    :degree (l / less)))
                        :ARG1-of (p2 / produce-01
                              :ARG0 (b2 / bacteria
                                    :quant (s2 / some)
                                    :example (o / or
                                          :op1 (o2 / organism :name (n2 / name :op1 "Pseudomonas" :op2 "aeruginosa"))
                                          :op2 (o3 / organism :name (n3 / name :op1 "Porphyromonas" :op2 "gingivalis"))
                                          :op3 (o4 / organism :name (n4 / name :op1 "Proteus" :op2 "mirabilis")))))
                        :mod (o5 / other))
                  :ARG1 (a / and
                        :op1 (p3 / protein :name (n5 / name :op1 "IgA"))
                        :op2 (p4 / protein :name (n6 / name :op1 "Ig")
                              :mod (o6 / other)))
                  :ARG1-of (c2 / complete-02))
            :ARG1-of (d / describe-01
                  :ARG0 (p5 / publication
                        :ARG1-of (c3 / cite-01
                              :ARG2 (a2 / and :op1 9 :op2 14 :op3 24)))))
      :ARG2 (a3 / achieve-01 :polarity -
            :ARG0 e
            :ARG1 (a4 / affect-01
                  :ARG2 b)))

# ::id bio.chicago_2015.72284 ::date 2015-11-11T02:43:43 ::annotator SDL-AMR-09 ::preferred
# ::snt UBPs also have been found to stimulate protein degradation by editing the size of  polyubiquitin chains, releasing  ubiquitin after the protein has been targeted to the  proteasome, or disassembling  polyubiquitin chains to restore the cellular pool of free  ubiquitin.
# ::save-date Sat Feb 13, 2016 ::file bio_chicago_2015_72284.txt
(f / find-01
      :ARG1 (s / stimulate-01
            :ARG0 (s3 / small-molecule :name (n / name :op1 "UBP"))
            :ARG1 (d / degrade-01
                  :ARG1 (p / protein))
            :ARG2 (o / or
                  :op1 (e / edit-01
                        :ARG0 s3
                        :ARG1 (s2 / size-01
                              :ARG1 (c / chain-01
                                    :ARG1 (p2 / protein :name (n2 / name :op1 "polyubiquitin")))))
                  :op2 (r / release-01
                        :ARG0 s3
                        :ARG1 (p3 / protein :name (n3 / name :op1 "ubiquitin"))
                        :time (a / after
                              :op1 (t / target-01
                                    :ARG0 s3
                                    :ARG1 p3)))
                  :op3 (d2 / disassemble-01
                        :ARG0 s3
                        :ARG1 c
                        :purpose (r2 / restore-02
                              :ARG0 s3
                              :ARG1 (p4 / pool-01
                                    :ARG1 (p5 / protein :name (n4 / name :op1 "ubiquitin")
                                          :ARG1-of (f2 / free-04))
                                    :mod (c2 / cell))))))
      :mod (a2 / also))

# ::id bio.chicago_2015.72524 ::date 2015-11-11T03:06:30 ::annotator SDL-AMR-09 ::preferred
# ::snt B,  Rats were restrained for the indicated time (  x axis), then returned to their cages for the remainder of the time period (up to 60 minutes), at which time they were euthanatized and analyzed for  hsp70 expression.
# ::save-date Mon Jan 4, 2016 ::file bio_chicago_2015_72524.txt
(a / and
      :op1 (r / restrain-01
            :ARG1 (r2 / rat)
            :duration (t / time
                  :ARG1-of (i / indicate-01
                        :ARG0 (a2 / axis
                              :ARG1-of (l / label-01
                                    :ARG2 (s / string-entity :value "x"))))))
      :op2 (r3 / return-04
            :ARG1 r2
            :ARG2 (c / cage-01
                  :ARG1 r2)
            :duration (r4 / remain-01
                  :ARG1 (p / period
                        :mod (t2 / time-01
                              :ARG2 (u / up-to
                                    :op1 (t3 / temporal-quantity :quant 60
                                          :unit (m / minute)))))
                  :time-of (a3 / and
                        :op1 (e / euthanize-00
                              :ARG1 r2)
                        :op2 (a4 / analyze-01
                              :ARG1 r2
                              :purpose (e2 / express-03
                                    :ARG2 (p2 / protein :name (n2 / name :op1 "hsp70"))))))
            :time (t4 / then))
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod "B")))

# ::id bio.chicago_2015.72571 ::date 2015-11-11T03:33:16 ::annotator SDL-AMR-09 ::preferred
# ::snt So, although both the   GAPDH and   CA genes exhibit hyperacetylation of  H3 and  H4 only at the 5''-end of the genes, in contrast to the  betaA-globin gene, it is not at present possible to conclude that this is a promoter-specific effect, particularly as regards histone H4.
# ::save-date Mon Jan 4, 2016 ::file bio_chicago_2015_72571.txt
(i / infer-01
      :ARG1 (p / possible-01 :polarity -
            :ARG1 (c / conclude-01
                  :ARG1 (a / affect-01
                        :ARG2 (t / this)
                        :ARG1-of (s / specific-02
                              :ARG2 (m / molecular-physical-entity
                                    :ARG0-of (p2 / promote-01)))
                        :ARG0-of (r / regard-01
                              :ARG1 (p3 / protein :name (n / name :op1 "histone" :op2 "H4"))
                              :mod (p4 / particular))))
            :time (p5 / present)
            :concession (c2 / contrast-01
                  :ARG1 (e / exhibit-01
                        :ARG0 (a2 / and
                              :op1 (g / gene :name (n2 / name :op1 "GAPDH"))
                              :op2 (g2 / gene :name (n3 / name :op1 "CA")))
                        :ARG1 (h / hyperacetylate-00
                              :ARG1 (a3 / and
                                    :op1 (p6 / protein :name (n4 / name :op1 "H3"))
                                    :op2 p3))
                        :location (d / dna-sequence :name (n6 / name :op1 "5''-end")
                              :mod (o / only)
                              :part-of a2))
                  :ARG2 (e3 / exhibit-01 :polarity -
                        :ARG0 (g3 / gene :name (n5 / name :op1 "betaA-globin"))
                        :ARG1 h))))

# ::id bio.chicago_2015.72676 ::date 2015-11-11T03:50:57 ::annotator SDL-AMR-09 ::preferred
# ::snt In hepatocytes, inhibition of cAMP-PDE activity in the absence of additional effectors has no effect on the activity of  PKA (attributable to a low basal level of  adenylate cyclase activity).
# ::save-date Sun Jan 17, 2016 ::file bio_chicago_2015_72676.txt
(a / affect-01 :polarity -
      :ARG0 (i / inhibit-01
            :ARG1 (a2 / activity-06
                  :ARG0 (e / enzyme :name (n / name :op1 "PDE"))
                  :ARG1-of (s / specific-02
                        :ARG2 (s2 / small-molecule :name (n2 / name :op1 "cAMP"))))
            :ARG2-of (a3 / absent-01
                  :ARG1 (e2 / effector
                        :ARG1-of (a4 / add-02))))
      :ARG1 (a5 / activity-06
            :ARG0 (e3 / enzyme :name (n3 / name :op1 "PKA")))
      :ARG1-of (a6 / attribute-01
            :ARG2 (l / level
                  :quant-of (a7 / activity-06
                        :ARG0 (e4 / enzyme :name (n4 / name :op1 "adenylate" :op2 "cyclase")))
                  :mod (b / basal)
                  :ARG1-of (l2 / low-04))
            :ARG1-of (p / possible-01))
      :location (c / cell :name (n5 / name :op1 "hepatocyte")))

# ::id bio.chicago_2015.72680 ::date 2015-11-11T04:03:05 ::annotator SDL-AMR-09 ::preferred
# ::snt However, bypassing this reaction with pyruvate,  dihydroxyacetone, or glycerol uncovers constraints imposed by mitochondrial metabolism, each of which attains a similar maximal limit of insulin secretion.
# ::save-date Tue Jan 12, 2016 ::file bio_chicago_2015_72680.txt
(h / have-concession-91
      :ARG2 (u / uncover-01
            :ARG0 (b / bypass-01
                  :ARG0 (o / or
                        :op1 (s2 / small-molecule :wiki "Pyruvic_acid"
                              :name (n / name :op1 "pyruvate"))
                        :op2 (s3 / small-molecule :wiki "Dihydroxyacetone"
                              :name (n2 / name :op1 "dihydroxyacetone"))
                        :op3 (s4 / small-molecule :wiki "Glycerol"
                              :name (n3 / name :op1 "glycerol"))
                        :ARG0-of (a / attain-01
                              :ARG1 (l / limit-01
                                    :ARG1 (s / secrete-01
                                          :ARG1 (p / protein :wiki "Insulin"
                                                :name (n4 / name :op1 "insulin")))
                                    :mod (m4 / maximal)
                                    :ARG1-of (r / resemble-01))
                              :mod (e / each)))
                  :ARG1 (r2 / react-01
                        :mod (t / this)))
            :ARG1 (t2 / thing
                  :ARG1-of (c / constrain-01)
                  :ARG1-of (i2 / impose-01
                        :ARG0 (m5 / metabolize-01
                              :ARG1 (m6 / mitochondrium))))))

# ::id bio.chicago_2015.72720 ::date 2015-11-11T04:26:22 ::annotator SDL-AMR-09 ::preferred
# ::snt p53 may act synergistically with  E2A, to activate  p21 expression in wild-type cells.
# ::save-date Fri Feb 5, 2016 ::file bio_chicago_2015_72720.txt
(p / possible-01
      :ARG1 (s / synergize-01
            :ARG0 (p2 / protein :name (n / name :op1 "p53"))
            :ARG1 (p3 / protein :name (n2 / name :op1 "E2A"))
            :ARG2 (a3 / activate-01
                  :ARG0 (a2 / and
                        :op1 p2
                        :op2 p3)
                  :ARG1 (e / express-03
                        :ARG2 (p4 / protein :name (n3 / name :op1 "p21")))
                  :location (c / cell
                        :mod (w / wild-type)))))

# ::id bio.chicago_2015.72786 ::date 2015-11-11T04:33:58 ::annotator SDL-AMR-09 ::preferred
# ::snt Earlier studies also reported that  ERK depolymerizes  interphase microtubules and forms mitotic microtubules in   Xenopus cell extracts ( 19).
# ::save-date Sat Jan 16, 2016 ::file bio_chicago_2015_72786.txt
(r / report-01
      :ARG0 (t / thing
            :ARG1-of (s / study-01
                  :time (e / early
                        :degree (m / more))))
      :ARG1 (a / and
            :op1 (d / depolymerize-00
                  :ARG0 (e2 / enzyme :name (n / name :op1 "ERK"))
                  :ARG1 (m2 / microtubule
                        :mod (i / interphase)))
            :op2 (f / form-01
                  :ARG0 e2
                  :ARG1 (m3 / microtubule
                        :mod (m4 / mitosis)))
            :location (c / cell
                  :ARG1-of (e3 / extract-01)
                  :part-of (o / organism :name (n2 / name :op1 "Xenopus"))))
      :mod (a2 / also)
      :ARG1-of (d2 / describe-01
            :ARG0 (p / publication
                  :ARG1-of (c2 / cite-01
                        :ARG2 19))))

# ::id bio.chicago_2015.72820 ::date 2015-11-11T04:43:24 ::annotator SDL-AMR-09 ::preferred
# ::snt Cytochalasin D disassembles  bcl10 filament and  bcl10-induced  NF-kappaB activation.
# ::save-date Sat Feb 13, 2016 ::file bio_chicago_2015_72820.txt
(d / disassemble-01
      :ARG0 (s / small-molecule :name (n / name :op1 "Cytochalasin" :op2 "D"))
      :ARG1 (a / and
            :op1 (f / filament
                  :mod (p / protein :name (n2 / name :op1 "bcl10")))
            :op2 (a2 / activate-01
                  :ARG1 (m2 / macro-molecular-complex :name (n3 / name :op1 "NF-kappaB"))
                  :ARG2-of (i / induce-01
                        :ARG0 p))))

# ::id bio.chicago_2015.72824 ::date 2015-11-11T04:51:24 ::annotator SDL-AMR-09 ::preferred
# ::snt The insert encodes the cleavage site of  TEV protease that can proteolyze  target proteins  in vivo,  in vitro, or on the extracellular side of whole cells when the recognition sequence is surface accessible.
# ::save-date Wed Nov 11, 2015 ::file bio_chicago_2015_72824.txt
(e / encode-01
      :ARG0 (t / thing
            :ARG1-of (i / insert-01))
      :ARG1 (s / site
            :mod (c / cleave-01
                  :ARG1 (e2 / enzyme :name (n / name :op1 "TEV" :op2 "protease")))
            :ARG0-of (p / proteolyze-00
                  :ARG1 (p2 / protein
                        :ARG1-of (t2 / target-01))
                  :manner (o / or
                        :op1 (i2 / in-vivo)
                        :op2 (i3 / in-vitro))
                  :location (o2 / or
                        :op2 (s2 / side
                              :mod (e3 / extracellular)
                              :part-of (c2 / cell
                                    :mod (w / whole))))
                  :ARG1-of (p3 / possible-01)
                  :time (p4 / possible-01
                        :ARG1 (a / access-01
                              :ARG1 (s3 / sequence
                                    :ARG1-of (r / recognize-02)))
                        :mod (s4 / surface)))))

# ::id bio.chicago_2015.72930 ::date 2015-11-11T05:06:35 ::annotator SDL-AMR-09 ::preferred
# ::snt LC spontaneous discharge and activation by intracerebroventricularly administered  CRF, hypotensive challenge, sciatic nerve stimulation, and  carbachol were compared in adrenalectomized and sham-operated halothane-anesthetized  rats.
# ::save-date Sat Feb 13, 2016 ::file bio_chicago_2015_72930.txt
(c / compare-01
      :ARG1 (d / discharge-101
            :ARG0 (c3 / ceruleus
                  :mod (l / locus))
            :manner (s / spontaneous))
      :ARG2 (a / activate-01
            :ARG0 (a2 / and
                  :op1 (s5 / small-molecule :name (n2 / name :op1 "CRF")
                        :ARG1-of (a3 / administer-01
                              :manner (i / intracerebroventricularly)))
                  :op2 (c2 / challenge-01
                        :ARG1 (m / molecular-physical-entity)
                        :mod (h / hypotensive))
                  :op3 (s2 / stimulate-01
                        :ARG1 (n3 / nerve
                              :mod (s3 / sciatic)))
                  :op4 (s7 / small-molecule :name (n4 / name :op1 "carbachol")))
            :ARG1 m)
      :location (r / rat
            :ARG1-of (a4 / adrenalectomize-00)
            :ARG1-of (a5 / anesthetize-01
                  :ARG2 (s6 / small-molecule :name (n5 / name :op1 "halothane")))
            :ARG1-of (o / operate-02
                  :manner (s4 / sham))))

# ::id bio.chicago_2015.73032 ::date 2015-11-11T05:06:44 ::annotator SDL-AMR-09 ::preferred
# ::snt In order to investigate the importance of the  chitin deacetylation process to  cell wall assembly, we took advantage of the natural fluorescence that wild type spores emit when excited by ultraviolet light, as well as their resistance to hydrolytic enzymes, ether, and  heat shock ( 8,  10).
# ::save-date Wed Nov 18, 2015 ::file bio_chicago_2015_73032.txt
(t / take-01
      :ARG0 (w / we)
      :ARG1 (a / advantage)
      :ARG2 (a2 / and
            :op1 (f / fluorescence
                  :ARG1-of (n / natural-03)
                  :ARG1-of (e / emit-01
                        :ARG0 (s / spore
                              :mod (w2 / wild-type))
                        :time (e2 / excite-01
                              :ARG0 (l / light
                                    :mod (u / ultraviolet))
                              :ARG1 s)))
            :op2 (r / resist-01
                  :ARG0 s
                  :ARG1 (a3 / and
                        :op1 (e3 / enzyme
                              :mod (h / hydrolytic))
                        :op2 (e4 / ether)
                        :op3 (s2 / shock-01
                              :ARG0 (h2 / heat)
                              :ARG1 s))))
      :purpose (i / investigate-01
            :ARG0 w
            :ARG1 (i2 / importance
                  :poss (p / process-01
                        :ARG1 (d / deacetylate-01
                              :ARG1 (m / macro-molecular-complex :name (n2 / name :op1 "chitin"))))
                  :beneficiary (a4 / assemble-01
                        :ARG1 (w3 / wall
                              :mod (c / cell)))))
      :ARG1-of (d2 / describe-01
            :ARG0 (p2 / publication
                  :ARG1-of (c2 / cite-01
                        :ARG2 (a5 / and :op1 8 :op2 10)))))

# ::id bio.chicago_2015.73037 ::date 2015-11-04T08:59:26 ::annotator SDL-AMR-09 ::preferred
# ::snt Spontaneous or induced deamination of cytosine,  adenine,  guanine or 5-methylcytosine converts these bases to the  miscoding uracil,  hypoxanthine,  xanthine and  thymine, respectively 4.
# ::save-date Sat Feb 13, 2016 ::file bio_chicago_2015_73037.txt
(c / convert-01
      :ARG0 (o / or
            :op1 (d / deaminate-01
                  :ARG1 o2
                  :mod (s / spontaneous))
            :op2 (d2 / deaminate-01
                  :ARG1 (o2 / or
                        :op1 (s2 / small-molecule :name (n / name :op1 "cytosine"))
                        :op2 (s3 / small-molecule :name (n2 / name :op1 "adenine"))
                        :op3 (s4 / small-molecule :name (n3 / name :op1 "guanine"))
                        :op4 (s5 / small-molecule :name (n4 / name :op1 "5-methylcytosine")))
                  :ARG2-of (i / induce-01)))
      :ARG1 (b / base
            :mod (t / this))
      :ARG2 (a / and
            :op1 (s6 / small-molecule :name (n5 / name :op1 "uracil"))
            :op2 (s7 / small-molecule :name (n6 / name :op1 "hypoxanthine"))
            :op3 (s8 / small-molecule :name (n7 / name :op1 "xanthine"))
            :op4 (s9 / small-molecule :name (n8 / name :op1 "thymine"))
            :ARG0-of (m9 / miscode-00)
            :manner (r / respective))
      :ARG1-of (d3 / describe-01
            :ARG0 (p / publication
                  :ARG1-of (c2 / cite-01
                        :ARG2 4))))

# ::id bio.chicago_2015.73068 ::date 2015-11-05T12:21:05 ::annotator SDL-AMR-09 ::preferred
# ::snt pRb indicates hypophosphorylated  retinoblastoma protein; ppRb, hyperphosphorylated  pRb.
# ::save-date Mon Nov 16, 2015 ::file bio_chicago_2015_73068.txt
(a / and
      :op1 (i / indicate-01
            :ARG0 (p / protein :name (n / name :op1 "pRb"))
            :ARG1 (p4 / protein :name (n4 / name :op1 "retinoblastoma" :op2 "protein")
                  :ARG1-of (h / hypophosphorylate-00)))
      :op2 (i2 / indicate-01
            :ARG0 (p2 / protein :name (n2 / name :op1 "ppRb"))
            :ARG1 (p3 / protein :name (n3 / name :op1 "pRb")
                  :ARG1-of (h2 / hyperphosphorylate-01))))

# ::id bio.chicago_2015.73070 ::date 2015-11-05T12:24:54 ::annotator SDL-AMR-09 ::preferred
# ::snt Toll receptors,  CD14, and macrophage activation and deactivation by  LPS.
# ::save-date Mon Nov 16, 2015 ::file bio_chicago_2015_73070.txt
(a / and
      :op1 (p / protein-family :name (n / name :op1 "Toll" :op2 "receptor"))
      :op2 (p2 / protein :name (n2 / name :op1 "CD14"))
      :op1 (a2 / and
            :op1 (a3 / activate-01
                  :ARG0 (m / molecular-physical-entity :name (n3 / name :op1 "LPS"))
                  :ARG1 (m2 / macrophage))
            :op2 (d / deactivate-01
                  :ARG0 m
                  :ARG1 m2)))

# ::id bio.chicago_2015.73119 ::date 2015-11-05T12:32:14 ::annotator SDL-AMR-09 ::preferred
# ::snt CpG island methylation and deacetylation of  histone are involved in the creation of transcription suppressive domains ( 54).
# ::save-date Thu Nov 5, 2015 ::file bio_chicago_2015_73119.txt
(i / involve-01
      :ARG1 (a / and
            :op1 (m / methylate-01
                  :ARG1 (d / dna-sequence :name (n / name :op1 "CpG" :op2 "island")))
            :op2 (d2 / deacetylate-01
                  :ARG1 (p / protein :name (n2 / name :op1 "histone"))))
      :ARG2 (c / create-01
            :ARG1 (d3 / domain
                  :ARG0-of (s / suppress-01
                        :ARG1 (t / transcribe-01))))
      :ARG1-of (d4 / describe-01
            :ARG0 (p2 / publication
                  :ARG1-of (c2 / cite-01
                        :ARG2 54))))

# ::id bio.chicago_2015.73121 ::date 2015-11-05T12:37:18 ::annotator SDL-AMR-09 ::preferred
# ::snt The signaling from  Ras through  Raf prompted us to ask whether  Raf itself could elicit senescence.
# ::save-date Sat Jan 16, 2016 ::file bio_chicago_2015_73121.txt
(p4 / prompt-01
      :ARG0 (s / signal-07
            :ARG0 (e2 / enzyme :name (n / name :op1 "Ras"))
            :path (e3 / enzyme :name (n2 / name :op1 "Raf")))
      :ARG1 (a / ask-01
            :ARG0 (w / we)
            :ARG1 (p3 / possible-01 :mode interrogative
                  :ARG1 (e / elicit-01
                        :ARG0 e3
                        :ARG1 (s2 / senescence)))))

# ::id bio.chicago_2015.73158 ::date 2015-11-05T12:42:47 ::annotator SDL-AMR-09 ::preferred
# ::snt Assuming  a 100% increase in  LC discharge rate as the maximum effect produced by  CRF (Curtis et al., 1997  ), the  CRF ED50 value in naive  rats was 0.9 mug, similar to the value previously reported by this laboratory (Curtis et al., 1997  ).
# ::save-date Fri Feb 12, 2016 ::file bio_chicago_2015_73158.txt
(h / have-percentage-maximal-effective-dose-01
      :ARG1 (s / small-molecule :name (n2 / name :op1 "CRF"))
      :ARG2 50
      :ARG4 (m4 / mass-quantity :quant 0.9
            :unit (m5 / microgram)
            :ARG1-of (r3 / resemble-01
                  :ARG2 (v2 / value
                        :ARG1-of (r4 / report-01
                              :ARG0 (l / laboratory
                                    :mod (t2 / this))
                              :time (p / previous))
                        :ARG1-of (d4 / describe-01
                              :ARG0 a3))))
      :ARG5 (r2 / rat
            :mod (n3 / naive))
      :condition (a / assume-01
            :ARG1 (a2 / affect-01
                  :mod (m3 / maximum)
                  :ARG1-of (p3 / produce-01
                        :ARG0 s))
            :ARG2 (i / increase-01
                  :ARG1 (r5 / rate
                        :degree-of (d2 / discharge-01
                              :ARG0 (c2 / ceruleus
                                    :mod (l2 / locus))))
                  :ARG2 (p2 / percentage-entity :value 100))
            :ARG1-of (d3 / describe-01
                  :ARG0 (p4 / publication-91
                        :ARG0 (a3 / and
                              :op1 (p5 / person :name (n5 / name :op1 "Curtis"))
                              :op2 (p6 / person
                                    :mod (o / other)))
                        :time (d / date-entity :year 1997)))))

# ::id bio.chicago_2015.73159 ::date 2015-11-05T13:12:30 ::annotator SDL-AMR-09 ::preferred
# ::snt HPLC was used to resolve the 3H-labeled inositol phosphates ( polarity  Ins P2) in DDT1  MF-2 cells (Figure  2); there were three diphosphorylated compounds ( PP-Ins P4, peak v;  PP-Ins P5,  peak vii;  [PP]2-Ins  P4, peak  viii), all of which have been observed previously in other mammalian cells (Menniti  et al., 1993  ;
# ::save-date Fri Feb 5, 2016 ::file bio_chicago_2015_73159.txt
(m / multi-sentence
      :snt1 (u / use-01
            :ARG1 (t / thing :name (n / name :op1 "HPLC"))
            :ARG2 (r / resolve-03
                  :ARG0 t
                  :ARG1 (s / small-molecule :name (n2 / name :op1 "inositol" :op2 "phosphates")
                        :ARG1-of (l / label-01
                              :ARG0 (s5 / small-molecule :name (n3 / name :op1 "3H")))
                        :mod (p / polarity
                              :mod (t3 / thing :name (n4 / name :op1 "Ins" :op2 "P2"))))
                  :location (c / cell :name (n5 / name :op1 "DDT1" :op2 "MF-2"))
                  :ARG1-of (d2 / describe-01
                        :ARG0 (f / figure :mod 2))))
      :snt2 (o / observe-01
            :ARG1 (c2 / compound :quant 3
                  :ARG1-of (m3 / mean-01
                        :ARG2 (a3 / and
                              :op1 (s2 / small-molecule :name (n7 / name :op1 "PP-Ins" :op2 "P4")
                                    :ARG1-of (d5 / describe-01
                                          :ARG0 (p6 / peak :li "v")))
                              :op2 (s3 / small-molecule :name (n8 / name :op1 "PP-Ins" :op2 "P5")
                                    :ARG1-of (d6 / describe-01
                                          :ARG0 (p7 / peak :li "vii")))
                              :op3 (s4 / small-molecule :name (n9 / name :op1 "[PP]2-Ins" :op2 "P4")
                                    :ARG1-of (d7 / describe-01
                                          :ARG0 (p8 / peak :li "viii")))))
                  :ARG1-of (d3 / diphosphorylate-00)
                  :mod (a / all))
            :time (p2 / previous)
            :location (c3 / cell
                  :mod (m2 / mammal)
                  :mod (o2 / other))
            :ARG1-of (d4 / describe-01
                  :ARG0 (p3 / publication-91
                        :ARG0 (a2 / and
                              :op1 (p4 / person :name (n6 / name :op1 "Menniti"))
                              :op2 (p5 / person
                                    :mod (o3 / other)))
                        :time (d / date-entity :year 1993)))))

# ::id bio.chicago_2015.73189 ::date 2015-11-05T13:56:12 ::annotator SDL-AMR-09 ::preferred
# ::snt Gfi-1B was  in vitro transcribed and translated by the  TNTtm T7 coupled reticulocyte lysate system (Promega).
# ::save-date Mon Nov 16, 2015 ::file bio_chicago_2015_73189.txt
(a / and
      :op1 (t / transcribe-01
            :ARG0 (t3 / thing :name (n2 / name :op1 "TNTtm" :op2 "T7" :op3 "coupled" :op4 "reticulocyte" :op5 "lysate" :op6 "system")
                  :mod (c / company :name (n3 / name :op1 "Promega")))
            :ARG1 (g / gene :name (n / name :op1 "Gfi-1B")))
      :op2 (t2 / translate-02
            :ARG1 g)
      :manner (i / in-vitro))

# ::id bio.chicago_2015.73212 ::date 2015-11-05T14:03:16 ::annotator SDL-AMR-09 ::preferred
# ::snt This would suggest that the capacity for anaerobic glycolysis is adequate to stoichiometrically replace the  ATP attributable to oxidative metabolism.
# ::save-date Mon Nov 16, 2015 ::file bio_chicago_2015_73212.txt
(s / suggest-01
      :ARG0 (t / this)
      :ARG1 (a / adequate
            :domain (c / capacity
                  :prep-for (g / glycolysis
                        :mod (a2 / anaerobic)))
            :purpose (r / replace-01
                  :ARG1 (s3 / small-molecule :name (n / name :op1 "ATP")
                        :ARG1-of (a3 / attribute-01
                              :ARG2 (m / metabolize-01
                                    :ARG1-of (o / oxidize-01))
                              :ARG1-of (p / possible-01)))
                  :manner (s2 / stoichiometric))))

# ::id bio.chicago_2015.73264 ::date 2015-11-05T14:12:57 ::annotator SDL-AMR-09 ::preferred
# ::snt NE10790 specifically inhibits  Rab prenylation by  Rab GGTase, demonstrating for the first time that  Rab proteins are also required for osteoclastic bone resorption.
# ::save-date Tue Jan 19, 2016 ::file bio_chicago_2015_73264.txt
(i / inhibit-01
      :ARG0 (s / small-molecule :name (n / name :op1 "NE10790"))
      :ARG1 (p / prenylate-00
            :ARG0 (e / enzyme :name (n3 / name :op1 "Rab" :op2 "GGTase"))
            :ARG1 (p2 / protein-family :name (n2 / name :op1 "Rab")))
      :ARG1-of (s2 / specific-02)
      :ARG0-of (d / demonstrate-01
            :ARG1 (r / require-01
                  :ARG0 (r2 / resorb-01
                        :ARG0 (o2 / osteoclast)
                        :ARG1 (b / bone))
                  :ARG1 p2
                  :mod (a / also))
            :ord (o / ordinal-entity :value 1)))

# ::id bio.chicago_2015.73355 ::date 2015-11-05T14:25:08 ::annotator SDL-AMR-09 ::preferred
# ::snt It has been shown that both  Tris-HCl and  sodium phosphate buffers hydrolyse  FDA to fluorescein and neither are particularly suitable for use in the  FDA assay.
# ::save-date Sat Feb 13, 2016 ::file bio_chicago_2015_73355.txt
(s / show-01
      :ARG1 (a / and
            :op1 (h / hydrolyze-01
                  :ARG1 (s6 / small-molecule :name (n3 / name :op1 "FDA"))
                  :ARG2 (a2 / and
                        :op1 (b / buffer
                              :mod (m / macro-molecular-complex :name (n / name :op1 "Tris-HC1")))
                        :op2 (b2 / buffer
                              :mod (s3 / small-molecule :name (n2 / name :op1 "sodium" :op2 "phosphate"))))
                  :ARG3 (s4 / small-molecule :name (n4 / name :op1 "fluorescein")))
            :op2 (s5 / suit-01 :polarity -
                  :ARG1 a2
                  :ARG2 (u / use-01
                        :ARG1 a2
                        :ARG2 (a3 / assay-01
                              :ARG1 s6))
                  :manner (p / particular))))

# ::id bio.chicago_2015.73390 ::date 2015-11-05T14:38:03 ::annotator SDL-AMR-09 ::preferred
# ::snt Divergence times for  hedgehog and  primate apo(a)s were calculated according to  Li and Graur ( 15), by using the divergence times for the rhesus/ human split (25 Myr ago),  rodent/ primate split (75 Myr), and cow/ primate split (80 Myr) of  Li  et al. ( 16).
# ::save-date Fri Nov 27, 2015 ::file bio_chicago_2015_73390.txt
(c / calculate-01
      :ARG1 (t / time
            :time-of (d / diverge-01
                  :ARG0 (p / protein :name (n2 / name :op1 "Apo(a)")
                        :mod (h / hedgehog))
                  :ARG1 (p2 / protein :name (n3 / name :op1 "Apo(a)")
                        :mod (p3 / primate))))
      :manner (t2 / thing
            :ARG1-of (s / say-01
                  :ARG0 (a / and
                        :op1 (p4 / person :name (n4 / name :op1 "Li"))
                        :op2 (p5 / person :name (n5 / name :op1 "Graur"))))
            :ARG1-of (d2 / describe-01
                  :ARG0 (p6 / publication
                        :ARG1-of (c2 / cite-01
                              :ARG2 15))))
      :manner (u / use-01
            :ARG1 (a2 / and
                  :op1 (t3 / time
                        :time-of (d5 / diverge-01
                              :ARG1 (s2 / split-01
                                    :ARG1 (r / rhesus)
                                    :ARG3 (h2 / human)
                                    :time (b2 / before
                                          :op1 (n6 / now)
                                          :duration (t4 / temporal-quantity :quant 25000000
                                                :unit (y / year))))))
                  :op2 (t7 / time
                        :time-of (d6 / diverge-01
                              :ARG1 (s3 / split-01
                                    :ARG1 (r2 / rodent)
                                    :ARG3 p3
                                    :time (b / before
                                          :op1 n6
                                          :duration (t5 / temporal-quantity :quant 75000000
                                                :unit y)))))
                  :op3 (t8 / time
                        :time-of (d7 / diverge-01
                              :ARG1 (s4 / split-01
                                    :ARG1 (c3 / cow)
                                    :ARG3 p3
                                    :time (b3 / before
                                          :op1 n6
                                          :duration (t6 / temporal-quantity :quant 80000000
                                                :unit y)))))
                  :poss (a3 / and
                        :op1 p4
                        :op2 (p9 / person
                              :mod (o / other))
                        :ARG1-of (d4 / describe-01
                              :ARG0 (p10 / publication
                                    :ARG1-of (c4 / cite-01
                                          :ARG2 16)))))))

# ::id bio.chicago_2015.73401 ::date 2015-11-05T14:59:54 ::annotator SDL-AMR-09 ::preferred
# ::snt Within these  tumors, one subgroup (a) had additional methylation in   HOXA5,   WT1, and   uPA loci, whereas the other  subgroup (b) acquired frequent hypermethylation of   3OST3B,   BRCA1, and   DAPK1 genes (see Figure 5B   ).
# ::save-date Tue Jan 19, 2016 ::file bio_chicago_2015_73401.txt
(c / contrast-01
      :ARG1 (h / have-03
            :ARG0 (s / subgroup :quant 1 :li "a"
                  :ARG1-of (i / include-91
                        :ARG2 (t / tumor
                              :mod (t2 / this))))
            :ARG1 (m / methylate-01
                  :ARG1 (a3 / and
                        :op1 (l / locus
                              :mod (g4 / gene :name (n / name :op1 "HOXA5")))
                        :op2 (l2 / locus
                              :mod (g5 / gene :name (n2 / name :op1 "WT1")))
                        :op3 (l3 / locus
                              :mod (g6 / gene :name (n3 / name :op1 "uPA"))))
                  :mod (a2 / additional)))
      :ARG2 (a4 / acquire-01
            :ARG0 (s2 / subgroup :li "b"
                  :mod (o / other)
                  :ARG1-of i)
            :ARG1 (h2 / hypermethylate-01
                  :ARG2 (a5 / and
                        :op1 (g / gene :name (n4 / name :op1 "3OST3B"))
                        :op2 (g2 / gene :name (n5 / name :op1 "BRCA1"))
                        :op3 (g3 / gene :name (n6 / name :op1 "DAPK1")))
                  :ARG1-of (f2 / frequent-02)))
      :ARG1-of (s3 / see-01
            :medium (f / figure :mod "5B")))

# ::id bio.chicago_2015.73405 ::date 2015-11-06T09:56:02 ::annotator SDL-AMR-09 ::preferred
# ::snt Recombinant ADAM 12-S partially purified from conditioned medium on a  heparin-Sepharose column also proteolyzed  IGFBP-3.
# ::save-date Sat Feb 13, 2016 ::file bio_chicago_2015_73405.txt
(p / proteolyze-00
      :ARG0 (e / enzyme :name (n / name :op1 "ADAM" :op2 "12-S")
            :ARG1-of (p3 / purify-01
                  :ARG2 (m / medium
                        :ARG1-of (c / condition-02)
                        :location (c2 / column
                              :consist-of (a2 / and
                                    :op1 (s / small-molecule :name (n4 / name :op1 "heparin"))
                                    :op2 (s2 / small-molecule :name (n5 / name :op1 "Sepharose")))))
                  :degree (p2 / part))
            :ARG3-of (r / recombine-01))
      :ARG1 (p5 / protein :name (n3 / name :op1 "IGFBP-3"))
      :mod (a / also))

# ::id bio.chicago_2015.73467 ::date 2015-11-06T10:15:39 ::annotator SDL-AMR-09 ::preferred
# ::snt High and nonperiodic  APC-Cdh1 activity apparently supported progressive accumulation of  Skp2 F-box protein, a crucial  SCF component, and thus created conditions permissive for a rapid turnover of  p27 CDK inhibitor that would otherwise restrain  S-phase-promoting CDK activities.
# ::save-date Wed Jan 13, 2016 ::file bio_chicago_2015_73467.txt
(s / support-01
      :ARG0 (a2 / activity-06
            :ARG0 (p / protein :name (n / name :op1 "APC-Cdh1"))
            :ARG1-of (h / high-02)
            :frequency (p2 / periodic :polarity -))
      :ARG1 (a4 / accumulate-01
            :ARG1 (p4 / protein :name (n2 / name :op1 "Skp2" :op2 "F-box")
                  :mod (c / component
                        :mod (p8 / protein :name (n3 / name :op1 "SCF"))
                        :mod (c2 / crucial)))
            :ARG1-of (p3 / progress-01))
      :ARG1-of (a3 / appear-02)
      :ARG0-of (c3 / cause-01
            :ARG1 (c4 / create-01
                  :ARG0 a2
                  :ARG1 (c5 / condition-01
                        :ARG0-of (p5 / permit-01
                              :ARG1 (t2 / turn-over-12
                                    :ARG1 (p6 / protein :name (n5 / name :op1 "p27")
                                          :ARG0-of (r2 / restrain-01
                                                :ARG1 (a / activity-06
                                                      :ARG0 e
                                                      :ARG1 (p7 / promote-01
                                                            :ARG1 (e2 / event :name (n6 / name :op1 "S-phase"))))
                                                :mod (o / otherwise))
                                          :ARG0-of (i2 / inhibit-01
                                                :ARG1 (e / enzyme :name (n4 / name :op1 "CDK"))))
                                    :mod (r / rapid)))))))

# ::id bio.chicago_2015.73500 ::date 2015-11-06T10:35:41 ::annotator SDL-AMR-09 ::preferred
# ::snt The activated insulin-like  growth factor I receptor induces depolarization in breast epithelial cells characterized by  actin filament disassembly and tyrosine dephosphorylation of  FAK,  Cas, and  paxillin.
# ::save-date Sun Jan 17, 2016 ::file bio_chicago_2015_73500.txt
(i / induce-01
      :ARG0 (p5 / protein :name (n / name :op1 "growth" :op2 "factor" :op3 "I" :op4 "receptor")
            :ARG1-of (a / activate-01)
            :ARG1-of (r / resemble-01
                  :ARG2 (p6 / protein :name (n7 / name :op1 "insulin"))))
      :ARG2 (d / depolarize-00
            :ARG1 (c / cell
                  :mod (e / epithelium)
                  :mod (b / breast))
            :ARG1-of (c2 / characterize-01
                  :ARG2 (a2 / and
                        :op1 (d2 / disassemble-01
                              :ARG0 (f / filament
                                    :mod (p / protein :name (n2 / name :op1 "actin"))))
                        :op2 (d3 / dephosphorylate-01
                              :ARG1 (a4 / and
                                    :op1 (e2 / enzyme :name (n4 / name :op1 "FAK"))
                                    :op2 (p3 / protein :name (n5 / name :op1 "Cas"))
                                    :op3 (p4 / protein :name (n6 / name :op1 "paxillin")))
                              :ARG2 (a3 / amino-acid :name (n3 / name :op1 "tyrosine")))))))

# ::id bio.chicago_2015.73683 ::date 2015-11-06T10:44:09 ::annotator SDL-AMR-09 ::preferred
# ::snt Myristoylated  ARF1 and  ARF6 (referred in the text as  ARF1 and  ARF6), myristoylated  ARF1 mutant N52R-ARF1 (referred in the text as  N52R-ARF1), and PITPalpha were expressed in   Escherichia coli and purified exactly as described ( 7,  37).
# ::save-date Mon Nov 16, 2015 ::file bio_chicago_2015_73683.txt
(a / and
      :op1 (e / express-03
            :ARG2 (a2 / and
                  :op1 (a3 / and
                        :op1 (p2 / protein :name (n / name :op1 "ARF1"))
                        :op2 (p3 / protein :name (n2 / name :op1 "ARF6"))
                        :ARG1-of (m / myristoylate-00)
                        :ARG1-of (r / refer-01
                              :ARG2 (a4 / and
                                    :op1 p2
                                    :op2 p3)
                              :location (t / text)))
                  :op2 (p4 / protein :name (n3 / name :op1 "N52R-ARF1")
                        :ARG2-of (m2 / mutate-01
                              :ARG1 p2)
                        :ARG1-of m
                        :ARG1-of (r2 / refer-01
                              :ARG2 p4
                              :location t))
                  :op3 (p5 / protein :name (n4 / name :op1 "PITPalpha")))
            :ARG3 (o / organism :name (n5 / name :op1 "Escherichia" :op2 "coli")))
      :op2 (p / purify-01
            :ARG1 p5
            :manner (e2 / exact)
            :ARG1-of (d / describe-01
                  :ARG0 (p6 / publication
                        :ARG1-of (c / cite-01
                              :ARG2 (a5 / and :op1 7 :op2 37))))))

# ::id bio.chicago_2015.73782 ::date 2015-11-06T10:58:30 ::annotator SDL-AMR-09 ::preferred
# ::snt Confirmation that  Narf specifically recognizes preAct, and not just a prenylated  cysteine residue, came from  in vitro binding assays.
# ::save-date Sat Feb 13, 2016 ::file bio_chicago_2015_73782.txt
(c / come-03
      :ARG1 (c2 / confirm-01
            :ARG1 (c3 / contrast-01
                  :ARG1 (r / recognize-02
                        :ARG0 (p / protein :name (n2 / name :op1 "Narf"))
                        :ARG1 (s2 / small-molecule :name (n / name :op1 "preAct"))
                        :ARG1-of (s / specific-02))
                  :ARG2 (r3 / recognize-02 :polarity -
                        :ARG0 p
                        :ARG1 (r2 / residue
                              :mod (a2 / amino-acid :name (n3 / name :op1 "cysteine")
                                    :ARG1-of (p2 / prenylate-00)))
                        :mod (j / just))))
      :ARG2 (a3 / assay-01
            :ARG1 (b / bind-01)
            :manner (i / in-vitro)))

# ::id bio.chicago_2015.73823 ::date 2015-11-06T11:08:11 ::annotator SDL-AMR-09 ::preferred
# ::snt Esterified lipids of  LDL are hydrolysed by lipases like  phospholipase A2 or  lipoprotein lipase.
# ::save-date Fri Nov 6, 2015 ::file bio_chicago_2015_73823.txt
(h / hydrolyze-01
      :ARG0 (e2 / enzyme :name (n2 / name :op1 "lipase")
            :example (o / or
                  :op1 (e3 / enzyme :name (n3 / name :op1 "phospholipase" :op2 "A2"))
                  :op2 (e4 / enzyme :name (n4 / name :op1 "lipoprotein" :op2 "lipase"))))
      :ARG1 (l / lipid
            :ARG1-of (e / esterify-00)
            :mod (p / protein :name (n / name :op1 "LDL"))))

# ::id bio.chicago_2015.73906 ::date 2015-11-06T11:12:55 ::annotator SDL-AMR-09 ::preferred
# ::snt Enlargement of  plant cells is constrained by a resistant  cell wall composed of cellulose microfibrils, crosslinked by other polysaccharides such as xyloglucans ( 16).
# ::save-date Sat Feb 13, 2016 ::file bio_chicago_2015_73906.txt
(c / constrain-01
      :ARG0 (w / wall
            :mod (c2 / cell)
            :ARG0-of (r / resist-01)
            :ARG1-of (c4 / compose-01
                  :ARG2 (m / microfibril
                        :mod (c5 / cellulose)
                        :ARG1-of (c6 / crosslink-00
                              :ARG0 (p3 / polysaccharide
                                    :mod (o / other)
                                    :example (s / small-molecule :name (n2 / name :op1 "xyloglucan")))))))
      :ARG1 (e / enlarge-01
            :ARG1 (c3 / cell
                  :mod (p / plant)))
      :ARG1-of (d / describe-01
            :ARG0 (p2 / publication
                  :ARG1-of (c7 / cite-01
                        :ARG2 16))))

# ::id bio.chicago_2015.73940 ::date 2015-11-06T11:24:19 ::annotator SDL-AMR-09 ::preferred
# ::snt Only sagittal and oblique sections following  BDA injections in the rostral prelimbic area are presented here because  coronal sections severed most of the rostral prelimbic  PFC to  NAc projecting fibers.
# ::save-date Sat Feb 13, 2016 ::file bio_chicago_2015_73940.txt
(p / present-01
      :ARG1 (a / and
            :op1 (s / section-01
                  :mod (s2 / sagittal))
            :op2 (s3 / section-01
                  :mod (o / oblique))
            :mod (o2 / only)
            :ARG1-of (f2 / follow-01
                  :ARG2 (i / inject-01
                        :ARG1 (s4 / small-molecule :name (n / name :op1 "BDA"))
                        :ARG2 (a3 / area
                              :mod (p2 / prelimb
                                    :mod (r / rostral))))))
      :medium (h / here)
      :ARG1-of (c / cause-01
            :ARG0 (s5 / sever-01
                  :ARG0 (s6 / section-01
                        :mod (c2 / coronal))
                  :ARG1 (f / fiber
                        :ARG1-of (p3 / project-01
                              :mod (t2 / thing :name (n3 / name :op1 "NAc")))
                        :mod (t / thing :name (n2 / name :op1 "PFC")
                              :mod p2)
                        :quant (m / most)))))

# ::id bio.chicago_2015.73959 ::date 2015-11-06T11:48:52 ::annotator SDL-AMR-09 ::preferred
# ::snt ( C) Both N-terminal bacterially expressed hCdc20 and  hCdh1 bind the N-terminal fragment of   Xenopus cyclin B containing the D box, but fail to recover the D-box deleted N-terminal  cyclin B. ( D) In vitro-translated  cyc A binds MTCdc20 and MTCdh1, but not to  MT alone.
# ::save-date Sat Feb 13, 2016 ::file bio_chicago_2015_73959.txt
(m / multi-sentence
      :snt1 (c / contrast-01 :li "C"
            :ARG1 (b / bind-01
                  :ARG1 (a / and
                        :op1 (p / protein :name (n / name :op1 "hCdc20"))
                        :op2 (p2 / protein :name (n2 / name :op1 "hCdh1"))
                        :ARG1-of (e / express-03
                              :manner (b2 / bacterial))
                        :mod (p9 / protein-segment :name (n10 / name :op1 "N-terminal")))
                  :ARG2 (f / fragment
                        :part-of (p3 / protein :name (n3 / name :op1 "cyclin" :op2 "B")
                              :mod (o / organism :name (n11 / name :op1 "Xenopus")))
                        :ARG0-of (c2 / contain-01
                              :ARG1 (t / thing :name (n4 / name :op1 "D" :op2 "box")))
                        :mod p9))
            :ARG2 (f2 / fail-01
                  :ARG0 a
                  :ARG1 (r / recover-02
                        :ARG0 a
                        :ARG1 (p4 / protein :name (n5 / name :op1 "cyclin" :op2 "B")
                              :ARG1-of (d / delete-01
                                    :ARG0 t)
                              :mod p9))))
      :snt2 (c3 / contrast-01 :li "D"
            :ARG1 (b3 / bind-01
                  :ARG1 (p5 / protein :name (n6 / name :op1 "cyc" :op2 "A")
                        :ARG2-of (t2 / translate-02
                              :manner (i / in-vitro)))
                  :ARG2 (a2 / and
                        :op1 (p6 / protein :name (n7 / name :op1 "MTCdc20"))
                        :op2 (p7 / protein :name (n8 / name :op1 "MTCdh1"))))
            :ARG2 (b4 / bind-01 :polarity -
                  :ARG1 p5
                  :ARG2 (p8 / protein :name (n9 / name :op1 "MT"))
                  :mod (a3 / alone))))

# ::id bio.chicago_2015.73961 ::date 2015-11-06T13:44:38 ::annotator SDL-AMR-09 ::preferred
# ::snt In the case of  histone H3, both   RPD3 and   HDA1 deacetylate the five  lysines (K9,  K14,  K18,  K23 and  K27; Figure  1D) that are acetylated by   GCN5 (Figure  1D).
# ::save-date Mon Nov 16, 2015 ::file bio_chicago_2015_73961.txt
(d / deacetylate-01
      :ARG0 (a / and
            :op1 (p / protein :name (n / name :op1 "RPD3"))
            :op2 (p2 / protein :name (n2 / name :op1 "HDA1")))
      :ARG1 (a2 / amino-acid :quant 5 :name (n3 / name :op1 "lysine")
            :ARG2-of (m / mean-01
                  :ARG1 (a3 / and
                        :op1 (a4 / amino-acid :mod 9 :name (n4 / name :op1 "lysine"))
                        :op2 (a5 / amino-acid :mod 14 :name (n5 / name :op1 "lysine"))
                        :op3 (a6 / amino-acid :mod 18 :name (n6 / name :op1 "lysine"))
                        :op4 (a7 / amino-acid :mod 23 :name (n7 / name :op1 "lysine"))
                        :op5 (a8 / amino-acid :mod 27 :name (n8 / name :op1 "lysine"))))
            :ARG1-of (d2 / describe-01
                  :ARG0 (f / figure :mod "1D"))
            :ARG1-of (a9 / acetylate-01
                  :ARG2 (p3 / protein :name (n9 / name :op1 "GCN5"))
                  :ARG1-of (d3 / describe-01
                        :ARG0 f)))
      :topic (p4 / protein :name (n10 / name :op1 "histone" :op2 "H3")))

# ::id bio.chicago_2015.73964 ::date 2015-11-06T13:55:01 ::annotator SDL-AMR-09 ::preferred
# ::snt Loss of DNA methylation may also result from active mechanisms involving either an enzymatic activity, which removes methylcytosine and replaces it by cytosine, or a deamination of methylated  CpGs, creating a mismatch that is then repaired (Jost and Saluz 1993  ; Weiss et al. 1996  ).
# ::save-date Sat Feb 13, 2016 ::file bio_chicago_2015_73964.txt
(p / possible-01
      :ARG1 (r / result-01
            :ARG1 (m2 / mechanism
                  :ARG0-of (a / activity-06)
                  :ARG2-of (i / involve-01
                        :ARG1 (o / or
                              :op1 (a2 / activity-06
                                    :ARG1 (e / enzymatic)
                                    :ARG0-of (r2 / remove-01
                                          :ARG1 (s / small-molecule :name (n3 / name :op1 "methylcytosine")))
                                    :ARG0-of (r3 / replace-01
                                          :ARG1 s
                                          :ARG2 (s2 / small-molecule :name (n4 / name :op1 "cytosine"))))
                              :op2 (d5 / deaminate-01
                                    :ARG1 (d6 / dna-sequence :name (n5 / name :op1 "CpG")
                                          :ARG1-of (m3 / methylate-01))
                                    :ARG0-of (c / create-01
                                          :ARG1 (m4 / mismatch
                                                :ARG1-of (r4 / repair-01
                                                      :time (t / then))))))))
            :ARG2 (l / lose-02
                  :ARG1 (m / methylate-01
                        :ARG1 (n / nucleic-acid :wiki "DNA" :name (n2 / name :op1 "DNA")))))
      :ARG1-of (d4 / describe-01
            :ARG0 (a4 / and
                  :op1 (p2 / publication-91
                        :ARG0 (a5 / and
                              :op1 (p4 / person :name (n6 / name :op1 "Jost"))
                              :op2 (p5 / person :name (n8 / name :op1 "Saluz")))
                        :time (d2 / date-entity :year 1993))
                  :op2 (p3 / publication-91
                        :ARG0 (a6 / and
                              :op1 (p6 / person :name (n7 / name :op1 "Weiss"))
                              :op2 (p7 / person
                                    :mod (o2 / other)))
                        :time (d3 / date-entity :year 1996))))
      :mod (a7 / also))

# ::id bio.chicago_2015.74011 ::date 2015-11-06T14:09:36 ::annotator SDL-AMR-09 ::preferred
# ::snt This demonstrates the testis-specific demethylation of the   Pgk-2/CAT transgenes, the ubiquitous hypomethylation of the  transferrin/ CAT transgene, and the ubiquitous hypermethylation of the  CAT-only transgene.
# ::save-date Tue Jan 19, 2016 ::file bio_chicago_2015_74011.txt
(d / demonstrate-01
      :ARG0 (t / this)
      :ARG1 (a / and
            :op1 (d2 / demethylate-01
                  :ARG1 (t3 / transgene :name (n / name :op1 "Pgk-2/CAT"))
                  :ARG1-of (s / specific-02
                        :ARG2 (t2 / testis)))
            :op2 (h / hypomethylate-00
                  :ARG1 (t4 / transgene :name (n2 / name :op1 "transferrin/CAT"))
                  :mod (u / ubiquitous))
            :op3 (h2 / hypermethylate-01
                  :ARG2 (t5 / transgene :name (n3 / name :op1 "CAT-only"))
                  :mod u)))

# ::id bio.chicago_2015.74036 ::date 2015-11-06T14:14:22 ::annotator SDL-AMR-09 ::preferred
# ::snt When a lesion is detected, the  UvrB protein hydrolyses its  bound ATP molecule, leading to formation of the  pro-pre-incision complex ( Moolenaar  et al., 2000b).
# ::save-date Mon Dec 21, 2015 ::file bio_chicago_2015_74036.txt
(h / hydrolyze-01
      :ARG1 (s2 / small-molecule :name (n2 / name :op1 "ATP")
            :ARG1-of (b / bind-01)
            :poss p)
      :ARG2 (p / protein :name (n / name :op1 "UvrB"))
      :ARG0-of (l / lead-03
            :ARG1 (f / form-01
                  :ARG1 (c / complex
                        :ARG0-of (f2 / favor-01
                              :ARG1 (p2 / preincise-00)))))
      :time (d2 / detect-01
            :ARG1 (l2 / lesion))
      :ARG1-of (d3 / describe-01
            :ARG0 (p3 / publication-91
                  :ARG0 (a / and
                        :op1 (p4 / person :name (n3 / name :op1 "Moolenaar"))
                        :op2 (p5 / person
                              :mod (o / other)))
                  :time (d / date-entity :year 2000 :li "b"))))

# ::id bio.chicago_2015.74144 ::date 2015-11-06T14:20:21 ::annotator SDL-AMR-09 ::preferred
# ::snt As phosphatidylinositol (PI)  3-kinase and  Akt play a critical role in survival pathways in response to both  growth factors and extracellular stimuli, these observations prompted us to explore whether  E-cadherins could affect intracellular molecules regulating the activity of the PI  3-kinase/Akt signaling cascade.
# ::save-date Wed Feb 24, 2016 ::file bio_chicago_2015_74144.txt
(c / cause-01
      :ARG0 (p2 / play-02
            :ARG0 (a5 / and
                  :op1 (e3 / enzyme :name (n2 / name :op1 "phosphatidylinositol" :op2 "3-kinase"))
                  :op2 (e4 / enzyme :name (n3 / name :op1 "Akt")))
            :ARG1 (r / role
                  :ARG1-of (c3 / critical-02)
                  :topic (p3 / pathway
                        :mod (s / survive-01)))
            :ARG2-of (r2 / respond-01
                  :ARG1 (a / and
                        :op1 (g / growth-factor)
                        :op2 (s3 / stimulus
                              :mod (e / extracellular)))))
      :ARG1 (p4 / prompt-01
            :ARG0 (o / observe-01
                  :mod (t / this))
            :ARG1 (e2 / explore-01
                  :ARG0 (w / we)
                  :ARG1 (p5 / possible-01 :mode interrogative
                        :ARG1 (a2 / affect-01
                              :ARG0 (p / protein :name (n4 / name :op1 "E-cadherin"))
                              :ARG1 (m / molecule
                                    :ARG0-of (r3 / regulate-01
                                          :ARG1 (a3 / activity-06
                                                :ARG1 (p6 / pathway :name (n5 / name :op1 "PI" :op2 "3-kinase/Akt")
                                                      :ARG0-of (s4 / signal-07))))
                                    :mod (i / intracellular)))))))

# ::id bio.chicago_2015.74146 ::date 2015-11-06T14:34:34 ::annotator SDL-AMR-09 ::preferred
# ::snt Furthermore,  HDL inhibited thromboxane  A2 liberation, and addition of  HDL to clotting blood diminished platelet thromboxane  A2 formation capacity.
# ::save-date Sun Jan 17, 2016 ::file bio_chicago_2015_74146.txt
(a / and
      :op2 (a2 / and
            :op1 (i / inhibit-01
                  :ARG0 (p2 / protein :name (n / name :op1 "HDL"))
                  :ARG1 (l / liberate-01
                        :ARG1 (s / small-molecule :name (n2 / name :op1 "thromboxane" :op2 "A2"))))
            :op2 (d / diminish-01
                  :ARG0 (a3 / add-02
                        :ARG1 p2
                        :ARG2 (b / blood
                              :ARG0-of (c / clot-00)))
                  :ARG1 (c2 / capable-01
                        :ARG2 (f / form-01
                              :ARG1 (s2 / small-molecule :name (n3 / name :op1 "thromboxane" :op2 "A2")
                                    :mod (p / platelet)))))))

# ::id bio.chicago_2015.74199 ::date 2015-11-06T14:45:26 ::annotator SDL-AMR-09 ::preferred
# ::snt These data indicate that  NHERF-1 specifically associates with  Pin1, but only when  NHERF-1 is hyperphosphorylated by  cyclin-dependent kinases in  mitosis phase.
# ::save-date Sun Jan 17, 2016 ::file bio_chicago_2015_74199.txt
(i / indicate-01
      :ARG0 (d / data
            :mod (t / this))
      :ARG1 (a / associate-01
            :ARG1 (p / protein :name (n2 / name :op1 "NHERF-1"))
            :ARG2 (e2 / enzyme :name (n3 / name :op1 "Pin1"))
            :ARG1-of (s / specific-02)
            :condition (h / hyperphosphorylate-01
                  :ARG1 p
                  :ARG2 (k / kinase
                        :ARG0-of (d2 / depend-01
                              :ARG1 (p2 / protein :name (n4 / name :op1 "cyclin"))))
                  :time (p3 / phase
                        :mod (m / mitosis))
                  :mod (o / only))))

# ::id bio.chicago_2015.74221 ::date 2015-11-06T14:51:07 ::annotator SDL-AMR-09 ::preferred
# ::snt Elafin also reduces the liberation of matrix-bound   growth factors which may be responsible for the proliferation  of vascular smooth  muscle cells.
# ::save-date Wed Feb 24, 2016 ::file bio_chicago_2015_74221.txt
(r / reduce-01
      :ARG0 (p / protein :name (n2 / name :op1 "elafin"))
      :ARG1 (l / liberate-01
            :ARG1 (g / growth-factor
                  :ARG1-of (b / bind-01
                        :ARG2 (m / matrix))))
      :mod (a / also)
      :ARG0-of (r2 / responsible-01
            :ARG1 (p3 / proliferate-01
                  :ARG0 (c / cell
                        :mod (m2 / muscle
                              :mod (s2 / smooth))
                        :mod (v / vascular)))
            :ARG1-of (p2 / possible-01)))

# ::id bio.chicago_2015.74264 ::date 2015-11-08T01:07:28 ::annotator SDL-AMR-09 ::preferred
# ::snt Such  bacteria may be responsible for the high rates of  H2-dependent 14CO2 reduction to formate observed in the  P1 section of  C. orthognathus (Fig.  4B).
# ::save-date Sat Feb 13, 2016 ::file bio_chicago_2015_74264.txt
(p / possible-01
      :ARG1 (r / responsible-01
            :ARG0 (b / bacteria
                  :mod (s / such))
            :ARG1 (r2 / rate
                  :ARG1-of (h / high-02)
                  :degree-of (r3 / reduce-01
                        :ARG1 (s2 / small-molecule :name (n2 / name :op1 "14CO2"))
                        :ARG4 (s4 / small-molecule :name (n3 / name :op1 "formate"))
                        :ARG0-of (d2 / depend-01
                              :ARG1 (s3 / small-molecule :name (n / name :op1 "H2"))))
                  :ARG1-of (o / observe-01
                        :location (s5 / section :mod "P1"
                              :part-of (o2 / organism :name (n5 / name :op1 "C." :op2 "orthognathus"))))))
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod "4B")))

# ::id bio.chicago_2015.74340 ::date 2015-11-08T01:14:07 ::annotator SDL-AMR-09 ::preferred
# ::snt The  PLC-   isozymes have a multidomain array (a  PH domain  split  by two  SH2 domains and an  SH3 domain) inserted between two halves of the catalytic domain.
# ::save-date Sat Nov 21, 2015 ::file bio_chicago_2015_74340.txt
(h / have-03
      :ARG0 (i2 / isozyme :name (n / name :op1 "PLC"))
      :ARG1 (a / array-01
            :ARG1 (m2 / multidomain)
            :ARG1-of (m3 / mean-01
                  :ARG2 (p / protein-segment :name (n2 / name :op1 "PH")
                        :ARG1-of (s / split-01
                              :ARG2 (a2 / and
                                    :op1 (p3 / protein-segment :quant 2 :name (n3 / name :op1 "SH2"))
                                    :op2 (p2 / protein-segment :name (n4 / name :op1 "SH3"))))))
            :ARG1-of (i / insert-01
                  :ARG2 (h2 / half :quant 2
                        :mod (d4 / domain
                              :mod (c / catalysis))))))

# ::id bio.chicago_2015.74386 ::date 2015-11-08T01:23:14 ::annotator SDL-AMR-09 ::preferred
# ::snt Recent accumulating evidences suggest that induction of  histone hyperacetylation by  HDAC inhibitors is responsible for the antiproliferative activity and reversal of neoplastic characteristics through selective induction of genes, which play important roles in the cell cycle and cell morphology ( 14).
# ::save-date Thu Feb 4, 2016 ::file bio_chicago_2015_74386.txt
(s / suggest-01
      :ARG0 (e / evidence-01
            :ARG1-of (a / accumulate-01)
            :time (r / recent))
      :ARG1 (r2 / responsible-01
            :ARG0 (i2 / induce-01
                  :ARG0 (e2 / enzyme :name (n2 / name :op1 "HDAC")
                        :ARG0-of (i / inhibit-01))
                  :ARG2 (h / hyperacetylate-00
                        :ARG1 (p / protein :name (n / name :op1 "histone"))))
            :ARG1 (a2 / and
                  :op1 (a3 / activity-06
                        :ARG1 (c / counter-01
                              :ARG1 (p2 / proliferate-01)))
                  :op1 (r3 / reverse-01
                        :ARG1 (t / thing
                              :ARG2-of (c2 / characteristic-02
                                    :ARG1 (n3 / neoplasm))))
                  :manner (i3 / induce-01
                        :ARG1 (g / gene)
                        :mod (s2 / selective))
                  :ARG0-of (p3 / play-02
                        :ARG1 (r4 / role
                              :mod (i4 / important)
                              :time (a4 / and
                                    :op1 (c3 / cycle-02
                                          :mod (c4 / cell))
                                    :op2 (m / morphology
                                          :mod c4))))))
      :ARG1-of (d / describe-01
            :ARG0 (p4 / publication
                  :ARG1-of (c5 / cite-01
                        :ARG2 14))))

# ::id bio.chicago_2015.74432 ::date 2015-11-08T01:32:45 ::annotator SDL-AMR-09 ::preferred
# ::snt Treatment with  DNase I failed to liberate  GAPDH from the nuclear fraction (Fig.  6 B).
# ::save-date Mon Nov 16, 2015 ::file bio_chicago_2015_74432.txt
(f / fail-01
      :ARG1 (t / treat-04
            :ARG2 (e / enzyme :name (n / name :op1 "DNase" :op2 "I")))
      :ARG2 (l / liberate-01
            :ARG0 t
            :ARG1 (e2 / enzyme :name (n2 / name :op1 "GAPDH"))
            :ARG2 (f2 / fraction-01
                  :ARG1 (n3 / nucleus)))
      :ARG1-of (d / describe-01
            :ARG0 (f3 / figure :mod "6B")))

# ::id bio.chicago_2015.74470 ::date 2015-11-08T01:35:48 ::annotator SDL-AMR-09 ::preferred
# ::snt Here, we report that a short incubation of  control cells with the  F-actin depolymerizing agent cytochalasin D triggered  cytochrome  c release and  procaspase 3-like activation.
# ::save-date Sun Nov 8, 2015 ::file bio_chicago_2015_74470.txt
(r / report-01
      :ARG0 (w / we)
      :ARG1 (t / trigger-01
            :ARG0 (i / incubate-01
                  :ARG1 (c / cell
                        :mod (c2 / control))
                  :ARG2 (s2 / small-molecule :name (n / name :op1 "cytochalasin" :op2 "D")
                        :mod (a / agent)
                        :ARG0-of (d / depolymerize-00
                              :ARG1 (p / protein :name (n2 / name :op1 "F-actin"))))
                  :ARG1-of (s / short-07))
            :ARG1 (a2 / and
                  :op1 (r2 / release-01
                        :ARG1 (p2 / protein :name (n3 / name :op1 "cytochrome" :op2 "c")))
                  :op2 (a3 / activate-01
                        :ARG1 (p3 / protein :name (n4 / name :op1 "procaspase" :op2 "3-like")))))
      :medium (h / here))

# ::id bio.chicago_2015.74541 ::date 2015-11-08T01:46:22 ::annotator SDL-AMR-09 ::preferred
# ::snt p-Nitroanilines liberated by  trypsin activity were measured with a spectrophotometer at 410 nm. Dependency of the reactions on enterokinase activation was studied by performing the same reaction in the absence of enterokinase and comparing the results.
# ::save-date Sat Feb 13, 2016 ::file bio_chicago_2015_74541.txt
(m3 / multi-sentence
      :snt1 (m / measure-01
            :ARG1 (s4 / small-molecule :name (n2 / name :op1 "p-Nitroaniline")
                  :ARG1-of (l / liberate-01
                        :ARG0 (a2 / activity-06
                              :ARG0 (e / enzyme :name (n / name :op1 "trypsin")))))
            :ARG2 (s / spectrophotometer)
            :condition (f / frequence :value 410
                  :unit (n3 / nanometer)))
      :snt2 (s2 / study-01
            :ARG1 (d / depend-01
                  :ARG0 (r / react-01)
                  :ARG1 (a3 / activate-01
                        :ARG1 (e2 / enzyme :name (n4 / name :op1 "enterokinase"))))
            :manner (a6 / and
                  :op1 (p / perform-01
                        :ARG1 (r2 / react-01
                              :ARG1-of (s3 / same-01))
                        :condition (a4 / absent-01
                              :ARG1 e2))
                  :op2 (c / compare-01
                        :ARG1 (t / thing
                              :ARG2-of (r3 / result-01))))))

# ::id bio.chicago_2015.74615 ::date 2015-11-08T01:57:37 ::annotator SDL-AMR-09 ::preferred
# ::snt Proteins in the pathways that regulate contractility and  actin depolymerization downstream of  Rho and  ROK, such as  myosin light-chain kinase and  phosphatase and  cofilin, are candidate targets for  aPKCs, but the precise mechanism by which  Cdc42 and  aPKCs regulate stress fibers is not yet clear.
# ::save-date Sat Nov 21, 2015 ::file bio_chicago_2015_74615.txt
(c / contrast-01
      :ARG1 (t / thing
            :mod (c2 / candidate)
            :ARG1-of (t2 / target-01
                  :ARG0 (e / enzyme :name (n7 / name :op1 "aPKC")))
            :domain (p / protein
                  :part-of (p2 / pathway)
                  :ARG0-of (r / regulate-01
                        :ARG1 (a / and
                              :op1 (c3 / contractility)
                              :op2 (d / depolymerize-00
                                    :ARG1 (p3 / protein :name (n / name :op1 "actin"))))
                        :location (r3 / relative-position
                              :op1 (a2 / and
                                    :op1 (p4 / protein :name (n2 / name :op1 "Rho"))
                                    :op2 (p5 / protein :name (n3 / name :op1 "ROK")))
                              :direction (d2 / downstream)))
                  :example (a3 / and
                        :op1 (e2 / enzyme :name (n4 / name :op1 "myosin" :op2 "light-chain" :op3 "kinase"))
                        :op2 (e3 / enzyme :name (n5 / name :op1 "phosphatase"))
                        :op3 (p8 / protein :name (n6 / name :op1 "cofilin")))))
      :ARG2 (c4 / clear-06 :polarity -
            :ARG1 (m / mechanism
                  :mod (p9 / precise)
                  :instrument-of (r2 / regulate-01
                        :ARG0 (a4 / and
                              :op1 (p10 / protein :name (n8 / name :op1 "Cdc42"))
                              :op2 e)
                        :ARG1 (f / fiber
                              :mod (s / stress))))
            :time (y / yet)))

# ::id bio.chicago_2015.74675 ::date 2015-11-08T02:16:34 ::annotator SDL-AMR-09 ::preferred
# ::snt Strikingly, while  Bdf1 prefers hyperacetylated forms of  histone H4,  Bdf2 binds equally well to all  histone H4 species   (Figure 2B).
# ::save-date Mon Nov 16, 2015 ::file bio_chicago_2015_74675.txt
(c / contrast-01
      :ARG1 (b / bind-01
            :ARG1 (p4 / protein :name (n3 / name :op1 "Bdf2"))
            :ARG2 (s / species
                  :mod p3
                  :mod (a / all))
            :ARG1-of (g / good-02
                  :degree (e / equal)))
      :ARG2 (p / prefer-01
            :ARG0 (p2 / protein :name (n / name :op1 "Bdf1"))
            :ARG1 (f / form
                  :ARG1-of (h / hyperacetylate-00)
                  :mod (p3 / protein :name (n2 / name :op1 "histone" :op2 "H4"))))
      :ARG1-of (s2 / strike-04)
      :ARG1-of (d / describe-01
            :ARG0 (f2 / figure :mod "2B")))

# ::id bio.chicago_2015.74682 ::date 2015-11-08T02:24:32 ::annotator SDL-AMR-09 ::preferred
# ::snt Reasoning that  dC dU deamination of the retroviral reverse transcripts ( cDNA) could give rise to inactivating mutations of the  GFP gene, we speculated that some of the  GFP-negative target cells could nevertheless have been infected but with the  GFP gene having been rendered nonfunctional by  CEM15/APOBEC3G-induced mutations.
# ::save-date Sat Feb 13, 2016 ::file bio_chicago_2015_74682.txt
(c / cause-01
      :ARG0 (r / reason-01
            :ARG0 (w / we)
            :ARG1 (p2 / possible-01
                  :ARG1 (g / give-rise-to-10
                        :ARG0 (d / deaminate-01
                              :ARG1 (t / transcript
                                    :mod (r2 / reverse-01)
                                    :mod (r3 / retrovirus))
                              :ARG2 (s3 / small-molecule :name (n2 / name :op1 "dC" :op2 "dU")))
                        :ARG2 (m / mutate-01
                              :ARG1 (g2 / gene :name (n / name :op1 "GFP"))
                              :ARG0-of (a / activate-01 :polarity -)))))
      :ARG1 (s / speculate-01
            :ARG0 w
            :ARG1 (p / possible-01
                  :ARG1 (h / have-concession-91
                        :ARG1 (i / infect-01
                              :ARG0 (g4 / gene :name (n5 / name :op1 "GFP")
                                    :ARG1-of (r4 / render-01
                                          :ARG0 (m3 / mutate-01
                                                :ARG2-of (i2 / induce-01
                                                      :ARG0 (e / enzyme :name (n6 / name :op1 "CEM15/APOBEC3G"))))
                                          :ARG2 (f / function-01 :polarity -
                                                :ARG0 g4)))
                              :ARG1 (c3 / cell
                                    :quant (s2 / some)
                                    :ARG1-of (i3 / include-91
                                          :ARG2 (c2 / cell
                                                :ARG1-of (t2 / target-01)
                                                :mod (g3 / gene :name (n3 / name :op1 "GFP")
                                                      :ARG2-of (m4 / mutate-01 :mod "-/-"))))))))))

# ::id bio.chicago_2015.74687 ::date 2015-11-08T02:43:50 ::annotator SDL-AMR-09 ::preferred
# ::snt Compared with  PMNs  receiving inputs that lacked oscillations  ( Fig. 2 F), discharge  patterns of  PMNs receiving inputs with consistent oscillations showed much  less variability for consecutive spontaneous bursts  ( Fig. 2 E).
# ::save-date Mon Feb 1, 2016 ::file bio_chicago_2015_74687.txt
(s / show-01
      :ARG0 (p / pattern
            :mod (d / discharge-01)
            :mod (c / cell :name (n / name :op1 "PMN")
                  :ARG0-of (r / receive-01
                        :ARG1 (i / input
                              :ARG1-of (o / oscillate-01
                                    :ARG1-of (c2 / consistent-02)))))
            :compared-to (c4 / cell :name (n2 / name :op1 "PMN")
                  :ARG0-of (r2 / receive-01
                        :ARG1 (i2 / input
                              :ARG0-of (l2 / lack-01
                                    :ARG1 (o2 / oscillate-01))))
                  :ARG1-of (d2 / describe-01
                        :ARG0 (f / figure :mod "2F"))))
      :ARG1 (v / variability
            :degree (l / less
                  :quant (m / much))
            :mod (b / burst-01
                  :mod (s2 / spontaneous)
                  :mod (c3 / consecutive))
            :ARG1-of (d3 / describe-01
                  :ARG0 (f2 / figure :mod "2E"))))

# ::id bio.chicago_2015.74732 ::date 2015-11-08T13:10:25 ::annotator SDL-AMR-09 ::preferred
# ::snt In addition to  GST-CIIS, the   S. pombe FTase also efficiently  farnesylated another  C AAX protein,   S. cerevisiae Rho3, while prenylating two different  C AAL proteins,  Cdc42 and  RhoA, with very low efficiency (Fig.  3 C).
# ::save-date Mon Nov 16, 2015 ::file bio_chicago_2015_74732.txt
(a4 / and
      :op1 (f / farnesylate-01
            :ARG1 (a2 / and
                  :op1 (p / protein :name (n2 / name :op1 "GST-CIIS"))
                  :op2 (p5 / protein
                        :mod (a3 / another)
                        :ARG1-of (i / include-91
                              :ARG2 (p2 / protein-family :name (n3 / name :op1 "C" :op2 "AAX")))
                        :ARG1-of (m / mean-01
                              :ARG2 (p3 / protein :name (n4 / name :op1 "Rho3")
                                    :mod (o2 / organism :name (n9 / name :op1 "S." :op2 "cerevisiae"))))))
            :ARG2 (e / enzyme :name (n / name :op1 "FTase")
                  :mod (o / organism :name (n8 / name :op1 "S." :op2 "pombe")))
            :mod (a / also)
            :ARG1-of (e2 / efficient-01))
      :op2 (p4 / prenylate-00
            :ARG1 (p6 / protein :quant 2
                  :ARG1-of (d / differ-02)
                  :ARG1-of (i2 / include-91
                        :ARG2 (p7 / protein-family :name (n5 / name :op1 "C" :op2 "AAL")))
                  :ARG1-of (m2 / mean-01
                        :ARG2 (a5 / and
                              :op1 (p8 / protein :name (n6 / name :op1 "Cdc42"))
                              :op2 (p9 / protein :name (n7 / name :op1 "RhoA")))))
            :ARG2 e
            :ARG1-of (e3 / efficient-01
                  :ARG1-of (l / low-04
                        :degree (v / very))))
      :ARG1-of (d2 / describe-01
            :ARG0 (f2 / figure :mod "3C")))

# ::id bio.chicago_2015.74770 ::date 2015-11-08T13:23:09 ::annotator SDL-AMR-09 ::preferred
# ::snt In the case of I B, which holds the  transcription factor NF B in an inactive cytoplasmic complex, cytokines induce the phosphorylation of the two  serine residues (Ser32 and Ser36) in the I B destruction motif, leading to its ubiquitination by  SCF -TrCP1, destruction by the  proteasome, and liberation of  NF B    (Winston et al., 1999a  ; Yaron et al., 1998  ;  Li and Verma, 2002  ).
# ::save-date Sat Jan 30, 2016 ::file bio_chicago_2015_74770.txt
(i / induce-01
      :ARG0 (p2 / protein :name (n2 / name :op1 "cytokine"))
      :ARG2 (p3 / phosphorylate-01
            :ARG1 (r / residue :quant 2
                  :mod (a / amino-acid :name (n / name :op1 "serine"))
                  :ARG1-of (m / mean-01
                        :ARG2 (a2 / and
                              :op1 (a3 / amino-acid :mod 32 :name (n3 / name :op1 "serine"))
                              :op2 (a4 / amino-acid :mod 36 :name (n5 / name :op1 "serine")))))
            :ARG0-of (l / lead-03
                  :ARG2 (a5 / and
                        :op1 (u / ubiquitinate-01
                              :ARG1 m2
                              :ARG2 (p / protein :name (n6 / name :op1 "SCF-TrCP1")))
                        :op2 (d4 / destroy-01
                              :ARG0 (m4 / macro-molecular-complex :name (n7 / name :op1 "proteasome"))
                              :ARG1 m2)
                        :op3 (l2 / liberate-01
                              :ARG0 m2
                              :ARG1 f2)))
            :location (m2 / motif
                  :ARG0-of (d6 / destroy-01)
                  :mod p6))
      :ARG1-of (d5 / describe-01
            :ARG0 (a7 / and
                  :op1 (p8 / publication-91
                        :ARG0 (a8 / and
                              :op1 (p11 / person :name (n11 / name :op1 "Winston"))
                              :op2 (p12 / person
                                    :mod (o / other)))
                        :time (d / date-entity :year 1999 :li "a"))
                  :op2 (p9 / publication-91
                        :ARG0 (a9 / and
                              :op1 (p13 / person :name (n12 / name :op1 "Yaron"))
                              :op2 (p14 / person
                                    :mod (o2 / other)))
                        :time (d2 / date-entity :year 1998))
                  :op3 (p10 / publication-91
                        :ARG0 (a10 / and
                              :op1 (p15 / person :name (n13 / name :op1 "Li"))
                              :op2 (p16 / person :name (n14 / name :op1 "Verma")))
                        :time (d3 / date-entity :year 2002))))
      :topic (p6 / protein :name (n9 / name :op1 "I" :op2 "B")
            :ARG0-of (h / hold-01
                  :ARG1 (f2 / factor :name (n10 / name :op1 "NF" :op2 "B")
                        :ARG0-of (t2 / transcribe-01))
                  :ARG3 (m3 / macro-molecular-complex
                        :mod (c3 / cytoplasm)
                        :ARG0-of (a6 / activity-06 :polarity -)))))

# ::id bio.chicago_2015.74847 ::date 2015-11-08T13:47:47 ::annotator SDL-AMR-09 ::preferred
# ::snt It is conceivable that  Mxi2 could somehow interfere with  MEK retrophosphorylation by  ERKs, something that would hinder the negative feedback control of  MEK exerted by  ERKs ( 2), resulting in prolonged  MEK activity.
# ::save-date Fri Feb 5, 2016 ::file bio_chicago_2015_74847.txt
(p3 / possible-01
      :ARG1 (c / conceive-01
            :ARG1 (p4 / possible-01
                  :ARG1 (i / interfere-01
                        :ARG0 (p5 / protein :name (n2 / name :op1 "Mxi2"))
                        :ARG1 (r / retrophosphorylate-00
                              :ARG1 (e3 / enzyme :name (n / name :op1 "MEK"))
                              :ARG2 (p / protein-family :name (n3 / name :op1 "ERK")))
                        :ARG0-of (h / hinder-01
                              :ARG1 (c2 / control-01
                                    :ARG0 e3
                                    :mod (f / feedback
                                          :ARG0-of (n4 / negative-03))
                                    :ARG1-of (e2 / exert-01
                                          :ARG0 p))
                              :ARG1-of (d / describe-01
                                    :ARG0 (p6 / publication
                                          :ARG1-of (c3 / cite-01
                                                :ARG2 2)))
                              :ARG1-of (r2 / result-01
                                    :ARG2 (a / activity-06
                                          :ARG1 e3
                                          :ARG1-of (p7 / prolong-01))))
                        :manner (s / somehow)))))

# ::id bio.chicago_2015.74892 ::date 2015-11-08T13:53:32 ::annotator SDL-AMR-09 ::preferred
# ::snt Injection of  lefty into  mouse blastocysts leads to neurogenesis, a function attributable to  BMP inhibitors such as  chordin, noggin, and  follistatin ( 41,  44-47).
# ::save-date Sun Nov 8, 2015 ::file bio_chicago_2015_74892.txt
(l / lead-03
      :ARG0 (i2 / inject-01
            :ARG1 (p / protein :name (n / name :op1 "lefty"))
            :ARG2 (b2 / blastocyst
                  :mod (m / mouse)))
      :ARG2 (n2 / neurogenesis
            :mod (f / function-01
                  :ARG1-of (a / attribute-01
                        :ARG2 (m2 / molecular-physical-entity
                              :ARG0-of (i / inhibit-01
                                    :ARG1 (p3 / protein :name (n3 / name :op1 "BMP")))
                              :example (a2 / and
                                    :op1 (p4 / protein :name (n4 / name :op1 "chordin"))
                                    :op2 (p5 / protein :name (n5 / name :op1 "noggin"))
                                    :op3 (p6 / protein :name (n6 / name :op1 "follistatin"))))
                        :ARG1-of (p2 / possible-01))))
      :ARG1-of (d / describe-01
            :ARG0 (p7 / publication
                  :ARG1-of (c / cite-01
                        :ARG2 (a3 / and :op1 41
                              :op2 (v / value-interval
                                    :quant (b / between :op1 44 :op2 47)))))))

# ::id bio.chicago_2015.74899 ::date 2015-11-08T13:59:54 ::annotator SDL-AMR-09 ::preferred
# ::snt The  ADAM 12 propeptide remains bound to the protease after cleavage by  furin [ 9], therefore the  cysteine switch is potentially still functional in  furin-cleaved ADAM 12-S. Cu(II) could conceivably disengage the  cysteine switch by binding to or oxidizing Cys179, similar to the way in which  ADAM 12 or  MMP proforms can be activated by alkylation of the free  cysteine in the propeptide [ 11 and  13].
# ::save-date Tue Jan 19, 2016 ::file bio_chicago_2015_74899.txt
(m / multi-sentence
      :snt1 (r2 / remain-01
            :ARG1 (p2 / propeptide :name (n / name :op1 "ADAM" :op2 "12"))
            :ARG3 (b / bind-01
                  :ARG1 p2
                  :ARG2 (e2 / enzyme :name (n2 / name :op1 "protease")))
            :time (a / after
                  :op1 (c / cleave-01
                        :ARG0 (p3 / protein :name (n3 / name :op1 "furin"))
                        :ARG1 p2))
            :ARG1-of (d / describe-01
                  :ARG0 (p4 / publication
                        :ARG1-of (c2 / cite-01
                              :ARG2 9)))
            :ARG0-of (c3 / cause-01
                  :ARG1 (f / function-01
                        :ARG0 (s / switch-01
                              :ARG1 (a2 / amino-acid :name (n4 / name :op1 "cysteine")))
                        :manner (p5 / potential)
                        :mod (s2 / still)
                        :location (e3 / enzyme :name (n5 / name :op1 "ADAM" :op2 "12-S")
                              :ARG1-of (c4 / cleave-01
                                    :ARG0 p3)))))
      :snt2 (p6 / possible-01
            :ARG1 (d2 / disengage-01
                  :ARG0 (s3 / small-molecule :name (n6 / name :op1 "Cu(II)"))
                  :ARG1 (s4 / switch-01
                        :ARG1 (a3 / amino-acid :name (n7 / name :op1 "cysteine")))
                  :manner (o / or
                        :op1 (b2 / bind-01
                              :ARG1 s3
                              :ARG2 (a8 / amino-acid :mod 179 :name (n8 / name :op1 "cysteine")))
                        :op2 (o2 / oxidize-01
                              :ARG0 s3
                              :ARG1 a8))
                  :ARG1-of (r3 / resemble-01
                        :ARG2 (w / way
                              :manner-of (p7 / possible-01
                                    :ARG1 (a4 / activate-01
                                          :ARG1 (o4 / or
                                                :op1 (p / proform
                                                      :mod (e4 / enzyme :name (n9 / name :op1 "ADAM" :op2 "12")))
                                                :op2 (p11 / proform
                                                      :mod (e5 / enzyme :name (n10 / name :op1 "MMP"))))
                                          :manner (a5 / alkylate-01
                                                :ARG1 (a6 / amino-acid :name (n11 / name :op1 "cysteine")
                                                      :ARG1-of (f2 / free-04))
                                                :location (p9 / propeptide)))))))
            :ARG1-of (c5 / conceive-01)
            :ARG1-of (d3 / describe-01
                  :ARG0 (p10 / publication
                        :ARG1-of (c6 / cite-01
                              :ARG2 (a7 / and :op1 11 :op2 13))))))

# ::id bio.chicago_2015.74919 ::date 2015-11-08T14:22:55 ::annotator SDL-AMR-09 ::preferred
# ::snt The 432-bp 2 coding sequence is interrupted by two introns, the first ( I1) splitting  codon 32 and the second ( I2) separating  codons 101 and 102.
# ::save-date Sat Nov 21, 2015 ::file bio_chicago_2015_74919.txt
(i / interrupt-01
      :ARG0 (d / dna-sequence :quant 2 :name (n / name :op1 "intron")
            :ARG1-of (m / mean-01
                  :ARG2 (a / and
                        :op1 (i2 / intron
                              :ARG0-of (s / split-01
                                    :ARG1 (c / codon :mod 32))
                              :ord (o / ordinal-entity :value 1)
                              :ARG1-of (l / label-01
                                    :ARG2 (n4 / name :op1 "I1")))
                        :op2 (i3 / intron
                              :ARG0-of (s2 / separate-01
                                    :ARG1 (a2 / and
                                          :op1 (c2 / codon :mod 101)
                                          :op2 (c3 / codon :mod 102)))
                              :ord (o2 / ordinal-entity :value 2)
                              :ARG1-of (l2 / label-01
                                    :ARG2 (n3 / name :op1 "I2"))))))
      :ARG1 (d2 / dna-sequence :name (n2 / name :op1 "432-bp" :op2 "2")
            :ARG0-of (c4 / code-01)))

# ::id bio.chicago_2015.75018 ::date 2015-11-08T02:44:47 ::annotator SDL-AMR-09 ::preferred
# ::snt COX-1 mediates epithelial regeneration in a model of irradiation-induced intestinal  injury in  mice ( 9), which supports the cytoprotective role attributed to  COX-1 in gastrointestinal  inflammation.
# ::save-date Sat Nov 21, 2015 ::file bio_chicago_2015_75018.txt
(m / mediate-01
      :ARG0 (e / enzyme :name (n / name :op1 "COX-1"))
      :ARG1 (r / regenerate-01
            :ARG1 (e2 / epithelium)
            :location (m2 / model-01
                  :ARG1 (i / injure-01
                        :ARG1 (i2 / intestine)
                        :ARG2-of (i3 / induce-01
                              :ARG0 (i4 / irradiate-01))
                        :location (m3 / mouse)))
            :ARG1-of (d / describe-01
                  :ARG0 (p / publication
                        :ARG1-of (c / cite-01
                              :ARG2 9)))
            :ARG0-of (s / support-01
                  :ARG1 (r2 / role
                        :mod (c2 / cytoprotective)
                        :ARG1-of (a / attribute-01
                              :ARG2 e
                              :time (i5 / inflame-01
                                    :ARG1 (g / gastrointestine)))))))

# ::id bio.chicago_2015.75030 ::date 2015-11-05T05:30:30 ::annotator SDL-AMR-09 ::preferred
# ::snt The initial observations that  marijuana produced unique behavioral and pharmacological effects in  humans and  laboratory animals prompted chemists to prepare  synthetic agonists and antagonists.
# ::save-date Fri Nov 6, 2015 ::file bio_chicago_2015_75030.txt
(p / prompt-01
      :ARG0 (o / observe-01
            :ARG1 (p2 / produce-01
                  :ARG0 (m / marijuana)
                  :ARG1 (a / affect-01
                        :ARG0 m
                        :ARG1 (a3 / and
                              :op1 (h / human)
                              :op2 (a4 / animal
                                    :mod (l / laboratory)))
                        :ARG2 (a2 / and
                              :op1 (b / behave-01)
                              :op2 (p3 / pharmacology))
                        :mod (u / unique)))
            :time (i / initial))
      :ARG1 (p4 / prepare-01
            :ARG0 (c / chemist)
            :ARG1 (a5 / and
                  :op1 (a6 / agonist)
                  :op2 (a7 / antagonist)
                  :mod (s / synthetic))))

# ::id bio.chicago_2015.75156 ::date 2015-11-05T05:37:14 ::annotator SDL-AMR-09 ::preferred
# ::snt The uniqueness of the incomplete inhibition by  BoNT A was indicated by the finding that  Tetx or  BoNT B and  BoNT C, which extensively proteolyzed  synaptobrevin and  syntaxin, respectively (not shown), completely inhibited Ca2+-activated secretion in  ATP-primed cells (Fig.  4 B).
# ::save-date Wed Nov 11, 2015 ::file bio_chicago_2015_75156.txt
(i / indicate-01
      :ARG0 (f / find-01
            :ARG1 (i3 / inhibit-01
                  :ARG0 (o2 / or
                        :op1 (p2 / protein :name (n2 / name :op1 "Tetx"))
                        :op2 (a / and
                              :op1 (p3 / protein :name (n3 / name :op1 "BoNT" :op2 "B")
                                    :ARG0-of (p5 / proteolyze-00
                                          :ARG1 (p6 / protein :name (n5 / name :op1 "synaptobrevin"))
                                          :ARG1-of (e / extensive-03)))
                              :op2 (p4 / protein :name (n4 / name :op1 "BoNT" :op2 "C")
                                    :ARG0-of (p7 / proteolyze-00
                                          :ARG1 (p8 / protein :name (n6 / name :op1 "syntaxin"))
                                          :ARG1-of e))
                              :manner (r / respective)
                              :ARG1-of (s / show-01 :polarity -)))
                  :ARG1 (s2 / secrete-01
                        :ARG0 (c3 / cell
                              :ARG1-of (p9 / prime-01
                                    :ARG0 (s4 / small-molecule :name (n8 / name :op1 "ATP"))))
                        :ARG1-of (a2 / activate-01
                              :ARG0 (s3 / small-molecule :name (n7 / name :op1 "calcium")
                                    :ARG1-of (i4 / ionize-01 :value "2+"))))
                  :ARG1-of (c2 / complete-02)))
      :ARG1 (u / uniqueness
            :poss (i2 / inhibit-01
                  :ARG0 (p / protein :name (n / name :op1 "BoNT" :op2 "A"))
                  :ARG1-of (c / complete-02 :polarity -)))
      :ARG1-of (d / describe-01
            :ARG0 (f2 / figure :mod "4B")))

# ::id bio.chicago_2015.75158 ::date 2015-11-05T05:52:24 ::annotator SDL-AMR-09 ::preferred
# ::snt These results indicated that  LPA-induced  actin depolymerization through  alpha-actinin was involved in regulation of growth cone morphology of primary neurons.
# ::save-date Thu Nov 5, 2015 ::file bio_chicago_2015_75158.txt
(i / indicate-01
      :ARG0 (t / thing
            :mod (t2 / this)
            :ARG2-of (r / result-01))
      :ARG1 (i2 / involve-01
            :ARG1 (p / polymerize-01 :polarity -
                  :ARG1 (p2 / protein :name (n / name :op1 "actin"))
                  :ARG2 (p3 / protein :name (n3 / name :op1 "alpha-actinin"))
                  :ARG2-of (i3 / induce-01
                        :ARG0 (s / small-molecule :name (n2 / name :op1 "LPA"))))
            :ARG2 (r2 / regulate-01
                  :ARG1 (m / morphology
                        :poss (c / cone
                              :mod (g / growth)
                              :part-of (n4 / neuron
                                    :mod (p4 / primary)))))))

# ::id bio.chicago_2015.75270 ::date 2015-11-05T05:59:47 ::annotator SDL-AMR-09 ::preferred
# ::snt IKACh activation by  adenosine may be responsible for the profound transient  bradycardia and  atrioventricular block seen in  humans after administration of  adenosine (   DiMarco et al. 1983  ; Clemo and Belardinelli 1986  ; Kurachi et al. 1986  ).
# ::save-date Fri Nov 6, 2015 ::file bio_chicago_2015_75270.txt
(p / possible-01
      :ARG1 (r / responsible-03
            :ARG0 (a2 / activate-01
                  :ARG0 (s / small-molecule :name (n2 / name :op1 "adenosine"))
                  :ARG1 (p2 / protein :name (n / name :op1 "IKACh")))
            :ARG1 (a3 / and
                  :op1 (b / bradycardia
                        :ARG1-of (t / transient-02)
                        :mod (p3 / profound))
                  :op2 (b2 / block-01
                        :mod (a / atrioventricular))
                  :ARG1-of (s2 / see-01
                        :location (h / human)
                        :time (a6 / after
                              :op1 (a7 / administer-01
                                    :ARG1 s)))))
      :ARG1-of (d4 / describe-01
            :ARG0 (a8 / and
                  :op1 (p4 / publication-91
                        :ARG0 (a9 / and
                              :op1 (p5 / person :name (n3 / name :op1 "Di" :op2 "Marco"))
                              :op1 (p6 / person
                                    :mod (o / other)))
                        :time (d2 / date-entity :year 1983))
                  :op2 (p7 / publication-91
                        :ARG0 (a10 / and
                              :op1 (p8 / person :name (n4 / name :op1 "Clemo"))
                              :op2 (p9 / person :name (n5 / name :op1 "Belardinelli")))
                        :time (d3 / date-entity :year 1986))
                  :op3 (p10 / publication-91
                        :ARG0 (a11 / and
                              :op1 (p11 / person :name (n6 / name :op1 "Kurachi"))
                              :op2 p6)
                        :time d3))))

# ::id bio.chicago_2015.75329 ::date 2015-11-05T06:08:19 ::annotator SDL-AMR-09 ::preferred
# ::snt The global burden of disease and  injury attributable to selected  risk factors in 1990 ( 12).
# ::save-date Fri Nov 6, 2015 ::file bio_chicago_2015_75329.txt
(b / burden-01
      :ARG2 (a / and
            :op1 (d2 / disease)
            :op2 (i / injure-01))
      :mod (g / globe)
      :ARG1-of (a2 / attribute-01
            :ARG2 (f / factor
                  :mod (r / risk)
                  :ARG1-of (s / select-01))
            :ARG1-of (p / possible-01)
            :time (d / date-entity :year 1990))
      :ARG1-of (d3 / describe-01
            :ARG0 (p2 / publication
                  :ARG1-of (c / cite-01
                        :ARG2 12))))

# ::id bio.chicago_2015.75347 ::date 2015-11-05T06:11:11 ::annotator SDL-AMR-09 ::preferred
# ::snt Abeta peptides (amyloid plaques), hyperphosphorylated  tau proteins (NFTs,  NTs), and alpha-synuclein (LBs, GCIs).
# ::save-date Sat Feb 13, 2016 ::file bio_chicago_2015_75347.txt
(a / and
      :op1 (p / protein-segment :name (n / name :op1 "abeta" :op2 "peptide")
            :part-of (p2 / plaque
                  :mod (a4 / amyloid)))
      :op2 (p4 / protein :name (n3 / name :op1 "tau")
            :ARG1-of (h / hyperphosphorylate-01)
            :part-of (a2 / and
                  :op1 (p3 / protein-family :name (n4 / name :op1 "NFT"))
                  :op2 (p5 / protein-family :name (n5 / name :op1 "NT"))))
      :op3 (p7 / protein :name (n6 / name :op1 "alpha-synuclein")
            :part-of (a3 / and
                  :op1 (p6 / protein-family :name (n8 / name :op1 "LB"))
                  :op2 (p8 / protein-family :name (n7 / name :op1 "GCI")))))

# ::id bio.chicago_2015.75367 ::date 2015-11-05T06:19:53 ::annotator SDL-AMR-09 ::preferred
# ::snt It contains all six motifs ( PM1-PM3,   G1-G3) involved in nucleotide binding ( Valencia  et al.,  1991), and a recombinant protein isolated from   E. coli  indeed  binds and hydrolyses  GTP.
# ::save-date Fri Nov 6, 2015 ::file bio_chicago_2015_75367.txt
(a / and
      :op1 (c / contain-01
            :ARG0 (i / it)
            :ARG1 (p / protein-segment :quant 6
                  :mod (a2 / all)
                  :ARG1-of (m / mean-01
                        :ARG2 (a3 / and
                              :op1 (p2 / protein-segment
                                    :mod (v / value-interval
                                          :op1 (p8 / protein-segment :name (n5 / name :op1 "PM1"))
                                          :op2 (p9 / protein-segment :name (n6 / name :op1 "PM3"))))
                              :op2 (p3 / protein-segment
                                    :mod (v2 / value-interval
                                          :op1 (p10 / protein-segment :name (n7 / name :op1 "G1"))
                                          :op2 (p11 / protein-segment :name (n8 / name :op1 "G3"))))))
                  :ARG1-of (i2 / involve-01
                        :ARG2 (b / bind-01
                              :ARG1 p
                              :ARG2 (n2 / nucleotide))))
            :ARG1-of (d2 / describe-01
                  :ARG0 (p4 / publication-91
                        :ARG0 (a4 / and
                              :op1 (p5 / person :name (n3 / name :op1 "Valencia"))
                              :op2 (p6 / person
                                    :mod (o / other)))
                        :time (d / date-entity :year 1991))))
      :op2 (a5 / and
            :op1 (b2 / bind-01
                  :ARG1 (p7 / protein
                        :ARG1-of (r / recombine-01)
                        :ARG1-of (i3 / isolate-01
                              :ARG2 (o2 / organism :name (n4 / name :op1 "E." :op2 "coli"))))
                  :ARG2 s)
            :op2 (h / hydrolyze-01
                  :ARG1 (s / small-molecule :name (n / name :op1 "GTP"))
                  :ARG2 p7)
            :mod (i4 / indeed)))

# ::id bio.chicago_2015.75388 ::date 2015-11-05T07:00:28 ::annotator SDL-AMR-09 ::preferred
# ::snt In  budding yeast,  Mad1p becomes hyperphosphorylated and associates with  Bub1p and  Bub3p, and the formation of this complex occurs in  a Mad2p- and  Mps1p-dependent fashion and is crucial for checkpoint function ( 8).
# ::save-date Sun Nov 15, 2015 ::file bio_chicago_2015_75388.txt
(a / and
      :op1 (a2 / and
            :op1 (b / become-01
                  :ARG1 (p / protein :name (n / name :op1 "Mad1p"))
                  :ARG2 (h / hyperphosphorylate-01
                        :ARG1 p))
            :op2 (a3 / associate-01
                  :ARG1 p
                  :ARG2 (a4 / and
                        :op1 (e / enzyme :name (n2 / name :op1 "Bub1p"))
                        :op2 (e2 / enzyme :name (n3 / name :op1 "Bub3p")))))
      :op2 (f / form-01
            :ARG1 (m / macro-molecular-complex
                  :part p
                  :part e
                  :part e2
                  :mod (t / this))
            :ARG0-of (d / depend-01
                  :ARG1 (a5 / and
                        :op1 (p2 / protein :name (n4 / name :op1 "Mad2p"))
                        :op2 (e3 / enzyme :name (n5 / name :op1 "Mps1p")))))
      :op3 (c / crucial
            :domain f
            :purpose (f3 / function-01
                  :ARG1 (c2 / checkpoint)))
      :ARG1-of (d2 / describe-01
            :ARG0 (p3 / publication
                  :ARG1-of (c3 / cite-01
                        :ARG2 8)))
      :location (y / yeast
            :ARG1-of (b2 / bud-01)))

# ::id bio.chicago_2015.75391 ::date 2015-11-05T07:09:42 ::annotator SDL-AMR-09 ::preferred
# ::snt The structural and functional conservation of basal transcription machineries between  yeast and  mammals prompted us to investigate whether  TFIIH is involved in  rDNA transcription in vivo.
# ::save-date Thu Nov 5, 2015 ::file bio_chicago_2015_75391.txt
(p / prompt-01
      :ARG0 (c / conserve-01
            :ARG1 (a / and
                  :op1 (s / structure-01
                        :ARG1 (m / machinery
                              :ARG0-of (t / transcribe-01)
                              :mod (b / basal)))
                  :op2 (f / function-01
                        :ARG0 m))
            :location (a2 / and
                  :op1 (y / yeast)
                  :op2 (m2 / mammal)))
      :ARG1 (i / investigate-01
            :ARG0 (w / we)
            :ARG1 (i2 / involve-01 :mode interrogative
                  :ARG1 (p2 / protein :name (n / name :op1 "TFIIH"))
                  :ARG2 (t2 / transcribe-01
                        :ARG1 (n2 / nucleic-acid :name (n3 / name :op1 "rDNA")))
                  :manner (i3 / in-vivo))))

# ::id bio.chicago_2015.75414 ::date 2015-11-05T07:40:44 ::annotator SDL-AMR-09 ::preferred
# ::snt Of the 30 tests (data not shown), all but 1 received  P values > 0.05, and the one exception,  reductase constrained to the  ammonia ligase consensus, received a  P value of 0.0338.
# ::save-date Tue Dec 15, 2015 ::file bio_chicago_2015_75414.txt
(a / and
      :op1 (r / receive-01
            :ARG0 (t2 / test
                  :mod (a2 / all)
                  :ARG1-of (i / include-01
                        :ARG2 (t / test :quant 30
                              :ARG1-of (d2 / describe-01
                                    :ARG0 (d / data
                                          :ARG1-of (s / show-01 :polarity -)))))
                  :ARG2-of (e / except-01
                        :ARG1 (t3 / test :quant 1
                              :ARG1-of (m2 / mean-01
                                    :ARG2 (c / constrain-01
                                          :ARG0 (c2 / consent-01
                                                :ARG0 (e3 / enzyme :name (n2 / name :op1 "ammonia" :op2 "ligase")))
                                          :ARG1 (e2 / enzyme :name (n / name :op1 "reductase")))))))
            :ARG1 (s2 / statistical-test-91
                  :ARG1 t2
                  :ARG2 (m / more-than :op1 0.05)))
      :op2 (r2 / receive-01
            :ARG0 t3
            :ARG1 (s3 / statistical-test-91
                  :ARG1 t3
                  :ARG2 0.0338)))

# ::id bio.chicago_2015.75551 ::date 2015-11-05T08:06:35 ::annotator SDL-AMR-09 ::preferred
# ::snt GLP-1-(1-36)-amide and  GLP-1(1137)  synthetic peptides were iodinated by the  chloramine-T method.
# ::save-date Wed Nov 11, 2015 ::file bio_chicago_2015_75551.txt
(i / iodinate-00
      :ARG0 (m / method
            :mod (s2 / small-molecule :name (n3 / name :op1 "chloramine-T")))
      :ARG1 (a / and
            :op1 (p / peptide :name (n / name :op1 "GLP-1-(1-36)-amide"))
            :op2 (p2 / peptide :name (n2 / name :op1 "GLP-1(1137)"))
            :mod (s / synthetic)))

# ::id bio.chicago_2015.79572 ::date 2015-11-05T08:11:56 ::annotator SDL-AMR-09 ::preferred
# ::snt A strong FRET signal is detected from DABCYL-tagged PLCbeta2 in the presence of  coumarin-tagged prenylated betagamma complex.
# ::save-date Fri Nov 6, 2015 ::file bio_chicago_2015_79572.txt
(d / detect-01
      :ARG1 (s / signal-07
            :ARG0 (e / enzyme :name (n2 / name :op1 "PLCbeta2")
                  :ARG1-of (t2 / tag-01
                        :ARG0 (s3 / small-molecule :name (n3 / name :op1 "DABCYL"))))
            :ARG1 (t / thing :name (n / name :op1 "FRET"))
            :ARG1-of (s2 / strong-02))
      :condition (p / present-02
            :ARG1 (m / macro-molecular-complex
                  :part (p2 / protein :name (n4 / name :op1 "beta"))
                  :part (p3 / protein :name (n5 / name :op1 "gamma"))
                  :ARG1-of (p4 / prenylate-00)
                  :ARG1-of (t3 / tag-01
                        :ARG0 (s4 / small-molecule :name (n6 / name :op1 "coumarin"))))))

# ::id bio.chicago_2015.79887 ::date 2015-11-05T08:20:20 ::annotator SDL-AMR-09 ::preferred
# ::snt Elevated  A{beta}42 in Skeletal Muscle of  Alzheimer Disease Patients Suggests Peripheral Alterations of  A{beta}PP Metabolism.
# ::save-date Thu Dec 10, 2015 ::file bio_chicago_2015_79887.txt
(s / suggest-01
      :ARG0 (p / protein
            :name (n2 / name :op1 "A-beta" :op2 42)
            :ARG1-of (e / elevate-01)
            :location (m / muscle
                  :mod (s2 / skeleton)
                  :poss (p2 / person
                        :ARG0-of (h / have-rel-role-91
                              :ARG2 (p3 / patient))
                        :ARG0-of (h2 / have-03
                              :ARG1 (d / disease :wiki "Alzheimer's_disease"
                                    :name (n / name :op1 "Alzheimer" :op2 "disease"))))))
      :ARG1 (a / alter-01
            :ARG1 (m2 / metabolize-01
                  :ARG1 (p5 / protein
                        :name (n3 / name :op1 "A-beta" :op2 "PP")))
            :mod (p4 / peripheral)))

# ::id bio.chicago_2015.79978 ::date 2015-11-05T08:26:23 ::annotator SDL-AMR-09 ::preferred
# ::snt Cystic Fibrosis Phenotype Associated with  Pancreatic Insufficiency Does Not Always Reflect the cAMP-dependent Chloride Conductive Pathway Defect.
# ::save-date Sat Feb 13, 2016 ::file bio_chicago_2015_79978.txt
(r / reflect-01 :polarity -
      :ARG1 (p / phenotype
            :mod (d / disease :name (n / name :op1 "cystic" :op2 "fibrosis"))
            :ARG1-of (a / associate-01
                  :ARG2 (m2 / medical-condition :name (n2 / name :op1 "pancreatic" :op2 "insufficiency"))))
      :ARG2 (d3 / defect-01
            :ARG0 (p2 / pathway
                  :mod (s2 / small-molecule :name (n3 / name :op1 "chloride"))
                  :ARG1-of (c / conduct-03)
                  :ARG0-of (d4 / depend-01
                        :ARG1 (s / small-molecule :name (n4 / name :op1 "cAMP")))))
      :time (a2 / always))

# ::id bio.chicago_2015.80319 ::date 2015-11-05T08:34:49 ::annotator SDL-AMR-09 ::preferred
# ::snt Potential Mechanisms for Exacerbation of  Diabetic Retinopathy by  Hypertension.
# ::save-date Wed Nov 11, 2015 ::file bio_chicago_2015_80319.txt
(m / mechanism
      :mod (p / potential)
      :instrument-of (e / exacerbate-01
            :ARG0 (h / hypertension)
            :ARG1 (r / retinopathy
                  :mod (d / disease :name (n / name :op1 "diabetes")))))

# ::id bio.chicago_2015.80327 ::date 2015-11-05T08:36:39 ::annotator SDL-AMR-09 ::preferred
# ::snt D,  HT-induced phosphorylation of myrAkt  delta4-129-ER.
# ::save-date Mon Jan 4, 2016 ::file bio_chicago_2015_80327.txt
(p / phosphorylate-01 :li "D"
      :ARG1 (g / gene :name (n / name :op1 "myrAKT" :op2 "Delta4-129-ER"))
      :ARG2-of (i / induce-01
            :ARG0 (s / small-molecule :name (n2 / name :op1 "HT"))))

# ::id bio.chicago_2015.80330 ::date 2015-11-05T08:43:03 ::annotator SDL-AMR-09 ::preferred
# ::snt In vivo,  iNOS concentrations increase in parallel with  diabetes onset in a model of  T-cell transfer 69 and after  cyclophosphamide treatment of insulitic animals 70; moreover, an inhibitor of  iNOS activity can block  diabetes transfer 69.
# ::save-date Sun Nov 15, 2015 ::file bio_chicago_2015_80330.txt
(m / multi-sentence
      :snt1 (i2 / increase-01
            :ARG1 (c / concentrate-02
                  :ARG1 (e / enzyme :name (n / name :op1 "iNOS")))
            :manner (i3 / in-vivo)
            :ARG0-of (p / parallel-01
                  :ARG1 (o / onset
                        :mod (d4 / disease :name (n2 / name :op1 "diabetes"))))
            :location (m2 / model
                  :mod (t2 / transfer-01
                        :ARG1 (c2 / cell :name (n4 / name :op1 "T")))
                  :ARG1-of (d2 / describe-01
                        :ARG0 (p2 / publication
                              :ARG1-of (c3 / cite-01
                                    :ARG2 69))))
            :time (a / after
                  :op1 (t3 / treat-04
                        :ARG1 (a2 / animal
                              :mod (i4 / insulitic))
                        :ARG2 (s / small-molecule :name (n3 / name :op1 "cyclophosphamide")))
                  :ARG1-of (d3 / describe-01
                        :ARG0 (p3 / publication
                              :ARG1-of (c4 / cite-01
                                    :ARG2 70)))))
      :snt2 (a3 / and
            :op2 (p4 / possible-01
                  :ARG1 (b / block-01
                        :ARG0 (m3 / molecular-physical-entity
                              :ARG0-of (i5 / inhibit-01
                                    :ARG1 (a4 / activity-06
                                          :ARG0 (e2 / enzyme :name (n5 / name :op1 "iNOS")))))
                        :ARG1 (t4 / transfer-01
                              :ARG1 (d6 / disease :name (n6 / name :op1 "diabetes")))))
            :ARG1-of (d5 / describe-01
                  :ARG0 (p5 / publication
                        :ARG1-of (c5 / cite-01
                              :ARG2 69)))))

# ::id bio.chicago_2015.80669 ::date 2015-11-05T08:59:36 ::annotator SDL-AMR-09 ::preferred
# ::snt Consistent with this prediction, when families were divided into two groups according to the presence or absence in the probands of the risk allele of  SNP V26 (the most  significant SNP in BLOCK I), significance of the  schizophrenia associations with  BLOCK I SNPs V23-27 increased dramatically in families with the V26 risk allele present.
# ::save-date Sat Feb 13, 2016 ::file bio_chicago_2015_80669.txt
(i / increase-01
      :ARG1 (s / signify-01
            :ARG0 (a / associate-01
                  :ARG1 (m2 / medical-condition :name (n / name :op1 "schizophrenia"))
                  :ARG2 (p5 / polymorphism
                        :mod (n4 / nucleotide
                              :ARG1-of (s3 / single-02))
                        :mod (v / value-interval
                              :op1 (m3 / molecular-physical-entity
                                    :ARG1-of (s4 / substitute-01 :value "V23"))
                              :op2 (m4 / molecular-physical-entity
                                    :ARG1-of (s5 / substitute-01 :value "V27")))
                        :location b)))
      :ARG2 (d2 / dramatic)
      :location (f / family
            :ARG2-of (p / present-02
                  :ARG1 a2))
      :ARG1-of (c / consistent-01
            :ARG2 (t2 / thing
                  :ARG1-of (p2 / predict-01)
                  :mod (t3 / this)))
      :time (d3 / divide-02
            :ARG1 (f2 / family)
            :ARG2 (g / group :quant 2)
            :ARG1-of (a3 / accord-02
                  :ARG2 (o2 / or
                        :op1 (p3 / present-02
                              :ARG1 (a2 / allele
                                    :mod (r / risk)
                                    :mod (p6 / polymorphism
                                          :mod n4
                                          :ARG1-of (s2 / significant-02
                                                :degree (m / most)
                                                :location (b / block
                                                      :ord (o / ordinal-entity :value 1)))
                                          :mod (m5 / molecular-physical-entity
                                                :ARG1-of (s6 / substitute-01 :value "V26"))))
                              :ARG2 (p4 / proband))
                        :op2 (a4 / absent-01
                              :ARG1 a2
                              :ARG2 p4)))))

# ::id bio.chicago_2015.80727 ::date 2015-11-05T09:22:20 ::annotator SDL-AMR-09 ::preferred
# ::snt Mice and  rats with spontaneously occurring   Lepr mutations affecting the expression of all (  db3J,  dbPas,  faf, fa), or only one (  db), of the  LEPR isoforms have provided useful models for determining the physiological function(s) of  LEPR isoforms in various tissues.
# ::save-date Fri Feb 5, 2016 ::file bio_chicago_2015_80727.txt
(p / provide-01
      :ARG0 (a / and
            :op1 (m / mouse)
            :op2 (r / rat)
            :ARG0-of (h / have-03
                  :ARG1 (m2 / mutate-01
                        :ARG1 (p7 / protein :wiki "Leptin_receptor" :name (n / name :op1 "Lepr"))
                        :mod (s / spontaneous)
                        :ARG0-of (a2 / affect-01
                              :ARG1 (a3 / and
                                    :op1 (e / express-03
                                          :ARG2 (i / isoform
                                                :mod (a4 / all)
                                                :ARG1-of (m3 / mean-01
                                                      :ARG2 (a5 / and
                                                            :op1 (i6 / isoform :name (n2 / name :op1 "db3J"))
                                                            :op2 (i7 / isoform :name (n3 / name :op1 "dbPas"))
                                                            :op3 (i8 / isoform :name (n4 / name :op1 "faf"))
                                                            :op4 (i9 / isoform :name (n5 / name :op1 "fa"))))
                                                :ARG1-of (i4 / include-91
                                                      :ARG2 (i3 / isoform
                                                            :mod p7))))
                                    :op2 (e2 / express-03
                                          :ARG2 (i2 / isoform :quant 1
                                                :mod (o / only)
                                                :ARG1-of (m4 / mean-01
                                                      :ARG2 (i10 / isoform :name (n6 / name :op1 "db")))
                                                :ARG1-of i4)))))))
      :ARG1 (m5 / model
            :ARG1-of (u / useful-05
                  :ARG2 (d / determine-01
                        :ARG1 (f / function-01
                              :ARG0 (i5 / isoform
                                    :mod p7)
                              :mod (p8 / physiology)
                              :location (t / tissue
                                    :mod (v / various)))))))

# ::id bio.chicago_2015.80768 ::date 2015-11-05T09:26:37 ::annotator SDL-AMR-09 ::preferred
# ::snt Linkage and association of  tumor necrosis factor receptor 2 locus with  hypertension,  hypercholesterolemia and  plasma shed receptor.
# ::save-date Wed Nov 11, 2015 ::file bio_chicago_2015_80768.txt
(a / and
      :op1 (l / link-01
            :ARG1 (l2 / locus
                  :ARG0-of (c / contain-01
                        :ARG1 (p / protein :name (n / name :op1 "tumor" :op2 "necrosis" :op3 "factor" :op4 "receptor" :op5 "2"))))
            :ARG2 (a3 / and
                  :op1 (h / hypertension)
                  :op2 (h2 / hypercholesterolemia)
                  :op3 (p2 / protein :name (n2 / name :op1 "shed" :op2 "receptor")
                        :mod (p3 / plasma))))
      :op2 (a2 / associate-01
            :ARG1 l2
            :ARG2 a3))

# ::id bio.chicago_2015.80775 ::date 2015-11-06T00:13:21 ::annotator SDL-AMR-09 ::preferred
# ::snt However, little is known about how  chronic hypoxia and/or  pulmonary hypertension affect  PDE expression and activity.
# ::save-date Sun Nov 15, 2015 ::file bio_chicago_2015_80775.txt
(h / have-concession-91
      :ARG1 (k / know-01
            :ARG1 (t / thing
                  :manner-of (a / affect-01
                        :ARG0 (a2 / and-or
                              :op1 (h2 / hypoxia
                                    :mod (c / chronic))
                              :op2 (h3 / hypertension
                                    :mod (l2 / lung)))
                        :ARG1 (a3 / and
                              :op1 (e / express-03
                                    :ARG2 (e2 / enzyme :name (n / name :op1 "PDE")))
                              :op2 (a4 / activity-06
                                    :ARG0 e2)))
                  :degree (l / little))))

# ::id bio.chicago_2015.80886 ::date 2015-11-06T00:19:20 ::annotator SDL-AMR-09 ::preferred
# ::snt Association between  schizophrenia and  T102C polymorphism of the 5-hydroxytryptamine  type 2a-receptor gene.
# ::save-date Wed Nov 11, 2015 ::file bio_chicago_2015_80886.txt
(a / associate-01
      :ARG1 (s / schizophrenia)
      :ARG2 (p / polymorphism
            :mod (g / gene
                  :ARG0-of (e / encode-01
                        :ARG1 (p2 / protein :name (n / name :op1 "5-hydroxytryptamine" :op2 "type" :op3 "2a-receptor")))
                  :ARG1-of (m / mutate-01 :value "T102C"))))

# ::id bio.chicago_2015.80961 ::date 2015-11-06T00:22:53 ::annotator SDL-AMR-09 ::preferred
# ::snt PPL in the  NIDDM group resulted in the production of  TG rich lipoproteins, with AUC for  TG content of  HDL,  LDL and  VLDL being significantly greater in the  NIDDM group than controls ( Table 3).
# ::save-date Tue Jan 12, 2016 ::file bio_chicago_2015_80961.txt
(a3 / and
      :op1 (r / result-01
            :ARG1 (d4 / disease :wiki -
                  :name (n8 / name :op1 "postprandial" :op2 "lipaemia")
                  :location (g2 / group
                        :mod (d / disease :wiki "Diabetes_mellitus_type_2"
                              :name (n / name :op1 "diabetes" :op2 "mellitus" :op3 "type" :op4 2))))
            :ARG2 (p / produce-01
                  :ARG1 (p2 / protein :wiki "Lipoprotein"
                        :name (n3 / name :op1 "lipoprotein")
                        :mod (r2 / rich
                              :topic (s / small-molecule :wiki "Triglyceride"
                                    :name (n4 / name :op1 "triglyceride"))))))
      :op2 (h / have-03
            :ARG0 (c2 / contain-01
                  :ARG0 (a2 / and
                        :op1 (p3 / protein :wiki "Lipoprotein"
                              :name (n5 / name :op1 "lipoprotein")
                              :mod (d2 / density
                                    :ARG1-of (h2 / high-02)))
                        :op2 (p4 / protein :wiki "Lipoprotein"
                              :name (n6 / name :op1 "lipoprotein")
                              :mod (d5 / density
                                    :ARG1-of (l / low-04)))
                        :op3 (p5 / protein :wiki "Lipoprotein"
                              :name (n7 / name :op1 "lipoprotein")
                              :mod (d6 / density
                                    :ARG1-of (l2 / low-04
                                          :degree (v / very)))))
                  :ARG1 s)
            :ARG1 (a / area
                  :location (u / under
                        :op1 (c / curve)))
            :mod (g3 / great
                  :degree (m2 / more)
                  :ARG1-of (s2 / significant-02)
                  :location g2
                  :compared-to (c3 / control)))
      :ARG1-of (d3 / describe-01
            :ARG0 (t / table :mod 3)))

# ::id bio.chicago_2015.81024 ::date 2015-11-06T00:33:33 ::annotator SDL-AMR-09 ::preferred
# ::snt To examine this point,  tetanic stimulation of the  CF in current clamp mode was applied twice with a 5 min interval (  Figure 3).
# ::save-date Wed Nov 11, 2015 ::file bio_chicago_2015_81024.txt
(a / apply-02
      :ARG1 (s / stimulate-01
            :ARG1 (f2 / fiber
                  :ARG0-of (c4 / climb-01))
            :mod (t / tetanic)
            :manner (m / mode
                  :mod (c2 / clamp-01
                        :ARG1 (c3 / current))))
      :purpose (e / examine-01
            :ARG1 (p / point
                  :mod (t3 / this)))
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod 3))
      :frequency (r / rate-entity-91
            :ARG1 (t4 / twice)
            :ARG3 (i / interval
                  :duration (t2 / temporal-quantity :quant 5
                        :unit (m2 / minute)))))

# ::id bio.chicago_2015.81034 ::date 2015-11-06T00:43:17 ::annotator SDL-AMR-09 ::preferred
# ::snt In fact, our results indicate that DNA derived from the sputum  of patients with  cystic fibrosis initiates an  inflammatory response in the lower respiratory tract.
# ::save-date Thu Dec 10, 2015 ::file bio_chicago_2015_81034.txt
(i / indicate-01
      :ARG0 (t / thing
            :poss (w / we)
            :ARG2-of (r / result-01))
      :ARG1 (i2 / initiate-01
            :ARG0 (n3 / nucleic-acid :name (n4 / name :op1 "DNA")
                  :ARG1-of (d / derive-01
                        :ARG2 (s / sputum
                              :poss (p / person
                                    :ARG0-of (h / have-rel-role-91
                                          :ARG2 (p2 / patient))
                                    :ARG0-of (h2 / have-03
                                          :ARG1 (d2 / disease :name (n5 / name :op1 "cystic" :op2 "fibrosis")))))))
            :ARG1 (r2 / respond-01
                  :ARG2 (i3 / inflame-01))
            :location (t2 / tract
                  :ARG1-of (l / low-04
                        :degree (m / more))
                  :ARG0-of (r3 / respire-01)))
      :mod (i4 / in-fact))

# ::id bio.chicago_2015.81265 ::date 2015-11-06T00:48:43 ::annotator SDL-AMR-09 ::preferred
# ::snt After exclusion of subjects who were being treated for  hypertension,  hypercholesterolemia, or  diabetes, substitution of  SBP,  HDL and  LDL cholesterol, and blood glucose levels for  hypertension,  hypercholesterolemia, and  diabetes, respectively, yielded very close results.
# ::save-date Wed Nov 11, 2015 ::file bio_chicago_2015_81265.txt
(y / yield-01
      :ARG0 (a / and
            :op1 (s / substitute-01
                  :ARG1 (p / pressure-01
                        :ARG0 b
                        :mod (s11 / systole))
                  :ARG2 (h / hypertension))
            :op2 (s3 / substitute-01
                  :ARG1 (a2 / and
                        :op1 (s4 / small-molecule :name (n2 / name :op1 "HDL" :op2 "cholesterol"))
                        :op2 (s5 / small-molecule :name (n3 / name :op1 "LDL" :op2 "cholesterol")))
                  :ARG2 (h2 / hypercholesterolemia))
            :op3 (s6 / substitute-01
                  :ARG1 (l3 / level
                        :quant-of (s7 / small-molecule :name (n5 / name :op1 "glucose")
                              :mod (b / blood)))
                  :ARG2 (d / disease :name (n / name :op1 "diabetes")))
            :manner (r2 / respective))
      :ARG1 (t / thing
            :ARG2-of (r / result-01)
            :ARG1-of (c / close-10
                  :degree (v / very)))
      :time (a3 / after
            :op1 (e / exclude-01
                  :ARG1 (o / or
                        :op1 (s8 / subject
                              :ARG1-of (t2 / treat-03
                                    :ARG2 h))
                        :op2 (s9 / subject
                              :ARG1-of (t3 / treat-03
                                    :ARG2 h2))
                        :op3 (s10 / subject
                              :ARG1-of (t4 / treat-03
                                    :ARG2 d))))))

# ::id bio.chicago_2015.81467 ::date 2015-11-06T01:07:49 ::annotator SDL-AMR-09 ::preferred
# ::snt Neutrophil elastase in respiratory epithelial lining fluid of individuals with  cystic fibrosis induces  interleukin-8 gene expression in a  human bronchial epithelial cell line.
# ::save-date Thu Dec 10, 2015 ::file bio_chicago_2015_81467.txt
(i / induce-01
      :ARG0 (e / enzyme :name (n / name :op1 "neutrophil" :op2 "elastase")
            :location (f / fluid
                  :ARG0-of (l / line-01
                        :ARG1 (e2 / epithelium
                              :ARG0-of (r / respire-01)
                              :part-of (i2 / individual
                                    :ARG0-of (h / have-03
                                          :ARG1 (d / disease :name (n2 / name :op1 "cystic" :op2 "fibrosis"))))))))
      :ARG2 (e3 / express-03
            :ARG1 (g / gene
                  :ARG0-of (e4 / encode-01
                        :ARG1 (p / protein :name (n3 / name :op1 "interleukin-8"))))
            :ARG3 (c / cell-line
                  :part-of (e5 / epithelium
                        :part-of (b / bronchus
                              :mod (h2 / human))))))

# ::id bio.chicago_2015.81509 ::date 2015-11-06T01:15:45 ::annotator SDL-AMR-09 ::preferred
# ::snt Hypertension Associated with  Decreased Testosterone Levels in  Natriuretic Peptide Receptor-A Gene-Knockout and Gene-Duplicated  Mutant Mouse Models.
# ::save-date Sun Nov 15, 2015 ::file bio_chicago_2015_81509.txt
(a / associate-01
      :ARG1 (h / hypertension)
      :ARG2 (l / level
            :ARG1-of (d / decrease-01)
            :quant-of (s / small-molecule :name (n / name :op1 "testosterone")))
      :location (a2 / and
            :op1 (m / model
                  :mod (m5 / mouse
                        :mod (g / gene
                              :ARG0-of (e / encode-01
                                    :ARG1 (p / protein :name (n2 / name :op1 "natriuretic" :op2 "peptide" :op3 "receptor-A")))
                              :ARG1-of (k / knock-out-03))
                        :ARG1-of m4))
            :op2 (m2 / model
                  :mod (m3 / mouse
                        :ARG2-of (m4 / mutate-01)
                        :mod (g3 / gene
                              :ARG1-of (d2 / duplicate-01))))))

# ::id bio.chicago_2015.81555 ::date 2015-11-06T01:23:08 ::annotator SDL-AMR-09 ::preferred
# ::snt APL modulation of spontaneous  diabetes in  NOD mice.
# ::save-date Sun Nov 15, 2015 ::file bio_chicago_2015_81555.txt
(m / modulate-01
      :ARG0 (p / protein :name (n / name :op1 "APL"))
      :ARG1 (d2 / disease :name (n2 / name :op1 "diabetes")
            :mod (s / spontaneous))
      :location (m2 / mouse
            :mod (o / obese :polarity -)
            :mod d2))

# ::id bio.chicago_2015.81850 ::date 2015-11-06T01:26:36 ::annotator SDL-AMR-09 ::preferred
# ::snt Refractory  hypertension is associated with the  haptoglobin 2-2 phenotype.
# ::save-date Fri Nov 6, 2015 ::file bio_chicago_2015_81850.txt
(a / associate-01
      :ARG1 (h / hypertension
            :mod (r / refractory))
      :ARG2 (p / phenotype
            :mod (p2 / protein :name (n / name :op1 "haptoglobin" :op2 "2-2"))))

# ::id bio.chicago_2015.81979 ::date 2015-11-06T01:27:59 ::annotator SDL-AMR-09 ::preferred
# ::snt 14 Studies in  men revealed a dose-dependent vasodilation of forearm arterioles in healthy subjects as well as in patients with  essential hypertension, which was inhibited by the  NOS inhibitor L-NMMA.
# ::save-date Thu Dec 10, 2015 ::file bio_chicago_2015_81979.txt
(r / reveal-01
      :ARG0 (s / study-01 :quant 14
            :ARG1 (m / man))
      :ARG1 (d3 / dilate-01
            :ARG1 (a / arteriole
                  :part-of (f / forearm))
            :ARG0-of (d / depend-01
                  :ARG1 (d2 / dose-01))
            :ARG1-of (i / inhibit-01
                  :ARG0 (s3 / small-molecule :name (n / name :op1 "L-NMMA")
                        :ARG0-of (i2 / inhibit-01
                              :ARG1 (e2 / enzyme :name (n2 / name :op1 "NOS"))))))
      :location (a2 / and
            :op1 (s2 / subject
                  :mod (h / healthy))
            :op2 (p / person
                  :ARG0-of (h2 / have-rel-role-91
                        :ARG2 (p2 / patient))
                  :ARG0-of (h3 / have-03
                        :ARG1 (h4 / hypertension
                              :mod (e / essential))))))

# ::id bio.chicago_2015.82087 ::date 2015-11-06T01:34:30 ::annotator SDL-AMR-09 ::preferred
# ::snt Subgroup analysis on  men showed a significant association of  tPA and  diabetes, smoking,  hypertension, BMI, cholesterol, and  apoA-I in multivariate conditional logistic regression, whereas no significant association could be shown when  PAI-1,  vWF,  TM, or DHEAS was included in the model (data not shown).
# ::save-date Wed Nov 11, 2015 ::file bio_chicago_2015_82087.txt
(c / contrast-01
      :ARG1 (s / show-01
            :ARG0 (a / analyze-01
                  :ARG1 (m / man
                        :mod (s2 / subgroup)))
            :ARG1 (a2 / associate-01
                  :ARG1 (e / enzyme :name (n / name :op1 "tPA"))
                  :ARG2 (a3 / and
                        :op1 (d4 / disease :name (n8 / name :op1 "diabetes"))
                        :op2 (s4 / smoke-02)
                        :op3 (h / hypertension)
                        :op4 (i2 / index-01
                              :ARG1 (m4 / mass
                                    :mod (b2 / body)))
                        :op5 (s5 / small-molecule :name (n2 / name :op1 "cholesterol"))
                        :op6 (p2 / protein :name (n3 / name :op1 "apoA-I")))
                  :ARG1-of (s3 / significant-02))
            :condition (r / regress-01
                  :mod (l / logistic)
                  :mod (c2 / condition)
                  :mod (m2 / multivariate)))
      :ARG2 (p / possible-01 :polarity -
            :ARG1 (s6 / show-01
                  :ARG1 (a4 / associate-01
                        :ARG1-of (s7 / significant-02)))
            :time (i / include-01
                  :ARG1 (o / or
                        :op1 (p3 / protein :name (n4 / name :op1 "PAI-1"))
                        :op2 (p4 / protein :name (n5 / name :op1 "vWF"))
                        :op3 (p5 / protein :name (n6 / name :op1 "TM"))
                        :op4 (s8 / small-molecule :name (n7 / name :op1 "DHEAS")))
                  :ARG2 (m3 / model)))
      :ARG1-of (d2 / describe-01
            :ARG0 (d3 / data
                  :ARG1-of (s9 / show-01 :polarity -))))

# ::id bio.chicago_2015.82191 ::date 2015-11-06T01:45:18 ::annotator SDL-AMR-09 ::preferred
# ::snt The observation that the hypophosphorylated  CUG-BP/ hNab50 form (CUG-BP2) was accumulated in the nuclei of patients with  DM (containing low levels of  DMPK) suggested that  DMPK activity may be required for  CUG-BP/ hNab50 phosphorylation.
# ::save-date Thu Dec 10, 2015 ::file bio_chicago_2015_82191.txt
(s / suggest-01
      :ARG0 (o / observe-01
            :ARG1 (a / accumulate-01
                  :ARG0 (n2 / nucleus
                        :poss (p3 / person
                              :ARG0-of (h / have-rel-role-91
                                    :ARG2 (p4 / patient))
                              :ARG0-of (h2 / have-03
                                    :ARG1 (d / dystrophy
                                          :mod (m / myotonic))))
                        :ARG0-of (c2 / contain-01
                              :ARG1 (l2 / level
                                    :ARG1-of (l3 / low-04)
                                    :quant-of (e / enzyme :name (n3 / name :op1 "DMPK")))))
                  :ARG1 (p2 / protein :name (n / name :op1 "CUG-BP/hNab50")
                        :ARG1-of (l / label-01
                              :ARG2 (n5 / name :op1 "CUG-BP2"))
                        :ARG1-of (h3 / hypophosphorylate-00))))
      :ARG1 (p5 / possible-01
            :ARG1 (r / require-01
                  :ARG0 (p / phosphorylate-01
                        :ARG1 p2)
                  :ARG1 (a2 / activity-06
                        :ARG0 e))))

# ::id bio.chicago_2015.82428 ::date 2015-11-06T01:58:16 ::annotator SDL-AMR-09 ::preferred
# ::snt These studies provide compelling support for the view that one mechanism by which these  mutant PS1 cause AD is by increasing the extracellular concentration of A  peptides terminating at 42(43), species that foster A  deposition.
# ::save-date Sun Nov 15, 2015 ::file bio_chicago_2015_82428.txt
(p / provide-01
      :ARG0 (s / study-01
            :mod (t / this))
      :ARG1 (s2 / support-01
            :ARG0 s
            :ARG1 (v / view-02
                  :ARG1 (m / mechanism :quant 1
                        :instrument-of (c2 / cause-01
                              :ARG0 (p2 / protein
                                    :name (n / name :op1 "PS1")
                                    :ARG1-of (m2 / mutate-01)
                                    :mod t)
                              :ARG1 (d2 / disease :wiki "Alzheimer's_disease"
                                    :name (n3 / name :op1 "Alzheimer's")))
                        :domain (i / increase-01
                              :ARG0 p2
                              :ARG1 (c3 / concentrate-02
                                    :ARG1 (p3 / protein-segment
                                          :name (n2 / name :op1 "Abeta" :op2 "peptide")
                                          :ARG1-of (t2 / terminate-01
                                                :location (a2 / amino-acid :mod 42))
                                          :mod (s3 / species
                                                :ARG0-of (f / foster-01
                                                      :ARG1 (d / depose-03
                                                            :ARG1 p3))))
                                    :mod (e / extracellular))
                              :ARG1-of (d3 / describe-01
                                    :ARG0 (p4 / publication
                                          :ARG1-of (c4 / cite-01 :ARG2 43))))))
            :ARG0-of (c / compel-01)))

# ::id bio.chicago_2015.83036 ::date 2015-11-06T02:10:09 ::annotator SDL-AMR-09 ::preferred
# ::snt Mutation of the  beta-amyloid precursor protein in  familial Alzheimer's disease increases  beta-protein production.
# ::save-date Fri Nov 6, 2015 ::file bio_chicago_2015_83036.txt
(i / increase-01
      :ARG0 (m / mutate-01
            :ARG1 (p / protein :name (n2 / name :op1 "beta-amyloid" :op2 "precursor"))
            :location (d / disease :wiki "Alzheimer's_disease" :name (n / name :op1 "Alzheimer")
                  :mod (f / family)))
      :ARG1 (p2 / produce-01
            :ARG1 (p3 / protein :name (n4 / name :op1 "beta"))))

# ::id bio.chicago_2015.83072 ::date 2015-11-06T02:12:04 ::annotator SDL-AMR-09 ::preferred
# ::snt Wnt/{ beta}-Catenin/ cf Signaling Induces the Transcription of  Axin2, a  Negative Regulator of the Signaling Pathway.
# ::save-date Fri Nov 6, 2015 ::file bio_chicago_2015_83072.txt
(i / induce-01
      :ARG0 (s / signal-07
            :ARG0 (p / pathway :name (n / name :op1 "Wnt/beta-catenin/Tcf")))
      :ARG2 (t / transcribe-01
            :ARG1 (p2 / protein :name (n2 / name :op1 "Axin2")
                  :ARG2-of (d / downregulate-01
                        :ARG1 p))))

# ::id bio.chicago_2015.83176 ::date 2015-11-06T02:16:33 ::annotator SDL-AMR-09 ::preferred
# ::snt Insulin-dependent  diabetes mellitus (IDDM) is associated with  CTLA4 polymorphisms in multiple ethnic groups.
# ::save-date Sun Jan 17, 2016 ::file bio_chicago_2015_83176.txt
(a / associate-01
      :ARG1 (d3 / disease :name (n2 / name :op1 "diabetes")
            :mod (m / mellitus)
            :ARG0-of (d2 / depend-01
                  :ARG1 (p3 / protein :name (n3 / name :op1 "insulin")))
            :ARG1-of (l / label-01
                  :ARG2 (n4 / name :op1 "IDDM")))
      :ARG2 (p / polymorphism
            :mod (p2 / protein :name (n / name :op1 "CTLA4")))
      :location (e2 / ethnic-group
            :mod (m2 / multiple)))

# ::id bio.chicago_2015.83187 ::date 2015-11-06T02:19:16 ::annotator SDL-AMR-09 ::preferred
# ::snt Although the underlying mechanisms remain unknown, based on our results that A , an AD-related molecule,  upregulated SCD-1 in macrophages, it can be considered that there is a link between  SCD-1 and AD.
# ::save-date Wed Nov 11, 2015 ::file bio_chicago_2015_83187.txt
(h / have-concession-91
      :ARG1 (p / possible-01
            :ARG1 (c / consider-01
                  :ARG1 (l / link-01
                        :ARG1 (p2 / protein
                              :name (n / name :op1 "SCD-1"))
                        :ARG2 (d / disease :wiki "Alzheimer's_disease"
                              :name (n3 / name :op1 "Alzheimer's"))))
            :ARG1-of (b / base-02
                  :ARG2 (t / thing
                        :ARG2-of (r2 / result-01)
                        :poss (w / we)
                        :topic (u2 / upregulate-01
                              :ARG1 p2
                              :ARG2 (p3 / protein
                                    :name (n2 / name :op1 "Abeta")
                                    :ARG1-of (r3 / relate-01
                                          :ARG2 d))
                              :location (m2 / macrophage)))))
      :ARG2 (r / remain-01
            :ARG1 (m / mechanism
                  :ARG0-of (u / underlie-01))
            :ARG3 (k / know-01 :polarity -
                  :ARG1 m)))

# ::id bio.chicago_2015.83472 ::date 2015-11-06T02:28:11 ::annotator SDL-AMR-09 ::preferred
# ::snt The column, absorbed with   bc1 complexes, was then subjected to a sequence of washings with  TN buffer (50 mM Tris-Cl (pH 8.0 at 4  degrees C) and 200 mM NaCl) containing  0.01% DM,  TN buffer containing 5  mM histidine and 0.01%  DM, and  TN buffer containing 5  mM histidine and 0.5% octyl glucoside.
# ::save-date Wed Nov 11, 2015 ::file bio_chicago_2015_83472.txt
(s / subject-01
      :ARG1 (c / column
            :ARG0-of (a2 / absorb-01
                  :ARG1 (m4 / macro-molecular-complex :name (n2 / name :op1 "bc1"))))
      :ARG2 (s2 / sequence
            :consist-of (a3 / and
                  :op1 (w / wash-01
                        :ARG1 c
                        :ARG2 (b / buffer
                              :mod (s3 / small-molecule :name (n3 / name :op1 "TN")
                                    :consist-of (a4 / and
                                          :op1 (s5 / small-molecule :name (n / name :op1 "tris(hydroxymethyl)aminomethane")
                                                :quant (c3 / concentration-quantity :quant 50
                                                      :unit (m5 / millimolar))
                                                :mod (a5 / acidity-quantity :quant 8.0
                                                      :scale (p4 / ph))
                                                :mod (t / temperature-quantity :quant 4
                                                      :scale (c5 / celsius)))
                                          :op2 (s6 / small-molecule :name (n5 / name :op1 "sodium" :op2 "chloride")
                                                :quant (c4 / concentration-quantity :quant 200
                                                      :unit m5))))
                              :ARG0-of (c2 / contain-01
                                    :ARG1 (s4 / small-molecule :name (n4 / name :op1 "DM")
                                          :quant (p2 / percentage-entity :value 0.01)))))
                  :op2 (w2 / wash-01
                        :ARG1 c
                        :ARG2 (b2 / buffer
                              :mod s3
                              :ARG0-of (c6 / contain-01
                                    :ARG1 (a6 / and
                                          :op1 (a7 / amino-acid :name (n7 / name :op1 "histidine")
                                                :quant (c8 / concentration-quantity :quant 5
                                                      :unit m5))
                                          :op2 s4))))
                  :op3 (w3 / wash-01
                        :ARG1 c
                        :ARG2 (b3 / buffer
                              :mod s3
                              :ARG0-of (c7 / contain-01
                                    :ARG1 (a8 / and
                                          :op1 a7
                                          :op2 (s7 / small-molecule :name (n8 / name :op1 "octyl" :op2 "glucoside")
                                                :quant (p5 / percentage-entity :value 0.5))))))))
      :time (t2 / then))

# ::id bio.chicago_2015.83519 ::date 2015-11-06T02:56:33 ::annotator SDL-AMR-09 ::preferred
# ::snt Reduced second phase insulin secretion in carriers of a  sulphonylurea receptor gene variant associating with  Type II diabetes mellitus.
# ::save-date Sun Jan 17, 2016 ::file bio_chicago_2015_83519.txt
(s / secrete-01
      :ARG0 (p2 / person
            :ARG0-of (c / carry-01
                  :ARG1 (v / vary-01
                        :ARG1 (g / gene
                              :ARG0-of (e / encode-01
                                    :ARG1 (p3 / protein :name (n / name :op1 "sulphonylurea" :op2 "receptor")))))))
      :ARG1 (p4 / protein :name (n2 / name :op1 "insulin"))
      :ARG1-of (r / reduce-01)
      :time (p / phase
            :ord (o2 / ordinal-entity :value 2))
      :ARG1-of (a / associate-01
            :ARG2 (d2 / disease :name (n3 / name :op1 "diabetes")
                  :mod (m / mellitus)
                  :mod (t / type
                        :ord o2))))

# ::id bio.chicago_2015.83813 ::date 2015-11-06T03:03:37 ::annotator SDL-AMR-09 ::preferred
# ::snt In  humans,  insulin-receptor mutations cause  diabetes rather than longevity; however, these mutations lead ultimately to a severe loss of insulin production and so may not mimic the weak signalling mutations of   C. elegans.
# ::save-date Sun Jan 17, 2016 ::file bio_chicago_2015_83813.txt
(h / have-concession-91
      :ARG1 (a / and
            :op1 (l2 / lead-03
                  :ARG0 m
                  :ARG2 (l3 / lose-01
                        :ARG1 (p2 / produce-01
                              :ARG1 (p4 / protein :name (n3 / name :op1 "insulin")))
                        :ARG2 (s / severe))
                  :time (u / ultimate))
            :op2 (p3 / possible-01
                  :ARG1 (m2 / mimic-01 :polarity -
                        :ARG0 m
                        :ARG1 (m3 / mutate-01
                              :ARG1 (o / organism :name (n2 / name :op1 "C" :op2 "elegan"))
                              :ARG1-of (w / weak-02)
                              :ARG0-of (s2 / signal-07)))
                  :ARG1-of (c2 / cause-01
                        :ARG0 l3)))
      :ARG2 (c / cause-01
            :ARG0 (m / mutate-01
                  :ARG1 (p / protein :name (n / name :op1 "insulin" :op2 "receptor")))
            :ARG1 (d2 / diabetes
                  :ARG1-of (i / instead-of-91
                        :ARG2 (l / longevity)))
            :location (h2 / human)))

# ::id bio.chicago_2015.83846 ::date 2015-11-06T03:12:15 ::annotator SDL-AMR-09 ::preferred
# ::snt We conclude that lack of  HNF-6 results in  diabetes.
# ::save-date Wed Nov 11, 2015 ::file bio_chicago_2015_83846.txt
(c / conclude-01
      :ARG0 (w / we)
      :ARG1 (r / result-01
            :ARG1 (l / lack-01
                  :ARG1 (p / protein :name (n / name :op1 "HNF-6")))
            :ARG2 (d2 / disease :name (n2 / name :op1 "diabetes"))))

# ::id bio.chicago_2015.83848 ::date 2015-11-06T03:13:37 ::annotator SDL-AMR-09 ::preferred
# ::snt Early-onset type-II diabetes mellitus (MODY4) linked to  IPF-1.
# ::save-date Sun Nov 15, 2015 ::file bio_chicago_2015_83848.txt
(l / link-01
      :ARG1 (d2 / disease :name (n2 / name :op1 "diabetes")
            :mod (m / mellitus)
            :mod (o / onset
                  :time (e / early))
            :mod (t / type
                  :ord (o2 / ordinal-entity :value 2))
            :ARG1-of (l2 / label-01
                  :ARG2 (n3 / name :op1 "MODY4")))
      :ARG2 (p / protein :name (n / name :op1 "IPF-1")))

# ::id bio.chicago_2015.84036 ::date 2015-11-06T03:15:44 ::annotator SDL-AMR-09 ::preferred
# ::snt Two Novel Mutations of the  Vasopressin Gene Associated with  Familial Diabetes Insipidus and Identification of an Asymptomatic Carrier Infant.
# ::save-date Mon Jan 4, 2016 ::file bio_chicago_2015_84036.txt
(a / associate-01
      :ARG1 (m / mutate-01 :quant 2
            :ARG1 (g / gene
                  :ARG0-of (e / encode-01
                        :ARG1 (s / small-molecule :name (n2 / name :op1 "vasopressin"))))
            :mod (n / novel))
      :ARG2 (a2 / and
            :op1 (d / disease :name (n4 / name :op1 "familial" :op2 "diabetes"))
            :op2 (i2 / identify-01
                  :ARG1 (i3 / infant
                        :mod (s2 / symptom :polarity -)
                        :mod (c / carrier
                              :mod m)))))

# ::id bio.chicago_2015.84144 ::date 2015-11-06T03:18:45 ::annotator SDL-AMR-09 ::preferred
# ::snt Confirmation of the genetic association of  interleukin-1A with early onset sporadic  Alzheimer's disease.
# ::save-date Wed Nov 11, 2015 ::file bio_chicago_2015_84144.txt
(c / confirm-01
      :ARG1 (a / associate-01
            :ARG1 (p / protein :name (n2 / name :op1 "interleukin-1A"))
            :ARG2 (d / disease :wiki "Alzheimer's_disease" :name (n / name :op1 "Alzheimer")
                  :mod (o / onset
                        :time (e / early))
                  :mod (s / sporadic))
            :mod (g / gene)))

# ::id bio.chicago_2015.84177 ::date 2015-11-06T03:20:03 ::annotator SDL-AMR-09 ::preferred
# ::snt Specifically,  LTD was induced by low-frequency pairing of  CF and  PF activity, while  PF-mediated Ca2+ signals were measured following  high-frequency PF activity.
# ::save-date Sun Nov 15, 2015 ::file bio_chicago_2015_84177.txt
(c2 / contrast-01
      :ARG1 (i2 / induce-01
            :ARG0 (p / pair-01
                  :ARG1 (a / activity-06
                        :ARG0 (f4 / fiber
                              :ARG0-of (c / climb-01)))
                  :ARG2 (a2 / activity-06
                        :ARG0 (f5 / fiber
                              :mod (p3 / parallel)))
                  :mod (f / frequency
                        :ARG1-of (l2 / low-04)))
            :ARG2 (d / depress-01
                  :ARG1 (s4 / synapse)
                  :duration (t / term
                        :ARG1-of (l3 / long-03))))
      :ARG2 (m / measure-01
            :ARG1 (s / signal-07
                  :ARG0 (s2 / small-molecule :name (n / name :op1 "calcium")
                        :ARG1-of (i / ionize-01 :value "2+"))
                  :ARG1-of (m2 / mediate-01
                        :ARG0 f5))
            :ARG1-of (f2 / follow-01
                  :ARG2 (a3 / activity-06
                        :ARG0 f5
                        :mod (f3 / frequency
                              :ARG1-of (h / high-02)))))
      :ARG1-of (s3 / specific-02))

# ::id bio.chicago_2015.84183 ::date 2015-11-06T03:27:30 ::annotator SDL-AMR-09 ::preferred
# ::snt The distribution of  DR4 haplotypes in Sardinia suggests a primary association of  type I diabetes with  DRB1 and  DQB1 loci.
# ::save-date Wed Nov 11, 2015 ::file bio_chicago_2015_84183.txt
(s / suggest-01
      :ARG0 (d / distribute-01
            :ARG1 (h / haplotype
                  :mod (p / protein :name (n / name :op1 "DR4")))
            :location (c / country-region :name (n2 / name :op1 "Sardinia")))
      :ARG1 (a / associate-01
            :ARG1 (d3 / disease :name (n5 / name :op1 "diabetes")
                  :mod (t / type
                        :ord (o / ordinal-entity :value 1)))
            :ARG2 (a2 / and
                  :op1 (l / locus
                        :mod (g / gene :name (n3 / name :op1 "DRB1")))
                  :op2 (l2 / locus
                        :mod (g2 / gene :name (n4 / name :op1 "DQB1"))))
            :mod (p2 / primary)))

# ::id bio.chicago_2015.84212 ::date 2015-11-06T01:51:06 ::annotator SDL-AMR-09 ::preferred
# ::snt The identification of    APP,   PS1, and   PS2 mutations associated with hereditary  Alzheimer's disease [  34] has increased our understanding of its molecular basis [  32].
# ::save-date Fri Jan 15, 2016 ::file bio_chicago_2015_84212.txt
(i / increase-01
      :ARG0 (i2 / identify-01
            :ARG1 (m / mutate-01
                  :ARG1 (a / and
                        :op1 (p3 / protein :name (n2 / name :op1 "APP"))
                        :op2 (p4 / protein :name (n3 / name :op1 "PS1"))
                        :op3 (p5 / protein :name (n4 / name :op1 "PS2")))
                  :ARG1-of (a2 / associate-01
                        :ARG2 (d / disease :wiki "Alzheimer's_disease" :name (n / name :op1 "Alzheimer")
                              :mod (h / hereditary))
                        :ARG1-of (d2 / describe-01
                              :ARG0 (p / publication
                                    :ARG1-of (c / cite-01
                                          :ARG2 34))))))
      :ARG1 (u / understand-01
            :ARG0 (w / we)
            :ARG1 (b / basis
                  :mod (m2 / molecule)
                  :poss d))
      :ARG1-of (d3 / describe-01
            :ARG0 (p2 / publication
                  :ARG1-of (c2 / cite-01
                        :ARG2 32))))

# ::id bio.chicago_2015.84243 ::date 2015-11-08T06:31:12 ::annotator SDL-AMR-09 ::preferred
# ::snt No association between  DLST gene and  Alzheimer s disease or  Wernicke - Korsakoff syndrome.
# ::save-date Sun Nov 8, 2015 ::file bio_chicago_2015_84243.txt
(a / associate-01 :polarity -
      :ARG1 (g / gene :name (n2 / name :op1 "DLST"))
      :ARG2 (o / or
            :op1 (d / disease :wiki "Alzheimer's_disease" :name (n / name :op1 "Alzheimer"))
            :op2 (d2 / disease :name (n3 / name :op1 "Wernicke-Kirsakoff" :op2 "syndrome"))))

# ::id bio.chicago_2015.84567 ::date 2015-11-08T06:50:49 ::annotator SDL-AMR-09 ::preferred
# ::snt A mutation in the  insulin 2 gene induces  diabetes with severe pancreatic  beta-cell dysfunction in the  Mody mouse.
# ::save-date Tue Nov 10, 2015 ::file bio_chicago_2015_84567.txt
(i / induce-01
      :ARG0 (m / mutate-01
            :ARG1 (g / gene :name (n / name :op1 "insulin" :op2 "2"))
            :ARG0-of (c / cause-01
                  :ARG1 (f / function-01 :polarity -
                        :ARG1 (c2 / cell :name (n3 / name :op1 "beta-cell")
                              :mod (p / pancreas))
                        :degree (s / severe)
                        :location (o / organism :name (n4 / name :op1 "Mody" :op2 "mouse")))))
      :ARG2 (d / disease :name (n2 / name :op1 "diabetes")))

# ::id bio.chicago_2015.84636 ::date 2015-11-08T06:57:44 ::annotator SDL-AMR-09 ::preferred
# ::snt The   ob gene and  leptin  Recessive mutations in the  mouse  obese (  ob) and   diabetes ( db) genes result in  obesity and  diabetes in a  syndrome resembling morbid  human obesity 3, 7.
# ::save-date Sun Jan 17, 2016 ::file bio_chicago_2015_84636.txt
(m3 / multi-sentence
      :snt1 (a3 / and
            :op1 (g / gene :name (n / name :op1 "ob"))
            :op2 (p2 / protein :name (n3 / name :op1 "leptin")))
      :snt2 (r / result-01
            :ARG1 (m / mutate-01
                  :ARG1 (a2 / and
                        :op1 (g3 / gene
                              :mod m2
                              :mod m6)
                        :op2 (g2 / gene
                              :mod (m2 / mouse)
                              :mod d2))
                  :ARG0-of (r2 / recede-01))
            :ARG2 (a / and
                  :op1 (m6 / medical-condition :name (n5 / name :op1 "obesity"))
                  :op2 (d2 / disease :name (n6 / name :op1 "diabetes"))
                  :ARG1-of (m4 / mean-01
                        :ARG2 (s2 / syndrome
                              :ARG1-of (r3 / resemble-01
                                    :ARG2 (m7 / medical-condition :name (n7 / name :op1 "obesity")
                                          :mod (h / human)
                                          :mod (m5 / morbid))))))
            :ARG1-of (d4 / describe-01
                  :ARG0 (p / publication
                        :ARG1-of (c / cite-01
                              :ARG2 (a4 / and :op1 3 :op2 7))))))

# ::id bio.chicago_2015.84698 ::date 2015-11-08T07:20:08 ::annotator SDL-AMR-09 ::preferred
# ::snt Lane 1,  GST-Grb2;   lane 2,  GST only;   lane 3,  GST-neuron isoform (containing exons AD); and   lane 4,  GST-astrocyte isoform (containing  exons BD).
# ::save-date Sun Nov 8, 2015 ::file bio_chicago_2015_84698.txt
(a / and
      :op1 (m / macro-molecular-complex
            :location (l / lane :mod 1)
            :part (e2 / enzyme :name (n / name :op1 "GST"))
            :part (p / protein :name (n3 / name :op1 "Grb2")))
      :op2 (e / enzyme :name (n2 / name :op1 "GST")
            :mod (o / only)
            :location (l2 / lane :mod 2))
      :op3 (i / isoform :name (n4 / name :op1 "GST-neuron")
            :ARG0-of (c / contain-01
                  :ARG1 (e3 / exon :name (n5 / name :op1 "AD")))
            :location (l3 / lane :mod 3))
      :op4 (i2 / isoform :name (n6 / name :op1 "GST-astrocyte")
            :ARG0-of (c2 / contain-01
                  :ARG1 (e4 / exon :name (n7 / name :op1 "BD")))
            :location (l4 / lane :mod 4)))

# ::id bio.chicago_2015.84741 ::date 2015-11-08T07:33:13 ::annotator SDL-AMR-09 ::preferred
# ::snt A P387L Variant in  Protein Tyrosine Phosphatase-1B (PTP-1B) Is  Associated With Type 2 Diabetes and  Impaired Serine Phosphorylation of  PTP-1B In Vitro.
# ::save-date Sun Nov 8, 2015 ::file bio_chicago_2015_84741.txt
(a2 / associate-01
      :ARG1 (p3 / protein-segment
            :name (n4 / name :op1 "P387L")
            :part-of (p2 / protein
                  :name (n3 / name :op1 "Tyrosine" :op2 "Phosphatase-1B")))
      :ARG2 (a3 / and
            :op1 (d / disease :wiki "Diabetes_mellitus_type_2"
                  :name (n / name :op1 "type" :op2 2 :op3 "diabetes"))
            :op2 (p / phosphorylate-01
                  :ARG1 (a / amino-acid
                        :name (n2 / name :op1 "serine")
                        :part-of p2)
                  :ARG1-of (i / impair-01)
                  :manner (i2 / in-vitro))))

# ::id bio.chicago_2015.85035 ::date 2015-11-08T07:47:05 ::annotator SDL-AMR-09 ::preferred
# ::snt Dominant negative mutations in  human PPARgamma associated with severe  insulin resistance,  diabetes mellitus and  hypertension.
# ::save-date Fri Feb 5, 2016 ::file bio_chicago_2015_85035.txt
(a / associate-01
      :ARG1 (m / mutate-01 :mod "-/-"
            :ARG1 (p / protein :name (n / name :op1 "PPARgamma")
                  :mod (h / human))
            :ARG0-of (d / dominate-01))
      :ARG2 (a2 / and
            :op1 (r / resist-01
                  :ARG1 (i / insulin)
                  :degree (s / severe))
            :op2 (d2 / disease :name (n3 / name :op1 "diabetes" :op2 "mellitus"))
            :op3 (h2 / hypertension)))

# ::id bio.chicago_2015.85089 ::date 2015-11-08T07:52:59 ::annotator SDL-AMR-09 ::preferred
# ::snt Among the genes induced by  TNF-alpha, secreted  VCAM-1,  fibronectin,  tenascin C,  ceruloplasmin,  PAI-1, and  adrenomedullin have been associated with  type 2 diabetes or an excessive rate of  cardiovascular diseases ( 51 -  53).
# ::save-date Tue Nov 10, 2015 ::file bio_chicago_2015_85089.txt
(a / associate-01
      :ARG1 (a2 / and
            :op1 (g / gene
                  :name (n2 / name :op1 "VCAM-1")
                  :ARG1-of (s / secrete-01))
            :op2 (g2 / gene
                  :name (n3 / name :op1 "fibronectin"))
            :op2 (g6 / gene
                  :name (n7 / name :op1 "adrenomedullin"))
            :op3 (g3 / gene
                  :name (n4 / name :op1 "tenascin" :op2 "C"))
            :op4 (g4 / gene
                  :name (n5 / name :op1 "ceruloplasmin"))
            :op5 (g5 / gene
                  :name (n6 / name :op1 "PAI-1"))
            :ARG1-of (i / include-91
                  :ARG2 (g7 / gene
                        :ARG2-of (i2 / induce-01
                              :ARG0 (p / protein
                                    :name (n8 / name :op1 "TNF-alpha"))))))
      :ARG2 (o / or
            :op1 (d / disease :wiki "Diabetes_mellitus_type_2"
                  :name (n / name :op1 "type" :op2 2 :op3 "diabetes"))
            :op2 (r / rate
                  :ARG1-of (e / excessive-02)
                  :mod (d2 / disease
                        :mod (c2 / cardiovascular))))
      :ARG1-of (d3 / describe-01
            :ARG0 (p2 / publication
                  :ARG1-of (c / cite-01
                        :ARG2 (v / value-interval :op1 51 :op2 53)))))

# ::id bio.chicago_2015.85434 ::date 2015-11-08T08:10:11 ::annotator SDL-AMR-09 ::preferred
# ::snt The findings that both  SR-A and  SR-BI are expressed by monocytes and macrophages from adult  mice and  humans, 1, 7- 9  by microglia from newborn  mice, 36  and Bell et al 13 , but not by adult  mouse or  human microglia, and that  SR-A, but not  SR-BI, is expressed on microglia associated with  senile plaques in AD brains, 2, 3 indicate that microglia can regulate  SR-A and  SR-BI expression by independent mechanisms.
# ::save-date Tue Nov 10, 2015 ::file bio_chicago_2015_85434.txt
(i / indicate-01
      :ARG0 (f / find-01
            :ARG1 (a / and
                  :op1 (e / express-03
                        :ARG2 (a3 / and
                              :op1 (p / protein
                                    :name (n3 / name :op1 "SR-A"))
                              :op2 (p2 / protein
                                    :name (n4 / name :op1 "SR-BI")))
                        :ARG3 (a2 / and
                              :op1 (c / cell
                                    :name (n / name :op1 "monocytes"))
                              :op2 (c2 / cell
                                    :name (n2 / name :op1 "macrophages"))
                              :source (a5 / and
                                    :op1 (m / mouse
                                          :mod (a4 / adult))
                                    :op2 (h / human)))
                        :ARG1-of (d / describe-01
                              :ARG0 (p3 / publication
                                    :ARG1-of (c3 / cite-01
                                          :ARG2 (a6 / and :op1 1
                                                :op2 (v / value-interval :op1 7 :op2 9))))))
                  :op2 (e2 / express-03
                        :ARG2 a3
                        :ARG3 (c4 / cell
                              :name (n5 / name :op1 "microglia")
                              :source (m2 / mouse
                                    :mod (n6 / newborn)))
                        :ARG1-of (d2 / describe-01
                              :ARG0 (a7 / and
                                    :op1 (p4 / publication
                                          :ARG1-of (c5 / cite-01 :ARG2 36))
                                    :op2 (p5 / publication-91
                                          :ARG0 (a8 / and
                                                :op1 (p6 / person
                                                      :name (n7 / name :op1 "Bell"))
                                                :op2 (p7 / person
                                                      :mod (o / other)))
                                          :ARG1-of (c6 / cite-01 :ARG2 13))))
                        :ARG1-of (c7 / contrast-01
                              :ARG2 (e3 / express-03
                                    :ARG1 (c8 / cell
                                          :name (n8 / name :op1 "microglia")
                                          :source a5))))
                  :op3 (e4 / express-03
                        :ARG2 p
                        :ARG3 (c9 / cell
                              :name (n9 / name :op1 "microglia")
                              :ARG1-of (a9 / associate-01
                                    :ARG2 (p8 / plaque
                                          :mod (s / senile)
                                          :location (b2 / brain
                                                :mod (d3 / disease :wiki "Alzheimer's_disease"
                                                      :name (n10 / name :op1 "Alzheimer's"))))))
                        :ARG1-of (d4 / describe-01
                              :ARG0 (p9 / publication
                                    :ARG1-of (c10 / cite-01
                                          :ARG2 (a10 / and :op1 2 :op2 3))))
                        :ARG1-of (c11 / contrast-01
                              :ARG2 (e6 / express-03 :polarity -
                                    :ARG2 p2)))))
      :ARG1 (p10 / possible-01
            :ARG1 (r / regulate-01
                  :ARG0 c4
                  :ARG1 (e5 / express-03
                        :ARG2 a3)
                  :instrument (m3 / mechanism
                        :ARG0-of (d5 / depend-01 :polarity -)))))

# ::id bio.chicago_2015.85464 ::date 2015-11-08T08:43:12 ::annotator SDL-AMR-09 ::preferred
# ::snt Localization of  P. aeruginosa and beads in transported and stationary  ASL (mucus) produced by planar  CF cultures.
# ::save-date Thu Dec 10, 2015 ::file bio_chicago_2015_85464.txt
(l / localize-01
      :ARG1 (a / and
            :op1 (o / organism :name (n / name :op1 "Pseudomonas" :op2 "aeruginosa"))
            :op2 (b / bead)
            :location (l2 / liquid
                  :ARG1-of (m / mean-01
                        :ARG2 (m2 / mucus))
                  :mod (s / stationary)
                  :ARG1-of (t2 / transport-01)
                  :ARG1-of (p / produce-01
                        :ARG0 (c / culture
                              :mod (p2 / planar)
                              :mod (d / disease :name (n3 / name :op1 "cystic" :op2 "fibrosis"))))
                  :mod (s2 / surface
                        :part-of (a2 / airway)))))

# ::id bio.chicago_2015.85539 ::date 2015-11-08T09:08:09 ::annotator SDL-AMR-09 ::preferred
# ::snt Here we show that   mab-23 encodes a  DM (Doublesex/ MAB-3) domain transcription factor necessary for specific aspects of differentiation in sex-specific tissues of the male.
# ::save-date Tue Nov 10, 2015 ::file bio_chicago_2015_85539.txt
(s / show-01
      :ARG0 (w / we)
      :ARG1 (e / encode-01
            :ARG0 (g / gene :name (n2 / name :op1 "mab-23"))
            :ARG1 (p / protein-segment :name (n4 / name :op1 "doublesex/mab-3" :op2 "transcription" :op3 "factor")
                  :ARG1-of (n / need-01
                        :ARG0 (a / aspect
                              :ARG1-of (s2 / specific-02
                                    :ARG2 (d / differentiate-101
                                          :ARG1 (t / tissue
                                                :ARG1-of (s3 / specific-02
                                                      :ARG2 (s4 / sex))
                                                :poss (m / male))))))))
      :location (h / here))

# ::id bio.chicago_2015.85555 ::date 2015-11-08T10:49:04 ::annotator SDL-AMR-09 ::preferred
# ::snt We then used the radiometric technique to test the hypothesis that  P. aeruginosa  in  CF sputum produces  acyl-HSL signals.
# ::save-date Thu Dec 10, 2015 ::file bio_chicago_2015_85555.txt
(u / use-01
      :ARG0 (w / we)
      :ARG1 (t2 / technique
            :mod (r / radiometric))
      :ARG2 (t3 / test-01
            :ARG0 (w2 / we)
            :ARG1 (h / hypothesize-01
                  :ARG0 w
                  :ARG1 (p / produce-01
                        :ARG0 (o / organism :name (n / name :op1 "P." :op2 "aeruginosa")
                              :location (s / sputum
                                    :mod (d / disease :name (n2 / name :op1 "cystic" :op2 "fibrosis"))))
                        :ARG1 (s2 / signal-07
                              :ARG0 (s3 / small-molecule :name (n3 / name :op1 "acyl-HSL"))))))
      :time (t / then))

# ::id bio.chicago_2015.85798 ::date 2015-11-08T11:20:59 ::annotator SDL-AMR-09 ::preferred
# ::snt Interestingly, it is this stretch of amino acids in  GRF2 that contains the  PEST region and the  DB.
# ::save-date Sun Nov 8, 2015 ::file bio_chicago_2015_85798.txt
(c / contain-01
      :ARG0 (s / stretch
            :poss (a / amino-acid
                  :part-of (p / protein :name (n / name :op1 "GRF2")))
            :mod (t / this))
      :ARG1 (a2 / and
            :op1 (p2 / protein-segment :name (n2 / name :op1 "PEST"))
            :op2 (p3 / protein-segment :name (n3 / name :op1 "DB")))
      :ARG2-of (i / interest-01))

# ::id bio.chicago_2015.85825 ::date 2015-11-08T11:31:54 ::annotator SDL-AMR-09 ::preferred
# ::snt Early-onset type-II diabetes mellitus (MODY4) linked to  IPF1.
# ::save-date Sun Nov 8, 2015 ::file bio_chicago_2015_85825.txt
(l / link-01
      :ARG1 (o / onset
            :poss (d / disease :name (n2 / name :op1 "type-II" :op2 "diabetes" :op3 "mellitus"))
            :time (e / early))
      :ARG2 (p / protein :name (n / name :op1 "IPF1")))

# ::id bio.chicago_2015.85926 ::date 2015-11-08T11:38:43 ::annotator SDL-AMR-09 ::preferred
# ::snt The PGE2-induced sensitization of the  HT MS channels was presumably mediated by the cAMP-dependent protein kinase pathway, because the pretreatment of sensory neurons with  H-89 (10 muM), a membrane-permeable inhibitor of protein kinase A, completely blocked the sensitization of the channel by PGE2 (Fig.  7 B,C).
# ::save-date Tue Jan 19, 2016 ::file bio_chicago_2015_85926.txt
(m / mediate-01
      :ARG0 (p / pathway :name (n / name :op1 "cAMP-dependent" :op2 "protein" :op3 "kinase"))
      :ARG1 (s / sensitize-01
            :ARG1 (c / channel
                  :mod (m2 / mechanosensitive)
                  :mod (t2 / threshold
                        :ARG1-of (h / high-02)))
            :ARG2-of (i2 / induce-01
                  :ARG0 (s2 / small-molecule :name (n2 / name :op1 "PGE2"))))
      :ARG1-of (p2 / presume-01)
      :ARG1-of (c2 / cause-01
            :ARG0 (b / block-01
                  :ARG0 (p3 / pretreat-01
                        :ARG1 (n3 / neuron
                              :mod (s4 / sensory))
                        :ARG3 (s5 / small-molecule :name (n4 / name :op1 "H-89")
                              :quant (c3 / concentration-quantity :quant 10
                                    :unit (m3 / micromolar))
                              :ARG0-of (i / inhibit-01
                                    :ARG1 (e / enzyme :name (n5 / name :op1 "protein" :op2 "kinase" :op3 "A")))
                              :mod (p4 / permeable
                                    :mod (m4 / membrane))))
                  :ARG1 (s3 / sensitize-01
                        :ARG0 s2
                        :ARG1 c)
                  :ARG1-of (c4 / complete-02)))
      :ARG1-of (d / describe-01
            :ARG0 (a / and
                  :op1 (f / figure :mod "7B")
                  :op2 (f2 / figure :mod "7C"))))

# ::id bio.chicago_2015.86087 ::date 2015-11-08T12:20:15 ::annotator SDL-AMR-09 ::preferred
# ::snt Twenty-three of the 33 sera contained antibodies against  PcrV, a protein involved in translocation of type III cytotoxins into eukaryotic cells, and 11 of 33 had antibodies against  ExoS, while most  CF sera contained antibodies against  PopB and  PopD, components of the type III apparatus.
# ::save-date Thu Dec 10, 2015 ::file bio_chicago_2015_86087.txt
(c4 / contrast-01
      :ARG1 (a2 / and
            :op1 (c / contain-01
                  :ARG0 (s / serum :quant 23
                        :ARG1-of (i / include-91
                              :ARG2 (s2 / serum :quant 33)))
                  :ARG1 (a / antibody
                        :ARG0-of (c2 / counter-01
                              :ARG1 (p / protein :name (n / name :op1 "PcrV")
                                    :ARG1-of (i2 / involve-01
                                          :ARG2 (t / translocate-01
                                                :ARG1 (c8 / cytotoxins)
                                                :ARG2 (c3 / cell
                                                      :mod (e / eukaryotic))))))))
            :op2 (h / have-03
                  :ARG0 (s4 / serum :quant 11
                        :ARG1-of i)
                  :ARG1 (a3 / antibody
                        :ARG0-of (c5 / counter-01
                              :ARG1 (p2 / protein :name (n4 / name :op1 "ExoS"))))))
      :ARG2 (c6 / contain-01
            :ARG0 (s5 / serum
                  :mod (d / disease :name (n5 / name :op1 "cystic" :op2 "fibrosis"))
                  :quant (m / most))
            :ARG1 (a4 / antibody
                  :ARG0-of (c7 / counter-01
                        :ARG1 (a5 / and
                              :op1 (p3 / protein :name (n6 / name :op1 "PopB"))
                              :op2 (p4 / protein :name (n7 / name :op1 "PopD"))
                              :ARG1-of (i3 / include-91
                                    :ARG2 (p5 / protein-family :name (n8 / name :op1 "type" :op2 "III" :op3 "apparatus"))))))))

# ::id bio.chicago_2015.86563 ::date 2015-11-08T12:38:59 ::annotator SDL-AMR-09 ::preferred
# ::snt Interaction of  Tau Isoforms with  Alzheimer's Disease Abnormally Hyperphosphorylated Tau and in Vitro Phosphorylation into the Disease -like Protein.
# ::save-date Mon Jan 4, 2016 ::file bio_chicago_2015_86563.txt
(a / and
      :op1 (h / hyperphosphorylate-01
            :ARG1 (p2 / protein :name (n4 / name :op1 "Tau"))
            :ARG2 (i / interact-01
                  :ARG0 (i2 / isoform
                        :mod p2)
                  :ARG1 (d / disease :wiki "Alzheimer's_disease" :name (n / name :op1 "Alzheimer")))
            :ARG1-of (n3 / normal-02 :polarity -))
      :op2 (p / phosphorylate-01
            :ARG1 (p3 / protein
                  :ARG1-of (r / resemble-01
                        :ARG2 d))
            :manner (i3 / in-vitro)))

# ::id bio.chicago_2015.87018 ::date 2015-11-08T12:50:04 ::annotator SDL-AMR-09 ::preferred
# ::snt Scopolamine has been used as a pharmacological tool for understanding pathological impairments such as AD, because it produces  amnesiac effects similar to those identified in AD (Sakhakian et al., 1987  ).
# ::save-date Sun Nov 8, 2015 ::file bio_chicago_2015_87018.txt
(c / cause-01
      :ARG0 (p3 / produce-01
            :ARG0 s
            :ARG1 (a / affect-01
                  :ARG0 s
                  :ARG2 (a2 / amnesia)
                  :ARG1-of (r / resemble-01
                        :ARG2 (a3 / affect-01
                              :ARG1-of (i2 / identify-01
                                    :location d2)))))
      :ARG1 (u / use-01
            :ARG1 (s / small-molecule
                  :name (n / name :op1 "scopolamine"))
            :ARG2 (t / tool
                  :mod (p2 / pharmacologic)
                  :purpose (u2 / understand-01
                        :ARG1 (i / impair-01
                              :example (d2 / disease :wiki "Alzheimer's_disease"
                                          :name (n2 / name :op1 "Alzheimer's"))
                              :mod (p / pathology)))))
      :ARG1-of (d3 / describe-01
            :ARG0 (p4 / publication-91
                  :ARG0 (a4 / and
                        :op1 (p5 / person
                              :name (n3 / name :op1 "Sakhakian"))
                        :op2 (p6 / person
                              :mod (o / other)))
                  :time (d / date-entity :year 1987))))

# ::id bio.chicago_2015.87155 ::date 2015-11-08T13:10:50 ::annotator SDL-AMR-09 ::preferred
# ::snt If the pancreas is allowed to develop with an intact   pdx1 gene, and the   pdx1 gene is disrupted only in mature  beta cells,  diabetes ensues due to impaired  beta-cell function ( 3).
# ::save-date Tue Nov 10, 2015 ::file bio_chicago_2015_87155.txt
(h / have-condition-91
      :ARG1 (e / ensue-01
            :ARG1 (d3 / disease :name (n3 / name :op1 "diabetes"))
            :ARG1-of (c2 / cause-01
                  :ARG0 (f / function-01
                        :ARG0 (c4 / cell :name (n4 / name :op1 "beta"))
                        :ARG1-of (i2 / impair-01))))
      :ARG2 (a2 / and
            :op1 (a / allow-01
                  :ARG1 (d / develop-02
                        :ARG1 (p / pancreas)
                        :condition (h2 / have-03
                              :ARG0 p
                              :ARG1 (g / gene :name (n / name :op1 "pdx1")
                                    :mod (i / intact)))))
            :op2 (d2 / disrupt-01
                  :ARG1 g
                  :location (c / cell :name (n2 / name :op1 "beta")
                        :ARG1-of (m / mature-01))
                  :mod (o / only)))
      :ARG1-of (d4 / describe-01
            :ARG0 (p2 / publication
                  :ARG1-of (c3 / cite-01
                        :ARG2 3))))

# ::id bio.chicago_2015.87157 ::date 2015-11-08T13:19:59 ::annotator SDL-AMR-09 ::preferred
# ::snt Neurons in AD brains express fetal antigens, including the fetal type of  tau antigen  ( 112), the A68 protein recognized by the monoclonal antibody ALZ-50  ( 113), gangliosides recognized by the monoclonal antibody A2B5  ( 114), and a fetal form of  alpha-tubulin.
# ::save-date Tue Nov 10, 2015 ::file bio_chicago_2015_87157.txt
(e / express-03
      :ARG2 (a / antigen
            :mod (f / fetus)
            :ARG2-of (i / include-01
                  :ARG1 (a2 / and
                        :op1 (a3 / antigen
                              :mod (p / protein
                                    :name (n3 / name :op1 "tau"))
                              :mod (t / type
                                    :mod f)
                              :ARG1-of (d2 / describe-01
                                    :ARG0 (p2 / publication
                                          :ARG1-of (c / cite-01 :ARG2 112))))
                        :op2 (p3 / protein
                              :name (n4 / name :op1 "A68")
                              :ARG1-of (r / recognize-01
                                    :ARG0 (a4 / antibody
                                          :name (n5 / name :op1 "ALZ-50")
                                          :mod (m / monoclonal)))
                              :ARG1-of (d3 / describe-01
                                    :ARG0 (p4 / publication
                                          :ARG1-of (c2 / cite-01 :ARG2 113))))
                        :op3 (s / small-molecule
                              :name (n6 / name :op1 "ganglioside")
                              :ARG1-of (r2 / recognize-01
                                    :ARG0 (a5 / antibody
                                          :name (n7 / name :op1 "A2B5")
                                          :mod m))
                              :ARG1-of (d4 / describe-01
                                    :ARG0 (p5 / publication
                                          :ARG1-of (c3 / cite-01 :ARG2 114))))
                        :op4 (f2 / form
                              :mod f
                              :poss (p6 / protein
                                    :name (n8 / name :op1 "alpha-tubulin"))))))
      :ARG3 (n / neuron
            :part-of (b / brain
                  :mod (d / disease :wiki "Alzheimer's_disease"
                        :name (n2 / name :op1 "Alzheimer's")))))

# ::id bio.chicago_2015.87198 ::date 2015-11-08T13:34:41 ::annotator SDL-AMR-09 ::preferred
# ::snt To elucidate the role of C-AD in a physiological situation, full-length and C-AD-truncated  NDRFs were analysed in the  mouse IP3R1 promoter.
# ::save-date Mon Jan 4, 2016 ::file bio_chicago_2015_87198.txt
(a / analyze-01
      :ARG1 (a2 / and
            :op1 (p / protein :name (n / name :op1 "NDRF")
                  :mod (l / length
                        :ARG1-of (f / full-09)))
            :op2 (p2 / protein :name (n2 / name :op1 "NDRF")
                  :ARG1-of (t / truncate-01
                        :ARG2 (p3 / protein-segment :name (n3 / name :op1 "C-AD")))))
      :purpose (e / elucidate-01
            :ARG1 (r / role
                  :ARG1-of (h / have-03
                        :ARG0 p3)
                  :topic (s / situation
                        :mod (p4 / physiology))))
      :location (m2 / molecular-physical-entity
            :ARG0-of (p5 / promote-01
                  :ARG1 (p6 / protein :name (n4 / name :op1 "IP3R1")
                        :mod (m / mouse)))))

# ::id bio.chicago_2015.87332 ::date 2015-11-08T13:47:57 ::annotator SDL-AMR-09 ::preferred
# ::snt The major known genetic  risk factor for late-onset AD is the  4 allele of the  apolipoprotein E (ApoE) gene (ApoE4); however, at least half of the people who develop AD do not carry  ApoE4, and not all who carry  ApoE4 develop AD.
# ::save-date Tue Nov 10, 2015 ::file bio_chicago_2015_87332.txt
(m / multi-sentence
      :snt1 (a2 / allele :quant 4
            :part-of (g / gene
                  :name (n / name :op1 "apolipoprotein" :op2 "E"))
            :domain (f / factor
                  :ARG1-of (m2 / major-02)
                  :mod (g2 / genetics)
                  :ARG1-of (k / know-02)
                  :mod (r / risk-01
                        :ARG2 (o / onset
                              :mod (l / late)
                              :mod (d / disease :wiki "Alzheimer's_disease"
                                    :name (n2 / name :op1 "Alzheimer's"))))))
      :snt2 (h / have-concession-91
            :ARG1 (a3 / and
                  :op1 (c / carry-01 :polarity -
                        :ARG0 (p / person
                              :quant (a / at-least
                                    :op1 (h2 / half))
                              :ARG1-of (i / include-91
                                    :ARG2 (p2 / person
                                          :ARG0-of (d2 / develop-02
                                                :ARG1 d4))))
                        :ARG1 (g3 / gene
                              :name (n3 / name :op1 "ApoE4")))
                  :op2 (d3 / develop-02 :polarity -
                        :ARG0 (p4 / person
                              :mod (a4 / all)
                              :ARG0-of (c2 / carry-01
                                    :ARG1 g3))
                        :ARG1 (d4 / disease :wiki "Alzheimer's_disease"
                              :name (n4 / name :op1 "Alzheimer's"))))))

# ::id bio.chicago_2015.87380 ::date 2015-11-08T14:01:38 ::annotator SDL-AMR-09 ::preferred
# ::snt In addition, AD patients have increased serum levels of  TNF  and  IL-6 have been established in [  20 and   47].
# ::save-date Thu Dec 10, 2015 ::file bio_chicago_2015_87380.txt
(h / have-03
      :ARG0 (p / person
            :ARG0-of (h2 / have-org-role-91
                  :ARG2 (p2 / patient))
            :mod (d / disease :wiki "Alzheimer's_disease" :name (n / name :op1 "Alzheimer's")))
      :ARG1 (l / level
            :mod (s / serum)
            :ARG1-of (i / increase-01)
            :quant-of (a / and
                  :op1 (p3 / protein :name (n2 / name :op1 "TNF"))
                  :op2 (p4 / protein :name (n3 / name :op1 "IL-6")))
            :ARG1-of (e / establish-01))
      :ARG1-of (a2 / add-02)
      :ARG1-of (d2 / describe-01
            :ARG0 (p5 / publication
                  :ARG1-of (c / cite-01
                        :ARG2 (a3 / and :op1 20 :op2 47)))))

# ::id bio.chicago_2015.87430 ::date 2015-11-08T14:11:43 ::annotator SDL-AMR-09 ::preferred
# ::snt Indeed, Lad/Ad interacts with the  receptor tyrosine kinases PDGFR and vascular endothelial  cell growth factor receptor (VEGFR) KDR, as well as several components of receptor signaling networks, including  Grb2,  phosphatidylinositol 3-kinase, and phospholipase Cgamma ( PLC-gamma) ( 11,  41,  58).
# ::save-date Thu Jan 14, 2016 ::file bio_chicago_2015_87430.txt
(i / interact-01
      :ARG0 (p / protein :name (n2 / name :op1 "Lad/Ad"))
      :ARG1 (a / and
            :op1 (p2 / protein :name (n3 / name :op1 "receptor" :op2 "tyrosine" :op3 "kinases" :op4 "PDGFR"))
            :op2 (p3 / protein :name (n4 / name :op1 "vascular" :op2 "endothelial" :op3 "cell" :op4 "growth" :op5 "factor" :op6 "receptor"))
            :op3 (c / component
                  :quant (s2 / several)
                  :poss (n / network
                        :ARG0-of (s / signal-07)
                        :ARG2-of (i2 / include-01
                              :ARG1 (a2 / and
                                    :op1 (p4 / protein :name (n5 / name :op1 "Grb2"))
                                    :op2 (e / enzyme :name (n6 / name :op1 "phosphatidylinositol" :op2 "3-kinase"))
                                    :op3 (e2 / enzyme :name (n7 / name :op1 "phospholipase" :op2 "Cgamma")))))))
      :mod (i3 / indeed)
      :ARG1-of (d / describe-01
            :ARG0 (p6 / publication
                  :ARG1-of (c2 / cite-01
                        :ARG2 (a3 / and :op1 11 :op2 41 :op3 58)))))

# ::id bio.chicago_2015.87520 ::date 2015-11-08T14:30:53 ::annotator SDL-AMR-09 ::preferred
# ::snt Importantly, at least 10 of those known genes have been  previously characterized in AD, which include  p21ras,  mitogen-activated  protein kinase (MAPK) kinase 1,  alpha-enolase 1,  carbonyl reductase,   apolipoprotein D,  transferrin, phosphotriesterase protein,  glutamate  dehydrogenase,  calpain, and  Cu/Zn superoxide dismutase (SOD1).
# ::save-date Tue Nov 10, 2015 ::file bio_chicago_2015_87520.txt
(c / characterize-01
      :ARG1 (g / gene
            :quant (a / at-least :op1 10)
            :ARG1-of (i / include-91
                  :ARG2 (g2 / gene
                        :ARG1-of (k / know-01)
                        :ARG2-of (i2 / include-01
                              :ARG1 (a3 / and
                                    :op1 (g3 / gene
                                          :name (n4 / name :op1 "p21ras"))
                                    :op2 (g4 / gene
                                          :name (n5 / name :op1 "mitogen-activated" :op2 "protein" :op3 "kinase" :op4 1))
                                    :op3 (g5 / gene
                                          :name (n6 / name :op1 "alpha-enolase" :op2 1))
                                    :op4 (g6 / gene
                                          :name (n7 / name :op1 "carbonyl" :op2 "reductase"))
                                    :op5 (g7 / gene
                                          :name (n8 / name :op1 "apolipoprotein" :op2 "D"))
                                    :op6 (g8 / gene
                                          :name (n9 / name :op1 "transferrin"))
                                    :op7 (g9 / gene
                                          :name (n10 / name :op1 "phosphotriesterase"))
                                    :op8 (g10 / gene
                                          :name (n11 / name :op1 "glutamate" :op2 "dehydrogenase"))
                                    :op9 (g11 / gene
                                          :name (n12 / name :op1 "calpain"))
                                    :op10 (g12 / gene
                                          :name (n13 / name :op1 "Cu/Zn" :op2 "superoxide" :op3 "dismutase"))))
                        :mod (t / that))))
      :time (p3 / previous)
      :location (d / disease :wiki "Alzheimer's_disease"
            :name (n3 / name :op1 "Alzheimer's"))
      :mod (i3 / important))

# ::id bio.chicago_2015.88023 ::date 2015-11-08T14:44:07 ::annotator SDL-AMR-09 ::preferred
# ::snt Furthermore, cortical neurons of AD patients express  p75NTR, but this receptor is only infrequently expressed in cortical neurons of nonaffected aged-matched controls ( 15).
# ::save-date Thu Dec 10, 2015 ::file bio_chicago_2015_88023.txt
(a / and
      :op2 (c / contrast-01
            :ARG1 (e / express-03
                  :ARG2 (p3 / protein :name (n3 / name :op1 "75NTR")
                        :ARG3-of (p4 / phosphorylate-01))
                  :ARG3 (n / neuron
                        :mod (c2 / cortex)
                        :part-of (p / person
                              :ARG0-of (h / have-org-role-91
                                    :ARG2 (p2 / patient))
                              :mod (d / disease :wiki "Alzheimer's_disease" :name (n2 / name :op1 "Alzheimer's")))))
            :ARG2 (e2 / express-03
                  :ARG2 p3
                  :ARG3 (n4 / neuron
                        :mod c2
                        :poss (c3 / control
                              :ARG1-of (a2 / affect-01 :polarity -)
                              :ARG1-of (m / match-01
                                    :ARG2 (a3 / age))))
                  :ARG1-of (f / frequent-02 :polarity -
                        :mod (o / only))))
      :ARG1-of (d2 / describe-01
            :ARG0 (p5 / publication
                  :ARG1-of (c4 / cite-01
                        :ARG2 14))))

# ::id bio.chicago_2015.88844 ::date 2015-11-08T14:51:27 ::annotator SDL-AMR-09 ::preferred
# ::snt Considering the increasing evidence for neuronal apoptosis in  Alzheimer's disease ( 50-54), the transcriptional control of  PS1 and its down-regulation by  p53 may relate directly to the pathology of the disease.
# ::save-date Tue Nov 10, 2015 ::file bio_chicago_2015_88844.txt
(p / possible-01
      :ARG1 (r / relate-01
            :ARG1 (a / and
                  :op1 (c / control-01
                        :ARG0 p4
                        :ARG1 (p3 / protein :name (n2 / name :op1 "PS1"))
                        :ARG0-of (t / transcribe-01))
                  :op2 (d4 / downregulate-01
                        :ARG1 p3
                        :ARG2 (p4 / protein :name (n3 / name :op1 "p53"))))
            :ARG2 (p2 / pathology
                  :mod d2)
            :ARG1-of (d3 / direct-02))
      :condition (c2 / consider-02
            :ARG1 (e / evidence-01
                  :ARG1 (a2 / apoptosis
                        :mod (n4 / neuron)
                        :location (d2 / disease :wiki "Alzheimer's_disease" :name (n / name :op1 "Alzheimer")))
                  :ARG1-of (i / increase-01))
            :ARG1-of (d5 / describe-01
                  :ARG0 (p5 / publication
                        :ARG1-of (c3 / cite-01
                              :ARG2 (v / value-interval :op1 50 :op2 54))))))

# ::id bio.chicago_2015.88939 ::date 2015-11-08T05:13:19 ::annotator SDL-AMR-09 ::preferred
# ::snt Recombinant  Adenoviral Vectors and  Adenoviral Infection-- The  recombinant adenovirus vector AdCox-2, expressing COX-2, was constructed from replication-deficient  adenovirus type 5(Ad5) with deletions in the  E1 and  E3 genes, Ad dl327, and a  plasmid containing  Ad5 sequences from 22 to 5790 with a deletion of the  E1 region from  bp 342 to 3523, a polycloning site under control of the  cytomegalovirus promoter, the COX-2  cDNA, and the  simian virus 40 polyadenylation signal.
# ::save-date Sat Feb 13, 2016 ::file bio_chicago_2015_88939.txt
(m / multi-sentence
      :snt1 (a / and
            :op1 (v / vector
                  :mod (a6 / adenovirus
                        :ARG3-of (r / recombine-01)))
            :op2 (i / infect-01
                  :ARG2 (a7 / adenovirus)))
      :snt2 (c2 / construct-01
            :ARG1 (v3 / vector :name (n3 / name :op1 "AdCox-2")
                  :mod (a2 / adenovirus
                        :ARG3-of (r2 / recombine-01))
                  :ARG1-of (e / express-03
                        :ARG2 (e2 / enzyme :name (n4 / name :op1 "COX-2"))))
            :ARG2 (a4 / and
                  :op1 (a8 / adenovirus :mod 5
                        :ARG0-of (l / lack-01
                              :ARG1 (r3 / replicate-01
                                    :ARG1 a8))
                        :ARG2-of (d / delete-01
                              :ARG1 (a3 / and
                                    :op1 (g / gene :name (n6 / name :op1 "E1"))
                                    :op2 (g2 / gene :name (n7 / name :op1 "E3")))))
                  :op2 (s / small-molecule :name (n8 / name :op1 "Ad-dl327"))
                  :op3 (p / plasmid
                        :ARG0-of (c3 / contain-01
                              :ARG1 (s2 / sequence
                                    :mod (v6 / value-interval :op1 22 :op2 5790)
                                    :mod (d3 / dna-sequence :name (n9 / name :op1 "Ad5")
                                          :ARG2-of (d2 / delete-01
                                                :ARG1 (p3 / protein-segment
                                                      :mod (v7 / value-interval :op1 342 :op2 3523)
                                                      :ARG1-of (m2 / mean-01
                                                            :ARG2 (s3 / site
                                                                  :mod (p4 / polyclone)
                                                                  :ARG1-of (c4 / control-01
                                                                        :ARG0 (a5 / and
                                                                              :op1 (n5 / nucleic-acid :name (n / name :op1 "cDNA")
                                                                                    :ARG0-of (p7 / promote-01
                                                                                          :ARG1 (v8 / virus :name (n13 / name :op1 "cytomegalovirus")))
                                                                                    :mod e2)
                                                                              :op2 (s4 / signal-07
                                                                                    :ARG0 (s5 / small-molecule :name (n12 / name :op1 "simian" :op2 "virus" :op3 "40"))
                                                                                    :mod (p6 / polyadenylation))))))
                                                      :part-of g)))))))))

# ::id biomed_0004.1 ::date 2015-07-28T06:55:43 ::annotator SDL-AMR-09 ::preferred
# ::snt The receptor tyrosine kinase EGFR binds the growth factor ligand EGF.
# ::save-date Tue Jul 28, 2015 ::file biomed_0004_1.txt
(b / bind-01
      :ARG1 (r / receptor-tyrosine-kinase :name (n3 / name :op1 "EGFR"))
      :ARG2 (g / growth-factor-ligand :name (n / name :op1 "EGF")))

# ::id biomed_0004.2 ::date 2015-07-28T10:28:16 ::annotator SDL-AMR-09 ::preferred
# ::snt The EGFR-EGF complex binds another EGFR-EGF complex.
# ::save-date Tue Jul 28, 2015 ::file biomed_0004_2.txt
(b / bind-01
      :ARG1 (m / macro-molecular-complex
            :part (e / enzyme :wiki "Epidermal_growth_factor_receptor"
                  :name (n / name :op1 "EGFR"))
            :part (p / protein :wiki "Epidermal_growth_factor"
                  :name (n2 / name :op1 "EGF")))
      :ARG2 (m2 / macro-molecular-complex
            :part e
            :part p
            :mod (a / another)))

# ::id biomed_0004.3 ::date 2015-07-28T10:41:40 ::annotator SDL-AMR-09 ::preferred
# ::snt EGFR, bound to EGFR, transphosphorylates itself on a tyrosine residue.
# ::save-date Tue Feb 2, 2016 ::file biomed_0004_3.txt
(t / transphosphorylate-01
      :ARG0 (e / enzyme :name (n / name :op1 "EGFR")
            :ARG1-of (b / bind-01
                  :ARG2 (e2 / enzyme :name (n3 / name :op1 "EGFR"))))
      :ARG1 (r / residue
            :mod (a / amino-acid :name (n2 / name :op1 "tyrosine"))
            :part-of e))

# ::id biomed_0004.4 ::date 2015-07-28T10:50:58 ::annotator SDL-AMR-09 ::preferred
# ::snt The adaptor protein GRB2 can bind EGFR that is phosphorylated on tyrosine.
# ::save-date Tue Jul 28, 2015 ::file biomed_0004_4.txt
(p / possible-01
      :ARG1 (b / bind-01
            :ARG1 (p2 / protein :name (n2 / name :op1 "GRB2")
                  :mod (a2 / adaptor))
            :ARG2 (e / enzyme :name (n3 / name :op1 "EGFR")
                  :ARG3-of (p3 / phosphorylate-01
                        :ARG1 (a / amino-acid :name (n4 / name :op1 "tyrosine"))))))

# ::id biomed_0004.5 ::date 2015-07-28T10:57:58 ::annotator SDL-AMR-09 ::preferred
# ::snt EGFR-bound GRB2 binds SOS1 and the SOS1-GRB2 complex binds HRAS.
# ::save-date Tue Jul 28, 2015 ::file biomed_0004_5.txt
(a / and
      :op1 (b / bind-01
            :ARG1 (p / protein :name (n / name :op1 "GRB2")
                  :ARG1-of (b2 / bind-01
                        :ARG2 (e / enzyme :name (n2 / name :op1 "EGFR"))))
            :ARG2 (p2 / protein :name (n3 / name :op1 "SOS1")))
      :op2 (b3 / bind-01
            :ARG1 (m / macro-molecular-complex
                  :part p2
                  :part p)
            :ARG2 (e2 / enzyme :name (n4 / name :op1 "HRAS"))))

# ::id biomed_0004.6 ::date 2015-07-28T11:02:51 ::annotator SDL-AMR-09 ::preferred
# ::snt HRAS, bound to SOS1, binds GTP.
# ::save-date Tue Jul 28, 2015 ::file biomed_0004_6.txt
(b / bind-01
      :ARG1 (e / enzyme :name (n2 / name :op1 "HRAS")
            :ARG1-of (b2 / bind-01
                  :ARG2 (p / protein :name (n3 / name :op1 "SOS1"))))
      :ARG2 (s / small-molecule :name (n4 / name :op1 "GTP")))

# ::id biomed_0004.7 ::date 2015-07-28T11:06:15 ::annotator SDL-AMR-09 ::preferred
# ::snt HRAS, bound to GTP, binds RAF1.
# ::save-date Tue Jul 28, 2015 ::file biomed_0004_7.txt
(b / bind-01
      :ARG1 (e / enzyme :name (n2 / name :op1 "HRAS")
            :ARG1-of (b2 / bind-01
                  :ARG2 (s / small-molecule :name (n3 / name :op1 "GTP"))))
      :ARG2 (e2 / enzyme :name (n4 / name :op1 "RAF1")))

# ::id biomed_0004.8 ::date 2015-07-28T11:08:03 ::annotator SDL-AMR-09 ::preferred
# ::snt RAF1, bound to HRAS, phosphorylates itself at Thr491 and Ser494.
# ::save-date Tue Jul 28, 2015 ::file biomed_0004_8.txt
(p / phosphorylate-01
      :ARG1 (a / and
            :op1 (a2 / amino-acid :mod 491 :name (n3 / name :op1 "threonine"))
            :op2 (a3 / amino-acid :mod 494 :name (n4 / name :op1 "serine"))
            :part-of e)
      :ARG2 (e / enzyme :name (n / name :op1 "RAF1")
            :ARG1-of (b / bind-01
                  :ARG2 (e2 / enzyme :name (n2 / name :op1 "HRAS")))))

# ::id biomed_0004.9 ::date 2015-07-28T11:12:36 ::annotator SDL-AMR-09 ::preferred
# ::snt RAF1 phosphorylated at Thr491 and Ser494 is activated.
# ::save-date Tue Jul 28, 2015 ::file biomed_0004_9.txt
(a / activate-01
      :ARG1 (e / enzyme :name (n / name :op1 "RAF1")
            :ARG3-of (p / phosphorylate-01
                  :ARG1 (a2 / and
                        :op1 (a3 / amino-acid :mod 491 :name (n2 / name :op1 "threonine"))
                        :op2 (a4 / amino-acid :mod 494 :name (n3 / name :op1 "serine"))))))

# ::id biomed_0004.10 ::date 2015-07-28T11:16:55 ::annotator SDL-AMR-09 ::preferred
# ::snt Active RAF1 phosphorylates MEK1 at Ser218 and Ser222.
# ::save-date Mon Jan 4, 2016 ::file biomed_0004_10.txt
(p / phosphorylate-01
      :ARG1 (a / and
            :op1 (a2 / amino-acid :mod 218 :name (n / name :op1 "serine"))
            :op2 (a3 / amino-acid :mod 222 :name (n2 / name :op1 "serine"))
            :part-of (e / enzyme :name (n3 / name :op1 "MEK1")))
      :ARG2 (e2 / enzyme :name (n4 / name :op1 "RAF1")
            :ARG0-of (a4 / activity-06)))

# ::id biomed_0004.11 ::date 2015-07-28T11:19:40 ::annotator SDL-AMR-09 ::preferred
# ::snt MEK1 phosphorylated at Ser218 and Ser222 is activated.
# ::save-date Tue Jul 28, 2015 ::file biomed_0004_11.txt
(a / activate-01
      :ARG1 (e / enzyme :name (n / name :op1 "MEK1")
            :ARG3-of (p / phosphorylate-01
                  :ARG1 (a2 / and
                        :op1 (a3 / amino-acid :mod 218 :name (n2 / name :op1 "serine"))
                        :op2 (a4 / amino-acid :mod 222 :name (n3 / name :op1 "serine"))))))

# ::id biomed_0004.12 ::date 2015-07-28T11:21:29 ::annotator SDL-AMR-09 ::preferred
# ::snt Active MEK1 phosphorylates ERK2 at Tyr187 and Thr185.
# ::save-date Mon Jan 4, 2016 ::file biomed_0004_12.txt
(p / phosphorylate-01
      :ARG1 (a / and
            :op1 (a3 / amino-acid :mod 187 :name (n2 / name :op1 "tyrosine"))
            :op2 (a4 / amino-acid :mod 185 :name (n3 / name :op1 "threonine"))
            :part-of (e2 / enzyme :name (n4 / name :op1 "ERK2")))
      :ARG2 (e / enzyme :name (n / name :op1 "MEK1")
            :ARG0-of (a2 / activity-06)))

# ::id biomed_0004.13 ::date 2015-07-28T11:24:07 ::annotator SDL-AMR-09 ::preferred
# ::snt Ras bound to GTP binds to BRAF.
# ::save-date Tue Jul 28, 2015 ::file biomed_0004_13.txt
(b / bind-01
      :ARG1 (e / enzyme :name (n / name :op1 "Ras")
            :ARG1-of (b2 / bind-01
                  :ARG2 (s / small-molecule :name (n2 / name :op1 "GTP"))))
      :ARG2 (e2 / enzyme :name (n3 / name :op1 "BRAF")))

# ::id biomed_0004.14 ::date 2015-07-28T11:25:12 ::annotator SDL-AMR-09 ::preferred
# ::snt BRAF bound to Ras transphosphorylates itself at Thr598 and Ser601.
# ::save-date Tue Feb 2, 2016 ::file biomed_0004_14.txt
(t / transphosphorylate-01
      :ARG0 (e / enzyme :name (n2 / name :op1 "BRAF")
            :ARG1-of (b / bind-01
                  :ARG2 (e2 / enzyme :name (n3 / name :op1 "Ras"))))
      :ARG1 (a / and
            :op1 (a2 / amino-acid :mod 598 :name (n4 / name :op1 "threonine"))
            :op2 (a3 / amino-acid :mod 601 :name (n / name :op1 "serine"))
            :part-of e))

# ::id biomed_0004.15 ::date 2015-07-28T11:27:51 ::annotator SDL-AMR-09 ::preferred
# ::snt Phosphorylation at Thr598 and Ser601 activates BRAF.
# ::save-date Tue Jul 28, 2015 ::file biomed_0004_15.txt
(a / activate-01
      :ARG0 (p / phosphorylate-01
            :ARG1 (a2 / and
                  :op1 (a3 / amino-acid :mod 598 :name (n / name :op1 "threonine"))
                  :op2 (a4 / amino-acid :mod 601 :name (n2 / name :op1 "serine"))
                  :part-of e))
      :ARG1 (e / enzyme :name (n3 / name :op1 "BRAF")))

# ::id biomed_0004.16 ::date 2015-07-28T11:29:40 ::annotator SDL-AMR-09 ::preferred
# ::snt BRAF is activated by being phosphorylated at Thr598 and Ser601.
# ::save-date Tue Jul 28, 2015 ::file biomed_0004_16.txt
(a / activate-01
      :ARG0 (p / phosphorylate-01
            :ARG1 (a2 / and
                  :op1 (a3 / amino-acid :mod 598 :name (n2 / name :op1 "threonine"))
                  :op2 (a4 / amino-acid :mod 601 :name (n3 / name :op1 "serine"))
                  :part-of e))
      :ARG1 (e / enzyme :name (n / name :op1 "BRAF")))

# ::id biomed_0004.17 ::date 2015-07-28T11:32:19 ::annotator SDL-AMR-09 ::preferred
# ::snt Active BRAF phosphorylates MEK1 at Ser218 and Ser222.
# ::save-date Mon Jan 4, 2016 ::file biomed_0004_17.txt
(p / phosphorylate-01
      :ARG1 (a2 / and
            :op1 (a3 / amino-acid :mod 218 :name (n2 / name :op1 "serine"))
            :op2 (a4 / amino-acid :mod 222 :name (n3 / name :op1 "serine"))
            :part-of (e2 / enzyme :name (n4 / name :op1 "MEK1")))
      :ARG2 (e / enzyme :name (n / name :op1 "BRAF")
            :ARG0-of (a / activity-06)))

# ::id biomed_0004.18 ::date 2015-07-28T11:34:12 ::annotator SDL-AMR-09 ::preferred
# ::snt Phosphorylation at Ser218 and Ser222 activates MEK1.
# ::save-date Tue Jul 28, 2015 ::file biomed_0004_18.txt
(a / activate-01
      :ARG0 (p2 / phosphorylate-01
            :ARG1 (a2 / and
                  :op1 (a3 / amino-acid :mod 218 :name (n / name :op1 "serine"))
                  :op2 (a4 / amino-acid :mod 222 :name (n2 / name :op1 "serine"))
                  :part-of e))
      :ARG1 (e / enzyme :name (n3 / name :op1 "MEK1")))

# ::id biomed_0004.19 ::date 2015-07-28T11:35:32 ::annotator SDL-AMR-09 ::preferred
# ::snt MEK1 is activated by being phosphorylated at Ser218 and Ser222.
# ::save-date Tue Jul 28, 2015 ::file biomed_0004_19.txt
(a / activate-01
      :ARG0 (p / phosphorylate-01
            :ARG1 (a2 / and
                  :op1 (a3 / amino-acid :mod 218 :name (n2 / name :op1 "serine"))
                  :op2 (a4 / amino-acid :mod 222 :name (n3 / name :op1 "serine"))
                  :part-of e))
      :ARG1 (e / enzyme :name (n / name :op1 "MEK1")))

# ::id biomed_0004.20 ::date 2015-07-28T11:37:24 ::annotator SDL-AMR-09 ::preferred
# ::snt Active MEK1 phosphorylates ERK2 at Thr202 and Thr185.
# ::save-date Mon Jan 4, 2016 ::file biomed_0004_20.txt
(p / phosphorylate-01
      :ARG1 (a2 / and
            :op1 (a3 / amino-acid :mod 202 :name (n2 / name :op1 "threonine"))
            :op2 (a4 / amino-acid :mod 185 :name (n3 / name :op1 "threonine"))
            :part-of (e2 / enzyme :name (n4 / name :op1 "ERK2")))
      :ARG2 (e / enzyme :name (n / name :op1 "MEK1")
            :ARG0-of (a / activity-06)))

# ::id biomed_0004.21 ::date 2015-07-28T11:39:01 ::annotator SDL-AMR-09 ::preferred
# ::snt BRAF bound to Ras transphosphorylates itself at Thr598.
# ::save-date Tue Feb 2, 2016 ::file biomed_0004_21.txt
(t / transphosphorylate-01
      :ARG0 (e2 / enzyme :name (n2 / name :op1 "BRAF")
            :ARG1-of (b / bind-01
                  :ARG2 (e / enzyme :name (n / name :op1 "Ras"))))
      :ARG1 (a / amino-acid :mod 598 :name (n3 / name :op1 "threonine")
            :part-of e2))

# ::id biomed_0004.22 ::date 2015-07-28T11:40:37 ::annotator SDL-AMR-09 ::preferred
# ::snt BRAF bound to Ras transphosphorylates itself at Ser601.
# ::save-date Tue Feb 2, 2016 ::file biomed_0004_22.txt
(t / transphosphorylate-01
      :ARG0 (e2 / enzyme :name (n2 / name :op1 "BRAF")
            :ARG1-of (b / bind-01
                  :ARG2 (e / enzyme :name (n3 / name :op1 "Ras"))))
      :ARG1 (a / amino-acid :mod 601 :name (n4 / name :op1 "serine")
            :part-of e2))

# ::id biomed_0004.23 ::date 2015-07-28T11:42:48 ::annotator SDL-AMR-09 ::preferred
# ::snt Active BRAF phosphorylates MEK1 at Ser222.
# ::save-date Mon Jan 4, 2016 ::file biomed_0004_23.txt
(p / phosphorylate-01
      :ARG1 (a2 / amino-acid :mod 222 :name (n2 / name :op1 "serine")
            :part-of (e2 / enzyme :name (n3 / name :op1 "MEK1")))
      :ARG2 (e / enzyme :name (n / name :op1 "BRAF")
            :ARG0-of (a / activity-06)))

# ::id biomed_0004.24 ::date 2015-07-28T11:44:03 ::annotator SDL-AMR-09 ::preferred
# ::snt Active MEK1 phosphorylates ERK2 at Thr202.
# ::save-date Mon Jan 4, 2016 ::file biomed_0004_24.txt
(p / phosphorylate-01
      :ARG1 (a2 / amino-acid :mod 202 :name (n2 / name :op1 "threonine")
            :part-of (e2 / enzyme :name (n3 / name :op1 "ERK2")))
      :ARG2 (e / enzyme :name (n / name :op1 "MEK1")
            :ARG0-of (a / activity-06)))

# ::id biomed_0004.25 ::date 2015-07-28T11:45:10 ::annotator SDL-AMR-09 ::preferred
# ::snt Active MEK1 phosphorylates ERK2 at Thr185.
# ::save-date Mon Jan 4, 2016 ::file biomed_0004_25.txt
(p / phosphorylate-01
      :ARG1 (a2 / amino-acid :mod 185 :name (n2 / name :op1 "threonine")
            :part-of (e2 / enzyme :name (n3 / name :op1 "ERK2")))
      :ARG2 (e / enzyme :name (n / name :op1 "MEK1")
            :ARG0-of (a / activity-06)))

# ::id biomed_0004.26 ::date 2015-07-28T11:46:24 ::annotator SDL-AMR-09 ::preferred
# ::snt Phosphorylation of BRAF at Thr598 and Ser601 activates it.
# ::save-date Tue Jul 28, 2015 ::file biomed_0004_26.txt
(a / activate-01
      :ARG0 (p2 / phosphorylate-01
            :ARG1 (a2 / and
                  :op1 (a3 / amino-acid :mod 598 :wiki "Threonine"
                        :name (n / name :op1 "threonine"))
                  :op2 (a4 / amino-acid :mod 601 :wiki "Serine"
                        :name (n2 / name :op1 "serine"))
                  :part-of (e / enzyme :wiki -
                        :name (n3 / name :op1 "BRAF"))))
      :ARG1 e)

# ::id biomed_0004.27 ::date 2015-07-28T11:48:52 ::annotator SDL-AMR-09 ::preferred
# ::snt Active BRAF phosphorylates MEK1 at Ser218.
# ::save-date Mon Jan 4, 2016 ::file biomed_0004_27.txt
(p / phosphorylate-01
      :ARG1 (a / amino-acid :mod 218 :name (n / name :op1 "serine")
            :part-of (e2 / enzyme :name (n3 / name :op1 "MEK1")))
      :ARG2 (e / enzyme :name (n2 / name :op1 "BRAF")
            :ARG0-of (a2 / activity-06)))

# ::id biomed_0004.28 ::date 2015-07-28T11:50:06 ::annotator SDL-AMR-09 ::preferred
# ::snt Phosphorylation of MEK1 at Ser218 and Ser222 activates it.
# ::save-date Tue Jul 28, 2015 ::file biomed_0004_28.txt
(a / activate-01
      :ARG0 (p2 / phosphorylate-01
            :ARG1 (a2 / and
                  :op1 (a3 / amino-acid :mod 218 :name (n / name :op1 "serine"))
                  :op2 (a4 / amino-acid :mod 222 :name (n2 / name :op1 "serine")))
            :part-of (e / enzyme :name (n3 / name :op1 "MEK1")))
      :ARG1 e)

# ::id pmid_1177_7939.30 ::date 2015-02-26T03:44:12 ::annotator SDL-AMR-09 ::preferred
# ::snt Results
# ::save-date Mon Mar 30, 2015 ::file pmid_1177_7939_30.txt
(t2 / thing
      :ARG2-of (r / result-01))

# ::id pmid_1177_7939.31 ::date 2015-02-26T23:04:30 ::annotator SDL-AMR-09 ::preferred
# ::snt The S/E/E8 complex exists under physiological conditions
# ::save-date Sun Jan 17, 2016 ::file pmid_1177_7939_31.txt
(e / exist-01
      :ARG1 (m / macro-molecular-complex
            :part (s / slash
                  :op1 (p / protein :name (n / name :op1 "S"))
                  :op2 (p2 / protein :name (n2 / name :op1 "E"))
                  :op2 (p3 / protein :name (n3 / name :op1 "E8"))))
      :condition (p4 / physiology))

# ::id pmid_1177_7939.32 ::date 2015-02-27T00:14:25 ::annotator SDL-AMR-09 ::preferred
# ::snt In previous studies, we showed that Sos-1, E3b1, and Eps8 could form a trimeric complex in vivo upon concomitant overexpression of the three proteins.
# ::save-date Wed Jun 24, 2015 ::file pmid_1177_7939_32.txt
(s / show-01
      :ARG0 (w / we)
      :ARG1 (f / form-01
            :ARG0 (a / and
                  :op1 (p2 / protein :name (n / name :op1 "Sos-1"))
                  :op2 (p3 / protein :name (n2 / name :op1 "E3b1"))
                  :op3 (e2 / enzyme :name (n3 / name :op1 "Eps8")))
            :ARG1 (m / macro-molecular-complex
                  :mod (t / trimeric))
            :ARG1-of (p / possible-01)
            :manner (i / in-vivo)
            :condition (o / overexpress-01
                  :ARG1 a
                  :ARG2 (c / concomitant)))
      :medium (s2 / study
            :time (p5 / previous)))

# ::id pmid_1177_7939.33 ::date 2015-02-27T01:01:41 ::annotator SDL-AMR-09 ::preferred
# ::snt However, we failed to detect the existence of an endogenous S/E/E8 complex (<xref ref-type="bibr" rid="bib40">Scita et al., 1999</xref>).
# ::save-date Sun Jan 17, 2016 ::file pmid_1177_7939_33.txt
(c / contrast-01
      :ARG2 (f / fail-01
            :ARG1 (w / we)
            :ARG2 (d / detect-01
                  :ARG0 w
                  :ARG1 (e / exist-01
                        :ARG1 (m / macro-molecular-complex
                              :mod (e2 / endogenous)
                              :part (s / slash
                                    :op1 (p / protein :name (n / name :op1 "S"))
                                    :op2 (p2 / protein :name (n2 / name :op1 "E"))
                                    :op3 (p3 / protein :name (n3 / name :op1 "E8")))))))
      :ARG1-of (d2 / describe-01
            :ARG0 (p4 / publication-91
                  :ARG0 (a / and
                        :op1 (p5 / person :name (n4 / name :op1 "Scita"))
                        :op2 (p6 / person
                              :mod (o / other)))
                  :time (d3 / date-entity :year 1999))))

# ::id pmid_1177_7939.34 ::date 2015-02-28T11:06:35 ::annotator SDL-AMR-09 ::preferred
# ::snt We reasoned that this could be due to the low efficiency of the immunoprecipitating antibodies used.
# ::save-date Tue May 26, 2015 ::file pmid_1177_7939_34.txt
(r / reason-01
      :ARG0 (w / we)
      :ARG1 (p2 / possible-01
            :ARG1 (c / cause-01
                  :ARG0 (e / efficient-01
                        :ARG1 (a / antibody
                              :ARG1-of (u / use-01
                                    :ARG2 (i2 / immunoprecipitate-01)))
                        :ARG1-of (l / low-04))
                  :ARG1 (t / this))))

# ::id pmid_1177_7939.35 ::date 2015-03-01T22:52:23 ::annotator SDL-AMR-09 ::preferred
# ::snt We thus sought to exploit the availability of eps8<sup>−/−</sup> fibroblasts to circumvent this problem.
# ::save-date Sat Jul 25, 2015 ::file pmid_1177_7939_35.txt
(s / seek-01
      :ARG0 (w / we)
      :ARG1 (e / exploit-01
            :ARG0 w
            :ARG1 (a / available-02
                  :ARG2 (f2 / fibroblast
                        :ARG0-of (c3 / contain-01
                              :ARG1 (e2 / enzyme :name (n2 / name :op1 "eps8")
                                    :ARG2-of (m / mutate-01 :mod "−/−")))))
            :purpose (c2 / circumvent-01
                  :ARG0 w
                  :ARG1 (p / problem
                        :mod (t / this))))
      :ARG0-of (c / cause-01))

# ::id pmid_1177_7939.36 ::date 2015-03-02T23:59:41 ::annotator SDL-AMR-09 ::preferred
# ::snt To this end, we performed immunoprecipitation experiments using eps8<sup>−/−</sup> fibroblasts in which the expression of Eps8 was restored, to physiological levels, with an expression vector encoding a myc epitope-tagged Eps8 (−/− [Eps8myc] cells).
# ::save-date Fri Jan 1, 2016 ::file pmid_1177_7939_36.txt
(p / perform-02
      :ARG0 (w / we)
      :ARG1 (e / experiment-01
            :ARG2 (i / immunoprecipitate-01
                  :ARG2 (f / fibroblast
                        :location-of (r / restore-01
                              :ARG1 (e2 / express-03
                                    :ARG2 (e4 / enzyme :name (n2 / name :op1 "Eps8")))
                              :ARG2 (l / level
                                    :mod (p3 / physiology))
                              :instrument (v / vector
                                    :ARG0-of (e3 / encode-01
                                          :ARG1 (e6 / enzyme :name (n / name :op1 "Eps8")
                                                :ARG1-of (t2 / tag-01
                                                      :ARG2 (e7 / epitope
                                                            :mod (p2 / protein :name (n3 / name :op1 "myc"))))))
                                    :ARG2-of (e8 / express-03)))
                        :ARG0-of (c2 / contain-01
                              :ARG1 (e5 / enzyme :name (n4 / name :op1 "eps8")
                                    :ARG2-of (m / mutate-01 :mod "−/−"))))))
      :purpose (t / this))

# ::id pmid_1177_7939.37 ::date 2015-03-02T01:22:46 ::annotator SDL-AMR-09 ::preferred
# ::snt We selected transfected clones in which the levels of expression of Eps8myc were very similar to those present in wild-type fibroblasts (<xref ref-type="fig" rid="fig1">Fig. 1</xref> A).
# ::save-date Wed Jan 13, 2016 ::file pmid_1177_7939_37.txt
(s / select-01
      :ARG0 (w / we)
      :ARG1 (c / clone
            :ARG1-of (t / transfect-01)
            :ARG3-of (e / express-03
                  :ARG2 (p2 / protein :name (n2 / name :op1 "Eps8myc"))
                  :degree (l / level
                        :ARG1-of (r / resemble-01
                              :ARG2 (l2 / level
                                    :ARG1-of (p / present-02
                                          :ARG2 (f / fibroblast
                                                :mod (w2 / wild-type))))
                              :degree (v / very)))
                  :ARG1-of (d / describe-01
                        :ARG0 (f2 / figure :mod "1A")))))

# ::id pmid_1177_7939.38 ::date 2015-03-02T22:29:39 ::annotator SDL-AMR-09 ::preferred
# ::snt Endogenous Sos-1 and E3b1 could be detected in anti-myc immunoprecipitates from lysates of Eps8myc-reconstituted, but not from eps8<sup>−/−</sup> fibroblasts (<xref ref-type="fig" rid="fig1">Fig. 1</xref> B).
# ::save-date Wed Jan 13, 2016 ::file pmid_1177_7939_38.txt
(p / possible-01
      :ARG1 (d / detect-01
            :ARG1 (a / and
                  :op1 (p3 / protein :name (n / name :op1 "Sos-1"))
                  :op2 (p4 / protein :name (n2 / name :op1 "E3b1"))
                  :mod (e / endogenous))
            :location (p5 / protein
                  :ARG1-of (i3 / immunoprecipitate-01
                        :ARG2 (l / lysate
                              :source (f3 / fibroblast
                                    :ARG0-of (c5 / contain-01
                                          :ARG1 (p7 / protein :name (n7 / name :op1 "Eps8myc")
                                                :ARG1-of (r / reconstitute-01))))))
                  :ARG0-of (c / counter-01
                        :ARG1 (p2 / protein :name (n3 / name :op1 "myc"))))
            :ARG1-of (c4 / contrast-01
                  :ARG2 (d2 / detect-01 :polarity -
                        :ARG1 a
                        :location (p6 / protein
                              :ARG1-of (i / immunoprecipitate-01
                                    :ARG2 (f / fibroblast
                                          :ARG0-of (c2 / contain-01
                                                :ARG1 (e3 / enzyme :name (n4 / name :op1 "eps8")
                                                      :ARG2-of (m / mutate-01 :mod "−/−")))))))))
      :ARG1-of (d3 / describe-01
            :ARG0 (f2 / figure :mod "1B")))

# ::id pmid_1177_7939.39 ::date 2015-03-03T01:38:00 ::annotator SDL-AMR-09 ::preferred
# ::snt To determine whether E3b1 mediates the interaction between Eps8 and Sos-1, as it would be expected according to the tricomplex model, we performed coimmunoprecipitation experiments under conditions in which the association between Eps8 and E3b1 was disrupted.
# ::save-date Wed Dec 30, 2015 ::file pmid_1177_7939_39.txt
(p / perform-02
      :ARG0 (w / we)
      :ARG1 (e / experiment-01
            :ARG2 (c / coimmunoprecipitate-01)
            :condition (d / disrupt-01
                  :ARG1 (a / associate-01
                        :ARG1 (e3 / enzyme :name (n / name :op1 "Eps8"))
                        :ARG2 (p3 / protein :name (n2 / name :op1 "E3b1")))))
      :purpose (d2 / determine-01
            :ARG0 w
            :ARG1 (m / mediate-01 :mode interrogative
                  :ARG0 p3
                  :ARG1 (i / interact-01
                        :ARG0 (a2 / and
                              :op1 e3
                              :op2 (p4 / protein :name (n3 / name :op1 "Sos-1"))))
                  :ARG1-of (e2 / expect-01
                        :ARG1-of (s / say-01
                              :ARG0 (m2 / model
                                    :mod (t / tricomplex)))))))

# ::id pmid_1177_7939.40 ::date 2015-03-04T01:03:03 ::annotator SDL-AMR-09 ::preferred
# ::snt The binding site of E3b1 to the SH3 domain of Eps8 was previously mapped to the amino acid sequence, PPPPPVDYTEDEE, where the D and the Y residues are critical for efficient binding (<xref ref-type="bibr" rid="bib28">Mongiovi et al., 1999</xref>).
# ::save-date Sun Jan 17, 2016 ::file pmid_1177_7939_40.txt
(m / map-02
      :ARG1 (p / protein-segment
            :part-of (p3 / protein :name (n8 / name :op1 "E3b1"))
            :ARG1-of (b / bind-01
                  :ARG2 (p2 / protein-segment :name (n2 / name :op1 "SH3" :op2 "domain")
                        :part-of (e / enzyme :name (n3 / name :op1 "Eps8")))))
      :ARG2 (d3 / dna-sequence :name (n / name :op1 "PPPPPVDYTEDEE")
            :ARG2-of (i / include-91
                  :ARG1 (a2 / and
                        :op1 (r3 / residue
                              :mod (a4 / amino-acid :name (n5 / name :op1 "aspartic" :op2 "acid")))
                        :op2 (r / residue
                              :mod (a5 / amino-acid :name (n6 / name :op1 "tyrosine")))
                        :ARG1-of (c / critical-02
                              :ARG3 (e2 / efficient-01
                                    :ARG2 b))))
            :mod (a / amino-acid))
      :ARG1-of (d / describe-01
            :ARG0 (p4 / publication-91
                  :ARG0 (a3 / and
                        :op1 (p5 / person :name (n7 / name :op1 "Mongiovi"))
                        :op2 (p6 / person
                              :mod (o / other)))
                  :time (d2 / date-entity :year 1999)))
      :time (p7 / previous))

# ::id pmid_1177_7939.41 ::date 2015-03-04T02:21:56 ::annotator SDL-AMR-09 ::preferred
# ::snt Thus, a peptide encompassing this region should specifically disrupt the Eps8–E3b1 association.
# ::save-date Mon Dec 21, 2015 ::file pmid_1177_7939_41.txt
(i / infer-01
      :ARG1 (r / recommend-01
            :ARG1 (d / disrupt-01
                  :ARG0 (p / peptide
                        :ARG0-of (e / encompass-01
                              :ARG1 (r2 / region
                                    :mod (t / this))))
                  :ARG1 (a / associate-01
                        :ARG1 (e2 / enzyme :name (n / name :op1 "Eps8"))
                        :ARG2 (p3 / protein :name (n2 / name :op1 "E3b1")))
                  :ARG1-of (s / specific-02))))

# ::id pmid_1177_7939.42 ::date 2015-03-05T00:13:57 ::annotator SDL-AMR-09 ::preferred
# ::snt Indeed, no E3b1could be recovered in anti-myc immunoprecipitates from lysates of Eps8myc-reconstituted cells, when the immunoprecipitation was performed in the presence of an excess of the competing peptide.
# ::save-date Wed Jan 13, 2016 ::file pmid_1177_7939_42.txt
(p / possible-01 :polarity -
      :ARG1 (r / recover-02
            :ARG1 (p2 / protein :name (n / name :op1 "E3b1"))
            :location (p6 / protein
                  :ARG1-of (i3 / immunoprecipitate-01
                        :ARG2 (l / lysate
                              :source (c5 / cell
                                    :ARG0-of (c6 / contain-01
                                          :ARG1 (p8 / protein :name (n5 / name :op1 "Eps8myc")
                                                :ARG1-of (r2 / reconstitute-01)))))
                        :ARG0-of (c3 / counter-01
                              :ARG1 (p4 / protein :name (n4 / name :op1 "myc"))))))
      :mod (i2 / indeed)
      :condition (p3 / perform-02
            :ARG1 (i / immunoprecipitate-01)
            :condition (p7 / present-02
                  :ARG1 (e / exceed-01
                        :ARG0 (p5 / peptide
                              :ARG0-of (c4 / compete-01))))))

# ::id pmid_1177_7939.43 ::date 2015-03-06T22:25:08 ::annotator SDL-AMR-09 ::preferred
# ::snt The association was, however, preserved when a control peptide, bearing a Y→A substitution and unable to bind to Eps8 (<xref ref-type="bibr" rid="bib28">Mongiovi et al., 1999</xref>), was used (<xref ref-type="fig" rid="fig1">Fig. 1</xref> C).
# ::save-date Mon Jun 1, 2015 ::file pmid_1177_7939_43.txt
(c / contrast-01
      :ARG2 (p / preserve-01
            :ARG1 (a / associate-01)
            :condition (u / use-01
                  :ARG1 (p2 / peptide
                        :purpose (c2 / control-01)
                        :ARG0-of (b / bear-01
                              :ARG1 (s / substitute-01
                                    :ARG1 (a3 / amino-acid :name (n2 / name :op1 "alanine"))
                                    :ARG2 (a2 / amino-acid :name (n / name :op1 "tyrosine"))))
                        :ARG1-of (b2 / bind-01
                              :ARG2 (e / enzyme :name (n3 / name :op1 "Eps8"))
                              :ARG1-of (p4 / possible-01 :polarity -)))
                  :ARG1-of (d3 / describe-01
                        :ARG0 (f / figure :mod "1C")))
            :ARG1-of (d / describe-01
                  :ARG0 (p5 / publication-91
                        :ARG0 (a4 / and
                              :op1 (p6 / person :name (n4 / name :op1 "Mongiovi"))
                              :op2 (p7 / person
                                    :mod (o / other)))
                        :time (d2 / date-entity :year 1999)))))

# ::id pmid_1177_7939.44 ::date 2015-03-07T00:28:58 ::annotator SDL-AMR-09 ::preferred
# ::snt Similarly, no Sos-1 could be recovered in anti-myc immunoprecipitates in the presence of the competing, but not of the control, peptide (<xref ref-type="fig" rid="fig1">Fig. 1</xref> C).
# ::save-date Mon Jan 4, 2016 ::file pmid_1177_7939_44.txt
(p / possible-01 :polarity -
      :ARG1 (r2 / recover-02
            :ARG1 (p2 / protein :name (n / name :op1 "Sos-1"))
            :location (p5 / protein
                  :ARG0-of (c / counter-01
                        :ARG1 (p3 / protein :name (n2 / name :op1 "myc")))
                  :ARG1-of (i / immunoprecipitate-01)))
      :ARG1-of (r / resemble-01)
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod "1C"))
      :ARG1-of (c4 / contrast-01
            :ARG2 (p7 / possible-01
                  :ARG1 r2
                  :condition (p6 / peptide
                        :ARG0-of (c3 / control-01))))
      :condition (p8 / present-02
            :ARG1 (p4 / peptide
                  :ARG0-of (c2 / compete-01))))

# ::id pmid_1177_7939.45 ::date 2015-03-07T02:10:56 ::annotator SDL-AMR-09 ::preferred
# ::snt Thus, under physiological conditions, the coimmunoprecipitation of Eps8 and Sos-1 depends on the integrity of the Eps8–E3b1 interaction, pointing to the existence of a physiological S/E/E8 complex.
# ::save-date Sun Jan 17, 2016 ::file pmid_1177_7939_45.txt
(i / infer-01
      :ARG1 (d / depend-01
            :ARG0 (c / coimmunoprecipitate-01
                  :ARG1 (e2 / enzyme :name (n / name :op1 "Eps8"))
                  :ARG2 (p3 / protein :name (n2 / name :op1 "Sos-1")))
            :ARG1 (i2 / integrity
                  :mod (i3 / interact-01
                        :ARG0 e2
                        :ARG1 (p4 / protein :name (n3 / name :op1 "E3b1"))))
            :condition (p / physiology)
            :ARG0-of (p2 / point-01
                  :ARG1 (e / exist-01
                        :ARG1 (m / macro-molecular-complex
                              :mod (p5 / physiology)
                              :part (s / slash
                                    :op1 (p6 / protein :name (n4 / name :op1 "S"))
                                    :op2 (p7 / protein :name (n5 / name :op1 "E"))
                                    :op3 (p8 / protein :name (n6 / name :op1 "E8"))))))))

# ::id pmid_1177_7939.46 ::date 2015-03-07T03:24:51 ::annotator SDL-AMR-09 ::preferred
# ::snt It cannot be formally excluded that Eps8, E3b1, and Sos-1 associate after cell lysis, thus allowing coimmunoprecipitation.
# ::save-date Tue Feb 2, 2016 ::file pmid_1177_7939_46.txt
(p / possible-01 :polarity -
      :ARG1 (e / exclude-01
            :ARG1 (a / associate-01
                  :ARG1 (a2 / and
                        :op1 (e2 / enzyme :name (n / name :op1 "Eps8"))
                        :op2 (p3 / protein :name (n2 / name :op1 "E3b1")))
                  :ARG2 (p4 / protein :name (n3 / name :op1 "Sos-1"))
                  :time (a3 / after
                        :op1 (l / lyse-01
                              :ARG1 (c / cell)))
                  :ARG0-of (a4 / allow-01
                        :ARG1 (c3 / coimmunoprecipitate-01
                              :ARG1 a2
                              :ARG2 p4)))
            :mod (f / formal)))

# ::id pmid_1177_7939.47 ::date 2015-03-07T03:51:17 ::annotator SDL-AMR-09 ::preferred
# ::snt However, we have previously demonstrated (<xref ref-type="bibr" rid="bib42">Scita et al., 2001</xref>) that the three endogenous proteins also colocalize in vivo in dynamic actin structures.
# ::save-date Tue Feb 2, 2016 ::file pmid_1177_7939_47.txt
(c / contrast-01
      :ARG2 (d / demonstrate-01
            :ARG0 (w / we)
            :ARG1 (c2 / colocalize-01
                  :ARG1 (p5 / protein :quant 3
                        :mod (e / endogenous))
                  :ARG2 (s / structure
                        :mod (d4 / dynamic)
                        :mod (a3 / actin))
                  :mod (a2 / also)
                  :manner (i / in-vivo))
            :time (p / previous)
            :ARG1-of (d2 / describe-01
                  :ARG0 (p2 / publication-91
                        :ARG0 (a / and
                              :op1 (p3 / person :name (n / name :op1 "Scita"))
                              :op2 (p4 / person
                                    :mod (o / other)))
                        :time (d3 / date-entity :year 2001)))))

# ::id pmid_1177_7939.48 ::date 2015-03-07T08:59:18 ::annotator SDL-AMR-09 ::preferred
# ::snt Thus, the sum of our results strongly argues in favor of the existence of a physiological S/E/E8 complex.
# ::save-date Sun Jan 17, 2016 ::file pmid_1177_7939_48.txt
(i / infer-01
      :ARG1 (a / argue-01
            :ARG0 (s3 / sum
                  :mod (t / thing
                        :ARG2-of (r / result-01)
                        :poss (w / we)))
            :ARG1 (e / exist-01
                  :ARG1 (m / macro-molecular-complex
                        :mod (p / physiology)
                        :part (s2 / slash
                              :op1 (p2 / protein :name (n / name :op1 "S"))
                              :op2 (p3 / protein :name (n2 / name :op1 "E"))
                              :op3 (p4 / protein :name (n3 / name :op1 "E8")))))
            :ARG1-of (s / strong-02)))

# ::id pmid_1177_7939.49 ::date 2015-03-07T09:35:14 ::annotator SDL-AMR-09 ::preferred
# ::snt Similarly, it cannot be formally excluded that other interactors of the SH3 domain of Eps8, besides E3b1, mediate the formation of the endogenous trimeric complex.
# ::save-date Wed Apr 1, 2015 ::file pmid_1177_7939_49.txt
(p / possible-01 :polarity -
      :ARG1-of (r / resemble-01)
      :ARG1 (e / exclude-01
            :ARG1 (m / mediate-01
                  :ARG0 (i / interact-01
                        :ARG0 (p4 / protein-segment :name (n3 / name :op1 "SH3" :op2 "domain")
                              :part-of (e4 / enzyme :name (n2 / name :op1 "Eps8")))
                        :mod (o / other)
                        :ARG2-of (e2 / except-01
                              :ARG1 (p2 / protein :name (n / name :op1 "E3b1"))))
                  :ARG1 (f2 / form-01
                        :ARG1 (m2 / macro-molecular-complex
                              :mod (t / trimeric)
                              :mod (e3 / endogenous))))
            :mod (f / formal)))

# ::id pmid_1177_7939.50 ::date 2015-03-08T01:31:45 ::annotator SDL-AMR-09 ::preferred
# ::snt This is, however, unlikely since no coimmunoprecipitation between Eps8 and Sos-1 could be detected when the two proteins were overexpressed in cell lines with relative low levels of E3b1 (<xref ref-type="bibr" rid="bib40">Scita et al., 1999</xref>; unpublished data).
# ::save-date Wed Dec 30, 2015 ::file pmid_1177_7939_50.txt
(c / contrast-01
      :ARG2 (l3 / likely-01 :polarity -
            :ARG1 (t / this)
            :ARG1-of (c2 / cause-01
                  :ARG0 (p / possible-01 :polarity -
                        :ARG1 (d / detect-01
                              :ARG1 (c3 / coimmunoprecipitate-01
                                    :ARG1 (e2 / enzyme :wiki "EPS8"
                                          :name (n / name :op1 "Eps8"))
                                    :ARG2 (p3 / protein :wiki "SOS1"
                                          :name (n2 / name :op1 "Sos-1")))
                              :condition (o3 / overexpress-01
                                    :ARG1 (a4 / and
                                          :op1 e2
                                          :op2 p3)
                                    :location (c4 / cell-line
                                          :part (p4 / protein :wiki -
                                                :name (n3 / name :op1 "E3b1")
                                                :quant (l / level
                                                      :ARG1-of (l2 / low-04
                                                            :ARG2-of (r / relative-05))))))))))
      :ARG1-of (d2 / describe-01
            :ARG0 (a3 / and
                  :op1 (p5 / publication-91
                        :ARG0 (a2 / and
                              :op1 (p6 / person :wiki -
                                    :name (n4 / name :op1 "Scita"))
                              :op2 (p7 / person
                                    :mod (o2 / other)))
                        :time (d3 / date-entity :year 1999))
                  :op2 (d4 / data
                        :ARG1-of (p8 / publish-01 :polarity -)))))

# ::id pmid_1177_7939.51 ::date 2015-03-08T04:35:20 ::annotator SDL-AMR-09 ::preferred
# ::snt Moreover, neither RN-tre, nor JIK, two other known interactors of the SH3 domain of Eps8 (<xref ref-type="bibr" rid="bib5">Biesova et al., 1997</xref>; <xref ref-type="bibr" rid="bib28">Mongiovi et al., 1999</xref>), were able to bind to Sos-1 (unpublished data).
# ::save-date Tue Dec 22, 2015 ::file pmid_1177_7939_51.txt
(a / and
      :op2 (p / possible-01 :polarity -
            :ARG1 (b / bind-01
                  :ARG1 (a2 / and
                        :op1 (p4 / protein :name (n3 / name :op1 "RN-tre"))
                        :op2 (p5 / protein :name (n4 / name :op1 "JIK"))
                        :ARG0-of (i2 / interact-01
                              :ARG1 (p3 / protein-segment :name (n2 / name :op1 "SH3" :op2 "domain")
                                    :part-of (e / enzyme :name (n5 / name :op1 "Eps8")))
                              :mod (o / other)
                              :ARG1-of (k / know-01))
                        :ARG1-of (d / describe-01
                              :ARG0 (a3 / and
                                    :op1 (p7 / publication-91
                                          :ARG0 (a4 / and
                                                :op1 (p8 / person :name (n6 / name :op1 "Biesova"))
                                                :op2 (p9 / person
                                                      :mod (o2 / other)))
                                          :time (d2 / date-entity :year 1997))
                                    :op2 (p10 / publication-91
                                          :ARG0 (a5 / and
                                                :op1 (p11 / person :name (n7 / name :op1 "Mongiovi"))
                                                :op2 (p12 / person
                                                      :mod (o3 / other)))
                                          :time (d3 / date-entity :year 1999)))))
                  :ARG2 (p2 / protein :name (n / name :op1 "Sos-1"))))
      :ARG1-of (p13 / publish-01 :polarity -))

# ::id pmid_1177_7939.52 ::date 2015-03-04T23:27:16 ::annotator SDL-AMR-09 ::preferred
# ::snt The adaptor molecules, E3b1 and Grb2, compete for binding to Sos-1 both in vitro and in vivo
# ::save-date Wed Apr 1, 2015 ::file pmid_1177_7939_52.txt
(a3 / and
      :op1 (c / compete-01
            :ARG0 (a2 / and
                  :op1 (p3 / protein :name (n3 / name :op1 "E3b1"))
                  :op2 (p4 / protein :name (n4 / name :op1 "Grb2"))
                  :mod (a4 / adaptor))
            :ARG2 (b2 / bind-01
                  :ARG1 a2
                  :ARG2 (p / protein :name (n / name :op1 "Sos-1")))
            :manner (i / in-vitro))
      :op2 (c2 / compete-01
            :ARG0 a2
            :ARG1 b2
            :manner (i2 / in-vivo)))

# ::id pmid_1177_7939.53 ::date 2015-03-07T10:57:15 ::annotator SDL-AMR-09 ::preferred
# ::snt Sos-1 has been shown to be part of a signaling complex with Grb2, which mediates the activation of Ras upon RTK stimulation.
# ::save-date Fri Mar 13, 2015 ::file pmid_1177_7939_53.txt
(s / show-01
      :ARG1 (h / have-part-91
            :ARG1 (m / macro-molecular-complex
                  :ARG0-of (s2 / signal-07)
                  :part (p2 / protein :name (n2 / name :op1 "Grb2")
                        :ARG0-of (m2 / mediate-01
                              :ARG1 (a / activate-01
                                    :ARG1 (e / enzyme :name (n3 / name :op1 "Ras"))
                                    :condition (s3 / stimulate-01
                                          :ARG1 (e2 / enzyme :name (n4 / name :op1 "RTK")))))))
            :ARG2 (p / protein :name (n / name :op1 "Sos-1"))))

# ::id pmid_1177_7939.54 ::date 2015-03-08T05:24:21 ::annotator SDL-AMR-09 ::preferred
# ::snt Our finding that, under physiological conditions, Sos-1 also participates in a complex with Eps8 and E3b1 raises the question of the physical and functional relationships between these two Sos-1–containing complexes.
# ::save-date Mon May 11, 2015 ::file pmid_1177_7939_54.txt
(r / raise-01
      :ARG0 (f / find-01
            :ARG0 (w / we)
            :ARG1 (m / macro-molecular-complex
                  :part (a / and
                        :op1 (p2 / protein :name (n / name :op1 "Sos-1")
                              :mod (a2 / also))
                        :op2 (e / enzyme :name (n2 / name :op1 "Eps8"))
                        :op3 (p4 / protein :name (n3 / name :op1 "E3b1")))
                  :condition (p / physiology)))
      :ARG1 (q / question-01
            :ARG1 (r2 / relation-03
                  :ARG0 a
                  :ARG1 (a5 / and
                        :op1 (p5 / physical)
                        :op2 (f2 / functional))
                  :ARG2 (m2 / macro-molecular-complex
                        :part (a3 / and
                              :op1 p2
                              :op2 (p6 / protein :name (n4 / name :op1 "Grb2")))))))

# ::id pmid_1177_7939.55 ::date 2015-03-08T06:32:20 ::annotator SDL-AMR-09 ::preferred
# ::snt To gain insight into this issue, we initially mapped the region of E3b1 responsible for the interaction with Sos-1 by using a series of deletion mutants of E3b1 fused to glutathione <i>S</i>-transferase (GST).
# ::save-date Mon Jan 4, 2016 ::file pmid_1177_7939_55.txt
(m / map-01
      :ARG0 (w / we)
      :ARG1 (r2 / region
            :part-of (p / protein :name (n / name :op1 "E3b1"))
            :ARG0-of (r / responsible-01
                  :ARG1 (i2 / interact-01
                        :ARG1 (p2 / protein :name (n2 / name :op1 "Sos-1"))
                        :manner (u2 / use-01
                              :ARG0 w
                              :ARG1 (p3 / protein :name (n3 / name :op1 "E3b1")
                                    :ARG1-of (f / fuse-01
                                          :ARG3 (e2 / enzyme :name (n5 / name :op1 "glutathione" :op2 "S-transferase")))
                                    :quant (s / series)
                                    :ARG2-of (m2 / mutate-01
                                          :manner (d3 / delete-01)))))))
      :purpose (u / understand-01
            :ARG0 w
            :ARG1 (i3 / issue-02
                  :mod (t / this)))
      :time (i / initial))

# ::id pmid_1177_7939.56 ::date 2015-03-04T06:08:23 ::annotator SDL-AMR-09 ::preferred
# ::snt Native Sos-1 could be efficiently recovered onto GST-E3b1 full length (<xref ref-type="fig" rid="fig2">Fig. 2</xref> A, amino acids [aa] 2–480).
# ::save-date Mon Dec 21, 2015 ::file pmid_1177_7939_56.txt
(p2 / possible-01
      :ARG1 (r / recover-02
            :ARG1 (p / protein :name (n / name :op1 "Sos-1")
                  :mod (n2 / native))
            :ARG2-of (e / efficient-01)
            :manner (l / length
                  :degree (f / full)
                  :poss (p3 / protein :name (n3 / name :op1 "GST-E3b1"))))
      :ARG1-of (d / describe-01
            :ARG0 (f2 / figure :mod "2A"
                  :mod (b / between
                        :op1 (a2 / amino-acid :value 2)
                        :op2 (a3 / amino-acid :value 480)))))

# ::id pmid_1177_7939.57 ::date 2015-03-04T06:17:25 ::annotator SDL-AMR-09 ::preferred
# ::snt Further mapping revealed that the SH3 domain of E3b1 (aa 416–480) was necessary and sufficient for binding (<xref ref-type="fig" rid="fig2">Fig. 2</xref> A).
# ::save-date Tue Mar 10, 2015 ::file pmid_1177_7939_57.txt
(r / reveal-01
      :ARG0 (m / map-01
            :degree (f / further))
      :ARG1 (a / and
            :op1 (n / need-01
                  :ARG0 (b / bind-01
                        :ARG2 p)
                  :ARG1 (p / protein-segment :name (n2 / name :op1 "SH3")
                        :part-of (p2 / protein :name (n3 / name :op1 "E3b1"))
                        :consist-of (b2 / between
                              :op1 (a3 / amino-acid :value 416)
                              :op2 (a4 / amino-acid :value 480))))
            :op2 (s / suffice-01
                  :ARG0 p
                  :ARG1 b))
      :ARG1-of (d / describe-01
            :ARG0 (f2 / figure :mod "2A")))

# ::id pmid_1177_7939.58 ::date 2015-03-04T06:26:20 ::annotator SDL-AMR-09 ::preferred
# ::snt We have previously shown that E3b1 binds to the proline-rich, COOH-terminal tail of Sos-1 (aa 1131–1333) (<xref ref-type="bibr" rid="bib40">Scita et al., 1999</xref>), which also binds to the SH3 of Grb2 (<xref ref-type="bibr" rid="bib24">Li et al., 1993</xref>; <xref ref-type="bibr" rid="bib12">Cussac et al., 1994</xref>).
# ::save-date Tue Mar 10, 2015 ::file pmid_1177_7939_58.txt
(s / show-01
      :ARG0 (w / we)
      :ARG1 (b / bind-01
            :ARG1 (p / protein :name (n / name :op1 "E3b1"))
            :ARG2 (t / tail
                  :part-of (p2 / protein-segment :name (n2 / name :op1 "COOH-terminus")
                        :mod (r / rich
                              :topic (a / amino-acid :name (n3 / name :op1 "proline")))
                        :part-of (p3 / protein :name (n4 / name :op1 "Sos-1"))
                        :ARG1-of (b2 / bind-01
                              :ARG2 (p7 / protein-segment :name (n6 / name :op1 "SH3")
                                    :part-of (p8 / protein :name (n7 / name :op1 "Grb2")))
                              :mod (a3 / also)
                              :ARG1-of (d5 / describe-01
                                    :ARG0 (a4 / and
                                          :op1 (p9 / publication-91
                                                :ARG0 (a5 / and
                                                      :op1 (p10 / person :name (n8 / name :op1 "Li"))
                                                      :op2 (p11 / person
                                                            :mod (o2 / other)))
                                                :time (d2 / date-entity :year 1993))
                                          :op2 (p12 / publication-91
                                                :ARG0 (a6 / and
                                                      :op1 (p13 / person :name (n9 / name :op1 "Cussac"))
                                                      :op2 (p14 / person
                                                            :mod (o3 / other)))
                                                :time (d3 / date-entity :year 1994)))))
                        :ARG1-of (m / mean-01
                              :ARG2 (b3 / between
                                    :op1 (a8 / amino-acid :value 1131)
                                    :op2 (a9 / amino-acid :value 1333)))))
            :ARG1-of (d4 / describe-01
                  :ARG0 (p4 / publication-91
                        :ARG0 (a2 / and
                              :op1 (p5 / person :name (n5 / name :op1 "Scita"))
                              :op2 (p6 / person
                                    :mod (o / other)))
                        :time (d / date-entity :year 1999))))
      :time (p15 / previous))

# ::id pmid_1177_7939.59 ::date 2015-03-04T06:42:22 ::annotator SDL-AMR-09 ::preferred
# ::snt Thus, Grb2 and E3b1 might compete for binding to Sos-1.
# ::save-date Mon Mar 9, 2015 ::file pmid_1177_7939_59.txt
(i / infer-01
      :ARG1 (p / possible-01
            :ARG1 (c / compete-01
                  :ARG0 (p2 / protein :name (n / name :op1 "Grb2"))
                  :ARG1 (p3 / protein :name (n2 / name :op1 "E3b1"))
                  :ARG2 (b / bind-01
                        :ARG1 (a / and
                              :op1 p2
                              :op2 p3)
                        :ARG2 (p4 / protein :name (n3 / name :op1 "Sos-1"))))))

# ::id pmid_1177_7939.60 ::date 2015-03-04T06:45:24 ::annotator SDL-AMR-09 ::preferred
# ::snt This hypothesis was validated by a series of experiments performed both in vitro and in vivo.
# ::save-date Tue Jul 28, 2015 ::file pmid_1177_7939_60.txt
(v / validate-01
      :ARG0 (s / series
            :consist-of (e / experiment-01
                  :ARG1-of (p / perform-02
                        :manner (a / and
                              :op1 (i / in-vitro)
                              :op2 (i2 / in-vivo)))))
      :ARG1 (t / thing
            :ARG1-of (h / hypothesize-01)
            :mod (t2 / this)))

# ::id pmid_1177_7939.61 ::date 2015-03-04T06:49:10 ::annotator SDL-AMR-09 ::preferred
# ::snt We could demonstrate that <bold>(</bold>a) the SH3 of Grb2, but not of Eps8, efficiently competed with the SH3 of E3b1 for binding to the proline-rich COOH-terminal tail of Sos-1 in vitro (<xref ref-type="fig" rid="fig2">Fig. 2</xref> B); (b) the Sos-1 peptide VPVPPPVPPRRR, known to constitute a Grb2-SH3 binding site (<xref ref-type="bibr" rid="bib24">Li et al., 1993</xref>; <xref ref-type="bibr" rid="bib12">Cussac et al., 1994</xref>), competed equally well the binding of the COOH-terminal tail of Sos-1 to the SH3s of Grb2 or E3b1 (<xref ref-type="fig" rid="fig2">Fig. 2</xref> C); (c) the binding constants of the interaction between the proline rich COOH-terminal tail of Sos-1 and the SH3 domains of Grb2 and E3b1 were very similar (<xref ref-type="fig" rid="fig2">Fig. 2</xref> D); (d) overexpression of Grb2 abolished the ability of GST-E3b1 to bind to native Sos-1 (<xref ref-type="fig" rid="fig3">Fig. 3</xref> A); and (e) overexpression of E3b1 significantly decreased the coimmunoprecipitation between Grb2 and Sos-1 (<xref ref-type="fig" rid="fig3">Fig. 3</xref> B).
# ::save-date Mon Jan 25, 2016 ::file pmid_1177_7939_61.txt
(p / possible-01
      :ARG1 (d3 / demonstrate-01
            :ARG0 (w / we)
            :ARG1 (a2 / and
                  :op1 (c / compete-01 :li "a"
                        :ARG0 (p2 / protein-segment :name (n2 / name :op1 "SH3")
                              :part-of (p3 / protein :name (n3 / name :op1 "Grb2"))
                              :ARG1-of (i / instead-of-91
                                    :ARG2 (p4 / protein-segment :name (n4 / name :op1 "SH3")
                                          :part-of (e3 / enzyme :name (n5 / name :op1 "Eps8")))))
                        :ARG1 (p6 / protein-segment :name (n6 / name :op1 "SH3")
                              :part-of (p7 / protein :name (n7 / name :op1 "E3b1")))
                        :ARG2 (b / bind-01
                              :ARG2 (t2 / tail
                                    :part-of (p8 / protein-segment :name (n8 / name :op1 "COOH-terminus")
                                          :part-of (p19 / protein :name (n9 / name :op1 "Sos-1"))
                                          :mod (r2 / rich
                                                :topic (a3 / amino-acid :name (n10 / name :op1 "proline")))))
                              :manner (i2 / in-vitro))
                        :ARG2-of (e / efficient-01
                              :ARG1 p2)
                        :ARG1-of (d4 / describe-01
                              :ARG0 (f / figure :mod "2B")))
                  :op2 (c2 / compete-01 :li "b"
                        :ARG0 (p10 / peptide :name (n15 / name :op1 "VPVPPPVPPRRR")
                              :part-of p19
                              :ARG0-of (c3 / constitute-01
                                    :ARG1 (p9 / protein-segment
                                          :ARG1-of (b2 / bind-01
                                                :ARG2 p2))
                                    :ARG1-of (d5 / describe-01
                                          :ARG0 (a5 / and
                                                :op1 (p11 / publication-91
                                                      :ARG0 (a4 / and
                                                            :op1 (p12 / person :name (n11 / name :op1 "Li"))
                                                            :op2 (p13 / person
                                                                  :mod (o / other)))
                                                      :time (d / date-entity :year 1993))
                                                :op2 (p14 / publication-91
                                                      :ARG0 (a6 / and
                                                            :op1 (p15 / person :name (n12 / name :op1 "Cussac"))
                                                            :op2 (p16 / person
                                                                  :mod (o2 / other)))
                                                      :time (d2 / date-entity :year 1994))))
                                    :ARG1-of (k / know-01)))
                        :ARG1 (b3 / bind-01
                              :ARG1 t2
                              :ARG2 (o3 / or
                                    :op1 p2
                                    :op2 p6))
                        :mod (w2 / well
                              :degree (e2 / equal))
                        :ARG1-of (d6 / describe-01
                              :ARG0 (f2 / figure :mod "2C")))
                  :op3 (r / resemble-01 :li "c"
                        :ARG1 (c4 / constant
                              :value-of (i3 / interact-01
                                    :ARG0 t2
                                    :ARG1 p2
                                    :ARG0-of (b4 / bind-01)))
                        :ARG2 (c5 / constant
                              :value-of (i4 / interact-01
                                    :ARG0 t2
                                    :ARG1 p6
                                    :ARG0-of (b5 / bind-01)))
                        :degree (v / very)
                        :ARG1-of (d7 / describe-01
                              :ARG0 (f3 / figure :mod "2D")))
                  :op4 (a / abolish-01 :li "d"
                        :ARG0 (o4 / overexpress-01
                              :ARG1 p3)
                        :ARG1 (c7 / capable-01
                              :ARG1 (p18 / protein :name (n / name :op1 "GST-E3b1"))
                              :ARG2 (b6 / bind-01
                                    :ARG1 p18
                                    :ARG2 (p20 / protein :name (n13 / name :op1 "Sos-1")
                                          :mod (n14 / native))))
                        :ARG1-of (d8 / describe-01
                              :ARG0 (f4 / figure :mod "3A")))
                  :op5 (d9 / decrease-01 :li "e"
                        :ARG0 (o5 / overexpress-01
                              :ARG1 p7)
                        :ARG1 (p17 / precipitate-01
                              :ARG0 (a7 / antibody)
                              :ARG1 (m / macro-molecular-complex
                                    :part p3
                                    :part p19))
                        :ARG2 (s / significant-02)
                        :ARG1-of (d10 / describe-01
                              :ARG0 (f5 / figure :mod "3B"))))))

# ::id pmid_1177_7939.62 ::date 2015-03-04T07:36:03 ::annotator SDL-AMR-09 ::preferred
# ::snt Thus, Sos-1 binds either E3b1 or Grb2, in a mutually exclusive fashion, suggesting that two distinct pools of Sos-1 exist in the cells.
# ::save-date Wed Dec 30, 2015 ::file pmid_1177_7939_62.txt
(i / infer-01
      :ARG1 (b / bind-01
            :ARG1 (p / protein :name (n / name :op1 "Sos-1"))
            :ARG2 (o / or
                  :op1 (p2 / protein :name (n2 / name :op1 "E3b1"))
                  :op2 (p3 / protein :name (n3 / name :op1 "Grb2")))
            :ARG0-of (e / exclusive-02
                  :mod (m / mutual))
            :ARG0-of (s / suggest-01
                  :ARG1 (e2 / exist-01
                        :ARG1 (p4 / pool :quant 2
                              :consist-of p
                              :mod (d / distinct))
                        :location (c / cell)))))

# ::id pmid_1177_7939.63 ::date 2015-03-04T07:46:27 ::annotator SDL-AMR-09 ::preferred
# ::snt To test this possibility in vivo, we set out to perturb the equilibrium between the Sos-1–E3b1 (S/E) and Sos-1–Grb2 (S/G) complexes, by increasing the levels of E3b1 within the cell.
# ::save-date Sat Dec 19, 2015 ::file pmid_1177_7939_63.txt
(s / set-out-06
      :ARG0 (w / we)
      :ARG1 (p / perturb-01
            :ARG0 w
            :ARG1 (e / equilibrate-01
                  :ARG1 (a / and
                        :op1 (m / macro-molecular-complex
                              :part (p2 / protein :name (n / name :op1 "Sos-1"))
                              :part (p3 / protein :name (n2 / name :op1 "E3b1")))
                        :op2 (m2 / macro-molecular-complex
                              :part p2
                              :part (p4 / protein :name (n3 / name :op1 "Grb2")))))
            :instrument (i / increase-01
                  :ARG0 w
                  :ARG1 (l / level
                        :quant-of p3)
                  :location (c / cell)))
      :purpose (t / test-01
            :ARG0 w
            :ARG1 (p5 / possible-01
                  :ARG1 (t2 / this))
            :manner (i2 / in-vivo)))

# ::id pmid_1177_7939.64 ::date 2015-03-04T07:55:20 ::annotator SDL-AMR-09 ::preferred
# ::snt If the two complexes are functionally distinct, then the overexpression of E3b1, by competing the S/G interaction, should result in (a) reduced Sos-1 recruitment in vivo to active EGFR, (b) consequent reduction in Ras activation, as measured by reduced Ras-GTP levels, (c) reduced activation of Ras-dependent pathways, as measured by activation of MAPK, and finally (d) reduced proliferative response.
# ::save-date Sun Dec 20, 2015 ::file pmid_1177_7939_64.txt
(r / recommend-01
      :ARG1 (r2 / result-01
            :ARG1 (o / overexpress-01
                  :ARG1 (p2 / protein :name (n4 / name :op1 "E3b1")))
            :ARG2 (a / and
                  :op1 (r3 / recruit-01 :li "a"
                        :ARG1 p3
                        :ARG2 (e / enzyme :name (n / name :op1 "EGFR")
                              :ARG0-of (a2 / activity-06))
                        :ARG1-of (r4 / reduce-01)
                        :manner (i2 / in-vivo))
                  :op2 (r5 / reduce-01 :li "b"
                        :ARG1 (a3 / activate-01
                              :ARG1 (e2 / enzyme :name (n2 / name :op1 "Ras")))
                        :ARG1-of (c2 / cause-01
                              :ARG0 r3)
                        :ARG1-of (m / measure-01
                              :ARG2 (l / level
                                    :quant-of (m2 / macro-molecular-complex
                                          :part e2
                                          :part (s / small-molecule :name (n7 / name :op1 "GTP")))
                                    :ARG1-of (r6 / reduce-01))))
                  :op3 (a4 / activate-01 :li "c"
                        :ARG1 (p5 / pathway
                              :ARG0-of (d / depend-01
                                    :ARG1 e2))
                        :ARG1-of (r7 / reduce-01)
                        :ARG1-of (m3 / measure-01
                              :ARG2 (a5 / activate-01
                                    :ARG1 (p / pathway :name (n3 / name :op1 "MAPK")))))
                  :op4 (r8 / respond-01 :li "d" :li "-1"
                        :ARG1-of (r9 / reduce-01)
                        :mod (p6 / proliferate-01)))
            :manner (c / compete-01
                  :ARG0 o
                  :ARG1 (i / interact-01
                        :ARG0 (p3 / protein :name (n5 / name :op1 "Sos-1"))
                        :ARG1 (p4 / protein :name (n6 / name :op1 "Grb2")))))
      :condition (f2 / function-01
            :ARG0 (m4 / macro-molecular-complex :quant 2)
            :mod (d2 / distinct)))

# ::id pmid_1177_7939.65 ::date 2015-03-04T08:25:57 ::annotator SDL-AMR-09 ::preferred
# ::snt All of these predictions were confirmed experimentally (<xref ref-type="fig" rid="fig4">Fig. 4</xref>, A–C).
# ::save-date Wed Dec 30, 2015 ::file pmid_1177_7939_65.txt
(c / confirm-01
      :ARG1 (t / thing
            :ARG1-of (p / predict-01)
            :mod (a / all)
            :mod (t2 / this))
      :manner (e / experiment-01)
      :ARG1-of (d / describe-01
            :ARG0 (a2 / and
                  :op1 (f / figure :mod "A")
                  :op2 (f2 / figure :mod "B")
                  :op3 (f3 / figure :mod "C"))))

# ::id pmid_1177_7939.66 ::date 2015-03-04T08:29:36 ::annotator SDL-AMR-09 ::preferred
# ::snt We note that our mapping data are at variance with those recently reported by <xref ref-type="bibr" rid="bib16">Fan and Goff (2000)</xref>, who concluded that, in vivo<i>,</i> the interaction between Sos-1 and E3b1–Abi-1 is mediated by the NH<sub>2</sub>-terminal portion of the latter.
# ::save-date Wed Dec 30, 2015 ::file pmid_1177_7939_66.txt
(n2 / note-02
      :ARG0 (w / we)
      :ARG1 (v / vary-01
            :ARG1 (d3 / data
                  :topic (m / map-01)
                  :poss w)
            :compared-to (d4 / data
                  :mod (t / that)
                  :ARG1-of (r / report-01
                        :ARG0 (p / publication-91
                              :ARG0 (a / and
                                    :op1 (p2 / person :name (n / name :op1 "Fan"))
                                    :op2 (p3 / person :name (n3 / name :op1 "Goff"))
                                    :ARG0-of (c / conclude-01
                                          :ARG1 (m2 / mediate-01
                                                :ARG0 (p6 / protein-segment :name (n7 / name :op1 "NH2-terminus")
                                                      :part-of p4)
                                                :ARG1 (i / interact-01
                                                      :ARG0 (p5 / protein :name (n4 / name :op1 "Sos-1"))
                                                      :ARG1 (p4 / protein :name (n5 / name :op1 "E3b1–Abi-1")))
                                                :manner (i2 / in-vivo))))
                              :time (d / date-entity :year 2000))
                        :time (r2 / recent)))))

# ::id pmid_1177_7939.67 ::date 2015-03-04T08:42:04 ::annotator SDL-AMR-09 ::preferred
# ::snt Consistently, <xref ref-type="bibr" rid="bib16">Fan and Goff (2000)</xref> did not observe competition in vivo between Grb2 and E3b1 for binding to Sos-1.
# ::save-date Mon Feb 1, 2016 ::file pmid_1177_7939_67.txt
(o / observe-01 :polarity -
      :ARG0 (a / and
            :op1 (p2 / person :name (n / name :op1 "Fan"))
            :op2 (p3 / person :name (n2 / name :op1 "Goff"))
            :ARG0-of (p / publication-91
                  :time (d / date-entity :year 2000)))
      :ARG1 (c / compete-01
            :ARG0 (p4 / protein :name (n3 / name :op1 "Grb2"))
            :ARG1 (p5 / protein :name (n4 / name :op1 "E3b1"))
            :ARG2 (b / bind-01
                  :ARG2 (p6 / protein :name (n5 / name :op1 "Sos-1"))))
      :manner (c2 / consistent-02)
      :manner (i / in-vivo))

# ::id pmid_1177_7939.68 ::date 2015-03-04T08:49:13 ::annotator SDL-AMR-09 ::preferred
# ::snt Although we cannot exclude that the NH<sub>2</sub>-terminal region of E3b1–Abi-1 participates in binding, in vivo<i>,</i> we were not able to observe a high-affinity binding surface in that region by in vitro binding experiments (<xref ref-type="fig" rid="fig2">Fig. 2</xref> A; <xref ref-type="bibr" rid="bib40">Scita et al., 1999</xref>).
# ::save-date Sun Jul 26, 2015 ::file pmid_1177_7939_68.txt
(p / possible-01 :polarity -
      :ARG1 (o / observe-01
            :ARG0 (w / we)
            :ARG1 (s / surface
                  :location-of (b / bind-01)
                  :mod (a / affinity
                        :ARG1-of (h / high-02)))
            :location (r / region
                  :mod (t / that))
            :manner (e / experiment-01
                  :ARG1 (b2 / bind-01)
                  :manner (i / in-vitro)))
      :concession (p2 / possible-01 :polarity -
            :ARG1 (e2 / exclude-01
                  :ARG0 w
                  :ARG1 (p3 / participate-01
                        :ARG0 (p4 / protein-segment :name (n / name :op1 "NH2-terminus")
                              :part-of (p5 / protein :name (n2 / name :op1 "E3b1–Abi-1")))
                        :ARG1 (b3 / bind-01)
                        :manner (i2 / in-vivo))))
      :ARG1-of (d2 / describe-01
            :ARG0 (a3 / and
                  :op1 (p6 / publication-91
                        :ARG0 (a2 / and
                              :op1 (p7 / person :name (n4 / name :op1 "Scita"))
                              :op2 (p8 / person
                                    :mod (o2 / other)))
                        :time (d / date-entity :year 1999))
                  :op2 (f / figure :mod "2A"))))

# ::id pmid_1177_7939.69 ::date 2015-03-04T08:58:23 ::annotator SDL-AMR-09 ::preferred
# ::snt Conversely, under our conditions of analysis, the efficient competition of the SH3 domains of Grb2 and E3b1 for binding to the same Sos-1 peptide, coupled to the readily detectable biological competition, strongly suggests that the SH3-mediated contact is the major determinant of the interaction between Sos-1 and E3b1.
# ::save-date Sun Dec 20, 2015 ::file pmid_1177_7939_69.txt
(s / suggest-01
      :ARG0 (c / compete-01
            :ARG0 (p8 / protein-segment :name (n6 / name :op1 "SH3" :op2 "domain")
                  :part-of (p3 / protein :name (n3 / name :op1 "Grb2")))
            :ARG1 (p / protein-segment :name (n / name :op1 "SH3" :op2 "domain")
                  :part-of (p4 / protein :name (n4 / name :op1 "E3b1")))
            :ARG2 (b / bind-01
                  :ARG2 (p5 / peptide
                        :ARG1-of (s3 / same-01)
                        :part-of (p6 / protein :name (n5 / name :op1 "Sos-1"))))
            :ARG2-of (e / efficient-01
                  :ARG1 p)
            :ARG1-of (c2 / couple-01
                  :ARG2 (c3 / compete-01
                        :mod (b2 / biology)
                        :ARG1-of (d / detect-01
                              :ARG1-of (p7 / possible-01)
                              :manner (r / ready)))))
      :ARG1 (d2 / determine-01
            :ARG0 (c4 / contact
                  :ARG1-of (m / mediate-01
                        :ARG0 (p2 / protein-segment :name (n8 / name :op1 "SH3"))))
            :ARG1 (i / interact-01
                  :ARG0 p6
                  :ARG1 p4)
            :ARG1-of (m2 / major-02))
      :ARG1-of (s2 / strong-02)
      :ARG2-of (c6 / contrast-01)
      :condition (c5 / condition
            :mod (a / analyze-01)
            :poss (w / we)))

# ::id pmid_1177_7939.70 ::date 2015-03-04T09:13:40 ::annotator SDL-AMR-09 ::preferred
# ::snt E3b1 is a limiting factor in Rac activation
# ::save-date Wed Mar 4, 2015 ::file pmid_1177_7939_70.txt
(f / factor
      :ARG0-of (l / limit-01
            :ARG1 (a / activate-01
                  :ARG1 (e / enzyme :name (n2 / name :op1 "Rac"))))
      :domain (p / protein :name (n / name :op1 "E3b1")))

# ::id pmid_1177_7939.71 ::date 2015-03-04T09:16:18 ::annotator SDL-AMR-09 ::preferred
# ::snt The competition between E3b1 and Grb2 for the same binding site on Sos-1 implies that an individual Sos-1 molecule can only be part of one GEF complex at a time.
# ::save-date Tue Feb 23, 2016 ::file pmid_1177_7939_71.txt
(i / imply-01
      :ARG0 (c / compete-01
            :ARG0 (p / protein :name (n / name :op1 "E3b1"))
            :ARG1 (p2 / protein :name (n2 / name :op1 "Grb2"))
            :ARG2 (p7 / protein-segment
                  :ARG1-of (s2 / same-01)
                  :ARG1-of (b / bind-01)
                  :part-of (p3 / protein :name (n3 / name :op1 "Sos-1"))))
      :ARG1 (p4 / possible-01
            :ARG1 (h / have-part-91
                  :ARG1 (m / macro-molecular-complex :quant 1
                        :part (p6 / protein :name (n4 / name :op1 "GEF")))
                  :ARG2 (m2 / molecule
                        :mod p3
                        :mod (i2 / individual))
                  :mod (a / at-a-time)
                  :mod (o / only))))

# ::id pmid_1177_7939.72 ::date 2015-03-04T09:29:37 ::annotator SDL-AMR-09 ::preferred
# ::snt However, different pools of Sos-1, either bound to Grb2 or to E3b1, could exist in vivo.
# ::save-date Sun Jan 17, 2016 ::file pmid_1177_7939_72.txt
(c2 / contrast-01
      :ARG2 (p / possible-01
            :ARG1 (e / exist-01
                  :ARG1 (p2 / pool
                        :ARG1-of (d / differ-02)
                        :consist-of (p3 / protein :name (n / name :op1 "Sos-1")
                              :ARG1-of (b / bind-01
                                    :ARG2 (o / or
                                          :op1 (p4 / protein :name (n2 / name :op1 "Grb2"))
                                          :op2 (p5 / protein :name (n3 / name :op1 "E3b1")))))))
            :manner (i / in-vivo)))

# ::id pmid_1177_7939.73 ::date 2015-03-04T09:33:14 ::annotator SDL-AMR-09 ::preferred
# ::snt We tried to gain insight into this issue.
# ::save-date Mon Jul 20, 2015 ::file pmid_1177_7939_73.txt
(t2 / try-01
      :ARG0 (w / we)
      :ARG1 (g / gain-02
            :ARG0 w
            :ARG1 (i2 / insight
                  :topic (i / issue-02
                        :mod (t / this)))))

# ::id pmid_1177_7939.74 ::date 2015-03-04T09:34:54 ::annotator SDL-AMR-09 ::preferred
# ::snt We showed that BIAcore measurements revealed similar kinetic parameters for the SH3-mediated S/G and S/E interactions (<xref ref-type="fig" rid="fig2">Fig. 2</xref> D).
# ::save-date Sun Dec 20, 2015 ::file pmid_1177_7939_74.txt
(s / show-01
      :ARG0 (w / we)
      :ARG1 (r2 / reveal-01
            :ARG0 (t / thing
                  :ARG1-of (m / measure-01
                        :ARG0 (c / company :name (n / name :op1 "BIAcore"))))
            :ARG1 (p / parameter
                  :ARG1-of (r / resemble-01
                        :ARG2 (i2 / interact-01
                              :ARG0 (a / and
                                    :op1 p5
                                    :op2 (p4 / protein :name (n5 / name :op1 "E3b1")))
                              :ARG1-of m2))
                  :mod (k / kinetic)
                  :topic (i / interact-01
                        :ARG0 (p5 / protein :name (n3 / name :op1 "Sos-1"))
                        :ARG1 (p3 / protein :name (n4 / name :op1 "Grb2"))
                        :ARG1-of (m2 / mediate-01
                              :ARG0 (p2 / protein-segment :name (n2 / name :op1 "SH3"))))))
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod "2D")))

# ::id pmid_1177_7939.75 ::date 2015-03-04T09:46:33 ::annotator SDL-AMR-09 ::preferred
# ::snt However, when we measured the relative abundance of S/G and S/E complexes within the cell, we found a 10-fold excess of the former (<xref ref-type="fig" rid="fig5">Fig. 5</xref> A), under conditions in which quantitative immunoprecipitation of the adaptor molecules, Grb2 and E3b1, was achieved (<xref ref-type="fig" rid="fig5">Fig. 5</xref> A).
# ::save-date Wed Mar 2, 2016 ::file pmid_1177_7939_75.txt
(c3 / contrast-01
      :ARG2 (f / find-01
            :ARG0 (w / we)
            :ARG1 (e / exceed-01
                  :ARG0 (m / macro-molecular-complex
                        :part (p5 / protein :name (n / name :op1 "Sos-1"))
                        :part (p / protein :name (n2 / name :op1 "Grb2")))
                  :ARG1 (m2 / macro-molecular-complex
                        :part (p2 / protein :name (n3 / name :op1 "E3b1"))
                        :part p5)
                  :ARG2 (p3 / product-of :op1 10)
                  :ARG1-of (d / describe-01
                        :ARG0 (f2 / figure :mod "5A"))
                  :condition (a2 / achieve-01
                        :ARG1 (i / immunoprecipitate-01
                              :ARG1 (a5 / and
                                    :op1 p
                                    :op2 p2
                                    :mod (a4 / adaptor))
                              :mod (q / quantity))
                        :ARG1-of (d2 / describe-01
                              :ARG0 (f3 / figure :mod "5A"))))
            :time (m3 / measure-01
                  :ARG1 (a / abound-01
                        :ARG1 (a6 / and
                              :op1 m
                              :op2 m2)
                        :ARG2 (c / cell)
                        :ARG2-of (r / relative-05)))))

# ::id pmid_1177_7939.76 ::date 2015-03-04T09:51:03 ::annotator SDL-AMR-09 ::preferred
# ::snt Thus, the data indicate that two pools of Sos-1, associated with different adaptors, exist simultaneously in the cell.
# ::save-date Mon Mar 9, 2015 ::file pmid_1177_7939_76.txt
(i / infer-01
      :ARG1 (i2 / indicate-01
            :ARG0 (d / data)
            :ARG1 (e / exist-01
                  :ARG1 (p / pool :quant 2
                        :consist-of (p2 / protein :name (n / name :op1 "Sos-1"))
                        :ARG1-of (a / associate-01
                              :ARG2 (a2 / adaptor
                                    :ARG1-of (d2 / differ-02))))
                  :manner (s / simultaneous)
                  :location (c / cell))))

# ::id pmid_1177_7939.77 ::date 2015-02-26T23:45:48 ::annotator SDL-AMR-09 ::preferred
# ::snt They further suggest that the pool of E3b1, available for binding to Sos-1, is reduced relative to that of Grb2, and may be rate-limiting.
# ::save-date Sat Jul 25, 2015 ::file pmid_1177_7939_77.txt
(s / suggest-01
      :ARG0 (t / they)
      :ARG1 (a3 / and
            :op1 (r / reduce-01
                  :ARG1 (p / pool
                        :consist-of (p3 / protein :name (n / name :op1 "E3b1")
                              :ARG2-of (a / available-02
                                    :purpose (b / bind-01
                                          :ARG1 p
                                          :ARG2 (p4 / protein :name (n2 / name :op1 "Sos-1"))))))
                  :compared-to (p5 / pool
                        :consist-of (p6 / protein :name (n3 / name :op1 "Grb2"))))
            :op2 (p2 / possible-01
                  :ARG1 (l / limit-01
                        :ARG0 p
                        :ARG1 (r2 / rate))))
      :degree (f / further))

# ::id pmid_1177_7939.78 ::date 2015-02-27T01:24:36 ::annotator SDL-AMR-09 ::preferred
# ::snt Indeed, overexpression of E3b1 resulted in increased PAK65 activity, an indicator of Rac activation (<xref ref-type="bibr" rid="bib27">Manser et al., 1994</xref>) (<xref ref-type="fig" rid="fig5">Fig. 5</xref> B), which was abrogated by a dominant negative Rac mutant (<xref ref-type="fig" rid="fig5">Fig. 5</xref> B).
# ::save-date Fri Feb 5, 2016 ::file pmid_1177_7939_78.txt
(r / result-01
      :ARG1 (o / overexpress-01
            :ARG1 (p4 / protein :name (n / name :op1 "E3b1")))
      :ARG2 (a / activity-06
            :ARG0 (e4 / enzyme :name (n2 / name :op1 "PAK65"))
            :ARG1-of (i2 / increase-01)
            :ARG0-of (i / indicate-01
                  :ARG1 (a2 / activate-01
                        :ARG1 (e2 / enzyme :name (n3 / name :op1 "Rac"))
                        :ARG1-of (a3 / abrogate-01
                              :ARG2 (e3 / enzyme :name (n5 / name :op1 "Rac")
                                    :ARG0-of (d4 / dominate-01)
                                    :ARG1-of (m / mutate-01 :mod "-/-"))
                              :ARG1-of (d5 / describe-01
                                    :ARG0 f2)))))
      :ARG1-of (d2 / describe-01
            :ARG0 (a5 / and
                  :op1 (p / publication-91
                        :ARG0 (a4 / and
                              :op1 (p2 / person :name (n4 / name :op1 "Manser"))
                              :op2 (p5 / person
                                    :mod (o2 / other)))
                        :time (d3 / date-entity :year 1994))
                  :op2 (f2 / figure :mod "5B")))
      :mod (i3 / indeed))

# ::id pmid_1177_7939.79 ::date 2015-02-27T07:47:51 ::annotator SDL-AMR-09 ::preferred
# ::snt On the other hand, overexpression of Sos-1 did not lead to increased PAK65 activity.
# ::save-date Mon Jul 6, 2015 ::file pmid_1177_7939_79.txt
(c / contrast-01
      :ARG2 (l / lead-03 :polarity -
            :ARG0 (o2 / overexpress-01
                  :ARG1 (p / protein :name (n / name :op1 "Sos-1")))
            :ARG2 (a / activity-06
                  :ARG0 (e2 / enzyme :name (n2 / name :op1 "PAK65"))
                  :ARG1-of (i2 / increase-01))))

# ::id pmid_1177_7939.80 ::date 2015-02-28T11:11:55 ::annotator SDL-AMR-09 ::preferred
# ::snt An additional corollary of this hypothesis is that the overexpression of E3b1, by facilitating the formation of a trimeric complex with Eps8 and Sos-1, should directly lead to activation of Rac.
# ::save-date Sun Jan 17, 2016 ::file pmid_1177_7939_80.txt
(c / corollary
      :domain (r / recommend-01
            :ARG1 (l / lead-03
                  :ARG0 (o / overexpress-01
                        :ARG1 (p2 / protein :name (n2 / name :op1 "E3b1")))
                  :ARG2 (a / activate-01
                        :ARG1 (e / enzyme :name (n / name :op1 "Rac")))
                  :ARG1-of (d / direct-02)
                  :manner (f / facilitate-01
                        :ARG0 o
                        :ARG1 (f2 / form-01
                              :ARG1 (m / macro-molecular-complex
                                    :part p2
                                    :part (e2 / enzyme :name (n3 / name :op1 "Eps8"))
                                    :part (p3 / protein :name (n4 / name :op1 "Sos-1"))
                                    :mod (t3 / trimer))))))
      :ARG0-of (a2 / add-01
            :ARG1 (t2 / thing
                  :ARG1-of (h / hypothesize-01)
                  :mod (t / this))))

# ::id pmid_1177_7939.81 ::date 2015-02-28T11:17:40 ::annotator SDL-AMR-09 ::preferred
# ::snt To test this prediction E3b1 or a mutant of E3b1 (E3b1-DY), bearing alanine substitutions of the DY residues critical for the interaction with Eps8 (<xref ref-type="bibr" rid="bib28">Mongiovi et al., 1999</xref>), were used to infect wild-type and eps8<sup>−/−</sup> fibroblasts.
# ::save-date Mon Jan 25, 2016 ::file pmid_1177_7939_81.txt
(u / use-01
      :ARG1 (o / or
            :op1 (p / protein :name (n2 / name :op1 "E3b1"))
            :op2 (p2 / protein :name (n3 / name :op1 "E3b1-DY")
                  :ARG2-of (m / mutate-01
                        :ARG1 p)
                  :ARG0-of (b / bear-01
                        :ARG1 (s / substitute-01
                              :ARG1 (a / amino-acid :name (n / name :op1 "alanine"))
                              :ARG2 (r / residue
                                    :mod (p8 / protein-segment :name (n4 / name :op1 "DY"))
                                    :ARG1-of (c / critical-02
                                          :ARG3 (i / interact-01
                                                :ARG0 p2
                                                :ARG1 (e2 / enzyme :name (n5 / name :op1 "Eps8")))))))))
      :ARG2 (i2 / infect-01
            :ARG1 (a2 / and
                  :op1 (f / fibroblast
                        :mod (w / wild-type))
                  :op2 (f2 / fibroblast
                        :ARG0-of (m2 / mutate-01
                              :ARG1 e2)))
            :ARG2 o
            :purpose (t2 / test-01
                  :ARG1 (t3 / thing
                        :ARG1-of (p3 / predict-01)
                        :mod (t4 / this))
                  :ARG1-of (d2 / describe-01
                        :ARG0 (p4 / publication-91
                              :ARG0 (a3 / and
                                    :op1 (p6 / person :name (n7 / name :op1 "Mongiovi"))
                                    :op2 (p7 / person
                                          :mod (o2 / other)))
                              :time (d3 / date-entity :year 1999))))))

# ::id pmid_1177_7939.82 ::date 2015-03-01T03:29:06 ::annotator SDL-AMR-09 ::preferred
# ::snt The levels of GTP-bound Rac were then determined by in vitro binding assays using the immobilized CRIB domain of PAK65 (<xref ref-type="bibr" rid="bib27">Manser et al., 1994</xref>).
# ::save-date Sun Jan 17, 2016 ::file pmid_1177_7939_82.txt
(d2 / determine-01
      :ARG1 (l / level
            :quant-of (e / enzyme :name (n / name :op1 "Rac")
                  :ARG2-of (b / bind-01
                        :ARG1 (s / small-molecule :name (n2 / name :op1 "GTP")))))
      :ARG2 (a / assay-01
            :ARG1 (b2 / bind-01)
            :ARG0-of (u / use-01
                  :ARG1 (p5 / protein-segment :name (n6 / name :op1 "CRIB" :op2 "domain")
                        :ARG1-of (m / mobilize-01 :polarity -)
                        :ARG1-of (i2 / immobilize-01)
                        :part-of (e2 / enzyme :name (n4 / name :op1 "PAK65"))))
            :manner (i / in-vitro))
      :ARG1-of (d4 / describe-01
            :ARG0 (p2 / publication-91
                  :ARG0 (a2 / and
                        :op1 (p4 / person :name (n3 / name :op1 "Manser"))
                        :op2 (p6 / person
                              :mod (o / other)))
                  :time (d5 / date-entity :year 1994)))
      :time (t / then))

# ::id pmid_1177_7939.83 ::date 2015-03-02T01:43:31 ::annotator SDL-AMR-09 ::preferred
# ::snt E3b1, but not the E3b1 mutant impaired in Eps8 binding, caused a readily detectable increase in Rac-GTP levels in wild type, but not in eps8<sup>−/−</sup> fibroblasts (<xref ref-type="fig" rid="fig5">Fig. 5</xref> C).
# ::save-date Sun Jan 17, 2016 ::file pmid_1177_7939_83.txt
(c3 / contrast-01
      :ARG1 (c / cause-01
            :ARG0 (p / protein :name (n / name :op1 "E3b1"))
            :ARG1 (i / increase-01
                  :ARG1 (l / level
                        :quant-of (m3 / macro-molecular-complex
                              :part (e2 / enzyme :name (n2 / name :op1 "Rac"))
                              :part (s / small-molecule :name (n6 / name :op1 "GTP"))))
                  :ARG1-of (d3 / detect-01
                        :ARG1-of (p3 / possible-01)
                        :manner (r / ready))
                  :ARG1-of (b2 / be-located-at-91
                        :ARG2 (f4 / fibroblast
                              :mod (w2 / wild-type))
                        :ARG1-of (c2 / contrast-01
                              :ARG2 (b3 / be-located-at-91 :polarity -
                                    :ARG1 i
                                    :ARG2 (f3 / fibroblast
                                          :mod (e / enzyme :name (n3 / name :op1 "eps8")
                                                :ARG2-of (m2 / mutate-01 :mod "−/−"))))))))
      :ARG2 (c4 / cause-01 :polarity -
            :ARG0 (p4 / protein :name (n4 / name :op1 "E3b1")
                  :ARG1-of (m / mutate-01)
                  :ARG1-of (i2 / impair-01
                        :ARG0 (b / bind-01
                              :ARG1 p4
                              :ARG2 (e3 / enzyme :name (n5 / name :op1 "Eps8")))))
            :ARG1 i)
      :ARG1-of (d2 / describe-01
            :ARG0 (f / figure :mod "5C")))

# ::id pmid_1177_7939.84 ::date 2015-03-02T02:27:43 ::annotator SDL-AMR-09 ::preferred
# ::snt Thus, the overexpression of E3b1 is sufficient to activate Rac and this effect is strictly dependent on Eps8<bold>.</bold>
# ::save-date Sun Jan 17, 2016 ::file pmid_1177_7939_84.txt
(i2 / infer-01
      :ARG1 (a2 / and
            :op1 (s / suffice-01
                  :ARG0 (o / overexpress-01
                        :ARG1 (p / protein :name (n / name :op1 "E3b1")))
                  :ARG1 (a / activate-01
                        :ARG0 o
                        :ARG1 (e / enzyme :name (n2 / name :op1 "Rac"))))
            :op2 (d / depend-01
                  :ARG0 (e2 / effect
                        :mod (t / this))
                  :ARG1 (e3 / enzyme :name (n3 / name :op1 "Eps8"))
                  :mod (s2 / strict))))

# ::id pmid_1177_7939.85 ::date 2015-03-02T05:24:26 ::annotator SDL-AMR-09 ::preferred
# ::snt The indispensability of E3b1 in the cascade of events leading to Rac activation and Rac-dependent actin reorganization was further analyzed at the biological level.
# ::save-date Sun Jan 17, 2016 ::file pmid_1177_7939_85.txt
(a / analyze-01
      :ARG1 (i / indispensable-01
            :ARG1 (e / enzyme :name (n / name :op1 "E3b1"))
            :ARG2 (c / cascade-01
                  :subevent (e2 / event
                        :ARG0-of (l / lead-03
                              :ARG2 (a4 / and
                                    :op1 (a2 / activate-01
                                          :ARG1 (e3 / enzyme :name (n2 / name :op1 "Rac")))
                                    :op2 (r / reorganize-01
                                          :ARG1 (p2 / protein :name (n3 / name :op1 "actin")
                                                :ARG0-of (d2 / depend-01
                                                      :ARG1 e3))))))))
      :time (f / further)
      :manner (l2 / level
            :mod (b / biology)))

# ::id pmid_1177_7939.86 ::date 2015-03-02T05:50:46 ::annotator SDL-AMR-09 ::preferred
# ::snt We have previously shown that interference with E3b1 functions, by microinjection of anti-E3b1 antibodies, inhibited PDGF-induced ruffles (<xref ref-type="bibr" rid="bib40">Scita et al. 1999</xref>).
# ::save-date Tue Feb 2, 2016 ::file pmid_1177_7939_86.txt
(s / show-01
      :ARG0 (w2 / we)
      :ARG1 (i3 / inhibit-01
            :ARG0 (i / interfere-01
                  :ARG1 (f / function-01
                        :ARG0 (p6 / protein :name (n / name :op1 "E3b1")))
                  :manner (m / microinject-01
                        :ARG1 (a / antibody
                              :ARG0-of (c / counter-01
                                    :ARG1 f))
                        :ARG2 f))
            :ARG1 (r / ruffle-02
                  :ARG2-of (i4 / induce-01
                        :ARG0 (p5 / protein :name (n3 / name :op1 "PDGF")))))
      :time (p / previous)
      :ARG1-of (d2 / describe-01
            :ARG0 (p4 / publication-91
                  :ARG0 (a2 / and
                        :op1 (p2 / person :name (n2 / name :op1 "Scita"))
                        :op2 (p3 / person
                              :mod (o / other)))
                  :time (d3 / date-entity :year 1999))))

# ::id pmid_1177_7939.87 ::date 2015-03-02T06:26:55 ::annotator SDL-AMR-09 ::preferred
# ::snt We also showed that in eps8<sup>−/−</sup> cells, ruffling induced by PDGF and activated Ras, but not by activated Rac, was inhibited.
# ::save-date Sun Jan 17, 2016 ::file pmid_1177_7939_87.txt
(s / show-01
      :ARG0 (w / we)
      :ARG1 (i / inhibit-01
            :ARG1 (r / ruffle-02
                  :ARG2-of (i2 / induce-01
                        :ARG0 (a2 / and
                              :op1 (p / protein :name (n3 / name :op1 "PDGF"))
                              :op2 (e2 / enzyme :name (n4 / name :op1 "Ras")
                                    :ARG1-of (a3 / activate-01)))
                        :ARG1-of (c2 / contrast-01
                              :ARG2 (i3 / induce-01 :polarity -
                                    :ARG0 (e3 / enzyme :name (n5 / name :op1 "Rac")
                                          :ARG1-of a3)
                                    :ARG2 r)))))
      :mod (a / also)
      :location (c / cell
            :part (e / enzyme :name (n / name :op1 "eps8")
                  :ARG2-of (m / mutate-01 :mod "−/−"))))

# ::id pmid_1177_7939.88 ::date 2015-03-02T06:41:11 ::annotator SDL-AMR-09 ::preferred
# ::snt Ruffling, however, could be restored upon reexpression of Eps8, but not of an Eps8 mutant unable to bind to E3b1 (<xref ref-type="bibr" rid="bib40">Scita et al., 1999</xref>), suggesting that the Eps8–E3b1-based complex is implicated in the transmission of signal between Ras and Rac.
# ::save-date Sun Jan 17, 2016 ::file pmid_1177_7939_88.txt
(c2 / contrast-01
      :ARG2 (p / possible-01
            :ARG1 (r / restore-01
                  :ARG0 (e2 / express-03
                        :ARG2 (e5 / enzyme :name (n2 / name :op1 "Eps8")
                              :ARG1-of (c4 / contrast-01
                                    :ARG2 (p6 / possible-01 :polarity -
                                          :ARG1 (r3 / restore-01
                                                :ARG0 (e6 / express-03
                                                      :ARG2 (e7 / enzyme :name (n3 / name :op1 "Eps8")
                                                            :ARG1-of (m / mutate-01)
                                                            :ARG1-of (b / bind-01
                                                                  :ARG2 (p7 / protein :name (n4 / name :op1 "E3b1"))
                                                                  :ARG1-of (p4 / possible-01 :polarity -))))
                                                :ARG1 r2
                                                :mod a2))))
                        :mod (a2 / again))
                  :ARG1 (r2 / ruffle-02))
            :ARG0-of (s / suggest-01
                  :ARG1 (i / implicate-01
                        :ARG1 (c / complex
                              :ARG1-of (b2 / base-02
                                    :ARG2 (a / and
                                          :op1 e5
                                          :op2 p7)))
                        :ARG2 (t / transmit-01
                              :ARG0 (e / enzyme :name (n / name :op1 "Ras"))
                              :ARG1 (s2 / signal-07)
                              :ARG2 (e4 / enzyme :name (n6 / name :op1 "Rac"))))))
      :ARG1-of (d2 / describe-01
            :ARG0 (p5 / publication-91
                  :ARG0 (a3 / and
                        :op1 (p2 / person :name (n7 / name :op1 "Scita"))
                        :op2 (p3 / person
                              :mod (o / other)))
                  :time (d3 / date-entity :year 1999))))

# ::id pmid_1177_7939.89 ::date 2015-03-02T07:42:31 ::annotator SDL-AMR-09 ::preferred
# ::snt Thus, one might predict that a mutant of E3b1 unable to associate to Eps8 should function as a dominant negative on Ras-induced Rac-dependent ruffling.
# ::save-date Fri Feb 5, 2016 ::file pmid_1177_7939_89.txt
(i2 / infer-01
      :ARG1 (p5 / possible-01
            :ARG1 (p6 / predict-01
                  :ARG0 (o / one)
                  :ARG1 (r2 / recommend-01
                        :ARG1 (f / function-01
                              :ARG0 (p2 / protein :name (n / name :op1 "E3b1")
                                    :ARG1-of (m / mutate-01)
                                    :ARG1-of (a / associate-01
                                          :ARG2 (e2 / enzyme :name (n2 / name :op1 "Eps8"))
                                          :ARG1-of (p / possible-01 :polarity -)))
                              :ARG1 (m2 / mutate-01 :mod "-/-"
                                    :ARG0-of (d / dominate-01)
                                    :time (r3 / ruffle-02
                                          :ARG2-of (i / induce-01
                                                :ARG0 (e3 / enzyme :name (n4 / name :op1 "Ras")))
                                          :ARG0-of (d2 / depend-01
                                                :ARG1 (e4 / enzyme :name (n5 / name :op1 "Rac"))))))))))

# ::id pmid_1177_7939.90 ::date 2015-03-02T08:13:46 ::annotator SDL-AMR-09 ::preferred
# ::snt To test this, we cotransfected the activated versions of either Ras or Rac, together with E3b1 or the E3b1DY mutant.
# ::save-date Tue Jun 16, 2015 ::file pmid_1177_7939_90.txt
(c / cotransfect-01
      :ARG0 (w / we)
      :ARG2 (a3 / and
            :op1 (o2 / or
                  :op1 (v / version
                        :ARG1-of (a / activate-01)
                        :mod (e4 / enzyme :name (n5 / name :op1 "Ras")))
                  :op2 (v2 / version
                        :mod (e3 / enzyme :name (n2 / name :op1 "Rac"))
                        :ARG1-of (a2 / activate-01)))
            :op2 (o / or
                  :op1 (p / protein :name (n3 / name :op1 "E3b1")
                        :ARG1-of (m / mutate-01))
                  :op2 (p2 / protein :name (n4 / name :op1 "E3b1DY")
                        :ARG1-of (m2 / mutate-01))))
      :purpose (t3 / test-01
            :ARG0 w
            :ARG1 (t4 / this)))

# ::id pmid_1177_7939.91 ::date 2015-03-02T08:27:52 ::annotator SDL-AMR-09 ::preferred
# ::snt RasV12-induced, but not RacQL-induced, ruffles were efficiently inhibited by the coexpression of E3b1DY, but not of E3b1 wild type (<xref ref-type="fig" rid="fig6">Fig. 6</xref>), supporting the contention that the ability of E3b1 to form a complex with Eps8 is required to transmit signals from Ras to Rac.
# ::save-date Tue Feb 2, 2016 ::file pmid_1177_7939_91.txt
(i / inhibit-01
      :ARG0 (c / coexpress-01
            :ARG2 (p / protein :wiki - :name (n4 / name :op1 "E3b1")
                  :ARG2-of (m4 / mutate-01 :value "DY")))
      :ARG1 (r / ruffle-02
            :ARG2-of (i2 / induce-01
                  :ARG0 (e3 / enzyme :wiki "Ras_subfamily" :name (n2 / name :op1 "Ras")
                        :ARG1-of (c2 / contrast-01
                              :ARG2 (i4 / induce-01
                                    :ARG0 (e4 / enzyme :polarity - :wiki "Rac_(GTPase)" :name (n3 / name :op1 "Rac")
                                          :ARG2-of (m3 / mutate-01 :value "QL"))))
                        :ARG2-of (m2 / mutate-01 :value "V12"))))
      :ARG2-of (e / efficient-01
            :ARG1 c)
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod 6))
      :ARG0-of (s / support-01
            :ARG1 (c4 / contend-01
                  :ARG1 (r2 / require-01
                        :ARG1 (p3 / possible-01
                              :ARG1 (f2 / form-01
                                    :ARG1 (m / macro-molecular-complex
                                          :part p
                                          :part (e2 / enzyme :wiki "EPS8" :name (n6 / name :op1 "Eps8")))))
                        :purpose (t2 / transmit-01
                              :ARG0 (e6 / enzyme :wiki "Ras_subfamily" :name (n7 / name :op1 "Ras"))
                              :ARG1 (s2 / signal-07)
                              :ARG2 (e7 / enzyme :wiki "Rac_(GTPase)" :name (n8 / name :op1 "Rac"))))))
      :ARG1-of (c3 / contrast-01
            :ARG2 (i3 / inhibit-01 :polarity -
                  :ARG0 (c5 / coexpress-01 :polarity -
                        :ARG2 (p2 / protein :wiki - :name (n5 / name :op1 "E3b1")
                              :mod (w / wild-type))))))

# ::id pmid_1177_7939.92 ::date 2015-03-02T08:58:46 ::annotator SDL-AMR-09 ::preferred
# ::snt In conclusion, our data show that two pools of Sos-1 exist in the cell, coupled respectively to Grb2 or E3b1.
# ::save-date Wed Dec 30, 2015 ::file pmid_1177_7939_92.txt
(c / conclude-02
      :ARG1 (s / show-01
            :ARG0 (d / data
                  :poss (w / we))
            :ARG1 (e / exist-01
                  :ARG1 (p / pool :quant 2
                        :consist-of (p2 / protein :name (n / name :op1 "Sos-1"))
                        :ARG1-of (c3 / couple-01
                              :ARG2 (o / or
                                    :op1 (p4 / protein :name (n2 / name :op1 "Grb2"))
                                    :op2 (p3 / protein :name (n3 / name :op1 "E3b1")))
                              :mod (r / respective)))
                  :location (c2 / cell))))

# ::id pmid_1177_7939.93 ::date 2015-03-02T09:07:15 ::annotator SDL-AMR-09 ::preferred
# ::snt In addition, the availability of E3b1, but not of Sos-1, is indispensable and rate limiting in the pathway leading to Rac activation.
# ::save-date Sat Jul 25, 2015 ::file pmid_1177_7939_93.txt
(a / and
      :op2 (a2 / and
            :op1 (i / indispensable-01
                  :ARG1 (a5 / available-02
                        :ARG2 (p / protein :name (n / name :op1 "E3b1")))
                  :ARG1-of (c2 / contrast-01
                        :ARG2 (d / dispense-01
                              :ARG1 (a3 / available-02
                                    :ARG2 (p2 / protein :name (n2 / name :op1 "Sos-1"))))))
            :op2 (l / limit-01
                  :ARG0 a5
                  :ARG1 (r / rate)
                  :ARG1-of (c / contrast-01
                        :ARG2 (l3 / limit-01 :polarity -
                              :ARG0 (a6 / available-02
                                    :ARG2 p2)
                              :ARG1 r))
                  :location (p3 / pathway
                        :ARG0-of (l2 / lead-03
                              :ARG2 (a4 / activate-01
                                    :ARG1 (e / enzyme :name (n3 / name :op1 "Rac"))))))))

# ::id pmid_1177_7939.94 ::date 2015-03-03T12:58:05 ::annotator SDL-AMR-09 ::preferred
# ::snt The dual GEF activity of Sos-1 depends on its presence in distinct complexes
# ::save-date Mon Jan 4, 2016 ::file pmid_1177_7939_94.txt
(d / depend-01
      :ARG0 (a / activity-06
            :ARG0 (p / protein :name (n / name :op1 "Sos-1"))
            :ARG1 (p3 / protein :name (n2 / name :op1 "GEF"))
            :mod (d2 / dual))
      :ARG1 (p2 / present-02
            :ARG1 p
            :ARG2 (c / complex
                  :mod (d3 / distinct))))

# ::id pmid_1177_7939.95 ::date 2015-03-03T13:41:36 ::annotator SDL-AMR-09 ::preferred
# ::snt The existence of Sos-1 in two physically and functionally distinct pools suggests the hypothesis that its presence in a S/G or a S/E/E8 complex could dictate its Ras- or Rac-specific GEF activities, respectively.
# ::save-date Sat Jan 16, 2016 ::file pmid_1177_7939_95.txt
(s / suggest-01
      :ARG0 (e5 / exist-01
            :ARG1 (p / protein :name (n / name :op1 "Sos-1"))
            :location (p2 / pool :quant 2
                  :ARG0-of (f / function-01
                        :manner (d / distinct))
                  :mod (p3 / physical)))
      :ARG1 (h / hypothesize-01
            :ARG1 (p4 / possible-01
                  :ARG1 (d2 / dictate-01
                        :ARG0 (p7 / present-02
                              :ARG1 p
                              :ARG2 (o / or
                                    :op1 (m / macro-molecular-complex
                                          :part p
                                          :part (p5 / protein :name (n2 / name :op1 "Grb2")))
                                    :op2 (m2 / macro-molecular-complex
                                          :part p
                                          :part (p6 / protein :name (n3 / name :op1 "E3b1"))
                                          :part (e / enzyme :name (n4 / name :op1 "Eps8")))))
                        :ARG1 (a / activity-06
                              :ARG0 p
                              :ARG1 (p8 / protein :name (n5 / name :op1 "GEF"))
                              :mod (r / respective)
                              :ARG1-of (s2 / specific-02
                                    :ARG2 (o2 / or
                                          :op1 (p9 / protein-family :name (n6 / name :op1 "Ras"))
                                          :op2 (p10 / protein-family :name (n7 / name :op1 "Rac")))))))))

# ::id pmid_1177_7939.96 ::date 2015-03-03T15:27:23 ::annotator SDL-AMR-09 ::preferred
# ::snt To explore this possibility, we used an in vitro assay that can score GEF activities in Sos-1–containing immunoprecipitates.
# ::save-date Mon Jan 4, 2016 ::file pmid_1177_7939_96.txt
(u / use-01
      :ARG0 (w / we)
      :ARG1 (a / assay-01
            :ARG0-of (s / score-01
                  :ARG1 (a2 / activity-06
                        :ARG0 (p4 / protein :name (n / name :op1 "GEF"))
                        :location (m / molecular-physical-entity
                              :ARG1-of (i / immunoprecipitate-01)
                              :ARG0-of (c / contain-01
                                    :ARG1 (p / protein :name (n2 / name :op1 "Sos-1")))))
                  :ARG1-of (p2 / possible-01))
            :manner (i2 / in-vitro))
      :ARG2 (e2 / explore-01
            :ARG0 w
            :ARG1 (p3 / possible-01
                  :mod (t / this))))

# ::id pmid_1177_7939.97 ::date 2015-03-04T03:33:04 ::annotator SDL-AMR-09 ::preferred
# ::snt Cells were transfected with either Sos-1 alone (SosTfx) or a combination of S/E/E8 (Triple Tfx) (<xref ref-type="fig" rid="fig7">Fig. 7</xref> A).
# ::save-date Tue Mar 10, 2015 ::file pmid_1177_7939_97.txt
(t / transfect-01
      :ARG1 (c / cell)
      :ARG2 (o / or
            :op1 (p / protein :name (n / name :op1 "Sos-1")
                  :mod (a / alone))
            :op2 (c2 / combine-01
                  :ARG3 (m / macro-molecular-complex
                        :part p
                        :part (p2 / protein :name (n2 / name :op1 "E3b1"))
                        :part (e / enzyme :name (n3 / name :op1 "Eps8")))))
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod "7A")))

# ::id pmid_1177_7939.98 ::date 2015-03-04T05:11:10 ::annotator SDL-AMR-09 ::preferred
# ::snt When Sos-1 was immunoprecipitated from SosTfx, it displayed Ras-GEF, but not Rac-GEF, activity (<xref ref-type="fig" rid="fig7">Fig. 7</xref> B).
# ::save-date Mon Jan 4, 2016 ::file pmid_1177_7939_98.txt
(c / cause-01
      :ARG0 (i / immunoprecipitate-01
            :ARG1 (p / protein :name (n / name :op1 "Sos-1"))
            :ARG2 (p2 / protein :name (n2 / name :op1 "SosTfx")))
      :ARG1 (c2 / contrast-01
            :ARG1 (d / display-01
                  :ARG0 p
                  :ARG1 (a / activity-06
                        :ARG0 (p3 / protein :name (n4 / name :op1 "GEF"))
                        :ARG1 (e2 / enzyme :name (n5 / name :op1 "Ras"))))
            :ARG2 (d3 / display-01 :polarity -
                  :ARG0 p
                  :ARG1 (a2 / activity-06
                        :ARG0 p3
                        :ARG1 (e3 / enzyme :name (n7 / name :op1 "Rac")))))
      :ARG1-of (d2 / describe-01
            :ARG0 (f / figure :mod "7B")))

# ::id pmid_1177_7939.99 ::date 2015-03-04T06:28:34 ::annotator SDL-AMR-09 ::preferred
# ::snt Of note, little E3b1 and no Eps8 could be detected in Sos-1 immunoprecipitates (<xref ref-type="fig" rid="fig7">Fig. 7</xref> A).
# ::save-date Sat Feb 13, 2016 ::file pmid_1177_7939_99.txt
(a2 / and
      :op1 (p / possible-01
            :ARG1 (d / detect-01
                  :ARG1 (p2 / protein :name (n / name :op1 "E3b1")
                        :quant (l / little))
                  :location (p3 / protein :name (n4 / name :op1 "Sos-1")
                        :ARG1-of (i / immunoprecipitate-01))))
      :op2 (p4 / possible-01 :polarity -
            :ARG1 (d3 / detect-01
                  :ARG1 (e / enzyme :name (n2 / name :op1 "Eps8"))
                  :location p3))
      :ARG1-of (n3 / note-01
            :ARG1-of (r / recommend-01))
      :ARG1-of (d2 / describe-01
            :ARG0 (f / figure :mod "7A")))

# ::id pmid_1177_7939.100 ::date 2015-03-04T07:02:28 ::annotator SDL-AMR-09 ::preferred
# ::snt Conversely, Grb2 was readily recovered from the same immunoprecipitates (unpublished data).
# ::save-date Wed Dec 30, 2015 ::file pmid_1177_7939_100.txt
(c / contrast-01
      :ARG2 (r / recover-02
            :ARG1 (p / protein :name (n / name :op1 "Grb2"))
            :ARG2 (m / molecular-physical-entity
                  :ARG1-of (i / immunoprecipitate-01)
                  :ARG1-of (s / same-01))
            :manner (r2 / ready)
            :ARG1-of (d2 / describe-01
                  :ARG0 (d / data
                        :ARG1-of (p2 / publish-01 :polarity -)))))

# ::id pmid_1177_7939.101 ::date 2015-03-04T15:00:32 ::annotator SDL-AMR-09 ::preferred
# ::snt We then used the Triple Tfx and coimmunoprecipitated Sos-1 with anti-Eps8 antibodies (<xref ref-type="fig" rid="fig7">Fig. 7, A and B</xref>).
# ::save-date Tue Jun 16, 2015 ::file pmid_1177_7939_101.txt
(a / and
      :op1 (u / use-01
            :ARG0 (w / we)
            :ARG1 (m / macro-molecular-complex
                  :part (p / protein :name (n / name :op1 "Sos-1"))
                  :part (p2 / protein :name (n2 / name :op1 "E3b1"))
                  :part (e / enzyme :name (n4 / name :op1 "Eps8"))
                  :ARG2-of (t2 / transfect-01))
            :time (t / then))
      :op2 (c / coimmunoprecipitate-01
            :ARG1 p
            :ARG3 (a2 / antibody
                  :ARG0-of (c2 / counter-01
                        :ARG1 e)))
      :ARG1-of (d / describe-01
            :ARG0 (a3 / and
                  :op1 (f / figure :mod "7A")
                  :op2 (f2 / figure :mod "7B"))))

# ::id pmid_1177_7939.102 ::date 2015-03-04T16:06:19 ::annotator SDL-AMR-09 ::preferred
# ::snt Under these conditions, all of the coimmunoprecipitated Sos-1 is present in the S/E/E8 tricomplex (<xref ref-type="bibr" rid="bib40">Scita et al., 1999</xref>).
# ::save-date Tue Jul 14, 2015 ::file pmid_1177_7939_102.txt
(h / have-condition-91
      :ARG1 (p6 / present-02
            :ARG1 (p / protein :name (n / name :op1 "Sos-1")
                  :mod (a / all)
                  :ARG1-of (c / coimmunoprecipitate-01))
            :ARG2 (m / macro-molecular-complex
                  :part p
                  :part (p2 / protein :name (n2 / name :op1 "E3b1"))
                  :part (e / enzyme :name (n3 / name :op1 "Eps8"))))
      :ARG2 (t / this)
      :ARG1-of (d / describe-01
            :ARG0 (p3 / publication-91
                  :ARG0 (a2 / and
                        :op1 (p4 / person :name (n4 / name :op1 "Scita"))
                        :op2 (p5 / person
                              :mod (o / other)))
                  :time (d2 / date-entity :year 1999))))

# ::id pmid_1177_7939.103 ::date 2015-03-04T16:34:23 ::annotator SDL-AMR-09 ::preferred
# ::snt Despite lower levels of Sos-1 in the coimmunoprecipitate (with respect to a Sos-1 immunoprecipitate from SosTfx), Rac-GEF activity was now present (<xref ref-type="fig" rid="fig7">Fig. 7</xref> B).
# ::save-date Mon Jan 4, 2016 ::file pmid_1177_7939_103.txt
(p / present-02
      :ARG1 (a / activity-06
            :ARG0 (m3 / macro-molecular-complex
                  :part (p4 / protein :name (n2 / name :op1 "GEF"))
                  :part (e2 / enzyme :name (n3 / name :op1 "Rac"))))
      :time (n4 / now)
      :topic (i / immunoprecipitate-01
            :ARG1 p2
            :ARG2 (p3 / protein :name (n5 / name :op1 "SosTfx")))
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod "7B"))
      :concession (l2 / low-04
            :ARG1 (l / level
                  :location (m2 / molecular-physical-entity
                        :ARG1-of (c / coimmunoprecipitate-01))
                  :quant-of (p2 / protein :name (n / name :op1 "Sos-1")))
            :degree (m / more)))

# ::id pmid_1177_7939.104 ::date 2015-03-04T17:13:18 ::annotator SDL-AMR-09 ::preferred
# ::snt Conversely, no Ras-GEF activity could be detected (<xref ref-type="fig" rid="fig7">Fig. 7</xref> B).
# ::save-date Mon Jan 4, 2016 ::file pmid_1177_7939_104.txt
(c / contrast-01
      :ARG2 (p / possible-01 :polarity -
            :ARG1 (d / detect-01
                  :ARG1 (a / activity-06
                        :ARG0 (p2 / protein :name (n2 / name :op1 "GEF"))
                        :beneficiary (e2 / enzyme :name (n3 / name :op1 "Ras")))
                  :ARG1-of (d2 / describe-01
                        :ARG0 (f / figure :mod "7B")))))

# ::id pmid_1177_7939.105 ::date 2015-03-04T17:22:59 ::annotator SDL-AMR-09 ::preferred
# ::snt The lack of Ras-GEF activity was not due to the low levels of Sos-1.
# ::save-date Mon Jan 4, 2016 ::file pmid_1177_7939_105.txt
(c / cause-01 :polarity -
      :ARG0 (l / level
            :ARG1-of (l2 / low-04
                  :quant-of (p / protein :name (n / name :op1 "Sos-1"))))
      :ARG1 (l3 / lack-01
            :ARG1 (a / activity-06
                  :ARG0 (p2 / protein :name (n3 / name :op1 "GEF"))
                  :ARG1 (e2 / enzyme :name (n4 / name :op1 "Ras")))))

# ::id pmid_1177_7939.106 ::date 2015-03-05T01:18:29 ::annotator SDL-AMR-09 ::preferred
# ::snt To prove this point, we immunoprecipitated from SosTfx an amount of Sos-1 comparable to that present in anti-Eps8 immunoprecipitates from Triple Tfx (<xref ref-type="fig" rid="fig7">Fig. 7, A and B</xref>, lanes SosTfx1/10).
# ::save-date Wed Dec 30, 2015 ::file pmid_1177_7939_106.txt
(i / immunoprecipitate-01
      :ARG0 (w / we)
      :ARG1 (p / protein :name (n / name :op1 "SosTfx"))
      :ARG2 (p2 / protein :name (n2 / name :op1 "Sos-1")
            :quant (a / amount
                  :ARG1-of (c / comparable-03
                        :ARG2 (p3 / protein :name (n3 / name :op1 "Sos-1")
                              :quant-of (a2 / amount
                                    :ARG1-of (p8 / present-02
                                          :ARG2 (m / molecular-physical-entity
                                                :ARG1-of (i2 / immunoprecipitate-01
                                                      :ARG2 (m2 / macro-molecular-complex
                                                            :part p3
                                                            :part (p4 / protein :name (n5 / name :op1 "E3b1"))
                                                            :part e
                                                            :ARG2-of (t3 / transfect-01)))
                                                :ARG0-of (c2 / counter-01
                                                      :ARG1 (e / enzyme :name (n4 / name :op1 "Eps8")))
                                                :mod (t / that)))))
                        :ARG1-of (p5 / possible-01))))
      :purpose (p6 / prove-01
            :ARG0 w
            :ARG1 (p7 / point
                  :mod (t2 / this)))
      :ARG1-of (d / describe-01
            :ARG0 (l2 / lane
                  :ARG1-of (l / label-01
                        :ARG2 (s / string-entity :value "SosTfx1/10"))
                  :part-of (a3 / and
                        :op1 (f / figure :mod "7A")
                        :op2 (f2 / figure :mod "7B")))))

# ::id pmid_1177_7939.107 ::date 2015-03-05T13:41:12 ::annotator SDL-AMR-09 ::preferred
# ::snt Under these conditions, Ras-GEF activity was readily detectable (<xref ref-type="fig" rid="fig7">Fig. 7</xref> B).
# ::save-date Mon Jan 4, 2016 ::file pmid_1177_7939_107.txt
(h / have-condition-91
      :ARG1 (a / activity-06
            :ARG0 (p / protein :name (n2 / name :op1 "GEF"))
            :ARG1 (e2 / enzyme :name (n3 / name :op1 "Ras"))
            :ARG1-of (d / detect-01
                  :ARG1-of (p2 / possible-01)
                  :manner (r / ready)))
      :ARG2 (t / this)
      :ARG1-of (d2 / describe-01
            :ARG0 (f / figure :mod "7B")))

# ::id pmid_1177_7939.108 ::date 2015-03-05T13:59:01 ::annotator SDL-AMR-09 ::preferred
# ::snt The detection of Rac-specific GEF activity in anti-Eps8 immunoprecipitates strictly required the presence of Sos-1, since no GEF activity was detected in Eps8 immunoprecipitates, in the absence of coexpressed Sos-1 (<xref ref-type="bibr" rid="bib40">Scita et al., 1999</xref>; unpublished data).
# ::save-date Tue Feb 2, 2016 ::file pmid_1177_7939_108.txt
(r / require-01
      :ARG0 (d / detect-01
            :ARG1 (a / activity-06
                  :ARG0 (p7 / protein :name (n2 / name :op1 "GEF"))
                  :location (m / molecular-physical-entity
                        :ARG1-of (i / immunoprecipitate-01)
                        :ARG0-of (c / counter-01
                              :ARG1 (e3 / enzyme :name (n4 / name :op1 "Eps8"))))
                  :ARG1-of (s / specific-02
                        :ARG2 (e2 / enzyme :name (n3 / name :op1 "Rac")))))
      :ARG1 (p2 / present-02
            :ARG1 (p / protein :name (n / name :op1 "Sos-1")
                  :ARG2-of (c3 / coexpress-01)))
      :manner (s2 / strict)
      :ARG1-of (c2 / cause-01
            :ARG0 (d2 / detect-01 :polarity -
                  :ARG1 (a2 / activity-06
                        :ARG0 p7)
                  :manner (a3 / absent-01
                        :ARG1 p)
                  :location (m2 / molecular-physical-entity
                        :ARG1-of (i2 / immunoprecipitate-01
                              :ARG2 e3))))
      :ARG1-of (d3 / describe-01
            :ARG0 (a4 / and
                  :op1 (p3 / publication-91
                        :ARG0 (a5 / and
                              :op1 (p4 / person :name (n6 / name :op1 "Scita"))
                              :op2 (p5 / person
                                    :mod (o / other)))
                        :time (d4 / date-entity :year 1999))
                  :op2 (d5 / data
                        :ARG1-of (p6 / publish-01 :polarity -)))))

# ::id pmid_1177_7939.109 ::date 2015-03-05T14:53:09 ::annotator SDL-AMR-09 ::preferred
# ::snt Furthermore, no Rac-GEF activity could be detected in Eps8 immunoprecipitates from lysates of cells transfected with Sos-1, E3b1, and an Eps8 mutant that is impaired in its ability to bind E3b1 and thereby cannot form a trimeric complex (<xref ref-type="bibr" rid="bib40">Scita et al., 1999</xref>).
# ::save-date Mon Jan 4, 2016 ::file pmid_1177_7939_109.txt
(a / and
      :op2 (p / possible-01 :polarity -
            :ARG1 (d / detect-01
                  :ARG1 (a2 / activity-06
                        :ARG0 (p9 / protein :name (n2 / name :op1 "GEF"))
                        :ARG1 (e2 / enzyme :name (n3 / name :op1 "Rac")))
                  :ARG1-of (d2 / describe-01
                        :ARG0 (p6 / publication-91
                              :ARG0 (a4 / and
                                    :op1 (p7 / person :name (n7 / name :op1 "Scita"))
                                    :op2 (p8 / person
                                          :mod (o / other)))
                              :time (d3 / date-entity :year 1999)))
                  :location (e3 / enzyme :name (n4 / name :op1 "Eps8")
                        :ARG1-of (i / immunoprecipitate-01
                              :ARG2 (l / lysate
                                    :domain (c / cell)
                                    :ARG1-of (t / transfect-01
                                          :ARG2 (a3 / and
                                                :op1 (p2 / protein :name (n / name :op1 "Sos-1"))
                                                :op2 (p3 / protein :name (n5 / name :op1 "E3b1"))
                                                :op3 (e4 / enzyme :name (n6 / name :op1 "Eps8")
                                                      :ARG1-of (m2 / mutate-01)
                                                      :ARG0-of (b / bind-01
                                                            :ARG1 p3
                                                            :ARG1-of (p4 / possible-01
                                                                  :ARG1-of (i2 / impair-01
                                                                        :ARG0-of (c2 / cause-01
                                                                              :ARG1 (p5 / possible-01 :polarity -
                                                                                    :ARG1 (f / form-01
                                                                                          :ARG0 e4
                                                                                          :ARG1 (m3 / macro-molecular-complex
                                                                                                :mod (t2 / trimer)))))))))))))))))

# ::id pmid_1177_7939.110 ::date 2015-03-05T14:53:27 ::annotator SDL-AMR-09 ::preferred
# ::snt At this stage, we cannot formally exclude that an unknown GEF, coprecipitating with Sos-1, is responsible for the observed activity.
# ::save-date Tue Feb 2, 2016 ::file pmid_1177_7939_110.txt
(p / possible-01 :polarity -
      :ARG1 (e / exclude-01
            :ARG0 (w / we)
            :ARG1 (r / responsible-01
                  :ARG0 (p3 / protein :name (n2 / name :op1 "GEF")
                        :ARG1-of (k / know-01 :polarity -)
                        :op1-of (a2 / and
                              :op2 (p2 / protein :name (n3 / name :op1 "Sos-1"))
                              :ARG1-of (c / coprecipitate-01)))
                  :ARG1 (a / activity-06
                        :ARG1-of (o / observe-01)))
            :time (s / stage
                  :mod (t / this))
            :manner (f / formal)))

# ::id pmid_1177_7939.111 ::date 2015-03-05T16:08:58 ::annotator SDL-AMR-09 ::preferred
# ::snt However, such a hypothetical protein should not only be associated with Sos-1, but also be active only in the presence of Eps8 and E3b1, which are both required for the formation of the trimeric complex endowed with Rac-specific GEF activity (<xref ref-type="bibr" rid="bib40">Scita et al., 1999</xref>), making this possibility unlikely.
# ::save-date Mon Jan 4, 2016 ::file pmid_1177_7939_111.txt
(c / contrast-01
      :ARG2 (a / and
            :op1 (r / recommend-01
                  :ARG1 (a2 / associate-01
                        :ARG1 (p / protein
                              :ARG1-of (h / hypothetical-02)
                              :mod (s / such))
                        :ARG2 (p2 / protein :name (n / name :op1 "Sos-1"))
                        :mod (o / only)))
            :op2 (a3 / activity-06
                  :ARG0 p
                  :mod (a4 / also)
                  :condition (p3 / present-02
                        :ARG1 (a5 / and
                              :op1 (e / enzyme :name (n2 / name :op1 "Eps8"))
                              :op2 (p4 / protein :name (n3 / name :op1 "E3b1"))
                              :ARG1-of (r2 / require-01
                                    :purpose (f / form-01
                                          :ARG1 (m / macro-molecular-complex
                                                :mod (t / trimer)
                                                :ARG2-of (e2 / endow-01
                                                      :ARG1 (a6 / activity-06
                                                            :ARG0 (p9 / protein :name (n4 / name :op1 "GEF"))
                                                            :ARG1-of (s2 / specific-02
                                                                  :ARG2 (e4 / enzyme :name (n5 / name :op1 "Rac")))))))))))
            :ARG0-of (m2 / make-02
                  :ARG1 (l / likely-01 :polarity -
                        :ARG1 (p5 / possible-01
                              :ARG1 p
                              :mod (t2 / this)))))
      :ARG1-of (d / describe-01
            :ARG0 (p6 / publication-91
                  :ARG0 (a7 / and
                        :op1 (p7 / person :name (n6 / name :op1 "Scita"))
                        :op2 (p8 / person
                              :mod (o2 / other)))
                  :time (d2 / date-entity :year 1999))))

# ::id pmid_1177_7939.112 ::date 2015-03-05T16:09:22 ::annotator SDL-AMR-09 ::preferred
# ::snt It is reasonable, therefore, to propose that Sos-1 alone (or complexed with proteins, such as Grb2) is endowed with Ras-GEF activity.
# ::save-date Mon Jan 4, 2016 ::file pmid_1177_7939_112.txt
(c / cause-01
      :ARG1 (r / reasonable-02
            :ARG1 (p / propose-01
                  :ARG1 (e3 / endow-01
                        :ARG1 (a / activity-06
                              :ARG0 (p5 / protein :name (n3 / name :op1 "GEF"))
                              :ARG1 (e2 / enzyme :name (n4 / name :op1 "Ras")))
                        :ARG2 (o / or
                              :op1 (p2 / protein :name (n / name :op1 "Sos-1")
                                    :mod (a2 / alone))
                              :op2 (m / macro-molecular-complex
                                    :part p2
                                    :part (p3 / protein
                                          :example (p4 / protein :name (n2 / name :op1 "Grb2")))))))))

# ::id pmid_1177_7939.113 ::date 2015-03-06T01:55:36 ::annotator SDL-AMR-09 ::preferred
# ::snt However, upon interaction with Eps8 and E3b1, its specificity is switched toward Rac.
# ::save-date Sun Mar 22, 2015 ::file pmid_1177_7939_113.txt
(h / have-concession-91
      :ARG1 (s / switch-01
            :ARG1 (s2 / specificity
                  :poss (i2 / it))
            :ARG2 (e3 / enzyme :name (n3 / name :op1 "Rac")))
      :time (i / interact-01
            :ARG0 i2
            :ARG1 (a / and
                  :op1 (e / enzyme :name (n / name :op1 "Eps8"))
                  :op2 (p3 / protein :name (n2 / name :op1 "E3b1")))))

# ::id pmid_1177_7939.114 ::date 2015-03-06T06:56:14 ::annotator SDL-AMR-09 ::preferred
# ::snt A common feature of proteins endowed with GEF catalytic activity is their ability to bind to their specific nucleotide-depleted GTPase with relative high affinities.
# ::save-date Mon Jan 4, 2016 ::file pmid_1177_7939_114.txt
(f / feature
      :ARG1-of (s2 / share-01
            :ARG0 p)
      :domain (c / capable-01
            :ARG1 (p / protein
                  :ARG2-of (e2 / endow-01
                        :ARG1 (a / activity-06
                              :ARG0 (p2 / protein :name (n2 / name :op1 "GEF"))
                              :ARG1 (c2 / catalysis))))
            :ARG2 (b / bind-01
                  :ARG1 p
                  :ARG2 (e / enzyme :name (n / name :op1 "GTPase")
                        :ARG1-of (s3 / specific-02)
                        :ARG1-of (d / deplete-01
                              :ARG2 (n3 / nucleotide))
                        :poss p)
                  :manner (a2 / affinity
                        :ARG1-of (h / high-02
                              :ARG2-of (r / relative-05))))))

# ::id pmid_1177_7939.115 ::date 2015-03-06T09:11:13 ::annotator SDL-AMR-09 ::preferred
# ::snt Thus, one might postulate that Sos-1 associates with the nucleotide-free form of Rac exclusively when engaged in the S/E/E8 complex.
# ::save-date Mon Dec 21, 2015 ::file pmid_1177_7939_115.txt
(c / cause-01
      :ARG1 (p8 / possible-01
            :ARG1 (p5 / postulate-01
                  :ARG0 (p6 / person)
                  :ARG1 (a / associate-01
                        :ARG1 (p7 / protein :name (n / name :op1 "Sos-1"))
                        :ARG2 (f / form
                              :ARG1-of (f2 / free-04
                                    :ARG2 (n2 / nucleotide))
                              :mod (e / enzyme :name (n3 / name :op1 "Rac")))
                        :ARG0-of (e2 / exclusive-02)
                        :time (e3 / engage-01
                              :ARG1 p7
                              :ARG2 (m / macro-molecular-complex
                                    :part (p / protein :name (n4 / name :op1 "S"))
                                    :part (p3 / protein :name (n5 / name :op1 "E"))
                                    :part (p4 / protein :name (n6 / name :op1 "E8"))))))))

# ::id pmid_1177_7939.116 ::date 2015-03-06T09:48:01 ::annotator SDL-AMR-09 ::preferred
# ::snt Purified and nucleotide depleted, GST-Rac and GST-Cdc42 proteins were therefore used to test their ability to interact with Sos-1.
# ::save-date Thu Mar 12, 2015 ::file pmid_1177_7939_116.txt
(c2 / cause-01
      :ARG1 (u2 / use-01
            :ARG1 (a / and
                  :op1 (p2 / protein :name (n2 / name :op1 "GST-Rac"))
                  :op2 (p3 / protein :name (n3 / name :op1 "GST-Cdc42"))
                  :ARG1-of (p / purify-01)
                  :ARG1-of (d / deplete-01
                        :ARG2 (n / nucleotide)))
            :ARG2 (t2 / test-01
                  :ARG1 (c / capable-01
                        :ARG1 a
                        :ARG2 (i / interact-01
                              :ARG0 a
                              :ARG1 (p4 / protein :name (n4 / name :op1 "Sos-1")))))))

# ::id pmid_1177_7939.117 ::date 2015-03-07T13:01:08 ::annotator SDL-AMR-09 ::preferred
# ::snt Native Sos-1, present in lysates of −/− [Eps8myc] fibroblasts, could be specifically recovered with nucleotide-depleted immobilized GST-Rac, but not with GST-Cdc42 or GST alone (<xref ref-type="fig" rid="fig7">Fig. 7</xref> C).
# ::save-date Mon Dec 21, 2015 ::file pmid_1177_7939_117.txt
(p / possible-01
      :ARG1 (c / contrast-01
            :ARG1 (r / recover-01
                  :ARG1 (p2 / protein :name (n / name :op1 "Sos-1")
                        :mod (n2 / native)
                        :ARG1-of (p6 / present-02
                              :ARG2 (l / lysate
                                    :mod (f / fibroblast
                                          :mod (p5 / protein :name (n3 / name :op1 "Eps8myc")
                                                :ARG2-of (m / mutate-01 :mod "−/−"))))))
                  :instrument (p4 / protein :name (n4 / name :op1 "GST-Rac")
                        :ARG1-of (i / immobilize-01)
                        :ARG1-of (d / deplete-01
                              :ARG2 (n7 / nucleotide)))
                  :ARG1-of (s / specific-02))
            :ARG2 (r2 / recover-01 :polarity -
                  :ARG1 p2
                  :instrument (o / or
                        :op1 (p3 / protein :name (n5 / name :op1 "GST-Cdc42"))
                        :op2 (e2 / enzyme :name (n12 / name :op1 "GST"))
                        :mod (a / alone))))
      :ARG1-of (d2 / describe-01
            :ARG0 (f2 / figure :mod "7C")))

# ::id pmid_1177_7939.118 ::date 2015-03-08T03:48:57 ::annotator SDL-AMR-09 ::preferred
# ::snt Conversely, no Sos-1 could be recovered with GST-Rac from lysates of eps8<sup>−/−</sup> cells.
# ::save-date Wed Apr 1, 2015 ::file pmid_1177_7939_118.txt
(p / possible-01
      :ARG1 (r / recover-02
            :ARG1 (p2 / protein :polarity - :name (n / name :op1 "Sos-1"))
            :ARG2 (l / lysate
                  :mod (c2 / cell
                        :mod (e / enzyme :name (n3 / name :op1 "eps8")
                              :ARG2-of (m / mutate-01 :mod "−/−"))))
            :instrument (p3 / protein :name (n2 / name :op1 "GST-Rac")))
      :manner (c / converse))

# ::id pmid_1177_7939.119 ::date 2015-03-06T09:48:54 ::annotator SDL-AMR-09 ::preferred
# ::snt Thus, Eps8 is required for the association between Sos-1 and nucleotide-free Rac.
# ::save-date Sun Mar 22, 2015 ::file pmid_1177_7939_119.txt
(c / cause-01
      :ARG1 (r / require-01
            :ARG1 (e / enzyme :name (n / name :op1 "Eps8"))
            :purpose (a / associate-01
                  :ARG1 (p / protein :name (n2 / name :op1 "Sos-1"))
                  :ARG2 (e2 / enzyme :name (n3 / name :op1 "Rac")
                        :ARG1-of (f / free-04
                              :ARG2 (n4 / nucleotide))))))

# ::id pmid_1177_7939.120 ::date 2015-03-07T05:48:04 ::annotator SDL-AMR-09 ::preferred
# ::snt Furthermore, under conditions in which the Eps8–E3b1 or the E3b1–Sos-1 interactions were disrupted by specifically competing peptides, a reduction of >80% in the amount of Sos-1 bound to nucleotide-depleted Rac was observed (<xref ref-type="fig" rid="fig7">Fig. 7</xref> C).
# ::save-date Mon Dec 21, 2015 ::file pmid_1177_7939_120.txt
(a2 / and
      :op2 (o / observe-01
            :ARG1 (r / reduce-01
                  :ARG1 (a / amount
                        :quant-of (p3 / protein :name (n / name :op1 "Sos-1")
                              :ARG1-of (b / bind-01
                                    :ARG2 (e / enzyme :name (n2 / name :op1 "Rac")
                                          :ARG1-of (d / deplete-01
                                                :ARG2 (n3 / nucleotide))))))
                  :ARG2 (p / percentage-entity :value 80
                        :degree (m / more)))
            :condition (d2 / disrupt-01
                  :ARG0 (p2 / peptide
                        :ARG0-of (c / compete-01
                              :ARG1-of (s / specific-02)))
                  :ARG1 (o2 / or
                        :op1 (i / interact-01
                              :ARG0 (a3 / and
                                    :op1 (e2 / enzyme :name (n4 / name :op1 "Eps8"))
                                    :op2 (p5 / protein :name (n5 / name :op1 "E3b1"))))
                        :op2 (i2 / interact-01
                              :ARG0 (a4 / and
                                    :op1 p5
                                    :op2 p3)))))
      :ARG1-of (d3 / describe-01
            :ARG0 (f / figure :mod "7C")))

# ::id pmid_1177_7939.121 ::date 2015-03-08T04:14:26 ::annotator SDL-AMR-09 ::preferred
# ::snt This latter result strongly suggests that an intact S/E/E8 complex is required for binding to Rac, providing a molecular basis for the catalytic specificity of the complex.
# ::save-date Mon Jul 13, 2015 ::file pmid_1177_7939_121.txt
(s / suggest-01
      :ARG0 (t / thing
            :ARG2-of (r / result-01)
            :mod (l / latter)
            :mod (t2 / this))
      :ARG1 (r2 / require-01
            :ARG1 (m2 / macro-molecular-complex
                  :part (p2 / protein :name (n / name :op1 "S"))
                  :part (p3 / protein :name (n2 / name :op1 "E"))
                  :part (p4 / protein :name (n3 / name :op1 "E8"))
                  :mod (i / intact)
                  :ARG0-of (p / provide-01
                        :ARG1 (b2 / basis
                              :mod (m / molecule))
                        :ARG2 (s3 / specificity
                              :mod (c / catalysis)
                              :poss m2)))
            :purpose (b / bind-01
                  :ARG2 (e / enzyme :name (n4 / name :op1 "Rac"))))
      :ARG1-of (s2 / strong-02))

# ::id pmid_1177_7939.122 ::date 2015-03-06T08:14:47 ::annotator SDL-AMR-09 ::preferred
# ::snt RTK activation differentially regulates the S/G and S/E/E8 complexes
# ::save-date Thu Mar 12, 2015 ::file pmid_1177_7939_122.txt
(r / regulate-01
      :ARG0 (a / activate-01
            :ARG0 (e / enzyme :name (n / name :op1 "RTK")))
      :ARG1 (a2 / and
            :op1 (m / macro-molecular-complex
                  :part (p / protein :name (n2 / name :op1 "S"))
                  :part (p2 / protein :name (n3 / name :op1 "G")))
            :op2 (m2 / macro-molecular-complex
                  :part p
                  :part (p3 / protein :name (n4 / name :op1 "E"))
                  :part (p4 / protein :name (n5 / name :op1 "E8"))))
      :manner (d / differential))

# ::id pmid_1177_7939.123 ::date 2015-03-06T08:28:35 ::annotator SDL-AMR-09 ::preferred
# ::snt Since S/G and S/E complexes are present in the cells simultaneously, then both Sos-1-dependent Ras- and Rac-GEF activities are present at the same time.
# ::save-date Sun Jan 17, 2016 ::file pmid_1177_7939_123.txt
(a5 / and
      :op1 (a2 / activity-06
            :ARG0 (m / macro-molecular-complex
                  :part (e / enzyme :name (n / name :op1 "Ras"))
                  :part (p5 / protein :name (n2 / name :op1 "GEF"))
                  :ARG0-of (d / depend-01
                        :ARG1 (p6 / protein :name (n3 / name :op1 "Sos-1")))))
      :op2 (a / activity-06
            :ARG0 (m2 / macro-molecular-complex
                  :part (e3 / enzyme :name (n4 / name :op1 "Rac"))
                  :part p5))
      :ARG1-of (c / cause-01
            :ARG0 (a4 / and
                  :op1 (m3 / macro-molecular-complex
                        :part (p / protein :name (n6 / name :op1 "S"))
                        :part (p2 / protein :name (n7 / name :op1 "G")))
                  :ARG1-of (p4 / present-02
                        :ARG2 (c2 / cell)
                        :time (s / simultaneous))))
      :ARG1-of (p3 / present-02
            :time (t / time
                  :ARG1-of (s3 / same-01))))

# ::id pmid_1177_7939.124 ::date 2015-03-06T06:57:04 ::annotator SDL-AMR-09 ::preferred
# ::snt The question remains as to how these two complexes, and the ensuing Ras and Rac activities, are coordinated to achieve propagation of signals.
# ::save-date Sun Mar 22, 2015 ::file pmid_1177_7939_124.txt
(q / question-01
      :ARG1 (t / thing
            :manner-of (c / coordinate-01
                  :ARG1 (a2 / and
                        :op1 (m / macro-molecular-complex :quant 2
                              :mod (t2 / this))
                        :op2 (a3 / and
                              :op1 (a5 / act-01
                                    :ARG0 (e3 / enzyme :name (n2 / name :op1 "Ras")))
                              :op2 (a4 / act-02
                                    :ARG0 (e4 / enzyme :name (n3 / name :op1 "Rac")))
                              :ARG1-of (e2 / ensue-01)))
                  :purpose (a / achieve-01
                        :ARG0 m
                        :ARG1 (p / propagate-01
                              :ARG1 (s / signal)))))
      :ARG1-of (r / remain-01))

# ::id pmid_1177_7939.125 ::date 2015-03-06T07:12:35 ::annotator SDL-AMR-09 ::preferred
# ::snt We therefore looked for evidence of differential regulation of the S/G and S/E complex upon RTK stimulation.
# ::save-date Sat Mar 21, 2015 ::file pmid_1177_7939_125.txt
(c / cause-01
      :ARG1 (l2 / look-01
            :ARG0 (w / we)
            :ARG1 (e / evidence-01
                  :ARG1 (r / regulate-01
                        :ARG1 (a / and
                              :op1 (m / macro-molecular-complex
                                    :part (p / protein :name (n / name :op1 "S"))
                                    :part (p2 / protein :name (n2 / name :op1 "G")))
                              :op2 (m2 / macro-molecular-complex
                                    :part (p4 / protein :name (n5 / name :op1 "E"))
                                    :part p))
                        :mod (d / differential)
                        :condition (s / stimulate-01
                              :ARG2 (e4 / enzyme :name (n3 / name :op1 "RTK")))))))

# ::id pmid_1177_7939.126 ::date 2015-03-06T08:02:20 ::annotator SDL-AMR-09 ::preferred
# ::snt Upon PDGF stimulation, we observed decreased coimmunoprecipitation between Grb2 and Sos-1 and consequently between PDGFR and Sos-1 (<xref ref-type="fig" rid="fig8">Fig. 8, A and B</xref>), which correlated with the appearance of a mobility-retarded form of Sos-1.
# ::save-date Sun Jan 17, 2016 ::file pmid_1177_7939_126.txt
(o / observe-01
      :ARG0 (w / we)
      :ARG1 (a / and
            :op1 (c / coimmunoprecipitate-01
                  :ARG1 (p4 / protein :name (n / name :op1 "Grb2"))
                  :ARG2 (p3 / protein :name (n2 / name :op1 "Sos-1"))
                  :ARG1-of (d / decrease-01))
            :op2 (c3 / coimmunoprecipitate-01
                  :ARG1 (p / protein :name (n3 / name :op1 "PDGFR"))
                  :ARG2 p3
                  :ARG1-of (c2 / cause-01
                        :ARG0 c))
            :ARG1-of (c4 / correlate-01
                  :ARG2 (a2 / appear-01
                        :ARG1 (f4 / form
                              :mod p3
                              :ARG1-of (r / retard-01
                                    :ARG2 (m / mobility)))))
            :ARG1-of (d2 / describe-01
                  :ARG0 (a3 / and
                        :op1 (f / figure :mod "8A")
                        :op2 (f2 / figure :mod "8B"))))
      :condition (s / stimulate-01
            :ARG0 (p2 / protein :name (n4 / name :op1 "PDGF"))))

# ::id pmid_1177_7939.127 ::date 2015-03-08T08:55:41 ::annotator SDL-AMR-09 ::preferred
# ::snt This likely represents a hyperphosphorylated form of Sos-1, as previously demonstrated (<xref ref-type="bibr" rid="bib1">Baltensperger et al., 1993</xref>; <xref ref-type="bibr" rid="bib10">Cherniack et al., 1994</xref>; <xref ref-type="bibr" rid="bib31">Pronk et al., 1994</xref>).
# ::save-date Wed Dec 30, 2015 ::file pmid_1177_7939_127.txt
(l / likely-01
      :ARG1 (r / represent-01
            :ARG0 (t / this)
            :ARG1 (f / form
                  :ARG3-of (h / hyperphosphorylate-01)
                  :mod (p / protein :name (n / name :op1 "Sos-1")))
            :compared-to (d3 / demonstrate-01
                  :time (p2 / previous)))
      :ARG1-of (d4 / describe-01
            :ARG0 (a / and
                  :op1 (p3 / publication-91
                        :ARG0 (a2 / and
                              :op1 (p6 / person :name (n2 / name :op1 "Baltensperger"))
                              :op2 (p9 / person
                                    :mod (o / other)))
                        :time (d / date-entity :year 1993))
                  :op2 (p4 / publication-91
                        :ARG0 (a3 / and
                              :op1 (p7 / person :name (n3 / name :op1 "Cherniack"))
                              :op2 (p10 / person
                                    :mod (o2 / other)))
                        :time (d2 / date-entity :year 1994))
                  :op3 (p5 / publication-91
                        :ARG0 (a4 / and
                              :op1 (p8 / person :name (n4 / name :op1 "Pronk"))
                              :op2 (p11 / person
                                    :mod (o3 / other)))
                        :time (d5 / date-entity :year 1994)))))

# ::id pmid_1177_7939.128 ::date 2015-03-07T03:43:20 ::annotator SDL-AMR-09 ::preferred
# ::snt Conversely, under identical conditions, the coimmunoprecipitation between E3b1 and Sos-1 was not affected (<xref ref-type="fig" rid="fig8">Fig. 8</xref> A).
# ::save-date Wed Jun 17, 2015 ::file pmid_1177_7939_128.txt
(a / affect-01 :polarity -
      :ARG1 (c4 / coimmunoprecipitate-01
            :ARG1 (p3 / protein :name (n / name :op1 "E3b1"))
            :ARG2 (p2 / protein :name (n2 / name :op1 "Sos-1")))
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod "8A"))
      :mod (c / converse)
      :condition (c3 / condition
            :ARG1-of (i / identical-01)))

# ::id pmid_1177_7939.129 ::date 2015-03-07T12:11:25 ::annotator SDL-AMR-09 ::preferred
# ::snt Similarly, the stability of the endogenous trimeric complex, Sos-1/Eps8/E3b1 was not affected by treatment of cells with growth factors (<xref ref-type="fig" rid="fig8">Fig. 8</xref> C).
# ::save-date Wed Feb 24, 2016 ::file pmid_1177_7939_129.txt
(a / affect-01 :polarity -
      :ARG0 (t / treat-04
            :ARG1 (c / cell)
            :ARG2 (g / growth-factor))
      :ARG1 (s2 / stable-03
            :ARG1 (m / macro-molecular-complex
                  :mod (t2 / trimeric)
                  :mod (e / endogenous)
                  :part (p / protein :name (n / name :op1 "Sos-1"))
                  :part (e2 / enzyme :name (n2 / name :op1 "Eps8"))
                  :part (p3 / protein :name (n3 / name :op1 "E3b1"))))
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod "8C"))
      :ARG1-of (r / resemble-01))

# ::id pmid_1177_7939.130 ::date 2015-03-06T08:32:08 ::annotator SDL-AMR-09 ::preferred
# ::snt The above data indicate that, as a consequence of activation of RTKs, the S/G complex is disrupted, whereas the S/E/E8 complex persists in the cell.
# ::save-date Thu Mar 12, 2015 ::file pmid_1177_7939_130.txt
(i / indicate-01
      :ARG0 (d / data
            :location (a / above))
      :ARG1 (c / contrast-01
            :ARG1 (d2 / disrupt-01
                  :ARG1 (m / macro-molecular-complex
                        :part (p / protein :name (n / name :op1 "S"))
                        :part (p2 / protein :name (n2 / name :op1 "G"))))
            :ARG2 (p3 / persist-01
                  :ARG1 (m2 / macro-molecular-complex
                        :part (p5 / protein :name (n4 / name :op1 "E"))
                        :part (p6 / protein :name (n5 / name :op1 "E8"))
                        :part p)
                  :location (c2 / cell))
            :ARG1-of (c3 / cause-01
                  :ARG0 (a2 / activate-01
                        :ARG1 (e / enzyme :name (n6 / name :op1 "RTK"))))))

# ::id pmid_1177_7939.131 ::date 2015-03-06T08:03:19 ::annotator SDL-AMR-09 ::preferred
# ::snt This might lead to a transient peak in Ras activity vis a vis a more prolonged activation of Rac.
# ::save-date Fri Jul 24, 2015 ::file pmid_1177_7939_131.txt
(p / possible-01
      :ARG1 (l / lead-03
            :ARG0 (t / this)
            :ARG2 (p2 / peak-01
                  :ARG1 (a / activity-06
                        :ARG0 (e / enzyme :name (n / name :op1 "Ras")))
                  :ARG1-of (t2 / transient-02))
            :purpose (a2 / activate-01
                  :ARG1 (e2 / enzyme :name (n2 / name :op1 "Rac"))
                  :ARG1-of (p3 / prolong-01
                        :degree (m / more)))))

# ::id pmid_1177_7939.132 ::date 2015-03-06T12:52:24 ::annotator SDL-AMR-09 ::preferred
# ::snt Therefore, we measured the kinetic of RTK-induced activation of Ras and Rac.
# ::save-date Wed Dec 30, 2015 ::file pmid_1177_7939_132.txt
(c / cause-01
      :ARG1 (m / measure-01
            :ARG0 (w / we)
            :ARG1 (k / kinetics
                  :mod (a / activate-01
                        :ARG1 (a2 / and
                              :op1 (e / enzyme :name (n / name :op1 "Ras"))
                              :op2 (e2 / enzyme :name (n2 / name :op1 "Rac")))
                        :ARG2-of (i / induce-01
                              :ARG0 (e3 / enzyme :name (n3 / name :op1 "RTK")))))))

# ::id pmid_1177_7939.133 ::date 2015-03-06T13:02:18 ::annotator SDL-AMR-09 ::preferred
# ::snt As shown in <xref ref-type="fig" rid="fig8">Fig. 8</xref> D, activation of Ras was rapid and short lived, whereas activation of Rac was sustained over a longer period of time, compatible with the differential regulation of the corresponding activating complexes, S/G and S/E/E8.
# ::save-date Fri Dec 18, 2015 ::file pmid_1177_7939_133.txt
(c / contrast-01
      :ARG1 (a / and
            :op1 (r / rapid
                  :domain (a2 / activate-01
                        :ARG1 (e / enzyme :name (n / name :op1 "Ras"))))
            :op2 (l / live-01
                  :ARG0 a2
                  :ARG1-of (s / short-07)))
      :ARG2 (s2 / sustain-01
            :ARG1 (a3 / activate-01
                  :ARG1 (e2 / enzyme :name (n2 / name :op1 "Rac")))
            :ARG1-of (l2 / long-03
                  :degree (m / more)
                  :mod (c2 / compatible
                        :prep-with (r2 / regulate-01
                              :ARG1 (a4 / and
                                    :op1 (m2 / macro-molecular-complex
                                          :part (p2 / protein :name (n3 / name :op1 "S"))
                                          :part (p3 / protein :name (n5 / name :op1 "G")))
                                    :op2 (m3 / macro-molecular-complex
                                          :part (p5 / protein :name (n6 / name :op1 "E"))
                                          :part (p6 / protein :name (n7 / name :op1 "E8"))
                                          :part p2)
                                    :ARG0-of (a5 / activate-01
                                          :ARG1-of (c3 / correspond-02)))
                              :ARG1-of (d / differ-02)))))
      :ARG1-of (s3 / show-01
            :ARG0 (f / figure :mod "8D")))

# ::id pmid_1177_7939.198 ::date 2015-03-06T14:02:57 ::annotator SDL-AMR-09 ::preferred
# ::snt Figure 1.
# ::save-date Fri Mar 6, 2015 ::file pmid_1177_7939_198.txt
(f / figure :mod 1)

# ::id pmid_1177_7939.199 ::date 2015-03-06T14:03:38 ::annotator SDL-AMR-09 ::preferred
# ::snt <bold>The S/E/E8 complex exists under physiological conditions.</bold>
# ::save-date Sun Mar 22, 2015 ::file pmid_1177_7939_199.txt
(e / exist-01
      :ARG1 (m / macro-molecular-complex
            :part (p2 / protein :name (n / name :op1 "S"))
            :part (p3 / protein :name (n2 / name :op1 "E"))
            :part (p4 / protein :name (n3 / name :op1 "E8")))
      :condition (p / physiology))

# ::id pmid_1177_7939.200 ::date 2015-03-06T14:07:31 ::annotator SDL-AMR-09 ::preferred
# ::snt (A) Eps8<sup>−/−</sup> cells were transfected with a control vector (−/− lanes) or a vector coding a myc epitope–tagged Eps8 (−/− [Eps8myc] lanes), both carrying a hygromicin resistance gene.
# ::save-date Sat Feb 13, 2016 ::file pmid_1177_7939_200.txt
(t / transfect-01 :li "A"
      :ARG1 (c / cell
            :ARG0-of (c6 / contain-01
                  :ARG1 (e2 / enzyme :name (n / name :op1 "Eps8")
                        :ARG2-of m4)))
      :ARG2 (o / or
            :op1 (v / vector
                  :ARG0-of (c2 / control-01)
                  :ARG1-of (d / describe-01
                        :ARG2 (l / lane
                              :ARG2-of (m4 / mutate-01 :mod "−/−"))))
            :op2 (v2 / vector
                  :ARG0-of (c3 / code-01
                        :ARG1 (c4 / cell
                              :ARG0-of (c7 / contain-01
                                    :ARG1 (e3 / enzyme :name (n2 / name :op1 "Eps8")))
                              :ARG1-of (t2 / tag-01
                                    :ARG2 (e / epitope
                                          :mod (p / protein :name (n3 / name :op1 "myc"))))))
                  :ARG1-of (m2 / mean-01
                        :ARG2 (l2 / lane
                              :mod (p2 / protein :name (n5 / name :op1 "Eps8myc")
                                    :ARG2-of m4))))
            :ARG0-of (c5 / carry-01
                  :ARG1 (g / gene
                        :ARG0-of (r / resist-01
                              :ARG1 (s / small-molecule :name (n4 / name :op1 "hygromicin")))))))

# ::id pmid_1177_7939.201 ::date 2015-03-06T14:21:18 ::annotator SDL-AMR-09 ::preferred
# ::snt Hygromicin-resistant single-cell clones were established after 10 d of selection with hygromicin (0.2 mg/ml).
# ::save-date Sat Feb 13, 2016 ::file pmid_1177_7939_201.txt
(e / establish-01
      :ARG1 (c2 / cell
            :ARG1-of (s / single-02)
            :ARG0-of (r / resist-01
                  :ARG1 (s4 / small-molecule :name (n / name :op1 "hygromicin")))
            :ARG1-of (c / clone-01))
      :time (a / after
            :op1 (s2 / select-01
                  :ARG1 c2
                  :instrument (s3 / small-molecule :quant 0.2 :name (n2 / name :op1 "hygromicin")
                        :quant (c3 / concentration-quantity :quant 0.2
                              :unit (m3 / milligram-per-milliliter))))
            :quant (t / temporal-quantity :quant 10
                  :unit (d / day))))

# ::id pmid_1177_7939.202 ::date 2015-03-06T14:37:14 ::annotator SDL-AMR-09 ::preferred
# ::snt The levels of Eps8, PDGFR, and EGFR in individual clones of eps8<sup>−/−</sup>, −/− [Eps8myc], or in wild-type (WT) cells were determined by immunoblotting analysis of equal amounts of total cellular lysates (50 μg) using the indicated antibodies (WB), and clones with levels of expression of Eps8, PDGFR, and EGFR similar to wild-type fibroblasts were used.
# ::save-date Sun Dec 20, 2015 ::file pmid_1177_7939_202.txt
(a / and
      :op1 (d / determine-01
            :ARG0 (a3 / analyze-01
                  :ARG1 (a4 / amount
                        :ARG1-of (e2 / equal-01)
                        :quant-of (l4 / lysate
                              :mod (c3 / cell)
                              :ARG1-of (t / total-01
                                    :ARG2 (m / mass-quantity :quant 50
                                          :unit (m2 / microgram)))))
                  :manner (i2 / immunoblot-01)
                  :manner (u / use-01
                        :ARG1 (a5 / antibody
                              :ARG1-of (i3 / indicate-01)
                              :ARG1-of (d3 / describe-01
                                    :ARG2 (n6 / name :op1 "WB")))))
            :ARG1 (a2 / and
                  :op1 (l / level
                        :quant-of (e8 / enzyme :name (n2 / name :op1 "Eps8")))
                  :op2 (l2 / level
                        :quant-of (e4 / enzyme :name (n3 / name :op1 "PDGFR")))
                  :op3 (l3 / level
                        :quant-of (e3 / enzyme :name (n4 / name :op1 "EGFR")))
                  :location (o / or
                        :op1 (c / clone-01
                              :ARG1 (c5 / cell
                                    :ARG0-of (c6 / contain-01
                                          :ARG1 (e7 / enzyme :name (n5 / name :op1 "Eps8")
                                                :ARG2-of (m3 / mutate-01 :mod "−/−"))))
                              :mod (i / individual))
                        :op2 (c7 / clone-01
                              :ARG1 (c8 / cell
                                    :ARG0-of (c9 / contain-01
                                          :ARG1 (p / protein :name (n / name :op1 "Eps8myc")
                                                :ARG2-of m3))))
                        :op3 (c10 / clone-01
                              :ARG1 (c2 / cell
                                    :mod (w / wild-type
                                          :ARG1-of (d2 / describe-01
                                                :ARG2 (n7 / name :op1 "WT"))))))))
      :op2 (u2 / use-01
            :ARG1 (c4 / clone
                  :poss-of (a6 / and
                        :op1 (l5 / level
                              :degree-of (e / express-01
                                    :ARG1 e8))
                        :op2 (l6 / level
                              :degree-of (e5 / express-01
                                    :ARG1 e4))
                        :op3 (l7 / level
                              :degree-of (e6 / express-01
                                    :ARG1 e3))
                        :ARG1-of (r / resemble-01
                              :ARG2 (f / fibroblast
                                    :mod w))))))

# ::id pmid_1177_7939.203 ::date 2015-03-07T01:35:14 ::annotator SDL-AMR-09 ::preferred
# ::snt (B) Total cellular lysates (10 mg), obtained from the transfectants described in A, were immunoprecipitated (IP) with the antibody indicated at the bottom (ctr, irrelevant antibody), followed by immunoblot with indicated antibodies (WB).
# ::save-date Wed Dec 30, 2015 ::file pmid_1177_7939_203.txt
(i / immunoprecipitate-01
      :ARG1 (l / lysate
            :mod (c / cell)
            :ARG1-of (t / total-01
                  :ARG2 (m / mass-quantity :quant 10
                        :unit (m2 / milligram)))
            :ARG1-of (o / obtain-01
                  :ARG2 (m3 / molecular-physical-entity
                        :ARG1-of (t2 / transfect-01)
                        :ARG1-of (d / describe-01
                              :ARG0 (f3 / figure :mod "1A")))))
      :ARG3 (a2 / antibody
            :ARG1-of (i2 / indicate-01
                  :location (b / bottom))
            :ARG1-of (r / relevant-01 :polarity -)
            :ARG1-of (d3 / describe-01
                  :ARG2 (c2 / control)))
      :ARG2-of (f / follow-01
            :ARG1 (i3 / immunoblot-01
                  :ARG2 l
                  :ARG3 (a3 / antibody
                        :ARG1-of (i4 / indicate-01))))
      :ARG1-of (d5 / describe-01
            :ARG0 (f2 / figure :mod "1B")))

# ::id pmid_1177_7939.204 ::date 2015-03-07T01:48:19 ::annotator SDL-AMR-09 ::preferred
# ::snt The indicated lanes (lysates) were loaded with 100 μg of total cellular lysates.
# ::save-date Sun Mar 22, 2015 ::file pmid_1177_7939_204.txt
(l / load-01
      :ARG1 (l2 / lane
            :ARG1-of (i / indicate-01)
            :ARG1-of (d / describe-01
                  :ARG2 (l4 / lysate)))
      :ARG2 (l3 / lysate
            :mod (c / cell)
            :ARG1-of (t / total-01
                  :ARG2 (m / mass-quantity :quant 100
                        :unit (m2 / microgram)))))

# ::id pmid_1177_7939.205 ::date 2015-03-07T01:52:36 ::annotator SDL-AMR-09 ::preferred
# ::snt (C) Total cellular lysates (10 mg) obtained from −/− [Eps8myc] cells were immunoprecipitated (IP) with the antibody indicated at the top (ctr, irrelevant antibody) in the presence or absence (−) of 40 ng/ml of the indicated peptides (peptides).
# ::save-date Mon Jan 4, 2016 ::file pmid_1177_7939_205.txt
(i / immunoprecipitate-01
      :ARG2 (l / lysate
            :mod (c / cell)
            :ARG1-of (t / total-01
                  :ARG2 (m / mass-quantity :quant 10
                        :unit (m2 / milligram)))
            :ARG1-of (o / obtain-01
                  :ARG2 (c2 / cell
                        :ARG0-of (c4 / contain-01
                              :ARG1 (p2 / protein :name (n / name :op1 "EPS8myc")
                                    :ARG2-of (m3 / mutate-01 :mod "−/−"))))))
      :ARG3 (a / antibody
            :ARG1-of (i2 / indicate-01
                  :location (t2 / top))
            :ARG1-of (r / relevant-01 :polarity -))
      :condition (o2 / or
            :op1 (p3 / present-02
                  :ARG1 (p / peptide
                        :ARG1-of (i3 / indicate-01)
                        :quant (c6 / concentration-quantity :quant 40
                              :unit (n3 / nanogram-per-milliliter))))
            :op2 (a2 / absent-01
                  :ARG1 p))
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod "C")))

# ::id pmid_1177_7939.206 ::date 2015-03-07T02:02:49 ::annotator SDL-AMR-09 ::preferred
# ::snt The peptides used were PPPPPVD<bold>Y</bold>TEDEE (PXXDY) and PPPPPVD<bold>A</bold>TEDEE (PXXDA, used as a control).
# ::save-date Sun Mar 22, 2015 ::file pmid_1177_7939_206.txt
(u / use-01
      :ARG1 (a / and
            :op1 (p / peptide :name (n / name :op1 "PPPPPVDYTEDEE")
                  :ARG1-of (d / describe-01
                        :ARG2 (n3 / name :op1 "PXXDY")))
            :op2 (p2 / peptide :name (n2 / name :op1 "PPPPPVDATEDEE")
                  :ARG1-of (u2 / use-01
                        :ARG2 (c / control-01
                              :ARG0 p2))
                  :ARG1-of (d2 / describe-01
                        :ARG2 (n4 / name :op1 "PXXDA")))))

# ::id pmid_1177_7939.207 ::date 2015-03-07T02:04:58 ::annotator SDL-AMR-09 ::preferred
# ::snt Immunoblotting was with the indicated antibodies (WB).
# ::save-date Tue Jun 16, 2015 ::file pmid_1177_7939_207.txt
(i / immunoblot-01
      :ARG3 (a / antibody
            :ARG1-of (i2 / indicate-01)
            :ARG1-of (d / describe-01
                  :ARG2 (n / name :op1 "WB"))))

# ::id pmid_1177_7939.208 ::date 2015-03-07T02:06:04 ::annotator SDL-AMR-09 ::preferred
# ::snt The indicated lanes (lysates) were loaded with 100 μg of total cellular lysates.
# ::save-date Sun Mar 22, 2015 ::file pmid_1177_7939_208.txt
(l / load-01
      :ARG1 (l2 / lane
            :ARG1-of (i / indicate-01)
            :ARG1-of (d / describe-01
                  :ARG2 (l4 / lysate)))
      :ARG2 (l3 / lysate
            :ARG1-of (t / total-01
                  :ARG2 (m / mass-quantity :quant 100
                        :unit (m2 / microgram)))
            :mod (c / cell)))

# ::id pmid_1177_7939.209 ::date 2015-03-07T02:07:31 ::annotator SDL-AMR-09 ::preferred
# ::snt Figure 2.
# ::save-date Sat Mar 7, 2015 ::file pmid_1177_7939_209.txt
(f / figure :mod 2)

# ::id pmid_1177_7939.210 ::date 2015-03-07T02:08:33 ::annotator SDL-AMR-09 ::preferred
# ::snt <bold>In vitro competition between E3b1 and Grb2 for binding to Sos-1.</bold>
# ::save-date Sun Mar 8, 2015 ::file pmid_1177_7939_210.txt
(c / compete-01
      :ARG0 (p / protein :name (n / name :op1 "E3b1"))
      :ARG1 (p2 / protein :name (n2 / name :op1 "Grb2"))
      :ARG2 (b / bind-01
            :ARG2 (p3 / protein :name (n3 / name :op1 "Sos-1")))
      :manner (i / in-vitro))

# ::id pmid_1177_7939.211 ::date 2015-03-07T02:15:27 ::annotator SDL-AMR-09 ::preferred
# ::snt (A, Top) schematic of E3b1.
# ::save-date Fri Oct 23, 2015 ::file pmid_1177_7939_211.txt
(s / schematic
      :poss (p / protein :name (n / name :op1 "E3b1"))
      :ARG1-of (d / describe-01
            :location (f / figure :mod "A"
                  :location (t / top))))

# ::id pmid_1177_7939.212 ::date 2015-03-07T02:20:03 ::annotator SDL-AMR-09 ::preferred
# ::snt The ruler shows amino acid positions.
# ::save-date Sun Mar 22, 2015 ::file pmid_1177_7939_212.txt
(s / show-01
      :ARG0 (r / ruler)
      :ARG1 (l / location
            :ARG2-of (p / position-01
                  :ARG1 (a / amino-acid))))

# ::id pmid_1177_7939.213 ::date 2015-03-07T02:21:15 ::annotator SDL-AMR-09 ::preferred
# ::snt (Bottom) In vitro binding of various fragments of E3b1 (all engineered as GST fusions, amino acid boundaries are indicated on the top) to Sos-1 from lysates of Sos-1–transfected Cos-7 cells.
# ::save-date Wed Jan 13, 2016 ::file pmid_1177_7939_213.txt
(m / multi-sentence
      :snt1 (b / bind-01
            :ARG1 (p2 / protein-segment
                  :part-of (p / protein :name (n / name :op1 "E3b1"))
                  :mod (v / various))
            :ARG2 (p4 / protein :name (n3 / name :op1 "Sos-1")
                  :source (l / lysate
                        :mod (c / cell-line :name (n4 / name :op1 "Cos-7")
                              :ARG1-of (t / transfect-01
                                    :ARG2 p4))))
            :location (b2 / bottom)
            :manner (i / in-vitro))
      :snt2 (a2 / and
            :op1 (e / engineer-01
                  :ARG1 (a / all)
                  :ARG2 (p3 / protein :name (n2 / name :op1 "GST" :op2 "fusion")))
            :op2 (i2 / indicate-01
                  :ARG1 (b3 / boundary
                        :poss (a3 / amino-acid))
                  :location (t2 / top))))

# ::id pmid_1177_7939.214 ::date 2015-03-06T14:38:11 ::annotator SDL-AMR-09 ::preferred
# ::snt Detection was with anti–Sos-1 antibody.
# ::save-date Sun Mar 22, 2015 ::file pmid_1177_7939_214.txt
(d / detect-01
      :ARG2 (a / antibody
            :ARG0-of (c / counter-01
                  :ARG1 (p / protein :name (n / name :op1 "Sos-1")))))

# ::id pmid_1177_7939.215 ::date 2015-03-06T14:39:01 ::annotator SDL-AMR-09 ::preferred
# ::snt The lane “lysate” was loaded with 50 μg of total cellular lysates.
# ::save-date Sun Mar 22, 2015 ::file pmid_1177_7939_215.txt
(l / load-01
      :ARG1 (l2 / lane
            :ARG1-of (d / describe-01
                  :ARG2 (l4 / lysate)))
      :ARG2 (l3 / lysate
            :mod (c / cell)
            :ARG1-of (t / total-01
                  :ARG2 (m / mass-quantity :quant 50
                        :unit (m2 / microgram)))))

# ::id pmid_1177_7939.216 ::date 2015-03-06T14:47:40 ::annotator SDL-AMR-09 ::preferred
# ::snt P Rich, proline rich region; SH3, SH3 domain.
# ::save-date Sun Mar 22, 2015 ::file pmid_1177_7939_216.txt
(a2 / and
      :op1 (n4 / name :op1 "P" :op2 "Rich"
            :ARG2-of (d / describe-01
                  :ARG1 (r2 / rich
                        :mod a
                        :domain (r3 / region)
                        :mod (a / amino-acid :name (n / name :op1 "proline")))))
      :op2 (n5 / name :op1 "SH3"
            :ARG2-of (d2 / describe-01
                  :ARG1 (p2 / protein-segment :name (n3 / name :op1 "SH3" :op2 "domain")))))

# ::id pmid_1177_7939.217 ::date 2015-03-06T14:55:25 ::annotator SDL-AMR-09 ::preferred
# ::snt (B) A His-tagged COOH-terminal fragment (His-Sos, aa 1131–1333) of Sos-1 (10 pmoles) was bound to 60 pmoles of either immobilized GST (GST) or GST-E3b1–331–480 in the presence of increasing concentrations of the NH<sub>2</sub>-terminal SH3 domain of Grb2 or of Eps8 (SH3s, 0, 10, 100, 1,000 pmoles, as indicated on the top).
# ::save-date Mon Jan 4, 2016 ::file pmid_1177_7939_217.txt
(m4 / multi-sentence
      :snt1 (b / bind-01 :li "B"
            :ARG1 (p / protein-segment :name (n / name :op1 "COOH-terminus")
                  :part-of (p2 / protein :name (n2 / name :op1 "Sos-1"))
                  :ARG1-of (t / tag-01
                        :ARG2 (a / amino-acid :name (n3 / name :op1 "histidine")))
                  :quant (m / mass-quantity :quant 10
                        :unit (p3 / picomole))
                  :consist-of (a2 / amino-acid
                        :mod (v / value-interval :op1 1131 :op2 1333)))
            :ARG2 (o / or
                  :op1 (e / enzyme :name (n4 / name :op1 "GST")
                        :ARG1-of (i3 / immobilize-01)
                        :quant (m3 / mass-quantity :quant 60
                              :unit (p4 / picomole)))
                  :op2 (p5 / protein :name (n5 / name :op1 "GST-E3b1")
                        :consist-of (a3 / amino-acid
                              :mod (v2 / value-interval :op1 331 :op2 480))))
            :condition (p9 / present-02
                  :ARG1 (c / concentrate-02
                        :ARG1 (o2 / or
                              :op1 (p15 / protein-segment :name (n11 / name :op1 "SH3" :op2 "domain")
                                    :part-of (p6 / protein-segment :name (n6 / name :op1 "NH2-terminus")
                                          :part-of (p7 / protein :name (n7 / name :op1 "Grb2"))))
                              :op2 (p16 / protein-segment :name (n12 / name :op1 "SH3" :op2 "domain")
                                    :part-of (p8 / protein-segment :name (n8 / name :op1 "NH2-terminus")
                                          :part-of (e2 / enzyme :name (n9 / name :op1 "Eps8")))))
                        :ARG1-of (i / increase-01))))
      :snt2 (a4 / and
            :op1 (p10 / protein-segment :name (n10 / name :op1 "SH3"))
            :op2 (m5 / mass-quantity :quant 0
                  :unit (p11 / picomole))
            :op3 (m6 / mass-quantity :quant 10
                  :unit (p12 / picomole))
            :op4 (m7 / mass-quantity :quant 100
                  :unit (p13 / picomole))
            :op5 (m8 / mass-quantity :quant 1000
                  :unit (p14 / picomole))
            :ARG1-of (i2 / indicate-01
                  :location (t2 / top))))

# ::id pmid_1177_7939.218 ::date 2015-03-07T05:59:53 ::annotator SDL-AMR-09 ::preferred
# ::snt Detection was with antihistidine antibody.
# ::save-date Sun Mar 22, 2015 ::file pmid_1177_7939_218.txt
(d / detect-01
      :ARG2 (a / antibody
            :ARG0-of (c / counter-01
                  :ARG1 (a2 / amino-acid :name (n / name :op1 "histidine")))))

# ::id pmid_1177_7939.219 ::date 2015-03-07T06:01:10 ::annotator SDL-AMR-09 ::preferred
# ::snt I, input, 10 pmoles of His-Sos-1.
# ::save-date Mon Dec 21, 2015 ::file pmid_1177_7939_219.txt
(i / input
      :mod (p / protein :name (n / name :op1 "Sos-1")
            :ARG1-of (t / tag-01
                  :ARG2 (a / amino-acid :name (n2 / name :op1 "histidine")))
            :quant (m / mass-quantity :quant 10
                  :unit (p2 / picomole)))
      :ARG1-of (d / describe-01
            :ARG2 (n3 / name :op1 "I")))

# ::id pmid_1177_7939.220 ::date 2015-03-07T06:27:33 ::annotator SDL-AMR-09 ::preferred
# ::snt (C) His-Sos (10 pmoles) was bound to 60 pmoles of GST fusions encompassing the SH3s of either E3b1 (○ and •) or of Grb2 (□ and ▪).
# ::save-date Sun Mar 22, 2015 ::file pmid_1177_7939_220.txt
(b / bind-01
      :ARG1 (p / protein :name (n2 / name :op1 "Sos")
            :ARG1-of (t / tag-01
                  :ARG2 (a / amino-acid :name (n / name :op1 "histidine")))
            :quant (m2 / mass-quantity :quant 10
                  :unit (p2 / picomole)))
      :ARG2 (p3 / protein :name (n3 / name :op1 "GST" :op2 "fusion")
            :quant (m3 / mass-quantity :quant 60
                  :unit (p4 / picomole))
            :ARG0-of (e / encompass-01
                  :ARG1 (o / or
                        :op1 (p5 / protein-segment :name (n4 / name :op1 "SH3")
                              :part-of (p6 / protein :name (n5 / name :op1 "E3b1")))
                        :op2 (p7 / protein-segment :name (n6 / name :op1 "SH3")
                              :part-of (p8 / protein :name (n7 / name :op1 "Grb2"))))))
      :li "C")

# ::id pmid_1177_7939.221 ::date 2015-03-07T10:11:20 ::annotator SDL-AMR-09 ::preferred
# ::snt Binding was in the presence of the indicated amounts of the competing peptide NH2-VPVPPPVPPRRR-COOH (derived from the sequence of Sos-1, • and ▪), or of a scrambled control peptide (○ and □).
# ::save-date Wed Dec 30, 2015 ::file pmid_1177_7939_221.txt
(b / bind-01
      :condition (p2 / present-02
            :ARG1 (o / or
                  :op1 (a / amount
                        :quant-of (p / peptide :name (n / name :op1 "NH2-VPVPPPVPPRRR-COOH")
                              :ARG0-of (c / compete-01)
                              :ARG1-of (d / derive-01
                                    :ARG2 (s2 / sequence
                                          :mod (p3 / protein :name (n2 / name :op1 "Sos-1"))))))
                  :op2 (a2 / amount
                        :quant-of (p4 / peptide
                              :ARG0-of (c2 / control-01)
                              :ARG1-of (s / scramble-02)))
                  :ARG1-of (i / indicate-01))))

# ::id pmid_1177_7939.222 ::date 2015-03-07T06:34:50 ::annotator SDL-AMR-09 ::preferred
# ::snt Detection was by immunoblot with anti-His, followed by densitometric scanning.
# ::save-date Tue Jun 16, 2015 ::file pmid_1177_7939_222.txt
(d / detect-01
      :ARG2 (i / immunoblot-01
            :ARG3 (a / antibody
                  :ARG0-of (c / counter-01
                        :ARG1 (h / histidine)))
            :ARG2-of (f / follow-01
                  :ARG1 (s / scan-01
                        :mod (d2 / densitometric)))))

# ::id pmid_1177_7939.223 ::date 2015-03-07T06:36:41 ::annotator SDL-AMR-09 ::preferred
# ::snt (D) Kinetic analysis and rate constants for the binding of the SH3 domains of Grb2 and E3b1 to the proline-rich COOH-terminal of Sos-1 (aa 1131–1333).
# ::save-date Fri Jan 1, 2016 ::file pmid_1177_7939_223.txt
(a / and :li "D"
      :op1 (a2 / analyze-01
            :ARG1 (k / kinetics))
      :op2 (c / constant
            :mod (r / rate))
      :purpose (b / bind-01
            :ARG1 (a3 / and
                  :op1 (p / protein-segment :name (n / name :op1 "SH3" :op2 "domain")
                        :part-of (p2 / protein :name (n2 / name :op1 "Grb2")))
                  :op2 (p3 / protein-segment :name (n3 / name :op1 "SH3" :op2 "domain")
                        :part-of (p4 / protein :name (n4 / name :op1 "E3b1"))))
            :ARG2 (p5 / protein-segment :name (n5 / name :op1 "COOH-terminus")
                  :part-of (p6 / protein :name (n6 / name :op1 "Sos-1"))
                  :consist-of (a4 / amino-acid
                        :mod (b2 / between :op1 1131 :op2 1333))
                  :mod (r2 / rich
                        :mod (a5 / amino-acid :name (n7 / name :op1 "proline"))))))

# ::id pmid_1177_7939.224 ::date 2015-03-07T07:02:44 ::annotator SDL-AMR-09 ::preferred
# ::snt Increasing concentrations (10–400 nM) of His-Sos-1 were passed over the immobilized GST fusion proteins (GST-SH3-Grb2 and GST-SH3-E3b1) for 2.5 min at a flow rate of 50 μl/min.
# ::save-date Mon Jan 4, 2016 ::file pmid_1177_7939_224.txt
(p / pass-08
      :ARG0 (c / concentration
            :ARG1-of (i / increase-01)
            :mod (p2 / protein :name (n2 / name :op1 "Sos-1")
                  :ARG1-of (t3 / tag-01
                        :ARG2 (a / amino-acid :name (n / name :op1 "histidine"))))
            :quant (c2 / concentration-quantity
                  :quant (b / between :op1 10 :op2 400)
                  :unit (n3 / nanomolar)))
      :ARG1 (p3 / protein :name (n4 / name :op1 "GST" :op2 "fusion")
            :ARG1-of (i2 / immobilize-01)
            :ARG0-of (m3 / mean-01
                  :ARG1 (a2 / and
                        :op1 (p4 / protein :name (n5 / name :op1 "GST-SH3-Grb2"))
                        :op2 (p5 / protein :name (n6 / name :op1 "GST-SH3-E3b1")))))
      :duration (t / temporal-quantity :quant 2.5
            :unit (m4 / minute))
      :frequency (r / rate-entity-91
            :ARG1 (v / volume-quantity :quant 50
                  :unit (m5 / microliter))
            :ARG2 (t2 / temporal-quantity :quant 1
                  :unit (m6 / minute))))

# ::id pmid_1177_7939.225 ::date 2015-03-07T09:28:34 ::annotator SDL-AMR-09 ::preferred
# ::snt The kinetics of binding are shown in the graphs.
# ::save-date Sun Mar 22, 2015 ::file pmid_1177_7939_225.txt
(s / show-01
      :ARG0 (g / graph)
      :ARG1 (k / kinetics
            :mod (b / bind-01)))

# ::id pmid_1177_7939.226 ::date 2015-03-07T09:29:55 ::annotator SDL-AMR-09 ::preferred
# ::snt Coupling of equal amounts of the GST fusion proteins was performed with a goat anti-GST antibody covalently linked to CM5 sensor chip according to the manufacturer's instructions.
# ::save-date Tue Jul 28, 2015 ::file pmid_1177_7939_226.txt
(p / perform-02
      :ARG1 (c / couple-01
            :ARG1 (a / amount
                  :quant-of (p2 / protein :name (n / name :op1 "GST" :op2 "fusion"))
                  :ARG1-of (e / equal-01))
            :ARG2 (a2 / antibody
                  :mod (g / goat)
                  :ARG0-of (c5 / counter-01
                        :ARG1 (e2 / enzyme :name (n2 / name :op1 "GST")))
                  :ARG1-of (l / link-01
                        :ARG2 (c3 / chip :name (n3 / name :op1 "CM5")
                              :mod (s / sensor))
                        :manner (c2 / covalent))))
      :ARG1-of (s2 / say-01
            :ARG0 (i / instruct-01
                  :ARG0 (c4 / company
                        :ARG0-of (m / manufacture-01)))))

# ::id pmid_1177_7939.227 ::date 2015-03-07T09:49:18 ::annotator SDL-AMR-09 ::preferred
# ::snt k<sub>on</sub> and k<sub>off</sub> kinetic rates were obtained by simple Langmuir fitting model (biaevaluation software v2.1).
# ::save-date Thu Jan 28, 2016 ::file pmid_1177_7939_227.txt
(o / obtain-01
      :ARG1 (a / and
            :op1 (r / rate
                  :mod (k / kinetics
                        :ARG1-of (o2 / on-01)))
            :op2 (r2 / rate
                  :mod (k2 / kinetics
                        :mod (o3 / off))))
      :manner (m / model :name (n / name :op1 "Langmuir")
            :ARG0-of (f / fit-01)
            :ARG1-of (s / simple-02))
      :instrument (s2 / software
            :mod (b / biaevaluation)
            :mod (v / version :mod 2.1)))

# ::id pmid_1177_7939.228 ::date 2015-03-07T05:01:41 ::annotator SDL-AMR-09 ::preferred
# ::snt Figure 3.
# ::save-date Sat Mar 7, 2015 ::file pmid_1177_7939_228.txt
(f / figure :mod 3)

# ::id pmid_1177_7939.229 ::date 2015-03-07T05:05:11 ::annotator SDL-AMR-09 ::preferred
# ::snt <bold>In vivo competition between E3b1 and Grb2 for binding to Sos-1.</bold>
# ::save-date Sat Mar 7, 2015 ::file pmid_1177_7939_229.txt
(c / compete-01
      :ARG0 (p / protein :name (n / name :op1 "E3b1"))
      :ARG1 (p2 / protein :name (n2 / name :op1 "Grb2"))
      :ARG2 (b / bind-01
            :ARG2 (p3 / protein :name (n3 / name :op1 "Sos-1")))
      :manner (i / in-vivo))

# ::id pmid_1177_7939.230 ::date 2015-03-07T05:28:20 ::annotator SDL-AMR-09 ::preferred
# ::snt (A, Top) GST-E3b1-331–480, or control GST, was bound to Sos-1 present in Cos-7 cells transfected (Tfx) with either Sos-1 or S/G.
# ::save-date Wed Jan 13, 2016 ::file pmid_1177_7939_230.txt
(b / bind-01
      :ARG1 (o / or
            :op1 (m / macro-molecular-complex
                  :consist-of (a / amino-acid
                        :mod (v / value-interval :op1 331 :op2 480))
                  :part (e2 / enzyme :name (n / name :op1 "GST"))
                  :part (p4 / protein :name (n8 / name :op1 "E3b1")))
            :op2 (e / enzyme :name (n2 / name :op1 "GST")
                  :ARG0-of (c / control-01)))
      :ARG2 (p2 / protein :name (n3 / name :op1 "Sos-1")
            :ARG1-of (p5 / present-02
                  :ARG2 (c2 / cell-line :name (n4 / name :op1 "Cos-7")
                        :ARG1-of (t / transfect-01
                              :ARG2 (o2 / or
                                    :op1 (p3 / protein :name (n5 / name :op1 "Sos-1"))
                                    :op2 (m2 / macro-molecular-complex
                                          :part p3
                                          :part (p / protein :name (n7 / name :op1 "Grb2"))))))))
      :ARG1-of (d2 / describe-01
            :ARG0 (f / figure :mod "A"
                  :location (t2 / top))))

# ::id pmid_1177_7939.231 ::date 2015-03-07T02:26:19 ::annotator SDL-AMR-09 ::preferred
# ::snt Detection was with anti–Sos-1.
# ::save-date Sun Mar 22, 2015 ::file pmid_1177_7939_231.txt
(d / detect-01
      :ARG2 (a / antibody
            :ARG0-of (c / counter-01
                  :ARG1 (p / protein :name (n / name :op1 "Sos-1")))))

# ::id pmid_1177_7939.232 ::date 2015-03-07T02:27:29 ::annotator SDL-AMR-09 ::preferred
# ::snt (Bottom) The same cellular lysates (50 μg) were detected with anti-Grb2.
# ::save-date Sun Mar 22, 2015 ::file pmid_1177_7939_232.txt
(d / detect-01
      :ARG1 (l / lysate
            :mod (c / cell)
            :ARG1-of (s / same-01)
            :quant (m / mass-quantity :quant 50
                  :unit (m2 / microgram)))
      :ARG2 (a / antibody
            :ARG0-of (c2 / counter-01
                  :ARG1 (p / protein :name (n / name :op1 "Grb2"))))
      :location (b / bottom))

# ::id pmid_1177_7939.233 ::date 2015-03-07T02:30:07 ::annotator SDL-AMR-09 ::preferred
# ::snt (B) Lysates, from 293T cells transfected (Tfx) with E3b1 or a control vector (ctr), were immunoprecipitated (IP) with anti-Grb2 or an irrelevant antibody (ctr), followed by detection (WB) with anti–Sos-1 (top) or anti-Grb2 (middle).
# ::save-date Wed Jan 13, 2016 ::file pmid_1177_7939_233.txt
(i / immunoprecipitate-01
      :ARG1 (l / lysate)
      :ARG2 (c / cell-line :name (n / name :op1 "293T")
            :ARG1-of (t / transfect-01
                  :ARG2 (o / or
                        :op1 (p / protein :name (n2 / name :op1 "E3b1"))
                        :op2 (v / vector
                              :ARG0-of (c2 / control-01)))))
      :ARG3 (o2 / or
            :op1 (a / antibody
                  :ARG0-of (c3 / counter-01
                        :ARG1 p3))
            :op2 (a2 / antibody
                  :ARG1-of (r / relevant-01 :polarity -)))
      :ARG2-of (f / follow-01
            :ARG1 (d / detect-01
                  :ARG1 l
                  :ARG2 (o3 / or
                        :op1 (a3 / antibody
                              :ARG0-of (c4 / counter-01
                                    :ARG1 (p2 / protein :name (n4 / name :op1 "Sos-1")))
                              :ARG1-of (d7 / describe-01
                                    :location (t2 / top)))
                        :op2 (a4 / antibody
                              :ARG0-of (c5 / counter-01
                                    :ARG1 (p3 / protein :name (n10 / name :op1 "Grb2")))
                              :ARG1-of (d6 / describe-01
                                    :location (m / middle))))))
      :ARG1-of (d2 / describe-01
            :ARG0 (f2 / figure :mod "B")))

# ::id pmid_1177_7939.234 ::date 2015-03-07T02:36:43 ::annotator SDL-AMR-09 ::preferred
# ::snt The expression of E3b1 (bottom) was detected with an anti-E3b1 antibody.
# ::save-date Fri Jan 1, 2016 ::file pmid_1177_7939_234.txt
(d / detect-01
      :ARG1 (e / express-03
            :ARG2 (p / protein :name (n / name :op1 "E3b1"))
            :ARG1-of (d2 / describe-01
                  :location (b / bottom)))
      :ARG2 (a / antibody
            :ARG0-of (c / counter-01
                  :ARG1 p)))

# ::id pmid_1177_7939.235 ::date 2015-03-11T19:34:50 ::annotator SDL-AMR-09 ::preferred
# ::snt Figure 4.
# ::save-date Wed Mar 11, 2015 ::file pmid_1177_7939_235.txt
(f / figure :mod 4)

# ::id pmid_1177_7939.236 ::date 2015-03-11T19:34:24 ::annotator SDL-AMR-09 ::preferred
# ::snt <bold>The S/G and the S/E complexes are functionally distinct.</bold>
# ::save-date Wed Mar 11, 2015 ::file pmid_1177_7939_236.txt
(f / function-01
      :ARG0 (a / and
            :op1 (m / macro-molecular-complex
                  :part (p / protein :name (n / name :op1 "Sos-1"))
                  :part (p3 / protein :name (n3 / name :op1 "Grb2")))
            :op2 (m2 / macro-molecular-complex
                  :part p
                  :part (p2 / protein :name (n2 / name :op1 "E3b1"))))
      :mod (d / distinct))

# ::id pmid_1177_7939.237 ::date 2015-03-11T19:48:23 ::annotator SDL-AMR-09 ::preferred
# ::snt (A) Cos-7 cells were transfected with the indicated cDNAs (Tfx), and treated with EGF (3 min, +) or mock treated (−).
# ::save-date Sun Jan 17, 2016 ::file pmid_1177_7939_237.txt
(a / and :li "A"
      :op1 (t / transfect-01
            :ARG1 (c / cell-line :name (n / name :op1 "Cos-7"))
            :ARG2 (n3 / nucleic-acid :wiki "DNA" :name (n4 / name :op1 "DNA")
                  :ARG1-of (c2 / complement-01)
                  :ARG1-of (i / indicate-01)))
      :op2 (o / or
            :op1 (t2 / treat-04
                  :ARG1 c
                  :ARG2 (p / protein :name (n2 / name :op1 "EGF"))
                  :duration (t3 / temporal-quantity :quant 3
                        :unit (m / minute))
                  :ARG1-of (d2 / describe-01
                        :ARG2 (s3 / string-entity :value +)))
            :op2 (t4 / treat-04
                  :ARG1 c
                  :mod (m2 / mock)
                  :ARG1-of (d3 / describe-01
                        :ARG2 (s2 / string-entity :value "−")))))

# ::id pmid_1177_7939.238 ::date 2015-03-11T20:24:32 ::annotator SDL-AMR-09 ::preferred
# ::snt Immunoprecipitates (IP) with anti-EGFR or preimmune sera (ctr) were analyzed by immunoblotting (WB) with anti–EGFR or HA (for Sos-1 detection).
# ::save-date Wed Dec 30, 2015 ::file pmid_1177_7939_238.txt
(a / analyze-01
      :ARG1 (p / protein
            :ARG1-of (i / immunoprecipitate-01
                  :ARG3 (o / or
                        :op1 (a2 / antibody
                              :ARG0-of (c2 / counter-01
                                    :ARG1 (e / enzyme :name (n / name :op1 "EGFR"))))
                        :op2 (s2 / serum
                              :mod (p2 / preimmune)))))
      :manner (o4 / or
            :op1 (i2 / immunoblot-01
                  :ARG3 a2)
            :op2 (i3 / immunoblot-01
                  :ARG3 (a3 / antibody
                        :ARG0-of (c / counter-01
                              :ARG1 (p4 / protein :name (n2 / name :op1 "HA")))))
            :purpose (d / detect-01
                  :ARG1 (p3 / protein :name (n3 / name :op1 "Sos-1")))))

# ::id pmid_1177_7939.239 ::date 2015-03-11T21:04:18 ::annotator SDL-AMR-09 ::preferred
# ::snt Lysates (50 μg) were analyzed by immunoblotting with anti-EGFR, anti-HA (for Sos-1 detection), or anti-E3b1 antibody.
# ::save-date Wed Jun 17, 2015 ::file pmid_1177_7939_239.txt
(a / analyze-01
      :ARG1 (l / lysate
            :quant (m / mass-quantity :quant 50
                  :unit (m2 / microgram)))
      :manner (o5 / or
            :op1 (i / immunoblot-01
                  :ARG2 l
                  :ARG3 (a2 / antibody
                        :ARG0-of (c / counter-01
                              :ARG1 (e / enzyme :name (n / name :op1 "EGFR")))))
            :op2 (i2 / immunoblot-01
                  :ARG2 l
                  :ARG3 (a3 / antibody
                        :ARG0-of (c2 / counter-01
                              :ARG1 (p / protein :name (n2 / name :op1 "HA"))))
                  :purpose (d / detect-01
                        :ARG1 (p2 / protein :name (n3 / name :op1 "Sos-1"))))
            :op3 (i3 / immunoblot-01
                  :ARG2 l
                  :ARG3 (a4 / antibody
                        :ARG0-of (c3 / counter-01
                              :ARG1 (p3 / protein :name (n4 / name :op1 "E3b1")))))))

# ::id pmid_1177_7939.240 ::date 2015-03-11T21:17:43 ::annotator SDL-AMR-09 ::preferred
# ::snt HA-Sos, HA-epitope tagged Sos-1
# ::save-date Mon Mar 23, 2015 ::file pmid_1177_7939_240.txt
(m / mean-01
      :ARG1 (p / protein :name (n / name :op1 "HA-Sos"))
      :ARG2 (p2 / protein :name (n2 / name :op1 "Sos-1")
            :ARG1-of (t / tag-01
                  :ARG2 (e / epitope
                        :mod (p3 / protein :name (n3 / name :op1 "HA"))))))

# ::id pmid_1177_7939.241 ::date 2015-03-11T21:39:04 ::annotator SDL-AMR-09 ::preferred
# ::snt (B) Cos-7 cells were cotransfected (Tfx) with E3b1 (or a control empty vector, ctr) and either a myc-tagged Ras (left) or HA-tagged MAPK (right), followed by treatment with EGF (5 min, +) or mock-treatment (−).
# ::save-date Sat Jan 30, 2016 ::file pmid_1177_7939_241.txt
(c / cotransfect-01
      :ARG1 (c2 / cell-line :name (n3 / name :op1 "Cos-7"))
      :ARG2 (a / and
            :op1 (o / or
                  :op1 (p2 / protein :name (n4 / name :op1 "E3b1"))
                  :op2 (v / vector
                        :ARG1-of (e2 / empty-02)
                        :ARG2-of (c3 / control-01)))
            :op2 (o2 / or
                  :op1 (e / enzyme :name (n / name :op1 "Ras")
                        :ARG1-of (t / tag-01
                              :ARG2 (p / protein :name (n2 / name :op1 "myc")))
                        :ARG1-of (d / describe-01
                              :ARG1-of (l / left-20)))
                  :op2 (e3 / enzyme :name (n5 / name :op1 "MAPK")
                        :ARG1-of (t2 / tag-01
                              :ARG2 (p4 / protein :name (n6 / name :op1 "HA")))
                        :ARG1-of (d2 / describe-01
                              :ARG1-of (r / right-04)))))
      :ARG2-of (f3 / follow-01
            :ARG1 (o3 / or
                  :op1 (t3 / treat-04
                        :ARG2 (p3 / protein :name (n7 / name :op1 "EGF"))
                        :duration (t4 / temporal-quantity :quant 5
                              :unit (m / minute))
                        :ARG1-of (d3 / describe-01
                              :ARG2 (s3 / string-entity :value +)))
                  :op2 (t5 / treat-04
                        :mod (m2 / mock)
                        :ARG1-of (d4 / describe-01
                              :ARG2 (s2 / string-entity :value "−")))))
      :ARG1-of (d5 / describe-01
            :ARG0 (f / figure :mod "B")))

# ::id pmid_1177_7939.242 ::date 2015-03-11T22:10:16 ::annotator SDL-AMR-09 ::preferred
# ::snt (Top, left) Ras-GTP was recovered with the GST-RBD of Raf-1 followed by immunodetection with anti-myc antibodies.
# ::save-date Sat Jan 30, 2016 ::file pmid_1177_7939_242.txt
(r / recover-02
      :ARG1 (m / macro-molecular-complex
            :part (e / enzyme :name (n / name :op1 "Ras"))
            :part (s / small-molecule :name (n2 / name :op1 "GTP")))
      :ARG1-of (d / describe-01
            :location (a / and
                  :op1 (t / top)
                  :op2 (l / left-20)))
      :manner (p / protein-segment :name (n3 / name :op1 "GST-RBD")
            :part-of (e2 / enzyme :name (n4 / name :op1 "Raf-1"))
            :ARG2-of (f2 / follow-01
                  :ARG1 (i2 / immunodetect-01
                        :ARG1 m
                        :ARG3 (a2 / antibody
                              :ARG0-of (c / counter-01
                                    :ARG1 (p2 / protein :name (n5 / name :op1 "myc"))))))))

# ::id pmid_1177_7939.243 ::date 2015-03-12T00:15:55 ::annotator SDL-AMR-09 ::preferred
# ::snt (Top, right) Anti-HA immunoprecipitation, followed by immunodetection with an anti–phosphorylated MAPK antibody.
# ::save-date Sat Dec 19, 2015 ::file pmid_1177_7939_243.txt
(i / immunoprecipitate-01
      :ARG3 (a / antibody
            :ARG0-of (c / counter-01
                  :ARG1 (p / protein :name (n / name :op1 "HA"))))
      :ARG2-of (f / follow-01
            :ARG1 (i3 / immunodetect-01
                  :ARG3 (a2 / antibody
                        :ARG0-of (c2 / counter-01
                              :ARG1 (e / enzyme :name (n2 / name :op1 "MAPK")
                                    :ARG3-of (p3 / phosphorylate-01))))))
      :ARG1-of (d2 / describe-01
            :location (t / top)
            :ARG1-of (r / right-04)))

# ::id pmid_1177_7939.244 ::date 2015-03-12T00:31:07 ::annotator SDL-AMR-09 ::preferred
# ::snt The levels of expression of myc-Ras and HA-MAPK (middle) and E3b1 (bottom) are also shown.
# ::save-date Mon Mar 23, 2015 ::file pmid_1177_7939_244.txt
(s / show-01
      :ARG1 (l / level
            :mod (e / express-03
                  :ARG2 (a / and
                        :op1 (a3 / and
                              :op1 (m / macro-molecular-complex
                                    :part (p / protein :name (n / name :op1 "myc"))
                                    :part (e2 / enzyme :name (n2 / name :op1 "Ras")))
                              :op2 (m2 / macro-molecular-complex
                                    :part (p2 / protein :name (n3 / name :op1 "HA"))
                                    :part (e3 / enzyme :name (n4 / name :op1 "MAPK")))
                              :ARG1-of (d / describe-01
                                    :location (m3 / middle)))
                        :op2 (p4 / protein :name (n5 / name :op1 "E3b1")
                              :ARG1-of (d2 / describe-01
                                    :location (b / bottom))))))
      :mod (a2 / also))

# ::id pmid_1177_7939.245 ::date 2015-03-12T00:43:07 ::annotator SDL-AMR-09 ::preferred
# ::snt (C) Quiescent NIH-3T3 fibroblasts were microinjected with an empty vector together with rabbit IgG (left) or with an HA-tagged E3b1 expression vector (right) followed by treatment with 10% serum.
# ::save-date Tue Feb 2, 2016 ::file pmid_1177_7939_245.txt
(m / microinject-01 :li "C"
      :ARG1 (o / or
            :op1 (v / vector
                  :ARG1-of (e / empty-02)
                  :accompanier (p2 / protein :name (n2 / name :op1 "IgG")
                        :mod (r / rabbit))
                  :ARG1-of (d / describe-01
                        :location (l / left-20)))
            :op2 (v2 / vector
                  :ARG1-of (e2 / express-03
                        :ARG2 (p3 / protein :name (n3 / name :op1 "E3b1")
                              :ARG1-of (t / tag-01
                                    :ARG2 (p4 / protein :name (n4 / name :op1 "HA")))))
                  :ARG1-of (d2 / describe-01
                        :ARG1-of (r2 / right-04))
                  :ARG2-of (f2 / follow-01
                        :ARG1 (t2 / treat-04
                              :ARG2 (s / serum
                                    :mod (p / percentage-entity :value 10))))))
      :ARG2 (f / fibroblast
            :mod (c / cell-line :name (n / name :op1 "NIH-3T3"))
            :mod (q / quiescent)))

# ::id pmid_1177_7939.246 ::date 2015-03-12T01:15:23 ::annotator SDL-AMR-09 ::preferred
# ::snt After 15 h, BrdU was added and 3 h later the cells were fixed and stained to detect BrdU incorporation (top), E3b1 (anti-HA), or control (anti-IgG).
# ::save-date Sun Jan 17, 2016 ::file pmid_1177_7939_246.txt
(a / and
      :op1 (a2 / add-02
            :ARG1 (s2 / small-molecule :name (n / name :op1 "BrdU"))
            :time (a4 / after
                  :op1 (t / temporal-quantity :quant 15
                        :unit (h / hour))))
      :op2 (a3 / and
            :op1 (f / fix-02
                  :ARG1 (c / cell))
            :op2 (s / stain-01
                  :ARG1 c)
            :purpose (d / detect-01
                  :ARG1 (o / or
                        :op1 (i / incorporate-02
                              :ARG1 s2
                              :ARG1-of (d2 / describe-01
                                    :location (t2 / top)))
                        :op2 (p2 / protein :name (n2 / name :op1 "E3b1")
                              :ARG0-of (c3 / counter-01
                                    :ARG1 (p3 / protein :name (n3 / name :op1 "HA"))))
                        :op3 (c2 / control-01
                              :ARG0-of (c4 / counter-01
                                    :ARG1 (p4 / protein :name (n4 / name :op1 "IgG"))))))
            :time (l2 / late
                  :op1 (t3 / temporal-quantity :quant 3
                        :unit (h2 / hour))
                  :degree (m2 / more))))

# ::id pmid_1177_7939.247 ::date 2015-03-12T01:34:53 ::annotator SDL-AMR-09 ::preferred
# ::snt Nuclei were counterstained with Dapi (bottom).
# ::save-date Sat Feb 13, 2016 ::file pmid_1177_7939_247.txt
(s / stain-01
      :ARG1 (n / nucleus)
      :ARG2 (s2 / small-molecule :name (n2 / name :op1 "Dapi"))
      :ARG1-of (c / counter-01)
      :ARG1-of (d / describe-01
            :location (b / bottom)))

# ::id pmid_1177_7939.248 ::date 2015-03-12T01:53:22 ::annotator SDL-AMR-09 ::preferred
# ::snt A quantitative analysis of BrdU incorporation into control (empty bar) and E3b1 (closed bar) injected cells is shown on the right.
# ::save-date Sun Jan 17, 2016 ::file pmid_1177_7939_248.txt
(s / show-01
      :ARG1 (a / analyze-01
            :ARG1 (i / incorporate-02
                  :ARG1 (s2 / small-molecule :name (n / name :op1 "BrdU"))
                  :ARG2 (a2 / and
                        :op1 (c / cell
                              :mod (c3 / control-01)
                              :ARG1-of (m / mean-01
                                    :ARG2 (b / bar
                                          :ARG1-of (e / empty-02))))
                        :op2 (c2 / cell
                              :ARG1-of (m2 / mean-01
                                    :ARG2 (b2 / bar
                                          :ARG1-of (c4 / close-01)))
                              :ARG2-of (i2 / inject-01
                                    :ARG1 (p2 / protein :name (n2 / name :op1 "E3b1"))))))
            :mod (q / quantity))
      :ARG1-of (r / right-04))

# ::id pmid_1177_7939.249 ::date 2015-03-12T02:04:43 ::annotator SDL-AMR-09 ::preferred
# ::snt The data are the mean ± SEM of three independent experiments.
# ::save-date Mon Nov 2, 2015 ::file pmid_1177_7939_249.txt
(e4 / equal-01
      :ARG1 (d / data)
      :ARG2 (v / value-interval
            :op1 (e / error
                  :ARG1-of (s2 / standard-02
                        :ARG1-of (a / add-02
                              :ARG2 (m / mean
                                    :poss (e3 / experiment-01 :quant 3
                                          :ARG0-of (d2 / depend-01 :polarity -))))))
            :op2 (e2 / error
                  :ARG1-of (s / standard-02)
                  :ARG1-of (s3 / subtract-01
                        :ARG2 m))))

# ::id pmid_1177_7939.250 ::date 2015-03-12T02:15:51 ::annotator SDL-AMR-09 ::preferred
# ::snt Results are expressed as a percentage of injected cells incorporating BrdU respect to uninjected ones.
# ::save-date Sun Jan 17, 2016 ::file pmid_1177_7939_250.txt
(e / express-01
      :ARG1 (t / thing
            :ARG2-of (r / result-01))
      :manner (p / percentage
            :quant-of (c / cell
                  :ARG2-of (i / inject-01)
                  :ARG2-of (i2 / incorporate-02
                        :ARG1 (s / small-molecule :name (n / name :op1 "BrdU"))))
            :compared-to (c2 / cell
                  :ARG2-of (i3 / inject-01 :polarity -))))

# ::id pmid_1177_7939.251 ::date 2015-03-12T02:27:26 ::annotator SDL-AMR-09 ::preferred
# ::snt Serum treatment induces BrdU incorporation in >95% of not injected cells.
# ::save-date Sun Jan 17, 2016 ::file pmid_1177_7939_251.txt
(i / induce-01
      :ARG0 (t / treat-04
            :ARG2 (s / serum))
      :ARG2 (i2 / incorporate-02
            :ARG1 (s2 / small-molecule :name (n / name :op1 "BrdU"))
            :ARG2 (c / cell
                  :ARG2-of (i3 / inject-01 :polarity -)
                  :quant (m / more-than
                        :op1 (p2 / percentage-entity :value 95)))))

# ::id pmid_1177_7939.252 ::date 2015-03-12T02:39:11 ::annotator SDL-AMR-09 ::preferred
# ::snt Figure 5.
# ::save-date Thu Mar 12, 2015 ::file pmid_1177_7939_252.txt
(f / figure :mod 5)

# ::id pmid_1177_7939.253 ::date 2015-03-12T02:39:39 ::annotator SDL-AMR-09 ::preferred
# ::snt <bold>E3b1 is a limiting factor in Rac activation.</bold>
# ::save-date Tue Mar 24, 2015 ::file pmid_1177_7939_253.txt
(f / factor
      :ARG0-of (l / limit-01
            :ARG1 (a / activate-01
                  :ARG1 (e / enzyme :name (n2 / name :op1 "Rac"))))
      :domain (p / protein :name (n / name :op1 "E3b1")))

# ::id pmid_1177_7939.254 ::date 2015-03-12T02:48:39 ::annotator SDL-AMR-09 ::preferred
# ::snt (Top, left) Lysates of Cos-7 cells were immunoprecipitated (IP) with the antibody indicated on the top and immunoblotted with the antibody indicated on the right.
# ::save-date Sat Jan 30, 2016 ::file pmid_1177_7939_254.txt
(a / and
      :op1 (i / immunoprecipitate-01
            :ARG1 (l / lysate)
            :ARG2 (c / cell-line :wiki "COS_cells" :name (n / name :op1 "Cos-7"))
            :ARG3 (a2 / antibody
                  :ARG1-of (i2 / indicate-01
                        :location (t / top))))
      :op2 (i3 / immunoblot-01
            :ARG1 l
            :ARG3 (a3 / antibody
                  :ARG1-of (i4 / indicate-01
                        :ARG1-of (r / right-04))))
      :ARG1-of (d / describe-01
            :location (a4 / and
                  :op1 t
                  :op2 (l2 / left-20))))

# ::id pmid_1177_7939.255 ::date 2015-03-12T04:34:09 ::annotator SDL-AMR-09 ::preferred
# ::snt Lysate, 50 μg of total cellular lysate.
# ::save-date Tue Mar 24, 2015 ::file pmid_1177_7939_255.txt
(l / lysate
      :quant (m / mass-quantity :quant 50
                  :unit (m2 / microgram))
      :ARG1-of (i / include-91
            :ARG2 (l2 / lysate
                  :mod (c / cell)
                  :ARG2-of (t / total-01))))

# ::id pmid_1177_7939.256 ::date 2015-03-12T04:44:11 ::annotator SDL-AMR-09 ::preferred
# ::snt (Top, right) The efficiency of Grb2 and E3b1 immunoprecipitations was >95%, as determined by immunoblot analysis of the supernatants of the immunoprecipitations performed with either the specific antibody with (Grb2 and E3b1, respectively, as indicated) or with an irrelevant (ctr) antibody.
# ::save-date Sun Dec 20, 2015 ::file pmid_1177_7939_256.txt
(e / efficient-01
      :ARG1 (i / immunoprecipitate-01
            :ARG1 (a / and
                  :op1 (p2 / protein :name (n / name :op1 "Grb2"))
                  :op2 (p3 / protein :name (n2 / name :op1 "E3b1"))))
      :degree (m / more-than
            :op1 (p / percentage-entity :value 95))
      :ARG1-of (d / determine-01
            :ARG0 (a2 / analyze-01
                  :ARG1 (s / supernatant
                        :mod (i3 / immunoprecipitate-01
                              :ARG1-of (p4 / perform-02
                                    :instrument (o / or
                                          :op1 (a3 / antibody
                                                :ARG1-of (s2 / specific-02)
                                                :ARG1-of (m2 / mean-01
                                                      :ARG2 (a4 / and
                                                            :op1 p2
                                                            :op2 p3)
                                                      :mod (r / respective)
                                                      :ARG1-of (i4 / indicate-01)))
                                          :op2 (a5 / antibody
                                                :ARG1-of (r2 / relevant-01 :polarity -)
                                                :ARG1-of (m3 / mean-01
                                                      :ARG2 (c / control-01)))))))
                  :manner (i2 / immunoblot-01)))
      :ARG1-of (d2 / describe-01
            :location (t / top)
            :ARG1-of (r3 / right-04)))

# ::id pmid_1177_7939.257 ::date 2015-03-12T05:10:43 ::annotator SDL-AMR-09 ::preferred
# ::snt (Middle) Cos-7 cells were transfected (Tfx) with HA-tagged PAK65 (all lanes) together with the plasmids indicated on the top (ctr, empty vector) and serum starved for 24 h.
# ::save-date Sun Jan 17, 2016 ::file pmid_1177_7939_257.txt
(a3 / and
      :op1 (t / transfect-01
            :ARG1 (c / cell-line :name (n / name :op1 "Cos-7"))
            :ARG2 (a2 / and
                  :op1 (e2 / enzyme :name (n2 / name :op1 "PAK65")
                        :ARG1-of (t2 / tag-01
                              :ARG2 (p2 / protein :name (n3 / name :op1 "HA")))
                        :ARG1-of (m / mean-01
                              :ARG2 (l / lane
                                    :mod (a / all))))
                  :op2 (p3 / plasmid
                        :ARG1-of (i / indicate-01
                              :location (t3 / top))
                        :ARG1-of (m2 / mean-01
                              :ARG2 (v / vector
                                    :ARG2-of (c2 / control-01)
                                    :ARG1-of (e / empty-02))))))
      :op2 (s / starve-01
            :ARG1 c
            :ARG2 (s2 / serum)
            :duration (t4 / temporal-quantity :quant 24
                  :unit (h / hour)))
      :ARG1-of (d / describe-01
            :location (m3 / middle)))

# ::id pmid_1177_7939.258 ::date 2015-03-12T05:25:17 ::annotator SDL-AMR-09 ::preferred
# ::snt Equal amounts of anti-HA immunoprecipitated PAK65 were subjected to an in vitro kinase assay using myelin basic protein (MBP) as a substrate.
# ::save-date Sun Jan 17, 2016 ::file pmid_1177_7939_258.txt
(s / subject-01
      :ARG1 (e2 / enzyme :name (n / name :op1 "PAK65")
            :quant (a / amount
                  :ARG1-of (e / equal-01))
            :ARG1-of (i / immunoprecipitate-01
                  :ARG3 (a3 / antibody
                        :ARG0-of (c / counter-01
                              :ARG1 (p2 / protein :name (n2 / name :op1 "HA"))))))
      :ARG2 (a2 / assay-01
            :ARG1 (k / kinase)
            :mod (i2 / in-vitro)
            :ARG0-of (u / use-01
                  :ARG1 (p3 / protein :name (n3 / name :op1 "myelin" :op2 "basic" :op3 "protein"))
                  :ARG2 (s2 / substrate))))

# ::id pmid_1177_7939.259 ::date 2015-03-12T05:37:46 ::annotator SDL-AMR-09 ::preferred
# ::snt The levels of immunoprecipitated PAK65 and the expression of Sos-1, E3b1, and HARacN17 in the various transfectants are also shown.
# ::save-date Sun Jan 17, 2016 ::file pmid_1177_7939_259.txt
(s / show-01
      :ARG1 (a / and
            :op1 (l / level
                  :quant-of (e2 / enzyme :name (n / name :op1 "PAK65")
                        :ARG1-of (i / immunoprecipitate-01)))
            :op2 (e / express-03
                  :ARG2 (a2 / and
                        :op1 (p2 / protein :name (n2 / name :op1 "Sos-1"))
                        :op2 (p3 / protein :name (n3 / name :op1 "E3b1"))
                        :op3 (p4 / protein :name (n4 / name :op1 "HARacN17")))
                  :ARG3 (c / cell
                        :mod (v / various)
                        :ARG1-of (t / transfect-01))))
      :mod (a3 / also))

# ::id pmid_1177_7939.260 ::date 2015-03-12T05:51:19 ::annotator SDL-AMR-09 ::preferred
# ::snt Similar results were obtained using Cos-7 cells.
# ::save-date Tue Mar 24, 2015 ::file pmid_1177_7939_260.txt
(o / obtain-01
      :ARG1 (t / thing
            :ARG1-of (r / result-01)
            :ARG1-of (r2 / resemble-01))
      :manner (u / use-01
            :ARG1 (c / cell-line :name (n / name :op1 "Cos-7"))))

# ::id pmid_1177_7939.261 ::date 2015-03-12T05:54:56 ::annotator SDL-AMR-09 ::preferred
# ::snt (Bottom) Wild-type (+/+) and eps8<sup>−/−</sup> (−/−) mouse embryo fibroblasts were infected with retroviral vectors coding for E3b1 (E3b1) or the mutant of E3b1-DY (E3b1-DY), or with an empty vector as a control (ctr).
# ::save-date Sun Jul 26, 2015 ::file pmid_1177_7939_261.txt
(i / infect-01
      :ARG1 (a / and
            :op1 (f / fibroblast
                  :mod (w / wild-type)
                  :source (e / embryo
                        :mod (m2 / mouse)))
            :op2 (f2 / fibroblast
                  :ARG2-of (m / mutate-01 :mod "−/−")
                  :source e
                  :ARG0-of (c3 / contain-01
                        :ARG1 (e3 / enzyme :name (n3 / name :op1 "eps8")
                              :ARG2-of (m4 / mutate-01 :mod "−/−")))))
      :ARG2 (o / or
            :op1 (v / vector
                  :mod (r / retrovirus)
                  :ARG0-of (c2 / code-01
                        :ARG1 (p / protein :name (n / name :op1 "E3b1"))))
            :op2 (p2 / protein :name (n2 / name :op1 "E3b1-DY")
                  :ARG2-of (m3 / mutate-01))
            :op3 (v2 / vector
                  :ARG1-of (e2 / empty-02)
                  :ARG2-of (c / control-01)))
      :ARG1-of (d / describe-01
            :location (b / bottom)))

# ::id pmid_1177_7939.262 ::date 2015-03-12T06:40:40 ::annotator SDL-AMR-09 ::preferred
# ::snt >95% of the cells expressed the infected cDNA, as determined by immunostaining with anti-E3b1 (not shown).
# ::save-date Tue Jan 19, 2016 ::file pmid_1177_7939_262.txt
(e / express-03
      :ARG2 (n2 / nucleic-acid :wiki "DNA" :name (n3 / name :op1 "DNA")
            :ARG1-of (c2 / complement-01)
            :ARG1-of (i / infect-01))
      :ARG3 (c / cell
            :quant (m / more-than
                  :op1 (p / percentage-entity :value 95)))
      :ARG1-of (d2 / determine-01
            :ARG2 (i2 / immunostain-01
                  :ARG2 (a / antibody
                        :ARG0-of (c3 / counter-01
                              :ARG1 (p2 / protein :name (n / name :op1 "E3b1"))))))
      :ARG1-of (s / show-01 :polarity -))

# ::id pmid_1177_7939.263 ::date 2015-03-12T08:10:23 ::annotator SDL-AMR-09 ::preferred
# ::snt Equal amounts of lysates were subjected to in vitro binding assays with the immobilized CRIB domain of PAK65.
# ::save-date Sun Jan 17, 2016 ::file pmid_1177_7939_263.txt
(s / subject-01
      :ARG1 (a3 / and
            :op1 (l / lysate
                  :quant (a / amount
                        :ARG1-of (e / equal-01)))
            :op2 (p3 / protein-segment :name (n3 / name :op1 "CRIB" :op2 "domain")
                  :ARG1-of (i2 / immobilize-01)
                  :part-of (e2 / enzyme :name (n2 / name :op1 "PAK65"))))
      :ARG2 (a2 / assay-01
            :ARG1 (b / bind-01)
            :manner (i / in-vitro)))

# ::id pmid_1177_7939.264 ::date 2015-03-12T09:36:05 ::annotator SDL-AMR-09 ::preferred
# ::snt After washing, bound proteins were resolved by SDS-PAGE and immunoblotted with anti-Rac antibodies (Rac-GTP).
# ::save-date Sun Jan 31, 2016 ::file pmid_1177_7939_264.txt
(a / and
      :op1 (r / resolve-03
            :ARG1 (p / protein
                  :ARG1-of (b / bind-01))
            :ARG3 (t / thing :name (n / name :op1 "SDS-PAGE")))
      :op2 (i / immunoblot-01
            :ARG1 p
            :ARG3 (a2 / antibody
                  :ARG0-of (c / counter-01
                        :ARG1 (e / enzyme :name (n2 / name :op1 "Rac")))
                  :ARG1-of (m2 / mean-01
                        :ARG2 (m3 / macro-molecular-complex
                              :part e
                              :part (s / small-molecule :name (n3 / name :op1 "GTP"))))))
      :time (a3 / after
            :op1 (w / wash-01)))

# ::id pmid_1177_7939.265 ::date 2015-03-12T10:11:05 ::annotator SDL-AMR-09 ::preferred
# ::snt The levels of total Rac (Rac) and E3b1 proteins are also shown.
# ::save-date Sun Jan 17, 2016 ::file pmid_1177_7939_265.txt
(s / show-01
      :ARG1 (a2 / and
            :op1 (l / level
                  :quant-of (e / enzyme :name (n / name :op1 "Rac")
                        :mod (t / total)))
            :op2 (l2 / level
                  :quant-of (p2 / protein :name (n2 / name :op1 "E3b1"))))
      :mod (a / also))

# ::id pmid_1177_7939.266 ::date 2015-03-12T10:34:26 ::annotator SDL-AMR-09 ::preferred
# ::snt Figure 6.
# ::save-date Thu Mar 12, 2015 ::file pmid_1177_7939_266.txt
(f / figure :mod 6)

# ::id pmid_1177_7939.267 ::date 2015-03-12T10:40:08 ::annotator SDL-AMR-09 ::preferred
# ::snt <bold>The E3b1DY mutant inhibits actin remodeling induced by activated Ras, but not by activated Rac.</bold>
# ::save-date Wed Jun 3, 2015 ::file pmid_1177_7939_267.txt
(i / inhibit-01
      :ARG0 (p / protein :name (n / name :op1 "E3b1DY")
            :ARG2-of (m / mutate-01))
      :ARG1 (r / remodel-01
            :ARG1 (a / actin)
            :ARG2-of (i2 / induce-01
                  :ARG0 (e / enzyme :name (n2 / name :op1 "Ras")
                        :ARG1-of (a2 / activate-01))
                  :ARG1-of (c2 / contrast-01
                        :ARG2 (i3 / induce-01 :polarity -
                              :ARG0 (e2 / enzyme :name (n3 / name :op1 "Rac")
                                    :ARG1-of a2))))))

# ::id pmid_1177_7939.268 ::date 2015-03-12T11:08:21 ::annotator SDL-AMR-09 ::preferred
# ::snt Mouse embryo fibroblasts were transfected, as indicated on the top, with expression vectors for either RasV12 or RacQL, together with ECFP-tagged versions of either E3b1 or the E3b1DY mutant.
# ::save-date Sun Jan 17, 2016 ::file pmid_1177_7939_268.txt
(t / transfect-01
      :ARG1 (f / fibroblast
            :source (e / embryo
                  :mod (m / mouse)))
      :ARG2 (v / vector
            :ARG1-of (e2 / express-03
                  :ARG2 (o / or
                        :op1 (e3 / enzyme :name (n / name :op1 "RasV12"))
                        :op2 (e4 / enzyme :name (n2 / name :op1 "RacQL"))))
            :accompanier (o2 / or
                  :op1 (p2 / protein :name (n3 / name :op1 "E3b1"))
                  :op2 (p3 / protein :name (n4 / name :op1 "E3b1DY")
                        :ARG2-of (m2 / mutate-01))
                  :ARG1-of (t3 / tag-01
                        :ARG2 (p4 / protein :name (n5 / name :op1 "ECFP")))))
      :ARG1-of (i / indicate-01
            :location (t2 / top)))

# ::id pmid_1177_7939.269 ::date 2015-03-12T12:16:51 ::annotator SDL-AMR-09 ::preferred
# ::snt After serum starvation, cells were fixed and stained with rhodamine-conjugated phalloidine to detect F-actin (top, red).
# ::save-date Sat Feb 13, 2016 ::file pmid_1177_7939_269.txt
(a / and
      :op1 (f / fix-02
            :ARG1 (c / cell))
      :op2 (s / stain-01
            :ARG1 c
            :ARG2 (s4 / small-molecule :name (n / name :op1 "phalloidine")
                  :ARG1-of (c2 / conjugate-02
                        :ARG2 (s5 / small-molecule :name (n3 / name :op1 "rhodamine")))))
      :purpose (d / detect-01
            :ARG1 (p / protein :name (n2 / name :op1 "F-actin")))
      :time (a2 / after
            :op1 (s2 / starve-01
                  :ARG1 c
                  :ARG2 (s3 / serum)))
      :ARG1-of (d2 / describe-01
            :location (t / top)
            :mod (r / red)))

# ::id pmid_1177_7939.270 ::date 2015-03-12T12:30:21 ::annotator SDL-AMR-09 ::preferred
# ::snt Expression of the transfected proteins was detected (bottom, green) with either anti-Ras or anti-Rac antibodies or by epifluorescence (ECFP).
# ::save-date Fri Jan 1, 2016 ::file pmid_1177_7939_270.txt
(d / detect-01
      :ARG1 (e / express-03
            :ARG2 (p / protein
                  :ARG2-of (t / transfect-01)))
      :ARG2 (o / or
            :op1 (a / antibody
                  :ARG0-of (c / counter-01
                        :ARG1 (e2 / enzyme :name (n / name :op1 "Ras"))))
            :op2 (a2 / antibody
                  :ARG0-of (c2 / counter-01
                        :ARG1 (e4 / enzyme :name (n2 / name :op1 "Rac"))))
            :op3 (e3 / epifluorescence))
      :ARG1-of (d2 / describe-01
            :location (b / bottom))
      :ARG1-of (g / green-02))

# ::id pmid_1177_7939.271 ::date 2015-03-12T13:20:31 ::annotator SDL-AMR-09 ::preferred
# ::snt In the cotransfection experiments a molar ratio of 1:3 of the activated GTPases to the ECFP-E3b1 constructs was used, such as that all of the epifluorescent cells expressed also the corresponding GTPase (not shown).
# ::save-date Mon Jan 4, 2016 ::file pmid_1177_7939_271.txt
(u / use-01
      :ARG0 (e3 / experiment-01
            :ARG1 (c / cotransfect-01))
      :ARG1 (r / ratio-of
            :op1 (m2 / molar
                  :quant-of (e2 / enzyme :name (n2 / name :op1 "GTPase")
                        :ARG1-of (a / activate-01)))
            :op2 (m3 / molar
                  :quant-of (m / macro-molecular-complex
                        :part (p / protein :name (n3 / name :op1 "ECFP"))
                        :part (p2 / protein :name (n4 / name :op1 "E3b1"))))
            :ARG1-of (e7 / equal-01
                  :ARG2 "1/3"))
      :ARG0-of (c2 / cause-01
            :ARG1 (e4 / express-03
                  :ARG2 (e6 / enzyme :name (n5 / name :op1 "GTPase")
                        :ARG1-of (c4 / correspond-02))
                  :ARG3 (c3 / cell
                        :mod (a2 / all)
                        :mod (e / epifluorescent))
                  :mod (a3 / also)))
      :ARG1-of (s / show-01 :polarity -))

# ::id pmid_1177_7939.272 ::date 2015-03-12T13:59:38 ::annotator SDL-AMR-09 ::preferred
# ::snt The percent of transfected cells (mean ± SEM) undergoing ruffling was as follow: RasV12 = 65 ± 3%; RasV12 + E3b1 WT = 62 ± 4%; RasV12 + E3b1DY = 16 ± 2%; RacQL = 93 ± 3%; RacQL + E3b1 WT = 90 ± 4%; RacQL + E3b1DY = 95 ± 5%.
# ::save-date Sun Jan 17, 2016 ::file pmid_1177_7939_272.txt
(m3 / multi-sentence
      :snt1 (f / follow-04
            :ARG1 (p4 / percentage-entity
                  :quant-of (c / cell
                        :ARG1-of (t / transfect-01)
                        :ARG1-of (u / undergo-28
                              :ARG2 (r / ruffle-02))
                        :ARG1-of (m / mean-01
                              :ARG2 (m2 / mean
                                    :mod (s / slash
                                          :op1 (e / error
                                                :ARG1-of (s2 / standard-02))
                                          :op2 (e2 / error :polarity -
                                                :ARG1-of s2)))))))
      :snt2 (e3 / equal-01
            :ARG1 (s3 / sum-of :op1 65
                  :op2 (s4 / slash
                        :op1 (p / percentage-entity :value 3)
                        :op2 (p2 / percentage-entity :value "-3")))
            :ARG2 (e4 / enzyme :name (n / name :op1 "RasV12")))
      :snt3 (e5 / equal-01
            :ARG1 (s6 / sum-of :op1 62
                  :op2 (s7 / slash
                        :op1 (p5 / percentage-entity :value 4)
                        :op2 (p6 / percentage-entity :value "-4")))
            :ARG2 (s5 / sum-of
                  :op1 (e6 / enzyme :name (n2 / name :op1 "RasV12"))
                  :op2 (p3 / protein :name (n3 / name :op1 "E3b1")
                        :mod (w / wild-type))))
      :snt4 (e7 / equal-01
            :ARG1 (s9 / sum-of :op1 16
                  :op2 (s10 / slash
                        :op1 (p8 / percentage-entity :value 2)
                        :op2 (p9 / percentage-entity :value "-2")))
            :ARG2 (s8 / sum-of
                  :op1 (e8 / enzyme :name (n4 / name :op1 "RasV12"))
                  :op2 (p7 / protein :name (n5 / name :op1 "E3b1DY"))))
      :snt5 (e9 / equal-01
            :ARG1 (s11 / sum-of :op1 93
                  :op2 (s12 / slash
                        :op1 (p11 / percentage-entity :value 3)
                        :op2 (p12 / percentage-entity :value "-3")))
            :ARG2 (e14 / enzyme :name (n6 / name :op1 "RacQL")))
      :snt6 (e10 / equal-01
            :ARG1 (s14 / sum-of :op1 90
                  :op2 (s15 / slash
                        :op1 (p15 / percentage-entity :value 4)
                        :op2 (p16 / percentage-entity :value "-4")))
            :ARG2 (s13 / sum-of
                  :op1 (e13 / enzyme :name (n7 / name :op1 "RacQL"))
                  :op2 (p14 / protein :name (n8 / name :op1 "E3b1")
                        :mod (w2 / wild-type))))
      :snt7 (e11 / equal-01
            :ARG1 (s17 / sum-of :op1 95
                  :op2 (s18 / slash
                        :op1 (p19 / percentage-entity :value 5)
                        :op2 (p20 / percentage-entity :value "-5")))
            :ARG2 (s16 / sum-of
                  :op1 (e12 / enzyme :name (n9 / name :op1 "RacQL"))
                  :op2 (p18 / protein :name (n10 / name :op1 "E3b1DY")))))

# ::id pmid_1177_7939.273 ::date 2015-03-12T14:53:36 ::annotator SDL-AMR-09 ::preferred
# ::snt Bar, 10 μm.
# ::save-date Wed Dec 30, 2015 ::file pmid_1177_7939_273.txt
(b / bar
      :mod (d / distance-quantity :quant 10
            :unit (m / micrometer)))

# ::id pmid_1177_7939.274 ::date 2015-03-10T09:17:11 ::annotator SDL-AMR-09 ::preferred
# ::snt Figure 7.
# ::save-date Tue Mar 10, 2015 ::file pmid_1177_7939_274.txt
(f / figure :mod 7)

# ::id pmid_1177_7939.275 ::date 2015-03-10T09:22:02 ::annotator SDL-AMR-09 ::preferred
# ::snt <bold>The bifunctional guanine nucleotide exchange activity of Sos-1 is regulated by its assembly into distinct molecular complexes.</bold>
# ::save-date Mon Dec 21, 2015 ::file pmid_1177_7939_275.txt
(r / regulate-01
      :ARG0 (a / assemble-02
            :ARG0 (p2 / protein :name (n2 / name :op1 "Sos-1"))
            :ARG1 (c / complex
                  :mod (d / distinct)
                  :mod (m / molecule)))
      :ARG1 (a2 / activity-06
            :ARG0 p2
            :ARG1 (p / protein :name (n / name :op1 "guanine" :op2 "nucleotide" :op3 "exchange" :op4 "factor")
                  :ARG0-of (f / function-01 :quant 2))))

# ::id pmid_1177_7939.276 ::date 2015-03-10T10:35:56 ::annotator SDL-AMR-09 ::preferred
# ::snt (A) Cos-7 cells were transfected with expression vectors for Sos-1 (SosTfx) or for Sos-1, E3b1, and Eps8 (TripleTfx) or with the corresponding empty vectors (mock).
# ::save-date Sun Jan 17, 2016 ::file pmid_1177_7939_276.txt
(t / transfect-01
      :ARG1 (c / cell-line :name (n / name :op1 "Cos-7"))
      :ARG2 (o2 / or
            :op1 (v / vector
                  :ARG1-of (e / express-03
                        :ARG2 (p4 / protein :name (n5 / name :op1 "Sos-1")))
                  :ARG1-of (d2 / describe-01
                        :ARG2 (s / string-entity :value "SosTfx")))
            :op2 (v3 / vector
                  :ARG1-of (e3 / express-03
                        :ARG2 (m2 / macro-molecular-complex
                              :part (p2 / protein :name (n3 / name :op1 "E3b1"))
                              :part (e4 / enzyme :name (n4 / name :op1 "Eps8"))
                              :part p4))
                  :ARG1-of (d3 / describe-01
                        :ARG2 (s2 / string-entity :value "TripleTfx")))
            :op3 (v2 / vector
                  :ARG1-of (e2 / empty-02)
                  :ARG1-of (c2 / correspond-02)
                  :ARG1-of (d4 / describe-01
                        :ARG2 (m3 / mock))))
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod "A")))

# ::id pmid_1177_7939.277 ::date 2015-03-10T11:21:06 ::annotator SDL-AMR-09 ::preferred
# ::snt Total cellular lysates (100 μg, left), or immunoprecipitates (IP, right) with the antibody indicated on the top (ctr, irrelevant antibody), were immunoblotted (WB) with the indicated antibody.
# ::save-date Sat Jan 30, 2016 ::file pmid_1177_7939_277.txt
(i / immunoblot-01
      :ARG1 (a / and
            :op1 (l / lysate
                  :mod (c / cell)
                  :quant (m / mass-quantity :quant 100
                        :unit (m2 / microgram))
                  :ARG1-of (d / describe-01
                        :ARG0 (f / figure
                              :ARG1-of (l2 / left-20)))
                  :mod (t2 / total))
            :op2 (p / protein
                  :ARG1-of (d2 / describe-01
                        :ARG0 (f2 / figure
                              :ARG1-of (r / right-04)))
                  :ARG1-of (i2 / immunoprecipitate-01
                        :ARG3 (a2 / antibody
                              :ARG1-of (i4 / indicate-01
                                    :location (f4 / figure
                                          :mod (t / top)))
                              :ARG1-of (r2 / relevant-01 :polarity -)))))
      :ARG3 a2)

# ::id pmid_1177_7939.278 ::date 2015-03-10T13:20:46 ::annotator SDL-AMR-09 ::preferred
# ::snt 5 mg of total cellular lysates were used for the immunoprecipitations, except in the SosTfx 1/10 lanes, in which 0.5 mg were used.
# ::save-date Mon Jan 4, 2016 ::file pmid_1177_7939_278.txt
(u / use-01
      :ARG1 (l / lysate
            :mod (t / total)
            :mod (c / cell)
            :quant (m / mass-quantity :quant 5
                  :unit (m2 / milligram)))
      :ARG2 (i / immunoprecipitate-01)
      :ARG2-of (e / except-01
            :ARG1 (u2 / use-01
                  :ARG1 (l3 / lysate
                        :quant (m3 / mass-quantity :quant 0.5
                              :unit (m4 / milligram)))
                  :location (l2 / lane
                        :ARG1-of (d / describe-01
                              :ARG2 (n / name :op1 "SosTfx 1/10"))))))

# ::id pmid_1177_7939.279 ::date 2015-03-10T13:50:48 ::annotator SDL-AMR-09 ::preferred
# ::snt (B) Ras-GEF (empty bars) and Rac-GEF (closed bars) activities in aliquots of the same immunoprecipitates (IP) shown in B.
# ::save-date Wed Dec 30, 2015 ::file pmid_1177_7939_279.txt
(a2 / and
      :op1 (a3 / activity-06
            :ARG0 (p / protein :name (n3 / name :op1 "guanine" :op2 "nucleotide" :op3 "exchange" :op4 "factor"))
            :ARG1 (e / enzyme :name (n / name :op1 "Ras"))
            :ARG1-of (d2 / describe-01
                  :ARG2 (b / bar
                        :ARG1-of (e3 / empty-02)))
            :location (a / aliquot
                  :ARG1-of (i / include-91
                        :ARG2 (p2 / protein
                              :ARG1-of (i2 / immunoprecipitate-01)
                              :ARG1-of (s / same-01)))))
      :op2 (a4 / activity-06
            :ARG0 p
            :ARG1 (e2 / enzyme :name (n2 / name :op1 "Rac"))
            :ARG1-of (d3 / describe-01
                  :ARG2 (b2 / bar
                        :ARG1-of (c / close-01)))
            :location a)
      :ARG1-of (s2 / show-01
            :ARG0 (f / figure :mod "B")))

# ::id pmid_1177_7939.280 ::date 2015-03-10T14:13:52 ::annotator SDL-AMR-09 ::preferred
# ::snt Data are expressed as described in Material and methods.
# ::save-date Wed Apr 1, 2015 ::file pmid_1177_7939_280.txt
(r / resemble-01
      :ARG1 (e / express-01
            :ARG1 (d2 / data))
      :ARG2 (d / describe-01
            :ARG0 (t2 / thing
                  :ARG1-of (t / title-01
                        :ARG2 (a / and
                              :op1 (m / material)
                              :op2 (m2 / method))))))

# ::id pmid_1177_7939.281 ::date 2015-03-10T14:21:29 ::annotator SDL-AMR-09 ::preferred
# ::snt (C) Immobilized, purified GST-Rac (Rac) and GST-Cdc42 (Cdc42) were depleted of guanine nucleotide by extensive washing in 10 mM EDTA as described in Material and methods.
# ::save-date Sat Feb 13, 2016 ::file pmid_1177_7939_281.txt
(d2 / deplete-01
      :ARG1 (a / and
            :op1 (m4 / macro-molecular-complex
                  :ARG1-of (d3 / describe-01
                        :ARG2 (n7 / name :op1 "Rac"))
                  :ARG1-of (i / immobilize-01)
                  :ARG1-of (p / purify-01)
                  :part (e3 / enzyme :name (n / name :op1 "GST"))
                  :part (e / enzyme :name (n5 / name :op1 "Rac")))
            :op2 (m5 / macro-molecular-complex
                  :ARG1-of (d4 / describe-01
                        :ARG2 (n8 / name :op1 "Cdc42"))
                  :ARG1-of i
                  :ARG1-of p
                  :part e3
                  :part (p2 / protein :name (n2 / name :op1 "Cdc42"))))
      :ARG2 (n6 / nucleotide
            :mod (s / small-molecule :name (n3 / name :op1 "guanine")))
      :manner (w / wash-01
            :ARG1 (a2 / and
                  :op1 m4
                  :op2 m5)
            :ARG2 (s2 / small-molecule :name (n4 / name :op1 "EDTA")
                  :mod (c / concentration-quantity :quant 10
                        :unit (m / millimolar)))
            :ARG1-of (d5 / describe-01
                  :ARG0 (t2 / thing
                        :ARG1-of (t / title-01
                              :ARG2 (a3 / and
                                    :op1 (m6 / material)
                                    :op2 (m7 / method)))))
            :ARG1-of (e2 / extensive-03))
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod "C")))

# ::id pmid_1177_7939.282 ::date 2015-03-11T04:40:16 ::annotator SDL-AMR-09 ::preferred
# ::snt Equal amounts of the nucleotide-free GST-GTPases or GST alone (GST) were incubated with total cellular lysates from eps8<sup>−/−</sup> fibroblasts (−/−) or eps8<sup>−/−</sup> stably expressing Eps8myc (−/−[Eps8myc]) in the presence or absence (−) of the 40 ng/ml of the indicated peptides (peptides).
# ::save-date Fri Jan 1, 2016 ::file pmid_1177_7939_282.txt
(i / incubate-01
      :ARG0 (l / lysate
            :mod (t / total)
            :mod (c / cell)
            :ARG1-of (o / obtain-01
                  :ARG2 (o2 / or
                        :op1 (f2 / fibroblast
                              :part (e6 / enzyme :name (n4 / name :op1 "eps8")
                                    :ARG2-of (m4 / mutate-01 :mod "−/−")))
                        :op2 (f3 / fibroblast
                              :ARG3-of (e5 / express-03
                                    :ARG2 (p3 / protein :name (n5 / name :op1 "Eps8myc"))
                                    :ARG1-of (s / stable-03))
                              :ARG1-of (d3 / describe-01
                                    :ARG2 (s3 / string-entity :value "−/−[Eps8myc]"))
                              :part e6))))
      :ARG1 (a / and
            :op1 (a2 / amount
                  :quant-of (m / macro-molecular-complex
                        :part (e / enzyme :name (n / name :op1 "GST"))
                        :part (e2 / enzyme :name (n2 / name :op1 "GTPase"))
                        :ARG1-of (f / free-04
                              :ARG2 (n6 / nucleotide))))
            :op2 (a4 / amount
                  :quant-of e)
            :ARG1-of (e4 / equal-01))
      :ARG2 (o3 / or
            :op1 (p4 / present-02
                  :ARG1 (p / peptide
                        :ARG1-of (i2 / indicate-01)
                        :ARG1-of (d4 / describe-01
                              :ARG2 (p2 / peptide))
                        :mod (m3 / mass-quantity :quant 40
                              :unit (n7 / nanogram-per-milliliter))))
            :op2 (a3 / absent-01
                  :ARG1 p
                  :ARG1-of (d5 / describe-01
                        :ARG2 (s2 / string-entity :value "−")))))

# ::id pmid_1177_7939.283 ::date 2015-03-11T12:15:46 ::annotator SDL-AMR-09 ::preferred
# ::snt The peptide used were PPPPPPVDATEDEE (PXXDA), used as control (see text and <xref ref-type="fig" rid="fig1">Fig. 1</xref>); PPPPPVDYTEDEE (PXXDY), which corresponds to the E3b1 binding site for the SH3 domain of Eps8 and prevents Eps8-E3b1 association (refer to <xref ref-type="fig" rid="fig1">Fig. 1</xref> B); VPVPPPVPPRRR (PXXP), which corresponds to the Sos-1 binding site for the SH3 domain of E3b1 and readily competes the interaction between Sos-1 and E3b1 (refer to <xref ref-type="fig" rid="fig2">Fig. 2</xref> C).
# ::save-date Sat Jun 13, 2015 ::file pmid_1177_7939_283.txt
(u / use-01
      :ARG1 (a / and
            :op1 (p / peptide :name (n / name :op1 "PPPPPPVDATEDEE")
                  :ARG1-of (d / describe-01
                        :ARG0 (a2 / and
                              :op1 (t / text)
                              :op2 (f / figure :mod 1)
                              :ARG1-of (s / see-01 :mode imperative
                                    :ARG0 y))
                        :ARG2 (n7 / name :op1 "PXXDA"))
                  :ARG0-of (c / control-01))
            :op2 (p2 / peptide :name (n2 / name :op1 "PPPPPVDYTEDEE")
                  :ARG1-of (d2 / describe-01
                        :ARG0 (f2 / figure :mod "1B"
                              :ARG1-of (r2 / refer-03 :mode imperative
                                    :ARG0 (y / you)))
                        :ARG2 (n10 / name :op1 "PXXDY"))
                  :ARG0-of (p4 / prevent-01
                        :ARG1 (a3 / associate-01
                              :ARG1 (p6 / protein :name (n5 / name :op1 "E3b1"))
                              :ARG2 (e / enzyme :name (n4 / name :op1 "Eps8"))))
                  :ARG1-of (b2 / bind-01
                        :ARG2 (p9 / protein-segment :name (n8 / name :op1 "SH3" :op2 "domain")
                              :part-of e)
                        :ARG1-of (i3 / instead-of-91
                              :ARG2 (b3 / bind-01
                                    :ARG1 p6
                                    :ARG2 e))))
            :op3 (p3 / peptide :name (n3 / name :op1 "VPVPPPVPPRRR")
                  :ARG1-of (d3 / describe-01
                        :ARG0 (f3 / figure :mod "2C")
                        :ARG2 (n11 / name :op1 "PXXP"))
                  :ARG0-of (c3 / compete-01
                        :ARG1 (p7 / protein :name (n6 / name :op1 "Sos-1"))
                        :ARG2 (i2 / interact-01
                              :ARG0 (a4 / and
                                    :op1 p7
                                    :op2 p6))
                        :manner (r / ready))
                  :ARG1-of (b4 / bind-01
                        :ARG2 (p5 / protein-segment :name (n9 / name :op1 "SH3" :op2 "domain")
                              :part-of p6)
                        :ARG1-of (i4 / instead-of-91
                              :ARG2 (b5 / bind-01
                                    :ARG1 p7
                                    :ARG2 p6))))))

# ::id pmid_1177_7939.284 ::date 2015-03-11T07:10:31 ::annotator SDL-AMR-09 ::preferred
# ::snt Bound proteins were resolved by SDS-PAGE.
# ::save-date Sun Jan 31, 2016 ::file pmid_1177_7939_284.txt
(r / resolve-03
      :ARG1 (p / protein
            :ARG1-of (b / bind-01))
      :ARG3 (t / thing :name (n / name :op1 "SDS-PAGE")))

# ::id pmid_1177_7939.285 ::date 2015-03-11T07:15:04 ::annotator SDL-AMR-09 ::preferred
# ::snt Detection was with anti–Sos-1 antibody (Sos-1).
# ::save-date Wed Mar 18, 2015 ::file pmid_1177_7939_285.txt
(d / detect-01
      :ARG0 (a / antibody
            :ARG1-of (d2 / describe-01
                  :ARG2 (n2 / name :op1 "Sos-1"))
            :ARG0-of (c / counter-01
                  :ARG1 (p / protein :name (n / name :op1 "Sos-1")))))

# ::id pmid_1177_7939.286 ::date 2015-03-11T07:17:42 ::annotator SDL-AMR-09 ::preferred
# ::snt The indicted lanes (lysate) were loaded with 50 μg of total cellular lysates.
# ::save-date Wed Dec 30, 2015 ::file pmid_1177_7939_286.txt
(l / load-01
      :ARG1 (l2 / lane
            :ARG1-of (i / indicate-01)
            :ARG1-of (d / describe-01
                  :ARG2 (l5 / lysate)))
      :ARG2 (l3 / lysate
            :mod (t / total)
            :mod (c / cell)
            :mod (m / mass-quantity :quant 50
                  :unit (m2 / microgram))))

# ::id pmid_1177_7939.287 ::date 2015-03-11T07:09:30 ::annotator SDL-AMR-09 ::preferred
# ::snt Figure 8.
# ::save-date Wed Mar 11, 2015 ::file pmid_1177_7939_287.txt
(f / figure :mod 8)

# ::id pmid_1177_7939.288 ::date 2015-03-11T12:53:51 ::annotator SDL-AMR-09 ::preferred
# ::snt <bold>The differential regulation of the S/G and S/E/E8 complexes by RTKs correlates with the kinetics of activation of Ras and Rac.</bold>
# ::save-date Mon Mar 16, 2015 ::file pmid_1177_7939_288.txt
(c / correlate-01
      :ARG1 (r / regulate-01
            :ARG0 (e2 / enzyme :name (n2 / name :op1 "RTK"))
            :ARG1 (a2 / and
                  :op1 (m / macro-molecular-complex :name (n3 / name :op1 "S/G"))
                  :op2 (m2 / macro-molecular-complex :name (n4 / name :op1 "S/E/E8")))
            :ARG1-of (d / differ-02))
      :ARG2 (k / kinetics
            :mod (a / activate-01
                  :ARG1 (a3 / and
                        :op1 (e / enzyme :name (n / name :op1 "Ras"))
                        :op2 (e3 / enzyme :name (n5 / name :op1 "Rac"))))))

# ::id pmid_1177_7939.289 ::date 2015-03-11T11:55:17 ::annotator SDL-AMR-09 ::preferred
# ::snt (A) Mouse embryo fibroblasts cells were treated with PDGF for 15 min (+) or mock treated (−).
# ::save-date Wed Dec 30, 2015 ::file pmid_1177_7939_289.txt
(a / and :li "A"
      :op1 (t / treat-03
            :ARG1 (f / fibroblast
                  :part-of (e / embryo
                        :mod (m / mouse)))
            :ARG3 (p / protein :name (n / name :op1 "PDGF")
                  :ARG1-of (d / describe-01
                        :ARG2 (s2 / string-entity :value +)))
            :duration (t3 / temporal-quantity :quant 15
                  :unit (m2 / minute)))
      :op2 (t2 / treat-04 :polarity -
            :ARG1 f
            :ARG2 (m3 / mock)
            :ARG1-of (d2 / describe-01
                  :ARG2 (s / string-entity :value "−"))))

# ::id pmid_1177_7939.290 ::date 2015-03-13T04:54:45 ::annotator SDL-AMR-09 ::preferred
# ::snt Lysates were immunoprecipitated (IP) with anti-Grb2 (left) or anti-E3b1 (right) antibody and detected with anti–Sos-1 antibody (top) or anti-Grb2 (bottom, left), or anti-E3b1 (bottom, right).
# ::save-date Sat Jan 30, 2016 ::file pmid_1177_7939_290.txt
(a / and
      :op1 (i / immunoprecipitate-01
            :ARG1 (l / lysate)
            :ARG3 (o / or
                  :op1 (a2 / antibody
                        :ARG0-of (c / counter-01
                              :ARG1 (p3 / protein :name (n / name :op1 "Grb2")))
                        :ARG1-of (l2 / left-20))
                  :op2 (a9 / antibody
                        :ARG0-of (c2 / counter-01
                              :ARG1 (p4 / protein :name (n2 / name :op1 "E3b1")))
                        :ARG1-of (r2 / right-04))))
      :op2 (d / detect-01
            :ARG1 l
            :ARG2 (o2 / or
                  :op1 (a7 / antibody
                        :ARG0-of (c3 / counter-01
                              :ARG1 (p / protein :name (n3 / name :op1 "Sos-1")))
                        :location (t / top))
                  :op2 (a10 / antibody
                        :ARG0-of (c4 / counter-01
                              :ARG1 p3)
                        :location (b / bottom
                              :ARG1-of l2))
                  :op3 (a4 / antibody
                        :ARG0-of (c5 / counter-01
                              :ARG1 p4)
                        :location (b2 / bottom
                              :ARG1-of r2)))))

# ::id pmid_1177_7939.291 ::date 2015-03-13T07:50:52 ::annotator SDL-AMR-09 ::preferred
# ::snt The indicated lanes (lysate) (50 μg) were detected with anti–Sos-1 antibody to show the mobility shift after PDGF stimulation.
# ::save-date Fri Mar 27, 2015 ::file pmid_1177_7939_291.txt
(h / have-purpose-91
      :ARG1 (d / detect-01
            :ARG1 (l / lane
                  :ARG1-of (i / indicate-01)
                  :quant (m2 / mass-quantity :quant 50
                        :unit (m3 / microgram))
                  :ARG1-of (d2 / describe-01
                        :ARG2 (n3 / name :op1 "lysate")))
            :ARG2 (a2 / antibody
                  :ARG0-of (c / counter-01
                        :ARG1 (p2 / protein :name (n2 / name :op1 "Sos-1")))))
      :ARG2 (s / show-01
            :ARG1 (s2 / shift-01
                  :ARG1 (m / mobility)
                  :time (a / after
                        :op1 (s4 / stimulate-01
                              :ARG0 (p / protein :name (n / name :op1 "PDGF")))))))

# ::id pmid_1177_7939.292 ::date 2015-03-13T07:59:15 ::annotator SDL-AMR-09 ::preferred
# ::snt Similar results were obtained upon EGF stimulation in Cos-7 cells (not shown).
# ::save-date Fri Mar 20, 2015 ::file pmid_1177_7939_292.txt
(o / obtain-01
      :ARG1 (t / thing
            :ARG2-of (r2 / result-01
                  :ARG1 (s / stimulate-01
                        :ARG0 (p / protein :name (n / name :op1 "EGF"))
                        :location (c / cell-line :mod 7 :name (n2 / name :op1 "Cos"))))
            :ARG1-of (r / resemble-01))
      :ARG1-of (s2 / show-01 :polarity -))

# ::id pmid_1177_7939.293 ::date 2015-03-13T08:05:11 ::annotator SDL-AMR-09 ::preferred
# ::snt (B) Fibroblasts were treated with PDGF for the indicated lengths of time.
# ::save-date Mon Dec 21, 2015 ::file pmid_1177_7939_293.txt
(t / treat-04 :li "B"
      :ARG0 (p / protein :name (n / name :op1 "PDGF"))
      :ARG1 (f / fibroblast)
      :duration (t2 / temporal-quantity
            :ARG1-of (i / indicate-01)))

# ::id pmid_1177_7939.294 ::date 2015-03-13T08:08:34 ::annotator SDL-AMR-09 ::preferred
# ::snt Lysates were immunoprecipitated (IP) with anti-PDGFR (PDGFR) or an irrelevant antibody as a control (ctr) and detected with the indicated antibodies (WB).
# ::save-date Wed Dec 30, 2015 ::file pmid_1177_7939_294.txt
(a / and
      :op1 (i / immunoprecipitate-01
            :ARG1 (l / lysate)
            :ARG3 o)
      :op2 (d / detect-01
            :ARG0 (o / or
                  :op1 (a2 / antibody
                        :ARG0-of (c2 / counter-01
                              :ARG1 (p / protein :name (n / name :op1 "PDGFR"))))
                  :op2 (a3 / antibody
                        :ARG1-of (r / relevant-01 :polarity -)
                        :ARG0-of (a4 / act-01
                              :ARG1 (c / control-01)))
                  :ARG1-of (i3 / indicate-01))
            :ARG1 l))

# ::id pmid_1177_7939.295 ::date 2015-03-13T09:35:36 ::annotator SDL-AMR-09 ::preferred
# ::snt (C) −/− [Eps8myc] cells were treated with 20 ng/ml of PDGF (+) or mock treated (−), and total cellular lysates were prepared.
# ::save-date Wed Dec 30, 2015 ::file pmid_1177_7939_295.txt
(a / and
      :op1 (o / or
            :op1 (t / treat-04
                  :ARG1 (p / protein :name (n / name :op1 "PDGF")
                        :quant (c4 / concentration-quantity :quant 20
                              :unit (n3 / nanogram-per-milliliter))
                        :ARG1-of (d2 / describe-01
                              :ARG2 (s / string-entity :name (n4 / name :op1 "+"))))
                  :ARG2 (c / cell
                        :part (p3 / protein :name (n2 / name :op1 "Eps8myc")
                              :ARG2-of (m3 / mutate-01 :mod "−/−"))))
            :op2 (t3 / treat-04
                  :ARG1 c
                  :manner (m / mock-01)
                  :ARG1-of (d / describe-01
                        :ARG2 (s2 / string-entity :name (n5 / name :op1 "−")))))
      :op2 (p2 / prepare-01
            :ARG1 (l / lysate
                  :mod (c2 / cellular
                        :mod (t2 / total))))
      :ARG1-of (d3 / describe-01
            :ARG0 (f / figure :mod "C")))

# ::id pmid_1177_7939.296 ::date 2015-03-13T09:40:49 ::annotator SDL-AMR-09 ::preferred
# ::snt Immmunoprecipitations (IP) were performed with anti-myc antibody or with an irrelevant (ctr) antibody, followed by immunoblot with the antibody indicated on the right (WB).
# ::save-date Fri Jan 1, 2016 ::file pmid_1177_7939_296.txt
(p / perform-02
      :ARG1 (i / immunoprecipitate-01
            :ARG3 (o / or
                  :op1 (a / antibody
                        :ARG0-of (c3 / counter-01
                              :ARG1 (p2 / protein :name (n / name :op1 "myc"))))
                  :op2 (a2 / antibody
                        :ARG2-of (r2 / relevant-01 :polarity -))))
      :ARG2-of (f / follow-01
            :ARG1 (i3 / immunoblot-01
                  :ARG3 (a3 / antibody
                        :ARG1-of (i4 / indicate-01
                              :ARG1-of (r / right-04))))))

# ::id pmid_1177_7939.297 ::date 2015-03-13T09:44:27 ::annotator SDL-AMR-09 ::preferred
# ::snt The indicated lanes (lysates) were loaded with 100 μg of total cellular lysates.
# ::save-date Wed Dec 30, 2015 ::file pmid_1177_7939_297.txt
(l / load-01
      :ARG1 (l2 / lane
            :ARG1-of (i / indicate-01)
            :ARG1-of (d / describe-01
                  :ARG2 (l3 / lysate)))
      :ARG2 (l4 / lysate
            :ARG1-of (t / total-01
                  :ARG2 (m / mass-quantity :quant 100
                        :unit (m2 / microgram)))
            :mod (c / cell)))

# ::id pmid_1177_7939.298 ::date 2015-03-13T09:45:07 ::annotator SDL-AMR-09 ::preferred
# ::snt (D) Fibroblasts were treated with PDGF for the indicated lengths of time.
# ::save-date Mon Dec 21, 2015 ::file pmid_1177_7939_298.txt
(t / treat-04 :li "D"
      :ARG1 (f / fibroblast)
      :ARG2 (p / protein :name (n / name :op1 "PDGF"))
      :duration (t2 / temporal-quantity
            :ARG1-of (i / indicate-01)))

# ::id pmid_1177_7939.299 ::date 2015-03-14T12:13:21 ::annotator SDL-AMR-09 ::preferred
# ::snt The levels of Ras-GTP and Rac-GTP in total cellular lysates were determined by affinity precipitation using GST-RBD and GST-CRIB, as described in Materials and methods.
# ::save-date Wed Apr 1, 2015 ::file pmid_1177_7939_299.txt
(d / determine-01
      :ARG1 (l / level
            :quant-of (a / and
                  :op1 (m3 / macro-molecular-complex
                        :part (s2 / small-molecule :name (n3 / name :op1 "GTP"))
                        :part (e / enzyme :name (n / name :op1 "Ras")))
                  :op2 (m4 / macro-molecular-complex
                        :part (e2 / enzyme :name (n4 / name :op1 "Rac"))
                        :part s2))
            :location (l3 / lysate
                  :quant (t / total)
                  :source (c / cell)))
      :ARG2 (p / precipitate-01
            :mod (a2 / affinity)
            :manner (u / use-01
                  :ARG1 (a5 / and
                        :op1 (p2 / protein :name (n2 / name :op1 "GST-RBD"))
                        :op2 (p3 / protein :name (n5 / name :op1 "GST-CRIB")))))
      :ARG1-of (d2 / describe-01
            :location (a4 / and
                  :op1 (m / material)
                  :op2 (m2 / method))))

# ::id pmid_1177_7939.300 ::date 2015-03-14T12:27:42 ::annotator SDL-AMR-09 ::preferred
# ::snt Elevated levels of Rac-GTP could be observed ≤30 min of RTK stimulation (not shown).
# ::save-date Thu Mar 26, 2015 ::file pmid_1177_7939_300.txt
(p / possible-01
      :ARG1 (o / observe-01
            :ARG1 (l / level
                  :degree-of (m / macro-molecular-complex
                        :part (s / small-molecule :name (n / name :op1 "GTP"))
                        :part (e / enzyme :name (n2 / name :op1 "Rac")))
                  :ARG1-of (e2 / elevate-01))
            :time (b2 / before
                  :op1 (s2 / stimulate-01
                        :ARG0 (e3 / enzyme :name (n3 / name :op1 "RTK")))
                  :duration (t / temporal-quantity :quant 30
                        :unit (m2 / minute))))
      :ARG1-of (s3 / show-01 :polarity -))

# ::id pmid_1177_7939.301 ::date 2015-03-14T12:33:52 ::annotator SDL-AMR-09 ::preferred
# ::snt The expression levels of Ras (total Ras) and Rac (total Rac), in the same lysates, were determined by immunoblotting with anti-Ras and anti-Rac antibodies, respectively.
# ::save-date Wed Jun 17, 2015 ::file pmid_1177_7939_301.txt
(d / determine-01
      :ARG1 (e2 / express-03
            :ARG1 (l / level
                  :degree-of (a / and
                        :op1 (e3 / enzyme :name (n2 / name :op1 "Ras")
                              :ARG1-of (d2 / describe-01
                                    :ARG2 (t / total-01
                                          :ARG1 e3)))
                        :op2 (e4 / enzyme :name (n3 / name :op1 "Rac")
                              :ARG1-of (d3 / describe-01
                                    :ARG2 (t2 / total-01
                                          :ARG1 e4)))))
            :location (l2 / lysate
                  :ARG1-of (s / same-01)))
      :manner (i / immunoblot-01
            :ARG1 e3
            :ARG2 l2
            :ARG3 (a2 / and
                  :op1 (a3 / antibody
                        :ARG0-of (c / counter-01
                              :ARG1 e3))
                  :op2 (a4 / antibody
                        :ARG0-of (c2 / counter-01
                              :ARG1 e4)))))

# ::id pmid_1177_7939.302 ::date 2015-03-14T12:38:20 ::annotator SDL-AMR-09 ::preferred
# ::snt The kinetic of the mobility shift of Sos-1, after PDGF stimulation, was determined by immunoblotting with anti–Sos-1 antibodies.
# ::save-date Tue Jun 16, 2015 ::file pmid_1177_7939_302.txt
(d / determine-01
      :ARG1 (k / kinetics
            :poss (s / shift-01
                  :mod (m / mobility
                        :poss (p / protein :name (n / name :op1 "Sos-1")))))
      :ARG2 (i / immunoblot-01
            :ARG1 p
            :ARG3 (a2 / antibody
                  :ARG0-of (c / counter-01
                        :ARG1 p)))
      :time (a / after
            :op1 (s2 / stimulate-01
                  :ARG0 (p2 / protein :name (n2 / name :op1 "PDGF")))))

# ::id pmid_1563_0473.1 ::date 2015-03-17T07:32:50 ::annotator SDL-AMR-09 ::preferred
# ::snt A Signaling Pathway Involving TGF-β2 and Snail in Hair Follicle Morphogenesis (PMID:15630473)
# ::save-date Thu Jan 14, 2016 ::file pmid_1563_0473_1.txt
(i / involve-01
      :ARG0 (p / pathway
            :ARG0-of (s / signal-07))
      :ARG1 (a / and
            :op1 (p3 / protein :name (n / name :op1 "TGF-β2"))
            :op2 (p4 / protein :name (n2 / name :op1 "Snail")))
      :ARG2 (m / morphogenesis
            :mod (f / follicle
                  :mod (h / hair)))
      :ARG1-of (d / describe-01
            :ARG0 (p2 / publication-91
                  :ARG8 "PMID15630473")))

# ::id pmid_1563_0473.2 ::date 2015-03-17T07:45:03 ::annotator SDL-AMR-09 ::preferred
# ::snt In a common theme of organogenesis, certain cells within a multipotent epithelial sheet exchange signals with their neighbors and develop into a bud structure.
# ::save-date Sun Jun 21, 2015 ::file pmid_1563_0473_2.txt
(a / and
      :op1 (e / exchange-01
            :ARG0 (c / cell
                  :location (s / sheet
                        :mod (m / multipotent)
                        :mod (e2 / epithelium))
                  :mod (c2 / certain))
            :ARG1 (t2 / thing
                  :ARG1-of (s2 / signal-07))
            :ARG2 (c4 / cell
                  :ARG1-of (n / neighbor-01
                        :ARG2 c)))
      :op2 (d / develop-02
            :ARG1 (s3 / structure
                  :mod (b / bud))
            :ARG2 c)
      :subevent-of (t / theme
            :mod (c3 / common)
            :purpose (g / genesis
                  :mod (o / organ))))

# ::id pmid_1563_0473.3 ::date 2015-03-17T07:54:47 ::annotator SDL-AMR-09 ::preferred
# ::snt Using hair bud morphogenesis as a paradigm, we employed mutant mouse models and cultured keratinocytes to dissect the contributions of multiple extracellular cues in orchestrating adhesion dynamics and proliferation to shape the cluster of cells involved.
# ::save-date Wed Apr 29, 2015 ::file pmid_1563_0473_3.txt
(e / employ-02
      :ARG0 (w / we)
      :ARG1 (a / and
            :op1 (m / model
                  :topic (m2 / mouse)
                  :ARG1-of (m3 / mutate-01))
            :op2 (c / cell :name (n / name :op1 "keratinocyte")
                  :ARG1-of (c2 / culture-01)))
      :purpose (d / dissect-01
            :ARG0 w
            :ARG1 (c3 / contribute-01
                  :ARG0 (c6 / cue
                        :location (e3 / extracellular)
                        :quant (m4 / multiple))
                  :ARG2 (o / orchestrate-01
                        :ARG1 (a2 / and
                              :op1 (d2 / dynamic
                                    :mod (a3 / adhere-01))
                              :op2 (p / proliferate-01))
                        :purpose (s / shape-01
                              :ARG0 c6
                              :ARG1 (c4 / cluster
                                    :consist-of (c5 / cell)
                                    :ARG1-of (i / involve-01))))))
      :manner (u / use-01
            :ARG1 (m5 / morphogenesis
                  :mod (b / bud
                        :mod (h / hair)))
            :ARG2 (p2 / paradigm)))

# ::id pmid_1563_0473.4 ::date 2015-03-17T08:16:50 ::annotator SDL-AMR-09 ::preferred
# ::snt We found that transforming growth factor β2 signaling is necessary to transiently induce the transcription factor Snail and activate the Ras-mitogen-activated protein kinase (MAPK) pathway in the bud.
# ::save-date Thu Jan 14, 2016 ::file pmid_1563_0473_4.txt
(f / find-01
      :ARG0 (w / we)
      :ARG1 (n2 / need-01
            :ARG1 (s2 / signal-07
                  :ARG0 (p2 / protein :name (n / name :op1 "transforming" :op2 "growth" :op3 "factor" :op4 "β2")))
            :purpose (a / and
                  :op1 (i / induce-01
                        :ARG2 (p3 / protein :name (n4 / name :op1 "Snail")
                              :mod (f2 / factor
                                    :ARG0-of (t2 / transcribe-01)))
                        :ARG1-of (t / transient-02))
                  :op2 (a2 / activate-01
                        :ARG1 (p / pathway :name (n3 / name :op1 "Ras-mitogen-activated" :op2 "protein" :op3 "kinase"))
                        :location (b / bud)))))

# ::id pmid_1563_0473.5 ::date 2015-03-17T08:25:10 ::annotator SDL-AMR-09 ::preferred
# ::snt In the epidermis, <i>Snail</i> misexpression leads to hyperproliferation and a reduction in intercellular adhesion.
# ::save-date Sun Jan 17, 2016 ::file pmid_1563_0473_5.txt
(l / lead-03
      :ARG0 (e / express-03
            :ARG1 (g / gene :name (n / name :op1 "Snail"))
            :ARG1-of (w / wrong-04))
      :ARG2 (a / and
            :op1 (p / proliferate-01
                  :degree (h / hyper))
            :op2 (r / reduce-01
                  :ARG1 (a2 / adhere-01
                        :ARG1 (c / cell)
                        :ARG2 (c2 / cell))))
      :location (e3 / epidermis))

# ::id pmid_1563_0473.6 ::date 2015-03-17T08:31:52 ::annotator SDL-AMR-09 ::preferred
# ::snt When <i>E-cadherin</i> is transcriptionally down-regulated, associated adhesion proteins with dual functions in signaling are released from cell-cell contacts, a process which we demonstrate leads to Ras-MAPK activation.
# ::save-date Sun Jan 17, 2016 ::file pmid_1563_0473_6.txt
(r / release-01
      :ARG1 (p / proteins
            :ARG0-of (a / adhere-01)
            :ARG1-of (a2 / associate-01)
            :ARG0-of (f / function-01
                  :ARG1 (s / signal-07)
                  :mod (d / dual)))
      :ARG2 (c / contact-01
            :ARG0 (c2 / cell)
            :ARG1 (c3 / cell))
      :time (d2 / downregulate-01
            :ARG1 (g / gene :name (n / name :op1 "E-cadherin"))
            :manner (t / transcribe-01))
      :ARG0-of (l / lead-03
            :ARG1 (a3 / activate-01
                  :ARG1 (p3 / pathway :name (n2 / name :op1 "Ras-MAPK")))
            :ARG1-of (d3 / demonstrate-01
                  :ARG0 (w / we))))

# ::id pmid_1563_0473.7 ::date 2015-03-17T08:43:27 ::annotator SDL-AMR-09 ::preferred
# ::snt These studies provide insights into how multipotent cells within a sheet are stimulated to undergo transcriptional changes that result in proliferation, junctional remodeling, and bud formation.
# ::save-date Wed Mar 25, 2015 ::file pmid_1563_0473_7.txt
(p / provide-01
      :ARG0 (s / study
            :mod (t / this))
      :ARG1 (i / insight
            :topic (t3 / thing
                  :manner-of (s2 / stimulate-01
                        :ARG1 (c / cell
                              :mod (m2 / multipotent)
                              :location (s3 / sheet))
                        :purpose (u / undergo-28
                              :ARG1 c
                              :ARG2 (c2 / change-01
                                    :ARG1 (t2 / transcribe-01)
                                    :ARG1-of (r / result-01
                                          :ARG2 (a / and
                                                :op1 (p2 / proliferate-01
                                                      :ARG0 c)
                                                :op2 (r2 / remodel-01
                                                      :ARG1 c
                                                      :mod (j / junction))
                                                :op3 (f / form-01
                                                      :ARG1 (b / bud))))))))))

# ::id pmid_1563_0473.8 ::date 2015-03-17T08:58:08 ::annotator SDL-AMR-09 ::preferred
# ::snt This novel signaling pathway further weaves together the web of different morphogens and downstream transcriptional events that guide hair bud formation within the developing skin.
# ::save-date Wed Mar 25, 2015 ::file pmid_1563_0473_8.txt
(w / weave-01
      :ARG0 (p / pathway
            :ARG0-of (s / signal-07)
            :mod (n / novel)
            :mod (t / this))
      :ARG1 (w2 / web
            :consist-of (a / and
                  :op1 (s2 / small-molecule :name (n2 / name :op1 "morphogen")
                        :ARG1-of (d / differ-02))
                  :op2 (e / event
                        :mod (t2 / transcribe-01)
                        :location (d2 / downstream))
                  :ARG0-of (g / guide-01
                        :ARG1 (f2 / form-01
                              :ARG1 (b / bud
                                    :mod (h / hair))
                              :location (s3 / skin
                                    :ARG1-of (d3 / develop-02))))))
      :degree (f / further))

# ::id pmid_1563_0473.9 ::date 2015-03-17T09:07:12 ::annotator SDL-AMR-09 ::preferred
# ::snt The study of hair follicle morphogenesis provides insights into how cells within a sheet can be triggered to proliferate, remodel, and form buds - a recurring theme in development
# ::save-date Fri Jan 1, 2016 ::file pmid_1563_0473_9.txt
(p / provide-01
      :ARG0 (s / study-01
            :ARG1 (m / morphogenesis
                  :mod (f / follicle
                        :mod (h / hair))))
      :ARG1 (i / insight
            :topic (t / thing
                  :manner-of (p2 / possible-01
                        :ARG1 (t4 / trigger-01
                              :ARG1 (c / cell
                                    :location (s2 / sheet))
                              :purpose (a / and
                                          :op1 (p3 / proliferate-01
                                                :ARG0 t4)
                                          :op2 (r / remodel-01
                                                :ARG1 t4)
                                          :op3 (f2 / form-01
                                                :ARG0 t4
                                                :ARG1 (b / bud))
                                          :ARG1-of (m2 / mean-01
                                                :ARG2 (t3 / theme
                                                      :ARG0-of (r2 / recur-01)
                                                      :subevent-of (d / develop-02)))))))))

# ::id pmid_1563_0473.10 ::date 2015-03-17T09:15:05 ::annotator SDL-AMR-09 ::preferred
# ::snt Introduction
# ::save-date Wed Mar 25, 2015 ::file pmid_1563_0473_10.txt
(i / introduce-01)

# ::id pmid_1563_0473.11 ::date 2015-03-17T09:15:29 ::annotator SDL-AMR-09 ::preferred
# ::snt Mammalian development involves the morphogenesis of complex three-dimensional structures from seemingly uniform sheets or masses of cells.
# ::save-date Mon Jul 27, 2015 ::file pmid_1563_0473_11.txt
(i / involve-01
      :ARG0 (d / develop-02
            :ARG1 (m / mammal))
      :ARG1 (m2 / morphogenesis
            :mod (s / structure
                  :mod (c / complex)
                  :mod (d2 / dimension :quant 3))
            :source (o / or
                  :op1 (s2 / sheet)
                  :op2 (m3 / mass)
                  :ARG1-of (u / uniform-02
                        :ARG1-of (s3 / seem-01))
                  :consist-of (c2 / cell))))

# ::id pmid_1563_0473.12 ::date 2015-03-17T09:21:44 ::annotator SDL-AMR-09 ::preferred
# ::snt A simple bud-like structure initiates the formation of many organs, including lungs, spinal cord, mammary glands, and hair follicles [<xref ref-type="bibr" rid="pbio-0030011-b01">1</xref>].
# ::save-date Sun Jul 26, 2015 ::file pmid_1563_0473_12.txt
(i / initiate-01
      :ARG0 (s / structure
            :ARG1-of (r / resemble-01
                  :ARG2 (b / bud))
            :ARG1-of (s2 / simple-02))
      :ARG1 (f / form-01
            :ARG1 (o / organ
                  :quant (m / many)
                  :ARG2-of (i2 / include-01
                        :ARG1 (a / and
                              :op1 (l / lung)
                              :op2 (c / cord
                                    :mod (s3 / spine))
                              :op3 (g / gland
                                    :source (b2 / breast))
                              :op4 (f2 / follicle
                                    :mod (h / hair))))))
      :ARG1-of (d / describe-01
            :ARG0 (p / publication-91
                  :ARG1-of (c2 / cite-01
                        :ARG2 1))))

# ::id pmid_1563_0473.13 ::date 2015-03-17T09:26:06 ::annotator SDL-AMR-09 ::preferred
# ::snt The multipotent, adhering epithelial cells are typically attached to an underlying basal lamina that polarizes the epithelial sheet and separates it from surrounding mesenchyme.
# ::save-date Sun Jul 26, 2015 ::file pmid_1563_0473_13.txt
(a / attach-01
      :ARG1 (c / cell
            :part-of (e / epithelium)
            :mod (m / multipotent)
            :ARG1-of (a2 / adhere-01))
      :ARG2 (l / lamina
            :ARG0-of (u / underlay-01
                  :ARG1 c)
            :mod (b / basal)
            :ARG0-of (p / polarize-01
                  :ARG1 (s / sheet
                        :mod e))
            :ARG0-of (s2 / separate-01
                  :ARG1 s
                  :ARG2 (m2 / mesenchyme
                        :ARG1-of (s3 / surround-01
                              :ARG2 s))))
      :ARG1-of (t / typical-02))

# ::id pmid_1563_0473.14 ::date 2015-03-17T09:39:04 ::annotator SDL-AMR-09 ::preferred
# ::snt Budding morphogenesis is guided by a reciprocal exchange of signals between epithelium and mesenchyme to specify the identity of the organ that will form and to govern its growth.
# ::save-date Wed Mar 25, 2015 ::file pmid_1563_0473_14.txt
(g / guide-01
      :ARG0 (e / exchange-01
            :ARG0 (e2 / epithelium)
            :ARG1 (t / thing
                  :ARG0-of (s / signal-07))
            :ARG2 (m2 / mesenchyme)
            :mod (r / reciprocal))
      :ARG1 (m / morphogenesis
            :ARG1-of (b / bud-01))
      :purpose (a / and
            :op1 (s2 / specify-01
                  :ARG1 (i / identity
                        :mod (o / organ
                              :ARG1-of (f / form-01))))
            :op2 (g2 / govern-01
                  :ARG1 (g3 / grow-01
                        :ARG1 o))))

# ::id pmid_1563_0473.15 ::date 2015-03-17T09:45:22 ::annotator SDL-AMR-09 ::preferred
# ::snt At the helm of these molecular communication pathways are Wnts, bone morphogenic proteins (BMPs), transforming growth factor βs (TGF-βs), and fibroblast growth factors (FGFs).
# ::save-date Mon Jan 4, 2016 ::file pmid_1563_0473_15.txt
(b / be-located-at-91
      :ARG1 (a / and
            :op1 (p / pathway :name (n2 / name :op1 "Wnt"))
            :op2 (p2 / protein :name (n / name :op1 "bone" :op2 "morphogenic" :op3 "protein"))
            :op3 (p4 / protein :name (n3 / name :op1 "transforming" :op2 "growth" :op3 "factor" :op4 "β"))
            :op4 (p5 / protein :name (n4 / name :op1 "fibroblast" :op2 "growth" :op3 "factor")))
      :ARG2 (h / helm
            :location (r / relative-position
                  :op1 (p3 / pathway
                        :mod (t / this)
                        :path-of (c / communication
                              :mod (m / molecule))))))

# ::id pmid_1563_0473.16 ::date 2015-03-17T09:52:24 ::annotator SDL-AMR-09 ::preferred
# ::snt Through activation of cell surface transmembrane receptors, these external signaling molecules trigger distinct cascades of intracellular events that culminate in changes in gene expression, growth, and differentiation [<xref ref-type="bibr" rid="pbio-0030011-b02">2</xref>].
# ::save-date Wed Mar 18, 2015 ::file pmid_1563_0473_16.txt
(t / trigger-01
      :ARG0 (m / molecule
            :mod (t2 / this)
            :mod (e / external)
            :ARG0-of (s / signal-07))
      :ARG1 (c / cascade
            :consist-of (e2 / event
                  :location (c2 / cell))
            :mod (d / distinct)
            :ARG1-of (c3 / culminate-01
                  :ARG2 (c4 / change-01
                        :ARG1 (a / and
                              :op1 (e3 / express-03
                                    :ARG1 (g / gene))
                              :op2 (g2 / grow-01
                                    :ARG1 c2)
                              :op3 (d2 / differentiate-01
                                    :ARG1 c2)))))
      :ARG2 (a2 / activate-01
            :ARG1 (r / receptor
                  :mod (t3 / transmembrane)
                  :location (s2 / surface
                        :poss (c5 / cell))))
      :ARG1-of (d3 / describe-01
            :ARG0 (p / publication-91
                  :ARG1-of (c6 / cite-01
                        :ARG2 2))))

# ::id pmid_1563_0473.17 ::date 2015-03-17T10:01:41 ::annotator SDL-AMR-09 ::preferred
# ::snt How this constellation of signals collaborates in tailoring each budding process so that it executes a distinct morphogenetic program has yet to be comprehensively defined.
# ::save-date Mon Jul 13, 2015 ::file pmid_1563_0473_17.txt
(h / have-11
      :ARG1 (y / yet)
      :ARG2 (d / define-01
            :ARG1 (t / thing
                  :manner-of (c2 / collaborate-01
                        :ARG0 (c3 / constellation
                              :consist-of (t3 / thing
                                    :ARG1-of (s / signal-07))
                              :mod (t4 / this))
                        :ARG2 (t2 / tailor-01
                              :ARG1 (p / process-02
                                    :ARG1 (b / bud-01)
                                    :mod (e / each)))
                        :purpose (e2 / execute-02
                              :ARG0 p
                              :ARG1 (p2 / program
                                    :topic (m / morphogenesis)
                                    :mod (d2 / distinct)))))
            :manner (c / comprehensive)))

# ::id pmid_1563_0473.18 ::date 2015-03-17T10:12:27 ::annotator SDL-AMR-09 ::preferred
# ::snt However, the process appears to be patterned at the initial stages of bud formation, since the relative importance of these pathways and their downstream effectors differ as buds begin to develop and cell fates are specified.
# ::save-date Wed Dec 30, 2015 ::file pmid_1563_0473_18.txt
(c / contrast-01
      :ARG2 (a / appear-02
            :ARG1 (p / process-02
                  :ARG1-of (p2 / pattern-01
                        :time (s / stage
                              :mod (i / initial)
                              :subevent-of (f / form-01
                                    :ARG1 (b / bud)))))
            :ARG1-of (c2 / cause-01
                  :ARG0 (d / differ-02
                        :ARG1 (i2 / important
                              :ARG2-of (r / relative-05)
                              :domain (p3 / pathway
                                    :mod (t / this)))
                        :ARG2 (e / effector
                              :location (d2 / downstream)
                              :poss p3)
                        :condition (a3 / and
                              :op1 (b2 / begin-01
                                    :ARG0 b
                                    :ARG1 (d3 / develop-01
                                          :ARG2 b))
                              :op2 (s2 / specify-01
                                    :ARG1 (f2 / fate-01
                                          :ARG1 (c3 / cell))))))))

# ::id pmid_1563_0473.19 ::date 2015-03-17T10:25:12 ::annotator SDL-AMR-09 ::preferred
# ::snt The development of a bud requires a number of coordinated changes in the behavior of the targeted cells within an epithelial sheet.
# ::save-date Thu Mar 19, 2015 ::file pmid_1563_0473_19.txt
(r / require-01
      :ARG0 (d / develop-02
            :ARG1 (b / bud))
      :ARG1 (c / change-01
            :ARG1 (b2 / behave-01
                  :ARG0 (c3 / cell
                        :ARG1-of (t / target-01)
                        :location (s / sheet
                              :mod (e / epithelium))))
            :quant (n / number)
            :ARG1-of (c2 / coordinate-01)))

# ::id pmid_1563_0473.20 ::date 2015-03-17T10:29:25 ::annotator SDL-AMR-09 ::preferred
# ::snt The process must be accompanied by alterations in the proliferation, polarity, shape, and adhesiveness of selected cells, as well as by modifications in their underlying basal lamina.
# ::save-date Mon Jul 13, 2015 ::file pmid_1563_0473_20.txt
(o / obligate-01
      :ARG2 (a / accompany-01
            :ARG0 (a5 / and
                  :op1 (a2 / alter-01
                        :ARG1 (a3 / and
                              :op1 (p2 / proliferate-01
                                    :ARG0 (c / cell
                                          :ARG1-of (s2 / select-01)))
                              :op2 (p3 / polarity
                                    :poss c)
                              :op3 (s / shape
                                    :poss c)
                              :op4 (c2 / capable-01
                                    :ARG1 c
                                    :ARG2 (a4 / adhere-01))))
                  :op2 (m / modify-01
                        :ARG1 (l / lamina
                              :ARG0-of (u / underlay-01
                                    :ARG1 c)
                              :mod (b / base))))
            :ARG1 (p / process-02)))

# ::id pmid_1563_0473.21 ::date 2015-03-17T10:36:22 ::annotator SDL-AMR-09 ::preferred
# ::snt Thus, extracellular epithelial-mesenchymal crosstalk must be intricately orchestrated to couple the determination of distinct cell fates with the contemporaneous remodeling of the physical and structural properties of the cell.
# ::save-date Wed Apr 29, 2015 ::file pmid_1563_0473_21.txt
(i / infer-01
      :ARG1 (o / obligate-01
            :ARG2 (o2 / orchestrate-01
                  :ARG1 (c / crosstalk
                        :mod (e / extracellular)
                        :location (b / between
                              :op1 (e2 / epithelium)
                              :op2 (m / mesenchyme)))
                  :manner (i2 / intricate)
                  :purpose (c2 / couple-01
                        :ARG1 (d / determine-01
                              :ARG1 (f / fate-01
                                    :ARG1 (c3 / cell)
                                    :mod (d2 / distinct)))
                        :ARG2 (r / remodel-01
                              :ARG1 (a / and
                                    :op1 (p / property
                                          :mod (p2 / physical)
                                          :poss c3)
                                    :op2 (p3 / property
                                          :mod (s / structure)
                                          :poss c3))
                              :mod (c4 / contemporaneous))))))

# ::id pmid_1563_0473.22 ::date 2015-03-17T10:44:13 ::annotator SDL-AMR-09 ::preferred
# ::snt Among the few dispensable organs, hair follicles offer an excellent model system to study epithelial bud formation.
# ::save-date Sun Jul 26, 2015 ::file pmid_1563_0473_22.txt
(o / offer-01
      :ARG0 (f / follicle
            :mod (h / hair)
            :ARG1-of (i / include-91
                  :ARG2 (o2 / organ
                        :quant (f3 / few)
                        :ARG1-of (d / dispense-01
                              :ARG1-of (p / possible-01)))))
      :ARG1 (s / system
            :mod (m / model)
            :ARG1-of (e / excellent-02
                  :ARG2 (s2 / study-01
                        :ARG1 (f2 / form-01
                              :ARG1 (b / bud)
                              :location (e2 / epithelium))))))

# ::id pmid_1563_0473.23 ::date 2015-03-17T14:17:30 ::annotator SDL-AMR-09 ::preferred
# ::snt Mammalian skin epithelium begins as a single sheet of multipotent ectodermal cells.
# ::save-date Mon Dec 21, 2015 ::file pmid_1563_0473_23.txt
(b / begin-01
      :ARG1 (e / epithelium
            :part-of (s / skin
                  :part-of (m / mammal)))
      :ARG2 (s2 / sheet
            :consist-of (c / cell
                  :mod (m2 / multipotent)
                  :part-of (e2 / ectoderm))
            :ARG1-of (s3 / single-02)))

# ::id pmid_1563_0473.24 ::date 2015-03-17T14:19:18 ::annotator SDL-AMR-09 ::preferred
# ::snt During development, specialized mesenchymal cells populate the skin in a spatially defined pattern to initiate the complex epithelial-mesenchymal crosstalk that will specify the bud [<xref ref-type="bibr" rid="pbio-0030011-b03">3</xref>].
# ::save-date Wed Apr 29, 2015 ::file pmid_1563_0473_24.txt
(p / populate-01
      :ARG1 (s2 / skin)
      :ARG2 (c / cell
            :part-of (m / mesenchyme)
            :ARG0-of (s / specialize-01))
      :manner (p2 / pattern
            :ARG1-of (d / define-01
                  :mod (s3 / space)))
      :purpose (i / initiate-01
            :ARG0 c
            :ARG1 (c2 / crosstalk
                  :mod (c3 / complex)
                  :location (b / between
                        :op1 (e / epithelium)
                        :op2 m)
                  :ARG0-of (s4 / specify-01
                        :ARG1 (b2 / bud-01))))
      :ARG1-of (d2 / describe-01
            :ARG0 (p3 / publication-91
                  :ARG1-of (c4 / cite-01
                        :ARG2 3)))
      :time (d3 / develop-02))

# ::id pmid_1563_0473.25 ::date 2015-03-17T14:20:25 ::annotator SDL-AMR-09 ::preferred
# ::snt Once committed, a small cluster of epithelial cells, the placode, instructs a group of underlying mesenchymal cells to condense and form the nascent dermal papilla, which will be a permanent fixture of the hair follicle.
# ::save-date Sun Aug 9, 2015 ::file pmid_1563_0473_25.txt
(i / instruct-01
      :ARG0 (c / cluster-01
            :ARG1 (c2 / cell
                  :part-of (e / epithelium))
            :mod (s / small)
            :ARG1-of (m2 / mean-01
                  :ARG2 (p3 / placode)))
      :ARG1 (g / group
            :consist-of (c3 / cell
                  :part-of (m / mesenchyme)
                  :ARG0-of (u / underlay-01)))
      :ARG2 (a / and
            :op1 (c4 / condense-01
                  :ARG1 c3)
            :op2 (f / form-01
                  :ARG0 c3
                  :ARG1 (p / papilla
                        :part-of (d / dermis)
                        :ARG1-of (b / bear-02)
                        :ARG0-of (f2 / fix-03
                              :ARG1 (f3 / follicle
                                    :mod (h / hair))
                              :manner (p2 / permanent)))))
      :time (a2 / after
            :op1 (c5 / commit-01
                  :ARG1 c)))

# ::id pmid_1563_0473.26 ::date 2015-03-17T14:22:00 ::annotator SDL-AMR-09 ::preferred
# ::snt Subsequent exchanges between the placode and nascent dermal papilla result in further growth of the follicle into the underlying dermis, or down-growth, and eventual differentiation into the six concentric layers of the mature follicle.
# ::save-date Mon Dec 21, 2015 ::file pmid_1563_0473_26.txt
(r / result-01
      :ARG1 (e / exchange-01
            :ARG0 (p / placode)
            :ARG2 (p2 / papilla
                  :ARG1-of (b / bear-02)
                  :part-of d)
            :time (s / subsequent))
      :ARG2 (a / and
            :op1 (o / or
                  :op1 (g / grow-01
                        :ARG1 (f2 / follicle)
                        :ARG2 (f / further)
                        :direction (d / dermis
                              :ARG0-of (u5 / underlay-01)))
                  :op2 (g2 / grow-01
                        :ARG1 f2
                        :ARG1-of (d2 / down-03)))
            :op2 (d3 / differentiate-01
                  :ARG1 f2
                  :direction (l / layer :quant 6
                        :mod (c / concentric)
                        :part-of (f3 / follicle
                              :ARG1-of (m / mature-02)))
                  :time (e2 / eventual))))

# ::id pmid_1563_0473.27 ::date 2015-03-17T14:25:15 ::annotator SDL-AMR-09 ::preferred
# ::snt Previously, we delineated how two respective epithelial and mesenchymal signals, Wnts and the BMP-inhibitory factor noggin, function in concert to induce lymphoid enhancer factor-1/β-catenin (LEF-1/β-catenin)-mediated gene transcription within the follicle placode [<xref ref-type="bibr" rid="pbio-0030011-b04">4</xref>].
# ::save-date Wed Jun 3, 2015 ::file pmid_1563_0473_27.txt
(d / delineate-01
      :ARG0 (w / we)
      :ARG1 (t / thing
            :manner-of (f / function-01
                  :ARG0 (t3 / thing :quant 2
                        :ARG1-of (s / signal-07)
                        :ARG1-of (m / mean-01
                              :ARG2 (a / and
                                    :op1 (p5 / pathway :name (n2 / name :op1 "Wnt")
                                          :source (e / epithelium))
                                    :op2 (p / protein :name (n3 / name :op1 "noggin")
                                          :ARG0-of (i2 / inhibit-01
                                                :ARG1 (p6 / protein :name (n4 / name :op1 "BMP")))
                                          :source (m3 / mesenchyme)))
                              :manner (r / respective)))
                  :manner (i3 / in-concert)
                  :purpose (i / induce-01
                        :ARG0 t3
                        :ARG2 (t2 / transcribe-01
                              :ARG1 (g / gene)
                              :ARG1-of (m2 / mediate-01
                                    :ARG0 (p7 / pathway :name (n5 / name :op1 "lymphoid" :op2 "enhancer" :op3 "factor-1/β-catenin")))
                              :location (p2 / placode
                                    :part-of (f2 / follicle))))))
      :time (p3 / previous)
      :ARG1-of (d2 / describe-01
            :ARG0 (p4 / publication-91
                  :ARG1-of (c2 / cite-01
                        :ARG2 4))))

# ::id pmid_1563_0473.28 ::date 2015-03-17T14:33:33 ::annotator SDL-AMR-09 ::preferred
# ::snt The downstream changes elicited through convergence of these two early signaling pathways include down-regulation of the gene encoding E-cadherin, the prototypical epithelial cadherin that forms the transmembrane core of intercellular adherens junctions (AJs) [<xref ref-type="bibr" rid="pbio-0030011-b05">5</xref>].
# ::save-date Fri Mar 27, 2015 ::file pmid_1563_0473_28.txt
(i / include-01
      :ARG1 (d / downregulate-01
            :ARG1 (g / gene
                  :ARG0-of (e3 / encode-01
                        :ARG1 (p2 / protein :name (n / name :op1 "E-cadherin")
                              :ARG1-of (m / mean-01
                                    :ARG2 (p4 / protein :name (n2 / name :op1 "cadherin")
                                          :location (e4 / epithelium)
                                          :mod (p3 / prototype)
                                          :ARG0-of (f / form-01
                                                :ARG1 (c3 / core
                                                      :mod (t2 / transmembrane)
                                                      :part-of (m3 / macro-molecular-complex :name (n4 / name :op1 "adherens" :op2 "junction")
                                                            :location (i2 / intercellular))))))))))
      :ARG2 (c / change-01
            :location (d2 / downstream)
            :ARG1-of (e / elicit-01
                  :ARG0 (c2 / converge-01
                        :ARG0 (p / pathway :quant 2
                              :mod (t / this)
                              :time (e2 / early)
                              :ARG0-of (s / signal-07)))))
      :ARG1-of (d3 / describe-01
            :ARG0 (p5 / publication-91
                  :ARG1-of (c4 / cite-01
                        :ARG2 5))))

# ::id pmid_1563_0473.29 ::date 2015-03-17T14:37:12 ::annotator SDL-AMR-09 ::preferred
# ::snt We subsequently showed that when E-cadherin is transgenically elevated in mouse skin, hair follicle morphogenesis is blocked, suggesting that E-cadherin down-regulation is a critical event in governing the adhesion dynamics necessary for budding morphogenesis [<xref ref-type="bibr" rid="pbio-0030011-b04">4</xref>].
# ::save-date Fri Jan 1, 2016 ::file pmid_1563_0473_29.txt
(s / show-01
      :ARG0 (w / we)
      :ARG1 (b / block-01
            :ARG1 (m / morphogenesis
                  :mod (f / follicle
                        :mod (h / hair)))
            :ARG0-of (s2 / suggest-01
                  :ARG1 (c / critical-02
                        :ARG1 (d / downregulate-01
                              :ARG1 (p / protein :name (n2 / name :op1 "E-cadherin")))
                        :ARG2 (g / govern-01
                              :ARG1 (d2 / dynamic
                                    :ARG0-of (a / adhere-01)
                                    :ARG1-of (n3 / need-01
                                          :purpose (m2 / morphogenesis
                                                :ARG1-of (b2 / bud-01)))))))
            :time (e2 / elevate-01
                  :ARG1 p
                  :manner (t / transgene)
                  :location (s4 / skin
                        :part-of (m3 / mouse))))
      :time (s3 / subsequent)
      :ARG1-of (d3 / describe-01
            :ARG0 (p2 / publication-91
                  :ARG1-of (c2 / cite-01
                        :ARG2 4))))

# ::id pmid_1563_0473.30 ::date 2015-03-19T10:01:38 ::annotator SDL-AMR-09 ::preferred
# ::snt Like LEF-1, E-cadherin also binds to β-catenin.
# ::save-date Sun Mar 22, 2015 ::file pmid_1563_0473_30.txt
(b / bind-01
      :ARG1 (p3 / protein :name (n / name :op1 "E-cadherin"))
      :ARG2 (p / protein :name (n2 / name :op1 "β-catenin")
            :ARG1-of (r / resemble-01
                  :ARG2 (p2 / protein :name (n3 / name :op1 "LEF-1"))))
      :mod (a / also))

# ::id pmid_1563_0473.31 ::date 2015-03-21T03:39:27 ::annotator SDL-AMR-09 ::preferred
# ::snt At sites of cell-cell contact, however, E-cadherin-β-catenin complexes recruit α-catenin, which in turn coordinates the associated actin polymerization dynamics necessary to stabilize nascent AJs and integrate the cytoskeleton across an epithelial sheet [<xref ref-type="bibr" rid="pbio-0030011-b06">6</xref>,<xref ref-type="bibr" rid="pbio-0030011-b07">7</xref>,<xref ref-type="bibr" rid="pbio-0030011-b08">8</xref>].
# ::save-date Sun Mar 29, 2015 ::file pmid_1563_0473_31.txt
(h / have-concession-91
      :ARG2 (r / recruit-01
            :ARG0 (m2 / macro-molecular-complex
                  :part (p7 / protein :name (n / name :op1 "E-cadherin"))
                  :part (p8 / protein :name (n9 / name :op1 "β-catenin")))
            :ARG1 (p / protein :name (n3 / name :op1 "α-catenin"))
            :location (s / site
                  :location-of (c3 / contact-01
                        :ARG1 (a5 / and
                              :op1 (c5 / cell)
                              :op2 (c6 / cell))))
            :ARG0-of (c / coordinate-01
                  :ARG1 (a / associate-01
                        :ARG1 (p3 / protein :name (n4 / name :op1 "actin")
                              :ARG1-of (p2 / polymerize-01)
                              :mod (d / dynamic))
                        :ARG1-of (n5 / need-01
                              :ARG0 (a2 / and
                                    :op1 (s2 / stabilize-01
                                          :ARG1 (p4 / protein :name (n6 / name :op1 "AJ")
                                                :mod (n7 / nascent)))
                                    :op2 (i2 / integrate-01
                                          :ARG1 (c4 / cytoskeleton)
                                          :ARG2 (a3 / across
                                                :op1 (s3 / sheet
                                                      :consist-of (e / epithelium)))))))
                  :mod (i / in-turn)))
      :ARG1-of (d2 / describe-01
            :ARG0 (p6 / publication
                  :ARG1-of (c2 / cite-01
                        :ARG2 (a4 / and :op1 6 :op2 7 :op3 8)))))

# ::id pmid_1563_0473.32 ::date 2015-03-21T04:53:14 ::annotator SDL-AMR-09 ::preferred
# ::snt α-Catenin also binds to the class III Lin-1, Isl-1, Mec-3 (LIM) protein Ajuba (a member of the zyxin family of proteins), which appears to function dually in both adhesion and in activation of the Ras-mitogen-activated protein kinase (MAPK) pathway [<xref ref-type="bibr" rid="pbio-0030011-b09">9</xref>,<xref ref-type="bibr" rid="pbio-0030011-b10">10</xref>].
# ::save-date Fri Jan 1, 2016 ::file pmid_1563_0473_32.txt
(b / bind-01
      :ARG0 (p2 / protein :name (n2 / name :op1 "α-Catenin"))
      :ARG1 (p5 / protein :name (n5 / name :op1 "Ajuba")
            :ARG1-of (m3 / mean-01
                  :ARG2 (m / member
                        :ARG1-of (i / include-91
                              :ARG2 (p8 / protein-family :name (n7 / name :op1 "zyxin")))))
            :ARG0-of (f2 / function-01
                  :ARG1 (a4 / and
                        :op1 (a5 / adhere-01)
                        :op2 (a6 / activate-01
                              :ARG1 (p / pathway :name (n / name :op1 "Ras-mitogen-activated" :op2 "protein" :op3 "kinase"))))
                  :ARG1-of (a2 / appear-02)
                  :manner (d / dual)))
      :ARG2 (a / and
            :op1 (p3 / protein :name (n3 / name :op1 "Lin-1"))
            :op2 (p4 / protein :name (n4 / name :op1 "Isl-1"))
            :op3 (p6 / protein :name (n6 / name :op1 "Mec-3"))
            :ARG1-of (m2 / mean-01
                  :ARG2 (n10 / name :op1 "LIM"))
            :part-of (c2 / class
                  :ord (o / ordinal-entity :value 3)))
      :mod (a3 / also)
      :ARG1-of (d2 / describe-01
            :ARG0 (p10 / publication
                  :ARG1-of (c / cite-01
                        :ARG2 (a9 / and :op1 9 :op2 10)))))

# ::id pmid_1563_0473.33 ::date 2015-03-21T04:55:21 ::annotator SDL-AMR-09 ::preferred
# ::snt Through these links, AJs appear able to couple adhesion with cytoskeletal dynamics as well as with nuclear and cytoplasmic signaling.
# ::save-date Sun Mar 29, 2015 ::file pmid_1563_0473_33.txt
(h / have-condition-91
      :ARG1 (l / link-01
            :mod (t / this))
      :ARG2 (p2 / possible-01
            :ARG1 (c / couple-01
                  :ARG0 (p3 / protein :name (n / name :op1 "AJ"))
                  :ARG1 (a / adhere-01)
                  :ARG2 (a2 / and
                        :op1 (d / dynamic
                              :mod (c3 / cytoskeleton))
                        :op2 (s / signal-07
                              :ARG0 (a3 / and
                                    :op1 (n3 / nucleus)
                                    :op2 (c2 / cytoplasm))))
                  :ARG1-of (a4 / appear-02))))

# ::id pmid_1563_0473.34 ::date 2015-03-21T04:56:44 ::annotator SDL-AMR-09 ::preferred
# ::snt This provides a framework for conceptualizing why E-cadherin levels appear to impact upon a plethora of developmental processes (reviewed in [<xref ref-type="bibr" rid="pbio-0030011-b11">11</xref>]).
# ::save-date Sun Dec 20, 2015 ::file pmid_1563_0473_34.txt
(p / provide-01
      :ARG0 (t / this)
      :ARG1 (f / framework)
      :ARG2 (c / conceptualize-00
            :ARG1 (t2 / thing
                  :ARG0-of (c3 / cause-01
                        :ARG1 (a / appear-02
                              :ARG1 (l / level
                                    :quant-of (p5 / protein :name (n / name :op1 "E-cadherin"))
                                    :ARG0-of (i / impact-01
                                          :ARG1 (p2 / process-02
                                                :ARG1 (g2 / growth)
                                                :quant (p3 / plethora))))))))
      :ARG1-of (r / review-02
            :ARG2 (p4 / publication
                  :ARG1-of (c2 / cite-01
                        :ARG2 11))))

# ::id pmid_1563_0473.35 ::date 2015-03-21T04:56:59 ::annotator SDL-AMR-09 ::preferred
# ::snt As we probed more deeply into the underlying mechanisms governing <i>E-cadherin</i> promoter activity, we were intrigued by the close proximity of the LEF-1/β-catenin binding site to a site known to bind the Snail/Slug family of zinc finger transcriptional repressor proteins [<xref ref-type="bibr" rid="pbio-0030011-b12">12</xref>,<xref ref-type="bibr" rid="pbio-0030011-b13">13</xref>,<xref ref-type="bibr" rid="pbio-0030011-b14">14</xref>,<xref ref-type="bibr" rid="pbio-0030011-b15">15</xref>].
# ::save-date Sun Jan 17, 2016 ::file pmid_1563_0473_35.txt
(c3 / cause-01
      :ARG0 (p2 / probe-01
            :ARG0 w2
            :ARG1 (m / mechanism
                  :ARG0-of (u / underlie-01)
                  :ARG0-of (g / govern-01
                        :ARG1 (a / activity-06
                              :ARG0 (m3 / molecular-physical-entity
                                    :ARG0-of (p3 / promote-01
                                          :ARG1 (g2 / gene :name (n / name :op1 "E-cadherin")))))))
            :ARG1-of (d / deep-02
                  :degree (m2 / more)))
      :ARG1 (i2 / intrigue-01
            :ARG0 (c / close-10
                  :ARG1 (s / site
                        :location-of (b / bind-01
                              :ARG1 (p4 / protein :name (n2 / name :op1 "LEF-1"))
                              :ARG2 (p5 / protein :name (n3 / name :op1 "β-catenin"))))
                  :ARG2 (s2 / site
                        :location-of (b2 / bind-01
                              :ARG1 (p6 / protein
                                    :ARG0-of (r2 / repress-01
                                          :ARG1 (t / transcribe-01
                                                :ARG1 (p8 / protein :name (n6 / name :op1 "zinc" :op2 "finger"))))
                                    :part-of (s3 / slash
                                          :op1 (p9 / protein-family :name (n4 / name :op1 "Snail"))
                                          :op2 (p10 / protein-family :name (n5 / name :op1 "Slug"))))
                              :ARG1-of (k / know-01))))
            :ARG1 (w2 / we))
      :ARG1-of (d2 / describe-01
            :ARG0 (p7 / publication
                  :ARG1-of (c2 / cite-01
                        :ARG2 (a5 / and :op1 12 :op2 13 :op3 14 :op4 15)))))

# ::id pmid_1563_0473.36 ::date 2015-03-21T10:06:54 ::annotator SDL-AMR-09 ::preferred
# ::snt Both activity of Snail and down-regulation of E-cadherin play pivotal roles in epithelial to mesenchymal transitions (EMTs), typified by the transformation of polarized, adhering epithelial cells into motile mesenchymal cells [<xref ref-type="bibr" rid="pbio-0030011-b16">16</xref>,<xref ref-type="bibr" rid="pbio-0030011-b17">17</xref>].
# ::save-date Sun Jan 17, 2016 ::file pmid_1563_0473_36.txt
(p / play-02
      :ARG0 (a / and
            :op1 (a2 / activity-06
                  :ARG0 (p6 / protein :name (n / name :op1 "Snail")))
            :op2 (d / downregulate-01
                  :ARG1 (p5 / protein :name (n2 / name :op1 "E-cadherin"))))
      :ARG1 (r / role
            :mod (p2 / pivotal)
            :topic (t / transition-01
                  :ARG1 (e / epithelium)
                  :ARG2 (m / mesenchyme)
                  :ARG1-of (t2 / typify-01
                        :ARG0 (t3 / transform-01
                              :ARG1 (c / cell
                                    :mod (e2 / epithelium)
                                    :ARG1-of (p3 / polarize-01)
                                    :ARG1-of (a4 / adhere-01))
                              :ARG2 (c4 / cell
                                    :mod (m3 / motile)
                                    :part-of m)))))
      :ARG1-of (d2 / describe-01
            :ARG0 (p4 / publication
                  :ARG1-of (c5 / cite-01
                        :ARG2 (a5 / and :op1 16 :op2 17)))))

# ::id pmid_1563_0473.37 ::date 2015-03-21T10:07:09 ::annotator SDL-AMR-09 ::preferred
# ::snt Bud formation differs from an EMT in that E-cadherin activity needs to be down-regulated but not prevented, so that adhesive junctions are remodeled rather than quantitatively impaired.
# ::save-date Wed Dec 30, 2015 ::file pmid_1563_0473_37.txt
(d / differ-02
      :ARG1 (f / form-01
            :ARG1 (b / bud))
      :ARG2 (t / transition-01
            :ARG2 (c3 / cell
                  :mod (m / mesenchymal))
            :ARG3 (c2 / cell
                  :mod (e / epithelial)))
      :ARG3 (n2 / need-01
            :ARG1 (d2 / downregulate-01
                  :ARG1 (a / activity-06
                        :ARG0 (p / protein :name (n / name :op1 "E-cadherin")))
                  :ARG1-of (c / contrast-01
                        :ARG2 (p2 / prevent-01 :polarity -
                              :ARG1 a))
                  :purpose (r / remodel-01
                              :ARG1 (p3 / protein :name (n3 / name :op1 "adhesive" :op2 "junctions"))
                              :ARG1-of (i / instead-of-91
                                    :ARG2 (i2 / impair-01
                                          :ARG1 p3
                                          :manner (q / quantitative)))))))

# ::id pmid_1563_0473.38 ::date 2015-03-21T10:07:28 ::annotator SDL-AMR-09 ::preferred
# ::snt Supportive of an underlying ability to fine-tune cadherin expression at the transcriptional level, Snail seems to have an additive effect with LEF-1/β-catenin in negatively modulating <i>E-cadherin</i> promoter activity [<xref ref-type="bibr" rid="pbio-0030011-b04">4</xref>].
# ::save-date Fri Feb 5, 2016 ::file pmid_1563_0473_38.txt
(c2 / cause-01
      :ARG0 (s / support-01
            :ARG1 (c3 / capable-01
                  :ARG2 (f / finetune-01
                        :ARG1 (e / express-03
                              :ARG2 (p7 / protein :name (n / name :op1 "cadherin"))
                              :ARG3 (l / level
                                    :mod (t / transcribe-01))))
                  :ARG0-of (u / underlie-01))
            :ARG1-of (d / describe-01
                  :ARG0 (p5 / publication-91
                        :ARG0-of (c / cite-01
                              :ARG2 4))))
      :ARG1 (s2 / seem-01
            :ARG1 (a2 / affect-01
                  :ARG0 (a3 / and
                        :op1 (p6 / protein :name (n2 / name :op1 "Snail"))
                        :op2 (a4 / and
                              :op1 (p / protein :name (n3 / name :op1 "LEF-1"))
                              :op2 (p2 / protein :name (n4 / name :op1 "β-catenin"))))
                  :ARG2 (m / modulate-01
                        :ARG1 (a / activity-06
                              :ARG0 (m2 / molecular-physical-entity
                                    :ARG0-of (p3 / promote-01
                                          :ARG1 (g / gene :name (n5 / name :op1 "E-cadherin")))))
                        :ARG1-of (n6 / negative-02))
                  :mod (a5 / additive))))

# ::id pmid_1563_0473.39 ::date 2015-03-21T10:07:43 ::annotator SDL-AMR-09 ::preferred
# ::snt In the present study, we discovered that Snail is expressed briefly at an early stage of hair bud formation, when E-cadherin down-regulation and activation of proliferation take place.
# ::save-date Sun Dec 20, 2015 ::file pmid_1563_0473_39.txt
(d / discover-01
      :ARG0 (w / we)
      :ARG1 (e / express-03
            :ARG1 (g / gene :name (n / name :op1 "Snail"))
            :duration (b / brief)
            :time (e2 / early
                  :op1 (s / stage
                        :part-of (f / form-01
                              :ARG1 (b2 / bud
                                    :mod (h2 / hair))))))
      :medium (s2 / study-01
            :time (p / present))
      :time (a / and
            :op1 (d2 / downregulate-01
                  :ARG1 (p2 / protein :name (n2 / name :op1 "E-cadherin")))
            :op2 (a2 / activate-01
                  :ARG1 (p3 / proliferate-01))))

# ::id pmid_1563_0473.40 ::date 2015-03-21T10:07:59 ::annotator SDL-AMR-09 ::preferred
# ::snt Thereafter, Snail disappears and remains absent during subsequent follicle down-growth and maturation.
# ::save-date Wed Mar 9, 2016 ::file pmid_1563_0473_40.txt
(a / and
      :op1 (d / disappear-01
            :ARG1 (p / protein :name (n / name :op1 "Snail")))
      :op2 (r / remain-01
            :ARG1 p
            :ARG3 (a2 / absent-01
                  :ARG1 p)
            :time (a3 / and
                  :op1 (g2 / grow-01
                        :ARG1 (f / follicle)
                        :ARG1-of (d2 / down-03))
                  :op2 (m / maturate-03
                        :ARG1 f)
                  :mod (s / subsequent)))
      :time (t / thereafter))

# ::id pmid_1563_0473.41 ::date 2015-03-21T10:08:12 ::annotator SDL-AMR-09 ::preferred
# ::snt This exquisite pattern appears to be functionally relevant since altering it in vivo correspondingly affects features associated with hair bud formation, including down-regulation of E-cadherin, increased proliferation, and repressed terminal differentiation.
# ::save-date Wed Apr 29, 2015 ::file pmid_1563_0473_41.txt
(c2 / cause-01
      :ARG0 (a2 / alter-01
            :ARG1 p
            :manner (i / in-vivo)
            :ARG1-of (c / correspond-02)
            :ARG0-of (a3 / affect-01
                  :ARG1 (f2 / feature
                        :ARG1-of (a4 / associate-01
                              :ARG2 (f3 / form-01
                                    :ARG1 (b / bud
                                          :mod (h / hair))))
                        :ARG1-of (i2 / include-01
                              :ARG2 (a5 / and
                                    :op1 (d / downregulate-01
                                          :ARG1 (p2 / protein :name (n / name :op1 "E-cadherin")))
                                    :op2 (p3 / proliferate-01
                                          :ARG1-of (i3 / increase-01))
                                    :op3 (d2 / differentiate-01
                                          :ARG1 (t2 / terminus)
                                          :ARG1-of (r2 / repress-01)))))))
      :ARG1 (a / appear-02
            :ARG1 (r / relevant-01
                  :ARG1 (p / pattern
                        :mod (t / this)
                        :mod (e / exquisite))
                  :ARG2 (f / function-01))))

# ::id pmid_1563_0473.42 ::date 2015-03-19T10:03:48 ::annotator SDL-AMR-09 ::preferred
# ::snt Although the temporal spike of Snail in the hair bud is reflected at the mRNA level and seems to follow Wnt signaling and BMP inhibition, LEF-1/β-catenin activation does not appear to induce <i>Snail</i> gene expression in embryonic skin keratinocytes.
# ::save-date Fri Jan 1, 2016 ::file pmid_1563_0473_42.txt
(a / and
      :op1 (r / reflect-01
            :ARG1 (l / level
                  :mod (n8 / nucleic-acid :name (n7 / name :op1 "mRNA")))
            :ARG2 (s / spike-04
                  :ARG1 (g / gene :name (n / name :op1 "Snail"))
                  :mod (t / time)
                  :location (b / bud
                        :mod (h / hair))))
      :op2 (s2 / seem-01
            :ARG1 (f / follow-01
                  :ARG1 s
                  :ARG2 (a2 / and
                        :op1 (s3 / signal-07
                              :ARG0 (p / pathway :name (n2 / name :op1 "Wnt")))
                        :op2 (i / inhibit-01
                              :ARG1 (p2 / protein :name (n3 / name :op1 "BMP"))))))
      :concession-of (a5 / appear-02 :polarity -
                  :ARG1 (i2 / induce-01
                        :ARG0 (a3 / activate-01
                              :ARG1 (a4 / and
                                    :op1 (p3 / protein :name (n4 / name :op1 "LEF-1"))
                                    :op2 (p4 / protein :name (n5 / name :op1 "β-catenin"))))
                        :ARG2 (e / express-03
                              :ARG1 g)
                        :location (c / cell :name (n6 / name :op1 "keratinocyte")
                              :mod (e2 / embryo)
                              :part-of (s4 / skin)))))

# ::id pmid_1563_0473.43 ::date 2015-03-19T10:03:16 ::annotator SDL-AMR-09 ::preferred
# ::snt In contrast, we provide in vitro, transgenic (Tg), and gene targeting evidence to show that TGF-β2 and small phenotype– and mothers against decapentaplegic–related protein 2 (SMAD2) signaling are upstream inducers of <i>Snail</i> gene expression in skin epithelium.
# ::save-date Wed Jun 3, 2015 ::file pmid_1563_0473_43.txt
(p / provide-01
      :ARG0 (w / we)
      :ARG1 (a / and
            :op1 (e / evidence
                  :ARG1-of (t / target-01
                        :mod (t2 / transgenic
                              :ARG1-of (m / mean-01
                                    :ARG2 (n5 / name :op1 "Tg")))))
            :op2 (e2 / evidence
                  :ARG1-of (t3 / target-01
                        :ARG0 (g / gene))))
      :manner (i / in-vitro)
      :ARG2-of (c / contrast-01)
      :purpose (s / show-01
            :ARG0 a
            :ARG1 (a2 / and
                  :op1 (p2 / protein :name (n / name :op1 "TGF-β2"))
                  :op2 (p5 / protein :name (n3 / name :op1 "protein" :op2 "2")
                        :ARG1-of (r / relate-01
                              :ARG2 (p4 / phenotype
                                    :mod (s2 / small))))
                  :op3 (p6 / protein :name (n2 / name :op1 "mothers" :op2 "against" :op3 "decapentaplegic" :op4 "protein" :op5 "2"))
                  :ARG0-of (s3 / signal-07
                        :ARG0-of (i2 / induce-01
                              :ARG2 (e3 / express-03
                                    :ARG1 (g2 / gene :name (n4 / name :op1 "Snail")))
                              :direction (u / upstream)
                              :location (e4 / epithelium
                                    :mod (s4 / skin)))))))

# ::id pmid_1563_0473.44 ::date 2015-03-19T10:02:54 ::annotator SDL-AMR-09 ::preferred
# ::snt In the absence of TGF-β2 signaling and <i>Snail</i> gene expression, hair placodes can form, but further follicle down-growth is blocked.
# ::save-date Mon Dec 21, 2015 ::file pmid_1563_0473_44.txt
(a / absent-01
      :ARG1 (a2 / and
            :op1 (s / signal-07
                  :ARG0 (p / protein :name (n / name :op1 "TGF-β2")))
            :op2 (e / express-03
                  :ARG1 (g / gene :name (n2 / name :op1 "Snail"))))
      :condition-of (p2 / possible-01
                  :ARG1 (f / form-01
                        :ARG1 (p3 / placode
                              :mod (h2 / hair)))
                  :ARG1-of (c / contrast-01
                        :ARG2 (b / block-01
                              :ARG1 (g2 / grow-01
                                    :ARG1 (f2 / follicle)
                                    :ARG1-of (d / down-03)
                                    :degree (f3 / further))))))

# ::id pmid_1563_0473.45 ::date 2015-03-19T10:02:28 ::annotator SDL-AMR-09 ::preferred
# ::snt Our studies point to the view that Snail likely functions downstream of cell fate specification, at a stage where the bud begins to exhibit enhanced proliferation and migration.
# ::save-date Thu Jan 14, 2016 ::file pmid_1563_0473_45.txt
(p / point-01
      :ARG0 (s / study-01
            :ARG0 (w / we))
      :ARG1 (v / view-01
            :ARG1 (l / likely-01
                  :ARG1 (f / function-01
                        :ARG0 (p3 / protein :name (n / name :op1 "Snail"))
                        :location (r / relative-position
                              :op1 (s2 / specify-01
                                    :ARG1 (f2 / fate
                                          :mod (c / cell)))
                              :direction (d2 / downstream)))))
      :time (s3 / stage
            :time-of (b / begin-01
                  :ARG0 (b2 / bud)
                  :ARG1 (e / exhibit-01
                        :ARG0 b2
                        :ARG1 (a / and
                              :op1 (p2 / proliferate-01)
                              :op2 (m / migrate-01)
                              :ARG1-of (e2 / enhance-01))))))

# ::id pmid_1563_0473.46 ::date 2015-03-23T06:44:15 ::annotator SDL-AMR-09 ::preferred
# ::snt Results
# ::save-date Thu Mar 26, 2015 ::file pmid_1563_0473_46.txt
(t / thing
      :ARG2-of (r2 / result-01))

# ::id pmid_1563_0473.47 ::date 2015-03-23T06:54:40 ::annotator SDL-AMR-09 ::preferred
# ::snt <i>Snail</i> mRNA and Protein Are Expressed Transiently at the Hair Bud Stage of Follicle Morphogenesis
# ::save-date Thu Jan 14, 2016 ::file pmid_1563_0473_47.txt
(e / express-03
      :ARG2 (a / and
            :op1 (n3 / nucleic-acid :name (n / name :op1 "mRNA")
                  :ARG0-of (e2 / encode-01
                        :ARG1 (g / gene :name (n4 / name :op1 "Snail"))))
            :op2 (p / protein :name (n2 / name :op1 "Snail")))
      :ARG1-of (t / transient-02)
      :time (s / stage
            :subevent-of (m / morphogenesis
                  :mod (f / follicle))
            :mod (b / bud
                  :mod (h / hair))))

# ::id pmid_1563_0473.48 ::date 2015-03-23T07:28:59 ::annotator SDL-AMR-09 ::preferred
# ::snt Although Snail family members are most frequently associated with EMTs, they also participate in many malignant processes involving a down-regulation but not a quantitative abrogation of intercellular junctions [<xref ref-type="bibr" rid="pbio-0030011-b18">18</xref>].
# ::save-date Fri Jan 1, 2016 ::file pmid_1563_0473_48.txt
(p / participate-01
      :ARG0 (m3 / member
            :ARG1-of (i / include-91
                  :ARG2 (p2 / protein-family :name (n / name :op1 "Snail"))))
      :ARG1 (p3 / process-02
            :ARG2-of (m / malignant-02)
            :quant (m2 / many)
            :ARG2-of (i2 / involve-01
                  :ARG1 (d / downregulate-01
                        :ARG1 j
                        :ARG1-of (c2 / contrast-01
                              :ARG2 (i4 / involve-01 :polarity -
                                    :ARG1 (a2 / abrogate-01
                                          :ARG1 (j / junction
                                                :mod (i3 / intercellular))
                                          :mod (q / quantity)))))))
      :concession (a / associate-01
            :ARG1 m3
            :ARG2 (t / transition-01
                  :ARG2 (c3 / cell
                        :mod (m5 / mesenchymal))
                  :ARG3 (c4 / cell
                        :mod (e / epithelial)))
            :ARG1-of (f2 / frequent-02
                  :degree (m4 / most)))
      :ARG1-of (d2 / describe-01
            :ARG0 (p4 / publication
                  :ARG1-of (c / cite-01
                        :ARG2 18)))
      :mod (a3 / also))

# ::id pmid_1563_0473.49 ::date 2015-03-23T07:55:07 ::annotator SDL-AMR-09 ::preferred
# ::snt The range of developmental processes in which Snail family members have been implicated thus includes the type of epithelial remodeling that is observed in hair follicle bud formation.
# ::save-date Fri Jan 1, 2016 ::file pmid_1563_0473_49.txt
(i4 / infer-01
      :ARG1 (i / include-01
            :ARG1 (r / remodel-01
                  :ARG1 (e / epithelium)
                  :ARG1-of (o / observe-01
                        :time (f2 / form-01
                              :ARG1 (b / bud
                                    :part-of (f3 / follicle
                                          :mod (h / hair)))))
                  :ARG1-of (t / type-03))
            :ARG2 (r2 / range-01
                  :ARG1 (p / process-02
                        :ARG1 (g / growth)
                        :ARG2-of (i2 / implicate-01
                              :ARG1 (m / member
                                    :ARG1-of (i3 / include-91
                                          :ARG2 (p2 / protein-family :name (n / name :op1 "Snail")))))))))

# ::id pmid_1563_0473.50 ::date 2015-03-24T06:15:25 ::annotator SDL-AMR-09 ::preferred
# ::snt Given our prior observation that exogenously added Snail can participate with LEF-1/β-catenin in down-regulating <i>E-cadherin</i> expression in keratinocytes [<xref ref-type="bibr" rid="pbio-0030011-b04">4</xref>], coupled with the established requirement for LEF-1/β-catenin in hair follicle morphogenesis [<xref ref-type="bibr" rid="pbio-0030011-b04">4</xref>,<xref ref-type="bibr" rid="pbio-0030011-b19">19</xref>], we turned to addressing whether Snail/Slug family members might also participate in the process.
# ::save-date Sun Jan 17, 2016 ::file pmid_1563_0473_50.txt
(a / address-02
      :ARG0 (w / we)
      :ARG1 (p2 / participate-01 :mode interrogative
            :ARG0 (m / member
                  :ARG1-of (i / include-91
                        :ARG2 (a2 / and
                              :op1 (p3 / protein-family :name (n / name :op1 "Snail"))
                              :op2 (p4 / protein-family :name (n2 / name :op1 "Slug")))))
            :ARG1 (p5 / process-02)
            :mod (a6 / also))
      :ARG1-of (c / cause-01
            :ARG0 (a4 / and
                  :op1 (o / observe-01
                        :ARG0 (w2 / we)
                        :ARG1 (p / possible-01
                              :ARG1 (p7 / participate-01
                                    :ARG0 (p8 / protein-family :name (n3 / name :op1 "Snail")
                                          :ARG1-of (a3 / add-02
                                                :manner (e / exogenous))
                                          :accompanier (m2 / macro-molecular-complex
                                                :part (p12 / protein :name (n6 / name :op1 "LEF-1"))
                                                :part (p13 / protein :name (n7 / name :op1 "β-catenin"))))
                                    :ARG1 (d / downregulate-01
                                          :ARG1 (e2 / express-03
                                                :ARG1 (g / gene :name (n5 / name :op1 "E-cadherin"))
                                                :ARG3 (k / keratinocyte)))))
                        :time (p6 / prior)
                        :ARG1-of (d2 / describe-01
                              :ARG0 (p10 / publication
                                    :ARG1-of (c2 / cite-01
                                          :ARG2 4))))
                  :op2 (r / require-01
                        :ARG0 (m3 / morphogenesis
                              :mod (f2 / follicle
                                    :mod (h / hair)))
                        :ARG1 m2
                        :ARG1-of (d3 / describe-01
                              :ARG0 (p11 / publication
                                    :ARG1-of (c3 / cite-01
                                          :ARG2 (a5 / and :op1 4 :op2 19))))
                        :ARG1-of (e3 / establish-01)))))

# ::id pmid_1563_0473.51 ::date 2015-03-23T08:18:54 ::annotator SDL-AMR-09 ::preferred
# ::snt PCR analyses identified transient <i>Snail</i> mRNA expression during a period of skin embryogenesis when waves of hair follicles are forming (unpublished data).
# ::save-date Thu Jan 14, 2016 ::file pmid_1563_0473_51.txt
(i / identify-01
      :ARG0 (a2 / analyze-01
            :instrument (r / react-01
                  :ARG0 (p3 / polymerase)
                  :ARG1-of (c / chain-01)))
      :ARG1 (e / express-03
            :ARG1 (n3 / nucleic-acid :name (n2 / name :op1 "mRNA")
                  :mod (g / gene :name (n / name :op1 "Snail")))
            :ARG1-of (t / transient-02)
            :time (p2 / period
                  :time-of (e2 / embryogenesis
                        :mod (s / skin))
                  :time-of (f2 / form-01
                        :ARG1 (w / wave-04
                              :ARG1 (f / follicle
                                    :mod (h / hair))))))
      :ARG1-of (d / describe-01
            :ARG0 (d2 / data
                  :ARG1-of (p / publish-01 :polarity -))))

# ::id pmid_1563_0473.52 ::date 2015-03-23T08:33:46 ::annotator SDL-AMR-09 ::preferred
# ::snt To pinpoint specifically where <i>Snail</i> mRNA is expressed in the developing skin, we conducted in situ hybridization using a cRNA probe unique to the <i>Snail</i> 3′ untranslated region (UTR).
# ::save-date Thu Feb 4, 2016 ::file pmid_1563_0473_52.txt
(h / hybridize-01
      :ARG0 (w / we)
      :purpose (p / pinpoint-01
            :ARG0 w
            :ARG1 (l / location
                  :ARG3-of (e / express-03
                        :ARG1 (n5 / nucleic-acid :name (n / name :op1 "mRNA")
                              :ARG0-of (e2 / encode-01
                                    :ARG1 g2)))
                  :part-of (s2 / skin
                        :ARG1-of (d / develop-02)))
            :ARG1-of (s / specific-02))
      :ARG2-of (u / use-01
            :ARG0 w
            :ARG1 (p2 / probe
                  :mod (n6 / nucleic-acid :name (n2 / name :op1 "complementary" :op2 "RNA"))
                  :mod (u2 / unique
                        :topic (d2 / dna-sequence :name (n3 / name :op1 "3′" :op2 "untranslated" :op3 "region")
                              :part-of (g2 / gene :name (n4 / name :op1 "Snail"))))))
      :manner (i / in-situ))

# ::id pmid_1563_0473.53 ::date 2015-03-23T09:00:34 ::annotator SDL-AMR-09 ::preferred
# ::snt Embryonic day 17.5 (E17.5) was chosen, since the multiple waves of follicle morphogenesis occurring at this time enabled us to evaluate Snail expression at different stages of the process.
# ::save-date Thu Jan 14, 2016 ::file pmid_1563_0473_53.txt
(c / choose-01
      :ARG0 w2
      :ARG1 (t / temporal-quantity :quant 17.5
            :unit (d2 / day)
            :age-of (e / embryo))
      :ARG1-of (c2 / cause-01
            :ARG0 (e2 / enable-01
                  :ARG0 (w / wave-04
                        :ARG1 (m2 / morphogenesis
                              :mod (f / follicle))
                        :quant (m / multiple)
                        :time (a / age-01
                              :ARG1 e
                              :ARG2 t))
                  :ARG1 (e3 / evaluate-101
                        :ARG0 (w2 / we)
                        :ARG2 (e4 / express-03
                              :ARG2 (p / protein :name (n / name :op1 "Snail"))
                              :time (s / stage
                                    :subevent-of m2
                                    :ARG1-of (d3 / differ-02))))
                  :ARG2 w2)))

# ::id pmid_1563_0473.54 ::date 2015-03-23T09:48:36 ::annotator SDL-AMR-09 ::preferred
# ::snt As shown in <xref ref-type="fig" rid="pbio-0030011-g001">Figure 1</xref>A, specific hybridization was detected within the epithelium of nascent hair buds.
# ::save-date Fri Jul 24, 2015 ::file pmid_1563_0473_54.txt
(d / detect-01
      :ARG1 (h / hybridize-01
            :ARG1-of (s / specific-02))
      :location (e / epithelium
            :part-of (b / bud
                  :mod (h2 / hair)
                  :mod (n / nascent)))
      :ARG1-of (s2 / show-01
            :ARG0 (f / figure :mod "1A")))

# ::id pmid_1563_0473.55 ::date 2015-03-23T09:52:54 ::annotator SDL-AMR-09 ::preferred
# ::snt By contrast, as follicles progressed further through their development (e.g., germ and peg stages), they exhibited no signs of hybridization (<xref ref-type="fig" rid="pbio-0030011-g001">Figure 1</xref>A).
# ::save-date Fri Dec 18, 2015 ::file pmid_1563_0473_55.txt
(c / contrast-01
      :ARG2 (e / exhibit-01 :polarity -
            :ARG0 f
            :ARG1 (s3 / signal-07
                  :ARG1 (h / hybridize-01))
            :time (d / develop-02
                  :ARG1 (f / follicle)
                  :example (a / and
                        :op1 (s / stage
                              :mod (g / germ))
                        :op2 (s2 / stage
                              :mod (p / peg)))
                  :degree (f3 / further)))
      :ARG1-of (d2 / describe-01
            :ARG2 (f2 / figure :mod "1A")))

# ::id pmid_1563_0473.56 ::date 2015-03-23T10:13:04 ::annotator SDL-AMR-09 ::preferred
# ::snt The transient nature of <i>Snail</i> mRNA expression during follicle development was most apparent in hybridized skin sections containing follicles from two different waves of morphogenesis (as shown in <xref ref-type="fig" rid="pbio-0030011-g001">Figure 1</xref>).
# ::save-date Thu Jan 14, 2016 ::file pmid_1563_0473_56.txt
(a / apparent
      :degree (m / most)
      :domain (e / express-03
            :ARG1 (n2 / nucleic-acid :name (n / name :op1 "mRNA")
                  :ARG0-of (e2 / encode-01
                        :ARG1 (g / gene :name (n3 / name :op1 "Snail"))))
            :ARG1-of (t / transient-02)
            :time (d / develop-02
                  :ARG1 (f / follicle)))
      :location (s / section
            :part-of (s2 / skin
                  :ARG1-of (h / hybridize-01))
            :ARG0-of (c / contain-01
                  :ARG1 (f2 / follicle
                        :source (w / wave-04 :quant 2
                              :ARG1 (m2 / morphogenesis)
                              :ARG1-of (d2 / differ-02)))))
      :ARG1-of (s3 / show-01
            :ARG0 (f3 / figure :mod 1)))

# ::id pmid_1563_0473.57 ::date 2015-03-24T02:06:17 ::annotator SDL-AMR-09 ::preferred
# ::snt Hybridizing hair buds from a later wave appeared juxtaposed with nonhybridizing follicles from an earlier wave.
# ::save-date Mon Dec 21, 2015 ::file pmid_1563_0473_57.txt
(a / appear-01
      :ARG1 (j / juxtapose-01
            :ARG1 (b / bud
                  :ARG1-of (h / hybridize-01)
                  :mod (h2 / hair)
                  :time (w / wave-01
                        :mod (l / late
                              :degree (m / more))))
            :ARG2 (f / follicle
                  :ARG1-of (h3 / hybridize-01 :polarity -)
                  :source (w2 / wave-04
                        :time (e / early
                              :degree (m2 / more))))))

# ::id pmid_1563_0473.58 ::date 2015-03-24T02:18:39 ::annotator SDL-AMR-09 ::preferred
# ::snt To determine whether this transient nature of <i>Snail</i> mRNA expression is reflected at the protein level, we generated an antibody against the N-terminal sequence that resides upstream of the more conserved zinc finger domains.
# ::save-date Thu Jan 14, 2016 ::file pmid_1563_0473_58.txt
(g / generate-01
      :ARG0 (w / we)
      :ARG1 (a / antibody
            :ARG0-of (o / oppose-01
                  :ARG1 (s / sequence
                        :mod (p2 / protein-segment :name (n2 / name :op1 "N" :op2 "terminus")
                              :ARG0-of (r3 / reside-01
                                    :ARG1 (r4 / relative-position
                                          :op1 (p3 / protein-segment :name (n3 / name :op1 "zinc" :op2 "finger" :op3 "domain")
                                                :ARG1-of (c / conserve-01
                                                      :degree (m / more)))
                                          :direction (u / upstream)))))))
      :purpose (d / determine-01
            :ARG0 w
            :ARG1 (r / reflect-01 :mode interrogative
                  :ARG1 (l / level
                        :mod (p / protein))
                  :ARG2 (n4 / nature
                        :mod (t2 / this)
                        :ARG1-of (t / transient-02
                              :manner-of (e / express-03
                                    :ARG1 (n5 / nucleic-acid :name (n / name :op1 "mRNA")
                                          :ARG0-of (e2 / encode-01
                                                :ARG1 (g2 / gene :name (n6 / name :op1 "Snail"))))))))))

# ::id pmid_1563_0473.59 ::date 2015-03-24T02:42:37 ::annotator SDL-AMR-09 ::preferred
# ::snt As judged by Western blot analysis, the antibody did not detect endogenous proteins from cultured keratinocytes, but it did yield a band of the expected size from keratinocytes transiently expressing a hemagglutinin (HA)-tagged Snail protein (<xref ref-type="fig" rid="pbio-0030011-g001">Figure 1</xref>B).
# ::save-date Sun Dec 13, 2015 ::file pmid_1563_0473_59.txt
(c / contrast-01
      :ARG1 (d / detect-01 :polarity -
            :ARG0 (a2 / antibody)
            :ARG1 (p / protein
                  :mod (e / endogenous))
            :ARG2 (k / keratinocyte
                  :ARG1-of (c2 / culture-01)))
      :ARG2 (y / yield-01
            :ARG0 a2
            :ARG1 (b / band
                  :mod (s2 / size
                        :ARG1-of (e3 / expect-01)))
            :source (k2 / keratinocyte
                  :ARG3-of (e2 / express-03
                        :ARG2 (p2 / protein :name (n3 / name :op1 "Snail")
                              :ARG1-of (t2 / tag-01
                                    :ARG2 (s / small-molecule :name (n4 / name :op1 "hemagglutinin"))))
                        :ARG1-of (t / transient-02))))
      :ARG2-of (j / judge-01
            :ARG3 (i / immunoblot-01)
            :ARG1-of (d3 / describe-01
                  :ARG2 (f / figure :mod "1B"))))

# ::id pmid_1563_0473.60 ::date 2015-03-24T03:09:37 ::annotator SDL-AMR-09 ::preferred
# ::snt The antibody also recognized a band corresponding to the size of endogenous Snail (approximately 28 kDa) in lysates from embryonic mouse skin, the temporal appearance of which corresponded to the waves of hair follicle morphogenesis from E15.5 to newborn when over 90% of the hair on the mouse is formed (<xref ref-type="fig" rid="pbio-0030011-g001">Figure 1</xref>B).
# ::save-date Wed Mar 2, 2016 ::file pmid_1563_0473_60.txt
(r / recognize-02
      :ARG0 (a3 / antibody)
      :ARG1 (b / band
            :ARG1-of (c / correspond-02
                  :ARG2 (s / size
                        :poss (p2 / protein :name (n / name :op1 "Snail")
                              :mod (e / endogenous))
                        :ARG1-of (e2 / equal-01
                              :ARG2 (a4 / approximately
                                    :op1 (m / mass-quantity :quant 28
                                          :unit (k / kilodalton))))))
            :ARG1-of (a5 / appear-01
                  :ARG1-of (c2 / correspond-02
                        :ARG2 (w / wave-04
                              :ARG1 (m3 / morphogenesis
                                    :mod (f / follicle
                                          :mod (h / hair)))
                              :time (d / date-interval
                                    :op1 (a2 / age-01
                                          :ARG1 (e4 / embryo)
                                          :ARG2 (t2 / temporal-quantity :quant 15.5
                                                :unit (d2 / day)))
                                    :op2 (b2 / bear-02
                                          :ARG1 (m5 / mouse)
                                          :time (n2 / new-01))
                                    :time-of (f2 / form-01
                                          :ARG1 (h2 / hair
                                                :mod (p / percentage-entity
                                                      :value (o2 / over :op1 90))
                                                :part-of (m4 / mouse))))))
                  :mod (t / time)))
      :location (l / lysate
            :source (s2 / skin
                  :mod (e3 / embryo)
                  :mod (m2 / mouse)))
      :mod (a / also))

# ::id pmid_1563_0473.61 ::date 2015-03-24T05:04:57 ::annotator SDL-AMR-09 ::preferred
# ::snt Consistent with the Western blot data, immunohistochemical analysis did not detect Snail in single-layered E13.5 epidermis (<xref ref-type="fig" rid="pbio-0030011-g001">Figure 1</xref>C) nor in the placode, which is the earliest morphological sign of the commitment of multipotent cells of the embryonic ectoderm to a hair cell fate (<xref ref-type="fig" rid="pbio-0030011-g001">Figure 1</xref>D).
# ::save-date Mon Dec 21, 2015 ::file pmid_1563_0473_61.txt
(d / detect-01 :polarity -
      :ARG0 (a2 / analyze-01
            :mod (i / immunohistochemistry))
      :ARG1 (p / protein :name (n3 / name :op1 "Snail"))
      :ARG1-of (c / consistent-01
            :ARG2 (d2 / data
                  :ARG2-of (r / result-01
                        :ARG1 (i2 / immunoblot-01))))
      :location (a3 / and
            :op1 (e / epidermis
                  :mod (l / layer
                        :ARG1-of (s / single-02))
                  :ARG1-of (d4 / describe-01
                        :ARG0 (f / figure :mod "1C"))
                  :part-of (e2 / embryo
                        :age (t / temporal-quantity :quant 13.5
                              :unit (d3 / day))))
            :op2 (p2 / placode
                  :ARG1-of (d5 / describe-01
                        :ARG0 (f2 / figure :mod "1D"))
                  :ARG0-of (s3 / signal-07
                        :ARG1 (c2 / commit-01
                              :ARG1 (c3 / cell
                                    :mod (m3 / multipotent)
                                    :part-of (e4 / ectoderm
                                          :mod (e5 / embryo)))
                              :ARG2 (f3 / fate
                                    :mod (c4 / cell
                                          :mod (h / hair))))
                        :mod (e3 / early
                              :degree (m / most))
                        :mod (m2 / morphology)))))

# ::id pmid_1563_0473.62 ::date 2015-03-24T03:13:30 ::annotator SDL-AMR-09 ::preferred
# ::snt Consistent with the in situ hybridization results, anti-Snail antibody labeled only hair buds and not follicles at more mature stages of development (<xref ref-type="fig" rid="pbio-0030011-g001">Figure 1</xref>E).
# ::save-date Fri Jun 5, 2015 ::file pmid_1563_0473_62.txt
(a2 / and
      :op1 (l / label-01
            :ARG0 (a / antibody
                  :ARG0-of (c2 / counter-01
                        :ARG1 (p / protein :name (n / name :op1 "Snail"))))
            :ARG1 (b / bud
                  :mod (h2 / hair)
                  :mod (o / only))
            :ARG1-of (c / consistent-01
                  :ARG2 (t / thing
                        :ARG2-of (r / result-01
                              :ARG1 (h / hybridize-01
                                    :manner (i / in-situ))))))
      :op2 (l2 / label-01 :polarity -
            :ARG0 a
            :ARG1 (f / follicle)
            :time (s / stage
                  :subevent-of (d / develop-02)
                  :ARG1-of (m / mature-02
                        :degree (m2 / more))))
      :ARG1-of (d2 / describe-01
            :ARG2 (f2 / figure :mod "1E")))

# ::id pmid_1563_0473.63 ::date 2015-03-24T03:31:23 ::annotator SDL-AMR-09 ::preferred
# ::snt Taken together, the anti-Snail antibody appeared to be specific for its target protein.
# ::save-date Fri Jul 24, 2015 ::file pmid_1563_0473_63.txt
(a2 / appear-01
      :ARG1 (s / specific-02
            :ARG1 (a / antibody
                  :ARG0-of (c / counter-01
                        :ARG1 (p / protein :name (n / name :op1 "Snail"))))
            :ARG2 (p2 / protein
                  :ARG1-of (t / target-01
                        :ARG0 a)))
      :ARG1-of (c2 / cause-01
            :ARG0 (t2 / take-01
                  :mod (t3 / together))))

# ::id pmid_1563_0473.64 ::date 2015-03-24T03:40:24 ::annotator SDL-AMR-09 ::preferred
# ::snt It did not detect other Snail family members known to be expressed in keratinocytes and/or skin (unpublished data).
# ::save-date Fri Jan 1, 2016 ::file pmid_1563_0473_64.txt
(d / detect-01 :polarity -
      :ARG0 (i / it)
      :ARG1 (m / member
            :ARG1-of (i2 / include-91
                  :ARG2 (p / protein-family :name (n / name :op1 "Snail")
                        :ARG2-of (e / express-03
                              :ARG3 (a / and-or
                                    :op1 (k2 / keratinocyte)
                                    :op2 (s / skin))
                              :ARG1-of (k / know-01))))
            :mod (o / other))
      :ARG1-of (d2 / describe-01
            :ARG0 (d3 / data
                  :ARG1-of (p2 / publish-01 :polarity -))))

# ::id pmid_1563_0473.65 ::date 2015-03-24T03:48:50 ::annotator SDL-AMR-09 ::preferred
# ::snt Furthermore, the immunohistochemical data paralleled our <i>Snail</i> in situ hybridization data revealing transient <i>Snail</i> expression at the hair bud stage (<xref ref-type="fig" rid="pbio-0030011-g001">Figure 1</xref>A).
# ::save-date Thu Jan 14, 2016 ::file pmid_1563_0473_65.txt
(a / and
      :op2 (p / parallel-01
            :ARG0 (d / data
                  :mod (i / immunohistochemistry))
            :ARG1 (d2 / data
                  :topic (h / hybridize-01
                        :ARG0 (w / we)
                        :ARG1 (g / gene :name (n / name :op1 "Snail"))
                        :manner (i2 / in-situ))
                  :ARG0-of (r / reveal-01
                        :ARG1 (e / express-03
                              :ARG2 g
                              :ARG1-of (t / transient-02)
                              :time (s / stage
                                    :mod (b / bud
                                          :mod (h2 / hair)))
                              :ARG1-of (d3 / describe-01
                                    :ARG0 (f / figure :mod "1A")))))))

# ::id pmid_1563_0473.66 ::date 2015-03-19T00:29:08 ::annotator SDL-AMR-09 ::preferred
# ::snt As judged by immunohistochemistry, Snail protein was localized to the nuclei of the hair bud cells (<xref ref-type="fig" rid="pbio-0030011-g001">Figure 1</xref>E).
# ::save-date Sat Mar 28, 2015 ::file pmid_1563_0473_66.txt
(j / judge-01
      :ARG0 (i / immunohistochemistry)
      :ARG1 (b2 / be-located-at-91
            :ARG1 (p2 / protein :name (n2 / name :op1 "Snail"))
            :ARG2 (n / nucleus
                  :poss (c2 / cell
                        :part-of (b / bud
                              :part-of (h2 / hair)))))
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod "1E")))

# ::id pmid_1563_0473.67 ::date 2015-03-19T00:48:44 ::annotator SDL-AMR-09 ::preferred
# ::snt This feature was consistent with Snail's known function as a transcriptional repressor [<xref ref-type="bibr" rid="pbio-0030011-b12">12</xref>,<xref ref-type="bibr" rid="pbio-0030011-b13">13</xref>].
# ::save-date Tue Dec 22, 2015 ::file pmid_1563_0473_67.txt
(c / consistent-01
      :ARG1 (f / feature
            :mod (t / this))
      :ARG2 (f2 / function-01
            :ARG0 (p2 / protein :name (n / name :op1 "Snail"))
            :ARG1 (r2 / repress-01
                  :ARG1 (t2 / transcribe-01))
            :ARG1-of (k / know-01))
      :ARG1-of (d / describe-01
            :ARG0 (p3 / publication
                  :ARG1-of (c2 / cite-01
                        :ARG2 (a / and :op1 12 :op2 13)))))

# ::id pmid_1563_0473.68 ::date 2015-03-19T01:31:27 ::annotator SDL-AMR-09 ::preferred
# ::snt Additionally, anti-Snail labeling was detected in only three of the four major waves of follicle morphogenesis.
# ::save-date Mon Dec 21, 2015 ::file pmid_1563_0473_68.txt
(a / and
      :op2 (d / detect-01
            :ARG1 (l / label-01
                  :ARG0-of (o / oppose-01
                        :ARG1 (p / protein :name (n / name :op1 "Snail"))))
            :location (t / thing :quant 3
                  :ARG1-of (i / include-91
                        :ARG2 (w2 / wave-04 :quant 4
                              :ARG1 (m2 / morphogenesis
                                    :mod (f / follicle))
                              :ARG1-of (m / major-02)))
                  :mod (o2 / only))))

# ::id pmid_1563_0473.69 ::date 2015-03-19T01:48:11 ::annotator SDL-AMR-09 ::preferred
# ::snt Snail was not found in the buds of guard hairs that are the earliest of all hairs to form (at E13.5), and which constitute less than 5% of the mouse coat (unpublished data).
# ::save-date Thu Apr 30, 2015 ::file pmid_1563_0473_69.txt
(f4 / find-01 :polarity -
      :ARG1 (p2 / protein :name (n / name :op1 "Snail"))
      :location (b / bud
            :poss (h / hair
                  :mod (g / guard)
                  :ARG1-of (f2 / form-01
                        :time (e / early
                              :mod (m / most)
                              :compared-to (h2 / hair
                                    :mod (a / all)))
                        :op1-of (a2 / and
                              :op2 (c / constitute-01
                                    :ARG0 h))
                        :time (a3 / age-01
                              :ARG1 (e2 / embryo)
                              :ARG2 (t / temporal-quantity :quant 13.5
                                    :unit (d / day))))
                  :ARG1-of (i / include-91
                        :ARG2 (c2 / coat
                              :poss (m2 / mouse))
                        :ARG3 (l2 / less-than
                              :op1 (p3 / percentage-entity :value 5))
                        :ARG1-of (d2 / describe-01
                              :ARG0 (d3 / data
                                    :ARG1-of (p4 / publish-01 :polarity -)))))))

# ::id pmid_1563_0473.70 ::date 2015-03-19T02:21:51 ::annotator SDL-AMR-09 ::preferred
# ::snt As judged by immunofluorescence with antibodies against the proliferating nuclear antigen Ki67, the timing of Snail expression coincided with the stage at which the developing follicle enhanced its proliferation and down-growth (<xref ref-type="fig" rid="pbio-0030011-g001">Figure 1</xref>F).
# ::save-date Tue Feb 2, 2016 ::file pmid_1563_0473_70.txt
(j / judge-01
      :ARG0 (i / immunofluoresce-01
            :ARG2 (a / antibody
                  :ARG0-of (o / oppose-01
                        :ARG1 (p5 / protein :name (n4 / name :op1 "Ki67")
                              :mod (n5 / nucleus)
                              :ARG0-of (p / proliferate-01)
                              :mod (a2 / antigen)))))
      :ARG1 (c / coincide-01
            :ARG1 (t / time-02
                  :ARG1 (e / express-03
                        :ARG2 (p2 / protein :name (n / name :op1 "Snail"))))
            :ARG2 (s / stage
                  :time-of (e2 / enhance-01
                        :ARG0 (f / follicle
                              :ARG1-of (d / develop-02))
                        :ARG1 (a5 / and
                              :op1 (p3 / proliferate-01
                                    :ARG0 f)
                              :op2 (g / grow-01
                                    :ARG1 f
                                    :ARG1-of (d2 / down-03))))))
      :ARG1-of (d3 / describe-01
            :ARG0 (f2 / figure :mod "1F")))

# ::id pmid_1563_0473.71 ::date 2015-03-21T04:50:41 ::annotator SDL-AMR-09 ::preferred
# ::snt Immunohistochemistry with antibodies against the active (phosphorylated) form of MAPK (pMAPK) marked a subset of the proliferating (Ki67-positive) cells, and pMAPK-positive cells were enriched in the hair bud (<xref ref-type="fig" rid="pbio-0030011-g001">Figure 1</xref>G).
# ::save-date Sun Dec 13, 2015 ::file pmid_1563_0473_71.txt
(a3 / and
      :op1 (m / mark-02
            :ARG0 (i / immunohistochemistry
                  :mod (a / antibody)
                  :ARG0-of (o2 / oppose-01
                        :ARG1 (e2 / enzyme :name (n2 / name :op1 "MAPK")
                              :ARG0-of (a2 / activity-06)
                              :ARG3-of (p2 / phosphorylate-01))))
            :ARG2 (s / subset
                  :quant-of (c2 / cell
                        :ARG0-of (p4 / proliferate-01)
                        :part (p5 / protein :name (n3 / name :op1 "Ki67")))))
      :op2 (e / enrich-01
            :ARG1 (c3 / cell
                  :location (b / bud
                        :mod (h2 / hair))
                  :part e2))
      :ARG1-of (d / describe-01
            :ARG0 (f2 / figure :mod "1G")))

# ::id pmid_1563_0473.72 ::date 2015-03-22T02:43:10 ::annotator SDL-AMR-09 ::preferred
# ::snt The timing of Snail induction and Ki67 and pMAPK enrichment in the hair bud appeared to follow closely the induction of LEF-1/β-catenin activity, known to initiate in the hair placode stage [<xref ref-type="bibr" rid="pbio-0030011-b20">20</xref>].
# ::save-date Fri Dec 18, 2015 ::file pmid_1563_0473_72.txt
(a / appear-02
      :ARG1 (f / follow-01
            :ARG1 (t / time-02
                  :ARG1 (a5 / and
                        :op1 (i / induce-01
                              :ARG2 (p / protein :name (n / name :op1 "Snail")))
                        :op2 (e / enrich-01
                              :ARG1 (a3 / and
                                    :op1 (p2 / protein :name (n2 / name :op1 "Ki67"))
                                    :op2 (e2 / enzyme :name (n3 / name :op1 "MAPK")
                                          :ARG3-of (p7 / phosphorylate-01)))
                              :location (b / bud
                                    :poss (h / hair)))))
            :ARG2 (i2 / induce-01
                  :ARG2 (a2 / activity-06
                        :ARG0 (m / macro-molecular-complex
                              :part (p4 / protein :name (n4 / name :op1 "LEF-1"))
                              :part (p3 / protein :name (n5 / name :op1 "β-catenin")))
                        :ARG1-of (i3 / initiate-01
                              :time (s / stage
                                    :mod (p5 / placode)
                                    :mod (h2 / hair))
                              :ARG1-of (k / know-01))))
            :ARG1-of (c2 / close-10))
      :ARG1-of (d / describe-01
            :ARG0 (p6 / publication
                  :ARG1-of (c / cite-01
                        :ARG2 20))))

# ::id pmid_1563_0473.73 ::date 2015-03-22T05:00:06 ::annotator SDL-AMR-09 ::preferred
# ::snt However, like placodes, hair buds exhibited down-regulation in E-cadherin expression (<xref ref-type="fig" rid="pbio-0030011-g001">Figure 1</xref>H; see also [<xref ref-type="bibr" rid="pbio-0030011-b04">4</xref>]).
# ::save-date Wed Dec 30, 2015 ::file pmid_1563_0473_73.txt
(c / contrast-01
      :ARG2 (e / exhibit-01
            :ARG0 (b / bud
                  :poss (h / hair)
                  :ARG1-of (r2 / resemble-01
                        :ARG2 (p3 / placode)))
            :ARG1 (d / downregulate-01
                  :ARG1 (e2 / express-03
                        :ARG2 (p / protein :name (n / name :op1 "E-cadherin")))))
      :ARG1-of (d2 / describe-01
            :ARG0 (a / and
                  :op1 (f / figure :mod "1H")
                  :op2 (p2 / publication
                        :ARG1-of (c2 / cite-01
                              :ARG2 4)
                        :ARG1-of (s / see-01 :mode imperative
                              :ARG0 (y / you)
                              :mod (a2 / also))))))

# ::id pmid_1563_0473.74 ::date 2015-03-22T05:16:34 ::annotator SDL-AMR-09 ::preferred
# ::snt Sustained Expression of Snail Results in Epidermal Hyperproliferation and Differentiation Defects in Tg Mouse Skin
# ::save-date Sat Mar 28, 2015 ::file pmid_1563_0473_74.txt
(r / result-01
      :ARG1 (e / express-03
            :ARG2 (p / protein :name (n / name :op1 "Snail"))
            :ARG1-of (s / sustain-01))
      :ARG2 (a / and
            :op1 (p2 / proliferate-01
                  :ARG0 (e2 / epidermis)
                  :degree (h / hyper))
            :op2 (d / defect
                  :location (s2 / skin
                        :part-of (m / mouse
                              :mod (t / transgenic)))
                  :mod (d2 / differentiate-01))))

# ::id pmid_1563_0473.75 ::date 2015-03-22T05:30:29 ::annotator SDL-AMR-09 ::preferred
# ::snt The striking spike of Snail expression coincident with hair bud formation and enhanced proliferation prompted us to examine the consequences of ectopically expressing Snail elsewhere in mouse skin epidermis.
# ::save-date Tue Jun 16, 2015 ::file pmid_1563_0473_75.txt
(p / prompt-02
      :ARG0 (c2 / coincide-01
            :ARG1 (s3 / spike-04
                  :ARG1 (e / express-03
                        :ARG2 (p2 / protein :name (n3 / name :op1 "Snail")))
                  :ARG1-of (s / strike-04))
            :ARG2 (a2 / and
                  :op1 (f / form-01
                        :ARG1 (b / bud
                              :poss (h / hair)))
                  :op2 (p3 / proliferate-01
                        :ARG1-of (e2 / enhance-01))))
      :ARG1 (w / we)
      :ARG2 (e3 / examine-01
            :ARG0 w
            :ARG1 (c3 / consequence
                  :poss (e4 / express-03
                        :ARG2 p2
                        :ARG3 (e6 / epidermis
                              :part-of (s2 / skin
                                    :part-of (m / mouse))
                              :mod (e7 / elsewhere))
                        :manner (e5 / ectopic)))))

# ::id pmid_1563_0473.76 ::date 2015-03-22T05:50:04 ::annotator SDL-AMR-09 ::preferred
# ::snt To distinguish Tg from endogenous Snail, we used the HA-epitope, shown previously not to alter Snail's transcriptional activity [<xref ref-type="bibr" rid="pbio-0030011-b12">12</xref>].
# ::save-date Mon Jul 6, 2015 ::file pmid_1563_0473_76.txt
(u / use-01
      :ARG0 (w / we)
      :ARG1 (d / dna-sequence :name (n / name :op1 "HA-epitope")
            :ARG0-of (a / alter-01 :polarity -
                  :ARG1 (a2 / activity-06
                        :ARG0 (p2 / protein :name (n2 / name :op1 "Snail"))
                        :ARG1 (t / transcribe-01))
                  :ARG1-of (s / show-01
                        :time (p / previous))))
      :purpose (d2 / distinguish-01
            :ARG0 w
            :ARG1 (p5 / protein :name (n4 / name :op1 "Snail")
                  :mod (t2 / transgenic))
            :ARG2 (p3 / protein :name (n3 / name :op1 "Snail")
                  :mod (e / endogenous)))
      :ARG1-of (d3 / describe-01
            :ARG0 (p4 / publication
                  :ARG1-of (c / cite-01
                        :ARG2 12))))

# ::id pmid_1563_0473.77 ::date 2015-03-22T06:15:03 ::annotator SDL-AMR-09 ::preferred
# ::snt Of 20 <i>K14-Snail[HA]</i> Tg animals generated, three expressed the transgene and all exhibited analogous phenotypes.
# ::save-date Wed Mar 25, 2015 ::file pmid_1563_0473_77.txt
(g / generate-01
      :ARG1 (a / animal :quant 20
            :mod (t / transgene)
            :part (p / protein :name (n / name :op1 "K14-Snail")
                  :part (p2 / protein :name (n2 / name :op1 "HA")))
            :ARG2-of (i / include-91
                  :ARG1 (a2 / animal :quant 3
                        :ARG1-of (e / express-03
                              :ARG2 t)))
            :ARG0-of (e2 / exhibit-01
                  :ARG1 (p3 / phenotype
                        :mod (a3 / analogue)))))

# ::id pmid_1563_0473.78 ::date 2015-03-22T06:45:22 ::annotator SDL-AMR-09 ::preferred
# ::snt Mice that integrated the transgene at the single-cell stage died at or shortly after birth.
# ::save-date Fri Dec 18, 2015 ::file pmid_1563_0473_78.txt
(d / die-01
      :ARG1 (m / mouse
            :ARG0-of (i / integrate-01
                  :ARG1 (t / transgene)
                  :time (s / stage
                        :mod (c / cell
                              :ARG1-of (s2 / single-02)))))
      :time (o / or
            :op1 (b / bear-02)
            :op2 (a / after
                  :op1 b
                  :quant (s3 / short-07))))

# ::id pmid_1563_0473.79 ::date 2015-03-22T06:50:07 ::annotator SDL-AMR-09 ::preferred
# ::snt The three surviving full-Tg founder mice harbored transgene integrations that gave stable transmission of mosaic <i>Snail</i> gene expression through the germline.
# ::save-date Fri Jan 1, 2016 ::file pmid_1563_0473_79.txt
(h / harbor-01
      :ARG0 (m / mouse :quant 3
            :ARG0-of (f / found-01)
            :ARG0-of (s / survive-01)
            :mod (t / transgene
                  :ARG1-of (f2 / full-09)))
      :ARG1 (i / integrate-01
            :ARG1 (t3 / transgene)
            :ARG0-of (g / give-01
                  :ARG1 (t2 / transmit-01
                        :ARG1 (e / express-03
                              :ARG1 (g3 / gene :name (n / name :op1 "Snail"))
                              :mod (m2 / mosaic))
                        :instrument (g2 / germline)
                        :ARG1-of (s2 / stable-03)))))

# ::id pmid_1563_0473.80 ::date 2015-03-22T06:59:12 ::annotator SDL-AMR-09 ::preferred
# ::snt Progressively poor health necessitated our sacrificing most offspring from these lines within a year of birth.
# ::save-date Mon Nov 2, 2015 ::file pmid_1563_0473_80.txt
(n / necessitate-01
      :ARG0 (h / healthy :polarity -
            :ARG1-of (p / progress-01))
      :ARG1 (s / sacrifice-01
            :ARG0 (w / we)
            :ARG1 (o / offspring
                  :mod (m / most)
                  :source (l / line
                        :mod (t2 / this)))
            :time (a / after
                  :op1 (b / bear-02)
                  :quant (u / up-to
                        :op1 (t3 / temporal-quantity :quant 1
                              :unit (y2 / year))))))

# ::id pmid_1563_0473.81 ::date 2015-03-22T07:11:11 ::annotator SDL-AMR-09 ::preferred
# ::snt As <i>Snail</i> Tg animals grew, they became distinguished by their small size, short tails, and flaky skin (<xref ref-type="fig" rid="pbio-0030011-g002">Figure 2</xref>A).
# ::save-date Thu Jan 14, 2016 ::file pmid_1563_0473_81.txt
(d / distinguish-01
      :ARG0 (a2 / and
            :op1 (s / size
                  :mod (s4 / small)
                  :poss a)
            :op2 (t2 / tail
                  :ARG1-of (s2 / short-07)
                  :poss a)
            :op3 (s3 / skin
                  :mod (f / flake)
                  :poss a))
      :ARG1 (a / animal
            :mod (g3 / gene :name (n / name :op1 "Snail"))
            :mod (t / transgene))
      :time (g / grow-01
            :ARG1 a)
      :ARG1-of (d2 / describe-01
            :ARG0 (f2 / figure :mod "2A")))

# ::id pmid_1563_0473.82 ::date 2015-03-22T07:58:30 ::annotator SDL-AMR-09 ::preferred
# ::snt Histological analyses of 3-d old (P3) mice revealed mosaic patches marked by epidermal thickening (<xref ref-type="fig" rid="pbio-0030011-g002">Figure 2</xref>B).
# ::save-date Thu Apr 30, 2015 ::file pmid_1563_0473_82.txt
(r / reveal-01
      :ARG0 (a / analyze-01
            :ARG1 (m / mouse
                  :age (t / temporal-quantity :quant 3
                              :unit (d / day)))
            :mod (h / histology))
      :ARG1 (p / patch
            :mod (m2 / mosaic)
            :ARG1-of (m3 / mark-02
                  :ARG3 (t2 / thicken-01
                        :ARG1 (e / epidermis))))
      :ARG1-of (d2 / describe-01
            :ARG0 (f / figure :mod "2B")))

# ::id pmid_1563_0473.83 ::date 2015-03-22T08:08:44 ::annotator SDL-AMR-09 ::preferred
# ::snt The mosaic morphology was reflected at the level of Tg Snail protein, with only the hyperthickened regions expressing nuclear HA-tagged Snail (<xref ref-type="fig" rid="pbio-0030011-g002">Figure 2</xref>C).
# ::save-date Fri Jan 1, 2016 ::file pmid_1563_0473_83.txt
(a / and
      :op1 (r / reflect-01
            :ARG1 (l / level
                  :poss (p / protein :name (n / name :op1 "Snail")
                        :mod (t3 / transgene)))
            :ARG2 (m / morphology
                  :mod (m2 / mosaic))
            :ARG1-of (d / describe-01
                  :ARG0 (f / figure :mod "2C")))
      :op2 (e / express-03
            :ARG2 (p2 / protein :name (n3 / name :op1 "Snail")
                  :ARG1-of (t2 / tag-01
                        :ARG2 (p3 / protein :name (n4 / name :op1 "HA")))
                  :mod (n5 / nucleus))
            :ARG3 (r2 / region
                  :ARG1-of (t / thicken-01
                        :degree (h2 / hyper))
                  :mod (o / only))))

# ::id pmid_1563_0473.84 ::date 2015-03-22T08:24:20 ::annotator SDL-AMR-09 ::preferred
# ::snt These hyperthickened areas were marked by excessive proliferation, as revealed by antibodies against the proliferating nuclear antigen Ki67 (<xref ref-type="fig" rid="pbio-0030011-g002">Figure 2</xref>D and <xref ref-type="fig" rid="pbio-0030011-g002">2</xref>E).
# ::save-date Fri Jul 24, 2015 ::file pmid_1563_0473_84.txt
(m / mark-02
      :ARG1 (a / area
            :ARG1-of (t / thicken-01
                  :degree (h / hyper))
            :mod (t2 / this))
      :ARG3 (p / proliferate-01
            :ARG1-of (e / excessive-02))
      :ARG1-of (r / reveal-01
            :ARG0 (a2 / antibody
                  :ARG0-of (o / oppose-01
                        :ARG1 (p2 / protein :name (n / name :op1 "Ki67")
                              :ARG0-of (p3 / proliferate-01)
                              :mod (n2 / nucleus)
                              :mod (a3 / antigen)))))
      :ARG1-of (d / describe-01
            :ARG0 (a4 / and
                  :op1 (f / figure :mod "2D")
                  :op2 (f2 / figure :mod "2E"))))

# ::id pmid_1563_0473.85 ::date 2015-03-22T08:31:56 ::annotator SDL-AMR-09 ::preferred
# ::snt Activated, pMAPK-positive cells were also prevalent in these areas (<xref ref-type="fig" rid="pbio-0030011-g002">Figure 2</xref>F and <xref ref-type="fig" rid="pbio-0030011-g002">2</xref>G), as were cells expressing keratin 6, a keratin induced in the suprabasal layers of hyperproliferative skin (<xref ref-type="fig" rid="pbio-0030011-g002">Figure 2</xref>H and <xref ref-type="fig" rid="pbio-0030011-g002">2</xref>I).
# ::save-date Sun Dec 13, 2015 ::file pmid_1563_0473_85.txt
(p5 / prevail-02
      :ARG1 (a4 / and
            :op1 (c / cell
                  :part (e2 / enzyme :name (n / name :op1 "MAPK")
                        :ARG1-of (a / activate-01)
                        :ARG3-of (p / phosphorylate-01)))
            :op2 (c2 / cell
                  :ARG3-of (e / express-03
                        :ARG2 (p3 / protein :name (n2 / name :op1 "keratin-6")
                              :ARG2-of (i / induce-01
                                    :location (l / layer
                                          :mod (s3 / suprabasal)
                                          :part-of (s2 / skin
                                                :ARG0-of (p4 / proliferate-01
                                                      :degree (h / hyper)))))))
                  :ARG1-of (d2 / describe-01
                        :ARG0 (a5 / and
                              :op1 (f3 / figure :mod "2H")
                              :op2 (f4 / figure :mod "2I")))))
      :location (a2 / area
            :mod (t / this)
            :mod (a8 / also))
      :ARG1-of (d / describe-01
            :ARG0 (a3 / and
                  :op1 (f / figure :mod "2F")
                  :op2 (f2 / figure :mod "2G"))))

# ::id pmid_1563_0473.86 ::date 2015-03-22T08:51:10 ::annotator SDL-AMR-09 ::preferred
# ::snt Expression of the <i>Snail</i> transgene did not block terminal differentiation in the hyperproliferative epidermis, but it distorted it markedly (<xref ref-type="fig" rid="pbio-0030011-g003">Figure 3</xref>A–<xref ref-type="fig" rid="pbio-0030011-g003">3</xref>H).
# ::save-date Thu Jan 14, 2016 ::file pmid_1563_0473_86.txt
(c / contrast-01
      :ARG1 (b / block-01 :polarity -
            :ARG0 (e / express-03
                  :ARG1 (t2 / transgene
                        :mod (g / gene :name (n / name :op1 "Snail"))))
            :ARG1 (d / differentiate-01
                  :ARG1 (e2 / epidermis
                        :ARG0-of (p2 / proliferate-01
                              :degree (h / hyper)))
                  :mod (t / terminus)))
      :ARG2 (d2 / distort-01
            :ARG0 e
            :ARG1 d
            :manner (m / marked))
      :ARG1-of (d3 / describe-01
            :ARG0 (a / and
                  :op1 (f / figure :mod "3A")
                  :op2 (f2 / figure :mod "3B")
                  :op3 (f3 / figure :mod "3C")
                  :op4 (f4 / figure :mod "3D")
                  :op5 (f5 / figure :mod "3E")
                  :op6 (f6 / figure :mod "3F")
                  :op7 (f7 / figure :mod "3G")
                  :op8 (f8 / figure :mod "3H"))))

# ::id pmid_1563_0473.87 ::date 2015-03-22T09:02:18 ::annotator SDL-AMR-09 ::preferred
# ::snt Typical of most hyperproliferating conditions, Snail expression led to a large expansion in layers with spinous and granular morphology.
# ::save-date Sun Jul 26, 2015 ::file pmid_1563_0473_87.txt
(l / lead-03
      :ARG0 (e / express-03
            :ARG2 (p / protein :name (n / name :op1 "Snail")))
      :ARG2 (e2 / expand-01
            :location (l2 / layer
                  :mod (m / morphology
                        :mod (s / spine)
                        :mod (g / granule)))
            :degree (l3 / large))
      :ARG1-of (t / typical-02)
      :condition (p2 / proliferate-01
            :degree (h / hyper)
            :mod (m2 / most)))

# ::id pmid_1563_0473.88 ::date 2015-03-22T09:12:12 ::annotator SDL-AMR-09 ::preferred
# ::snt Additionally, however, was a marked and variable expansion of keratin 5 (K5), normally restricted to the innermost basal layer (see <xref ref-type="fig" rid="pbio-0030011-g003">Figure 3</xref>).
# ::save-date Fri Jul 24, 2015 ::file pmid_1563_0473_88.txt
(a2 / and
      :op2 (c / contrast-01
            :ARG2 (e / expand-01
                  :ARG1 (p / protein :name (n / name :op1 "keratin-5"))
                  :ARG1-of (r / restrict-01
                        :ARG2 (l / layer
                              :mod (b / basal)
                              :mod (i / inner
                                    :degree (m2 / most)))
                        :ARG1-of (n2 / normal-02))
                  :ARG1-of (m / mark-01)
                  :ARG1-of (v / vary-01)))
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod 3
                  :ARG1-of (s / see-01 :mode imperative
                        :ARG0 (y / you)))))

# ::id pmid_1563_0473.89 ::date 2015-03-23T07:16:25 ::annotator SDL-AMR-09 ::preferred
# ::snt Although the failure of <i>Snail</i>-null mice to develop past gastrulation [<xref ref-type="bibr" rid="pbio-0030011-b21">21</xref>] precluded our ability to study the loss of Snail function in skin development, a good correlation emerged between the expression of Snail protein and the extension of K5, Ki67, and pMAPK suprabasally (compare data in <xref ref-type="fig" rid="pbio-0030011-g002">Figures 2</xref> and <xref ref-type="fig" rid="pbio-0030011-g003">3</xref>).
# ::save-date Sun Dec 20, 2015 ::file pmid_1563_0473_89.txt
(m / multi-sentence
      :snt1 (h / have-concession-91
            :ARG1 (e / emerge-02
                  :ARG0 (c / correlate-01
                        :ARG1 (e2 / express-03
                              :ARG2 (p / protein :name (n / name :op1 "Snail")))
                        :ARG2 (e3 / extend-01
                              :ARG1 (a / and
                                    :op1 (p7 / protein :mod 7 :name (n2 / name :op1 "K5"))
                                    :op2 (p2 / protein :name (n3 / name :op1 "Ki67"))
                                    :op3 (e4 / enzyme :name (n4 / name :op1 "MAPK")
                                          :ARG3-of (p8 / phosphorylate-01)))
                              :manner (s / suprabasal))
                        :ARG1-of (g / good-02)))
            :ARG2 (p4 / preclude-01
                  :ARG0 (f / fail-01
                        :ARG1 (m2 / mouse
                              :mod (p9 / protein :name (n5 / name :op1 "Snail")
                                    :ARG2-of (m3 / mutate-01 :mod "−/−")))
                        :ARG2 (d / develop-02
                              :ARG1 m2
                              :time (a2 / after
                                    :op1 (g2 / gastrulate-00)))
                        :ARG1-of (d5 / describe-01
                              :ARG0 (p5 / publication
                                    :ARG1-of (c2 / cite-01
                                          :ARG2 21))))
                  :ARG1 (p6 / possible-01
                        :ARG1 (s2 / study-01
                              :ARG0 (w / we)
                              :ARG1 (l / lose-02
                                    :ARG1 (f2 / function
                                          :mod p)
                                    :location (d2 / develop-01
                                          :ARG2 (s3 / skin)))))))
      :snt2 (c3 / compare-01
            :ARG1 (d3 / data
                  :ARG1-of (d4 / describe-01
                        :ARG0 (a3 / and
                              :op1 (f3 / figure :mod 2)
                              :op2 (f4 / figure :mod 3))))))

# ::id pmid_1563_0473.90 ::date 2015-03-23T07:54:23 ::annotator SDL-AMR-09 ::preferred
# ::snt The changes in hyperproliferation and differentiation were not initially accompanied by gross signs of epithelial invaginations.
# ::save-date Wed Dec 30, 2015 ::file pmid_1563_0473_90.txt
(a / accompany-01 :polarity -
      :ARG0 (c / change-01
            :ARG1 (a2 / and
                  :op1 (p / proliferate-01
                        :degree (h / hyper))
                  :op2 (d / differentiate-01)))
      :ARG1 (s / signal-07
            :ARG1 (e / epithelium
                  :ARG1-of (i2 / invaginate-01))
            :ARG1-of (g / gross-04))
      :time (i / initial))

# ::id pmid_1563_0473.91 ::date 2015-03-23T08:17:02 ::annotator SDL-AMR-09 ::preferred
# ::snt With age, however, epidermal folds and undulations developed in areas where Snail was expressed, and proliferative markers persisted in these regions (<xref ref-type="fig" rid="pbio-0030011-g003">Figure 3</xref>I and <xref ref-type="fig" rid="pbio-0030011-g003">3</xref>J; anti-cyclin D staining).
# ::save-date Mon Dec 21, 2015 ::file pmid_1563_0473_91.txt
(h / have-concession-91
      :ARG1 (a2 / and
            :op1 (c / cause-01
                  :ARG0 (a / age-01)
                  :ARG1 (a5 / and
                        :op1 (d / develop-02
                              :ARG1 (a3 / and
                                    :op1 (f / fold-03
                                          :ARG1 (e / epidermis))
                                    :op2 (u / undulate-01
                                          :ARG1 e))
                              :location (a4 / area
                                    :location-of (e2 / express-03
                                          :ARG2 (p / protein :name (n / name :op1 "Snail")))))
                        :op2 (p2 / persist-01
                              :ARG0 (m / marker
                                    :ARG0-of (p3 / proliferate-01))
                              :location a4))))
      :ARG1-of (d2 / describe-01
            :ARG0 (a6 / and
                  :op1 (f2 / figure :mod "3I")
                  :op2 (f3 / figure :mod "3J"))
            :ARG2 (s / stain-01
                  :ARG2 (m2 / molecular-physical-entity
                        :ARG0-of (c3 / counter-01
                              :ARG1 (p4 / protein :name (n4 / name :op1 "cyclin" :op2 "D")))))))

# ::id pmid_1563_0473.92 ::date 2015-04-13T13:46:04 ::annotator SDL-AMR-09 ::preferred
# ::snt The undulations were accompanied by partial dissolution of the underlying basement membrane (<xref ref-type="fig" rid="pbio-0030011-g003">Figure 3</xref>K and <xref ref-type="fig" rid="pbio-0030011-g003">3</xref>L).
# ::save-date Wed Dec 30, 2015 ::file pmid_1563_0473_92.txt
(a / accompany-01
      :ARG0 (d / dissolute-00
            :ARG1 (m / membrane
                  :mod (b / basement)
                  :ARG1-of (u / underlie-01))
            :degree (p / part))
      :ARG1 (u2 / undulate-01)
      :ARG1-of (d2 / describe-01
            :ARG0 (a2 / and
                  :op1 (f / figure :mod "3K")
                  :op2 (f2 / figure :mod "3L"))))

# ::id pmid_1563_0473.93 ::date 2015-03-23T10:59:36 ::annotator SDL-AMR-09 ::preferred
# ::snt Aberrant staining was also observed with antibodies against components of the hemidesmosomes, which provide strong adhesion of basal epidermal cells to the underlying basal lamina (<xref ref-type="fig" rid="pbio-0030011-g003">Figure 3</xref>M and <xref ref-type="fig" rid="pbio-0030011-g003">3</xref>N).
# ::save-date Mon Jul 13, 2015 ::file pmid_1563_0473_93.txt
(o / observe-01
      :ARG1 (s / stain-01
            :ARG2 (a2 / antibody
                  :ARG0-of (c / counter-01
                        :ARG1 (c2 / component
                              :part-of (h / hemidesmosome
                                    :ARG0-of (p / provide-01
                                          :ARG1 (a4 / adhere-01
                                                :ARG1 (c3 / cell
                                                      :mod (e / epidermis
                                                            :mod (b / basal)))
                                                :ARG2 (l2 / lamina
                                                      :mod (b2 / basal)
                                                      :ARG1-of (u / underlie-01))
                                                :ARG1-of (s2 / strong-02)))))))
            :manner (a / aberrant))
      :mod (a3 / also)
      :ARG1-of (d / describe-01
            :ARG0 (a5 / and
                  :op1 (f / figure :mod "3M")
                  :op2 (f2 / figure :mod "3N"))))

# ::id pmid_1563_0473.94 ::date 2015-03-23T11:10:16 ::annotator SDL-AMR-09 ::preferred
# ::snt Interestingly, similar types of alterations occur in the basement membrane in the hair bud of embryonic and newborn mice when Snail is normally expressed.
# ::save-date Mon Dec 21, 2015 ::file pmid_1563_0473_94.txt
(a / alter-01
      :location (m / membrane
            :mod (b / basement)
            :part-of (b2 / bud
                  :mod (h / hair)
                  :poss (a2 / and
                        :op1 (e / embryo
                              :mod (m2 / mouse))
                        :op2 (m3 / mouse
                              :ARG1-of (b3 / bear-02
                                    :time (n / new-01))))))
      :time (e2 / express-03
            :ARG2 (p / protein :name (n2 / name :op1 "Snail"))
            :ARG1-of (n3 / normal-02))
      :ARG2-of (t / type-03
            :ARG1-of (r / resemble-01))
      :ARG2-of (i2 / interest-01))

# ::id pmid_1563_0473.95 ::date 2015-03-23T11:16:49 ::annotator SDL-AMR-09 ::preferred
# ::snt The fact that the basement membrane separating the epidermis from the dermis is altered only in the adult Tg animals suggests the involvement of intermediary factors not as readily available in the epidermis as they are in the follicle.
# ::save-date Sat Jul 25, 2015 ::file pmid_1563_0473_95.txt
(s / suggest-01
      :ARG0 (a / alter-01
            :ARG1 (m / membrane
                  :mod (b / basement)
                  :ARG0-of (s2 / separate-01
                        :ARG1 (e / epidermis)
                        :ARG2 (d / dermis)))
            :location (a2 / animal
                  :mod (a3 / adult)
                  :mod (t / transgenic))
            :mod (o / only))
      :ARG1 (i / involve-01
            :ARG1 (f2 / factor
                  :mod (i2 / intermediary)
                  :ARG2-of (a4 / available-02 :polarity -
                        :manner (r / ready)
                        :location (e2 / epidermis)
                        :compared-to (f3 / follicle)))))

# ::id pmid_1563_0473.96 ::date 2015-03-23T13:15:15 ::annotator SDL-AMR-09 ::preferred
# ::snt Possible Links between Epidermal Hyperproliferation and Down-regulation of AJ Proteins in <i>Snail</i> Tg Mice
# ::save-date Thu Jan 14, 2016 ::file pmid_1563_0473_96.txt
(p / possible-01
      :ARG1 (l / link-01
            :ARG1 (p4 / proliferate-01
                  :ARG0 (e / epidermis)
                  :degree (h / hyper))
            :ARG2 (d / downregulate-01
                  :ARG1 (p3 / protein :name (n / name :op1 "AJ")))
            :location (m / mouse
                  :mod (g / gene :name (n3 / name :op1 "Snail"))
                  :mod (t / transgenic))))

# ::id pmid_1563_0473.97 ::date 2015-03-24T02:26:54 ::annotator SDL-AMR-09 ::preferred
# ::snt Given that the <i>E-cadherin</i> promoter is a direct target for Snail-mediated repression in vitro [<xref ref-type="bibr" rid="pbio-0030011-b04">4</xref>,<xref ref-type="bibr" rid="pbio-0030011-b12">12</xref>,<xref ref-type="bibr" rid="pbio-0030011-b13">13</xref>], and that E-cadherin was down-regulated in Snail-expressing hair buds, we examined the status of E-cadherin and other AJ proteins within regions of hyperproliferative epidermis where Tg Snail was present (<xref ref-type="fig" rid="pbio-0030011-g004">Figure 4</xref>A).
# ::save-date Fri Jan 1, 2016 ::file pmid_1563_0473_97.txt
(c2 / cause-01
      :ARG0 (a / and
            :op1 (t / target-01
                  :ARG0 (r / repress-01
                        :ARG1-of (m / mediate-01
                              :ARG0 (p2 / protein :name (n2 / name :op1 "Snail")))
                        :manner (i / in-vitro))
                  :ARG1 (m2 / molecular-physical-entity
                        :ARG0-of (p4 / promote-01
                              :ARG1 (p / protein :name (n / name :op1 "E-cadherin"))))
                  :ARG1-of (d3 / direct-02)
                  :ARG1-of (d4 / describe-01
                        :ARG0 (p5 / publication
                              :ARG1-of (c / cite-01
                                    :ARG2 (a3 / and :op1 4 :op2 12 :op3 13)))))
            :op2 (d / downregulate-01
                  :ARG1 p
                  :location (b / bud
                        :mod (h / hair)
                        :ARG3-of (e / express-03
                              :ARG2 p2))))
      :ARG1 (e2 / examine-01
            :ARG0 (w / we)
            :ARG1 (a2 / and
                  :op1 (s / status
                        :poss p)
                  :op2 (s2 / status
                        :poss (p3 / protein :name (n3 / name :op1 "AJ")
                              :mod (o / other)))
                  :location (r2 / region
                        :poss (e3 / epidermis
                              :ARG0-of (p8 / proliferate-01
                                    :degree (h2 / hyper)))
                        :ARG2-of (p7 / present-02
                              :ARG1 (p6 / protein :name (n4 / name :op1 "Snail")
                                    :mod (t2 / transgenic)))))
            :ARG1-of (d2 / describe-01
                  :ARG0 (f / figure :mod "4A"))))

# ::id pmid_1563_0473.98 ::date 2015-03-24T09:44:53 ::annotator SDL-AMR-09 ::preferred
# ::snt In these regions, immunofluorescence staining of E-cadherin and α-catenin were markedly diminished.
# ::save-date Tue Feb 2, 2016 ::file pmid_1563_0473_98.txt
(d / diminish-01
      :ARG1 (s / stain-01
            :ARG1 (a2 / and
                  :op1 (p / protein :name (n / name :op1 "E-cadherin"))
                  :op2 (p2 / protein :name (n2 / name :op1 "α-catenin")))
            :ARG2 (i / immunofluoresce-01))
      :degree (m / marked)
      :location (r / region
            :mod (t / this)))

# ::id pmid_1563_0473.99 ::date 2015-03-24T09:51:15 ::annotator SDL-AMR-09 ::preferred
# ::snt In contrast, the intensity of antibody staining for two other AJ proteins, β-catenin and Ajuba, was still strong.
# ::save-date Mon Jul 13, 2015 ::file pmid_1563_0473_99.txt
(c / contrast-01
      :ARG2 (i / intensity
            :degree-of (s / stain-01
                  :ARG1 (p / protein :quant 2 :name (n / name :op1 "AJ")
                        :example (a2 / and
                              :op1 (p2 / protein :name (n2 / name :op1 "β-catenin"))
                              :op2 (p3 / protein :name (n3 / name :op1 "Ajuba")))
                        :mod (o / other))
                  :ARG2 (a / antibody))
            :ARG1-of (s2 / strong-02
                  :mod (s3 / still))))

# ::id pmid_1563_0473.100 ::date 2015-03-24T09:59:38 ::annotator SDL-AMR-09 ::preferred
# ::snt Interestingly, however, despite appreciable immunofluorescence, localization of β-catenin and Ajuba appeared to be largely cytoplasmic rather than at cell-cell borders (<xref ref-type="fig" rid="pbio-0030011-g004">Figure 4</xref>A insets).
# ::save-date Tue Feb 2, 2016 ::file pmid_1563_0473_100.txt
(h / have-concession-91
      :ARG1 (a / appear-02
            :ARG1 (c / cytoplasmic
                  :location-of (a2 / and
                              :op1 (p / protein :name (n / name :op1 "β-catenin"))
                              :op2 (p2 / protein :name (n2 / name :op1 "Ajuba")))
                  :ARG1-of (i / instead-of-91
                        :ARG2 (b / border-01
                              :ARG1 (c2 / cell)
                              :ARG2 (c3 / cell))))
            :degree (l2 / large))
      :ARG2 (i2 / immunofluoresce-01
            :ARG1-of (a3 / appreciate-03
                  :ARG1-of (p3 / possible-01)))
      :ARG1-of (d / describe-01
            :ARG2 (f / figure :mod "4A"
                  :mod (i4 / inset)))
      :ARG2-of (i3 / interest-01))

# ::id pmid_1563_0473.101 ::date 2015-03-24T10:05:56 ::annotator SDL-AMR-09 ::preferred
# ::snt Architectural differences in the epidermis made Western blot analyses somewhat difficult to gauge.
# ::save-date Mon Dec 21, 2015 ::file pmid_1563_0473_101.txt
(m / make-02
      :ARG0 (d3 / differ-02
            :ARG3 (a2 / architecture)
            :location (e / epidermis))
      :ARG1 (d / difficult
            :domain (g / gauge-01
                  :ARG1 (a / analyze-01
                        :manner (i / immunoblot-01)))
            :degree (s / somewhat)))

# ::id pmid_1563_0473.102 ::date 2015-03-25T03:59:46 ::annotator SDL-AMR-09 ::preferred
# ::snt However, in regions such as ear skin, where the highest levels of Snail protein were expressed, the effects were accentuated.
# ::save-date Sun Jul 26, 2015 ::file pmid_1563_0473_102.txt
(h / have-concession-91
      :ARG1 (a / accentuate-01
            :ARG1 (a2 / affect-01)
            :location (r / region
                  :example (s / skin
                        :mod (e / ear))
                  :location-of (l / level
                        :ARG1-of (h2 / high-02
                              :degree (m2 / most))
                        :quant-of (p / protein :name (n / name :op1 "Snail")
                              :ARG2-of (e2 / express-03))))))

# ::id pmid_1563_0473.103 ::date 2015-03-25T04:05:07 ::annotator SDL-AMR-09 ::preferred
# ::snt In both back skin and ear skin, overall levels of E-cadherin and α-catenin were reduced, under conditions where β-catenin and Ajuba levels remained unchanged relative to controls (<xref ref-type="fig" rid="pbio-0030011-g004">Figure 4</xref>B).
# ::save-date Tue Mar 31, 2015 ::file pmid_1563_0473_103.txt
(r / reduce-01
      :ARG1 (a4 / and
            :op1 (l / level
                  :quant-of (p / protein :name (n / name :op1 "E-cadherin")))
            :op2 (l3 / level
                  :quant-of (p2 / protein :name (n2 / name :op1 "α-catenin")))
            :degree (o / overall))
      :location (a2 / and
            :op1 (s / skin
                  :mod (b / back))
            :op2 (s2 / skin
                  :mod (e / ear)))
      :condition (r2 / remain-01
            :ARG1 (c / change-01 :polarity -
                  :ARG1 (a / and
                        :op1 (l2 / level
                              :quant-of (p3 / protein :name (n3 / name :op1 "β-catenin")))
                        :op2 (l4 / level
                              :quant-of (p4 / protein :name (n4 / name :op1 "Ajuba")))))
            :ARG1-of (r3 / relate-01
                  :ARG2 (c2 / control-01)))
      :ARG1-of (d / describe-01
            :ARG2 (f / figure :mod "4B")))

# ::id pmid_1563_0473.104 ::date 2015-03-25T04:14:43 ::annotator SDL-AMR-09 ::preferred
# ::snt Taken together, these data were consistent with our results obtained from immunofluorescence microscopy.
# ::save-date Tue Feb 2, 2016 ::file pmid_1563_0473_104.txt
(h / have-condition-91
      :ARG1 (d / data
            :ARG1-of (c / consistent-01
                  :ARG2 (t3 / thing
                        :ARG2-of (r / result-01
                              :ARG1-of (o / obtain-01
                                    :ARG0 w
                                    :ARG2 (m / microscopy
                                          :mod (i / immunofluoresce-01))))
                        :poss (w / we)))
            :mod (t4 / this))
      :ARG2 (t / take-01
            :mod (t5 / together)))

# ::id pmid_1563_0473.105 ::date 2015-03-25T04:18:56 ::annotator SDL-AMR-09 ::preferred
# ::snt A priori, the decrease in α-catenin levels could be due to either direct transcriptional repression by Snail or perturbations in AJ formation caused by the decrease in <i>E-cadherin</i> gene expression.
# ::save-date Sun Jan 17, 2016 ::file pmid_1563_0473_105.txt
(p / possible-01
      :ARG1 (d / decrease-01
            :ARG1 (l / level
                  :quant-of (p2 / protein :name (n / name :op1 "α-catenin")))
            :ARG1-of (c / cause-01
                  :ARG0 (o / or
                        :op1 (r / repress-01
                              :ARG0 (p3 / protein :name (n2 / name :op1 "Snail"))
                              :ARG2 (t / transcribe-01
                                    :ARG1-of (d2 / direct-02)))
                        :op2 (p4 / perturb-01
                              :ARG1 (f / form-01
                                    :ARG1 (p5 / protein :name (n3 / name :op1 "AJ")))
                              :ARG1-of (c2 / cause-01
                                    :ARG0 (d3 / decrease-01
                                          :ARG1 (e / express-03
                                                :ARG1 (g2 / gene :name (n4 / name :op1 "E-cadherin")))))))))
      :time (a / a-priori))

# ::id pmid_1563_0473.106 ::date 2015-03-25T04:29:19 ::annotator SDL-AMR-09 ::preferred
# ::snt To distinguish between these possibilities, we tested whether α-catenin levels could be restored by exogenous expression of <i>E-cadherin</i> in Snail-expressing keratinocytes.
# ::save-date Tue Mar 31, 2015 ::file pmid_1563_0473_106.txt
(t / test-01
      :ARG0 (w / we)
      :ARG1 (p / possible-01
            :ARG1 (r / restore-01 :mode interrogative
                  :ARG0 w
                  :ARG1 (l / level
                        :quant-of (p2 / protein :name (n / name :op1 "α-catenin")))
                  :manner (e / express-03
                        :ARG2 (p3 / protein :name (n2 / name :op1 "E-cadherin"))
                        :mod (e2 / exogenous)
                        :location (c / cell :name (n3 / name :op1 "keratinocyte")
                              :ARG3-of (e3 / express-03
                                    :ARG2 (p4 / protein :name (n4 / name :op1 "Snail")))))))
      :purpose (d / distinguish-01
                  :ARG0 w
                  :ARG1 (p5 / possible-01
                        :mod (t2 / this))))

# ::id pmid_1563_0473.107 ::date 2015-03-25T04:37:46 ::annotator SDL-AMR-09 ::preferred
# ::snt As shown in <xref ref-type="fig" rid="pbio-0030011-g004">Figure 4</xref>C, transiently transfected keratinocytes expressing HA-tagged Snail displayed a loss of E-cadherin and α-catenin at cell-cell borders.
# ::save-date Mon Dec 21, 2015 ::file pmid_1563_0473_107.txt
(d / display-01
      :ARG0 (c / cell :name (n / name :op1 "keratinocyte")
            :ARG1-of (t / transfect-01
                  :ARG1-of (t2 / transient-02))
            :ARG3-of (e / express-03
                  :ARG2 (p / protein :name (n2 / name :op1 "Snail")
                        :ARG1-of (t3 / tag-01
                              :ARG2 (p4 / protein :name (n6 / name :op1 "HA"))))))
      :ARG1 (l / lose-02
            :ARG0 c
            :ARG1 (a / and
                  :op1 (p2 / protein :name (n4 / name :op1 "E-cadherin"))
                  :op2 (p3 / protein :name (n5 / name :op1 "α-catenin")))
            :location (b / border-01
                  :ARG1 (c2 / cell)
                  :ARG2 (c3 / cell)))
      :ARG1-of (s / show-01
            :ARG0 (f / figure :mod "4C")))

# ::id pmid_1563_0473.108 ::date 2015-03-25T04:47:07 ::annotator SDL-AMR-09 ::preferred
# ::snt Coexpression of exogenous HA-tagged E-cadherin not only enabled cell-cell border localization of E-cadherin protein, but also rescued the cell-cell border staining of α-catenin (<xref ref-type="fig" rid="pbio-0030011-g004">Figure 4</xref>C).
# ::save-date Tue Feb 2, 2016 ::file pmid_1563_0473_108.txt
(e / enable-01
      :ARG0 (c / coexpress-01
            :ARG2 (p / protein :name (n / name :op1 "E-cadherin")
                  :ARG1-of (t / tag-01
                        :ARG2 (p4 / protein :name (n5 / name :op1 "HA")))
                  :mod (e3 / exogenous)))
      :ARG1 (a / and
            :op1 (b2 / be-located-at-91
                  :ARG1 p
                  :mod (b / border-01
                        :ARG1 (c2 / cell)
                        :ARG2 (c3 / cell)))
            :op2 (r / rescue-01
                  :ARG1 (s / stain-01
                        :ARG1 (p3 / protein :name (n4 / name :op1 "α-catenin"))
                        :mod b)
                  :mod (a2 / also)))
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod "4C")))

# ::id pmid_1563_0473.109 ::date 2015-03-25T07:19:55 ::annotator SDL-AMR-09 ::preferred
# ::snt The ability to restore α-catenin expression and localization under these conditions argues against the notion that Snail transcriptionally represses <i>α-catenin.</i>
# ::save-date Thu Jun 18, 2015 ::file pmid_1563_0473_109.txt
(a3 / argue-01
      :ARG1 (p / possible-01
            :ARG1 (r / restore-01
                  :ARG1 (a / and
                        :op1 (e / express-03
                              :ARG2 p4)
                        :op2 (l / localize-01
                              :ARG1 p4))
                  :condition (t / this)))
      :ARG0-of (c / counter-01
            :ARG1 (n2 / notion
                  :topic (r2 / repress-01
                        :ARG0 (p3 / protein :name (n3 / name :op1 "Snail"))
                        :ARG1 (p4 / protein :name (n4 / name :op1 "α-catenin"))
                        :ARG2 (t2 / transcribe-01)))))

# ::id pmid_1563_0473.110 ::date 2015-03-17T05:47:58 ::annotator SDL-AMR-09 ::preferred
# ::snt Rather, the findings are consistent with a previous report that E-cadherin is required for the translation of <i>α-catenin</i> mRNA [<xref ref-type="bibr" rid="pbio-0030011-b22">22</xref>].
# ::save-date Mon Oct 26, 2015 ::file pmid_1563_0473_110.txt
(c / consistent-01
      :ARG1 (t / thing
            :ARG1-of (f / find-01))
      :ARG2 (r2 / report-01
            :ARG1 (r3 / require-01
                  :ARG0 (t2 / translate-02
                        :ARG1 (n4 / nucleic-acid :name (n2 / name :op1 "mRNA")
                              :ARG0-of (e / encode-01
                                    :ARG1 (p3 / protein :name (n3 / name :op1 "α-catenin")))))
                  :ARG1 (p2 / protein :name (n / name :op1 "E-cadherin")))
            :time (p / previous))
      :mod (r / rather)
      :ARG1-of (d / describe-01
            :ARG0 (p4 / publication
                  :ARG1-of (c2 / cite-01
                        :ARG2 22))))

# ::id pmid_1563_0473.111 ::date 2015-03-18T08:31:32 ::annotator SDL-AMR-09 ::preferred
# ::snt Despite the reductions in AJ markers, Tg skin still displayed sealed membranes and intercellular junctions that were largely intact, as judged by ultrastructural analyses (unpublished data).
# ::save-date Mon Mar 30, 2015 ::file pmid_1563_0473_111.txt
(d / display-01
      :ARG0 (s / skin
            :mod (t / transgenic))
      :ARG1 (a / and
            :op1 (m / membrane
                  :ARG1-of (s3 / seal-01))
            :op2 (j / junction
                  :mod (i2 / intercellular))
            :mod (i / intact
                  :degree (l / large)
                  :ARG1-of (j2 / judge-01
                        :ARG3 (a2 / analyze-01
                              :mod (u / ultrastructural)))))
      :mod (s2 / still)
      :concession (r / reduce-01
            :ARG1 (m2 / marker
                  :mod (p2 / protein :name (n2 / name :op1 "AJ"))))
      :ARG1-of (d2 / describe-01
            :ARG0 (d3 / data
                  :ARG1-of (p / publish-01 :polarity -))))

# ::id pmid_1563_0473.112 ::date 2015-03-19T01:30:29 ::annotator SDL-AMR-09 ::preferred
# ::snt In this respect, the skin epithelium resembled that of the hair bud, where the down-regulation in junction proteins is permissive for cell-cell remodeling without abrogating intercellular adhesion.
# ::save-date Wed Mar 9, 2016 ::file pmid_1563_0473_112.txt
(r / resemble-01
      :ARG1 (e / epithelium
            :part-of (s / skin))
      :ARG2 (e2 / epithelium
            :poss (b / bud
                  :mod (h / hair))
            :location-of (p / permissive-02
                  :ARG0 (d / downregulate-01
                        :location (p2 / protein
                              :mod (j / junction)))
                  :ARG1 (r3 / remodel-01
                        :ARG0 d
                        :ARG1 (a / and
                              :op1 (c / cell)
                              :op2 (c2 / cell)))
                  :ARG0-of (a2 / abrogate-01 :polarity -
                        :ARG1 (a3 / adhere-01
                              :mod (i / intercellular)))))
      :mod (i2 / in-respect
            :mod (t / this)))

# ::id pmid_1563_0473.113 ::date 2015-03-18T12:02:19 ::annotator SDL-AMR-09 ::preferred
# ::snt The similarities between <i>Snail</i> Tg epidermis and hair buds extended to the hyperproliferative state, leading us to wonder whether the down-regulation of AJ proteins might contribute to this condition.
# ::save-date Thu Jan 14, 2016 ::file pmid_1563_0473_113.txt
(e3 / extend-01
      :ARG0 (t2 / thing
            :ARG1-of (r2 / resemble-01
                  :ARG2 (a / and
                        :op1 (e2 / epidermis
                              :mod (g / gene :name (n2 / name :op1 "Snail")
                                    :mod (t3 / transgenic)))
                        :op2 (b / bud
                              :mod (h / hair)))))
      :ARG4 (s / state
            :mod (p2 / proliferate-01
                  :degree (h2 / hyper)))
      :ARG0-of (l / lead-03
            :ARG1 (w / we)
            :ARG2 (w2 / wonder-01
                  :ARG0 w
                  :ARG1 (p / possible-01 :mode interrogative
                        :ARG1 (c2 / contribute-01
                              :ARG0 (d / downregulate-01
                                    :ARG1 (p3 / protein :name (n / name :op1 "AJ")))
                              :ARG2 (c3 / condition
                                    :mod (t / this)))))))

# ::id pmid_1563_0473.114 ::date 2015-03-18T12:40:19 ::annotator SDL-AMR-09 ::preferred
# ::snt Given the increase in pMAPK staining in <i>Snail</i> Tg epidermis (see <xref ref-type="fig" rid="pbio-0030011-g002">Figure 2</xref>G), we used pMAPK levels as our assay to test whether the loss of E-cadherin contributed to the Snail-mediated increase in proliferation.
# ::save-date Thu Jan 14, 2016 ::file pmid_1563_0473_114.txt
(c / cause-01
      :ARG0 (i / increase-01
            :ARG1 (s / stain-01
                  :ARG1 (e2 / enzyme :name (n2 / name :op1 "MAPK")
                        :location (e / epidermis
                              :mod (g / gene :name (n / name :op1 "Snail")
                                    :mod (t2 / transgenic)))
                        :ARG3-of (p2 / phosphorylate-01)))
            :ARG1-of (s2 / see-01
                  :ARG2 (f / figure :mod "2G")))
      :ARG1 (u / use-01
            :ARG0 (w / we)
            :ARG1 (l / level
                  :quant-of e2)
            :ARG2 (a / assay-01
                  :ARG0 w
                  :purpose (t / test-01
                        :ARG0 w
                        :ARG1 l
                        :ARG2 (c2 / contribute-01 :mode interrogative
                              :ARG0 (l2 / lose-02
                                    :ARG1 (p4 / protein :name (n3 / name :op1 "E-cadherin")))
                              :ARG2 (i2 / increase-01
                                    :ARG1 (p5 / proliferate-01)
                                    :ARG1-of (m / mediate-01
                                          :ARG0 g)))))))

# ::id pmid_1563_0473.115 ::date 2015-03-18T09:02:36 ::annotator SDL-AMR-09 ::preferred
# ::snt Consistent with our in vivo observations, transfected keratinocytes expressing Snail exhibited a substantial increase in pMAPK levels relative to control cells (<xref ref-type="fig" rid="pbio-0030011-g004">Figure 4</xref>D).
# ::save-date Fri Jan 1, 2016 ::file pmid_1563_0473_115.txt
(e / exhibit-01
      :ARG0 (k / keratinocyte
            :ARG1-of (t / transfect-01)
            :ARG3-of (e2 / express-03
                  :ARG2 (p / protein :name (n / name :op1 "Snail"))))
      :ARG1 (i / increase-01
            :ARG1 (l / level
                  :quant-of (e3 / enzyme :name (n2 / name :op1 "MAPK")
                        :ARG3-of (p2 / phosphorylate-01))
                  :ARG1-of (r / relative-05
                        :ARG3 (c / cell
                              :ARG0-of (c2 / control-01))))
            :mod (s / substantial))
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod "4D"))
      :ARG1-of (c3 / consistent-01
            :ARG2 (t2 / thing
                  :ARG1-of (o / observe-01
                        :ARG0 (w / we)
                        :manner (i2 / in-vivo)))))

# ::id pmid_1563_0473.116 ::date 2015-03-17T08:16:55 ::annotator SDL-AMR-09 ::preferred
# ::snt Coexpression of E-cadherin with Snail appeared to abrogate this effect.
# ::save-date Fri Jan 1, 2016 ::file pmid_1563_0473_116.txt
(a / appear-02
      :ARG1 (a2 / abrogate-01
            :ARG0 (e2 / express-03
                  :ARG2 (a3 / and
                        :op1 (p / protein :name (n / name :op1 "E-cadherin"))
                        :op2 (p2 / protein :name (n2 / name :op1 "Snail"))))
            :ARG1 (a4 / affect-01
                  :mod (t / this))))

# ::id pmid_1563_0473.117 ::date 2015-03-17T09:08:20 ::annotator SDL-AMR-09 ::preferred
# ::snt Together, these findings raised the possibility that an AJ-associated protein that is normally sequestered at the plasma membrane may participate in a proliferation signaling pathway when AJs are deconstructed.
# ::save-date Fri Jul 24, 2015 ::file pmid_1563_0473_117.txt
(r / raise-01
      :ARG0 (t / thing
            :ARG1-of (f / find-01)
            :mod (t2 / this))
      :ARG1 (p6 / possible-01
            :ARG1 (p2 / possible-01
                  :ARG1 (p3 / participate-01
                        :ARG0 (p7 / protein
                              :ARG1-of (a / associate-01
                                    :ARG2 (p8 / protein :name (n2 / name :op1 "AJ")))
                              :ARG1-of (s2 / sequester-01
                                    :ARG1-of (n / normal-02)
                                    :location (m / membrane
                                          :part-of (p9 / plasma))))
                        :ARG1 (p4 / proliferate-01
                              :ARG0 (p5 / pathway
                                    :ARG0-of (s / signal-07)))
                        :time (c / construct-01 :polarity -
                              :ARG1 p8))))
      :mod (t3 / together))

# ::id pmid_1563_0473.118 ::date 2015-03-18T13:48:01 ::annotator SDL-AMR-09 ::preferred
# ::snt Numerous studies have correlated a down-regulation of E-cadherin with a translocation of β-catenin to the nucleus and a transactivation of genes that are regulated by the LEF-1/T cell factor (TCF) family of DNA binding proteins [<xref ref-type="bibr" rid="pbio-0030011-b23">23</xref>,<xref ref-type="bibr" rid="pbio-0030011-b24">24</xref>,<xref ref-type="bibr" rid="pbio-0030011-b25">25</xref>].
# ::save-date Fri Jan 1, 2016 ::file pmid_1563_0473_118.txt
(c / correlate-01
      :ARG0 (s / study-01
            :quant (n / numerous))
      :ARG1 (d3 / downregulate-01
            :ARG1 (p / protein :name (n2 / name :op1 "E-cadherin")))
      :ARG2 (a / and
            :op1 (t / translocate-01
                  :ARG1 (p2 / protein :name (n3 / name :op1 "β-catenin"))
                  :ARG2 (n4 / nucleus))
            :op2 (t2 / transactivate-01
                  :ARG1 (g / gene
                        :ARG1-of (r2 / regulate-01
                              :ARG0 (p5 / protein-family :name (n9 / name :op1 "LEF-1/T" :op2 "cell" :op3 "factor")
                                    :poss (p3 / protein
                                          :ARG1-of (b / bind-01
                                                :ARG2 (n7 / nucleic-acid :wiki "DNA" :name (n8 / name :op1 "DNA")))))))))
      :ARG1-of (d2 / describe-01
            :ARG0 (p4 / publication
                  :ARG1-of (c3 / cite-01
                        :ARG2 (a3 / and :op1 23 :op2 24 :op3 25)))))

# ::id pmid_1563_0473.119 ::date 2015-03-18T11:29:58 ::annotator SDL-AMR-09 ::preferred
# ::snt The presence of nuclear cyclin D in hyperproliferative <i>Snail</i> Tg epidermis was particularly intriguing since prior studies have reported <i>cyclin D</i> gene as a direct target of TCF/β-catenin transcription [<xref ref-type="bibr" rid="pbio-0030011-b26">26</xref>].
# ::save-date Thu Jan 14, 2016 ::file pmid_1563_0473_119.txt
(i / intrigue-01
      :ARG0 (p8 / present-02
            :ARG1 (p9 / protein :name (n7 / name :op1 "cyclin" :op2 "D")
                  :mod (n2 / nucleus))
            :ARG2 (e / epidermis
                  :mod (g2 / gene :name (n3 / name :op1 "Snail")
                        :mod (t3 / transgenic))
                  :ARG0-of (p / proliferate-01
                        :degree (h / hyper))))
      :manner (p3 / particular)
      :ARG1-of (c5 / cause-01
            :ARG0 (r / report-01
                  :ARG0 (s / study-01
                        :time (p4 / prior))
                  :ARG1 (t / target-01
                        :ARG0 (t2 / transcribe-01
                              :ARG1 (s2 / slash
                                    :op1 (p7 / protein :name (n6 / name :op1 "TCF"))
                                    :op2 (p5 / protein :name (n5 / name :op1 "β-catenin"))))
                        :ARG1 (g / gene :name (n4 / name :op1 "cyclin" :op2 "D"))
                        :ARG1-of (d / direct-02))))
      :ARG1-of (d2 / describe-01
            :ARG0 (p6 / publication
                  :ARG1-of (c3 / cite-01
                        :ARG2 26))))

# ::id pmid_1563_0473.120 ::date 2015-03-18T12:01:19 ::annotator SDL-AMR-09 ::preferred
# ::snt This said, we did not detect nuclear β-catenin in our Tg epidermis, and mating the Snail Tg mice against the TOPGal reporter mouse [<xref ref-type="bibr" rid="pbio-0030011-b20">20</xref>] gave no signs of ectopic LEF-1/Tcf/β-catenin activity (unpublished data).
# ::save-date Sun Jan 17, 2016 ::file pmid_1563_0473_120.txt
(c2 / cause-01
      :ARG0 (s2 / say-01
            :ARG1 (t2 / this))
      :ARG1 (a3 / and
            :op1 (d / detect-01 :polarity -
                  :ARG0 (w / we)
                  :ARG1 (p2 / protein :name (n / name :op1 "β-catenin")
                        :mod (n7 / nucleus))
                  :location (e / epidermis
                        :mod (t3 / transgenic)
                        :poss w))
            :op2 (g / give-01 :polarity -
                  :ARG0 (m / mate-02
                        :ARG0 w
                        :ARG1 (m2 / mouse
                              :mod (p4 / protein :name (n3 / name :op1 "Snail")
                                    :mod (t / transgenic)))
                        :ARG2 (m5 / mouse :name (n9 / name :op1 "TopGal")
                              :ARG0-of (r / report-01)
                              :ARG1-of (d2 / describe-01
                                    :ARG0 (p / publication
                                          :ARG0-of (c / cite-01
                                                :ARG2 20)))))
                  :ARG1 (s / signal-07
                        :ARG1 (a / activity-06
                              :ARG0 (m4 / macro-molecular-complex
                                    :part (p7 / protein :name (n4 / name :op1 "LEF-1"))
                                    :part (p5 / protein :name (n5 / name :op1 "Tcf"))
                                    :part (p8 / protein :name (n6 / name :op1 "β-catenin"))
                                    :mod (e2 / ectopic)))))
            :ARG1-of (d4 / describe-01
                  :ARG0 (d5 / data
                        :ARG1-of (p6 / publish-01 :polarity -)))))

# ::id pmid_1563_0473.121 ::date 2015-03-17T09:49:36 ::annotator SDL-AMR-09 ::preferred
# ::snt We next turned to the presence of cytoplasmic Ajuba for a possible mechanistic link to the proliferative increase in our <i>Snail</i> Tg epidermis.
# ::save-date Thu Jan 14, 2016 ::file pmid_1563_0473_121.txt
(t / turn-01
      :ARG1 (w / we)
      :direction (p / present-02
            :ARG1 (p4 / protein :name (n / name :op1 "Ajuba")
                  :mod (c / cytoplasm)))
      :purpose (l / link-01
            :ARG1 p4
            :ARG2 (i / increase-01
                  :ARG1 (e / epidermis
                        :mod (g / gene :name (n2 / name :op1 "Snail")
                              :mod (t2 / transgenic)))
                  :ARG0-of (p3 / proliferate-01))
            :ARG1-of (p2 / possible-01)
            :mod (m / mechanistic))
      :time (n3 / next))

# ::id pmid_1563_0473.122 ::date 2015-03-18T05:27:34 ::annotator SDL-AMR-09 ::preferred
# ::snt In addition to its documented ability to bind α-catenin [<xref ref-type="bibr" rid="pbio-0030011-b10">10</xref>], Ajuba can also associate with growth factor receptor-bound protein-2 (Grb-2)/son of sevenless (Sos), the nucleotide exchange factor for Ras, which is upstream from activation of MAPK [<xref ref-type="bibr" rid="pbio-0030011-b09">9</xref>].
# ::save-date Wed Feb 24, 2016 ::file pmid_1563_0473_122.txt
(a / and
      :op1 (c3 / capable-01
            :ARG1 p3
            :ARG2 (b2 / bind-01
                  :ARG1 p3
                  :ARG2 (p8 / protein :name (n / name :op1 "α-catenin")))
            :ARG1-of (d2 / document-01)
            :ARG1-of (d3 / describe-01
                  :ARG0 (p9 / publication
                        :ARG0-of (c4 / cite-01
                              :ARG2 10))))
      :op2 (p2 / possible-01
            :ARG1 (a2 / associate-01
                  :ARG0 (p3 / protein :name (n4 / name :op1 "Ajuba"))
                  :ARG1 (s / slash
                        :op1 (p12 / protein :name (n10 / name :op1 "protein-2")
                              :ARG1-of (b / bind-01
                                    :ARG2 (r2 / receptor
                                          :mod (g / growth-factor)))
                              :ARG1-of (m / mean-01
                                    :ARG2 (p5 / protein :name (n5 / name :op1 "Grb-2"))))
                        :op2 (p4 / protein :name (n9 / name :op1 "son" :op2 "of" :op3 "sevenless")
                              :ARG1-of (m2 / mean-01
                                    :ARG2 (p11 / protein :name (n2 / name :op1 "Sos")))))
                  :ARG2 (f / factor
                        :mod (e / exchange-01
                              :ARG1 (n7 / nucleotide))
                        :purpose (e2 / enzyme :name (n8 / name :op1 "Ras"))
                        :location (r / relative-position
                              :op1 (a4 / activate-01
                                    :ARG1 (p / pathway :name (n3 / name :op1 "MAPK")))
                              :direction (u / upstream)))
                  :mod (a3 / also))
            :ARG1-of (d / describe-01
                  :ARG0 (p7 / publication
                        :ARG0-of (c2 / cite-01
                              :ARG2 9)))))

# ::id pmid_1563_0473.123 ::date 2015-03-18T05:28:28 ::annotator SDL-AMR-09 ::preferred
# ::snt Given the increase in pMAPK staining in Tg skin, we examined the possibility that Ajuba might have changed its binding partner in Snail-expressing epidermis.
# ::save-date Sun Jan 17, 2016 ::file pmid_1563_0473_123.txt
(c2 / cause-01
      :ARG0 (i / increase-01
            :ARG1 (s2 / stain-01
                  :ARG1 (e / enzyme :name (n3 / name :op1 "MAPK")
                        :location (s / skin
                                    :mod (t / transgenic))
                        :ARG3-of (p / phosphorylate-01))))
      :ARG1 (e4 / examine-01
            :ARG0 (w / we)
            :ARG1 (p2 / possible-01
                  :ARG1 (p3 / possible-01
                        :ARG1 (c / change-01
                              :ARG0 (p7 / protein :name (n / name :op1 "Ajuba"))
                              :ARG1 (p4 / partner
                                    :ARG2-of (b / bind-01
                                          :ARG1 p4)
                                    :location (e2 / epidermis
                                                :ARG1-of (e3 / express-03
                                                      :ARG2 (p5 / protein :name (n2 / name :op1 "Snail"))))))))))

# ::id pmid_1563_0473.124 ::date 2015-03-18T06:35:46 ::annotator SDL-AMR-09 ::preferred
# ::snt Interestingly, Ajuba was readily detected in anti-Grb-2 immunoprecipitates of protein lysates from skins of <i>Snail</i> Tg mice but not from the corresponding wild-type (WT) animals (<xref ref-type="fig" rid="pbio-0030011-g004">Figure 4</xref>E).
# ::save-date Thu Jan 14, 2016 ::file pmid_1563_0473_124.txt
(c / contrast-01
      :ARG1 (d / detect-01
            :ARG1 (p5 / protein :name (n / name :op1 "Ajuba"))
            :manner (r / ready)
            :location (m2 / molecular-physical-entity
                  :ARG1-of (i / immunoprecipitate-01
                        :ARG2 (l / lysate
                              :mod (p / protein)
                              :source (s / skin
                                    :part-of (m / mice
                                          :mod (g / gene :name (n4 / name :op1 "Snail")))
                                    :mod (t / transgenic))))
                  :ARG0-of (c3 / counter-01
                        :ARG1 (p2 / protein :name (n3 / name :op1 "Grb2")))))
      :ARG2 (d3 / detect-01 :polarity -
            :ARG1 p5
            :location (m4 / molecular-physical-entity
                  :source (a / animal
                        :mod (w / wild-type
                              :ARG1-of (m3 / mean-01
                                    :ARG2 (n2 / name :op1 "WT")))
                        :ARG1-of (c2 / correspond-02))
                  :ARG1-of i
                  :ARG0-of c3))
      :manner (i2 / interesting)
      :ARG1-of (d2 / describe-01
            :ARG0 (f / figure :mod "4E")))

# ::id pmid_1563_0473.125 ::date 2015-03-18T07:34:56 ::annotator SDL-AMR-09 ::preferred
# ::snt When these experiments were repeated with <i>α-catenin</i>-null epidermis, a similar Grb-2-Ajuba association was detected, and again, this interaction was not detected in the protein extracts from control littermate skin (<xref ref-type="fig" rid="pbio-0030011-g004">Figure 4</xref>E).
# ::save-date Tue Mar 24, 2015 ::file pmid_1563_0473_125.txt
(a / and
      :op1 (d / detect-01
            :ARG1 (a3 / associate-01
                  :ARG1 (m / macro-molecular-complex
                        :part (p2 / protein :name (n3 / name :op1 "Grb-2"))
                        :part (p3 / protein :name (n2 / name :op1 "Ajuba")))
                  :ARG1-of (r2 / resemble-01)))
      :op2 (d2 / detect-01 :polarity -
            :ARG1 (i / interact-01
                  :ARG0 e2
                  :ARG1 p3
                  :mod (t3 / this))
            :location (e3 / extract-01
                  :ARG1 (p4 / protein)
                  :ARG2 (s / skin
                        :mod (l / littermate)
                        :ARG0-of (c / control-01)))
            :mod (a2 / again))
      :time (r / repeat-01
            :ARG1 (t / thing
                  :ARG1-of (e / experiment-01
                        :ARG2 (e2 / epidermis :polarity -
                              :mod (p / protein :name (n / name :op1 "α-catenin"))
                              :mod (n4 / null)))
                  :mod (t2 / this)))
      :ARG1-of (d3 / describe-01
            :ARG0 (f / figure :mod "4E")))

# ::id pmid_1563_0473.126 ::date 2015-03-18T09:02:01 ::annotator SDL-AMR-09 ::preferred
# ::snt Together, these data demonstrate that the reduction in α-catenin levels, either by Snail-mediated down-regulation of <i>E-cadherin</i> or by <i>α-catenin</i> conditional targeting, allows Ajuba to interact with Grb-2/Sos.
# ::save-date Thu Jan 14, 2016 ::file pmid_1563_0473_126.txt
(d / demonstrate-01
      :ARG0 (d2 / data
            :mod (t / this))
      :ARG1 (a / allow-02
            :ARG0 (r / reduce-01
                  :ARG0 (o / or
                        :op1 (d3 / downregulate-01
                              :ARG1 (g2 / gene :name (n6 / name :op1 "E-cadherin")
                                    :ARG1-of (m2 / mediate-01
                                          :ARG0 (p5 / protein :name (n5 / name :op1 "Snail")))))
                        :op2 (t2 / target-01
                              :ARG1 g
                              :mod (c2 / conditional)))
                  :ARG1 (l / level
                        :degree-of (g / gene :name (n4 / name :op1 "α-catenin"))))
            :ARG1 (p / protein :name (n / name :op1 "Ajuba"))
            :ARG2 (i / interact-01
                  :ARG0 p
                  :ARG1 (m / macro-molecular-complex
                        :part (p2 / protein :name (n2 / name :op1 "Grb-2"))
                        :part (p3 / protein :name (n3 / name :op1 "Sos")))))
      :mod (t3 / together))

# ::id pmid_1563_0473.127 ::date 2015-03-19T00:03:50 ::annotator SDL-AMR-09 ::preferred
# ::snt If the competition between Grb-2/Sos and α-catenin for Ajuba is functionally relevant to the hyperproliferative state of a keratinocyte, then overexpression of Ajuba would be expected to bypass the competition and promote activation of the Ras-MAPK pathway in WT keratinocytes.
# ::save-date Wed Dec 30, 2015 ::file pmid_1563_0473_127.txt
(e / expect-01
      :ARG1 (a / and
            :op1 (b / bypass-01
                  :ARG0 (o / overexpress-01
                        :ARG1 p2)
                  :ARG1 c)
            :op2 (p / promote-01
                  :ARG0 o
                  :ARG1 (a2 / activate-01
                        :ARG1 (p8 / pathway :name (n5 / name :op1 "Ras-MAPK"))
                        :location (k2 / keratinocyte
                              :mod (w / wild-type)))))
      :condition (r / relevant-01
            :ARG1 (c / compete-01
                  :ARG0 (m / macro-molecular-complex
                        :part (p4 / protein :name (n2 / name :op1 "Grb-2"))
                        :part (p5 / protein :name (n3 / name :op1 "Sos")))
                  :ARG1 (p3 / protein :name (n4 / name :op1 "α-catenin"))
                  :ARG2 (p2 / protein :name (n / name :op1 "Ajuba")))
            :ARG2 (s / state
                  :mod (p6 / proliferate-01
                        :degree (h / hyper))
                  :mod (k / keratinocyte))
            :manner (f / functional)))

# ::id pmid_1563_0473.128 ::date 2015-03-18T13:51:34 ::annotator SDL-AMR-09 ::preferred
# ::snt Indeed, when serum-starved keratinocytes were transiently transfected with an Ajuba expression vector, the levels of pMAPK were not only elevated but also comparable to those transfected with the <i>K14-HASnail</i> transgene (<xref ref-type="fig" rid="pbio-0030011-g004">Figure 4</xref>F).
# ::save-date Fri Jan 1, 2016 ::file pmid_1563_0473_128.txt
(a / and
      :op1 (e / elevate-01
            :ARG1 (l / level
                  :quant-of (e3 / enzyme :name (n / name :op1 "MAPK")
                        :ARG3-of (p / phosphorylate-01)))
            :mod (o / only))
      :op2 (c / comparable-03
            :ARG1 l
            :ARG2 (l2 / level
                  :location (k2 / keratinocyte
                        :ARG1-of (t4 / transfect-01
                              :ARG2 (t5 / transgene :name (n3 / name :op1 "K14-HASnail"))))
                  :quant-of e3))
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod "4F"))
      :mod (i / indeed)
      :time (t / transfect-01
            :ARG1 (k / keratinocyte
                  :ARG1-of (s / starve-01
                        :ARG2 (s2 / serum)))
            :ARG2 (v / vector
                  :ARG1-of (e2 / express-03
                        :ARG2 (p2 / protein :name (n2 / name :op1 "Ajuba"))))
            :ARG1-of (t2 / transient-02)))

# ::id pmid_1563_0473.129 ::date 2015-03-17T09:09:39 ::annotator SDL-AMR-09 ::preferred
# ::snt This activation was abolished when cells were treated with a small peptide inhibitor that specifically interrupts the Grb-2/Sos interaction (<xref ref-type="fig" rid="pbio-0030011-g004">Figure 4</xref>F; see lanes marked “inh”) [<xref ref-type="bibr" rid="pbio-0030011-b27">27</xref>].
# ::save-date Sun Dec 20, 2015 ::file pmid_1563_0473_129.txt
(a / abolish-01
      :ARG1 (a2 / activate-01
            :mod (t3 / this))
      :ARG1-of (d / describe-01
            :ARG0 (a3 / and
                  :op1 (f / figure :mod "4F")
                  :op2 (s3 / see-01
                        :ARG1 (l / lane
                              :ARG1-of (m / mark-01
                                    :ARG0 (s4 / string-entity :value "inh"))))))
      :ARG1-of (d2 / describe-01
            :ARG0 (p4 / publication
                  :ARG0-of (c3 / cite-01
                        :ARG2 27)))
      :time (t2 / treat-04
            :ARG1 (c2 / cell)
            :ARG2 (m2 / molecular-physical-entity
                  :ARG0-of (i / inhibit-01
                        :ARG1 (p / peptide))
                  :mod (s / small)
                  :ARG0-of (i2 / interrupt-01
                        :ARG1 (i3 / interact-01
                              :ARG0 (p2 / protein :name (n / name :op1 "Grb-2"))
                              :ARG1 (p3 / protein :name (n2 / name :op1 "Sos")))
                        :ARG1-of (s2 / specific-02)))))

# ::id pmid_1563_0473.130 ::date 2015-03-18T07:45:18 ::annotator SDL-AMR-09 ::preferred
# ::snt Ajuba's pre-LIM domain is the segment that associates with Grb-2's Src-homology 3 domain [<xref ref-type="bibr" rid="pbio-0030011-b09">9</xref>].
# ::save-date Thu Apr 30, 2015 ::file pmid_1563_0473_130.txt
(s / segment
      :ARG1-of (a / associate-01
            :ARG2 (p5 / protein-segment :name (n / name :op1 "Src-homology" :op2 "3" :op3 "domain")
                  :part-of (p2 / protein :name (n2 / name :op1 "Grb-2"))))
      :ARG1-of (d2 / describe-01
            :ARG0 (p / publication
                  :ARG1-of (c / cite-01
                        :ARG2 9)))
      :domain (d3 / domain
            :part-of (p3 / protein :name (n3 / name :op1 "Ajuba"))
            :mod (p4 / protein-segment :name (n4 / name :op1 "pre-LIM"))))

# ::id pmid_1563_0473.131 ::date 2015-03-19T06:20:35 ::annotator SDL-AMR-09 ::preferred
# ::snt When this domain was overexpressed in serum-starved keratinocytes, a comparable elevation in pMAPK was observed (<xref ref-type="fig" rid="pbio-0030011-g004">Figure 4</xref>F).
# ::save-date Sun Dec 13, 2015 ::file pmid_1563_0473_131.txt
(o / observe-01
      :ARG1 (e / elevate-01
            :ARG1 (e2 / enzyme :name (n / name :op1 "MAPK")
                  :ARG3-of (p2 / phosphorylate-01))
            :ARG1-of (c / comparable-03))
      :time (o2 / overexpress-01
            :ARG1 (d / domain
                  :mod (t / this))
            :location (c2 / cell :name (n2 / name :op1 "keratinocyte")
                  :ARG1-of (s / starve-01
                        :ARG2 (s2 / serum))))
      :ARG1-of (d2 / describe-01
            :ARG0 (f / figure :mod "4F")))

# ::id pmid_1563_0473.132 ::date 2015-03-19T08:33:20 ::annotator SDL-AMR-09 ::preferred
# ::snt As expected, the small peptide inhibitor that interrupts the Grb-2/Sos association blocked the effects.
# ::save-date Tue Mar 24, 2015 ::file pmid_1563_0473_132.txt
(b / block-01
      :ARG0 (m / molecular-physical-entity
            :ARG0-of (i / inhibit-01
                  :ARG1 (p / peptide
                        :mod (s / small)))
            :ARG0-of (i2 / interrupt-01
                  :ARG1 (a / associate-01
                        :ARG1 (p2 / protein :name (n2 / name :op1 "Grb-2"))
                        :ARG2 (p3 / protein :name (n3 / name :op1 "Sos")))))
      :ARG1 (e / effect)
      :ARG1-of (e2 / expect-01))

# ::id pmid_1563_0473.133 ::date 2015-03-19T09:08:38 ::annotator SDL-AMR-09 ::preferred
# ::snt These data suggested that by elevating cytosolic Ajuba levels, Ajuba's pre-LIM domain may associate with Grb-2/Sos in a manner that stimulates its nucleotide exchange activity and leads to activation of the Ras-MAPK pathway.
# ::save-date Fri Jan 1, 2016 ::file pmid_1563_0473_133.txt
(s / suggest-01
      :ARG0 (d / data
            :mod (t / this))
      :ARG1 (p / possible-01
            :ARG1 (a / associate-01
                  :ARG1 (p2 / protein-segment :name (n / name :op1 "pre-LIM")
                        :part-of (p3 / protein :name (n2 / name :op1 "Ajuba")
                              :location (c / cytosol)))
                  :ARG2 (m / macro-molecular-complex
                        :part (p4 / protein :name (n3 / name :op1 "Grb-2"))
                        :part (p5 / protein :name (n4 / name :op1 "Sos")))
                  :manner (a2 / and
                        :op1 (s2 / stimulate-01
                              :ARG0 a
                              :ARG1 (a3 / activity-06
                                    :ARG0 p2
                                    :ARG1 (e / exchange-01
                                          :ARG1 (n5 / nucleotide))))
                        :op2 (l / lead-03
                              :ARG0 a
                              :ARG2 (a4 / activate-01
                                    :ARG1 (p6 / pathway :name (n6 / name :op1 "Ras-MAPK")))))
                  :manner-of (e2 / elevate-01
                        :ARG1 (l2 / level
                              :degree-of p3)))))

# ::id pmid_1563_0473.134 ::date 2015-03-19T10:43:40 ::annotator SDL-AMR-09 ::preferred
# ::snt Although this pathway provides one mechanism by which Snail expression and proliferation may be coupled in skin epithelium, proliferative circuitries involving AJs are known to be complex and often interwoven.
# ::save-date Thu Mar 26, 2015 ::file pmid_1563_0473_134.txt
(k / know-01
      :ARG1 (a / and
            :op1 (c / complex
                  :domain (c2 / circuitry
                        :ARG0-of (p / proliferate-01)
                        :ARG2-of (i / involve-01
                              :ARG1 (p2 / protein :name (n / name :op1 "AJ")))))
            :op2 (i2 / interweave-01
                  :ARG1 c2
                  :frequency (o / often)))
      :concession (p3 / provide-01
            :ARG0 (p4 / pathway
                  :mod (t / this))
            :ARG1 (p5 / possible-01
                  :ARG1 (c3 / couple-01
                        :ARG1 (e / express-03
                              :ARG2 (p6 / protein :name (n2 / name :op1 "Snail")))
                        :ARG2 (p7 / proliferate-01
                              :ARG0 p6)
                        :location (e2 / epithelium
                              :part-of (s / skin))
                        :instrument (m / mechanism :quant 1)))))

# ::id pmid_1563_0473.135 ::date 2015-03-19T12:06:51 ::annotator SDL-AMR-09 ::preferred
# ::snt Future studies will be needed to systematically dissect these putative intricacies at a molecular level.
# ::save-date Tue Mar 24, 2015 ::file pmid_1563_0473_135.txt
(n / need-01
      :ARG1 (s / study-01
            :time (f / future))
      :purpose (d / dissect-01
            :ARG1 (i / intricacy
                  :mod (t / this)
                  :ARG2-of (t2 / think-01))
            :manner (s2 / systematic)
            :location (l / level
                  :mod (m / molecule))))

# ::id pmid_1563_0473.136 ::date 2015-03-19T12:28:00 ::annotator SDL-AMR-09 ::preferred
# ::snt Probing the Regulation of <i>Snail</i> Gene Expression Reveals an Essential Link to TGF-β2 Signaling in the Developing Hair Bud
# ::save-date Fri Jun 19, 2015 ::file pmid_1563_0473_136.txt
(r / reveal-01
      :ARG0 (p / probe-01
            :ARG1 (r2 / regulate-01
                  :ARG1 (e / express-03
                        :ARG1 (g / gene :name (n / name :op1 "Snail")))))
      :ARG1 (l / link-01
            :ARG2 (s / signal-07
                  :ARG0 (p2 / protein :name (n2 / name :op1 "TGF-β2"))
                  :location (b / bud
                        :ARG1-of (d / develop-02)
                        :mod (h / hair)))
            :mod (e2 / essential)))

# ::id pmid_1563_0473.137 ::date 2015-03-19T13:56:00 ::annotator SDL-AMR-09 ::preferred
# ::snt The temporal spike of <i>Snail</i> mRNA expression in the hair bud prompted us to consider what factor(s) may be regulating the <i>Snail</i> gene.
# ::save-date Thu Jan 14, 2016 ::file pmid_1563_0473_137.txt
(p / prompt-01
      :ARG0 (s / spike-04
            :ARG1 (e / express-03
                  :ARG1 (n3 / nucleic-acid :name (n / name :op1 "mRNA")
                        :ARG0-of (e2 / encode-01
                              :ARG1 (g / gene :name (n2 / name :op1 "Snail"))))
                  :location (b / bud
                        :mod (h / hair)))
            :time (t / temporal))
      :ARG1 (c / consider-02
            :ARG0 (w / we)
            :ARG1 (f / factor :mode interrogative
                  :ARG0-of (r2 / regulate-01
                        :ARG1 g
                        :ARG1-of (p2 / possible-01)))))

# ::id pmid_1563_0473.138 ::date 2015-03-20T03:55:03 ::annotator SDL-AMR-09 ::preferred
# ::snt A variety of extracellular signals have an impact on the cell type-specific expression of different Snail family members, and many of them, including Wnts, BMPs, FGFs, and TGF-βs, also affect hair bud development [<xref ref-type="bibr" rid="pbio-0030011-b02">2</xref>,<xref ref-type="bibr" rid="pbio-0030011-b16">16</xref>,<xref ref-type="bibr" rid="pbio-0030011-b28">28</xref>].
# ::save-date Fri Jan 1, 2016 ::file pmid_1563_0473_138.txt
(a / and
      :op1 (i / impact-01
            :ARG0 (s / signal-07
                  :location (e / extracellular)
                  :mod (v / variety))
            :ARG1 (e2 / express-03
                  :ARG2 (m3 / member
                        :ARG1-of (d / differ-02)
                        :ARG1-of (i2 / include-91
                              :ARG2 (p / protein-family :name (n / name :op1 "Snail"))))
                  :ARG1-of (s2 / specific-02
                        :ARG2 (t / type-03
                              :ARG1 (c / cell)))))
      :op2 (a2 / affect-01
            :ARG0 (s3 / signal-07
                  :quant (m2 / many)
                  :ARG1-of (i3 / include-91
                        :ARG2 s)
                  :ARG2-of (i4 / include-91
                        :ARG1 (a3 / and
                              :op1 (p2 / protein :name (n2 / name :op1 "Wnt"))
                              :op2 (p3 / protein :name (n3 / name :op1 "BMP"))
                              :op3 (p4 / protein :name (n4 / name :op1 "FGF"))
                              :op4 (p5 / protein :name (n5 / name :op1 "TGF-β")))))
            :ARG1 (d2 / develop-02
                  :ARG1 (b / bud
                        :mod (h / hair)))
            :mod (a4 / also))
      :ARG1-of (d3 / describe-01
            :ARG0 (p6 / publication
                  :ARG1-of (c2 / cite-01
                        :ARG2 (a5 / and :op1 2 :op2 16 :op3 28)))))

# ::id pmid_1563_0473.139 ::date 2015-03-20T06:25:42 ::annotator SDL-AMR-09 ::preferred
# ::snt Since Snail is not expressed in cultured skin keratinocytes that secrete active BMPs and FGFs (see <xref ref-type="fig" rid="pbio-0030011-g001">Figure 1</xref>B), we focused our attention on Wnt and TGF-β signaling as more likely candidates for Snail induction in this cell type.
# ::save-date Mon Dec 21, 2015 ::file pmid_1563_0473_139.txt
(c / cause-01
      :ARG0 (e / express-03 :polarity -
            :ARG2 (p / protein :name (n / name :op1 "Snail"))
            :ARG3 (k / keratinocyte
                  :mod (s / skin)
                  :ARG1-of (c2 / culture-01)
                  :ARG0-of (s2 / secrete-01
                        :ARG1 (a / and
                              :op1 (p2 / protein :name (n2 / name :op1 "BMP"))
                              :op2 (p3 / protein :name (n3 / name :op1 "FGF"))
                              :ARG0-of (a2 / activity-06))))
            :ARG1-of (s3 / see-01
                  :ARG2 (f / figure :mod "1B")))
      :ARG1 (f2 / focus-01
            :ARG0 (w / we)
            :ARG1 (a3 / attend-02
                  :ARG0 w
                  :ARG1 s4)
            :ARG2 (s4 / signal-07
                  :ARG0 (a4 / and
                        :op1 (p4 / protein :name (n4 / name :op1 "Wnt"))
                        :op2 (p5 / protein :name (n5 / name :op1 "TGF-β")))
                  :ARG0-of (a5 / act-01
                        :ARG1 (l / likely-01
                              :ARG1 (c3 / candidate
                                    :purpose (i / induce-01
                                          :ARG2 p
                                          :location (c4 / cell
                                                :ARG1-of (t / type-03)
                                                :mod (t2 / this))))
                              :degree (m / more))))))

# ::id pmid_1563_0473.140 ::date 2015-03-20T07:06:15 ::annotator SDL-AMR-09 ::preferred
# ::snt Previously, we showed that effective transmission of a Wnt-3a signal in cultured keratinocytes can be achieved through their exposure to the BMP inhibitor noggin, which induces LEF-1 expression [<xref ref-type="bibr" rid="pbio-0030011-b04">4</xref>].
# ::save-date Wed Jun 3, 2015 ::file pmid_1563_0473_140.txt
(s / show-01
      :ARG0 (w / we)
      :ARG1 (p / possible-01
            :ARG1 (a / achieve-01
                  :ARG1 (t / transmit-01
                        :ARG1 (s2 / signal-07
                              :ARG0 (p2 / protein :name (n / name :op1 "Wnt-3a"))
                              :location (c / cell :name (n2 / name :op1 "keratinocyte")
                                    :ARG1-of (c2 / culture-01)))
                        :ARG1-of (e / effective-04))
                  :manner (e2 / expose-01
                        :ARG1 c
                        :ARG2 (p3 / protein :name (n3 / name :op1 "noggin")
                              :ARG0-of (i / inhibit-01
                                    :ARG1 (p4 / protein :name (n4 / name :op1 "BMP")
                                          :ARG0-of (i2 / induce-01
                                                :ARG2 (e3 / express-03
                                                      :ARG2 (p5 / protein :name (n5 / name :op1 "LEF-1"))))))))))
      :time (p6 / previous)
      :ARG1-of (d / describe-01
            :ARG0 (p7 / publication
                  :ARG1-of (c3 / cite-01
                        :ARG2 4))))

# ::id pmid_1563_0473.141 ::date 2015-03-21T08:57:36 ::annotator SDL-AMR-09 ::preferred
# ::snt In vitro, these conditions down-regulated the <i>E-cadherin</i> promoter and induced a LEF-1/β-catenin-sensitive reporter gene, <i>TOPFLASH</i> [<xref ref-type="bibr" rid="pbio-0030011-b04">4</xref>].
# ::save-date Wed Jun 3, 2015 ::file pmid_1563_0473_141.txt
(a / and
      :op1 (d / downregulate-01
            :ARG0 (c / condition
                  :mod (t / this))
            :ARG1 (m / molecular-physical-entity
                  :ARG0-of (p / promote-01
                        :ARG1 (p2 / protein :name (n / name :op1 "E-cadherin")))))
      :op2 (i / induce-01
            :ARG0 c
            :ARG2 (g / gene :name (n2 / name :op1 "TOPFLASH")
                  :ARG0-of (r / report-01)
                  :ARG0-of (s / sensitive-03
                        :ARG1 (m2 / macro-molecular-complex
                              :part (p3 / protein :name (n3 / name :op1 "LEF-1"))
                              :part (p4 / protein :name (n4 / name :op1 "β-catenin"))))))
      :manner (i2 / in-vitro)
      :ARG1-of (d2 / describe-01
            :ARG0 (p5 / publication
                  :ARG1-of (c2 / cite-01
                        :ARG2 4))))

# ::id pmid_1563_0473.142 ::date 2015-03-21T09:31:40 ::annotator SDL-AMR-09 ::preferred
# ::snt In contrast, Snail expression was not induced by these conditions (<xref ref-type="fig" rid="pbio-0030011-g005">Figure 5</xref>A).
# ::save-date Wed Jun 3, 2015 ::file pmid_1563_0473_142.txt
(c / contrast-01
      :ARG2 (i / induce-01 :polarity -
            :ARG0 (c2 / condition
                  :mod (t / this))
            :ARG2 (e / express-03
                  :ARG2 (p / protein :name (n / name :op1 "Snail")))
            :ARG1-of (d / describe-01
                  :ARG0 (f / figure :mod "5A"))))

# ::id pmid_1563_0473.143 ::date 2015-03-21T09:38:48 ::annotator SDL-AMR-09 ::preferred
# ::snt Thus, despite essential roles for Wnts and noggin in hair follicle specification [<xref ref-type="bibr" rid="pbio-0030011-b04">4</xref>,<xref ref-type="bibr" rid="pbio-0030011-b29">29</xref>,<xref ref-type="bibr" rid="pbio-0030011-b30">30</xref>], our studies did not support an essential role for these signals in governing <i>Snail</i> expression in keratinocytes.
# ::save-date Thu Jan 14, 2016 ::file pmid_1563_0473_143.txt
(c / cause-01
      :ARG1 (s / support-01 :polarity -
            :ARG0 (s2 / study-01
                  :ARG0 (w / we))
            :ARG1 (r / role
                  :mod (e / essential)
                  :beneficiary (s3 / signal-07
                        :mod (t / this))
                  :topic (g / govern-01
                        :ARG1 (e2 / express-03
                              :ARG1 (g2 / gene :wiki -
                                    :name (n2 / name :op1 "Snail"))
                              :ARG3 (c2 / cell :wiki "Keratinocyte"
                                    :name (n / name :op1 "keratinocyte")))))
            :concession (r2 / role
                  :mod (e3 / essential)
                  :beneficiary (a / and
                        :op1 (p / protein :wiki -
                              :name (n3 / name :op1 "Wnt"))
                        :op2 (p2 / protein :wiki "Noggin_(protein)"
                              :name (n4 / name :op1 "noggin")))
                  :topic (s4 / specify-01
                        :ARG1 (f / follicle
                              :mod (h / hair)))
                  :ARG1-of (d / describe-01
                        :ARG0 (p3 / publication
                              :ARG1-of (c3 / cite-01
                                    :ARG2 (a2 / and :op1 4 :op2 29 :op3 30)))))))

# ::id pmid_1563_0473.144 ::date 2015-03-21T10:31:17 ::annotator SDL-AMR-09 ::preferred
# ::snt TGF-β1 has been shown to induce Snail family members in hepatocytes and heart [<xref ref-type="bibr" rid="pbio-0030011-b15">15</xref>, <xref ref-type="bibr" rid="pbio-0030011-b31">31</xref>].
# ::save-date Fri Jan 1, 2016 ::file pmid_1563_0473_144.txt
(s / show-01
      :ARG1 (i / induce-01
            :ARG0 (p / protein :name (n / name :op1 "TGF-β1"))
            :ARG2 (m / member
                  :ARG1-of (i2 / include-91
                        :ARG2 (p2 / protein-family :name (n2 / name :op1 "Snail"))))
            :location (a / and
                  :op1 (c / cell :name (n3 / name :op1 "hepatocyte"))
                  :op2 (h / heart)))
      :ARG1-of (d / describe-01
            :ARG0 (p3 / publication
                  :ARG1-of (c2 / cite-01
                        :ARG2 (a2 / and :op1 15 :op2 31)))))

# ::id pmid_1563_0473.145 ::date 2015-03-21T11:03:12 ::annotator SDL-AMR-09 ::preferred
# ::snt In keratinocytes, however, TGF-β1 inhibits keratinocyte growth and seems to be involved in triggering the destructive phase of the cycling hair follicle [<xref ref-type="bibr" rid="pbio-0030011-b32">32</xref>].
# ::save-date Mon Jul 20, 2015 ::file pmid_1563_0473_145.txt
(h / have-concession-91
      :ARG2 (a / and
            :op1 (i / inhibit-01
                  :ARG0 (p / protein :name (n / name :op1 "TGF-β1"))
                  :ARG1 (g / grow-01
                        :ARG1 (c / cell :name (n2 / name :op1 "keratinocyte"))))
            :op2 (s / seem-01
                  :ARG1 (i2 / involve-01
                        :ARG1 p
                        :ARG2 (t / trigger-01
                              :ARG0 p
                              :ARG1 (p2 / phase
                                    :ARG0-of (d / destroy-01)
                                    :part-of (f / follicle
                                          :mod (h2 / hair)
                                          :ARG1-of (c2 / cycle-02))))))
            :location c)
      :ARG1-of (d2 / describe-01
            :ARG0 (p3 / publication
                  :ARG1-of (c3 / cite-01
                        :ARG2 32))))

# ::id pmid_1563_0473.146 ::date 2015-03-21T11:42:53 ::annotator SDL-AMR-09 ::preferred
# ::snt Of the loss-of-function mutations generated in each of the <i>TGF-β</i> genes, only the <i>TGF-β2</i> null state blocked follicle development at the hair bud stage [<xref ref-type="bibr" rid="pbio-0030011-b32">32</xref>].
# ::save-date Tue Mar 24, 2015 ::file pmid_1563_0473_146.txt
(b / block-01
      :ARG0 (s / state
            :mod (n / null)
            :poss (g / gene :name (n2 / name :op1 "TGF-β2"))
            :mod (o / only)
            :ARG1-of (i / include-91
                  :ARG2 (m / mutate-01
                        :ARG2 (l / lose-02
                              :ARG1 (f2 / function-01))
                        :ARG1-of (g2 / generate-01
                              :ARG3 (g3 / gene :name (n3 / name :op1 "TGF-β")
                                    :mod (e / each))))))
      :ARG1 (f / follicle
            :ARG1-of (d / develop-02))
      :time (s2 / stage
            :mod (b2 / bud
                  :mod (h / hair)))
      :ARG1-of (d2 / describe-01
            :ARG0 (p / publication
                  :ARG1-of (c / cite-01
                        :ARG2 32))))

# ::id pmid_1563_0473.147 ::date 2015-03-21T12:38:11 ::annotator SDL-AMR-09 ::preferred
# ::snt Thus, we turned towards addressing whether TGF-β2 might be involved in regulating <i>Snail</i> expression in keratinocytes isolated from the basal layer of the epidermis.
# ::save-date Thu Jan 14, 2016 ::file pmid_1563_0473_147.txt
(c / cause-01
      :ARG1 (t / turn-01
            :ARG0 (w / we)
            :location (a / address-02
                  :ARG0 w
                  :ARG1 (p / possible-01 :mode interrogative
                        :ARG1 (i / involve-01
                              :ARG1 (p2 / protein :name (n / name :op1 "TGF-β2"))
                              :ARG2 (r / regulate-01
                                    :ARG0 p2
                                    :ARG1 (e / express-03
                                          :ARG1 (g / gene :name (n2 / name :op1 "Snail")))
                                    :location (c2 / cell :name (n3 / name :op1 "keratinocyte")
                                          :ARG1-of (i2 / isolate-01
                                                :ARG2 (l / layer
                                                      :mod (b / basal)
                                                      :part-of (e2 / epidermis))))))))))

# ::id pmid_1563_0473.148 ::date 2015-03-21T13:32:50 ::annotator SDL-AMR-09 ::preferred
# ::snt Though there is no cell culture system available to specifically study placodal cells, these keratinocytes are their progenitors and are the closest approximation available to study the behavior of epithelial cells of the placode.
# ::save-date Fri Jan 1, 2016 ::file pmid_1563_0473_148.txt
(a / and
      :op1 (h / have-rel-role-91
            :ARG0 (c / cell :name (n / name :op1 "keratinocyte")
                  :mod (t / this))
            :ARG1 (c2 / cell
                  :location (p2 / placode))
            :ARG2 (p / progenitor
                  :poss c))
      :op2 (a2 / available-02
            :ARG2 (a3 / approximate-01
                  :ARG0 c
                  :ARG1-of (c3 / close-11
                        :degree (m / most))
                  :purpose (s / study-01
                        :ARG1 (b / behave-01
                              :ARG0 (c4 / cell
                                    :location (e / epithelium)
                                    :part-of p2)))))
      :concession (a4 / available-02 :polarity -
            :ARG2 (s2 / system
                  :mod (c5 / culture-01
                        :ARG1 (c6 / cell)))
            :purpose (s3 / study-01
                  :ARG1 c2
                  :ARG1-of (s4 / specific-02))))

# ::id pmid_1563_0473.149 ::date 2015-03-22T02:46:07 ::annotator SDL-AMR-09 ::preferred
# ::snt Interestingly, treatment of cultured keratinocytes with as little as 5 ng/ml of TGF-β2 caused a rapid and transient induction of Snail (<xref ref-type="fig" rid="pbio-0030011-g005">Figure 5</xref>B).
# ::save-date Fri Jul 24, 2015 ::file pmid_1563_0473_149.txt
(c / cause-01
      :ARG0 (t / treat-04
            :ARG1 (c2 / cell :name (n / name :op1 "keratinocyte")
                  :ARG1-of (c3 / culture-01))
            :ARG2 (p / protein :name (n2 / name :op1 "TGF-β2")
                  :quant (c4 / concentration-quantity :quant 5
                        :mod (l / little)
                        :unit (n4 / nanogram-per-milliliter))))
      :ARG1 (i / induce-01
            :ARG0 t
            :ARG2 (p2 / protein :name (n3 / name :op1 "Snail"))
            :mod (r / rapid)
            :ARG1-of (t2 / transient-02))
      :manner (i2 / interesting)
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod "5B")))

# ::id pmid_1563_0473.150 ::date 2015-03-22T03:31:14 ::annotator SDL-AMR-09 ::preferred
# ::snt Following this treatment, Snail protein was detected within 30 min, peaked at 2 h, and then declined thereafter.
# ::save-date Fri Mar 27, 2015 ::file pmid_1563_0473_150.txt
(f / follow-01
      :ARG1 (a / and
            :op1 (d / detect-01
                  :ARG1 (p / protein :name (n / name :op1 "Snail"))
                  :time (a2 / after
                        :op1 (t / treat-04
                              :mod (t2 / this))
                        :quant (u / up-to
                              :op1 (t3 / temporal-quantity :quant 30
                                    :unit (m / minute)))))
            :op2 (p2 / peak-01
                  :ARG1 p
                  :time (a4 / after
                        :op1 (t4 / temporal-quantity :quant 2
                              :unit (h / hour))))
            :op3 (d2 / decline-01
                  :ARG1 p
                  :time (a3 / after
                        :op1 p2))))

# ::id pmid_1563_0473.151 ::date 2015-03-22T04:26:07 ::annotator SDL-AMR-09 ::preferred
# ::snt The induction of Snail appeared to be specific for the active form of the growth factor, as pretreatment of TGF-β2 for 10 min at 100 °C obliterated the response [<xref ref-type="fig" rid="pbio-0030011-g005">Figure 5</xref>B, lanes marked (–)].
# ::save-date Wed Feb 24, 2016 ::file pmid_1563_0473_151.txt
(c / cause-01
      :ARG0 (o / obliterate-01
            :ARG0 (p / pretreat-01
                  :ARG1 (p2 / protein :name (n / name :op1 "TGF-β2"))
                  :ARG3 (t / temperature-quantity :quant 100
                        :scale (c2 / celsius))
                  :duration (t2 / temporal-quantity :quant 10
                        :unit (m / minute)))
            :ARG1 (r / respond-01))
      :ARG1 (a / appear-02
            :ARG1 (i / induce-01
                  :ARG2 (p3 / protein :name (n2 / name :op1 "Snail"))
                  :ARG1-of (s / specific-02
                        :ARG2 (f / form
                              :ARG0-of (a2 / activity-06)
                              :mod (g / growth-factor)))))
      :ARG1-of (d / describe-01
            :ARG0 (f2 / figure :mod "5B")
            :ARG2-of (m2 / mark-02
                  :ARG1 (l / lane))))

# ::id pmid_1563_0473.152 ::date 2015-03-22T05:32:46 ::annotator SDL-AMR-09 ::preferred
# ::snt By contrast, although TGF-β receptor activation remained elevated during the duration of the experiment (as measured by the sustained phosphorylation of the downstream effector SMAD2) <i>Snail</i> expression could not be maintained (<xref ref-type="fig" rid="pbio-0030011-g005">Figure 5</xref>B).
# ::save-date Sun Jul 12, 2015 ::file pmid_1563_0473_152.txt
(c / contrast-01
      :ARG2 (p / possible-01 :polarity -
            :ARG1 (m / maintain-01
                  :ARG1 (e / express-03
                        :ARG2 (g / gene :wiki -
                              :name (n / name :op1 "Snail")))
                  :concession (r / remain-01
                        :ARG1 (a / activate-01
                              :ARG1 (r2 / receptor :wiki "TGF_beta_receptors"
                                    :name (n2 / name :op1 "TGF-β"))
                              :ARG1-of (m2 / measure-01
                                    :ARG0 (p2 / phosphorylate-01
                                          :ARG1 (e2 / effector
                                                :mod (p3 / protein :wiki "Mothers_against_decapentaplegic_homolog_2"
                                                      :name (n3 / name :op1 "SMAD2"))
                                                :mod (d / downstream))
                                          :ARG1-of (s / sustain-01))
                                    :ARG3 (e3 / elevate-01)))
                        :ARG3 e3
                        :time (e4 / experiment-01))))
      :ARG1-of (d3 / describe-01
            :ARG0 (f / figure :mod "5B")))

# ::id pmid_1563_0473.153 ::date 2015-03-22T07:36:33 ::annotator SDL-AMR-09 ::preferred
# ::snt Thus, although <i>Snail</i> expression correlated with phosphorylated SMAD2 (pSMAD2) induction, its decline seemed to rely on secondary downstream events.
# ::save-date Mon Jan 4, 2016 ::file pmid_1563_0473_153.txt
(c / cause-01
      :ARG1 (s / seem-01
            :ARG1 (r / rely-01
                  :ARG0 (d / decline-01
                        :ARG1 (e / express-03
                              :ARG1 (g / gene :name (n / name :op1 "Snail"))))
                  :ARG1 (e2 / event
                        :direction (d2 / downstream)
                        :mod (s2 / secondary)))
            :concession (c2 / correlate-01
                  :ARG1 e
                  :ARG2 (i / induce-01
                        :ARG2 (p / protein :name (n2 / name :op1 "SMAD2")
                              :ARG1-of (p2 / phosphorylate-01)
                              :ARG1-of (d3 / describe-01
                                    :ARG0 (p3 / protein :name (n3 / name :op1 "pSMAD2"))))))))

# ::id pmid_1563_0473.154 ::date 2015-03-21T14:59:41 ::annotator SDL-AMR-09 ::preferred
# ::snt The rapid kinetics of Snail expression were reflected at the mRNA level, suggesting that <i>Snail</i> promoter activity in keratinocytes might be sensitive to TGF-β2 signaling (<xref ref-type="fig" rid="pbio-0030011-g005">Figure 5</xref>C).
# ::save-date Wed Dec 30, 2015 ::file pmid_1563_0473_154.txt
(r / reflect-01
      :ARG1 (l / level
            :mod (n4 / nucleic-acid :name (n2 / name :op1 "mRNA")))
      :ARG2 (k / kinetics
            :mod (r2 / rapid)
            :poss (e / express-03
                  :ARG1 (g / gene :name (n / name :op1 "Snail"))))
      :ARG0-of (s / suggest-01
            :ARG1 (p / possible-01
                  :ARG1 (s2 / sensitive-03
                        :ARG0 (a / activity-06
                              :ARG0 (m / molecular-physical-entity
                                    :ARG0-of (p4 / promote-01
                                          :ARG1 g))
                              :location (k2 / keratinocyte))
                        :ARG1 (s3 / signal-07
                              :ARG0 (p3 / protein :name (n3 / name :op1 "TGF-β2"))))))
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod "5C")))

# ::id pmid_1563_0473.155 ::date 2015-03-22T00:28:57 ::annotator SDL-AMR-09 ::preferred
# ::snt To test this possibility, we engineered a transgene driving the β-galactosidase reporter under the control of approximately 2.2 kb of promoter sequence located 5′ from the transcription initiation site of the mouse <i>Snail</i> gene.
# ::save-date Mon Jan 4, 2016 ::file pmid_1563_0473_155.txt
(e / engineer-01
      :ARG0 (w / we)
      :ARG1 (t3 / transgene)
      :purpose (t / test-01
            :ARG0 w
            :ARG1 (t2 / this
                  :ARG1-of (p / possible-01)))
      :manner (d / drive-02
            :ARG0 w
            :ARG1 (e2 / enzyme :name (n / name :op1 "β-galactosidase")
                  :ARG0-of (r / report-01))
            :ARG2 (c / control-01
                  :ARG0 (s / sequence
                        :quant (a / approximately
                              :op1 (d2 / distance-quantity :quant 2.2
                                    :unit (k / kilo-base-pair)))
                        :location (r2 / relative-position
                              :op1 (p3 / protein-segment
                                    :location-of (i / initiate-01
                                          :ARG1 (t4 / transcribe-01))
                                    :part-of (g / gene :name (n2 / name :op1 "Snail")
                                          :mod (m2 / mouse)))
                              :direction (d3 / dna-sequence :name (n3 / name :op1 "5'")))
                        :mod (m / molecular-physical-entity
                              :ARG0-of (p2 / promote-02)))
                  :ARG1 e2)))

# ::id pmid_1563_0473.156 ::date 2015-03-22T01:19:41 ::annotator SDL-AMR-09 ::preferred
# ::snt At 2 d after transient transfection, keratinocytes were treated with TGF-β2 (t = 0) and then assayed for transgene activity over the same time course in which we had observed Snail protein induction.
# ::save-date Fri Jan 1, 2016 ::file pmid_1563_0473_156.txt
(a / and
      :op1 (t2 / treat-04
            :ARG1 (k / keratinocyte)
            :ARG2 (p / protein :name (n / name :op1 "TGF-β2"))
            :time (a3 / after
                  :op1 (t3 / transfect-01
                        :ARG1-of (t4 / transient-02))
                  :quant (t5 / temporal-quantity :quant 2
                        :unit (d / day)))
            :condition (e / equal-01
                  :ARG1 (t8 / time)
                  :ARG2 0))
      :op2 (a2 / assay-01
            :ARG1 (a4 / activity-06
                  :ARG0 k
                  :ARG1 (t7 / transgene))
            :time (t6 / then)
            :duration (c2 / course
                  :ARG1-of (s / same-01
                        :ARG2 (c / course
                              :time-of (o2 / observe-01
                                    :ARG0 (w / we)
                                    :ARG1 (i / induce-01
                                          :ARG2 (p2 / protein :name (n2 / name :op1 "Snail"))))
                              :mod t))
                  :mod (t / time))))

# ::id pmid_1563_0473.157 ::date 2015-03-22T12:33:25 ::annotator SDL-AMR-09 ::preferred
# ::snt The results of this experiment are presented in <xref ref-type="fig" rid="pbio-0030011-g005">Figure 5</xref>D.
# ::save-date Sun Mar 22, 2015 ::file pmid_1563_0473_157.txt
(p / present-01
      :ARG0 (f / figure :mod 5)
      :ARG1 (t / thing
            :ARG2-of (r / result-01
                  :ARG1 (e / experiment-01
                        :mod (t2 / this)))))

# ::id pmid_1563_0473.158 ::date 2015-03-22T12:52:36 ::annotator SDL-AMR-09 ::preferred
# ::snt Within 0.5 h of TGF-β2 treatment, <i>Snail</i> promoter activity had increased 3-fold, and by 2 h, it peaked to approximately 10-fold over control levels (<xref ref-type="fig" rid="pbio-0030011-g005">Figure 5</xref>D).
# ::save-date Mon Jul 6, 2015 ::file pmid_1563_0473_158.txt
(a / and
      :op1 (i / increase-01
            :ARG1 (a2 / activity-06
                  :ARG0 (m / molecular-physical-entity
                        :ARG0-of (p6 / promote-01
                              :ARG1 (g / gene :name (n / name :op1 "Snail")))))
            :ARG4 (p4 / product-of :op1 3
                  :op2 (l / level
                        :mod (c / control)))
            :time (a3 / after
                  :op1 (t / treat-04
                        :ARG2 (p2 / protein :name (n2 / name :op1 "TGF-β2")))
                  :quant (u / up-to
                        :op1 (t2 / temporal-quantity :quant 0.5
                              :unit (h / hour)))))
      :op2 (p3 / peak-01
            :ARG1 (a4 / approximately
                  :op1 (p5 / product-of :op1 10
                        :op2 l))
            :time (a5 / after
                  :op1 t
                  :quant (u2 / up-to
                        :op1 (t3 / temporal-quantity :quant 2
                              :unit h))))
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod "5D")))

# ::id pmid_1563_0473.159 ::date 2015-03-22T13:33:03 ::annotator SDL-AMR-09 ::preferred
# ::snt Thereafter, <i>Snail</i> promoter activity rapidly returned to the basal levels seen in unstimulated keratinocytes.
# ::save-date Wed Dec 30, 2015 ::file pmid_1563_0473_159.txt
(r / return-01
      :ARG1 (a / activity-06
            :ARG0 (m / molecular-physical-entity
                  :ARG0-of (p2 / promote-01
                        :ARG1 (g / gene :name (n / name :op1 "Snail")))))
      :ARG4 (l / level
            :ARG1-of (s / see-01
                  :location (k / keratinocyte
                        :ARG1-of (s2 / stimulate-01 :polarity -)))
            :mod (b / basal))
      :manner (r2 / rapid)
      :time (t / thereafter))

# ::id pmid_1563_0473.160 ::date 2015-03-22T13:40:11 ::annotator SDL-AMR-09 ::preferred
# ::snt The kinetics of <i>Snail</i> promoter activity closely paralleled those observed for Snail protein induction.
# ::save-date Sun Jan 17, 2016 ::file pmid_1563_0473_160.txt
(p / parallel-01
      :ARG0 (k / kinetics
            :mod (a / activity-06
                  :ARG0 (m / molecular-physical-entity
                        :ARG0-of (p4 / promote-01
                              :ARG1 (g / gene :name (n / name :op1 "Snail"))))))
      :ARG1 (k2 / kinetics
            :ARG1-of (o / observe-01
                  :topic (i / induce-01
                        :ARG2 (p3 / protein :name (n2 / name :op1 "Snail")))))
      :ARG1-of (c / close-10))

# ::id pmid_1563_0473.161 ::date 2015-03-22T13:59:01 ::annotator SDL-AMR-09 ::preferred
# ::snt Moreover, the stimulatory effects appeared to be specific to TGF-β2, since they were abrogated either by heat inactivation of the TGF-β2 protein or by mutation of a putative SMAD binding element located about 1.8 kb 5′ from the <i>Snail</i> transcription start site (<xref ref-type="fig" rid="pbio-0030011-g005">Figure 5</xref>D).
# ::save-date Mon Jan 4, 2016 ::file pmid_1563_0473_161.txt
(a / and
      :op1 (a2 / appear-02
            :ARG1 (s / specific-02
                  :ARG1 (e / effect-03
                        :ARG1 (s2 / stimulate-01))
                  :ARG2 (p / protein :name (n / name :op1 "TGF-β2")))
            :ARG1-of (c / cause-01
                  :ARG0 (a3 / abrogate-01
                        :ARG1 e
                        :ARG2 (o / or
                              :op1 (a4 / activate-01 :polarity -
                                    :ARG1 p
                                    :mod (h / heat))
                              :op2 (m / mutate-01
                                    :ARG1 (e2 / element
                                          :ARG1-of (b / bind-01
                                                :ARG2 (p2 / protein :name (n2 / name :op1 "SMAD"))
                                                :ARG1-of (t / think-01))
                                          :ARG1-of (l / locate-01
                                                :location (r / relative-position
                                                      :op1 (p3 / protein-segment
                                                            :location-of (s3 / start-01
                                                                  :ARG1 (t2 / transcribe-01
                                                                        :ARG1 (g / gene :name (n3 / name :op1 "Snail")))))
                                                      :quant (d / distance-quantity :quant 1.8
                                                            :unit (k / kilo-base-pair))
                                                      :direction (d3 / dna-sequence :name (n4 / name :op1 "5'"))))))))))
      :ARG1-of (d2 / describe-01
            :ARG0 (f / figure :mod "5D")))

# ::id pmid_1563_0473.162 ::date 2015-03-22T15:16:26 ::annotator SDL-AMR-09 ::preferred
# ::snt Taken together, these results suggested that in keratinocytes, TGF-β2 signaling results in a pSMAD2-dependent transient activation of the <i>Snail</i> gene, and that maintenance of Snail protein relies, in part, upon sustained promoter activity.
# ::save-date Mon Jan 4, 2016 ::file pmid_1563_0473_162.txt
(s / suggest-01
      :ARG0 (t / thing
            :mod (t2 / this)
            :ARG2-of (r / result-01)
            :ARG1-of (t3 / take-01
                  :mod (t4 / together)))
      :ARG1 (a / and
            :op1 (r2 / result-01
                  :ARG1 (s2 / signal-07
                        :ARG0 (p / protein :name (n / name :op1 "TGF-β2")))
                  :ARG2 (a2 / activate-01
                        :ARG1 (g / gene :name (n2 / name :op1 "Snail"))
                        :ARG1-of (t5 / transient-02)
                        :ARG0-of (d / depend-01
                              :ARG1 (p2 / protein :name (n3 / name :op1 "SMAD2")
                                    :ARG1-of (p3 / phosphorylate-01))))
                  :location (k / keratinocyte))
            :op2 (r3 / rely-01
                  :ARG0 (m / maintain-01
                        :ARG1 (p4 / protein :name (n4 / name :op1 "Snail")))
                  :ARG1 (a3 / activity-06
                        :ARG0 (m2 / molecular-physical-entity
                              :ARG0-of (p5 / promote-01))
                        :ARG1-of (s3 / sustain-01))
                  :degree (p6 / part))))

# ::id pmid_1563_0473.163 ::date 2015-03-22T15:29:22 ::annotator SDL-AMR-09 ::preferred
# ::snt The brevity of <i>Snail</i> gene and protein induction in TGF-β2 treated cultured keratinocytes resembled the temporal appearance of <i>Snail</i> mRNA and protein at the initiation of hair follicle morphogenesis in embryonic mouse skin.
# ::save-date Wed Jun 3, 2015 ::file pmid_1563_0473_163.txt
(r / resemble-01
      :ARG1 (a / and
            :op1 (b / brevity
                  :poss (g / gene :name (n / name :op1 "Snail")))
            :op2 (i / induce-01
                  :ARG2 (p / protein)
                  :location (k / keratinocyte
                        :ARG1-of (c / culture-01)
                        :ARG1-of (t / treat-04
                              :ARG2 (p2 / protein :name (n2 / name :op1 "TGF-β2"))))))
      :ARG2 (a2 / appear-01
            :ARG1 (a3 / and
                  :op1 (n3 / nucleic-acid :name (n4 / name :op1 "mRNA")
                        :part-of g)
                  :op2 (p3 / protein))
            :mod (t2 / time)
            :time (i2 / initiate-01
                  :ARG1 (m2 / morphogenesis
                        :mod (f / follicle
                              :mod (h / hair)))
                  :location (s / skin
                        :part-of (e / embryo
                              :mod (m3 / mouse))))))

# ::id pmid_1563_0473.164 ::date 2015-03-22T15:49:36 ::annotator SDL-AMR-09 ::preferred
# ::snt To test whether TGF-β2 might be required for <i>Snail</i> induction in hair bud formation in vivo, we first analyzed whether TGF-β2 was expressed in or around the hair bud.
# ::save-date Wed Jun 3, 2015 ::file pmid_1563_0473_164.txt
(a / analyze-01
      :ARG0 (w / we)
      :ARG1 (e / express-03 :mode interrogative
            :ARG2 (p / protein :name (n / name :op1 "TGF-β2"))
            :ARG3 (o / or
                  :op1 (b / bud
                        :mod (h / hair))
                  :op2 (a2 / around
                        :op1 h)))
      :mod (f / first)
      :purpose (t / test-01
            :ARG0 w
            :ARG1 (p2 / possible-01 :mode interrogative
                  :ARG1 (r / require-01
                        :ARG0 (i / induce-01
                              :ARG2 (g / gene :name (n2 / name :op1 "Snail"))
                              :subevent-of (f2 / form-01
                                    :ARG1 b
                                    :manner (i2 / in-vivo)))
                        :ARG1 p))))

# ::id pmid_1563_0473.165 ::date 2015-03-22T15:59:07 ::annotator SDL-AMR-09 ::preferred
# ::snt Consistent with previous observations [<xref ref-type="bibr" rid="pbio-0030011-b33">33</xref>], an anti-TGF-β2 antibody labeled developing hair buds (<xref ref-type="fig" rid="pbio-0030011-g006">Figure 6</xref>A).
# ::save-date Fri Jan 1, 2016 ::file pmid_1563_0473_165.txt
(l / label-01
      :ARG0 (a / antibody
            :ARG0-of (c3 / counter-01
                  :ARG1 (p3 / protein :name (n / name :op1 "TGF-β2"))))
      :ARG1 (b / bud
            :mod (h / hair)
            :ARG1-of (d / develop-01))
      :ARG1-of (c / consistent-01
            :ARG2 (t / thing
                  :ARG1-of (o / observe-01
                        :time (p / previous))
                  :ARG1-of (d3 / describe-01
                        :ARG0 (p2 / publication
                              :ARG1-of (c2 / cite-01
                                    :ARG2 33)))))
      :ARG1-of (d2 / describe-01
            :ARG0 (f / figure :mod "6A")))

# ::id pmid_1563_0473.166 ::date 2015-03-22T16:15:56 ::annotator SDL-AMR-09 ::preferred
# ::snt This labeling appeared to be specific as judged by the lack of staining in follicle buds from mice homozygous for a <i>TGF-β2</i> null mutation (<xref ref-type="fig" rid="pbio-0030011-g006">Figure 6</xref>A; [<xref ref-type="bibr" rid="pbio-0030011-b34">34</xref>]).
# ::save-date Fri Jul 24, 2015 ::file pmid_1563_0473_166.txt
(a / appear-02
      :ARG1 (s / specific-02
            :ARG1 (l / label-01
                  :mod (t / this)))
      :ARG2-of (j / judge-01
            :ARG3 (s2 / stain-01 :polarity -
                  :location (b2 / bud
                        :mod (f / follicle
                              :mod (m2 / mouse)
                              :mod (h / homozygous
                                    :topic (m / mutate-01
                                          :ARG2 (p / protein :name (n2 / name :op1 "TGF-β2")
                                                :mod (n / null))))))))
      :ARG1-of (d / describe-01
            :ARG0 (a2 / and
                  :op1 (f2 / figure :mod "6A")
                  :op2 (p2 / publication
                        :ARG1-of (c / cite-01
                              :ARG2 34)))))

# ::id pmid_1563_0473.167 ::date 2015-03-22T16:25:45 ::annotator SDL-AMR-09 ::preferred
# ::snt Moreover, the downstream effector of TGF-β2 signaling, pSMAD2, was also expressed in WT, but not <i>TGF-β2</i>-null, hair buds (<xref ref-type="fig" rid="pbio-0030011-g006">Figure 6</xref>B).
# ::save-date Thu Apr 30, 2015 ::file pmid_1563_0473_167.txt
(a / and
      :op2 (e / express-03
            :ARG2 (e2 / effector
                  :location (d / downstream)
                  :mod (s / signal-07
                        :ARG0 (p / protein :name (n / name :op1 "TGF-β2")))
                  :ARG1-of (m / mean-01
                        :ARG2 (p2 / protein :name (n2 / name :op1 "SMAD2")
                              :ARG1-of (p3 / phosphorylate-01))))
            :ARG3 (b / bud
                  :mod (h / hair)
                  :mod (w / wild-type))
            :mod (a2 / also)
            :ARG1-of (c / contrast-01
                  :ARG2 (e3 / express-03 :polarity -
                        :ARG2 p2
                        :ARG3 (b2 / bud
                              :mod (p5 / protein :name (n4 / name :op1 "TGF-β2")
                                    :ARG2-of (m2 / mutate-01 :mod "−/−"))
                              :mod (h2 / hair)))))
      :ARG1-of (d2 / describe-01
            :ARG0 (f / figure :mod "6B")))

# ::id pmid_1563_0473.168 ::date 2015-03-22T16:38:31 ::annotator SDL-AMR-09 ::preferred
# ::snt Together, these data underscore the importance of the TGF-β2 isoform despite expression of both TGF-β1 and TGF-β2 in developing hair buds at this stage.
# ::save-date Mon Nov 2, 2015 ::file pmid_1563_0473_168.txt
(u / underscore-01
      :ARG0 (d / data
            :mod (t / this)
            :mod (t2 / together))
      :ARG1 (i / important
            :domain (i2 / isoform
                  :mod (p / protein :name (n / name :op1 "TGF-β2")))
            :concession (e / express-03
                  :ARG2 (a / and
                        :op1 (p2 / protein :name (n2 / name :op1 "TGF-β1"))
                        :op2 p)
                  :ARG3 (b / bud
                        :mod (h / hair)
                        :ARG2-of (d2 / develop-01))
                  :time (s / stage
                        :mod (t3 / this)))))

# ::id pmid_1563_0473.169 ::date 2015-03-22T16:45:53 ::annotator SDL-AMR-09 ::preferred
# ::snt To further explore the possible relation between Snail and TGF-β2, we examined the status of Snail expression in <i>TGF-β2</i>-null hair buds.
# ::save-date Fri Dec 18, 2015 ::file pmid_1563_0473_169.txt
(e / examine-01
      :ARG0 (w / we)
      :ARG1 (s / status
            :mod (e2 / express-03
                  :ARG2 (p / protein :name (n / name :op1 "Snail"))
                  :ARG3 (b / bud
                        :mod (h / hair)
                        :mod (p2 / protein :name (n3 / name :op1 "TGF-β2")
                              :mod (n2 / null)))))
      :purpose (e3 / explore-01
            :ARG0 w
            :ARG1 (r / relation-03
                  :ARG0 p
                  :ARG2 p2
                  :ARG1-of (p3 / possible-01))
            :degree (f / further)))

# ::id pmid_1563_0473.170 ::date 2015-03-22T16:50:48 ::annotator SDL-AMR-09 ::preferred
# ::snt As judged by immunohistochemistry, Snail protein was absent from E17.5 skin of <i>TGF-β2-</i>null embryos but not from that of control littermates (<xref ref-type="fig" rid="pbio-0030011-g006">Figure 6</xref>C).
# ::save-date Tue Mar 31, 2015 ::file pmid_1563_0473_170.txt
(a / absent-01
      :ARG1 (p / protein :name (n / name :op1 "Snail"))
      :ARG2 (s / skin
            :part-of (e2 / embryo
                  :mod (n2 / null
                        :mod (p2 / protein :name (n3 / name :op1 "TGF-β2")))
                  :age (t / temporal-quantity :quant 17.5
                        :unit (d2 / day))))
      :ARG1-of (c / contrast-01
            :ARG2 (a2 / absent-01 :polarity -
                  :ARG1 p
                  :ARG2 (s2 / skin
                        :part-of (l / littermate
                              :mod (c2 / control)))))
      :ARG2-of (j / judge-01
            :ARG0 (i / immunohistochemistry))
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod "6C")))

# ::id pmid_1563_0473.171 ::date 2015-03-22T17:01:04 ::annotator SDL-AMR-09 ::preferred
# ::snt This effect appeared to be exerted at the transcriptional level, since <i>Snail</i> mRNAs were also not found in <i>TGF-β2</i> null hair buds under conditions in which the signal was readily detected in the hair buds of littermate skin (<xref ref-type="fig" rid="pbio-0030011-g006">Figure 6</xref>D).
# ::save-date Thu Jan 14, 2016 ::file pmid_1563_0473_171.txt
(a / appear-02
      :ARG1 (e2 / exert-01
            :ARG1 (e / effect-03
                  :mod (t / this))
            :location (l / level
                  :mod (t2 / transcribe-01)))
      :ARG1-of (c / cause-01
            :ARG0 (f / find-01 :polarity -
                  :ARG1 (n4 / nucleic-acid :name (n5 / name :op1 "mRNA")
                        :mod (g / gene :name (n / name :op1 "Snail")))
                  :mod (a2 / also)
                  :location (b / bud
                        :mod (h / hair)
                        :mod (p2 / protein :name (n3 / name :op1 "TGF-β2")
                              :mod (n2 / null)))
                  :condition (d / detect-01
                        :ARG1 (s / signal-07)
                        :manner (r / ready)
                        :location (b2 / bud
                              :mod h
                              :part-of (s2 / skin
                                    :part-of (l2 / littermate))))))
      :ARG1-of (d2 / describe-01
            :ARG0 (f2 / figure :mod "6D")))

# ::id pmid_1563_0473.172 ::date 2015-03-22T17:09:49 ::annotator SDL-AMR-09 ::preferred
# ::snt Conversely, in 2-wk-old <i>K14-Smad2</i> Tg mice, which display elevated TGF-β signaling in skin [<xref ref-type="bibr" rid="pbio-0030011-b35">35</xref>], Snail protein was readily detected by Western blot analyses, where it was not found in postnatal skin (<xref ref-type="fig" rid="pbio-0030011-g006">Figure 6</xref>E).
# ::save-date Sun Dec 13, 2015 ::file pmid_1563_0473_172.txt
(c / contrast-01
      :ARG2 (d / detect-01
            :ARG1 (p / protein :name (n / name :op1 "Snail"))
            :ARG2 (a / analyze-01
                  :manner (i / immunoblot-01))
            :manner (r / ready)
            :location (f / find-01 :polarity -
                  :ARG1 p
                  :location (s / skin
                        :mod (p2 / postnatal)))
            :ARG1-of (d2 / describe-01
                  :ARG0 (f2 / figure :mod "6A"))
            :location (m / mouse
                  :age (t / temporal-quantity :quant 2
                        :unit (w2 / week))
                  :mod (t2 / transgenic)
                  :mod (m2 / macro-molecular-complex
                        :part (p3 / protein :name (n2 / name :op1 "K14"))
                        :part (p4 / protein :name (n3 / name :op1 "Smad2")))
                  :ARG0-of (d3 / display-01
                        :ARG1 (s2 / signal-07
                              :ARG0 (p5 / protein :name (n4 / name :op1 "TGF-β"))
                              :ARG1-of (e / elevate-01))
                        :ARG2 (s3 / skin)
                        :ARG1-of (d4 / describe-01
                              :ARG0 (p6 / publication
                                    :ARG1-of (c2 / cite-01
                                          :ARG2 35)))))))

# ::id pmid_1563_0473.173 ::date 2015-03-22T18:10:35 ::annotator SDL-AMR-09 ::preferred
# ::snt Taken together, these results provide compelling evidence that TGF-β2 is functionally important for inducing <i>Snail</i> gene expression in a pSMAD-dependent manner in developing hair buds.
# ::save-date Fri Dec 18, 2015 ::file pmid_1563_0473_173.txt
(p / provide-01
      :ARG0 (t / thing
            :mod (t2 / this)
            :ARG2-of (r / result-01)
            :ARG1-of (t3 / take-01
                  :mod (t4 / together)))
      :ARG1 (e / evidence-01
            :ARG1 (i / important
                  :domain (p2 / protein :name (n / name :op1 "TGF-β2"))
                  :mod (f / function-01)
                  :purpose (i2 / induce-01
                        :ARG2 (e2 / express-03
                              :ARG1 (g / gene :name (n2 / name :op1 "Snail"))
                              :ARG3 (b / bud
                                    :mod (h / hair)
                                    :ARG2-of (d / develop-01)))
                        :ARG0-of (d2 / depend-01
                              :ARG1 (p3 / protein :name (n3 / name :op1 "SMAD")
                                    :ARG1-of (p4 / phosphorylate-01)))))
            :ARG0-of (c / compel-01)))

# ::id pmid_1563_0473.174 ::date 2015-03-22T18:27:49 ::annotator SDL-AMR-09 ::preferred
# ::snt Whether pMARK activity also contributes to Snail induction was not addressed in the present study [<xref ref-type="bibr" rid="pbio-0030011-b15">15</xref>].
# ::save-date Mon Jan 4, 2016 ::file pmid_1563_0473_174.txt
(a / address-02 :polarity -
      :ARG1 (c / contribute-01 :mode interrogative
            :ARG0 (a3 / activity-06
                  :ARG0 (e / enzyme :name (n / name :op1 "MAPK")
                        :ARG1-of (p2 / phosphorylate-01)))
            :ARG2 (i / induce-01
                  :ARG2 (p3 / protein :name (n2 / name :op1 "Snail")))
            :mod (a2 / also))
      :medium (s / study
            :time (p / present))
      :ARG1-of (d / describe-01
            :ARG0 (p4 / publication
                  :ARG1-of (c2 / cite-01
                        :ARG2 15))))

# ::id pmid_1563_0473.175 ::date 2015-03-22T18:36:33 ::annotator SDL-AMR-09 ::preferred
# ::snt Although some hair buds still formed in <i>TGF-β2</i> null skin, their number was reduced by approximately 50% [<xref ref-type="bibr" rid="pbio-0030011-b32">32</xref>].
# ::save-date Thu Apr 30, 2015 ::file pmid_1563_0473_175.txt
(h / have-concession-91
      :ARG1 (r / reduce-01
            :ARG1 (n3 / number
                  :quant-of b)
            :ARG2 (a / approximately
                  :op1 (p2 / percentage-entity :value 50)))
      :ARG2 (f / form-01
            :ARG1 (b / bud
                  :mod (h2 / hair)
                  :mod (s2 / some))
            :mod (s / still)
            :location (s3 / skin
                  :mod (p / protein :name (n2 / name :op1 "TGF-β2")
                        :ARG2-of (m / mutate-01 :mod "−/−"))))
      :ARG1-of (d / describe-01
            :ARG0 (p3 / publication
                  :ARG1-of (c / cite-01
                        :ARG2 32))))

# ::id pmid_1563_0473.176 ::date 2015-03-22T21:50:33 ::annotator SDL-AMR-09 ::preferred
# ::snt Thus, although the pathway mediated by TGF-β2 signaling impacts the earliest step of epithelial invagination, it does not appear to be essential for bud morphogenesis.
# ::save-date Sun Dec 20, 2015 ::file pmid_1563_0473_176.txt
(i / infer-01
      :ARG1 (h / have-concession-91
            :ARG1 (a / appear-02 :polarity -
                  :ARG1 (e3 / essential
                        :domain p
                        :purpose (m3 / morphogenesis
                              :mod (b / bud))))
            :ARG2 (i2 / impact-01
                  :ARG0 (p / pathway
                        :ARG1-of (m / mediate-01
                              :ARG0 (s / signal-07
                                    :ARG0 (p2 / protein :name (n / name :op1 "TGF-β2")))))
                  :ARG1 (s2 / step-01
                        :ARG1 (i3 / invaginate-01
                              :ARG1 (e2 / epithelium))
                        :mod (e / early
                              :degree (m2 / most))))))

# ::id pmid_1563_0473.177 ::date 2015-03-22T22:06:45 ::annotator SDL-AMR-09 ::preferred
# ::snt Consistent with this notion, basement membrane remodeling still took place in the <i>TGF-β2</i>-null buds, as judged by immunofluorescence with antibodies against β4 integrin, an integral component of keratinocyte-mediated adhesion to its underlying basement membrane (<xref ref-type="fig" rid="pbio-0030011-g006">Figure 6</xref>F).
# ::save-date Tue Feb 2, 2016 ::file pmid_1563_0473_177.txt
(c / consistent-01
      :ARG1 (r / remodel-01
            :ARG1 (m / membrane
                  :mod (b / basement))
            :location (b2 / bud
                  :mod (p / protein :name (n2 / name :op1 "TGF-β2")
                        :mod (n / null)))
            :mod (s / still)
            :ARG1-of (j / judge-01
                  :ARG3 (i / immunofluoresce-01
                        :ARG2 (a / antibody
                              :ARG0-of (c3 / counter-01
                                    :ARG1 (p2 / protein :name (n4 / name :op1 "β4" :op2 "integrin")
                                          :ARG1-of (m2 / mean-01
                                                :ARG2 (c2 / component
                                                      :mod (i2 / integral)
                                                      :mod (a2 / adhere-01
                                                            :ARG2 (m4 / membrane
                                                                  :mod (b3 / basement)
                                                                  :ARG1-of (u / underlie-01))
                                                            :ARG1-of (m3 / mediate-01
                                                                  :ARG0 (k / keratinocyte))))))))))
            :ARG1-of (d / describe-01
                  :ARG0 (f / figure :mod "6F")))
      :ARG2 (n3 / notion
            :mod (t / this)))

# ::id pmid_1563_0473.178 ::date 2015-03-22T22:26:32 ::annotator SDL-AMR-09 ::preferred
# ::snt In contrast, TGF-β2 signaling appeared to be an important factor for the early proliferation that occurs in the developing hair buds, as judged by anti-Ki67 and anti-pMAPK immunofluorescence (<xref ref-type="fig" rid="pbio-0030011-g006">Figure 6</xref>F and <xref ref-type="fig" rid="pbio-0030011-g006">6</xref>G).
# ::save-date Tue Feb 2, 2016 ::file pmid_1563_0473_178.txt
(c / contrast-01
      :ARG2 (a / appear-02
            :ARG1 (f / factor
                  :mod (i / important)
                  :mod (p / proliferate-01
                        :mod (e / early)
                        :location (b / bud
                              :mod (h / hair)
                              :ARG2-of (d / develop-01)))
                  :domain (s / signal-07
                        :ARG0 (p2 / protein :name (n / name :op1 "TGF-β2")))
                  :ARG1-of (j / judge-01
                        :ARG3 (i2 / immunofluoresce-01
                              :ARG0-of (c2 / counter-01
                                    :ARG1 (p3 / protein :name (n2 / name :op1 "Ki67")))
                              :ARG0-of (c3 / counter-01
                                    :ARG1 (e2 / enzyme :name (n3 / name :op1 "MAPK")
                                          :ARG3-of (p4 / phosphorylate-01)))))))
      :ARG1-of (d2 / describe-01
            :ARG0 (a5 / and
                  :op1 (f2 / figure :mod "6F")
                  :op2 (f3 / figure :mod "6G"))))

# ::id pmid_1563_0473.179 ::date 2015-03-22T22:33:21 ::annotator SDL-AMR-09 ::preferred
# ::snt If TGF-β2 stimulates <i>Snail</i> expression in developing buds, loss of this morphogen would be expected to affect the expression of genes that are typically repressed by Snail.
# ::save-date Sun Jul 26, 2015 ::file pmid_1563_0473_179.txt
(e / expect-01
      :ARG1 (a / affect-01
            :ARG0 (l / lose-02
                  :ARG1 m2)
            :ARG1 (e3 / express-03
                  :ARG1 (g / gene
                        :ARG1-of (r / repress-01
                              :ARG0 g2
                              :ARG1-of (t / typical-02)))))
      :condition (s / stimulate-01
            :ARG0 (m2 / morphogen :name (n / name :op1 "TGF-β2"))
            :ARG1 (e2 / express-03
                  :ARG1 (g2 / gene :name (n2 / name :op1 "Snail"))
                  :ARG3 (b / bud
                        :ARG2-of (d / develop-01)))))

# ::id pmid_1563_0473.180 ::date 2015-03-22T22:41:26 ::annotator SDL-AMR-09 ::preferred
# ::snt Since a major target for Snail-mediated repression is the <i>E-cadherin</i> gene [<xref ref-type="bibr" rid="pbio-0030011-b12">12</xref>,<xref ref-type="bibr" rid="pbio-0030011-b13">13</xref>], we investigated the status of E-cadherin in <i>TGF-β2</i>-null buds.
# ::save-date Fri Jul 31, 2015 ::file pmid_1563_0473_180.txt
(i / investigate-01
      :ARG0 (w / we)
      :ARG1 (s / status
            :mod (g / gene :name (n / name :op1 "E-cadherin"))
            :location (b / bud
                  :mod (p2 / protein :name (n3 / name :op1 "TGF-β2")
                        :ARG2-of (m3 / mutate-01 :mod "−/−"))))
      :ARG1-of (c / cause-01
            :ARG0 (t / target-01
                  :ARG0 (r / repress-01
                        :ARG1-of (m2 / mediate-01
                              :ARG0 (p / protein :name (n4 / name :op1 "Snail"))))
                  :ARG1 g
                  :ARG1-of (m / major-02)
                  :ARG1-of (d / describe-01
                        :ARG0 (p3 / publication
                              :ARG1-of (c2 / cite-01
                                    :ARG2 (a / and :op1 12 :op2 13)))))))

# ::id pmid_1563_0473.181 ::date 2015-03-22T22:51:49 ::annotator SDL-AMR-09 ::preferred
# ::snt As shown in <xref ref-type="fig" rid="pbio-0030011-g006">Figure 6</xref>H, hair buds in TGF-β2 null skin displayed elevated immunofluorescence staining relative to their WT counterparts.
# ::save-date Tue Feb 2, 2016 ::file pmid_1563_0473_181.txt
(d / display-01
      :ARG0 (b / bud
            :mod (h / hair)
            :location (s / skin
                  :mod (p / protein :name (n2 / name :op1 "TGF-β2")
                        :mod (n / null))))
      :ARG1 (s2 / stain-01
            :ARG1 b
            :mod (i / immunofluoresce-01)
            :ARG1-of (e / elevate-01
                  :compared-to (c / counterpart
                        :poss b
                        :mod (w / wild-type))))
      :ARG1-of (s3 / show-01
            :ARG0 (f / figure :mod "6H")))

# ::id pmid_1563_0473.182 ::date 2015-03-22T22:56:07 ::annotator SDL-AMR-09 ::preferred
# ::snt Previously we demonstrated that the concerted action of the extracellular signals Wnt and noggin are required for the generation of a LEF-1/β-catenin transcription complex to repress <i>E-cadherin</i> transcription at the onset of hair fate specification.
# ::save-date Fri Jan 1, 2016 ::file pmid_1563_0473_182.txt
(d / demonstrate-01
      :ARG0 (w / we)
      :ARG1 (r / require-01
            :ARG0 (r2 / repress-01
                  :ARG0 (g / generate-01
                        :ARG1 (m / macro-molecular-complex
                              :ARG0-of (t / transcribe-01)
                              :part (p3 / protein :name (n3 / name :op1 "LEF-1"))
                              :part (p4 / protein :name (n4 / name :op1 "β-catenin"))))
                  :ARG1 (t2 / transcribe-01
                        :ARG1 (g2 / gene :name (n5 / name :op1 "E-cadherin"))
                        :time (o / onset
                              :poss (s / specify-01
                                    :ARG1 (f / fate
                                          :poss (h / hair))))))
            :ARG1 (a / act-01
                  :ARG0 (a2 / and
                        :op1 (p / pathway :name (n6 / name :op1 "Wnt")
                              :mod (e / extracellular))
                        :op2 (p2 / pathway :name (n / name :op1 "noggin")
                              :mod e)
                        :ARG0-of (s2 / signal-07))
                  :mod (c / concerted)))
      :time (p5 / previous))

# ::id pmid_1563_0473.183 ::date 2015-03-22T23:31:27 ::annotator SDL-AMR-09 ::preferred
# ::snt As shown in <xref ref-type="fig" rid="pbio-0030011-g006">Figure 6</xref>I and <xref ref-type="fig" rid="pbio-0030011-g006">6</xref>J, both WT and TGF-β2 null buds exhibited nuclear LEF-1 and β-catenin localization, signs that the Wnt-noggin signaling pathway was intact.
# ::save-date Thu Mar 26, 2015 ::file pmid_1563_0473_183.txt
(e / exhibit-01
      :ARG0 (a / and
            :op1 (b / bud
                  :mod (w / wild-type))
            :op2 (b2 / bud
                  :mod (p / protein :name (n2 / name :op1 "TGF-β2")
                        :mod (n / null))))
      :ARG1 (b3 / be-located-at-91
            :ARG1 (a3 / and
                  :op1 (p2 / protein :name (n3 / name :op1 "LEF-1"))
                  :op2 (p4 / protein :name (n6 / name :op1 "β-catenin")))
            :ARG2 (n4 / nucleus))
      :ARG1-of (s / show-01
            :ARG0 (a2 / and
                  :op1 (f / figure :mod "6I")
                  :op2 (f2 / figure :mod "6J")))
      :ARG0-of (s2 / signal-07
            :ARG1 (i / intact
                  :domain (p3 / pathway :name (n5 / name :op1 "Wnt-noggin")
                        :ARG0-of (s3 / signal-07)))))

# ::id pmid_1563_0473.184 ::date 2015-03-22T23:41:39 ::annotator SDL-AMR-09 ::preferred
# ::snt These data suggest that during hair follicle morphogenesis, TGF-β2 functions subsequently to Wnt/noggin-mediated determination of hair fate.
# ::save-date Mon Mar 23, 2015 ::file pmid_1563_0473_184.txt
(s / suggest-01
      :ARG0 (d / data
            :mod (t / this))
      :ARG1 (f / function-01
            :ARG0 (p2 / protein :name (n2 / name :op1 "TGF-β2"))
            :time (m / morphogenesis
                  :mod (f2 / follicle
                        :mod (h / hair)))
            :time (s2 / subsequent
                  :op1 (d2 / determine-01
                        :ARG1 (f3 / fate
                              :poss (h2 / hair))
                        :ARG1-of (m2 / mediate-01
                              :ARG0 (p / pathway :name (n / name :op1 "Wnt/noggin")))))))

# ::id pmid_1563_0473.185 ::date 2015-03-22T23:49:06 ::annotator SDL-AMR-09 ::preferred
# ::snt Moreover, through activation of <i>Snail</i> gene expression, TGF-β2 appears to work in tandem with these other morphogens to down-regulate E-cadherin levels, which contributes to the activation of proliferative circuitries.
# ::save-date Thu Mar 26, 2015 ::file pmid_1563_0473_185.txt
(a / and
      :op2 (a2 / appear-02
            :ARG2 (w / work-01
                  :ARG0 (p / protein :name (n / name :op1 "TGF-β2"))
                  :ARG1 (d / downregulate-01
                        :ARG0 (a4 / and
                              :op1 p
                              :op2 m)
                        :ARG1 (l / level
                              :quant-of (g2 / gene :name (n3 / name :op1 "E-cadherin")))
                        :ARG0-of (c2 / contribute-01
                              :ARG2 (a5 / activate-01
                                    :ARG1 (c3 / circuitry
                                          :ARG0-of (p3 / proliferate-01)))))
                  :ARG3 (m / morphogen
                        :mod (o / other)
                        :mod (t2 / this))
                  :mod (t / tandem))
            :ARG1-of (c / cause-01
                  :ARG0 (a3 / activate-01
                        :ARG1 (e / express-03
                              :ARG1 (g / gene :name (n2 / name :op1 "Snail")))))))

# ::id pmid_1563_0473.186 ::date 2015-03-23T02:46:24 ::annotator SDL-AMR-09 ::preferred
# ::snt Discussion
# ::save-date Wed Mar 25, 2015 ::file pmid_1563_0473_186.txt
(d / discuss-01)

# ::id pmid_1563_0473.187 ::date 2015-03-23T02:47:25 ::annotator SDL-AMR-09 ::preferred
# ::snt During budding morphogenesis, intersecting signaling networks from the epithelium and mesenchyme govern transcriptional, adhesive, polarity, and motility programs in these select groups of cells.
# ::save-date Sun Dec 20, 2015 ::file pmid_1563_0473_187.txt
(g / govern-01
      :ARG0 (n2 / network
            :ARG0-of (s / signal-07)
            :ARG0-of (i / intersect-01)
            :source (a / and
                  :op1 (e / epithelium)
                  :op2 (m / mesenchyme)))
      :ARG1 (a4 / and
            :op1 (p3 / program
                  :topic (t3 / transcribe-01))
            :op2 (p4 / program
                  :topic (a3 / adhere-01))
            :op3 (p5 / program
                  :topic (p2 / polarize-01))
            :op4 (p6 / program
                  :topic (m2 / motility)))
      :location (g2 / group
            :consist-of (c / cell)
            :mod (t4 / this)
            :mod (s2 / select))
      :time (m3 / morphogenesis
            :ARG1-of (b / bud-01)))

# ::id pmid_1563_0473.188 ::date 2015-03-23T02:56:23 ::annotator SDL-AMR-09 ::preferred
# ::snt The dynamic nuclear and cytosolic changes that take place during this time form the cornerstone for organ morphogenesis.
# ::save-date Mon Mar 30, 2015 ::file pmid_1563_0473_188.txt
(f / form-01
      :ARG0 (c4 / change-01
            :ARG0 (a2 / and
                  :op1 (n / nucleus)
                  :op2 (c2 / cytosol))
            :mod (d / dynamic)
            :time (t / this))
      :ARG1 (c3 / cornerstone)
      :purpose (m / morphogenesis
            :mod (o / organ)))

# ::id pmid_1563_0473.189 ::date 2015-03-23T03:03:05 ::annotator SDL-AMR-09 ::preferred
# ::snt Two major challenges in understanding the mechanisms underlying a particular budding process are to order the temporal sequence of external cues involved and then to dissect how the cells of the developing bud translate these signals into the downstream events of cellular remodeling, proliferation, and differentiation.
# ::save-date Thu Jul 30, 2015 ::file pmid_1563_0473_189.txt
(a / and
      :op1 (o / order-03
            :ARG1 (s / sequence
                  :mod (t / time)
                  :consist-of (c / cue
                        :source (e / external)
                        :ARG1-of (i / involve-01))))
      :op2 (d / dissect-01
            :ARG1 (t3 / thing
                  :manner-of (t4 / translate-01
                        :ARG0 (c2 / cell
                              :part-of (b / bud
                                    :ARG1-of (d2 / develop-02)))
                        :ARG1 (t5 / thing
                              :ARG0-of (s2 / signal-07)
                              :mod (t6 / this))
                        :ARG2 (a2 / and
                              :op1 (e3 / event
                                    :mod (r / remodel-01
                                          :ARG1 c2))
                              :op2 (e4 / event
                                    :mod (d4 / differentiate-01
                                          :ARG1 c2))
                              :op3 (e5 / event
                                    :mod (p / proliferate-01
                                          :ARG0 c2))
                              :location (d3 / downstream))))
            :time (t2 / then))
      :domain (c3 / challenge-01 :quant 2
            :ARG2 (u / understand-01
                  :ARG1 (m2 / mechanism
                        :ARG0-of (u2 / underlie-01
                              :ARG1 (p2 / process-02
                                    :ARG1 (b2 / bud-01)
                                    :mod (p3 / particular)))))
            :ARG1-of (m / major-02)))

# ::id pmid_1563_0473.190 ::date 2015-03-23T03:16:56 ::annotator SDL-AMR-09 ::preferred
# ::snt Our studies here provide some insights into how these events are orchestrated during hair bud formation in developing skin.
# ::save-date Mon Mar 30, 2015 ::file pmid_1563_0473_190.txt
(p / provide-01
      :ARG0 (s / study-01
            :ARG0 (w / we)
            :mod (h / here))
      :ARG1 (i / insight
            :quant (s2 / some)
            :topic (t / thing
                  :manner-of (o / orchestrate-01
                        :ARG1 (e / event
                              :mod (t2 / this))
                        :time (f / form-01
                              :ARG1 (b / bud
                                    :mod (h2 / hair))
                              :location (s3 / skin
                                    :ARG1-of (d / develop-02)))))))

# ::id pmid_1563_0473.191 ::date 2015-03-23T03:22:39 ::annotator SDL-AMR-09 ::preferred
# ::snt Signaling during Early Hair Follicle Morphogenesis
# ::save-date Mon Mar 23, 2015 ::file pmid_1563_0473_191.txt
(s / signal-07
      :time (e / early
            :op1 (m / morphogenesis
                  :mod (f / follicle
                        :mod (h / hair)))))

# ::id pmid_1563_0473.192 ::date 2015-03-23T03:52:20 ::annotator SDL-AMR-09 ::preferred
# ::snt Recent studies on hair bud morphogenesis suggest that Wnt signals likely from the epithelium and BMP inhibitory signals from the underlying mesenchyme converge to produce an active transcription factor complex involving β-catenin and LEF-1, which in turn plays a key role in specifying the hair follicle fate [<xref ref-type="bibr" rid="pbio-0030011-b04">4</xref>,<xref ref-type="bibr" rid="pbio-0030011-b29">29</xref>,<xref ref-type="bibr" rid="pbio-0030011-b30">30</xref>,<xref ref-type="bibr" rid="pbio-0030011-b36">36</xref>,<xref ref-type="bibr" rid="pbio-0030011-b37">37</xref>].
# ::save-date Wed Dec 30, 2015 ::file pmid_1563_0473_192.txt
(s / suggest-01
      :ARG0 (s2 / study-01
            :ARG1 (m / morphogenesis
                  :mod (b / bud
                        :mod (h / hair)))
            :time (r / recent))
      :ARG1 (c / converge-01
            :ARG0 (s6 / signal-07
                  :ARG0 (p / pathway :name (n / name :op1 "Wnt"))
                  :source (l / likely-01
                        :ARG1 (e / epithelium)))
            :ARG1 (s3 / signal-07
                  :ARG0-of (i / inhibit-01
                        :ARG1 (p2 / protein :name (n2 / name :op1 "BMP")))
                  :source (m2 / mesenchyme
                        :ARG0-of (u / underlie-01)))
            :purpose (p3 / produce-01
                  :ARG0 (a / and
                        :op1 s6
                        :op2 s3)
                  :ARG1 (m3 / macro-molecular-complex
                        :part (f / factor
                              :ARG0-of (t3 / transcribe-01))
                        :ARG0-of (i2 / involve-01
                              :ARG1 (a3 / and
                                    :op1 (p4 / protein :name (n4 / name :op1 "β-catenin"))
                                    :op2 (p5 / protein :name (n5 / name :op1 "LEF-1"))))
                        :ARG0-of (a2 / activity-06)
                        :ARG0-of (p6 / play-02
                              :ARG1 (r2 / role
                                    :ARG1-of (k / key-02
                                          :ARG2 (s5 / specify-01
                                                :ARG1 (f2 / fate-01
                                                      :ARG1 (f3 / follicle
                                                            :mod (h2 / hair))))))
                              :mod (i3 / in-turn)))))
      :ARG1-of (d / describe-01
            :ARG0 (p7 / publication
                  :ARG1-of (c2 / cite-01
                        :ARG2 (a4 / and :op1 4 :op2 29 :op3 30 :op4 36 :op5 37)))))

# ::id pmid_1563_0473.193 ::date 2015-03-23T04:20:25 ::annotator SDL-AMR-09 ::preferred
# ::snt Sonic hedgehog (Shh) and TGF-β2 signaling also play essential roles in follicle morphogenesis, but in contrast to <i>β-catenin</i> null skin, in which follicle invaginations are absent [<xref ref-type="bibr" rid="pbio-0030011-b30">30</xref>], some hair buds still form in the absence of LEF-1, Shh, or TGF-β2 [<xref ref-type="bibr" rid="pbio-0030011-b32">32</xref>,<xref ref-type="bibr" rid="pbio-0030011-b38">38</xref>].
# ::save-date Mon Jan 4, 2016 ::file pmid_1563_0473_193.txt
(p / play-08
      :ARG0 (a / and
            :op1 (s2 / signal-07
                  :ARG0 (p2 / protein :name (n / name :op1 "Sonic" :op2 "hedgehog")
                        :ARG1-of (d3 / describe-01
                              :ARG2 (n5 / name :op1 "Shh"))))
            :op2 (s3 / signal-07
                  :ARG0 (p7 / protein :name (n2 / name :op1 "TGF-β2"))))
      :ARG1 (m / morphogenesis
            :mod (f / follicle))
      :mod (a2 / also)
      :concession (f2 / form-01
                  :ARG1 (b / bud
                        :mod (h2 / hair)
                        :quant (s4 / some))
                  :mod (s5 / still)
                  :condition (a5 / absent-01
                        :ARG1 (a3 / and
                              :op1 (p3 / protein :name (n3 / name :op1 "LEF-1"))
                              :op2 p2
                              :op3 p7)
                        :ARG1-of (d2 / describe-01
                              :ARG0 (p6 / publication
                                    :ARG1-of (c3 / cite-01
                                          :ARG2 (a4 / and :op1 32 :op2 38)))))
                  :ARG1-of (c / contrast-01
                        :ARG2 (s7 / skin
                              :ARG2-of (a6 / absent-01
                                    :ARG1 (i / invaginate-01
                                          :ARG1 (f3 / follicle)))
                              :ARG0-of (c4 / contain-01
                                    :ARG1 (p4 / protein :name (n4 / name :op1 "β-catenin")
                                          :ARG2-of (m2 / mutate-01 :mod "−/−")))
                              :ARG1-of (d / describe-01
                                    :ARG0 (p5 / publication
                                          :ARG1-of (c2 / cite-01
                                                :ARG2 30))))))
      :mod (e / essential))

# ::id pmid_1563_0473.194 ::date 2015-03-23T05:17:32 ::annotator SDL-AMR-09 ::preferred
# ::snt These likely reflect the first wave of follicle (i.e., guard hair) morphogenesis, which accounts for a small number (fewer than 5%) of hairs and is under distinct regulatory control.
# ::save-date Sun Jul 26, 2015 ::file pmid_1563_0473_194.txt
(l / likely-01
      :ARG1 (r / reflect-01
            :ARG1 (t / this)
            :ARG2 (w / wave-04
                  :ARG1 (m / morphogenesis
                        :mod (f / follicle))
                  :ord (o / ordinal-entity :value 1)
                  :ARG0-of (a / account-01
                        :ARG1 (h3 / hair
                              :quant (n / number
                                    :mod (s / small)
                                    :ARG0-of (m3 / mean-01
                                          :ARG1 (l2 / less-than
                                                :op1 (p / percentage-entity :value 5))))))
                  :ARG1-of (c / control-01
                        :mod (d / distinct)
                        :ARG0-of (r2 / regulate-01))
                  :ARG0-of (m2 / mean-01
                        :ARG1 (h2 / hair
                              :mod (g / guard))))))

# ::id pmid_1563_0473.195 ::date 2015-03-23T05:30:06 ::annotator SDL-AMR-09 ::preferred
# ::snt Guard hairs form in the absence of LEF-1 and TGF-β2, and we have found that they also fail to express Snail at the budding stage of development (unpublished data).
# ::save-date Wed Dec 30, 2015 ::file pmid_1563_0473_195.txt
(a / and
      :op1 (f / form-01
            :ARG1 (h / hair
                  :mod (g / guard))
            :condition (a4 / absent-01
                  :ARG1 (a2 / and
                        :op1 (p / protein :name (n / name :op1 "LEF-1"))
                        :op2 (p3 / protein :name (n2 / name :op1 "TGF-β2")))))
      :op2 (f2 / find-01
            :ARG0 (w / we)
            :ARG1 (f3 / fail-01
                  :ARG1 h
                  :ARG2 (e / express-03
                        :ARG1 h
                        :ARG2 (p4 / protein :name (n3 / name :op1 "Snail")))
                  :mod (a3 / also)
                  :time (s2 / stage
                        :subevent-of (d / develop-02)
                        :mod (b2 / bud-01))))
      :ARG1-of (d2 / describe-01
            :ARG0 (d3 / data
                  :ARG1-of (p2 / publish-01 :polarity -))))

# ::id pmid_1563_0473.196 ::date 2015-03-23T05:58:02 ::annotator SDL-AMR-09 ::preferred
# ::snt How E-cadherin is regulated in guard hairs remains to be determined.
# ::save-date Mon Mar 23, 2015 ::file pmid_1563_0473_196.txt
(r / remain-01
      :ARG1 (d / determine-01
            :ARG1 (t / thing
                  :manner-of (r2 / regulate-01
                        :ARG1 (p / protein :name (n / name :op1 "E-cadherin"))
                        :location (h / hair
                              :mod (g / guard))))))

# ::id pmid_1563_0473.197 ::date 2015-03-23T05:59:56 ::annotator SDL-AMR-09 ::preferred
# ::snt Several candidates include other Snail family members such as Slug or twist, or alternatively, transcription factors involving β-catenin and a different member of the LEF-1/TCF/<i>Sry</i>-type HMG box (commonly known as SOX) family [<xref ref-type="bibr" rid="pbio-0030011-b39">39</xref>,<xref ref-type="bibr" rid="pbio-0030011-b40">40</xref>].
# ::save-date Sat Feb 13, 2016 ::file pmid_1563_0473_197.txt
(i / include-01
      :ARG1 (o3 / or
            :op1 (m / member
                  :mod (o / other)
                  :example (o2 / or
                        :op1 (p8 / protein :name (n2 / name :op1 "Slug"))
                        :op2 (p9 / protein :name (n3 / name :op1 "twist")))
                  :ARG1-of (i3 / include-91
                        :ARG2 (p4 / protein-family :name (n / name :op1 "Snail"))))
            :op2 (f2 / factor
                  :ARG0-of (t / transcribe-01)
                  :ARG2-of (i2 / involve-01
                        :ARG1 (a2 / and
                              :op1 (p / protein :name (n4 / name :op1 "β-catenin"))
                              :op2 (m2 / member
                                    :ARG1-of (d / differ-02)
                                    :ARG1-of (i4 / include-91
                                          :ARG2 (s2 / slash
                                                :op1 (p2 / protein-family :name (n6 / name :op1 "LEF-1"))
                                                :op2 (p5 / protein-family :name (n7 / name :op1 "TCF"))
                                                :op3 (p6 / protein-family :name (n8 / name :op1 "Sry-type" :op2 "HMG" :op3 "box")
                                                      :ARG1-of (k / know-02
                                                            :ARG2 (n5 / name :op1 "SOX")
                                                            :manner (c2 / common)))))))))
            :manner (a / alternative))
      :ARG2 (c / candidate
            :quant (s / several))
      :ARG1-of (d2 / describe-01
            :ARG0 (p3 / publication
                  :ARG1-of (c3 / cite-01
                        :ARG2 (a4 / and :op1 39 :op2 40)))))

# ::id pmid_1563_0473.198 ::date 2015-03-23T06:31:38 ::annotator SDL-AMR-09 ::preferred
# ::snt Further investigation will be required to determine whether the signaling pathway we have elucidated here is a theme with multiple variations.
# ::save-date Fri Jan 1, 2016 ::file pmid_1563_0473_198.txt
(r / require-01
      :ARG1 (i / investigate-01
            :degree (f / further))
      :purpose (d / determine-01
            :ARG0 w
            :ARG1 (t / theme :mode interrogative
                  :domain (p / pathway
                        :ARG0-of (s / signal-07)
                        :ARG1-of (e / elucidate-01
                              :ARG0 (w / we)
                              :location (h / here)))
                  :ARG0-of (v / vary-01
                        :mod (m / multiple)))))

# ::id pmid_1563_0473.199 ::date 2015-03-23T06:43:10 ::annotator SDL-AMR-09 ::preferred
# ::snt TGF-βs are known to promote withdrawal of keratinocytes from the cell cycle [<xref ref-type="bibr" rid="pbio-0030011-b41">41</xref>].
# ::save-date Mon Jul 20, 2015 ::file pmid_1563_0473_199.txt
(k / know-01
      :ARG1 (p / promote-02
            :ARG0 (p3 / protein :name (n / name :op1 "TGF-β"))
            :ARG1 (w / withdraw-01
                  :ARG1 (c / cell :name (n2 / name :op1 "keratinocyte"))
                  :ARG2 (c2 / cycle-02
                        :ARG1 (c3 / cell))))
      :ARG1-of (d / describe-01
            :ARG0 (p2 / publication
                  :ARG1-of (c4 / cite-01
                        :ARG2 41))))

# ::id pmid_1563_0473.200 ::date 2015-03-23T06:46:50 ::annotator SDL-AMR-09 ::preferred
# ::snt Hence, when TGF-β2 protein was detected at the transition between the growing and destructive phases of the adult hair cycle, research initially and naturally focused on a role for this family member in cessation of growth and/or triggering apoptosis ([<xref ref-type="bibr" rid="pbio-0030011-b42">42</xref>] and references therein).
# ::save-date Wed Mar 9, 2016 ::file pmid_1563_0473_200.txt
(i2 / infer-01
      :ARG1 (f / focus-01
            :ARG1 (r / research-01)
            :ARG2 (r2 / role
                  :poss (m / member
                        :part-of (p5 / protein-family
                              :mod (t / this)))
                  :purpose (a4 / and-or
                        :op1 (c / cease-01
                              :ARG1 (g / grow-01))
                        :op2 (t2 / trigger-01
                              :ARG1 (a / apoptosis))))
            :time (i / initial)
            :ARG1-of (n / natural-03)
            :time (d / detect-01
                  :ARG1 (p / protein :name (n2 / name :op1 "TGF-β2")))
            :time (t3 / transition-01
                  :ARG2 (p3 / phase
                        :mod (d2 / destroy-01)
                        :subevent-of (c2 / cycle-02
                              :ARG1 (h / hair
                                    :mod (a2 / adult))))
                  :ARG3 (p2 / phase
                        :mod (g2 / grow-01)
                        :subevent-of c2)))
      :ARG1-of (d3 / describe-01
            :ARG0 (p4 / publication
                  :ARG1-of (c3 / cite-01
                        :ARG2 (a3 / and :op1 42
                              :op2 (r3 / reference
                                    :location (h2 / herein)))))))

# ::id pmid_1563_0473.201 ::date 2015-03-23T07:01:44 ::annotator SDL-AMR-09 ::preferred
# ::snt However, in contrast to <i>TGF-β1</i>-null skin, which exhibits an extended growing phase of postnatal hair follicles, <i>TGF-β2</i>-null skin displays an embryonic block in follicle bud progression [<xref ref-type="bibr" rid="pbio-0030011-b32">32</xref>].
# ::save-date Thu Apr 30, 2015 ::file pmid_1563_0473_201.txt
(h2 / have-concession-91
      :ARG2 (d / display-01
            :ARG0 (s / skin
                  :ARG0-of (c / contain-01
                        :ARG1 (p6 / protein :name (n / name :op1 "TGF-β2")
                              :ARG2-of (m / mutate-01 :mod "−/−"))))
            :ARG1 (b / block
                  :mod (e / embryo)
                  :time (p2 / progress-01
                        :ARG1 (b2 / bud
                              :mod (f / follicle))))
            :ARG1-of (c2 / contrast-01
                  :ARG2 (s2 / skin
                        :ARG0-of (e2 / exhibit-01
                              :ARG1 (p4 / phase
                                    :mod (g / grow-01
                                          :ARG1 (f2 / follicle
                                                :mod (h / hair)
                                                :mod (p5 / postnatal)))
                                    :ARG1-of (e3 / extend-01)))
                        :ARG0-of (c3 / contain-01
                              :ARG1 (p3 / protein :name (n2 / name :op1 "TGF-β1")
                                    :ARG2-of m)))))
      :ARG1-of (d2 / describe-01
            :ARG0 (p / publication
                  :ARG1-of (c4 / cite-01
                        :ARG2 32))))

# ::id pmid_1563_0473.202 ::date 2015-03-23T07:17:53 ::annotator SDL-AMR-09 ::preferred
# ::snt Although this phenotype is consistent with TGF-β2's embryonic expression patterns [<xref ref-type="bibr" rid="pbio-0030011-b33">33</xref>], about 50% of <i>TGF-β2</i> null buds appear unable to progress to the down-growth phase, a feature that cannot be explained readily on the basis of previously established effects of TGF-βs.
# ::save-date Mon Dec 21, 2015 ::file pmid_1563_0473_202.txt
(a / appear-02
      :ARG1 (i / include-91
            :ARG2 (b / bud
                  :ARG0-of (c4 / contain-01
                        :ARG1 (p3 / protein :name (n / name :op1 "TGF-β2")
                              :ARG2-of (m / mutate-01 :mod "−/−"))))
            :ARG3 (a4 / about
                  :op1 (p4 / percentage-entity :value 50))
            :ARG1-of (c / capable-01 :polarity -
                  :ARG2 (p5 / progress-01
                        :ARG4 (p6 / phase
                              :mod (g / grow-01
                                    :ARG1-of (d / down-03))))
                  :ARG0-of (m2 / mean-01
                        :ARG1 (f / feature
                              :ARG1-of (p2 / possible-01 :polarity -)
                              :ARG1-of (e / explain-01
                                    :ARG0 (a3 / affect-01
                                          :ARG0 (p10 / protein :name (n2 / name :op1 "TGF-β"))
                                          :ARG1-of (e2 / establish-01
                                                :time (p7 / previous)))
                                    :manner (r / ready))))))
      :concession (c2 / consistent-01
            :ARG1 (p / phenotype
                  :mod (t / this))
            :ARG2 (p9 / pattern
                  :path-of (e3 / express-03
                        :ARG2 p3
                        :ARG3 (e4 / embryo)))
            :ARG1-of (d2 / describe-01
                  :ARG0 (p8 / publication
                        :ARG1-of (c3 / cite-01
                              :ARG2 33)))))

# ::id pmid_1563_0473.203 ::date 2015-03-23T07:18:42 ::annotator SDL-AMR-09 ::preferred
# ::snt Our finding that TGF-β2 is upstream from Ki67 expression and MAPK activation lends further support to the notion that hair follicle keratinocytes at this early stage of development react to TGF-β2 signaling in a fashion opposite to that typically expected for TGF-β factors.
# ::save-date Sun Jan 17, 2016 ::file pmid_1563_0473_203.txt
(l / lend-01
      :ARG0 (f5 / find-01
            :ARG0 (w / we)
            :ARG1 (p2 / protein :name (n2 / name :op1 "TGF-β2")
                  :location (r / relative-position
                              :op1 (a / and
                                    :op1 (e / express-03
                                          :ARG2 (p3 / protein :name (n3 / name :op1 "Ki67")))
                                    :op2 (a2 / activate-01
                                          :ARG1 (p / pathway :name (n / name :op1 "MAPK"))))
                              :direction (u / upstream))))
      :ARG1 (s / support-01
            :ARG0 f5
            :degree (f2 / further))
      :ARG2 (n4 / notion
            :ARG0-of (m2 / mean-01
                  :ARG1 (r2 / react-01
                        :ARG0 (c / cell :name (n5 / name :op1 "keratinocyte")
                              :part-of (f3 / follicle
                                    :mod (h / hair)))
                        :ARG1 (s3 / signal-07
                              :ARG0 p2)
                        :ARG2 (f4 / fashion
                              :ARG1-of (o / opposite-01
                                    :ARG2 (f / fashion
                                          :ARG1-of (e2 / expect-01
                                                :ARG1-of (t / typical-02)
                                                :topic (p4 / protein :name (n6 / name :op1 "TGF-β" :op2 "factor"))))))
                        :time (e3 / early
                              :op1 (s2 / stage
                                    :subevent-of (d / develop-02)
                                    :mod (t4 / this)))))))

# ::id pmid_1563_0473.204 ::date 2015-03-23T07:22:07 ::annotator SDL-AMR-09 ::preferred
# ::snt This said, based upon pSMAD2 immunohistochemistry, the immediate steps of downstream signaling appeared to be intact.
# ::save-date Wed Dec 30, 2015 ::file pmid_1563_0473_204.txt
(a / appear-02
      :ARG1 (i2 / intact
            :domain (s / step-01
                  :ARG1 (s2 / signal-07
                        :location (d / downstream))
                  :mod (i / immediate)))
      :time (a2 / after
            :op1 (s3 / say-01
                  :ARG1 (t / this)))
      :ARG1-of (b / base-02
            :ARG2 (i3 / immunohistochemistry
                  :instrument (p2 / protein :name (n2 / name :op1 "SMAD2")
                        :ARG3-of (p / phosphorylate-01)))))

# ::id pmid_1563_0473.205 ::date 2015-03-23T07:29:46 ::annotator SDL-AMR-09 ::preferred
# ::snt Thus, we surmise that the proliferative outcome is likely to be rooted in differences in the repertoire of activated SMAD target genes.
# ::save-date Mon Mar 30, 2015 ::file pmid_1563_0473_205.txt
(i / infer-01
      :ARG1 (s / surmise-01
            :ARG0 (w / we)
            :ARG1 (l / likely-01
                  :ARG1 (r / root-02
                        :ARG1 (o / outcome
                              :ARG1-of (c / cause-01
                                    :ARG0 (p / proliferate-01)))
                        :ARG2 (d / differ-02
                              :ARG1 (r2 / repertoire
                                    :consist-of (g / gene
                                          :ARG1-of (a / activate-01)
                                          :ARG1-of (t / target-01
                                                :ARG0 (p2 / protein :name (n / name :op1 "SMAD"))))))))))

# ::id pmid_1563_0473.206 ::date 2015-03-23T07:37:51 ::annotator SDL-AMR-09 ::preferred
# ::snt In this regard, the positive effects of TGF-β2 on proliferation within the hair bud may be more analogous to what has been seen in progression of squamous cell carcinoma to metastatic carcinoma [<xref ref-type="bibr" rid="pbio-0030011-b43">43</xref>] rather than that typically observed for keratinocytes [<xref ref-type="bibr" rid="pbio-0030011-b44">44</xref>,<xref ref-type="bibr" rid="pbio-0030011-b45">45</xref>,<xref ref-type="bibr" rid="pbio-0030011-b46">46</xref>].
# ::save-date Wed Mar 2, 2016 ::file pmid_1563_0473_206.txt
(a4 / analogous
      :domain (a / affect-01
            :ARG0 (p3 / protein :name (n / name :op1 "TGF-β2"))
            :ARG1 (p4 / proliferate-01)
            :mod (p2 / positive)
            :location (b / bud
                  :mod (h / hair)))
      :purpose (t4 / this)
      :degree (m / more)
      :prep-to (t / thing
            :ARG1-of (s / see-01
                  :ARG2 (p5 / progress-01
                        :ARG1 (c / carcinoma
                              :mod (c6 / cell
                                    :mod (s2 / squamous)))
                        :ARG4 (c2 / carcinoma
                              :ARG1-of (m2 / metastasize-101))))
            :ARG1-of (d2 / describe-01
                  :ARG0 (p7 / publication
                        :ARG1-of (c5 / cite-01
                              :ARG2 43)))
            :ARG1-of (i / instead-of-91
                  :ARG2 (t2 / that
                        :ARG1-of (o / observe-01
                              :ARG1-of (t3 / typical-02)
                              :location (c3 / cell :name (n2 / name :op1 "keratinocyte"))))
                  :ARG1-of (d / describe-01
                        :ARG0 (p6 / publication
                              :ARG1-of (c4 / cite-01
                                    :ARG2 (a3 / and :op1 44 :op2 45 :op3 46))))))
      :ARG1-of (p / possible-01))

# ::id pmid_1563_0473.207 ::date 2015-03-23T07:56:26 ::annotator SDL-AMR-09 ::preferred
# ::snt The prior identification of the <i>Snail</i> gene as a potential target of TGF-β signaling [<xref ref-type="bibr" rid="pbio-0030011-b15">15</xref>] was intriguing, given the temporal wave of <i>Snail</i> gene expression that occurs in the developing hair bud.
# ::save-date Sun Jan 17, 2016 ::file pmid_1563_0473_207.txt
(i / intrigue-01
      :ARG0 (i2 / identify-01
            :ARG1 (g / gene :name (n / name :op1 "Snail"))
            :ARG2 (t / target-01
                  :ARG1-of (s / signal-07
                        :ARG0 (p4 / protein :name (n2 / name :op1 "TGF-β")))
                  :mod (p3 / potential))
            :time (p / prior)
            :ARG1-of (d / describe-01
                  :ARG0 (p2 / publication
                        :ARG1-of (c / cite-01
                              :ARG2 15))))
      :ARG1-of (c2 / cause-01
            :ARG0 (w / wave-04
                  :ARG1 (e / express-03
                        :ARG1 g
                        :location (b / bud
                              :mod (h / hair)
                              :ARG1-of (d2 / develop-02)))
                  :mod (t2 / time))))

# ::id pmid_1563_0473.208 ::date 2015-03-23T08:06:57 ::annotator SDL-AMR-09 ::preferred
# ::snt The additional correlation between epithelial hyperproliferation and <i>Snail</i> transgene expression further fostered our interest in a possible link between TGF-β2 and Snail.
# ::save-date Wed Dec 30, 2015 ::file pmid_1563_0473_208.txt
(f / foster-01
      :ARG0 (c / correlate-01
            :ARG1 (p / proliferate-01
                  :ARG0 (e / epithelium)
                  :degree (h / hyper))
            :ARG2 (e2 / express-03
                  :ARG1 (g / gene :name (n / name :op1 "Snail")
                        :ARG2-of (m / mutate-01)))
            :ARG1-of (a / add-02))
      :ARG1 (i / interest-01
            :ARG0 (w / we)
            :ARG2 (l / link-01
                  :ARG1 (p4 / protein :name (n2 / name :op1 "TGF-β2"))
                  :ARG2 (p3 / protein :name (n3 / name :op1 "Snail"))
                  :ARG1-of (p2 / possible-01)))
      :degree (f2 / further))

# ::id pmid_1563_0473.209 ::date 2015-03-23T08:12:25 ::annotator SDL-AMR-09 ::preferred
# ::snt Our functional studies demonstrate that without TGF-β2, <i>Snail</i> expression is abolished in the mutant hair buds, and conversely, in <i>K14-Smad2</i> skin, <i>Snail</i> is ectopically activated.
# ::save-date Wed Dec 30, 2015 ::file pmid_1563_0473_209.txt
(d / demonstrate-01
      :ARG0 (s / study-01
            :ARG0 (w / we)
            :mod (f / function-01))
      :ARG1 (a / and
            :op1 (a2 / abolish-01
                  :ARG1 (e / express-03
                        :ARG1 (g / gene :name (n / name :op1 "Snail")))
                  :location (b / bud
                        :ARG1-of (m / mutate-01)
                        :mod (h / hair)))
            :op2 (a3 / activate-01
                  :ARG1 g
                  :manner (e2 / ectopic)
                  :location (s2 / skin
                        :ARG0-of (c2 / contain-01
                              :ARG1 (g2 / gene :name (n3 / name :op1 "K14-Smad2"))))
                  :ARG2-of (c / contrast-01
                        :ARG1 a2)))
      :condition (b2 / be-located-at-91 :polarity -
            :ARG1 (p / protein :name (n2 / name :op1 "TGF-β2"))))

# ::id pmid_1563_0473.210 ::date 2015-03-23T08:23:04 ::annotator SDL-AMR-09 ::preferred
# ::snt Moreover, our in vitro studies indicate that even sustained TGF-β2 exposure may cause only a transient induction of Snail, offering a possible explanation as to why Snail is so briefly expressed during hair follicle morphogenesis.
# ::save-date Fri Jul 24, 2015 ::file pmid_1563_0473_210.txt
(a / and
      :op2 (i / indicate-01
            :ARG0 (s / study-01
                  :ARG0 (w / we)
                  :manner (i2 / in-vitro))
            :ARG1 (p / possible-01
                  :ARG1 (c / cause-01
                        :ARG0 (e / expose-01
                              :ARG1 (p4 / protein :name (n / name :op1 "TGF-β2"))
                              :ARG1-of (s3 / sustain-01)
                              :mod (e2 / even))
                        :ARG1 (i3 / induce-01
                              :ARG2 (p2 / protein :name (n2 / name :op1 "Snail"))
                              :ARG1-of (t / transient-02)
                              :mod (o / only))))
            :ARG0-of (o2 / offer-01
                  :ARG1 (e3 / explain-01
                        :ARG1 (t2 / thing
                              :ARG0-of (c2 / cause-01
                                    :ARG1 (e4 / express-03
                                          :ARG2 p2
                                          :manner (b / brief
                                                :degree (s4 / so))
                                          :time (m / morphogenesis
                                                :mod (f / follicle
                                                      :mod (h / hair))))))
                        :ARG1-of (p3 / possible-01)))))

# ::id pmid_1563_0473.211 ::date 2015-03-24T01:41:47 ::annotator SDL-AMR-09 ::preferred
# ::snt An additional point worth mentioning is that prolonged expression of Tg <i>Snail</i> in postnatal skin resulted in morphological and biochemical signs of epithelial to mesenchymal transitions (unpublished data), underscoring why transient Snail expression may be so important during normal hair follicle morphogenesis [<xref ref-type="bibr" rid="pbio-0030011-b18">18</xref>].
# ::save-date Wed Jan 20, 2016 ::file pmid_1563_0473_211.txt
(w / worth-02
      :ARG2 (m / mention-01
            :ARG1 (p / point
                  :ARG1-of (a / add-02)
                  :ARG0-of (m2 / mean-01
                        :ARG1 (r / result-01
                              :ARG1 (e / express-03
                                    :ARG1 (g / gene :name (n / name :op1 "Snail")
                                          :mod (t4 / transgenic))
                                    :ARG3 (s / skin
                                          :mod (p3 / postnatal))
                                    :ARG1-of (p2 / prolong-01))
                              :ARG2 (a2 / and
                                    :op1 (s4 / signal-07
                                          :ARG1 (t / transition-01
                                                :ARG2 (m5 / mesenchyme)
                                                :ARG3 (e2 / epithelium))
                                          :mod (m3 / morphological))
                                    :op2 (s5 / signal-07
                                          :ARG1 t
                                          :mod (b / biochemical)))
                              :ARG1-of (d / describe-01
                                    :ARG0 (d2 / data
                                          :ARG1-of (p4 / publish-01 :polarity -)))
                              :ARG0-of (u / underscore-01
                                    :ARG1 (t3 / thing
                                          :ARG0-of (c2 / cause-01
                                                :ARG1 (p5 / possible-01
                                                      :ARG1 (i / important
                                                            :degree (s3 / so)
                                                            :domain (e3 / express-03
                                                                  :ARG1 g
                                                                  :ARG1-of (t2 / transient-02))
                                                            :time (m6 / morphogenesis
                                                                  :ARG1-of (n2 / normal-02)
                                                                  :mod (f / follicle
                                                                        :mod (h / hair)))))))
                                    :ARG1-of (d3 / describe-01
                                          :ARG0 (p6 / publication
                                                :ARG1-of (c / cite-01
                                                      :ARG2 18)))))))))

# ::id pmid_1563_0473.212 ::date 2015-03-27T09:33:16 ::annotator SDL-AMR-09 ::preferred
# ::snt At first glance, the sparsity in hair coat of K14-<i>Snail</i> Tg mice seemed indicative of a defect in follicle formation (see <xref ref-type="fig" rid="pbio-0030011-g002">Figure 2</xref>A).
# ::save-date Thu Jan 14, 2016 ::file pmid_1563_0473_212.txt
(s / seem-01
      :ARG1 (i / indicate-01
            :ARG0 (s2 / sparse
                  :domain (c / coat
                        :mod (h / hair)
                        :part-of (m / mouse
                              :mod (t / transgenic)
                              :mod (p2 / protein :name (n2 / name :op1 "Snail")
                                    :ARG2-of (m3 / mutate-01 :value "K14")))))
            :ARG1 (d / defect-01
                  :ARG1 (f / form-01
                        :ARG1 (f2 / follicle))))
      :time (g / glance-01
            :mod (o / ordinal-entity :value 1))
      :ARG1-of (s3 / see-01
            :ARG2 (f3 / figure :mod "2A")))

# ::id pmid_1563_0473.213 ::date 2015-03-28T12:21:52 ::annotator SDL-AMR-09 ::preferred
# ::snt Closer inspection, however, revealed that not all hairs penetrated the hyperthickened Tg epidermis.
# ::save-date Mon Apr 6, 2015 ::file pmid_1563_0473_213.txt
(h3 / have-concession-91
      :ARG1 (r / reveal-01
            :ARG0 (i / inspect-01
                  :ARG1-of (c / close-10
                        :degree (m / more)))
            :ARG1 (p / penetrate-01 :polarity -
                  :ARG0 (h / hair
                        :mod (a / all))
                  :ARG1 (e / epidermis
                        :mod (t / transgenic)
                        :ARG1-of (t2 / thicken-01
                              :degree (h2 / hyper))))))

# ::id pmid_1563_0473.214 ::date 2015-03-29T07:16:48 ::annotator SDL-AMR-09 ::preferred
# ::snt Several factors may contribute to the seemingly normal follicle development in these mice.
# ::save-date Fri Jul 24, 2015 ::file pmid_1563_0473_214.txt
(p / possible-01
      :ARG1 (c / contribute-01
            :ARG0 (f / factor
                  :quant (s / several))
            :ARG2 (d2 / develop-02
                  :ARG1 (f2 / follicle
                        :ARG1-of (n / normal-02
                              :ARG1-of (s2 / seem-01)))
                  :location (m / mouse
                        :mod (t / this)))))

# ::id pmid_1563_0473.215 ::date 2015-03-29T07:22:37 ::annotator SDL-AMR-09 ::preferred
# ::snt One obvious factor is the K14 promoter, which is elevated in the basal layer of the epidermis and the outer root sheath (ORS) of the hair follicle, but is markedly down-regulated in developing embryonic hair buds as well as in the postnatal hair progenitor cells.
# ::save-date Wed Oct 28, 2015 ::file pmid_1563_0473_215.txt
(c / contrast-01
      :ARG1 (f / factor :quant 1
            :domain (m3 / molecular-physical-entity
                  :ARG0-of (p / promote-01
                        :ARG1 (p2 / protein :name (n / name :op1 "K14"))))
            :ARG1-of (o / obvious-01)
            :ARG1-of (e / elevate-01
                  :location (a / and
                        :op1 (l / layer
                              :mod (b / basal)
                              :part-of (e2 / epidermis))
                        :op2 (s / sheath
                              :part-of (r / root)
                              :mod (o2 / outer)
                              :part-of (f2 / follicle
                                    :mod (h / hair))))))
      :ARG2 (d / downregulate-01
            :ARG1 f
            :manner (m2 / marked)
            :location (a2 / and
                  :op1 (b2 / bud
                        :mod (h2 / hair)
                        :ARG1-of (d2 / develop-02)
                        :mod (e3 / embryo))
                  :op2 (c2 / cell
                        :mod (p3 / progenitor)
                        :part-of (h3 / hair)
                        :time (p4 / postnatal)))))

# ::id pmid_1563_0473.216 ::date 2015-03-30T03:47:01 ::annotator SDL-AMR-09 ::preferred
# ::snt The K14 promoter is also less active in the ORS than epidermis and hence this might also account for the lack of apparent response of the ORS to ectopic Snail.
# ::save-date Wed Dec 30, 2015 ::file pmid_1563_0473_216.txt
(c / cause-01
      :ARG0 (a / activity-06
            :ARG0 (m / molecular-physical-entity
                  :ARG0-of (p / promote-01
                        :ARG1 (p2 / protein :name (n / name :op1 "K14"))))
            :degree (l / less)
            :location (s / sheath
                  :part-of (r2 / root
                        :mod (o / outer)))
            :compared-to (e / epidermis))
      :ARG1 (p4 / possible-01
            :ARG1 (a2 / account-01
                  :ARG0 a
                  :ARG1 (l2 / lack-01
                        :ARG1 (r / respond-01
                              :ARG0 s
                              :ARG1 (p5 / protein :name (n3 / name :op1 "Snail")
                                    :mod (e2 / ectopic))
                              :ARG1-of (a4 / appear-02)))
                  :mod (a3 / also))))

# ::id pmid_1563_0473.217 ::date 2015-03-30T02:56:21 ::annotator SDL-AMR-09 ::preferred
# ::snt Additional contributing factors could be the multiplicity of Snail family members and their differential expression, the saturation, and/or diversity of regulatory mechanisms that govern AJ formation, migration, and proliferation in the follicle ORS.
# ::save-date Fri Jan 1, 2016 ::file pmid_1563_0473_217.txt
(p / possible-01
      :ARG1 (f / factor
            :domain (a / and
                  :op1 (m / multiply-01
                        :ARG1 (a3 / and
                              :op1 (m2 / member
                                    :ARG1-of (i / include-91
                                          :ARG2 (p2 / protein-family :name (n / name :op1 "Snail"))))))
                  :op2 (e / express-03
                        :ARG1 m2
                        :ARG1-of (d2 / differ-02))
                  :op3 (a5 / and-or
                        :op1 (s / saturate-01
                              :ARG1 m3)
                        :op2 (d / diversity
                              :domain (m3 / mechanism
                                    :ARG0-of (r / regulate-01)
                                    :ARG0-of (g / govern-01
                                          :ARG1 (a4 / and
                                                :op1 (f3 / form-01
                                                      :ARG1 (p4 / protein :name (n2 / name :op1 "AJ")))
                                                :op2 (m4 / migrate-01
                                                      :ARG0 p4)
                                                :op3 (p3 / proliferate-01
                                                      :ARG0 p4
                                                      :location (f4 / follicle :name (n3 / name :op1 "ORS")))))))))
            :ARG1-of (a2 / add-02)
            :ARG0-of (c / contribute-01)))

# ::id pmid_1563_0473.218 ::date 2015-03-29T09:06:50 ::annotator SDL-AMR-09 ::preferred
# ::snt Distinguishing between these possibilities must await the generation of mice harboring skin-specific loss-of-function <i>Snail</i> mutations.
# ::save-date Thu Jan 14, 2016 ::file pmid_1563_0473_218.txt
(o2 / obligate-01
      :ARG2 (a / await-01
            :ARG1 (d / distinguish-01
                  :ARG1 (t / thing
                        :ARG1-of (p / possible-01)
                        :mod (t2 / this)))
            :ARG2 (g / generation
                  :mod (m / mouse
                        :ARG0-of (h / harbor-01
                              :ARG1 (m3 / mutate-01
                                    :ARG1 (g2 / gene :name (n / name :op1 "Snail"))
                                    :ARG0-of (l / lose-02
                                          :ARG1 (f / function))
                                    :ARG1-of (s2 / specific-02
                                          :ARG2 (s / skin))))))))

# ::id pmid_1563_0473.219 ::date 2015-03-29T07:23:27 ::annotator SDL-AMR-09 ::preferred
# ::snt Links between Signaling, Transcriptional Cascades, Epithelial Remodeling, and Proliferation in the Hair Bud
# ::save-date Sun Dec 20, 2015 ::file pmid_1563_0473_219.txt
(l / link-01
      :ARG1 (s / signal-07)
      :ARG2 (a / and
            :op1 (c / cascade
                  :ARG0-of (t / transcribe-01))
            :op2 (r / remodel-01
                  :ARG1 (e / epithelium))
            :op2 (p / proliferate-01)
            :location (b / bud
                  :mod (h / hair))))

# ::id pmid_1563_0473.220 ::date 2015-03-29T07:27:35 ::annotator SDL-AMR-09 ::preferred
# ::snt Previously, we discovered that early during hair follicle morphogenesis, <i>E-cadherin</i> gene expression is down-regulated concomitantly with the invagination of developing bud cells into the skin [<xref ref-type="bibr" rid="pbio-0030011-b04">4</xref>].
# ::save-date Wed Jun 24, 2015 ::file pmid_1563_0473_220.txt
(d / discover-01
      :ARG0 (w / we)
      :ARG1 (d2 / downregulate-01
            :ARG1 (e / express-03
                  :ARG2 (g / gene :name (n / name :op1 "E-cadherin")))
            :time (i / invaginate-01
                  :ARG1 (c / cell
                        :part-of (b / bud)
                        :ARG1-of (d3 / develop-02))
                  :ARG2 (s / skin))
            :time (e2 / early
                  :op1 (m / morphogenesis
                        :mod (f / follicle
                              :mod (h / hair))))
            :manner (c3 / concomitant))
      :time (p / previous)
      :ARG1-of (d4 / describe-01
            :ARG0 (p2 / publication
                  :ARG1-of (c2 / cite-01
                        :ARG2 4))))

# ::id pmid_1563_0473.221 ::date 2015-03-29T07:46:39 ::annotator SDL-AMR-09 ::preferred
# ::snt Because the timing of this event correlated with the activation of a LEF-1/β-catenin transcription factor complex [<xref ref-type="bibr" rid="pbio-0030011-b20">20</xref>], we were intrigued by the presence of a putative LEF-1/TCF binding site in the <i>E-cadherin</i> promoter.
# ::save-date Sun Jan 17, 2016 ::file pmid_1563_0473_221.txt
(c / cause-01
      :ARG0 (c2 / correlate-01
            :ARG1 (t2 / time-02
                  :ARG1 (e / event
                        :mod (t3 / this)))
            :ARG2 (a / activate-01
                  :ARG1 (m2 / macro-molecular-complex
                        :part p7
                        :part (p5 / protein :name (n4 / name :op1 "β-catenin"))
                        :mod (f / factor
                              :ARG0-of (t4 / transcribe-01)))
                  :ARG1-of (d / describe-01
                        :ARG0 (p6 / publication
                              :ARG1-of (c3 / cite-01
                                    :ARG2 20)))))
      :ARG1 (i / intrigue-01
            :ARG0 (p3 / protein-segment
                  :ARG1-of (p4 / present-02
                        :ARG2 (m4 / molecular-physical-entity
                              :ARG0-of (p / promote-01
                                    :ARG1 (p2 / protein :name (n / name :op1 "E-cadherin")))))
                  :ARG1-of (b2 / bind-01
                        :ARG2 (m / macro-molecular-complex
                              :part (p7 / protein :name (n2 / name :op1 "LEF-1"))
                              :part (p8 / protein :name (n3 / name :op1 "TCF"))))
                  :ARG1-of (t5 / think-01))
            :ARG1 (w / we)))

# ::id pmid_1563_0473.222 ::date 2015-03-29T09:50:43 ::annotator SDL-AMR-09 ::preferred
# ::snt This prompted an investigation that subsequently led to our discovery that LEF-1/β-catenin can contribute to repression of <i>E-cadherin</i> gene expression in skin keratinocytes [<xref ref-type="bibr" rid="pbio-0030011-b04">4</xref>].
# ::save-date Sun Jan 17, 2016 ::file pmid_1563_0473_222.txt
(p / prompt-01
      :ARG0 (t / this)
      :ARG1 (i / investigate-01
            :ARG0-of (l / lead-03
                  :ARG2 (d / discover-01
                        :ARG0 (w / we)
                        :ARG1 (p5 / possible-01
                              :ARG1 (c / contribute-01
                                    :ARG0 (m / macro-molecular-complex
                                          :part (p3 / protein :name (n / name :op1 "LEF-1"))
                                          :part (p2 / protein :name (n2 / name :op1 "β-catenin")))
                                    :ARG2 (r / repress-01
                                          :ARG0 m
                                          :ARG1 (e / express-03
                                                :ARG1 (g2 / gene :name (n3 / name :op1 "E-cadherin"))
                                                :ARG3 (k / keratinocyte
                                                      :part-of (s2 / skin)))))))
                  :time (s / subsequent)))
      :ARG1-of (d2 / describe-01
            :ARG0 (p4 / publication
                  :ARG1-of (c2 / cite-01
                        :ARG2 4))))

# ::id pmid_1563_0473.223 ::date 2015-03-29T12:32:44 ::annotator SDL-AMR-09 ::preferred
# ::snt In the course of these studies, we also noted that Snail can also contribute to this process in keratinocytes in vitro, and our present studies revealed that Snail is expressed at the right place and time to be physiologically relevant in the process.
# ::save-date Wed Dec 30, 2015 ::file pmid_1563_0473_223.txt
(a / and
      :op1 (n / note-01
            :ARG0 (w / we)
            :ARG1 (p / possible-01
                  :ARG1 (c / contribute-01
                        :ARG0 (p2 / protein :name (n2 / name :op1 "Snail"))
                        :ARG2 (p3 / process-02
                              :mod t)
                        :mod (a2 / also)
                        :location (k / keratinocyte)
                        :manner (i / in-vitro)))
            :time (s / study-01
                  :mod (t / this))
            :mod (a3 / also))
      :op2 (r / reveal-01
            :ARG0 (s2 / study-01
                  :ARG0 w
                  :time (p4 / present))
            :ARG1 (e / express-03
                  :ARG2 p2
                  :ARG3 (p5 / place
                        :ARG1-of (r2 / right-03))
                  :purpose (r3 / relevant-01
                        :ARG1 p2
                        :ARG2 p3
                        :manner (p6 / physiological))
                  :time (t2 / time
                        :ARG1-of r2))))

# ::id pmid_1563_0473.224 ::date 2015-03-29T12:35:07 ::annotator SDL-AMR-09 ::preferred
# ::snt In <i>noggin</i>-null embryonic skin, LEF-1 expression and subsequent activation of the LEF-1/β-catenin reporter gene is abrogated in the developing placodes.
# ::save-date Sun Jan 17, 2016 ::file pmid_1563_0473_224.txt
(a4 / abrogate-01
      :ARG1 (a2 / and
            :op1 (e / express-03
                  :ARG2 (p4 / protein :name (n3 / name :op1 "LEF-1")))
            :op2 (a3 / activate-01
                  :ARG1 (g2 / gene
                        :ARG0-of (r / report-01
                              :ARG1 (m / macro-molecular-complex
                                    :part p4
                                    :part (p / protein :name (n4 / name :op1 "β-catenin")))))
                  :time (s2 / subsequent)))
      :location (p2 / placode
            :ARG1-of (d / develop-02))
      :location (s / skin
            :mod (e2 / embryo)
            :mod (p3 / protein :name (n / name :op1 "noggin")
                  :mod (n2 / null))))

# ::id pmid_1563_0473.225 ::date 2015-03-29T12:51:03 ::annotator SDL-AMR-09 ::preferred
# ::snt The corresponding failure of <i>E-cadherin</i> down-regulation underscores the importance of Wnt/noggin signaling in regulating this event in follicle morphogenesis [<xref ref-type="bibr" rid="pbio-0030011-b04">4</xref>].
# ::save-date Mon Apr 6, 2015 ::file pmid_1563_0473_225.txt
(u2 / underscore-01
      :ARG0 (f / fail-01
            :ARG1 (d / downregulate-01
                  :ARG1 (p / protein :name (n / name :op1 "E-cadherin")))
            :ARG1-of (c2 / correspond-02))
      :ARG1 (i / important
            :domain (s / signal-07
                  :ARG0 (s2 / slash
                        :op1 (p4 / protein :name (n5 / name :op1 "noggin"))
                        :op2 (p2 / pathway :name (n2 / name :op1 "Wnt"))))
            :purpose (r / regulate-01
                  :ARG1 (e / event
                        :mod (t / this))
                  :location (m / morphogenesis
                        :mod (f2 / follicle))))
      :ARG1-of (d2 / describe-01
            :ARG0 (p3 / publication
                  :ARG1-of (c3 / cite-01
                        :ARG2 4))))

# ::id pmid_1563_0473.226 ::date 2015-03-29T13:09:27 ::annotator SDL-AMR-09 ::preferred
# ::snt Conditional gene targeting studies will be necessary to establish whether Snail family members also contribute to the down-regulation in <i>E-cadherin</i> gene expression that occurs during follicle formation.
# ::save-date Fri Jan 1, 2016 ::file pmid_1563_0473_226.txt
(n / need-01
      :ARG1 (s / study-01
            :ARG1 (t / target-01
                  :ARG1 (g / gene)
                  :mod (c / conditional)))
      :purpose (e / establish-01
            :ARG1 (c2 / contribute-01 :mode interrogative
                  :ARG0 (m / member
                        :ARG1-of (i / include-91
                              :ARG2 (p / protein-family :name (n2 / name :op1 "Snail"))))
                  :ARG2 (d / downregulate-01
                        :ARG1 (e2 / express-03
                              :ARG2 (g2 / gene :name (n3 / name :op1 "E-cadherin"))
                              :time (f2 / form-01
                                    :ARG1 (f3 / follicle))))
                  :mod (a / also))))

# ::id pmid_1563_0473.227 ::date 2015-03-29T09:21:11 ::annotator SDL-AMR-09 ::preferred
# ::snt However, it is intriguing that <i>K14-Snail</i> Tg epidermis displayed a marked down-regulation in E-cadherin expression, thereby demonstrating its potential to do so in skin.
# ::save-date Mon Jan 25, 2016 ::file pmid_1563_0473_227.txt
(h / have-concession-91
      :ARG1 (c2 / cause-01
            :ARG0 (d2 / display-01
                  :ARG0 (e / epidermis
                        :mod (t / transgenic)
                        :mod (g / gene :name (n2 / name :op1 "Snail")
                              :ARG2-of (m / mutate-01 :value "K14")))
                  :ARG1 (d3 / downregulate-01
                        :ARG1 (e2 / express-03
                              :ARG2 (p3 / protein :name (n3 / name :op1 "E-cadherin")))
                        :ARG1-of (m2 / mark-01))
                  :ARG0-of (i / intrigue-01))
            :ARG1 (d / demonstrate-01
                  :ARG0 e
                  :ARG1 (p4 / potential
                        :topic d3
                        :location (s / skin)))))

# ::id pmid_1563_0473.228 ::date 2015-03-29T08:26:35 ::annotator SDL-AMR-09 ::preferred
# ::snt Our prior findings showed that by elevating E-cadherin levels or by conditionally ablating <i>α-catenin,</i> hair follicle morphogenesis can be impaired [<xref ref-type="bibr" rid="pbio-0030011-b04">4</xref>,<xref ref-type="bibr" rid="pbio-0030011-b07">7</xref>].
# ::save-date Fri Apr 3, 2015 ::file pmid_1563_0473_228.txt
(s2 / show-01
      :ARG0 (t / thing
            :ARG1-of (f2 / find-01
                  :ARG0 (w / we)))
      :ARG1 (p7 / possible-01
            :ARG1 (i / impair-01
                  :ARG0 (o / or
                        :op1 (e / elevate-01
                              :ARG1 (l / level
                                    :quant-of (p3 / protein :name (n / name :op1 "E-cadherin"))))
                        :op2 (a / ablate-01
                              :ARG1 (p4 / protein :name (n2 / name :op1 "α-catenin"))
                              :manner (c / conditional))
                        :ARG1-of (s / show-01))
                  :ARG1 (m / morphogenesis
                        :mod (f / follicle
                              :mod (h / hair)))))
      :time (p2 / prior)
      :ARG1-of (d / describe-01
            :ARG0 (a2 / and
                  :op1 (p5 / publication
                        :ARG1-of (c2 / cite-01
                              :ARG2 4))
                  :op2 (p6 / publication
                        :ARG1-of (c3 / cite-01
                              :ARG2 7)))))

# ::id pmid_1563_0473.229 ::date 2015-03-29T08:52:25 ::annotator SDL-AMR-09 ::preferred
# ::snt The marked epidermal hyperproliferation seen in the <i>K14-Snail</i> Tg skin, coupled with the converse suppression of proliferation and Snail in <i>TGF-β2</i>-null hair buds led us to wonder whether the down-regulation of E-cadherin during follicle morphogenesis might have a direct impact on elevating the proliferative state of these cells.
# ::save-date Thu Jan 14, 2016 ::file pmid_1563_0473_229.txt
(l / lead-03
      :ARG0 (p8 / proliferate-01
            :ARG0 (e / epidermis)
            :ARG1-of (m / mark-01)
            :ARG1-of (s / see-01
                  :location (s2 / skin
                        :mod (t / transgenic)
                        :mod (p2 / protein :name (n2 / name :op1 "Snail")
                              :ARG2-of (m4 / mutate-01 :value "K14"))))
            :ARG1-of (c / couple-01
                  :ARG2 (a / and
                        :op1 (s3 / suppress-01
                              :ARG1 (p3 / proliferate-01)
                              :mod (c2 / converse))
                        :op2 p2
                        :location (b2 / bud
                                    :mod (h2 / hair)
                                    :mod (p7 / protein :name (n4 / name :op1 "TGF-β2")
                                          :mod (n5 / null))))))
      :ARG1 (w / we)
      :ARG2 (w2 / wonder-01
            :ARG0 w
            :ARG1 (p6 / possible-01
                  :ARG1 (i / impact-01 :mode interrogative
                        :ARG0 (d2 / downregulate-01
                              :ARG1 (p4 / protein :name (n3 / name :op1 "E-cadherin"))
                              :time (m3 / morphogenesis
                                    :mod (f / follicle)))
                        :ARG1 (e2 / elevate-01
                              :ARG0 d2
                              :ARG1 (p5 / proliferate-01
                                    :ARG0 (c3 / cell
                                          :mod (t2 / this))))
                        :ARG1-of (d / direct-02)))))

# ::id pmid_1563_0473.230 ::date 2015-03-29T15:58:57 ::annotator SDL-AMR-09 ::preferred
# ::snt Our Tg studies suggested that, at least in part through its regulation of <i>E-cadherin</i>, Snail is able to influence the subcellular localization of a variety of AJ-associated proteins.
# ::save-date Thu Jan 14, 2016 ::file pmid_1563_0473_230.txt
(s / suggest-01
      :ARG0 (s2 / study-01
            :ARG0 (w / we)
            :ARG1 (t / transgenic))
      :ARG1 (p2 / possible-01
            :ARG1 (i / influence-01
                  :ARG0 (p3 / protein :name (n / name :op1 "Snail"))
                  :ARG1 (l / localize-01
                        :ARG1 (p / protein
                              :ARG1-of (a / associate-01
                                    :ARG2 (p6 / protein :name (n3 / name :op1 "AJ")))
                              :mod (v2 / variety))
                        :mod (s3 / subcellular))
                  :ARG1-of (c / cause-01
                        :ARG0 (r / regulate-01
                              :ARG0 p3
                              :ARG1 (g / gene :name (n2 / name :op1 "E-cadherin"))))
                  :degree (a2 / at-least
                        :op1 (p4 / part)))))

# ::id pmid_1563_0473.231 ::date 2015-03-29T07:47:09 ::annotator SDL-AMR-09 ::preferred
# ::snt One of these appears to be Ajuba, which was previously shown to have the dual capacity to bind Grb-2 as well as α-catenin [<xref ref-type="bibr" rid="pbio-0030011-b09">9</xref>,<xref ref-type="bibr" rid="pbio-0030011-b10">10</xref>].
# ::save-date Mon Apr 6, 2015 ::file pmid_1563_0473_231.txt
(a / appear-02
      :ARG1 (p / protein :quant 1 :name (n / name :op1 "Ajuba")
            :ARG1-of (i / include-91
                  :ARG2 (t2 / this))
            :ARG1-of (c / capable-01
                  :ARG2 (b / bind-01
                        :ARG1 p
                        :ARG2 (a2 / and
                              :op1 (p3 / protein :name (n2 / name :op1 "Grb-2"))
                              :op2 (p4 / protein :name (n3 / name :op1 "α-catenin"))))
                  :time (p2 / previous)
                  :ARG1-of (s / show-01)
                  :mod (d / dual)))
      :ARG1-of (d2 / describe-01
            :ARG0 (a3 / and
                  :op1 (p5 / publication
                        :ARG1-of (c2 / cite-01
                              :ARG2 (a4 / and :op1 9 :op2 10))))))

# ::id pmid_1563_0473.232 ::date 2015-03-29T08:25:47 ::annotator SDL-AMR-09 ::preferred
# ::snt Our studies revealed that in skin keratinocytes that either harbor a conditional null mutation in <i>α-catenin</i> or that overexpress Snail, Ajuba develops an interaction with Grb-2 that is otherwise not observed in WT keratinocytes.
# ::save-date Wed Jun 24, 2015 ::file pmid_1563_0473_232.txt
(r / reveal-01
      :ARG0 (s / study-01
            :ARG0 (w2 / we))
      :ARG1 (d / develop-02
            :ARG0 (p / protein :name (n / name :op1 "Ajuba"))
            :ARG1 (i / interact-01
                  :ARG0 p
                  :ARG1 (p2 / protein :name (n2 / name :op1 "Grb-2"))
                  :ARG1-of (o / observe-01 :polarity -
                        :mod (o2 / otherwise)
                        :location (k2 / keratinocyte
                              :mod (w / wild-type))))
            :location (o3 / or
                  :op1 (k / keratinocyte
                        :ARG0-of (h / harbor-01
                              :ARG1 (m / mutate-01
                                    :ARG1 (p3 / protein :name (n4 / name :op1 "α-catenin"))
                                    :mod (n3 / null)
                                    :mod (c / conditional)))
                        :mod (s2 / skin))
                  :op2 (k3 / keratinocyte
                        :location-of (o4 / overexpress-01
                              :ARG1 (p4 / protein :name (n5 / name :op1 "Snail")))))))

# ::id pmid_1563_0473.233 ::date 2015-03-29T15:57:50 ::annotator SDL-AMR-09 ::preferred
# ::snt The corresponding abilities of either <i>Snail</i>-transfected or <i>Ajuba</i>-transfected keratinocytes to exhibit elevated activation of the Ras-MAPK pathway suggest that the Grb-2 association of Ajuba under conditions of reduced levels of AJ proteins may be directly relevant to the parallel in hyperproliferation.
# ::save-date Thu Jan 14, 2016 ::file pmid_1563_0473_233.txt
(s / suggest-01
      :ARG0 (c / capable-01
            :ARG1 (o / or
                  :op1 (k / keratinocyte
                        :ARG1-of (t / transfect-01
                              :ARG2 (g / gene :name (n4 / name :op1 "Snail"))))
                  :op2 (k2 / keratinocyte
                        :ARG1-of (t2 / transfect-01
                              :ARG2 (g2 / gene :name (n5 / name :op1 "Ajuba")))))
            :ARG2 (e / exhibit-01
                  :ARG0 (a3 / and
                        :op1 k
                        :op2 k2)
                  :ARG1 (a2 / activate-01
                        :ARG1 (p8 / pathway :name (n6 / name :op1 "Ras-MAPK"))
                        :ARG1-of (e2 / elevate-01)))
            :ARG1-of (c2 / correspond-02))
      :ARG1 (p / possible-01
            :ARG1 (r / relevant-01
                  :ARG1 (a / associate-01
                        :ARG1 g2
                        :ARG2 (p3 / protein :name (n2 / name :op1 "Grb-2")))
                  :ARG2 (p5 / parallel
                        :location (p2 / proliferate-01
                                    :degree (h / hyper)))
                  :ARG1-of (d / direct-02))
            :condition (l / level
                  :quant-of (p4 / protein :name (n3 / name :op1 "AJ"))
                  :ARG1-of (r2 / reduce-01))))

# ::id pmid_1563_0473.234 ::date 2015-03-30T02:00:28 ::annotator SDL-AMR-09 ::preferred
# ::snt In stable epithelial (i.e., Madin-Darby canine kidney, or MDCK) cell lines, Snail has been shown to block cell cycle progression and promote motility and shape changes for invasion [<xref ref-type="bibr" rid="pbio-0030011-b47">47</xref>].
# ::save-date Wed Dec 30, 2015 ::file pmid_1563_0473_234.txt
(s / show-01
      :ARG1 (a2 / and
            :op1 (b / block-01
                  :ARG0 (p2 / protein :name (n / name :op1 "Snail"))
                  :ARG1 (p3 / progress-01
                        :ARG1 (c2 / cycle-02
                              :ARG1 (c / cell))))
            :op2 (p / promote-01
                  :ARG0 p2
                  :ARG1 (m2 / motility))
            :op3 (s3 / shape-01
                  :ARG1 (c3 / change-01)
                  :purpose (i / invade-01)))
      :location (c6 / cell-line
            :mod (e / epithelium)
            :ARG1-of (s2 / stable-03)
            :ARG1-of (m / mean-01
                  :ARG2 (c4 / cell-line :name (n2 / name :op1 "Madin-Darby" :op2 "canine" :op3 "kidney"))))
      :ARG1-of (d / describe-01
            :ARG0 (p4 / publication
                  :ARG1-of (c5 / cite-01
                        :ARG2 47))))

# ::id pmid_1563_0473.235 ::date 2015-03-29T13:45:17 ::annotator SDL-AMR-09 ::preferred
# ::snt While our in vivo studies are consistent with a role for Snail in motility and epithelial remodeling, they differ with respect to Snail's apparent proliferative effects.
# ::save-date Fri May 29, 2015 ::file pmid_1563_0473_235.txt
(h / have-concession-91
      :ARG1 (d2 / differ-01
            :ARG0 s
            :ARG2 (a3 / affect-01
                  :ARG0 (p2 / protein :name (n / name :op1 "Snail"))
                  :ARG2 (p / proliferate-01)
                  :ARG1-of (a / appear-01)))
      :ARG2 (c / consistent-01
            :ARG1 (s / study-01
                  :ARG0 (w / we)
                  :manner (i / in-vivo))
            :ARG2 (r / role
                  :topic (a2 / and
                        :op1 (m / motility)
                        :op2 (r2 / remodel-01
                              :ARG1 (e2 / epithelium)))
                  :purpose p2)))

# ::id pmid_1563_0473.236 ::date 2015-03-27T05:26:33 ::annotator SDL-AMR-09 ::preferred
# ::snt A priori, this could be simply due to variations in the response of different cell types to Snail expression.
# ::save-date Thu Jan 14, 2016 ::file pmid_1563_0473_236.txt
(i / infer-01
      :ARG1 (p / possible-01
            :ARG1 (c / cause-01
                  :ARG0 (v / vary-01
                        :ARG1 (r / respond-01
                              :ARG0 (c2 / cell
                                    :ARG1-of (t / type-03)
                                    :ARG1-of (d / differ-02))
                              :ARG1 (e / express-03
                                    :ARG2 (p2 / protein :name (n / name :op1 "Snail")))))
                  :ARG1 (t2 / this)
                  :ARG1-of (s / simple-02)))
      :mod (a / a-priori))

# ::id pmid_1563_0473.237 ::date 2015-03-27T12:59:47 ::annotator SDL-AMR-09 ::preferred
# ::snt Alternatively, these differences may be relevant to the benefit of using mouse models to reveal functions not always recapitulated in stable cell line models.
# ::save-date Tue Jun 9, 2015 ::file pmid_1563_0473_237.txt
(p / possible-01
      :manner (a / alternative)
      :ARG1 (r / relevant-01
            :ARG1 (t / thing
                  :ARG1-of (d / differ-02)
                  :mod (t2 / this))
            :ARG2 (b / benefit-01
                  :ARG0 (u / use-01
                        :ARG1 (m / model
                              :mod (m2 / mouse))
                        :ARG2 (r2 / reveal-01
                              :ARG1 (f / function-01
                                    :ARG1-of (r3 / recapitulate-01
                                          :time (a2 / always :polarity -)
                                          :location (m3 / model
                                                :mod (c / cell-line)
                                                :ARG1-of (s / stable-03)))))))))

# ::id pmid_1563_0473.238 ::date 2015-03-27T13:32:30 ::annotator SDL-AMR-09 ::preferred
# ::snt Future studies should highlight the underlying reasons for these opposing results.
# ::save-date Sat Apr 4, 2015 ::file pmid_1563_0473_238.txt
(r / recommend-01
      :ARG1 (h / highlight-01
            :ARG0 (s / study-01
                  :time (f / future))
            :ARG1 (t / thing
                  :ARG0-of (c / cause-01
                        :ARG1 (t2 / thing
                              :ARG2-of (r2 / result-01)
                              :mod (t3 / this)
                              :ARG0-of (o / oppose-01)))
                  :ARG0-of (u / underlie-01))))

# ::id pmid_1563_0473.239 ::date 2015-03-27T13:50:09 ::annotator SDL-AMR-09 ::preferred
# ::snt Irrespective of these differences, our in vivo studies do not stand alone, as there are many situations in which a down-regulation in AJ proteins correlate with enhanced proliferation.
# ::save-date Thu Jan 7, 2016 ::file pmid_1563_0473_239.txt
(s / stand-01 :polarity -
      :ARG1 (s2 / study-01
            :ARG0 (w / we)
            :manner (i / in-vivo))
      :manner (a / alone)
      :ARG1-of (c / cause-01
            :ARG0 (s3 / situation
                  :quant (m / many)
                  :mod (c2 / correlate-01
                        :ARG1 (d2 / downregulate-01
                              :ARG1 (p / protein :name (n / name :op1 "AJ")))
                        :ARG2 (p2 / proliferate-01
                              :ARG1-of (e / enhance-01)))))
      :ARG1-of (r / regardless-91
            :ARG2 (t / thing
                  :ARG1-of (d / differ-02)
                  :mod (t2 / this))))

# ::id pmid_1563_0473.240 ::date 2015-03-27T14:45:01 ::annotator SDL-AMR-09 ::preferred
# ::snt In fact, a myriad of diverse mechanisms have been implicated in activating epithelial proliferation upon down-regulation of AJ proteins [<xref ref-type="bibr" rid="pbio-0030011-b07">7</xref>,<xref ref-type="bibr" rid="pbio-0030011-b23">23</xref>,<xref ref-type="bibr" rid="pbio-0030011-b24">24</xref>,<xref ref-type="bibr" rid="pbio-0030011-b48">48</xref>].
# ::save-date Thu Apr 2, 2015 ::file pmid_1563_0473_240.txt
(i / implicate-01
      :ARG1 (m / mechanism
            :mod (d / diverse)
            :quant (m2 / myriad))
      :ARG2 (a / activate-01
            :ARG1 (p / proliferate-01
                  :ARG0 (e / epithelium))
            :time (d2 / downregulate-01
                  :ARG1 (p2 / protein :name (n / name :op1 "AJ"))))
      :mod (i2 / in-fact)
      :ARG1-of (d3 / describe-01
            :ARG0 (p3 / publication
                  :ARG1-of (c / cite-01
                        :ARG2 (a2 / and :op1 7 :op2 23 :op3 24 :op4 48)))))

# ::id pmid_1563_0473.241 ::date 2015-03-27T15:16:41 ::annotator SDL-AMR-09 ::preferred
# ::snt Sifting through these converging pathways is likely to be a difficult and painstaking process.
# ::save-date Mon Jul 13, 2015 ::file pmid_1563_0473_241.txt
(l / likely-01
      :ARG1 (p / process-02
            :ARG1 (s / sift-01
                  :ARG1 (p3 / pathway
                        :ARG0-of (c / converge-01)
                        :mod (t / this)))
            :mod (d / difficult)
            :mod (p2 / painstaking)))

# ::id pmid_1563_0473.242 ::date 2015-03-27T15:45:36 ::annotator SDL-AMR-09 ::preferred
# ::snt This said, by identifying the status of different players involved in specific cell types and at specific stages in development, our mechanistic understanding of how intercellular remodeling is linked to proliferation in epithelial morphogenesis should begin to surface in the future.
# ::save-date Wed Dec 30, 2015 ::file pmid_1563_0473_242.txt
(r / recommend-01
      :ARG1 (b / begin-01
            :ARG1 (s / surface-01
                  :ARG1 (u / understand-01
                        :ARG0 (w / we)
                        :ARG1 (l / link-01
                              :ARG1 (r2 / remodel-01
                                    :mod (i / intercellular))
                              :ARG2 (p / proliferate-01
                                    :ARG0 (m / morphogenesis
                                          :mod (e / epithelium)))
                              :manner (a2 / amr-unknown))
                        :mod (m2 / mechanism))
                  :time (f / future))
            :manner (i2 / identify-01
                  :ARG1 (s2 / status
                        :poss (t / thing
                              :ARG1-of (d / differ-02)
                              :ARG1-of (i3 / involve-01
                                    :ARG2 (c / cell
                                          :ARG2-of (t2 / type-03)
                                          :ARG1-of (s3 / specific-02))
                                    :time (s4 / stage
                                          :ARG1-of s3
                                          :subevent-of (d2 / develop-02)))
                              :ARG0-of (p2 / play-08)))))
      :time (a3 / after
            :op1 (s5 / say-01
                  :ARG1 (t3 / this))))

# ::id pmid_1563_0473.243 ::date 2015-03-28T11:07:10 ::annotator SDL-AMR-09 ::preferred
# ::snt Elucidating the molecular mechanisms through which these networks converge is also a prerequisite for understanding how these processes go awry during tumorigenesis.
# ::save-date Mon Jul 13, 2015 ::file pmid_1563_0473_243.txt
(r / require-01
      :ARG0 (u / understand-01
            :ARG1 (g / go-08
                  :ARG1 (p / process-02
                        :mod (t / this))
                  :ARG2 (a / awry)
                  :time (c / create-01
                        :ARG1 (t2 / tumor))
                  :manner (a2 / amr-unknown)))
      :ARG1 (e / elucidate-01
            :ARG1 (m / mechanism
                  :mod (m2 / molecule)
                  :manner-of (c2 / converge-01
                        :ARG0 (n / network
                              :mod (t3 / this)))))
      :mod (a3 / also))

# ::id pmid_1563_0473.244 ::date 2015-03-28T11:07:50 ::annotator SDL-AMR-09 ::preferred
# ::snt Materials and Methods
# ::save-date Sat Mar 28, 2015 ::file pmid_1563_0473_244.txt
(a / and
      :op1 (m / material)
      :op2 (m2 / method))

# ::id pmid_1563_0473.245 ::date 2015-03-28T11:43:16 ::annotator SDL-AMR-09 ::preferred
# ::snt Reagents
# ::save-date Sat Mar 28, 2015 ::file pmid_1563_0473_245.txt
(r / reagent)

# ::id pmid_1563_0473.246 ::date 2015-03-28T11:44:50 ::annotator SDL-AMR-09 ::preferred
# ::snt Primary antibodies used were against: E-cadherin (M. Takeichi, Kyoto University, Japan); α-catenin, β-catenin, pMAPK, tubulin (Sigma, St. Louis, Missouri, United States), Ajuba (G. Longmore, Washington University, St. Louis, Missouri, United States); β4 integrin/CD104 (BD Pharmingen, San Diego, California, United States), laminin 5 (R. Burgeson, Harvard University, Cambridge, Massachusetts, United States), K5, K1, loricrin (Fuchs Lab), involucrin, fillagrin (Covance, Berkeley, California, United States), MAPK, pSMAD2 (Cell Signaling, Beverly, Massachusetts, United States); Grb-2 (Santa Cruz Biotech, Santa Cruz, California, United States); P-cadherin (Zymed Laboratories, South San Francisco, California, United States); HA (Roche Biochemicals), vimentin (Chemicon, Temecula, California, United States), Ki67 (Novo Castra, Newcastle Upon Tyne, United Kingdom), keratin 6 (P. Coulombe, John Hopkins University, Baltimore, Maryland, United States), cyclin D (Oncogene, San Diego, California, United States), and TGF-β2 (L. Gold, New York University, New York, New York, United States).
# ::save-date Thu Feb 11, 2016 ::file pmid_1563_0473_246.txt
(u / use-01
      :ARG1 (a / and
            :op1 (a2 / antibody
                  :mod (p / primary)
                  :ARG0-of (o / oppose-01
                        :ARG1 (p2 / protein :name (n / name :op1 "E-cadherin")
                              :source (p3 / person :name (n2 / name :op1 "M." :op2 "Takeichi")
                                    :location (u2 / university :wiki "Kyoto_University" :name (n3 / name :op1 "Kyoto" :op2 "University")
                                          :location (c / country :wiki "Japan" :name (n4 / name :op1 "Japan")))))))
            :op2 (a7 / antibody
                  :mod p
                  :ARG0-of (o2 / oppose-01
                        :ARG1 (a3 / and
                              :op1 (p4 / protein :name (n5 / name :op1 "α-catenin"))
                              :op2 (p5 / protein :name (n6 / name :op1 "β-catenin"))
                              :op3 (e / enzyme :name (n7 / name :op1 "MAPK")
                                    :ARG1-of (p6 / phosphorylate-01))
                              :op4 (p7 / protein :name (n8 / name :op1 "tubulin"))
                              :source (c2 / company :name (n9 / name :op1 "Sigma")
                                    :location (c3 / city :wiki "St._Louis" :name (n10 / name :op1 "St." :op2 "Louis")
                                          :location (s / state :wiki "Missouri" :name (n11 / name :op1 "Missouri")
                                                :location (c4 / country :wiki "United_States" :name (n12 / name :op1 "United" :op2 "States"))))))))
            :op3 (a8 / antibody
                  :mod p
                  :ARG0-of (o3 / oppose-01
                        :ARG1 (p8 / protein :name (n13 / name :op1 "Ajuba")
                              :source (p9 / person :name (n14 / name :op1 "G." :op2 "Longmore")
                                    :location (u3 / university :wiki "Washington_University_in_St._Louis" :name (n15 / name :op1 "Washington" :op2 "University")
                                          :location c3)))))
            :op4 (a9 / antibody
                  :mod p
                  :ARG0-of (o4 / oppose-01
                        :ARG1 (p10 / protein :name (n16 / name :op1 "β4-integrin/CD104")
                              :source (c5 / company :name (n17 / name :op1 "BD" :op2 "Pharmingen")
                                    :location (c6 / city :wiki "San_Diego" :name (n18 / name :op1 "San" :op2 "Diego")
                                          :location (s2 / state :wiki "California" :name (n19 / name :op1 "California")
                                                :location c4))))))
            :op5 (a10 / antibody
                  :mod p
                  :ARG0-of (o5 / oppose-01
                        :ARG1 (p11 / protein :name (n20 / name :op1 "laminin-5")
                              :source (p12 / person :name (n21 / name :op1 "R." :op2 "Burgeson")
                                    :location (u4 / university :wiki "Harvard_University" :name (n22 / name :op1 "Harvard" :op2 "University")
                                          :location (c7 / city :wiki "Cambridge,_Massachusetts" :name (n23 / name :op1 "Cambridge")
                                                :location (s3 / state :wiki "Massachusetts" :name (n24 / name :op1 "Massachusetts")
                                                      :location c4)))))))
            :op6 (a11 / antibody
                  :mod p
                  :ARG0-of (o6 / oppose-01
                        :ARG1 (a4 / and
                              :op1 (p13 / protein :name (n25 / name :op1 "K5"))
                              :op2 (p14 / protein :name (n26 / name :op1 "K1"))
                              :op3 (p15 / protein :name (n27 / name :op1 "loricrin"))
                              :location (r / research-institute :name (n28 / name :op1 "Fuchs" :op2 "Lab")))))
            :op7 (a12 / antibody
                  :mod p
                  :ARG0-of (o7 / oppose-01
                        :ARG1 (a5 / and
                              :op1 (p16 / protein :name (n29 / name :op1 "involucrin"))
                              :op2 (p17 / protein :name (n30 / name :op1 "fillagrin"))
                              :source (c8 / company :wiki "Covance" :name (n31 / name :op1 "Covance")
                                    :location (c9 / city :wiki "Berkeley,_California" :name (n32 / name :op1 "Berkeley")
                                          :location s2)))))
            :op8 (a13 / antibody
                  :mod p
                  :ARG0-of (o8 / oppose-01
                        :ARG1 (a6 / and
                              :op1 e
                              :op2 (p18 / protein :name (n33 / name :op1 "SMAD2")
                                    :ARG1-of p6)
                              :source (c10 / company :name (n34 / name :op1 "Cell" :op2 "Signaling")
                                    :location (c11 / city :wiki "Beverly,_Massachusetts" :name (n35 / name :op1 "Beverly")
                                          :location s3)))))
            :op9 (a14 / antibody
                  :mod p
                  :ARG0-of (o9 / oppose-01
                        :ARG1 (p19 / protein :name (n36 / name :op1 "Grb-2")
                              :source (c12 / company :name (n37 / name :op1 "Santa" :op2 "Cruz" :op3 "Biotech")
                                    :location (c13 / city :wiki "Santa_Cruz,_California" :name (n38 / name :op1 "Santa" :op2 "Cruz")
                                          :location s2)))))
            :op10 (a15 / antibody
                  :mod p
                  :ARG0-of (o10 / oppose-01
                        :ARG1 (p20 / protein :name (n39 / name :op1 "P-cadherin")
                              :source (c14 / company :name (n40 / name :op1 "Zymed" :op2 "Laboratories")
                                    :location (c15 / city :wiki "South_San_Francisco,_California" :name (n41 / name :op1 "South" :op2 "San" :op3 "Francisco")
                                          :location s2)))))
            :op11 (a16 / antibody
                  :mod p
                  :ARG0-of (o11 / oppose-01
                        :ARG1 (p21 / protein :name (n42 / name :op1 "HA")
                              :source (c16 / company :name (n43 / name :op1 "Roche" :op2 "Biochemicals")))))
            :op12 (a17 / antibody
                  :mod p
                  :ARG0-of (o12 / oppose-01
                        :ARG1 (p22 / protein :name (n44 / name :op1 "vimentin")
                              :source (c17 / company :name (n45 / name :op1 "Chemicon")
                                    :location (c18 / city :wiki "Temecula,_California" :name (n46 / name :op1 "Temecula")
                                          :location s2)))))
            :op13 (a18 / antibody
                  :mod p
                  :ARG0-of (o13 / oppose-01
                        :ARG1 (p23 / protein :name (n47 / name :op1 "Ki67")
                              :source (c19 / company :name (n48 / name :op1 "Novo" :op2 "Castra")
                                    :location (c20 / city :wiki "Newcastle_upon_Tyne" :name (n49 / name :op1 "Newcastle" :op2 "Upon" :op3 "Tyne")
                                          :location (c21 / country :wiki "United_Kingdom" :name (n50 / name :op1 "United" :op2 "Kingdom")))))))
            :op14 (a19 / antibody
                  :mod p
                  :ARG0-of (o14 / oppose-01
                        :ARG1 (p24 / protein :name (n51 / name :op1 "keratin-6")
                              :source (p25 / person :name (n52 / name :op1 "P." :op2 "Coulombe")
                                    :location (u5 / university :wiki "Johns_Hopkins_University" :name (n53 / name :op1 "John" :op2 "Hopkins" :op3 "University")
                                          :location (c22 / city :wiki "Baltimore" :name (n54 / name :op1 "Baltimore")
                                                :location (s4 / state :wiki "Maryland" :name (n55 / name :op1 "Maryland")
                                                      :location c4)))))))
            :op15 (a20 / antibody
                  :mod p
                  :ARG0-of (o15 / oppose-01
                        :ARG1 (p26 / protein :name (n56 / name :op1 "cyclin-D")
                              :source (c23 / company :name (n57 / name :op1 "Oncogene")
                                    :location c6))))
            :op16 (a21 / antibody
                  :mod p
                  :ARG0-of (o16 / oppose-01
                        :ARG1 (p27 / protein :name (n58 / name :op1 "TGF-β2")
                              :source (p28 / person :name (n59 / name :op1 "L." :op2 "Gold")
                                    :location (u6 / university :wiki "New_York_University" :name (n60 / name :op1 "New" :op2 "York" :op3 "University")
                                          :location (c24 / city :wiki "New_York" :name (n61 / name :op1 "New" :op2 "York")
                                                :location (s5 / state :name n61
                                                      :location c4)))))))))

# ::id pmid_1563_0473.247 ::date 2015-03-28T15:44:45 ::annotator SDL-AMR-09 ::preferred
# ::snt FITC-, Texas Red-, or HRP-conjugated secondary antibodies were from Jackson ImmunoResearch (West Grove, Pennsylvania, United States).
# ::save-date Sat Feb 13, 2016 ::file pmid_1563_0473_247.txt
(a / antibody
      :mod (s / secondary)
      :ARG1-of (c / conjugate-02
            :ARG2 (o / or
                  :op1 (p / product :name (n / name :op1 "FITC"))
                  :op2 (p2 / product :name (n2 / name :op1 "Texas" :op2 "Red"))
                  :op3 (e / enzyme :name (n3 / name :op1 "HRP"))))
      :source (c2 / company :name (n4 / name :op1 "Jackson" :op2 "ImmunoResearch")
            :location (c3 / city :name (n5 / name :op1 "West" :op2 "Grove")
                  :location (s2 / state :wiki "Pennsylvania" :name (n6 / name :op1 "Pennsylvania")
                        :location (c4 / country :wiki "United_States" :name (n7 / name :op1 "United" :op2 "States"))))))

# ::id pmid_1563_0473.248 ::date 2015-03-28T16:06:14 ::annotator SDL-AMR-09 ::preferred
# ::snt Biotinylated secondary antibodies were from Vector Labs (Burlingame, California, United States).
# ::save-date Thu Feb 11, 2016 ::file pmid_1563_0473_248.txt
(a / antibody
      :mod (s / secondary)
      :ARG1-of (b / biotinylate-01)
      :source (c / company :name (n / name :op1 "Vector" :op2 "Labs")
            :location (c2 / city :wiki "Burlingame,_California" :name (n2 / name :op1 "Burlingame")
                  :location (s2 / state :wiki "California" :name (n3 / name :op1 "California")
                        :location (c3 / country :wiki "United_States" :name (n4 / name :op1 "United" :op2 "States"))))))

# ::id pmid_1563_0473.249 ::date 2015-03-28T16:19:15 ::annotator SDL-AMR-09 ::preferred
# ::snt Dilutions were according to the manufacturer's recommendation.
# ::save-date Fri May 15, 2015 ::file pmid_1563_0473_249.txt
(c / conform-01
      :ARG1 (d / dilute-01)
      :ARG2 (r / recommend-01
            :ARG0 (c2 / company
                  :ARG0-of (m / manufacture-01))
            :ARG4 d))

# ::id pmid_1563_0473.250 ::date 2015-03-28T16:26:28 ::annotator SDL-AMR-09 ::preferred
# ::snt The Snail antibody was generated in Guinea pigs by inoculating them with the N-terminal sequence of murine <i>Snail</i> fused to GST (Covance, Princeton, New Jersey, United States).
# ::save-date Thu Feb 11, 2016 ::file pmid_1563_0473_250.txt
(g / generate-01
      :ARG1 (a / antibody
            :ARG0-of (c4 / counter-01
                  :ARG1 (p / protein :name (n / name :op1 "Snail"))))
      :location (o2 / organism :name (n2 / name :op1 "Guinea" :op2 "pig"))
      :manner (i / inoculate-01
            :ARG1 o2
            :ARG3 (p2 / protein-segment :name (n3 / name :op1 "N" :op2 "terminus")
                  :part-of (p3 / protein :name (n4 / name :op1 "Snail")
                        :mod (m / mouse))
                  :ARG1-of (f / fuse-01
                        :ARG3 (e / enzyme :name (n6 / name :op1 "GST")
                              :source (c / company :wiki "Covance" :name (n7 / name :op1 "Covance")
                                    :location (c2 / city :wiki "Princeton,_New_Jersey" :name (n8 / name :op1 "Princeton")
                                          :location (s / state :wiki "New_Jersey" :name (n9 / name :op1 "New" :op2 "Jersey")
                                                :location (c3 / country :wiki "United_States" :name (n10 / name :op1 "United" :op2 "States"))))))))))

# ::id pmid_1563_0473.251 ::date 2015-03-29T08:20:56 ::annotator SDL-AMR-09 ::preferred
# ::snt Recombinant human TGF-β2 was purchased from R&D (Minneapolis, Minnesota, United States).
# ::save-date Sun Mar 29, 2015 ::file pmid_1563_0473_251.txt
(p / purchase-01
      :ARG1 (p2 / protein :name (n / name :op1 "TGF-β2")
            :mod (h / human)
            :ARG3-of (r / recombine-01))
      :ARG2 (c / company :name (n2 / name :op1 "R&D")
            :location (c2 / city :wiki "Minneapolis" :name (n3 / name :op1 "Minneapolis")
                  :location (s / state :wiki "Minnesota" :name (n4 / name :op1 "Minnesota")
                        :location (c3 / country :wiki "United_States" :name (n5 / name :op1 "United" :op2 "States"))))))

# ::id pmid_1563_0473.252 ::date 2015-03-29T08:36:13 ::annotator SDL-AMR-09 ::preferred
# ::snt Heat inactivated TGF-β2 was generated by heating the recombinant protein at 100 °C for 10 min.
# ::save-date Thu Apr 2, 2015 ::file pmid_1563_0473_252.txt
(g / generate-01
      :ARG1 (p / protein :name (n / name :op1 "TGF-β2")
            :ARG1-of (a / activate-01 :polarity -
                  :ARG0 (h / heat-01)))
      :manner (h2 / heat-01
            :ARG1 (p2 / protein
                  :ARG3-of (r / recombine-01))
            :destination (t / temperature-quantity :quant 100
                  :scale (c / celsius))
            :duration (t2 / temporal-quantity :quant 10
                  :unit (m / minute))))

# ::id pmid_1563_0473.253 ::date 2015-03-29T09:03:55 ::annotator SDL-AMR-09 ::preferred
# ::snt Mice
# ::save-date Sun Mar 29, 2015 ::file pmid_1563_0473_253.txt
(m / mouse)

# ::id pmid_1563_0473.254 ::date 2015-03-29T09:05:28 ::annotator SDL-AMR-09 ::preferred
# ::snt The <i>K14-Snail</i> Tg mouse was generated by digesting the pcDNA3-mm <i>Snail</i>-HA plasmid (G. de Herreros, Universitat Pompeu, Fabra, Barcelona, Spain) with BamHI and NotI and subcloned into the K14 vector [<xref ref-type="bibr" rid="pbio-0030011-b49">49</xref>].
# ::save-date Sat Feb 13, 2016 ::file pmid_1563_0473_254.txt
(a / and
      :op1 (g / generate-01
            :ARG1 (m / mouse
                  :mod (t / transgenic)
                  :mod (p2 / protein :name (n2 / name :op1 "Snail")
                        :ARG1-of (m5 / mutate-01 :value "K14")))
            :manner (d / digest-01
                  :ARG1 (s / small-molecule :name (n3 / name :op1 "plasmid")
                        :mod (m3 / macro-molecular-complex
                              :part (s3 / small-molecule :name (n4 / name :op1 "pcDNA3-mm"))
                              :part p2
                              :part (p3 / protein :name (n5 / name :op1 "HA")))
                        :source (p4 / person :name (n6 / name :op1 "G." :op2 "de" :op3 "Herreros")
                              :location (u / university :wiki "Pompeu_Fabra_University" :name (n7 / name :op1 "Universitat" :op2 "Pompeu" :op3 "Fabra")
                                    :location (c / city :wiki "Barcelona" :name (n8 / name :op1 "Barcelona")
                                          :location (c2 / country :wiki "Spain" :name (n9 / name :op1 "Spain"))))))
                  :instrument (a2 / and
                        :op1 (e / enzyme :name (n10 / name :op1 "BamHI"))
                        :op2 (e2 / enzyme :name (n11 / name :op1 "NotI")))))
      :op2 (s2 / subclone-01
            :ARG1 m
            :ARG3 (v / vector
                  :mod (p / protein)))
      :ARG1-of (d2 / describe-01
            :ARG0 (p5 / publication
                  :ARG1-of (c3 / cite-01
                        :ARG2 49))))

# ::id pmid_1563_0473.255 ::date 2015-03-29T10:28:13 ::annotator SDL-AMR-09 ::preferred
# ::snt The linearized construct was injected into the nucleus of embryos from CD1 mice.
# ::save-date Thu Apr 2, 2015 ::file pmid_1563_0473_255.txt
(i / inject-01
      :ARG1 (c / construct
            :ARG1-of (l / linearize-00))
      :ARG2 (n / nucleus
            :part-of (e / embryo
                  :source (o / organism :name (n2 / name :op1 "CD1" :op2 "mouse")))))

# ::id pmid_1563_0473.256 ::date 2015-03-29T10:52:51 ::annotator SDL-AMR-09 ::preferred
# ::snt The <i>K14-Smad 2</i> Tg mouse was reported in Ito et al., 2001.
# ::save-date Thu Apr 2, 2015 ::file pmid_1563_0473_256.txt
(r / report-01
      :ARG0 (p / publication-91
            :ARG0 (a / and
                  :op1 (p2 / person :name (n / name :op1 "Ito"))
                  :op2 (p3 / person
                        :mod (o / other)))
            :time (d / date-entity :year 2001))
      :ARG1 (m / mouse
            :mod (t / transgenic)
            :mod (m2 / macro-molecular-complex
                  :part (p4 / protein :name (n2 / name :op1 "K14"))
                  :part (p5 / protein :name (n3 / name :op1 "SMAD2")))))

# ::id pmid_1563_0473.257 ::date 2015-03-29T11:11:44 ::annotator SDL-AMR-09 ::preferred
# ::snt The <i>TGF-β2</i> knockout (KO) mouse was described in [<xref ref-type="bibr" rid="pbio-0030011-b34">34</xref>].
# ::save-date Thu Dec 17, 2015 ::file pmid_1563_0473_257.txt
(d / describe-01
      :ARG0 (p / publication-91
            :ARG1-of (c / cite-01
                  :ARG2 34))
      :ARG1 (m / mouse
            :location-of (k / knock-out-03
                  :ARG1 (g / gene :name (n / name :op1 "TGF-β2")))))

# ::id pmid_1563_0473.258 ::date 2015-03-29T11:32:51 ::annotator SDL-AMR-09 ::preferred
# ::snt The <i>shh</i> KO mouse [<xref ref-type="bibr" rid="pbio-0030011-b38">38</xref>] and TOPGal mouse [<xref ref-type="bibr" rid="pbio-0030011-b20">20</xref>] have previously been reported.
# ::save-date Sat Feb 13, 2016 ::file pmid_1563_0473_258.txt
(r / report-01
      :ARG1 (a / and
            :op1 (m / mouse
                  :location-of (k / knock-out-03
                        :ARG1 (g / gene :name (n / name :op1 "shh")))
                  :ARG1-of (d / describe-01
                        :ARG0 (p / publication
                              :ARG1-of (c / cite-01
                                    :ARG2 38))))
            :op2 (m4 / mouse :name (n3 / name :op1 "TOPGal")
                  :ARG1-of (d2 / describe-01
                        :ARG0 (p2 / publication
                              :ARG1-of (c2 / cite-01
                                    :ARG2 20)))))
      :time (p3 / previous))

# ::id pmid_1563_0473.259 ::date 2015-03-29T11:33:10 ::annotator SDL-AMR-09 ::preferred
# ::snt Western blot and immunoprecipitation
# ::save-date Sun Dec 13, 2015 ::file pmid_1563_0473_259.txt
(a / and
      :op1 (i2 / immunoblot-01)
      :op2 (i / immunoprecipitate-01))

# ::id pmid_1563_0473.260 ::date 2015-03-29T11:57:59 ::annotator SDL-AMR-09 ::preferred
# ::snt Protein extracts from primary keratinocytes were generated either by lysing cells in lysis buffer (1% NP-40, 1% sodium deoxycholate, 20 mM Tris-Cl [pH 7.4], 140 mM NaCl containing 1 mM sodium vanadate, 2 mM phenylmethylsulfonyl fluoride, and protease inhibitors) or directly in Laemmli bβuffer and boiled.
# ::save-date Sat Feb 13, 2016 ::file pmid_1563_0473_260.txt
(a / and
      :op1 (g / generate-01
            :ARG1 (e / extract-01
                  :ARG1 (p / protein)
                  :ARG2 (k / keratinocyte
                        :mod (p2 / primary)))
            :ARG2 (o / or
                  :op1 (l / lyse-01
                        :ARG1 (c / cell)
                        :location (b / buffer
                              :ARG2-of (l2 / lyse-01)
                              :consist-of (a2 / and
                                    :op1 (s / small-molecule :name (n / name :op1 "NP-40")
                                          :quant (p3 / percentage-entity :value 1))
                                    :op2 (s2 / small-molecule :name (n2 / name :op1 "sodium" :op2 "deoxycholate")
                                          :quant p3)
                                    :op3 (s5 / small-molecule :name (n3 / name :op1 "Tris-Cl")
                                          :quant (c2 / concentration-quantity :quant 20
                                                :unit (m4 / millimolar))
                                          :mod (a3 / acidity-quantity :quant 7.4
                                                :scale (p4 / ph)))
                                    :op4 (s3 / small-molecule :name (n4 / name :op1 "NaCl")
                                          :quant (c3 / concentration-quantity :quant 140
                                                :unit m4)
                                          :ARG0-of (c4 / contain-01
                                                :ARG1 (a4 / and
                                                      :op1 (s6 / small-molecule :name (n5 / name :op1 "sodium" :op2 "vanadate")
                                                            :quant (c5 / concentration-quantity :quant 1
                                                                  :unit m4))
                                                      :op2 (s4 / small-molecule :name (n6 / name :op1 "phenylmethylsulfonyl" :op2 "fluoride")
                                                            :quant (c6 / concentration-quantity :quant 2
                                                                  :unit m4))
                                                      :op3 (m8 / molecular-physical-entity
                                                            :ARG0-of (i / inhibit-01
                                                                  :ARG1 (e2 / enzyme :name (n7 / name :op1 "protease"))))))))))
                  :op2 (l3 / lyse-01
                        :ARG1 c
                        :location (t / thing :name (n8 / name :op1 "Laemmli" :op2 "buffer"))
                        :ARG1-of (d / direct-02))))
      :op2 (b2 / boil-01
            :ARG1 e))

# ::id pmid_1563_0473.261 ::date 2015-03-29T13:50:27 ::annotator SDL-AMR-09 ::preferred
# ::snt For skin tissue: Frozen tissue was pulverized in a liquid nitrogen-cooled Gevebesmascher and the powder scraped into a chilled microcentrifuge tube.
# ::save-date Sat Feb 13, 2016 ::file pmid_1563_0473_261.txt
(a / and
      :op1 (p / pulverize-01
            :ARG1 (t / tissue
                  :ARG1-of (f / freeze-01))
            :location (s3 / small-molecule :name (n / name :op1 "Gevebesmascher")
                  :ARG1-of (c / cool-01
                        :instrument (n2 / nitrogen))
                  :mod (l / liquid)))
      :op2 (s / scrape-02
            :ARG1 (p2 / powder)
            :ARG3 (t2 / tube
                  :mod (m2 / microcentrifuge)
                  :ARG1-of (c2 / chill-01)))
      :topic (t3 / tissue
            :part-of (s2 / skin)))

# ::id pmid_1563_0473.262 ::date 2015-03-29T14:24:10 ::annotator SDL-AMR-09 ::preferred
# ::snt RIPA buffer (1% Triton X-100 in PBS with 10 mM EDTA, 150 mN NaCl, 1% sodium deoxycholate, and 0.1% SDS) and protease inhibitors or Laemmli buffer was added.
# ::save-date Sat Feb 13, 2016 ::file pmid_1563_0473_262.txt
(a / add-02
      :ARG1 (a2 / and
            :op1 (t / thing :name (n / name :op1 "RIPA" :op2 "buffer")
                  :consist-of (a3 / and
                        :op1 (i / include-01
                              :ARG1 (s / small-molecule :name (n2 / name :op1 "Triton" :op2 "X-100")
                                    :quant (p / percentage-entity :value 1))
                              :ARG2 (s5 / small-molecule :name (n3 / name :op1 "PBS"))
                              :accompanier (s4 / small-molecule :name (n4 / name :op1 "EDTA")
                                    :quant (c / concentration-quantity :quant 10
                                          :unit (m5 / millimolar))))
                        :op2 (m6 / molecular-physical-entity :name (n5 / name :op1 "NaCl")
                              :quant (c2 / concentration-quantity :quant 150
                                    :unit m5))
                        :op3 (s3 / small-molecule :name (n6 / name :op1 "sodium" :op2 "deoxycholate")
                              :quant p)
                        :op4 (s2 / small-molecule :name (n7 / name :op1 "SDS")
                              :quant (p2 / percentage-entity :value 0.1))))
            :op2 (o / or
                  :op1 (m9 / molecular-physical-entity
                        :ARG0-of (i2 / inhibit-01
                              :ARG1 (e / enzyme :name (n8 / name :op1 "protease"))))
                  :op2 (t2 / thing :name (n9 / name :op1 "Laemmli" :op2 "buffer")))))

# ::id pmid_1563_0473.263 ::date 2015-03-29T14:56:33 ::annotator SDL-AMR-09 ::preferred
# ::snt The cell suspension was sonicated three times for 15 s and centrifuged at 14,000 rpm at 4 °C.
# ::save-date Sun Mar 29, 2015 ::file pmid_1563_0473_263.txt
(a / and
      :op1 (s / sonicate-00 :frequency 3
            :ARG1 (s2 / suspend-02
                  :ARG1 (c / cell))
            :duration (t / temporal-quantity :quant 15
                  :unit (s3 / second)))
      :op2 (c2 / centrifuge-00
            :ARG1 s2
            :ARG2 (t2 / temperature-quantity :quant 4
                  :scale (c3 / celsius))
            :frequency (s4 / speed-quantity :quant 14000
                  :unit (r / rotation-per-minute))))

# ::id pmid_1563_0473.264 ::date 2015-03-27T19:20:18 ::annotator SDL-AMR-09 ::preferred
# ::snt The supernatant was separated from the pellet and used in the experiments.
# ::save-date Sat Mar 28, 2015 ::file pmid_1563_0473_264.txt
(a / and
      :op1 (s / separate-01
            :ARG1 (s2 / supernatant)
            :ARG2 (p / pellet))
      :op2 (u / use-01
            :ARG1 s2
            :ARG2 (e / experiment-01)))

# ::id pmid_1563_0473.265 ::date 2015-03-27T19:20:35 ::annotator SDL-AMR-09 ::preferred
# ::snt Extracts subjected to immunoprecipitation were precleared with Protein G Sepharose (Amersham, Piscataway, New York, United States) and incubated with antibody with rocking overnight at 4 °C.
# ::save-date Thu Apr 2, 2015 ::file pmid_1563_0473_265.txt
(a / and
      :op1 (p / preclear-00
            :ARG1 (e / extract-01
                  :ARG1-of (s2 / subject-01
                        :ARG2 (i / immunoprecipitate-01)))
            :ARG2 (p3 / product :name (n6 / name :op1 "Protein" :op2 "G" :op3 "Sepharose")
                  :source (c3 / company :name (n5 / name :op1 "Amersham")
                        :location (c5 / city :name (n4 / name :op1 "Piscataway")
                              :location (s / state :wiki "New_York" :name (n2 / name :op1 "New" :op2 "York")
                                    :location (c2 / country :wiki "United_States" :name (n3 / name :op1 "United" :op2 "States")))))))
      :op2 (i2 / incubate-01
            :ARG1 e
            :ARG2 (a2 / and
                  :op1 (a3 / antibody)
                  :op2 (r / rock-01
                        :ARG1 e))
            :time (o / overnight)
            :mod (t / temperature-quantity :quant 4
                  :scale (c4 / celsius))))

# ::id pmid_1563_0473.266 ::date 2015-03-27T19:21:06 ::annotator SDL-AMR-09 ::preferred
# ::snt Protein G Sepharose was added and samples were incubated for 1 h at 4 °C with rocking.
# ::save-date Mon Dec 21, 2015 ::file pmid_1563_0473_266.txt
(a / and
      :op1 (a2 / add-02
            :ARG1 (p2 / product :wiki -
                  :name (n2 / name :op1 "Protein" :op2 "G" :op3 "Sepharose")))
      :op2 (i / incubate-01
            :ARG1 (t3 / thing
                  :ARG1-of (s / sample-01))
            :ARG2 (r / rock-01
                  :ARG1 t3)
            :duration (t / temporal-quantity :quant 1
                  :unit (h / hour))
            :mod (t2 / temperature-quantity :quant 4
                  :scale (c / celsius))))

# ::id pmid_1563_0473.267 ::date 2015-03-27T19:21:23 ::annotator SDL-AMR-09 ::preferred
# ::snt Samples were washed three times for 5 min each in lysis buffer, and the Protein G Sepharose-antibody-antigen pellet was resuspended in Laemmli buffer and boiled for 10 min.
# ::save-date Tue Feb 2, 2016 ::file pmid_1563_0473_267.txt
(a / and
      :op1 (w / wash-01 :frequency 3
            :ARG1 (t3 / thing
                  :mod (e / each)
                  :ARG1-of (s / sample-01))
            :ARG2 (b / buffer
                  :ARG2-of (l / lyse-01))
            :duration (t / temporal-quantity :quant 5
                  :unit (m / minute)))
      :op2 (a4 / and
            :op1 (s2 / suspend-02
                  :ARG1 (p / pellet
                        :mod (a2 / antigen)
                        :mod (a3 / antibody)
                        :mod (p3 / product :name (n4 / name :op1 "Protein" :op2 "G" :op3 "Sepharose")))
                  :location (b2 / buffer :name (n2 / name :op1 "Laemmli"))
                  :mod (a5 / again))
            :op2 (b3 / boil-01
                  :ARG1 p
                  :duration (t2 / temporal-quantity :quant 10
                        :unit (m2 / minute)))))

# ::id pmid_1563_0473.268 ::date 2015-03-27T19:21:44 ::annotator SDL-AMR-09 ::preferred
# ::snt Samples were run on SDS-PAGE and transferred to nitrocellulose membrane (Schleicher and Schuell Bioscience, Keene, New Hampshire, United States).
# ::save-date Sun Jan 17, 2016 ::file pmid_1563_0473_268.txt
(a / and
      :op1 (r / run-01
            :ARG1 (t2 / thing
                  :ARG1-of (s2 / sample-01))
            :manner (t3 / thing :name (n7 / name :op1 "SDS-PAGE")))
      :op2 (t / transfer-01
            :ARG1 t2
            :ARG2 (m / membrane
                  :mod (n4 / nitrocellulose)
                  :source (c2 / company :name (n5 / name :op1 "Schleicher" :op2 "and" :op3 "Schuell" :op4 "Bioscience")
                        :location (c4 / city :name (n6 / name :op1 "Keene")
                              :location (s / state :wiki "New_Hampshire" :name (n / name :op1 "New" :op2 "Hampshire")
                                    :location (c / country :wiki "United_States" :name (n2 / name :op1 "United" :op2 "States"))))))))

# ::id pmid_1563_0473.269 ::date 2015-03-27T19:22:09 ::annotator SDL-AMR-09 ::preferred
# ::snt Western blot signals were developed using the enhanced chemiluminescence kit from Amersham
# ::save-date Sun Dec 13, 2015 ::file pmid_1563_0473_269.txt
(d / develop-02
      :ARG1 (s / signal-07
            :ARG0 (i / immunoblot-01))
      :ARG2-of (u / use-01
            :ARG1 (k / kit
                  :ARG1-of (e / enhance-01)
                  :mod (c / chemiluminescence)
                  :source (c2 / company :wiki "Amersham_plc"
                        :name (n2 / name :op1 "Amersham")))))

# ::id pmid_1563_0473.270 ::date 2015-03-27T19:22:25 ::annotator SDL-AMR-09 ::preferred
# ::snt Cell culture
# ::save-date Sun Mar 29, 2015 ::file pmid_1563_0473_270.txt
(c / culture
      :mod (c2 / cell))

# ::id pmid_1563_0473.271 ::date 2015-03-27T19:22:43 ::annotator SDL-AMR-09 ::preferred
# ::snt Primary keratinocytes were culture in low-calcium medium as previously described [<xref ref-type="bibr" rid="pbio-0030011-b04">4</xref>].
# ::save-date Sat May 23, 2015 ::file pmid_1563_0473_271.txt
(c / culture-01
      :ARG1 (k / keratinocyte
            :mod (p / primary))
      :location (m / medium
            :ARG1-of (l / low-04
                  :ARG2 (c2 / calcium)))
      :ARG1-of (d2 / describe-01
            :ARG0 (p3 / publication
                  :ARG1-of (c3 / cite-01
                        :ARG2 4))
            :time (p2 / previous)))

# ::id pmid_1563_0473.272 ::date 2015-03-27T19:22:59 ::annotator SDL-AMR-09 ::preferred
# ::snt Transient transfections were carried out with FuGENE6 reagent (Roche, Indianapolis, Indiana, United States) according to the manufacturer's protocol.
# ::save-date Fri Jul 24, 2015 ::file pmid_1563_0473_272.txt
(c4 / carry-out-03
      :ARG1 (t / transfect-01
            :ARG1-of (t2 / transient-02))
      :ARG1-of (s2 / say-01
            :ARG0 (p / protocol
                  :poss c5))
      :instrument (r / reagent :name (n5 / name :op1 "FuGENE6")
            :source (c5 / company :name (n4 / name :op1 "Roche")
                  :location (c / city :wiki "Indianapolis" :name (n / name :op1 "Indianapolis")
                        :location (s / state :wiki "Indiana" :name (n2 / name :op1 "Indiana")
                              :location (c2 / country :wiki "United_States" :name (n3 / name :op1 "United" :op2 "States"))))
                  :ARG0-of (m / manufacture-01))))

# ::id pmid_1563_0473.273 ::date 2015-03-27T19:23:25 ::annotator SDL-AMR-09 ::preferred
# ::snt Measurement of β-galactosidase or luciferase levels in promoter activity studies were carried out with the Galacto-Lite assay kit (TROPIX, Bedford, Massachusetts, United States) and the Dual luciferase (Promega, Madison, Wisconsin, United States), respectively.
# ::save-date Sun Dec 20, 2015 ::file pmid_1563_0473_273.txt
(c6 / carry-out-03
      :ARG1 (m / measure-01
            :ARG1 (o / or
                  :op1 (l3 / level
                        :quant-of (e / enzyme :name (n4 / name :op1 "β-galactosidase")))
                  :op2 (l / level
                        :quant-of (l2 / luciferase)))
            :subevent-of (s3 / study-01
                  :ARG1 (a2 / activity-06
                        :ARG0 (m2 / molecular-physical-entity
                              :ARG0-of (p / promote-01)))))
      :mod (r / respective)
      :instrument (a3 / and
            :op1 (p3 / product :name (n7 / name :op1 "Galacto-Lite")
                  :mod (k2 / kit
                        :instrument-of (a / assay-01))
                  :source (c3 / company :name (n5 / name :op1 "TROPIX")
                        :location (c4 / city :name (n6 / name :op1 "Bedford")
                              :location (s / state :wiki "Massachusetts" :name (n / name :op1 "Massachusetts")
                                    :location (c / country :wiki "United_States" :name (n2 / name :op1 "United" :op2 "States"))))))
            :op2 (p2 / product :name (n8 / name :op1 "Dual" :op2 "luciferase")
                  :source (c2 / company :name (n9 / name :op1 "Promega")
                        :location (c5 / city :name (n10 / name :op1 "Madison")
                              :location (s2 / state :wiki "Wisconsin" :name (n3 / name :op1 "Wisconsin")
                                    :location c))))))

# ::id pmid_1563_0473.274 ::date 2015-03-27T19:23:58 ::annotator SDL-AMR-09 ::preferred
# ::snt Runella luciferase was cotransfected into cells to correct for transfection efficiency.
# ::save-date Tue Jun 16, 2015 ::file pmid_1563_0473_274.txt
(c / cotransfect-01
      :ARG1 (c2 / cell)
      :ARG2 (l / luciferase :name (n / name :op1 "Runella"))
      :ARG0-of (c3 / correct-01
            :ARG1 (e / efficient-01
                  :ARG1 (t / transfect-01))))

# ::id pmid_1563_0473.275 ::date 2015-03-27T19:24:14 ::annotator SDL-AMR-09 ::preferred
# ::snt Experiments were done in triplicate and repeated at least three times.
# ::save-date Thu Apr 2, 2015 ::file pmid_1563_0473_275.txt
(e2 / experiment-01
      :quant (t / triplicate)
      :ARG1-of (r / repeat-01 :frequency 3
            :mod (a / at-least)))

# ::id pmid_1563_0473.276 ::date 2015-03-28T04:57:30 ::annotator SDL-AMR-09 ::preferred
# ::snt Measurements were done on a luminometer (MGM Instruments, Hamden, Connecticut, United States).
# ::save-date Thu Apr 2, 2015 ::file pmid_1563_0473_276.txt
(m2 / measure-01
      :instrument (l / luminometer
            :source (c2 / company :name (n3 / name :op1 "MGM" :op2 "Instruments")
                  :location (c3 / city :name (n4 / name :op1 "Hamden")
                        :location (s / state :wiki "Connecticut" :name (n / name :op1 "Connecticut")
                              :location (c / country :wiki "United_States" :name (n2 / name :op1 "United" :op2 "States")))))))

# ::id pmid_1563_0473.277 ::date 2015-03-28T11:38:29 ::annotator SDL-AMR-09 ::preferred
# ::snt For experiments measuring phosphorylation of MAPK, keratinocytes were serum starved for 3 h prior to harvesting of cells by incubation in medium lacking serum.
# ::save-date Thu Apr 2, 2015 ::file pmid_1563_0473_277.txt
(h / have-purpose-91
      :ARG1 (s / starve-01
            :ARG1 (k / keratinocyte)
            :ARG2 (s2 / serum)
            :duration (t / temporal-quantity :quant 3
                  :unit (h2 / hour))
            :time (p3 / prior
                  :op1 (h3 / harvest-01
                        :ARG1 (c / cell)))
            :manner (i / incubate-01
                  :ARG1 k
                  :location (m / medium
                        :ARG0-of (l / lack-01
                              :ARG1 s2))))
      :ARG2 (m2 / measure-01
            :ARG0 (e / experiment-01)
            :ARG1 (p / phosphorylate-01
                  :ARG1 (e2 / enzyme :name (n / name :op1 "MAPK")))))

# ::id pmid_1563_0473.278 ::date 2015-03-28T14:25:45 ::annotator SDL-AMR-09 ::preferred
# ::snt Treatment of cells with Wnt- and noggin-conditioned medium was previously described [<xref ref-type="bibr" rid="pbio-0030011-b04">4</xref>].
# ::save-date Thu Apr 2, 2015 ::file pmid_1563_0473_278.txt
(t / treat-04
      :ARG1 (c / cell)
      :ARG2 (m / medium
            :ARG1-of (c2 / condition-01
                  :ARG2 (a / and
                        :op1 (p / protein :name (n / name :op1 "Wnt"))
                        :op2 (p2 / protein :name (n2 / name :op1 "noggin")))))
      :ARG1-of (d2 / describe-01
            :ARG0 (p4 / publication
                  :ARG1-of (c3 / cite-01
                        :ARG2 4))
            :time (p3 / previous)))

# ::id pmid_1563_0473.279 ::date 2015-03-28T14:38:17 ::annotator SDL-AMR-09 ::preferred
# ::snt Constructs
# ::save-date Sat Mar 28, 2015 ::file pmid_1563_0473_279.txt
(c / construct-01)

# ::id pmid_1563_0473.280 ::date 2015-03-28T14:39:39 ::annotator SDL-AMR-09 ::preferred
# ::snt The 2.2-kb murine <i>Snail</i> promoter was generated by PCR using a forward primer with an XbaI linker sequence, 5′-TCTAGAATTGTTTGCTGCTGTATGGTCTTC-3′, along with a reverse primer with a BglII linker sequence, 5′-AGATCTGTTGGCCAGAGCGACCTAG-GTAG-3′, and mouse genomic DNA as a template.
# ::save-date Sun Jan 17, 2016 ::file pmid_1563_0473_280.txt
(g / generate-01
      :ARG0 (r2 / react-01
            :ARG0 (p / polymerase)
            :ARG1-of (c / chain-01))
      :ARG1 (m2 / molecular-physical-entity
            :ARG0-of (p2 / promote-01
                  :ARG1 (g2 / gene :name (n2 / name :op1 "Snail")
                        :quant (d / distance-quantity :quant 2.2
                              :unit (k / kilo-base-pair))
                        :mod (o / organism :name (n7 / name :op1 "Murinae")))))
      :ARG2-of (u / use-01
            :ARG1 (a / and
                  :op1 (p3 / primer :value "5′-TCTAGAATTGTTTGCTGCTGTATGGTCTTC-3′"
                        :ARG1-of (f / forward-01)
                        :part (p5 / protein-segment :name (n8 / name :op1 "XbaI")
                              :ARG0-of (l / link-01)))
                  :op2 (p4 / primer :value "5′-AGATCTGTTGGCCAGAGCGACCTAGGTAG-3′"
                        :ARG1-of (r / reverse-01)
                        :part (p6 / protein-segment :name (n3 / name :op1 "BglII")
                              :ARG0-of (l2 / link-01)))
                  :op3 (t / template
                        :mod (n4 / nucleic-acid :wiki "DNA" :name (n5 / name :op1 "DNA")
                              :mod (g3 / genome)
                              :mod (m4 / mouse))))))

# ::id pmid_1563_0473.281 ::date 2015-03-28T16:07:59 ::annotator SDL-AMR-09 ::preferred
# ::snt The PCR product was purified with the Gel Extraction Kit (Qiagen, Valencia, California, United States) and ligated into pCRII-TOPO TA vector (Invitrogen, Carlsbad, California, United States).
# ::save-date Sun Jan 17, 2016 ::file pmid_1563_0473_281.txt
(a / and
      :op1 (p / purify-01
            :ARG1 (r / react-01
                  :ARG0 (p5 / polymerase)
                  :ARG1-of (c6 / chain-01))
            :instrument (p3 / product :name (n4 / name :op1 "Gel" :op2 "Extraction" :op3 "Kit")
                  :source (c2 / company :name (n5 / name :op1 "Qiagen")
                        :location (c3 / city :name (n6 / name :op1 "Valencia")
                              :location (s / state :wiki "California" :name (n / name :op1 "California")
                                    :location (c / country :wiki "United_States" :name (n2 / name :op1 "United" :op2 "States")))))))
      :op2 (l / ligate-01
            :ARG1 (p2 / product)
            :ARG2 (p4 / product :name (n7 / name :op1 "pCRII-TOPO" :op2 "TA")
                  :mod (v / vector)
                  :source (c4 / company :name (n8 / name :op1 "Invitrogen")
                        :location (c5 / city :name (n9 / name :op1 "Carlsbad")
                              :location s)))))

# ::id pmid_1563_0473.282 ::date 2015-03-29T03:52:29 ::annotator SDL-AMR-09 ::preferred
# ::snt The promoter was verified by sequencing and digested with XbaI and BglII and subcloned into the pβ-gal BASIC vector (BD Biosciences Clontech, Palo Alto, California, United States).
# ::save-date Tue Feb 2, 2016 ::file pmid_1563_0473_282.txt
(a / and
      :op1 (v / verify-01
            :ARG1 (m / molecular-physical-entity
                  :ARG0-of (p / promote-01))
            :manner (s2 / sequence-01
                  :ARG1 m))
      :op2 (d / digest-01
            :ARG1 m
            :instrument (a2 / and
                  :op1 (p2 / protein-segment :name (n3 / name :op1 "XbaI"))
                  :op2 (p3 / protein-segment :name (n4 / name :op1 "BglII"))))
      :op3 (s3 / subclone-01
            :ARG1 m
            :ARG3 (p4 / product :name (n5 / name :op1 "pβ-gal" :op2 "BASIC")
                  :mod (v2 / vector)
                  :source (c2 / company :name (n6 / name :op1 "BD" :op2 "Biosciences" :op3 "Clontech")
                        :location (c3 / city :name (n7 / name :op1 "Palo" :op2 "Alto")
                              :location (s / state :wiki "California" :name (n / name :op1 "California")
                                    :location (c / country :wiki "United_States" :name (n2 / name :op1 "United" :op2 "States"))))))))

# ::id pmid_1563_0473.283 ::date 2015-03-29T04:18:52 ::annotator SDL-AMR-09 ::preferred
# ::snt The point mutations in the SMAD binding element was generated with the Quik-Change Kit (Stratagene, La Jolla, California, United States) using the forward primer 5′-GGGCGGGCTTAGGTGTTTTCATTTACTCTTGAGGAAAAGCTTGGC-3′ and the reverse primer 5′-GCTTTT-CCTCAAGAGTAAATGAAAACACCTAAGCCCGCCCTGCCC-3′.
# ::save-date Thu Dec 10, 2015 ::file pmid_1563_0473_283.txt
(g / generate-01
      :ARG1 (m / mutate-01
            :mod (p / point)
            :location (e / element
                  :ARG0-of (b / bind-01
                        :ARG1 (p2 / protein :name (n3 / name :op1 "SMAD")))))
      :instrument (p3 / product :name (n4 / name :op1 "Quik-Change" :op2 "Kit")
            :source (c2 / company :name (n5 / name :op1 "Stratagene")
                  :location (c3 / city :name (n6 / name :op1 "La" :op2 "Jolla")
                        :location (s / state :wiki "California" :name (n / name :op1 "California")
                              :location (c / country :wiki "United_States" :name (n2 / name :op1 "United" :op2 "States"))))))
      :ARG2-of (u / use-01
            :ARG1 (a / and
                  :op1 (p4 / primer :value "5′-GGGCGGGCTTAGGTGTTTTCATTTACTCTTGAGGAAAAGCTTGGC-3′"
                        :ARG1-of (f / forward-01))
                  :op2 (p5 / primer :value "5′-GCTTTTCCTCAAGAGTAAATGAAAACACCTAAGCCCGCCCTGCCC-3′"
                        :ARG1-of (r / reverse-01)))))

# ::id pmid_1563_0473.284 ::date 2015-03-29T04:41:26 ::annotator SDL-AMR-09 ::preferred
# ::snt The probes for the <i>Snail</i> in situ hybridization were generated against the 3′ UTR by PCR using the forward primer 5′-ACCTTCTCCCGCATGTCCTTGCTCC-3′ and the reverse primer 5′-CTGCTGAGGCATGGTTACAGCTGG-3′, and genomic DNA as a template.
# ::save-date Fri Jan 1, 2016 ::file pmid_1563_0473_284.txt
(g4 / generate-01
      :ARG0 (r3 / react-01
            :ARG0 (p5 / polymerase)
            :ARG1-of (c / chain-01))
      :ARG1 (p / probe-01
            :ARG2 (h / hybridize-01
                  :ARG1 (g2 / gene :name (n / name :op1 "Snail"))
                  :manner (i2 / in-situ)))
      :prep-against (r2 / region :value 3 :wiki "Three_prime_untranslated_region"
            :ARG1-of (t2 / translate-02 :polarity -)
            :ARG0-of (t3 / trail-01))
      :ARG2-of (u / use-01
            :ARG1 (a / and
                  :op1 (p3 / primer :value "5′-ACCTTCTCCCGCATGTCCTTGCTCC-3′"
                        :ARG1-of (f / forward-01))
                  :op2 (p4 / primer :value "5′-CTGCTGAGGCATGGTTACAGCTGG-3′"
                        :ARG1-of (r / reverse-01))
                  :op3 (t / template
                        :mod (n3 / nucleic-acid :wiki "DNA" :name (n6 / name :op1 "DNA")
                              :mod (g3 / genomic))))))

# ::id pmid_1563_0473.285 ::date 2015-03-29T05:24:23 ::annotator SDL-AMR-09 ::preferred
# ::snt The PCR product was gel purified and ligated into pCRII-TOPO TA vector.
# ::save-date Sun Jan 17, 2016 ::file pmid_1563_0473_285.txt
(a / and
      :op1 (p / purify-01
            :ARG1 (r / react-01
                  :ARG0 (p4 / polymerase)
                  :ARG1-of (c / chain-01))
            :mod (g / gel))
      :op2 (l / ligate-01
            :ARG1 (p2 / product)
            :ARG3 (p3 / product :name (n2 / name :op1 "pCRII-TOPO" :op2 "TA")
                  :mod (v / vector))))

# ::id pmid_1563_0473.286 ::date 2015-03-29T05:31:33 ::annotator SDL-AMR-09 ::preferred
# ::snt The pre-LIM domain of Ajuba was generated essentially as described [<xref ref-type="bibr" rid="pbio-0030011-b09">9</xref>], but was fused to GFP by subcloning from the pEGFP-N1 20 vector (BD Biosciences Clontech)
# ::save-date Tue Feb 2, 2016 ::file pmid_1563_0473_286.txt
(c3 / contrast-01
      :ARG1 (g / generate-01
            :ARG1 (p5 / protein-segment :name (n6 / name :op1 "pre-LIM")
                  :part-of (p / protein :name (n / name :op1 "Ajuba")))
            :ARG1-of (d3 / describe-01
                  :ARG0 (p2 / publication
                        :ARG1-of (c / cite-01
                              :ARG2 9))
                  :mod (e / essential)))
      :ARG2 (f / fuse-01
            :ARG0 (s / subclone-01
                  :ARG2 (v2 / vector :name (n5 / name :op1 "pEGFP-N1" :op2 "20")
                        :source (c2 / company :name (n4 / name :op1 "BD" :op2 "Biosciences" :op3 "Clontech"))))
            :ARG1 p5
            :ARG2 (p3 / protein :name (n2 / name :op1 "GFP"))))

# ::id pmid_1563_0473.287 ::date 2015-03-29T05:40:34 ::annotator SDL-AMR-09 ::preferred
# ::snt In situ hybridization
# ::save-date Fri Apr 3, 2015 ::file pmid_1563_0473_287.txt
(h / hybridize-01
      :manner (i / in-situ))

# ::id pmid_1563_0473.288 ::date 2015-03-29T05:40:48 ::annotator SDL-AMR-09 ::preferred
# ::snt The pCRII-TOPO TA vector containing a region of the 3′ UTR of <i>Snail</i> was used as a template to generate digoxigenin-labeled sense and antisense riboprobes (Roche).
# ::save-date Thu Feb 4, 2016 ::file pmid_1563_0473_288.txt
(u / use-01
      :ARG1 (p / product :name (n / name :op1 "pCRII-TOPO" :op2 "TA")
            :mod (v / vector)
            :ARG0-of (c / contain-01
                  :ARG1 (d2 / dna-sequence :name (n4 / name :op1 "3′" :op2 "untranslated" :op3 "region")
                        :part-of (g / gene :name (n2 / name :op1 "Snail")))))
      :ARG2 (t / template)
      :purpose (g2 / generate-01
            :ARG1 (a / and
                  :op1 (r2 / riboprobe
                        :mod (s / sense)
                        :ARG1-of (l / label-01
                              :ARG2 (d / digoxigenin)))
                  :op2 (r3 / riboprobe
                        :ARG1-of l
                        :mod (a3 / antisense))
                  :source (c2 / company :name (n3 / name :op1 "Roche")))))

# ::id pmid_1563_0473.289 ::date 2015-03-29T06:26:44 ::annotator SDL-AMR-09 ::preferred
# ::snt The respective probes were obtained by XhoI and BamH1 digestions.
# ::save-date Sun Mar 29, 2015 ::file pmid_1563_0473_289.txt
(o / obtain-01
      :ARG1 (p / probe-01
            :mod (r / respective))
      :ARG2 (d / digest-01
            :ARG1 (a / and
                  :op1 (p2 / product :name (n / name :op1 "XhoI"))
                  :op2 (p3 / product :name (n2 / name :op1 "BamH1")))))

# ::id pmid_1563_0473.290 ::date 2015-03-29T06:30:27 ::annotator SDL-AMR-09 ::preferred
# ::snt In situ hybridizations were performed on 10-μm thick sections of E17.5 mouse embryos.
# ::save-date Sun Aug 9, 2015 ::file pmid_1563_0473_290.txt
(p / perform-02
      :ARG1 (h / hybridize-01
            :manner (i / in-situ))
      :location (s / section-01
            :ARG2 (a / area-quantity :quant 10
                  :unit (m4 / micrometer))
            :ARG3 (e / embryo
                  :mod (m3 / mouse)
                  :age (t2 / temporal-quantity :quant 17.5
                        :unit (d / day)))
            :ARG1-of (t / thick-03)))

# ::id pmid_1563_0473.291 ::date 2015-03-29T06:30:42 ::annotator SDL-AMR-09 ::preferred
# ::snt The sections were fixed with 4% PFA for 10 min at room temperature, prehybridized at room temperature for 4.5 h, hybridized with the probe (2 μg/ml) at 55 °C for 12–14 h, blocked with 10% NGS, and treated with anti-dig Fab-AP antibody (Roche #1093274) at a 1:2,500 dilution for 3 h.
# ::save-date Fri Jan 1, 2016 ::file pmid_1563_0473_291.txt
(a / and
      :op1 (f / fix-02
            :ARG1 (s2 / section-01)
            :instrument (p3 / product :name (n / name :op1 "PFA")
                  :quant (p / percentage-entity :value 4))
            :duration (t / temporal-quantity :quant 10
                  :unit (m / minute))
            :mod (t2 / temperature
                  :mod (r / room)))
      :op2 (p4 / prehybridize-00
            :ARG1 s2
            :mod t2
            :duration (t3 / temporal-quantity :quant 4.5
                  :unit (h / hour)))
      :op3 (h2 / hybridize-01
            :ARG1 s2
            :ARG2 (p5 / probe-01
                  :quant (c / concentration-quantity :quant 2
                        :unit (m2 / microgram-per-milliliter)))
            :manner (t4 / temperature-quantity :quant 55
                  :scale (c2 / celsius))
            :duration (b2 / between
                  :op1 (t6 / temporal-quantity :quant 12
                        :unit (h3 / hour))
                  :op2 (t7 / temporal-quantity :quant 14
                        :unit (h4 / hour))))
      :op4 (b / block-01
            :ARG1 s2
            :ARG3 (p6 / product :name (n2 / name :op1 "NGS")
                  :quant (p2 / percentage-entity :value 10)))
      :op5 (t8 / treat-04
            :ARG1 s2
            :ARG2 (a2 / antibody :name (n3 / name :op1 "anti-dig" :op2 "Fab-AP")
                  :source (c3 / company :name (n4 / name :op1 "Roche"))
                  :ARG1-of (d2 / describe-01
                        :ARG2 (s3 / string-entity :value 1093274)))
            :manner (d / dilute-01
                  :ARG1-of (e / equal-01
                        :ARG2 "1/2500"))
            :duration (t9 / temporal-quantity :quant 3
                  :unit (h5 / hour))))

# ::id pmid_1563_0473.292 ::date 2015-03-28T05:23:09 ::annotator SDL-AMR-09 ::preferred
# ::snt The sections were incubated with NBT and BCIP until adequate signal was detected.
# ::save-date Fri Apr 3, 2015 ::file pmid_1563_0473_292.txt
(i / incubate-01
      :ARG1 (s / section-01)
      :ARG2 (a / and
            :op1 (p / product :name (n / name :op1 "NBT"))
            :op2 (p2 / product :name (n2 / name :op1 "BCIP")))
      :time (u / until
            :op1 (d / detect-01
                  :ARG1 (s2 / signal-07
                        :mod (a2 / adequate)))))

# ::id pmid_1563_0473.293 ::date 2015-03-28T14:24:01 ::annotator SDL-AMR-09 ::preferred
# ::snt Immunofluorescence and immunohistochemistry
# ::save-date Tue Feb 2, 2016 ::file pmid_1563_0473_293.txt
(a / and
      :op1 (i / immunofluoresce-01)
      :op2 (i2 / immunohistochemistry))

# ::id pmid_1563_0473.294 ::date 2015-03-28T14:30:59 ::annotator SDL-AMR-09 ::preferred
# ::snt Tissue samples for immunofluorescence were frozen in OCT and sectioned 10 μm thick on a cryostat.
# ::save-date Tue Feb 2, 2016 ::file pmid_1563_0473_294.txt
(a / and
      :op1 (f / freeze-01
            :ARG1 (t / tissue
                  :ARG1-of (s2 / sample-01
                        :purpose (i / immunofluoresce-01)))
            :instrument (t3 / thing :name (n / name :op1 "Optimal" :op2 "Cutting" :op3 "Temperature")))
      :op2 (s / section-01
            :ARG1 t
            :ARG2 (t2 / thick-03
                  :mod (d / distance-quantity :quant 10
                        :unit (m / micrometer)))
            :location (c / cryostat)))

# ::id pmid_1563_0473.295 ::date 2015-03-28T15:37:20 ::annotator SDL-AMR-09 ::preferred
# ::snt Sections were fixed in 4% paraformaldehyde for 10 min at room temperature, blocked, and stained with antibodies.
# ::save-date Sat Feb 13, 2016 ::file pmid_1563_0473_295.txt
(a / and
      :op1 (f / fix-00
            :ARG1 (t / thing
                  :ARG2-of (s2 / section-01))
            :ARG2 (s3 / small-molecule :name (n / name :op1 "paraformaldehyde")
                  :mod (p / percentage-entity :value 4))
            :duration (t2 / temporal-quantity :quant 10
                  :unit (m2 / minute))
            :mod (t3 / temperature
                  :poss (r / room)))
      :op2 (b / block-01
            :ARG1 t)
      :op2 (s / stain-01
            :ARG1 t
            :ARG2 (a2 / antibody)))

# ::id pmid_1563_0473.296 ::date 2015-03-29T01:58:17 ::annotator SDL-AMR-09 ::preferred
# ::snt Tissue samples for immunohistochemistry were fixed in 4% paraformaldehyde, dehydrated, and embedded in paraffin.
# ::save-date Sat Feb 13, 2016 ::file pmid_1563_0473_296.txt
(a / and
      :op1 (f / fix-03
            :ARG1 (t / tissue
                  :ARG1-of (s / sample-01
                        :purpose (i / immunohistochemistry)))
            :ARG2 (s2 / small-molecule :name (n / name :op1 "paraformaldehyde")
                  :mod (p / percentage-entity :value 4)))
      :op2 (d / dehydrate-01
            :ARG1 t)
      :op3 (e / embed-01
            :ARG1 t
            :ARG2 (p2 / paraffin)))

# ::id pmid_1563_0473.297 ::date 2015-03-29T02:09:33 ::annotator SDL-AMR-09 ::preferred
# ::snt Samples were sectioned on a microtome (10 μm thick) and rehydrated prior to staining with antibody.
# ::save-date Wed Dec 30, 2015 ::file pmid_1563_0473_297.txt
(a / and
      :op1 (s / section-01
            :ARG1 (t2 / thing
                  :ARG1-of (s2 / sample-01)
                  :ARG1-of (t / thick-03
                        :mod (d / distance-quantity :quant 10
                              :unit (m2 / micrometer))))
            :instrument (m / microtome))
      :op2 (h / hydrate-01
            :ARG1 t2
            :mod (a3 / again))
      :time (p / prior
            :op1 (s3 / stain-01
                  :ARG1 t2
                  :ARG2 (a2 / antibody))))

# ::id pmid_1563_0473.298 ::date 2015-03-29T03:04:21 ::annotator SDL-AMR-09 ::preferred
# ::snt Samples stained with Snail, pMAPK, pSmad2, and cyclin D were antigen unmasked with 10 mM sodium citrate (pH 6) in an Antigen Retriever 2100 (Pickcell Laboratories, Leiden, Netherlands).
# ::save-date Sun Dec 13, 2015 ::file pmid_1563_0473_298.txt
(u / unmask-01
      :ARG1 (t / thing
            :ARG1-of (s / sample-01)
            :ARG1-of (s2 / stain-01
                  :ARG2 (a / and
                        :op1 (p / protein
                              :name (n / name :op1 "Snail"))
                        :op2 (e / enzyme
                              :name (n2 / name :op1 "MAPK")
                              :ARG3-of (p2 / phosphorylate-01))
                        :op3 (p3 / protein
                              :name (n3 / name :op1 "Smad2")
                              :ARG1-of p2)
                        :op4 (p4 / protein
                              :name (n4 / name :op1 "cyclin" :op2 "D")))))
      :topic (a2 / antigen)
      :instrument (s3 / small-molecule
            :name (n5 / name :op1 "sodium" :op2 "citrate")
            :mod (c / concentration-quantity :quant 10
                  :unit (m2 / micromolar))
            :mod (a3 / acidity-quantity :quant 6
                  :scale (p6 / ph)))
      :location (p5 / product
            :name (n6 / name :op1 "Antigen" :op2 "Retriever" :op3 2100)
            :ARG1-of (m3 / manufacture-01
                  :ARG0 (c2 / company
                        :name (n7 / name :op1 "Pickcell" :op2 "Laboratories")
                        :location (c3 / city
                              :name (n8 / name :op1 "Leiden")
                              :location (c4 / country :wiki "Netherlands"
                                    :name (n9 / name :op1 "Netherlands")))))))

# ::id pmid_1563_0473.299 ::date 2015-03-29T03:52:50 ::annotator SDL-AMR-09 ::preferred
# ::snt The DAB substrate kit (Vector Labs) was used according to manufacturer's instructions to develop the signal.
# ::save-date Mon Apr 20, 2015 ::file pmid_1563_0473_299.txt
(u / use-01
      :ARG1 (k2 / kit :name (n2 / name :op1 "DAB")
            :ARG1-of (m2 / manufacture-01
                  :ARG0 (c2 / company :name (n / name :op1 "Vector" :op2 "Labs")))
            :mod (s / substrate))
      :ARG2-of (i / instruct-01
            :ARG0 c2)
      :purpose (d / develop-02
            :ARG1 (s2 / signal-07)))

# ::id pmid_1563_0473.300 ::date 2015-03-29T04:19:39 ::annotator SDL-AMR-09 ::preferred
# ::snt RT-PCR
# ::save-date Wed Dec 30, 2015 ::file pmid_1563_0473_300.txt
(r2 / react-01
      :ARG0 (p / polymerase)
      :ARG1-of (c / chain-01)
      :mod (t / transcribe-01
            :ARG1-of (r3 / reverse-01)))

# ::id pmid_1563_0473.301 ::date 2015-03-29T04:31:43 ::annotator SDL-AMR-09 ::preferred
# ::snt RNA was extracted from keratinocytes or skin tissue with Trizol (Invitrogen) according to the manufacturer's protocol.
# ::save-date Sun Jan 17, 2016 ::file pmid_1563_0473_301.txt
(e / extract-01
      :ARG1 (n / nucleic-acid :name (n4 / name :op1 "RNA"))
      :ARG2 (o / or
            :op1 (k / keratinocyte)
            :op2 (t / tissue
                  :part-of (s / skin)))
      :instrument (s2 / small-molecule :name (n2 / name :op1 "Trizol")
            :mod (c2 / company :name (n3 / name :op1 "Invitrogen")))
      :ARG1-of (s4 / say-01
            :ARG0 (p / protocol
                  :poss (c / company
                        :ARG0-of (m2 / manufacture-01)))))

# ::id pmid_1563_0473.302 ::date 2015-03-29T10:38:56 ::annotator SDL-AMR-09 ::preferred
# ::snt cDNA was generated using oligo-dT primers and the Superscript II kit (Invitrogen).
# ::save-date Sun Jan 17, 2016 ::file pmid_1563_0473_302.txt
(g / generate-01
      :ARG1 (n4 / nucleic-acid :wiki "DNA" :name (n5 / name :op1 "DNA")
            :ARG1-of (c / complement-01))
      :ARG2 (u / use-01
            :ARG1 (a / and
                  :op1 (d / dna-sequence :name (n3 / name :op1 "oligo-dT" :op2 "primer"))
                  :op2 (k / kit
                        :mod (e / enzyme :name (n / name :op1 "Superscript" :op2 "II")))
                  :source (c2 / company :name (n2 / name :op1 "Invitrogen")))))

# ::id pmid_1563_0473.303 ::date 2015-03-29T10:57:10 ::annotator SDL-AMR-09 ::preferred
# ::snt The primers used for PCR were <i>Snail</i> forward: 5′-CAGCTGGCCAGGCTCTCGGT-3′; <i>Snail</i> reverse: 5′-GCGAGGGCCTCCGGAGCA-3′; GAPDH forward 5′-CGTAGACAAAATGGTGAAGGTCGG-3′; and GAPDH reverse: 5′-AAGCAGTTGGTGGTGCAGGATG-3′.
# ::save-date Thu Feb 4, 2016 ::file pmid_1563_0473_303.txt
(u / use-01
      :ARG1 (a / and
            :op1 (p / primer :value "5′-CAGCTGGCCAGGCTCTCGGT-3′"
                  :ARG1-of (f / forward-01)
                  :part-of (g / gene :name (n2 / name :op1 "Snail")))
            :op2 (p2 / primer :value "5′-GCGAGGGCCTCCGGAGCA-3′"
                  :ARG1-of (r / reverse-01)
                  :part-of g)
            :op3 (p3 / primer :value "5′-CGTAGACAAAATGGTGAAGGTCGG-3′"
                  :mod (g2 / gene :name (n3 / name :op1 "GAPDH"))
                  :ARG1-of f)
            :op4 (p4 / primer :value "5′-AAGCAGTTGGTGGTGCAGGATG-3′"
                  :ARG1-of r
                  :part-of g2))
      :ARG2 (r2 / react-01
            :ARG0 (p5 / polymerase)
            :ARG1-of (c / chain-01)))

# ::id pmid_1563_0473.304 ::date 2015-03-29T11:53:22 ::annotator SDL-AMR-09 ::preferred
# ::snt Figure 1
# ::save-date Sun Mar 29, 2015 ::file pmid_1563_0473_304.txt
(f / figure :mod 1)

# ::id pmid_1563_0473.305 ::date 2015-03-29T11:54:06 ::annotator SDL-AMR-09 ::preferred
# ::snt Embryos were either frozen in OCT embedding compound (A, F, and H) or embedded in paraffin (C, D, E, and G), and then sectioned (8 μm).
# ::save-date Wed Dec 30, 2015 ::file pmid_1563_0473_305.txt
(a / and
      :op1 (o / or
            :op1 (f / freeze-01
                  :ARG1 (e2 / embryo)
                  :ARG1-of (d / describe-01
                        :ARG0 (a2 / and
                              :op1 (f2 / figure :mod "A")
                              :op2 (f3 / figure :mod "F")
                              :op3 (f4 / figure :mod "H")))
                  :instrument (c3 / compound :name (n / name :op1 "OCT")
                        :ARG2-of (e4 / embed-01)))
            :op2 (e / embed-01
                  :ARG1 e2
                  :ARG2 (p / paraffin)
                  :ARG1-of (d2 / describe-01
                        :ARG0 (a3 / and
                              :op1 (f5 / figure :mod "C")
                              :op2 (f6 / figure :mod "D")
                              :op3 (f7 / figure :mod "E")
                              :op4 (f8 / figure :mod "G")))))
      :op2 (s / section-01
            :ARG1 e2
            :ARG2 (d3 / distance-quantity :quant 8
                  :unit (m / micrometer))
            :time (t / then)))

# ::id pmid_1563_0473.306 ::date 2015-03-29T12:09:54 ::annotator SDL-AMR-09 ::preferred
# ::snt (A) In situ hybridizations with <i>Snail</i> sense or antisense cRNA probes.
# ::save-date Thu Jan 14, 2016 ::file pmid_1563_0473_306.txt
(h / hybridize-01
      :ARG2 (o / or
            :op1 (p / probe-01
                  :ARG1 (n3 / nucleic-acid :name (n / name :op1 "cRNA"))
                  :ARG2 (g / gene :name (n2 / name :op1 "Snail"))
                  :mod (s / sense))
            :op2 (p3 / probe-01
                  :ARG1 n3
                  :ARG2 g
                  :mod (a / antisense)))
      :manner (i / in-situ)
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod "A")))

# ::id pmid_1563_0473.307 ::date 2015-03-29T12:26:43 ::annotator SDL-AMR-09 ::preferred
# ::snt Black dotted lines demarcate the basement membrane that separates the epidermis (epi) from dermis (der).
# ::save-date Wed Oct 28, 2015 ::file pmid_1563_0473_307.txt
(d / demarcate-01
      :ARG0 (l / line
            :ARG1-of (b / black-04)
            :ARG1-of (d2 / dot-01))
      :ARG1 (m / membrane
            :mod (b2 / basement)
            :ARG0-of (s / separate-01
                  :ARG1 (e / epidermis
                        :ARG1-of (d5 / describe-01
                              :ARG2 (s2 / string-entity :value "epi")))
                  :ARG2 (d3 / dermis
                        :ARG1-of (d6 / describe-01
                              :ARG2 (s3 / string-entity :value "der"))))))

# ::id pmid_1563_0473.308 ::date 2015-03-29T12:30:42 ::annotator SDL-AMR-09 ::preferred
# ::snt Arrows point to <i>Snail</i> RNA expression, restricted to the hair bud stage of follicle morphogenesis.
# ::save-date Thu Jan 14, 2016 ::file pmid_1563_0473_308.txt
(p / point-01
      :ARG0 (a / arrow)
      :ARG1 (e / express-03
            :ARG2 (n3 / nucleic-acid :name (n / name :op1 "RNA")
                  :mod (g / gene :name (n2 / name :op1 "Snail")))
            :ARG1-of (r2 / restrict-01
                  :ARG2 (s / stage
                        :mod (b / bud
                              :mod (h / hair))
                        :subevent-of (m / morphogenesis
                              :mod (f / follicle))))))

# ::id pmid_1563_0473.309 ::date 2015-03-29T12:44:32 ::annotator SDL-AMR-09 ::preferred
# ::snt It was not seen in later hair germ or peg stages.
# ::save-date Mon Apr 20, 2015 ::file pmid_1563_0473_309.txt
(s / see-01 :polarity -
      :ARG1 (i / it)
      :topic (o / or
            :op1 (g / germ
                  :mod (h / hair)
                  :time (l / late
                        :degree (m / more)))
            :op2 (s2 / stage
                  :mod (p / peg)
                  :time l)))

# ::id pmid_1563_0473.310 ::date 2015-03-29T12:53:17 ::annotator SDL-AMR-09 ::preferred
# ::snt (B) Expression of Snail protein coincides with hair development.
# ::save-date Fri Oct 23, 2015 ::file pmid_1563_0473_310.txt
(c / coincide-01
      :ARG1 (e / express-03
            :ARG2 (p / protein :name (n / name :op1 "Snail")))
      :ARG2 (d / develop-01
            :ARG2 (h / hair))
      :ARG1-of (d2 / describe-01
            :ARG0 (f / figure :mod "B")))

# ::id pmid_1563_0473.311 ::date 2015-03-29T12:56:42 ::annotator SDL-AMR-09 ::preferred
# ::snt Protein extracts were prepared from keratinocytes transfected with empty expression vector (K14), containing the K14 promoter or with the vector driving HA-tagged <i>Snail</i> (K14-<i>Snail</i>); or from whole skin from E13.5 to P5 animals, including newborn (nb).
# ::save-date Thu Jan 14, 2016 ::file pmid_1563_0473_311.txt
(p / prepare-01
      :ARG1 (e / extract-01
            :ARG1 (p2 / protein))
      :ARG2 (o / or
            :op1 (k / keratinocyte
                  :ARG1-of (t / transfect-01
                        :ARG2 (o3 / or
                              :op1 (v / vector
                                    :mod (e2 / express-03)
                                    :ARG1-of (e3 / empty-02)
                                    :ARG1-of (m / mean-01
                                          :ARG2 (p3 / protein :name (n / name :op1 "K14")))
                                    :ARG0-of (c / contain-01
                                          :ARG1 (m4 / molecular-physical-entity
                                                :ARG0-of (p8 / promote-01
                                                      :ARG1 p3))))
                              :op2 (v2 / vector
                                    :ARG0-of (d / drive-02
                                          :ARG1 (p5 / protein :name (n2 / name :op1 "Snail")
                                                :ARG1-of (t2 / tag-01
                                                      :ARG2 (p6 / protein :name (n3 / name :op1 "HA")))))
                                    :ARG1-of (m2 / mean-01
                                          :ARG2 (g / gene :name (n4 / name :op1 "Snail")
                                                :ARG1-of (m5 / mutate-01 :value "K14")))))))
            :op2 (s / skin
                  :mod (w / whole)
                  :part-of (o2 / or
                        :op1 (e4 / embryo
                              :age (a4 / at-least
                                    :op1 (t3 / temporal-quantity :quant 13.5
                                          :unit (d3 / day))))
                        :op2 (a / animal
                              :ARG2-of (i / include-91
                                    :ARG1 (a2 / animal
                                          :ARG1-of (b / bear-02
                                                :time (n5 / new-01))))
                              :age (a5 / at-most
                                    :op1 (t4 / temporal-quantity :quant 5
                                          :unit (d4 / day))))))))

# ::id pmid_1563_0473.312 ::date 2015-03-29T13:47:16 ::annotator SDL-AMR-09 ::preferred
# ::snt Equal amounts of proteins were then resolved by SDS-PAGE through 12% gels and subjected to Western blotting using either an affinity-purified Snail polyclonal antiserum, which we generated, or anti-tubulin (loading control).
# ::save-date Sun Jan 31, 2016 ::file pmid_1563_0473_312.txt
(a / and
      :op1 (r / resolve-03
            :ARG1 (p / protein
                  :quant (a2 / amount
                        :ARG1-of (e / equal-01)))
            :ARG3 (t2 / thing :name (n / name :op1 "SDS-PAGE")
                  :instrument (g / gel
                        :mod (p2 / percentage-entity :value 12)))
            :time (t / then))
      :op2 (s / subject-01
            :ARG1 p
            :ARG2 (i / immunoblot-01
                  :ARG3 (o / or
                        :op1 (s2 / serum
                              :ARG0-of (c / counter-01
                                    :ARG1 (p3 / protein :name (n3 / name :op1 "Snail")))
                              :mod (p4 / polyclonal)
                              :ARG1-of (p5 / purify-01
                                    :ARG2 (a4 / affinity))
                              :ARG1-of (g2 / generate-01
                                    :ARG0 (w / we)))
                        :op2 (m / molecular-physical-entity
                              :ARG0-of (c2 / counter-01
                                    :ARG1 (p6 / protein :name (n4 / name :op1 "tubulin")))
                              :ARG0-of (c3 / control-01
                                    :ARG1 (l / load-01)))))))

# ::id pmid_1563_0473.313 ::date 2015-03-29T14:06:54 ::annotator SDL-AMR-09 ::preferred
# ::snt (C–E) Immunohistochemistry shows expression of Snail protein in the nuclei of cells within the hair and skin.
# ::save-date Wed Dec 30, 2015 ::file pmid_1563_0473_313.txt
(s / show-01
      :ARG0 (i / immunohistochemistry)
      :ARG1 (e / express-03
            :ARG2 (p / protein :name (n / name :op1 "Snail"))
            :ARG3 (n2 / nucleus
                  :part-of (c / cell
                        :part-of (a / and
                              :op1 (h / hair)
                              :op2 (s2 / skin)))))
      :ARG1-of (d / describe-01
            :ARG0 (a2 / and
                  :op1 (f / figure :mod "C")
                  :op2 (f2 / figure :mod "D")
                  :op3 (f3 / figure :mod "E"))))

# ::id pmid_1563_0473.314 ::date 2015-03-29T14:12:09 ::annotator SDL-AMR-09 ::preferred
# ::snt (C) E13.5 skin with a single layered epidermis (epi) shows no Snail expression.
# ::save-date Mon Dec 21, 2015 ::file pmid_1563_0473_314.txt
(s / show-01
      :ARG0 (s2 / skin
            :part (e2 / epidermis
                  :mod (l / layer
                        :ARG1-of (s3 / single-02)))
            :time (d2 / day :mod 13.5
                  :mod (e3 / embryo)))
      :ARG1 (e / express-03 :polarity -
            :ARG2 (p / protein :name (n / name :op1 "Snail")))
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod "C")))

# ::id pmid_1563_0473.315 ::date 2015-03-29T14:17:06 ::annotator SDL-AMR-09 ::preferred
# ::snt (D) The first morphological sign that cells have adopted a hair follicle fate is a cluster of cells called a placode in E16.5 skin.
# ::save-date Wed Dec 30, 2015 ::file pmid_1563_0473_315.txt
(s / signal-07
      :ARG0 (c / cluster-01
            :ARG1 (c2 / cell)
            :ARG1-of (c3 / call-01
                  :ARG2 (p / placode))
            :location (s2 / skin
                  :part-of (e / embryo
                        :age (t / temporal-quantity :quant 16.5
                              :unit (d2 / day)))))
      :ARG1 (a / adopt-01
            :ARG0 c2
            :ARG1 (f / fate
                  :poss (f2 / follicle
                        :mod (h / hair))))
      :ord (o / ordinal-entity :value 1)
      :mod (m / morphological)
      :ARG1-of (d / describe-01
            :ARG0 (f3 / figure :mod "D")))

# ::id pmid_1563_0473.316 ::date 2015-03-29T14:27:35 ::annotator SDL-AMR-09 ::preferred
# ::snt Snail is not expressed at this stage of development.
# ::save-date Sun Mar 29, 2015 ::file pmid_1563_0473_316.txt
(e / express-03 :polarity -
      :ARG2 (p / protein :name (n / name :op1 "Snail"))
      :time (s / stage
            :mod (t / this)
            :subevent-of (d / develop-01)))

# ::id pmid_1563_0473.317 ::date 2015-03-29T14:28:51 ::annotator SDL-AMR-09 ::preferred
# ::snt (E) Snail is expressed in the hair bud of E17.5 skin but not in later stages of development such as the germ or peg.
# ::save-date Wed Dec 30, 2015 ::file pmid_1563_0473_317.txt
(e / express-03
      :ARG2 (p / protein :name (n / name :op1 "Snail"))
      :ARG3 (b / bud
            :mod (h / hair)
            :part-of (s / skin
                  :part-of (e4 / embryo
                        :age (t / temporal-quantity :quant 17.5
                              :unit (d4 / day)))))
      :ARG1-of (c / contrast-01
            :ARG2 (e2 / express-03 :polarity -
                  :ARG2 p
                  :ARG3 (s2 / stage
                        :time (l / late
                              :degree (m / more))
                        :subevent-of (d / develop-01)
                        :example (o2 / or
                              :op1 (g / germ)
                              :op2 (p2 / peg)))))
      :ARG1-of (d2 / describe-01
            :ARG0 (f / figure :mod "E")))

# ::id pmid_1563_0473.318 ::date 2015-03-29T14:32:14 ::annotator SDL-AMR-09 ::preferred
# ::snt (F) Immunofluorescence with anti-Ki67 (green) identifies the proliferating cells of the skin, restricted to the basal layer of the epidermis and developing hair follicles.
# ::save-date Tue Feb 2, 2016 ::file pmid_1563_0473_318.txt
(i / identify-01
      :ARG0 (i2 / immunofluoresce-01
            :ARG2 (a / antibody
                  :ARG0-of (c / counter-01
                        :ARG1 (p / protein :name (n / name :op1 "Ki67")))
                  :ARG1-of (g / green-02)))
      :ARG1 (c2 / cell
            :part-of (s / skin)
            :ARG0-of (p2 / proliferate-01)
            :ARG1-of (r / restrict-01
                  :ARG2 (l / layer
                        :mod (b / basal)
                        :part-of (a2 / and
                              :op1 (e / epidermis)
                              :op2 (f / follicle
                                    :mod (h / hair)
                                    :ARG2-of (d / develop-01))))))
      :ARG1-of (d2 / describe-01
            :ARG0 (f2 / figure :mod "F")))

# ::id pmid_1563_0473.319 ::date 2015-03-29T14:37:51 ::annotator SDL-AMR-09 ::preferred
# ::snt Anti-β4 int labeling reveals the presence of the hemidesmosomal integrin β4, restricted to the base of cells adhering to the underlying basement membrane.
# ::save-date Mon Jan 4, 2016 ::file pmid_1563_0473_319.txt
(r / reveal-01
      :ARG0 (l / label-01
            :ARG0 (a2 / antibody
                  :ARG0-of (c / counter-01
                        :ARG1 (p2 / protein :name (n / name :op1 "β4" :op2 "integrin")))))
      :ARG1 (p3 / present-02
            :ARG1 (p / protein :name (n2 / name :op1 "β4" :op2 "integrin")
                  :mod (h / hemidesmosome)
                  :ARG1-of (r2 / restrict-01
                        :ARG2 (b2 / base
                              :part-of (c2 / cell
                                    :ARG1-of (a / adhere-01
                                          :ARG2 (m3 / membrane
                                                :mod (b3 / basement)
                                                :ARG0-of (u / underlie-01)))))))))

# ::id pmid_1563_0473.320 ::date 2015-03-29T14:48:56 ::annotator SDL-AMR-09 ::preferred
# ::snt The white dotted line marks the outermost surface of the skin.
# ::save-date Sun Dec 20, 2015 ::file pmid_1563_0473_320.txt
(m / mark-01
      :ARG0 (l / line
            :ARG1-of (w / white-03)
            :ARG1-of (d / dot-01))
      :ARG1 (s / surface
            :part-of (s2 / skin
                  :mod (o / outer
                        :degree (m2 / most)))))

# ::id pmid_1563_0473.321 ::date 2015-03-29T14:52:33 ::annotator SDL-AMR-09 ::preferred
# ::snt (G) Immunohistochemistry with pMAPK marks a subset of proliferating cells within the epidermis and hair bud.
# ::save-date Wed Dec 30, 2015 ::file pmid_1563_0473_321.txt
(m / mark-01
      :ARG0 (i / immunohistochemistry
            :instrument (e / enzyme :name (n / name :op1 "MAPK")
                  :ARG3-of (p / phosphorylate-01)))
      :ARG1 (s / subset
            :ARG1-of (i2 / include-91
                  :ARG2 (c / cell
                        :ARG0-of (p2 / proliferate-01)
                        :location (a / and
                              :op1 (e2 / epidermis)
                              :op2 (b / bud
                                    :mod (h / hair))))))
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod "G")))

# ::id pmid_1563_0473.322 ::date 2015-03-29T14:55:13 ::annotator SDL-AMR-09 ::preferred
# ::snt Anti-pMAPK labeling was consistently robust within the hair bud.
# ::save-date Mon Feb 1, 2016 ::file pmid_1563_0473_322.txt
(r / robust
      :manner (c / consistent-02)
      :domain (l / label-01
            :ARG0-of (c2 / counter-01
                  :ARG1 (e / enzyme :name (n / name :op1 "MAPK")
                        :ARG3-of (p / phosphorylate-01)))
            :location (b / bud
                  :mod (h / hair))))

# ::id pmid_1563_0473.323 ::date 2015-03-29T14:58:20 ::annotator SDL-AMR-09 ::preferred
# ::snt (H) Immunofluorescence with anti-laminin 5 (lam5), which demarcates the basement membrane, and anti-E-cadherin (E-cad), a component of AJs.
# ::save-date Tue Feb 2, 2016 ::file pmid_1563_0473_323.txt
(i / immunofluoresce-01
      :ARG2 (a / and
            :op1 (m / molecular-physical-entity
                  :ARG0-of (c / counter-01
                        :ARG1 (p / protein :name (n / name :op1 "laminin" :op2 "5")
                              :ARG0-of (d / demarcate-01
                                    :ARG1 (m2 / membrane
                                          :mod (b / basement))))))
            :op1 (m3 / molecular-physical-entity
                  :ARG0-of (c2 / counter-01
                        :ARG1 (p2 / protein :name (n2 / name :op1 "E-cadherin")
                              :part-of (m4 / macro-molecular-complex :name (n3 / name :op1 "adherens" :op2 "junction"))))))
      :ARG1-of (d2 / describe-01
            :ARG0 (f / figure :mod "H")))

# ::id pmid_1563_0473.324 ::date 2015-03-29T15:09:34 ::annotator SDL-AMR-09 ::preferred
# ::snt At the leading edge of the growing bud, cell-cell borders show markedly diminished anti-E-cadherin labeling (arrowheads).
# ::save-date Sun May 17, 2015 ::file pmid_1563_0473_324.txt
(s / show-01
      :ARG0 (b / border-01
            :ARG1 (c / cell)
            :ARG2 (c2 / cell))
      :ARG1 (l2 / label-01
            :ARG1-of (d / diminish-01
                  :manner (m / marked))
            :ARG0-of (c3 / counter-01
                  :ARG1 (p / protein :name (n / name :op1 "E-cadherin"))))
      :location (e / edge
            :ARG0-of (l / lead-01)
            :part-of (b2 / bud
                  :ARG1-of (g / grow-01)))
      :ARG1-of (d2 / describe-01
            :ARG0 (a2 / arrowhead)))

# ::id pmid_1563_0473.325 ::date 2015-03-29T15:15:20 ::annotator SDL-AMR-09 ::preferred
# ::snt Figure 2
# ::save-date Sun Mar 29, 2015 ::file pmid_1563_0473_325.txt
(f / figure :mod 2)

# ::id pmid_1563_0473.326 ::date 2015-03-29T15:15:49 ::annotator SDL-AMR-09 ::preferred
# ::snt Three different surviving Tg founder mice harbored a <i>K14-Snail</i> transgene that was integrated into a locus that resulted in inheritable, mosaic expression of the transgene in skin epidermis.
# ::save-date Thu Jan 14, 2016 ::file pmid_1563_0473_326.txt
(h / harbor-01
      :ARG0 (m / mouse :quant 3
            :mod (t / transgenic)
            :ARG0-of (f / found-01)
            :ARG1-of (d / differ-02)
            :ARG0-of (s / survive-01))
      :ARG1 (t2 / transgene
            :ARG1-of (i / integrate-01
                  :ARG2 (l / locus
                        :ARG1-of (r / result-01
                              :ARG2 (e / express-03
                                    :ARG1 (t3 / transgene)
                                    :ARG3 (e2 / epidermis
                                          :part-of (s2 / skin))
                                    :ARG1-of (i2 / inherit-01
                                          :ARG1-of (p3 / possible-01))
                                    :mod (m3 / mosaic)))))
            :mod (g / gene :name (n2 / name :op1 "Snail")
                  :ARG2-of (m4 / mutate-01 :value "K14"))))

# ::id pmid_1563_0473.327 ::date 2015-03-29T15:28:40 ::annotator SDL-AMR-09 ::preferred
# ::snt All displayed similar abnormalities, as did their offspring.
# ::save-date Sun Mar 29, 2015 ::file pmid_1563_0473_327.txt
(d / display-01
      :ARG0 (a3 / and
            :op1 (a / all)
            :op2 (o / offspring
                  :poss a))
      :ARG1 (a2 / abnormality
            :ARG1-of (r / resemble-01)))

# ::id pmid_1563_0473.328 ::date 2015-03-29T15:33:38 ::annotator SDL-AMR-09 ::preferred
# ::snt (A) P16 WT and <i>K14-Snail</i> Tg mice.
# ::save-date Sun Jan 17, 2016 ::file pmid_1563_0473_328.txt
(a / and
      :op1 (m3 / mouse
            :mod (w / wild-type)
            :time (a3 / after
                  :op1 (b / bear-02)
                  :quant (t2 / temporal-quantity :quant 16
                        :unit (d3 / day))))
      :op2 (m / mouse
            :mod (t / transgenic)
            :mod (g / gene :name (n3 / name :op1 "Snail")
                  :ARG2-of (m2 / mutate-01 :value "K14")))
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod "A")))

# ::id pmid_1563_0473.329 ::date 2015-03-29T15:36:49 ::annotator SDL-AMR-09 ::preferred
# ::snt Insets denote magnified tail segments, which displayed a mosaic, flaky appearance in Tg mice.
# ::save-date Sun Mar 29, 2015 ::file pmid_1563_0473_329.txt
(d / denote-01
      :ARG0 (i / inset)
      :ARG1 (s / segment
            :part-of (t / tail)
            :ARG1-of (m / magnify-01)
            :ARG0-of (d2 / display-01
                  :ARG1 (a / appear-02
                        :ARG1 s
                        :mod (m2 / mosaic)
                        :mod (f / flake)
                        :location (m3 / mouse
                              :mod (t2 / transgenic))))))

# ::id pmid_1563_0473.330 ::date 2015-03-29T15:42:09 ::annotator SDL-AMR-09 ::preferred
# ::snt Size differences appeared with age, and are likely due to K14-promoter activity in the tongue and oral epithelium, resulting in progressive defects and reduced food intake.
# ::save-date Mon Jul 6, 2015 ::file pmid_1563_0473_330.txt
(a / and
      :op1 (a2 / appear-01
            :ARG1 (d / differ-02
                  :ARG3 (s / size))
            :time (a3 / age))
      :op2 (l / likely-01
            :ARG1 (c / cause-01
                  :ARG0 (a4 / activity-06
                        :ARG0 (m2 / molecular-physical-entity
                              :ARG0-of (p4 / promote-01
                                    :ARG1 (p / protein :name (n / name :op1 "K14"))))
                        :location (a5 / and
                              :op1 (t / tongue)
                              :op2 (e / epithelium
                                    :part-of (m / mouth)))
                        :ARG1-of (r / result-01
                              :ARG2 (a6 / and
                                    :op1 (d2 / defect
                                          :ARG1-of (p3 / progress-01))
                                    :op2 (i / intake
                                          :mod (f / food)
                                          :ARG1-of (r2 / reduce-01)))))
                  :ARG1 d)))

# ::id pmid_1563_0473.331 ::date 2015-03-29T15:50:38 ::annotator SDL-AMR-09 ::preferred
# ::snt Hence, skin sections from young (P3) mice were analyzed (B–I).
# ::save-date Wed Dec 30, 2015 ::file pmid_1563_0473_331.txt
(c / cause-01
      :ARG1 (a / analyze-01
            :ARG1 (t / thing
                  :ARG2-of (s / section-01
                        :ARG1 (s2 / skin
                              :source (m / mouse
                                    :mod (y / young)
                                    :ARG1-of (m2 / mean-01
                                          :ARG2 (a2 / after
                                                :op1 (b / bear-02)
                                                :quant (t2 / temporal-quantity :quant 3
                                                      :unit (d3 / day))))))))
            :ARG1-of (d / describe-01
                  :ARG0 (a3 / and
                        :op1 (f / figure :mod "B")
                        :op2 (f2 / figure :mod "C")
                        :op3 (f3 / figure :mod "D")
                        :op4 (f4 / figure :mod "E")
                        :op5 (f5 / figure :mod "F")
                        :op6 (f6 / figure :mod "G")
                        :op7 (f7 / figure :mod "H")
                        :op8 (f8 / figure :mod "I")))))

# ::id pmid_1563_0473.332 ::date 2015-03-29T15:54:47 ::annotator SDL-AMR-09 ::preferred
# ::snt (B) Hematoxylin- and eosin-stained Tg skin section.
# ::save-date Sat Feb 13, 2016 ::file pmid_1563_0473_332.txt
(t / thing
      :ARG1-of (s3 / stain-01
            :ARG2 (a / and
                  :op1 (s4 / small-molecule :name (n / name :op1 "hematoxylin"))
                  :op2 (s5 / small-molecule :name (n2 / name :op1 "eosin"))))
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod "B"))
      :ARG2-of (s / section-01
            :ARG1 (s2 / skin)))

# ::id pmid_1563_0473.333 ::date 2015-03-29T15:57:31 ::annotator SDL-AMR-09 ::preferred
# ::snt Double arrows demarcate the border of mosaic histology, with seemingly normal epidermis (epi) and a mature hair follicle (hf) at left and hyperthickened epidermis at right.
# ::save-date Sat Jan 30, 2016 ::file pmid_1563_0473_333.txt
(d / demarcate-01
      :ARG0 (a / arrow
            :mod (d2 / double))
      :ARG1 (b / border-01
            :ARG1 (h / histology
                  :mod (m / mosaic)
                  :part (e / epidermis
                        :ARG1-of (n / normal-02
                              :ARG1-of (s / seem-01)))
                  :part (f / follicle
                        :mod (h2 / hair)
                        :ARG1-of (m2 / mature-02)
                        :ARG1-of (l / left-20))
                  :part (e2 / epidermis
                        :ARG1-of (t / thicken-01
                              :degree (h3 / hyper))
                        :ARG1-of (r / right-04)))))

# ::id pmid_1563_0473.334 ::date 2015-03-29T16:03:44 ::annotator SDL-AMR-09 ::preferred
# ::snt (C) Immunofluorescence of Tg skin section labeled with antibodies as color-coded on frame.
# ::save-date Tue Feb 2, 2016 ::file pmid_1563_0473_334.txt
(i / immunofluoresce-01
      :ARG1 (t2 / thing
            :ARG1-of (l / label-01
                  :ARG2 (a / antibody)
                  :ARG1-of (c / code-01
                        :ARG0 (c2 / color)
                        :location (f / frame)))
            :ARG1-of (d / describe-01
                  :ARG0 (f2 / figure :mod "C"))
            :ARG2-of (s / section-01
                  :ARG1 (s2 / skin
                        :mod (t / transgenic)))))

# ::id pmid_1563_0473.335 ::date 2015-03-29T16:06:54 ::annotator SDL-AMR-09 ::preferred
# ::snt Double arrows demarcate the border of mosaic anti-Snail (green), revealing Snail expression coincident with regions of hyperthickened epidermis (at left) and absent in regions of normal epidermis (at right).
# ::save-date Sat Jan 30, 2016 ::file pmid_1563_0473_335.txt
(d / demarcate-01
      :ARG0 (a / arrow
            :mod (d2 / double)
            :ARG1-of (g / green-02))
      :ARG1 (b / border-01
            :ARG1 (m / molecular-physical-entity
                  :ARG0-of (c / counter-01
                        :ARG1 (p / protein :name (n / name :op1 "Snail")))
                  :mod (m2 / mosaic)))
      :ARG0-of (r / reveal-01
            :ARG1 (a2 / and
                  :op1 (c2 / coincide-01
                        :ARG1 (e / express-03
                              :ARG2 p)
                        :ARG2 (r2 / region
                              :part-of (e2 / epidermis
                                    :ARG1-of (t / thicken-01
                                          :degree (h / hyper)))
                              :ARG1-of (l / left-20)))
                  :op2 (a4 / absent-01
                        :ARG1 e
                        :ARG2 (r3 / region
                              :part-of (e3 / epidermis
                                    :ARG1-of (n2 / normal-02)))
                        :ARG1-of (r4 / right-04)))))

# ::id pmid_1563_0473.336 ::date 2015-03-29T16:15:17 ::annotator SDL-AMR-09 ::preferred
# ::snt (D–I) Sections of P3 WT or Tg skin (affected region) subjected to either immunofluorescence (D, E, H, and I) or immunohistochemistry (F and G) with antibodies as indicated on the panel.
# ::save-date Tue Feb 2, 2016 ::file pmid_1563_0473_336.txt
(s / subject-01
      :ARG1 (t2 / thing
            :ARG2-of (s2 / section-01
                  :ARG1 (o / or
                        :op1 (s3 / skin
                              :mod (w / wild-type)
                              :time (a5 / after
                                    :op1 (b / bear-02)
                                    :quant (t3 / temporal-quantity :quant 3
                                          :unit (d3 / day))))
                        :op2 (s4 / skin
                              :mod (t / transgenic))
                        :ARG1-of (m / mean-01
                              :ARG2 (r / region
                                    :ARG1-of (a / affect-01))))))
      :ARG2 (o3 / or
            :op1 (i / immunofluoresce-01
                  :ARG1 t2
                  :ARG2 a2
                  :ARG1-of (d / describe-01
                        :ARG0 (a3 / and
                              :op1 (f3 / figure :mod "D")
                              :op2 (f4 / figure :mod "E")
                              :op3 (f5 / figure :mod "H")
                              :op4 (f6 / figure :mod "I"))))
            :op2 (i3 / immunohistochemistry
                  :instrument (a2 / antibody
                        :ARG1-of (i4 / indicate-01
                              :location (p / panel)))
                  :ARG1-of (d4 / describe-01
                        :ARG0 (a4 / and
                              :op1 (f / figure :mod "F")
                              :op2 (f7 / figure :mod "G")))))
      :ARG1-of (d2 / describe-01
            :ARG0 (a6 / and
                  :op1 f3
                  :op2 f4
                  :op3 f
                  :op4 f7
                  :op5 f5)))

# ::id pmid_1563_0473.337 ::date 2015-03-27T09:09:53 ::annotator SDL-AMR-09 ::preferred
# ::snt Anti-keratin 5 indicates K5, normally restricted to the basal layer of the epidermis; anti-keratin 6 detects keratin 6, expressed in postnatal epidermis under conditions such as wounding, in which hyperproliferation occurs.
# ::save-date Wed Dec 30, 2015 ::file pmid_1563_0473_337.txt
(m / multi-sentence
      :snt1 (i / indicate-01
            :ARG0 (a / antibody
                  :ARG0-of (c / counter-01
                        :ARG1 (p / protein :name (n / name :op1 "keratin" :op2 "5")
                              :ARG1-of (r / restrict-01
                                    :ARG2 (l / layer
                                          :part-of (e / epidermis)
                                          :mod (b / basal))
                                    :ARG1-of (n2 / normal-02)))))
            :ARG1 p)
      :snt2 (d / detect-01
            :ARG0 (a2 / antibody
                  :ARG0-of (c2 / counter-01
                        :ARG1 (p2 / protein :name (n3 / name :op1 "keratin" :op2 "6")
                              :ARG2-of (e2 / express-03
                                    :ARG3 (e3 / epidermis
                                          :mod (p3 / postnatal))
                                    :ARG1-of (c3 / condition-01
                                          :example (w / wound-01
                                                :time-of (p4 / proliferate-01
                                                      :degree (h / hyper))))))))
            :ARG1 p2))

# ::id pmid_1563_0473.338 ::date 2015-03-27T09:42:17 ::annotator SDL-AMR-09 ::preferred
# ::snt All other antibodies are as in the legend to <xref ref-type="fig" rid="pbio-0030011-g002">Figure 2</xref>.
# ::save-date Fri Apr 3, 2015 ::file pmid_1563_0473_338.txt
(r / resemble-01
      :ARG1 (a / antibody
            :mod (a2 / all)
            :mod (o / other))
      :ARG2 (a3 / antibody
            :location (l / legend
                  :mod (f / figure :mod 2))))

# ::id pmid_1563_0473.339 ::date 2015-03-27T09:45:13 ::annotator SDL-AMR-09 ::preferred
# ::snt Comparison of D and E provide representative examples that illustrate that pMAPK is found in only a subset of all proliferating (Ki67-positive) cells.
# ::save-date Fri Jan 1, 2016 ::file pmid_1563_0473_339.txt
(p2 / provide-01
      :ARG0 (c / compare-01
            :ARG1 (f / figure :mod "D")
            :ARG2 (f2 / figure :mod "E"))
      :ARG1 (e / example
            :ARG0-of (r2 / represent-01)
            :ARG0-of (i / illustrate-01
                  :ARG1 (b / be-located-at-91
                        :ARG1 (e2 / enzyme :name (n / name :op1 "MAPK")
                              :ARG3-of (p / phosphorylate-01))
                        :ARG2 (s / subset
                              :mod (o / only)
                              :ARG1-of (i2 / include-91
                                    :ARG2 (c2 / cell
                                          :ARG0-of (p4 / proliferate-01)
                                          :mod (p5 / positive
                                                :mod (p6 / protein :name (n2 / name :op1 "Ki67")))
                                          :mod (a / all))))))))

# ::id pmid_1563_0473.340 ::date 2015-03-27T10:39:46 ::annotator SDL-AMR-09 ::preferred
# ::snt Note also the presence of Ki67- (E) and pMAPK-positive (G) cells in some suprabasal areas; Ki67-positive cells colabeled with anti-Snail (E).
# ::save-date Fri Jan 1, 2016 ::file pmid_1563_0473_340.txt
(m / multi-sentence
      :snt1 (n / note-02 :mode imperative
            :ARG0 (y / you)
            :ARG1 (p8 / present-02
                  :ARG1 (a / and
                        :op1 (c / cell
                              :mod (p / positive
                                    :mod (p2 / protein :name (n2 / name :op1 "Ki67")))
                              :ARG1-of (d / describe-01
                                    :ARG0 (f / figure :mod "E")))
                        :op2 (c2 / cell
                              :mod (p3 / positive
                                    :mod (e / enzyme :name (n3 / name :op1 "MAPK")
                                          :ARG3-of (p4 / phosphorylate-01)))
                              :ARG1-of (d2 / describe-01
                                    :ARG0 (f2 / figure :mod "G"))))
                  :ARG2 (a2 / area
                        :quant (s / some)
                        :mod (s2 / suprabasal)))
            :mod (a4 / also))
      :snt2 (c3 / colabel-00
            :ARG1 (c5 / cell
                  :mod (p6 / positive
                        :mod (p7 / protein :name (n5 / name :op1 "Ki67"))))
            :ARG2 (a3 / antibody
                  :ARG0-of (c4 / counter-01
                        :ARG1 (p5 / protein :name (n4 / name :op1 "Snail"))))
            :ARG1-of (d3 / describe-01
                  :ARG0 f)))

# ::id pmid_1563_0473.341 ::date 2015-03-28T03:49:54 ::annotator SDL-AMR-09 ::preferred
# ::snt Figure 3
# ::save-date Sat Mar 28, 2015 ::file pmid_1563_0473_341.txt
(f / figure :mod 3)

# ::id pmid_1563_0473.342 ::date 2015-03-28T03:53:43 ::annotator SDL-AMR-09 ::preferred
# ::snt (A–H) Immunofluorescence of skin sections from P3 WT and Tg mice.
# ::save-date Tue Feb 2, 2016 ::file pmid_1563_0473_342.txt
(i / immunofluoresce-01
      :ARG1 (s2 / section-01
            :ARG1 (s / skin
                  :source (a / and
                        :op1 (m / mouse
                              :mod (w / wild-type))
                        :op2 (m2 / mouse
                              :mod (t2 / transgenic))
                        :age (t / temporal-quantity :quant 3
                                    :unit (d / day)))))
      :ARG1-of (d2 / describe-01
            :ARG0 (a3 / and
                  :op1 (f / figure :mod "A")
                  :op2 (f2 / figure :mod "B")
                  :op3 (f3 / figure :mod "C")
                  :op4 (f4 / figure :mod "D")
                  :op5 (f5 / figure :mod "E")
                  :op6 (f6 / figure :mod "F")
                  :op7 (f7 / figure :mod "G")
                  :op8 (f8 / figure :mod "H"))))

# ::id pmid_1563_0473.343 ::date 2015-03-28T04:29:12 ::annotator SDL-AMR-09 ::preferred
# ::snt Shown are affected areas of Tg skin; in areas where Snail protein was not expressed, stainings were normal.
# ::save-date Fri Jul 24, 2015 ::file pmid_1563_0473_343.txt
(m / multi-sentence
      :snt1 (s / show-01
            :ARG1 (a / area
                  :mod (s2 / skin
                        :mod (t / transgenic))
                  :ARG1-of (a2 / affect-01)))
      :snt2 (n / normal-02
            :ARG1 (s3 / stain-01)
            :location (a3 / area
                  :ARG3-of (e / express-03 :polarity -
                        :ARG2 (p / protein :name (n2 / name :op1 "Snail"))))))

# ::id pmid_1563_0473.344 ::date 2015-03-28T04:38:05 ::annotator SDL-AMR-09 ::preferred
# ::snt Sections were labeled with antibodies as indicated and color-coded on each frame.
# ::save-date Mon Dec 21, 2015 ::file pmid_1563_0473_344.txt
(l / label-01
      :ARG1 (t / thing
            :ARG1-of (s / section-01))
      :ARG2 (a / antibody
            :ARG1-of (i / indicate-01
                  :location (f / frame
                        :mod (e / each)))
            :ARG1-of (c / code-01
                  :ARG0 (c2 / color)
                  :location f)))

# ::id pmid_1563_0473.345 ::date 2015-03-28T04:49:48 ::annotator SDL-AMR-09 ::preferred
# ::snt Antibodies are against markers of normal epidermal differentiation, and include K5 (a basally expressed keratin), K1 (a suprabasal keratin, expressed in spinous layer cells), involucrin (Inv; a suprabasally expressed cornified envelope protein found in upper spinous and granular layer cells), loricrin (Lor; a cornified envelope protein expressed in the granular layer), and filaggrin (Fil; a protein that bundles keratin filaments in the granular layer and stratum corneum).
# ::save-date Tue Feb 2, 2016 ::file pmid_1563_0473_345.txt
(a / antibody
      :ARG0-of (c / counter-01
            :ARG1 (m / marker
                  :ARG0-of (d / differentiate-101
                        :ARG1 (e / epidermis)
                        :ARG1-of (n / normal-02))))
      :ARG2-of (i / include-01
            :ARG1 (a2 / and
                  :op1 (p / protein :name (n2 / name :op1 "keratin" :op2 "5")
                        :ARG1-of (m2 / mean-01
                              :ARG2 (k / keratin
                                    :ARG2-of (e2 / express-03
                                          :manner (b / basal)))))
                  :op2 (p2 / protein :name (n3 / name :op1 "keratin" :op2 "1")
                        :ARG1-of (m3 / mean-01
                              :ARG2 (k2 / keratin
                                    :ARG2-of (e3 / express-03
                                          :ARG3 (c2 / cell
                                                :part-of (l / layer
                                                      :mod (s / spinous)))
                                          :manner (s2 / suprabasal)))))
                  :op3 (p3 / protein :name (n4 / name :op1 "involucrin")
                        :ARG1-of (m4 / mean-01
                              :ARG2 (p7 / protein
                                    :mod (e6 / envelope
                                          :ARG1-of (c6 / cornify-01))
                                    :ARG2-of (e4 / express-03
                                          :ARG3 (a3 / and
                                                :op1 (c3 / cell
                                                      :part-of (l2 / layer
                                                            :mod (g / granular)))
                                                :op2 (c4 / cell
                                                      :part-of (l3 / layer
                                                            :mod (s4 / spinous)
                                                            :mod (u / upper))))
                                          :manner (s3 / suprabasal)))))
                  :op4 (p4 / protein :name (n5 / name :op1 "loricrin")
                        :ARG1-of (m5 / mean-01
                              :ARG2 (p8 / protein
                                    :mod (e7 / envelope
                                          :ARG1-of (c7 / cornify-01))
                                    :ARG2-of (e5 / express-03
                                          :ARG3 (c5 / cell
                                                :part-of l2)))))
                  :op5 (p5 / protein :name (n6 / name :op1 "filaggrin")
                        :ARG1-of (m6 / mean-01
                              :ARG2 (p9 / protein
                                    :ARG0-of (b2 / bundle-01
                                          :ARG2 (f / filament
                                                :mod (p6 / protein :name (n7 / name :op1 "keratin")))
                                          :location (a4 / and
                                                :op1 l2
                                                :op2 (c8 / corneum
                                                      :mod (s5 / stratum))))))))))

# ::id pmid_1563_0473.346 ::date 2015-03-28T05:33:32 ::annotator SDL-AMR-09 ::preferred
# ::snt Note abnormal extension of anti-K5 suprabasally, often present in anti-K1 positive suprabasal Tg cells.
# ::save-date Fri Jul 24, 2015 ::file pmid_1563_0473_346.txt
(n / note-02 :mode imperative
      :ARG0 (y / you)
      :ARG1 (e / extend-01
            :ARG1 (a / antibody
                  :ARG0-of (c / counter-01
                        :ARG1 (p / protein :name (n3 / name :op1 "keratin" :op2 "5"))))
            :ARG4 (s / suprabasal)
            :ARG1-of (n2 / normal-02 :polarity -)
            :ARG1-of (p4 / present-02
                  :ARG2 (c2 / cell
                        :mod (t / transgenic)
                        :mod (s2 / suprabasal)
                        :mod (p2 / positive
                              :mod (a2 / antibody
                                    :ARG0-of (c3 / counter-01
                                          :ARG1 (p3 / protein :name (n4 / name :op1 "keratin" :op2 "1"))))))
                  :frequency (o / often))))

# ::id pmid_1563_0473.347 ::date 2015-03-28T05:57:44 ::annotator SDL-AMR-09 ::preferred
# ::snt (I–N) Immunohistochemistry (I and J) or immunofluorescence (K–N) of sections of P30 Wt (I, K, and M) and Tg (J, L, and N) (affected areas) skins using the antibodies indicated.
# ::save-date Tue Feb 2, 2016 ::file pmid_1563_0473_347.txt
(a / and
      :op1 (i / immunohistochemistry
            :ARG1-of (d2 / describe-01
                  :ARG0 (a2 / and
                        :op1 (f2 / figure :mod "I")
                        :op2 (f6 / figure :mod "J")))
            :manner (u / use-01
                  :ARG1 (a8 / antibody
                        :ARG1-of (i3 / indicate-01)))
            :mod (t3 / thing
                  :ARG2-of (s / section-01
                        :ARG1 (a3 / and
                              :op1 (s2 / skin
                                    :mod (w / wild-type)
                                    :ARG1-of (d5 / describe-01
                                          :ARG0 (a4 / and
                                                :op1 (f4 / figure :mod "I")
                                                :op2 (f7 / figure :mod "K")
                                                :op3 (f8 / figure :mod "M")))
                                    :age (t2 / temporal-quantity :quant 30
                                                :unit (d4 / day)))
                              :op2 (s3 / skin
                                    :mod (t / transgenic)
                                    :ARG1-of (d6 / describe-01
                                          :ARG0 (a5 / and
                                                :op1 (f5 / figure :mod "J")
                                                :op2 (f9 / figure :mod "L")
                                                :op3 (f10 / figure :mod "N")))
                                    :age t2
                                    :ARG1-of (d7 / describe-01
                                          :ARG2 (a6 / area
                                                :ARG1-of (a7 / affect-01))))))))
      :op2 (i2 / immunofluoresce-01
            :ARG1 t3
            :ARG2 a8
            :ARG1-of (d3 / describe-01
                  :ARG0 (a11 / and
                        :op1 f7
                        :op2 f9
                        :op3 f8
                        :op4 f10)))
      :ARG1-of (d / describe-01
            :ARG0 (a12 / and
                  :op1 f4
                  :op2 f5
                  :op3 f7
                  :op4 f9
                  :op5 f8
                  :op6 f10)))

# ::id pmid_1563_0473.348 ::date 2015-03-28T06:12:20 ::annotator SDL-AMR-09 ::preferred
# ::snt Note that with age, affected areas of the Tg epidermis became increasingly undulating, often exhibiting papilloma-like invaginations (J).
# ::save-date Thu Dec 17, 2015 ::file pmid_1563_0473_348.txt
(n / note-02 :mode imperative
      :ARG0 (y / you)
      :ARG1 (a5 / and
            :op1 (b / become-01
                  :ARG1 (a / area
                        :part-of (e / epidermis
                              :mod (t / transgenic))
                        :ARG1-of (a2 / affect-01)
                        :ARG1-of (d / describe-01
                              :ARG0 (f / figure :mod "J")))
                  :ARG2 (u / undulate-01
                        :ARG1 a
                        :degree (i / increase-01))
                  :ARG1-of (c / cause-01
                        :ARG0 (a3 / age-01)))
            :op2 (e2 / exhibit-01
                  :ARG0 a
                  :ARG1 (i2 / invaginate-01
                        :ARG1-of (r / resemble-01
                              :ARG2 (p / papilloma)))
                  :frequency (o / often))))

# ::id pmid_1563_0473.349 ::date 2015-03-28T06:17:50 ::annotator SDL-AMR-09 ::preferred
# ::snt Insets in I and J are magnified views of the boxed areas, illustrating the absence (Wt) or presence (Tg) of nuclear anti-cyclin D staining.
# ::save-date Mon Jan 4, 2016 ::file pmid_1563_0473_349.txt
(i / inset
      :location (a / and
            :op1 (f / figure :mod "I")
            :op2 (f2 / figure :mod "J"))
      :domain (v / view-01
            :ARG1 (a2 / area
                  :ARG1-of (b / box-02))
            :ARG1-of (m / magnify-01)
            :ARG0-of (i2 / illustrate-01
                  :ARG1 (o / or
                        :op1 (a3 / absent-01
                              :ARG1 (s / stain-01
                                    :ARG1 (n5 / nucleus)
                                    :ARG2 (a4 / antibody
                                          :ARG0-of (c / counter-01
                                                :ARG1 (p2 / protein :name (n6 / name :op1 "cyclin" :op2 "D")))))
                              :ARG1-of (d / describe-01
                                    :ARG2 (n / name :op1 "Wt")))
                        :op2 (p / present-02
                              :ARG1 s
                              :ARG1-of (d2 / describe-01
                                    :ARG2 (n3 / name :op1 "Tg")))))))

# ::id pmid_1563_0473.350 ::date 2015-03-28T06:34:28 ::annotator SDL-AMR-09 ::preferred
# ::snt With age, affected areas of the Tg epidermis also displayed perturbations within the basement membrane, as judged by antibody labeling against either basement membrane (K and L) or hemidesmosomal (M and N) components.
# ::save-date Fri Apr 3, 2015 ::file pmid_1563_0473_350.txt
(d / display-01
      :ARG0 (a / area
            :ARG1-of (a2 / affect-01)
            :part-of (e / epidermis
                  :mod (t / transgenic)))
      :ARG1 (p / perturb-01
            :ARG1 a)
      :ARG2 (m / membrane
            :mod (b / basement))
      :mod (a3 / also)
      :ARG2-of (j / judge-01
            :ARG3 (l / label-01
                  :ARG1 (o / or
                        :op1 (m2 / membrane
                              :mod (b2 / basement)
                              :ARG1-of (d2 / describe-01
                                    :ARG0 (a6 / and
                                          :op1 (f / figure :mod "K")
                                          :op2 (f3 / figure :mod "L"))))
                        :op2 (c / component
                              :mod (h / hemidesmosomal)
                              :ARG1-of (d3 / describe-01
                                    :ARG0 (a7 / and
                                          :op1 (f2 / figure :mod "M")
                                          :op2 (f4 / figure :mod "N")))))
                  :instrument (a5 / antibody)))
      :ARG1-of (c2 / cause-01
            :ARG0 (a4 / age-01)))

# ::id pmid_1563_0473.351 ::date 2015-03-29T02:33:19 ::annotator SDL-AMR-09 ::preferred
# ::snt Double arrows in L demarcate mosaic zones, revealing that perturbations were restricted to hyperthickened, i.e., Snail-positive zones (to left of double arrows).
# ::save-date Sat Jan 30, 2016 ::file pmid_1563_0473_351.txt
(d2 / demarcate-01
      :ARG0 (a / arrow
            :quant (d / double)
            :location (f / figure :mod "L")
            :ARG0-of (r / reveal-01
                  :ARG1 (r2 / restrict-01
                        :ARG1 (p / perturb-01)
                        :ARG2 (z2 / zone
                              :ARG1-of (t / thicken-01
                                    :degree (h / hyper)
                                    :ARG1-of (m2 / mean-01
                                          :ARG2 (p2 / positive
                                                :mod (p3 / protein :name (n / name :op1 "Snail")))))
                              :location (r3 / relative-position
                                    :op1 a
                                    :direction (l / left-20))))))
      :ARG1 (z / zone
            :mod (m / mosaic)))

# ::id pmid_1563_0473.352 ::date 2015-03-29T02:43:10 ::annotator SDL-AMR-09 ::preferred
# ::snt Other abbreviations are as noted in the legend to <xref ref-type="fig" rid="pbio-0030011-g002">Figure 2</xref>.
# ::save-date Sun Mar 29, 2015 ::file pmid_1563_0473_352.txt
(r / resemble-01
      :ARG1 (t / thing
            :ARG1-of (a / abbreviate-01)
            :mod (o / other))
      :ARG2 (n / note-01
            :location (l / legend
                  :mod (f / figure :mod 2))))

# ::id pmid_1563_0473.353 ::date 2015-03-29T02:47:33 ::annotator SDL-AMR-09 ::preferred
# ::snt Figure 4
# ::save-date Sun Mar 29, 2015 ::file pmid_1563_0473_353.txt
(f / figure :mod 4)

# ::id pmid_1563_0473.354 ::date 2015-03-29T02:47:53 ::annotator SDL-AMR-09 ::preferred
# ::snt (A) Immunofluorescence of skin sections from P30 Wt and Tg mice.
# ::save-date Tue Feb 2, 2016 ::file pmid_1563_0473_354.txt
(i / immunofluoresce-01
      :ARG1 (t3 / thing
            :ARG2-of (s / section-01
                  :ARG1 (s2 / skin
                        :source (a / and
                              :op1 (m / mouse
                                    :mod (w / wild-type)
                                    :age (t2 / temporal-quantity :quant 30
                                          :unit (d2 / day)))
                              :op2 (m2 / mouse
                                    :mod (t / transgenic)
                                    :age t2)))))
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod "A")))

# ::id pmid_1563_0473.355 ::date 2015-03-29T02:52:52 ::annotator SDL-AMR-09 ::preferred
# ::snt Shown are affected areas of Tg skin; in areas where Snail protein was not expressed, stainings were normal.
# ::save-date Fri Jul 24, 2015 ::file pmid_1563_0473_355.txt
(m / multi-sentence
      :snt1 (s / show-01
            :ARG1 (a / area
                  :ARG1-of (a2 / affect-01)
                  :mod (s2 / skin
                        :mod (t / transgenic))))
      :snt2 (n / normal-02
            :ARG1 (s3 / stain-01)
            :location (a3 / area
                  :ARG3-of (e / express-03 :polarity -
                        :ARG2 (p / protein :wiki "SNAI1"
                              :name (n2 / name :op1 "Snail"))))))

# ::id pmid_1563_0473.356 ::date 2015-03-29T02:56:40 ::annotator SDL-AMR-09 ::preferred
# ::snt Antibodies used are against AJ proteins and include E-cadherin (E-cad), the transmembrane core protein; β-catenin (β-cat), which binds E-cadherin at AJs and which can also participate as a transcription cofactor when associated with LEF-1/TCF proteins in the nucleus; α-catenin (α-cat) which binds to both β-catenin and Ajuba, a close relative of zyxin; and Ajuba, which can associate with proteins that bind to the actin cytoskeleton, as well as with Grb-2, a mediator of the GTP nucleotide-exchange protein Sos, involved in activation of the Ras-MAPK signaling cascade.
# ::save-date Fri Jan 1, 2016 ::file pmid_1563_0473_356.txt
(a / antibody
      :ARG0-of (c / counter-01
            :ARG1 (m / macro-molecular-complex :name (n10 / name :op1 "adherens" :op2 "junction")))
      :ARG2-of (i / include-01
            :ARG1 (a2 / and
                  :op1 (p3 / protein :name (n3 / name :op1 "E-cadherin")
                        :mod (t / transmembrane)
                        :mod (c2 / core))
                  :op2 (p4 / protein :name (n4 / name :op1 "β-catenin")
                        :ARG0-of (b / bind-01
                              :ARG1 p3
                              :ARG2 m)
                        :ARG0-of (p7 / participate-01
                              :ARG1-of (p8 / possible-01)
                              :mod (c3 / cofactor
                                    :ARG0-of (t2 / transcribe-01))
                              :condition (a3 / associate-01
                                    :ARG1 p4
                                    :ARG2 (p16 / protein :name (n14 / name :op1 "LEF-1" :op2 "TCF"))
                                    :location (n8 / nucleus))
                              :mod (a8 / also)))
                  :op3 (p5 / protein :name (n5 / name :op1 "α-catenin")
                        :ARG0-of (b2 / bind-01
                              :ARG2 (a4 / and
                                    :op1 p4
                                    :op2 p6)))
                  :op4 (p6 / protein :name (n6 / name :op1 "Ajuba")
                        :ARG1-of (r / relate-01
                              :ARG2 (p10 / protein :name (n9 / name :op1 "zyxin"))
                              :ARG1-of (c4 / close-10))
                        :ARG1-of (a5 / associate-01
                              :ARG2 (a6 / and
                                    :op1 (p12 / protein
                                          :ARG1-of (b3 / bind-01
                                                :ARG2 (c5 / cytoskeleton
                                                      :mod (a9 / actin))))
                                    :op2 (p13 / protein :name (n11 / name :op1 "Grb-2")
                                          :ARG0-of (m2 / mediate-01
                                                :ARG1 (p / protein :name (n7 / name :op1 "Sos")
                                                      :ARG1-of (i2 / involve-01
                                                            :ARG2 (a7 / activate-01
                                                                  :ARG1 (p15 / pathway :name (n13 / name :op1 "Ras" :op2 "MAPK")
                                                                        :ARG0-of (s / signal-07))))
                                                      :mod (p9 / protein :name (n / name :op1 "GTP" :op2 "nucleotide" :op3 "exchange" :op4 "factor"))))))
                              :ARG1-of (p11 / possible-01)))))
      :ARG1-of (u / use-01))

# ::id pmid_1563_0473.357 ::date 2015-03-29T03:53:22 ::annotator SDL-AMR-09 ::preferred
# ::snt In Snail-expressing Tg regions, there was a reduced staining with anti-E-cad and anti-α-cat and a more diffuse staining with anti-Ajuba.
# ::save-date Fri Apr 3, 2015 ::file pmid_1563_0473_357.txt
(a / and
      :op1 (s / stain-01
            :ARG2 (a2 / and
                  :op1 (a3 / antibody
                        :ARG0-of (c / counter-01
                              :ARG1 (p / protein :name (n / name :op1 "E-cadherin"))))
                  :op2 (a4 / antibody
                        :ARG0-of (c2 / counter-01
                              :ARG1 (p2 / protein :name (n2 / name :op1 "α-catenin")))))
            :ARG1-of (r2 / reduce-01))
      :op2 (s2 / stain-01
            :ARG2 (a5 / antibody
                  :ARG0-of (c3 / counter-01
                        :ARG1 (p4 / protein :name (n4 / name :op1 "Ajuba"))))
            :mod (d / diffuse
                  :degree (m / more)))
      :location (r / region
            :ARG3-of (e / express-03
                  :ARG2 (p3 / protein :name (n3 / name :op1 "Snail")))
            :mod (t / transgenic)))

# ::id pmid_1563_0473.358 ::date 2015-03-29T04:02:05 ::annotator SDL-AMR-09 ::preferred
# ::snt Insets in the panels for β-catenin and Ajuba staining are magnified views of the boxed areas.
# ::save-date Mon Jan 4, 2016 ::file pmid_1563_0473_358.txt
(i / inset
      :location (a / and
            :op1 (p4 / panel
                  :purpose (s / stain-01
                        :ARG1 (p2 / protein :name (n / name :op1 "β-catenin"))))
            :op2 (p5 / panel
                  :purpose (s2 / stain-01
                        :ARG1 (p3 / protein :name (n2 / name :op1 "Ajuba")))))
      :domain (v / view-01
            :ARG1 (a2 / area
                  :ARG1-of (b / box-02))
            :ARG1-of (m / magnify-01)))

# ::id pmid_1563_0473.359 ::date 2015-03-29T04:09:08 ::annotator SDL-AMR-09 ::preferred
# ::snt Arrows mark membrane localization of the protein and asterisks mark cells with elevated levels of cytoplasmic β-catenin or Ajuba.
# ::save-date Fri Apr 3, 2015 ::file pmid_1563_0473_359.txt
(a / and
      :op1 (m / mark-01
            :ARG0 (a2 / arrow)
            :ARG1 (b / be-located-at-91
                  :ARG1 (p / protein)
                  :ARG2 (m3 / membrane)))
      :op2 (m2 / mark-01
            :ARG0 (a3 / asterisk)
            :ARG1 (c / cell
                  :ARG0-of (h / have-03
                        :ARG1 (l / level
                              :ARG1-of (e / elevate-01)
                              :quant-of (o / or
                                    :op1 (p2 / protein :name (n / name :op1 "β-catenin")
                                          :mod (c2 / cytoplasm))
                                    :op2 (p3 / protein :name (n2 / name :op1 "Ajuba")
                                          :mod c2)))))))

# ::id pmid_1563_0473.360 ::date 2015-03-29T04:17:31 ::annotator SDL-AMR-09 ::preferred
# ::snt (B) Western blot analyses of protein extracts from P30 Wt and Tg back and ear skins.
# ::save-date Sun Dec 20, 2015 ::file pmid_1563_0473_360.txt
(i / immunoblot-01
      :ARG1 (p / protein
            :ARG1-of (e / extract-01
                  :ARG2 (a4 / and
                        :op1 (s2 / skin
                              :mod (w2 / wild-type)
                              :part-of (a3 / and
                                    :op1 (b / back)
                                    :op2 (e2 / ear))
                              :age (t2 / temporal-quantity :quant 30
                                          :unit (d2 / day)))
                        :op2 (s3 / skin
                              :mod (t / transgenic)
                              :part-of a3
                              :age t2))))
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod "B")))

# ::id pmid_1563_0473.361 ::date 2015-03-29T04:24:07 ::annotator SDL-AMR-09 ::preferred
# ::snt Antibodies are as in (A) except anti-P-cad, which detects P-cadherin, whose expression in the hair follicle was not affected, and anti-tubulin, which detects tubulin, a control for equal protein loadings.
# ::save-date Fri Apr 3, 2015 ::file pmid_1563_0473_361.txt
(r / resemble-01
      :ARG1 (a / antibody)
      :ARG2 (a6 / antibody
            :location (f / figure :mod "A"))
      :ARG2-of (e / except-01
            :ARG1 (a2 / and
                  :op1 (a3 / antibody
                        :ARG0-of (c / counter-01
                              :ARG1 (p / protein :wiki -
                                    :name (n / name :op1 "P-cadherin")
                                    :ARG2-of (e2 / express-03
                                          :ARG3 (f2 / follicle
                                                :mod (h / hair))
                                          :ARG1-of (a5 / affect-01 :polarity -))))
                        :ARG0-of (d / detect-01
                              :ARG1 p))
                  :op2 (a4 / antibody
                        :ARG0-of (c2 / counter-01
                              :ARG1 (p2 / protein :wiki "Tubulin"
                                    :name (n2 / name :op1 "tubulin")
                                    :ARG0-of (c3 / control-01
                                          :ARG1 (l2 / load-01
                                                :ARG1 (p3 / protein)
                                                :ARG1-of (e3 / equal-01)))))
                        :ARG0-of (d2 / detect-01
                              :ARG1 p2)))))

# ::id pmid_1563_0473.362 ::date 2015-03-29T04:36:43 ::annotator SDL-AMR-09 ::preferred
# ::snt Note that the reductions seen in E-cadherin and α-catenin are likely to be underestimates of the actual differences in affected regions, since the Tg skin expressed Snail mosaically.
# ::save-date Fri Jan 1, 2016 ::file pmid_1563_0473_362.txt
(n / note-02 :mode imperative
      :ARG0 (y / you)
      :ARG1 (l / likely-01
            :ARG1 (u / underestimate-01
                  :ARG0 (r / reduce-01
                        :ARG1 (a / and
                              :op1 (p / protein :name (n2 / name :op1 "E-cadherin"))
                              :op2 (p2 / protein :name (n3 / name :op1 "α-catenin")))
                        :ARG1-of (s2 / see-01))
                  :ARG1 (d / differ-02
                        :ARG1-of (a2 / actual-02)
                        :location (r2 / region
                              :ARG1-of (a3 / affect-01))))
            :ARG1-of (c / cause-01
                  :ARG0 (e / express-03
                        :ARG2 (p3 / protein :name (n4 / name :op1 "Snail"))
                        :ARG3 (s / skin
                              :mod (t / transgenic))
                        :manner (m / mosaical)))))

# ::id pmid_1563_0473.363 ::date 2015-03-29T04:48:50 ::annotator SDL-AMR-09 ::preferred
# ::snt (C) In the presence of elevated Snail, α-catenin levels can be restored by overexpression of E-cadherin.
# ::save-date Tue Jul 14, 2015 ::file pmid_1563_0473_363.txt
(p / possible-01
      :ARG1 (r / restore-01
            :ARG1 (l / level
                  :quant-of (p2 / protein :name (n / name :op1 "α-catenin")))
            :manner (o / overexpress-01
                  :ARG1 (p3 / protein :name (n2 / name :op1 "E-cadherin"))))
      :condition (p4 / present-02
            :ARG1 (p5 / protein :name (n3 / name :op1 "Snail")
                  :ARG1-of (e2 / elevate-01)))
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod "C")))

# ::id pmid_1563_0473.364 ::date 2015-04-01T00:13:55 ::annotator SDL-AMR-09 ::preferred
# ::snt Keratinocytes were transfected with either HA-tagged Snail (Snail[HA]; images on the left) or Snail(HA) and Ecad(HA) (images on the right).
# ::save-date Sat Jan 30, 2016 ::file pmid_1563_0473_364.txt
(t / transfect-01
      :ARG1 (c / cell :name (n / name :op1 "keratinocyte"))
      :ARG2 (o2 / or
            :op1 (p / protein :name (n2 / name :op1 "Snail")
                  :ARG1-of (t2 / tag-01
                        :ARG2 (p2 / protein :name (n3 / name :op1 "HA")))
                  :ARG1-of (d / describe-01
                        :ARG0 (i / image
                              :ARG1-of (l / left-20))))
            :op2 (a / and
                  :op1 p
                  :op2 (p4 / protein :name (n5 / name :op1 "E-cadherin")
                        :ARG1-of (t4 / tag-01
                              :ARG2 p2))
                  :ARG1-of (d2 / describe-01
                        :ARG0 (i2 / image
                              :ARG1-of (r / right-04))))))

# ::id pmid_1563_0473.365 ::date 2015-04-01T00:35:54 ::annotator SDL-AMR-09 ::preferred
# ::snt 2 d after transfection, cells were switched from low-calcium growth medium to high-calcium medium for 6 h to induce AJ formation.
# ::save-date Sun Jul 26, 2015 ::file pmid_1563_0473_365.txt
(s / switch-01
      :ARG1 (c / cell)
      :ARG2 (m2 / medium
            :mod (g2 / grow-01)
            :mod (c3 / calcium
                  :ARG1-of (h / high-02)))
      :ARG3 (m / medium
            :mod (g / grow-01)
            :ARG1-of (l / low-04
                  :ARG2 (c2 / calcium)))
      :duration (t / temporal-quantity :quant 6
            :unit (h2 / hour))
      :purpose (i / induce-01
            :ARG2 (f / form-01
                  :ARG1 (p / protein :name (n / name :op1 "AJ"))))
      :time (a / after
            :op1 (t2 / transfect-01)
            :quant (t3 / temporal-quantity :quant 2
                  :unit (d / day))))

# ::id pmid_1563_0473.366 ::date 2015-04-01T00:56:05 ::annotator SDL-AMR-09 ::preferred
# ::snt Cells were stained with antibodies as indicated on the panels.
# ::save-date Wed Apr 1, 2015 ::file pmid_1563_0473_366.txt
(s / stain-01
      :ARG1 (c / cell)
      :ARG2 (a / antibody)
      :ARG1-of (i / indicate-01
            :location (p / panel)))

# ::id pmid_1563_0473.367 ::date 2015-04-01T00:57:43 ::annotator SDL-AMR-09 ::preferred
# ::snt Arrowheads point to sites of intercellular contact between a Snail-transfected keratinocyte and its neighboring untransfected cell.
# ::save-date Sun Jun 21, 2015 ::file pmid_1563_0473_367.txt
(p / point-01
      :ARG0 (a / arrowhead)
      :ARG2 (s / site
            :location-of (c / contact-01
                  :ARG0 (c2 / cell :name (n / name :op1 "keratinocyte")
                        :ARG1-of (t / transfect-01
                              :ARG2 (p2 / protein :name (n2 / name :op1 "Snail"))))
                  :ARG1 (c3 / cell
                        :ARG1-of (t2 / transfect-01 :polarity -)
                        :ARG1-of (n3 / neighbor-01
                              :ARG2 c2))
                  :mod (i / intercellular))))

# ::id pmid_1563_0473.368 ::date 2015-04-01T01:17:52 ::annotator SDL-AMR-09 ::preferred
# ::snt (D) Reintroduction <i>of E-cadherin</i> in keratinocytes expressing Snail returns pMAPK to basal levels.
# ::save-date Sun Jan 17, 2016 ::file pmid_1563_0473_368.txt
(r / return-04
      :ARG0 (r3 / reintroduce-01
            :ARG1 (g / gene :name (n / name :op1 "E-cadherin"))
            :ARG2 (c / cell :name (n2 / name :op1 "keratinocyte")
                  :ARG1-of (e / express-03
                        :ARG2 (p2 / protein :name (n3 / name :op1 "Snail")))))
      :ARG1 (e2 / enzyme :name (n4 / name :op1 "MAPK")
            :ARG3-of (p4 / phosphorylate-01))
      :ARG2 (l / level
            :mod (b / basal))
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod "D")))

# ::id pmid_1563_0473.369 ::date 2015-04-01T01:25:01 ::annotator SDL-AMR-09 ::preferred
# ::snt Keratinocytes were transfected with control vector (K14), or <i>Snail(HA),</i> or <i>Snail(HA)</i> + <i>E-cad(HA)</i>.
# ::save-date Thu Jan 14, 2016 ::file pmid_1563_0473_369.txt
(t / transfect-01
      :ARG1 (c / cell :name (n / name :op1 "keratinocyte"))
      :ARG2 (o / or
            :op1 (v2 / vector :name (n2 / name :op1 "K14")
                  :ARG0-of (c2 / control-01))
            :op2 (g / gene :name (n3 / name :op1 "Snail(HA)"))
            :op3 (a / and
                  :op1 g
                  :op2 (g2 / gene :name (n4 / name :op1 "E-cad(HA)")))))

# ::id pmid_1563_0473.370 ::date 2015-04-01T01:32:34 ::annotator SDL-AMR-09 ::preferred
# ::snt After 2 d, cells were serum starved for 4 h and whole cell lysates were made and Western blotted with antibodies to pMAPK, HA to recognize the HA-tagged Snail and E-cadherin protein, 20or tubulin as a loading control.
# ::save-date Sun Dec 13, 2015 ::file pmid_1563_0473_370.txt
(a / and
      :op1 (s / starve-01
            :ARG1 (c / cell)
            :ARG2 (s2 / serum)
            :duration (t / temporal-quantity :quant 4
                  :unit (h / hour)))
      :op2 (m / make-01
            :ARG1 (l / lysate
                  :mod (w2 / whole)
                  :mod (c2 / cell)))
      :op3 (i / immunoblot-01
            :ARG2 l
            :ARG3 (a2 / and
                  :op1 (a3 / antibody
                        :ARG0-of (o / oppose-01
                              :ARG1 (e / enzyme :name (n2 / name :op1 "MAPK")
                                    :ARG3-of (p2 / phosphorylate-01))))
                  :op2 (p6 / protein :name (n3 / name :op1 "HA")
                        :purpose (r / recognize-02
                              :ARG1 (a4 / and
                                    :op1 (p3 / protein :name (n4 / name :op1 "Snail")
                                          :ARG1-of (t2 / tag-01
                                                :ARG2 p6))
                                    :op2 (p4 / protein :name (n5 / name :op1 "E-cadherin")
                                          :ARG1-of t2))))
                  :accompanier (p5 / protein :name (n6 / name :op1 "tubulin")
                        :ARG0-of (c3 / control-01
                              :ARG0-of (l2 / load-01)))))
      :time (a5 / after
            :quant (t3 / temporal-quantity :quant 2
                  :unit (d2 / day))))

# ::id pmid_1563_0473.371 ::date 2015-04-01T02:15:38 ::annotator SDL-AMR-09 ::preferred
# ::snt (E) Ajuba interacts with Grb-2 under conditions where α-catenin levels are reduced.
# ::save-date Wed Apr 15, 2015 ::file pmid_1563_0473_371.txt
(i / interact-01
      :ARG0 (p3 / protein :name (n / name :op1 "Ajuba"))
      :ARG1 (p / protein :name (n2 / name :op1 "Grb-2"))
      :condition (r / reduce-01
            :ARG1 (l / level
                  :quant-of (p2 / protein :name (n3 / name :op1 "α-catenin"))))
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod "E")))

# ::id pmid_1563_0473.372 ::date 2015-04-02T06:04:11 ::annotator SDL-AMR-09 ::preferred
# ::snt Protein extracts were made from skins of P30 Wt and <i>K14-Snail</i> Tg P30 mice (blots on the left) and of newborn Wt and <i>K14-Cre/α-catenin (fl/fl)</i> conditionally null animals (blots on the right) [<xref ref-type="bibr" rid="pbio-0030011-b07">7</xref>].
# ::save-date Sat Jan 30, 2016 ::file pmid_1563_0473_372.txt
(e / extract-01
      :ARG1 (p / protein)
      :ARG2 (a2 / and
            :op1 (a6 / and
                  :op1 (s / skin
                        :part-of (m / mouse
                              :mod (w / wild-type)
                              :age (t / temporal-quantity :quant 30
                                          :unit (d / day))))
                  :op2 (s2 / skin
                        :part-of (m2 / mouse
                              :mod (t2 / transgenic)
                              :mod (g / gene :name (n / name :op1 "Snail")
                                    :ARG2-of (m5 / mutate-01 :value "K14"))
                              :age (t3 / temporal-quantity :quant 30
                                          :unit (d2 / day))))
                  :ARG1-of (d4 / describe-01
                        :ARG0 (b2 / blot
                              :ARG1-of (l / left-20))))
            :op2 (a7 / and
                  :op1 (s3 / skin
                        :part-of (a4 / animal
                              :mod (w2 / wild-type)
                              :ARG1-of (b / bear-02
                                    :time (n4 / new-01))))
                  :op2 (s4 / skin
                        :part-of (a5 / animal
                              :mod (m3 / macro-molecular-complex
                                    :part (p3 / protein :name (n2 / name :op1 "K14-Cre"))
                                    :part (p4 / protein :name (n3 / name :op1 "α-catenin"))
                                    :ARG2-of (m4 / mutate-01 :mod "−/−"
                                          :mod (c2 / conditional)))))
                  :ARG1-of (d5 / describe-01
                        :ARG0 (b3 / blot
                              :ARG1-of (r / right-04)))))
      :ARG1-of (d3 / describe-01
            :ARG0 (p5 / publication
                  :ARG1-of (c / cite-01
                        :ARG2 7))))

# ::id pmid_1563_0473.373 ::date 2015-04-02T06:11:30 ::annotator SDL-AMR-09 ::preferred
# ::snt Equal amounts of protein extracts were treated with anti-Grb-2 antibody (+) or control isotype antibody (–), and following centrifugation, immunoprecipitates were subjected to SDS-PAGE and Western blot analysis with anti-Ajuba and anti-Grb-2 antibodies.
# ::save-date Sun Dec 20, 2015 ::file pmid_1563_0473_373.txt
(a4 / and
      :op1 (t / treat-04
            :ARG1 (a / amount
                  :ARG1-of (e2 / equal-01)
                  :quant-of (t2 / thing
                        :ARG1-of (e / extract-01
                              :ARG2 (p4 / protein))))
            :ARG2 (o2 / or
                  :op1 (a2 / antibody
                        :ARG0-of (o / oppose-01
                              :ARG1 (p2 / protein :name (n2 / name :op1 "Grb-2"))))
                  :op2 (a3 / antibody
                        :mod (i / isotype
                              :ARG1-of (c / control-01)))))
      :op2 (s / subject-01
            :ARG1 (m / molecular-physical-entity
                  :ARG1-of (i2 / immunoprecipitate-01))
            :ARG2 (a9 / and
                  :op1 (a5 / analyze-01
                        :ARG1 m
                        :mod (t5 / thing :name (n / name :op1 "SDS-PAGE")))
                  :op2 (a8 / analyze-01
                        :ARG1 m
                        :manner (i3 / immunoblot-01
                              :ARG1 m
                              :ARG3 (a10 / and
                                    :op1 (a6 / antibody
                                          :ARG0-of (o3 / oppose-01
                                                :ARG1 (p3 / protein :name (n3 / name :op1 "Ajuba"))))
                                    :op2 (a7 / antibody
                                          :ARG0-of (o4 / oppose-01
                                                :ARG1 p2))))))
            :ARG1-of (f / follow-01
                  :ARG2 (c2 / centrifugate))))

# ::id pmid_1563_0473.374 ::date 2015-04-02T06:27:02 ::annotator SDL-AMR-09 ::preferred
# ::snt Note the presence of Ajuba only under conditions where levels of α-catenin and other AJ proteins were aberrantly low or absent.
# ::save-date Tue Jul 14, 2015 ::file pmid_1563_0473_374.txt
(n / note-02
      :ARG0 (y / you)
      :ARG1 (p / present-02
            :ARG1 (p2 / protein :name (n2 / name :op1 "Ajuba"))
            :condition (o / or
                  :op1 (l / low-04
                        :ARG1 (a4 / and
                              :op1 (l2 / level
                                    :quant-of (p3 / protein :name (n3 / name :op1 "α-catenin")))
                              :op2 (l3 / level
                                    :quant-of (p4 / protein :name (n4 / name :op1 "AJ")
                                          :mod (o2 / other))))
                        :mod (a2 / aberrant))
                  :op2 (a / absent-01
                        :ARG1 a4))
            :mod (o3 / only)))

# ::id pmid_1563_0473.375 ::date 2015-04-02T06:36:49 ::annotator SDL-AMR-09 ::preferred
# ::snt (F) Transgene expression of excess Ajuba or the Grb-2-interacting domain (pre-LIM) of Ajuba in keratinocytes results in the activation of the Ras-MAPK pathway.
# ::save-date Fri Jan 1, 2016 ::file pmid_1563_0473_375.txt
(r / result-01
      :ARG1 (e / express-03
            :ARG2 (o / or
                  :op1 (p / protein :name (n / name :op1 "Ajuba")
                        :ARG0-of (e3 / exceed-01))
                  :op2 (p5 / protein-segment :name (n6 / name :op1 "pre-LIM")
                        :ARG0-of (i2 / interact-01
                              :ARG1 (p2 / protein :name (n2 / name :op1 "Grb-2")))
                        :location (c / cell :name (n3 / name :op1 "keratinocyte"))
                        :part-of p))
            :mod (t / transgene))
      :ARG2 (a / activate-01
            :ARG1 (p3 / pathway :name (n4 / name :op1 "Ras-MAPK")))
      :ARG1-of (d2 / describe-01
            :ARG0 (f / figure :mod "F")))

# ::id pmid_1563_0473.376 ::date 2015-04-02T07:14:46 ::annotator SDL-AMR-09 ::preferred
# ::snt Primary newborn mouse keratinocytes were transfected with either the empty K14 expression vector (K14), or the expression vector driving Snail, full length Ajuba, or the pre-LIM domain of Ajuba in the absence or presence of a peptide inhibitor (inh) that disrupts the interaction between Grb-2 and Sos.
# ::save-date Sun Jan 17, 2016 ::file pmid_1563_0473_376.txt
(t2 / transfect-01
      :ARG1 (c / cell :name (n / name :op1 "keratinocyte")
            :part-of (m / mouse
                  :mod (p / primary)
                  :ARG1-of (b / bear-02
                        :time (n2 / new-01))))
      :ARG2 (o / or
            :op1 (v / vector
                  :ARG1-of (e / express-03
                        :ARG2 (p8 / protein :name (n3 / name :op1 "K14")))
                  :ARG1-of (e3 / empty-02))
            :op2 (v2 / vector
                  :ARG1-of (e4 / express-03)
                  :ARG0-of (d / drive-02
                        :ARG1 (p2 / protein :name (n4 / name :op1 "Snail"))))
            :op3 (p7 / protein :name (n5 / name :op1 "Ajuba")
                  :ARG1-of (l / long-03
                        :degree (f2 / full)))
            :op4 (p6 / protein-segment :name (n10 / name :op1 "pre-LIM")
                  :part-of p7))
      :condition (o2 / or
            :op1 (a / absence
                  :domain (m2 / molecular-physical-entity
                        :ARG0-of (i2 / inhibit-01
                              :ARG1 (s / small-molecule :name (n7 / name :op1 "peptide"))
                              :ARG0-of (d3 / disrupt-01
                                    :ARG1 (i3 / interact-01
                                          :ARG0 (p4 / protein :name (n8 / name :op1 "Grb-2"))
                                          :ARG1 (p5 / protein :name (n9 / name :op1 "Sos")))))))
            :op2 (p3 / present-02
                  :ARG1 m2)))

# ::id pmid_1563_0473.377 ::date 2015-04-05T00:51:37 ::annotator SDL-AMR-09 ::preferred
# ::snt 48 h posttransfection, protein extracts were prepared and subjected to SDS-PAGE and Western blot analyses with antibodies against pMAPK, total MAPK, Ajuba (also recognizing the smaller, pre-LIM domain), and Snail.
# ::save-date Sun Dec 20, 2015 ::file pmid_1563_0473_377.txt
(a / and
      :op1 (p2 / prepare-02
            :ARG1 (t4 / thing
                  :ARG1-of (e2 / extract-01
                        :ARG2 (p8 / protein))))
      :op2 (s / subject-01
            :ARG1 t4
            :ARG2 (a2 / and
                  :op1 (a3 / analyze-01
                        :ARG1 t4
                        :mod (t5 / thing :name (n / name :op1 "SDS-PAGE")))
                  :op2 (a4 / analyze-01
                        :ARG1 t4
                        :manner (i / immunoblot-01
                              :ARG1 t4
                              :ARG3 (a5 / antibody
                                    :ARG0-of (o / oppose-01
                                          :ARG1 (a6 / and
                                                :op1 (e / enzyme :name (n2 / name :op1 "MAPK")
                                                      :ARG3-of (p4 / phosphorylate-01))
                                                :op2 (e3 / enzyme :name (n5 / name :op1 "MAPK")
                                                      :mod (t / total))
                                                :op3 (p6 / protein :name (n6 / name :op1 "Ajuba"))
                                                :op4 (p7 / protein :name (n7 / name :op1 "Snail"))))
                                    :ARG0-of (r / recognize-02
                                          :ARG1 (p9 / protein-segment :name (n9 / name :op1 "pre-LIM")
                                                :mod (s2 / small
                                                      :degree (m / more)))
                                          :mod (a8 / also)))))))
      :time (a7 / after
            :op1 (t2 / transfect-01)
            :quant (t3 / temporal-quantity :quant 48
                  :unit (h / hour))))

# ::id pmid_1563_0473.378 ::date 2015-04-05T01:28:06 ::annotator SDL-AMR-09 ::preferred
# ::snt Figure 5
# ::save-date Sun Apr 5, 2015 ::file pmid_1563_0473_378.txt
(f / figure :mod 5)

# ::id pmid_1563_0473.379 ::date 2015-04-05T01:29:31 ::annotator SDL-AMR-09 ::preferred
# ::snt (A) Failure of Wnt and noggin signaling to induce Snail in cultured keratinocytes.
# ::save-date Wed Jun 3, 2015 ::file pmid_1563_0473_379.txt
(f / fail-01
      :ARG1 (a / and
            :op1 (s / signal-07
                  :ARG0 (p / pathway :name (n / name :op1 "Wnt")))
            :op2 (s2 / signal-07
                  :ARG0 (p2 / protein :name (n2 / name :op1 "noggin"))))
      :ARG2 (i / induce-01
            :ARG0 a
            :ARG2 (p3 / protein :name (n3 / name :op1 "Snail"))
            :location (c / cell :name (n4 / name :op1 "keratinocyte")
                  :ARG1-of (c2 / culture-01)))
      :ARG1-of (d / describe-01
            :ARG0 (f2 / figure :mod "A")))

# ::id pmid_1563_0473.380 ::date 2015-04-05T01:34:24 ::annotator SDL-AMR-09 ::preferred
# ::snt Primary mouse keratinocytes were treated with Wnt- and/or noggin-conditioned medium (+) or the corresponding control medium (–).
# ::save-date Thu Apr 16, 2015 ::file pmid_1563_0473_380.txt
(t / treat-04
      :ARG1 (c / cell :name (n / name :op1 "keratinocyte")
            :part-of (m / mouse)
            :mod (p / primary))
      :ARG2 (o3 / or
            :op1 (m2 / medium
                  :ARG1-of (c2 / condition-02
                        :ARG2 (a2 / and-or
                              :op1 (p2 / pathway :name (n2 / name :op1 "Wnt"))
                              :op2 (p3 / protein :name (n3 / name :op1 "noggin")))))
            :op2 (m3 / medium
                  :ARG2-of (c3 / correspond-02)
                  :ARG0-of (c4 / control-01))))

# ::id pmid_1563_0473.381 ::date 2015-04-05T02:08:44 ::annotator SDL-AMR-09 ::preferred
# ::snt These conditions are known to activate the LEF-1/β-catenin reporter TOPGal and down-regulate the <i>E-cadherin</i> promoter (see [<xref ref-type="bibr" rid="pbio-0030011-b04">4</xref>] for details).
# ::save-date Sat Feb 13, 2016 ::file pmid_1563_0473_381.txt
(k / know-01
      :ARG1 (a2 / and
            :op1 (a / activate-01
                  :ARG0 (c / condition
                        :mod (t / this))
                  :ARG1 (t2 / thing :name (n3 / name :op1 "TOPGal")
                        :ARG0-of (r2 / report-01
                              :ARG1 (m3 / macro-molecular-complex
                                    :part (p2 / protein :name (n / name :op1 "LEF-1"))
                                    :part (p3 / protein :name (n2 / name :op1 "β-catenin"))))))
            :op2 (d4 / downregulate-01
                  :ARG1 (m / molecular-physical-entity
                        :ARG0-of (p4 / promote-01
                              :ARG1 (g / gene :name (n4 / name :op1 "E-cadherin"))))))
      :ARG1-of (s2 / see-01
            :ARG0 (y / you)
            :purpose (d / detail-01)
            :location (p6 / publication
                  :ARG1-of (c2 / cite-01
                        :ARG2 4))))

# ::id pmid_1563_0473.382 ::date 2015-04-05T02:26:25 ::annotator SDL-AMR-09 ::preferred
# ::snt Using Western blot analyses, cellular proteins were then analyzed for Snail, LEF-1, β-catenin, and tubulin.
# ::save-date Sun Dec 13, 2015 ::file pmid_1563_0473_382.txt
(a / analyze-01
      :ARG1 (p / protein
            :mod (c / cell))
      :purpose (f / find-01
            :ARG1 (a2 / and
                  :op1 (p2 / protein :name (n2 / name :op1 "Snail"))
                  :op2 (p3 / protein :name (n3 / name :op1 "LEF-1"))
                  :op3 (p4 / protein :name (n4 / name :op1 "β-catenin"))
                  :op4 (p5 / protein :name (n5 / name :op1 "tubulin"))))
      :ARG0-of (u / use-01
            :ARG1 (i / immunoblot-01)))

# ::id pmid_1563_0473.383 ::date 2015-04-05T03:57:22 ::annotator SDL-AMR-09 ::preferred
# ::snt Proteins from keratinocytes transfected with K14-<i>Snail</i> were used as a positive control for Snail expression.
# ::save-date Thu Jan 14, 2016 ::file pmid_1563_0473_383.txt
(u / use-01
      :ARG1 (p / protein
            :source (c / cell :name (n / name :op1 "keratinocyte")
                  :ARG1-of (t / transfect-01
                        :ARG2 (g / gene :name (n2 / name :op1 "Snail")
                              :ARG2-of (m / mutate-01 :value "K14")))))
      :ARG2 (c2 / control-01
            :ARG0 p
            :ARG1 (e2 / express-03
                  :ARG2 (p4 / protein :name (n4 / name :op1 "Snail")))
            :mod (p3 / positive)))

# ::id pmid_1563_0473.384 ::date 2015-04-05T05:05:55 ::annotator SDL-AMR-09 ::preferred
# ::snt (B) TGF-β2 can induce Snail protein.
# ::save-date Wed Jun 3, 2015 ::file pmid_1563_0473_384.txt
(p / possible-01
      :ARG1 (i / induce-01
            :ARG0 (p2 / protein :name (n / name :op1 "TGF-β2"))
            :ARG2 (p3 / protein :name (n2 / name :op1 "Snail")))
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod "B")))

# ::id pmid_1563_0473.385 ::date 2015-04-05T05:09:20 ::annotator SDL-AMR-09 ::preferred
# ::snt Primary keratinocytes were treated for the indicated times with recombinant TGF-β2 (+) or heat inactivated TGF-β2 (–).
# ::save-date Fri Jan 1, 2016 ::file pmid_1563_0473_385.txt
(t / treat-04
      :ARG1 (c / cell :name (n / name :op1 "keratinocyte")
            :mod (p / primary))
      :ARG2 (o / or
            :op1 (p2 / protein :name (n2 / name :op1 "TGF-β2")
                  :ARG1-of (r / recombine-01)
                  :ARG1-of (d / describe-01
                        :ARG2 (s / string-entity :value +)))
            :op2 (p3 / protein :name (n3 / name :op1 "TGF-β2")
                  :ARG1-of (a2 / activate-01 :polarity -
                        :ARG0 (h / heat))
                  :ARG1-of (d2 / describe-01
                        :ARG2 (s2 / string-entity :value -))))
      :time (t2 / time
            :ARG1-of (i / indicate-01)))

# ::id pmid_1563_0473.386 ::date 2015-04-05T05:15:47 ::annotator SDL-AMR-09 ::preferred
# ::snt Total cellular proteins were then isolated and analyzed by Western blot for Snail, pSMAD2 (reflective of activated TGF- signaling), and tubulin.
# ::save-date Sun Jan 17, 2016 ::file pmid_1563_0473_386.txt
(a / and
      :op1 (i / isolate-01
            :ARG1 (p / protein
                  :mod (c / cell)
                  :mod (t / total)))
      :op2 (a2 / analyze-01
            :ARG1 p
            :manner (i2 / immunoblot-01
                  :ARG1 (a3 / and
                        :op1 (p2 / protein :name (n2 / name :op1 "Snail"))
                        :op2 (p5 / protein :name (n3 / name :op1 "SMAD2")
                              :ARG3-of (p3 / phosphorylate-01)
                              :ARG1-of (r / reflect-01
                                    :ARG2 (s / signal-07
                                          :ARG1 (p6 / protein :name (n4 / name :op1 "TGF"))
                                          :ARG1-of (a5 / activate-01))))
                        :op3 (p4 / protein :name (n5 / name :op1 "tubulin")))
                  :ARG2 p))
      :time (t2 / then))

# ::id pmid_1563_0473.387 ::date 2015-04-05T05:25:57 ::annotator SDL-AMR-09 ::preferred
# ::snt Note the activation of Snail expression, peaking at 2 h post-TGF-β2 treatment and then disappearing thereafter.
# ::save-date Sat Apr 25, 2015 ::file pmid_1563_0473_387.txt
(n2 / note-02
      :ARG0 (y / you)
      :ARG1 (a / and
            :op1 (p / peak-01
                  :ARG1 (a2 / activate-01
                        :ARG1 (e / express-03
                              :ARG1 (p2 / protein :name (n / name :op1 "Snail"))))
                  :time (a3 / after
                        :op1 (t / treat-04
                              :ARG2 (p3 / protein :name (n3 / name :op1 "TGF-β2")))
                        :quant (t3 / temporal-quantity :quant 2
                              :unit (h / hour))))
            :op2 (d / disappear-01
                  :ARG1 a2
                  :time (t2 / then))))

# ::id pmid_1563_0473.388 ::date 2015-04-05T05:45:41 ::annotator SDL-AMR-09 ::preferred
# ::snt (C) <i>Snail</i> mRNA expression is transiently induced by TGF-β2.
# ::save-date Thu Jan 14, 2016 ::file pmid_1563_0473_388.txt
(i / induce-01
      :ARG0 (p2 / protein :name (n3 / name :op1 "TGF-β2"))
      :ARG2 (e / express-03
            :ARG2 (n4 / nucleic-acid :name (n / name :op1 "mRNA")
                  :ARG0-of (e2 / encode-01
                        :ARG1 (g / gene :name (n2 / name :op1 "Snail")))))
      :ARG1-of (t / transient-02)
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod "C")))

# ::id pmid_1563_0473.389 ::date 2015-04-05T05:50:37 ::annotator SDL-AMR-09 ::preferred
# ::snt The experiment in (B) was repeated, and this time, total RNAs were isolated from keratinocytes treated with TGF-β2 for the indicated times.
# ::save-date Thu Apr 16, 2015 ::file pmid_1563_0473_389.txt
(a / and
      :op1 (r / repeat-01
            :ARG1 (e / experiment-01
                  :ARG1-of (d / describe-01
                        :ARG0 (f / figure :mod "B"))))
      :op2 (i / isolate-01
            :ARG1 (n4 / nucleic-acid :name (n / name :op1 "RNA")
                  :mod (t / total))
            :ARG2 (c / cell :name (n2 / name :op1 "keratinocyte")
                  :ARG1-of (t2 / treat-04
                        :ARG2 (p / protein :name (n3 / name :op1 "TGF-β2"))
                        :duration (t3 / time
                              :ARG1-of (i2 / indicate-01))))
            :time (t4 / time
                  :mod (t5 / this))))

# ::id pmid_1563_0473.390 ::date 2015-04-05T05:58:33 ::annotator SDL-AMR-09 ::preferred
# ::snt RT-PCR was then used with (+) or without (–) reverse transcriptase (RT) and with primer sets specific for <i>Snail</i> and GAPDH mRNAs.
# ::save-date Sun Jan 17, 2016 ::file pmid_1563_0473_390.txt
(u / use-01
      :ARG1 (t2 / thing :name (n / name :op1 "RT-PCR")
            :manner (a6 / and
                  :op1 (o / or
                        :op1 (a / accompany-01
                              :ARG0 (e / enzyme :name (n2 / name :op1 "transcriptase")
                                    :ARG1-of (r / reverse-01)))
                        :op2 (a2 / accompany-01 :polarity -
                              :ARG0 e))
                  :op2 (a3 / accompany-01
                        :ARG0 (s / set
                              :mod (d / dna-sequence :name (n3 / name :op1 "primer"))
                              :ARG1-of (s2 / specific-02
                                    :ARG2 (a4 / and
                                          :op1 (g / gene :name (n4 / name :op1 "Snail"))
                                          :op2 (n7 / nucleic-acid :name (n5 / name :op1 "mRNA")
                                                :part-of (e2 / enzyme :name (n6 / name :op1 "GAPDH")))))))))
      :time (t / then))

# ::id pmid_1563_0473.391 ::date 2015-04-05T06:11:53 ::annotator SDL-AMR-09 ::preferred
# ::snt Note that <i>Snail</i> mRNA expression also peaked at 2 h, paralleling Snail protein.
# ::save-date Sat Apr 18, 2015 ::file pmid_1563_0473_391.txt
(n3 / note-02
      :ARG0 (y / you)
      :ARG1 (p / peak-01
            :ARG1 (e / express-03
                  :ARG2 (n4 / nucleic-acid :name (n / name :op1 "mRNA")
                        :part (p2 / protein :name (n2 / name :op1 "Snail")))
                  :ARG0-of (p3 / parallel-01
                        :ARG1 (e2 / express-03
                              :ARG2 p2)))
            :mod (a / also))
      :time (a2 / after
            :op1 (t / temporal-quantity :quant 2
                  :unit (h / hour))))

# ::id pmid_1563_0473.392 ::date 2015-04-05T06:21:50 ::annotator SDL-AMR-09 ::preferred
# ::snt (D) TGF-β2 treatment results in enhanced activity of a <i>Snail</i> promoter-β-galactosidase reporter.
# ::save-date Thu Jan 14, 2016 ::file pmid_1563_0473_392.txt
(r2 / result-01
      :ARG1 (t / treat-04
            :ARG2 (p2 / protein :name (n / name :op1 "TGF-β2")))
      :ARG2 (a / activity-06
            :ARG0 (m / molecular-physical-entity
                  :ARG0-of (p3 / promote-01
                        :ARG1 (g / gene :name (n2 / name :op1 "Snail")))
                  :ARG0-of (r3 / report-01
                        :ARG1 (e2 / enzyme :name (n3 / name :op1 "β-galactosidase")
                              :ARG0-of p3)))
            :ARG1-of (e / enhance-01))
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod "D")))

# ::id pmid_1563_0473.393 ::date 2015-04-05T06:27:46 ::annotator SDL-AMR-09 ::preferred
# ::snt Keratinocytes were transfected with a β-galactosidase reporter driven by a <i>Snail</i> promoter that is either WT (wt prom) or harbors a mutation in a putative pSMAD2/pSMAD4 binding site (mt prom).
# ::save-date Tue Jan 12, 2016 ::file pmid_1563_0473_393.txt
(t / transfect-01
      :ARG1 (c / cell :wiki "Keratinocyte"
            :name (n / name :op1 "keratinocyte"))
      :ARG2 (m2 / molecular-physical-entity
            :ARG0-of (r2 / report-01
                  :ARG1 (e / enzyme :wiki "Beta-galactosidase"
                        :name (n2 / name :op1 "β-galactosidase")))
            :ARG1-of (d / drive-02
                  :ARG0 (o / or
                        :op1 (m3 / molecular-physical-entity
                              :ARG0-of (p2 / promote-01
                                    :ARG1 (g / gene :wiki -
                                          :name (n3 / name :op1 "Snail")
                                          :mod (w / wild-type)))
                              :ARG0-of (h / harbor-01
                                    :ARG1 (m / mutate-01
                                          :ARG2 (p6 / protein-segment
                                                :ARG1-of (b / bind-01
                                                      :ARG2 (p8 / protein :wiki "Mothers_against_decapentaplegic_homolog_4"
                                                            :name (n5 / name :op1 "SMAD4")
                                                            :ARG1-of (p5 / phosphorylate-01)))
                                                :part-of (p7 / protein :wiki "Mothers_against_decapentaplegic_homolog_2"
                                                      :name (n6 / name :op1 "SMAD2")
                                                      :ARG1-of (p4 / phosphorylate-01))
                                                :ARG1-of (t2 / think-01)))))
                        :op2 (m4 / molecular-physical-entity
                              :ARG0-of (p / promote-01
                                    :ARG1 g)
                              :ARG0-of h)))))

# ::id pmid_1563_0473.394 ::date 2015-04-05T07:33:55 ::annotator SDL-AMR-09 ::preferred
# ::snt At 2 d posttransfection, cells were treated with either TGF-β or heat-inactivated TGF-β2 (inact) for the times indicated.
# ::save-date Mon Dec 21, 2015 ::file pmid_1563_0473_394.txt
(t / treat-04
      :ARG1 (c / cell)
      :ARG2 (o / or
            :op1 (p / protein :name (n / name :op1 "TGF-β"))
            :op2 (p2 / protein :name (n2 / name :op1 "TGF-β")
                  :ARG1-of (a3 / activate-01 :polarity -
                        :ARG0 (h / heat))))
      :duration (t2 / temporal-quantity
            :ARG1-of (i / indicate-01))
      :time (a2 / after
            :op1 (t3 / transfect-01)
            :quant (t4 / temporal-quantity :quant 2
                  :unit (d / day))))

# ::id pmid_1563_0473.395 ::date 2015-04-05T07:40:18 ::annotator SDL-AMR-09 ::preferred
# ::snt β-galactosidase assays were then conducted, and results are reported as fold increase over a basal level of activity of 1.
# ::save-date Mon Jul 6, 2015 ::file pmid_1563_0473_395.txt
(a / and
      :op1 (c / conduct-01
            :ARG1 (a2 / assay-01
                  :ARG1 (e / enzyme :name (n / name :op1 "β-galactosidase")))
            :time (t / then))
      :op2 (r / report-01
            :ARG1 (t2 / thing
                  :ARG2-of (r2 / result-01))
            :manner (i / increase-01
                  :ARG3 (l / level
                        :mod (b / basal)
                        :degree-of (a3 / activity-06)
                        :ARG1-of (e2 / equal-01
                              :ARG2 1))
                  :mod (f / fold))))

# ::id pmid_1563_0473.396 ::date 2015-04-05T07:51:52 ::annotator SDL-AMR-09 ::preferred
# ::snt The experiment was repeated three times in triplicate, and error bars reflect variations in the results.
# ::save-date Mon May 18, 2015 ::file pmid_1563_0473_396.txt
(a / and
      :op1 (r / repeat-01
            :ARG1 (e / experiment-01 :quant 3)
            :ARG3 3)
      :op2 (r2 / reflect-01
            :ARG1 (b / bar
                  :mod (e2 / error))
            :ARG2 (v / vary-01
                  :ARG1 (t / thing
                        :ARG2-of (r3 / result-01)))))

# ::id pmid_1563_0473.397 ::date 2015-04-05T07:55:35 ::annotator SDL-AMR-09 ::preferred
# ::snt Figure 6
# ::save-date Sun Apr 5, 2015 ::file pmid_1563_0473_397.txt
(f / figure :mod 6)

# ::id pmid_1563_0473.398 ::date 2015-04-05T07:56:04 ::annotator SDL-AMR-09 ::preferred
# ::snt (A–D) Skins from TGF-β2 WT or KO E17.5 embryos were analyzed for expression of TGF-β2 protein (A), which is present in the epidermis and dermis as previously described [<xref ref-type="bibr" rid="pbio-0030011-b33">33</xref>] and in the hair bud, pSMAD2 (B), Snail (C), and <i>Snail</i> mRNA (D).
# ::save-date Thu Dec 31, 2015 ::file pmid_1563_0473_398.txt
(a3 / and
      :op1 (a / analyze-01
            :ARG1 (o2 / or
                  :op1 (s / skin
                        :source (e / embryo
                              :mod (p / protein :name (n / name :op1 "TGF-β2")
                                    :mod (w / wild-type))))
                  :op2 (s3 / skin
                        :source (e5 / embryo
                              :mod (e3 / enzyme :name (n2 / name :op1 "KO"))
                              :age (t / temporal-quantity :quant 17.5
                                          :unit (d4 / day)))))
            :purpose (f / find-01
                  :ARG1 (e4 / express-03
                        :ARG2 (p2 / protein :name (n3 / name :op1 "TGF-β2")
                              :ARG1-of (p8 / present-02
                                    :ARG2 (a2 / and
                                          :op1 (a5 / and
                                                :op1 (e2 / epidermis)
                                                :op2 (d / dermis)
                                                :ARG1-of (d2 / describe-01
                                                      :ARG0 (p4 / publication
                                                            :ARG1-of (c / cite-01
                                                                  :ARG2 33))
                                                      :time (p3 / previous)))
                                          :op2 (a6 / and
                                                :op1 (b / bud
                                                      :mod (h / hair))
                                                :op2 (p7 / protein :name (n4 / name :op1 "SMAD2")
                                                      :ARG1-of (p5 / phosphorylate-01)
                                                      :ARG1-of (d6 / describe-01
                                                            :ARG0 (f4 / figure :mod "B")))
                                                :op3 (p6 / protein :name (n5 / name :op1 "Snail")
                                                      :ARG1-of (d7 / describe-01
                                                            :ARG0 (f5 / figure :mod "C")))
                                                :op4 (n7 / nucleic-acid :name (n6 / name :op1 "mRNA")
                                                      :part p6
                                                      :ARG1-of (d8 / describe-01
                                                            :ARG0 (f6 / figure :mod "D")))))))))
            :ARG1-of (d5 / describe-01
                  :ARG0 (f3 / figure :mod "A")))
      :ARG1-of (d3 / describe-01
            :ARG0 (a4 / and
                  :op1 f3
                  :op2 f4
                  :op3 f5
                  :op4 f6)))

# ::id pmid_1563_0473.399 ::date 2015-04-05T08:15:28 ::annotator SDL-AMR-09 ::preferred
# ::snt Arrows point to the hair buds.
# ::save-date Tue Apr 21, 2015 ::file pmid_1563_0473_399.txt
(p / point-01
      :ARG0 (a / arrow)
      :ARG2 (b / bud
            :mod (h / hair)))

# ::id pmid_1563_0473.400 ::date 2015-04-05T08:16:37 ::annotator SDL-AMR-09 ::preferred
# ::snt (E) Western blot analyses of Snail expression in the skins of 2-wk-old <i>K14-Smad2</i> transgenic (SMAD2 TG) and WT littermate (WT) mice.
# ::save-date Sun Jan 17, 2016 ::file pmid_1563_0473_400.txt
(i / immunoblot-01
      :ARG1 (e / express-03
            :ARG2 (p / protein :name (n2 / name :op1 "Snail"))
            :ARG3 (a / and
                  :op1 (s / skin
                        :mod (m / mouse
                              :mod (g / gene :name (n3 / name :op1 "K14-Smad2"))
                              :age (t / temporal-quantity :quant 2
                                          :unit (w2 / week))
                              :mod (t2 / transgenic)))
                  :op2 (s2 / skin
                        :mod (m2 / mouse
                              :mod (l / littermate)
                              :mod (w / wild-type)))))
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod "E")))

# ::id pmid_1563_0473.401 ::date 2015-04-05T08:24:24 ::annotator SDL-AMR-09 ::preferred
# ::snt Antibody to tubulin was used as a control for equal protein loadings.
# ::save-date Tue Apr 21, 2015 ::file pmid_1563_0473_401.txt
(u / use-01
      :ARG1 (a / antibody
            :ARG0-of (o / oppose-01
                  :ARG1 (p / protein :name (n / name :op1 "tubulin"))))
      :ARG2 (c / control-01
            :ARG1 (l / load-01
                  :ARG1 (p2 / protein)
                  :ARG1-of (e / equal-01))
            :ARG2 a))

# ::id pmid_1563_0473.402 ::date 2015-04-05T08:30:14 ::annotator SDL-AMR-09 ::preferred
# ::snt The K14-Smad2 Tg mouse was previously shown to possess activated TGF-β signaling [<xref ref-type="bibr" rid="pbio-0030011-b35">35</xref>].
# ::save-date Sat May 23, 2015 ::file pmid_1563_0473_402.txt
(s / show-01
      :ARG1 (p / possess-01
            :ARG0 (m / mouse
                  :mod (e / enzyme :name (n2 / name :op1 "K14-Smad2"))
                  :mod (t / transgenic))
            :ARG1 (s2 / signal-07
                  :ARG0 (p2 / protein :name (n3 / name :op1 "TGF-β")
                        :ARG1-of (a / activate-01))))
      :ARG1-of (d / describe-01
            :ARG0 (p3 / publication
                  :ARG1-of (c / cite-01
                        :ARG2 35)))
      :time (p4 / previous))

# ::id pmid_1563_0473.403 ::date 2015-04-05T08:36:00 ::annotator SDL-AMR-09 ::preferred
# ::snt (F–G) Proliferation markers Ki67 (F) and pMAPK (G) are diminished in <i>TGF-β2</i>-null hair relative to its WT counterpart.
# ::save-date Thu Dec 31, 2015 ::file pmid_1563_0473_403.txt
(d / diminish-01
      :ARG1 (a2 / and
            :op1 (p / protein :name (n5 / name :op1 "Ki67")
                  :ARG1-of (d3 / describe-01
                        :ARG0 (f2 / figure :mod "F")))
            :op2 (e / enzyme :name (n6 / name :op1 "MAPK")
                  :ARG3-of (p4 / phosphorylate-01)
                  :ARG1-of (d4 / describe-01
                        :ARG0 (f3 / figure :mod "G")))
            :ARG0-of (m4 / mark-01
                  :ARG1 (p2 / proliferate-01)))
      :location (h / hair
            :mod (p5 / protein :name (n3 / name :op1 "TGF-β2")
                  :ARG2-of (m / mutate-01 :mod "−/−")))
      :ARG1-of (c / compare-01
            :ARG2 (c2 / counterpart
                  :mod (w / wild-type)))
      :ARG1-of (d2 / describe-01
            :ARG0 (a / and
                  :op1 f2
                  :op2 f3)))

# ::id pmid_1563_0473.404 ::date 2015-04-05T08:43:21 ::annotator SDL-AMR-09 ::preferred
# ::snt (H–J) <i>TGF-β2</i>-null hair fails to down-regulate E-cadherin (H).
# ::save-date Thu Dec 31, 2015 ::file pmid_1563_0473_404.txt
(d3 / downregulate-01 :polarity -
      :ARG0 (h / hair
            :mod (p / protein :name (n / name :op1 "TGF-β2")
                  :ARG2-of (m / mutate-01 :mod "−/−")))
      :ARG1 (p2 / protein :name (n2 / name :op1 "E-cadherin"))
      :ARG1-of (d2 / describe-01
            :ARG0 (a / and
                  :op1 (f2 / figure :mod "H")
                  :op2 (f3 / figure :mod "I")
                  :op3 (f4 / figure :mod "J"))))

# ::id pmid_1563_0473.405 ::date 2015-04-05T08:45:45 ::annotator SDL-AMR-09 ::preferred
# ::snt Wnt and noggin signaling pathways are still intact in the TGF-β2 null hair as nuclear LEF-1 (I) and nuclear β-catenin (J) are still expressed.
# ::save-date Tue May 5, 2015 ::file pmid_1563_0473_405.txt
(i / intact
      :location (h / hair
            :mod (p2 / protein :name (n / name :op1 "TGF-β2")
                  :ARG2-of (m / mutate-01 :mod "−/−")))
      :ARG1-of (c / cause-01
            :ARG0 (e / express-03
                  :ARG2 (a2 / and
                        :op1 (p3 / protein :name (n2 / name :op1 "LEF-1")
                              :mod (n3 / nucleus)
                              :ARG1-of (d / describe-01
                                    :ARG0 (f / figure :mod "I")))
                        :op2 (p4 / protein :name (n4 / name :op1 "β-catenin")
                              :mod (n5 / nucleus)
                              :ARG1-of (d2 / describe-01
                                    :ARG0 (f2 / figure :mod "J"))))
                  :mod s2))
      :domain (a3 / and
            :op1 (p5 / pathway :name (n7 / name :op1 "Wnt")
                  :ARG0-of (s3 / signal-07))
            :op2 (p6 / pathway :name (n8 / name :op1 "noggin")
                  :ARG0-of s3)
            :mod (s2 / still)))

# ::id pmid_1627_1139.1 ::date 2015-08-11T01:04:58 ::annotator SDL-AMR-09 ::preferred
# ::snt Transformation of human bronchial epithelial cells alters responsiveness to inflammatory cytokines (PMID:16271139)
# ::save-date Thu Nov 19, 2015 ::file pmid_1627_1139_1.txt
(a / alter-01
      :ARG0 (t / transform-01
            :ARG1 (c / cell
                  :mod (h / human)
                  :mod (b / bronchus)
                  :mod (e / epithelium)))
      :ARG1 (r / responsive-02
            :ARG1 (c2 / cytokine
                  :ARG0-of (i / inflame-01)))
      :ARG1-of (d / describe-01
            :ARG0 (p / publication-91
                  :ARG8 "PMID16271139")))

# ::id pmid_1627_1139.11 ::date 2015-08-11T07:51:06 ::annotator SDL-AMR-09 ::preferred
# ::snt <sec-title level="1" sec-area="abstract">Results</sec-title>
# ::save-date Tue Aug 11, 2015 ::file pmid_1627_1139_11.txt
(t / thing
      :ARG2-of (r / result-01))

# ::id pmid_1627_1139.12 ::date 2015-08-11T11:54:58 ::annotator SDL-AMR-09 ::preferred
# ::snt Normal epithelial cells respond strongly to OSM, IFNγ and EGF, and respond moderately to IL-6, and do not exhibit a detectable response to LIF.
# ::save-date Sun Jan 17, 2016 ::file pmid_1627_1139_12.txt
(a / and
      :op1 (r / respond-01
            :ARG0 (c / cell
                  :mod (n / normal)
                  :source (e / epithelium))
            :ARG1 (a2 / and
                  :op1 (p / protein :name (n2 / name :op1 "OSM"))
                  :op2 (p2 / protein :name (n3 / name :op1 "IFNγ"))
                  :op3 (p6 / protein :name (n4 / name :op1 "EGF")))
            :ARG1-of (s / strong-02))
      :op2 (r2 / respond-01
            :ARG0 c
            :ARG1 (p3 / protein :name (n5 / name :op1 "IL-6"))
            :manner (m / moderate))
      :op3 (e2 / exhibit-01 :polarity -
            :ARG0 c
            :ARG1 (r3 / respond-01
                  :ARG0 c
                  :ARG1 (p5 / protein :name (n6 / name :op1 "LIF"))
                  :ARG1-of (d / detect-01
                        :ARG1-of (p4 / possible-01)))))

# ::id pmid_1627_1139.13 ::date 2015-08-11T12:26:12 ::annotator SDL-AMR-09 ::preferred
# ::snt In preneoplastic cells, the aberrant signaling that was detected most frequently was an elevated activation of ERK, a reduced or increased IL-6 and EGF response, and an increased LIF response.
# ::save-date Sun Jan 17, 2016 ::file pmid_1627_1139_13.txt
(a / and
      :op1 (a2 / activate-01
            :ARG1 (e2 / enzyme :name (n / name :op1 "ERK"))
            :ARG1-of (e / elevate-01))
      :op2 (a3 / and
            :op1 (o / or
                  :op1 (r2 / respond-01
                        :ARG1 (p2 / protein :name (n2 / name :op1 "IL-6"))
                        :ARG1-of (r / reduce-01))
                  :op2 (r3 / respond-01
                        :ARG1 p2
                        :ARG1-of (i / increase-01)))
            :op2 (o2 / or
                  :op1 (r4 / respond-01
                        :ARG1 (p / protein :name (n4 / name :op1 "EGF"))
                        :ARG1-of r)
                  :op2 (r5 / respond-01
                        :ARG1 p
                        :ARG1-of i)))
      :op3 (r6 / respond-01
            :ARG1 (p3 / protein :name (n3 / name :op1 "LIF"))
            :ARG1-of i)
      :domain (s2 / signal-07
            :mod (a4 / aberrant)
            :ARG1-of (d / detect-01
                  :ARG1-of (f / frequent-02
                        :degree (m / most)))
            :location (c / cell
                  :mod (p4 / preneoplasm))))

# ::id pmid_1627_1139.14 ::date 2015-08-11T13:12:15 ::annotator SDL-AMR-09 ::preferred
# ::snt Some of these changes in preneoplastic cell signaling approach those observed in established lung cancer cell lines.
# ::save-date Wed Dec 9, 2015 ::file pmid_1627_1139_14.txt
(a / approach-02
      :ARG0 (c / change-01
            :ARG1-of (i / include-91
                  :ARG2 (c2 / change-01
                        :ARG1 (s / signal-07
                              :ARG0 (c3 / cell
                                    :mod (p / preneoplasm))))
                  :ARG3 (s2 / some))
            :mod (t / this))
      :ARG1 (c4 / change-01
            :ARG1-of (o / observe-01
                  :location (c5 / cell-line
                        :mod (d / disease :wiki "Lung_cancer" :name (n / name :op1 "lung" :op2 "cancer")
                              :ARG1-of (e / establish-01))))))

# ::id pmid_1627_1139.15 ::date 2015-08-11T13:29:31 ::annotator SDL-AMR-09 ::preferred
# ::snt Epigenetic control of LIF receptor expression by histone acetylation can account for the gain of LIF responsiveness.
# ::save-date Sun Jan 17, 2016 ::file pmid_1627_1139_15.txt
(p / possible-01
      :ARG1 (a / account-01
            :ARG0 (c / control-01
                  :ARG1 (e2 / express-03
                        :ARG2 (r2 / receptor
                              :mod p2)
                        :ARG3-of (a2 / acetylate-01
                              :ARG1 (p3 / protein :name (n3 / name :op1 "histone"))))
                  :mod (e / epigenetic))
            :ARG1 (g / gain-02
                  :ARG1 (r / responsive-02
                        :ARG1 (p2 / protein :name (n / name :op1 "LIF"))))))

# ::id pmid_1627_1139.16 ::date 2015-08-11T13:51:10 ::annotator SDL-AMR-09 ::preferred
# ::snt OSM and macrophage-derived cytokines suppressed proliferation of normal epithelial cells, but reduced inhibition or even stimulated proliferation was noted for preneoplastic cells.
# ::save-date Mon Aug 17, 2015 ::file pmid_1627_1139_16.txt
(c / contrast-01
      :ARG1 (s / suppress-01
            :ARG0 (a / and
                  :op1 (c6 / cytokine :name (n / name :op1 "OSM"))
                  :op2 (c3 / cytokine
                        :ARG1-of (d / derive-01
                              :ARG0 (m / macrophage))))
            :ARG1 (p2 / proliferate-01
                  :ARG0 (c4 / cell
                        :mod (n2 / normal)
                        :source (e / epithelium))))
      :ARG2 (n3 / note-01
            :ARG1 (o / or
                  :op1 (i / inhibit-01
                        :ARG1-of (r / reduce-01))
                  :op2 (p3 / proliferate-01
                        :ARG1-of (s2 / stimulate-01)
                        :mod (e2 / even)))
            :location (c5 / cell
                  :mod (p4 / preneoplasm))))

# ::id pmid_1627_1139.17 ::date 2015-08-11T14:12:22 ::annotator SDL-AMR-09 ::preferred
# ::snt These alterations likely contribute to the supporting effects that inflammation has on lung tumor progression.
# ::save-date Mon Aug 17, 2015 ::file pmid_1627_1139_17.txt
(c / contribute-01
      :ARG0 (a / alter-01
            :mod (t / this))
      :ARG2 (a2 / affect-01
            :ARG0 (i / inflame-01)
            :ARG1 (p / progress-01
                  :ARG1 (t2 / tumor
                        :mod (l2 / lung)))
            :ARG0-of (s / support-01))
      :ARG1-of (l / likely-01))

# ::id pmid_1627_1139.123 ::date 2015-08-11T14:23:13 ::annotator SDL-AMR-09 ::preferred
# ::snt <sec-title level="1">Results</sec-title>
# ::save-date Tue Aug 11, 2015 ::file pmid_1627_1139_123.txt
(t / thing
      :ARG2-of (r / result-01))

# ::id pmid_1627_1139.124 ::date 2015-08-11T14:28:30 ::annotator SDL-AMR-09 ::preferred
# ::snt <sec-title level="2">Transformed lung epithelial cell lines have grossly abnormal patterns of cytokine responsiveness</sec-title>
# ::save-date Mon Aug 17, 2015 ::file pmid_1627_1139_124.txt
(h / have-03
      :ARG0 (c / cell-line
            :source (e / epithelium)
            :mod (l / lung)
            :ARG1-of (t / transform-01))
      :ARG1 (p / pattern-01
            :ARG1 (r / responsive-02
                  :ARG1 (c2 / cytokine))
            :ARG1-of (n / normal-02 :polarity -
                  :ARG1-of (g / gross-06))))

# ::id pmid_1627_1139.125 ::date 2015-08-11T15:16:01 ::annotator SDL-AMR-09 ::preferred
# ::snt We predicted that if oncogenic transformation of lung epithelial cells is associated with altered responsiveness to inflammation and reduced growth-inhibition, then the most prominent deviations from the regulatory phenotype should be seen in advanced lung cancer cells.
# ::save-date Wed Dec 9, 2015 ::file pmid_1627_1139_125.txt
(p / predict-01
      :ARG0 (w / we)
      :ARG1 (r / recommend-01
            :ARG1 (s / see-01
                  :ARG1 (d / deviate-01
                        :ARG1 (p3 / phenotype
                              :ARG0-of (r2 / regulate-01))
                        :mod (p2 / prominent
                              :degree (m / most)))
                  :location (c / cell
                        :mod (d2 / disease :wiki "Lung_cancer"
                              :name (n / name :op1 "lung" :op2 "cancer")
                              :ARG1-of (a / advance-01))))
            :condition (a2 / associate-01
                        :ARG1 (t / transform-01
                              :ARG1 (c3 / cell
                                    :mod (l2 / lung)
                                    :source (e / epithelium))
                              :ARG0-of (c4 / cause-01
                                    :ARG1 (d3 / disease :wiki "Cancer"
                                          :name (n2 / name :op1 "cancer"))))
                        :ARG2 (a3 / and
                              :op1 (r3 / responsive-02
                                    :ARG1 (i / inflame-01)
                                    :ARG1-of (a4 / alter-01))
                              :op2 (i2 / inhibit-01
                                    :ARG1 (g / grow-01)
                                    :ARG1-of (r4 / reduce-01))))))

# ::id pmid_1627_1139.126 ::date 2015-08-11T15:44:07 ::annotator SDL-AMR-09 ::preferred
# ::snt Therefore, as first step, we determined if responsiveness to members of the IL-6 family (IL-6, OSM and LIF) were detectable in <i>established </i>lines of malignant human non-small cell lung carcinoma cells.
# ::save-date Thu Dec 10, 2015 ::file pmid_1627_1139_126.txt
(c / cause-01
      :ARG1 (d / determine-01
            :ARG0 (w / we)
            :ARG1 (d2 / detect-01
                  :ARG1 (r / responsive-02
                        :ARG1 (m / member
                              :ARG1-of (i / include-91
                                    :ARG2 (p2 / protein-family :name (n / name :op1 "IL-6")))
                              :example (a / and
                                    :op1 (p3 / protein :name (n2 / name :op1 "IL-6"))
                                    :op2 (p4 / protein :name (n3 / name :op1 "OSM"))
                                    :op3 (p5 / protein :name (n4 / name :op1 "LIF")))))
                  :ARG1-of (p / possible-01 :mode interrogative)
                  :location (c4 / cell-line
                        :ARG1-of (e / establish-01)
                        :mod (m3 / medical-condition :name (n5 / name :op1 "carcinoma")
                              :mod (l2 / lung
                                    :mod (c3 / cell
                                          :mod (h / human)
                                          :mod (s2 / small :polarity -)
                                          :ARG1-of (m2 / malignant-02))))))
            :ARG4-of (s / step-01
                  :ord (o / ordinal-entity :value 1))))

# ::id pmid_1627_1139.127 ::date 2015-08-11T16:17:32 ::annotator SDL-AMR-09 ::preferred
# ::snt The responsiveness to the cytokines was defined by measurable phosphorylation of STAT and ERK.
# ::save-date Sat Jan 16, 2016 ::file pmid_1627_1139_127.txt
(d / define-01
      :ARG0 (p / phosphorylate-01
            :ARG1 (a / and
                  :op1 (p3 / protein :name (n / name :op1 "STAT"))
                  :op2 (e / enzyme :name (n2 / name :op1 "ERK")))
            :ARG1-of (m / measure-01
                  :ARG1-of (p2 / possible-01)))
      :ARG1 (r / responsive-02
            :ARG1 (c / cytokine)))

# ::id pmid_1627_1139.128 ::date 2015-08-11T16:23:40 ::annotator SDL-AMR-09 ::preferred
# ::snt This is a treatment reaction that is a measure for the level of active cytokine receptors and downstream signaling pathways in the target cells [<xref ref-type="bibr" rid="B14">14</xref>,<xref ref-type="bibr" rid="B16">16</xref>].
# ::save-date Mon Aug 17, 2015 ::file pmid_1627_1139_128.txt
(r / react-01
      :ARG1 (t2 / treat-04)
      :domain (t / this)
      :ARG0-of (m / measure-01
            :ARG1 (a2 / and
                  :op1 (l / level
                        :degree-of (r2 / receptor
                              :mod (c / cytokine)
                              :ARG0-of (a / activity-06)))
                  :op2 (l2 / level
                        :degree-of (p / pathway
                              :ARG0-of (s / signal-07
                                    :source (d / downstream)))))
            :location (c2 / cell
                  :ARG1-of (t3 / target-01)))
      :ARG1-of (d2 / describe-01
            :ARG0 (p2 / publication
                  :ARG1-of (c3 / cite-01
                        :ARG2 (a3 / and :op1 14 :op2 16)))))

# ::id pmid_1627_1139.129 ::date 2015-08-12T05:01:57 ::annotator SDL-AMR-09 ::preferred
# ::snt Normal type II epithelial cells and pulmonary fibroblasts were included in the analyses to gauge cell type-specific differences in signaling reactions (Fig. <xref ref-type="fig" rid="F1">1</xref>).
# ::save-date Mon Aug 17, 2015 ::file pmid_1627_1139_129.txt
(i / include-01
      :ARG1 (a / and
            :op1 (c / cell
                  :source (e / epithelium)
                  :mod (n / normal)
                  :mod (t / type :name (n2 / name :op1 "II")))
            :op2 (f / fibroblast
                  :part-of (l / lung)))
      :ARG2 (a2 / analyze-01)
      :purpose (g / gauge-01
            :ARG1 (d / differ-02
                  :ARG1 (c2 / cell)
                  :ARG3 (r / react-01
                        :ARG0-of (s2 / signal-07))
                  :ARG1-of (s / specific-02
                        :ARG2 (t2 / type))))
      :ARG1-of (d2 / describe-01
            :ARG0 (f2 / figure :mod 1)))

# ::id pmid_1627_1139.130 ::date 2015-08-12T05:23:22 ::annotator SDL-AMR-09 ::preferred
# ::snt Phosphorylation of STAT3 and ERK was sufficient for identifying responsiveness to cytokines in specific cell types (Fig. <xref ref-type="fig" rid="F1">1A</xref> shows representative immunoblots and Fig. <xref ref-type="fig" rid="F1">1B</xref> presents the quantitative data from independently performed experiments involving 5 separate matched cultures of type II epithelial cells and fibroblasts).
# ::save-date Sat Jan 16, 2016 ::file pmid_1627_1139_130.txt
(s / suffice-01
      :ARG0 (p / phosphorylate-01
            :ARG1 (a / and
                  :op1 (p2 / protein :name (n / name :op1 "STAT3"))
                  :op2 (e3 / enzyme :name (n2 / name :op1 "ERK"))))
      :ARG1 (i / identify-01
            :ARG1 (r / responsive-02
                  :ARG1 (c / cytokine))
            :location (c2 / cell
                  :mod (t / type)
                  :ARG1-of (s2 / specific-02)))
      :ARG1-of (d / describe-01
            :ARG0 (a2 / and
                  :op1 (f / figure :mod "1A"
                        :ARG0-of (s3 / show-01
                              :ARG1 (i2 / immunoblot-01
                                    :ARG0-of (r2 / represent-01))))
                  :op2 (f2 / figure :mod "1B"
                        :ARG0-of (p4 / present-01
                              :ARG1 (d2 / data
                                    :mod (q / quantity)
                                    :source (e / experiment-01
                                          :ARG1-of (p5 / perform-02
                                                :ARG0-of (d3 / depend-01 :polarity -))
                                          :ARG2-of (i4 / involve-01
                                                :ARG1 (c3 / culture :quant 5
                                                      :ARG1-of (s4 / separate-02)
                                                      :ARG1-of (m / match-01)
                                                      :consist-of (a3 / and
                                                            :op1 (c4 / cell
                                                                  :source (e2 / epithelium)
                                                                  :mod (t2 / type :name (n3 / name :op1 "II")))
                                                            :op2 (f3 / fibroblast)))))))))))

# ::id pmid_1627_1139.131 ::date 2015-08-12T05:41:08 ::annotator SDL-AMR-09 ::preferred
# ::snt In brief, normal type II epithelial cells showed the following features (Fig. <xref ref-type="fig" rid="F1">1A</xref>, top panel): OSM strongly activated phosphorylation of STAT3 and ERK, while IL-6 was less effective, and LIF did not produce any detectable response.
# ::save-date Sat Jan 16, 2016 ::file pmid_1627_1139_131.txt
(s / show-01
      :ARG0 (c / cell
            :mod (t / type :name (n / name :op1 "II"))
            :source (e / epithelium)
            :ARG1-of (n2 / normal-02))
      :ARG1 (f / feature
            :ARG1-of (f2 / follow-04)
            :example (c2 / contrast-01
                        :ARG1 (a2 / activate-01
                              :ARG0 (p / protein :name (n3 / name :op1 "OSM"))
                              :ARG1 (p2 / phosphorylate-01
                                    :ARG1 (a3 / and
                                          :op1 (p3 / protein :name (n4 / name :op1 "STAT3"))
                                          :op2 (e4 / enzyme :name (n5 / name :op1 "ERK"))))
                              :ARG1-of (s2 / strong-02))
                        :ARG2 (a4 / and
                              :op1 (e3 / effective-04
                                    :ARG0 (p5 / protein :name (n6 / name :op1 "IL-6"))
                                    :degree (l / less))
                              :op2 (p6 / produce-01 :polarity -
                                    :ARG0 (p7 / protein :name (n7 / name :op1 "LIF"))
                                    :ARG1 (r / respond-01
                                          :ARG1-of (d / detect-01
                                                :ARG1-of (p8 / possible-01)))))))
      :ARG1-of (d2 / describe-01
            :ARG0 (f3 / figure :mod "1A"
                  :location (p9 / panel
                        :mod (t2 / top))))
      :ARG2-of (b / brief-01))

# ::id pmid_1627_1139.132 ::date 2015-08-12T09:26:08 ::annotator SDL-AMR-09 ::preferred
# ::snt EGF stimulated phosphorylation of ERK in the range of OSM, while insulin was minimally effective.
# ::save-date Sun Jan 17, 2016 ::file pmid_1627_1139_132.txt
(c / contrast-01
      :ARG1 (s / stimulate-01
            :ARG0 (p2 / protein :name (n / name :op1 "EGF"))
            :ARG1 (p / phosphorylate-01
                  :ARG1 (e2 / enzyme :name (n2 / name :op1 "ERK"))
                  :part-of (r / range-01
                        :ARG1 (p3 / protein :name (n3 / name :op1 "OSM")))))
      :ARG2 (e / effective-04
            :ARG0 (p4 / protein :name (n4 / name :op1 "insulin"))
            :degree (m / minimal-02)))

# ::id pmid_1627_1139.133 ::date 2015-08-12T10:11:45 ::annotator SDL-AMR-09 ::preferred
# ::snt Fibroblasts exhibited a prominent LIF response and a several-fold higher activation of ERK relative to STAT3 by IL-6 cytokines (Fig. <xref ref-type="fig" rid="F1">1A</xref>, bottom panel), in contrast to normal epithelial cells.
# ::save-date Sat Jan 16, 2016 ::file pmid_1627_1139_133.txt
(c / contrast-01
      :ARG1 (f / fibroblast
            :ARG0-of (e / exhibit-01
                  :ARG1 (a / and
                        :op1 (r / respond-01
                              :ARG0 f
                              :ARG1 (p2 / protein :name (n / name :op1 "LIF"))
                              :mod (p / prominent))
                        :op2 (a2 / activate-01
                              :ARG0 (c4 / cytokine :name (n5 / name :op1 "IL-6"))
                              :ARG1 (e2 / enzyme :name (n2 / name :op1 "ERK"))
                              :ARG1-of (h / high-02
                                    :degree (m / more
                                          :quant (p4 / product-of
                                                :op1 (s / several)))
                                    :ARG1-of (r2 / relative-05
                                          :ARG3 (p5 / protein :name (n6 / name :op1 "STAT3")))))))
            :ARG1-of (d / describe-01
                  :ARG0 (f2 / figure :mod "1A")
                  :location (p6 / panel
                        :mod (b / bottom))))
      :ARG2 (c2 / cell
            :ARG1-of (n4 / normal-02)
            :source (e3 / epithelium)))

# ::id pmid_1627_1139.134 ::date 2015-08-12T11:29:32 ::annotator SDL-AMR-09 ::preferred
# ::snt The maximal level of receptor action in epithelial cells was reached after 15 min agonist treatment (Fig. <xref ref-type="fig" rid="F1">1D</xref>, example of OSM on normal type II epithelial cells).
# ::save-date Mon Aug 17, 2015 ::file pmid_1627_1139_134.txt
(r / reach-01
      :ARG1 (l / level
            :degree (m / maximal)
            :degree-of (a / act-02
                  :ARG0 (r2 / receptor))
            :location (c / cell
                  :source (e / epithelium)))
      :time (a2 / after
            :op1 (t / treat-04
                  :ARG2 (a3 / agonist)
                  :duration (t2 / temporal-quantity :quant 15
                        :unit (m2 / minute))))
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod "1D"
                  :example-of (p / protein :name (n / name :op1 "OSM")
                              :location (c2 / cell
                                    :ARG1-of (n2 / normal-02)
                                    :mod (t3 / type :name (n3 / name :op1 "II"))
                                    :source (e3 / epithelium))))))

# ::id pmid_1627_1139.135 ::date 2015-08-12T11:59:37 ::annotator SDL-AMR-09 ::preferred
# ::snt Deviations from the normal regulatory phenotype of epithelial cells were already evident in immortalized bronchial epithelial cells, HBE4 (Fig. <xref ref-type="fig" rid="F1">1A</xref>) and HBE137 (not shown).
# ::save-date Thu Jan 28, 2016 ::file pmid_1627_1139_135.txt
(e / evidence-01
      :ARG1 (d / deviate-01
            :ARG1 (p / phenotype
                  :ARG1-of (n / normal-02)
                  :ARG0-of (r / regulate-01)
                  :poss (c / cell
                        :source (e2 / epithelium))))
      :time (a / already)
      :location (c2 / cell
            :source (e3 / epithelium)
            :mod (b / bronchus)
            :ARG1-of (i / immortalize-03)
            :ARG1-of (m / mean-01
                  :ARG2 (a2 / and
                        :op1 (c3 / cell-line :name (n2 / name :op1 "HBE4")
                              :ARG1-of (d2 / describe-01
                                    :ARG0 (f / figure :mod "1A")))
                        :op2 (c4 / cell-line :name (n3 / name :op1 "HBE137")
                              :ARG1-of (s / show-01 :polarity -))))))

# ::id pmid_1627_1139.136 ::date 2015-08-12T12:28:08 ::annotator SDL-AMR-09 ::preferred
# ::snt These cell lines responded to IL-6 cytokines like normal epithelial cells, but showed a detectable STAT3 signaling by LIF and a ~2-fold higher ERK activation by OSM and IL-6.
# ::save-date Sat Jan 16, 2016 ::file pmid_1627_1139_136.txt
(c / contrast-01
      :ARG1 (r / respond-01
            :ARG0 (c2 / cell-line
                  :mod (t / this))
            :ARG1 (c3 / cytokine :name (n / name :op1 "IL-6"))
            :ARG1-of (r2 / resemble-01
                  :ARG2 (r3 / respond-01
                        :ARG0 (c4 / cell
                              :ARG1-of (n2 / normal-02)
                              :source (e / epithelium)))))
      :ARG2 (s / show-01
            :ARG0 c2
            :ARG1 (a / and
                  :op1 (s2 / signal-07
                        :ARG0 (p / protein :name (n3 / name :op1 "STAT3"))
                        :ARG2 (p3 / protein :name (n4 / name :op1 "LIF"))
                        :ARG1-of (d / detect-01
                              :ARG1-of (p2 / possible-01)))
                  :op2 (a2 / activate-01
                        :ARG0 (a3 / and
                              :op1 (p4 / protein :name (n5 / name :op1 "OSM"))
                              :op2 c3)
                        :ARG1 (e2 / enzyme :name (n7 / name :op1 "ERK"))
                        :ARG1-of (h / high-02
                              :degree (m / more
                                    :quant (a4 / approximately
                                          :op1 (p6 / product-of :op1 2))))))))

# ::id pmid_1627_1139.137 ::date 2015-08-12T13:08:41 ::annotator SDL-AMR-09 ::preferred
# ::snt More profound differences were detected in carcinoma lines (Fig. <xref ref-type="fig" rid="F1">1A</xref> and not shown).
# ::save-date Thu Dec 10, 2015 ::file pmid_1627_1139_137.txt
(d / detect-01
      :ARG1 (d2 / differ-02
            :mod (p / profound
                  :degree (m / more)))
      :location (l / line
            :source (m2 / medical-condition :name (n / name :op1 "carcinoma")))
      :ARG1-of (d4 / describe-01
            :ARG0 (a / and
                  :op1 (f / figure :mod "1A")
                  :op2 (d5 / data
                        :ARG1-of (s / show-01 :polarity -)))))

# ::id pmid_1627_1139.138 ::date 2015-08-12T13:21:10 ::annotator SDL-AMR-09 ::preferred
# ::snt In carcinoma cell lines, the major trends included a strong STAT3 activation by LIF (ADLC, H125), an increased (ADLC, H23) or decreased STAT3 activation by IL-6 (H125, H324), a decreased ERK activation by EGF (H522), and a treatment-independent, constitutive activation of the ERK pathway (H23).
# ::save-date Sun Jan 17, 2016 ::file pmid_1627_1139_138.txt
(i / include-91
      :ARG1 (a / and
            :op1 (a2 / activate-01
                  :ARG0 (p / protein :name (n2 / name :op1 "LIF")
                        :location (a3 / and
                              :op1 (c3 / cell-line :name (n4 / name :op1 "ADLC"))
                              :op2 (c8 / cell-line :name (n5 / name :op1 "H125"))))
                  :ARG1 (p2 / protein :name (n3 / name :op1 "STAT3"))
                  :ARG1-of (s / strong-02))
            :op2 (o2 / or
                  :op1 (a4 / activate-01
                        :ARG0 (p5 / protein :name (n6 / name :op1 "IL-6")
                              :location (a7 / and
                                    :op1 c3
                                    :op2 (c4 / cell-line :name (n11 / name :op1 "H23"))))
                        :ARG1 p2
                        :ARG1-of (i2 / increase-01))
                  :op2 (a5 / activate-01
                        :ARG0 (p3 / protein :name (n18 / name :op1 "IL-6")
                              :location (a6 / and
                                    :op1 c8
                                    :op2 (c5 / cell-line :name (n8 / name :op1 "H324"))))
                        :ARG1 p2
                        :ARG1-of (d2 / decrease-01)))
            :op3 (a8 / activate-01
                  :ARG0 (p4 / protein :name (n14 / name :op1 "EGF")
                        :location (c7 / cell-line :name (n15 / name :op1 "H522")))
                  :ARG1 (p12 / pathway :name (n13 / name :op1 "ERK"))
                  :ARG1-of d2)
            :op4 (a9 / activate-01
                  :ARG1 (p13 / pathway :name (n16 / name :op1 "ERK")
                        :location c4)
                  :mod (c2 / constitutive)
                  :ARG0-of (d4 / depend-01 :polarity -
                        :ARG1 (t2 / treat-04))))
      :ARG2 (t / trend-01
            :ARG1-of (m / major-02))
      :location (c / cell-line
            :source (m2 / medical-condition :name (n / name :op1 "carcinoma"))))

# ::id pmid_1627_1139.139 ::date 2015-08-12T14:17:12 ::annotator SDL-AMR-09 ::preferred
# ::snt Despite the substantial changes in response patterns, STAT and ERK signaling in response to OSM was consistently high in all analyzed lung cancer cell lines.
# ::save-date Mon Feb 1, 2016 ::file pmid_1627_1139_139.txt
(h / high-02
      :ARG1 (s / signal-07
            :ARG0 (a / and
                  :op1 (p / protein :name (n / name :op1 "STAT"))
                  :op2 (e / enzyme :name (n2 / name :op1 "ERK")))
            :ARG0-of (r / respond-01
                  :ARG1 (p3 / protein :name (n3 / name :op1 "OSM"))))
      :manner (c / consistent-02)
      :location (c2 / cell-line
            :mod (a2 / all)
            :ARG1-of (a3 / analyze-01)
            :mod (d / disease :wiki "Lung_cancer" :name (n4 / name :op1 "lung" :op2 "cancer")))
      :concession (c4 / change-01
                  :ARG1 (p4 / pattern
                        :ARG1-of (r2 / respond-01))
                  :degree (s2 / substantial)))

# ::id pmid_1627_1139.140 ::date 2015-08-12T14:36:10 ::annotator SDL-AMR-09 ::preferred
# ::snt Moreover, the cell-type and line specific differences in STAT3 and ERK signaling were not due different expression of the signaling proteins as demonstrated by the comparable expression level of total STAT3 and ERK proteins among the cell types (Fig. <xref ref-type="fig" rid="F1">1C</xref>).
# ::save-date Sat Jan 16, 2016 ::file pmid_1627_1139_140.txt
(a4 / and
      :op2 (c / cause-01 :polarity -
            :ARG0 (e / express-03
                  :ARG2 (p3 / protein
                        :ARG0-of (s3 / signal-07))
                  :ARG1-of (d3 / differ-02))
            :ARG1 (a2 / and
                  :op1 (d / differ-02
                        :ARG1 (t / type
                              :mod (c2 / cell))
                        :ARG3 (s2 / signal-07
                              :ARG0 (a / and
                                    :op1 (p / protein :name (n / name :op1 "STAT3"))
                                    :op2 (e4 / enzyme :name (n2 / name :op1 "ERK")))))
                  :op2 (d2 / differ-02
                        :ARG3 s2
                        :ARG1-of (s / specific-02
                              :ARG2 (l / line))))
            :ARG1-of (d4 / demonstrate-01
                  :ARG0 (l2 / level
                        :degree-of (e2 / express-03
                              :ARG2 (a3 / and
                                    :op1 (p4 / protein :name (n3 / name :op1 "STAT3")
                                          :mod (t2 / total))
                                    :op2 (e3 / enzyme :name (n4 / name :op1 "ERK")
                                          :mod t2)))
                        :ARG1-of (c3 / comparable-03)
                        :location t)))
      :ARG1-of (d5 / describe-01
            :ARG0 (f / figure :mod "1C")))

# ::id pmid_1627_1139.141 ::date 2015-08-12T15:31:09 ::annotator SDL-AMR-09 ::preferred
# ::snt <sec-title level="2">Cell line-specific effect of cytokines on proliferation</sec-title>
# ::save-date Wed Aug 19, 2015 ::file pmid_1627_1139_141.txt
(a / affect-01
      :ARG0 (c / cytokine)
      :ARG1 (p / proliferate-01)
      :ARG1-of (s2 / specific-02
            :ARG2 (c2 / cell-line)))

# ::id pmid_1627_1139.142 ::date 2015-08-12T15:35:09 ::annotator SDL-AMR-09 ::preferred
# ::snt To relate cytokine signaling with effects on cell proliferation, representative lung cell types were cultured for 6 days in growth medium containing in addition increasing concentrations of OSM, IL-6 or LIF (Fig. <xref ref-type="fig" rid="F2">2</xref>).
# ::save-date Tue Dec 29, 2015 ::file pmid_1627_1139_142.txt
(c / culture-01
      :ARG1 (t / type
            :mod (c2 / cell
                  :mod (l / lung))
            :ARG0-of (r / represent-01))
      :duration (t2 / temporal-quantity :quant 6
            :unit (d / day))
      :location (m / medium
            :mod (g / grow-01)
            :ARG0-of (c3 / contain-01
                  :ARG1 (c4 / concentrate-02
                        :ARG1 (o / or
                              :op1 (p / protein :name (n / name :op1 "OSM"))
                              :op2 (p2 / protein :name (n2 / name :op1 "IL-6"))
                              :op3 (p3 / protein :name (n3 / name :op1 "LIF")))
                        :ARG1-of (i / increase-01)
                        :ARG1-of (a / add-02))))
      :ARG1-of (d2 / describe-01
            :ARG0 (f / figure :mod 2))
      :purpose (r2 / relate-01
            :ARG1 (s / signal-07
                  :ARG0 (c5 / cytokine))
            :ARG2 (a2 / affect-01
                  :ARG0 s
                  :ARG1 (p4 / proliferate-01
                        :ARG0 (c6 / cell)))))

# ::id pmid_1627_1139.143 ::date 2015-08-12T15:53:57 ::annotator SDL-AMR-09 ::preferred
# ::snt In all cell types, OSM reduced in a dose-dependent manner proliferation, with maximal effect at a concentration of 20 to 100 ng/ml.
# ::save-date Tue Aug 18, 2015 ::file pmid_1627_1139_143.txt
(r / reduce-01
      :ARG0 (p / protein :name (n / name :op1 "OSM"))
      :ARG1 (p2 / proliferate-01)
      :location (t / type
            :mod (c / cell)
            :mod (a / all))
      :manner (d / depend-01
            :ARG1 (d2 / dose))
      :ARG1-of (a2 / affect-01
            :degree (m / maximal
                  :quant (c2 / concentration-quantity
                        :unit (n2 / nanogram-per-milliliter)
                        :quant (v / value-interval :op1 20 :op2 100)))))

# ::id pmid_1627_1139.144 ::date 2015-08-12T16:22:34 ::annotator SDL-AMR-09 ::preferred
# ::snt Maximal inhibition varied among the cell types and ranged from >80% (normal primary epithelial cells) to ~40% (HBE137, A549, fibroblasts) and ~20% (H23).
# ::save-date Tue Aug 18, 2015 ::file pmid_1627_1139_144.txt
(a / and
      :op1 (v / vary-01
            :ARG1 (i / inhibit-01
                  :degree (m / maximal))
            :ARG5 (t / type
                  :mod (c / cell)))
      :op2 (r / range-01
            :ARG1 i
            :ARG3 (m2 / more-than
                  :op1 (p / percentage-entity :value 80
                        :location (c2 / cell
                              :ARG1-of (n / normal-02)
                              :mod (p2 / primary)
                              :source (e / epithelium))))
            :ARG4 (a2 / and
                  :op1 (a3 / approximately
                        :op1 (p3 / percentage-entity :value 40
                              :location (a4 / and
                                    :op1 (c3 / cell-line :name (n2 / name :op1 "HBE137"))
                                    :op2 (c4 / cell-line :name (n3 / name :op1 "A549"))
                                    :op3 (f / fibroblast))))
                  :op2 (a5 / approximately
                        :op1 (p4 / percentage-entity :value 20
                              :location (c5 / cell-line :name (n4 / name :op1 "H23")))))))

# ::id pmid_1627_1139.145 ::date 2015-08-10T12:32:26 ::annotator SDL-AMR-09 ::preferred
# ::snt IL-6 and LIF did not appreciably alter proliferation of epithelial or fibroblastic cells.
# ::save-date Tue Dec 29, 2015 ::file pmid_1627_1139_145.txt
(a / alter-01 :polarity -
      :ARG0 (a2 / and
            :op1 (p / protein :wiki "Interleukin_6"
                  :name (n / name :op1 "IL-6"))
            :op2 (p2 / protein :wiki "Leukemia_inhibitory_factor"
                  :name (n2 / name :op1 "LIF")))
      :ARG1 (p3 / proliferate-01
            :ARG0 (o / or
                  :op1 (c / cell
                        :mod (e / epithelium))
                  :op2 (c2 / cell
                        :mod (f / fibroblast))))
      :ARG1-of (a4 / appreciate-03
            :ARG1-of (p4 / possible-01)))

# ::id pmid_1627_1139.146 ::date 2015-08-10T19:49:01 ::annotator SDL-AMR-09 ::preferred
# ::snt The comparative analyses also indicated that immortalization of epithelial cells with the E6E7 gene (HBE4 or HBE137) or constitutive activation of ERK pathway (H23) correlated with a lower growth inhibition by OSM.
# ::save-date Thu Jan 28, 2016 ::file pmid_1627_1139_146.txt
(i / indicate-01
      :ARG0 (a / analyze-01
            :ARG0-of (c / compare-01))
      :ARG1 (o / or
            :op1 (i2 / immortalize-03
                  :ARG1 (c3 / cell
                        :mod (e / epithelium)
                        :ARG1-of (m2 / mean-01
                              :ARG2 (o2 / or
                                    :op1 (c5 / cell-line :name (n4 / name :op1 "HBE4"))
                                    :op2 (c6 / cell-line :name (n5 / name :op1 "HBE137")))))
                  :ARG2 (g / gene :name (n / name :op1 "E6E7")))
            :op2 (a4 / activate-01
                  :ARG1 (p / pathway :name (n3 / name :op1 "ERK"))
                  :ARG0-of (c4 / constitute-01)
                  :location (c7 / cell-line :name (n6 / name :op1 "H23")))
            :ARG1-of (c2 / correlate-01
                  :ARG2 (i3 / inhibit-01
                        :ARG0 (p2 / protein :name (n2 / name :op1 "OSM"))
                        :ARG1-of (g2 / grow-01)
                        :ARG1-of (l2 / low-04
                              :degree (m / more)))))
      :mod (a2 / also))

# ::id pmid_1627_1139.147 ::date 2015-08-10T20:12:21 ::annotator SDL-AMR-09 ::preferred
# ::snt The same cells were tested for growth in the presence of conditioned medium from lipopolysaccaride (LPS) activated macrophages.
# ::save-date Thu Aug 20, 2015 ::file pmid_1627_1139_147.txt
(t / test-01
      :ARG1 (c / cell
            :ARG1-of (s / same-01))
      :ARG2 (g / grow-01
            :condition (p / present-02
                  :ARG1 (m / medium
                        :source (m2 / macrophage
                              :ARG1-of (a / activate-01
                                    :ARG0 (m4 / molecular-physical-entity :name (n / name :op1 "lipopolysaccaride"))))
                        :ARG1-of (c2 / condition-02)))))

# ::id pmid_1627_1139.148 ::date 2015-08-10T20:27:48 ::annotator SDL-AMR-09 ::preferred
# ::snt Such medium is considered to contain a physiologically relevant mixture of inflammatory mediators (Table <xref ref-type="table" rid="T1">1</xref>).
# ::save-date Thu Aug 20, 2015 ::file pmid_1627_1139_148.txt
(c / consider-01
      :ARG1 (c2 / contain-01
            :ARG0 (m / medium
                  :mod (s / such))
            :ARG1 (m2 / mix-01
                  :ARG1 (m4 / molecular-physical-entity
                        :ARG1-of (i / inflame-01)
                        :ARG0-of (m3 / mediate-01))
                  :ARG1-of (r2 / relevant-01
                        :mod (p / physiological))))
      :ARG1-of (d / describe-01
            :ARG0 (t / table :mod 1)))

# ::id pmid_1627_1139.149 ::date 2015-08-10T20:37:37 ::annotator SDL-AMR-09 ::preferred
# ::snt The LPS macrophage medium suppressed the proliferation of epithelial cells in a dose-dependent fashion (Fig. <xref ref-type="fig" rid="F2">2</xref>).
# ::save-date Wed Dec 30, 2015 ::file pmid_1627_1139_149.txt
(s / suppress-01
      :ARG0 (m / medium
            :mod (m2 / molecular-physical-entity :name (n / name :op1 "LPS")
                  :mod (m3 / macrophage)))
      :ARG1 (p / proliferate-01
            :ARG0 (c / cell
                  :mod (e / epithelium))
            :manner (f / fashion
                  :ARG0-of (d / depend-01
                        :ARG1 (d2 / dose))))
      :ARG1-of (d3 / describe-01
            :ARG0 (f2 / figure :mod 2)))

# ::id pmid_1627_1139.150 ::date 2015-08-10T20:52:14 ::annotator SDL-AMR-09 ::preferred
# ::snt Suppression ranged from >80% (primary epithelial cells and A549) to <20% in HBE137 and H23.
# ::save-date Mon Aug 17, 2015 ::file pmid_1627_1139_150.txt
(r / range-01
      :ARG1 (s / suppress-01)
      :ARG3 (m2 / more-than
            :op1 (p / percentage-entity :value 80
                  :location (a / and
                        :op1 (c / cell
                              :mod (e / epithelium
                                    :mod (p3 / primary)))
                        :op2 (c2 / cell-line :name (n / name :op1 "A549")))))
      :ARG4 (l2 / less-than
            :op1 (p2 / percentage-entity :value 20
                  :location (a2 / and
                        :op1 (c3 / cell-line :name (n2 / name :op1 "HBE137"))
                        :op2 (c4 / cell-line :name (n3 / name :op1 "H23"))))))

# ::id pmid_1627_1139.151 ::date 2015-08-10T21:08:13 ::annotator SDL-AMR-09 ::preferred
# ::snt In contrast, the same treatment led to enhanced proliferation of fibroblasts.
# ::save-date Mon Aug 17, 2015 ::file pmid_1627_1139_151.txt
(c / contrast-01
      :ARG2 (l / lead-03
            :ARG0 (t / treat-04
                  :ARG1-of (s / same-01))
            :ARG2 (p / proliferate-01
                  :ARG0 (f / fibroblast)
                  :ARG1-of (e / enhance-01))))

# ::id pmid_1627_1139.152 ::date 2015-08-10T21:15:29 ::annotator SDL-AMR-09 ::preferred
# ::snt Taken together, these data indicated that cytokine responsiveness and growth regulation by OSM and inflammatory mediators are indeed subject to alterations in lung epithelial cells in part as a function of immortalization and transformation.
# ::save-date Thu Jan 28, 2016 ::file pmid_1627_1139_152.txt
(i / indicate-01
      :ARG0 (d / data
            :mod (t / this)
            :ARG1-of (t2 / take-01
                  :mod (t3 / together)))
      :ARG1 (s / subject-02
            :ARG1 (a2 / and
                  :op1 (r / responsive-02
                        :ARG1 (c2 / cytokine))
                  :op2 (r2 / regulate-01
                        :ARG0 (a3 / and
                              :op1 (p3 / protein :name (n2 / name :op1 "OSM"))
                              :op2 (m3 / molecular-physical-entity
                                    :ARG0-of (m / mediate-01)
                                    :ARG0-of (i3 / inflame-01)))
                        :ARG1 (g / grow-01)))
            :ARG2 (a / alter-01
                  :location (c / cell
                        :mod (e2 / epithelium)
                        :mod (l / lung)))
            :mod (i2 / indeed)
            :ARG1-of (f / function-01
                  :ARG0 (a4 / and
                        :op1 (i4 / immortalize-03)
                        :op2 (t5 / transform-01))
                  :mod (p2 / part))))

# ::id pmid_1627_1139.153 ::date 2015-08-10T21:43:03 ::annotator SDL-AMR-09 ::preferred
# ::snt Characteristic changes in the cellular response patterns may serve as markers for the transformation process or may even contribute functionally to tumorigenesis.
# ::save-date Thu Nov 19, 2015 ::file pmid_1627_1139_153.txt
(p / possible-01
      :ARG1 (o / or
            :op1 (s / serve-01
                  :ARG0 (c / change-01
                        :ARG1 (p2 / pattern-01
                              :ARG1 (r / respond-01
                                    :ARG0 (c3 / cell)))
                        :ARG1-of (c2 / characteristic-02))
                  :ARG1 (m2 / marker
                        :purpose (p3 / process-02
                              :ARG1 (t3 / transform-01))))
            :op2 (c4 / contribute-01
                  :ARG0 c
                  :ARG2 (c5 / create-01
                        :ARG1 (t / tumor))
                  :manner (f / function-01)
                  :mod (e / even))))

# ::id pmid_1627_1139.154 ::date 2015-08-10T22:06:09 ::annotator SDL-AMR-09 ::preferred
# ::snt One of the key questions is at what stage in the transformation of lung epithelial cells are these changes established.
# ::save-date Thu Aug 20, 2015 ::file pmid_1627_1139_154.txt
(q / question-01 :quant 1
      :ARG1 (s / stage-02
            :time (a / amr-unknown)
            :subevent-of (t / transform-01
                  :ARG1 (c / cell
                        :mod (l / lung)
                        :mod (e / epithelium)))
            :time-of (c2 / change-01
                  :mod (t2 / this)
                  :ARG1-of (e2 / establish-01)))
      :ARG1-of (i / include-91
            :ARG2 (q2 / question
                  :ARG2-of (k / key-02))))

# ::id pmid_1627_1139.155 ::date 2015-08-10T22:31:32 ::annotator SDL-AMR-09 ::preferred
# ::snt To address this question, we used short-term primary cultures of non-immortalized epithelial cells derived from normal and pathologically distinct stages of premalignant lesions sampled by brushing during bronchoscopy of patients.
# ::save-date Thu Jan 28, 2016 ::file pmid_1627_1139_155.txt
(u / use-01
      :ARG0 (w / we)
      :ARG1 (c / culture-01
            :ARG1 (c2 / cell
                  :mod (e / epithelium)
                  :ARG1-of (d / derive-01
                        :ARG2 (a2 / and
                              :op1 (s2 / stage
                                    :ARG1-of (n / normal-02))
                              :op2 (s3 / stage)
                              :mod (d2 / distinct
                                    :mod (p3 / pathology))
                              :topic (l / lesion
                                    :mod (p2 / premalignant)
                                    :ARG1-of (s4 / sample-01
                                          :time (b2 / bronchoscopy
                                                :beneficiary (p5 / person
                                                      :ARG0-of (h / have-rel-role-91
                                                            :ARG2 (p4 / patient))))
                                          :manner (b / brush-01)))))
                  :ARG1-of (i / immortalize-03 :polarity -))
            :mod (p / primary)
            :mod (t2 / term
                  :ARG1-of (s / short-07)))
      :purpose (a / address-01
            :ARG0 w
            :ARG1 (q / question-01
                  :mod (t / this))))

# ::id pmid_1627_1139.156 ::date 2015-08-10T23:25:53 ::annotator SDL-AMR-09 ::preferred
# ::snt The experimental approach also allowed us to establish the more basic information of what is the cytokine responsiveness of normal epithelial cells and what is the range among individuals.
# ::save-date Wed Dec 30, 2015 ::file pmid_1627_1139_156.txt
(a / allow-01
      :ARG0 (a2 / approach-02
            :ARG1-of (e / experiment-01))
      :ARG1 (e2 / establish-01
            :ARG0 (w / we)
            :ARG1 (i / information
                  :mod (b / basic
                        :degree (m / more))
                  :topic (a4 / and
                        :op1 (r / responsive-02
                              :ARG0 (c / cell
                                    :mod (e3 / epithelium)
                                    :ARG1-of (n2 / normal-02))
                              :ARG1 (c2 / cytokine)
                              :degree (a5 / amr-unknown))
                        :op2 (r2 / range-01
                              :ARG2 (a6 / amr-unknown)
                              :ARG5 (i2 / individual
                                    :ARG1-of (i3 / include-91
                                          :ARG2 (i4 / individual)))))))
      :mod (a3 / also))

# ::id pmid_1627_1139.157 ::date 2015-08-10T23:41:17 ::annotator SDL-AMR-09 ::preferred
# ::snt <sec-title level="2">Application of primary epithelial cells derived from bronchial brushing</sec-title>
# ::save-date Mon Aug 17, 2015 ::file pmid_1627_1139_157.txt
(a2 / apply-02
      :ARG1 (c / cell
            :mod (p / primary)
            :mod (e / epithelium)
            :ARG1-of (d / derive-01
                  :ARG2 (b / brush-01
                        :mod (b2 / bronchus)))))

# ::id pmid_1627_1139.158 ::date 2015-08-10T23:46:55 ::annotator SDL-AMR-09 ::preferred
# ::snt Epithelial cell cultures were established from the brushed bronchial epithelium.
# ::save-date Mon Aug 10, 2015 ::file pmid_1627_1139_158.txt
(e / establish-01
      :ARG1 (c / culture-01
            :ARG1 (c2 / cell
                  :mod (e2 / epithelium)))
      :source (e3 / epithelium
            :mod (b / bronchus)
            :ARG1-of (b2 / brush-01)))

# ::id pmid_1627_1139.159 ::date 2015-08-10T23:50:34 ::annotator SDL-AMR-09 ::preferred
# ::snt Biopsies of the same sites were processed for pathological and cytological evaluation.
# ::save-date Mon Aug 17, 2015 ::file pmid_1627_1139_159.txt
(p / process-01
      :ARG1 (b / biopsy-101
            :ARG1 (s / site
                  :ARG1-of (s2 / same-01)))
      :purpose (a / and
            :op1 (e / evaluate-01
                  :mod (p2 / pathology))
            :op2 (e2 / evaluate-01
                  :mod (c / cytology))))

# ::id pmid_1627_1139.160 ::date 2015-08-10T23:55:26 ::annotator SDL-AMR-09 ::preferred
# ::snt The pathological findings (normal, metaplasia, dysplasia or non-invasive carcinoma <i>in situ</i>) were subsequently applied in the interpretation of the signaling data (Table <xref ref-type="table" rid="T2">2</xref>).
# ::save-date Thu Aug 20, 2015 ::file pmid_1627_1139_160.txt
(a / apply-02
      :ARG1 (t2 / thing
            :ARG1-of (f / find-01)
            :mod (p / pathology)
            :example (o / or
                        :op1 (n / normal-02)
                        :op2 (m / metaplasia)
                        :op3 (d / dysplasia)
                        :op4 (c / carcinoma
                              :ARG0-of (i / invade-01 :polarity -
                                    :ARG1 (s / situ)))))
      :ARG2 (i2 / interpret-01
            :ARG1 (d2 / data
                  :ARG0-of (s3 / signal-07)))
      :manner (s2 / subsequent)
      :ARG1-of (d3 / describe-01
            :ARG0 (t / table :mod 2)))

# ::id pmid_1627_1139.161 ::date 2015-08-11T00:03:03 ::annotator SDL-AMR-09 ::preferred
# ::snt No cases of invasive carcinoma or advanced lung cancer were included.
# ::save-date Sat Jan 30, 2016 ::file pmid_1627_1139_161.txt
(i / include-01
      :ARG1 (o2 / or
            :op1 (c / case-04 :polarity -
                  :ARG1 (c2 / carcinoma
                        :ARG0-of (i3 / invade-01)))
            :op2 (c3 / case-04 :polarity -
                  :ARG1 (d / disease :wiki "Lung_cancer" :name (n / name :op1 "lung" :op2 "cancer")
                        :ARG1-of (a / advance-01)))))

# ::id pmid_1627_1139.162 ::date 2015-08-11T00:11:17 ::annotator SDL-AMR-09 ::preferred
# ::snt From May 2000 to March 2005, 192 separate brushings were taken from 96 patients (EC-1 to EC-96).
# ::save-date Thu Dec 10, 2015 ::file pmid_1627_1139_162.txt
(t / take-01
      :ARG1 (b / brush-01 :quant 192
            :ARG1-of (s / separate-02))
      :ARG2 (p / person :quant 96
            :ARG0-of (h / have-rel-role-91
                  :ARG2 (p2 / patient)))
      :time (d / date-interval
            :op1 (d2 / date-entity :month 5 :year 2000)
            :op2 (d3 / date-entity :month 3 :year 2005))
      :mod (v / value-interval
            :op1 (c / cell-line :name (n / name :op1 "EC-1"))
            :op2 (c2 / cell-line :name (n2 / name :op1 "EC-96"))))

# ::id pmid_1627_1139.163 ::date 2015-08-11T00:42:33 ::annotator SDL-AMR-09 ::preferred
# ::snt From these, 113 brushings (59%) yielded sufficient epithelial cells that expanded to cultures suitable for functional analyses.
# ::save-date Mon Aug 17, 2015 ::file pmid_1627_1139_163.txt
(y / yield-01
      :ARG0 (b / brush-01 :quant 113
            :ARG1-of (i / include-91
                  :ARG2 (b2 / brush-01
                        :mod (t / this))
                  :ARG3 (p / percentage-entity :value 59)))
      :ARG1 (c / cell
            :mod (e / epithelium)
            :ARG0-of (s / suffice-01)
            :ARG1-of (e2 / expand-01
                  :ARG4 (c2 / culture
                        :ARG1-of (s2 / suitable-04
                              :ARG2 (a / analyze-01
                                    :ARG1-of (f2 / function-01)))))))

# ::id pmid_1627_1139.164 ::date 2015-08-11T01:04:40 ::annotator SDL-AMR-09 ::preferred
# ::snt Approximately 50% of sites initially judged to be abnormal by bronchoscopy proved to be normal by histology.
# ::save-date Thu Aug 20, 2015 ::file pmid_1627_1139_164.txt
(p2 / prove-01
      :ARG0 (h / histology)
      :ARG1 (n2 / normal-02
            :ARG1 (s / site
                  :ARG1-of (i / include-91
                        :ARG2 (s2 / site
                              :ARG1-of (j / judge-01
                                    :ARG0 (b / bronchoscopy)
                                    :ARG2 (n / normal-02 :polarity -
                                          :ARG1 s2)
                                    :time (i2 / initial)))
                        :ARG3 (a2 / approximately
                              :op1 (p / percentage-entity :value 50))))))

# ::id pmid_1627_1139.165 ::date 2015-08-11T01:25:52 ::annotator SDL-AMR-09 ::preferred
# ::snt Based on immunostaining, every cell preparation consisted of >95% cytokeratin-positive epithelial cells.
# ::save-date Tue Jan 19, 2016 ::file pmid_1627_1139_165.txt
(c / consist-01
      :ARG1 (p / prepare-01
            :ARG1 (c2 / cell)
            :mod (e / every))
      :ARG2 (c3 / cell
            :mod (e2 / epithelium)
            :mod (p3 / positive
                  :topic (p4 / protein :name (n / name :op1 "cytokeratin")))
            :quant (m2 / more-than
                  :op1 (p2 / percentage-entity :value 95)))
      :ARG1-of (b / base-02
            :ARG0 (i / immunostain-01)))

# ::id pmid_1627_1139.166 ::date 2015-08-11T01:40:31 ::annotator SDL-AMR-09 ::preferred
# ::snt All cultures derived from normal and abnormal sites showed essentially the same epithelial cell morphology.
# ::save-date Mon Aug 17, 2015 ::file pmid_1627_1139_166.txt
(s / show-01
      :ARG0 (c / culture
            :mod (a / all)
            :ARG1-of (d / derive-01
                  :ARG2 (a2 / and
                        :op1 (s2 / site
                              :ARG1-of (n / normal-02))
                        :op2 (s3 / site
                              :ARG1-of (n2 / normal-02 :polarity -)))))
      :ARG1 (m / morphology
            :poss (c2 / cell
                  :mod (e2 / epithelium))
            :ARG1-of (s4 / same-01))
      :manner (e / essential))

# ::id pmid_1627_1139.167 ::date 2015-08-11T01:48:45 ::annotator SDL-AMR-09 ::preferred
# ::snt To determine whether or not the primary cultures demonstrated any gross chromosomal abnormalities, cells were analyzed by SKY.
# ::save-date Wed Dec 30, 2015 ::file pmid_1627_1139_167.txt
(a / analyze-01
      :ARG1 (c / cell)
      :manner (k / karyotype
            :mod (s / spectrum))
      :purpose (d / determine-01
            :ARG1 (d2 / demonstrate-01 :mode interrogative
                  :ARG0 (c2 / culture
                        :mod (p / primary))
                  :ARG1 (n2 / normal-02 :polarity -
                        :ARG1 (c3 / chromosome)
                        :ARG1-of (g2 / gross-06)))))

# ::id pmid_1627_1139.168 ::date 2015-08-11T02:25:52 ::annotator SDL-AMR-09 ::preferred
# ::snt With the exception of one carcinoma, the cells showed normal karyotypes.
# ::save-date Mon Aug 17, 2015 ::file pmid_1627_1139_168.txt
(s / show-01
      :ARG0 (c / cell)
      :ARG1 (k / karyotype
            :ARG1-of (n / normal-02))
      :ARG2-of (e / except-01
            :ARG1 (c2 / carcinoma :quant 1)))

# ::id pmid_1627_1139.169 ::date 2015-08-11T02:39:08 ::annotator SDL-AMR-09 ::preferred
# ::snt The carcinoma cell culture carried a chromosome 10 deletion (q11.2-q22) in all metaphase spreads.
# ::save-date Mon Aug 17, 2015 ::file pmid_1627_1139_169.txt
(c / carry-01
      :ARG0 (c2 / culture
            :mod (c3 / cell
                  :mod (c4 / carcinoma)))
      :ARG1 (d / delete-01
            :ARG1 (c5 / chromosome :mod 10
                  :ARG1-of (m2 / mean-01
                        :ARG2 (v / value-interval
                              :op1 (d2 / dna-sequence :name (n / name :op1 "q11.2"))
                              :op2 (d3 / dna-sequence :name (n2 / name :op1 "q22")))))
            :location (s / spread-02
                  :mod (a / all)
                  :mod (m / metaphase))))

# ::id pmid_1627_1139.170 ::date 2015-08-11T02:44:45 ::annotator SDL-AMR-09 ::preferred
# ::snt <sec-title level="2">Paired epithelial cell cultures indicate the occurrence of altered cytokine responsiveness at early stage of transformation</sec-title>
# ::save-date Thu Aug 20, 2015 ::file pmid_1627_1139_170.txt
(i / indicate-01
      :ARG0 (c / culture
            :mod (c2 / cell
                  :mod (e / epithelium)
                  :mod (p / paired)
                  :ARG1-of (p2 / pair-01)))
      :ARG1 (r / responsive-02
            :ARG1 (c3 / cytokine
                  :ARG1-of (a / alter-01))
            :time (s / stage
                  :mod (e2 / early)
                  :poss (t / transform-01))))

# ::id pmid_1627_1139.171 ::date 2015-08-11T23:42:06 ::annotator SDL-AMR-09 ::preferred
# ::snt The cytokine responsiveness of the epithelial cells was determined by the activation of signaling and by the effect on DNA synthesis.
# ::save-date Thu Aug 20, 2015 ::file pmid_1627_1139_171.txt
(d / determine-01
      :ARG0 (a2 / and
            :op1 (a / activate-01
                  :ARG1 (s2 / signal-07))
            :op2 (a3 / affect-01
                  :ARG1 (s / synthesize-01
                        :ARG1 (n / nucleic-acid :wiki "DNA" :name (n2 / name :op1 "DNA")))))
      :ARG1 (r / responsive-02
            :ARG0 (c2 / cell
                  :mod (e / epithelium))
            :ARG1 (c / cytokine)))

# ::id pmid_1627_1139.172 ::date 2015-08-11T23:51:29 ::annotator SDL-AMR-09 ::preferred
# ::snt Signaling was measured in first passage subcultures by treatment with cytokines and growth factors for 15 min followed by immunodetection of the phosphorylated signaling proteins (representative example in Fig. <xref ref-type="fig" rid="F3">3</xref>).
# ::save-date Mon Aug 17, 2015 ::file pmid_1627_1139_172.txt
(m / measure-01
      :ARG1 (s / signal-07)
      :ARG2 (t / treat-04
            :ARG2 (a / and
                  :op1 (c / cytokine)
                  :op2 (s4 / small-molecule :name (n / name :op1 "growth_factor")))
            :duration (t2 / temporal-quantity :quant 15
                  :unit (m2 / min))
            :ARG2-of (f2 / follow-01
                  :ARG1 (i / immunodetect-01
                        :ARG1 (s3 / signal-07
                              :ARG0 (p2 / protein
                                    :ARG3-of (p3 / phosphorylate-01))))))
      :location (p / pass-03
            :ARG1 (s2 / subculture)
            :mod (o / ordinal-entity :value 1))
      :ARG1-of (d / describe-01
            :ARG0 (e / example
                  :ARG0-of (r / represent-01)
                  :mod (f3 / figure :mod 3))))

# ::id pmid_1627_1139.173 ::date 2015-08-12T00:21:31 ::annotator SDL-AMR-09 ::preferred
# ::snt The level of phosphorylated STAT1, STAT3 and ERK1/2 were quantified and expressed relative to the level of these proteins in OSM-treated normal cultures in each pair (Fig. <xref ref-type="fig" rid="F4">4A–F</xref>).
# ::save-date Wed Dec 30, 2015 ::file pmid_1627_1139_173.txt
(a3 / and
      :op1 (q / quantify-01
            :ARG1 (a / and
                  :op1 (l3 / level
                        :quant-of (p / protein :name (n / name :op1 "STAT1")
                              :ARG3-of (p3 / phosphorylate-01)))
                  :op2 (l4 / level
                        :quant-of (p2 / protein :name (n2 / name :op1 "STAT3")
                              :ARG3-of p3))
                  :op3 (l5 / level
                        :quant-of (e4 / enzyme :name (n3 / name :op1 "ERK1/2")
                              :ARG3-of p3))))
      :op2 (e2 / express-01
            :ARG2 a)
      :ARG1-of (r / relative-05
            :ARG3 (a4 / and
                  :op1 l3
                  :op2 l4
                  :op3 l5
                  :location (c / culture
                        :ARG1-of (n4 / normal-02)
                        :ARG1-of (t / treat-04
                              :ARG2 (p4 / protein :name (n5 / name :op1 "OSM"))
                              :location (p5 / pair
                                    :mod (e / each))))))
      :ARG1-of (d / describe-01
            :ARG0 (a2 / and
                  :op1 (f / figure :mod "4A")
                  :op2 (f2 / figure :mod "4B")
                  :op3 (f3 / figure :mod "4C")
                  :op4 (f4 / figure :mod "4D")
                  :op5 (f5 / figure :mod "4E")
                  :op6 (f6 / figure :mod "4F"))))

# ::id pmid_1627_1139.174 ::date 2015-08-12T00:43:33 ::annotator SDL-AMR-09 ::preferred
# ::snt The analyses of normal bronchial epithelial cells defined the following response pattern.
# ::save-date Mon Aug 17, 2015 ::file pmid_1627_1139_174.txt
(d / define-01
      :ARG0 (a / analyze-01
            :ARG1 (c / cell
                  :mod (b / bronchus)
                  :mod (e / epithelium)
                  :ARG1-of (n / normal-02)))
      :ARG1 (p / pattern-01
            :ARG1 (r / respond-01
                  :ARG1-of (f / follow-04))))

# ::id pmid_1627_1139.175 ::date 2015-08-10T15:13:54 ::annotator SDL-AMR-09 ::preferred
# ::snt The reaction to cytokine treatment (Fig. <xref ref-type="fig" rid="F3">3</xref>) was comparable to that of type II epithelial cells (Fig. <xref ref-type="fig" rid="F1">1A</xref>).
# ::save-date Wed Dec 30, 2015 ::file pmid_1627_1139_175.txt
(c / comparable-03
      :ARG1 (r / react-01
            :ARG1 (t / treat-04
                  :ARG2 (c3 / cytokine))
            :ARG1-of (d / describe-01
                  :ARG0 (f / figure :mod 3)))
      :ARG2 (r2 / react-01
            :ARG0 (c2 / cell-line
                  :mod (e / epithelium)
                  :mod (t2 / type :mod "II"))
            :ARG1-of (d2 / describe-01
                  :ARG0 (f2 / figure :mod "1A"))))

# ::id pmid_1627_1139.176 ::date 2015-08-10T15:14:09 ::annotator SDL-AMR-09 ::preferred
# ::snt Data from 63 separate preparations of normal bronchial epithelial cell cultures indicated that basal level of phosphorylated ERK was consistently low (7.5 ± 5.6 % of OSM level; mean ± SD) and the basal levels of phosphorylated STAT3 and STAT1 were generally low to non-detectable.
# ::save-date Mon Feb 1, 2016 ::file pmid_1627_1139_176.txt
(i / indicate-01
      :ARG0 (d / data
            :source (p / prepare-01 :quant 63
                  :ARG1 (c / culture-01
                        :ARG1 (c2 / cell
                              :mod (e / epithelium)
                              :mod (b / bronchus)
                              :ARG1-of (n / normal-02)))
                  :ARG1-of (s3 / separate-01)))
      :ARG1 (a / and
            :op1 (l / low-04
                  :ARG1 (l2 / level
                        :quant-of (e2 / enzyme :name (n2 / name :op1 "ERK")
                              :ARG3-of (p2 / phosphorylate-01))
                        :mod (b2 / basal)
                        :ARG1-of (e3 / equal-01
                              :ARG2 (v2 / value-interval
                                    :op1 (p3 / product-of
                                          :op1 (p4 / percentage-entity :value 7.5
                                                :ARG2-of (a2 / add-02
                                                      :ARG1 (p5 / percentage-entity :value 5.6)))
                                          :op2 (l3 / level
                                                :quant-of (p6 / protein :name (n3 / name :op1 "OSM"))))
                                    :op2 (p8 / product-of
                                          :op1 (p11 / percentage-entity :value 7.5
                                                :ARG2-of (s / subtract-01
                                                      :ARG1 p5))
                                          :op2 l3)
                                    :condition (d3 / deviate-01
                                          :mod (m / mean)
                                          :ARG1-of (s2 / standard-02)))))
                  :manner (c3 / consistent-02))
            :op2 (v / value-interval
                  :op1 (l5 / low-04)
                  :op2 (d2 / detect-01
                        :ARG1-of (p10 / possible-01 :polarity -))
                  :domain (l4 / level
                        :quant-of (a3 / and
                              :op1 (p7 / protein :name (n4 / name :op1 "STAT3")
                                    :ARG3-of p2)
                              :op2 (p9 / protein :name (n5 / name :op1 "STAT1")
                                    :ARG3-of p2))
                        :mod b2)
                  :ARG1-of (g / general-02))))

# ::id pmid_1627_1139.177 ::date 2015-08-10T15:33:45 ::annotator SDL-AMR-09 ::preferred
# ::snt OSM prominently activated ERK (Fig. <xref ref-type="fig" rid="F4">4A</xref> &<xref ref-type="fig" rid="F4">4B</xref>) and STAT3 (Fig. <xref ref-type="fig" rid="F4">4C</xref> &<xref ref-type="fig" rid="F4">4D</xref>).
# ::save-date Sat Jan 16, 2016 ::file pmid_1627_1139_177.txt
(a / and
      :op1 (a2 / activate-01
            :ARG0 (p / protein :name (n / name :op1 "OSM"))
            :ARG1 (e / enzyme :name (n2 / name :op1 "ERK"))
            :ARG1-of (d / describe-01
                  :ARG0 (a3 / and
                        :op1 (f / figure :mod "4A")
                        :op2 (f2 / figure :mod "4B"))))
      :op2 (a4 / activate-01
            :ARG0 p
            :ARG1 (p4 / protein :name (n3 / name :op1 "STAT3"))
            :ARG1-of (d2 / describe-01
                  :ARG0 (a5 / and
                        :op1 (f3 / figure :mod "4C")
                        :op2 (f4 / figure :mod "4D"))))
      :manner (p2 / prominent))

# ::id pmid_1627_1139.178 ::date 2015-08-10T15:37:57 ::annotator SDL-AMR-09 ::preferred
# ::snt The response was uniformly high among cultures from different individuals.
# ::save-date Mon Aug 10, 2015 ::file pmid_1627_1139_178.txt
(h / high-02
      :ARG1 (r / respond-01)
      :manner (u / uniform)
      :location (c / culture-01
            :source (i / individual
                  :ARG1-of (d / differ-02))))

# ::id pmid_1627_1139.179 ::date 2015-08-10T15:43:31 ::annotator SDL-AMR-09 ::preferred
# ::snt IL-6 response, although quite variable among individuals, was consistently below that of OSM.
# ::save-date Mon Feb 1, 2016 ::file pmid_1627_1139_179.txt
(h / have-concession-91
      :ARG1 (r / respond-01
            :ARG0 (p / protein :name (n / name :op1 "IL-6"))
            :ARG1-of (e / equal-01
                  :ARG2 (b / below
                        :op1 (r2 / respond-01
                              :ARG0 (p2 / protein :name (n2 / name :op1 "OSM")))
                        :manner (c / consistent-02))))
      :ARG2 (v / vary-01
            :ARG1 r
            :location (i / individual)
            :degree (q / quite)))

# ::id pmid_1627_1139.180 ::date 2015-08-10T15:49:14 ::annotator SDL-AMR-09 ::preferred
# ::snt The level of activated ERK was 37 ± 18% of OSM (Fig. <xref ref-type="fig" rid="F4">4A</xref> &<xref ref-type="fig" rid="F4">4B</xref>) and activated STAT3 was 63 ± + 27% (Fig. <xref ref-type="fig" rid="F4">4C</xref> &<xref ref-type="fig" rid="F4">4D</xref>).
# ::save-date Sat Jan 16, 2016 ::file pmid_1627_1139_180.txt
(a / and
      :op1 (l / level
            :quant-of (e / enzyme :name (n / name :op1 "ERK")
                  :ARG1-of (a2 / activate-01)
                  :ARG1-of (e2 / equal-01
                        :ARG2 (v / value-interval
                              :op1 (p / product-of
                                    :op1 (p2 / percentage-entity :value 37
                                          :ARG2-of (a3 / add-02
                                                :ARG1 (p3 / percentage-entity :value 18)))
                                    :op2 (p4 / protein :name (n3 / name :op1 "OSM")))
                              :op2 (p6 / product-of
                                    :op1 (p7 / percentage-entity :value 37
                                          :ARG2-of (s / subtract-01
                                                :ARG1 p3))
                                    :op2 p4))))
            :ARG1-of (d / describe-01
                  :ARG0 (a4 / and
                        :op1 (f / figure :mod "4A")
                        :op2 (f2 / figure :mod "4B"))))
      :op2 (p5 / protein :name (n2 / name :op1 "STAT3")
            :ARG1-of a2
            :ARG1-of (d2 / describe-01
                  :ARG0 (a6 / and
                        :op1 (f3 / figure :mod "4C")
                        :op2 (f4 / figure :mod "4D")))
            :ARG1-of (e3 / equal-01
                  :ARG2 (v2 / value-interval
                        :op1 (p10 / product-of
                              :op1 (p8 / percentage-entity :value 63
                                    :ARG2-of (a5 / add-02
                                          :ARG1 (p9 / percentage-entity :value 27)))
                              :op2 p4)
                        :op2 (p11 / product-of
                              :op1 (p12 / percentage-entity :value 63
                                    :ARG2-of (s2 / subtract-01
                                          :ARG1 p9))
                              :op2 p4)))))

# ::id pmid_1627_1139.181 ::date 2015-08-10T22:24:02 ::annotator SDL-AMR-09 ::preferred
# ::snt The two-fold lower activation of ERK relative to STAT3 by IL-6 is due to the difference in signaling by the IL-6 and OSM receptor [<xref ref-type="bibr" rid="B16">16</xref>,<xref ref-type="bibr" rid="B22">22</xref>].
# ::save-date Sat Jan 16, 2016 ::file pmid_1627_1139_181.txt
(c / cause-01
      :ARG0 (d / differ-02
            :ARG1 (s / signal-07
                  :ARG0 (r2 / receptor
                        :mod p))
            :ARG2 (s2 / signal-07
                  :ARG0 (r3 / receptor
                        :mod (p4 / protein :name (n4 / name :op1 "OSM")))))
      :ARG1 (a / activate-01
            :ARG0 (p / protein :name (n2 / name :op1 "IL-6"))
            :ARG1 (e / enzyme :name (n / name :op1 "ERK"))
            :ARG1-of (l / low-04
                  :degree (m / more)
                  :ARG2-of (r / relative-05
                        :ARG3 (p2 / protein :name (n3 / name :op1 "STAT3"))))
            :degree (p3 / product-of :op1 2))
      :ARG1-of (d2 / describe-01
            :ARG0 (p5 / publication
                  :ARG1-of (c2 / cite-01
                        :ARG2 (a2 / and :op1 16 :op2 22)))))

# ::id pmid_1627_1139.182 ::date 2015-08-10T22:37:47 ::annotator SDL-AMR-09 ::preferred
# ::snt LIF did not elicit a measurable ERK and STAT3 signaling in any of normal epithelial cell culture.
# ::save-date Sat Jan 16, 2016 ::file pmid_1627_1139_182.txt
(e / elicit-01 :polarity -
      :ARG0 (p / protein :name (n / name :op1 "LIF"))
      :ARG1 (s / signal-07
            :ARG0 (a / and
                  :op1 (e2 / enzyme :name (n2 / name :op1 "ERK"))
                  :op2 (p3 / protein :name (n3 / name :op1 "STAT3")))
            :ARG1-of (m / measure-01
                  :ARG1-of (p2 / possible-01)))
      :location (c / culture-01
            :ARG1 (c2 / cell
                  :mod (e3 / epithelium)
                  :ARG1-of (n4 / normal-02)
                  :mod (a2 / any))))

# ::id pmid_1627_1139.183 ::date 2015-08-10T22:44:35 ::annotator SDL-AMR-09 ::preferred
# ::snt EGF activated ERK to 90 ± 29% of OSM level (Fig. <xref ref-type="fig" rid="F4">4A</xref> &<xref ref-type="fig" rid="F4">4B</xref>).
# ::save-date Sat Jan 16, 2016 ::file pmid_1627_1139_183.txt
(a / activate-01
      :ARG0 (p / protein :name (n / name :op1 "EGF"))
      :ARG1 (e / enzyme :name (n2 / name :op1 "ERK")
            :ARG1-of (e2 / equal-01
                  :ARG2 (v / value-interval
                        :op1 (p2 / product-of
                              :op1 (p3 / percentage-entity :value 90
                                    :ARG2-of (a3 / add-02
                                          :ARG1 (p4 / percentage-entity :value 29)))
                              :op2 (l / level
                                    :quant-of (p5 / protein :name (n3 / name :op1 "OSM"))))
                        :op2 (p6 / product-of
                              :op1 (p7 / percentage-entity :value 90
                                    :ARG2-of (s / subtract-01
                                          :ARG1 p4))
                              :op2 l))))
      :ARG1-of (d / describe-01
            :ARG0 (a2 / and
                  :op1 (f / figure :mod "4A")
                  :op2 (f2 / figure :mod "4B"))))

# ::id pmid_1627_1139.184 ::date 2015-08-11T21:30:12 ::annotator SDL-AMR-09 ::preferred
# ::snt EGF generally had no measurable effect on STAT3 even when the cells were treated with EGF for longer than 15 minutes (not shown).
# ::save-date Mon Aug 17, 2015 ::file pmid_1627_1139_184.txt
(a / affect-01 :polarity -
      :ARG0 (p / protein :name (n / name :op1 "EGF"))
      :ARG1 (p2 / protein :name (n2 / name :op1 "STAT3"))
      :ARG1-of (m / measure-01
            :ARG1-of (p3 / possible-01))
      :ARG1-of (g / general-02)
      :concession (e / even-when
            :op1 (t / treat-04
                  :ARG1 (c / cell)
                  :ARG2 p
                  :duration (m2 / more-than
                        :op1 (t2 / temporal-quantity :quant 15
                              :unit (m3 / minute)))))
      :ARG1-of (s / show-01 :polarity -))

# ::id pmid_1627_1139.185 ::date 2015-08-11T21:50:18 ::annotator SDL-AMR-09 ::preferred
# ::snt In all cases, IFNγ did not appreciably activate ERK and STAT3, but yielded highest level of STAT1 phosphorylation (2441 ± 2073% of OSM level (Fig. <xref ref-type="fig" rid="F4">4E</xref> &<xref ref-type="fig" rid="F4">4F</xref>).
# ::save-date Sat Jan 30, 2016 ::file pmid_1627_1139_185.txt
(c / contrast-01
      :ARG1 (a / activate-01 :polarity -
            :ARG0 (p / protein :name (n / name :op1 "IFNγ"))
            :ARG1 (a2 / and
                  :op1 (e / enzyme :name (n2 / name :op1 "ERK"))
                  :op2 (p2 / protein :name (n3 / name :op1 "STAT3")))
            :degree (a3 / appreciate-03
                  :ARG1-of (p3 / possible-01)))
      :ARG2 (y / yield-01
            :ARG0 p
            :ARG1 (l / level
                  :ARG1-of (h / high-02
                        :degree (m / most))
                  :degree-of (p4 / phosphorylate-01
                        :ARG1 (p5 / protein :name (n4 / name :op1 "STAT1")))
                  :ARG1-of (e2 / equal-01
                        :ARG2 (v / value-interval
                              :op1 (p6 / product-of
                                    :op1 (p7 / percentage-entity :value 2441
                                          :ARG2-of (a4 / add-02
                                                :ARG1 (p8 / percentage-entity :value 2073)))
                                    :op2 (l2 / level
                                          :quant-of (p9 / protein :name (n5 / name :op1 "OSM"))))
                              :op2 (p10 / product-of
                                    :op1 (p11 / percentage-entity :value 2441
                                          :ARG2-of (s / subtract-01
                                                :ARG1 p8))
                                    :op2 l2)))))
      :ARG1-of (d / describe-01
            :ARG0 (a5 / and
                  :op1 (f / figure :mod "4E")
                  :op2 (f2 / figure :mod "4F")))
      :mod (c2 / case-04
            :mod (a6 / all)))

# ::id pmid_1627_1139.186 ::date 2015-08-11T22:09:11 ::annotator SDL-AMR-09 ::preferred
# ::snt The IFNγ response from patient to patient showed the highest variability among the cytokine responses, even though paired cultures from individual patients exhibited highly consistent levels of STAT1 activation by IFNγ.
# ::save-date Mon Feb 1, 2016 ::file pmid_1627_1139_186.txt
(s / show-01
      :ARG0 (r / respond-01
            :ARG0 (p / protein :name (n / name :op1 "IFNγ"))
            :source (p7 / person
                  :ARG0-of (h5 / have-org-role-91
                        :ARG2 (p5 / patient))))
      :ARG1 (h / high-02
            :ARG1 (v / vary-01
                  :ARG1 (r2 / respond-01
                        :ARG0 p
                        :ARG1-of (i / include-91
                              :ARG2 (r3 / respond-01
                                    :ARG1 (c3 / cytokine)))))
            :degree (m / most))
      :concession (e / exhibit-01
                  :ARG0 (c / culture-01
                        :ARG1-of (p3 / pair-01)
                        :source (p4 / person
                              :mod (i2 / individual)
                              :ARG0-of h5))
                  :ARG1 (l / level
                        :degree-of (a / activate-01
                              :ARG0 p
                              :ARG1 (p6 / protein :name (n3 / name :op1 "STAT1")))
                        :ARG1-of (c2 / consistent-02
                              :ARG1-of (h4 / high-02)))))

# ::id pmid_1627_1139.187 ::date 2015-08-11T22:27:25 ::annotator SDL-AMR-09 ::preferred
# ::snt The reproducibility of detecting comparable patterns in independently derived cell cultures was assessed in those paired cultures in which the samples were initially classified as "abnormal" (or "suspicious") by autofluorescence bronchoscopy but proved normal by subsequent pathological analysis (Fig. <xref ref-type="fig" rid="F4">4A,C</xref> &<xref ref-type="fig" rid="F4">4E</xref>).
# ::save-date Wed Dec 30, 2015 ::file pmid_1627_1139_187.txt
(a / assess-01
      :ARG1 (r / reproduce-01
            :ARG0 (d / detect-01
                  :ARG1 (p2 / pattern
                        :ARG1-of (c / comparable-03)))
            :ARG1-of (p / possible-01)
            :location (c2 / culture-01
                  :ARG1 (c3 / cell)
                  :ARG1-of (d2 / derive-01
                        :ARG1-of (d4 / depend-01 :polarity -))))
      :location (c4 / culture-01
            :ARG1-of (p3 / pair-01)
            :location-of (c5 / classify-01
                  :ARG0 (b / bronchoscopy
                        :mod (a3 / autofluorescence))
                  :ARG1 (t / thing
                        :ARG1-of (s / sample-01))
                  :ARG2 (o / or
                        :op1 (n / normal-02 :polarity -
                              :ARG1 c4)
                        :op2 (s2 / suspicious))
                  :ARG1-of (c6 / contrast-01
                        :ARG2 (p5 / prove-01
                              :ARG0 (a4 / analyze-01
                                    :mod (p6 / pathology)
                                    :mod (s3 / subsequent))
                              :ARG2 (n2 / normal-02
                                    :ARG1 c4)))
                  :time (i / initial))
            :mod (t2 / that))
      :ARG1-of (d3 / describe-01
            :ARG0 (a5 / and
                  :op1 (f / figure :mod "4A")
                  :op2 (f2 / figure :mod "4C")
                  :op3 (f3 / figure :mod "4E"))))

# ::id pmid_1627_1139.188 ::date 2015-08-12T10:40:38 ::annotator SDL-AMR-09 ::preferred
# ::snt When cell cultures were derived from histologically normal areas with abnormal fluorescence, the level and range of signaling reactions elicited by the treatments were essentially identical to those with normal histology and normal fluorescence.
# ::save-date Mon Aug 17, 2015 ::file pmid_1627_1139_188.txt
(h / have-condition-91
      :ARG1 (i / identical-01
            :ARG1 (a2 / and
                  :op1 (l / level
                        :degree-of (r2 / react-01
                              :ARG0 c
                              :ARG2 (s / signal-07)))
                  :op2 (r / range-01
                        :ARG1 r2)
                  :ARG1-of (e / elicit-01
                        :ARG0 (t / treat-04)))
            :ARG2 (c3 / culture-01
                  :ARG1 c2
                  :ARG0-of (h4 / have-03
                        :ARG1 (a3 / and
                              :op1 (h5 / histology
                                    :ARG1-of (n / normal-02))
                              :op2 (f2 / fluorescence
                                    :ARG1-of n))))
            :mod (e2 / essential))
      :ARG2 (d / derive-01
            :ARG1 (c / culture-01
                  :ARG1 (c2 / cell))
            :ARG2 (a / area
                  :ARG0-of (h3 / have-03
                        :ARG1 (f / fluorescence
                              :ARG1-of (n2 / normal-02 :polarity -)))
                  :poss h5)))

# ::id pmid_1627_1139.189 ::date 2015-08-12T11:10:22 ::annotator SDL-AMR-09 ::preferred
# ::snt ERK activation by OSM was 108 ± 35%, by IL-6 was 31 ± 15%, and by EGF was 85 ± 40%.
# ::save-date Sat Jan 16, 2016 ::file pmid_1627_1139_189.txt
(a / and
      :op1 (a2 / activate-01
            :ARG0 (p / protein :name (n / name :op1 "OSM"))
            :ARG1 (e / enzyme :name (n2 / name :op1 "ERK"))
            :ARG1-of (e2 / equal-01
                  :ARG2 (v3 / value-interval
                        :op1 (p2 / percentage-entity :value 108
                              :ARG2-of (a4 / add-02
                                    :ARG1 (p3 / percentage-entity :value 35)))
                        :op2 (p4 / percentage-entity :value 108
                              :ARG2-of (s / subtract-01
                                    :ARG1 p3)))))
      :op2 (a3 / activate-01
            :ARG0 (p5 / protein :name (n3 / name :op1 "IL-6"))
            :ARG1 p
            :ARG1-of (e3 / equal-01
                  :ARG2 (v2 / value-interval
                        :op1 (p6 / percentage-entity :value 31
                              :ARG2-of (a5 / add-02
                                    :ARG1 (p7 / percentage-entity :value 15)))
                        :op2 (p8 / percentage-entity
                              :ARG2-of (s2 / subtract-01
                                    :ARG1 p7)))))
      :op3 (a6 / activate-01
            :ARG0 (p9 / protein :name (n4 / name :op1 "EGF"))
            :ARG1 p
            :ARG1-of (e4 / equal-01
                  :ARG2 (v / value-interval
                        :op1 (p10 / percentage-entity :value 85
                              :ARG2-of (a7 / add-02
                                    :ARG1 (p11 / percentage-entity :value 40)))
                        :op2 (p12 / percentage-entity :value 85
                              :ARG2-of (s3 / subtract-01
                                    :ARG1 p11))))))

# ::id pmid_1627_1139.190 ::date 2015-08-12T11:26:55 ::annotator SDL-AMR-09 ::preferred
# ::snt STAT3 activation by OSM was 97 ± 31% and by IL-6 was 63 ± 27%.
# ::save-date Mon Aug 17, 2015 ::file pmid_1627_1139_190.txt
(a / and
      :op1 (a2 / activate-01
            :ARG0 (p / protein :name (n / name :op1 "OSM"))
            :ARG1 (p2 / protein :name (n2 / name :op1 "STAT3"))
            :ARG1-of (e / equal-01
                  :ARG2 (v / value-interval
                        :op1 (p3 / percentage-entity :value 97
                              :ARG2-of (a3 / add-02
                                    :ARG1 (p4 / percentage-entity :value 31)))
                        :op2 (p5 / percentage-entity :value 97
                              :ARG2-of (s / subtract-01
                                    :ARG1 p4)))))
      :op2 (a4 / activate-01
            :ARG0 (p6 / protein :name (n3 / name :op1 "IL-6"))
            :ARG1 p2
            :ARG1-of (e2 / equal-01
                  :ARG2 (v2 / value-interval
                        :op1 (p7 / percentage-entity :value 63
                              :ARG2-of (a5 / add-02
                                    :ARG1 (p8 / percentage-entity :value 27)))
                        :op2 (p9 / percentage-entity :value 63
                              :ARG2-of (s2 / subtract-01
                                    :ARG1 p8))))))

# ::id pmid_1627_1139.191 ::date 2015-08-12T11:35:53 ::annotator SDL-AMR-09 ::preferred
# ::snt The cytokine-induced activation of ERK and STAT3 in paired cultures indicated highly consistent response patterns (Fig. <xref ref-type="fig" rid="F4">4G</xref> and <xref ref-type="fig" rid="F4">4H</xref>, left side panels).
# ::save-date Mon Feb 1, 2016 ::file pmid_1627_1139_191.txt
(i / indicate-01
      :ARG0 (a / activate-01
            :ARG1 (a2 / and
                  :op1 (e / enzyme :name (n / name :op1 "ERK"))
                  :op2 (p / protein :name (n2 / name :op1 "STAT3")))
            :ARG2-of (i2 / induce-01
                  :ARG0 (c3 / cytokine))
            :location (c / culture
                  :ARG1-of (p3 / pair-01)))
      :ARG1 (p4 / pattern-01
            :ARG1 (r / respond-01)
            :ARG1-of (c2 / consistent-02
                  :ARG1-of (h / high-02)))
      :ARG1-of (d / describe-01
            :ARG0 (a3 / and
                  :op1 (f / figure :mod "4G")
                  :op2 (f2 / figure :mod "4H")
                  :location (p5 / panel
                        :location (s / side
                              :ARG1-of (l / left-20))))))

# ::id pmid_1627_1139.192 ::date 2015-08-12T11:59:30 ::annotator SDL-AMR-09 ::preferred
# ::snt Confirmed premalignant epithelial cells (metaplasia, dysplasia and carcinoma) exhibited two recurring aberrant phenotypes when compared with normal cells.
# ::save-date Mon Aug 17, 2015 ::file pmid_1627_1139_192.txt
(e / exhibit-01
      :ARG0 (c / cell
            :mod (e2 / epithelium)
            :mod (p / premalignant)
            :ARG1-of (c2 / confirm-01)
            :ARG1-of (m2 / mean-01
                  :ARG2 (a / and
                        :op1 (m / metaplasia)
                        :op2 (d / dysplasia)
                        :op3 (c3 / carcinoma))))
      :ARG1 (p2 / phenotype :quant 2
            :ARG0-of (r / recur-01)
            :mod (a2 / aberrant))
      :condition (c4 / compare-01
                  :ARG1 c
                  :ARG2 (c5 / cell
                        :ARG1-of (n / normal-02))))

# ::id pmid_1627_1139.193 ::date 2015-08-12T12:16:54 ::annotator SDL-AMR-09 ::preferred
# ::snt The first aberrancy was the elevated basal or cytokine-stimulated level of phosphorylated ERK (Fig. <xref ref-type="fig" rid="F4">4B</xref> and <xref ref-type="fig" rid="F4">4G</xref>, right panel) and the second was the reactivation of LIFR function (Fig. <xref ref-type="fig" rid="F4">4D</xref> and <xref ref-type="fig" rid="F4">4H</xref>, right panel).
# ::save-date Sat Jan 16, 2016 ::file pmid_1627_1139_193.txt
(a / and
      :op1 (a2 / aberrancy
            :ord (o / ordinal-entity :value 1)
            :domain (o2 / or
                  :op1 (l / level
                        :quant-of (e / enzyme :name (n / name :op1 "ERK")
                              :ARG3-of (p / phosphorylate-01))
                        :ARG1-of (e2 / elevate-01)
                        :mod (b / basal))
                  :op2 (l2 / level
                        :ARG1-of (s / stimulate-01
                              :ARG0 (c / cytokine))
                        :quant-of e
                        :ARG1-of e2))
            :ARG1-of (d / describe-01
                  :ARG0 (a3 / and
                        :op1 (f / figure :mod "4B")
                        :op2 (f2 / figure :mod "4G")
                        :location (p3 / panel
                              :ARG1-of (r / right-04)))))
      :op2 (a4 / aberrancy
            :ord (o3 / ordinal-entity :value 2)
            :domain (r2 / reactivate-01
                  :ARG1 (f3 / function-01
                        :ARG0 (p4 / protein :name (n3 / name :op1 "LIFR"))))
            :ARG1-of (d2 / describe-01
                  :ARG0 (a5 / and
                        :op1 (f4 / figure :mod "4D")
                        :op2 (f5 / figure :mod "4H")
                        :location p3))))

# ::id pmid_1627_1139.194 ::date 2015-08-12T12:43:16 ::annotator SDL-AMR-09 ::preferred
# ::snt In the 23 preneoplastic cell cultures, the basal level of phosphorylated ERK was increased to 22 ± 27% of the OSM value (p = 0.07).
# ::save-date Sat Jan 16, 2016 ::file pmid_1627_1139_194.txt
(i / increase-01
      :ARG1 (l / level
            :mod (b / basal)
            :quant-of (e / enzyme :name (n / name :op1 "ERK")
                  :ARG3-of (p / phosphorylate-01)))
      :ARG4 (v2 / value-interval
            :op1 (p2 / product-of
                  :op1 (p3 / percentage-entity :value 22
                        :ARG2-of (a / add-02
                              :ARG1 (p4 / percentage-entity :value 27)))
                  :op2 (v / value
                        :quant-of (p5 / protein :name (n2 / name :op1 "OSM"))))
            :op2 (p8 / product-of
                  :op1 (p9 / percentage-entity :value 22
                        :ARG2-of (s / subtract-01
                              :ARG1 p4))
                  :op2 v))
      :location (c / culture-01 :quant 23
            :ARG1 (c2 / cell)
            :mod (p7 / preneoplastic))
      :ARG1-of (s2 / statistical-test-91
            :ARG2 0.07))

# ::id pmid_1627_1139.195 ::date 2015-08-12T12:57:23 ::annotator SDL-AMR-09 ::preferred
# ::snt Based on two-sample Kolmogorov-Smirnov test, two cases that were cultured from metaplastic foci were above the 95% confidence interval.
# ::save-date Sat Jan 30, 2016 ::file pmid_1627_1139_195.txt
(a / above
      :op1 (p / percentage-entity :value 95
            :quant-of (i / interval
                  :mod (c / confidence)))
      :domain (c2 / case-04 :quant 2
            :ARG1-of (c3 / culture-01
                  :source (f / focus
                        :mod (m / metaplastic))))
      :ARG1-of (b / base-02
            :ARG2 (t / test
                  :mod (t2 / thing :quant 2
                        :ARG1-of (s / sample-01))
                  :mod (t3 / thing :name (n / name :op1 "Kolmogorov-Smirnov")))))

# ::id pmid_1627_1139.196 ::date 2015-08-12T13:15:45 ::annotator SDL-AMR-09 ::preferred
# ::snt Preneoplastic cells showed also an overall trend of increased ERK signaling when treated with OSM (133 ± 66%; p = 0.17) or IL-6 (53 ± 38%; p = 0.01) but not with EGF (85 ± 67%; p = 0.46).
# ::save-date Sat Jan 16, 2016 ::file pmid_1627_1139_196.txt
(s / show-01
      :ARG0 (c / cell
            :mod (p / preneoplastic))
      :ARG1 (t / trend-01
            :ARG1 (o4 / or
                  :op1 (i / increase-01
                        :ARG1 (s2 / signal-07
                              :ARG0 (e / enzyme :name (n5 / name :op1 "ERK")))
                        :ARG2 (v3 / value-interval
                              :op1 (p3 / percentage-entity :value 133
                                    :ARG2-of (a2 / add-02
                                          :ARG1 (p4 / percentage-entity :value 66)))
                              :op2 (p5 / percentage-entity :value 133
                                    :ARG2-of (s3 / subtract-01
                                          :ARG1 p4)))
                        :condition (t2 / treat-04
                                    :ARG1 c
                                    :ARG2 (p2 / protein :name (n2 / name :op1 "OSM")))
                        :ARG1-of (s6 / statistical-test-91
                              :ARG2 0.17))
                  :op2 (i2 / increase-01
                        :ARG1 s2
                        :ARG2 (v / value-interval
                              :op1 (p6 / percentage-entity :value 53
                                    :ARG2-of (a / add-02
                                          :ARG1 (p7 / percentage-entity :value 38)))
                              :op2 (p8 / percentage-entity :value 53
                                    :ARG2-of (s4 / subtract-01
                                          :ARG1 p7)))
                        :condition (t3 / treat-04
                                    :ARG1 c
                                    :ARG2 (p9 / protein :name (n3 / name :op1 "IL-6")))
                        :ARG1-of (s7 / statistical-test-91
                              :ARG2 0.01))
                  :ARG1-of (c2 / contrast-01
                        :ARG2 (i3 / increase-01
                              :ARG1 s2
                              :ARG2 (v2 / value-interval
                                    :op1 (p13 / percentage-entity :value 85
                                          :ARG2-of (a3 / add-02
                                                :ARG1 (p14 / percentage-entity :value 67)))
                                    :op2 (p15 / percentage-entity :value 85
                                          :ARG2-of (s5 / subtract-01
                                                :ARG1 p14)))
                              :condition (t4 / treat-04
                                    :ARG1 c
                                    :ARG2 (p12 / protein :name (n4 / name :op1 "EGF")
                                          :ARG1-of (e4 / equal-01)))
                              :ARG1-of (s8 / statistical-test-91
                                    :ARG2 0.46)))))
      :mod (o / overall)
      :mod (a4 / also))

# ::id pmid_1627_1139.197 ::date 2015-08-12T13:54:15 ::annotator SDL-AMR-09 ::preferred
# ::snt The ERK signaling by IL-6 and EGF included several cases that lie outside of the 95% confidence interval.
# ::save-date Sat Jan 30, 2016 ::file pmid_1627_1139_197.txt
(i / include-01
      :ARG1 (c / case-04
            :quant (s2 / several)
            :ARG1-of (l / lie-07
                  :ARG2 (o / outside
                        :op1 (p3 / percentage-entity :value 95
                              :quant-of (i2 / interval
                                    :mod (c2 / confidence))))))
      :ARG2 (s / signal-07
            :ARG0 (a / and
                  :op1 (p / protein :name (n / name :op1 "IL-6"))
                  :op2 (p2 / protein :name (n2 / name :op1 "EGF")))
            :ARG1 (e / enzyme :name (n3 / name :op1 "ERK"))))

# ::id pmid_1627_1139.198 ::date 2015-08-12T14:01:44 ::annotator SDL-AMR-09 ::preferred
# ::snt For the IL-6 response, 3/23 cases were above and 5/23 cases below the 95% confidence interval, and for EGF response, 4/23 cases were above and 3/23 cases below.
# ::save-date Sat Jan 30, 2016 ::file pmid_1627_1139_198.txt
(a / and
      :op1 (r / respond-01
            :ARG0 (p / protein :name (n / name :op1 "IL-6"))
            :ARG2 (a2 / above
                  :op1 (p2 / percentage-entity :value 95
                        :quant-of (i / interval
                              :mod (c / confidence))))
            :location (c2 / case-04 :quant 3
                  :ARG1-of (i2 / include-91
                        :ARG2 (c3 / case-04 :quant 23))))
      :op2 (r2 / respond-01
            :ARG0 p
            :ARG2 (b / below
                  :op1 p2)
            :location (c4 / case-04 :quant 5
                  :ARG1-of i2))
      :op3 (r3 / respond-01
            :ARG0 (p3 / protein :name (n2 / name :op1 "EGF"))
            :ARG2 a2
            :location (c5 / case-04 :quant 4
                  :ARG1-of i2))
      :op4 (r4 / respond-01
            :ARG0 p3
            :ARG2 b
            :location c2))

# ::id pmid_1627_1139.199 ::date 2015-08-12T14:21:44 ::annotator SDL-AMR-09 ::preferred
# ::snt STAT3 phosphorylation by OSM and IL-6, and STAT1 phosphorylation by OSM, IL-6 and IFNγ did not show significant differences among the cases tested (Fig. <xref ref-type="fig" rid="F4">4C–F</xref>), in contrast to ERK phosphorylation.
# ::save-date Sat Jan 30, 2016 ::file pmid_1627_1139_199.txt
(s / show-01 :polarity -
      :ARG0 (a / and
            :op1 (p / phosphorylate-01
                  :ARG1 (p2 / protein :name (n / name :op1 "STAT3"))
                  :ARG2 (a2 / and
                        :op1 (p3 / protein :name (n2 / name :op1 "OSM"))
                        :op3 (p4 / protein :name (n3 / name :op1 "IL-6"))))
            :op2 (p5 / phosphorylate-01
                  :ARG1 (p6 / protein :name (n4 / name :op1 "STAT1"))
                  :ARG2 (a3 / and
                        :op1 p3
                        :op2 p4
                        :op3 (p7 / protein :name (n5 / name :op1 "IFNγ"))))
            :ARG1-of (c2 / contrast-01
                  :ARG2 (p8 / phosphorylate-01
                        :ARG1 (e / enzyme :name (n6 / name :op1 "ERK")))))
      :ARG1 (d / differ-01
            :ARG1-of (s2 / significant-02))
      :location (c / case-04
            :ARG1-of (t / test-01)
            :ARG1-of (d2 / describe-01
                  :ARG0 (a4 / and
                        :op1 (f / figure :mod "4C")
                        :op2 (f2 / figure :mod "4D")
                        :op3 (f3 / figure :mod "4E")
                        :op4 (f4 / figure :mod "4F")))))

# ::id pmid_1627_1139.200 ::date 2015-08-12T14:34:20 ::annotator SDL-AMR-09 ::preferred
# ::snt Among the abnormal epithelial cells with elevated basal ERK phosphorylation (Fig. <xref ref-type="fig" rid="F4">4B</xref>), the two cell cultures from metaplastic foci in the airway were distinct because the basal ERK phosphorylation that was equivalent to the OSM-treated control culture (Fig. <xref ref-type="fig" rid="F5">5A</xref>).
# ::save-date Sat Jan 16, 2016 ::file pmid_1627_1139_200.txt
(i / include-91
      :ARG1 (c2 / culture-01 :quant 2
            :ARG1 (c3 / cell)
            :source (f2 / focus
                  :mod (m / metaplastic))
            :location (a / airway)
            :mod (d3 / distinct
                  :ARG0-of (c4 / cause-01
                        :ARG1 (e4 / equal-01
                              :ARG1 (p2 / phosphorylate-01
                                    :ARG1 e2
                                    :mod b)
                              :ARG2 (c5 / culture
                                    :mod (c6 / control)
                                    :ARG1-of (t / treat-04
                                          :ARG2 (p3 / protein :name (n3 / name :op1 "OSM")))))))
            :ARG1-of (d4 / describe-01
                  :ARG0 (f3 / figure :mod "5A")))
      :ARG2 (c / cell
            :mod (e / epithelium)
            :ARG1-of (n / normal-02 :polarity -)
            :ARG0-of (h / have-03
                  :ARG1 (p / phosphorylate-01
                        :ARG1 (e2 / enzyme :name (n2 / name :op1 "ERK"))
                        :ARG1-of (e3 / elevate-01)
                        :mod (b / basal)))
            :ARG1-of (d / describe-01
                  :ARG0 (f / figure :mod "4B"))))

# ::id pmid_1627_1139.201 ::date 2015-08-12T14:54:06 ::annotator SDL-AMR-09 ::preferred
# ::snt The increased phosphorylation of ERK, but not of STATs in these metaplastic cells was similar to the regulatory phenotype of NCI H23 tumor cell line (Fig. <xref ref-type="fig" rid="F1">1A</xref>).
# ::save-date Sat Jan 16, 2016 ::file pmid_1627_1139_201.txt
(r / resemble-01
      :ARG1 (p / phosphorylate-01
            :ARG1 (e / enzyme :name (n / name :op1 "ERK"))
            :ARG1-of (i / increase-01)
            :location (c / cell
                  :mod (m / metaplastic)
                  :mod (t2 / this))
            :ARG1-of (c3 / contrast-01
                  :ARG2 (p3 / phosphorylate-01
                        :ARG1 (p4 / protein :name (n3 / name :op1 "STAT")))))
      :ARG2 (p2 / phenotype
            :poss (c2 / cell-line :name (n2 / name :op1 "NCI" :op2 "H23")
                  :mod (t / tumor))
            :ARG0-of (r2 / regulate-01))
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod "1A")))

# ::id pmid_1627_1139.202 ::date 2015-08-12T15:08:56 ::annotator SDL-AMR-09 ::preferred
# ::snt Due to the elevated ERK phosphorylation, the response to EGF was obscured, even though a normal or even enhanced level of EGFR could be demonstrated (Fig. <xref ref-type="fig" rid="F5">5B</xref>).
# ::save-date Sat Jan 16, 2016 ::file pmid_1627_1139_202.txt
(o / obscure-02
      :ARG1 (r / respond-01
            :ARG1 (p / protein :name (n / name :op1 "EGF")))
      :ARG1-of (c / cause-01
            :ARG0 (e / elevate-01
                  :ARG1 (p2 / phosphorylate-01
                        :ARG1 (e2 / enzyme :name (n2 / name :op1 "ERK")))))
      :concession (p3 / possible-01
                  :ARG1 (d / demonstrate-01
                        :ARG1 (o2 / or
                              :op1 (l / level
                                    :quant-of (e3 / enzyme :name (n3 / name :op1 "EGFR"))
                                    :ARG1-of (n4 / normal-02))
                              :op2 (l2 / level
                                    :quant-of e3
                                    :ARG1-of (e4 / enhance-01
                                          :mod (e5 / even))))))
      :ARG1-of (d2 / describe-01
            :ARG0 (f / figure :mod "5B")))

# ::id pmid_1627_1139.203 ::date 2015-08-12T15:23:26 ::annotator SDL-AMR-09 ::preferred
# ::snt The high basal level phosphorylation of ERK was abrogated by treatment with U0126, an inhibitor for MEK1 (Fig. <xref ref-type="fig" rid="F5">5C</xref>), suggesting a constitutive activation of the MAPK pathway upstream of ERK in these metaplastic cells.
# ::save-date Sat Jan 16, 2016 ::file pmid_1627_1139_203.txt
(a / abrogate-01
      :ARG1 (l / level
            :degree-of (p / phosphorylate-01
                  :ARG1 (e / enzyme :name (n / name :op1 "ERK")))
            :mod (b / basal)
            :ARG1-of (h / high-02))
      :ARG2 (t / treat-04
            :ARG1 l
            :ARG2 (s / small-molecule :name (n2 / name :op1 "U0126")
                  :ARG1-of (m / mean-01
                        :ARG2 (s2 / small-molecule
                              :ARG0-of (i / inhibit-01
                                    :ARG1 (e2 / enzyme :name (n3 / name :op1 "MEK1")))))))
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod "5C"))
      :ARG0-of (s3 / suggest-01
            :ARG1 (a2 / activate-01
                  :ARG1 (p2 / pathway :name (n4 / name :op1 "MAPK"))
                  :mod (c / constitutive)
                  :location (u / upstream
                        :op1 e)
                  :location (c2 / cell
                        :mod (m2 / metaplastic)))))

# ::id pmid_1627_1139.204 ::date 2015-08-12T15:33:03 ::annotator SDL-AMR-09 ::preferred
# ::snt The pair-wise comparison also revealed that 5/23 of the abnormal cases (4 metaplasia and 1 carcinoma) had a LIF response detectable by the activation of ERK and STAT3 (Fig. <xref ref-type="fig" rid="F3">3</xref>, Fig. <xref ref-type="fig" rid="F4">4B,D,G</xref> and <xref ref-type="fig" rid="F4">4H</xref>).
# ::save-date Wed Mar 2, 2016 ::file pmid_1627_1139_204.txt
(r / reveal-01
      :ARG0 (c / compare-01
            :mod (p / pairwise))
      :ARG1 (h / have-03
            :ARG0 (c2 / case-04 :quant 5
                  :ARG1-of (i / include-91
                        :ARG2 (c3 / case-04 :quant 23
                              :ARG1-of (n4 / normal-02 :polarity -)))
                  :ARG1-of (m / mean-01
                        :ARG2 (a4 / and
                              :op1 (m2 / metaplasia :quant 4)
                              :op2 (c4 / carcinoma :quant 1))))
            :ARG1 (r2 / respond-01
                  :ARG0 (p2 / protein :name (n / name :op1 "LIF"))))
      :mod (a / also)
      :ARG1-of (d / detect-01
            :ARG2 (a2 / activate-01
                  :ARG1 (a3 / and
                        :op1 (e / enzyme :name (n2 / name :op1 "ERK"))
                        :op2 (p4 / protein :name (n3 / name :op1 "STAT3"))))
            :ARG1-of (p3 / possible-01))
      :ARG1-of (d2 / describe-01
            :ARG0 (a5 / and
                  :op1 (f / figure :mod 3)
                  :op2 (f2 / figure :mod "4B")
                  :op3 (f3 / figure :mod "4D")
                  :op4 (f4 / figure :mod "4G")
                  :op5 (f5 / figure :mod "4H"))))

# ::id pmid_1627_1139.205 ::date 2015-08-18T06:49:36 ::annotator SDL-AMR-09 ::preferred
# ::snt Three cases (2 metaplasia and 1 carcinoma) produced a signaling that lied outside of the 95% confidence interval.
# ::save-date Sat Jan 30, 2016 ::file pmid_1627_1139_205.txt
(p / produce-01
      :ARG0 (c / case-04 :quant 3
            :ARG1-of (m / mean-01
                  :ARG2 (a / and
                        :op1 (m2 / metaplasia :quant 2)
                        :op2 (m3 / medical-condition :name (n / name :op1 "carcinoma")))))
      :ARG1 (s / signal-07
            :ARG1-of (l / lay-01
                  :ARG2 (o / outside
                        :op1 (i / interval
                              :mod (c2 / confidence)
                              :mod (p2 / percentage-entity :value 95))))))

# ::id pmid_1627_1139.206 ::date 2015-08-18T09:43:53 ::annotator SDL-AMR-09 ::preferred
# ::snt The carcinoma case also included a prominent reduction of IL-6 receptor function (Fig. <xref ref-type="fig" rid="F6">6</xref>), which resulted in an overall cytokine response pattern comparable to that of the NCI H125 tumor cell line (Fig. <xref ref-type="fig" rid="F1">1A</xref>).
# ::save-date Sat Jan 30, 2016 ::file pmid_1627_1139_206.txt
(i / include-01
      :ARG1 (r / reduce-01
            :ARG1 (f / function-01
                  :ARG0 (r2 / receptor :name (n2 / name :op1 "IL-6")))
            :mod (p / prominent)
            :ARG1-of (r3 / result-01
                  :ARG2 (p2 / pattern
                        :ARG1-of (r4 / respond-01
                              :ARG0 (c2 / cytokine)
                              :mod (o / overall))
                        :ARG1-of (c3 / comparable-03
                              :ARG2 (p3 / pattern
                                    :ARG1-of (r5 / respond-01
                                          :ARG0 (c4 / cell-line :name (n3 / name :op1 "NCI" :op2 "H125")
                                                :mod (t / tumor))))))
                  :ARG1-of (d3 / describe-01
                        :ARG0 (f3 / figure :mod "1A"))))
      :ARG2 (c / case-04
            :ARG1 (m / medical-condition :name (n / name :op1 "carcinoma")))
      :ARG1-of (d2 / describe-01
            :ARG0 (f2 / figure :mod 6))
      :mod (a / also))

# ::id pmid_1627_1139.207 ::date 2015-08-18T10:10:39 ::annotator SDL-AMR-09 ::preferred
# ::snt The changes in signaling reactions correlated with receptor expression.
# ::save-date Tue Aug 18, 2015 ::file pmid_1627_1139_207.txt
(c / correlate-01
      :ARG1 (c2 / change-01
            :ARG1 (r / react-01
                  :ARG1 (s / signal-07)))
      :ARG2 (e / express-03
            :ARG2 (r2 / receptor)))

# ::id pmid_1627_1139.208 ::date 2015-08-18T10:16:50 ::annotator SDL-AMR-09 ::preferred
# ::snt The expression of LIFRα in normal cells was undetectable by immunoblotting whereas expression was observed in the 5 cultures of abnormal cells with LIF response.
# ::save-date Mon Aug 24, 2015 ::file pmid_1627_1139_208.txt
(c / contrast-01
      :ARG1 (d / detect-01
            :ARG1 (e / express-03
                  :ARG2 (p2 / protein :name (n / name :op1 "LIFRα"))
                  :ARG3 (c2 / cell
                        :ARG1-of (n3 / normal-02)))
            :ARG2 (i / immunoblot-01)
            :ARG1-of (p / possible-01 :polarity -))
      :ARG2 (o / observe-01
            :ARG1 (e2 / express-03
                  :ARG2 p2
                  :ARG3 (c3 / culture-01 :quant 5
                        :ARG1 (c4 / cell
                              :ARG1-of (n2 / normal-02 :polarity -)
                              :ARG0-of (r / respond-01
                                    :ARG1 (p3 / protein :name (n4 / name :op1 "LIF"))))))))

# ::id pmid_1627_1139.209 ::date 2015-08-18T10:37:15 ::annotator SDL-AMR-09 ::preferred
# ::snt The re-expression of LIFR in various cell types is controlled by an epigenetic process that depends on histone acetylation within CpG islands of the LIFR promoter region [<xref ref-type="bibr" rid="B22">22</xref>].
# ::save-date Mon Aug 24, 2015 ::file pmid_1627_1139_209.txt
(c / control-01
      :ARG1 (e / express-03
            :ARG2 (p / protein :name (n / name :op1 "LIFR"))
            :ARG3 (t / type
                  :mod (c2 / cell
                        :mod (v / various)))
            :mod (a / again))
      :ARG2 (p2 / process
            :mod (e2 / epigenetic)
            :ARG0-of (d / depend-01
                  :ARG1 (a2 / acetylate-01
                        :ARG1 (p3 / protein :name (n2 / name :op1 "histone"))
                        :location (i / island
                              :mod (d2 / dna-sequence :name (n3 / name :op1 "CpG"))
                              :location (r / region
                                          :ARG1-of (p4 / promote-01
                                                :ARG0 p))))))
      :ARG1-of (d3 / describe-01
            :ARG0 (p5 / publication
                  :ARG1-of (c3 / cite-01
                        :ARG2 22))))

# ::id pmid_1627_1139.210 ::date 2015-08-18T11:07:47 ::annotator SDL-AMR-09 ::preferred
# ::snt To determine whether altered protein acetylation could account for the switch in LIF responsiveness from normal to carcinoma cells, the normal epithelial cells were treated for 6 h with the histone deacetylase inhibitor FR901228.
# ::save-date Thu Dec 10, 2015 ::file pmid_1627_1139_210.txt
(t / treat-04
      :ARG1 (c / cell
            :source (e / epithelium)
            :ARG1-of (n / normal-02))
      :ARG2 (s2 / small-molecule :name (n2 / name :op1 "FR901228")
            :ARG0-of (i / inhibit-01
                  :ARG1 (p4 / protein :name (n4 / name :op1 "histone")
                        :ARG1-of (d3 / deacetylate-01))))
      :duration (t2 / temporal-quantity :quant 6
            :unit (h / hour))
      :purpose (d / determine-01
            :ARG1 (p2 / possible-01 :mode interrogative
                  :ARG1 (a4 / account-01
                        :ARG0 (a2 / acetylate-01
                              :ARG1 (p / protein
                                    :ARG1-of (a3 / alter-01)))
                        :ARG1 (s / switch-01
                              :ARG1 (r / responsive-02
                                    :ARG1 (p3 / protein :name (n3 / name :op1 "LIF")))
                              :ARG2 (c3 / cell
                                    :mod (m / medical-condition :name (n5 / name :op1 "carcinoma")))
                              :ARG3 (c2 / cell
                                    :ARG1-of n))))))

# ::id pmid_1627_1139.211 ::date 2015-08-18T11:17:24 ::annotator SDL-AMR-09 ::preferred
# ::snt The treatment induced the expression of LIFRα and established a LIF-dependent STAT3 and ERK signaling that was comparable to the level observed in the carcinoma cells (Fig. <xref ref-type="fig" rid="F6">6</xref>).
# ::save-date Sat Jan 16, 2016 ::file pmid_1627_1139_211.txt
(a / and
      :op1 (i / induce-01
            :ARG0 (t / treat-04)
            :ARG2 (e / express-03
                  :ARG2 (p / protein :name (n / name :op1 "LIFRα"))))
      :op2 (e2 / establish-01
            :ARG0 t
            :ARG1 (a2 / and
                  :op1 (s / signal-07
                        :ARG0 (p2 / protein :name (n3 / name :op1 "STAT3"))
                        :ARG0-of (d / depend-01
                              :ARG1 (p3 / protein :name (n4 / name :op1 "LIF"))))
                  :op2 (s2 / signal-07
                        :ARG0 (e3 / enzyme :name (n2 / name :op1 "ERK"))
                        :ARG0-of d)
                  :ARG1-of (c2 / comparable-03
                        :ARG2 (l / level
                              :ARG1-of (o / observe-01
                                    :location (c / cell
                                          :mod (m / medical-condition :name (n5 / name :op1 "carcinoma"))))))))
      :ARG1-of (d3 / describe-01
            :ARG0 (f / figure :mod 6)))

# ::id pmid_1627_1139.212 ::date 2015-08-18T12:36:25 ::annotator SDL-AMR-09 ::preferred
# ::snt A similar FR901228 treatment of the carcinoma cells further enhanced LIFR expression and LIF-dependent signaling (Fig. <xref ref-type="fig" rid="F6">6</xref>).
# ::save-date Thu Dec 10, 2015 ::file pmid_1627_1139_212.txt
(e / enhance-01
      :ARG1 (a / and
            :op1 (e2 / express-03
                  :ARG2 (p / protein :name (n3 / name :op1 "LIFR")))
            :op2 (s2 / signal-07
                  :ARG0-of (d2 / depend-01
                        :ARG1 (p2 / protein :name (n4 / name :op1 "LIF")))))
      :ARG2 (t / treat-04
            :ARG1 (c / cell
                  :mod (m / medical-condition :name (n2 / name :op1 "carcinoma")))
            :ARG2 (s / small-molecule :name (n / name :op1 "FR901228"))
            :ARG1-of (r / resemble-01))
      :mod (f / further)
      :ARG1-of (d3 / describe-01
            :ARG0 (f2 / figure :mod 6)))

# ::id pmid_1627_1139.213 ::date 2015-08-19T03:40:52 ::annotator SDL-AMR-09 ::preferred
# ::snt Interestingly, the same treatment reduced he expression of IL-6R in normal cells resulting in a response pattern as found in the corresponding carcinoma cells from the same patient (Fig. <xref ref-type="fig" rid="F6">6</xref>).
# ::save-date Thu Dec 10, 2015 ::file pmid_1627_1139_213.txt
(r / reduce-01
      :ARG0 (t / treat-04
            :ARG1-of (s / same-01))
      :ARG1 (e / express-03
            :ARG2 (p / protein :name (n / name :op1 "IL-6R"))
            :ARG3 (c / cell
                  :ARG1-of (n2 / normal-02)))
      :ARG1-of (r2 / result-01
            :ARG2 (p2 / pattern
                  :ARG1-of (r3 / respond-01)
                  :ARG1-of (r4 / resemble-01
                        :ARG2 (p3 / pattern
                              :ARG1-of (f / find-01
                                    :location (c2 / cell
                                          :mod (m / medical-condition :name (n3 / name :op1 "carcinoma"))
                                          :ARG2-of (c3 / correspond-02
                                                :ARG1 c)
                                          :source (p4 / person
                                                      :ARG0-of (h / have-rel-role-91
                                                            :ARG2 (p5 / patient))
                                                      :ARG1-of s)))))))
      :ARG1-of (d2 / describe-01
            :ARG0 (f2 / figure :mod 6))
      :ARG2-of (i2 / interest-01))

# ::id pmid_1627_1139.214 ::date 2015-08-19T08:34:57 ::annotator SDL-AMR-09 ::preferred
# ::snt <sec-title level="2">OSM and secreted macrophage factors attenuate proliferation of bronchial epithelial cells</sec-title>
# ::save-date Wed Aug 19, 2015 ::file pmid_1627_1139_214.txt
(a / attenuate-01
      :ARG0 (a2 / and
            :op1 (p / protein :name (n / name :op1 "OSM"))
            :op2 (f / factor
                  :mod (m / macrophage)
                  :ARG1-of (s / secrete-01)))
      :ARG1 (p2 / proliferate-01
            :ARG0 (c / cell
                  :source (e / epithelium)
                  :mod (b / bronchus))))

# ::id pmid_1627_1139.215 ::date 2015-08-19T10:33:45 ::annotator SDL-AMR-09 ::preferred
# ::snt DNA synthesis of the epithelial cells was inhibited by OSM and LPS conditioned medium from of activated macrophages in a dose-dependent fashion (Fig. <xref ref-type="fig" rid="F7">7</xref>).
# ::save-date Mon Aug 24, 2015 ::file pmid_1627_1139_215.txt
(i / inhibit-01
      :ARG0 (m / medium
            :ARG1-of (c2 / condition-01
                  :ARG2 (a / and
                        :op1 (p / protein :name (n / name :op1 "OSM"))
                        :op2 (m2 / molecular-physical-entity :name (n2 / name :op1 "LPS"))))
            :source (m3 / macrophage
                        :ARG1-of (a2 / activate-01)))
      :ARG1 (s / synthesize-01
            :ARG0 (n3 / nucleic-acid :wiki "DNA" :name (n4 / name :op1 "DNA"))
            :ARG1 (c / cell
                  :source (e / epithelium)))
      :manner (d2 / depend-01
            :ARG1 (d3 / dose))
      :ARG1-of (d4 / describe-01
            :ARG0 (f / figure :mod 7)))

# ::id pmid_1627_1139.216 ::date 2015-08-19T10:51:22 ::annotator SDL-AMR-09 ::preferred
# ::snt The data for all cultures identified as normal cells (Fig. <xref ref-type="fig" rid="F7">7A</xref>) indicated that low concentrations of OSM (≤ 0.1 ng/ml) or LPS conditioned macrophage medium (<10<sup>-3 </sup>dilution) had no appreciable modulating effects.
# ::save-date Mon Aug 24, 2015 ::file pmid_1627_1139_216.txt
(i / indicate-01
      :ARG0 (d / data
            :topic (c / culture
                  :mod (a / all)
                  :ARG1-of (i2 / identify-01
                        :ARG2 (c2 / cell
                              :ARG1-of (n / normal-02))
                        :ARG1-of (d2 / describe-01
                              :ARG0 (f / figure :mod "7A")))))
      :ARG1 (h / have-03 :polarity -
            :ARG0 (c3 / concentrate-02
                  :ARG1 (m / medium
                        :mod (m2 / macrophage)
                        :ARG1-of (c4 / condition-01
                              :ARG2 (o / or
                                    :op1 (p / protein :name (n2 / name :op1 "OSM")
                                          :quant (c5 / concentration-quantity
                                                :quant (o2 / or :op1 0.1
                                                      :op2 (l2 / less-than :op1 0.1))
                                                :unit (n4 / nanogram-per-milliliter)))
                                    :op2 (m3 / molecular-physical-entity :name (n3 / name :op1 "LPS")))))
                  :ARG1-of (l / low-04)
                  :ARG1-of (d4 / dilute-01
                        :ARG2 (l4 / less-than :op1 0.001)))
            :ARG1 (a2 / affect-01
                  :ARG0-of (m4 / modulate-01)
                  :ARG1-of (a3 / appreciate-02
                        :ARG1-of (p2 / possible-01)))))

# ::id pmid_1627_1139.217 ::date 2015-08-19T11:38:35 ::annotator SDL-AMR-09 ::preferred
# ::snt Only at higher concentrations, suppression of DNA synthesis became evident (p < 0.05).
# ::save-date Tue Dec 15, 2015 ::file pmid_1627_1139_217.txt
(h / have-condition-91
      :ARG1 (e / evidence-01
            :ARG1 (s / suppress-01
                  :ARG1 (s2 / synthesize-01
                        :ARG0 (n / nucleic-acid :wiki "DNA" :name (n2 / name :op1 "DNA"))))
            :ARG1-of (s3 / statistical-test-91
                  :ARG2 (l / less-than :op1 0.05)))
      :ARG2 (c / concentrate-02
            :ARG1-of (h2 / high-02
                  :degree (m / more
                        :mod (o / only)))))

# ::id pmid_1627_1139.218 ::date 2015-08-19T11:51:35 ::annotator SDL-AMR-09 ::preferred
# ::snt In contrast, several cultures of metaplastic and dysplastic cells exhibited the trend, in which the cells responded to low doses of OSM or conditioned medium from macrophages by a stimulation of DNA synthesis (Fig. <xref ref-type="fig" rid="F7">7B</xref>).
# ::save-date Mon Aug 24, 2015 ::file pmid_1627_1139_218.txt
(c / contrast-01
      :ARG2 (e / exhibit-01
            :ARG0 (c2 / culture-01
                  :ARG1 (a / and
                        :op1 (c3 / cell
                              :mod (m / metaplasia))
                        :op2 (c4 / cell
                              :mod (d / dysplasia)))
                  :quant (s / several))
            :ARG1 (t / trend-01
                  :ARG2 (r / respond-01
                        :ARG0 a
                        :ARG1 (o / or
                              :op1 (d2 / dose-01
                                    :ARG1 (c5 / cell)
                                    :ARG2 (p / protein :name (n / name :op1 "OSM"))
                                    :ARG1-of (l / low-04))
                              :op2 (m2 / medium
                                    :ARG1-of (c6 / condition-01)
                                    :source (m3 / macrophage)))
                        :ARG2 (s2 / stimulate-01
                              :ARG1 (s3 / synthesize-01
                                    :ARG0 (n2 / nucleic-acid :wiki "DNA" :name (n3 / name :op1 "DNA"))))))
            :ARG1-of (d4 / describe-01
                  :ARG0 (f / figure :mod "7B"))))

# ::id pmid_1627_1139.219 ::date 2015-08-19T12:22:44 ::annotator SDL-AMR-09 ::preferred
# ::snt The exact sign test using the paired samples (normal and abnormal) indicated a significant increase of DNA synthesis by low dose (10<sup>-3 </sup>dilution) of macrophage medium (p = 0.016).
# ::save-date Tue Dec 15, 2015 ::file pmid_1627_1139_219.txt
(i / indicate-01
      :ARG0 (t2 / test-01
            :ARG0-of (u / use-01
                  :ARG1 (a / and
                        :op1 (t / thing
                              :ARG1-of (n2 / normal-02)
                              :ARG1-of (s / sample-01))
                        :op2 (t3 / thing
                              :ARG1-of (n3 / normal-02 :polarity -)
                              :ARG1-of s)
                        :ARG1-of (p / pair-01)))
            :mod (s6 / sign)
            :mod (e / exact))
      :ARG1 (i2 / increase-01
            :ARG0 (d2 / dose-01
                  :ARG1 s3
                  :ARG2 (m / medium
                        :mod (m2 / macrophage))
                  :ARG1-of (l / low-04)
                  :ARG1-of (d4 / dilute-01
                        :ARG2 (l2 / less-than :op1 0.001)))
            :ARG1 (s3 / synthesize-01
                  :ARG0 (n / nucleic-acid :wiki "DNA" :name (n4 / name :op1 "DNA")))
            :ARG1-of (s4 / significant-02)
            :ARG1-of (s2 / statistical-test-91
                  :ARG2 0.016)))

# ::id pmid_1627_1139.220 ::date 2015-08-19T12:47:38 ::annotator SDL-AMR-09 ::preferred
# ::snt The comparison of the data from paired cultures by the Wilcoxon two-sample test also indicated that DNA synthesis in the abnormal epithelial cells was significantly increased at lowest concentration of OSM (p = 0.02) and macrophage medium (p = 0.005) relative to the normal cells.
# ::save-date Tue Dec 15, 2015 ::file pmid_1627_1139_220.txt
(i / indicate-01
      :ARG0 (c / compare-01
            :ARG0 (t2 / test-01
                  :mod (t3 / thing :quant 2
                        :ARG1-of (s3 / sample-01))
                  :mod (p5 / person :name (n / name :op1 "Wilcoxon")))
            :ARG1 (d / data
                  :source (c2 / culture
                        :ARG1-of (p / pair-01))))
      :ARG1 (a / and
            :op1 (i2 / increase-01
                  :ARG0 (c4 / concentrate-02
                        :ARG1 (p2 / protein :name (n3 / name :op1 "OSM"))
                        :ARG1-of (l / low-04
                              :degree (m / most)))
                  :ARG1 (s / synthesize-01
                        :ARG0 (n5 / nucleic-acid :wiki "DNA" :name (n6 / name :op1 "DNA")))
                  :ARG1-of (s4 / statistical-test-91
                        :ARG2 0.02))
            :op2 (i3 / increase-01
                  :ARG0 (c6 / concentrate-02
                        :ARG1 (m2 / medium
                              :mod (m3 / macrophage)))
                  :ARG1 s
                  :ARG1-of (s5 / statistical-test-91
                        :ARG2 0.005))
            :ARG1-of (s2 / significant-02
                  :ARG1-of (r / relative-05
                        :ARG3 (c5 / cell
                              :ARG1-of (n4 / normal-02))))
            :location (c3 / cell
                  :source (e / epithelium)
                  :ARG1-of (n2 / normal-02 :polarity -)))
      :mod (a2 / also))

# ::id pmid_1627_1139.221 ::date 2015-08-19T13:14:30 ::annotator SDL-AMR-09 ::preferred
# ::snt The reduced sensitivity for inhibited DNA synthesis in all cases could be correlated with metaplasia which shows enhanced ERK phosphorylation in response to cytokine treatment (example of dysplastic cells in Fig. <xref ref-type="fig" rid="F7">7C</xref>).
# ::save-date Sat Jan 30, 2016 ::file pmid_1627_1139_221.txt
(p3 / possible-01
      :ARG1 (c / correlate-01
            :ARG1 (s / sensitive-03
                  :ARG0 (s2 / synthesize-01
                        :ARG0 (n2 / nucleic-acid :wiki "DNA" :name (n3 / name :op1 "DNA")
                              :ARG1-of (i / inhibit-01)))
                  :ARG1-of (r / reduce-01)
                  :condition (c2 / case-04
                        :mod (a / all)))
            :ARG2 (m / metaplasia
                  :ARG0-of (s3 / show-01
                        :ARG1 (p2 / phosphorylate-01
                              :ARG1 (e / enzyme :name (n / name :op1 "ERK"))
                              :ARG1-of (e2 / enhance-01)
                              :ARG2-of (r2 / respond-01
                                    :ARG1 (t / treat-04
                                          :ARG2 (c3 / cytokine))))))
            :ARG1-of (d2 / describe-01
                  :ARG0 (f / figure :mod "7C")
                  :ARG2 (c4 / cell
                        :mod (d3 / dysplasia)))))

# ::id pmid_1627_1139.222 ::date 2015-08-19T13:50:09 ::annotator SDL-AMR-09 ::preferred
# ::snt In addition, we noted that in premalignant cells the basal ERK phosphorylation approached the level of OSM-treated cells or EGF-treated cells (Fig. <xref ref-type="fig" rid="F4">4B</xref>).
# ::save-date Sun Jan 17, 2016 ::file pmid_1627_1139_222.txt
(a / and
      :op2 (n / note-01
            :ARG0 (w / we)
            :ARG1 (a2 / approach-01
                  :ARG1 (p / phosphorylate-01
                        :ARG1 (e / enzyme :name (n2 / name :op1 "ERK"))
                        :mod (b / basal))
                  :ARG2 (l / level
                        :quant-of (o / or
                              :op1 (c / cell
                                    :ARG1-of (t / treat-04
                                          :ARG2 (p2 / protein :name (n3 / name :op1 "OSM"))))
                              :op2 (c2 / cell
                                    :ARG1-of (t2 / treat-04
                                          :ARG2 (p4 / protein :name (n4 / name :op1 "EGF"))))))
                  :location (c3 / cell
                        :mod (p3 / premalignant)))
            :ARG1-of (d / describe-01
                  :ARG0 (f / figure :mod "4B"))))

# ::id pmid_1627_1139.223 ::date 2015-08-19T14:01:02 ::annotator SDL-AMR-09 ::preferred
# ::snt In addition, the thymidine incorporation by premalignant cells maintained in growth medium was close to two-fold higher than in the corresponding normal cultures (Fig. <xref ref-type="fig" rid="F5">5D</xref>).
# ::save-date Sat Feb 13, 2016 ::file pmid_1627_1139_223.txt
(a / and
      :op2 (c / close-06
            :ARG1 (i / incorporate-02
                  :ARG0 (c2 / cell
                        :mod (p / premalignant))
                  :ARG1 (s / small-molecule :name (n / name :op1 "thymidine"))
                  :ARG1-of (m2 / maintain-01
                        :location (m3 / medium
                              :mod (g / grow-01))))
            :ARG2 (h / high-02
                  :degree (m4 / more)
                  :degree (p2 / product-of :op1 2)
                  :compared-to (c3 / culture
                        :ARG1-of (n2 / normal-02)
                        :ARG1-of (c4 / correspond-02
                              :ARG2 m3))))
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod "5D")))

# ::id pmid_1627_1139.224 ::date 2015-08-19T14:35:17 ::annotator SDL-AMR-09 ::preferred
# ::snt As expected, the ERK activity was reduced by treatment in both normal and carcinoma cells with U0126 which correlates with the suppression of DNA synthesis observed (Fig. <xref ref-type="fig" rid="F5">5C</xref>).
# ::save-date Sat Jan 16, 2016 ::file pmid_1627_1139_224.txt
(r / reduce-01
      :ARG1 (a / activity-06
            :ARG0 (e / enzyme :name (n / name :op1 "ERK")))
      :instrument (t / treat-04
            :ARG2 (s / small-molecule :name (n2 / name :op1 "U0126")))
      :location (a2 / and
            :op1 (c / cell
                  :ARG1-of (n3 / normal-02))
            :op2 (c2 / cell
                  :mod (m / medical-condition :name (n4 / name :op1 "carcinoma"))))
      :ARG1-of (e2 / expect-01)
      :ARG1-of (c3 / correlate-01
            :ARG2 (s2 / suppress-01
                  :ARG1 (s3 / synthesize-01
                        :ARG0 (n5 / nucleic-acid :wiki "DNA" :name (n6 / name :op1 "DNA")))
                  :ARG1-of (o / observe-01)))
      :ARG1-of (d3 / describe-01
            :ARG0 (f / figure :mod "5C")))

# ::id pmid_1627_1139.225 ::date 2015-08-19T14:46:32 ::annotator SDL-AMR-09 ::preferred
# ::snt High concentrations of OSM or macrophage factors were effective to reduce this intrinsically stimulated DNA synthesis in both normal and premalignant epithelial cell cultures.
# ::save-date Thu Nov 19, 2015 ::file pmid_1627_1139_225.txt
(e / effective-04
      :ARG0 (o / or
            :op1 (c / concentrate-02
                  :ARG1 (p / protein :name (n / name :op1 "OSM"))
                  :ARG1-of (h / high-02))
            :op2 (f / factor
                  :mod (m / macrophage)))
      :ARG1 (r / reduce-01
            :ARG0 o
            :ARG1 (s / synthesize-01
                  :ARG0 (n3 / nucleic-acid :wiki "DNA" :name (n4 / name :op1 "DNA"))
                  :ARG1-of (s2 / stimulate-01
                        :manner (i / intrinsic))
                  :mod (t / this))
            :location (c2 / culture-01
                  :ARG1 (a / and
                        :op1 (c3 / cell
                              :source (e2 / epithelium)
                              :ARG1-of (n2 / normal-02))
                        :op2 (c4 / cell
                              :mod (p2 / premalignant)
                              :source e2)))))

# ::id pmid_1859_7688.1 ::date 2015-07-06T08:26:01 ::annotator SDL-AMR-09 ::preferred
# ::snt TDAG51 is an ERK signaling target that opposes ERK-mediated HME16C mammary epithelial cell transformation (PMID:18597688)
# ::save-date Sun Jan 17, 2016 ::file pmid_1859_7688_1.txt
(o / oppose-01
      :ARG0 (p / protein :name (n / name :op1 "TDAG51")
            :ARG1-of (t / target-01
                  :ARG0 (e2 / enzyme :name (n2 / name :op1 "ERK")
                        :ARG0-of (s / signal-07))))
      :ARG1 (t2 / transform-01
            :ARG1 (c / cell-line :name (n4 / name :op1 "HME16C")
                  :mod (e3 / epithelium
                        :mod (m2 / mammary)))
            :ARG1-of (m / mediate-01
                  :ARG0 (e / enzyme :name (n3 / name :op1 "ERK"))))
      :ARG1-of (d / describe-01
            :ARG0 (p2 / publication-91
                  :ARG8 "PMID18597688")))

# ::id pmid_1859_7688.10 ::date 2015-07-06T08:29:23 ::annotator SDL-AMR-09 ::preferred
# ::snt Results
# ::save-date Mon Jul 6, 2015 ::file pmid_1859_7688_10.txt
(t / thing
      :ARG2-of (r / result-01))

# ::id pmid_1859_7688.11 ::date 2015-07-06T08:31:19 ::annotator SDL-AMR-09 ::preferred
# ::snt Activation of both the ERK and PI3K signaling pathways was sufficient to induce cellular transformation, which was accompanied by up-regulation of EGFR ligands, suggesting autocrine EGFR stimulation during the transformation process.
# ::save-date Fri Aug 14, 2015 ::file pmid_1859_7688_11.txt
(s / suggest-01
      :ARG0 (a / activate-01
            :ARG1 (a2 / and
                  :op1 (p / pathway :name (n / name :op1 "ERK"))
                  :op2 (p2 / pathway :name (n2 / name :op1 "PI3K"))
                  :mod (b / both)
                  :ARG0-of (s2 / signal-07))
            :ARG0-of (s3 / suffice-01
                  :ARG1 (i / induce-01
                        :ARG0 a
                        :ARG2 (t / transform-01
                              :ARG1 (c / cell)
                              :ARG1-of (a3 / accompany-01
                                    :ARG0 (u / upregulate-01
                                          :ARG1 (l / ligand
                                                :mod (e / enzyme :name (n3 / name :op1 "EGFR")))))))))
      :ARG1 (s4 / stimulate-01
            :ARG1 e
            :mod (a4 / autocrine)
            :time (p3 / process-02
                  :ARG1 (t2 / transform-01))))

# ::id pmid_1859_7688.12 ::date 2015-07-06T08:47:03 ::annotator SDL-AMR-09 ::preferred
# ::snt Only activation of the ERK pathway was sufficient to transform cells in the presence of EGFR inhibition and was sufficient for tumorigenesis in xenografts.
# ::save-date Fri Jul 24, 2015 ::file pmid_1859_7688_12.txt
(s / suffice-01
      :ARG0 (a / activate-01
            :ARG1 (p / pathway :name (n / name :op1 "ERK"))
            :mod (o / only))
      :ARG1 (a2 / and
            :op1 (t / transform-01
                  :ARG1 (c / cell
                        :condition (b / be-located-at-91
                              :ARG1 (e / enzyme :name (n2 / name :op1 "EGFR")
                                    :ARG1-of (i / inhibit-01)))))
            :op2 (c2 / create-01
                  :ARG1 (t2 / tumor)
                  :location (x / xenograft))))

# ::id pmid_1859_7688.13 ::date 2015-07-06T08:53:45 ::annotator SDL-AMR-09 ::preferred
# ::snt Up-regulation of the PHLDA1 gene product, TDAG51, was found to correlate with persistent ERK activation and anchorage-independent growth in the absence or presence of EGFR inhibition.
# ::save-date Sat Jan 16, 2016 ::file pmid_1859_7688_13.txt
(f / find-01
      :ARG1 (c / correlate-01
            :ARG1 (u / upregulate-01
                  :ARG1 (p / produce-01
                        :ARG0 (g / gene :name (n / name :op1 "PHLDA1"))
                        :ARG1 (p3 / protein :name (n2 / name :op1 "TDAG51"))))
            :ARG2 (a / and
                  :op1 (a2 / activate-01
                        :ARG1 (e / enzyme :name (n3 / name :op1 "ERK"))
                        :ARG1-of (p2 / persist-01))
                  :op2 (g3 / grow-01
                        :ARG0-of (d / depend-01 :polarity -
                              :ARG1 (a3 / anchorage))))
            :condition (o / or
                  :op1 (a4 / absent-01
                        :ARG1 (i / inhibit-01
                              :ARG1 (e2 / enzyme :name (n4 / name :op1 "EGFR"))))
                  :op2 (p4 / present-02
                        :ARG1 i))))

# ::id pmid_1859_7688.14 ::date 2015-07-06T09:11:58 ::annotator SDL-AMR-09 ::preferred
# ::snt Knockdown of this putative breast cancer tumor-suppressor gene resulted in increased ERK pathway activation and enhanced matrix-detached cellular proliferation of Ras/Raf transformed cells.
# ::save-date Wed Dec 9, 2015 ::file pmid_1859_7688_14.txt
(r / result-01
      :ARG1 (k / knock-down-02
            :ARG1 (g / gene
                  :ARG1-of (t3 / think-01
                        :ARG2 (s / suppress-01
                              :ARG0 g
                              :ARG1 (t / tumor
                                    :source (d2 / disease :wiki "Breast_cancer" :name (n4 / name :op1 "breast" :op2 "cancer")))))
                  :mod (t4 / this)))
      :ARG2 (a / and
            :op1 (i / increase-01
                  :ARG1 (a2 / activate-01
                        :ARG1 (p2 / pathway :name (n / name :op1 "ERK"))))
            :op2 (e / enhance-01
                  :ARG1 (p3 / proliferate-01
                        :ARG0 (c2 / cell
                              :ARG1-of (t2 / transform-01
                                    :ARG0 (s2 / slash
                                          :op1 (e2 / enzyme :name (n2 / name :op1 "Ras"))
                                          :op2 (e3 / enzyme :name (n3 / name :op1 "Raf"))))
                              :ARG1-of (d / detach-01
                                    :ARG2 (m / matrix)))))))

# ::id pmid_1859_7688.114 ::date 2015-07-07T05:44:35 ::annotator SDL-AMR-09 ::preferred
# ::snt Results
# ::save-date Tue Jul 7, 2015 ::file pmid_1859_7688_114.txt
(t / thing
      :ARG2-of (r / result-01))

# ::id pmid_1859_7688.115 ::date 2015-07-07T05:45:14 ::annotator SDL-AMR-09 ::preferred
# ::snt Generation of H-Ras- and Rlf-CAAX-expressing HME16C cell lines
# ::save-date Wed Jul 8, 2015 ::file pmid_1859_7688_115.txt
(g / generate-01
      :ARG1 (e / express-03
            :ARG2 (a / and
                  :op1 (e2 / enzyme :name (n / name :op1 "H-Ras"))
                  :op2 (e3 / enzyme :name (n2 / name :op1 "Rlf-CAAX")))
            :ARG3 (c / cell-line :name (n3 / name :op1 "HME16C"))))

# ::id pmid_1859_7688.116 ::date 2015-07-07T06:36:18 ::annotator SDL-AMR-09 ::preferred
# ::snt Retroviral vectors coding for amino terminal HA-tagged activated H-RasV12, the H-RasV12 effector domain mutants (EDM) H-RasV12G37, H-RasV12S35, and H-RasV12C40, and the constitutively activated version of a RalGEF, Rlf-CAAX, were used to infect telomerase immortalized HME16C human mammary epithelial cells.
# ::save-date Thu Jan 28, 2016 ::file pmid_1859_7688_116.txt
(u2 / use-01
      :ARG1 (a4 / and
            :op1 (v / vector
                  :mod (r / retrovirus)
                  :ARG0-of (c / code-01
                        :ARG1 (p4 / protein-segment :name (n12 / name :op1 "amino-terminus")
                              :part-of (e / enzyme :name (n2 / name :op1 "H-Ras")
                                    :ARG2-of (m / mutate-01 :value "V12")
                                    :ARG1-of (t2 / tag-01
                                          :ARG2 (p3 / protein :name (n10 / name :op1 "haemagglutinin" :op2 "A")))
                                    :ARG1-of (a / activate-01)))))
            :op2 (d / domain
                  :mod (e9 / effector)
                  :mod (e3 / enzyme :name (n3 / name :op1 "H-Ras")
                        :ARG2-of (m2 / mutate-01 :value "V12"))
                  :ARG1-of (m7 / mean-01
                        :ARG2 (a6 / and
                              :op1 (e4 / enzyme :name (n4 / name :op1 "H-Ras")
                                    :ARG2-of (m3 / mutate-01 :value "V12G37"))
                              :op2 (e5 / enzyme :name (n5 / name :op1 "H-Ras")
                                    :ARG2-of (m4 / mutate-01 :value "V12S35"))
                              :op3 (e6 / enzyme :name (n6 / name :op1 "H-Ras")
                                    :ARG2-of (m5 / mutate-01 :value "V12C40")))))
            :op3 (p2 / pathway :name (n7 / name :op1 "RalGEF")
                  :ARG1-of (a5 / activate-01
                        :mod (c2 / constitutive)
                        :ARG1-of (m6 / mean-01
                              :ARG2 (e7 / enzyme :name (n8 / name :op1 "Rlf-CAAX"))))))
      :ARG2 (i / infect-01
            :ARG0 a4
            :ARG1 (c3 / cell-line :name (n9 / name :op1 "HME16C")
                  :mod (e2 / epithelium
                        :mod (m8 / mammary
                              :mod (h / human)))
                  :ARG1-of (i2 / immortalize-03
                        :ARG2 (t / telomerase)))))

# ::id pmid_1859_7688.117 ::date 2015-07-07T06:40:35 ::annotator SDL-AMR-09 ::preferred
# ::snt Anti-Ras and anti-HA western blotting demonstrated approximately equal levels of ectopic Ras expression among Ras-infected cells, with slightly lower levels in HME16C RasV12-infected cells relative to EDM-infected cells (Figure 1A).
# ::save-date Sat Jan 16, 2016 ::file pmid_1859_7688_117.txt
(d / demonstrate-01
      :ARG0 (a / and
            :op1 (i4 / immunoblot-01
                  :ARG3 (a3 / antibody
                        :ARG0-of (c3 / counter-01
                              :ARG1 e5)))
            :op2 (i5 / immunoblot-01
                  :ARG3 (a4 / antibody
                        :ARG0-of (c5 / counter-01
                              :ARG1 (p / protein :name (n2 / name :op1 "HA"))))))
      :ARG1 (l / level
            :ARG1-of (e / equal-01
                  :ARG0-of (a2 / approximate-01))
            :degree-of (e2 / express-03
                  :ARG2 (e4 / enzyme :name (n5 / name :op1 "Ras")
                        :mod (e3 / ectopic))
                  :ARG3 (c / cell
                        :ARG1-of (i / infect-01
                              :ARG2 (e5 / enzyme :name (n6 / name :op1 "Ras")))))
            :prep-with (l2 / level
                  :ARG1-of (l3 / low-04
                        :degree (m / more
                              :degree (s / slight)))
                  :ARG1-of (r / relative-05
                        :ARG2 (l4 / level
                              :mod (c4 / cell
                                    :ARG1-of (i3 / infect-01
                                          :ARG2 (e7 / enzyme :name (n8 / name :op1 "EDM"))))))
                  :location (c2 / cell-line :name (n / name :op1 "HME16C")
                        :ARG1-of (i2 / infect-01
                              :ARG2 (e6 / enzyme :name (n7 / name :op1 "Ras")
                                    :ARG2-of (m2 / mutate-01 :value "V12"))))))
      :ARG1-of (d2 / describe-01
            :ARG0 (f / figure :mod "1A")))

# ::id pmid_1859_7688.118 ::date 2015-07-07T07:11:12 ::annotator SDL-AMR-09 ::preferred
# ::snt Analysis of activated, GTP-bound Ral A demonstrated highly elevated levels of activated Ral A only in Rlf-CAAX-expressing cells and not in Ras-infected cells grown under standard culture conditions (Figure 1B).
# ::save-date Sun Jan 17, 2016 ::file pmid_1859_7688_118.txt
(d / demonstrate-01
      :ARG0 (a / analyze-01
            :ARG1 (e2 / enzyme :name (n2 / name :op1 "Ral" :op2 "A")
                  :ARG1-of (a2 / activate-01)
                  :ARG2-of (b / bind-01
                        :ARG1 (s / small-molecule :name (n / name :op1 "GTP")))))
      :ARG1 (a4 / and
            :op1 (e3 / elevate-01
                  :ARG1 (l / level
                        :mod (a3 / activate-01
                              :ARG1 e2))
                  :ARG1-of (h / high-02)
                  :location (c / cell
                        :ARG3-of (e4 / express-03
                              :ARG2 (e5 / enzyme :name (n3 / name :op1 "Rlf-CAAX"))))
                  :mod (o / only))
            :op2 (e6 / elevate-01 :polarity -
                  :ARG1 l
                  :location (c2 / cell
                        :ARG1-of (i / infect-01
                              :ARG2 (e7 / enzyme :name (n4 / name :op1 "Ras")))
                        :ARG1-of (g / grow-03
                              :condition (c5 / culture-01
                                    :mod (s2 / standard))))))
      :ARG1-of (d2 / describe-01
            :ARG0 (f / figure :mod "1B")))

# ::id pmid_1859_7688.119 ::date 2015-07-07T07:28:50 ::annotator SDL-AMR-09 ::preferred
# ::snt To assess activation of the ERK pathway, anti-phospho Erk western blotting was performed and showed significantly elevated Erk phosphoprotein in RasV12- and RasV12S35-infected HME16C cells relative to control pLRT-infected cells (Figure 1A).
# ::save-date Sat Jan 16, 2016 ::file pmid_1859_7688_119.txt
(a / and
      :op1 (p / perform-01
            :ARG1 (i3 / immunoblot-01
                  :ARG0-of (c / counter-01
                        :ARG1 (e4 / enzyme :name (n2 / name :op1 "Erk")
                              :ARG3-of (p2 / phosphorylate-01))))
            :purpose (a2 / assess-01
                  :ARG1 (a3 / activate-01
                        :ARG1 (p3 / pathway :name (n3 / name :op1 "ERK")))))
      :op2 (s / show-01
            :ARG0 i3
            :ARG1 (e2 / elevate-01
                  :ARG1 e4
                  :location (c3 / cell-line :name (n4 / name :op1 "HME16C")
                        :ARG1-of (i / infect-01
                              :ARG2 (a4 / and
                                    :op1 (e / enzyme :name (n5 / name :op1 "Ras")
                                          :ARG2-of (m / mutate-01 :value "V12"))
                                    :op2 (e3 / enzyme :name (n6 / name :op1 "Ras")
                                          :ARG2-of (m2 / mutate-01 :value "V12S35")))))
                  :ARG1-of (r / relative-05
                        :ARG2 (c2 / cell
                              :ARG1-of (i2 / infect-01
                                    :ARG2 (p4 / protein :name (n7 / name :op1 "LRT")
                                          :ARG3-of (p5 / phosphorylate-01)))
                              :ARG0-of (c4 / control-01)))
                  :ARG1-of (s2 / significant-02)))
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod "1A")))

# ::id pmid_1859_7688.120 ::date 2015-07-07T07:48:46 ::annotator SDL-AMR-09 ::preferred
# ::snt Elevated levels of phosphorylated Erk were also observed in RasV12G37- and RasV12C40-infected cells, although at a much lower level than that found in RasV12- and RasV12S35-infected cells.
# ::save-date Sat Jan 16, 2016 ::file pmid_1859_7688_120.txt
(h / have-concession-91
      :ARG1 (o / observe-01
            :ARG1 (e / elevate-01
                  :ARG1 (l / level
                        :quant-of (e6 / enzyme :name (n / name :op1 "Erk")
                              :ARG3-of (p / phosphorylate-01))
                        :location (c / cell
                              :ARG1-of (i / infect-01
                                    :ARG2 (a / and
                                          :op1 (e5 / enzyme :name (n2 / name :op1 "Ras")
                                                :ARG2-of (m / mutate-01 :value "V12G37"))
                                          :op2 (e4 / enzyme :name (n3 / name :op1 "Ras")
                                                :ARG2-of (m2 / mutate-01 :value "V12C40")))))))
            :mod (a2 / also))
      :ARG2 (l3 / low-04
            :ARG1 l
            :degree (m3 / more)
            :ARG1-of (c2 / compare-01
                  :ARG2 (l2 / level
                        :ARG1-of (f2 / find-01)
                        :location (c3 / cell
                              :ARG1-of (i2 / infect-01
                                    :ARG2 (a3 / and
                                          :op1 (e2 / enzyme :name (n4 / name :op1 "Ras")
                                                :ARG2-of (m4 / mutate-01 :value "V12"))
                                          :op2 (e3 / enzyme :name (n5 / name :op1 "Ras")
                                                :ARG2-of (m5 / mutate-01 :value "V12S35")))))))
            :degree (m6 / much)))

# ::id pmid_1859_7688.121 ::date 2015-07-07T10:44:20 ::annotator SDL-AMR-09 ::preferred
# ::snt To assess activation of the PI3K signaling pathway, anti-phosphoAkt (Ser473) western blotting was performed to detect activated, phosphorylated Akt.
# ::save-date Sat Jan 2, 2016 ::file pmid_1859_7688_121.txt
(p / perform-01
      :ARG1 (i / immunoblot-01
            :ARG1 (a / amino-acid :mod 473 :name (n3 / name :op1 "Serine")
                  :part-of (e / enzyme :name (n2 / name :op1 "Akt")
                        :ARG3-of (p2 / phosphorylate-01))))
      :purpose (d / detect-01
            :ARG1 (a2 / and
                  :op1 (a3 / activate-01
                        :ARG1 e)
                  :op2 e))
      :purpose (a4 / assess-01
            :ARG1 (a5 / activate-01
                  :ARG1 (p3 / pathway :name (n4 / name :op1 "PI3K")
                        :ARG0-of (s / signal-07)))))

# ::id pmid_1859_7688.122 ::date 2015-07-07T10:49:40 ::annotator SDL-AMR-09 ::preferred
# ::snt In cells that were serum starved for 24 hours and matrix detached for 6 hours, elevated levels of phosphorylated Akt were observed in RasV12-, RasV12C40-, and RasV12G37-infected HME16C, with highest levels present in RasV12-infected cells (Figure 1C).
# ::save-date Mon Dec 21, 2015 ::file pmid_1859_7688_122.txt
(o / observe-01
      :ARG1 (e / elevate-01
            :ARG1 (l / level
                  :quant-of (e2 / enzyme :name (n / name :op1 "Akt")
                        :ARG3-of (p / phosphorylate-01))
                  :location (c2 / cell-line :name (n2 / name :op1 "HME16C")
                        :ARG1-of (i / infect-01
                              :ARG2 (a / and
                                    :op1 (e3 / enzyme :name (n3 / name :op1 "Ras")
                                          :ARG2-of (m2 / mutate-01 :value "V12"))
                                    :op2 (e4 / enzyme :name (n4 / name :op1 "Ras")
                                          :ARG2-of (m3 / mutate-01 :value "V12C40"))
                                    :op3 (e5 / enzyme :name (n5 / name :op1 "Ras")
                                          :ARG2-of (m4 / mutate-01 :value "V12G37")))))
                  :ARG1-of (h / high-02
                        :degree (m5 / most)
                        :location (c3 / cell
                                    :ARG1-of (i2 / infect-01
                                          :ARG2 e3)))))
      :location (c / cell
            :ARG1-of (s / starve-01
                  :ARG2 (s2 / serum)
                  :duration (t / temporal-quantity :quant 24
                        :unit (h4 / hour)))
            :ARG1-of (d / detach-01
                  :ARG2 (m / matrix)
                  :duration (t2 / temporal-quantity :quant 6
                        :unit h4)))
      :ARG1-of (d2 / describe-01
            :ARG2 (f / figure :mod "1C")))

# ::id pmid_1859_7688.123 ::date 2015-07-07T11:24:43 ::annotator SDL-AMR-09 ::preferred
# ::snt Anchorage-independent growth of mammary epithelial cell lines
# ::save-date Wed Jul 8, 2015 ::file pmid_1859_7688_123.txt
(g / grow-01
      :ARG1 (c / cell-line
            :mod (e / epithelium
                  :mod (m / mammary)))
      :ARG0-of (d / depend-01 :polarity -
            :ARG1 (a / anchorage)))

# ::id pmid_1859_7688.124 ::date 2015-07-07T11:28:43 ::annotator SDL-AMR-09 ::preferred
# ::snt To assess transformation by different Ras signaling pathways, anchorage-independent growth assays were performed in soft agar and in ultra-low attachment tissue culture plates.
# ::save-date Mon Dec 21, 2015 ::file pmid_1859_7688_124.txt
(p / perform-01
      :ARG1 (a / assay-01
            :ARG1 (g / grow-01
                  :ARG0-of (d / depend-01 :polarity -
                        :mod (a2 / anchorage))))
      :ARG2 (p2 / plate
            :mod (c / culture-01
                  :ARG1 (t / tissue
                        :ARG3-of (a5 / attach-01
                              :ARG1-of (l / low-04
                                    :degree (u / ultra))))
                  :instrument (a4 / agar
                        :ARG1-of (s / soft-02))))
      :purpose (a6 / assess-01
            :ARG1 (t2 / transform-01
                  :ARG0 (p3 / pathway :name (n / name :op1 "Ras")
                        :ARG0-of (s2 / signal-07)
                        :ARG1-of (d2 / differ-02)))))

# ::id pmid_1859_7688.125 ::date 2015-07-07T14:19:43 ::annotator SDL-AMR-09 ::preferred
# ::snt Ras- and Ras EDM-infected HME16C cells formed significantly more soft agar colonies >100 μm in diameter than pLRT vector-infected cells (Figure 2A).
# ::save-date Wed Mar 2, 2016 ::file pmid_1859_7688_125.txt
(f / form-01
      :ARG0 (c / cell-line :name (n / name :op1 "HME16C")
            :ARG1-of (i / infect-01
                  :ARG2 (a / and
                        :op1 (e / enzyme :name (n2 / name :op1 "Ras"))
                        :op2 (e2 / enzyme :name (n3 / name :op1 "Ras" :op2 "EDM")))))
      :ARG1 (c2 / colony
            :mod (a2 / agar
                  :ARG1-of (s / soft-02))
            :mod (d / diameter
                  :mod (m2 / more-than
                        :op1 (d2 / distance-quantity :quant 100
                              :unit (m / micrometer))))
            :quant (m3 / more
                  :ARG1-of (s2 / significant-02)
                  :ARG1-of (c3 / compare-01
                        :ARG2 (c4 / cell
                              :ARG1-of (i2 / infect-01
                                    :ARG2 (v / vector :name (n4 / name :op1 "LRT")
                                          :ARG3-of (p2 / phosphorylate-01)))))))
      :ARG1-of (d3 / describe-01
            :ARG0 (f2 / figure :mod "2A")))

# ::id pmid_1859_7688.126 ::date 2015-07-07T14:36:07 ::annotator SDL-AMR-09 ::preferred
# ::snt The RasV12-infected cells formed large colonies, many exceeding 1000 μm, although the total number exceeding 100 μm was typically less than that for the Ras EDM (Figure 2B).
# ::save-date Tue Dec 29, 2015 ::file pmid_1859_7688_126.txt
(f / form-01
      :ARG0 (c / cell
            :ARG1-of (i / infect-01
                  :ARG2 (e / enzyme :name (n / name :op1 "Ras")
                        :ARG2-of (m / mutate-01 :value "V12"))))
      :ARG1 (c2 / colony
            :mod (l / large)
            :quant (m2 / many)
            :ARG0-of (e4 / exceed-01
                  :ARG1 (d / distance-quantity :quant 1000
                        :unit (m3 / micrometer))))
      :concession (n2 / number
                  :mod (t / total)
                  :ARG0-of (e2 / exceed-01
                        :ARG1 (d2 / distance-quantity :quant 100
                              :unit m3))
                  :quant (l2 / less
                        :ARG1-of (t2 / typical-02))
                  :ARG1-of (c3 / compare-01
                        :ARG2 (n4 / number
                              :condition (e3 / enzyme :name (n3 / name :op1 "Ras" :op2 "EDM")))))
      :ARG1-of (d3 / describe-01
            :ARG0 (f2 / figure :mod "2B")))

# ::id pmid_1859_7688.127 ::date 2015-07-07T14:52:55 ::annotator SDL-AMR-09 ::preferred
# ::snt Among the Ras EDM-infected cells, the RasV12S35-infected cells formed the largest colonies.
# ::save-date Wed Jul 8, 2015 ::file pmid_1859_7688_127.txt
(f / form-01
      :ARG0 (c / cell
            :ARG1-of (i / infect-01
                  :ARG2 (e / enzyme :name (n / name :op1 "Ras")
                        :ARG2-of (m / mutate-01 :value "V12S35")))
            :ARG1-of (i2 / include-91
                  :ARG2 (c2 / cell
                        :ARG1-of (i3 / infect-01
                              :ARG2 (e2 / enzyme :name (n2 / name :op1 "Ras" :op2 "EDM"))))))
      :ARG1 (c3 / colony
            :mod (l / large
                  :degree (m2 / most))))

# ::id pmid_1859_7688.128 ::date 2015-07-07T14:56:41 ::annotator SDL-AMR-09 ::preferred
# ::snt These were similar to, but smaller than, the RasV12-infected cells.
# ::save-date Sat Aug 8, 2015 ::file pmid_1859_7688_128.txt
(c3 / contrast-01
      :ARG1 (r / resemble-01
            :ARG1 (t / this)
            :ARG2 (c / cell
                  :ARG1-of (i / infect-01
                        :ARG2 (e / enzyme :name (n / name :op1 "Ras")
                              :ARG2-of (m / mutate-01 :value "V12")))))
      :ARG2 (s / small
            :domain t
            :degree (m2 / more)
            :ARG1-of (c2 / compare-01
                  :ARG2 c)))

# ::id pmid_1859_7688.129 ::date 2015-07-07T15:04:54 ::annotator SDL-AMR-09 ::preferred
# ::snt For colonies above 100 μm in diameter, RasV12C40-infected cells were the most efficient at colony formation, despite the smaller mean size of colonies.
# ::save-date Wed Mar 2, 2016 ::file pmid_1859_7688_129.txt
(h / have-concession-91
      :ARG1 (e / efficient-01
            :ARG1 (c / cell
                  :ARG1-of (i / infect-01
                        :ARG2 (e2 / enzyme :name (n / name :op1 "Ras")
                              :ARG2-of (m / mutate-01 :value "V12C40"))))
            :ARG2 (f / form-01
                  :ARG1 (c2 / colony))
            :degree (m2 / most))
      :ARG2 (s / size-01
            :ARG1 c2
            :ARG2 (s2 / small
                  :degree (m4 / more))
            :mod (m3 / mean))
      :condition (c3 / colony
            :mod (d2 / diameter
                  :mod (a / above
                        :op1 (d / distance-quantity :quant 100
                              :unit (m5 / micrometer))))))

# ::id pmid_1859_7688.130 ::date 2015-07-07T23:27:10 ::annotator SDL-AMR-09 ::preferred
# ::snt Rlf-CAAX-infected cells formed slightly more colonies above 100 μm than vector-transfected control cells, but these were significantly smaller than those formed by Ras- and Ras EDM-infected cells.
# ::save-date Wed Mar 2, 2016 ::file pmid_1859_7688_130.txt
(c / contrast-01
      :ARG1 (f / form-01
            :ARG0 (c2 / cell
                  :ARG1-of (i / infect-01
                        :ARG2 (e / enzyme :name (n / name :op1 "Rlf-CAAX"))))
            :ARG1 (c3 / colony
                  :quant (m2 / more
                        :degree (s3 / slight))
                  :compared-to (c4 / cell
                        :ARG0-of (c5 / control-01)
                        :ARG1-of (t / transfect-01
                              :ARG2 (v / vector)))
                  :mod (a / above
                        :op1 (d / distance-quantity :quant 100
                              :unit (m / micrometer)))))
      :ARG2 (s / small
            :degree (m3 / more)
            :ARG1-of (s2 / significant-02)
            :domain c2
            :compared-to (c7 / colony
                  :ARG1-of (f2 / form-01
                        :ARG0 (c6 / cell
                              :ARG1-of (i2 / infect-01
                                    :ARG2 (a2 / and
                                          :op1 (e2 / enzyme :name (n2 / name :op1 "Ras"))
                                          :op2 (e3 / enzyme :name (n3 / name :op1 "Ras" :op2 "EDM")))))))))

# ::id pmid_1859_7688.131 ::date 2015-07-07T23:42:02 ::annotator SDL-AMR-09 ::preferred
# ::snt When grown under anchorage-independent conditions in ultra-low attachment plates, the accumulation of cells for the various infected cell lines roughly paralleled the total cell masses seen in soft agar growth assays (Figure 2C).
# ::save-date Mon Dec 21, 2015 ::file pmid_1859_7688_131.txt
(p / parallel-01
      :ARG0 (a / accumulate-01
            :ARG1 (c / cell)
            :mod (c2 / cell-line
                  :ARG1-of (i / infect-01)
                  :mod (v / various)))
      :ARG1 (m / mass-01
            :ARG0 (c3 / cell
                  :mod (t / total))
            :ARG1-of (s / see-01
                  :location (a2 / assay-01
                        :ARG1 (g / grow-01
                              :condition (a3 / agar
                                    :ARG1-of (s2 / soft-02))))))
      :degree (r / rough)
      :condition (g2 / grow-01
            :ARG0-of (d / depend-01 :polarity -
                  :ARG1 (a4 / anchorage))
            :location (p2 / plate
                  :ARG3-of (a5 / attach-01
                        :ARG1-of (l / low-04
                              :degree (u / ultra)))))
      :ARG1-of (d2 / describe-01
            :ARG0 (f / figure :mod "2C")))

# ::id pmid_1859_7688.132 ::date 2015-07-07T23:55:16 ::annotator SDL-AMR-09 ::preferred
# ::snt The RasV12- and RasV12 EDM-expressing cells grew well, while the growth of the Rlf-CAAX-expressing cells was significantly less.
# ::save-date Sat Aug 8, 2015 ::file pmid_1859_7688_132.txt
(c / contrast-01
      :ARG1 (g / grow-01
            :ARG1 (c2 / cell
                  :ARG3-of (e / express-03
                        :ARG2 (a / and
                              :op1 (e2 / enzyme :name (n / name :op1 "Ras")
                                    :ARG2-of (m / mutate-01 :value "V12"))
                              :op2 (e3 / enzyme :name (n2 / name :op1 "Ras" :op2 "EDM")
                                    :ARG2-of (m2 / mutate-01 :value "V12")))))
            :ARG1-of (w / well-09))
      :ARG2 (g2 / grow-01
            :ARG1 (c3 / cell
                  :ARG3-of (e4 / express-03
                        :ARG2 (e5 / enzyme :name (n3 / name :op1 "Rlf-CAAX"))))
            :mod (l / less
                  :ARG1-of (s / significant-02))
            :compared-to g))

# ::id pmid_1859_7688.133 ::date 2015-07-08T00:03:31 ::annotator SDL-AMR-09 ::preferred
# ::snt The HME16C cells maintained viability but did not increase in number.
# ::save-date Sat Aug 8, 2015 ::file pmid_1859_7688_133.txt
(c / contrast-01
      :ARG1 (m / maintain-01
            :ARG0 (c2 / cell-line :name (n / name :op1 "HME16C"))
            :ARG1 (v / viability))
      :ARG2 (i / increase-01 :polarity -
            :ARG1 c2
            :mod (n2 / number)))

# ::id pmid_1859_7688.134 ::date 2015-07-08T00:06:34 ::annotator SDL-AMR-09 ::preferred
# ::snt To compare our results to others, we verified the function of pLRT vector driven Ras EDM mutants and Rlf-CAAX in HEK-HT cells, which previously have been reported to form colonies in soft agar upon expression of H-RasV12G37 and Rlf-CAAX [27].
# ::save-date Sun Jan 17, 2016 ::file pmid_1859_7688_134.txt
(v / verify-01
      :ARG0 (w / we)
      :ARG1 (f / function-01
            :ARG0 (a / and
                  :op1 (e / enzyme :name (n2 / name :op1 "Ras" :op2 "EDM")
                        :ARG2-of (m / mutate-01))
                  :op2 (e2 / enzyme :name (n3 / name :op1 "Rlf-CAAX"))
                  :ARG1-of (d / drive-02
                        :ARG0 (v2 / vector :name (n / name :op1 "LRT")
                              :ARG3-of (p4 / phosphorylate-01))))
            :location (c / cell-line :name (n4 / name :op1 "HEK-HT")
                  :ARG0-of (f2 / form-01
                        :ARG1 (c2 / colony)
                        :location (a2 / agar
                              :ARG1-of (s / soft-02))
                        :condition (e3 / express-03
                              :ARG2 (a3 / and
                                    :op1 (e4 / enzyme :name (n5 / name :op1 "H-Ras")
                                          :ARG2-of (m2 / mutate-01 :value "V12G37"))
                                    :op2 e2))
                        :ARG1-of (r / report-01
                              :time (p2 / previous)))))
      :ARG1-of (d2 / describe-01
            :ARG0 (p3 / publication
                  :ARG1-of (c3 / cite-01
                        :ARG2 27)))
      :purpose (c4 / compare-01
            :ARG0 w
            :ARG1 (t2 / thing
                  :ARG2-of (r2 / result-01)
                  :poss w)
            :ARG2 (t / thing
                  :ARG2-of r2
                  :poss (p5 / person)
                  :mod (o / other))))

# ::id pmid_1859_7688.135 ::date 2015-07-08T00:07:46 ::annotator SDL-AMR-09 ::preferred
# ::snt In our hands, expression of H-RasV12, H-RasV12G37, and Rlf-CAAX from the pLRT vector induced efficient soft agar colony growth, and H-RasV12S35 and H-RasV12C40 did not (not shown), identical to previously reported results [27].
# ::save-date Sun Jan 17, 2016 ::file pmid_1859_7688_135.txt
(c / contrast-01
      :ARG1 (i / induce-01
            :ARG0 (e / express-03
                  :ARG2 (a / and
                        :op1 (e2 / enzyme :name (n2 / name :op1 "H-Ras")
                              :ARG2-of (m / mutate-01 :value "V12"))
                        :op2 (e3 / enzyme :name (n3 / name :op1 "H-Ras")
                              :ARG2-of (m2 / mutate-01 :value "V12G37"))
                        :op3 (e4 / enzyme :name (n4 / name :op1 "Rlf-CAAX"))
                        :source (v / vector :name (n / name :op1 "LRT")
                              :ARG3-of (p4 / phosphorylate-01))))
            :ARG2 (g / grow-01
                  :ARG2 (c2 / colony
                        :location (a2 / agar
                              :ARG1-of (s / soft-02)))
                  :ARG1-of (e5 / efficient-01)))
      :ARG2 (i3 / induce-01 :polarity -
            :ARG0 (a3 / and
                  :op1 (e6 / enzyme :name (n5 / name :op1 "H-ras")
                        :ARG2-of (m3 / mutate-01 :value "V12S35"))
                  :op2 (e7 / enzyme :name (n6 / name :op1 "H-ras")
                        :ARG2-of (m4 / mutate-01 :value "V12C40")))
            :ARG2 g
            :ARG1-of (s2 / show-01 :polarity -))
      :location (h / hand
            :part-of (w / we))
      :ARG1-of (i2 / identical-01
            :ARG2 (t / thing
                  :ARG2-of (r / result-01
                        :ARG1-of (r2 / report-01
                              :time (p2 / previous)))))
      :ARG1-of (d / describe-01
            :ARG0 (p3 / publication
                  :ARG1-of (c3 / cite-01
                        :ARG2 27))))

# ::id pmid_1859_7688.136 ::date 2015-07-08T00:26:16 ::annotator SDL-AMR-09 ::preferred
# ::snt Expression of exogenous H-Ras and Rlf-CAAX, and activation of endogenous RalA, in this cell line was similar to that observed in HME16C cells (not shown).
# ::save-date Sun Jan 17, 2016 ::file pmid_1859_7688_136.txt
(r / resemble-01
      :ARG1 (a / and
            :op1 (e / express-03
                  :ARG2 (a3 / and
                        :op1 (e2 / enzyme :name (n / name :op1 "H-Ras"))
                        :op2 (e3 / enzyme :name (n2 / name :op1 "Rlf-CAAX"))
                        :mod (e4 / exogene))
                  :ARG3 (c / cell-line
                        :mod (t / this)))
            :op2 (a2 / activate-01
                  :ARG1 (p / protein :name (n3 / name :op1 "RalA")
                        :mod (e6 / endogene))
                  :location c))
      :ARG2 (o / observe-01
            :ARG1 (a4 / and
                  :op1 e
                  :op2 a2)
            :location (c2 / cell-line :name (n4 / name :op1 "HME16C")
                  :ARG1-of (s / show-01 :polarity -))))

# ::id pmid_1859_7688.137 ::date 2015-07-08T01:00:01 ::annotator SDL-AMR-09 ::preferred
# ::snt Therefore, expression of Rlf-CAAX and subsequent RalA activation did not appear to be sufficient to induce anchorage-independent growth in the HME16C mammary epithelial cell line in contrast to HEK-HT and various other immortalized human cell types [27].
# ::save-date Thu Jan 28, 2016 ::file pmid_1859_7688_137.txt
(i / infer-01
      :ARG1 (a / appear-01 :polarity -
            :ARG1 (a2 / and
                  :op1 (e / express-03
                        :ARG2 (e2 / enzyme :name (n / name :op1 "Rlf-CAAX")))
                  :op1 (a3 / activate-01
                        :ARG1 (p2 / protein :name (n2 / name :op1 "RalA"))
                        :mod (s / subsequent)))
            :ARG0-of (s2 / suffice-01
                  :ARG1 (i2 / induce-01
                        :ARG0 a2
                        :ARG2 (g / grow-01
                              :ARG0-of (d / depend-01 :polarity -
                                    :ARG1 (a4 / anchorage)))
                        :location (c / cell-line :name (n3 / name :op1 "HME16C")
                              :mod (e4 / epithelium
                                    :mod (m / mammary))))
                  :ARG1-of (c2 / contrast-01
                        :ARG2 (a5 / and
                              :op1 (c3 / cell-line :name (n4 / name :op1 "HEK-HT"))
                              :op2 (t / type-03
                                    :ARG1 (c4 / cell
                                          :mod (h / human)
                                          :ARG1-of (i3 / immortalize-03))
                                    :mod (o / other)
                                    :mod (v / various))))))
      :ARG1-of (d2 / describe-01
            :ARG0 (p / publication
                  :ARG1-of (c5 / cite-01
                        :ARG2 27))))

# ::id pmid_1859_7688.138 ::date 2015-07-08T01:15:29 ::annotator SDL-AMR-09 ::preferred
# ::snt Tumorigenesis of HME16C cell lines in nude mice
# ::save-date Fri Nov 6, 2015 ::file pmid_1859_7688_138.txt
(c / create-01
      :ARG1 (t / tumor)
      :mod (c2 / cell-line :name (n / name :op1 "HME16C"))
      :location (m / mouse
            :mod (n2 / nude)))

# ::id pmid_1859_7688.139 ::date 2015-07-08T01:20:45 ::annotator SDL-AMR-09 ::preferred
# ::snt Anchorage-independent growth often predicts the ability of cells to grow as xenografted tumors in immuno-compromised mice.
# ::save-date Fri Feb 5, 2016 ::file pmid_1859_7688_139.txt
(p / predict-01
      :ARG0 (g / grow-01
            :ARG0-of (d / depend-01 :polarity -
                  :ARG1 (a / anchorage)))
      :ARG1 (c / capable-01
            :ARG1 (c2 / cell)
            :ARG2 (g2 / grow-01
                  :ARG1 c2
                  :manner (t / tumor
                        :mod (x / xenograft)
                        :location (m / mouse
                              :ARG1-of (i / immune-02
                                    :ARG1-of (c3 / compromise-02))))))
      :frequency (o / often))

# ::id pmid_1859_7688.140 ::date 2015-07-08T01:57:32 ::annotator SDL-AMR-09 ::preferred
# ::snt Tumor formation was assessed following subcutaneous inoculation.
# ::save-date Wed Dec 9, 2015 ::file pmid_1859_7688_140.txt
(a / assess-01
      :ARG1 (f / form-01
            :ARG1 (t / tumor))
      :ARG1-of (f2 / follow-01
            :ARG2 (i / inoculate-01
                  :mod (s / subcutaneous))))

# ::id pmid_1859_7688.141 ::date 2015-07-08T02:02:10 ::annotator SDL-AMR-09 ::preferred
# ::snt The RasV12-infected HME16C cells formed rapidly growing, fluid-filled tumors with an average latency of 4 weeks and a mean tumor volume of 808.8 mm3 at 6 weeks (Table 1).
# ::save-date Thu Feb 4, 2016 ::file pmid_1859_7688_141.txt
(f / form-01
      :ARG0 (c / cell-line :name (n / name :op1 "HME16C")
            :ARG1-of (i / infect-01
                  :ARG2 (e / enzyme :name (n2 / name :op1 "Ras")
                        :ARG2-of (m / mutate-01 :value "V12"))))
      :ARG1 (t / tumor
            :ARG1-of (g / grow-01
                  :manner (r2 / rapid))
            :ARG1-of (f2 / fill-01
                  :ARG2 (f3 / fluid))
            :mod (l / latency
                  :ARG1-of (a / average-01
                        :ARG2 (t2 / temporal-quantity :quant 4
                              :unit (w / week))))
            :mod (v / volume-quantity :quant 808.8
                  :mod (t3 / tumor
                        :mod (m2 / mean))
                  :unit (c2 / cubic-millimeter)
                  :time (a2 / after
                        :op1 (t4 / temporal-quantity :quant 6
                              :unit w))))
      :ARG1-of (d / describe-01
            :ARG0 (t5 / table :mod 1)))

# ::id pmid_1859_7688.142 ::date 2015-07-08T02:16:14 ::annotator SDL-AMR-09 ::preferred
# ::snt Approximately one-half of the tumors were aspirated prior to sacrifice, and a sero-sanguinous fluid was observed, on average accounting for roughly one-third of the measured tumor volume.
# ::save-date Fri Nov 6, 2015 ::file pmid_1859_7688_142.txt
(a / and
      :op1 (a2 / aspirate-101
            :ARG1 (t / tumor
                  :quant (h / half
                        :ARG1-of (a3 / approximate-01)))
            :time (p / prior
                  :op1 (s / sacrifice-01)))
      :op2 (o2 / observe-01
            :ARG1 (f / fluid
                  :mod (s2 / sero-sanguine)
                  :ARG0-of (a4 / account-01
                        :ARG1 (v / volume
                              :mod (t2 / tumor)
                              :ARG1-of (m / measure-01)
                              :quant (r2 / roughly :op1 "1/3"))
                        :ARG1-of (a5 / average-01)))))

# ::id pmid_1859_7688.143 ::date 2015-07-08T08:07:08 ::annotator SDL-AMR-09 ::preferred
# ::snt Histological analysis of H&E stained tumor sections revealed poorly differentiated spindle-shaped tumor cells with prominent squamous cell differentiation and extracellular keratin deposition (not shown).
# ::save-date Sat Feb 13, 2016 ::file pmid_1859_7688_143.txt
(r / reveal-01
      :ARG0 (a / analyze-01
            :ARG1 (s / section-01
                  :ARG1 (t / tumor)
                  :ARG1-of (s2 / stain-01
                        :ARG2 (a2 / and
                              :op1 (s7 / small-molecule :name (n / name :op1 "hematoxylin"))
                              :op2 (s8 / small-molecule :name (n2 / name :op1 "eosin")))))
            :mod (h / histology))
      :ARG1 (c / cell
            :mod t
            :ARG1-of (s3 / shape-01
                  :ARG2 (s4 / spindle))
            :ARG1-of (d / differentiate-101
                  :degree (p / poor))
            :ARG0-of (h2 / have-03
                  :ARG1 (a3 / and
                        :op1 (d2 / differentiate-101
                              :ARG1 (c2 / cell
                                    :mod (s5 / squamous))
                              :degree (p2 / prominent))
                        :op2 (d3 / deposit-01
                              :ARG1 (k / keratin)
                              :mod (e / extracellular)))))
      :ARG1-of (s6 / show-01 :polarity -))

# ::id pmid_1859_7688.144 ::date 2015-07-08T10:29:13 ::annotator SDL-AMR-09 ::preferred
# ::snt Tumors also contained a strong inflammatory component.
# ::save-date Wed Jul 8, 2015 ::file pmid_1859_7688_144.txt
(c / contain-01
      :ARG0 (t / tumor)
      :ARG1 (c2 / component
            :ARG0-of (i / inflame-01)
            :ARG1-of (s / strong-02))
      :mod (a / also))

# ::id pmid_1859_7688.145 ::date 2015-07-08T10:40:39 ::annotator SDL-AMR-09 ::preferred
# ::snt Of the other cell lines tested, only the RasV12S35-infected HME16C cells formed palpable tumors in 50% of injected animals with an average latency of approximately 12 weeks and a mean tumor volume of 109.0 mm3 at 16 weeks, considerably smaller than RasV12-expressing tumors (Table 1).
# ::save-date Sun Jan 17, 2016 ::file pmid_1859_7688_145.txt
(f / form-01
      :ARG1 (t / tumor
            :mod (p / palpable)
            :ARG0-of (h / have-03
                  :ARG1 (a3 / and
                        :op1 (l / latency
                              :duration (a4 / approximately
                                    :op1 (t3 / temporal-quantity :quant 12
                                          :unit (w / week))))
                        :op2 (v / volume
                              :mod t
                              :ARG1-of (a5 / average-01
                                    :ARG2 109.0
                                    :ARG3 (c3 / cubic-millimeter))
                              :time (a6 / after
                                    :quant (t4 / temporal-quantity :quant 16
                                          :unit w))
                              :degree (s / small
                                    :degree (m2 / more)
                                    :mod (c4 / considerable)
                                    :compared-to (t5 / tumor
                                          :ARG3-of (e2 / express-03
                                                :ARG2 (e3 / enzyme :name (n3 / name :op1 "Ras")
                                                      :ARG2-of (m3 / mutate-01 :value "V12")))))))))
      :ARG2 (c / cell-line :name (n / name :op1 "HME16C")
            :ARG1-of (i / infect-01
                  :ARG2 (e / enzyme :name (n2 / name :op1 "Ras")
                        :ARG2-of (m / mutate-01 :value "V12S35")))
            :ARG1-of (i2 / include-01
                  :ARG2 (c2 / cell-line
                        :ARG1-of (t2 / test-01)
                        :mod (o / other)))
            :mod (o2 / only))
      :location (a / animal
            :ARG1-of (i3 / include-91
                  :ARG2 (a2 / animal
                        :ARG2-of (i4 / inject-01))
                  :ARG3 (p2 / percentage-entity :value 50)))
      :ARG1-of (d / describe-01
            :ARG0 (t6 / table :mod 1)))

# ::id pmid_1859_7688.146 ::date 2015-07-08T21:54:15 ::annotator SDL-AMR-09 ::preferred
# ::snt Cells within RasV12S35-infected tumors resembled the histology of RasV12 tumor cells but with less keratin deposition and without the formation of fluid-filled spaces (not shown).
# ::save-date Thu Jul 23, 2015 ::file pmid_1859_7688_146.txt
(r / resemble-01
      :ARG1 (c / cell
            :location (t / tumor
                  :ARG1-of (i / infect-01
                        :ARG2 (e / enzyme :name (n / name :op1 "Ras")
                              :ARG2-of (m / mutate-01 :value "V12S35")))))
      :ARG2 (h / histology
            :poss (c2 / cell
                  :mod (t2 / tumor
                        :ARG1-of (i2 / infect-01
                              :ARG2 (e3 / enzyme :name (n2 / name :op1 "Ras")
                                    :ARG2-of (m2 / mutate-01 :value "V12"))))))
      :ARG1-of (c3 / contrast-01
            :ARG2 (a / and
                  :op1 (h2 / have-03
                        :ARG0 c
                        :ARG1 (d / deposit-01
                              :ARG1 (k / keratin)
                              :quant (l / less)))
                  :op2 (f / form-01 :polarity -
                        :ARG1 (s / space
                              :ARG1-of (f2 / fill-01
                                    :ARG2 (f3 / fluid)))
                        :ARG2 c)))
      :ARG1-of (s2 / show-01 :polarity -))

# ::id pmid_1859_7688.147 ::date 2015-07-08T22:06:57 ::annotator SDL-AMR-09 ::preferred
# ::snt Empty vector-, RasV12G37-, RasV12C40-, and Rlf-CAAX-infected cells failed to form palpable tumors four months after injection.
# ::save-date Fri Feb 5, 2016 ::file pmid_1859_7688_147.txt
(f / fail-01
      :ARG1 (a / and
            :op1 (c / cell
                  :ARG1-of (i / infect-01
                        :ARG2 (v / vector
                              :ARG2-of (e / empty-01))))
            :op2 (c2 / cell
                  :ARG1-of (i2 / infect-01
                        :ARG2 (e2 / enzyme :name (n / name :op1 "Ras")
                              :ARG2-of (m / mutate-01 :value "V12G37"))))
            :op3 (c3 / cell
                  :ARG1-of (i3 / infect-01
                        :ARG2 (e3 / enzyme :name (n2 / name :op1 "Ras")
                              :ARG2-of (m2 / mutate-01 :value "V12C40"))))
            :op4 (c4 / cell
                  :ARG1-of (i4 / infect-01
                        :ARG2 (e4 / enzyme :name (n3 / name :op1 "Rlf-CAAX")))))
      :ARG2 (f2 / form-01
            :ARG0 c
            :ARG1 (t / tumor
                  :mod (p2 / palpable)))
      :time (a2 / after
            :op1 (i5 / inject-01)
            :quant (t2 / temporal-quantity :quant 4
                  :unit (m3 / month))))

# ::id pmid_1859_7688.148 ::date 2015-07-08T22:27:50 ::annotator SDL-AMR-09 ::preferred
# ::snt The metastatic potential of RasV12- and RasV12G37-expressing cell lines was tested by tail-vein injection in nude mice, but no metastatic lesions were observed by histological analysis in lungs, liver, spleen, or kidneys at 16 weeks post injection (not shown).
# ::save-date Thu Jul 23, 2015 ::file pmid_1859_7688_148.txt
(c / contrast-01
      :ARG1 (t / test-01
            :ARG1 (p / potential
                  :mod (m / metastasize-101
                        :ARG2 (a / and
                              :op1 (c2 / cell-line
                                    :ARG3-of (e / express-03
                                          :ARG2 (e2 / enzyme :name (n / name :op1 "Ras")
                                                :ARG2-of (m2 / mutate-01 :value "V12"))))
                              :op2 (c3 / cell-line
                                    :ARG3-of (e3 / express-03
                                          :ARG2 (e4 / enzyme :name (n2 / name :op1 "Ras")
                                                :ARG2-of (m3 / mutate-01 :value "V12G37")))))))
            :manner (i / inject-01
                  :ARG2 (v / vein
                        :part-of (t2 / tail
                              :part-of (m4 / mouse
                                    :mod (n3 / nude))))))
      :ARG2 (o / observe-01 :polarity -
            :ARG1 (l / lesion
                  :mod m)
            :manner (a2 / analyze-01
                  :mod (h / histology))
            :location (o2 / or
                  :op1 (l2 / lung)
                  :op2 (l3 / liver)
                  :op3 (s / spleen)
                  :op4 (k / kidney))
            :time (a3 / after
                  :op1 (i2 / inject-01)
                  :quant (t3 / temporal-quantity :quant 16
                        :unit (w / week))))
      :ARG1-of (s2 / show-01 :polarity -))

# ::id pmid_1859_7688.149 ::date 2015-07-08T22:44:22 ::annotator SDL-AMR-09 ::preferred
# ::snt Autocrine EGFR signaling is required for RasV12G37- and RasV12C40-mediated, but not RasV12S35-mediated, HME16C cell anchorage- independent growth
# ::save-date Sun Jan 17, 2016 ::file pmid_1859_7688_149.txt
(r / require-01
      :ARG0 (g / grow-01
            :ARG0-of (d / depend-01 :polarity -
                  :ARG1 (a / anchor-01
                        :ARG1 (c / cell-line :name (n / name :op1 "HME16C"))))
            :ARG1-of (m / mediate-01
                  :ARG0 (a2 / and
                        :op1 (e / enzyme :name (n2 / name :op1 "Ras")
                              :ARG2-of (m2 / mutate-01 :value "V12G37"))
                        :op2 (e2 / enzyme :name (n3 / name :op1 "Ras")
                              :ARG2-of (m3 / mutate-01 :value "V12C40")))))
      :ARG1 (s / signal-07
            :ARG0 (a3 / autocrine)
            :ARG1 (e4 / enzyme :name (n4 / name :op1 "EGFR")))
      :ARG1-of (c2 / contrast-01
            :ARG2 (r2 / require-01 :polarity -
                  :ARG0 (g2 / grow-01
                        :ARG0-of d
                        :ARG1-of (m4 / mediate-01
                              :ARG0 (e3 / enzyme :name (n5 / name :op1 "Ras")
                                    :ARG2-of (m5 / mutate-01 :value "V12S35"))))
                  :ARG1 s)))

# ::id pmid_1859_7688.150 ::date 2015-07-08T23:06:02 ::annotator SDL-AMR-09 ::preferred
# ::snt EGFR signaling is frequently altered in breast cancer, where EGFR and ErbB2 over-expression are common events.
# ::save-date Sun Jan 17, 2016 ::file pmid_1859_7688_150.txt
(a / alter-01
      :ARG1 (s / signal-07
            :ARG1 (e2 / enzyme :name (n / name :op1 "EGFR")))
      :ARG1-of (f / frequent-02)
      :location (d / disease :wiki "Breast_cancer" :name (n2 / name :op1 "breast" :op2 "cancer")
            :location-of (e / event
                  :mod (c2 / common)
                  :domain (o / overexpress-01
                        :ARG1 (a2 / and
                              :op1 e2
                              :op2 (p / protein :name (n3 / name :op1 "ErbB2")))))))

# ::id pmid_1859_7688.151 ::date 2015-07-08T23:15:36 ::annotator SDL-AMR-09 ::preferred
# ::snt cDNA microarray and real-time RT-PCR analysis of HME16C RasV12- and Ras EDM-infected cells (Additional file 1) revealed increased levels of mRNAs for EGFR ligands, including epiregulin, amphiregulin, and TGFa (Table 2).
# ::save-date Sun Jan 17, 2016 ::file pmid_1859_7688_151.txt
(r / reveal-01
      :ARG0 (a / and
            :op1 (a2 / analyze-01
                  :ARG1 (a3 / and
                        :op1 (c / cell-line :name (n / name :op1 "HME16C")
                              :ARG1-of (i / infect-01
                                    :ARG2 (e / enzyme :name (n2 / name :op1 "Ras")
                                          :ARG2-of (m / mutate-01 :value "V12"))))
                        :op2 (c2 / cell-line :name (n3 / name :op1 "HME16C")
                              :ARG1-of (i2 / infect-01
                                    :ARG2 (e2 / enzyme :name (n4 / name :op1 "Ras" :op2 "EDM")))))
                  :instrument (m2 / microarray
                        :consist-of (n5 / nucleic-acid :name (n13 / name :op1 "cDNA"))))
            :op2 (a4 / analyze-01
                  :ARG1 a3
                  :mod (r3 / react-01
                        :ARG0 (p / polymerase)
                        :mod (c3 / chain)
                        :subevent (t / transcribe-01
                              :ARG1-of (r4 / reverse-01))
                        :mod (r2 / real-time)))
            :ARG1-of (d / describe-01
                  :ARG0 (f / file :mod 1
                        :ARG1-of (a5 / add-02))))
      :ARG1 (l / level
            :quant-of (n12 / nucleic-acid :name (n7 / name :op1 "mRNA"))
            :ARG1-of (i3 / increase-01))
      :location (l2 / ligand :name (n8 / name :op1 "EGFR")
            :ARG2-of (i4 / include-91
                  :ARG1 (a6 / and
                        :op1 (l3 / ligand :name (n9 / name :op1 "epiregulin"))
                        :op2 (l4 / ligand :name (n10 / name :op1 "amphiregulin"))
                        :op3 (l5 / ligand :name (n11 / name :op1 "TGFa")))))
      :ARG1-of (d2 / describe-01
            :ARG0 (t3 / table :mod 2)))

# ::id pmid_1859_7688.152 ::date 2015-07-08T23:42:09 ::annotator SDL-AMR-09 ::preferred
# ::snt In addition, increased levels of phospho-Erk were unexpectedly seen in RasV12G37- and RasV12C40-infected cells, possibly the result of autocrine activation of endogenous EGFR by secreted EGFR ligands.
# ::save-date Sat Jan 16, 2016 ::file pmid_1859_7688_152.txt
(a / and
      :op2 (s / see-01
            :ARG1 (l / level
                  :quant-of (e4 / enzyme :name (n / name :op1 "Erk")
                        :ARG3-of (p / phosphorylate-01))
                  :ARG1-of (i / increase-01))
            :ARG1-of (e2 / expect-01 :polarity -)
            :location (a2 / and
                  :op1 (c / cell
                        :ARG1-of (i2 / infect-01
                              :ARG2 (e / enzyme :name (n2 / name :op1 "Ras")
                                    :ARG2-of (m / mutate-01 :value "V12G37"))))
                  :op2 (c2 / cell
                        :ARG1-of (i3 / infect-01
                              :ARG2 (e3 / enzyme :name (n3 / name :op1 "Ras")
                                    :ARG2-of (m2 / mutate-01 :value "V12C40")))))
            :ARG2-of (r / result-01
                  :ARG1 (a3 / activate-01
                        :ARG0 (l2 / ligand :name (n4 / name :op1 "EGFR")
                              :ARG1-of (s2 / secrete-01))
                        :ARG1 (e5 / enzyme :name (n5 / name :op1 "EGFR")
                              :mod (e6 / endogenous))
                        :mod (a4 / autocrine))
                  :ARG1-of (p2 / possible-01))))

# ::id pmid_1859_7688.153 ::date 2015-07-08T23:58:31 ::annotator SDL-AMR-09 ::preferred
# ::snt The presence of EGFR was established using Western blots (not shown).
# ::save-date Sun Dec 13, 2015 ::file pmid_1859_7688_153.txt
(e / establish-01
      :ARG1 (b / be-located-at-91
            :ARG1 (e2 / enzyme :name (n / name :op1 "EGFR")))
      :ARG2-of (u / use-01
            :ARG1 (i / immunoblot-01))
      :ARG1-of (s / show-01 :polarity -))

# ::id pmid_1859_7688.154 ::date 2015-07-09T00:03:47 ::annotator SDL-AMR-09 ::preferred
# ::snt Therefore, we sought to determine if autocrine signaling by the EGFR was required for the anchorage-independent growth of Ras- or Ras EDM-infected cells.
# ::save-date Fri Jul 24, 2015 ::file pmid_1859_7688_154.txt
(c / cause-01
      :ARG1 (s / seek-01
            :ARG0 (w / we)
            :ARG1 (d / determine-01
                  :ARG0 w
                  :ARG1 (r / require-01 :mode interrogative
                        :ARG0 (g / grow-01
                              :ARG1 (o / or
                                    :op1 (c2 / cell
                                          :ARG1-of (i / infect-01
                                                :ARG2 (e / enzyme :name (n / name :op1 "Ras"))))
                                    :op2 (c3 / cell
                                          :ARG1-of (i2 / infect-01
                                                :ARG2 (e2 / enzyme :name (n2 / name :op1 "Ras" :op2 "EDM")))))
                              :ARG0-of (d2 / depend-01 :polarity -
                                    :ARG1 (a / anchor-01)))
                        :ARG1 (s2 / signal-07
                              :ARG0 (e3 / enzyme :name (n3 / name :op1 "EGFR"))
                              :mod (a2 / autocrine))))))

# ::id pmid_1859_7688.155 ::date 2015-07-09T00:18:43 ::annotator SDL-AMR-09 ::preferred
# ::snt RasV12- and Ras EDM-infected HME16C cells were grown in soft agar in the presence or absence of the EGFR-specific inhibitors, PD153035 and PD168393.
# ::save-date Sun Jan 17, 2016 ::file pmid_1859_7688_155.txt
(g / grow-01
      :ARG1 (a / and
            :op1 (c / cell-line :name (n / name :op1 "HME16C")
                  :ARG1-of (i / infect-01
                        :ARG2 (e / enzyme :name (n2 / name :op1 "Ras")
                              :ARG2-of (m / mutate-01 :value "V12"))))
            :op2 (c2 / cell-line :name (n3 / name :op1 "HME16C")
                  :ARG1-of (i2 / infect-01
                        :ARG2 (e2 / enzyme :name (n4 / name :op1 "Ras" :op2 "EDM")))))
      :location (a2 / agar
            :ARG1-of (s / soft-02))
      :manner (o / or
            :op1 (b / be-located-at-91
                  :ARG1 (a3 / and
                        :op1 (s2 / small-molecule :name (n5 / name :op1 "PD153035"))
                        :op2 (s3 / small-molecule :name (n6 / name :op1 "PD168393"))
                        :ARG0-of (i3 / inhibit-01)
                        :ARG1-of (s4 / specific-02
                              :ARG2 (e3 / enzyme :name (n7 / name :op1 "EGFR")))))
            :op2 (a4 / absent-01
                  :ARG1 a3)))

# ::id pmid_1859_7688.156 ::date 2015-07-09T00:58:21 ::annotator SDL-AMR-09 ::preferred
# ::snt Complete inhibition of colony formation for RasV12G37-infected and RasV12C40-infected cells was observed at 0.25 μM PD153035, a concentration that specifically inhibits EGFR [28], whereas both the RasV12- and RasV12S35-infected cells formed colonies efficiently at this same concentration of inhibitor (Figure 3A and 3B).
# ::save-date Mon Dec 21, 2015 ::file pmid_1859_7688_156.txt
(c / contrast-01
      :ARG1 (o / observe-01
            :ARG1 (i / inhibit-01
                  :ARG1 (f / form-01
                        :ARG0 (a / and
                              :op1 (c2 / cell
                                    :ARG1-of (i2 / infect-01
                                          :ARG2 (e / enzyme :name (n / name :op1 "Ras")
                                                :ARG2-of (m / mutate-01 :value "V12G37"))))
                              :op2 (c3 / cell
                                    :ARG1-of (i3 / infect-01
                                          :ARG2 (e2 / enzyme :name (n2 / name :op1 "Ras")
                                                :ARG2-of (m2 / mutate-01 :value "V12C40")))))
                        :ARG1 (c4 / colony))
                  :degree (c5 / complete-01))
            :manner (s / small-molecule :name (n3 / name :op1 "PD153035")
                  :quant (c6 / concentration-quantity :quant 0.25
                        :unit (m3 / micromolar)
                        :ARG0-of (i4 / inhibit-01
                              :ARG1 (e3 / enzyme :name (n4 / name :op1 "EGFR"))
                              :ARG1-of (s2 / specific-02))))
            :ARG1-of (d / describe-01
                  :ARG0 (p / publication
                        :ARG1-of (c7 / cite-01
                              :ARG2 28))))
      :ARG2 (f2 / form-01
            :ARG0 (a2 / and
                  :op1 (c8 / cell
                        :ARG1-of (i5 / infect-01
                              :ARG2 (e4 / enzyme :name (n5 / name :op1 "Ras")
                                    :ARG2-of (m4 / mutate-01 :value "V12"))))
                  :op2 (c9 / cell
                        :ARG1-of (i6 / infect-01
                              :ARG2 (e5 / enzyme :name (n6 / name :op1 "Ras")
                                    :ARG2-of (m5 / mutate-01 :value "V12S35")))))
            :ARG1 c4
            :ARG2-of (e6 / efficient-01)
            :manner s)
      :ARG1-of (d2 / describe-01
            :ARG0 (a3 / and
                  :op1 (f3 / figure :mod "3A")
                  :op2 (f4 / figure :mod "3B"))))

# ::id pmid_1859_7688.157 ::date 2015-07-09T01:54:35 ::annotator SDL-AMR-09 ::preferred
# ::snt Identical results were found for the EGFR-specific inhibitor PD168393 used at 0.1 μM, a concentration that specifically inhibits EGFR and Her-2 receptors [29](not shown).
# ::save-date Sun Jan 17, 2016 ::file pmid_1859_7688_157.txt
(f / find-01
      :ARG1 (t / thing
            :ARG2-of (r / result-01)
            :ARG2-of (i / identical-01))
      :ARG2 (s / small-molecule :name (n / name :op1 "PD168393")
            :ARG0-of (i2 / inhibit-01)
            :ARG1-of (s2 / specific-02
                  :ARG2 (e / enzyme :name (n2 / name :op1 "EGFR")))
            :ARG1-of (u / use-01
                  :manner (c / concentration-quantity :quant 0.1
                        :unit (m / micromolar)
                        :ARG0-of (i3 / inhibit-01
                              :ARG1 (a / and
                                    :op1 (e2 / enzyme :name (n3 / name :op1 "EGFR"))
                                    :op2 (r3 / receptor :name (n4 / name :op1 "Her-2")))
                              :ARG1-of (s3 / specific-02)))))
      :ARG1-of (d / describe-01
            :ARG0 (p / publication
                  :ARG1-of (c2 / cite-01
                        :ARG2 29)))
      :ARG1-of (s4 / show-01 :polarity -))

# ::id pmid_1859_7688.158 ::date 2015-07-09T02:12:45 ::annotator SDL-AMR-09 ::preferred
# ::snt Similarly, treatment of cells grown in ultra-low-attachment plates also demonstrated that EGFR inhibition substantially inhibited growth of RasV12G37-and RasV12C40-expressing cells relative to that of RasV12- and RasV12S35-expressing HME16C (Figure 2C).
# ::save-date Sun Jan 17, 2016 ::file pmid_1859_7688_158.txt
(d / demonstrate-01
      :ARG0 (t / treat-04
            :ARG1 (c / cell
                  :ARG1-of (g / grow-01
                        :location (p / plate
                              :ARG2-of (a / attach-01
                                    :ARG1-of (l / low-04
                                          :degree (u / ultra)))))))
      :ARG1 (i / inhibit-01
            :ARG0 (i2 / inhibit-01
                  :ARG1 (e / enzyme :name (n / name :op1 "EGFR")))
            :ARG1 (g2 / grow-01
                  :ARG1 (c2 / cell
                        :ARG3-of (e2 / express-03
                              :ARG2 (a2 / and
                                    :op1 (e3 / enzyme :name (n2 / name :op1 "Ras")
                                          :ARG2-of (m / mutate-01 :value "V12G37"))
                                    :op2 (e4 / enzyme :name (n3 / name :op1 "Ras")
                                          :ARG2-of (m2 / mutate-01 :value "V12C40"))))))
            :degree (s / substantial)
            :ARG1-of (r / relative-05
                  :ARG3 (g3 / grow-01
                        :ARG1 (c3 / cell-line :name (n4 / name :op1 "HME16C")
                              :ARG3-of (e5 / express-03
                                    :ARG2 (a3 / and
                                          :op1 (e6 / enzyme :name (n5 / name :op1 "Ras")
                                                :ARG2-of (m3 / mutate-01 :value "V12"))
                                          :op2 (e7 / enzyme :name (n6 / name :op1 "Ras")
                                                :ARG2-of (m4 / mutate-01 :value "V12S35"))))))))
      :mod (a4 / also)
      :ARG1-of (r2 / resemble-01)
      :ARG1-of (d2 / describe-01
            :ARG0 (f / figure :mod "2C")))

# ::id pmid_1859_7688.159 ::date 2015-07-09T02:45:18 ::annotator SDL-AMR-09 ::preferred
# ::snt Western blotting of cellular lysates from cells treated with 0.25 μM PD153035 showed that high levels of phosphorylated Erk were maintained only in RasV12- and RasV12S35-infected cells, but were significantly reduced in RasV12G37- or RasV12C40-infected cells treated with the inhibitor (Figure 3C), while phoshorylated Akt was minimally affected (not shown).
# ::save-date Sat Jan 16, 2016 ::file pmid_1859_7688_159.txt
(c / contrast-01
      :ARG1 (s / show-01
            :ARG0 (i6 / immunoblot-01
                  :ARG1 (l / lysate
                        :mod (c2 / cell)
                        :source (c3 / cell
                              :ARG1-of (t / treat-04
                                    :ARG2 (s2 / small-molecule :name (n / name :op1 "PD153035")
                                          :quant (c4 / concentration-quantity :quant 0.25
                                                :unit (m / micromolar))
                                          :ARG0-of (i / inhibit-01))))))
            :ARG1 (c5 / contrast-01
                  :ARG1 (m2 / maintain-01
                        :ARG1 (l2 / level
                              :quant-of (e / enzyme :name (n3 / name :op1 "Erk")
                                    :ARG3-of (p / phosphorylate-01))
                              :ARG1-of (h / high-02))
                        :location (a2 / and
                              :op1 (c6 / cell
                                    :ARG1-of (i2 / infect-01
                                          :ARG2 (e5 / enzyme :name (n4 / name :op1 "Ras")
                                                :ARG2-of (m3 / mutate-01 :value "V12"))))
                              :op2 (c7 / cell
                                    :ARG1-of (i3 / infect-01
                                          :ARG2 (e4 / enzyme :name (n5 / name :op1 "Ras")
                                                :ARG2-of (m4 / mutate-01 :value "V12S35"))))
                              :mod (o / only)))
                  :ARG2 (r / reduce-01
                        :ARG1 l2
                        :ARG2 (s3 / significant-02)
                        :location (o2 / or
                              :op1 (c8 / cell
                                    :ARG1-of (i4 / infect-01
                                          :ARG2 (e2 / enzyme :name (n6 / name :op1 "Ras")
                                                :ARG2-of (m5 / mutate-01 :value "V12G37"))))
                              :op2 (c9 / cell
                                    :ARG1-of (i5 / infect-01
                                          :ARG2 (e3 / enzyme :name (n7 / name :op1 "Ras")
                                                :ARG2-of (m6 / mutate-01 :value "V12C40"))))
                              :ARG1-of (t3 / treat-04
                                    :ARG2 s2))))
            :ARG1-of (d / describe-01
                  :ARG0 (f / figure :mod "3C")))
      :ARG2 (a3 / affect-01
            :ARG1 (e6 / enzyme :name (n8 / name :op1 "Akt")
                  :ARG3-of p)
            :ARG1-of (m7 / minimal-02)
            :ARG1-of (s4 / show-01 :polarity -)))

# ::id pmid_1859_7688.160 ::date 2015-07-09T03:12:41 ::annotator SDL-AMR-09 ::preferred
# ::snt Anchorage-independent growth therefore correlated with maintenance of high Erk activity in HME16C cells.
# ::save-date Sun Jan 17, 2016 ::file pmid_1859_7688_160.txt
(c / cause-01
      :ARG1 (c2 / correlate-01
            :ARG1 (g / grow-01
                  :ARG0-of (d / depend-01 :polarity -
                        :ARG1 (a / anchor-01)))
            :ARG2 (m / maintain-01
                  :ARG1 (a2 / activity-06
                        :ARG0 (e / enzyme :name (n / name :op1 "Erk"))
                        :ARG1-of (h / high-02))
                  :location (c3 / cell-line :name (n2 / name :op1 "HME16C")))))

# ::id pmid_1859_7688.161 ::date 2015-07-09T03:16:46 ::annotator SDL-AMR-09 ::preferred
# ::snt Consistent with this observation, inhibition of MEK, and therefore ERK signaling, using the MEK-specific inhibitor PD98059 at 10 μM, significantly inhibited soft agar colony formation by all cell lines (not shown).
# ::save-date Sat Jan 16, 2016 ::file pmid_1859_7688_161.txt
(i / inhibit-01
      :ARG0 (a / and
            :op1 (i2 / inhibit-01
                  :ARG1 (s / signal-07
                        :ARG0 (e / enzyme :name (n / name :op1 "MEK"))))
            :op2 (i3 / inhibit-01
                  :ARG1 (s2 / signal-07
                        :ARG0 (e2 / enzyme :name (n2 / name :op1 "Erk")))
                  :ARG1-of (c / cause-01
                        :ARG0 i2))
            :ARG2-of (u / use-01
                  :ARG1 (s3 / small-molecule :name (n3 / name :op1 "PD98059")
                        :ARG0-of (i4 / inhibit-01
                              :ARG1 e)
                        :ARG1-of (s4 / specific-02
                              :ARG2 e)
                        :quant (c2 / concentration-quantity :quant 10
                              :unit (m / micromolar)))))
      :ARG1 (f / form-01
            :ARG1 (c3 / colony
                  :mod (a2 / agar
                        :ARG1-of (s5 / soft-02)))
            :ARG2 (c4 / cell-line
                  :mod (a3 / all)))
      :ARG1-of (s6 / significant-02)
      :ARG1-of (c5 / consistent-01
            :ARG2 (o / observe-01
                  :mod (t / this)))
      :ARG1-of (s7 / show-01 :polarity -))

# ::id pmid_1859_7688.162 ::date 2015-07-09T03:39:35 ::annotator SDL-AMR-09 ::preferred
# ::snt Microarray analysis of gene expression changes in RasV12-, RasV12G37-, RasV12S35-, and RasV12C40-infected HME16C cells
# ::save-date Tue Jan 12, 2016 ::file pmid_1859_7688_162.txt
(a / analyze-01
      :ARG1 (c / change-01
            :ARG1 (e / express-03
                  :ARG1 (g / gene)))
      :mod (m / microarray)
      :location (a2 / and
            :op1 (c2 / cell-line :wiki -
                  :name (n / name :op1 "HME16C")
                  :ARG1-of (i / infect-01
                        :ARG2 (e2 / enzyme :wiki "Ras_subfamily"
                              :name (n2 / name :op1 "Ras")
                              :ARG2-of (m2 / mutate-01 :value "V12"))))
            :op2 (c3 / cell-line :wiki -
                  :name (n3 / name :op1 "HME16C")
                  :ARG1-of (i2 / infect-01
                        :ARG2 (e3 / enzyme :wiki "Ras_subfamily"
                              :name (n4 / name :op1 "Ras")
                              :ARG2-of (m3 / mutate-01 :value "V12G37"))))
            :op3 (c4 / cell-line :wiki -
                  :name (n5 / name :op1 "HME16C")
                  :ARG1-of (i3 / infect-01
                        :ARG2 (e4 / enzyme :wiki "Ras_subfamily"
                              :name (n6 / name :op1 "Ras")
                              :ARG2-of (m4 / mutate-01 :value "V12S35"))))
            :op4 (c5 / cell-line :wiki -
                  :name (n7 / name :op1 "HME16C")
                  :ARG1-of (i4 / infect-01
                        :ARG2 (e5 / enzyme :wiki "Ras_subfamily"
                              :name (n8 / name :op1 "Ras")
                              :ARG2-of (m5 / mutate-01 :value "V12C40"))))))

# ::id pmid_1859_7688.163 ::date 2015-07-09T03:44:45 ::annotator SDL-AMR-09 ::preferred
# ::snt Activation of the Ras oncogene is accompanied by the stimulation of multiple signal transduction pathways leading to the activation or repression of numerous transcription factors as well as changes in mRNA translation and stability, and thus, the modulation of gene expression.
# ::save-date Fri Feb 5, 2016 ::file pmid_1859_7688_163.txt
(a / accompany-01
      :ARG0 (s / stimulate-01
            :ARG1 (p / pathway
                  :ARG2-of (t / transduce-01
                        :ARG1 (s2 / signal-07))
                  :quant (m / multiple)))
      :ARG1 (a2 / activate-01
            :ARG1 (e2 / enzyme :name (n / name :op1 "Ras")
                  :ARG0-of (c3 / cause-01
                        :ARG1 (d / disease :wiki "Cancer" :name (n5 / name :op1 "cancer")))))
      :ARG0-of (l / lead-03
            :ARG2 (a3 / and
                  :op1 (a4 / and
                        :op1 (o2 / or
                              :op1 (a5 / activate-01
                                    :ARG1 (f / factor
                                          :ARG0-of (t2 / transcribe-01)
                                          :quant (n2 / numerous)))
                              :op2 (r / repress-01
                                    :ARG1 f))
                        :op2 (c / change-01
                              :ARG1 (a6 / and
                                    :op1 (t3 / translate-02
                                          :ARG1 (n4 / nucleic-acid :name (n3 / name :op1 "mRNA")))
                                    :op2 (s3 / stable-03
                                          :ARG1 n4))))
                  :op2 (c2 / cause-01
                        :ARG0 a4
                        :ARG1 (m2 / modulate-01
                              :ARG1 (e / express-03
                                    :ARG1 (g / gene)))))))

# ::id pmid_1859_7688.164 ::date 2015-07-09T04:17:05 ::annotator SDL-AMR-09 ::preferred
# ::snt To determine which gene expression changes accompany the transformation of HME16C human epithelial cells by activated Ras, we examined our transformed HME16C cells by cDNA microarray analysis.
# ::save-date Sun Jan 17, 2016 ::file pmid_1859_7688_164.txt
(e / examine-01
      :ARG0 (w / we)
      :ARG1 (c / cell-line :name (n / name :op1 "HME16C")
            :ARG1-of (t / transform-01)
            :ARG1-of (a / analyze-01
                  :instrument (m / microarray
                        :consist-of (n2 / nucleic-acid :name (n5 / name :op1 "cDNA"))))
            :poss w)
      :purpose (d / determine-01
            :ARG0 w
            :ARG1 (a2 / accompany-01
                  :ARG0 (c2 / change-01
                        :ARG1 (e2 / express-03
                              :ARG1 (g / gene)))
                  :ARG1 (t3 / transform-01
                        :ARG0 (e3 / enzyme :name (n3 / name :op1 "Ras")
                              :ARG1-of (a3 / activate-01))
                        :ARG1 (c3 / cell-line :name (n4 / name :op1 "HME16C")
                              :mod (e4 / epithelium
                                    :part-of (h / human)))))))

# ::id pmid_1859_7688.165 ::date 2015-07-09T04:37:52 ::annotator SDL-AMR-09 ::preferred
# ::snt To do this, RNA was isolated from H-RasV12 and H-RasV12 EDM expressing cells after treatment with doxycycline to fully induce gene expression and compared to RNA from identically treated pLRT vector-infected control cells.
# ::save-date Fri Feb 5, 2016 ::file pmid_1859_7688_165.txt
(a / and
      :op1 (i / isolate-01
            :ARG1 (n4 / nucleic-acid :name (n5 / name :op1 "RNA"))
            :ARG2 (a2 / and
                  :op1 (c / cell
                        :ARG3-of (e / express-03
                              :ARG2 (e2 / enzyme :name (n / name :op1 "H-Ras")
                                    :ARG2-of (m / mutate-01 :value "V12"))))
                  :op2 (c2 / cell
                        :ARG3-of (e3 / express-03
                              :ARG2 (e4 / enzyme :name (n2 / name :op1 "H-Ras" :op2 "EDM")
                                    :ARG2-of m))))
            :time (a3 / after
                  :op1 (t / treat-04
                        :ARG1 a2
                        :ARG2 (d / doxycycline)))
            :purpose (i2 / induce-01
                  :ARG0 n4
                  :ARG2 (e5 / express-03
                        :ARG1 (g / gene))
                  :degree (f / full)))
      :op2 (c3 / compare-01
            :ARG1 i
            :ARG2 (i3 / isolate-01
                  :ARG1 n4
                  :ARG2 (c4 / cell
                        :ARG2-of (c5 / control-01)
                        :ARG1-of (i4 / infect-01
                              :ARG2 (v / vector :name (n3 / name :op1 "LRT")
                                    :ARG3-of (p / phosphorylate-01)))
                        :ARG1-of (t2 / treat-04
                              :ARG2 d
                              :ARG2-of (i5 / identical-01)))))
      :purpose (d2 / do-02
            :ARG1 (t3 / this)))

# ::id pmid_1859_7688.166 ::date 2015-07-09T05:01:44 ::annotator SDL-AMR-09 ::preferred
# ::snt Statistical analysis of microarray (SAM) data analysis was performed for the datasets, and a delta value of 0.4 was chosen for each dataset, which maintains the estimated false discovery rate (FDR) below 1% for each.
# ::save-date Tue Nov 10, 2015 ::file pmid_1859_7688_166.txt
(a / and
      :op1 (p / perform-01
            :ARG1 (a2 / analyze-01
                  :ARG1 (d5 / data
                        :topic (m2 / microarray))
                  :purpose (d / dataset)
                  :mod (s / statistics)))
      :op2 (c / choose-01
            :ARG1 (v / value :quant 0.4
                  :mod (d2 / delta))
            :ARG3 (d3 / dataset
                  :mod (e / each))
            :ARG0-of (m / maintain-01
                  :ARG1 (r / rate
                        :mod (d4 / discover-01)
                        :mod (f / false)
                        :ARG1-of (e2 / estimate-01))
                  :ARG2 (b / below
                        :quant (p2 / percentage-entity :value 1)))
            :beneficiary d3))

# ::id pmid_1859_7688.167 ::date 2015-07-09T05:19:32 ::annotator SDL-AMR-09 ::preferred
# ::snt A summary of the genes up- or down-regulated greater than 2-fold in the H-RasV12- and Ras effector domain mutant-infected HME16C cell lines is presented in Additional file 1, organized according to broad categories of gene function.
# ::save-date Sat Jan 16, 2016 ::file pmid_1859_7688_167.txt
(p / present-01
      :ARG1 (s / summarize-01
            :ARG1 (o / or
                  :op1 (g / gene
                        :ARG1-of (u / upregulate-01))
                  :op2 (g2 / gene
                        :ARG1-of (d / downregulate-01))
                  :quant (m2 / more-than
                        :op1 (p2 / product-of :quant 2))
                  :location (a / and
                        :op1 (c / cell-line :name (n / name :op1 "HME16C")
                              :ARG1-of (i / infect-01
                                    :ARG2 (e / enzyme :name (n2 / name :op1 "H-Ras")
                                          :ARG2-of (m / mutate-01 :value "V12"))))
                        :op2 (c2 / cell-line :name (n3 / name :op1 "HME16C")
                              :ARG1-of (i2 / infect-01
                                    :ARG2 (d2 / domain
                                          :part-of (e2 / effector
                                                :mod (p3 / protein-family :name (n4 / name :op1 "Ras")))
                                          :ARG2-of (m3 / mutate-01))))))
            :ARG1-of (o2 / organize-01
                  :ARG1-of (c3 / consistent-01
                        :ARG2 (c4 / categorize-01
                              :ARG1 (f / function
                                    :mod (g4 / gene))
                              :ARG1-of (b / broad-02)))))
      :location (f2 / file :mod 1
            :ARG1-of (a2 / add-02)))

# ::id pmid_1859_7688.168 ::date 2015-07-09T05:57:59 ::annotator SDL-AMR-09 ::preferred
# ::snt To validate gene expression changes identified by cDNA microarray analysis, quantitative RT-PCR was performed using RNA from the same samples used in microarray analysis, and is presented in Additional file 2.
# ::save-date Sun Dec 20, 2015 ::file pmid_1859_7688_168.txt
(a / and
      :op1 (p / perform-01
            :ARG1 (r / react-01
                  :ARG0 (p3 / polymerase)
                  :mod (q / quantitative)
                  :mod (c2 / chain)
                  :subevent (t / transcribe-01
                        :ARG1-of (r2 / reverse-01)))
            :ARG2-of (u / use-01
                  :ARG1 (n3 / nucleic-acid :name (n4 / name :op1 "RNA")
                        :source (t2 / thing
                              :ARG1-of (s / sample-01)
                              :ARG1-of (s2 / same-01
                                    :ARG2 (t3 / thing
                                          :ARG1-of (s3 / sample-01)
                                          :ARG1-of (u2 / use-01
                                                :ARG2 (a2 / analyze-01
                                                      :mod (m / microarray
                                                            :consist-of (n5 / nucleic-acid :name (n6 / name :op1 "cDNA")))))))))))
      :op2 (p2 / present-01
            :ARG1 r
            :location (f / file :mod 2
                  :ARG1-of (a3 / add-02)))
      :purpose (v / validate-01
            :ARG1 (c / change-01
                  :ARG1 (e / express-03
                        :ARG1 (g / gene))
                  :ARG1-of (i / identify-01
                        :ARG0 a2))))

# ::id pmid_1859_7688.169 ::date 2015-07-09T06:10:53 ::annotator SDL-AMR-09 ::preferred
# ::snt Results for 22 of 26 genes chosen to reflect genes up- or down-regulated both strongly or weakly showed strong agreement with microarray data, demonstrating that the microarray dataset represents a reliable quantification of gene expression changes.
# ::save-date Fri Feb 5, 2016 ::file pmid_1859_7688_169.txt
(s / show-01
      :ARG0 (t / thing
            :ARG2-of (r / result-01
                  :ARG1 (g / gene :quant 22
                        :ARG1-of (i / include-91
                              :ARG2 (g2 / gene :quant 26
                                    :ARG2-of (c / choose-01
                                          :ARG1 g
                                          :ARG4 (r2 / reflect-01
                                                :ARG1 g
                                                :ARG2 (o / or
                                                      :op1 (g3 / gene
                                                            :ARG1-of (u / upregulate-01
                                                                  :degree (o2 / or
                                                                        :op1 (s2 / strong-02)
                                                                        :op2 (w / weak-02))))
                                                      :op2 (g4 / gene
                                                            :ARG1-of (d / downregulate-01
                                                                  :degree o2))))))))))
      :ARG1 (a / agree-01
            :ARG0 t
            :ARG1 (d2 / data
                  :mod (m / microarray))
            :degree s2)
      :ARG0-of (d3 / demonstrate-01
            :ARG1 (r3 / represent-01
                  :ARG0 (d4 / dataset
                        :mod m)
                  :ARG1 (q / quantify-01
                        :ARG1 (c2 / change-01
                              :ARG1 (e / express-03
                                    :ARG1 o))
                        :ARG1-of (r4 / rely-01
                              :ARG1-of (p / possible-01))))))

# ::id pmid_1859_7688.170 ::date 2015-07-09T06:27:48 ::annotator SDL-AMR-09 ::preferred
# ::snt To evaluate the effect of EGFR inhibition on gene expression, RasV12-, RasV12S35-, and RasV12G37-infected cells were induced with doxycycline and subsequently incubated either in the presence or absence of 0.25 μM PD153035, and microarray analysis comparisons were made to vehicle-treated pLRT-infected cells.
# ::save-date Sun Jan 17, 2016 ::file pmid_1859_7688_170.txt
(a / and
      :op1 (a2 / and
            :op1 (i / induce-01
                  :ARG0 (d / doxycycline)
                  :ARG2 (a3 / and
                        :op1 (c / cell
                              :ARG1-of (i2 / infect-01
                                    :ARG2 (e / enzyme :name (n / name :op1 "Ras")
                                          :ARG2-of (m / mutate-01 :value "V12"))))
                        :op2 (c2 / cell
                              :ARG1-of (i3 / infect-01
                                    :ARG2 (e2 / enzyme :name (n2 / name :op1 "Ras")
                                          :ARG2-of (m2 / mutate-01 :value "V12S35"))))
                        :op3 (c3 / cell
                              :ARG1-of (i4 / infect-01
                                    :ARG2 (e3 / enzyme :name (n3 / name :op1 "Ras")
                                          :ARG2-of (m3 / mutate-01 :value "V12G37"))))))
            :op2 (i5 / incubate-01
                  :ARG1 a3
                  :ARG2 (o / or
                        :op1 (b / be-located-at-91
                              :ARG1 (s / small-molecule :name (n4 / name :op1 "PD153035")
                                    :ARG0-of (i6 / inhibit-01)
                                    :quant (c4 / concentration-quantity :quant 0.25
                                          :unit (m4 / micromolar))))
                        :op2 (a4 / absent-01
                              :ARG1 s)
                        :mod (e4 / either))
                  :time (s2 / subsequent)))
      :op2 (m5 / make-01
            :ARG1 (c5 / compare-01
                  :ARG1 a3
                  :ARG2 (c6 / cell
                        :ARG1-of (i7 / infect-01
                              :ARG2 (p2 / protein :name (n5 / name :op1 "LRT")
                                    :ARG3-of (p / phosphorylate-01)))
                        :ARG1-of (t / treat-04
                              :ARG2 (v / vehicle)))
                  :mod (m7 / microarray)))
      :purpose (e5 / evaluate-01
            :ARG1 (a5 / affect-01
                  :ARG0 (i8 / inhibit-01
                        :ARG1 (e7 / enzyme :name (n6 / name :op1 "EGFR")))
                  :ARG1 (e6 / express-03
                        :ARG1 (g / gene)))))

# ::id pmid_1859_7688.171 ::date 2015-07-09T06:56:08 ::annotator SDL-AMR-09 ::preferred
# ::snt Almost all Ras and Ras EDM-induced upregulated transcriptional responses were blocked by pharmacological inhibition of EGFR, consistent with previous reports for inhibition of Raf-regulated transcription [30].
# ::save-date Mon Feb 15, 2016 ::file pmid_1859_7688_171.txt
(b / block-01
      :ARG0 (i / inhibit-01
            :ARG1 (e4 / enzyme :name (n / name :op1 "EGFR"))
            :mod (p2 / pharmacology))
      :ARG1 (t / thing
            :ARG2-of (r / respond-01)
            :ARG1-of (t2 / transcribe-01)
            :ARG1-of (u / upregulate-01)
            :ARG2-of (i2 / induce-01
                  :ARG0 (a / and
                        :op1 (e / enzyme :name (n2 / name :op1 "Ras"))
                        :op2 (e2 / enzyme :name (n3 / name :op1 "Ras" :op2 "EDM"))))
            :mod (a2 / all
                  :degree (a3 / almost)))
      :ARG1-of (c / consistent-01
            :ARG2 (r2 / report-01
                  :ARG1 (i3 / inhibit-01
                        :ARG1 (t3 / transcribe-01
                              :ARG1-of (r3 / regulate-01
                                    :ARG0 (e3 / enzyme :name (n4 / name :op1 "Raf")))))
                  :time (p3 / previous)))
      :ARG1-of (d / describe-01
            :ARG0 (p4 / publication
                  :ARG1-of (c2 / cite-01
                        :ARG2 30))))

# ::id pmid_1859_7688.172 ::date 2015-07-09T15:10:23 ::annotator SDL-AMR-09 ::preferred
# ::snt Our analysis identified PHLDA1 as an up-regulated gene in both vehicle-treated and PD153035-treated RasV12 and RasV12S35 cells, although the relative fold increase was reduced following EGFR inhibition.
# ::save-date Mon Jul 27, 2015 ::file pmid_1859_7688_172.txt
(h / have-concession-91
      :ARG1 (i / identify-01
            :ARG0 (a / analyze-01
                  :ARG0 (w / we))
            :ARG1 (g2 / gene :wiki -
                  :name (n2 / name :op1 "PHLDA1"))
            :ARG2 (g3 / gene
                  :ARG1-of (u / upregulate-01))
            :location (a2 / and
                  :op1 (c2 / cell
                        :ARG1-of (t2 / treat-04
                              :ARG2 (s / small-molecule :wiki -
                                    :name (n3 / name :op1 "PD153035")))
                        :mod (e / enzyme :wiki "Ras_subfamily"
                              :name (n4 / name :op1 "Ras")
                              :ARG2-of (m2 / mutate-01 :value "V12")))
                  :op2 (c3 / cell
                        :ARG1-of (t / treat-04
                              :ARG0 (v / vehicle))
                        :mod (e2 / enzyme :wiki "Ras_subfamily"
                              :name (n5 / name :op1 "Ras")
                              :ARG2-of (m3 / mutate-01 :value "V12S35")))))
      :ARG2 (r / reduce-01
            :ARG1 (i2 / increase-01
                  :ARG2 (p / product-of)
                  :ARG1-of (r2 / relative-05))
            :ARG1-of (f2 / follow-01
                  :ARG2 (i3 / inhibit-01
                        :ARG1 (e3 / enzyme :wiki "Epidermal_growth_factor_receptor"
                              :name (n / name :op1 "EGFR"))))))

# ::id pmid_1859_7688.173 ::date 2015-07-10T06:05:56 ::annotator SDL-AMR-09 ::preferred
# ::snt By comparison, PHLDA1 was down-regulated in PD153035-treated RasV12G37 relative to vehicle-treated cells (not shown).
# ::save-date Thu Jul 23, 2015 ::file pmid_1859_7688_173.txt
(d / downregulate-01
      :ARG1 (g / gene :name (n / name :op1 "PHLDA1"))
      :ARG1-of (c / compare-01)
      :location (c3 / cell
            :mod (e / enzyme
                  :ARG2-of (m / mutate-01 :value "V12G37")
                  :ARG1-of (t / treat-04
                        :ARG2 (s2 / small-molecule :name (n2 / name :op1 "PD153035"))))
            :ARG1-of (r / relative-05
                  :ARG3 (c2 / cell
                        :ARG1-of (t2 / treat-04
                              :ARG0 (v / vehicle)))))
      :ARG1-of (s / show-01 :polarity -))

# ::id pmid_1859_7688.174 ::date 2015-07-10T06:22:26 ::annotator SDL-AMR-09 ::preferred
# ::snt Therefore, PHLDA1 represents a Raf/ERK-responsive gene whose expression parallels EGFR-independent HME16C mammary epithelial cell transformation.
# ::save-date Sun Jan 17, 2016 ::file pmid_1859_7688_174.txt
(c2 / cause-01
      :ARG1 (r / represent-01
            :ARG0 (g / gene :name (n / name :op1 "PHLDA1"))
            :ARG1 (p2 / pathway :name (n2 / name :op1 "Raf/ERK")
                  :ARG0-of (r2 / responsive-02)
                  :ARG1-of (e / express-01
                        :ARG0-of (p / parallel-01
                              :ARG1 (t / transform-01
                                    :ARG1 (c / cell-line :name (n3 / name :op1 "HME16C")
                                          :location (e2 / epithelium)
                                          :mod (m / mammary)
                                          :ARG0-of (d / depend-01 :polarity -
                                                :ARG1 (e3 / enzyme :name (n4 / name :op1 "EGFR"))))))))))

# ::id pmid_1859_7688.175 ::date 2015-07-10T03:22:41 ::annotator SDL-AMR-09 ::preferred
# ::snt TDAG51 expression is up-regulated by Ras signaling in a ERK-dependent manner, and is associated with EGFR-independent transformation
# ::save-date Sat Jan 16, 2016 ::file pmid_1859_7688_175.txt
(a / and
      :op1 (u2 / upregulate-01
            :ARG1 (e / express-03
                  :ARG2 (p2 / protein :name (n / name :op1 "TDAG51")))
            :ARG2 (s / signal-07
                  :ARG1 (e2 / enzyme :name (n2 / name :op1 "Ras"))
                  :manner (d / depend-01
                        :ARG1 (e4 / enzyme :name (n3 / name :op1 "ERK")))))
      :op2 (a2 / associate-01
            :ARG1 e
            :ARG2 (t / transform-01
                  :ARG0-of (d2 / depend-01
                        :ARG1 (e3 / enzyme :name (n4 / name :op1 "EGFR"))))))

# ::id pmid_1859_7688.176 ::date 2015-07-10T03:49:59 ::annotator SDL-AMR-09 ::preferred
# ::snt The PHLDA1 gene is of interest as it has been suggested to be a tumor suppressor in breast adenocarcinoma and melanoma [17,18].
# ::save-date Thu Jan 14, 2016 ::file pmid_1859_7688_176.txt
(c / cause-01
      :ARG0 (s / suggest-01
            :ARG1 (s2 / suppress-01
                  :ARG0 g
                  :ARG1 (t / tumor)
                  :location (a / and
                        :op1 (m2 / medical-condition :name (n2 / name :op1 "adenocarcinoma"))
                        :op2 (m / medical-condition :name (n3 / name :op1 "melanoma"))
                        :mod (b / breast))))
      :ARG1 (i / interest-01
            :ARG0 (g / gene :name (n / name :op1 "PHLDA1")))
      :ARG1-of (d / describe-01
            :ARG0 (p / publication
                  :ARG1-of (c2 / cite-01
                        :ARG2 (a3 / and :op1 17 :op2 18)))))

# ::id pmid_1859_7688.177 ::date 2015-07-10T04:15:47 ::annotator SDL-AMR-09 ::preferred
# ::snt We further analyzed the signal dependent expression of the PHLDA1 gene and its protein product, TDAG51.
# ::save-date Thu Jul 23, 2015 ::file pmid_1859_7688_177.txt
(a / analyze-01
      :ARG0 (w / we)
      :ARG1 (a2 / and
            :op1 (e / express-03
                  :ARG1 (g / gene :name (n2 / name :op1 "PHLDA1")
                        :ARG0-of (d / depend-01
                              :ARG1 (s / signal))))
            :op2 (p2 / protein :name (n / name :op1 "TDAG51")
                  :ARG1-of (p / produce-01
                        :ARG0 g)))
      :degree (f / further))

# ::id pmid_1859_7688.178 ::date 2015-07-10T04:23:06 ::annotator SDL-AMR-09 ::preferred
# ::snt Microarray analysis identified the PHLDA1 gene as being dramatically up-regulated in RasV12- and Ras EDM-infected cells to levels that correlated with the level of ERK activation and the extent of anchorage-independent growth (Additional file 1).
# ::save-date Sat Jan 16, 2016 ::file pmid_1859_7688_178.txt
(i / identify-01
      :ARG0 (a2 / analyze-01
            :ARG1 (m / microarray))
      :ARG1 (u / upregulate-01
            :ARG1 (g / gene :name (n / name :op1 "PHLDA1"))
            :location (a3 / and
                  :op1 (c / cell
                        :ARG1-of (i2 / infect-01
                              :ARG2 (e / enzyme :name (n2 / name :op1 "Ras")
                                    :ARG2-of (m2 / mutate-01 :value "V12"))))
                  :op2 (c2 / cell
                        :ARG1-of (i3 / infect-01
                              :ARG0 (e2 / enzyme :name (n3 / name :op1 "EDM")))))
            :manner (d2 / dramatic)
            :degree (l / level
                  :ARG1-of (c3 / correlate-01
                        :ARG2 (a5 / and
                              :op1 (l2 / level
                                    :degree-of (a4 / activate-01
                                          :ARG1 (e3 / enzyme :name (n4 / name :op1 "ERK"))))
                              :op2 (e4 / extent
                                    :degree-of (g2 / grow-01
                                          :ARG0-of (d3 / depend-01 :polarity -
                                                :ARG1 (a6 / anchorage))))))))
      :ARG1-of (d / describe-01
            :ARG0 (f / file :mod 1
                  :mod (a / additional))))

# ::id pmid_1859_7688.179 ::date 2015-07-10T16:37:38 ::annotator SDL-AMR-09 ::preferred
# ::snt Western blotting confirmed that TDAG51 was also upregulated in a similar manner (Figure 4A).
# ::save-date Wed Dec 30, 2015 ::file pmid_1859_7688_179.txt
(c / confirm-01
      :ARG0 (i / immunoblot-01)
      :ARG1 (u / upregulate-01
            :ARG1 (p / protein :name (n2 / name :op1 "TDAG51"))
            :mod (a2 / also)
            :ARG1-of (r / resemble-01
                  :ARG2 (m / manner)))
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod "4A")))

# ::id pmid_1859_7688.180 ::date 2015-07-10T16:44:18 ::annotator SDL-AMR-09 ::preferred
# ::snt The PHLDA1 gene was elevated in PD153035-treated RasV12- and RasV12S35-infected cells but was significantly dependent upon EGFR tyrosine kinase activity for upregulation in RasV12G37- and RasV12C40-infected cells (not shown), and the expression of the encoded TDAG51 protein approximately paralleled PHLDA1 RNA expression (Figure 4B).
# ::save-date Mon Dec 21, 2015 ::file pmid_1859_7688_180.txt
(a / and
      :op1 (c / contrast-01
            :ARG1 (e4 / elevate-01
                  :ARG1 (g2 / gene :wiki -
                        :name (n7 / name :op1 "PHLDA1"))
                  :location (a3 / and
                        :op1 (c2 / cell
                              :ARG1-of (i / infect-01
                                    :ARG2 (e6 / enzyme :wiki "Ras_subfamily"
                                          :name (n4 / name :op1 "Ras")
                                          :ARG2-of (m / mutate-01 :value "V12"))))
                        :op2 (c3 / cell
                              :ARG1-of (i2 / infect-01
                                    :ARG2 (e7 / enzyme :wiki "Ras_subfamily"
                                          :name (n5 / name :op1 "Ras")
                                          :ARG2-of (m2 / mutate-01 :value "V12S35"))))
                        :ARG1-of (t / treat-04
                              :ARG2 (s / small-molecule :wiki -
                                    :name (n6 / name :op1 "PD153035")))))
            :ARG2 (d2 / depend-01
                  :ARG0 g2
                  :ARG1 (a4 / activity-06
                        :ARG0 (k / kinase
                              :mod (e10 / enzyme :wiki "Epidermal_growth_factor_receptor"
                                    :name (n11 / name :op1 "EGFR"))
                              :mod (t2 / tyrosine))
                        :ARG1 (u / upregulate-01
                              :ARG1 (a5 / and
                                    :op1 (c4 / cell
                                          :ARG1-of (i3 / infect-01
                                                :ARG2 (e8 / enzyme :wiki "Ras_subfamily"
                                                      :name (n9 / name :op1 "Ras")
                                                      :ARG2-of (m3 / mutate-01 :value "V12G37"))))
                                    :op2 (c5 / cell
                                          :ARG1-of (i4 / infect-01
                                                :ARG2 (e9 / enzyme :wiki "Ras_subfamily"
                                                      :name (n10 / name :op1 "Ras")
                                                      :ARG2-of (m4 / mutate-01 :value "V12C40")))))
                              :ARG1-of (s3 / show-01 :polarity -)))
                  :ARG1-of (s2 / significant-02)))
      :op2 (p / parallel-01
            :ARG0 (e3 / express-03
                  :ARG2 (p2 / protein :wiki "PHLDA1"
                        :name (n / name :op1 "TDAG51")
                        :ARG1-of (e2 / encode-01)))
            :ARG1 (e / express-03
                  :ARG1 (n8 / nucleic-acid :wiki "RNA"
                        :name (n3 / name :op1 "RNA")
                        :ARG0-of (e5 / encode-01
                              :ARG1 (g / gene :wiki -
                                    :name (n2 / name :op1 "PHLDA1")))))
            :degree (a2 / approximate))
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod "4B")))

# ::id pmid_1859_7688.181 ::date 2015-07-11T04:11:30 ::annotator SDL-AMR-09 ::preferred
# ::snt As shown in Figure 3C, EGFR inhibition significantly reduced ERK signaling in RasV12G37- and RasV12C40-infected cells without affecting RasV12- and RasV12S35-infected cells.
# ::save-date Sat Jan 16, 2016 ::file pmid_1859_7688_181.txt
(r / reduce-01
      :ARG0 (i / inhibit-01
            :ARG1 (e / enzyme :name (n / name :op1 "EGFR")))
      :ARG1 (s3 / signal-07
            :ARG0 (e6 / enzyme :name (n2 / name :op1 "ERK"))
            :location (a / and
                  :op1 (c2 / cell
                        :ARG1-of (i2 / infect-01
                              :ARG2 (e4 / enzyme :name (n3 / name :op1 "Ras")
                                    :ARG2-of (m / mutate-01 :value "V12G37"))))
                  :op2 (c / cell
                        :ARG1-of (i5 / infect-01
                              :ARG2 (e5 / enzyme :name (n6 / name :op1 "Ras")
                                    :ARG2-of (m2 / mutate-01 :value "V12C40"))))))
      :ARG2 (s2 / significant-02)
      :ARG1-of (s / show-01
            :ARG0 (f / figure :mod "3C"))
      :ARG0-of (a2 / affect-01 :polarity -
            :ARG1 (a3 / and
                  :op1 (c3 / cell
                        :ARG1-of (i3 / infect-01
                              :ARG2 (e3 / enzyme :name (n4 / name :op1 "Ras")
                                    :ARG2-of (m3 / mutate-01 :value "V12"))))
                  :op2 (c4 / cell
                        :ARG1-of (i4 / infect-01
                              :ARG2 (e2 / enzyme :name (n5 / name :op1 "Ras")
                                    :ARG2-of (m4 / mutate-01 :value "V12S35")))))))

# ::id pmid_1859_7688.182 ::date 2015-07-10T16:46:21 ::annotator SDL-AMR-09 ::preferred
# ::snt To confirm that TDAG51 up-regulation was induced specifically by ERK activation, we treated pLRT-, RasV12-, and RasV12S35-infected cells with the MEK-specific inhibitor PD98059.
# ::save-date Sun Jan 17, 2016 ::file pmid_1859_7688_182.txt
(t / treat-04
      :ARG0 w
      :ARG1 (a2 / and
            :op1 (c2 / cell
                  :mod (p4 / protein :name (n5 / name :op1 "LRT")
                        :ARG1-of (p2 / phosphorylate-01)))
            :op2 (c3 / cell
                  :ARG1-of (i4 / infect-01
                        :ARG2 (e / enzyme :name (n6 / name :op1 "Ras")
                              :ARG2-of (m2 / mutate-01 :value "V12"))))
            :op3 (c4 / cell
                  :ARG1-of (i5 / infect-01
                        :ARG2 (e5 / enzyme :name (n7 / name :op1 "Ras")
                              :ARG2-of (m3 / mutate-01 :value "V12S35")))))
      :ARG2 (s2 / small-molecule :name (n3 / name :op1 "PD98059")
            :ARG0-of (i2 / inhibit-01
                  :ARG1 (p3 / protein-family :name (n4 / name :op1 "MEK")))
            :ARG1-of (s / specific-02))
      :purpose (c / confirm-01
            :ARG0 (w / we)
            :ARG1 (i / induce-01
                  :ARG0 (a / activate-01
                        :ARG1 (e4 / enzyme :name (n2 / name :op1 "ERK")))
                  :ARG2 (u / upregulate-01
                        :ARG1 (p / protein :name (n / name :op1 "TDAG51")))
                  :ARG1-of s)))

# ::id pmid_1859_7688.183 ::date 2015-07-10T17:01:48 ::annotator SDL-AMR-09 ::preferred
# ::snt PD98059 used at 20 μM appears to be specific for MEK1 as it does not nonspecifically inhibit a variety of other protein kinases that have been assayed.
# ::save-date Mon Dec 21, 2015 ::file pmid_1859_7688_183.txt
(a3 / appear-02
      :ARG1 (s / specific-02
            :ARG1 (s3 / small-molecule :name (n / name :op1 "PD98059")
                  :ARG1-of (u / use-01
                        :ARG2 (c2 / concentration-quantity :quant 20
                              :unit (n2 / nanomolar))))
            :ARG2 (e / enzyme :name (n3 / name :op1 "MEK1")))
      :ARG1-of (c3 / cause-01
            :ARG0 (i / inhibit-01 :polarity -
                  :ARG0 s3
                  :ARG1 (k / kinase
                        :mod (o / other)
                        :ARG1-of (a2 / assay-01)
                        :mod (v / variety)
                        :mod (p / protein))
                  :ARG1-of (s2 / specific-02 :polarity -))))

# ::id pmid_1859_7688.184 ::date 2015-07-10T17:41:09 ::annotator SDL-AMR-09 ::preferred
# ::snt [31].
# ::save-date Thu Jul 23, 2015 ::file pmid_1859_7688_184.txt
(p / publication
      :ARG1-of (c / cite-01
            :ARG2 31))

# ::id pmid_1859_7688.185 ::date 2015-07-10T09:26:08 ::annotator SDL-AMR-09 ::preferred
# ::snt TDAG51 up-regulation was attenuated by MEK inhibition (Figure 5).
# ::save-date Thu Jul 23, 2015 ::file pmid_1859_7688_185.txt
(a / attenuate-01
      :ARG0 (i / inhibit-01
            :ARG1 (e / enzyme :name (n2 / name :op1 "MEK")))
      :ARG1 (u / upregulate-01
            :ARG1 (p / protein :name (n / name :op1 "TDAG51")))
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod 5)))

# ::id pmid_1859_7688.186 ::date 2015-07-10T09:28:20 ::annotator SDL-AMR-09 ::preferred
# ::snt TDAG51 therefore represents an ERK-inducible gene whose up-regulation in HME16C is correlated with an EGFR-independent, ERK-mediated transformation.
# ::save-date Sun Jan 17, 2016 ::file pmid_1859_7688_186.txt
(c2 / cause-01
      :ARG1 (r2 / represent-01
            :ARG0 (g2 / gene :name (n / name :op1 "TDAG51"))
            :ARG1 (g / gene
                  :ARG2-of (i / induce-01
                        :ARG1 (e / enzyme :name (n2 / name :op1 "ERK"))
                        :ARG1-of (p / possible-01))
                  :ARG1-of (u / upregulate-01
                        :location (c3 / cell-line :name (n3 / name :op1 "HME16C"))
                        :ARG1-of (c / correlate-01
                              :ARG2 (t / transform-01
                                    :ARG0-of (d / depend-01 :polarity -
                                          :ARG1 (e2 / enzyme :name (n4 / name :op1 "EGFR")))
                                    :ARG1-of (m2 / mediate-01
                                          :ARG0 e)))))))

# ::id pmid_1859_7688.187 ::date 2015-07-10T13:15:43 ::annotator SDL-AMR-09 ::preferred
# ::snt TDAG51 up-regulation opposes ERK-mediated HME16C transformation
# ::save-date Sun Jan 17, 2016 ::file pmid_1859_7688_187.txt
(o / oppose-01
      :ARG0 (u / upregulate-01
            :ARG1 (p / protein :name (n / name :op1 "TDAG51")))
      :ARG1 (t / transform-01
            :ARG1 (c / cell-line :name (n2 / name :op1 "HME16C")
                  :ARG1-of (m2 / mediate-01
                        :ARG0 (e / enzyme :name (n3 / name :op1 "ERK"))))))

# ::id pmid_1859_7688.188 ::date 2015-07-10T14:41:07 ::annotator SDL-AMR-09 ::preferred
# ::snt To analyze the role of TDAG51 in ERK-dependent growth, we reduced TDAG51 expression in RasV12- and RasV12S35-infected cells to a level comparable to that in non-transformed vector-infected control cells using stably expressed TDAG51-specific shRNA (Figure 6A).
# ::save-date Sat Jan 16, 2016 ::file pmid_1859_7688_188.txt
(r / reduce-01
      :ARG0 w
      :ARG1 (e2 / express-03
            :ARG2 p
            :ARG3 (a2 / and
                  :op1 (c / cell
                        :ARG1-of (i3 / infect-01
                              :ARG2 (e3 / enzyme :name (n3 / name :op1 "Ras")
                                    :ARG2-of (m / mutate-01 :value "V12"))))
                  :op2 (c2 / cell)
                  :ARG1-of (i / infect-01
                        :ARG2 (e4 / enzyme :name n3
                              :ARG2-of (m2 / mutate-01 :value "V12S35")))))
      :ARG4 (l / level
            :ARG1-of (c3 / comparable-03
                  :ARG2 (l2 / level
                        :location (c4 / cell
                                    :ARG1-of (i2 / infect-01
                                          :ARG2 (v / vector))
                                    :ARG0-of (c5 / control-01)
                                    :ARG1-of (t / transform-01 :polarity -)))))
      :manner (u / use-01
            :ARG0 w
            :ARG1 (n5 / nucleic-acid :name (n4 / name :op1 "shRNA")
                  :ARG1-of (s / specific-02
                        :ARG2 p)
                  :ARG2-of (e5 / express-03
                        :ARG1-of (s2 / stable-03))))
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod "6A"))
      :purpose (a / analyze-01
            :ARG0 (w / we)
            :ARG1 (r2 / role
                  :poss (p / protein :name (n / name :op1 "TDAG51"))
                  :topic (g / grow-01
                        :ARG0-of (d2 / depend-01
                              :ARG1 (e / enzyme :name (n2 / name :op1 "ERK")))))))

# ::id pmid_1859_7688.189 ::date 2015-07-11T06:00:17 ::annotator SDL-AMR-09 ::preferred
# ::snt Cell proliferation of attached cells grown on tissue culture plastic was unaffected by lowered TDAG51 protein levels (not shown).
# ::save-date Mon Jul 27, 2015 ::file pmid_1859_7688_189.txt
(a / affect-01 :polarity -
      :ARG0 (l / level
            :quant-of (p3 / protein :name (n / name :op1 "TDAG51"))
            :ARG1-of (l2 / low-04))
      :ARG1 (p / proliferate-01
            :ARG0 (c / cell
                  :ARG1-of (a2 / attach-01)
                  :ARG1-of (g / grow-01
                        :location (p2 / plastic
                              :mod (c3 / culture
                                    :source (t / tissue))))))
      :ARG1-of (s / show-01 :polarity -))

# ::id pmid_1859_7688.190 ::date 2015-07-11T05:27:41 ::annotator SDL-AMR-09 ::preferred
# ::snt However, cell growth under anchorage-independent conditions in ultra-low attachment plates was significantly enhanced by TDAG51 knock-down in RasV12S35-infected cells (Figure 6B).
# ::save-date Wed Dec 30, 2015 ::file pmid_1859_7688_190.txt
(c / contrast-01
      :ARG2 (e / enhance-01
            :ARG1 (g / grow-01
                  :ARG1 (c3 / cell)
                  :location (p / plate
                        :ARG3-of (a2 / attach-01)
                        :ARG1-of (l / low-04
                              :degree (u / ultra)))
                  :condition (d2 / depend-01 :polarity -
                        :ARG1 (a / anchorage)))
            :ARG2 (k / knock-down-02
                  :ARG1 (p2 / protein :name (n / name :op1 "TDAG51")))
            :ARG1-of (s / significant-02)
            :location (c5 / cell
                  :ARG1-of (i / infect-01
                        :ARG2 (e2 / enzyme :name (n2 / name :op1 "Ras")
                              :ARG2-of (m / mutate-01 :value "V12S35")))))
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod "6B")))

# ::id pmid_1859_7688.191 ::date 2015-07-11T05:37:30 ::annotator SDL-AMR-09 ::preferred
# ::snt Likewise, results with RasV12-infected cells stably infected with TDAG51-targeting shRNA also showed enhanced growth relative to vector-infected control cells, although to a lesser extent than that seen with RasV12S35-infected cells (Figure 6C).
# ::save-date Sun Dec 20, 2015 ::file pmid_1859_7688_191.txt
(c / contrast-01
      :ARG1 (s / show-01
            :ARG0 (t / thing
                  :ARG2-of (r2 / result-01
                        :ARG1 (c4 / cell
                              :ARG1-of (i2 / infect-01
                                    :ARG2 (e2 / enzyme :wiki "Ras_subfamily"
                                          :name (n / name :op1 "Ras")
                                          :ARG2-of (m / mutate-01 :value "V12")))
                              :ARG1-of (i3 / infect-01
                                    :ARG2 (n5 / nucleic-acid :wiki "Small_hairpin_RNA"
                                          :name (n2 / name :op1 "shRNA")
                                          :ARG0-of (t2 / target-01
                                                :ARG1 (p / protein :wiki "PHLDA1"
                                                      :name (n3 / name :op1 "TDAG51"))))
                                    :ARG1-of (s3 / stable-03)))))
            :ARG1 (g / grow-01
                  :ARG1-of (e / enhance-01)
                  :ARG1-of (r3 / relative-05
                        :ARG2 (c2 / cell
                              :ARG0-of (c3 / control-01)
                              :ARG1-of (i / infect-01
                                    :ARG0 (v / vector)))))
            :mod (a / also))
      :ARG2 (s2 / show-01
            :ARG0 t
            :ARG1 (g2 / grow-01
                  :degree (l / less
                        :degree (m2 / more))
                  :compared-to (g3 / grow-01
                        :ARG1-of (s4 / see-01
                              :location (c5 / cell
                                    :ARG1-of (i4 / infect-01
                                          :ARG2 (e3 / enzyme :wiki "Ras_subfamily"
                                                :name (n4 / name :op1 "Ras")
                                                :ARG2-of (m3 / mutate-01 :value "V12S35"))))))))
      :ARG1-of (r / resemble-01)
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod "6C")))

# ::id pmid_1859_7688.192 ::date 2015-07-10T16:45:12 ::annotator SDL-AMR-09 ::preferred
# ::snt This suggests that Ras signaling pathways other than ERK compensate partially for the negative growth effects of TDAG51, or that RasV12-infected cells are already close to maximally transformed under anchorage-independent growth conditions.
# ::save-date Fri Feb 5, 2016 ::file pmid_1859_7688_192.txt
(s / suggest-01
      :ARG0 (t / this)
      :ARG1 (o / or
            :op1 (c / compensate-01
                  :ARG0 (p2 / pathway :name (n / name :op1 "Ras")
                        :ARG0-of (s2 / signal-07)
                        :ARG2-of (e2 / except-01
                              :ARG1 (p3 / pathway :name (n2 / name :op1 "ERK"))))
                  :ARG1 (a2 / affect-01
                        :ARG0 (g / grow-01
                              :ARG1 (p4 / protein :name (n4 / name :op1 "TDAG51")))
                        :ARG2-of (n3 / negative-05))
                  :degree (p / part))
            :op2 (c2 / close-10
                  :ARG1 (c4 / cell
                        :ARG1-of (i / infect-01
                              :ARG2 (e / enzyme :name (n5 / name :op1 "Ras")
                                    :ARG2-of (m2 / mutate-01 :value "V12"))))
                  :ARG2 (t2 / transform-01
                        :ARG1 c4
                        :degree (m / maximal))
                  :time (a3 / already)
                  :condition (g2 / grow-01
                        :ARG0-of (d / depend-01 :polarity -
                              :ARG1 (a / anchorage))))))

# ::id pmid_1859_7688.193 ::date 2015-07-10T14:42:06 ::annotator SDL-AMR-09 ::preferred
# ::snt Loss of TDAG51 expression in transformed cells stimulates both cell cycle progression and apoptosis
# ::save-date Mon Dec 21, 2015 ::file pmid_1859_7688_193.txt
(s / stimulate-01
      :ARG0 (l / lose-02
            :ARG1 (e / express-03
                  :ARG1 (p / protein :name (n / name :op1 "TDAG51"))
                  :ARG3 (c / cell
                        :ARG1-of (t / transform-01))))
      :ARG1 (a / and
            :op1 (p2 / progress-01
                  :ARG1 (c2 / cycle-02
                        :ARG1 (c3 / cell)))
            :op2 (a2 / apoptosis
                  :mod c3)))

# ::id pmid_1859_7688.194 ::date 2015-07-10T15:11:06 ::annotator SDL-AMR-09 ::preferred
# ::snt To characterize the effect of TDAG51 on cell proliferation under anchorage-independent conditions, cell cycle analysis and cell proliferation assays for RasV12S35- and RasV12-infected cells were performed.
# ::save-date Mon Dec 21, 2015 ::file pmid_1859_7688_194.txt
(p / perform-01
      :ARG1 (a / and
            :op1 (a2 / analyze-01
                  :ARG1 (c2 / cycle-02
                        :ARG1 (c3 / cell)))
            :op2 (a3 / assay-01
                  :ARG1 (p2 / proliferate-01
                        :ARG0 c3))
            :purpose (a4 / and
                  :op1 (c4 / cell
                        :ARG1-of (i2 / infect-01
                              :ARG2 (e / enzyme :name (n / name :op1 "Ras")
                                    :ARG2-of (m / mutate-01 :value "V12S35"))))
                  :op2 (c5 / cell
                        :ARG1-of (i / infect-01
                              :ARG2 (e2 / enzyme :name (n2 / name :op1 "Ras")
                                    :ARG2-of (m2 / mutate-01 :value "V12"))))))
      :purpose (c / characterize-01
            :ARG1 (a5 / affect-01
                  :ARG0 (p3 / protein :name (n3 / name :op1 "TDAG51"))
                  :ARG1 (p4 / proliferate-01
                        :ARG0 c3
                        :condition (d / depend-01
                              :ARG1 (a6 / anchorage))))))

# ::id pmid_1859_7688.195 ::date 2015-07-10T16:03:42 ::annotator SDL-AMR-09 ::preferred
# ::snt Both RasV12S35- and RasV12- TDAG51 shRNA-expressing cells demonstrated an increased S-phase fraction versus pLVTHM vector control cells at various time points during anchorage-independent growth (Figure 7A).
# ::save-date Wed Mar 9, 2016 ::file pmid_1859_7688_195.txt
(d / demonstrate-01
      :ARG0 (a / and
            :op1 (c / cell
                  :ARG3-of (e / express-03
                        :ARG2 (n4 / nucleic-acid :name (n2 / name :op1 "shRNA")
                              :ARG0-of (e5 / encode-01
                                    :ARG1 (p4 / protein :name (n5 / name :op1 "TDAG51")
                                          :ARG1-of (i2 / infect-01
                                                :ARG2 (e3 / enzyme :name (n / name :op1 "Ras")
                                                      :ARG2-of (m / mutate-01 :value "V12S35"))))))))
            :op2 (c2 / cell
                  :ARG3-of (e2 / express-03
                        :ARG1 (e4 / enzyme :name (n6 / name :op1 "Ras")
                              :ARG2-of (m2 / mutate-01 :value "V12"))
                        :ARG2 n4)))
      :ARG1 (f2 / fraction
            :ARG1-of (i / increase-01)
            :part-of (p / phase
                  :mod (s / synthesize-01)))
      :ARG1-of (d2 / describe-01
            :ARG0 (f / figure :mod "7A"))
      :compared-to (c3 / cell
            :ARG0-of (c4 / control-01)
            :mod (v / vector :name (n3 / name :op1 "LVTHM")
                  :ARG3-of (p2 / phosphorylate-01)))
      :time (p3 / point
            :mod (t / time)
            :ARG1-of (v2 / vary-01))
      :time (g / grow-01
            :ARG0-of (d3 / depend-01 :polarity -
                  :ARG1 (a2 / anchorage))))

# ::id pmid_1859_7688.196 ::date 2015-07-11T09:32:12 ::annotator SDL-AMR-09 ::preferred
# ::snt In concordance with these results, RasV12S35 and RasV12 cells expressing the TDAG51-specific shRNA showed enhanced incorporation of 5-ethynyl-2'-deoxyuridine (EdU) in cell proliferation assays, indicating a higher rate of DNA synthesis in cells with reduced TDAG51 protein (Figure 7C).
# ::save-date Sat Feb 13, 2016 ::file pmid_1859_7688_196.txt
(s / show-01
      :ARG0 (a / and
            :op1 (c2 / cell
                  :mod (e / enzyme :wiki "Ras_subfamily" :name (n / name :op1 "Ras")
                        :ARG2-of (m / mutate-01 :value "V12S35")))
            :op2 (c3 / cell
                  :mod (e5 / enzyme :wiki "Ras_subfamily" :name (n6 / name :op1 "Ras")
                        :ARG2-of (m2 / mutate-01 :value "V12")))
            :ARG3-of (e3 / express-03
                  :ARG1 (n7 / nucleic-acid :wiki "Small_hairpin_RNA" :name (n2 / name :op1 "shRNA")
                        :ARG1-of (s2 / specific-02
                              :ARG2 (p / protein :wiki "PHLDA1" :name (n3 / name :op1 "TDAG51"))))))
      :ARG1 (i2 / incorporate-01
            :ARG0 n7
            :ARG1 (s4 / small-molecule :wiki "5-Ethynyl-2'-deoxyuridine" :name (n4 / name :op1 "5-ethynyl-2'-deoxyuridine"))
            :ARG1-of (e4 / enhance-01)
            :location (a2 / assay-01
                  :ARG1 (p2 / proliferate-01
                        :ARG0 (c4 / cell))))
      :ARG0-of (i / indicate-01
            :ARG1 (r3 / rate-entity-91
                  :ARG4 (s3 / synthesize-01
                        :ARG1 (n8 / nucleic-acid :wiki "DNA" :name (n9 / name :op1 "DNA")))
                  :ARG1-of (h / high-02
                        :degree (m4 / more)))
            :location (c5 / cell
                  :ARG0-of (h2 / have-03
                        :ARG1 (p4 / protein :wiki "PHLDA1" :name (n5 / name :op1 "TDAG51")
                              :ARG1-of (r4 / reduce-01)))))
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod "7C"))
      :ARG1-of (r5 / resemble-01
            :ARG2 (t / thing
                  :ARG2-of (r / result-01)
                  :mod (t2 / this))))

# ::id pmid_1859_7688.197 ::date 2015-07-10T15:19:46 ::annotator SDL-AMR-09 ::preferred
# ::snt Since cell growth under anchorage-independent conditions is a balance between cell proliferation and cell death, we sought to evaluate the effect upon cellular death of TDAG51 knock-down.
# ::save-date Mon Jul 27, 2015 ::file pmid_1859_7688_197.txt
(c / cause-01
      :ARG0 (b / balance-01
            :ARG0 (g / grow-01
                  :ARG1 (c3 / cell)
                  :condition (d3 / depend-01 :polarity -
                        :ARG1 (a2 / anchorage)))
            :ARG1 (a3 / and
                  :op1 (p2 / proliferate-01
                        :ARG0 (c5 / cell))
                  :op2 (d2 / die-01
                        :ARG1 c5)))
      :ARG1 (s / seek-01
            :ARG0 (w / we)
            :ARG1 (e / evaluate-01
                  :ARG0 w
                  :ARG1 (a / affect-01
                        :ARG0 (k / knock-down-02
                              :ARG1 (p / protein :name (n / name :op1 "TDAG51")))
                        :ARG1 (d / die-01
                              :ARG1 (c2 / cell))))))

# ::id pmid_1859_7688.198 ::date 2015-07-10T04:38:09 ::annotator SDL-AMR-09 ::preferred
# ::snt We used an assay of cellular cytotoxicity that measures the release of the lactose deydrogenase enzyme, LDH.
# ::save-date Thu Jul 23, 2015 ::file pmid_1859_7688_198.txt
(u / use-01
      :ARG0 (w / we)
      :ARG1 (a / assay-01
            :ARG1 (c / cytotoxicity
                  :mod (c2 / cell))
            :ARG0-of (m / measure-01
                  :ARG1 (r / release-01
                        :ARG1 (e / enzyme :name (n / name :op1 "lactose" :op2 "deydrogenase"))))))

# ::id pmid_1859_7688.199 ::date 2015-07-10T04:43:14 ::annotator SDL-AMR-09 ::preferred
# ::snt LDH release was increased by TDAG51 shRNA-expressing RasV12S35 cells relative to pLVTHM-infected cells at various time points after the initiation of matrix-detached growth (Figure 8).
# ::save-date Wed Mar 9, 2016 ::file pmid_1859_7688_199.txt
(i / increase-01
      :ARG0 (c / cell
            :ARG3-of (e2 / express-03
                  :ARG2 (n6 / nucleic-acid :name (n5 / name :op1 "shRNA")
                        :ARG0-of (e4 / encode-01
                              :ARG1 (p / protein :name (n2 / name :op1 "TDAG51")))))
            :mod (e3 / enzyme :name (n3 / name :op1 "Ras")
                  :ARG2-of (m / mutate-01 :value "V12S35")))
      :ARG1 (r / release-01
            :ARG1 (e / enzyme :name (n / name :op1 "LDH")))
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod 8))
      :ARG1-of (r2 / relative-05
            :ARG3 (c2 / cell
                  :ARG1-of (i2 / infect-01
                        :ARG2 (v2 / vector :name (n4 / name :op1 "LVTHM")
                              :ARG3-of (p2 / phosphorylate-01)))))
      :time (p3 / point
            :mod (t / time)
            :ARG1-of (v / vary-01))
      :time (a / after
            :op1 (i3 / initiate-01
                  :ARG1 (g / grow-01
                        :ARG1-of (d2 / detach-01
                              :ARG2 (m3 / matrix))))))

# ::id pmid_1859_7688.200 ::date 2015-07-10T07:22:49 ::annotator SDL-AMR-09 ::preferred
# ::snt The difference in LDH release for TDAG51 shRNA-expressing RasV12 cells was minimal and rarely approached statistical significance.
# ::save-date Sun Dec 20, 2015 ::file pmid_1859_7688_200.txt
(a / and
      :op1 (m / minimal-02
            :ARG1 (d / differ-02
                  :ARG1 (r2 / release-01
                        :ARG0 (c / cell
                              :ARG3-of (e2 / express-03
                                    :ARG2 (n5 / nucleic-acid :name (n3 / name :op1 "shRNA")
                                          :ARG0-of (e4 / encode-01
                                                :ARG1 (p / protein :name (n2 / name :op1 "TDAG51")))))
                              :mod (e3 / enzyme :name (n4 / name :op1 "Ras")
                                    :ARG2-of (m2 / mutate-01 :value "V12")))
                        :ARG1 (e / enzyme :name (n / name :op1 "LDH")))))
      :op2 (a2 / approach-01
            :ARG1 d
            :ARG2 (s / significant-02
                  :ARG1 d
                  :mod (s2 / statistics))
            :ARG1-of (r / rare-02)))

# ::id pmid_1859_7688.201 ::date 2015-07-10T05:34:16 ::annotator SDL-AMR-09 ::preferred
# ::snt Sub-G1 peaks indicative of dead cells were sometimes seen with cell cycle analysis at late time points, but varied from experiment to experiment.
# ::save-date Mon Dec 21, 2015 ::file pmid_1859_7688_201.txt
(s / see-01
      :ARG1 (p / peak
            :ARG0-of (i / indicate-01
                  :ARG1 (c / cell
                        :ARG1-of (d / die-01)))
            :mod (s4 / sub
                  :op1 (p2 / phase :mod 1
                        :mod (g / grow-01))))
      :frequency (s2 / sometimes)
      :instrument (a / analyze-01
            :ARG1 (c2 / cycle-02
                  :ARG1 (c3 / cell)))
      :time (p3 / point
            :mod (t / time
                  :time (l / late)))
      :ARG1-of (c4 / contrast-01
            :ARG2 (v / vary-01
                  :ARG1 p
                  :ARG3 (e / experiment-01)
                  :ARG4 e)))

# ::id pmid_1859_7688.202 ::date 2015-07-10T05:25:14 ::annotator SDL-AMR-09 ::preferred
# ::snt Therefore, for RasV12S35-infected cells, the differences in cell growth after TDAG51 reduction under anchorage-independent conditions resulted from an enhanced rate of cellular proliferation that exceeded a concomitant increase in cell death.
# ::save-date Mon Jul 27, 2015 ::file pmid_1859_7688_202.txt
(c7 / cause-01
      :ARG1 (r / result-01
            :ARG1 (r2 / rate
                  :ARG1-of (e / enhance-01)
                  :ARG0-of (e2 / exceed-01
                        :ARG1 (i / increase-01
                              :ARG1 (d / die-01
                                    :ARG1 (c3 / cell))
                              :time (c2 / concomitant)))
                  :degree-of (p / proliferate-01
                        :ARG0 (c / cell)))
            :ARG2 (d2 / differ-02
                  :ARG1 (c6 / cell)
                  :ARG3 (g / grow-01
                        :ARG1 (c4 / cell
                              :ARG1-of (i2 / infect-01
                                    :ARG2 (e3 / enzyme :name (n2 / name :op1 "Ras")
                                          :ARG2-of (m / mutate-01 :value "V12S35"))))
                        :time (a / after
                              :op1 (r3 / reduce-01
                                    :ARG1 (p2 / protein :name (n / name :op1 "TDAG51"))
                                    :condition (d3 / depend-01 :polarity -
                                          :ARG1 (a2 / anchorage))))))))

# ::id pmid_1859_7688.203 ::date 2015-07-10T04:43:41 ::annotator SDL-AMR-09 ::preferred
# ::snt Reduction of TDAG51 in transformed cells enhances proximal ERK signaling
# ::save-date Sat Jan 16, 2016 ::file pmid_1859_7688_203.txt
(e / enhance-01
      :ARG0 (r / reduce-01
            :ARG1 (p2 / protein :name (n / name :op1 "TDAG51"))
            :location (c / cell
                  :ARG1-of (t / transform-01)))
      :ARG1 (s / signal-07
            :ARG1 (e2 / enzyme :name (n2 / name :op1 "ERK")
                  :mod (p / proximal))))

# ::id pmid_1859_7688.204 ::date 2015-07-10T04:46:15 ::annotator SDL-AMR-09 ::preferred
# ::snt Reducing TDAG51 protein levels in ERK-driven cellular transformation enhanced cell growth under anchorage-independent, but not attached, conditions.
# ::save-date Sat Jan 16, 2016 ::file pmid_1859_7688_204.txt
(e / enhance-01
      :ARG0 (r / reduce-01
            :ARG1 (l / level
                  :quant-of (p / protein :name (n / name :op1 "TDAG51")))
            :time (t / transform-01
                  :ARG1 (c / cell)
                  :ARG1-of (d / drive-02
                        :ARG0 (e2 / enzyme :name (n2 / name :op1 "ERK")))))
      :ARG1 (g / grow-01
            :ARG1 c)
      :condition (d2 / depend-01 :polarity -
            :ARG1 (a / anchorage)
            :ARG1-of (c2 / contrast-01
                  :ARG2 (a2 / attach-01 :polarity -))))

# ::id pmid_1859_7688.205 ::date 2015-07-10T04:49:46 ::annotator SDL-AMR-09 ::preferred
# ::snt To test whether TDAG51 might affect proximal ERK signaling, we examined the activation status of Erk in cells expressing TDAG51-specific shRNA.
# ::save-date Sat Jan 16, 2016 ::file pmid_1859_7688_205.txt
(e / examine-01
      :ARG0 (w / we)
      :ARG1 (s / status
            :mod (a / activate-01
                  :ARG1 (e2 / enzyme :name (n / name :op1 "Erk"))
                  :location (c / cell
                        :ARG3-of (e3 / express-03
                              :ARG1 (n4 / nucleic-acid :name (n2 / name :op1 "shRNA")
                                    :ARG1-of (s2 / specific-02
                                          :ARG2 (p / protein :name (n3 / name :op1 "TDAG51"))))))))
      :purpose (t / test-01
            :ARG0 w
            :ARG1 (p2 / possible-01 :mode interrogative
                  :ARG1 (a2 / affect-01
                        :ARG0 p
                        :ARG1 (s3 / signal-07
                              :ARG1 e2
                              :mod (p3 / proximal))))))

# ::id pmid_1859_7688.206 ::date 2015-07-10T05:12:06 ::annotator SDL-AMR-09 ::preferred
# ::snt Interestingly, the levels of phosphorylated Erk were enhanced when TDAG51 protein levels were reduced in RasV12S35 and RasV12 cells grown under anchorage-independent, but not attached, conditions (Figure 9).
# ::save-date Sat Jan 16, 2016 ::file pmid_1859_7688_206.txt
(e / enhance-01
      :ARG1 (l / level
            :quant-of (e2 / enzyme :name (n / name :op1 "Erk")
                  :ARG3-of (p / phosphorylate-01)))
      :time (r / reduce-01
            :ARG1 (l2 / level
                  :quant-of (p2 / protein :name (n2 / name :op1 "TDAG51")))
            :location (a / and
                  :op1 (c4 / cell
                        :mod (e3 / enzyme :name (n3 / name :op1 "Ras")
                              :ARG2-of (m2 / mutate-01 :value "V12S35")))
                  :op2 (c5 / cell
                        :mod (e4 / enzyme :name n3
                              :ARG2-of (m / mutate-01 :value "V12")))
                  :ARG1-of (g / grow-01
                        :condition (d / depend-01 :polarity -
                              :ARG1 (a2 / anchorage)
                              :ARG1-of (c / contrast-01
                                    :ARG2 (a3 / attach-01 :polarity -))))))
      :ARG1-of (d2 / describe-01
            :ARG0 (f / figure :mod 9))
      :ARG0-of (i / interest-01))

# ::id pmid_1859_7688.207 ::date 2015-07-10T08:10:38 ::annotator SDL-AMR-09 ::preferred
# ::snt The fact that the activation status of Erk was unchanged in cells grown under attached conditions suggests that reducing TDAG51 expression had no selective effect with regard to ERK activation in these cells.
# ::save-date Sat Jan 16, 2016 ::file pmid_1859_7688_207.txt
(s / suggest-01
      :ARG0 (c2 / change-01 :polarity -
            :ARG1 (s3 / status
                  :mod (a3 / activate-01
                        :ARG1 (e2 / enzyme :name (n3 / name :op1 "Erk"))))
            :location (c3 / cell
                  :ARG1-of (g / grow-01)
                  :condition (a4 / attach-01)))
      :ARG1 (a / affect-01 :polarity -
            :ARG0 (r / reduce-01
                  :ARG1 (e / express-03
                        :ARG2 (p / protein :name (n / name :op1 "TDAG51"))))
            :manner (s2 / selective)
            :topic (a2 / activate-01
                  :ARG1 (e3 / enzyme :name (n2 / name :op1 "ERK")
                        :location c3))))

# ::id pmid_1859_7688.208 ::date 2015-07-10T05:51:12 ::annotator SDL-AMR-09 ::preferred
# ::snt Rather, the enhanced activation of Erk was specific to anchorage-independent growth conditions.
# ::save-date Sat Jan 16, 2016 ::file pmid_1859_7688_208.txt
(i / instead-of-91
      :ARG1 (s / specific-02
            :ARG1 (a / activate-01
                  :ARG1 (e2 / enzyme :name (n / name :op1 "Erk"))
                  :ARG1-of (e / enhance-01))
            :ARG2 (c / condition
                  :mod (g / grow-01)
                  :ARG0-of (d / depend-01 :polarity -
                        :ARG1 (a2 / anchorage)))))

# ::id pmid_1901_4680.1 ::date 2015-06-16T04:05:04 ::annotator SDL-AMR-09 ::preferred
# ::snt Activation of MEK1 or MEK2 isoform is sufficient to fully transform intestinal epithelial cells and induce the formation of metastatic tumors (PMID:19014680)
# ::save-date Tue Dec 29, 2015 ::file pmid_1901_4680_1.txt
(s / suffice-01
      :ARG0 (a / activate-01
            :ARG1 (o / or
                  :op1 (i / isoform
                        :mod (e / enzyme :name (n / name :op1 "MEK1")))
                  :op2 (i2 / isoform
                        :mod (e2 / enzyme :name (n2 / name :op1 "MEK2")))))
      :ARG1 (a2 / and
            :op1 (t / transform-01
                  :ARG0 a
                  :ARG1 (c / cell
                        :part-of (e3 / epithelium
                              :part-of (i3 / intestine)))
                  :degree (f / full))
            :op2 (i4 / induce-01
                  :ARG0 a
                  :ARG2 (f2 / form-01
                        :ARG2 (t2 / tumor
                              :mod (m / metastasis)))))
      :ARG1-of (d / describe-01
            :ARG0 (p / publication-91
                  :ARG8 "PMID19014680")))

# ::id pmid_1901_4680.10 ::date 2015-06-16T04:07:04 ::annotator SDL-AMR-09 ::preferred
# ::snt <sec-title level="1" sec-area="abstract">Results</sec-title>
# ::save-date Tue Jun 16, 2015 ::file pmid_1901_4680_10.txt
(t / thing
      :ARG2-of (r / result-01))

# ::id pmid_1901_4680.11 ::date 2015-06-16T04:07:52 ::annotator SDL-AMR-09 ::preferred
# ::snt We found that expression of activated MEK1 or MEK2 is sufficient to morphologically transform intestinal epithelial cells, dysregulate cell proliferation and induce the formation of high-grade adenocarcinomas after orthotopic transplantation in mice.
# ::save-date Mon Dec 21, 2015 ::file pmid_1901_4680_11.txt
(f / find-01
      :ARG0 (w / we)
      :ARG1 (s / suffice-01
            :ARG0 (e / express-03
                  :ARG2 (o / or
                        :op1 (e2 / enzyme :name (n / name :op1 "MEK1"))
                        :op2 (e3 / enzyme :name (n2 / name :op1 "MEK2"))
                        :ARG1-of (a / activate-01)))
            :ARG1 (a2 / and
                  :op1 (t / transform-01
                        :ARG0 e
                        :ARG1 (c / cell
                              :part-of (e4 / epithelium
                                    :part-of (i / intestine)))
                        :manner (m / morphological))
                  :op2 (d / dysregulate-01
                        :ARG0 e
                        :ARG1 (p / proliferate-01
                              :ARG0 (c2 / cell)))
                  :op3 (i2 / induce-01
                        :ARG0 e
                        :ARG2 (f2 / form-01
                              :ARG1 (m3 / medical-condition :name (n3 / name :op1 "adenocarcinoma")
                                    :mod (g / grade
                                          :ARG1-of (h / high-02))))))
            :condition (t2 / transplant-01
                  :ARG2 (m2 / mouse)
                  :mod (o2 / orthotopic))))

# ::id pmid_1901_4680.12 ::date 2015-06-16T04:22:43 ::annotator SDL-AMR-09 ::preferred
# ::snt A large proportion of these intestinal tumors metastasize to the liver and lung.
# ::save-date Thu Jun 18, 2015 ::file pmid_1901_4680_12.txt
(m / metastasize-101
      :ARG1 (t / tumor
            :mod (i / intestine)
            :quant (p / proportion
                  :mod (l / large))
            :mod (t2 / this))
      :ARG2 (a / and
            :op1 (l2 / liver)
            :op2 (l3 / lung)))

# ::id pmid_1901_4680.13 ::date 2015-06-16T04:24:45 ::annotator SDL-AMR-09 ::preferred
# ::snt Mechanistically, activation of MEK1 or MEK2 up-regulates the expression of matrix metalloproteinases, promotes invasiveness and protects cells from undergoing anoikis.
# ::save-date Wed Jun 24, 2015 ::file pmid_1901_4680_13.txt
(a / and
      :op1 (u / upregulate-01
            :ARG1 (e3 / express-03
                  :ARG2 (e4 / enzyme :name (n3 / name :op1 "matrix" :op2 "metalloproteinase")))
            :ARG2 (a2 / activate-01
                  :ARG1 (o / or
                        :op1 (e / enzyme :name (n / name :op1 "MEK1"))
                        :op2 (e2 / enzyme :name (n2 / name :op1 "MEK2")))))
      :op2 (p / promote-01
            :ARG0 a2
            :ARG1 (i / invade-01))
      :op3 (p2 / protect-01
            :ARG0 a2
            :ARG1 (c / cell)
            :ARG2 (u2 / undergo-28
                  :ARG1 c
                  :ARG2 (a3 / anoikis)))
      :manner (m / mechanistic))

# ::id pmid_1901_4680.14 ::date 2015-06-16T04:32:55 ::annotator SDL-AMR-09 ::preferred
# ::snt Importantly, we show that silencing of MEK2 expression completely suppresses the proliferation of human colon carcinoma cell lines, whereas inactivation of MEK1 has a much weaker effect.
# ::save-date Thu Dec 10, 2015 ::file pmid_1901_4680_14.txt
(s / show-01
      :ARG0 (w / we)
      :ARG1 (c / contrast-01
            :ARG1 (s2 / suppress-01
                  :ARG0 (s3 / silence-01
                        :ARG1 (e / express-03
                              :ARG2 (e2 / enzyme :name (n / name :op1 "MEK2"))))
                  :ARG1 (p / proliferate-01
                        :ARG0 (c3 / cell-line
                              :mod (m3 / medical-condition :name (n2 / name :op1 "carcinoma")
                                    :mod (c4 / colon))
                              :mod (h / human)))
                  :degree (c2 / complete))
            :ARG2 (a / affect-01
                  :ARG0 (a2 / activate-01 :polarity -
                        :ARG1 (e3 / enzyme :name (n3 / name :op1 "MEK1")))
                  :ARG1 p
                  :ARG1-of (w2 / weak-02
                        :degree (m / more
                              :degree (m2 / much)))))
      :mod (i / important))

# ::id pmid_1901_4680.126 ::date 2015-06-16T04:39:05 ::annotator SDL-AMR-09 ::preferred
# ::snt <sec-title level="1">Results</sec-title>
# ::save-date Tue Jun 16, 2015 ::file pmid_1901_4680_126.txt
(t / thing
      :ARG2-of (r / result-01))

# ::id pmid_1901_4680.127 ::date 2015-06-16T04:39:57 ::annotator SDL-AMR-09 ::preferred
# ::snt <sec-title level="2">Constitutive activation of MEK1 or MEK2 is sufficient for transformation of intestinal epithelial cells and formation of tumors <i>in vivo</i></sec-title>
# ::save-date Thu Jun 18, 2015 ::file pmid_1901_4680_127.txt
(s / suffice-01
      :ARG0 (a / activate-01
            :ARG1 (o / or
                  :op1 (e / enzyme :name (n / name :op1 "MEK1"))
                  :op2 (e2 / enzyme :name (n2 / name :op1 "MEK2")))
            :mod (c / constitutive))
      :ARG1 (a2 / and
            :op1 (t / transform-01
                  :ARG1 (c2 / cell
                        :part-of (e3 / epithelium
                              :part-of (i / intestine))))
            :op2 (f / form-01
                  :ARG1 (t2 / tumor)
                  :manner (i2 / in-vivo))))

# ::id pmid_1901_4680.128 ::date 2015-06-16T04:45:50 ::annotator SDL-AMR-09 ::preferred
# ::snt Immunohistochemistry analysis of a colorectal cancer tissue microarray containing over 400 colorectal cancer and 50 normal colon tissue biopsies revealed that 44% of colorectal cancers display high cytoplasmic expression of phosphorylated MEK1/MEK2 as compared to 10% of normal tissues (analysis to be published elsewhere).
# ::save-date Wed Dec 30, 2015 ::file pmid_1901_4680_128.txt
(r / reveal-01
      :ARG0 (a / analyze-01
            :ARG1 (m / microarray
                  :mod (t2 / tissue
                        :mod (d6 / disease :wiki "Colorectal_cancer" :name (n10 / name :op1 "colorectal" :op2 "cancer")))
                  :ARG0-of (c2 / contain-01
                        :ARG1 (a2 / and
                              :op1 (b / biopsy
                                    :mod t2
                                    :quant (o / over :op1 400))
                              :op2 (b2 / biopsy :quant 50
                                    :mod (t3 / tissue
                                          :part-of (c3 / colon)
                                          :ARG1-of (n2 / normal-02))))))
            :instrument (i3 / immunohistochemistry)
            :ARG1-of (s / suppose-02
                  :ARG2 (p4 / publish-01
                        :ARG1 a
                        :location (e4 / elsewhere))))
      :ARG1 (d2 / display-01
            :ARG0 (d5 / disease :wiki "Cancer" :name (n8 / name :op1 "cancer")
                  :ARG1-of (i / include-91
                        :ARG2 d6
                        :ARG3 (p / percentage-entity :value 44))
                  :compared-to (t / tissue
                        :ARG0-of (d4 / display-01
                              :ARG1 e)
                        :ARG1-of (i2 / include-91
                              :ARG2 (t4 / tissue
                                    :ARG1-of n2)
                              :ARG3 (p3 / percentage-entity :value 10))))
            :ARG1 (e / express-03
                  :ARG2 (a4 / and
                        :op1 (e2 / enzyme :name (n5 / name :op1 "MEK1"))
                        :op2 (e3 / enzyme :name (n6 / name :op1 "MEK2"))
                        :ARG3-of (p2 / phosphorylate-01))
                  :ARG3 (c5 / cytoplasm)
                  :ARG1-of (h / high-02))))

# ::id pmid_1901_4680.129 ::date 2015-06-16T05:00:35 ::annotator SDL-AMR-09 ::preferred
# ::snt To assess the functional significance of MEK1/MEK2 activation in colorectal cancer, we ectopically expressed wild type and constitutively active (DD mutant) versions of MEK1 and MEK2 by retroviral gene transfer in the normal undifferentiated intestinal epithelial cell line IEC-6 [<xref ref-type="bibr" rid="B27">27</xref>].
# ::save-date Mon Dec 21, 2015 ::file pmid_1901_4680_129.txt
(e / express-03
      :ARG2 (a / and
            :op1 (e3 / enzyme :name (n / name :op1 "MEK1")
                  :mod (w2 / wild-type))
            :op2 (e4 / enzyme :name (n2 / name :op1 "MEK1")
                  :ARG1-of (a5 / activate-01
                        :manner (c4 / constitutive)
                        :ARG1-of (m / mean-01
                              :ARG2 (p2 / protein-segment :name (n10 / name :op1 "DD")
                                    :ARG2-of (m2 / mutate-01)))))
            :op3 (e5 / enzyme :name (n3 / name :op1 "MEK2")
                  :mod (w3 / wild-type))
            :op4 (e6 / enzyme :name (n4 / name :op1 "MEK2")
                  :ARG0-of a5))
      :manner (e2 / ectopic)
      :purpose (a2 / assess-01
            :ARG0 w
            :ARG1 (s / significant-02
                  :ARG1 (a3 / activate-01
                        :ARG1 (a4 / and
                              :op1 (e7 / enzyme :name (n5 / name :op1 "MEK1"))
                              :op2 (e8 / enzyme :name (n6 / name :op1 "MEK2")))
                        :prep-in (d4 / disease :wiki "Colorectal_cancer" :name (n11 / name :op1 "colorectal" :op2 "cancer")))
                  :ARG0-of (f / function-01)))
      :manner (t / transfer-01
            :ARG1 (g / gene)
            :mod (r / retroviral)
            :location (c2 / cell-line :name (n8 / name :op1 "IEC-6")
                  :part-of (e9 / epithelium
                        :part-of (i / intestine))
                  :ARG1-of (n7 / normal-02)
                  :ARG1-of (d2 / differentiate-01 :polarity -)))
      :ARG1-of (d3 / describe-01
            :ARG0 (p / publication
                  :ARG1-of (c3 / cite-01
                        :ARG2 27)))
      :ARG1-of (c5 / cause-01
            :ARG0 (w / we)))

# ::id pmid_1901_4680.130 ::date 2015-06-16T05:09:27 ::annotator SDL-AMR-09 ::preferred
# ::snt Polyclonal populations of infected clones were selected in puromycin and used for subsequent experiments.
# ::save-date Wed Jun 17, 2015 ::file pmid_1901_4680_130.txt
(a / and
      :op1 (s / select-01
            :ARG1 (p / population
                  :mod (c / clone
                        :ARG1-of (i / infect-01))
                  :mod (p2 / polyclonal))
            :location (s2 / small-molecule :name (n / name :op1 "puromycin")))
      :op2 (u / use-01
            :ARG1 p
            :purpose (e / experiment-01
                  :time (s3 / subsequent))))

# ::id pmid_1901_4680.131 ::date 2015-06-17T10:31:44 ::annotator SDL-AMR-09 ::preferred
# ::snt Immunoblot analysis confirmed that ectopic MEK isoforms are expressed at comparable levels in IEC-6 transduced populations (Fig. <xref ref-type="fig" rid="F1">1A</xref>).
# ::save-date Tue Jan 19, 2016 ::file pmid_1901_4680_131.txt
(c / confirm-01
      :ARG0 (a2 / analyze-01
            :manner (i2 / immunoblot-01))
      :ARG1 (p / possible-01
            :ARG1 (c2 / compare-01
                  :ARG1 (l / level
                        :quant-of (e2 / express-03
                              :ARG2 (i / isoform
                                    :mod (e / enzyme :name (n / name :op1 "MEK"))
                                    :mod (e3 / ectopic))
                              :ARG3 (p2 / population
                                    :ARG1-of (t / transduce-01
                                          :ARG2 (c3 / cell-line :name (n3 / name :op1 "IEC-6"))))))))
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod "1A")))

# ::id pmid_1901_4680.132 ::date 2015-06-17T10:44:10 ::annotator SDL-AMR-09 ::preferred
# ::snt Overexpression of wild type MEK1 or MEK2 did not affect the expression of endogenous MEK isoforms.
# ::save-date Thu Dec 17, 2015 ::file pmid_1901_4680_132.txt
(a / affect-01 :polarity -
      :ARG0 (o / overexpress-01
            :ARG1 (o2 / or
                  :op1 (e / enzyme :name (n / name :op1 "MEK1"))
                  :op2 (e2 / enzyme :name (n2 / name :op1 "MEK2"))
                  :mod (w / wild-type)))
      :ARG1 (e3 / express-03
            :ARG2 (i / isoform
                  :mod (e4 / enzyme :name (n3 / name :op1 "MEK"))
                  :mod (e5 / endogenous))))

# ::id pmid_1901_4680.133 ::date 2015-06-17T11:12:36 ::annotator SDL-AMR-09 ::preferred
# ::snt However, ectopic expression or MEK2DD slightly increased the steady-state levels of endogenous MEK1, while overexpression of MEK1DD had a similar effect on MEK2 levels (Fig. <xref ref-type="fig" rid="F1">1B</xref>).
# ::save-date Thu Dec 17, 2015 ::file pmid_1901_4680_133.txt
(c2 / contrast-01
      :ARG2 (c / contrast-01
            :ARG1 (i / increase-01
                  :ARG0 (e / express-03
                        :ARG2 (e3 / enzyme :name (n / name :op1 "MEK2DD"))
                        :mod (e2 / ectopic))
                  :ARG1 (l / level
                        :quant-of (e4 / enzyme :name (n2 / name :op1 "MEK1")
                              :mod (e5 / endogenous))
                        :mod (s / state
                              :mod (s2 / steady)))
                  :ARG2 (s3 / slight))
            :ARG2 (r / resemble-01
                  :ARG1 (a / affect-01
                        :ARG0 (o / overexpress-01
                              :ARG1 (e6 / enzyme :name (n3 / name :op1 "MEK1DD")))
                        :ARG1 (l2 / level
                              :quant-of (e7 / enzyme :name (n4 / name :op1 "MEK2"))))
                  :ARG2 i)
            :ARG1-of (d / describe-01
                  :ARG0 (f / figure :mod "1B"))))

# ::id pmid_1901_4680.134 ::date 2015-06-17T11:21:40 ::annotator SDL-AMR-09 ::preferred
# ::snt As expected, substitution of the activation loop Ser phosphorylation sites by Asp residues strongly potentiated the enzymatic activity of MEK1 and MEK2, but no reproducible difference in activity was observed between the two isoforms (Fig. <xref ref-type="fig" rid="F1">1C</xref>).
# ::save-date Mon Dec 21, 2015 ::file pmid_1901_4680_134.txt
(c / contrast-01
      :ARG1 (p2 / potentiate-01
            :ARG1 (a / activity-06
                  :ARG0 (a2 / and
                        :op1 (e / enzyme :name (n / name :op1 "MEK1"))
                        :op2 (e2 / enzyme :name (n2 / name :op1 "MEK2"))
                        :mod (e3 / enzyme)))
            :ARG2 (s / substitute-01
                  :ARG1 (r / residue
                        :mod (a6 / amino-acid :name (n3 / name :op1 "aspartic" :op2 "acid")))
                  :ARG2 (s4 / site
                        :location-of (p / phosphorylate-01
                              :ARG1 (a3 / amino-acid :name (n4 / name :op1 "serine")))
                        :mod (l / loop
                              :mod (a4 / activate-01))))
            :manner (s2 / strong)
            :ARG1-of (e4 / expect-01))
      :ARG2 (o / observe-01 :polarity -
            :ARG1 (d / differ-02
                  :ARG1 e
                  :ARG2 e2
                  :ARG3 (a5 / activity-06)
                  :ARG1-of (r2 / reproduce-01
                        :ARG1-of (p3 / possible-01))))
      :ARG1-of (d2 / describe-01
            :ARG0 (f / figure :mod "1C")))

# ::id pmid_1901_4680.135 ::date 2015-06-17T11:35:49 ::annotator SDL-AMR-09 ::preferred
# ::snt IEC-6 cells grow as a monolayer and display a typical epithelial morphology with organized cell-cell adhesions (Fig. <xref ref-type="fig" rid="F1">1D</xref>).
# ::save-date Mon Dec 21, 2015 ::file pmid_1901_4680_135.txt
(a / and
      :op1 (g / grow-01
            :ARG1 (c / cell-line :name (n / name :op1 "IEC-6"))
            :manner (m / monolayer))
      :op2 (d / display-01
            :ARG0 c
            :ARG1 (m2 / morphology
                  :ARG1-of (t / typical-02)
                  :mod (e / epithelium)
                  :accompanier (a2 / adhere-01
                        :ARG1 (c2 / cell)
                        :ARG2 (c3 / cell)
                        :ARG1-of (o / organize-01))))
      :ARG1-of (d2 / describe-01
            :ARG0 (f / figure :mod "1D")))

# ::id pmid_1901_4680.136 ::date 2015-06-17T11:40:38 ::annotator SDL-AMR-09 ::preferred
# ::snt Overexpression of wild type MEK isoforms had no noticeable effect on the morphology of IEC-6 cells.
# ::save-date Thu Dec 17, 2015 ::file pmid_1901_4680_136.txt
(p / possible-01 :polarity -
      :ARG1 (n3 / notice-01
            :ARG1 (a / affect-01
                  :ARG0 (o / overexpress-01
                        :ARG1 (i / isoform
                              :mod (e / enzyme :name (n / name :op1 "MEK")
                                    :mod (w / wild-type))))
                  :ARG1 (m / morphology
                        :mod (c / cell-line :name (n2 / name :op1 "IEC-6"))))))

# ::id pmid_1901_4680.137 ::date 2015-06-17T11:42:38 ::annotator SDL-AMR-09 ::preferred
# ::snt In contrast, expression of activated MEK1 or MEK2 led to drastic morphological changes accompanied by loss of cell-cell contacts; the cells adopted a spindle-like fibroblast morphology, were more refractile and formed multilayers.
# ::save-date Fri Dec 18, 2015 ::file pmid_1901_4680_137.txt
(m / multi-sentence
      :snt1 (c / contrast-01
            :ARG2 (l / lead-03
                  :ARG0 (e / express-03
                        :ARG2 (o / or
                              :op1 (e2 / enzyme :name (n / name :op1 "MEK1"))
                              :op2 (e3 / enzyme :name (n2 / name :op1 "MEK2"))
                              :ARG1-of (a / activate-01)))
                  :ARG2 (c2 / change-01
                        :ARG1 (m2 / morphology)
                        :mod (d / drastic)
                        :ARG1-of (a2 / accompany-01
                              :ARG0 (l2 / lose-02
                                    :ARG1 (c3 / contact-01
                                          :ARG0 (c4 / cell)
                                          :ARG1 (c5 / cell)))))))
      :snt2 (a3 / and
            :op1 (a4 / adopt-01
                  :ARG0 (c6 / cell)
                  :ARG1 (m3 / morphology
                        :mod (f / fibroblast)
                        :ARG1-of (r / resemble-01
                              :ARG2 (s / spindle))))
            :op2 (r2 / refractile
                  :domain c6
                  :degree (m4 / more))
            :op3 (f2 / form-01
                  :ARG0 c6
                  :ARG1 (m5 / multilayer))))

# ::id pmid_1901_4680.138 ::date 2015-06-18T01:25:38 ::annotator SDL-AMR-09 ::preferred
# ::snt These changes are characteristic of epithelial-mesenchymal transitions (EMT) that play an important role in tumor progression [<xref ref-type="bibr" rid="B39">39</xref>].
# ::save-date Wed Jun 24, 2015 ::file pmid_1901_4680_138.txt
(c / characteristic-02
      :ARG1 (e / event :name (n / name :op1 "epithelial-mesenchymal" :op2 "transition")
            :ARG0-of (p / play-02
                  :ARG1 (r / role
                        :prep-in (p2 / progress-01
                              :ARG1 (t2 / tumor))
                        :mod (i / important))))
      :ARG2 (c2 / change-01
            :mod (t / this))
      :ARG1-of (d / describe-01
            :ARG0 (p3 / publication
                  :ARG1-of (c3 / cite-01
                        :ARG2 39))))

# ::id pmid_1901_4680.139 ::date 2015-06-18T01:29:24 ::annotator SDL-AMR-09 ::preferred
# ::snt To determine whether MEK1DD- and MEK2DD-expressing cells undergo an EMT, we examined the localization and measured the expression levels of various epithelial and mesenchymal markers.
# ::save-date Wed Jun 24, 2015 ::file pmid_1901_4680_139.txt
(a / and
      :op1 (e / examine-01
            :ARG0 (w / we)
            :ARG1 (b / be-located-at-91
                  :ARG1 a3))
      :op2 (m / measure-01
            :ARG0 w
            :ARG1 (l2 / level
                  :quant-of (e7 / express-03
                        :ARG2 (a3 / and
                              :op1 (m2 / marker
                                    :mod (e8 / epithelium))
                              :op2 (m3 / marker
                                    :mod (m4 / mesenchymal))
                              :mod (v / various)))))
      :purpose (d / determine-01
            :ARG0 w
            :ARG1 (u / undergo-28 :mode interrogative
                  :ARG1 (a2 / and
                        :op1 (c / cell
                              :ARG3-of (e2 / express-03
                                    :ARG2 (e3 / enzyme :name (n / name :op1 "MEK1DD"))))
                        :op2 (c2 / cell
                              :ARG3-of (e4 / express-03
                                    :ARG2 (e5 / enzyme :name (n2 / name :op1 "MEK2DD")))))
                  :ARG2 (e6 / event :name (n3 / name :op1 "epithelial-mesenchymal" :op2 "transition")))))

# ::id pmid_1901_4680.140 ::date 2015-06-18T01:34:20 ::annotator SDL-AMR-09 ::preferred
# ::snt Parental and vector-infected IEC-6 cells showed a polarized basolateral membrane distribution of the epithelial marker E-cadherin, with basal expression of the fibroblast marker vimentin (Fig. <xref ref-type="fig" rid="F1">1E</xref>).
# ::save-date Sun Jan 17, 2016 ::file pmid_1901_4680_140.txt
(s / show-01
      :ARG0 (a / and
            :op1 (c / cell-line :name (n / name :op1 "IEC-6")
                  :mod (p / parent))
            :op2 (c2 / cell-line :name (n2 / name :op1 "IEC-6")
                  :ARG1-of (i / infect-01
                        :ARG2 (v / vector))))
      :ARG1 (d / distribute-01
            :ARG1 (m4 / marker :name (n3 / name :op1 "E-cadherin")
                  :mod (e / epithelium))
            :ARG2 (m / membrane
                  :mod (b / basolateral))
            :ARG1-of (p2 / polarize-01)
            :accompanier (e2 / express-03
                  :ARG2 (m3 / marker
                        :mod (f / fibroblast)
                        :mod (p4 / protein :name (n4 / name :op1 "vimentin")))
                  :mod (b2 / basal)))
      :ARG1-of (d2 / describe-01
            :ARG0 (f2 / figure :mod "1E")))

# ::id pmid_1901_4680.141 ::date 2015-06-18T01:43:10 ::annotator SDL-AMR-09 ::preferred
# ::snt Ectopic expression of MEK1DD or MEK2DD resulted in the loss of E-cadherin staining at the plasma membrane (Fig. <xref ref-type="fig" rid="F1">1E</xref>), concomitant with a marked reduction of E-cadherin protein and mRNA levels (Fig. <xref ref-type="fig" rid="F1">1F</xref> and <xref ref-type="fig" rid="F1">1G</xref>).
# ::save-date Wed Jun 24, 2015 ::file pmid_1901_4680_141.txt
(r / result-01
      :ARG1 (e / express-03
            :ARG2 (o / or
                  :op1 (e3 / enzyme :name (n / name :op1 "MEK1DD"))
                  :op2 (e4 / enzyme :name (n2 / name :op1 "MEK2DD")))
            :mod (e2 / ectopic))
      :ARG2 (l / lose-02
            :ARG1 (s / stain-01
                  :ARG1 (p / protein :name (n3 / name :op1 "E-cadherin"))
                  :location (m / membrane
                        :mod (p2 / plasma)))
            :ARG1-of (d / describe-01
                  :ARG0 (f / figure :mod "1E"))
            :time (r2 / reduce-01
                  :ARG1 (a / and
                        :op1 (l2 / level
                              :quant-of p)
                        :op2 (l3 / level
                              :quant-of (n5 / nucleic-acid :name (n4 / name :op1 "mRNA"))))
                  :ARG2 (m2 / mark-01)
                  :manner (c / concomitant)
                  :ARG1-of (d2 / describe-01
                        :ARG0 (a2 / and
                              :op1 (f2 / figure :mod "1F")
                              :op2 (f3 / figure :mod "1G"))))))

# ::id pmid_1901_4680.142 ::date 2015-06-18T01:54:31 ::annotator SDL-AMR-09 ::preferred
# ::snt No significant change in the expression of keratins and no induction of the mesenchymal proteins vimentin and smooth muscle α-actin (we instead observed a decreased expression) were observed in these cells (Fig. <xref ref-type="fig" rid="F1">1F</xref>).
# ::save-date Sun Dec 20, 2015 ::file pmid_1901_4680_142.txt
(o / observe-01
      :ARG1 (a / and
            :op1 (c / change-01
                  :ARG1 (e / express-03
                        :ARG2 (p / protein :name (n / name :op1 "keratin")))
                  :ARG1-of (s / significant-02))
            :op2 (i / induce-01
                  :ARG2 (a2 / and
                        :op1 (p2 / protein :name (n2 / name :op1 "vimentin"))
                        :op2 (p3 / protein :name (n3 / name :op1 "smooth" :op2 "muscle" :op3 "α-actin"))
                        :mod (m / mesenchymal))))
      :location (c2 / cell
            :mod (t / this))
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod "1F"))
      :ARG2-of (i2 / instead-of-91
            :ARG1 (o2 / observe-01
                  :ARG0 (w / we)
                  :ARG1 (e2 / express-03
                        :ARG1-of (d2 / decrease-01)))))

# ::id pmid_1901_4680.143 ::date 2015-06-18T02:01:30 ::annotator SDL-AMR-09 ::preferred
# ::snt These results indicate that constitutive activation of MEK1 or MEK2, while disrupting normal epithelial morphology and polarization, is not sufficient to induce a full EMT in intestinal epithelial cells.
# ::save-date Wed Dec 30, 2015 ::file pmid_1901_4680_143.txt
(i / indicate-01
      :ARG0 (t / thing
            :ARG2-of (r / result-01)
            :mod (t2 / this))
      :ARG1 (c3 / contrast-01
            :ARG1 (d / disrupt-01
                  :ARG0 a
                  :ARG1 (a2 / and
                        :op1 (m / morphology
                              :ARG1-of (n4 / normal-02)
                              :mod (e5 / epithelium))
                        :op2 (p / polarize-01
                              :ARG1 e5)))
            :ARG2 (s / suffice-01 :polarity -
                  :ARG0 (a / activate-01
                        :ARG1 (o / or
                              :op1 (e / enzyme :name (n / name :op1 "MEK1"))
                              :op2 (e2 / enzyme :name (n2 / name :op1 "MEK2")))
                        :mod (c / constitutive))
                  :ARG1 (i2 / induce-01
                        :ARG0 a
                        :ARG1 (c2 / cell
                              :part-of (e4 / epithelium
                                    :part-of (i3 / intestine)))
                        :ARG2 (e3 / event :name (n3 / name :op1 "epithelial-mesenchymal" :op2 "transition")
                              :ARG1-of (f / full-09))))))

# ::id pmid_1901_4680.144 ::date 2015-06-18T02:11:08 ::annotator SDL-AMR-09 ::preferred
# ::snt This epithelial plasticity change has been referred to as scattering and is distinct from EMT [<xref ref-type="bibr" rid="B40">40</xref>].
# ::save-date Wed Jun 24, 2015 ::file pmid_1901_4680_144.txt
(a / and
      :op1 (r / reference-04
            :ARG1 (c / change-01
                  :ARG1 (p / plasticity
                        :mod (e / epithelium))
                  :mod (t / this))
            :ARG2 (s / scatter-01))
      :op2 (d / distinct
            :domain c
            :compared-to (e3 / event :name (n2 / name :op1 "epithelial-mesenchymal" :op2 "transition")))
      :ARG1-of (d2 / describe-01
            :ARG0 (p2 / publication
                  :ARG1-of (c2 / cite-01
                        :ARG2 40))))

# ::id pmid_1901_4680.145 ::date 2015-06-18T02:15:33 ::annotator SDL-AMR-09 ::preferred
# ::snt We examined whether constitutive activation of MEK1 or MEK2 was conferring some proliferation advantage to intestinal epithelial cells.
# ::save-date Thu Jun 18, 2015 ::file pmid_1901_4680_145.txt
(e / examine-01
      :ARG0 (w / we)
      :ARG1 (c / confer-02 :mode interrogative
            :ARG0 (a / activate-01
                  :ARG1 (o / or
                        :op1 (e2 / enzyme :name (n / name :op1 "MEK1"))
                        :op2 (e3 / enzyme :name (n2 / name :op1 "MEK2"))
                        :mod (c2 / constitutive)))
            :ARG1 (a2 / advantage
                  :mod (p / proliferate-01)
                  :mod (s / some))
            :ARG2 (c3 / cell
                  :part-of (e4 / epithelium
                        :part-of (i / intestine)))))

# ::id pmid_1901_4680.146 ::date 2015-06-18T02:17:42 ::annotator SDL-AMR-09 ::preferred
# ::snt Ectopic expression of either activated MEK1 or MEK2 significantly increased the proliferation rate of IEC-6 cells grown in 10% serum containing-medium when compared to vector-infected cells or cells overexpressing wild type MEK isoforms (Fig. <xref ref-type="fig" rid="F2">2A</xref>).
# ::save-date Fri Dec 18, 2015 ::file pmid_1901_4680_146.txt
(i / increase-01
      :ARG0 (e2 / express-03
            :ARG2 (o / or
                  :op1 (e4 / enzyme :name (n2 / name :op1 "MEK1"))
                  :op2 (e5 / enzyme :name (n3 / name :op1 "MEK2"))
                  :ARG1-of (a / activate-01))
            :mod (e3 / ectopic))
      :ARG1 (r / rate
            :mod (p2 / proliferate-01
                  :ARG0 (c / cell-line :name (n4 / name :op1 "IEC-6")
                        :ARG1-of (g / grow-01
                              :location (m / medium
                                    :ARG0-of (c2 / contain-01
                                          :ARG1 (s2 / serum
                                                :mod (p / percentage-entity :value 10)))))
                        :compared-to (o2 / or
                              :op1 (c3 / cell
                                    :ARG1-of (i2 / infect-01
                                          :ARG2 (v / vector)))
                              :op2 (c4 / cell
                                    :location-of (o3 / overexpress-01
                                          :ARG1 (i3 / isoform
                                                :mod (e / enzyme :name (n / name :op1 "MEK")
                                                      :mod (w / wild-type)))))))))
      :ARG2 (s / significant-02)
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod "2A")))

# ::id pmid_1901_4680.147 ::date 2015-06-18T02:25:21 ::annotator SDL-AMR-09 ::preferred
# ::snt This increase in proliferation was not observed in low serum (2%) containing-medium (data not shown).
# ::save-date Wed Jun 24, 2015 ::file pmid_1901_4680_147.txt
(o / observe-01 :polarity -
      :ARG1 (i / increase-01
            :ARG1 (p2 / proliferate-01)
            :mod (t / this)
            :location (m / medium
                  :ARG0-of (c / contain-01
                        :ARG1 (s / serum
                              :mod (p / percentage-entity :value 2)
                              :ARG1-of (l / low-04)))))
      :ARG1-of (d / describe-01
            :ARG0 (d2 / data
                  :ARG1-of (s2 / show-01 :polarity -))))

# ::id pmid_1901_4680.148 ::date 2015-06-18T02:27:59 ::annotator SDL-AMR-09 ::preferred
# ::snt Both activated MEK1 and MEK2 conferred anchorage-independence growth to IEC-6 cells (Fig. <xref ref-type="fig" rid="F2">2B</xref>).
# ::save-date Thu Jun 18, 2015 ::file pmid_1901_4680_148.txt
(c / confer-02
      :ARG0 (a / and
            :op1 (e / enzyme :name (n / name :op1 "MEK1"))
            :op2 (e2 / enzyme :name (n2 / name :op1 "MEK2"))
            :ARG1-of (a2 / activate-01))
      :ARG1 (g / grow-01
            :ARG0-of (d / depend-01 :polarity -
                  :ARG1 (a3 / anchorage)))
      :ARG2 (c2 / cell-line :name (n3 / name :op1 "IEC-6"))
      :ARG1-of (d2 / describe-01
            :ARG0 (f / figure :mod "2B")))

# ::id pmid_1901_4680.149 ::date 2015-06-18T02:30:47 ::annotator SDL-AMR-09 ::preferred
# ::snt To test the tumorigenic potential of IEC-6 transduced cell populations <i>in vivo</i>, the cells were injected subcutaneously into athymic mice.
# ::save-date Tue Jan 19, 2016 ::file pmid_1901_4680_149.txt
(i / inject-01
      :ARG1 (c / cell)
      :ARG2 (m / mouse
            :mod (a / athymic))
      :manner (s / subcutaneous)
      :purpose (t / test-01
            :ARG1 (p / potential
                  :mod (c2 / cause-01
                        :ARG0 (p2 / population
                              :ARG1-of (t2 / transduce-01
                                    :ARG2 (c3 / cell-line :name (n / name :op1 "IEC-6"))))
                        :ARG1 (t3 / tumor))
                  :mod (i2 / in-vivo))))

# ::id pmid_1901_4680.150 ::date 2015-06-18T02:35:18 ::annotator SDL-AMR-09 ::preferred
# ::snt Cells infected with vector or wild type MEK isoforms never formed any tumor (Fig. <xref ref-type="fig" rid="F2">2C</xref>).
# ::save-date Thu Jun 18, 2015 ::file pmid_1901_4680_150.txt
(f / form-01 :polarity -
      :ARG0 (c / cell
            :ARG1-of (i / infect-01
                  :ARG2 (o / or
                        :op1 (v / vector)
                        :op2 (i2 / isoform
                              :mod (e / enzyme :name (n / name :op1 "MEK")
                                    :mod (w / wild-type))))))
      :ARG1 (t / tumor
            :mod (a / any))
      :time (e2 / ever)
      :ARG1-of (d / describe-01
            :ARG0 (f2 / figure :mod "2C")))

# ::id pmid_1901_4680.151 ::date 2015-06-18T02:37:28 ::annotator SDL-AMR-09 ::preferred
# ::snt In contrast, both MEK1DD- and MEK2DD-expressing cells generated rapidly growing tumors in all injected mice.
# ::save-date Wed Jun 24, 2015 ::file pmid_1901_4680_151.txt
(c / contrast-01
      :ARG2 (g / generate-01
            :ARG0 (a / and
                  :op1 (c2 / cell
                        :ARG3-of (e / express-03
                              :ARG2 (e2 / enzyme :name (n / name :op1 "MEK1DD"))))
                  :op2 (c3 / cell
                        :ARG3-of (e3 / express-03
                              :ARG2 (e4 / enzyme :name (n2 / name :op1 "MEK2DD")))))
            :ARG1 (t / tumor
                  :ARG1-of (g2 / grow-01
                        :manner (r / rapid)))
            :location (m / mouse
                  :ARG2-of (i / inject-01)
                  :mod (a2 / all))))

# ::id pmid_1901_4680.152 ::date 2015-06-18T02:40:07 ::annotator SDL-AMR-09 ::preferred
# ::snt Injection of as low as 3 × 10<sup>4 </sup>cells produced tumors of ~1,000 mm<sup>3 </sup>after 2 weeks.
# ::save-date Tue Mar 1, 2016 ::file pmid_1901_4680_152.txt
(p / produce-01
      :ARG0 (i / inject-01
            :ARG1 (c / cell :quant 30000
                  :ARG3-of (l / low-04)))
      :ARG1 (t2 / tumor
            :mod (a / approximately
                  :op1 (v / volume-quantity :quant 1000
                        :unit (c2 / cubic-millimeter))))
      :time (a2 / after
            :op1 (t / temporal-quantity :quant 2
                  :unit (w / week))))

# ::id pmid_1901_4680.153 ::date 2015-06-18T02:45:12 ::annotator SDL-AMR-09 ::preferred
# ::snt No major difference was observed in the growth rate of tumors expressing activated MEK1 or MEK2 (Fig. <xref ref-type="fig" rid="F2">2D</xref>).
# ::save-date Sun Dec 20, 2015 ::file pmid_1901_4680_153.txt
(o / observe-01
      :ARG1 (d / differ-02 :polarity -
            :ARG1 (r / rate
                  :mod (g / grow-01
                        :ARG1 (t / tumor
                              :ARG3-of (e / express-03
                                    :ARG2 (o2 / or
                                          :op1 (e2 / enzyme :name (n / name :op1 "MEK1"))
                                          :op2 (e3 / enzyme :name (n2 / name :op1 "MEK2"))
                                          :ARG1-of (a / activate-01))))))
            :ARG1-of (m / major-02))
      :ARG1-of (d2 / describe-01
            :ARG0 (f / figure :mod "2D")))

# ::id pmid_1901_4680.154 ::date 2015-06-18T02:47:59 ::annotator SDL-AMR-09 ::preferred
# ::snt To analyze the impact of active MEK isoforms on tumorigenesis in a more pathologically relevant model, IEC-6 transduced cells were orthotopically transplanted into the caecum of athymic mice.
# ::save-date Tue Jan 19, 2016 ::file pmid_1901_4680_154.txt
(t / transplant-01
      :ARG1 (c / cell
            :ARG1-of (t2 / transduce-01
                  :ARG2 (c4 / cell-line :name (n2 / name :op1 "IEC-6"))))
      :ARG2 (c2 / caecum
            :part-of (m / mouse
                  :mod (a / athymic)))
      :manner (o / orthotopic)
      :purpose (a2 / analyze-01
            :ARG1 (i / impact-01
                  :ARG0 (i2 / isoform
                        :mod (e / enzyme :name (n / name :op1 "MEK"))
                        :ARG1-of (a3 / activate-01))
                  :ARG1 (c3 / cause-01
                        :ARG1 (t3 / tumor)))
            :prep-in (m2 / model
                  :ARG1-of (r / relevant-01
                        :ARG2 (p / pathology)
                        :degree (m3 / more)))))

# ::id pmid_1901_4680.155 ::date 2015-06-16T09:31:40 ::annotator SDL-AMR-09 ::preferred
# ::snt This model more closely recapitulates human colorectal cancer progression, in particular the spontaneous metastatic process that is highly dependent on the host environment [<xref ref-type="bibr" rid="B41">41</xref>].
# ::save-date Mon Dec 21, 2015 ::file pmid_1901_4680_155.txt
(r / recapitulate-01
      :ARG0 (m / model
            :mod (t / this))
      :ARG1 (a / and
            :op1 (p / progress-01
                  :ARG1 (d3 / disease :wiki "Colorectal_cancer" :name (n / name :op1 "colorectal" :op2 "cancer")
                        :mod (h / human)))
            :op2 (p2 / process-02
                  :ARG1 (m3 / metastasize-101)
                  :mod (s / spontaneous)
                  :mod (p3 / particular)
                  :ARG0-of (d / depend-01
                        :ARG1 (e / environment
                              :ARG0-of (h3 / host-01))
                        :ARG1-of (h2 / high-02))))
      :ARG1-of (c / close-10
            :degree (m2 / more))
      :ARG1-of (d2 / describe-01
            :ARG0 (p4 / publication
                  :ARG1-of (c4 / cite-01
                        :ARG2 41))))

# ::id pmid_1901_4680.156 ::date 2015-06-16T10:00:03 ::annotator SDL-AMR-09 ::preferred
# ::snt Strikingly, 100% of the mice transplanted with 10<sup>5 </sup>IEC-6 cells expressing either MEK1DD or MEK2DD developed massive intestinal tumors, while the control group remained tumor-free (Fig. <xref ref-type="fig" rid="F2">2C</xref> and <xref ref-type="fig" rid="F2">2E</xref>).
# ::save-date Fri Dec 18, 2015 ::file pmid_1901_4680_156.txt
(c / contrast-01
      :ARG1 (d / develop-02
            :ARG0 (m / mouse
                  :ARG1-of (i2 / include-91
                        :ARG2 (m3 / mouse
                              :ARG2-of (t / transplant-01
                                    :ARG1 (c2 / cell-line :quant 100000 :name (n / name :op1 "IEC-6")
                                          :ARG3-of (e / express-03
                                                :ARG2 (o / or
                                                      :op1 (e2 / enzyme :name (n2 / name :op1 "MEK1DD"))
                                                      :op2 (e3 / enzyme :name (n3 / name :op1 "MEK2DD")))))))
                        :ARG3 (p / percentage-entity :value 100)))
            :ARG1 (t2 / tumor
                  :mod (i / intestine)
                  :mod (m2 / massive)))
      :ARG2 (r / remain-01
            :ARG1 (g / group
                  :mod (c3 / control))
            :ARG3 (f / free-04
                  :ARG1 g
                  :ARG2 t2))
      :ARG1-of (d2 / describe-01
            :ARG0 (a / and
                  :op1 (f2 / figure :mod "2C")
                  :op2 (f3 / figure :mod "2E")))
      :ARG1-of (s / strike-04))

# ::id pmid_1901_4680.157 ::date 2015-06-16T10:40:42 ::annotator SDL-AMR-09 ::preferred
# ::snt The mice were sacrificed when they became moribund or presented symptoms of weight loss, respiratory distress, or a palpable abdominal mass.
# ::save-date Sun Dec 20, 2015 ::file pmid_1901_4680_157.txt
(s / sacrifice-01
      :ARG1 (m / mouse)
      :time (o / or
            :op1 (b / become-01
                  :ARG1 m
                  :ARG2 (m2 / moribund))
            :op2 (p / present-102
                  :ARG0 m
                  :ARG1 (o2 / or
                        :op1 (s2 / symptom
                              :mod (l / lose-02
                                    :ARG1 (w / weight)))
                        :op2 (s3 / symptom
                              :mod (d / distress-01
                                    :ARG1 (r / respiration)))
                        :op3 (s4 / symptom
                              :mod (m3 / mass
                                    :ARG1-of (p2 / palpate-00
                                          :ARG1-of (p3 / possible-01))
                                    :mod (a2 / abdomen)))))))

# ::id pmid_1901_4680.158 ::date 2015-06-16T11:20:56 ::annotator SDL-AMR-09 ::preferred
# ::snt Microscopic examination of the tumors revealed a poorly differentiated morphology with occasional signet-ring cells (inset) corresponding to a high-grade adenocarcinoma (Fig. <xref ref-type="fig" rid="F2">2E</xref>).
# ::save-date Mon Dec 21, 2015 ::file pmid_1901_4680_158.txt
(r / reveal-01
      :ARG0 (e / examine-01
            :ARG1 (t / tumor)
            :mod (m / microscopic))
      :ARG1 (m2 / morphology
            :ARG1-of (d / differentiate-01
                  :manner (p / poor))
            :consist-of (c / cell-line :name (n / name :op1 "signet-ring")
                  :ARG1-of (m3 / mean-01
                        :ARG2 (i / inset))
                  :ARG1-of (c2 / correspond-02
                        :ARG2 (m4 / medical-condition :name (n2 / name :op1 "adenocarcinoma")
                              :mod (g / grade
                                    :ARG1-of (h / high-02))))
                  :frequency (o / occasional)))
      :ARG1-of (d3 / describe-01
            :ARG0 (f / figure :mod "2E")))

# ::id pmid_1901_4680.159 ::date 2015-06-16T11:33:57 ::annotator SDL-AMR-09 ::preferred
# ::snt The tumors are invasive and diffusely infiltrate the lamina propria and the underlying muscular layers (muscularis propria and muscularis mucosae).
# ::save-date Wed Jun 24, 2015 ::file pmid_1901_4680_159.txt
(a / and
      :op1 (i / invade-01
            :ARG0 (t / tumor))
      :op2 (i2 / infiltrate-01
            :ARG0 t
            :ARG1 (a2 / and
                  :op1 (l / lamina-propria)
                  :op2 (l2 / layer
                        :mod (m / muscle)
                        :ARG1-of (u / underlie-01)
                        :ARG1-of (m2 / mean-01
                              :ARG2 (a3 / and
                                    :op1 (l3 / layer :name (n / name :op1 "muscularis" :op2 "propria"))
                                    :op2 (l4 / layer :name (n2 / name :op1 "muscularis" :op2 "mucosae"))))))
            :manner (d / diffuse)))

# ::id pmid_1901_4680.160 ::date 2015-06-16T11:48:25 ::annotator SDL-AMR-09 ::preferred
# ::snt Together, these data demonstrate that constitutive activation of MEK1 or MEK2 is sufficient to transform intestinal epithelial cells and induce the formation of invasive colon adenocarcinomas.
# ::save-date Thu Dec 10, 2015 ::file pmid_1901_4680_160.txt
(d / demonstrate-01
      :ARG0 (d2 / data
            :mod (t / this)
            :mod (t2 / together))
      :ARG1 (s / suffice-01
            :ARG0 (a / activate-01
                  :ARG1 (a2 / and
                        :op1 (e / enzyme :name (n / name :op1 "MEK1"))
                        :op2 (e2 / enzyme :name (n2 / name :op1 "MEK2")))
                  :mod (c3 / constitutive))
            :ARG1 (a3 / and
                  :op1 (t3 / transform-01
                        :ARG0 a
                        :ARG1 (c / cell
                              :mod (e3 / epithelium)
                              :part-of (i2 / intestine)))
                  :op2 (i / induce-01
                        :ARG0 a
                        :ARG2 (f / form-01
                              :ARG1 (m / medical-condition :name (n3 / name :op1 "adenocarcinoma")
                                    :mod (c2 / colon)
                                    :ARG0-of (i3 / invade-01)))))))

# ::id pmid_1901_4680.161 ::date 2015-06-16T11:55:45 ::annotator SDL-AMR-09 ::preferred
# ::snt <sec-title level="2">Constitutive activation of MEK1 or MEK2 confers metastatic properties to transformed intestinal epithelial cells</sec-title>
# ::save-date Wed Jun 24, 2015 ::file pmid_1901_4680_161.txt
(c / confer-02
      :ARG0 (a / activate-01
            :ARG1 (a2 / and
                  :op1 (e / enzyme :name (n / name :op1 "MEK1"))
                  :op2 (e2 / enzyme :name (n2 / name :op1 "MEK2")))
            :mod (c2 / constitutive))
      :ARG1 (p / property
            :mod (m / metastasize-101))
      :ARG2 (c3 / cell
            :mod (e3 / epithelium)
            :part-of (i / intestine)
            :ARG1-of (t / transform-01)))

# ::id pmid_1901_4680.162 ::date 2015-06-16T12:01:26 ::annotator SDL-AMR-09 ::preferred
# ::snt Activation of the ERK1/2 MAP kinase pathway has been implicated in the regulation of cell motility and invasion [<xref ref-type="bibr" rid="B42">42</xref>].
# ::save-date Tue Jun 16, 2015 ::file pmid_1901_4680_162.txt
(i / implicate-01
      :ARG1 (a / activate-01
            :ARG1 (p / pathway :name (n / name :op1 "ERK1/2" :op2 "MAP-kinase")))
      :ARG2 (r / regulate-01
            :ARG0 a
            :ARG1 (a2 / and
                  :op1 (m / motility
                        :mod (c / cell))
                  :op2 (i2 / invade-01
                        :ARG0 c)))
      :ARG1-of (d / describe-01
            :ARG0 (p2 / publication
                  :ARG1-of (c2 / cite-01
                        :ARG2 42))))

# ::id pmid_1901_4680.163 ::date 2015-06-16T12:10:00 ::annotator SDL-AMR-09 ::preferred
# ::snt Notably, treatment of colon carcinoma cells with the MEK1/2 inhibitor PD184352 was shown to inhibit HGF-induced cell scattering and to reduce their invasive properties [<xref ref-type="bibr" rid="B20">20</xref>].
# ::save-date Mon Dec 21, 2015 ::file pmid_1901_4680_163.txt
(s / show-01
      :ARG1 (a / and
            :op1 (i2 / inhibit-01
                  :ARG0 (t / treat-04
                        :ARG1 (c / cell
                              :mod (m / medical-condition :name (n / name :op1 "carcinoma"))
                              :part-of (c2 / colon))
                        :ARG2 (s2 / small-molecule :name (n2 / name :op1 "PD184352")
                              :ARG0-of (i / inhibit-01
                                    :ARG1 (e / enzyme :name (n3 / name :op1 "MEK1/2")))))
                  :ARG1 (s3 / scatter-01
                        :ARG1 (c3 / cell)
                        :ARG2-of (i3 / induce-01
                              :ARG0 (p / protein :name (n4 / name :op1 "HGF")))))
            :op2 (r / reduce-01
                  :ARG0 t
                  :ARG1 (p2 / property
                        :mod (i4 / invade-01
                              :ARG0 c3)
                        :poss c3)))
      :ARG1-of (n5 / notable-04)
      :ARG1-of (d2 / describe-01
            :ARG0 (p3 / publication
                  :ARG1-of (c4 / cite-01
                        :ARG2 20))))

# ::id pmid_1901_4680.164 ::date 2015-06-16T12:34:13 ::annotator SDL-AMR-09 ::preferred
# ::snt We examined the impact of MEK1 or MEK2 activation on the motility of IEC-6 cells using two different cell migration assays.
# ::save-date Wed Jun 24, 2015 ::file pmid_1901_4680_164.txt
(e / examine-01
      :ARG0 (w / we)
      :ARG1 (i / impact-01
            :ARG0 (a / activate-01
                  :ARG1 (o / or
                        :op1 (e2 / enzyme :name (n / name :op1 "MEK1"))
                        :op2 (e3 / enzyme :name (n2 / name :op1 "MEK2"))))
            :ARG1 (m / motility
                  :poss (c / cell-line :name (n3 / name :op1 "IEC-6"))))
      :ARG2-of (u / use-01
            :ARG0 w
            :ARG1 (a2 / assay-01 :quant 2
                  :ARG1 (m2 / migrate-01
                        :ARG0 (c2 / cell))
                  :ARG1-of (d / differ-02))))

# ::id pmid_1901_4680.165 ::date 2015-06-16T13:27:53 ::annotator SDL-AMR-09 ::preferred
# ::snt No difference in the migration rate of the different IEC-6 transduced populations was observed in a standard chemotaxis assay with serum as chemoattractant (Fig. <xref ref-type="fig" rid="F3">3A</xref>).
# ::save-date Tue Jan 19, 2016 ::file pmid_1901_4680_165.txt
(o / observe-01
      :ARG1 (d / differ-02 :polarity -
            :ARG1 (r / rate
                  :mod (m / migrate-01
                        :ARG1 (p / population
                              :ARG1-of (t / transduce-01
                                    :ARG2 (c / cell-line :name (n / name :op1 "IEC-6")))))))
      :location (a / assay-01
            :ARG1 (c2 / chemotaxis)
            :mod (s / standard)
            :instrument (s2 / serum
                  :purpose (c3 / chemoattractant)))
      :ARG1-of (d2 / describe-01
            :ARG0 (f / figure :mod "3A")))

# ::id pmid_1901_4680.166 ::date 2015-06-16T13:59:23 ::annotator SDL-AMR-09 ::preferred
# ::snt Similar results were obtained using a wound-healing assay (data not shown).
# ::save-date Sun Dec 20, 2015 ::file pmid_1901_4680_166.txt
(o / obtain-01
      :ARG1 (t / thing
            :ARG2-of (r / result-01)
            :ARG1-of (r2 / resemble-01))
      :ARG2-of (u / use-01
            :ARG1 (a / assay-01
                  :ARG1 (h / heal-01
                        :ARG2 (w / wound))))
      :ARG1-of (d / describe-01
            :ARG0 (d2 / data
                  :ARG1-of (s / show-01 :polarity -))))

# ::id pmid_1901_4680.167 ::date 2015-06-16T14:08:51 ::annotator SDL-AMR-09 ::preferred
# ::snt We next analyzed the ability of the cells to migrate through a Matrigel-coated membrane as a reflection of their invasive properties.
# ::save-date Wed Jun 24, 2015 ::file pmid_1901_4680_167.txt
(a / analyze-01
      :ARG0 (w / we)
      :ARG1 (c / capable-01
            :ARG1 (c2 / cell)
            :ARG2 (m / migrate-01
                  :ARG0 c2
                  :ARG1 (m2 / membrane
                        :ARG1-of (c3 / coat-01
                              :ARG2 (p3 / protein :name (n3 / name :op1 "Matrigel")))))
            :ARG1-of (r / reflect-01
                  :ARG2 (p2 / property
                        :mod (i / invade-01
                              :ARG0 c2)
                        :poss c2)))
      :time (n2 / next))

# ::id pmid_1901_4680.168 ::date 2015-06-16T14:16:12 ::annotator SDL-AMR-09 ::preferred
# ::snt Ectopic expression of activated MEK1 or MEK2 significantly enhanced the invasive capacity of IEC-6 cells, while the wild type MEK isoforms had no effect (Fig. <xref ref-type="fig" rid="F3">3B</xref>).
# ::save-date Wed Jun 24, 2015 ::file pmid_1901_4680_168.txt
(c / contrast-01
      :ARG1 (e / enhance-01
            :ARG0 (e2 / express-03
                  :ARG2 (o / or
                        :op1 (e4 / enzyme :name (n / name :op1 "MEK1")
                              :ARG1-of (a / activate-01))
                        :op2 (e5 / enzyme :name (n2 / name :op1 "MEK2")
                              :ARG1-of a))
                  :mod (e3 / ectopic))
            :ARG1 (c2 / capable-01
                  :ARG1 (c3 / cell-line :name (n3 / name :op1 "IEC-6"))
                  :ARG2 (i / invade-01))
            :ARG1-of (s / significant-02))
      :ARG2 (a2 / affect-01 :polarity -
            :ARG0 (i2 / isoform
                  :mod (e6 / enzyme :name (n4 / name :op1 "MEK"))
                  :mod (w / wild-type)))
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod "3B")))

# ::id pmid_1901_4680.169 ::date 2015-06-16T14:34:56 ::annotator SDL-AMR-09 ::preferred
# ::snt Interestingly, the MEK2DD-transduced cells appeared more invasive than cells expressing MEK1DD in this assay.
# ::save-date Tue Jan 19, 2016 ::file pmid_1901_4680_169.txt
(a / appear-02
      :ARG1 (i / invade-01
            :ARG0 (c / cell
                  :ARG1-of (t / transduce-01
                        :ARG2 (e / enzyme :name (n / name :op1 "MEK2DD"))))
            :degree (m / more)
            :compared-to (c2 / cell
                  :ARG3-of (e2 / express-03
                        :ARG2 (e3 / enzyme :name (n2 / name :op1 "MEK1DD")))))
      :mod (i2 / interesting)
      :location (a2 / assay-01
            :mod (t2 / this)))

# ::id pmid_1901_4680.170 ::date 2015-06-16T14:44:00 ::annotator SDL-AMR-09 ::preferred
# ::snt The invasive properties of the cells <i>in vitro </i>and the histology of the intestinal tumors suggest that MEK1DD- and MEK2DD-expressing IEC-6 cells may have metastatic properties <i>in vivo</i>.
# ::save-date Wed Jun 24, 2015 ::file pmid_1901_4680_170.txt
(s / suggest-01
      :ARG0 (a / and
            :op1 (p / property
                  :mod (i / invade-01
                        :ARG0 (c / cell)
                        :manner (i2 / in-vitro)))
            :op2 (h / histology
                  :poss (t / tumor
                        :location (i3 / intestine))))
      :ARG1 (p2 / possible-01
            :ARG1 (h2 / have-03
                  :ARG0 (c2 / cell-line :name (n / name :op1 "IEC-6")
                        :ARG3-of (e / express-03
                              :ARG2 (a2 / and
                                    :op1 (e2 / enzyme :name (n2 / name :op1 "MEK1DD"))
                                    :op2 (e3 / enzyme :name (n3 / name :op1 "MEK2DD")))))
                  :ARG1 (p3 / property
                        :mod (m / metastasize-101))
                  :manner (i4 / in-vivo))))

# ::id pmid_1901_4680.171 ::date 2015-06-16T14:58:30 ::annotator SDL-AMR-09 ::preferred
# ::snt Detailed histological examination of a subset of mice that develop orthotopic tumors revealed the presence of metastasis in the lymph nodes, the lungs and the liver in both the MEK1DD and MEK2DD groups (Fig. <xref ref-type="fig" rid="F3">3C</xref> and <xref ref-type="fig" rid="F3">3D</xref>).
# ::save-date Fri Jun 26, 2015 ::file pmid_1901_4680_171.txt
(r / reveal-01
      :ARG0 (e / examine-01
            :ARG1 (s / subset
                  :ARG1-of (i / include-91
                        :ARG2 (m / mouse
                              :ARG1-of (d2 / develop-01
                                    :ARG2 (t / tumor
                                          :mod (o / orthotopic))))))
            :ARG1-of (d / detail-01)
            :mod (h / histology))
      :ARG1 (m2 / metastasize-101
            :ARG2 (a / and
                  :op1 (n / node
                        :mod (l / lymph))
                  :op2 (l2 / lung)
                  :op3 (l3 / liver)))
      :location (a2 / and
            :op1 (g / group
                  :mod (e2 / enzyme :name (n2 / name :op1 "MEK1DD")))
            :op2 (g2 / group
                  :mod (e3 / enzyme :name (n3 / name :op1 "MEK2DD"))))
      :ARG1-of (d3 / describe-01
            :ARG0 (a3 / and
                  :op1 (f / figure :mod "3C")
                  :op2 (f2 / figure :mod "3D"))))

# ::id pmid_1901_4680.172 ::date 2015-06-16T15:12:30 ::annotator SDL-AMR-09 ::preferred
# ::snt These observations indicate that constitutive activation of either MEK1 or MEK2 is sufficient to confer a metastatic phenotype to intestinal tumor cells.
# ::save-date Wed Jun 24, 2015 ::file pmid_1901_4680_172.txt
(i / indicate-01
      :ARG0 (o / observe-01
            :mod (t / this))
      :ARG1 (s / suffice-01
            :ARG0 (a / activate-01
                  :ARG1 (o2 / or
                        :op1 (e / enzyme :name (n / name :op1 "MEK1"))
                        :op2 (e2 / enzyme :name (n2 / name :op1 "MEK2")))
                  :mod (c3 / constitutive))
            :ARG1 (c / confer-02
                  :ARG0 a
                  :ARG1 (p / phenotype
                        :mod (m / metastasize-101))
                  :ARG2 (c2 / cell
                        :mod (t2 / tumor)
                        :part-of (i2 / intestine)))))

# ::id pmid_1901_4680.173 ::date 2015-06-17T10:28:20 ::annotator SDL-AMR-09 ::preferred
# ::snt The acquisition of invasiveness does not result from changes in cellular motility.
# ::save-date Wed Jun 17, 2015 ::file pmid_1901_4680_173.txt
(r / result-01 :polarity -
      :ARG1 (c / change-01
            :ARG1 (m / motility
                  :mod (c2 / cell)))
      :ARG2 (a / acquire-01
            :ARG1 (i / invade-01)))

# ::id pmid_1901_4680.174 ::date 2015-06-17T10:41:39 ::annotator SDL-AMR-09 ::preferred
# ::snt To identify downstream targets of MEK1/MEK2 involved in intestinal tumor progression, we analyzed the transcriptional profile of MEK1DD- and MEK2DD-expressing IEC-6 cells using Affymetrix GeneChip arrays.
# ::save-date Wed Jun 17, 2015 ::file pmid_1901_4680_174.txt
(a / analyze-01
      :ARG0 (w / we)
      :ARG1 (p / profile-01
            :ARG1 (c / cell-line :name (n / name :op1 "IEC-6")
                  :ARG3-of (e / express-03
                        :ARG2 (a3 / and
                              :op1 (e2 / enzyme :name (n2 / name :op1 "MEK1DD"))
                              :op2 (e3 / enzyme :name (n3 / name :op1 "MEK2DD")))))
            :mod (t4 / transcribe-01
                  :ARG0 c))
      :ARG2-of (u / use-01
            :ARG1 (a2 / array-01
                  :mod (t / thing :name (n4 / name :op1 "Affymetrix" :op2 "GeneChip"))))
      :purpose (i / identify-01
            :ARG0 w
            :ARG1 (t2 / target-01
                  :ARG0 (s / slash
                        :op1 (e4 / enzyme :name (n5 / name :op1 "MEK1"))
                        :op2 (e5 / enzyme :name (n6 / name :op1 "MEK2")))
                  :location (d / downstream)
                  :ARG1-of (i2 / involve-01
                        :ARG2 (p2 / progress-01
                              :ARG1 (t3 / tumor
                                    :location (i3 / intestine)))))))

# ::id pmid_1901_4680.175 ::date 2015-06-17T11:17:24 ::annotator SDL-AMR-09 ::preferred
# ::snt Analysis of the gene expression data identified several genes that were up-regulated or down-regulated in MEK1DD- and MEK2DD-expressing cells as compared to control IEC-6 cells (Additional files <xref ref-type="supplementary-material" rid="S1">1</xref> and <xref ref-type="supplementary-material" rid="S2">2</xref>).
# ::save-date Fri Jun 26, 2015 ::file pmid_1901_4680_175.txt
(i / identify-01
      :ARG0 (a / analyze-01
            :ARG1 (d / data
                  :topic (g / gene
                        :ARG1-of (e / express-03))))
      :ARG1 (o / or
            :op1 (g2 / gene
                  :quant (s / several)
                  :ARG1-of (u / upregulate-01))
            :op2 (g3 / gene
                  :quant s
                  :ARG1-of (d2 / downregulate-01))
            :location (c / cell
                  :ARG3-of (e2 / express-03
                        :ARG2 (a2 / and
                              :op1 (e3 / enzyme :name (n / name :op1 "MEK1DD"))
                              :op2 (e4 / enzyme :name (n2 / name :op1 "MEK2DD"))))
                  :ARG1-of (c2 / compare-01
                        :ARG2 (c3 / cell-line :name (n3 / name :op1 "IEC-6")
                              :mod (c4 / control-01)))))
      :ARG1-of (d3 / describe-01
            :ARG0 (a3 / and
                  :op1 (f / file :mod 1
                        :ARG1-of (a4 / add-02))
                  :op2 (f2 / file :mod 2
                        :ARG1-of a4))))

# ::id pmid_1901_4680.176 ::date 2015-06-17T11:47:33 ::annotator SDL-AMR-09 ::preferred
# ::snt The list of modulated genes included growth factors, signaling molecules, drug metabolism enzymes and, interestingly, several proteases.
# ::save-date Wed Feb 24, 2016 ::file pmid_1901_4680_176.txt
(i / include-01
      :ARG1 (a / and
            :op1 (g2 / growth-factor)
            :op2 (m2 / molecule
                  :ARG0-of (s2 / signal-07))
            :op3 (e / enzyme
                  :ARG0-of (m3 / metabolize-01
                        :ARG1 (d / drug)))
            :op4 (p / protease
                  :quant (s3 / several)))
      :ARG2 (l / list
            :consist-of (g / gene
                  :ARG1-of (m / modulate-01)))
      :mod (i2 / interesting))

# ::id pmid_1901_4680.177 ::date 2015-06-17T11:58:02 ::annotator SDL-AMR-09 ::preferred
# ::snt The matrix metalloproteinases (MMPs) MMP-3 and MMP-13 were up-regulated in both MEK1DD- and MEK2DD-expressing cells, while up-regulation of MMP-10 reached significance only in MEK2DD cells.
# ::save-date Wed Jun 17, 2015 ::file pmid_1901_4680_177.txt
(c / contrast-01
      :ARG1 (u / upregulate-01
            :ARG1 (a / and
                  :op1 (e5 / enzyme :name (n / name :op1 "MMP-3"))
                  :op2 (e6 / enzyme :name (n2 / name :op1 "MMP-13"))
                  :ARG1-of (i / include-91
                        :ARG2 (e7 / enzyme :name (n7 / name :op1 "matrix" :op2 "metalloproteinase"))))
            :location (c2 / cell
                  :ARG3-of (e / express-03
                        :ARG2 (a2 / and
                              :op1 (e2 / enzyme :name (n3 / name :op1 "MEK1DD"))
                              :op2 (e3 / enzyme :name (n4 / name :op1 "MEK2DD"))))))
      :ARG2 (r / reach-01
            :ARG0 (u2 / upregulate-01
                  :ARG1 (e8 / enzyme :name (n5 / name :op1 "MMP-10")))
            :ARG1 (s / significant-02)
            :location (c3 / cell
                  :mod e3)
            :mod (o / only)))

# ::id pmid_1901_4680.178 ::date 2015-06-17T12:14:42 ::annotator SDL-AMR-09 ::preferred
# ::snt Expression of the urokinase receptor was also up-regulated in IEC-6 cells expressing activated MEK2.
# ::save-date Wed Jun 24, 2015 ::file pmid_1901_4680_178.txt
(u / upregulate-01
      :ARG1 (e / express-03
            :ARG2 (r / receptor
                  :mod (e2 / enzyme :name (n / name :op1 "urokinase"))))
      :mod (a / also)
      :location (c / cell-line :name (n2 / name :op1 "IEC-6")
            :ARG1-of (e3 / express-03
                  :ARG2 (e4 / enzyme :name (n3 / name :op1 "MEK2")
                        :ARG1-of (a2 / activate-01)))))

# ::id pmid_1901_4680.179 ::date 2015-06-17T12:21:07 ::annotator SDL-AMR-09 ::preferred
# ::snt Because of the importance of MMPs and urokinase receptor in tumor progression [<xref ref-type="bibr" rid="B43">43</xref>,<xref ref-type="bibr" rid="B44">44</xref>], we further validated the regulation of these genes by MEK1 and MEK2 signaling to confirm the data from the arrays.
# ::save-date Mon Nov 2, 2015 ::file pmid_1901_4680_179.txt
(v / validate-01
      :ARG0 (w / we)
      :ARG1 (r / regulate-01
            :ARG0 (s / signal-07
                  :ARG0 (a / and
                        :op1 (e / enzyme :name (n / name :op1 "MEK1"))
                        :op2 (e2 / enzyme :name (n2 / name :op1 "MEK2"))))
            :ARG1 (g / gene
                  :mod (t / this)))
      :time (f / further)
      :purpose (c / confirm-01
            :ARG0 w
            :ARG1 (d / data
                  :source (a2 / array)))
      :ARG1-of (c2 / cause-01
            :ARG0 (i / important
                  :domain (a3 / and
                        :op1 (e3 / enzyme :name (n3 / name :op1 "MMP"))
                        :op2 (r2 / receptor
                              :mod (e4 / enzyme :name (n4 / name :op1 "urokinase"))))
                  :purpose (p / progress-01
                        :ARG1 (t2 / tumor)))
            :ARG1-of (d2 / describe-01
                  :ARG0 (p2 / publication
                        :ARG1-of (c3 / cite-01
                              :ARG2 (a4 / and :op1 43 :op2 44))))))

# ::id pmid_1901_4680.180 ::date 2015-06-17T13:29:33 ::annotator SDL-AMR-09 ::preferred
# ::snt No expression or activity of MMPs could be detected in empty vector-infected IEC-6 cells.
# ::save-date Mon Dec 21, 2015 ::file pmid_1901_4680_180.txt
(p / possible-01
      :ARG1 (d / detect-01
            :ARG1 (o / or
                  :op1 (e / express-03 :polarity -
                        :ARG2 (e2 / enzyme :name (n / name :op1 "MMP")))
                  :op2 (a / activity-06 :polarity -
                        :ARG0 e2))
            :location (c / cell-line :name (n2 / name :op1 "IEC-6")
                  :ARG1-of (i / infect-01
                        :ARG2 (v / vector
                              :ARG1-of (e3 / empty-01))))))

# ::id pmid_1901_4680.181 ::date 2015-06-17T13:45:02 ::annotator SDL-AMR-09 ::preferred
# ::snt However, activation of either MEK1 or MEK2 markedly up-regulated the expression of MMP-13 protein (Fig. <xref ref-type="fig" rid="F4">4A</xref>).
# ::save-date Sun Jan 17, 2016 ::file pmid_1901_4680_181.txt
(c / contrast-01
      :ARG2 (u / upregulate-01
            :ARG0 (a / activate-01
                  :ARG1 (o / or
                        :op2 (e2 / enzyme :name (n2 / name :op1 "MEK1"))
                        :op2 (e3 / enzyme :name (n3 / name :op1 "MEK2"))))
            :ARG1 (e / express-03
                  :ARG2 (e4 / enzyme :name (n / name :op1 "MMP-13")))
            :manner (m / marked))
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod "4A")))

# ::id pmid_1901_4680.182 ::date 2015-06-17T14:13:17 ::annotator SDL-AMR-09 ::preferred
# ::snt Notably, higher levels of MMP-13 protein were detected in IEC-6 cells expressing the activated MEK2 isoform.
# ::save-date Sun Jan 17, 2016 ::file pmid_1901_4680_182.txt
(d / detect-01
      :ARG1 (l / level
            :quant-of (e3 / enzyme :name (n / name :op1 "MMP-13"))
            :ARG1-of (h / high-02
                  :degree (m / more)))
      :location (c / cell-line :name (n2 / name :op1 "IEC-6")
            :ARG3-of (e / express-03
                  :ARG2 (i / isoform
                        :ARG1-of (a / activate-01)
                        :mod (e2 / enzyme :name (n3 / name :op1 "MEK2")))))
      :ARG1-of (n4 / notable-04))

# ::id pmid_1901_4680.183 ::date 2015-06-17T14:16:47 ::annotator SDL-AMR-09 ::preferred
# ::snt The expression of MMP-3/10 was analyzed by measuring their activity by zymography in casein-containing gels.
# ::save-date Mon Dec 21, 2015 ::file pmid_1901_4680_183.txt
(a / analyze-01
      :ARG1 (e / express-03
            :ARG2 (e2 / enzyme :name (n / name :op1 "MMP-3/10")))
      :manner (m / measure-01
            :ARG1 (a2 / activity-06
                  :ARG0 e2)
            :ARG2 (z / zymography)
            :location (g / gel
                  :ARG0-of (c / contain-01
                        :ARG1 (p / protein :name (n3 / name :op1 "casein"))))))

# ::id pmid_1901_4680.184 ::date 2015-06-17T14:29:24 ::annotator SDL-AMR-09 ::preferred
# ::snt Again, we observed that MEK2DD increased MMP-3/10 enzymatic activity more robustly than MEK1DD (Fig. <xref ref-type="fig" rid="F4">4A</xref>).
# ::save-date Mon Dec 21, 2015 ::file pmid_1901_4680_184.txt
(o / observe-01
      :ARG0 (w / we)
      :ARG1 (i / increase-01
            :ARG0 (e / enzyme :name (n / name :op1 "MEK2DD"))
            :ARG1 (a / activity-06
                  :ARG0 (e2 / enzyme :name (n2 / name :op1 "MMP-3/10"))
                  :mod (e3 / enzyme))
            :manner (r / robust
                  :degree (m / more)
                  :compared-to (e4 / enzyme :name (n3 / name :op1 "MEK1DD"))))
      :mod (a2 / again)
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod "4A")))

# ::id pmid_1901_4680.185 ::date 2015-06-17T14:48:02 ::annotator SDL-AMR-09 ::preferred
# ::snt Quantitative PCR analysis confirmed that constitutive activation of MEK1 or MEK2 induces the expression of urokinase receptor mRNA (Fig. <xref ref-type="fig" rid="F4">4B</xref>).
# ::save-date Sun Jan 17, 2016 ::file pmid_1901_4680_185.txt
(c / confirm-01
      :ARG0 (a / analyze-01
            :manner (r2 / react-01
                  :ARG0 (p / polymerase
                        :ARG1-of (c3 / chain-01))
                  :mod (q / quantitative)))
      :ARG1 (i / induce-01
            :ARG0 (a2 / activate-01
                  :ARG1 (o / or
                        :op1 (e / enzyme :name (n2 / name :op1 "MEK1"))
                        :op2 (e2 / enzyme :name (n3 / name :op1 "MEK2")))
                  :mod (c2 / constitutive))
            :ARG2 (e3 / express-03
                  :ARG2 (n6 / nucleic-acid :name (n5 / name :op1 "mRNA")
                        :mod (r / receptor
                              :mod (e4 / enzyme :name (n4 / name :op1 "urokinase"))))))
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod "4B")))

# ::id pmid_1901_4680.186 ::date 2015-06-17T15:04:12 ::annotator SDL-AMR-09 ::preferred
# ::snt As observed for the MMPs, the extent of induction of the urokinase receptor gene was higher in MEK2DD-expressing cells.
# ::save-date Mon Dec 21, 2015 ::file pmid_1901_4680_186.txt
(h / high-02
      :ARG1 (e / extent
            :extent-of (i / induce-01
                  :ARG2 (g / gene
                        :mod (r / receptor
                              :mod (e2 / enzyme :name (n / name :op1 "urokinase"))))))
      :degree (m / more)
      :location (c / cell
            :ARG3-of (e3 / express-03
                  :ARG2 (e4 / enzyme :name (n2 / name :op1 "MEK2DD"))))
      :ARG1-of (o / observe-01
            :topic (e5 / enzyme :name (n3 / name :op1 "MMP"))))

# ::id pmid_1901_4680.187 ::date 2015-06-17T15:15:03 ::annotator SDL-AMR-09 ::preferred
# ::snt In a previous study, Komatsu et al. [<xref ref-type="bibr" rid="B45">45</xref>] have used oligonucleotide microarrays to analyze the gene expression profile of intestinal epithelial cells expressing a conditional allele of activated MEK1.
# ::save-date Wed Jun 24, 2015 ::file pmid_1901_4680_187.txt
(u / use-01
      :ARG0 (a / and
            :op1 (p / person :name (n / name :op1 "Komatsu"))
            :op2 (p2 / person
                  :mod (o / other)))
      :ARG1 (m / microarray
            :mod (o2 / oligonucleotide))
      :ARG2 (a4 / analyze-01
            :ARG0 a
            :ARG1 (p3 / profile-01
                  :ARG1 (e3 / express-03
                        :ARG2 (a2 / allele
                              :mod (c2 / conditional)
                              :part-of (e4 / enzyme :name (n3 / name :op1 "MEK1")
                                    :ARG1-of (a3 / activate-01)))
                        :ARG3 (c / cell
                              :mod (e2 / epithelium)
                              :part-of (i / intestine)))
                  :mod (g / gene)))
      :location (t / thing
            :ARG1-of (s2 / study-01
                  :time (p4 / previous)))
      :ARG1-of (d / describe-01
            :ARG0 (p5 / publication
                  :ARG1-of (c3 / cite-01
                        :ARG2 45))))

# ::id pmid_1901_4680.188 ::date 2015-06-17T15:34:03 ::annotator SDL-AMR-09 ::preferred
# ::snt We have compared the results of our transcriptional profiling analysis with this study.
# ::save-date Wed Jun 24, 2015 ::file pmid_1901_4680_188.txt
(c / compare-01
      :ARG0 (w / we)
      :ARG1 (t / thing
            :ARG2-of (r / result-01
                  :ARG1 (a / analyze-01
                        :ARG0 w
                        :ARG0-of (p / profile-01)
                        :mod (t2 / transcribe-01))))
      :ARG2 (s / study-01
            :mod (t4 / this)))

# ::id pmid_1901_4680.189 ::date 2015-06-17T15:40:10 ::annotator SDL-AMR-09 ::preferred
# ::snt Of the 69 gene transcripts that showed altered expression in the study of Komatsu, 18 (26%) were found to be modulated in IEC-6 cells expressing constitutively active MEK1 or MEK2.
# ::save-date Wed Jun 24, 2015 ::file pmid_1901_4680_189.txt
(f / find-01
      :ARG1 (m / modulate-01
            :ARG1 (t3 / transcribe-01 :quant 18
                  :ARG1 (g2 / gene)
                  :ARG1-of (i / include-91
                        :ARG2 (t / transcribe-01 :quant 69
                              :ARG1 (g / gene)
                              :ARG0-of (s / show-01
                                    :ARG1 (e / express-03
                                          :ARG1-of (a / alter-01))
                                    :location (s2 / study-01
                                          :ARG0 (p / person :name (n / name :op1 "Komatsu")))))
                        :ARG3 (p2 / percentage-entity :value 26)))
            :location (c / cell-line :name (n2 / name :op1 "IEC-6")
                  :ARG3-of (e2 / express-03
                        :ARG2 (o / or
                              :op1 (e3 / enzyme :name (n3 / name :op1 "MEK1")
                                    :ARG1-of (a2 / activate-01
                                          :manner (c2 / constitutive)))
                              :op2 (e4 / enzyme :name (n4 / name :op1 "MEK2")
                                    :ARG1-of a2
                                    :manner c2))))))

# ::id pmid_1901_4680.190 ::date 2015-06-17T16:01:57 ::annotator SDL-AMR-09 ::preferred
# ::snt Importantly, the two studies converge on a series of genes involved in cell proliferation, cell invasion, tumor suppression and drug metabolism.
# ::save-date Wed Jun 24, 2015 ::file pmid_1901_4680_190.txt
(c / converge-01
      :ARG0 (s / study-01 :quant 2)
      :ARG2 (g / gene
            :quant (s2 / series)
            :ARG1-of (i / involve-01
                  :ARG2 (a / and
                        :op1 (p / proliferate-01
                              :ARG0 (c2 / cell))
                        :op2 (i2 / invade-01
                              :ARG0 c2)
                        :op3 (s3 / suppress-01
                              :ARG1 (t2 / tumor))
                        :op4 (m / metabolize-01
                              :ARG1 (d / drug)))))
      :mod (i3 / important))

# ::id pmid_1901_4680.191 ::date 2015-06-17T16:09:56 ::annotator SDL-AMR-09 ::preferred
# ::snt <sec-title level="2">Constitutive activation of MEK1 or MEK2 protects intestinal epithelial cells against anoikis</sec-title>
# ::save-date Wed Jun 17, 2015 ::file pmid_1901_4680_191.txt
(p / protect-01
      :ARG0 (a / activate-01
            :ARG1 (o / or
                  :op1 (e / enzyme :name (n / name :op1 "MEK1"))
                  :op2 (e2 / enzyme :name (n2 / name :op1 "MEK2")))
            :mod (c / constitutive))
      :ARG1 (c2 / cell
            :mod (e3 / epithelium)
            :part-of (i / intestine))
      :ARG2 (a2 / anoikis))

# ::id pmid_1901_4680.192 ::date 2015-06-17T14:50:57 ::annotator SDL-AMR-09 ::preferred
# ::snt Epithelial cancer progression and metastasis is associated with the acquisition of resistance to anoikis [<xref ref-type="bibr" rid="B46">46</xref>].
# ::save-date Wed Jun 24, 2015 ::file pmid_1901_4680_192.txt
(a / associate-01
      :ARG1 (a2 / and
            :op1 (p / progress-01
                  :ARG1 (d / disease :wiki "Cancer"
                        :name (n / name :op1 "cancer")
                        :mod (e / epithelium)))
            :op2 (m / metastasize-101
                  :ARG1 d))
      :ARG2 (a3 / acquire-01
            :ARG1 (r / resist-01
                  :ARG1 (a4 / anoikis)))
      :ARG1-of (d2 / describe-01
            :ARG0 (p2 / publication
                  :ARG1-of (c / cite-01 :ARG2 46))))

# ::id pmid_1901_4680.193 ::date 2015-06-17T15:07:19 ::annotator SDL-AMR-09 ::preferred
# ::snt To further explore the mechanism by which MEK1 and MEK2 promote tumor metastasis, we asked whether activated MEK isoforms protect intestinal epithelial cells from cell death induced by loss of adhesion.
# ::save-date Wed Jun 24, 2015 ::file pmid_1901_4680_193.txt
(a / ask-01
      :ARG0 (w / we)
      :ARG1 (p / protect-01 :mode interrogative
            :ARG0 (i / isoform
                  :mod (e / enzyme :name (n / name :op1 "MEK"))
                  :ARG1-of (a2 / activate-01))
            :ARG1 (c / cell
                  :mod (e2 / epithelium
                        :mod (i2 / intestine)))
            :ARG2 (d / die-01
                  :ARG1 c
                  :ARG2-of (i3 / induce-01
                        :ARG0 (l / lose-02
                              :ARG1 (a3 / adhere-01)))))
      :purpose (e3 / explore-01
            :ARG0 w
            :ARG1 (m / mechanism
                  :instrument-of (p2 / promote-01
                        :ARG0 (a4 / and
                              :op1 (e4 / enzyme :name (n2 / name :op1 "MEK1"))
                              :op2 (e5 / enzyme :name (n3 / name :op1 "MEK2")))
                        :ARG1 (m2 / metastasize-101
                              :ARG1 (t / tumor))))
            :mod (f / further)))

# ::id pmid_1901_4680.194 ::date 2015-06-17T15:22:14 ::annotator SDL-AMR-09 ::preferred
# ::snt IEC-6-transduced populations were placed on poly-HEMA-coated plates in normal growth medium and the extent of apoptosis was measured at different times by TUNEL.
# ::save-date Sat Feb 13, 2016 ::file pmid_1901_4680_194.txt
(a / and
      :op1 (p / place-01
            :ARG1 (p2 / population
                  :ARG1-of (t / transduce-01
                        :ARG2 (c / cell-line :name (n / name :op1 "IEC-6"))))
            :ARG2 (p3 / plate
                  :ARG1-of (c2 / coat-01
                        :ARG2 (s / small-molecule :name (n2 / name :op1 "poly-HEMA"))))
            :location (m2 / medium
                  :mod (g / grow-01)
                  :ARG1-of (n3 / normal-02)))
      :op2 (m3 / measure-01
            :ARG1 (e / extent
                  :degree-of (a2 / apoptosis))
            :frequency (t2 / time
                  :ARG1-of (d / differ-02))
            :instrument (t3 / thing :name (n4 / name :op1 "TUNEL"))))

# ::id pmid_1901_4680.195 ::date 2015-06-17T15:36:05 ::annotator SDL-AMR-09 ::preferred
# ::snt Detachment from matrix induced high levels of apoptosis of control IEC-6 cells, which was already detectable at 6 h and increased up to 24 h (Fig. <xref ref-type="fig" rid="F5">5A</xref>).
# ::save-date Sun Dec 20, 2015 ::file pmid_1901_4680_195.txt
(i / induce-01
      :ARG0 (d / detach-01
            :ARG2 (m / matrix))
      :ARG2 (l / level
            :quant-of (a / apoptosis
                  :poss (c / cell-line :name (n / name :op1 "IEC-6")
                        :ARG2-of (c2 / control-01)))
            :ARG1-of (h / high-02))
      :ARG1-of (d2 / detect-01
            :ARG1-of (p / possible-01)
            :time (a2 / after
                  :quant (t / temporal-quantity :quant 6
                        :unit (h2 / hour)))
            :time (a3 / already))
      :ARG1-of (i2 / increase-01
            :time (a4 / after
                  :quant (u / up-to
                        :op1 (t2 / temporal-quantity :quant 24
                              :unit h2))))
      :ARG1-of (d3 / describe-01
            :ARG0 (f / figure :mod "5A")))

# ::id pmid_1901_4680.196 ::date 2015-06-17T16:05:13 ::annotator SDL-AMR-09 ::preferred
# ::snt Strikingly, expression of either MEK1DD or MEK2DD almost completely protected IEC-6 cells from undergoing anoikis.
# ::save-date Sun Jan 17, 2016 ::file pmid_1901_4680_196.txt
(p / protect-01
      :ARG0 (e / express-03
            :ARG2 (o / or
                  :op1 (e2 / enzyme :name (n / name :op1 "MEK1DD"))
                  :op2 (e3 / enzyme :name (n2 / name :op1 "MEK2DD"))))
      :ARG1 (c / cell-line :name (n3 / name :op1 "IEC-6"))
      :ARG2 (u / undergo-28
            :ARG1 c
            :ARG2 (a / anoikis))
      :degree (c2 / complete-01
            :degree (a2 / almost))
      :ARG1-of (s / strike-04))

# ::id pmid_1901_4680.197 ::date 2015-06-17T16:19:02 ::annotator SDL-AMR-09 ::preferred
# ::snt As a step to understand the molecular mechanism by which activated MEK isoforms suppress anoikis, we monitored the expression of Bcl-2 anti-apoptotic and pro-apoptotic family proteins.
# ::save-date Wed Jun 24, 2015 ::file pmid_1901_4680_197.txt
(m / monitor-01
      :ARG0 (w / we)
      :ARG1 (e / express-03
            :ARG2 (a / and
                  :op1 (p / protein :name (n / name :op1 "Bcl-2")
                        :mod (f / family)
                        :ARG0-of (c / counter-01
                              :ARG1 (a2 / apoptosis)))
                  :op2 (p2 / protein :name (n2 / name :op1 "Bcl-2")
                        :mod f
                        :ARG0-of (f2 / favor-01
                              :ARG1 a2))))
      :ARG4-of (s / step-01
            :ARG2 (u / understand-01
                  :ARG0 w
                  :ARG1 (m2 / mechanism
                        :mod (m3 / molecule)
                        :instrument-of (s2 / suppress-01
                              :ARG0 (i / isoform
                                    :mod (e2 / enzyme :name (n3 / name :op1 "MEK"))
                                    :ARG1-of (a3 / activate-01))
                              :ARG1 (a4 / anoikis))))))

# ::id pmid_1901_4680.198 ::date 2015-06-17T16:31:37 ::annotator SDL-AMR-09 ::preferred
# ::snt Constitutive activation of MEK1 or MEK2 resulted in the up-regulation of the pro-survival proteins Mcl-1, Bcl-2 and, to a lesser extent, Bcl-x<sub>L </sub>in IEC-6 cells (Fig. <xref ref-type="fig" rid="F5">5B</xref>).
# ::save-date Wed Jun 24, 2015 ::file pmid_1901_4680_198.txt
(r / result-01
      :ARG1 (a / activate-01
            :ARG1 (o / or
                  :op1 (e / enzyme :name (n / name :op1 "MEK1"))
                  :op2 (e2 / enzyme :name (n2 / name :op1 "MEK2")))
            :mod (c / constitutive))
      :ARG2 (u / upregulate-01
            :ARG1 (a2 / and
                  :op1 (p / protein :name (n3 / name :op1 "Mcl-1"))
                  :op2 (p2 / protein :name (n4 / name :op1 "Bcl-2"))
                  :op3 (p3 / protein :name (n5 / name :op1 "Bcl-xL")
                        :degree (e3 / extent
                              :quant (l / less
                                    :degree (m / more))))
                  :ARG0-of (f / favor-01
                        :ARG1 (s / survive-01)))
            :location (c2 / cell-line :name (n6 / name :op1 "IEC-6")))
      :ARG1-of (d / describe-01
            :ARG0 (f2 / figure :mod "5B")))

# ::id pmid_1901_4680.199 ::date 2015-06-17T16:42:31 ::annotator SDL-AMR-09 ::preferred
# ::snt Our results confirm and extend previous observations [<xref ref-type="bibr" rid="B47">47</xref>,<xref ref-type="bibr" rid="B48">48</xref>] by demonstrating that both MEK1 and MEK2 isoforms share the property to induce the accumulation of Bcl-2 family pro-survival members.
# ::save-date Sun Jan 17, 2016 ::file pmid_1901_4680_199.txt
(a / and
      :op1 (c / confirm-01
            :ARG0 (t / thing
                  :ARG2-of (r / result-01)
                  :poss (w / we))
            :ARG1 (o / observe-01
                  :mod (p / previous)))
      :op2 (e / extend-01
            :ARG0 t
            :ARG1 o)
      :ARG1-of (d / describe-01
            :ARG0 (p2 / publication
                  :ARG1-of (c2 / cite-01
                        :ARG2 (a2 / and :op1 47 :op2 48))))
      :manner (d2 / demonstrate-01
            :ARG0 t
            :ARG1 (s / share-01
                  :ARG0 (a3 / and
                        :op1 (i / isoform
                              :mod (e2 / enzyme :name (n / name :op1 "MEK1")))
                        :op2 (i2 / isoform
                              :mod (e3 / enzyme :name (n2 / name :op1 "MEK2"))))
                  :ARG1 (p3 / property
                        :mod (i3 / induce-01
                              :ARG0 a3
                              :ARG2 (a4 / accumulate-01
                                    :ARG1 (m / member
                                          :ARG1-of (i4 / include-91
                                                :ARG2 (p4 / protein-family :name (n3 / name :op1 "Bcl-2")))
                                          :ARG0-of (f2 / favor-01
                                                :ARG1 (s2 / survive-01)))))))))

# ::id pmid_1901_4680.200 ::date 2015-06-17T16:56:10 ::annotator SDL-AMR-09 ::preferred
# ::snt Reciprocally, induction of the BH3-only pro-apoptotic protein Bim was completely suppressed in cells expressing MEK1DD or MEK2DD (Fig. <xref ref-type="fig" rid="F5">5C</xref>).
# ::save-date Sun Dec 20, 2015 ::file pmid_1901_4680_200.txt
(s / suppress-01
      :ARG1 (i / induce-01
            :ARG2 (p / protein :name (n / name :op1 "BH3-only" :op2 "protein" :op3 "Bim")
                  :ARG0-of (f / favor-01
                        :ARG1 (a / apoptosis))))
      :location (c / cell
            :ARG3-of (e / express-03
                  :ARG2 (o / or
                        :op1 (e2 / enzyme :name (n2 / name :op1 "MEK1DD"))
                        :op2 (e3 / enzyme :name (n3 / name :op1 "MEK2DD")))))
      :degree (c2 / complete-01)
      :manner (r / reciprocal)
      :ARG1-of (d / describe-01
            :ARG0 (f2 / figure :mod "5C")))

# ::id pmid_1901_4680.201 ::date 2015-06-17T17:14:40 ::annotator SDL-AMR-09 ::preferred
# ::snt This finding is consistent with previous reports documenting the role of the ERK1/2 MAP kinase pathway in promoting the degradation of Bim [<xref ref-type="bibr" rid="B49">49</xref>,<xref ref-type="bibr" rid="B50">50</xref>].
# ::save-date Wed Jun 17, 2015 ::file pmid_1901_4680_201.txt
(c / consistent-01
      :ARG1 (f / find-01
            :mod (t / this))
      :ARG2 (t2 / thing
            :ARG1-of (r / report-01)
            :mod (p / previous)
            :ARG0-of (d / document-01
                  :ARG1 (r2 / role
                        :poss (p2 / pathway :name (n / name :op1 "ERK1/2" :op2 "MAP-kinase"))
                        :topic (p3 / promote-01
                              :ARG0 p2
                              :ARG1 (d2 / degrade-01
                                    :ARG1 (p4 / protein :name (n2 / name :op1 "Bim")))))))
      :ARG1-of (d3 / describe-01
            :ARG0 (p5 / publication
                  :ARG1-of (c2 / cite-01
                        :ARG2 (a / and :op1 49 :op2 50)))))

# ::id pmid_1901_4680.202 ::date 2015-06-17T17:25:00 ::annotator SDL-AMR-09 ::preferred
# ::snt MEK1 or MEK2 activation had no significant effect on the expression of the pro-apoptotic proteins Bax and Bak in these cells (data not shown).
# ::save-date Wed Jun 24, 2015 ::file pmid_1901_4680_202.txt
(a / affect-01 :polarity -
      :ARG0 (a2 / activate-01
            :ARG1 (o / or
                  :op1 (e / enzyme :name (n / name :op1 "MEK1"))
                  :op2 (e2 / enzyme :name (n2 / name :op1 "MEK2"))))
      :ARG1 (e3 / express-03
            :ARG2 (a3 / and
                  :op1 (p / protein :name (n3 / name :op1 "Bax"))
                  :op2 (p2 / protein :name (n4 / name :op1 "Bak"))
                  :ARG0-of (f / favor-01
                        :ARG1 (a4 / apoptosis)))
            :ARG3 (c / cell
                  :mod (t / this)))
      :ARG1-of (s / significant-02)
      :ARG1-of (d / describe-01
            :ARG0 (d2 / data
                  :ARG1-of (s2 / show-01 :polarity -))))

# ::id pmid_1901_4680.203 ::date 2015-06-17T17:33:44 ::annotator SDL-AMR-09 ::preferred
# ::snt <sec-title level="2">Silencing of MEK2 expression markedly inhibits the proliferation of human colon cancer cells</sec-title>
# ::save-date Wed Dec 9, 2015 ::file pmid_1901_4680_203.txt
(i / inhibit-01
      :ARG0 (s / silence-01
            :ARG1 (e / express-03
                  :ARG2 (e2 / enzyme :name (n / name :op1 "MEK2"))))
      :ARG1 (p / proliferate-01
            :ARG0 (c / cell
                  :mod (d2 / disease :wiki "Colorectal_cancer" :name (n3 / name :op1 "colon" :op2 "cancer")
                        :mod (h / human))))
      :degree (m / marked))

# ::id pmid_1901_4680.204 ::date 2015-06-17T17:39:47 ::annotator SDL-AMR-09 ::preferred
# ::snt The results presented above clearly demonstrate that constitutive activation of either MEK isoform, MEK1 or MEK2, is sufficient to fully transform intestinal epithelial cells to the metastatic stage.
# ::save-date Tue Dec 22, 2015 ::file pmid_1901_4680_204.txt
(d / demonstrate-01
      :ARG0 (t / thing
            :ARG2-of (r / result-01)
            :ARG1-of (p / present-01
                  :location (a / above)))
      :ARG1 (s / suffice-01
            :ARG0 (a2 / activate-01
                  :ARG1 (o / or
                        :op1 (e / enzyme :name (n / name :op1 "MEK1"))
                        :op2 (e2 / enzyme :name (n3 / name :op1 "MEK2"))
                        :ARG1-of (m / mean-01
                              :ARG2 (i / isoform
                                    :mod (e3 / enzyme :name (n2 / name :op1 "MEK"))))
                        :mod (e4 / either))
                  :mod (c / constitutive))
            :ARG1 (t2 / transform-01
                  :ARG0 a2
                  :ARG1 (c2 / cell
                        :mod (e5 / epithelium
                              :mod (i2 / intestine)))
                  :ARG2 (s2 / stage-02
                        :ARG2 (m2 / metastasize-101))
                  :degree (f / full)))
      :ARG1-of (c3 / clear-06))

# ::id pmid_1901_4680.205 ::date 2015-06-17T17:52:08 ::annotator SDL-AMR-09 ::preferred
# ::snt We next wanted to determine if human colon cancer cells depend on the activity of MEK isoforms for cell proliferation.
# ::save-date Mon Dec 21, 2015 ::file pmid_1901_4680_205.txt
(w / want-01
      :ARG0 (w2 / we)
      :ARG1 (d / determine-01
            :ARG0 w2
            :ARG1 (d2 / depend-01 :mode interrogative
                  :ARG0 (c / cell
                        :mod (d4 / disease :wiki "Colorectal_cancer" :name (n4 / name :op1 "colon" :op2 "cancer")
                              :mod (h / human)))
                  :ARG1 (a / activity-06
                        :ARG0 (i / isoform
                              :mod (e / enzyme :name (n2 / name :op1 "MEK"))))
                  :purpose (p / proliferate-01
                        :ARG0 c)))
      :time (n3 / next))

# ::id pmid_1901_4680.206 ::date 2015-06-17T18:09:15 ::annotator SDL-AMR-09 ::preferred
# ::snt Several human colon carcinoma cell lines display constitutive phosphorylation of ERK1/ERK2 MAP kinases [<xref ref-type="bibr" rid="B20">20</xref>], likely resulting from activation of MEK1/MEK2.
# ::save-date Wed Jun 17, 2015 ::file pmid_1901_4680_206.txt
(d / display-01
      :ARG0 (c / cell-line
            :mod (c2 / carcinoma
                  :mod (c3 / colon
                        :part-of (h / human)))
            :quant (s / several))
      :ARG1 (p / phosphorylate-01
            :ARG1 (e / enzyme :name (n / name :op1 "ERK1/ERK2" :op2 "MAP-kinase"))
            :mod (c4 / constitutive))
      :ARG1-of (d2 / describe-01
            :ARG0 (p2 / publication
                  :ARG1-of (c5 / cite-01
                        :ARG2 20)))
      :ARG2-of (r / result-01
            :ARG1 (a / activate-01
                  :ARG1 (e2 / enzyme :name (n2 / name :op1 "MEK1/MEK2")))
            :ARG1-of (l / likely-01)))

# ::id pmid_1901_4680.207 ::date 2015-06-17T18:16:31 ::annotator SDL-AMR-09 ::preferred
# ::snt The HCT116 cell line, which represents one of the best studied model of colorectal cancer cells, display constitutive activation of the two MEK isoforms (Fig. <xref ref-type="fig" rid="F6">6A</xref>).
# ::save-date Wed Dec 9, 2015 ::file pmid_1901_4680_207.txt
(d / display-01
      :ARG0 (c / cell-line :name (n / name :op1 "HCT116")
            :ARG0-of (r / represent-01
                  :ARG1 (m / model :quant 1
                        :ARG1-of (i / include-91
                              :ARG2 (m2 / model
                                    :ARG1-of (s / study-01
                                          :ARG1-of (w / well-09))
                                    :mod (c2 / cell
                                          :mod (d2 / disease :wiki "Colorectal_cancer" :name (n2 / name :op1 "colorectal" :op2 "cancer"))))))))
      :ARG1 (a / activate-01
            :ARG1 (i2 / isoform :quant 2
                  :mod (e / enzyme :name (n3 / name :op1 "MEK")))
            :mod (c4 / constitutive))
      :ARG1-of (d3 / describe-01
            :ARG0 (f / figure :mod "6A")))

# ::id pmid_1901_4680.208 ::date 2015-06-17T18:35:21 ::annotator SDL-AMR-09 ::preferred
# ::snt To assess the individual roles of MEK1 and MEK2, we expressed short-hairpin (sh) RNAs specifically targeting MEK1 or MEK2 gene in HCT116 cells using VSV-pseudotyped lentiviral vectors.
# ::save-date Mon Dec 21, 2015 ::file pmid_1901_4680_208.txt
(e / express-03
      :ARG1 (n6 / nucleic-acid :name (n / name :op1 "short-hairpin" :op2 "RNA")
            :ARG0-of (t / target-01
                  :ARG1 (o / or
                        :op1 (g / gene :name (n2 / name :op1 "MEK1"))
                        :op2 (g2 / gene :name (n3 / name :op1 "MEK2")))
                  :ARG1-of (s / specific-02)))
      :ARG3 (c / cell-line :name (n4 / name :op1 "HCT116"))
      :manner (u / use-01
            :ARG0 (w / we)
            :ARG1 (v / vector :name (n5 / name :op1 "VSV-pseudotyped" :op2 "lentiviral" :op3 "vector")))
      :purpose (a / assess-01
            :ARG0 w
            :ARG1 (r2 / role
                  :poss (a2 / and
                        :op1 g
                        :op2 g2)
                  :mod (i / individual))))

# ::id pmid_1901_4680.209 ::date 2015-06-17T18:51:12 ::annotator SDL-AMR-09 ::preferred
# ::snt We tested the effect of 5 distinct shRNAs for MEK1 and 3 shRNAs for MEK2, using as control a GFP-encoding vector.
# ::save-date Wed Jun 24, 2015 ::file pmid_1901_4680_209.txt
(t / test-01
      :ARG0 (w / we)
      :ARG1 (a / and
            :op1 (a2 / affect-01
                  :ARG0 (n6 / nucleic-acid :quant 5 :name (n / name :op1 "shRNA")
                        :mod (d / distinct))
                  :ARG1 (g / gene :name (n2 / name :op1 "MEK1")))
            :op2 (a3 / affect-01
                  :ARG0 (n7 / nucleic-acid :quant 3 :name (n3 / name :op1 "shRNA"))
                  :ARG1 (g2 / gene :name (n4 / name :op1 "MEK2"))))
      :manner (u / use-01
            :ARG0 w
            :ARG1 (v / vector
                  :ARG0-of (e / encode-01
                        :ARG1 (p / protein :name (n5 / name :op1 "GFP")))
                  :ARG2-of (c / control-01))))

# ::id pmid_1901_4680.210 ::date 2015-06-17T18:59:05 ::annotator SDL-AMR-09 ::preferred
# ::snt We selected the two most efficient shRNAs to MEK1 and MEK2 genes (Additional file <xref ref-type="supplementary-material" rid="S3">3</xref>).
# ::save-date Wed Jun 17, 2015 ::file pmid_1901_4680_210.txt
(s / select-01
      :ARG0 (w / we)
      :ARG1 (n4 / nucleic-acid :quant 2 :name (n / name :op1 "shRNA")
            :ARG1-of (e / efficient-01
                  :degree (m / most))
            :ARG0-of (a / affect-01
                  :ARG1 (a2 / and
                        :op1 (g / gene :name (n2 / name :op1 "MEK1"))
                        :op2 (g2 / gene :name (n3 / name :op1 "MEK2")))))
      :ARG1-of (d / describe-01
            :ARG0 (f / file :mod 3
                  :ARG1-of (a3 / add-02))))

# ::id pmid_1901_4680.211 ::date 2015-06-17T19:06:35 ::annotator SDL-AMR-09 ::preferred
# ::snt A non-silencing inactive MEK1 shRNA was used as additional negative control in these experiments.
# ::save-date Fri Feb 5, 2016 ::file pmid_1901_4680_211.txt
(u / use-01
      :ARG1 (n4 / nucleic-acid :name (n / name :op1 "shRNA")
            :mod (g / gene :name (n2 / name :op1 "MEK1"))
            :ARG1-of (a / activate-01 :polarity -)
            :ARG0-of (s / silence-01 :polarity -)
            :ARG2-of (c / control-01
                  :ARG2-of (n3 / negative-01))
            :ARG1-of (a2 / add-02))
      :location (e / experiment-01
            :mod (t / this)))

# ::id pmid_1901_4680.212 ::date 2015-06-17T19:14:46 ::annotator SDL-AMR-09 ::preferred
# ::snt The efficiency of transduction estimated by GFP immunofluorescence was over 90%, and therefore the experiments were performed without cellular selection.
# ::save-date Tue Feb 2, 2016 ::file pmid_1901_4680_212.txt
(c / cause-01
      :ARG0 (e / estimate-01
            :ARG0 (i / immunofluoresce-01
                  :ARG2 (p / protein :name (n2 / name :op1 "GFP")))
            :ARG1 (e2 / efficient-01
                  :ARG1 (t / transduce-01))
            :ARG2 (o / over
                  :quant (p2 / percentage-entity :value 90)))
      :ARG1 (p3 / perform-01
            :ARG1 (e3 / experiment-01)
            :manner (s / select-01 :polarity -
                  :ARG1 (c2 / cell))))

# ::id pmid_1901_4680.213 ::date 2015-06-17T19:24:47 ::annotator SDL-AMR-09 ::preferred
# ::snt As shown by immunoblot analysis, lentivirus-mediated delivery of MEK1 shRNAs resulted in complete silencing of MEK1 expression with no effect on MEK2, whereas the two MEK2 shRNAs markedly knocked-down MEK2 expression without affecting MEK1 isoform (Fig. <xref ref-type="fig" rid="F6">6B</xref>).
# ::save-date Sun Jan 17, 2016 ::file pmid_1901_4680_213.txt
(c / contrast-01
      :ARG1 (r / result-01
            :ARG1 (d / deliver-01
                  :ARG1 (n8 / nucleic-acid :name (n / name :op1 "shRNA")
                        :mod (g / gene :name (n2 / name :op1 "MEK1")))
                  :ARG1-of (m / mediate-01
                        :ARG0 (l / lentivirus)))
            :ARG2 (s / silence-01
                  :ARG1 (e / express-03
                        :ARG2 (e2 / enzyme :name (n3 / name :op1 "MEK1")))
                  :degree (c2 / complete-01)
                  :ARG0-of (a / affect-01 :polarity -
                        :ARG1 (e3 / enzyme :name (n4 / name :op1 "MEK2")))))
      :ARG2 (k / knock-down-02
            :ARG0 (n9 / nucleic-acid :quant 2 :name (n5 / name :op1 "shRNA")
                  :mod (g2 / gene :name (n6 / name :op1 "MEK2")))
            :ARG1 (e4 / express-03
                  :ARG2 e3)
            :ARG0-of (a2 / affect-01 :polarity -
                  :ARG1 (e5 / enzyme :name (n10 / name :op1 "MEK1")
                        :mod (i / isoform)))
            :degree (m2 / marked))
      :ARG1-of (s2 / show-01
            :ARG0 (a3 / analyze-01
                  :manner (i2 / immunoblot-01)))
      :ARG1-of (d2 / describe-01
            :ARG0 (f / figure :mod "6B")))

# ::id pmid_1901_4680.214 ::date 2015-06-17T19:47:42 ::annotator SDL-AMR-09 ::preferred
# ::snt We then analyzed the functional consequence of MEK1 or MEK2 silencing on the proliferation rate of the cells.
# ::save-date Thu Jun 25, 2015 ::file pmid_1901_4680_214.txt
(a / analyze-01
      :ARG0 (w / we)
      :ARG1 (c / consequence
            :ARG1-of (c2 / cause-01
                  :ARG0 (s / silence-01
                        :ARG1 (o / or
                              :op1 (e / enzyme :name (n / name :op1 "MEK1"))
                              :op2 (e2 / enzyme :name (n2 / name :op1 "MEK2")))))
            :topic (r / rate
                  :degree-of (p / proliferate-01
                        :ARG0 (c3 / cell)))
            :mod (f / function-01))
      :mod (t / then))

# ::id pmid_1901_4680.215 ::date 2015-06-17T19:57:10 ::annotator SDL-AMR-09 ::preferred
# ::snt Strikingly, lowering of MEK2 expression with the two shRNAs completely suppressed the proliferation of HCT116 cells, whereas MEK1 shRNAs exerted a significant but much weaker effect (Fig. <xref ref-type="fig" rid="F6">6B</xref>).
# ::save-date Sun Dec 20, 2015 ::file pmid_1901_4680_215.txt
(c / contrast-01
      :ARG1 (s / suppress-01
            :ARG0 (l / lower-05
                  :ARG1 (e / express-03
                        :ARG2 (e2 / enzyme :name (n / name :op1 "MEK2"))
                        :instrument (n7 / nucleic-acid :quant 2 :name (n2 / name :op1 "shRNA"))))
            :ARG1 (p / proliferate-01
                  :ARG0 (c2 / cell-line :name (n3 / name :op1 "HCT116")))
            :degree (c3 / complete))
      :ARG2 (e3 / exert-01
            :ARG0 (n6 / nucleic-acid :name (n4 / name :op1 "shRNA")
                  :mod (g / gene :name (n5 / name :op1 "MEK1")))
            :ARG1 (a / affect-01
                  :ARG1-of (s2 / significant-02
                        :ARG1-of (c4 / contrast-01
                              :ARG2 (w / weak-02
                                    :degree (m / more
                                          :degree (m2 / much)))))))
      :manner (s3 / strike-04)
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod "6B")))

# ::id pmid_1901_4680.216 ::date 2015-06-17T20:07:52 ::annotator SDL-AMR-09 ::preferred
# ::snt The extent of inhibition observed with MEK2 shRNAs was similar to that obtained by treating cells with the non-selective MEK1/2 inhibitor U0126.
# ::save-date Sun Jan 17, 2016 ::file pmid_1901_4680_216.txt
(r / resemble-01
      :ARG1 (e / extent
            :degree-of (i / inhibit-01)
            :ARG1-of (o / observe-01
                  :topic (n5 / nucleic-acid :name (n / name :op1 "shRNA")
                        :mod (g / gene :name (n2 / name :op1 "MEK2")))))
      :ARG2 (e2 / extent
            :degree-of i
            :ARG1-of (o2 / obtain-01
                  :manner (t / treat-04
                        :ARG1 (c / cell)
                        :ARG2 (s2 / small-molecule :name (n3 / name :op1 "U0126")
                              :ARG0-of (i2 / inhibit-01
                                    :ARG1 (e3 / enzyme :name (n4 / name :op1 "MEK1/2")))
                              :ARG0-of (s / select-01 :polarity -))))))

# ::id pmid_1901_4680.217 ::date 2015-06-17T20:26:26 ::annotator SDL-AMR-09 ::preferred
# ::snt We also showed that silencing of MEK1 or MEK2 expression significantly reduces the extent of ERK1 and ERK2 activating phosphorylation (Fig. <xref ref-type="fig" rid="F7">7</xref>).
# ::save-date Fri Dec 18, 2015 ::file pmid_1901_4680_217.txt
(s / show-01
      :ARG0 (w / we)
      :ARG1 (r / reduce-01
            :ARG0 (s2 / silence-01
                  :ARG1 (e / express-03
                        :ARG2 (o / or
                              :op1 (e2 / enzyme :name (n / name :op1 "MEK1"))
                              :op2 (e3 / enzyme :name (n2 / name :op1 "MEK2")))))
            :ARG1 (e4 / extent
                  :degree-of (p / phosphorylate-01
                        :ARG0-of (a / activate-01
                              :ARG1 (a2 / and
                                    :op1 (e5 / enzyme :name (n3 / name :op1 "ERK1"))
                                    :op2 (e6 / enzyme :name (n4 / name :op1 "ERK2"))))))
            :ARG2 (s3 / significant-02))
      :mod (a3 / also)
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod 7)))

# ::id pmid_1901_4680.218 ::date 2015-06-17T20:33:27 ::annotator SDL-AMR-09 ::preferred
# ::snt To verify whether this differential contribution of MEK isoforms could be generalized to other colorectal cancer cells, we examined the impact of MEK1 or MEK2 silencing on the proliferation of two other human colon cancer cell lines.
# ::save-date Wed Dec 9, 2015 ::file pmid_1901_4680_218.txt
(e / examine-01
      :ARG0 (w / we)
      :ARG1 (i / impact-01
            :ARG0 (s / silence-01
                  :ARG1 (o / or
                        :op1 (e2 / enzyme :name (n / name :op1 "MEK1"))
                        :op2 (e3 / enzyme :name (n2 / name :op1 "MEK2"))))
            :ARG1 (p / proliferate-01
                  :ARG0 (c / cell-line :quant 2
                        :mod (o2 / other)
                        :mod (d4 / disease :wiki "Colorectal_cancer" :name (n6 / name :op1 "colorectal" :op2 "cancer")
                              :mod (h / human)))))
      :purpose (v / verify-01
            :ARG0 w
            :ARG1 (p2 / possible-01 :mode interrogative
                  :ARG1 (g / generalize-01
                        :ARG1 (c3 / contribute-01
                              :ARG0 (i2 / isoform
                                    :mod (e4 / enzyme :name (n4 / name :op1 "MEK")))
                              :mod (d2 / differential)
                              :mod (t / this))
                        :ARG2 (c4 / cell
                              :mod d4)))))

# ::id pmid_1901_4680.219 ::date 2015-06-17T20:47:59 ::annotator SDL-AMR-09 ::preferred
# ::snt We specifically chose the human colon carcinoma cell lines SW480 (which harbors a <i>KRAS </i>mutation like HCT116) and HT-29 (harboring a <i>BRAF </i>mutation).
# ::save-date Sat Jan 16, 2016 ::file pmid_1901_4680_219.txt
(c / choose-01
      :ARG0 (w / we)
      :ARG1 (a / and
            :op1 (c2 / cell-line :name (n / name :op1 "SW480")
                  :ARG0-of (h / harbor-01
                        :ARG1 (m / mutate-01
                              :ARG2 (e / enzyme :name (n2 / name :op1 "KRAS"))))
                  :ARG1-of (r / resemble-01
                        :ARG2 (c3 / cell-line :name (n3 / name :op1 "HCT116"))))
            :op2 (c4 / cell-line :name (n4 / name :op1 "HT-29")
                  :ARG0-of (h2 / harbor-01
                        :ARG1 (m2 / mutate-01
                              :ARG2 (g / gene :name (n5 / name :op1 "BRAF")))))
            :mod (c5 / carcinoma
                  :mod (c6 / colon
                        :part-of (h3 / human))))
      :ARG1-of (s / specific-02))

# ::id pmid_1901_4680.220 ::date 2015-06-17T20:56:49 ::annotator SDL-AMR-09 ::preferred
# ::snt SW480 cells display a comparable expression pattern of MEK1 and MEK2 proteins as HCT116 cells (Fig. <xref ref-type="fig" rid="F6">6A</xref>).
# ::save-date Thu Jun 25, 2015 ::file pmid_1901_4680_220.txt
(d / display-01
      :ARG0 (c / cell-line :name (n / name :op1 "SW480"))
      :ARG1 (p / pattern-01
            :ARG1 (e3 / express-03
                  :ARG2 (a / and
                        :op1 (e / enzyme :name (n2 / name :op1 "MEK1"))
                        :op2 (e2 / enzyme :name (n3 / name :op1 "MEK2"))))
            :ARG1-of (c2 / compare-01
                  :ARG2 (c3 / cell-line :name (n4 / name :op1 "HCT116"))
                  :ARG1-of (p2 / possible-01)))
      :ARG1-of (d2 / describe-01
            :ARG0 (f / figure :mod "6A")))

# ::id pmid_1901_4680.221 ::date 2015-06-17T21:06:45 ::annotator SDL-AMR-09 ::preferred
# ::snt Similar to HCT116 cells, knock-down of MEK2 expression dramatically suppressed the proliferation of SW480 cells, whereas MEK1 silencing induced a significant but much lower decrease of cell proliferation (Fig. <xref ref-type="fig" rid="F6">6C</xref>).
# ::save-date Wed Jun 24, 2015 ::file pmid_1901_4680_221.txt
(c / contrast-01
      :ARG1 (s / suppress-01
            :ARG0 (k / knock-down-02
                  :ARG1 (e / express-03
                        :ARG2 (e2 / enzyme :name (n / name :op1 "MEK2"))))
            :ARG1 (p / proliferate-01
                  :ARG0 (c2 / cell-line :name (n2 / name :op1 "SW480")))
            :degree (d / dramatic))
      :ARG2 (i / induce-01
            :ARG0 (s2 / silence-01
                  :ARG1 (e3 / enzyme :name (n3 / name :op1 "MEK1")))
            :ARG2 (d2 / decrease-01
                  :ARG1 p
                  :ARG1-of (s3 / significant-02
                        :ARG1-of (c3 / contrast-01
                              :ARG2 (l / low-04
                                    :degree (m / more
                                          :quant (m2 / much)))))))
      :ARG1-of (r / resemble-01
            :ARG2 (c4 / cell-line :name (n4 / name :op1 "HCT116")))
      :ARG1-of (d3 / describe-01
            :ARG0 (f / figure :mod "6C")))

# ::id pmid_1901_4680.222 ::date 2015-06-17T21:18:32 ::annotator SDL-AMR-09 ::preferred
# ::snt Similar results were obtained in HT-29 cells, except that the inhibitory effect of MEK1 shRNAs on proliferation was quantitatively more important than on HCT116 and SW480 cells (Fig. <xref ref-type="fig" rid="F6">6D</xref>).
# ::save-date Mon Dec 14, 2015 ::file pmid_1901_4680_222.txt
(o / obtain-01
      :ARG1 (t / thing
            :ARG2-of (r / result-01)
            :ARG1-of (r2 / resemble-01))
      :location (c / cell-line :name (n / name :op1 "HT-29"))
      :ARG2-of (e / except-01
            :ARG1 (a / affect-01
                  :ARG0 (n6 / nucleic-acid :name (n2 / name :op1 "shRNA")
                        :mod (g / gene :name (n3 / name :op1 "MEK1")))
                  :ARG1 (p / proliferate-01)
                  :ARG2 (i / inhibit-01)
                  :mod (i2 / important
                        :degree (m / more)
                        :manner (q / quantitative))
                  :compared-to (a2 / affect-01
                        :ARG0 n6
                        :ARG1 (a3 / and
                              :op1 (c2 / cell-line :name (n4 / name :op1 "HCT116"))
                              :op2 (c3 / cell-line :name (n5 / name :op1 "SW480"))))))
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod "6D")))

# ::id pmid_1901_4680.223 ::date 2015-06-18T00:09:55 ::annotator SDL-AMR-09 ::preferred
# ::snt This observation could be explained by the much higher expression of MEK1 in the HT-29 cell line as compared to HCT116 or SW480 cells (Fig. <xref ref-type="fig" rid="F6">6A</xref>), which may have a more important contribution to total MEK1/2 signaling.
# ::save-date Tue Jan 12, 2016 ::file pmid_1901_4680_223.txt
(p / possible-01
      :ARG1 (e / explain-01
            :ARG1 (t / thing
                  :ARG1-of (o / observe-01)
                  :mod (t2 / this))
            :manner (e2 / express-03
                  :ARG2 (e3 / enzyme :wiki "MAP2K1"
                        :name (n / name :op1 "MEK1"))
                  :ARG3 (c / cell-line :wiki -
                        :name (n2 / name :op1 "HT-29"))
                  :compared-to (e4 / express-03
                        :ARG2 e3
                        :ARG3 (o2 / or
                              :op1 (c2 / cell-line :wiki -
                                    :name (n3 / name :op1 "HCT116"))
                              :op2 (c3 / cell-line :wiki -
                                    :name (n4 / name :op1 "SW480"))))
                  :ARG0-of (c4 / contribute-01
                        :ARG2 (s / signal-07
                              :ARG0 (e5 / enzyme :wiki "Mitogen-activated_protein_kinase_kinase"
                                    :name (n5 / name :op1 "MEK1/2"))
                              :mod (t3 / total-01))
                        :mod (i / important
                              :degree (m / more))
                        :ARG1-of (p2 / possible-01))
                  :ARG1-of (h / high-02
                        :degree (m2 / more
                              :quant (m3 / much)))))
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod "6A")))

# ::id pmid_1901_4680.224 ::date 2015-06-18T00:24:32 ::annotator SDL-AMR-09 ::preferred
# ::snt However, the single inactivation of MEK2 was still capable of abolishing the proliferation of HT-29 cells even in the presence of high MEK1 levels.
# ::save-date Mon Dec 21, 2015 ::file pmid_1901_4680_224.txt
(c / contrast-01
      :ARG2 (c2 / capable-01
            :ARG1 (a / activate-01 :polarity -
                  :ARG1 (e / enzyme :name (n / name :op1 "MEK2"))
                  :ARG1-of (s / single-02))
            :ARG2 (a2 / abolish-01
                  :ARG0 a
                  :ARG1 (p / proliferate-01
                        :ARG0 (c3 / cell-line :name (n2 / name :op1 "HT-29"))))
            :concession (l / level
                  :quant-of (e2 / enzyme :name (n3 / name :op1 "MEK1"))
                  :ARG1-of (h / high-02))
            :mod (s2 / still)))

# ::id pmid_1901_4680.225 ::date 2015-06-18T00:32:27 ::annotator SDL-AMR-09 ::preferred
# ::snt For all colorectal cancer cell lines tested, the inhibition of proliferation seen with MEK2 shRNAs was comparable to that achieved with the MEK1/2 inhibitor U0126.
# ::save-date Sun Jan 17, 2016 ::file pmid_1901_4680_225.txt
(p / possible-01
      :ARG1 (c / compare-01
            :ARG1 (i / inhibit-01
                  :ARG0 (n6 / nucleic-acid :name (n / name :op1 "shRNA")
                        :mod (g / gene :name (n2 / name :op1 "MEK2")))
                  :ARG1 (p2 / proliferate-01)
                  :ARG1-of (s / see-01))
            :ARG2 (i2 / inhibit-01
                  :ARG1 p2
                  :ARG1-of (a / achieve-01
                        :instrument (s2 / small-molecule :name (n3 / name :op1 "U0126")
                              :ARG0-of (i3 / inhibit-01
                                    :ARG1 (e / enzyme :name (n4 / name :op1 "MEK1/2")))))))
      :location (c2 / cell-line
            :ARG1-of (t / test-01)
            :mod (a2 / all)
            :mod (d / disease :wiki "Colorectal_cancer" :name (n5 / name :op1 "colorectal" :op2 "cancer"))))

# ::id pmid_1901_4680.226 ::date 2015-06-18T00:52:30 ::annotator SDL-AMR-09 ::preferred
# ::snt To further extend our investigation to non-colorectal carcinomas, we tested the effect of MEK1 and MEK2 shRNAs on the human breast adenocarcinoma cell line MDA-MB-231, which exhibit strong constitutive activation of MEK1/MEK2 signaling (Fig. <xref ref-type="fig" rid="F6">6A</xref>).
# ::save-date Wed Jun 24, 2015 ::file pmid_1901_4680_226.txt
(t / test-01
      :ARG0 (w / we)
      :ARG1 (a / affect-01
            :ARG0 (a2 / and
                  :op1 (n7 / nucleic-acid :name (n / name :op1 "shRNA")
                        :mod (g / gene :name (n2 / name :op1 "MEK1")))
                  :op2 (n8 / nucleic-acid :name (n3 / name :op1 "shRNA")
                        :mod (g2 / gene :name (n4 / name :op1 "MEK2"))))
            :ARG1 (c / cell-line :name (n5 / name :op1 "MDA-MB-231")
                  :mod (a3 / adenocarcinoma
                        :mod (b / breast
                              :part-of (h / human)))
                  :ARG0-of (e / exhibit-01
                        :ARG1 (a4 / activate-01
                              :ARG1 (s / signal-07
                                    :ARG0 (e2 / enzyme :name (n6 / name :op1 "MEK1/MEK2")))
                              :mod (c2 / constitutive)
                              :degree (s2 / strong)))))
      :purpose (e3 / extend-01
            :ARG0 w
            :ARG1 (i / investigate-01
                  :ARG0 w
                  :ARG1 (c3 / carcinoma
                        :mod (c4 / colorectal :polarity -)))
            :mod (f / further))
      :ARG1-of (d / describe-01
            :ARG0 (f2 / figure :mod "6A")))

# ::id pmid_1901_4680.227 ::date 2015-06-18T01:00:44 ::annotator SDL-AMR-09 ::preferred
# ::snt Interestingly, the MEK2 shRNA-06 completely inhibited the proliferation of MDA-MB-231 cells to the same extent as the drug inhibitor U0126 (Additional file <xref ref-type="supplementary-material" rid="S4">4</xref>).
# ::save-date Sun Jan 17, 2016 ::file pmid_1901_4680_227.txt
(i / inhibit-01
      :ARG0 (n5 / nucleic-acid :name (n / name :op1 "shRNA-06")
            :mod (g / gene :name (n2 / name :op1 "MEK2")))
      :ARG1 (p / proliferate-01
            :ARG0 (c / cell-line :name (n3 / name :op1 "MDA-MB-231")))
      :degree (e / extent
            :ARG1-of (s / same-01
                  :ARG2 (e2 / extent
                        :degree-of (i2 / inhibit-01
                              :ARG0 (s2 / small-molecule :name (n4 / name :op1 "U0126")
                                    :ARG0-of (i3 / inhibit-01
                                          :ARG1 (d / drug)))
                              :ARG1 p))))
      :degree (c2 / complete)
      :manner (i4 / interesting)
      :ARG1-of (d2 / describe-01
            :ARG0 (f / file :mod 4
                  :ARG1-of (a / add-02))))

# ::id pmid_1901_4680.228 ::date 2015-06-18T01:10:49 ::annotator SDL-AMR-09 ::preferred
# ::snt The other MEK2 shRNA-08 also markedly but not completely inhibited cell proliferation, consistent with its lower silencing activity in these cells.
# ::save-date Mon Dec 21, 2015 ::file pmid_1901_4680_228.txt
(i / inhibit-01
      :ARG0 (n3 / nucleic-acid :name (n / name :op1 "shRNA-08")
            :mod (g / gene :name (n2 / name :op1 "MEK2"))
            :mod (o / other))
      :ARG1 (p / proliferate-01
            :ARG0 (c2 / cell))
      :degree (m / marked
            :ARG1-of (c / contrast-01
                  :ARG2 (c3 / complete :polarity -)))
      :mod (a / also)
      :ARG1-of (c4 / consistent-01
            :ARG2 (a2 / activity-06
                  :ARG0 n3
                  :ARG1 (s / silence-01)
                  :ARG1-of (l / low-04
                        :degree (m2 / more))
                  :location (c5 / cell
                        :mod (t / this)))))

# ::id pmid_1901_4680.229 ::date 2015-06-18T01:18:59 ::annotator SDL-AMR-09 ::preferred
# ::snt Expression of MEK1 shRNAs suppressed cell proliferation by approximately 50%.
# ::save-date Wed Jun 24, 2015 ::file pmid_1901_4680_229.txt
(s / suppress-01
      :ARG0 (e / express-03
            :ARG1 (n3 / nucleic-acid :name (n / name :op1 "shRNA")
                  :mod (g / gene :name (n2 / name :op1 "MEK1"))))
      :ARG1 (p / proliferate-01
            :ARG0 (c / cell))
      :quant (a / approximately
            :op1 (p2 / percentage-entity :value 50)))

# ::id pmid_1943_2991.1 ::date 2015-08-16T01:00:09 ::annotator SDL-AMR-09 ::preferred
# ::snt Identification of the B-Raf/Mek/Erk MAP kinase pathway as a target for all-trans retinoic acid during skin cancer promotion (PMID:19432991)
# ::save-date Wed Dec 9, 2015 ::file pmid_1943_2991_1.txt
(i / identify-01
      :ARG1 (p / pathway :name (n2 / name :op1 "B-Raf/Mek/Erk")
            :mod (k / kinase :name (n3 / name :op1 "MAP")))
      :ARG2 (t / target-01
            :ARG0 (s3 / small-molecule :name (n5 / name :op1 "all-trans-retinoic-acid"))
            :ARG1 p
            :time (p2 / promote-01
                  :ARG1 (d / disease :wiki "Skin_cancer" :name (n / name :op1 "skin" :op2 "cancer"))))
      :ARG1-of (d3 / describe-01
            :ARG0 (p3 / publication-91
                  :ARG8 "PMID19432991")))

# ::id pmid_1943_2991.6 ::date 2015-08-16T01:21:32 ::annotator SDL-AMR-09 ::preferred
# ::snt <sec-title level="1" sec-area="abstract">Results</sec-title>
# ::save-date Sun Aug 16, 2015 ::file pmid_1943_2991_6.txt
(t / thing
      :ARG2-of (r / result-01))

# ::id pmid_1943_2991.7 ::date 2015-08-16T01:22:05 ::annotator SDL-AMR-09 ::preferred
# ::snt We have used the 2-stage dimethylbenzanthracene (DMBA)/12-<i>O</i>-tetradecanoylphorbol-13-acetate (TPA) mouse skin carcinogenesis model to investigate the chemopreventive effects of ATRA.
# ::save-date Wed Dec 9, 2015 ::file pmid_1943_2991_7.txt
(u / use-01
      :ARG0 (w / we)
      :ARG1 (m / model
            :mod (c / carcinogenesis
                  :mod (s / skin
                        :poss (m2 / mouse)))
            :mod (s2 / slash
                  :op1 (s4 / small-molecule :name (n / name :op1 "dimethylbenzanthracene")
                        :mod (s3 / stage :quant 2))
                  :op2 (s5 / small-molecule :name (n2 / name :op1 "12-O-tetradecanoylphorbol-13-acetate"))))
      :ARG2 (i / investigate-01
            :ARG0 w
            :ARG1 (a / affect-01
                  :ARG0 (s6 / small-molecule :name (n4 / name :op1 "ATRA"))
                  :ARG2 (p / prevent-01
                        :ARG1 (d / disease :wiki "Breast_cancer" :name (n3 / name :op1 "breast" :op2 "cancer"))
                        :mod (c2 / chemistry)))))

# ::id pmid_1943_2991.8 ::date 2015-08-16T01:33:39 ::annotator SDL-AMR-09 ::preferred
# ::snt We have compared the gene expression profiles of control skin to skin subjected to the 2-stage protocol, with or without ATRA, using Affymetrix 430 2.0 DNA microarrays.
# ::save-date Thu Nov 19, 2015 ::file pmid_1943_2991_8.txt
(c / compare-01
      :ARG0 (w / we)
      :ARG1 (p / profile-01
            :ARG1 (s / skin
                  :ARG0-of (c2 / control-01))
            :topic (e / express-03
                  :ARG2 (g / gene)))
      :ARG2 (p2 / profile-01
            :ARG1 (s2 / skin
                  :ARG1-of (s3 / subject-01
                        :ARG2 (o / or
                              :op1 (p3 / protocol
                                    :mod (s4 / stage :quant 2)
                                    :accompanier (s5 / small-molecule :name (n / name :op1 "ATRA")))
                              :op2 p3)))
            :topic e)
      :instrument (m / microarray :mod 430 :mod 2.0
            :mod (n2 / nucleic-acid :wiki "DNA" :name (n4 / name :op1 "DNA"))
            :mod (c3 / company :name (n3 / name :op1 "Affymetrix"))))

# ::id pmid_1943_2991.9 ::date 2015-08-16T01:54:47 ::annotator SDL-AMR-09 ::preferred
# ::snt Approximately 49% of the genes showing altered expression with TPA treatment are conversely affected when ATRA is co-administered.
# ::save-date Mon Aug 24, 2015 ::file pmid_1943_2991_9.txt
(a3 / affect-01
      :ARG1 (g / gene
            :quant (p2 / percentage-entity :value 49
                  :ARG1-of (i / include-91
                        :ARG2 (g2 / gene
                              :ARG0-of (s / show-01
                                    :ARG1 (e / express-03
                                          :ARG1-of (a2 / alter-01))
                                    :condition (t / treat-04
                                          :ARG2 (s3 / small-molecule :name (n / name :op1 "TPA")))))
                        :ARG3 (a / approximate-01))))
      :manner (c / converse)
      :condition (a4 / administer-01
            :ARG1 (a5 / and
                  :op1 s3
                  :op2 (s2 / small-molecule :name (n2 / name :op1 "ATRA")))))

# ::id pmid_1943_2991.10 ::date 2015-08-16T02:02:18 ::annotator SDL-AMR-09 ::preferred
# ::snt The activity of these genes, which we refer to as 'counter-regulated', may contribute to chemoprevention by ATRA.
# ::save-date Wed Dec 9, 2015 ::file pmid_1943_2991_10.txt
(p / possible-01
      :ARG1 (c / contribute-01
            :ARG1 (a / activity-06
                  :ARG0 (g / gene
                        :mod (t / this))
                  :ARG1-of (r / refer-01
                        :ARG0 (w / we)
                        :ARG2 (r2 / regulate-01
                              :ARG1 a
                              :ARG1-of (c2 / counter-01))))
            :ARG2 (p2 / prevent-01
                  :ARG1 (d / disease :wiki "Breast_cancer" :name (n / name :op1 "breast" :op2 "cancer"))
                  :ARG3 (s / small-molecule :name (n2 / name :op1 "ATRA"))
                  :mod (c3 / chemistry))))

# ::id pmid_1943_2991.11 ::date 2015-08-16T02:08:09 ::annotator SDL-AMR-09 ::preferred
# ::snt The counter-regulated genes have been clustered into functional categories and bioinformatic analysis has identified the B-Raf/Mek/Erk branch of the MAP kinase pathway as one containing several genes whose upregulation by TPA is blocked by ATRA.
# ::save-date Sun Jan 17, 2016 ::file pmid_1943_2991_11.txt
(a / and
      :op1 (c / cluster-01
            :ARG1 (g / gene
                  :ARG1-of (r / regulate-01
                        :ARG1-of (c2 / counter-01)))
            :ARG2 (c3 / category
                  :ARG0-of (f / function-01)))
      :op2 (i / identify-01
            :ARG0 (a2 / analyze-01
                  :mod (b / bioinformatic))
            :ARG1 (b2 / branch
                  :mod (s / slash
                        :op1 (e / enzyme :name (n / name :op1 "B-Raf"))
                        :op2 (e2 / enzyme :name (n2 / name :op1 "Mek"))
                        :op3 (e3 / enzyme :name (n3 / name :op1 "Erk")))
                  :part-of (p / pathway :name (n4 / name :op1 "MAP" :op2 "kinase")))
            :ARG2 (c4 / contain-01
                  :ARG0 b2
                  :ARG1 (g2 / gene
                        :quant (s2 / several)
                        :ARG1-of (u / upregulate-01
                              :ARG2 (s3 / small-molecule :name (n5 / name :op1 "TPA"))
                              :ARG1-of (b3 / block-01
                                    :ARG0 (s4 / small-molecule :name (n6 / name :op1 "ATRA"))))))))

# ::id pmid_1943_2991.12 ::date 2015-08-16T03:18:18 ::annotator SDL-AMR-09 ::preferred
# ::snt We also show that ATRA blocks signaling through this pathway, as revealed by immunohistochemistry and Western blotting.
# ::save-date Sun Dec 13, 2015 ::file pmid_1943_2991_12.txt
(s / show-01
      :ARG0 (w2 / we)
      :ARG1 (b / block-01
            :ARG0 (s3 / small-molecule :name (n2 / name :op1 "ATRA"))
            :ARG1 (s2 / signal-07
                  :ARG0 (p / pathway
                        :mod (t / this))))
      :ARG1-of (r / reveal-01
            :ARG0 (a2 / and
                  :op1 (i / immunohistochemistry)
                  :op2 (i2 / immunoblot-01)))
      :mod (a / also))

# ::id pmid_1943_2991.13 ::date 2015-08-17T05:52:16 ::annotator SDL-AMR-09 ::preferred
# ::snt Finally, we found that blocking the B-Raf/Mek/Erk pathway with a pharmacological inhibitor, Sorafenib (BAY43-9006), induces squamous differentiation of existing skin SCCs formed in the 2-stage model.
# ::save-date Thu Dec 10, 2015 ::file pmid_1943_2991_13.txt
(f4 / find-01
      :ARG0 (w / we)
      :ARG1 (i2 / induce-01
            :ARG0 (b / block-01
                  :ARG1 (p / pathway :name (n / name :op1 "B-Raf/Mek/Erk"))
                  :ARG3 (s5 / small-molecule :name (n2 / name :op1 "Sorafenib")
                        :ARG0-of (i / inhibit-01)
                        :mod (p2 / pharmacology)
                        :ARG1-of (n4 / name-01
                              :ARG2 (n6 / name :op1 "BAY43-9006"))))
            :ARG2 (d / differentiate-01
                  :ARG1 (m2 / medical-condition :name (n3 / name :op1 "carcinoma")
                        :mod (c / cell)
                        :mod (s2 / squamous)
                        :mod (s3 / skin)
                        :ARG1-of (f3 / form-01
                              :location (m / model
                                    :ARG0-of (h / have-03
                                          :ARG1 (s4 / stage :quant 2)))))
                  :mod (s / squamous)))
      :time (f5 / final))

# ::id pmid_1943_2991.49 ::date 2015-08-17T06:08:21 ::annotator SDL-AMR-09 ::preferred
# ::snt <sec-title level="1">Results</sec-title>
# ::save-date Mon Aug 17, 2015 ::file pmid_1943_2991_49.txt
(t / thing
      :ARG2-of (r / result-01))

# ::id pmid_1943_2991.50 ::date 2015-08-17T06:08:53 ::annotator SDL-AMR-09 ::preferred
# ::snt <sec-title level="2">ATRA reverses many of the gene expression changes caused by TPA in mouse skin: microarray-based analysis</sec-title>
# ::save-date Sat Aug 22, 2015 ::file pmid_1943_2991_50.txt
(m2 / multi-sentence
      :snt1 (r / reverse-01
            :ARG0 (s2 / small-molecule :wiki "Tretinoin"
                  :name (n / name :op1 "ATRA"))
            :ARG1 (c / change-01
                  :ARG1 (e / express-03
                        :ARG2 (g / gene))
                  :ARG1-of (c2 / cause-01
                        :ARG0 (s3 / small-molecule :wiki "12-O-Tetradecanoylphorbol-13-acetate"
                              :name (n2 / name :op1 "TPA"))
                        :location (s / skin
                              :mod (m / mouse)))
                  :mod (m3 / many)
                  :ARG1-of (i / include-91
                        :ARG2 (c3 / change-01
                              :ARG1 (e2 / express-03
                                    :ARG2 (g3 / gene))))))
      :snt2 (a2 / analyze-01
            :ARG1-of (b / base-02
                  :ARG2 (m4 / microarray))))

# ::id pmid_1943_2991.51 ::date 2015-08-17T06:33:06 ::annotator SDL-AMR-09 ::preferred
# ::snt Our group and others have shown that ATRA can suppress tumor promotion by TPA in the 2-stage model, but only as long as it is being co-administered with TPA [<xref ref-type="bibr" rid="B9">9</xref>,<xref ref-type="bibr" rid="B20">20</xref>].
# ::save-date Sat Aug 22, 2015 ::file pmid_1943_2991_51.txt
(s / show-01
      :ARG0 (a2 / and
            :op1 (g / group
                  :poss (w / we))
            :op2 (o / other))
      :ARG1 (p / possible-01
            :ARG1 (s2 / suppress-01
                  :ARG0 (s4 / small-molecule :name (n / name :op1 "ATRA"))
                  :ARG1 (p2 / promote-01
                        :ARG0 (s5 / small-molecule :name (n2 / name :op1 "TPA"))
                        :ARG1 (t / tumor))
                  :location (m / model
                        :ARG0-of (h / have-03
                              :ARG1 (s3 / stage :quant 2)))
                  :condition (a / as-long-as
                        :op1 (a4 / administer-01
                              :ARG1 (a5 / and
                                    :op1 s4
                                    :op2 s5)
                              :mod (o2 / only)))))
      :ARG1-of (d / describe-01
            :ARG0 (p4 / publication
                  :ARG1-of (c / cite-01
                        :ARG2 (a6 / and :op1 9 :op2 20)))))

# ::id pmid_1943_2991.52 ::date 2015-08-17T06:42:55 ::annotator SDL-AMR-09 ::preferred
# ::snt If ATRA treatment is discontinued while TPA treatment is maintained, the mice showed a linear increase in tumor multiplicity with time after stopping the last treatment [<xref ref-type="bibr" rid="B20">20</xref>].
# ::save-date Sat Aug 22, 2015 ::file pmid_1943_2991_52.txt
(s / show-01
      :ARG0 (m / mouse)
      :ARG1 (i / increase-01
            :ARG1 (m2 / multiply-01
                  :ARG1 (t / tumor))
            :mod (l / linear)
            :ARG0-of (h / have-03
                  :ARG1 (t2 / time
                        :time (a / after
                              :op1 (s2 / stop-01
                                    :ARG1 (t3 / treat-04
                                          :mod (l2 / last)))))))
      :condition (a2 / and
            :op1 (d / discontinue-01
                  :ARG1 (t4 / treat-04
                        :ARG2 (s3 / small-molecule :name (n / name :op1 "ATRA"))))
            :op2 (m3 / maintain-01
                  :ARG1 (t5 / treat-04
                        :ARG2 (s4 / small-molecule :name (n2 / name :op1 "TPA")))))
      :ARG1-of (d2 / describe-01
            :ARG0 (p2 / publication
                  :ARG1-of (c / cite-01
                        :ARG2 20))))

# ::id pmid_1943_2991.53 ::date 2015-08-17T06:50:45 ::annotator SDL-AMR-09 ::preferred
# ::snt This suggests that ATRA may be primarily acting to suppress promotion by TPA, but has little apparent effect on initiation.
# ::save-date Sat Aug 22, 2015 ::file pmid_1943_2991_53.txt
(c / contrast-01
      :ARG1 (s / suggest-01
            :ARG0 (t / this)
            :ARG1 (p / possible-01
                  :ARG1 (a / act-01
                        :ARG0 (s3 / small-molecule :name (n / name :op1 "ATRA"))
                        :purpose (s2 / suppress-01
                              :ARG0 s3
                              :ARG1 (p2 / promote-01
                                    :ARG0 (s4 / small-molecule :name (n2 / name :op1 "TPA"))))
                        :mod (p4 / primary))))
      :ARG2 (a3 / affect-01
            :ARG0 s3
            :ARG1 (i / initiate-01
                  :ARG1 p2)
            :degree (l / little)
            :ARG1-of (a4 / appear-01)))

# ::id pmid_1943_2991.54 ::date 2015-08-17T06:57:15 ::annotator SDL-AMR-09 ::preferred
# ::snt In order to explore the mechanism of the chemopreventive effect of ATRA at an early step during TPA-induced tumor promotion, we performed Affymetrix DNA microarray analyses for mouse skin subjected to the 2-stage protocol for 3 weeks, with and without co-administration of ATRA.
# ::save-date Wed Mar 2, 2016 ::file pmid_1943_2991_54.txt
(p / perform-01
      :ARG0 (w2 / we)
      :ARG1 (o / or
            :op1 (a2 / and
                  :op1 (a / analyze-01
                        :ARG1 (s / skin
                              :mod (m / mouse)
                              :ARG1-of (s2 / subject-01
                                    :ARG2 (p2 / protocol
                                          :ARG0-of (h / have-03
                                                :ARG1 (s3 / stage :quant 2)))
                                    :duration (t2 / temporal-quantity :quant 3
                                          :unit (w3 / week))))
                        :mod (m3 / microarray
                              :mod (n / nucleic-acid :wiki "DNA" :name (n6 / name :op1 "DNA"))
                              :source (c / company :name (n2 / name :op1 "Affymetrix"))))
                  :op2 (a3 / administer-01
                        :ARG1 (s5 / small-molecule :name (n3 / name :op1 "ATRA"))))
            :op2 (a5 / and
                  :op1 a
                  :op2 (a6 / administer-01 :polarity -
                        :ARG1 s5)))
      :purpose (e / explore-01
            :ARG0 w2
            :ARG1 (m2 / mechanism
                  :poss (a7 / affect-01
                        :ARG0 s5
                        :ARG2 (p3 / prevent-01
                              :ARG1 (d / disease :wiki "Breast_cancer" :name (n7 / name :op1 "breast" :op2 "cancer"))
                              :mod (c2 / chemistry))
                        :time (s4 / step
                              :mod (e2 / early)
                              :subevent-of (p4 / promote-01
                                    :ARG1 (t / tumor)
                                    :ARG2-of (i / induce-01
                                          :ARG0 (s6 / small-molecule :name (n5 / name :op1 "TPA")))))))))

# ::id pmid_1943_2991.55 ::date 2015-08-18T01:39:53 ::annotator SDL-AMR-09 ::preferred
# ::snt We chose the 3 week time point because this precedes the appearance of tumors but is after the TPA treated skin exhibits pronounced hyperplasia (Fig. <xref ref-type="fig" rid="F1">1</xref>); and this time point proved to be advantageous for identifying genes regulated by TPA plus retinoid combinations in mouse skin in a previous study from our laboratory [<xref ref-type="bibr" rid="B20">20</xref>].
# ::save-date Wed Dec 9, 2015 ::file pmid_1943_2991_55.txt
(a3 / and
      :op1 (c / choose-01
            :ARG0 (w2 / we)
            :ARG1 (p / point
                  :mod (t2 / time
                        :ARG1-of (e / equal-01
                              :ARG2 (t3 / temporal-quantity :quant 3
                                    :unit (w3 / week)))))
            :ARG1-of (c2 / cause-01
                  :ARG0 (c3 / contrast-01
                        :ARG1 (p2 / precede-01
                              :ARG1 p
                              :ARG2 (a / appear-01
                                    :ARG1 (t4 / tumor)))
                        :ARG2 (a2 / after
                              :op1 (e2 / exhibit-01
                                    :ARG0 (s / skin
                                          :ARG1-of (t5 / treat-04
                                                :ARG2 (s5 / small-molecule :name (n / name :op1 "TPA"))))
                                    :ARG1 (m / medical-condition :name (n2 / name :op1 "hyperplasia")
                                          :ARG1-of (p4 / pronounced-02)))
                              :domain p)))
            :ARG1-of (d2 / describe-01
                  :ARG0 (f / figure :mod 1)))
      :op2 (p5 / prove-01
            :ARG0 p
            :ARG1 (a4 / advantageous
                  :purpose (i / identify-01
                        :ARG1 (g / gene
                              :ARG1-of (r / regulate-01
                                    :ARG0 (a5 / and
                                          :op1 s5
                                          :op2 (c4 / combine-01
                                                :ARG1 (s4 / small-molecule :name (n3 / name :op1 "retinoid"))
                                                :time (s2 / study-01
                                                      :mod (p6 / previous)
                                                      :location (l / laboratory
                                                            :poss (w4 / we)))
                                                :location (s3 / skin
                                                      :mod (m2 / mouse))))))))
            :ARG1-of (d3 / describe-01
                  :ARG0 (p7 / publication
                        :ARG1-of (c5 / cite-01
                              :ARG2 20)))))

# ::id pmid_1943_2991.56 ::date 2015-08-18T02:01:17 ::annotator SDL-AMR-09 ::preferred
# ::snt We reason that at least a portion of important TPA-induced promotion events will have taken place by this time.
# ::save-date Sat Aug 22, 2015 ::file pmid_1943_2991_56.txt
(r / reason-01
      :ARG0 (w / we)
      :ARG1 (p3 / portion
            :mod (a / at-least)
            :part-of (e / event
                  :ARG0-of (p / promote-01)
                  :ARG1-of (i / induce-01
                        :ARG0 (s / small-molecule :name (n / name :op1 "TPA")))
                  :mod (i3 / important))
            :time (u / up-to
                  :op1 (t / time
                        :mod (t2 / this)))))

# ::id pmid_1943_2991.57 ::date 2015-08-18T02:10:26 ::annotator SDL-AMR-09 ::preferred
# ::snt Of the ~45,000 probe sets (representing ~39,000 transcripts and variants from over 34,000 characterized mouse genes) on the 430 2.0 GeneChip, expression of 3,948 were altered by TPA, upwards or downwards, relative to untreated controls (fold changes between treatment groups ≥ 1.5, with p ≤ 0.05).
# ::save-date Tue Dec 15, 2015 ::file pmid_1943_2991_57.txt
(m2 / multi-sentence
      :snt1 (a / alter-01
            :ARG0 (s3 / small-molecule :name (n2 / name :op1 "TPA"))
            :ARG1 (e / express-03
                  :ARG2 (s / set :quant 3948
                        :mod (p / probe)
                        :ARG1-of (i / include-91
                              :ARG2 (s2 / set
                                    :mod (p2 / probe)
                                    :quant (a2 / approximately :op1 45000)
                                    :ARG0-of (r / represent-01
                                          :ARG1 (a3 / and
                                                :op1 (t / transcribe-01
                                                      :ARG1 (g / gene
                                                            :mod (m / mouse)
                                                            :ARG1-of (c / characterize-01)
                                                            :quant (o / over :op1 34000)))
                                                :op2 (v / vary-01
                                                      :ARG1 g)
                                                :quant (a4 / approximately :op1 39000)))
                                    :location (t2 / thing :mod 2.0 :mod 430 :name (n / name :op1 "GeneChip"))))))
            :direction (o2 / or
                  :op1 (u / upward)
                  :op2 (d / downward))
            :ARG1-of (r2 / relate-01
                  :ARG2 (c2 / control-01
                        :ARG1-of (t3 / treat-04 :polarity -))))
      :snt2 (c3 / change-01
            :mod (f / fold)
            :location (b2 / between
                  :op1 (g2 / group
                        :mod (t4 / treat-04)))
            :ARG1-of (e2 / equal-01
                  :ARG2 (o3 / over :op1 1.5))
            :ARG1-of (s4 / statistical-test-91
                  :ARG2 (o4 / or :op1 0.05
                        :op2 (l / less-than :op1 0.05)))))

# ::id pmid_1943_2991.58 ::date 2015-08-18T03:52:24 ::annotator SDL-AMR-09 ::preferred
# ::snt This group of genes was divided into clusters as described in Materials and Methods.
# ::save-date Sat Aug 22, 2015 ::file pmid_1943_2991_58.txt
(d / divide-02
      :ARG1 (g / group
            :consist-of (g2 / gene)
            :mod (t / this))
      :ARG2 (c / cluster)
      :ARG1-of (d2 / describe-01
            :medium (a / and
                  :op1 (m / material)
                  :op2 (m2 / method))))

# ::id pmid_1943_2991.59 ::date 2015-08-18T03:56:18 ::annotator SDL-AMR-09 ::preferred
# ::snt The heatmap in figure <xref ref-type="fig" rid="F2">2</xref> represents the genes that fall into each subcluster, with expression patterns produced by normalized raw scores for the subcluster indicated in the panels on the right.
# ::save-date Tue Aug 18, 2015 ::file pmid_1943_2991_59.txt
(r / represent-01
      :ARG0 (h / heatmap
            :location (f / figure :mod 2))
      :ARG1 (g / gene
            :ARG1-of (f2 / fall-01
                  :ARG4 (s / subcluster
                        :mod (e / each)))
            :ARG0-of (h2 / have-03
                  :ARG1 (p / pattern
                        :topic (e2 / express-03)
                        :ARG1-of (p2 / produce-01
                              :ARG0 (s2 / score
                                    :mod (r2 / raw)
                                    :ARG1-of (n / normalize-01))
                              :ARG3 (s3 / subcluster
                                    :ARG1-of (i / indicate-01
                                          :location (p3 / panel
                                                :ARG1-of (r3 / right-04)))))))))

# ::id pmid_1943_2991.60 ::date 2015-08-18T04:04:42 ::annotator SDL-AMR-09 ::preferred
# ::snt Amongst the 3,948 total TPA regulated genes, 49.5% were found to be in the C1A and C2A subclusters.
# ::save-date Sun Jan 17, 2016 ::file pmid_1943_2991_60.txt
(f / find-01
      :ARG1 (g / gene
            :ARG1-of (i / include-91
                  :ARG2 (g2 / gene :quant 3948
                        :mod (t / total)
                        :ARG1-of (r / regulate-01
                              :ARG0 (s3 / small-molecule :name (n / name :op1 "TPA"))))
                  :ARG3 (p / percentage-entity :value 49.5)))
      :location (a / and
            :op1 (s / subcluster
                  :part-of (g3 / gene :name (n2 / name :op1 "C1A")))
            :op2 (s2 / subcluster
                  :part-of (g4 / gene :name (n3 / name :op1 "C2A")))))

# ::id pmid_1943_2991.61 ::date 2015-08-18T04:09:27 ::annotator SDL-AMR-09 ::preferred
# ::snt We are calling these genes 'counter-regulated' because their direction of expression (increase or decrease) in TPA + ATRA treated skin compared to TPA treated skin is opposite to that of TPA treated skin compared to control skin.
# ::save-date Sun Aug 23, 2015 ::file pmid_1943_2991_61.txt
(c / call-01
      :ARG0 (w / we)
      :ARG1 (g / gene
            :mod (t / this))
      :ARG2 (g2 / gene
            :ARG1-of (r / regulate-01
                  :ARG1-of (c2 / counter-01)))
      :ARG1-of (c3 / cause-01
            :ARG0 (o / opposite-01
                  :ARG1 (d / direct-01
                        :ARG1 (e / express-03
                              :ARG2 g
                              :ARG3 (s / skin
                                    :ARG1-of (t2 / treat-04
                                          :ARG2 (a / and
                                                :op1 (s5 / small-molecule :name (n / name :op1 "TPA"))
                                                :op2 (s6 / small-molecule :name (n2 / name :op1 "ATRA"))))
                                    :compared-to (s2 / skin
                                          :ARG1-of (t3 / treat-04
                                                :ARG2 s5))))
                        :ARG1-of (m / mean-01
                              :ARG2 (o2 / or
                                    :op1 (i / increase-01)
                                    :op2 (d2 / decrease-01))))
                  :ARG2 (s3 / skin
                        :ARG1-of (t4 / treat-04
                              :ARG2 s5)
                        :compared-to (s4 / skin
                              :ARG0-of (c4 / control-01))))))

# ::id pmid_1943_2991.62 ::date 2015-08-18T04:19:30 ::annotator SDL-AMR-09 ::preferred
# ::snt This data can also be represented graphically as scatterplots (Fig. S1, additional file <xref ref-type="supplementary-material" rid="S1">1</xref>).
# ::save-date Sun Aug 23, 2015 ::file pmid_1943_2991_62.txt
(p / possible-01
      :ARG1 (r / represent-01
            :ARG1 (d / data
                  :mod (t / this))
            :ARG2 (s / scatterplot)
            :mod (g / graphic)
            :mod (a3 / also))
      :ARG1-of (d2 / describe-01
            :ARG0 (a / and
                  :op1 (f / figure :mod "S1")
                  :op2 (f2 / file :mod 1
                        :ARG1-of (a2 / add-02)))))

# ::id pmid_1943_2991.63 ::date 2015-08-18T04:23:14 ::annotator SDL-AMR-09 ::preferred
# ::snt We note that when comparing control skin with TPA + ATRA skin, the majority of counter-regulated genes lie close the x = y diagonal, indicating that ATRA can suppress TPA effects on expression of these genes completely or near completely (Fig. S1C, additional file <xref ref-type="supplementary-material" rid="S1">1</xref>, see C1A and C2A subclusters).
# ::save-date Sun Jan 17, 2016 ::file pmid_1943_2991_63.txt
(m2 / multi-sentence
      :snt1 (n / note-01
            :ARG0 (w / we)
            :ARG1 (l / lie-07
                  :ARG1 (g / gene
                        :quant (m / majority)
                        :ARG1-of (i / include-91
                              :ARG2 (g2 / gene
                                    :ARG1-of (r / regulate-01
                                          :ARG1-of (c2 / counter-01)))))
                  :ARG2 (c / close-10
                        :ARG1 g
                        :ARG2 (d / diagonal
                              :location-of (e2 / equal-01
                                    :ARG1 (s10 / string-entity :value "x")
                                    :ARG2 (s11 / string-entity :value "y"))))
                  :time (c3 / compare-01
                        :ARG0 w
                        :ARG1 (s / skin
                              :ARG0-of (c4 / control-01))
                        :ARG2 (s2 / skin
                              :ARG1-of (t / treat-04
                                    :ARG2 (a / and
                                          :op1 (s8 / small-molecule :name (n3 / name :op1 "TPA"))
                                          :op2 (s9 / small-molecule :name (n4 / name :op1 "ATRA"))))))
                  :ARG0-of (i2 / indicate-01
                        :ARG1 (p / possible-01
                              :ARG1 (o / or
                                    :op1 (s3 / suppress-01
                                          :ARG1 (a3 / affect-01
                                                :ARG0 s8
                                                :ARG1 (e / express-03
                                                      :ARG2 g))
                                          :ARG1-of (c6 / complete-02))
                                    :op2 (s4 / suppress-01
                                          :ARG1 a3
                                          :ARG1-of (c7 / complete-02
                                                :degree (n5 / near)))))))
            :ARG1-of (d2 / describe-01
                  :ARG0 (a4 / and
                        :op1 (f / figure :mod "S1C")
                        :op2 (f2 / file :mod 1
                              :ARG1-of (a5 / add-02)))))
      :snt2 (s5 / see-01
            :ARG0 (y / you)
            :ARG1 (a6 / and
                  :op1 (s6 / subcluster
                        :part-of (g3 / gene :name (n2 / name :op1 "C1A")))
                  :op2 (s7 / subcluster
                        :part-of (g4 / gene :name (n6 / name :op1 "C2A"))))))

# ::id pmid_1943_2991.64 ::date 2015-08-18T04:36:59 ::annotator SDL-AMR-09 ::preferred
# ::snt A subset of the C1A and C2A genes are listed in Table S1 in additional file <xref ref-type="supplementary-material" rid="S2">2</xref>, sorted according to their known function in cellular signaling pathways, using the GeneSifter program.
# ::save-date Sun Aug 23, 2015 ::file pmid_1943_2991_64.txt
(l / list-01
      :ARG1 (s / subset
            :consist-of (a / and
                  :op1 (g / gene :name (n / name :op1 "C1A"))
                  :op2 (g2 / gene :name (n2 / name :op1 "C2A")))
            :ARG1-of (s2 / sort-01
                  :ARG2 (f2 / function-01
                        :ARG0 a
                        :ARG1 (p / pathway
                              :ARG0-of (s4 / signal-07
                                    :mod (c / cell)))
                        :ARG1-of (k / know-01))))
      :ARG2 (t / table :mod "S1"
            :location (f / file :mod 2))
      :manner (u / use-01
            :ARG1 (p2 / program :name (n5 / name :op1 "GeneSifter"))))

# ::id pmid_1943_2991.65 ::date 2015-08-18T04:46:30 ::annotator SDL-AMR-09 ::preferred
# ::snt The table lists genes in the major signaling pathways in epithelial cells that have the highest Z-scores.
# ::save-date Sun Aug 23, 2015 ::file pmid_1943_2991_65.txt
(l / list-01
      :ARG0 (t / table)
      :ARG1 (g / gene
            :location (p / pathway
                  :ARG0-of (s / signal-07)
                  :ARG1-of (m2 / major-02)
                  :location (c / cell
                        :mod (e / epithelium)
                        :ARG0-of (h2 / have-03
                              :ARG1 (s2 / score :name (n / name :op1 "Z")
                                    :ARG1-of (h / high-02
                                          :degree (m / most))))))))

# ::id pmid_1943_2991.66 ::date 2015-08-18T04:58:58 ::annotator SDL-AMR-09 ::preferred
# ::snt Z-score is a measure of the significance of over-representation for a particular gene list within an ontology group [<xref ref-type="bibr" rid="B21">21</xref>].
# ::save-date Sun Aug 23, 2015 ::file pmid_1943_2991_66.txt
(m / measure-01
      :ARG1 (s2 / significant-02
            :ARG1 (r / represent-01
                  :ARG2 (l / list
                        :topic (g / gene)
                        :location (g2 / group
                              :mod (o2 / ontology))
                        :mod (p2 / particular))
                  :degree (o / over)))
      :ARG2 (s / score :name (n / name :op1 "Z"))
      :ARG1-of (d / describe-01
            :ARG0 (p / publication
                  :ARG1-of (c / cite-01
                        :ARG2 21))))

# ::id pmid_1943_2991.67 ::date 2015-08-18T05:06:22 ::annotator SDL-AMR-09 ::preferred
# ::snt We also identified several counter-regulated genes that were previously determined to be TPA regulated (Table S2, additional file <xref ref-type="supplementary-material" rid="S3">3</xref>).
# ::save-date Sun Aug 23, 2015 ::file pmid_1943_2991_67.txt
(i / identify-01
      :ARG0 (w / we)
      :ARG1 (g / gene
            :quant (s / several)
            :ARG1-of (r / regulate-01
                  :ARG1-of (c / counter-01))
            :ARG1-of (d / determine-01
                  :ARG3 (r2 / regulate-01
                        :ARG0 (s2 / small-molecule :name (n / name :op1 "TPA"))
                        :ARG1 g)
                  :time (p / previous)))
      :mod (a / also)
      :ARG1-of (d2 / describe-01
            :ARG0 (a2 / and
                  :op1 (t / table :mod "S2")
                  :op2 (f / file :mod 3
                        :ARG1-of (a3 / add-02)))))

# ::id pmid_1943_2991.68 ::date 2015-08-18T05:10:40 ::annotator SDL-AMR-09 ::preferred
# ::snt This abrogation of TPA effect on gene expression by ATRA is consistent with the findings of numerous investigators who have shown that TPA activates the AP-1 transcription factor complex, and that AP-1 activity is inhibited by ATRA through the retinoid receptors [<xref ref-type="bibr" rid="B10">10</xref>] for review and [<xref ref-type="bibr" rid="B14">14</xref>,<xref ref-type="bibr" rid="B22">22</xref>].
# ::save-date Sun Aug 23, 2015 ::file pmid_1943_2991_68.txt
(c / consistent-01
      :ARG1 (a / abrogate-01
            :ARG0 (s2 / small-molecule :name (n3 / name :op1 "ATRA"))
            :ARG1 (a2 / affect-01
                  :ARG0 (s3 / small-molecule :name (n2 / name :op1 "TPA"))
                  :ARG1 (e / express-03
                        :ARG2 (g / gene)))
            :mod (t / this))
      :ARG2 (f / find-01
            :ARG0 (p3 / person
                  :ARG0-of (i / investigate-01)
                  :quant (n4 / numerous)
                  :ARG0-of (s / show-01
                        :ARG1 (a5 / and
                              :op1 (a4 / activate-01
                                    :ARG0 s3
                                    :ARG1 (c2 / complex
                                          :mod (f2 / factor
                                                :ARG0-of (t2 / transcribe-01))
                                          :ARG1-of (m / mean-01
                                                :ARG2 (p4 / protein :name (n5 / name :op1 "AP-1")))))
                              :op2 (i2 / inhibit-01
                                    :ARG0 s2
                                    :ARG1 (a3 / activity-06
                                          :ARG0 p4)
                                    :instrument (r / receptor
                                          :mod (r2 / retinoid))
                                    :ARG1-of (d / describe-01
                                          :ARG0 (p5 / publication
                                                :ARG1-of (c3 / cite-01
                                                      :ARG2 (a7 / and :op1 10 :op2 14 :op3 22))))))))))

# ::id pmid_1943_2991.69 ::date 2015-08-18T05:20:23 ::annotator SDL-AMR-09 ::preferred
# ::snt <sec-title level="2">ATRA suppresses B-Raf/Mek/Erk signaling in early and late tumor progression times in the 2-stage skin carcinogenesis model</sec-title>
# ::save-date Wed Dec 9, 2015 ::file pmid_1943_2991_69.txt
(s / suppress-01
      :ARG0 (s5 / small-molecule :name (n / name :op1 "ATRA"))
      :ARG1 (s2 / signal-07
            :ARG0 (p / pathway :name (n2 / name :op1 "B-Raf/Mek/Erk")))
      :time (a2 / and
            :op1 (p2 / progress-01
                  :ARG1 (t2 / tumor)
                  :mod (e / early))
            :op2 (p3 / progress-01
                  :ARG1 t2
                  :mod (l / late)))
      :location (m / model
            :ARG0-of (h / have-03
                  :ARG1 (s4 / stage :quant 2))
            :mod (c / carcinogenesis
                  :mod (s3 / skin))))

# ::id pmid_1943_2991.70 ::date 2015-08-18T05:26:03 ::annotator SDL-AMR-09 ::preferred
# ::snt Examination of the above microarray results revealed altered expression of a disproportionate number of genes involved in the MAP kinase signaling pathway, in particular the B-Raf/Mek/Erk pathway (Table S1, additional file <xref ref-type="supplementary-material" rid="S2">2</xref>).
# ::save-date Sun Jan 17, 2016 ::file pmid_1943_2991_70.txt
(r / reveal-01
      :ARG0 (e / examine-01
            :ARG1 (m / microarray
                  :ARG1-of (r2 / result-01)
                  :location (a / above)))
      :ARG1 (e2 / express-03
            :ARG2 (n2 / number
                  :quant-of (g / gene
                        :ARG1-of (i / involve-01
                              :ARG2 (a3 / and
                                    :op1 (p4 / pathway :name (n / name :op1 "MAP" :op2 "kinase")
                                          :ARG0-of (s / signal-07))
                                    :op2 (p2 / pathway :name (n4 / name :op1 "B-Raf/Mek/Erk")
                                          :mod (p3 / particular)))))
                  :mod (d / disproportionate))
            :ARG1-of (a2 / alter-01))
      :ARG1-of (d2 / describe-01
            :ARG0 (a4 / and
                  :op1 (t2 / table :mod "S1")
                  :op2 (f / file :mod 2
                        :ARG1-of (a5 / add-02)))))

# ::id pmid_1943_2991.71 ::date 2015-08-18T05:34:00 ::annotator SDL-AMR-09 ::preferred
# ::snt We next performed a 2-stage skin carcinogenesis experiment as above, except that in this study the protocol was carried out for 30 weeks.
# ::save-date Wed Dec 9, 2015 ::file pmid_1943_2991_71.txt
(c / contrast-01
      :ARG1 (p / perform-02
            :ARG0 (w2 / we)
            :ARG1 (e / experiment-01
                  :ARG1 (c3 / carginogenesis
                        :mod (s / skin))
                  :ARG0-of (h / have-03
                        :ARG1 (s2 / stage :quant 2))
                  :ARG1-of (r / resemble-01
                        :ARG2 (a / above)))
            :time (n / next))
      :ARG2 (c2 / carry-out-03
            :ARG0 w2
            :ARG1 (p2 / protocol)
            :duration (t2 / temporal-quantity :quant 30
                  :unit (w3 / week))
            :location (s3 / study
                  :mod (t3 / this))))

# ::id pmid_1943_2991.72 ::date 2015-08-18T05:45:11 ::annotator SDL-AMR-09 ::preferred
# ::snt Tumor counts were recorded each week and mice were sacrificed at multiple time points (6 hours, 3, 7, 10, and 30 weeks of treatment), for subsequent analysis of B-Raf/Mek/Erk pathway signaling.
# ::save-date Sun Aug 23, 2015 ::file pmid_1943_2991_72.txt
(a / and
      :op1 (r / record-01
            :ARG1 (c / count-01
                  :ARG1 (t3 / tumor))
            :time (w2 / week
                  :mod (e / each)))
      :op2 (s / sacrifice-01
            :ARG1 (m / mouse)
            :time (p / point
                  :mod (t4 / time)
                  :quant (m2 / multiple)
                  :ARG1-of (m3 / mean-01
                        :ARG2 (a2 / and
                              :op1 (a4 / after
                                    :op1 (t7 / treat-04
                                          :quant (t / temporal-quantity :quant 6
                                                :unit (h / hour))))
                              :op2 (a5 / after
                                    :op1 (t8 / treat-04
                                          :quant (t5 / temporal-quantity :quant 3
                                                :unit (w3 / week))))
                              :op3 (a6 / after
                                    :op1 (t9 / treat-04
                                          :quant (t6 / temporal-quantity :quant 7
                                                :unit (w4 / week))))
                              :op4 (a7 / after
                                    :op1 (t10 / treat-04
                                          :quant (t11 / temporal-quantity :quant 10
                                                :unit (w5 / week))))
                              :op5 (a8 / after
                                    :op1 (t12 / treat-04
                                          :quant (t13 / temporal-quantity :quant 30
                                                :unit (w6 / week)))))))
            :purpose (a3 / analyze-01
                  :ARG1 (s2 / signal-07
                        :ARG0 (p2 / pathway :name (n / name :op1 "B-Raf/Mek/Erk")))
                  :time (s3 / subsequent))))

# ::id pmid_1943_2991.73 ::date 2015-08-18T05:54:03 ::annotator SDL-AMR-09 ::preferred
# ::snt The reduced tumor multiplicity and increased tumor latency for mice treated with TPA+ATRA, compared to mice treated with TPA alone, indicated the potent tumor suppressive activity of ATRA, in agreement with previous results (Fig. <xref ref-type="fig" rid="F3">3A</xref>, compare black line with blue line) [<xref ref-type="bibr" rid="B8">8</xref>,<xref ref-type="bibr" rid="B9">9</xref>].
# ::save-date Fri Feb 5, 2016 ::file pmid_1943_2991_73.txt
(m4 / multi-sentence
      :snt1 (i / indicate-01
            :ARG0 (a / and
                  :op1 (m / multiply-01
                        :ARG1 (t / tumor)
                        :ARG1-of (r / reduce-01))
                  :op2 (l / latent
                        :domain t
                        :ARG1-of (i2 / increase-01))
                  :location (m2 / mouse
                        :ARG1-of (t2 / treat-04
                              :ARG2 (a2 / and
                                    :op1 (s2 / small-molecule :name (n / name :op1 "TPA"))
                                    :op2 (s3 / small-molecule :name (n2 / name :op1 "ATRA")))))
                  :compared-to (m3 / mouse
                        :ARG1-of (t3 / treat-04
                              :ARG2 s2
                              :mod (a4 / alone))))
            :ARG1 (a3 / activity-06
                  :ARG0 s3
                  :ARG1 (s / suppress-01
                        :ARG1 t)
                  :mod (p2 / potent)
                  :ARG0-of (a6 / agree-01
                        :ARG2 (t5 / thing
                              :ARG2-of (r2 / result-01
                                    :time (p3 / previous)))))
            :ARG1-of (d / describe-01
                  :ARG0 (f / figure :mod "3A")))
      :snt2 (c / compare-01
            :ARG0 (y / you)
            :ARG1 (l2 / line
                  :ARG1-of (b / black-04))
            :ARG2 (l3 / line
                  :mod (b2 / blue)))
      :ARG1-of (d2 / describe-01
            :ARG0 (p4 / publication
                  :ARG1-of (c2 / cite-01
                        :ARG2 (a7 / and :op1 8 :op2 9)))))

# ::id pmid_1943_2991.74 ::date 2015-08-18T06:11:42 ::annotator SDL-AMR-09 ::preferred
# ::snt However a small number of tumors were observed in the mice treated with TPA+ATRA.
# ::save-date Sun Aug 23, 2015 ::file pmid_1943_2991_74.txt
(h / have-concession-91
      :ARG1 (o / observe-01
            :ARG1 (n / number
                  :quant-of (t / tumor)
                  :mod (s / small))
            :location (m / mouse
                  :ARG1-of (t2 / treat-04
                        :ARG2 (a / and
                              :op1 (s2 / small-molecule :name (n2 / name :op1 "TPA"))
                              :op2 (s3 / small-molecule :name (n3 / name :op1 "ATRA")))))))

# ::id pmid_1943_2991.75 ::date 2015-08-18T06:15:36 ::annotator SDL-AMR-09 ::preferred
# ::snt Interestingly, histological examination of these ATRA resistant tumors revealed a less differentiated phenotype than for the tumors that arose in the mice treated with TPA alone (Fig. <xref ref-type="fig" rid="F3">3B</xref>).
# ::save-date Sun Aug 23, 2015 ::file pmid_1943_2991_75.txt
(r / reveal-01
      :ARG0 (e / examine-01
            :ARG1 (t / tumor
                  :ARG0-of (r2 / resist-01
                        :ARG1 (s / small-molecule :name (n / name :op1 "ATRA")
                              :mod (t2 / this))))
            :mod (h / histology))
      :ARG1 (p / phenotype
            :ARG1-of (d / differentiate-01
                  :degree (l / less)
                  :compared-to (t3 / tumor
                        :ARG1-of (a2 / arise-02
                              :location (m / mouse
                                    :ARG1-of (t4 / treat-04
                                          :ARG2 (s2 / small-molecule :name (n2 / name :op1 "TPA")
                                                :mod (a3 / alone))))))))
      :ARG2-of (i / interest-01)
      :ARG1-of (d2 / describe-01
            :ARG0 (f / figure :mod "3B")))

# ::id pmid_1943_2991.76 ::date 2015-08-18T06:22:35 ::annotator SDL-AMR-09 ::preferred
# ::snt These tumors closely resembled advanced SCC, while the tumors in the TPA mice were papillary, with a high degree of keratinization as confirmed by a immunohistochemical (IHC) staining for cytokeratin 10 (Fig. <xref ref-type="fig" rid="F3">3B</xref>, lower panels).
# ::save-date Thu Dec 10, 2015 ::file pmid_1943_2991_76.txt
(c3 / contrast-01
      :ARG1 (r / resemble-01
            :ARG1 (t / tumor
                  :mod (t2 / this))
            :ARG2 (m / medical-condition :name (n / name :op1 "carcinoma")
                  :mod (c2 / cell)
                  :mod (s / squamous)
                  :ARG1-of (a / advance-01))
            :ARG1-of (c / close-10))
      :ARG2 (p / papilla
            :domain (t3 / tumor
                  :location (m2 / mouse
                        :ARG1-of (t4 / treat-04
                              :ARG2 (s3 / small-molecule :name (n2 / name :op1 "TPA"))))
                  :ARG0-of (h / have-03
                        :ARG1 (d2 / degree
                              :degree-of (k / keratinize-00)
                              :ARG1-of (h2 / high-02))
                        :ARG1-of (c4 / confirm-01
                              :ARG0 (s2 / stain-01
                                    :mod (i / immunohistochemical)
                                    :purpose (p3 / protein :name (n3 / name :op1 "cytokeratin" :op2 "10")))))))
      :ARG1-of (d3 / describe-01
            :ARG0 (a2 / and
                  :op1 (f / figure :mod "3B")
                  :op2 (p4 / panel
                        :ARG1-of (l / low-04
                              :degree (m3 / more))))))

# ::id pmid_1943_2991.77 ::date 2015-08-18T06:45:31 ::annotator SDL-AMR-09 ::preferred
# ::snt In order to investigate the effects of ATRA on TPA-induced activation of the B-Raf/Mek/Erk pathway, we performed IHC staining of paraffin sections from mouse skin treated with TPA, ATRA, TPA+ATRA, or acetone solvent, with phosphorylation site-specific antibodies to B-Raf (phospho-Ser 445), Mek1/2 (phospho-Ser 217/221), and Erk1/2 (phospho-Thr202/Tyr 204).
# ::save-date Mon Aug 24, 2015 ::file pmid_1943_2991_77.txt
(p2 / perform-02
      :ARG0 (w / we)
      :ARG1 (s / stain-01
            :ARG1 (s2 / section
                  :source (s3 / skin
                        :mod (m / mouse)
                        :ARG1-of (t2 / treat-04
                              :ARG2 (o / or
                                    :op1 (s11 / small-molecule :name (n4 / name :op1 "TPA"))
                                    :op2 (s12 / small-molecule :name (n5 / name :op1 "ATRA"))
                                    :op3 (a3 / and
                                          :op1 s11
                                          :op2 s12)
                                    :op4 (s4 / solvent
                                          :mod (a / acetone)))))
                  :mod (p3 / paraffin))
            :ARG2 (a5 / and
                  :op1 (a4 / antibody
                        :ARG1-of (s5 / specific-02
                              :ARG2 (s6 / site
                                    :ARG1-of (p / phosphorylate-01)
                                    :ARG1-of (m2 / mean-01
                                          :ARG2 (a7 / amino-acid :mod 445 :name (n8 / name :op1 "serine")
                                                :ARG3-of (p4 / phosphorylate-01)))))
                        :ARG0-of (c / counter-01
                              :ARG1 (e / enzyme :name (n / name :op1 "B-Raf"))))
                  :op2 (a6 / antibody
                        :ARG0-of (c2 / counter-01
                              :ARG1 (s7 / slash
                                    :op1 (e3 / enzyme :name (n6 / name :op1 "Mek1"))
                                    :op2 (e4 / enzyme :name (n7 / name :op1 "Mek2"))))
                        :ARG1-of (s13 / specific-02
                              :ARG2 (s14 / site
                                    :ARG1-of (m3 / mean-01
                                          :ARG2 (s10 / slash
                                                :op1 (a12 / amino-acid :mod 217 :name (n9 / name :op1 "serine")
                                                      :ARG3-of (p5 / phosphorylate-01))
                                                :op2 (a13 / amino-acid :mod 221 :name (n14 / name :op1 "serine")))))))
                  :op3 (a9 / antibody
                        :ARG0-of (c3 / counter-01
                              :ARG1 (s8 / slash
                                    :op1 (e5 / enzyme :name (n10 / name :op1 "Erk1"))
                                    :op2 (e6 / enzyme :name (n11 / name :op1 "Erk2"))))
                        :ARG1-of (s15 / specific-02
                              :ARG2 (s16 / site
                                    :ARG1-of (m4 / mean-01
                                          :ARG2 (s9 / slash
                                                :op1 (a10 / amino-acid :mod 202 :name (n12 / name :op1 "threonine"))
                                                :op2 (a11 / amino-acid :mod 204 :name (n13 / name :op1 "tyrosine"))))))))
            :mod (i / immunohistochemistry))
      :purpose (i2 / investigate-01
            :ARG0 w
            :ARG1 (a14 / affect-01
                  :ARG0 s12
                  :ARG1 (a15 / activate-01
                        :ARG1 (p6 / pathway :name (n15 / name :op1 "B-Raf/Mek/Erk"))
                        :ARG2-of (i3 / induce-01
                              :ARG0 s11))
                  :ARG1-of p)))

# ::id pmid_1943_2991.78 ::date 2015-08-18T07:16:34 ::annotator SDL-AMR-09 ::preferred
# ::snt The 6 h, 3, 7, 10 and 30 week time points were selected for sample isolation in order to obtain data prior to tumor formation (6 h and 3 weeks), just as tumors are beginning to be detectable (7 weeks), after the majority of mice have tumors (10 weeks), and after tumors had grown substantially (30 weeks).
# ::save-date Sun Aug 23, 2015 ::file pmid_1943_2991_78.txt
(s / select-01
      :ARG1 (a / and
            :op1 (p / point
                  :mod (t5 / time
                        :ARG1-of (e2 / equal-01
                              :ARG2 (t6 / temporal-quantity :quant 6
                                    :unit (h / hour)))))
            :op2 (p2 / point
                  :mod (t7 / time
                        :ARG1-of (e3 / equal-01
                              :ARG2 (t2 / temporal-quantity :quant 3
                                    :unit (w2 / week)))))
            :op3 (p3 / point
                  :mod (t8 / time
                        :ARG1-of (e4 / equal-01
                              :ARG2 (t3 / temporal-quantity :quant 7
                                    :unit (w3 / week)
                                    :ARG1-of (e / equal-01)))))
            :op4 (p4 / point
                  :mod (t9 / time
                        :ARG1-of (e5 / equal-01
                              :ARG2 (t4 / temporal-quantity :quant 10
                                    :unit (w4 / week)))))
            :op5 (p5 / point
                  :mod (t10 / time
                        :ARG1-of (e6 / equal-01
                              :ARG2 (t / temporal-quantity :quant 30
                                    :unit (w / week))))))
      :ARG3 (i / isolate-01
            :ARG1 (t13 / thing
                  :ARG1-of (s2 / sample-01))
            :purpose (o / obtain-01
                  :ARG1 (a4 / and
                        :op1 (d / data
                              :time (p6 / prior
                                    :op1 (f / form-01
                                          :ARG1 (t11 / tumor))
                                    :ARG1-of (m / mean-01
                                          :ARG2 (a2 / and
                                                :op1 t6
                                                :op2 t2))))
                        :op2 (d3 / data
                              :time (b / begin-01
                                    :ARG0 t11
                                    :ARG1 (d2 / detect-01
                                          :ARG1 t11)
                                    :ARG1-of (m5 / mean-01
                                          :ARG2 t3)))
                        :op3 (d4 / data
                              :time (a5 / after
                                    :op1 (h3 / have-03
                                          :ARG0 (m2 / mouse
                                                :quant (m3 / majority)
                                                :ARG1-of (i2 / include-91
                                                      :ARG2 (m7 / mouse)))
                                          :ARG1 t11)
                                    :ARG1-of (m6 / mean-01
                                          :ARG2 t4)))
                        :op4 (d5 / data
                              :time (a3 / after
                                    :op1 (g / grow-01
                                          :ARG1 t11
                                          :degree (s3 / substantial))
                                    :ARG1-of (m4 / mean-01
                                          :ARG2 t)))))))

# ::id pmid_1943_2991.79 ::date 2015-08-18T07:43:21 ::annotator SDL-AMR-09 ::preferred
# ::snt In the TPA treated skin, hyperproliferation was correlated with increased levels of activated (phosphorylated) B-Raf, Mek1/2, and Erk1/2, as detected by increased red fluorescence from the Alexa 546-coupled secondary antibody.
# ::save-date Tue Feb 2, 2016 ::file pmid_1943_2991_79.txt
(c / correlate-01
      :ARG1 (h / hyperproliferate-01)
      :ARG2 (a / and
            :op1 (l / level
                  :ARG1-of (i / increase-01)
                  :quant-of (e3 / enzyme :name (n3 / name :op1 "B-Raf")
                        :ARG1-of (a2 / activate-01
                              :ARG1-of (m / mean-01
                                    :ARG2 (p / phosphorylate-01)))))
            :op2 (l2 / level
                  :ARG1-of i
                  :quant-of (s / slash
                        :op1 (e4 / enzyme :name (n4 / name :op1 "Mek1")
                              :ARG1-of a2)
                        :op2 (e5 / enzyme :name (n5 / name :op1 "Mek2")
                              :ARG1-of a2)))
            :op3 (l3 / level
                  :ARG1-of i
                  :quant-of (s2 / slash
                        :op1 (e6 / enzyme :name (n6 / name :op1 "Erk1")
                              :ARG1-of a2)
                        :op2 (e7 / enzyme :name (n7 / name :op1 "Erk2")
                              :ARG1-of a2))))
      :ARG1-of (d / detect-01
            :ARG0 (f / fluoresce-01
                  :ARG1 (a3 / antibody
                        :mod (s3 / secondary)
                        :ARG1-of (c2 / couple-01
                              :ARG2 (s6 / small-molecule :name (n8 / name :op1 "Alexa" :op2 "546"))))
                  :ARG1-of (r / red-02)
                  :ARG1-of i))
      :location (s4 / skin
            :ARG1-of (t2 / treat-04
                  :ARG2 (s5 / small-molecule :name (n9 / name :op1 "TPA")))))

# ::id pmid_1943_2991.80 ::date 2015-08-18T07:51:55 ::annotator SDL-AMR-09 ::preferred
# ::snt Results are shown for a representative (3 week) time point (Fig. <xref ref-type="fig" rid="F4">4A</xref>; compare TPA panels to Control panels for all 3 rows).
# ::save-date Sun Aug 23, 2015 ::file pmid_1943_2991_80.txt
(m2 / multi-sentence
      :snt1 (s / show-01
            :ARG1 (t2 / thing
                  :ARG2-of (r2 / result-01))
            :purpose (p2 / point
                  :mod (t3 / time)
                  :ARG0-of (r3 / represent-01)
                  :ARG1-of (m / mean-01
                        :ARG2 (a2 / after
                              :op1 (t / temporal-quantity :quant 3
                                    :unit (w / week)))))
            :ARG1-of (d / describe-01
                  :ARG0 (f / figure :mod "4A")))
      :snt2 (c / compare-01
            :ARG0 (y / you)
            :ARG1 (p3 / panel
                  :consist-of (s2 / small-molecule :name (n / name :op1 "TPA")))
            :ARG2 (p5 / panel
                  :ARG0-of (c2 / control-01))
            :purpose (r4 / row :quant 3
                  :mod (a / all))))

# ::id pmid_1943_2991.81 ::date 2015-08-18T07:58:10 ::annotator SDL-AMR-09 ::preferred
# ::snt Skin treated with a single application of TPA, ATRA or TPA+ATRA showed no notable changes in staining for any of the phosphoproteins (data not shown).
# ::save-date Sun Aug 23, 2015 ::file pmid_1943_2991_81.txt
(s5 / show-01
      :ARG0 (s2 / skin
            :ARG1-of (t / treat-04
                  :ARG2 (o / or
                        :op1 (a / apply-02
                              :ARG1 (s6 / small-molecule :name (n / name :op1 "TPA"))
                              :ARG1-of (s3 / single-02))
                        :op2 (a2 / apply-02
                              :ARG1 (s7 / small-molecule :name (n2 / name :op1 "ATRA"))
                              :ARG1-of s3)
                        :op3 (a4 / apply-02
                              :ARG1 (a5 / and
                                    :op1 s6
                                    :op2 s7)
                              :ARG1-of s3))))
      :ARG1 (c / change-01
            :ARG1 (s4 / stain-01
                  :ARG1 (p2 / protein
                        :mod (a6 / any)
                        :ARG1-of (p3 / phosphorylate-01)))
            :ARG1-of (n3 / notable-04))
      :ARG1-of (d / describe-01
            :ARG0 (d2 / data
                  :ARG1-of (s / show-01 :polarity -))))

# ::id pmid_1943_2991.82 ::date 2015-08-18T08:16:33 ::annotator SDL-AMR-09 ::preferred
# ::snt pB-Raf was expressed predominantly in the cytoplasm in TPA treated skin at all time points, and this effect was blocked with co-administration of ATRA with TPA (Fig. <xref ref-type="fig" rid="F4">4A</xref>, upper rows and data not shown).
# ::save-date Sun Aug 23, 2015 ::file pmid_1943_2991_82.txt
(a / and
      :op1 (e / express-03
            :ARG2 (e2 / enzyme :name (n / name :op1 "B-Raf")
                  :ARG3-of (p / phosphorylate-01))
            :ARG3 (c / cytoplasm
                  :location (s / skin
                        :ARG1-of (t / treat-04
                              :ARG2 (s3 / small-molecule :name (n2 / name :op1 "TPA")))))
            :ARG1-of (p2 / predominate-01)
            :time (p4 / point
                  :mod (t2 / time)
                  :mod (a2 / all)))
      :op2 (b / block-01
            :ARG1 (a4 / affect-01
                  :mod (t3 / this))
            :ARG3 (a5 / administer-01
                  :ARG1 (a6 / and
                        :op1 (s4 / small-molecule :name (n3 / name :op1 "ATRA"))
                        :op2 s3)))
      :ARG1-of (d / describe-01
            :ARG0 (a3 / and
                  :op1 (f / figure :mod "4A"
                        :location (r / row))
                  :op2 (d2 / data
                        :ARG1-of (s2 / show-01 :polarity -)))))

# ::id pmid_1943_2991.83 ::date 2015-08-18T10:55:59 ::annotator SDL-AMR-09 ::preferred
# ::snt We did not observe any changes in phosphorylation of c-Raf (RAF1), the other Raf family member present in skin, with any of the treatments using an antibody to phospho-serine 338 (Fig. S2, additional file <xref ref-type="supplementary-material" rid="S4">4</xref>).
# ::save-date Sun Aug 23, 2015 ::file pmid_1943_2991_83.txt
(o / observe-01 :polarity -
      :ARG0 (w / we)
      :ARG1 (c / change-01
            :ARG1 (p / phosphorylate-01
                  :ARG1 (e / enzyme :name (n / name :op1 "c-Raf")))
            :mod (a6 / any))
      :condition (p3 / present
            :location (s / skin)
            :domain (m2 / member
                  :ARG1-of (i / include-91
                        :ARG2 (p2 / protein-family :name (n3 / name :op1 "Raf")
                              :ARG1-of (m / mean-01
                                    :ARG2 e)))
                  :mod (o2 / other)))
      :condition (t / treat-04
            :mod (a / any)
            :ARG0-of (u / use-01
                  :ARG1 (a2 / antibody
                        :ARG0-of (c2 / counter-01
                              :ARG1 (a3 / amino-acid :mod 338 :name (n5 / name :op1 "serine")
                                    :ARG3-of (p4 / phosphorylate-01))))))
      :ARG1-of (d / describe-01
            :ARG0 (a4 / and
                  :op1 (f / figure :mod "S2")
                  :op2 (f2 / file :mod 4
                        :ARG1-of (a5 / add-02)))))

# ::id pmid_1943_2991.84 ::date 2015-08-18T11:07:07 ::annotator SDL-AMR-09 ::preferred
# ::snt pMek1/2 levels were increased and expression was localized predominantly to the inner surface of the cell membrane in TPA treated skin (Fig. <xref ref-type="fig" rid="F4">4A</xref>, middle rows).
# ::save-date Sun Aug 23, 2015 ::file pmid_1943_2991_84.txt
(a / and
      :op1 (i / increase-01
            :ARG1 (s / slash
                  :op1 (l / level
                        :quant-of (e / enzyme :name (n / name :op1 "Mek1")
                              :ARG3-of (p / phosphorylate-01)))
                  :op2 (l2 / level
                        :quant-of (e2 / enzyme :name (n2 / name :op1 "Mek2"))
                        :ARG3-of p)))
      :op2 (l3 / localize-01
            :ARG1 (e3 / express-03)
            :ARG1-of (p2 / predominate-01)
            :location (s2 / surface
                  :mod (i2 / inner)
                  :part-of (m / membrane
                        :mod (c / cell)
                        :location (s3 / skin
                              :ARG1-of (t / treat-04
                                    :ARG2 (s4 / small-molecule :name (n3 / name :op1 "TPA")))))))
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod "4A"
                  :part (r / row
                        :location (m2 / middle)))))

# ::id pmid_1943_2991.85 ::date 2015-08-17T09:31:09 ::annotator SDL-AMR-09 ::preferred
# ::snt This observation is notable since it has been shown that the translocation of pMek to the cell membrane results in lowering the threshold for activation of MAP kinase signal output [<xref ref-type="bibr" rid="B23">23</xref>].
# ::save-date Mon Aug 24, 2015 ::file pmid_1943_2991_85.txt
(c / cause-01
      :ARG0 (s / show-01
            :ARG1 (r / result-01
                  :ARG1 (t / translocate-01
                        :ARG1 (e / enzyme :name (n / name :op1 "Mek")
                              :ARG3-of (p / phosphorylate-01))
                        :ARG2 (m / membrane
                              :mod (c2 / cell)))
                  :ARG2 (l / lower-05
                        :ARG1 (t2 / threshold
                              :degree-of (a / activate-01
                                    :ARG1 (o / output
                                          :mod (s2 / signal-07
                                                :ARG0 (k / kinase :name (n2 / name :op1 "MAP")))))))))
      :ARG1 (n3 / notable-04
            :ARG1 (t3 / thing
                  :ARG1-of (o2 / observe-01)
                  :mod (t4 / this)))
      :ARG1-of (d / describe-01
            :ARG0 (p2 / publication
                  :ARG1-of (c3 / cite-01
                        :ARG2 23))))

# ::id pmid_1943_2991.86 ::date 2015-08-17T09:31:21 ::annotator SDL-AMR-09 ::preferred
# ::snt As was observed for pB-Raf, the increased levels of pMek1/2 was blocked with co-administration of ATRA.
# ::save-date Mon Dec 21, 2015 ::file pmid_1943_2991_86.txt
(b / block-01
      :ARG1 (l / level
            :quant-of (e / enzyme :name (n / name :op1 "Mek1/2")
                  :ARG3-of (p / phosphorylate-01))
            :ARG1-of (i / increase-01))
      :ARG3 (c / coadminister-00
            :ARG1 (s / small-molecule :name (n2 / name :op1 "ATRA")))
      :ARG2-of (r / resemble-01
            :ARG1 (o / observe-01
                  :ARG1 (e2 / enzyme :name (n3 / name :op1 "B-Raf")
                        :ARG3-of p))))

# ::id pmid_1943_2991.87 ::date 2015-08-17T09:57:38 ::annotator SDL-AMR-09 ::preferred
# ::snt Staining for pErk1/2 was observed in pairs of scattered nuclei in control skin, with an increase in staining intensity for TPA treated skin, as would be predicted accompanying hyperproliferation.
# ::save-date Tue Feb 2, 2016 ::file pmid_1943_2991_87.txt
(o / observe-01
      :ARG1 (s / stain-01
            :purpose (e / enzyme :wiki "Extracellular_signal-regulated_kinases" :name (n / name :op1 "Erk1/2")
                        :ARG3-of (p / phosphorylate-01))
            :ARG0-of (h3 / have-03
                  :ARG1 (i / intensity
                        :ARG1-of (i2 / increase-01
                              :location (s4 / skin
                                    :ARG1-of (t / treat-04
                                          :ARG2 (s5 / small-molecule :wiki "12-O-Tetradecanoylphorbol-13-acetate" :name (n3 / name :op1 "TPA"))))
                              :ARG1-of (c2 / cause-01
                                    :ARG0 (p3 / predict-01
                                          :ARG0 i2
                                          :ARG1 (h2 / hyperproliferate-01
                                                :ARG0-of (a / accompany-01))))))))
      :location (p2 / pair-01
            :ARG1 (n2 / nucleus
                  :ARG1-of (s2 / scatter-01)
                  :location (s3 / skin
                        :mod (c / control)))))

# ::id pmid_1943_2991.88 ::date 2015-08-17T10:38:00 ::annotator SDL-AMR-09 ::preferred
# ::snt Fewer nuclei were stained for TPA+ATRA treated skin than for TPA treatment alone (Fig. <xref ref-type="fig" rid="F4">4A</xref>, bottom rows).
# ::save-date Mon Aug 24, 2015 ::file pmid_1943_2991_88.txt
(s / stain-01
      :ARG1 (n / nucleus
            :quant (f / few
                  :degree (m / more)
                  :compared-to (t2 / treat-04
                        :ARG2 s3
                        :mod (a2 / alone))))
      :ARG1-of (d / describe-01
            :ARG0 (f2 / figure :mod "4A"
                  :location (r / row
                        :location (b / bottom))))
      :purpose (s2 / skin
                  :ARG1-of (t / treat-04
                        :ARG2 (a / and
                              :op1 (s3 / small-molecule :name (n2 / name :op1 "TPA"))
                              :op2 (s4 / small-molecule :name (n3 / name :op1 "ATRA"))))))

# ::id pmid_1943_2991.89 ::date 2015-08-17T10:42:24 ::annotator SDL-AMR-09 ::preferred
# ::snt We attempted to quantitate pErk1/2 levels by determining the percent positive nuclei in the treated skin.
# ::save-date Tue Jan 19, 2016 ::file pmid_1943_2991_89.txt
(a / attempt-01
      :ARG0 (w / we)
      :ARG1 (q / quantitate-01
            :ARG0 w
            :ARG1 (l / level
                  :quant-of (e / enzyme :name (n / name :op1 "Erk1/2")
                        :ARG3-of (p / phosphorylate-01))))
      :instrument (d / determine-01
            :ARG0 w
            :ARG1 (p2 / percent
                  :quant-of (n2 / nucleus
                        :mod (p3 / positive))
                  :location (s / skin
                        :ARG1-of (t / treat-04)))))

# ::id pmid_1943_2991.90 ::date 2015-08-17T10:48:07 ::annotator SDL-AMR-09 ::preferred
# ::snt At all time points except 30 weeks, the percent positive pErk staining nuclei actually decreased in TPA treated skin compared to controls and TPA+ATRA skin (data not shown).
# ::save-date Thu Feb 11, 2016 ::file pmid_1943_2991_90.txt
(d / decrease-01
      :ARG1 (p / percent
            :mod (p2 / positive)
            :quant-of (n / nucleus
                  :ARG1-of (s6 / stain-01
                        :purpose (e / enzyme :name (n4 / name :op1 "Erk")
                              :ARG3-of (p3 / phosphorylate-01)))))
      :ARG1-of (a / actual-02)
      :location (s / skin
            :ARG1-of (t / treat-04
                  :ARG2 (s2 / small-molecule :name (n2 / name :op1 "TPA"))))
      :time (p4 / point
            :mod (t2 / time)
            :mod (a3 / all)
            :ARG2-of (e2 / except-01
                  :ARG1 (t3 / temporal-quantity :quant 30
                        :unit (w / week))))
      :ARG1-of (d2 / describe-01
            :ARG0 (d3 / data
                  :ARG1-of (s7 / show-01 :polarity -)))
      :compared-to (a2 / and
            :op1 (s3 / skin
                  :mod (c / control))
            :op2 (s4 / skin
                  :mod (s5 / small-molecule :name (n3 / name :op1 "ATRA"))
                  :mod s2)))

# ::id pmid_1943_2991.91 ::date 2015-08-17T11:24:48 ::annotator SDL-AMR-09 ::preferred
# ::snt This was due to the far greater number of total cells in the hyperplastic TPA treated skin.
# ::save-date Mon Aug 24, 2015 ::file pmid_1943_2991_91.txt
(c / cause-01
      :ARG0 (n / number
            :quant-of (c2 / cell
                  :mod (t / total)
                  :location (s / skin
                        :mod (h / hyperplasia)
                        :ARG1-of (t2 / treat-04
                              :ARG2 (s2 / small-molecule :name (n2 / name :op1 "TPA")))))
            :mod (g / great
                  :degree (m / more
                        :degree (f / far))))
      :ARG1 (t3 / this))

# ::id pmid_1943_2991.92 ::date 2015-08-17T12:14:24 ::annotator SDL-AMR-09 ::preferred
# ::snt To more precisely measure the levels of phosphorylation of the MAP kinase signaling proteins in this model, we performed Western blot analysis on epidermal lysates pooled from 5 mice per treatment group for each time point, from skin adjacent to the tissue that was embedded for sectioning and IHC.
# ::save-date Sun Jan 17, 2016 ::file pmid_1943_2991_92.txt
(p / perform-02
      :ARG0 (w / we)
      :ARG1 (i / immunoblot-01
            :ARG2 (l / lysate
                  :mod (e / epidermis)
                  :ARG1-of (p2 / pool-01
                        :source (m / mouse :quant 5
                              :ARG1-of (r / rate-entity-91
                                    :ARG2 (g / group
                                          :ARG1-of (t2 / treat-04))))
                        :time (p3 / point
                              :mod (t3 / time)
                              :mod (e2 / each)))
                  :source (s / skin
                        :ARG2-of (b / border-01
                              :ARG1 (t4 / tissue
                                    :ARG1-of (e3 / embed-01
                                          :purpose (a2 / and
                                                      :op1 (s2 / section-01)
                                                      :op2 (i2 / immunohistochemistry))))))))
      :purpose (m2 / measure-01
                  :ARG0 w
                  :ARG1 (l2 / level
                        :degree-of (p4 / phosphorylate-01
                              :ARG1 (e4 / enzyme :name (n3 / name :op1 "MAP" :op2 "kinase")
                                    :ARG0-of (s3 / signal-07))))
                  :location (m3 / model
                        :mod (t6 / this))
                  :manner (p6 / precise
                        :degree (m4 / more))))

# ::id pmid_1943_2991.93 ::date 2015-08-17T12:14:51 ::annotator SDL-AMR-09 ::preferred
# ::snt Using 10 weeks as a representative time point, co-administration of ATRA with TPA resulted in a lower level of pB-Raf, pMek1/2 and pErk1/2, than with TPA treatment alone (Fig. <xref ref-type="fig" rid="F4">4B</xref> compare TPA and TPA+ATRA lanes).
# ::save-date Mon Dec 21, 2015 ::file pmid_1943_2991_93.txt
(r / result-01
      :ARG1 (c / coadminister-00
            :ARG1 (a / and
                  :op1 (s / small-molecule :name (n / name :op1 "ATRA"))
                  :op2 (s2 / small-molecule :name (n2 / name :op1 "TPA"))))
      :ARG2 (l / low-04
            :ARG1 (a2 / and
                  :op1 (l2 / level
                        :quant-of (e / enzyme :name (n3 / name :op1 "B-Raf")
                              :ARG3-of (p / phosphorylate-01))
                        :mod (s4 / small-molecule))
                  :op2 (l3 / level
                        :quant-of (e2 / enzyme :name (n4 / name :op1 "Mek1/2")
                              :ARG3-of p))
                  :op3 (l4 / level
                        :quant-of (e3 / enzyme :name (n5 / name :op1 "Erk1/2")
                              :ARG3-of p)))
            :degree (m / more)
            :compared-to (t / treat-04
                  :ARG2 (s3 / small-molecule :name (n6 / name :op1 "TPA")
                        :mod (a3 / alone))))
      :ARG2-of (u / use-01
            :ARG1 (t2 / temporal-quantity :quant 10
                  :unit (w / week)
                  :ARG0-of (r2 / represent-01
                        :ARG1 (p2 / point
                              :mod (t3 / time)))))
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod "4B"
                  :ARG0-of (c2 / compare-01
                        :ARG1 (l5 / lane
                              :mod s2)
                        :ARG2 (l7 / lane
                              :mod s
                              :mod s2)))))

# ::id pmid_1943_2991.94 ::date 2015-08-18T14:02:26 ::annotator SDL-AMR-09 ::preferred
# ::snt At the same time there is an increase in the protein levels of total Erk1/2 with TPA treatment that is suppressed by ATRA.
# ::save-date Mon Aug 24, 2015 ::file pmid_1943_2991_94.txt
(i / increase-01
      :ARG1 (l / level
            :quant-of (e / enzyme :name (n / name :op1 "Erk1/2")
                  :mod (t3 / total)))
      :condition (t / treat-04
            :ARG2 (s / small-molecule :name (n2 / name :op1 "TPA")))
      :time (t2 / time
            :ARG1-of (s4 / same-01))
      :ARG1-of (s2 / suppress-01
            :ARG0 (s3 / small-molecule :name (n3 / name :op1 "ATRA"))))

# ::id pmid_1943_2991.95 ::date 2015-08-18T14:10:30 ::annotator SDL-AMR-09 ::preferred
# ::snt The results from both IHC and Western blot analysis indicate that suppression of pB-Raf, pMek1/2, and pErk1/2 levels by ATRA.
# ::save-date Sun Jan 17, 2016 ::file pmid_1943_2991_95.txt
(i / indicate-01
      :ARG0 (t / thing
            :ARG2-of (r / result-01)
            :source (a / and
                  :op1 (a3 / analyze-01
                        :mod (i3 / immunohistochemistry))
                  :op2 (a2 / analyze-01
                        :manner (i2 / immunoblot-01))))
      :ARG1 (s / suppress-01
            :ARG0 (s2 / small-molecule :name (n3 / name :op1 "ATRA"))
            :ARG1 (a4 / and
                  :op1 (l / level
                        :quant-of (e / enzyme :name (n4 / name :op1 "B-Raf")
                              :ARG3-of (p / phosphorylate-01)))
                  :op2 (l2 / level
                        :quant-of (e2 / enzyme :name (n5 / name :op1 "Mek1/2")
                              :ARG3-of p))
                  :op3 (l3 / level
                        :quant-of (e3 / enzyme :name (n6 / name :op1 "Erk1/2")
                              :ARG3-of p)))))

# ::id pmid_1943_2991.96 ::date 2015-08-18T14:24:40 ::annotator SDL-AMR-09 ::preferred
# ::snt <sec-title level="2">P38 and JNK branches of the MAP Kinase cascade are not suppressed by ATRA treatment</sec-title>
# ::save-date Mon Aug 24, 2015 ::file pmid_1943_2991_96.txt
(s / suppress-01 :polarity -
      :ARG0 (t / treat-04
            :ARG2 (s2 / small-molecule :name (n / name :op1 "ATRA")))
      :ARG1 (a / and
            :op1 (b / branch
                  :mod (e / enzyme :name (n2 / name :op1 "P38")))
            :op2 (b2 / branch-01
                  :mod (e2 / enzyme :name (n3 / name :op1 "JNK")))
            :part-of (p / pathway :name (n4 / name :op1 "MAP" :op2 "Kinase"))))

# ::id pmid_1943_2991.97 ::date 2015-08-18T14:35:45 ::annotator SDL-AMR-09 ::preferred
# ::snt The two other major MAP kinase signaling pathways besides the B-Raf/Mek/Erk pathway are the Jun N-terminal kinase (JNK) and p38 MAP kinase pathways.
# ::save-date Wed Aug 26, 2015 ::file pmid_1943_2991_97.txt
(p3 / pathway :quant 2 :name (n3 / name :op1 "MAP" :op2 "kinase")
      :ARG0-of (s / signal-07)
      :mod (o / other)
      :ARG1-of (m / major-02)
      :ARG2-of (e / except-01
            :ARG1 (p4 / pathway :name (n4 / name :op1 "B-Raf/Mek/Erk")))
      :domain (a / and
            :op1 (p / pathway :name (n / name :op1 "Jun" :op2 "N-terminal" :op3 "kinase"))
            :op2 (p2 / pathway :name (n2 / name :op1 "p38" :op2 "MAP" :op3 "kinase"))))

# ::id pmid_1943_2991.98 ::date 2015-08-18T14:49:15 ::annotator SDL-AMR-09 ::preferred
# ::snt In order to confirm our previous microarray results, which suggested that these pathways were less important in regards to ATRA suppression of TPA induced tumor promotion, we performed IHC on tissue sections taken at the 7 week time point from the same 2-stage skin carcinogenesis experiment as above.
# ::save-date Sun Jan 17, 2016 ::file pmid_1943_2991_98.txt
(p / perform-02
      :ARG0 (w / we)
      :ARG1 (i3 / immunohistochemistry)
      :location (s / section-01
            :ARG1 (t2 / tissue)
            :ARG1-of (t3 / take-01
                  :ARG2 (e / experiment-01
                        :ARG1 (c / carcinogenesis
                              :mod (s2 / skin))
                        :mod (s3 / stage :mod 2)
                        :ARG1-of (r / resemble-01
                              :ARG2 (a / above))
                        :ARG1-of (s8 / same-01))
                  :time (p2 / point
                        :mod (t4 / time)
                        :mod (t5 / temporal-quantity :quant 7
                              :unit (w2 / week)))))
      :purpose (c2 / confirm-01
                  :ARG0 w
                  :ARG1 (t6 / thing
                        :ARG2-of (r2 / result-01)
                        :time (p3 / previous)
                        :mod (m / microarray)
                        :poss w
                        :ARG0-of (s4 / suggest-01
                              :ARG1 (i / important
                                    :degree (l / less)
                                    :domain (p4 / pathway
                                          :mod (t7 / this))
                                    :topic (s5 / suppress-01
                                          :ARG0 (s6 / small-molecule :name (n2 / name :op1 "ATRA"))
                                          :ARG1 (p5 / promote-01
                                                :ARG1 (t8 / tumor
                                                      :ARG2-of (i2 / induce-01
                                                            :ARG0 (s7 / small-molecule :name (n3 / name :op1 "TPA")))))))))))

# ::id pmid_1943_2991.99 ::date 2015-08-18T15:11:55 ::annotator SDL-AMR-09 ::preferred
# ::snt Using antibodies to phosphorylated (activated) p38 (Thr180/Tyr182), and JNK (Thr183/Tyr185) we observed that, unlike the B-Raf, Mek1/2 and Erk1/2 proteins, neither p38 nor JNK were increased in phosphorylation upon TPA treatment (Fig. <xref ref-type="fig" rid="F5">5A</xref>, compare TPA panels to Control).
# ::save-date Thu Jan 14, 2016 ::file pmid_1943_2991_99.txt
(o / observe-01
      :ARG0 (w / we)
      :ARG1 (i / increase-01 :polarity -
            :ARG1 (p / phosphorylate-01
                  :ARG1 (a3 / and
                        :op1 (e / enzyme :name (n / name :op1 "p38"))
                        :op2 (e2 / enzyme :name (n2 / name :op1 "JNK")))
                  :ARG1-of (r / resemble-01 :polarity -
                        :ARG2 (a2 / and
                              :op1 (e5 / enzyme :name (n4 / name :op1 "B-Raf"))
                              :op2 (e6 / enzyme :name (n5 / name :op1 "Mek1/2"))
                              :op3 (e7 / enzyme :name (n6 / name :op1 "Erk1/2")))))
            :condition (t / treat-04
                  :ARG0 a3
                  :ARG2 (s / small-molecule :name (n3 / name :op1 "TPA"))))
      :ARG2-of (u / use-01
            :ARG1 (a / antibody
                  :ARG0-of (c3 / counter-01
                        :ARG1 (a7 / and
                              :op1 (e3 / enzyme :name (n7 / name :op1 "p38")
                                    :ARG3-of (p2 / phosphorylate-01
                                          :ARG1 (s3 / slash
                                                :op1 (a5 / amino-acid :mod 180 :name (n8 / name :op1 "threonine"))
                                                :op2 (a6 / amino-acid :mod 182 :name (n9 / name :op1 "threonine")))
                                          :ARG1-of (m / mean-01
                                                :ARG2 (a11 / activate-01))))
                              :op2 (e4 / enzyme :name (n10 / name :op1 "JNK")
                                    :ARG3-of (p6 / phosphorylate-01
                                          :ARG1 (s2 / slash
                                                :op1 (a9 / amino-acid :mod 183 :name (n11 / name :op1 "threonine"))
                                                :op2 (a10 / amino-acid :mod 185 :name (n12 / name :op1 "threonine")))))))))
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod "5A"
                  :ARG0-of (c / compare-01
                        :ARG1 (p7 / panel
                              :mod s)
                        :ARG2 (c2 / control)))))

# ::id pmid_1943_2991.100 ::date 2015-08-18T15:44:13 ::annotator SDL-AMR-09 ::preferred
# ::snt Importantly, the phosphorylation levels of p38 and JNK were not suppressed by co-administration of ATRA with TPA (Fig. <xref ref-type="fig" rid="F5">5A</xref>, compare TPA and TPA+ATRA panels).
# ::save-date Mon Dec 21, 2015 ::file pmid_1943_2991_100.txt
(s / suppress-01 :polarity -
      :ARG0 (c / coadminister-00
            :ARG1 (a / and
                  :op1 (s2 / small-molecule :name (n / name :op1 "ATRA"))
                  :op2 (s3 / small-molecule :name (n2 / name :op1 "TPA"))))
      :ARG1 (l / level
            :degree-of (p / phosphorylate-01
                  :ARG1 (a2 / and
                        :op1 (e / enzyme :name (n3 / name :op1 "p38"))
                        :op2 (e2 / enzyme :name (n4 / name :op1 "JNK")))))
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod "5A"
                  :ARG0-of (c2 / compare-01
                        :ARG1 (p2 / panel
                              :mod s3)
                        :ARG2 (a3 / and
                              :op1 (p3 / panel
                                    :mod s3)
                              :op2 (p4 / panel
                                    :mod s2)))))
      :mod (i / important))

# ::id pmid_1943_2991.101 ::date 2015-08-18T15:56:01 ::annotator SDL-AMR-09 ::preferred
# ::snt This observation was confirmed by Western blotting using the same phospho-specific antibodies, as well as antibodies to total p38 and total JNK (Fig. <xref ref-type="fig" rid="F5">5B</xref>).
# ::save-date Thu Feb 4, 2016 ::file pmid_1943_2991_101.txt
(c / confirm-01
      :ARG0 (i / immunoblot-01)
      :ARG1 (o / observe-01
            :mod (t / this))
      :ARG2-of (u / use-01
            :ARG1 (a / and
                  :op1 (a2 / antibody
                        :ARG1-of (s / specific-02
                              :ARG2 (p / phosphorylate-01))
                        :ARG1-of (s2 / same-01))
                  :op2 (a3 / antibody
                        :ARG0-of (c2 / counter-01
                              :ARG1 (a4 / and
                                    :op1 (e / enzyme :name (n2 / name :op1 "p38")
                                          :mod (t3 / total))
                                    :op2 (e2 / enzyme :name (n3 / name :op1 "JNK")
                                          :mod t3)))
                        :ARG1-of (d / describe-01
                              :ARG0 (f / figure :mod "5B"))))))

# ::id pmid_1943_2991.102 ::date 2015-08-18T16:08:38 ::annotator SDL-AMR-09 ::preferred
# ::snt Interestingly we observed a modest increase in p38 phosphorylation in the skin treated with ATRA alone, suggesting that the p38 pathway could play a role in mediating retinoid effects in skin.
# ::save-date Mon Jan 4, 2016 ::file pmid_1943_2991_102.txt
(o / observe-01
      :ARG0 (w / we)
      :ARG1 (i / increase-01
            :ARG1 (p / phosphorylate-01
                  :ARG1 p4)
            :ARG2 (m / modest)
            :location (s / skin
                  :ARG1-of (t / treat-04
                        :ARG2 (s2 / small-molecule :name (n2 / name :op1 "ATRA")
                              :mod (a2 / alone))))
            :ARG0-of (s3 / suggest-01
                  :ARG1 (p2 / possible-01
                        :ARG1 (p3 / play-02
                              :ARG0 (p4 / pathway :name (n3 / name :op1 "p38"))
                              :ARG1 (m2 / mediate-01
                                    :ARG1 (a / affect-01
                                          :ARG0 (s4 / small-molecule :name (n4 / name :op1 "retinoid"))
                                          :ARG1 (s5 / skin)))))))
      :ARG2-of (i2 / interest-01))

# ::id pmid_1943_2991.103 ::date 2015-08-18T16:21:45 ::annotator SDL-AMR-09 ::preferred
# ::snt <sec-title level="2">Sorafenib suppresses cell growth in TPA-induced tumors</sec-title>
# ::save-date Wed Aug 19, 2015 ::file pmid_1943_2991_103.txt
(s / suppress-01
      :ARG0 (s2 / small-molecule :name (n / name :op1 "Sorafenib"))
      :ARG1 (g / grow-01
            :ARG1 (c / cell))
      :location (t / tumor
            :ARG2-of (i / induce-01
                  :ARG0 (s3 / small-molecule :name (n2 / name :op1 "TPA")))))

# ::id pmid_1943_2991.104 ::date 2015-08-18T16:24:08 ::annotator SDL-AMR-09 ::preferred
# ::snt We hypothesize that ATRA exerts its tumor suppressive effect by blocking B-Raf/Mek/Erk signaling.
# ::save-date Mon Aug 24, 2015 ::file pmid_1943_2991_104.txt
(h / hypothesize-01
      :ARG0 (w / we)
      :ARG1 (e / exert-01
            :ARG0 (s / small-molecule :name (n / name :op1 "ATRA"))
            :ARG1 (a / affect-01
                  :ARG0 s
                  :ARG2 (s2 / suppress-01
                        :ARG0 s
                        :ARG1 (t / tumor)))
            :instrument (b / block-01
                  :ARG1 (s3 / signal-07
                        :ARG0 (p / pathway :name (n2 / name :op1 "B-Raf/Mek/Erk")))
                  :ARG3 s)))

# ::id pmid_1943_2991.105 ::date 2015-08-18T16:35:19 ::annotator SDL-AMR-09 ::preferred
# ::snt This predicts that blocking this pathway through another means should also suppress tumorigenesis and/or the growth of tumors.
# ::save-date Thu Feb 4, 2016 ::file pmid_1943_2991_105.txt
(p / predict-01
      :ARG0 (t / this)
      :ARG1 (r / recommend-01
            :ARG1 (s / suppress-01
                  :ARG0 (b / block-01
                        :ARG1 (p2 / pathway
                              :mod t)
                        :manner (m / mean
                              :mod (a2 / another)))
                  :ARG1 (a / and-or
                        :op1 (c / create-01
                              :ARG1 (t2 / tumor))
                        :op2 (g / grow-01
                              :ARG1 (t3 / tumor)))
                  :mod (a3 / also))))

# ::id pmid_1943_2991.106 ::date 2015-08-18T16:43:33 ::annotator SDL-AMR-09 ::preferred
# ::snt To test this prediction we have used a novel Raf inhibiting bi-aryl urea compound from Bayer Pharmaceuticals called BAY 43-9006, or Sorafenib [<xref ref-type="bibr" rid="B24">24</xref>].
# ::save-date Tue Jan 12, 2016 ::file pmid_1943_2991_106.txt
(u / use-01
      :ARG0 (w / we)
      :ARG1 (c / compound
            :mod (u2 / urea)
            :source (c2 / company :wiki "Bayer"
                  :name (n2 / name :op1 "Bayer" :op2 "Pharmaceuticals"))
            :ARG0-of (i / inhibit-01
                  :ARG1 (e / enzyme :wiki "RAF_kinase"
                        :name (n5 / name :op1 "Raf")))
            :mod (b / biaryl)
            :ARG1-of (c3 / call-01
                  :ARG2 (o / or
                        :op1 (s / small-molecule :wiki -
                              :name (n / name :op1 "BAY" :op2 "43-9006"))
                        :op2 (s2 / small-molecule :wiki "Sorafenib"
                              :name (n3 / name :op1 "Sorafenib")))))
      :ARG2 (t / test-01
            :ARG0 w
            :ARG1 (p / predict-01
                  :mod (t2 / this)))
      :ARG1-of (d / describe-01
            :ARG0 (p2 / publication
                  :ARG0-of (c4 / cite-01 :ARG2 24))))

# ::id pmid_1943_2991.107 ::date 2015-08-22T11:59:06 ::annotator SDL-AMR-09 ::preferred
# ::snt This compound has been shown to inhibit MAP kinase signaling in colon, pancreatic and breast cancer cell lines, as well as inhibit tumor growth in colon, breast and non-small-cell lung cancer mouse xenograft models.
# ::save-date Wed Dec 9, 2015 ::file pmid_1943_2991_107.txt
(s / show-01
      :ARG1 (a / and
            :op1 (i / inhibit-01
                  :ARG0 (c / compound
                        :mod (t / this))
                  :ARG1 (s2 / signal-07
                        :ARG0 (k / kinase :name (n / name :op1 "MAP")))
                  :location (a2 / and
                        :op1 (c2 / cell-line
                              :mod (d / disease :wiki "Pancreatic_cancer" :name (n2 / name :op1 "pancreatic" :op2 "cancer")))
                        :op2 (c4 / cell-line
                              :mod (d2 / disease :wiki "Colorectal_cancer" :name (n3 / name :op1 "colon" :op2 "cancer")))
                        :op3 (c7 / cell-line
                              :mod (d3 / disease :wiki "Breast_cancer" :name (n4 / name :op1 "breast" :op2 "cancer")))))
            :op2 (i2 / inhibit-01
                  :ARG0 c
                  :ARG1 (g / grow-01
                        :ARG1 (t2 / tumor))
                  :location (a3 / and
                        :op1 (m / model
                              :mod (m2 / mouse)
                              :mod (x / xenograft)
                              :mod d2)
                        :op2 (m3 / model
                              :mod m2
                              :mod x
                              :mod d3)
                        :op3 (m4 / model
                              :mod m2
                              :mod x
                              :mod (d4 / disease :wiki "Lung_cancer" :name (n5 / name :op1 "lung" :op2 "cancer")
                                    :mod (c10 / cell
                                          :mod (s3 / small :polarity -))))))))

# ::id pmid_1943_2991.108 ::date 2015-08-18T23:04:15 ::annotator SDL-AMR-09 ::preferred
# ::snt Tumor-bearing SENCAR mice that had been treated topically with TPA, twice weekly for 27 weeks, were treated with Sorafenib either topically or by gavage, as described in the Materials and Methods.
# ::save-date Thu Nov 19, 2015 ::file pmid_1943_2991_108.txt
(t / treat-04
      :ARG1 (m / mouse
            :ARG0-of (b / bear-01
                  :ARG1 (t3 / tumor))
            :ARG1-of (t4 / treat-04
                  :ARG2 (s / small-molecule :name (n2 / name :op1 "TPA"))
                  :duration (t5 / temporal-quantity :quant 27
                        :unit (w / week))
                  :frequency (r / rate-entity-91
                        :ARG1 2
                        :ARG2 (t6 / temporal-quantity :quant 1
                              :unit w))
                  :manner (t7 / topic))
            :ARG0-of (s3 / sensitive-03
                  :ARG1 (c / carcinogen)))
      :ARG2 (s2 / small-molecule :name (n3 / name :op1 "Sorafenib"))
      :manner (o / or
            :op1 t7
            :op2 (g / gavage))
      :ARG1-of (d / describe-01
            :ARG0 (t9 / title-01
                  :ARG1 (a / and
                        :op1 (m2 / material)
                        :op2 (m3 / method)))))

# ::id pmid_1943_2991.109 ::date 2015-08-18T23:41:30 ::annotator SDL-AMR-09 ::preferred
# ::snt Mice were photographed twice weekly to monitor tumor morphology and size.
# ::save-date Mon Aug 24, 2015 ::file pmid_1943_2991_109.txt
(p / photograph-01
      :ARG1 (m / mouse)
      :frequency (r / rate-entity-91
            :ARG1 2
            :ARG2 (t / temporal-quantity :quant 1
                  :unit (w / week)))
      :purpose (m2 / monitor-01
                  :ARG1 (a / and
                        :op1 (m3 / morphology
                              :mod (t2 / tumor))
                        :op2 (s / size
                              :mod t2))))

# ::id pmid_1943_2991.110 ::date 2015-08-18T23:45:29 ::annotator SDL-AMR-09 ::preferred
# ::snt Tumors that received only topical acetone solvent, along with the TPA treatment, displayed the exophytic papilloma morphology normally observed in TPA-treated mice in this model (Fig. <xref ref-type="fig" rid="F6">6A</xref>).
# ::save-date Thu Nov 19, 2015 ::file pmid_1943_2991_110.txt
(d / display-01
      :ARG0 (t / tumor
            :ARG0-of (r / receive-01
                  :ARG1 (a / and
                        :op1 (s / solvent
                              :mod (t2 / topic)
                              :mod (s3 / solvent))
                        :op2 (t3 / treat-04
                              :ARG1 t
                              :ARG2 (s2 / small-molecule :name (n2 / name :op1 "TPA"))))
                  :mod (o / only)))
      :ARG1 (m / morphology
            :mod (p / papilloma)
            :mod (e / exophytic)
            :ARG1-of (o2 / observe-01
                  :location (m2 / mouse
                        :ARG1-of (t4 / treat-04
                              :ARG2 s2))
                  :ARG1-of (n3 / normal-02)
                  :location (m3 / model
                        :mod (t5 / this))))
      :ARG1-of (d2 / describe-01
            :ARG0 (f / figure :mod "6A")))

# ::id pmid_1943_2991.111 ::date 2015-08-19T00:00:36 ::annotator SDL-AMR-09 ::preferred
# ::snt The histological appearance of these tumors was also typical of TPA-induced papillomas (Fig. <xref ref-type="fig" rid="F6">6E</xref>).
# ::save-date Mon Aug 24, 2015 ::file pmid_1943_2991_111.txt
(t / typical-02
      :ARG1 (a / appear-01
            :ARG1 (t2 / tumor
                  :mod (t3 / this))
            :mod (h / histology))
      :ARG2 (p / papilloma
            :ARG2-of (i / induce-01
                  :ARG0 (s / small-molecule :name (n / name :op1 "TPA"))))
      :mod (a2 / also)
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod "6E")))

# ::id pmid_1943_2991.112 ::date 2015-08-19T00:05:57 ::annotator SDL-AMR-09 ::preferred
# ::snt Tumors receiving topical Sorafenib at either concentration displayed a dried and darkened appearance that was reminiscent of human keratoacanthoma (Fig. <xref ref-type="fig" rid="F6">6</xref>, compare A to B and data not shown).
# ::save-date Wed Dec 30, 2015 ::file pmid_1943_2991_112.txt
(d / display-01
      :ARG0 (t / tumor
            :ARG0-of (r / receive-01
                  :ARG1 (s / small-molecule :name (n / name :op1 "Sorafenib")
                        :ARG1-of (c / concentrate-02
                              :mod (e / either)))))
      :ARG1 (a2 / appear-01
            :ARG1 t
            :ARG1-of (d2 / dry-08)
            :ARG1-of (d3 / dark-02)
            :ARG0-of (r2 / reminisce-01
                  :ARG1 (k / keratoacanthoma
                        :mod (h / human))))
      :ARG1-of (d4 / describe-01
            :ARG0 (a4 / and
                  :op1 (f / figure :mod 6
                        :ARG0-of (c2 / compare-01
                              :ARG1 (f2 / figure :mod "6A")
                              :ARG2 (f3 / figure :mod "6B")))
                  :op2 (d5 / data
                        :ARG1-of (s2 / show-01 :polarity -)))))

# ::id pmid_1943_2991.113 ::date 2015-08-19T00:29:18 ::annotator SDL-AMR-09 ::preferred
# ::snt Histological analysis of these tumors revealed that the bulk of the tumor mass was non-cellular keratin, indicating a greatly enhanced level of squamous differentiation compared to the control TPA-induced tumors (Fig. <xref ref-type="fig" rid="F6">6</xref>, compare E to F).
# ::save-date Thu Nov 19, 2015 ::file pmid_1943_2991_113.txt
(r / reveal-01
      :ARG0 (a / analyze-01
            :ARG1 (t / tumor
                  :mod (t2 / this))
            :mod (h / histology))
      :ARG1 (p / protein :name (n / name :op1 "keratin")
            :mod (c / cell :polarity -)
            :domain (m / mass
                  :mod (t3 / tumor)
                  :quant (b / bulk))
            :ARG0-of (i / indicate-01
                  :ARG1 (l / level
                        :degree-of (d / differentiate-101
                              :mod (s / squamous))
                        :ARG1-of (e / enhance-01
                              :compared-to (t4 / tumor
                                    :mod (c2 / control)
                                    :ARG2-of (i2 / induce-01
                                          :ARG0 (s2 / small-molecule :name (n2 / name :op1 "TPA"))))
                              :degree (g / great)))))
      :ARG1-of (d2 / describe-01
            :ARG0 (f / figure :mod 6
                  :ARG0-of (c3 / compare-01
                        :ARG1 (f2 / figure :mod "6E")
                        :ARG2 (f3 / figure :mod "6F")))))

# ::id pmid_1943_2991.114 ::date 2015-08-19T00:46:34 ::annotator SDL-AMR-09 ::preferred
# ::snt Interestingly, the tumors of mice treated with Sorafenib by oral gavage did not differ drastically in outward appearance from the control TPA-induced tumors.
# ::save-date Wed Aug 19, 2015 ::file pmid_1943_2991_114.txt
(d / differ-02 :polarity -
      :ARG1 (t / tumor
            :poss (m / mouse
                  :ARG1-of (t2 / treat-04
                        :ARG2 (s / small-molecule :name (n / name :op1 "Sorafenib"))
                        :manner (g / gavage
                              :mod (o / oral)))))
      :ARG2 (t3 / tumor
            :mod (c / control)
            :ARG2-of (i / induce-01
                  :ARG0 (s2 / small-molecule :name (n2 / name :op1 "TPA"))))
      :ARG3 (a / appear-01
            :mod (o2 / outward))
      :mod (d2 / drastic)
      :ARG2-of (i2 / interest-01))

# ::id pmid_1943_2991.115 ::date 2015-08-19T00:56:13 ::annotator SDL-AMR-09 ::preferred
# ::snt However upon histological examination these tumors appear very similar to the tumors that received topical Sorafenib (Fig. <xref ref-type="fig" rid="F6">6C</xref> and <xref ref-type="fig" rid="F6">6G</xref>).
# ::save-date Mon Aug 24, 2015 ::file pmid_1943_2991_115.txt
(h2 / have-concession-91
      :ARG2 (a / appear-02
            :ARG1 (r / resemble-01
                  :ARG1 (t / tumor
                        :mod (t2 / this))
                  :ARG2 (t3 / tumor
                        :ARG0-of (r2 / receive-01
                              :ARG1 (s / small-molecule :name (n / name :op1 "Sorafenib")
                                    :mod (t4 / topic))))
                  :degree (v / very))
            :condition (e / examine-01
                  :mod (h / histology)))
      :ARG1-of (d / describe-01
            :ARG0 (a2 / and
                  :op1 (f / figure :mod "6C")
                  :op2 (f2 / figure :mod "6G"))))

# ::id pmid_1943_2991.116 ::date 2015-08-19T01:23:57 ::annotator SDL-AMR-09 ::preferred
# ::snt It was previously shown in the breast and colon tumor xenograft models that inhibition of tumor growth was closely associated with suppression of Erk1/2 phosphorylation [<xref ref-type="bibr" rid="B24">24</xref>].
# ::save-date Thu Feb 4, 2016 ::file pmid_1943_2991_116.txt
(s / show-01
      :ARG0 (a / and
            :op1 (m / model
                  :mod (x / xenograft)
                  :mod (b / breast))
            :op2 (m2 / model
                  :mod x
                  :mod (c / colon)))
      :ARG1 (a2 / associate-01
            :ARG1 (i / inhibit-01
                  :ARG1 (g / grow-01
                        :ARG1 (t / tumor)))
            :ARG2 (s2 / suppress-01
                  :ARG1 (p2 / phosphorylate-01
                        :ARG1 (e / enzyme :name (n / name :op1 "Erk1/2"))))
            :ARG1-of (c2 / close-10))
      :time (p / previous)
      :ARG1-of (d / describe-01
            :ARG0 (p3 / publication
                  :ARG1-of (c3 / cite-01
                        :ARG2 24))))

# ::id pmid_1943_2991.117 ::date 2015-08-19T01:32:42 ::annotator SDL-AMR-09 ::preferred
# ::snt We therefore stained paraffin-embedded sections of the TPA-induced tumors, with and without Sorafenib treatment, with the pErk1/2 antibody.
# ::save-date Mon Aug 24, 2015 ::file pmid_1943_2991_117.txt
(c / cause-01
      :ARG1 (s / stain-01
            :ARG0 (w / we)
            :ARG1 (s2 / section-01
                  :ARG1 (a2 / and
                        :op1 (t / tumor
                              :ARG2-of (i / induce-01
                                    :ARG0 (s3 / small-molecule :name (n / name :op1 "TPA")))
                              :ARG1-of (t2 / treat-04
                                    :ARG2 (s4 / small-molecule :name (n3 / name :op1 "Sorafenib"))))
                        :op2 (t3 / tumor
                              :ARG1-of (t4 / treat-04 :polarity -
                                    :ARG2 s4)
                              :ARG2-of i))
                  :ARG1-of (e / embed-01
                        :ARG2 (p / paraffin)))
            :ARG2 (a / antibody
                  :ARG0-of (c2 / counter-01
                        :ARG1 (e2 / enzyme :name (n2 / name :op1 "Erk1/2")
                              :ARG3-of (p2 / phosphorylate-01))))))

# ::id pmid_1943_2991.118 ::date 2015-08-19T01:55:23 ::annotator SDL-AMR-09 ::preferred
# ::snt The number of nuclei and intensity of staining was reduced for Sorafenib treated tumors compared to the TPA only-treated tumors (Fig. <xref ref-type="fig" rid="F6">6H</xref>).
# ::save-date Mon Aug 24, 2015 ::file pmid_1943_2991_118.txt
(r / reduce-01
      :ARG1 (a / and
            :op1 (n / number
                  :quant-of (n2 / nucleus))
            :op2 (i / intensity
                  :degree-of (s / stain-01)))
      :location (t / tumor
            :ARG1-of (t2 / treat-04
                  :ARG2 (s2 / small-molecule :name (n3 / name :op1 "Sorafenib"))))
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod "6H"))
      :compared-to (t3 / tumor
            :ARG1-of (t4 / treat-04
                  :ARG2 (s3 / small-molecule :name (n4 / name :op1 "TPA"))
                  :mod (o / only))))

# ::id pmid_1965_4571.1 ::date 2015-08-05T04:57:06 ::annotator SDL-AMR-09 ::preferred
# ::snt Combination of cetuximab with chemoradiation, trastuzumab or MAPK inhibitors: mechanisms of sensitisation of cervical cancer cells (PMID:19654571)
# ::save-date Mon Jan 4, 2016 ::file pmid_1965_4571_1.txt
(c / combine-01
      :ARG1 (s2 / small-molecule :name (n3 / name :op1 "cetuximab"))
      :ARG2 (o / or
            :op1 (c4 / chemoradiate-00)
            :op2 (s3 / small-molecule :name (n5 / name :op1 "trastuzumab"))
            :op3 (m / molecular-physical-entity
                  :ARG0-of (i2 / inhibit-01
                        :ARG1 (p2 / protein-family :name (n6 / name :op1 "MAPK")))))
      :ARG1-of (m2 / mean-01
            :ARG2 (m3 / mechanism
                  :instrument-of (s / sensitize-01
                        :ARG1 (c2 / cell
                              :mod (d2 / disease :wiki "Cervical_cancer" :name (n / name :op1 "cervical" :op2 "cancer"))))))
      :ARG1-of (d / describe-01
            :ARG0 (p / publication-91
                  :ARG8 "PMID19654571")))

# ::id pmid_1965_4571.9 ::date 2015-08-05T05:30:11 ::annotator SDL-AMR-09 ::preferred
# ::snt <sec-title level="1" sec-area="abstract">Results:</sec-title>
# ::save-date Wed Aug 5, 2015 ::file pmid_1965_4571_9.txt
(t / thing
      :ARG2-of (r / result-01))

# ::id pmid_1965_4571.10 ::date 2015-08-05T05:31:02 ::annotator SDL-AMR-09 ::preferred
# ::snt Cetuximab with cisplatin and radiation achieved maximum cytotoxic effects for A431, Caski and C33A cells (high, intermediate and low EGFR expression, respectively) in CA.
# ::save-date Sun Jan 17, 2016 ::file pmid_1965_4571_10.txt
(a / achieve-01
      :ARG0 (a6 / and
            :op1 (s / small-molecule :name (n3 / name :op1 "cetuximab"))
            :op2 (s2 / small-molecule :name (n4 / name :op1 "cisplatin"))
            :op3 (r2 / radiate-01))
      :ARG1 (a3 / affect-01
            :ARG1 (a4 / and
                  :op1 (c2 / cell-line :name (n5 / name :op1 "A431"))
                  :op2 (c3 / cell-line :name (n6 / name :op1 "Caski"))
                  :op3 (c4 / cell-line :name (n7 / name :op1 "C33A")))
            :mod (c / cytotoxic)
            :ARG1-of (m2 / mean-01
                  :ARG2 (a5 / and
                        :op1 (e2 / express-03
                              :ARG2 (e / enzyme :name (n / name :op1 "EGFR"))
                              :ARG1-of (h2 / high-02))
                        :op2 (e3 / express-03
                              :ARG2 e
                              :degree (i / intermediate))
                        :op3 (e4 / express-03
                              :ARG2 e
                              :ARG1-of (l2 / low-04))
                        :mod (r3 / respective)))
            :degree (m / maximum)
            :time (a2 / assay-01
                  :mod (c5 / clonogenic))))

# ::id pmid_1965_4571.11 ::date 2015-08-06T00:09:49 ::annotator SDL-AMR-09 ::preferred
# ::snt Cetuximab efficiently decreased MAPK and AKT phosphorylation in A431 cells but slightly less in Caski and C33A cells.
# ::save-date Sun Jan 17, 2016 ::file pmid_1965_4571_11.txt
(c2 / contrast-01
      :ARG1 (d / decrease-01
            :ARG0 (s2 / small-molecule :name (n2 / name :op1 "cetuximab"))
            :ARG1 (p2 / phosphorylate-01
                  :ARG1 (a3 / and
                        :op1 (e3 / enzyme :name (n / name :op1 "MAPK"))
                        :op2 (e2 / enzyme :name (n3 / name :op1 "AKT"))))
            :manner (e / efficient-01)
            :location (c / cell-line :name (n4 / name :op1 "A431")))
      :ARG2 (d2 / decrease-01
            :ARG0 s2
            :ARG1 a3
            :ARG2 (l / less
                  :mod (s / slight))
            :location (a2 / and
                  :op1 (c3 / cell-line :name (n5 / name :op1 "Caski"))
                  :op2 (c4 / cell-line :name (n6 / name :op1 "C33A")))
            :compared-to d))

# ::id pmid_1965_4571.12 ::date 2015-08-06T01:01:31 ::annotator SDL-AMR-09 ::preferred
# ::snt To check whether further EGFR, HER2 or MAPK inhibition would improve cetuximab's cytotoxicity, we combined it with an EGFR tyrosine kinase inhibitor (TKI), trastuzumab or a MEK1/2 inhibitor (PD98059).
# ::save-date Sun Jan 17, 2016 ::file pmid_1965_4571_12.txt
(c / combine-01
      :ARG0 (w / we)
      :ARG1 (i / inhibit-01
            :ARG1 (o / or
                  :op1 (e3 / enzyme :name (n4 / name :op1 "EGFR"))
                  :op2 (e4 / enzyme :name (n5 / name :op1 "HER2"))
                  :op3 (e / enzyme :name (n6 / name :op1 "MAPK")))
            :degree (f / further))
      :ARG2 (o2 / or
            :op1 (m / molecular-physical-entity
                  :ARG0-of (i2 / inhibit-01
                        :ARG1 e3))
            :op2 (s / small-molecule :name (n8 / name :op1 "trastuzumab"))
            :op3 (m2 / molecular-physical-entity
                  :ARG0-of (i3 / inhibit-01
                        :ARG1 (e2 / enzyme :name (n9 / name :op1 "MEK1/2")))
                  :ARG1-of (m3 / mean-01
                        :ARG2 (s3 / small-molecule :name (n / name :op1 "PD98059")))))
      :purpose (c2 / check-01
            :ARG0 w
            :ARG1 (i4 / improve-01 :mode interrogative
                  :ARG0 i
                  :ARG1 (c3 / cytotoxic
                        :domain (s2 / small-molecule :name (n10 / name :op1 "cetuximab"))))))

# ::id pmid_1965_4571.13 ::date 2015-08-06T01:20:05 ::annotator SDL-AMR-09 ::preferred
# ::snt In Caski, but not in C33A cells, cetuximab cooperated with the TKI, reducing cell survival and AKT and MAPK phosphorylation.
# ::save-date Sun Jan 17, 2016 ::file pmid_1965_4571_13.txt
(c3 / contrast-01
      :ARG1 (c / cooperate-01
            :ARG0 (s2 / small-molecule :name (n2 / name :op1 "cetuximab"))
            :ARG1 (m / molecular-physical-entity
                  :ARG0-of (i / inhibit-01
                        :ARG1 (k / kinase
                              :mod (t / tyrosine))))
            :ARG2 (r2 / reduce-01
                  :ARG0 s2
                  :ARG1 (a / and
                        :op1 (s / survive-01
                              :ARG0 (c6 / cell))
                        :op2 (p2 / phosphorylate-01
                              :ARG1 (a2 / and
                                    :op1 (e / enzyme :name (n6 / name :op1 "AKT"))
                                    :op2 (e2 / enzyme :name (n / name :op1 "MAPK"))))))
            :location (c2 / cell-line :name (n4 / name :op1 "Caski")))
      :ARG2 (c4 / cooperate-01 :polarity -
            :ARG0 s2
            :ARG1 m
            :location (c5 / cell-line :name (n5 / name :op1 "C33A"))))

# ::id pmid_1965_4571.14 ::date 2015-08-06T01:30:11 ::annotator SDL-AMR-09 ::preferred
# ::snt However, cetuximab with trastuzumab or PD98059 reduced survival and MAPK phosphorylation of both cell lines.
# ::save-date Sun Jan 17, 2016 ::file pmid_1965_4571_14.txt
(h / have-concession-91
      :ARG2 (r / reduce-01
            :ARG0 (a2 / and
                  :op1 (s3 / small-molecule :name (n2 / name :op1 "cetuximab"))
                  :op2 (o / or
                        :op1 (s4 / small-molecule :name (n3 / name :op1 "trastuzumab"))
                        :op2 (s / small-molecule :name (n4 / name :op1 "PD98059"))))
            :ARG1 (a / and
                  :op1 (s2 / survive-01
                        :ARG0 (c / cell-line
                              :mod (b / both)))
                  :op2 (p2 / phosphorylate-01
                        :ARG1 (e / enzyme :name (n / name :op1 "MAPK"))
                        :location c))))

# ::id pmid_1965_4571.85 ::date 2015-08-06T01:41:19 ::annotator SDL-AMR-09 ::preferred
# ::snt <sec-title level="1">Results</sec-title>
# ::save-date Thu Aug 6, 2015 ::file pmid_1965_4571_85.txt
(t / thing
      :ARG2-of (r / result-01))

# ::id pmid_1965_4571.86 ::date 2015-08-06T01:41:54 ::annotator SDL-AMR-09 ::preferred
# ::snt <sec-title level="2">Differential effects of RxT, cisplatin and cetuximab on cell proliferation and cell-cycle kinetics</sec-title>
# ::save-date Thu Aug 13, 2015 ::file pmid_1965_4571_86.txt
(a / affect-01
      :ARG0 (a2 / and
            :op1 (r2 / radiotherapy)
            :op2 (s / small-molecule :name (n2 / name :op1 "cisplatin"))
            :op3 (s2 / small-molecule :name (n3 / name :op1 "cetuximab")))
      :ARG1 (a3 / and
            :op1 (p2 / proliferate-01
                  :ARG0 (c / cell))
            :op2 (k / kinetics
                  :mod (c2 / cycle-02
                        :ARG1 (c3 / cell))))
      :mod (d / differential))

# ::id pmid_1965_4571.87 ::date 2015-08-06T03:28:54 ::annotator SDL-AMR-09 ::preferred
# ::snt We examined the antiproliferative effects of isolated RxT, cisplatin and cetuximab treatments on A431, Caski and C33A cells (<xref ref-type="fig" rid="fig1">Figures 1A–F</xref>), which express high to low EGFR levels, respectively (see Figures 3A and 5A).
# ::save-date Sun Jan 17, 2016 ::file pmid_1965_4571_87.txt
(e2 / examine-01
      :ARG0 (w / we)
      :ARG1 (a / affect-01
            :ARG0 (a2 / and
                  :op1 (r3 / radiotherapy
                        :ARG1-of (i / isolate-01))
                  :op2 (t3 / treat-04
                        :ARG2 (s2 / small-molecule :name (n3 / name :op1 "cisplatin")))
                  :op3 (t2 / treat-04
                        :ARG2 (s3 / small-molecule :name (n4 / name :op1 "cetuximab"))))
            :ARG1 (a3 / and
                  :op1 (c / cell-line :name (n5 / name :op1 "A431"))
                  :op2 (c2 / cell-line :name (n6 / name :op1 "Caski"))
                  :op3 (c3 / cell-line :name (n7 / name :op1 "C33A"))
                  :ARG3-of (e3 / express-03
                        :ARG2 (v2 / value-interval
                              :op1 (l / level
                                    :quant-of (e / enzyme :name (n / name :op1 "EGFR"))
                                    :ARG1-of (h / high-02))
                              :op2 (l2 / level
                                    :quant-of e
                                    :ARG1-of (l3 / low-04)))
                        :mod (r2 / respective)
                        :ARG1-of (d2 / describe-01
                              :ARG0 (a4 / and
                                    :op1 (f3 / figure :mod "3A")
                                    :op2 (f4 / figure :mod "5A")
                                    :ARG1-of (s / see-01
                                          :ARG0 (y / you))))))
            :ARG0-of (o / oppose-01
                  :ARG1 (p / proliferate-01)))
      :ARG1-of (d / describe-01
            :ARG0 (v / value-interval
                  :op1 (f / figure :mod "1A")
                  :op2 (f2 / figure :mod "1F"))))

# ::id pmid_1965_4571.88 ::date 2015-08-06T03:47:03 ::annotator SDL-AMR-09 ::preferred
# ::snt A431 growth is impaired by EGFR inhibitors (<xref ref-type="other" rid="bib9">Janmaat <i>et al</i>, 2003</xref>), so we used this cell line for comparison with the CC cell lines.
# ::save-date Thu Dec 10, 2015 ::file pmid_1965_4571_88.txt
(i2 / impair-01
      :ARG0 (m / molecular-physical-entity
            :ARG0-of (i3 / inhibit-01
                  :ARG1 (e2 / enzyme :name (n2 / name :op1 "EGFR"))))
      :ARG1 (g / grow-01
            :ARG1 (c / cell-line :name (n3 / name :op1 "A431")))
      :ARG1-of (d2 / describe-01
            :ARG0 (p / publication-91
                  :ARG0 (a / and
                        :op1 (p2 / person :name (n4 / name :op1 "Janmaat"))
                        :op2 (p3 / person
                              :mod (o / other)))
                  :time (d / date-entity :year 2003)))
      :ARG0-of (c2 / cause-01
            :ARG1 (u / use-01
                  :ARG0 (w / we)
                  :ARG1 c
                  :ARG2 (c4 / compare-01
                        :ARG1 c
                        :ARG2 (c5 / cell-line
                              :mod (d3 / disease :wiki "Cervical_cancer" :name (n / name :op1 "cervical" :op2 "cancer")))))))

# ::id pmid_1965_4571.89 ::date 2015-08-06T04:21:11 ::annotator SDL-AMR-09 ::preferred
# ::snt A431 and Caski cells showed similar resistance to RxT and low cisplatin concentrations (IC<sub>30</sub>) in CA and MTT assays (<xref ref-type="fig" rid="fig1">Figures 1A and B</xref>), but Caski cells showed increased resistance at higher cisplatin concentrations (IC<sub>50</sub> and IC<sub>80</sub>; <xref ref-type="fig" rid="fig1">Figure 1B</xref>).
# ::save-date Sat Feb 13, 2016 ::file pmid_1965_4571_89.txt
(c4 / contrast-01
      :ARG1 (s2 / show-01
            :ARG0 (a / and
                  :op1 (c / cell-line :name (n2 / name :op1 "A431"))
                  :op2 (c2 / cell-line :name (n3 / name :op1 "Caski")))
            :ARG1 (a2 / and
                  :op1 (r2 / resist-01
                        :ARG0 a
                        :ARG1 (r / radiotherapy)
                        :ARG1-of (r3 / resemble-01))
                  :op2 (h2 / have-percentage-maximal-inhibitory-concentration-01
                        :ARG1 (s / small-molecule :name (n5 / name :op1 "cisplatin"))
                        :ARG2 30
                        :ARG1-of (l / low-04)
                        :time (a3 / and
                              :op1 (a4 / assay-01
                                    :mod (c5 / clonogenic))
                              :op2 (a5 / assay-01
                                    :instrument (s4 / small-molecule :name (n / name :op1 "MTT"))))
                        :ARG1-of (m4 / mean-01
                              :ARG2 (c7 / concentrate-02
                                    :mod (i2 / inhibit-01
                                          :degree (p / percentage-entity :value 30))))))
            :ARG1-of (d / describe-01
                  :ARG0 (a6 / and
                        :op1 (f / figure :mod "1A")
                        :op2 (f2 / figure :mod "1B"))))
      :ARG2 (s3 / show-01
            :ARG0 c2
            :ARG1 (r4 / resist-01
                  :ARG0 c2
                  :ARG1-of (i / increase-01))
            :condition (c6 / concentrate-02
                  :ARG1 s
                  :ARG1-of (m / mean-01
                        :ARG2 (a7 / and
                              :op1 (h3 / have-percentage-maximal-inhibitory-concentration-01
                                    :ARG1 s
                                    :ARG2 50)
                              :op2 (h4 / have-percentage-maximal-inhibitory-concentration-01
                                    :ARG1 s
                                    :ARG2 80)))
                  :ARG1-of (h / high-02
                        :degree (m2 / more)))
            :ARG1-of (d2 / describe-01
                  :ARG0 (f3 / figure :mod "1B"))))

# ::id pmid_1965_4571.90 ::date 2015-08-06T04:39:14 ::annotator SDL-AMR-09 ::preferred
# ::snt C33A cells were, in turn, quite sensitive to both treatments (<xref ref-type="fig" rid="fig1">Figures 1A and B</xref>).
# ::save-date Sun Jan 17, 2016 ::file pmid_1965_4571_90.txt
(s / sensitive-03
      :ARG0 (c / cell-line :name (n / name :op1 "C33A"))
      :ARG1 (t / treat-04
            :mod (b / both))
      :degree (q / quite)
      :mod (i / in-turn)
      :ARG1-of (d / describe-01
            :ARG0 (a / and
                  :op1 (f / figure :mod "1A")
                  :op2 (f2 / figure :mod "1B"))))

# ::id pmid_1965_4571.91 ::date 2015-08-06T05:32:04 ::annotator SDL-AMR-09 ::preferred
# ::snt Cetuximab treatment decreased the viability of all cell lines in CA and MTT experiments at all concentrations tested (<xref ref-type="fig" rid="fig1">Figures 1C and D</xref>).
# ::save-date Sat Feb 13, 2016 ::file pmid_1965_4571_91.txt
(d / decrease-01
      :ARG0 (t / treat-04
            :ARG2 (s / small-molecule :name (n2 / name :op1 "cetuximab")))
      :ARG1 (v / viable
            :mod (c / cell-line
                  :mod (a2 / all)
                  :time (e / experiment-01
                        :ARG1 (a3 / and
                              :op1 (a4 / assay-01
                                    :mod (c3 / clonogenic))
                              :op2 (a5 / assay-01
                                    :instrument (s2 / small-molecule :name (n / name :op1 "MTT")))))))
      :condition (c2 / concentrate-02
            :ARG1-of (t2 / test-01)
            :mod (a6 / all))
      :ARG1-of (d2 / describe-01
            :ARG0 (a7 / and
                  :op1 (f / figure :mod "1C")
                  :op2 (f2 / figure :mod "1D"))))

# ::id pmid_1965_4571.92 ::date 2015-08-06T05:40:15 ::annotator SDL-AMR-09 ::preferred
# ::snt These effects were related to an increase of 14.1, 12.6 and 6.5% in cell number at G<sub>0</sub>/G<sub>1</sub> for A431, Caski and C33A cells on cetuximab treatment, respectively (<xref ref-type="fig" rid="fig1">Figure 1E</xref>) and a decrease in the population of cells at S and G<sub>2</sub>/M phases when compared to controls (CT; <xref ref-type="fig" rid="fig1">Figure 1E</xref>).
# ::save-date Sun Jan 17, 2016 ::file pmid_1965_4571_92.txt
(r / relate-01
      :ARG1 (a5 / affect-01
            :mod (t / this))
      :ARG2 (a3 / and
            :op1 (i / increase-01
                  :ARG1 (n / number
                        :quant-of (c2 / cell-line :name (n2 / name :op1 "A431")))
                  :ARG2 (a / and
                        :op1 (p / percentage-entity :value 14.1))
                  :time (s / slash
                        :op1 (e / event :name (n8 / name :op1 "G0"))
                        :op2 (e2 / event :name (n9 / name :op1 "G1")))
                  :condition (t2 / treat-04
                        :ARG2 (s3 / small-molecule :name (n5 / name :op1 "cetuximab"))))
            :op2 (i2 / increase-01
                  :ARG1 (n6 / number
                        :quant-of (c3 / cell-line :name (n3 / name :op1 "Caski")))
                  :ARG2 (p2 / percentage-entity :value 12.6)
                  :time s
                  :condition t2)
            :op3 (i3 / increase-01
                  :ARG1 (n7 / number
                        :quant-of (c4 / cell-line :name (n4 / name :op1 "C33A")))
                  :ARG2 (p3 / percentage-entity :value 6.5)
                  :time s
                  :condition t2)
            :op4 (d2 / decrease-01
                  :ARG1 (p5 / population
                        :mod (c5 / cell))
                  :time (a4 / and
                        :op1 (p7 / phase
                              :mod (s4 / synthesize-01))
                        :op2 (t3 / time
                              :mod (s2 / slash
                                    :op1 (e3 / event :name (n10 / name :op1 "G2" :op2 "phase"))
                                    :op2 (e4 / event :name (n11 / name :op1 "M" :op2 "phase")))))
                  :ARG1-of (d3 / describe-01
                        :ARG0 (f2 / figure :mod "1E"))
                  :condition (c / compare-01
                        :ARG1 (c6 / control))))
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod "1E")))

# ::id pmid_1965_4571.93 ::date 2015-08-07T03:22:02 ::annotator SDL-AMR-09 ::preferred
# ::snt Apoptotic cells are usually found in the sub-G<sub>1</sub> phases and, accordingly, 24-h cetuximab treatment increased this cell population by 4.6, 3.9 and 2.9% in A431, Caski and C33A cells, respectively (<xref ref-type="fig" rid="fig1">Figure 1E</xref>).
# ::save-date Sun Jan 17, 2016 ::file pmid_1965_4571_93.txt
(a2 / and
      :op1 (f / find-01
            :ARG1 (c / cell
                  :mod (a / apoptotic))
            :time (u / usual)
            :location (e / event :name (n / name :op1 "sub-G1" :op2 "phase")))
      :op2 (a5 / and
            :op1 (i / increase-01
                  :ARG0 (t / treat-04
                        :ARG2 (s / small-molecule :name (n2 / name :op1 "cetuximab"))
                        :duration (t2 / temporal-quantity :quant 24
                              :unit (h / hour)))
                  :ARG1 (p2 / population
                        :mod (c3 / cell-line :name (n3 / name :op1 "A431")))
                  :ARG2 (p3 / percentage-entity :value 4.6))
            :op2 (i2 / increase-01
                  :ARG0 t
                  :ARG1 (p6 / population
                        :mod (c4 / cell-line :name (n4 / name :op1 "Caski")))
                  :ARG2 (p4 / percentage-entity :value 3.9))
            :op3 (i3 / increase-01
                  :ARG0 t
                  :ARG1 (p7 / population
                        :mod (c2 / cell-line :name (n5 / name :op1 "C33A")))
                  :ARG2 (p5 / percentage-entity :value 2.9)))
      :ARG1-of (d / describe-01
            :ARG0 (f2 / figure :mod "1E")))

# ::id pmid_1965_4571.94 ::date 2015-08-07T03:29:29 ::annotator SDL-AMR-09 ::preferred
# ::snt Additionally, apoptotic cells were also observed by Hoechst staining in all cell lines after cetuximab treatment (<xref ref-type="fig" rid="fig1">Figure 1F</xref>) and, even in C33A cells, which express low EGFR levels, a reduction of 21% in cell proliferation was obtained, especially at high MAb concentration (100 <i>μ</i>g ml<sup>−1</sup>; <xref ref-type="fig" rid="fig1">Figure 1D</xref>).
# ::save-date Sat Feb 13, 2016 ::file pmid_1965_4571_94.txt
(a6 / and
      :op2 (a7 / and
            :op1 (a / add-01
                  :ARG1 (o / observe-01
                        :ARG1 (c / cell
                              :mod (a2 / apoptotic))
                        :instrument (s / stain-01
                              :ARG2 (p3 / product :name (n5 / name :op1 "Hoechst")))
                        :time (a4 / after
                              :op1 (t / treat-04
                                    :ARG2 (s2 / small-molecule :name (n2 / name :op1 "cetuximab"))))
                        :ARG1-of (d / describe-01
                              :ARG0 (f / figure :mod "1F"))
                        :location (c2 / cell-line
                              :mod (a3 / all))
                        :mod (a8 / also)))
            :op2 (o2 / obtain-01
                  :ARG1 (r2 / reduce-01
                        :ARG1 (p2 / proliferate-01
                              :ARG0 (c4 / cell))
                        :ARG2 (p / percentage-entity :value 21))
                  :location (c3 / cell-line :name (n3 / name :op1 "C33A")
                        :ARG1-of (e2 / express-03
                              :ARG2 (l / level
                                    :quant-of (e / enzyme :name (n / name :op1 "EGFR"))
                                    :ARG1-of (l3 / low-04)))
                        :mod (e5 / even))
                  :condition (c5 / concentrate-02
                        :ARG1 (a5 / antibody
                              :mod (m2 / monoclone))
                        :degree (e3 / especially)
                        :ARG1-of (e4 / equal-01
                              :ARG2 (c6 / concentration-quantity :quant 100
                                    :unit (m / microgram-per-milliliter)))
                        :ARG1-of (h2 / high-02))
                  :ARG1-of (d2 / describe-01
                        :ARG0 (f2 / figure :mod "1D")))))

# ::id pmid_1965_4571.95 ::date 2015-08-07T03:45:53 ::annotator SDL-AMR-09 ::preferred
# ::snt <sec-title level="2">Cetuximab induces chemo/radiosensitisation of CC cells</sec-title>
# ::save-date Thu Dec 10, 2015 ::file pmid_1965_4571_95.txt
(i / induce-01
      :ARG0 (s2 / small-molecule :name (n / name :op1 "cetuximab"))
      :ARG1 (s / slash
            :op1 (c / chemosensitize-00
                  :ARG1 (c2 / cell-line
                        :mod (d / disease :wiki "Cervical_cancer" :name (n2 / name :op1 "cervical" :op2 "cancer"))))
            :op2 (r / radiosensitize-00
                  :ARG1 c2)))

# ::id pmid_1965_4571.96 ::date 2015-08-07T03:48:58 ::annotator SDL-AMR-09 ::preferred
# ::snt We evaluated whether the combination of cetuximab (100 <i>μ</i>g ml<sup>−1</sup>) with RxT and/or cisplatin could enhance the cytotoxic effects observed in CA.
# ::save-date Sun Aug 16, 2015 ::file pmid_1965_4571_96.txt
(e / evaluate-01
      :ARG0 (w / we)
      :ARG1 (p / possible-01
            :ARG1 (e2 / enhance-01 :mode interrogative
                  :ARG0 (c / combine-01
                        :ARG1 (s / small-molecule :name (n2 / name :op1 "cetuximab")
                              :quant (c2 / concentration-quantity :quant 100
                                    :unit (m / microgram-per-milliliter)))
                        :ARG2 (a / and-or
                              :op1 (r / radiotherapy)
                              :op2 (s2 / small-molecule :name (n4 / name :op1 "cisplatin"))))
                  :ARG1 (a2 / affect-01
                        :ARG2 (c3 / cytotoxic)
                        :ARG1-of (o / observe-01
                              :time (a3 / assay-01
                                    :mod (c4 / clonogenic)))))))

# ::id pmid_1965_4571.97 ::date 2015-08-07T03:56:06 ::annotator SDL-AMR-09 ::preferred
# ::snt Isolated cetuximab, cisplatin and RxT treatments decreased the survival of all cell lines (<xref ref-type="fig" rid="fig2">Figures 2A–D</xref>) but the combination of cetuximab with either RxT or cisplatin enhanced these effects (<i>P</i><0.05).
# ::save-date Tue Dec 15, 2015 ::file pmid_1965_4571_97.txt
(c2 / contrast-01
      :ARG1 (d / decrease-01
            :ARG0 (a / and
                  :op1 (t2 / treat-04
                        :ARG2 (s2 / small-molecule :name (n / name :op1 "cetuximab")
                              :ARG1-of (i / isolate-01)))
                  :op2 (t3 / treat-04
                        :ARG2 (s3 / small-molecule :name (n2 / name :op1 "cisplatin")))
                  :op3 (t4 / treat-04
                        :ARG2 (r / radiotherapy)))
            :ARG1 (s / survive-01
                  :ARG0 (c / cell-line
                        :mod (a2 / all)))
            :ARG1-of (d2 / describe-01
                  :ARG0 (v / value-interval
                        :op1 (f / figure :mod "2A")
                        :op2 (f2 / figure :mod "2D"))))
      :ARG2 (e / enhance-01
            :ARG0 (c3 / combine-01
                  :ARG1 s2
                  :ARG2 (o / or
                        :op1 r
                        :op2 s3))
            :ARG1 (a3 / affect-01
                  :mod (t5 / this))
            :ARG1-of (s4 / statistical-test-91
                  :ARG2 (l2 / less-than :op1 0.05))))

# ::id pmid_1965_4571.98 ::date 2015-08-07T04:15:06 ::annotator SDL-AMR-09 ::preferred
# ::snt Furthermore, the triple combination of cetuximab, cisplatin and RxT achieved maximum effects for all cell lines in CA (demonstrative pictures of A431 cells are shown in <xref ref-type="fig" rid="fig2">Figure 2D</xref>).
# ::save-date Sun Jan 17, 2016 ::file pmid_1965_4571_98.txt
(m2 / multi-sentence
      :snt1 (a / and
            :op2 (a2 / achieve-01
                  :ARG0 (c / combine-01
                        :ARG1 (s / small-molecule :name (n2 / name :op1 "cetuximab"))
                        :ARG2 (a3 / and
                              :op1 (s2 / small-molecule :name (n3 / name :op1 "cisplatin"))
                              :op2 (r / radiotherapy))
                        :mod (t / triple))
                  :ARG1 (a4 / affect-01
                        :degree (m / maximum))
                  :location (c2 / cell-line
                        :mod (a5 / all))
                  :ARG1-of (d / describe-01)
                  :time (a6 / assay-01
                        :mod (c4 / clonogenic))))
      :snt2 (s3 / show-01
            :ARG1 (p / picture
                  :ARG0-of (d2 / demonstrate-01
                        :ARG1 (c3 / cell-line :name (n6 / name :op1 "A431"))))
            :location (f / figure :mod "2D")))

# ::id pmid_1965_4571.99 ::date 2015-08-07T04:20:31 ::annotator SDL-AMR-09 ::preferred
# ::snt Caski cells are HPV-positive and express intermediate levels of EGFR and HER2, resembling typical CC tumours.
# ::save-date Sun Jan 17, 2016 ::file pmid_1965_4571_99.txt
(a / and
      :op1 (p / positive
            :topic (d / disease :name (n3 / name :op1 "HPV"))
            :domain (c / cell-line :name (n4 / name :op1 "Caski")
                  :ARG1-of (r / resemble-01
                        :ARG2 (t / tumor
                              :ARG0-of (t2 / typify-01)
                              :mod (d2 / disease :wiki "Cervical_cancer" :name (n5 / name :op1 "cervical" :op2 "cancer"))))))
      :op2 (e3 / express-03
            :ARG2 (a2 / and
                  :op1 (l / level
                        :quant-of (e / enzyme :name (n / name :op1 "EGFR"))
                        :degree (i / intermediate))
                  :op2 (l2 / level
                        :quant-of (e2 / enzyme :name (n2 / name :op1 "HER2"))
                        :degree i))
            :ARG3 c))

# ::id pmid_1965_4571.100 ::date 2015-08-07T04:25:51 ::annotator SDL-AMR-09 ::preferred
# ::snt In this cell line, the triple combination reached up to 70% inhibition in CA (<xref ref-type="fig" rid="fig2">Figure 2B</xref>) whereas in C33A cells, an inhibition of 60% was observed (<xref ref-type="fig" rid="fig2">Figure 2C</xref>).
# ::save-date Sun Jan 17, 2016 ::file pmid_1965_4571_100.txt
(c3 / contrast-01
      :ARG1 (r / reach-01
            :ARG0 (c2 / combine-01
                  :mod (t2 / triple))
            :ARG1 (i / inhibit-01
                  :degree (p / percentage-entity :value 70))
            :location (c / cell-line
                  :mod (t / this))
            :ARG1-of (d / describe-01
                  :ARG0 (f / figure :mod "2B"))
            :time (a / assay-01
                  :mod (c4 / clonogenic)))
      :ARG2 (o / observe-01
            :ARG1 (i2 / inhibit-01
                  :degree (p2 / percentage-entity :value 60))
            :ARG1-of (d2 / describe-01
                  :ARG0 (f2 / figure :mod "2C"))
            :location (c5 / cell-line :name (n / name :op1 "C33A"))))

# ::id pmid_1965_4571.101 ::date 2015-08-07T04:51:09 ::annotator SDL-AMR-09 ::preferred
# ::snt <sec-title level="2">The CC cell lines express different basal levels of total and phosphorylated EGFR, HER-2, AKT and ERK1/2</sec-title>
# ::save-date Wed Dec 9, 2015 ::file pmid_1965_4571_101.txt
(e2 / express-03
      :ARG2 (a2 / and
            :op1 (a / and
                  :op1 (l / level
                        :ARG0-of (d / differ-01)
                        :quant-of (e / enzyme :name (n / name :op1 "EGFR")
                              :mod (t / total))
                        :mod (b / basal))
                  :op2 (l2 / level
                        :quant-of (e3 / enzyme :name (n3 / name :op1 "EGFR")
                              :ARG3-of (p / phosphorylate-01))
                        :mod b
                        :ARG0-of d))
            :op2 (a3 / and
                  :op1 (l3 / level
                        :quant-of (e4 / enzyme :name (n4 / name :op1 "HER-2")
                              :mod t)
                        :mod b
                        :ARG0-of d)
                  :op2 (l4 / level
                        :quant-of (e5 / enzyme :name (n5 / name :op1 "HER-2")
                              :ARG3-of p)
                        :mod b))
            :op3 (a4 / and
                  :op1 (l5 / level
                        :quant-of (e6 / enzyme :name (n6 / name :op1 "AKT")
                              :mod t)
                        :mod b
                        :ARG0-of d)
                  :op2 (l6 / level
                        :quant-of (e7 / enzyme :name (n7 / name :op1 "AKT")
                              :ARG3-of p)
                        :mod b
                        :ARG0-of d))
            :op4 (a5 / and
                  :op1 (l7 / level
                        :quant-of (s / slash
                              :op1 (e8 / enzyme :name (n8 / name :op1 "ERK1")
                                    :mod t)
                              :op2 (e9 / enzyme :name (n9 / name :op1 "ERK2")
                                    :mod t))
                        :mod b
                        :ARG0-of d)
                  :op2 (l8 / level
                        :quant-of (s2 / slash
                              :op1 (e10 / enzyme :name (n10 / name :op1 "ERK1")
                                    :ARG3-of p)
                              :op2 (e11 / enzyme :name (n11 / name :op1 "ERK2")
                                    :ARG3-of p))
                        :mod b
                        :ARG0-of d)))
      :ARG3 (c / cell-line
            :mod (d2 / disease :wiki "Cervical_cancer" :name (n2 / name :op1 "cervical" :op2 "cancer"))))

# ::id pmid_1965_4571.102 ::date 2015-08-07T05:16:37 ::annotator SDL-AMR-09 ::preferred
# ::snt A431 cells strongly express EGFR (<xref ref-type="other" rid="bib9">Janmaat <i>et al</i>, 2003</xref>) whereas Caski and C33A cells show moderate and low expression levels, respectively (<xref ref-type="fig" rid="fig3">Figure 3A</xref>).
# ::save-date Sun Jan 17, 2016 ::file pmid_1965_4571_102.txt
(c2 / contrast-01
      :ARG1 (e2 / express-03
            :ARG2 (e / enzyme :name (n / name :op1 "EGFR"))
            :ARG3 (c / cell-line :name (n2 / name :op1 "A431"))
            :manner (s / strong)
            :ARG1-of (d2 / describe-01
                  :ARG0 (p / publication-91
                        :ARG0 (a / and
                              :op1 (p2 / person :name (n3 / name :op1 "Janmaat"))
                              :op2 (p3 / person
                                    :mod (o / other)))
                        :time (d3 / date-entity :year 2003))))
      :ARG2 (s2 / show-01
            :ARG0 (a2 / and
                  :op1 (c3 / cell-line :name (n4 / name :op1 "Caski"))
                  :op2 (c4 / cell-line :name (n5 / name :op1 "C33A")))
            :ARG1 (a3 / and
                  :op1 (l / level
                        :degree-of (e3 / express-03
                              :ARG1-of (m / moderate-03)))
                  :op2 (l2 / level
                        :degree-of (e4 / express-03
                              :ARG1-of (l3 / low-04))))
            :mod (r / respective)
            :ARG1-of (d4 / describe-01
                  :ARG0 (f / figure :mod "3A"))))

# ::id pmid_1965_4571.103 ::date 2015-08-07T05:23:28 ::annotator SDL-AMR-09 ::preferred
# ::snt Additionally, we confirmed EGFR expression by real-time RT-PCR and by FACS analysis.
# ::save-date Sat Jan 2, 2016 ::file pmid_1965_4571_103.txt
(a / and
      :op2 (c / confirm-01
            :ARG0 (w / we)
            :ARG1 (e2 / express-03
                  :ARG2 (e / enzyme :name (n / name :op1 "EGFR")))
            :instrument (a3 / and
                  :op1 (a2 / analyze-01
                        :manner (r / real-time)
                        :mod (r3 / react-01
                              :ARG0 (p / polymerase)
                              :mod (c2 / chain)
                              :subevent (t / transcribe-01
                                    :ARG1-of (r2 / reverse-01))))
                  :op2 (a4 / analyze-01
                        :mod r
                        :mod (s / sort-01
                              :ARG1 (c3 / cell)
                              :ARG1-of (a5 / activate-01
                                    :ARG0 (f / fluorescence)))))))

# ::id pmid_1965_4571.104 ::date 2015-08-07T05:27:44 ::annotator SDL-AMR-09 ::preferred
# ::snt The relative <i>EGFR</i> mRNA level of A431 is high and Caski cells express two times more <i>EGFR</i> than C33A (Figure 5A).
# ::save-date Fri Feb 26, 2016 ::file pmid_1965_4571_104.txt
(a / and
      :op1 (h / high-02
            :ARG1 (l / level
                  :quant-of (n7 / nucleic-acid :name (n2 / name :op1 "mRNA")
                        :ARG0-of (e4 / encode-01
                              :ARG1 (e / enzyme :name (n / name :op1 "EGFR"))))
                  :quant-of (c / cell-line :name (n3 / name :op1 "A431"))
                  :ARG1-of (r2 / relative-05)))
      :op2 (e2 / express-03
            :ARG2 (e3 / enzyme :name (n5 / name :op1 "EGFR")
                  :quant (p / product-of :op1 2
                        :op2 (m / mass-quantity
                              :quant-of (e5 / enzyme :name (n8 / name :op1 "EGFR")
                                    :ARG2-of (e6 / express-03
                                          :ARG3 (c3 / cell-line :name (n6 / name :op1 "C33A")))))))
            :ARG3 (c2 / cell-line :name (n4 / name :op1 "Caski")))
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod "5A")))

# ::id pmid_1965_4571.105 ::date 2015-08-07T05:34:56 ::annotator SDL-AMR-09 ::preferred
# ::snt Moreover, FACS analysis showed that both a murine anti-EGFR MAb and cetuximab could detect high EGFR expression on the surface of A431 cells and intermediate and low levels in Caski and C33A cells, respectively (Figure 5B).
# ::save-date Sun Jan 17, 2016 ::file pmid_1965_4571_105.txt
(a / and
      :op2 (s / show-01
            :ARG0 (a2 / analyze-01
                  :mod (s4 / sort-01
                        :ARG1 (c4 / cell)
                        :ARG1-of (a4 / activate-01
                              :ARG0 (f2 / fluorescence))))
            :ARG1 (p / possible-01
                  :ARG1 (d / detect-01
                        :ARG0 (a3 / and
                              :op1 (a7 / antibody
                                    :ARG0-of (o / oppose-01
                                          :ARG1 (e / enzyme :name (n / name :op1 "EGFR")))
                                    :mod (m / mouse))
                              :op2 (s3 / small-molecule :name (n3 / name :op1 "cetuximab")))
                        :ARG1 (a5 / and
                              :op1 (e2 / express-03
                                    :ARG2 e
                                    :ARG3 (s2 / surface
                                          :poss (c / cell-line :name (n4 / name :op1 "A431")))
                                    :ARG1-of (h2 / high-02))
                              :op2 (a6 / and
                                    :op1 (l / level
                                          :degree (i / intermediate)
                                          :location (c2 / cell-line :name (n5 / name :op1 "Caski")))
                                    :op2 (l2 / level
                                          :ARG1-of (l3 / low-04)
                                          :location (c3 / cell-line :name (n6 / name :op1 "C33A")))
                                    :mod (r2 / respective))))))
      :ARG1-of (d2 / describe-01
            :ARG0 (f / figure :mod "5B"))
      :mod (m2 / monoclone))

# ::id pmid_1965_4571.106 ::date 2015-08-07T05:42:00 ::annotator SDL-AMR-09 ::preferred
# ::snt HER2 expression was more homogenous among the cell lines with Caski and C33A cells expressing 20 and 40% more HER2 than A431 cells, respectively.
# ::save-date Sun Jan 17, 2016 ::file pmid_1965_4571_106.txt
(h / homogenous
      :domain (e2 / express-03
            :ARG2 (e3 / enzyme :name (n2 / name :op1 "HER2")))
      :degree (m / more)
      :location (a / and
            :op1 (c / cell-line :name (n3 / name :op1 "Caski")
                  :ARG3-of (e4 / express-03
                        :ARG2 (e5 / enzyme :name (n5 / name :op1 "HER2")
                              :quant (p2 / percentage-entity :value 20
                                    :mod (m2 / more)
                                    :compared-to (c3 / cell-line :name (n6 / name :op1 "A431"))))))
            :op2 (c2 / cell-line :name (n4 / name :op1 "C33A")
                  :ARG3-of (e6 / express-03
                        :ARG2 (e7 / enzyme :name (n7 / name :op1 "HER2")
                              :quant (p3 / percentage-entity :value 40
                                    :mod (m3 / more)
                                    :compared-to c3))))))

# ::id pmid_1965_4571.107 ::date 2015-08-07T05:48:13 ::annotator SDL-AMR-09 ::preferred
# ::snt The basal phosphorylation status of EGFR and HER2 was inversely correlated, with higher levels of p-EGFR in A431 cells and higher levels of p-HER2 in C33A and Caski cells (<xref ref-type="fig" rid="fig3">Figure 3A</xref>).
# ::save-date Sun Jan 17, 2016 ::file pmid_1965_4571_107.txt
(c / correlate-01
      :ARG1 (s / status
            :topic (p / phosphorylate-01)
            :mod (b / basal)
            :poss (e / enzyme :name (n / name :op1 "EGFR")))
      :ARG2 (s2 / status
            :topic p
            :mod b
            :poss (e2 / enzyme :name (n2 / name :op1 "HER2")))
      :manner (i / inverse)
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod "3A"))
      :ARG0-of (h2 / have-03
            :ARG1 (a / and
                  :op1 (l / level
                        :ARG1-of (h / high-02
                              :degree (m / more))
                        :quant-of (e3 / enzyme :name (n3 / name :op1 "EGFR")
                              :ARG3-of p)
                        :location (c2 / cell-line :name (n4 / name :op1 "A431")))
                  :op2 (l2 / level
                        :ARG1-of h
                        :quant-of (e4 / enzyme :name (n5 / name :op1 "HER2")
                              :ARG3-of p)
                        :location (a3 / and
                              :op1 (c3 / cell-line :name (n6 / name :op1 "C33A"))
                              :op2 (c4 / cell-line :name (n7 / name :op1 "Caski")))))))

# ::id pmid_1965_4571.108 ::date 2015-08-07T05:53:45 ::annotator SDL-AMR-09 ::preferred
# ::snt On EGF binding, the major signalling pathways activated are the MAPK and AKT cascades (<xref ref-type="other" rid="bib5">Citri and Yarden, 2006</xref>).
# ::save-date Sun Jan 17, 2016 ::file pmid_1965_4571_108.txt
(p / pathway
      :ARG0-of (s / signal-07)
      :ARG1-of (a / activate-01
            :condition (b / bind-01
                  :ARG1 (p4 / protein :name (n2 / name :op1 "EGF")))
            :ARG1-of (d2 / describe-01
                  :ARG0 (p5 / publication-91
                        :ARG0 (a3 / and
                              :op1 (p6 / person :name (n5 / name :op1 "Citri"))
                              :op2 (p7 / person :name (n6 / name :op1 "Yarden")))
                        :time (d3 / date-entity :year 2006))))
      :mod (m / major)
      :domain (a2 / and
            :op1 (p2 / pathway :name (n / name :op1 "MAPK"))
            :op2 (p3 / pathway :name (n3 / name :op1 "AKT"))))

# ::id pmid_1965_4571.109 ::date 2015-08-07T05:58:36 ::annotator SDL-AMR-09 ::preferred
# ::snt A431 and Caski cells show low basal levels of p-AKT whereas C33A cells have a much higher level.
# ::save-date Sun Jan 17, 2016 ::file pmid_1965_4571_109.txt
(c3 / contrast-01
      :ARG1 (s / show-01
            :ARG0 (a / and
                  :op1 (c / cell-line :name (n / name :op1 "A431"))
                  :op2 (c2 / cell-line :name (n2 / name :op1 "Caski")))
            :ARG1 (l / level
                  :ARG1-of (l2 / low-04)
                  :mod (b / basal)
                  :quant-of (e / enzyme :name (n3 / name :op1 "AKT")
                        :ARG3-of (p / phosphorylate-01))))
      :ARG2 (h2 / have-03
            :ARG0 (c4 / cell-line :name (n4 / name :op1 "C33A"))
            :ARG1 (l3 / level
                  :ARG1-of (h / high-02
                        :degree (m / more
                              :mod (m2 / much))))))

# ::id pmid_1965_4571.110 ::date 2015-08-07T06:01:28 ::annotator SDL-AMR-09 ::preferred
# ::snt A431 and C33A cells had higher levels of activated ERK1/2 (p-p44/42 MAPK) but no significant differences in total MAPK were observed among the cell lines (<xref ref-type="fig" rid="fig3">Figure 3A</xref>).
# ::save-date Sun Jan 17, 2016 ::file pmid_1965_4571_110.txt
(c / contrast-01
      :ARG1 (h2 / have-03
            :ARG0 (a / and
                  :op1 (c2 / cell-line :name (n2 / name :op1 "A431"))
                  :op2 (c3 / cell-line :name (n3 / name :op1 "C33A")))
            :ARG1 (l / level
                  :ARG1-of (h / high-02
                        :degree (m / more))
                  :quant-of (s / slash
                        :op1 (e / enzyme :name (n4 / name :op1 "ERK1")
                              :ARG1-of (a2 / activate-01))
                        :op2 (e2 / enzyme :name (n5 / name :op1 "ERK2")
                              :ARG1-of a2))
                  :ARG1-of (m2 / mean-01
                        :ARG2 (s2 / slash
                              :op1 (e3 / enzyme :name (n8 / name :op1 "p44" :op2 "MAPK")
                                    :ARG3-of (p2 / phosphorylate-01))
                              :op2 (e4 / enzyme :name (n / name :op1 "p42" :op2 "MAPK")
                                    :ARG3-of p2)))))
      :ARG2 (o / observe-01 :polarity -
            :ARG1 (d / differ-02
                  :ARG1 (e5 / enzyme :name (n7 / name :op1 "MAPK")
                        :mod (t / total))
                  :ARG1-of (s3 / significant-02))
            :location (c4 / cell-line))
      :ARG1-of (d2 / describe-01
            :ARG0 (f / figure :mod "3A")))

# ::id pmid_1965_4571.111 ::date 2015-08-07T06:09:06 ::annotator SDL-AMR-09 ::preferred
# ::snt <sec-title level="2">Cetuximab inhibits EGFR and HER2 phosphorylation</sec-title>
# ::save-date Fri Aug 14, 2015 ::file pmid_1965_4571_111.txt
(i / inhibit-01
      :ARG0 (s / small-molecule :name (n3 / name :op1 "cetuximab"))
      :ARG1 (p2 / phosphorylate-01
            :ARG1 (a / and
                  :op1 (e / enzyme :name (n / name :op1 "EGFR"))
                  :op2 (e2 / enzyme :name (n2 / name :op1 "HER2")))))

# ::id pmid_1965_4571.112 ::date 2015-08-07T06:10:35 ::annotator SDL-AMR-09 ::preferred
# ::snt To investigate the molecular determinants for cetuximab's effects in MTT and CA, we analysed EGFR phosphorylation by WB in cells treated with cetuximab (100 <i>μ</i>g ml<sup>−1</sup>) alone or in the presence of EGF.
# ::save-date Sat Feb 13, 2016 ::file pmid_1965_4571_112.txt
(a / analyze-01
      :ARG0 (w / we)
      :ARG1 (p / phosphorylate-01
            :ARG1 (e / enzyme :name (n2 / name :op1 "EGFR")))
      :location (c / cell
            :ARG1-of (t / treat-04
                  :ARG2 (o / or
                        :op1 (s / small-molecule :name (n3 / name :op1 "cetuximab")
                              :quant (c2 / concentration-quantity :quant 100
                                    :unit (m / microgram-per-milliliter))
                              :mod (a2 / alone))
                        :op2 (s2 / small-molecule :name (n4 / name :op1 "cetuximab")
                              :quant c2
                              :condition (p2 / present-02
                                    :ARG1 (p3 / protein :name (n5 / name :op1 "EGF")))))))
      :purpose (i / investigate-01
            :ARG0 w
            :ARG1 (t2 / thing
                  :ARG0-of (d / determine-01
                        :ARG1 (a3 / affect-01
                              :ARG0 s
                              :time (a4 / and
                                    :op1 (a5 / assay-01
                                          :instrument (s3 / small-molecule :name (n / name :op1 "MTT")))
                                    :op2 (a6 / assay-01
                                          :mod (c3 / clonogenic)))))
                  :mod (m2 / molecule)))
      :manner (i2 / immunoblot-01
            :ARG0 w))

# ::id pmid_1965_4571.113 ::date 2015-08-07T06:18:13 ::annotator SDL-AMR-09 ::preferred
# ::snt Receptor phosphorylation was increased by EGF in A431 and Caski cells, whereas cetuximab reduced it (<xref ref-type="fig" rid="fig3">Figures 3B and C</xref>).
# ::save-date Sun Jan 17, 2016 ::file pmid_1965_4571_113.txt
(c3 / contrast-01
      :ARG1 (i / increase-01
            :ARG0 (p2 / protein :name (n / name :op1 "EGF"))
            :ARG1 (p / phosphorylate-01
                  :ARG1 (r / receptor))
            :location (a / and
                  :op1 (c / cell-line :name (n2 / name :op1 "A431"))
                  :op2 (c2 / cell-line :name (n3 / name :op1 "Caski"))))
      :ARG2 (r2 / reduce-01
            :ARG0 (s2 / small-molecule :name (n4 / name :op1 "cetuximab"))
            :ARG1 p)
      :ARG1-of (d / describe-01
            :ARG0 (a2 / and
                  :op1 (f / figure :mod "3B")
                  :op2 (f2 / figure :mod "3C"))))

# ::id pmid_1965_4571.114 ::date 2015-08-07T06:20:52 ::annotator SDL-AMR-09 ::preferred
# ::snt Epidermal growth factor and cetuximab also induced a slight decrease in the total amount of EGFR in these cells (<xref ref-type="fig" rid="fig3">Figures 3B and C</xref>).
# ::save-date Sun Jan 17, 2016 ::file pmid_1965_4571_114.txt
(i / induce-01
      :ARG0 (a / and
            :op1 (p / protein :name (n4 / name :op1 "epidermal" :op2 "growth" :op3 "factor"))
            :op2 (s / small-molecule :name (n3 / name :op1 "cetuximab")))
      :ARG2 (d / decrease-01
            :ARG1 (a3 / amount
                  :mod (t / total)
                  :quant-of (e / enzyme :name (n2 / name :op1 "EGFR")))
            :degree (s2 / slight)
            :location (c / cell
                  :mod (t2 / this)))
      :mod (a2 / also)
      :ARG1-of (d2 / describe-01
            :ARG0 (a4 / and
                  :op1 (f / figure :mod "3B")
                  :op2 (f2 / figure :mod "3C"))))

# ::id pmid_1965_4571.115 ::date 2015-08-04T07:50:24 ::annotator SDL-AMR-09 ::preferred
# ::snt Epidermal growth factor receptor can interact with another member of the ErbB family, HER2, to form heterodimers that are very potent in activating signal transduction pathways (<xref ref-type="other" rid="bib5">Citri and Yarden, 2006</xref>).
# ::save-date Fri Feb 5, 2016 ::file pmid_1965_4571_115.txt
(p / possible-01
      :ARG1 (i / interact-01
            :ARG0 (e / enzyme :name (n3 / name :op1 "epidermal" :op2 "growth" :op3 "factor" :op4 "receptor"))
            :ARG1 (m / member
                  :mod (a / another)
                  :ARG1-of (i2 / include-91
                        :ARG2 (p2 / protein-family :name (n4 / name :op1 "ErbB")))
                  :ARG1-of (m2 / mean-01
                        :ARG2 (e3 / enzyme :name (n5 / name :op1 "HER2"))))
            :purpose (f2 / form-01
                  :ARG0 e
                  :ARG1 (h / heterodimer
                        :ARG1-of (c / capable-01
                              :ARG2 (a2 / activate-01
                                    :ARG1 (p3 / pathway
                                          :ARG2-of (t / transduce-01
                                                :ARG1 (s2 / signal-07))))
                              :degree (v / very)))
                  :ARG2 (a4 / and
                        :op1 e
                        :op2 m)))
      :ARG1-of (d2 / describe-01
            :ARG0 (p4 / publication-91
                  :ARG0 (a3 / and
                        :op1 (p5 / person :name (n7 / name :op1 "Citri"))
                        :op2 (p6 / person :name (n8 / name :op1 "Yarden"))
                        :time (d / date-entity :year 2006)))))

# ::id pmid_1965_4571.116 ::date 2015-08-04T08:49:30 ::annotator SDL-AMR-09 ::preferred
# ::snt On cetuximab treatment there were no changes in total HER2 in the CC cell lines, whereas EGF-induced HER2 phosphorylation was inhibited in A431 and Caski cells (<xref ref-type="fig" rid="fig3">Figures 3B and C</xref>).
# ::save-date Sun Jan 17, 2016 ::file pmid_1965_4571_116.txt
(c / contrast-01
      :ARG1 (h / have-condition-91
            :ARG1 (c2 / change-01 :polarity -
                  :ARG1 (e / enzyme :name (n / name :op1 "HER2")
                        :mod (t2 / total))
                  :location (c3 / cell-line
                        :mod (d / disease :wiki "Cervical_cancer" :name (n3 / name :op1 "cervical" :op2 "cancer"))))
            :ARG2 (t / treat-04
                  :ARG2 (s / small-molecule :name (n2 / name :op1 "cetuximab"))))
      :ARG2 (i / inhibit-01
            :ARG1 (p / phosphorylate-01
                  :ARG1 e
                  :ARG2-of (i2 / induce-01
                        :ARG0 (p2 / protein :name (n4 / name :op1 "EGF"))))
            :location (a / and
                  :op1 (c4 / cell-line :name (n5 / name :op1 "A431"))
                  :op2 (c5 / cell-line :name (n6 / name :op1 "Caski"))))
      :ARG1-of (d2 / describe-01
            :ARG0 (a2 / and
                  :op1 (f / figure :mod "3B")
                  :op2 (f2 / figure :mod "3C"))))

# ::id pmid_1965_4571.117 ::date 2015-08-04T09:24:51 ::annotator SDL-AMR-09 ::preferred
# ::snt Interestingly, in C33A cells, which express more HER2 than EGFR (<xref ref-type="fig" rid="fig3">Fig 3A</xref>), cetuximab markedly reduced EGF-induced HER2 phosphorylation (<xref ref-type="fig" rid="fig3">Figure 3D</xref>).
# ::save-date Sun Jan 17, 2016 ::file pmid_1965_4571_117.txt
(r / reduce-01
      :ARG0 (s / small-molecule :name (n3 / name :op1 "cetuximab"))
      :ARG1 (p / phosphorylate-01
            :ARG1 (e / enzyme :name (n / name :op1 "HER2"))
            :ARG2-of (i / induce-01
                  :ARG0 (p2 / protein :name (n2 / name :op1 "EGF"))))
      :manner (m / marked)
      :location (c / cell-line :name (n4 / name :op1 "C33A")
            :ARG3-of (e3 / express-03
                  :ARG2 e
                  :ARG1-of (d / describe-01
                        :ARG0 (f / figure :mod "3A"))
                  :degree (m2 / more)
                  :compared-to (e2 / enzyme :name (n5 / name :op1 "EGFR"))))
      :ARG1-of (d2 / describe-01
            :ARG0 (f2 / figure :mod "3D"))
      :mod (i2 / interesting))

# ::id pmid_1965_4571.118 ::date 2015-08-04T09:45:20 ::annotator SDL-AMR-09 ::preferred
# ::snt There were no changes in total AKT and MAPK proteins in all cell lines on cetuximab treatment (<xref ref-type="fig" rid="fig3">Figures 3B–D</xref>).
# ::save-date Sun Jan 17, 2016 ::file pmid_1965_4571_118.txt
(c / change-01 :polarity -
      :ARG1 (a / and
            :op1 (p2 / protein-family :name (n2 / name :op1 "AKT"))
            :op2 (p / protein-family :name (n / name :op1 "MAPK"))
            :mod (t2 / total))
      :location (c2 / cell-line
            :mod (a2 / all)
            :ARG1-of (t / treat-04
                  :ARG2 (s / small-molecule :name (n3 / name :op1 "cetuximab"))))
      :ARG1-of (d / describe-01
            :ARG0 (v / value-interval
                  :op1 (f / figure :mod "3B")
                  :op2 (f2 / figure :mod "3D"))))

# ::id pmid_1965_4571.119 ::date 2015-08-04T10:32:43 ::annotator SDL-AMR-09 ::preferred
# ::snt Epidermal growth factor increased AKT and ERK1/2 phosphorylation in A431 and Caski cells but in C33A cells there was only a slight increase.
# ::save-date Sun Jan 17, 2016 ::file pmid_1965_4571_119.txt
(c / contrast-01
      :ARG1 (i / increase-01
            :ARG0 (p2 / protein :name (n2 / name :op1 "epidermal" :op2 "growth" :op3 "factor"))
            :ARG1 (a / and
                  :op1 (p / phosphorylate-01
                        :ARG1 (e / enzyme :name (n3 / name :op1 "AKT")))
                  :op1 (p3 / phosphorylate-01
                        :ARG1 (e2 / enzyme :name (n4 / name :op1 "ERK1/2"))))
            :location (a2 / and
                  :op1 (c2 / cell-line :name (n5 / name :op1 "A431"))
                  :op2 (c3 / cell-line :name (n6 / name :op1 "Caski"))))
      :ARG2 (i2 / increase-01
            :ARG0 p2
            :ARG1 a
            :location (c4 / cell-line :name (n7 / name :op1 "C33A"))
            :mod (o / only)
            :degree (s2 / slight)))

# ::id pmid_1965_4571.120 ::date 2015-08-04T10:54:11 ::annotator SDL-AMR-09 ::preferred
# ::snt This was not unexpected, because both pathways are activated in this cell line (<xref ref-type="fig" rid="fig3">Figure 3A</xref>).
# ::save-date Wed Aug 5, 2015 ::file pmid_1965_4571_120.txt
(c / cause-01
      :ARG0 (a / activate-01
            :ARG1 (p / pathway
                  :mod (b / both))
            :location (c2 / cell-line
                  :mod (t / this)))
      :ARG1 (e / expect-01 :polarity -
            :ARG1 (t2 / this))
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod "3A")))

# ::id pmid_1965_4571.121 ::date 2015-08-04T11:10:51 ::annotator SDL-AMR-09 ::preferred
# ::snt Cetuximab inhibited EGF-induced AKT phosphorylation more strongly in A431 cells and less so in Caski and C33A cells.
# ::save-date Sun Jan 17, 2016 ::file pmid_1965_4571_121.txt
(a2 / and
      :op1 (i / inhibit-01
            :ARG0 (s / small-molecule :name (n / name :op1 "cetuximab"))
            :ARG1 (p / phosphorylate-01
                  :ARG1 (e / enzyme :name (n2 / name :op1 "AKT"))
                  :ARG2-of (i2 / induce-01
                        :ARG0 (p2 / protein :name (n3 / name :op1 "EGF"))))
            :ARG1-of (s2 / strong-02
                  :degree (m / more))
            :location (c / cell-line :name (n4 / name :op1 "A431")))
      :op2 (i3 / inhibit-01
            :ARG0 s
            :ARG1 p
            :degree (l / less)
            :location (a / and
                  :op1 (c2 / cell-line :name (n5 / name :op1 "Caski"))
                  :op2 (c3 / cell-line :name (n6 / name :op1 "C33A")))))

# ::id pmid_1965_4571.122 ::date 2015-08-04T11:17:17 ::annotator SDL-AMR-09 ::preferred
# ::snt Indeed, it markedly reduced EGF-induced ERK1/2 phosphorylation in A431 cells, but in Caski and C33A cells the reduction was more modest (60 and 20% inhibition, respectively; <xref ref-type="fig" rid="fig3">Figures 3B–D</xref>), suggesting that persistent signalling through these pathways led to increased survival of Caski and C33A cells, when compared to A431 cells in the presence of cetuximab.
# ::save-date Sun Jan 17, 2016 ::file pmid_1965_4571_122.txt
(c / contrast-01
      :ARG1 (r / reduce-01
            :ARG0 (i / it)
            :ARG1 (p2 / phosphorylate-01
                  :ARG1 (e / enzyme :name (n / name :op1 "ERK1/2"))
                  :ARG2-of (i2 / induce-01
                        :ARG0 (p3 / protein :name (n2 / name :op1 "EGF"))))
            :location (c2 / cell-line :name (n3 / name :op1 "A431"))
            :manner (m4 / marked))
      :ARG2 (r3 / reduce-01
            :ARG1 p2
            :mod (m / modest
                  :degree (m2 / more))
            :location (a / and
                  :op1 (c3 / cell-line :name (n4 / name :op1 "Caski"))
                  :op2 (c4 / cell-line :name (n5 / name :op1 "C33A")))
            :ARG1-of (m3 / mean-01
                  :ARG2 (a2 / and
                        :op1 (i3 / inhibit-01
                              :quant (p4 / percentage-entity :value 60)
                              :location c3)
                        :op2 (i4 / inhibit-01
                              :quant (p / percentage-entity :value 20)
                              :location c4)
                        :mod (r2 / respective))))
      :ARG0-of (s / suggest-01
            :ARG1 (l / lead-03
                  :ARG0 (s2 / signal-07
                        :ARG0 (p6 / pathway
                              :mod (t / this))
                        :ARG1-of (p5 / persist-01))
                  :ARG2 (s3 / survive-01
                        :ARG1 (a3 / and
                              :op1 c3
                              :op2 c4)
                        :ARG1-of (i5 / increase-01))
                  :time (c5 / compare-01
                        :ARG2 (c6 / cell-line :name (n6 / name :op1 "A431")
                              :ARG2-of (p7 / present-02
                                    :ARG1 (s4 / small-molecule :name (n7 / name :op1 "cetuximab")))))))
      :mod (i6 / indeed)
      :ARG1-of (d / describe-01
            :ARG0 (v / value-interval
                  :op1 (f / figure :mod "3B")
                  :op2 (f2 / figure :mod "3D"))))

# ::id pmid_1965_4571.123 ::date 2015-08-04T11:34:42 ::annotator SDL-AMR-09 ::preferred
# ::snt <sec-title level="2">Cetuximab combined with trastuzumab synergistically reduces cell proliferation and activation of downstream signalling pathways in CC cells</sec-title>
# ::save-date Tue Feb 2, 2016 ::file pmid_1965_4571_123.txt
(r / reduce-01
      :ARG0 (s / small-molecule :name (n / name :op1 "cetuximab")
            :ARG1-of (c / combine-01
                  :ARG2 (s2 / small-molecule :name (n2 / name :op1 "trastuzumab"))))
      :ARG1 (a / and
            :op1 (p / proliferate-01
                  :ARG0 (c2 / cell))
            :op2 (a2 / activate-01
                  :ARG1 (p2 / pathway
                        :ARG0-of (s3 / signal-07
                              :location (d / downstream)))))
      :location (c3 / cell-line
            :mod (d2 / disease :wiki "Cervical_cancer" :name (n3 / name :op1 "cervical" :op2 "cancer")))
      :manner (s4 / synergize-01))

# ::id pmid_1965_4571.124 ::date 2015-08-04T11:41:50 ::annotator SDL-AMR-09 ::preferred
# ::snt We speculated that cells expressing higher EGFR/HER2 ratios, such as A431 cells, rely more on EGFR signalling for MAPK pathway activation and cell proliferation, whereas cells with a lower EGFR/HER2 ratio, such as C33A cells, depend more on EGFR/HER2 heterodimer signalling.
# ::save-date Wed Dec 30, 2015 ::file pmid_1965_4571_124.txt
(s / speculate-01
      :ARG0 (w / we)
      :ARG1 (c / contrast-01
            :ARG1 (r / rely-01
                  :ARG0 (c2 / cell-line
                        :ARG3-of (e2 / express-03
                              :ARG2 (r2 / ratio-of
                                    :op1 (m3 / macro-molecular-complex
                                          :part (e3 / enzyme :name (n3 / name :op1 "EGFR"))
                                          :part (e4 / enzyme :name (n4 / name :op1 "HER2")))
                                    :ARG1-of (h2 / high-02
                                          :degree (m4 / more))
                                    :part e3))
                        :example (c3 / cell-line :name (n5 / name :op1 "A431")))
                  :ARG1 (a / and
                        :op1 (a2 / activate-01
                              :ARG1 (p2 / pathway :name (n6 / name :op1 "MAPK")
                                    :ARG0-of (s2 / signal-07
                                          :ARG1 e3)))
                        :op2 (p3 / proliferate-01
                              :ARG0 (c4 / cell)))
                  :degree m4)
            :ARG2 (d / depend-01
                  :ARG0 (c5 / cell-line
                        :ARG0-of (h3 / have-03
                              :ARG1 (r3 / ratio-of
                                    :op1 m3
                                    :ARG1-of (l2 / low-04
                                          :degree m4)
                                    :part e4))
                        :example (c6 / cell-line :name (n7 / name :op1 "C33A")))
                  :ARG1 (s3 / signal-07
                        :ARG1 (h / heterodimer
                              :mod m3))
                  :degree m4)))

# ::id pmid_1965_4571.125 ::date 2015-08-04T11:51:49 ::annotator SDL-AMR-09 ::preferred
# ::snt Based on this assumption, the inhibition of the EGFR/HER2 heterodimer by anti-EGFR (cetuximab) and anti-HER2 (trastuzumab) MAbs should interfere with C33A cell proliferation.
# ::save-date Thu Jan 14, 2016 ::file pmid_1965_4571_125.txt
(p / possible-01
      :ARG1 (i / interfere-01
            :ARG0 (i2 / inhibit-01
                  :ARG0 (a3 / antibody
                        :mod (m3 / monoclone)
                        :ARG1-of (m / mean-01
                              :ARG2 (a / and
                                    :op1 (s / small-molecule :name (n / name :op1 "cetuximab")
                                          :ARG0-of (c / counter-01
                                                :ARG1 e))
                                    :op2 (s2 / small-molecule :name (n5 / name :op1 "trastuzumab")
                                          :ARG0-of (c2 / counter-01
                                                :ARG1 e2)))))
                  :ARG1 (h / heterodimer
                        :part (e / enzyme :name (n2 / name :op1 "EGFR"))
                        :part (e2 / enzyme :name (n3 / name :op1 "HER2"))))
            :ARG1 (p2 / proliferate-01
                  :ARG0 (c3 / cell-line :name (n7 / name :op1 "C33A"))))
      :ARG1-of (b / base-02
            :ARG2 (a2 / assume-02
                  :mod (t / this))))

# ::id pmid_1965_4571.126 ::date 2015-08-04T13:29:57 ::annotator SDL-AMR-09 ::preferred
# ::snt As expected, this combination markedly reduced C33A cell colony formation leading to a synergistic interaction (<i>R</i>=0.58; <xref ref-type="fig" rid="fig4">Figures 4A and B</xref>), with concomitant reduction of MAPK and AKT phosphorylation (<xref ref-type="fig" rid="fig4">Figure 4D</xref>).
# ::save-date Tue Feb 2, 2016 ::file pmid_1965_4571_126.txt
(r / reduce-01
      :ARG0 (c / combine-01
            :mod (t / this))
      :ARG1 (f / form-01
            :ARG1 (c2 / colony
                  :mod (c3 / cell-line :name (n2 / name :op1 "C33A"))))
      :manner (m / marked)
      :ARG0-of (l / lead-03
            :ARG2 (i / interact-01
                  :ARG0-of (s / synergize-01)
                  :ARG0-of (h / have-03
                        :ARG1 (r3 / reduce-01
                              :ARG1 (a3 / and
                                    :op1 (p2 / phosphorylate-01
                                          :ARG1 (e4 / enzyme :name (n / name :op1 "MAPK")))
                                    :op2 (p3 / phosphorylate-01
                                          :ARG1 (e / enzyme :name (n3 / name :op1 "AKT"))))
                              :mod (c4 / concomitant)
                              :ARG1-of (d2 / describe-01
                                    :ARG0 (f4 / figure :mod "4D"))))
                  :ARG1-of (m2 / mean-01
                        :ARG2 (s2 / string-entity :value "R"
                              :ARG1-of (e3 / equal-01
                                    :ARG2 0.58)))))
      :ARG1-of (d / describe-01
            :ARG0 (a2 / and
                  :op1 (f2 / figure :mod "4A")
                  :op2 (f3 / figure :mod "4B")))
      :ARG1-of (e2 / expect-01))

# ::id pmid_1965_4571.127 ::date 2015-08-04T13:47:05 ::annotator SDL-AMR-09 ::preferred
# ::snt Indeed, an additive effect (<i>R</i>=0.84) was also noted for Caski cells, that express intermediate levels of EGFR and HER2 (<xref ref-type="fig" rid="fig3">Figure 3A</xref>), with a decrease of almost 60% in cell survival (<xref ref-type="fig" rid="fig4">Figures 4A and B</xref>) and inhibition of downstream signalling pathways (MAPK and AKT; <xref ref-type="fig" rid="fig4">Figure 4C</xref>).
# ::save-date Wed Dec 30, 2015 ::file pmid_1965_4571_127.txt
(n4 / note-02
      :ARG1 (a / affect-01
            :ARG1-of (a2 / add-02)
            :ARG1-of (m2 / mean-01
                  :ARG2 (s3 / string-entity :value "R"
                        :ARG1-of (e4 / equal-01
                              :ARG2 0.84))))
      :ARG2 (c / cell-line :name (n5 / name :op1 "Caski")
            :ARG3-of (e3 / express-03
                  :ARG2 (a4 / and
                        :op1 (l / level
                              :quant-of (e / enzyme :name (n / name :op1 "EGFR")))
                        :op2 (l2 / level
                              :quant-of (e2 / enzyme :name (n2 / name :op1 "HER2")))
                        :mod (i2 / intermediate))
                  :ARG1-of (d / describe-01
                        :ARG0 (f / figure :mod "3A")))
            :ARG0-of (h / have-03
                  :ARG1 (d2 / decrease-01
                        :ARG1 (a5 / and
                              :op1 (s / survive-01
                                    :ARG1 (c2 / cell)
                                    :ARG1-of (d3 / describe-01
                                          :ARG0 (a6 / and
                                                :op1 (f2 / figure :mod "4A")
                                                :op2 (f3 / figure :mod "4B"))))
                              :op2 (i3 / inhibit-01
                                    :ARG1 (p3 / pathway
                                          :ARG0-of (s2 / signal-07
                                                :location (d4 / downstream))
                                          :ARG1-of (m / mean-01
                                                :ARG2 (a7 / and
                                                      :op1 (p2 / pathway :name (n3 / name :op1 "MAPK"))
                                                      :op2 (p4 / pathway :name (n6 / name :op1 "AKT")))))
                                    :ARG1-of (d5 / describe-01
                                          :ARG0 (f4 / figure :mod "4C"))))
                        :ARG2 (p / percentage-entity :value 60
                              :mod (a8 / almost)))))
      :mod (a3 / also)
      :mod (i / indeed))

# ::id pmid_1965_4571.128 ::date 2015-08-04T14:02:11 ::annotator SDL-AMR-09 ::preferred
# ::snt There were no changes in total AKT and MAPK proteins in Caski and C33A cell lines on treatments (data not shown).
# ::save-date Sun Jan 17, 2016 ::file pmid_1965_4571_128.txt
(c / change-01 :polarity -
      :ARG1 (a / and
            :op1 (p2 / protein-family :name (n2 / name :op1 "AKT")
                  :mod (t / total))
            :op2 (p / protein-family :name (n / name :op1 "MAPK")))
      :location (a2 / and
            :op1 (c2 / cell-line :name (n3 / name :op1 "Caski"))
            :op2 (c3 / cell-line :name (n4 / name :op1 "C33A"))
            :ARG1-of (t2 / treat-04))
      :ARG1-of (d / describe-01
            :ARG0 (d2 / data
                  :ARG1-of (s / show-01 :polarity -))))

# ::id pmid_1965_4571.129 ::date 2015-08-04T14:07:16 ::annotator SDL-AMR-09 ::preferred
# ::snt <sec-title level="2">The combination of cetuximab with a TKI inhibits cell proliferation and MAPK phosphorylation in Caski but not in C33A cells</sec-title>
# ::save-date Sun Jan 17, 2016 ::file pmid_1965_4571_129.txt
(c / contrast-01
      :ARG1 (i / inhibit-01
            :ARG0 (c2 / combine-01
                  :ARG1 (s / small-molecule :name (n2 / name :op1 "cetuximab"))
                  :ARG2 (s2 / small-molecule :name (n3 / name :op1 "TKI")))
            :ARG1 (a / and
                  :op1 (p3 / proliferate-01
                        :ARG0 (c3 / cell))
                  :op2 (p2 / phosphorylate-01
                        :ARG1 (e / enzyme :name (n / name :op1 "MAPK"))))
            :location (c4 / cell-line :name (n4 / name :op1 "Caski")))
      :ARG2 (i2 / inhibit-01 :polarity -
            :ARG0 c2
            :ARG1 a
            :location (c5 / cell-line :name (n5 / name :op1 "C33A"))))

# ::id pmid_1965_4571.130 ::date 2015-08-04T14:12:43 ::annotator SDL-AMR-09 ::preferred
# ::snt Based on the idea of an EGFR/HER2 heterodimer signalling dependency of C33A cells, we investigated whether further EGFR inhibition with another targeted drug, such as TKIs, affected more Caski than C33A cells.
# ::save-date Tue Jan 12, 2016 ::file pmid_1965_4571_130.txt
(i / investigate-01
      :ARG0 (w / we)
      :ARG1 (a / affect-01 :mode interrogative
            :ARG0 (i2 / inhibit-01
                  :ARG0 (d / drug
                        :mod (a2 / another)
                        :ARG1-of (t / target-01)
                        :example (s / small-molecule :wiki "Tyrosine-kinase_inhibitor"
                                    :name (n2 / name :op1 "TKI")))
                  :ARG1 (e / enzyme :wiki "Epidermal_growth_factor_receptor"
                        :name (n / name :op1 "EGFR"))
                  :degree (f / further))
            :ARG1 (c / cell-line :wiki -
                  :name (n3 / name :op1 "Caski"))
            :degree (m2 / more)
            :compared-to (c2 / cell-line :wiki -
                  :name (n4 / name :op1 "C33A")))
      :ARG1-of (b / base-02
            :ARG0 (i3 / idea
                  :topic (d2 / depend-01
                        :ARG0 c2
                        :ARG1 (s2 / signal-07
                              :ARG1 (h / heterodimer
                                    :part e
                                    :part (e2 / enzyme :wiki "HER2/neu"
                                          :name (n6 / name :op1 "HER2"))))))))

# ::id pmid_1965_4571.131 ::date 2015-08-04T14:20:43 ::annotator SDL-AMR-09 ::preferred
# ::snt Therefore, we tested the combination of cetuximab with a specific EGFR TKI (PD153035).
# ::save-date Tue Aug 4, 2015 ::file pmid_1965_4571_131.txt
(c / cause-01
      :ARG1 (t / test-01
            :ARG0 (w / we)
            :ARG1 (c2 / combine-01
                  :ARG1 (s / small-molecule :name (n2 / name :op1 "cetuximab"))
                  :ARG2 (s2 / small-molecule :name (n3 / name :op1 "TKI")
                        :mod (s3 / specific)
                        :ARG0-of (i / inhibit-01
                              :ARG1 (e / enzyme :name (n / name :op1 "EGFR")))
                        :ARG1-of (m / mean-01
                              :ARG2 (s4 / small-molecule :name (n4 / name :op1 "PD153035")))))))

# ::id pmid_1965_4571.132 ::date 2015-08-05T09:07:28 ::annotator SDL-AMR-09 ::preferred
# ::snt As expected, combined treatments reduced Caski cell survival leading to an additive interaction (<i>R</i>=0.94) when compared to treatments alone (<xref ref-type="fig" rid="fig4">Figure 4E</xref>).
# ::save-date Wed Dec 30, 2015 ::file pmid_1965_4571_132.txt
(r / reduce-01
      :ARG0 (t / treat-04
            :ARG1-of (c / combine-01))
      :ARG1 (s / survive-01
            :ARG1 (c2 / cell-line :name (n / name :op1 "Caski")))
      :ARG0-of (l / lead-03
            :ARG2 (i / interact-01
                  :ARG1-of (a / add-02)
                  :ARG1-of (m / mean-01
                        :ARG2 (s2 / string-entity :value "R"
                              :ARG1-of (e2 / equal-01
                                    :ARG2 0.94))))
            :condition (c3 / compare-01
                        :ARG1 t
                        :ARG2 (t2 / treat-04
                              :mod (a2 / alone))))
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod "4E"))
      :ARG1-of (e / expect-01))

# ::id pmid_1965_4571.133 ::date 2015-08-05T09:20:24 ::annotator SDL-AMR-09 ::preferred
# ::snt Additionally, the double treatment in Caski cells was accompanied by a greater reduction of EGFR, HER2, AKT and MAPK phosphorylation (<xref ref-type="fig" rid="fig4">Figure 4G</xref>).
# ::save-date Sun Jan 17, 2016 ::file pmid_1965_4571_133.txt
(a / and
      :op2 (a2 / accompany-01
            :ARG0 (r / reduce-01
                  :ARG1 (a3 / and
                        :op1 (p2 / phosphorylate-01
                              :ARG1 (e / enzyme :name (n / name :op1 "EGFR")))
                        :op2 (p3 / phosphorylate-01
                              :ARG1 (e2 / enzyme :name (n2 / name :op1 "HER2")))
                        :op3 (p4 / phosphorylate-01
                              :ARG1 (e3 / enzyme :name (n5 / name :op1 "AKT")))
                        :op4 (p5 / phosphorylate-01
                              :ARG1 (e4 / enzyme :name (n3 / name :op1 "MAPK"))))
                  :mod (g / great
                        :degree (m / more)))
            :ARG1 (t / treat-04
                  :ARG1 (c / cell-line :name (n4 / name :op1 "Caski"))
                  :mod (d / double)))
      :ARG1-of (d2 / describe-01
            :ARG0 (f / figure :mod "4G")))

# ::id pmid_1965_4571.134 ::date 2015-08-05T09:29:36 ::annotator SDL-AMR-09 ::preferred
# ::snt Isolated cetuximab or PD153035 treatments reduced the survival of C33A cells in CA by the same proportion, reaching a more modest inhibition of HER2, AKT and MAPK phosphorylation than in Caski cells (<xref ref-type="fig" rid="fig4">Figures 4E and G</xref>).
# ::save-date Sun Jan 17, 2016 ::file pmid_1965_4571_134.txt
(r / reduce-01
      :ARG0 (o / or
            :op1 (t / treat-04
                  :ARG2 (s2 / small-molecule :name (n4 / name :op1 "cetuximab")
                        :ARG1-of (i / isolate-01)))
            :op2 (t2 / treat-04
                  :ARG2 (s3 / small-molecule :name (n5 / name :op1 "PD153035"))))
      :ARG1 (s4 / survive-01
            :ARG1 (c / cell-line :name (n6 / name :op1 "C33A")))
      :ARG2 (p3 / proportion-01
            :ARG1-of (s5 / same-01))
      :ARG0-of (c2 / cause-01
            :ARG1 (r2 / reach-01
                  :ARG1 (i2 / inhibit-01
                        :ARG1 (a / and
                              :op1 (p2 / phosphorylate-01
                                    :ARG1 (e / enzyme :name (n2 / name :op1 "HER2")))
                              :op2 (p4 / phosphorylate-01
                                    :ARG1 (e2 / enzyme :name (n8 / name :op1 "AKT")))
                              :op3 (p5 / phosphorylate-01
                                    :ARG1 (e3 / enzyme :name (n3 / name :op1 "MAPK"))))
                        :mod (m / modest
                              :degree (m2 / more))
                        :compared-to (c3 / cell-line :name (n9 / name :op1 "Caski")))))
      :ARG1-of (d / describe-01
            :ARG0 (a2 / and
                  :op1 (f / figure :mod "4E")
                  :op2 (f2 / figure :mod "4G")))
      :time (a3 / assay-01
            :mod (c4 / clonogenic)))

# ::id pmid_1965_4571.135 ::date 2015-08-05T09:46:52 ::annotator SDL-AMR-09 ::preferred
# ::snt In contrast, the combined treatment proved to be antagonistic (<i>R</i>=1.28), with no decrease in phosphorylated proteins when compared to either drug alone (<xref ref-type="fig" rid="fig4">Figures 4E and G</xref>).
# ::save-date Wed Dec 30, 2015 ::file pmid_1965_4571_135.txt
(c / contrast-01
      :ARG2 (a2 / and
            :op1 (p / prove-01
                  :ARG1 (a / antagonize-01
                        :ARG0 (t / treat-04
                              :ARG1-of (c2 / combine-01))
                        :ARG1-of (m / mean-01
                              :ARG2 (s / string-entity :value "R"
                                    :ARG1-of (e2 / equal-01
                                          :ARG2 1.28)))))
            :op2 (d / decrease-01 :polarity -
                  :ARG1 (p2 / protein
                        :ARG3-of (p3 / phosphorylate-01))
                  :time (c3 / compare-01
                        :ARG1 t
                        :ARG2 (d2 / drug
                              :mod (e / either)
                              :mod (a3 / alone)))))
      :ARG1-of (d3 / describe-01
            :ARG0 (a4 / and
                  :op1 (f / figure :mod "4E")
                  :op2 (f2 / figure :mod "4G"))))

# ::id pmid_1965_4571.136 ::date 2015-08-05T09:57:43 ::annotator SDL-AMR-09 ::preferred
# ::snt Altogether, these data corroborate with our hypothesis that C33A cells are not so dependent on EGFR signalling for proliferation, as double EGFR inhibition with different drugs did not enhance the toxicity achieved by either agent alone.
# ::save-date Tue Aug 11, 2015 ::file pmid_1965_4571_136.txt
(c / corroborate-01
      :ARG0 (a / and
            :op1 (d / data
                  :mod (t2 / this))
            :op2 (t / thing
                  :ARG1-of (h / hypothesize-01
                        :ARG0 (w / we))))
      :ARG1 (d2 / depend-01 :polarity -
            :ARG0 (c2 / cell-line :name (n2 / name :op1 "C33A"))
            :ARG1 (s / signal-07
                  :ARG1 (e / enzyme :name (n / name :op1 "EGFR")))
            :purpose (p / proliferate-01)
            :ARG1-of (c3 / cause-01
                  :ARG0 (e2 / enhance-01 :polarity -
                        :ARG0 (i / inhibit-01
                              :ARG0 (d3 / drug
                                    :ARG1-of (d4 / differ-02))
                              :ARG1 e
                              :mod (d5 / double))
                        :ARG1 (t3 / toxicity
                              :ARG1-of (a2 / achieve-01
                                    :ARG0 (a3 / agent
                                          :mod (e3 / either)
                                          :mod (a4 / alone))))))
            :mod (s2 / so))
      :mod (a5 / altogether))

# ::id pmid_1965_4571.137 ::date 2015-08-05T10:07:59 ::annotator SDL-AMR-09 ::preferred
# ::snt Additionally, the targeting of EGFR and HER2 with two different MAbs showed synergistic inhibitory effects (<xref ref-type="fig" rid="fig4">Figures 4A and B</xref>) demonstrating that heterodimer signalling is necessary for C33A cell proliferation.
# ::save-date Tue Feb 2, 2016 ::file pmid_1965_4571_137.txt
(a / and
      :op2 (s / show-01
            :ARG0 (t / target-01
                  :ARG1 (a2 / and
                        :op1 (e / enzyme :name (n / name :op1 "EGFR"))
                        :op2 (e2 / enzyme :name (n2 / name :op1 "HER2")))
                  :ARG2 (a5 / antibody
                        :ARG1-of (d / differ-02)))
            :ARG1 (a3 / affect-01
                  :ARG2 (s2 / synergize-01)
                  :ARG0-of (i / inhibit-01))
            :ARG1-of (d2 / describe-01
                  :ARG0 (a4 / and
                        :op1 (f / figure :mod "4A")
                        :op2 (f2 / figure :mod "4B")))
            :ARG0-of (d3 / demonstrate-01
                  :ARG1 (n3 / need-01
                        :ARG1 (s4 / signal-07
                              :ARG1 (h / heterodimer))
                        :purpose (p / proliferate-01
                              :ARG0 (c / cell-line :name (n6 / name :op1 "C33A")))))))

# ::id pmid_1965_4571.138 ::date 2015-08-05T10:15:32 ::annotator SDL-AMR-09 ::preferred
# ::snt Furthermore, these data indicate that the successful inhibition of the MAPK and/or AKT pathways is a determinant factor for cetuximab efficacy in all CC cell lines.
# ::save-date Tue Aug 11, 2015 ::file pmid_1965_4571_138.txt
(a / and
      :op2 (i / indicate-01
            :ARG0 (d / data
                  :mod (t / this))
            :ARG1 (f / factor
                  :domain (i2 / inhibit-01
                        :ARG1 (a3 / and-or
                              :op1 (p / pathway :name (n / name :op1 "MAPK"))
                              :op2 (p2 / pathway :name (n2 / name :op1 "AKT")))
                        :ARG0-of (s / succeed-01))
                  :ARG1-of (d2 / determine-01
                        :ARG3 (e / efficient-01
                              :ARG1 (s3 / small-molecule :name (n3 / name :op1 "cetuximab"))
                              :location (c / cell-line
                                    :mod (d3 / disease :name (n4 / name :op1 "CC"))
                                    :mod (a2 / all)))))))

# ::id pmid_1965_4571.139 ::date 2015-08-05T10:23:05 ::annotator SDL-AMR-09 ::preferred
# ::snt <sec-title level="2">Cetuximab combined with PD98059 synergistically reduces cell proliferation and MAPK pathway activation in CC cells</sec-title>
# ::save-date Tue Feb 2, 2016 ::file pmid_1965_4571_139.txt
(r / reduce-01
      :ARG0 (s / small-molecule :name (n2 / name :op1 "cetuximab")
            :ARG1-of (c / combine-01
                  :ARG2 (s2 / small-molecule :name (n3 / name :op1 "PD98059"))))
      :ARG1 (a / and
            :op1 (p2 / proliferate-01
                  :ARG0 (c2 / cell))
            :op2 (a2 / activate-01
                  :ARG1 (p / pathway :name (n / name :op1 "MAPK"))))
      :manner (s3 / synergize-01)
      :location (c3 / cell-line
            :mod (d / disease :name (n4 / name :op1 "CC"))))

# ::id pmid_1965_4571.140 ::date 2015-08-05T10:29:40 ::annotator SDL-AMR-09 ::preferred
# ::snt To confirm that the MAPK pathway is relevant for cetuximab response, drug combination experiments with PD98059 (MEK1/2 inhibitor) were performed.
# ::save-date Wed Aug 5, 2015 ::file pmid_1965_4571_140.txt
(p2 / perform-01
      :ARG1 (e / experiment-01
            :ARG1 (s / small-molecule :name (n2 / name :op1 "PD98059")
                  :ARG0-of (i / inhibit-01
                        :ARG1 (e2 / enzyme :name (n3 / name :op1 "MEK1/2"))))
            :ARG2 (c / combine-01
                  :ARG1 (d / drug)))
      :purpose (c2 / confirm-01
            :ARG1 (r / relevant-01
                  :ARG1 (p / pathway :name (n / name :op1 "MAPK"))
                  :ARG2 (r2 / respond-01
                        :ARG1 (s2 / small-molecule :name (n4 / name :op1 "cetuximab"))))))

# ::id pmid_1965_4571.141 ::date 2015-08-05T11:05:10 ::annotator SDL-AMR-09 ::preferred
# ::snt Both treatments inhibited Caski and C33A cell proliferation by the same magnitude, with a reduction of 50% and an additive effect for the combination over single-drug treatment in both cell lines (<i>R</i>=0.88 and <i>R</i>=0.92, respectively; <xref ref-type="fig" rid="fig4">Figure 4F</xref>).
# ::save-date Wed Dec 30, 2015 ::file pmid_1965_4571_141.txt
(i / inhibit-01
      :ARG0 (t / treat-04
            :mod (b / both))
      :ARG1 (a / and
            :op1 (p2 / proliferate-01
                  :ARG0 (c / cell-line :name (n / name :op1 "Caski")))
            :op2 (p3 / proliferate-01
                  :ARG0 (c2 / cell-line :name (n2 / name :op1 "C33A"))))
      :manner (m / magnitude
            :ARG1-of (s / same-01))
      :ARG0-of (c3 / cause-01
            :ARG1 (a2 / and
                  :op1 (r / reduce-01
                        :ARG2 (p / percentage-entity :value 50)
                        :ARG1-of (m2 / mean-01
                              :ARG2 (s3 / string-entity :value "R"
                                    :ARG1-of (e / equal-01
                                          :ARG2 0.88))))
                  :op2 (a3 / affect-01
                        :ARG1 (c4 / combine-01
                              :compared-to (t2 / treat-01
                                    :ARG1 (c5 / cell-line)
                                    :ARG2 (d / drug
                                          :ARG1-of (s2 / single-02))))
                        :ARG1-of (a4 / add-02)
                        :ARG1-of (m3 / mean-01
                              :ARG2 (s4 / string-entity :value "R"
                                    :ARG1-of (e2 / equal-01
                                          :ARG2 0.92))))
                  :mod (r2 / respective)))
      :ARG1-of (d2 / describe-01
            :ARG0 (f / figure :mod "4F")))

# ::id pmid_1965_4571.142 ::date 2015-08-05T11:14:16 ::annotator SDL-AMR-09 ::preferred
# ::snt As expected, <xref ref-type="fig" rid="fig4">Figure 4H</xref> shows that a strong inhibition of MAPK phosphorylation was seen in both cell lines on treatment with PD98059 alone or in combination with cetuximab.
# ::save-date Sun Jan 17, 2016 ::file pmid_1965_4571_142.txt
(s / show-01
      :ARG0 (f / figure :mod "4H")
      :ARG1 (s2 / see-01
            :ARG1 (i / inhibit-01
                  :ARG1 (p2 / phosphorylate-01
                        :ARG1 (e2 / enzyme :name (n5 / name :op1 "MAPK")))
                  :ARG1-of (s3 / strong-02))
            :location (c / cell-line
                  :mod (b / both)
                  :ARG1-of (t / treat-04
                        :ARG2 (o / or
                              :op1 (s4 / small-molecule :name (n2 / name :op1 "PD98059")
                                    :mod (a / alone))
                              :op2 (c2 / combine-01
                                    :ARG1 (s5 / small-molecule :name (n3 / name :op1 "PD98059"))
                                    :ARG2 (s6 / small-molecule :name (n4 / name :op1 "cetuximab")))))))
      :ARG1-of (e / expect-01))

# ::id pmid_1965_4571.143 ::date 2015-08-05T11:26:24 ::annotator SDL-AMR-09 ::preferred
# ::snt As the combination of both treatments led to a near complete MAPK cascade blockage, accompanied by a significant reduction of CC cell proliferation, we confirmed that the inhibition of this pathway plays an important role in cetuximab's efficacy.
# ::save-date Wed Dec 30, 2015 ::file pmid_1965_4571_143.txt
(c / confirm-01
      :ARG0 (w / we)
      :ARG1 (p2 / play-02
            :ARG0 (i / inhibit-01
                  :ARG1 p)
            :ARG1 (r / role
                  :topic (e / efficient-01
                        :ARG1 (s / small-molecule :name (n2 / name :op1 "cetuximab")))
                  :mod (i2 / important)))
      :ARG1-of (c2 / cause-01
            :ARG0 (l / lead-03
                  :ARG0 (c3 / combine-01
                        :ARG1 (t / treat-04
                              :mod (b / both)))
                  :ARG2 (b2 / block-01
                        :ARG1 (p / pathway :name (n / name :op1 "MAPK"))
                        :ARG1-of (c5 / complete-01
                              :degree (n3 / near))
                        :ARG1-of (a / accompany-01
                              :ARG0 (r2 / reduce-01
                                    :ARG1 (p3 / proliferate-01
                                          :ARG0 (c6 / cell-line
                                                :mod (d / disease :wiki "Cervical_cancer" :name (n4 / name :op1 "cervical" :op2 "cancer"))))
                                    :ARG1-of (s2 / significant-02)))))))

# ::id pmid_1965_4571.144 ::date 2015-08-05T11:34:29 ::annotator SDL-AMR-09 ::preferred
# ::snt <sec-title level="2">Cetuximab induces ADCC in A431 and Caski, but not in C33A cells</sec-title>
# ::save-date Tue Aug 11, 2015 ::file pmid_1965_4571_144.txt
(c3 / contrast-01
      :ARG1 (i / induce-01
            :ARG0 (s / small-molecule :name (n / name :op1 "cetuximab"))
            :ARG1 (c5 / cytotoxicity
                  :mod (c6 / cellular)
                  :ARG0-of (d / depend-01
                        :ARG1 (a2 / antibody)))
            :location (a / and
                  :op1 (c / cell-line :name (n3 / name :op1 "A431"))
                  :op2 (c2 / cell-line :name (n4 / name :op1 "Caski"))))
      :ARG2 (i2 / induce-01 :polarity -
            :ARG0 s
            :ARG2 (t / thing)
            :location (c4 / cell-line :name (n5 / name :op1 "C33A"))))

# ::id pmid_1965_4571.145 ::date 2015-08-05T11:44:06 ::annotator SDL-AMR-09 ::preferred
# ::snt Antibody-dependent cellular cytotoxicity response is dependent on the number of EGFR molecules per cell and on how efficiently cetuximab recognises its target (<xref ref-type="other" rid="bib21">Vincenzi <i>et al</i>, 2008</xref>).
# ::save-date Tue Aug 11, 2015 ::file pmid_1965_4571_145.txt
(d2 / depend-01
      :ARG0 (r / respond-01
            :ARG2 (c / cytotoxicity
                  :mod (c2 / cell)
                  :ARG0-of (d3 / depend-01
                        :ARG1 (a / antibody))))
      :ARG1 (a2 / and
            :op1 (r2 / rate-entity-91
                  :ARG1 (n2 / number
                        :quant-of (m / molecule
                              :mod (e / enzyme :name (n / name :op1 "EGFR"))))
                  :ARG2 (c3 / cell))
            :op2 (r3 / recognize-02
                  :ARG0 (s / small-molecule :name (n3 / name :op1 "cetuximab"))
                  :ARG1 (t2 / thing
                        :ARG1-of (t / target-01
                              :ARG0 s))
                  :ARG1-of (e2 / efficient-01)))
      :ARG1-of (d4 / describe-01
            :ARG0 (p / publication-91
                  :ARG0 (a3 / and
                        :op1 (p2 / person :name (n4 / name :op1 "Vincenzi"))
                        :op2 (p3 / person
                              :mod (o / other)))
                  :time (d / date-entity :year 2008))))

# ::id pmid_1965_4571.146 ::date 2015-08-05T12:02:50 ::annotator SDL-AMR-09 ::preferred
# ::snt FACS analysis showed that cetuximab detected even more cell surface receptors in A431 and Caski cells (<i>P</i><0.05), when compared to a commercially available murine anti-EGFR MAb, although the same was not observed for C33A cells (<xref ref-type="fig" rid="fig5">Figure 5B</xref>).
# ::save-date Wed Jan 13, 2016 ::file pmid_1965_4571_146.txt
(s / show-01
      :ARG0 (a / analyze-01
            :mod (t / thing :name (n / name :op1 "FACS")))
      :ARG1 (d / detect-01
            :ARG0 (s2 / small-molecule :name (n2 / name :op1 "cetuximab"))
            :ARG1 (r / receptor
                  :mod (s3 / surface
                        :mod (c / cell))
                  :degree (m2 / more
                        :mod (e3 / even)))
            :location (a2 / and
                  :op1 (c2 / cell-line :name (n3 / name :op1 "A431"))
                  :op2 (c3 / cell-line :name (n4 / name :op1 "Caski")))
            :time (c4 / compare-01
                  :ARG1 s2
                  :ARG2 (a4 / antibody
                        :ARG0-of (c5 / counter-01
                              :ARG1 (e2 / enzyme :name (n6 / name :op1 "EGFR")))
                        :ARG2-of (a3 / available-02
                              :manner (c6 / commerce))
                        :mod (o2 / organism :name (n8 / name :op1 "Muridae"))
                        :mod (m / monoclone)))
            :concession (o / observe-01 :polarity -
                        :ARG1 (s5 / same-01)
                        :location (c7 / cell-line :name (n7 / name :op1 "C33A")))
            :ARG1-of (s6 / statistical-test-91
                  :ARG2 (l / less-than :op1 0.05)))
      :ARG1-of (d2 / describe-01
            :ARG0 (f / figure :mod "5B")))

# ::id pmid_1965_4571.147 ::date 2015-08-05T12:30:23 ::annotator SDL-AMR-09 ::preferred
# ::snt Accordingly, at E/T ratios of 20 : 1, cetuximab mediated ADCC in 26.4 and 15.1% of A431 and Caski cells, respectively, but not in C33A cells (1.75%; <xref ref-type="fig" rid="fig5">Figure 5C</xref>).
# ::save-date Tue Aug 11, 2015 ::file pmid_1965_4571_147.txt
(c3 / contrast-01
      :ARG1 (m / mediate-01
            :ARG0 (s / small-molecule :name (n / name :op1 "cetuximab"))
            :ARG1 (c5 / cytotoxicity
                  :mod (c6 / cellular)
                  :ARG0-of (d2 / depend-01
                        :ARG1 (a3 / antibody)))
            :location (a / and
                  :op1 (c / cell-line :name (n3 / name :op1 "A431")
                        :quant (p3 / percentage-entity :value 26.4))
                  :op2 (c2 / cell-line :name (n4 / name :op1 "Caski")
                        :quant (p / percentage-entity :value 15.1))
                  :mod (r / respective))
            :manner (a2 / accordingly))
      :ARG2 (m2 / mediate-01 :polarity -
            :ARG0 s
            :ARG1 (t / thing)
            :location (c4 / cell-line :name (n5 / name :op1 "C33A")
                  :quant (p2 / percentage-entity :value 1.75)))
      :condition (e / equal-01
                  :ARG1 (r3 / ratio-of
                        :op1 (e2 / effector)
                        :op2 (t2 / target-01))
                  :ARG2 (r4 / ratio-of :op1 20 :op2 1))
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod "5C")))

# ::id pmid_1965_4571.148 ::date 2015-08-05T12:47:00 ::annotator SDL-AMR-09 ::preferred
# ::snt <sec-title level="2">Cetuximab and RxT cooperate in an additive manner to inhibit VEGF secretion</sec-title>
# ::save-date Wed Aug 12, 2015 ::file pmid_1965_4571_148.txt
(c / cooperate-01
      :ARG0 (s / small-molecule :name (n / name :op1 "cetuximab"))
      :ARG1 (r / radiotherapy)
      :ARG2 (i / inhibit-01
            :ARG0 (a2 / and
                  :op1 s
                  :op2 r)
            :ARG1 (s3 / secrete-01
                  :ARG1 (p / protein :name (n3 / name :op1 "VEGF"))))
      :manner (a / additive))

# ::id pmid_1965_4571.149 ::date 2015-08-05T12:52:37 ::annotator SDL-AMR-09 ::preferred
# ::snt Anti-EGFR MAbs show suppressive effects on VEGF expression <i>in vitro</i> and <i>in vivo</i> (<xref ref-type="other" rid="bib21">Vincenzi <i>et al</i>, 2008</xref>; <xref ref-type="other" rid="bib16">Meira <i>et al</i>, 2009</xref>).
# ::save-date Tue Aug 11, 2015 ::file pmid_1965_4571_149.txt
(s / show-01
      :ARG0 (s2 / small-molecule :name (n / name :op1 "MAbs")
            :ARG0-of (c / counter-01
                  :ARG1 (e / enzyme :name (n2 / name :op1 "EGFR"))))
      :ARG1 (a / affect-01
            :ARG1 (e2 / express-03
                  :ARG2 (p / protein :name (n3 / name :op1 "VEGF"))
                  :manner (a2 / and
                        :op1 (i / in-vitro)
                        :op2 (i2 / in-vivo)))
            :ARG0-of (s3 / suppress-01))
      :ARG1-of (d3 / describe-01
            :ARG0 (a3 / and
                  :op1 (p2 / publication-91
                        :ARG0 (a4 / and
                              :op1 (p3 / person :name (n4 / name :op1 "Vincenzi"))
                              :op2 (p4 / person
                                    :mod (o / other)))
                        :time (d / date-entity :year 2008))
                  :op2 (p5 / publication-91
                        :ARG0 (a5 / and
                              :op1 (p6 / person :name (n5 / name :op1 "Meira"))
                              :op2 p4)
                        :time (d2 / date-entity :year 2009)))))

# ::id pmid_1965_4571.150 ::date 2015-08-05T13:41:18 ::annotator SDL-AMR-09 ::preferred
# ::snt To examine whether cetuximab (100 <i>μ</i>g ml<sup>−1</sup>) had this effect in CC cells, we tested it alone or combined with RxT (5 Gy) and VEGF expression was analysed by ELISA.
# ::save-date Thu Dec 10, 2015 ::file pmid_1965_4571_150.txt
(a / and
      :op1 (t / test-01
            :ARG0 (w / we)
            :ARG1 (o / or
                  :op1 s4
                  :op2 (c / combine-01
                        :ARG1 s4
                        :ARG2 (r2 / radiotherapy
                              :quant (r / radiation-quantity :quant 5
                                    :unit (g / gray))))))
      :op2 (a3 / analyze-01
            :ARG0 (t2 / thing :name (n5 / name :op1 "ELISA"))
            :ARG1 (e / express-03
                  :ARG2 (p / protein :name (n4 / name :op1 "VEGF"))))
      :purpose (e2 / examine-01
            :ARG0 w
            :ARG1 (h / have-03 :mode interrogative
                  :ARG0 (s4 / small-molecule :name (n7 / name :op1 "cetuximab")
                        :quant (v / volume-quantity :quant 100
                              :unit (m / microgram-per-milliliter)))
                  :ARG1 (a4 / affect-01
                        :location (c2 / cell-line
                              :mod (d / disease :wiki "Cervical_cancer" :name (n / name :op1 "cervical" :op2 "cancer")))))))

# ::id pmid_1965_4571.151 ::date 2015-08-05T13:55:48 ::annotator SDL-AMR-09 ::preferred
# ::snt Cetuximab or RxT treatments decreased VEGF secretion in all cell lines (<xref ref-type="fig" rid="fig5">Figures 5D–F</xref>; <i>P</i><0.05).
# ::save-date Tue Dec 15, 2015 ::file pmid_1965_4571_151.txt
(d / decrease-01
      :ARG0 (o / or
            :op1 (t / treat-04
                  :ARG2 (s / small-molecule :name (n / name :op1 "cetuximab")))
            :op2 (t2 / treat-04
                  :ARG2 (r / radiotherapy)))
      :ARG1 (s3 / secrete-01
            :ARG1 (p / protein :name (n3 / name :op1 "VEGF")))
      :location (c / cell-line
            :mod (a / all))
      :ARG1-of (d2 / describe-01
            :ARG0 (v / value-interval
                  :op1 (f / figure :mod "5D")
                  :op2 (f2 / figure :mod "5F")))
      :ARG1-of (s2 / statistical-test-91
            :ARG2 (l / less-than :op1 0.05)))

# ::id pmid_1965_4571.152 ::date 2015-08-05T13:59:31 ::annotator SDL-AMR-09 ::preferred
# ::snt The combination of cetuximab with RxT for 24 h had an additive effect and, after 48 h of treatment, a further reduction was observed (<xref ref-type="fig" rid="fig5">Figures 5D–F</xref>), suggesting that these treatments have the potential of interfering with angiogenesis even in cells that do not express high EGFR levels.
# ::save-date Wed Dec 30, 2015 ::file pmid_1965_4571_152.txt
(a / and
      :op1 (h / have-03
            :ARG0 (c / combine-01
                  :ARG1 (s / small-molecule :name (n2 / name :op1 "cetuximab"))
                  :ARG2 (r2 / radiotherapy)
                  :duration (t / temporal-quantity :quant 24
                        :unit (h2 / hour)))
            :ARG1 (a2 / affect-01
                  :ARG1-of (a3 / add-02)))
      :op2 (o / observe-01
            :ARG1 (r / reduce-01
                  :degree (f / further)
                  :ARG0-of (s3 / suggest-01
                        :ARG1 (c2 / capable-01
                              :ARG1 (t2 / treat-04
                                    :mod (t3 / this))
                              :ARG2 (i / interfere-01
                                    :ARG0 t2
                                    :ARG1 (a4 / angiogenesis)
                                    :location (c3 / cell-line
                                          :mod (e2 / even)
                                          :ARG3-of (e3 / express-03 :polarity -
                                                :ARG2 (l / level
                                                      :quant-of (e4 / enzyme :name (n4 / name :op1 "EGFR"))
                                                      :ARG1-of (h3 / high-02))))))))
            :ARG1-of (d / describe-01
                  :ARG0 (a6 / and
                        :op1 (f2 / figure :mod "5D")
                        :op2 (f3 / figure :mod "5E")
                        :op3 (f4 / figure :mod "5F")))
            :time (a5 / after
                  :op1 (t4 / treat-04)
                  :quant (t5 / temporal-quantity :quant 48
                        :unit (h4 / hour)))))

# ::id pmid_2023_3444.1 ::date 2015-08-03T12:21:47 ::annotator SDL-AMR-09 ::preferred
# ::snt A rapid, sensitive, reproducible and cost-effective method for mutation profiling of colon cancer and metastatic lymph nodes (PMID:20233444)
# ::save-date Thu Dec 10, 2015 ::file pmid_2023_3444_1.txt
(p3 / publication-91 :ARG8 "PMID20233444"
      :ARG1 (m / method
            :ARG1-of (d / describe-01)
            :mod (r / rapid)
            :ARG0-of (s / sensitive-03)
            :ARG1-of (r2 / reproduce-01
                  :ARG1-of (p2 / possible-01))
            :ARG0-of (a2 / affect-01
                  :ARG1 (c / cost))
            :purpose (p / profile-01
                  :ARG0 (m2 / mutate-01
                        :ARG1 (a3 / and
                              :op1 (d2 / disease :wiki "Colorectal_cancer"
                                    :name (n2 / name :op1 "colon" :op2 "cancer"))
                              :op2 (n / node
                                    :mod (l / lymph)
                                    :ARG1-of (m3 / metastasize-101)))))))

# ::id pmid_2023_3444.7 ::date 2015-08-03T12:28:45 ::annotator SDL-AMR-09 ::preferred
# ::snt <sec-title level="1" sec-area="abstract">Results</sec-title>
# ::save-date Mon Aug 3, 2015 ::file pmid_2023_3444_7.txt
(t / thing
      :ARG2-of (r / result-01))

# ::id pmid_2023_3444.8 ::date 2015-08-03T12:33:34 ::annotator SDL-AMR-09 ::preferred
# ::snt Among the 238 common hot-spot cancer mutations in 19 genes interrogated by the OncoCarta panel, mutations were detected in 7 different genes at 26 different nucleotide positions in our colon cancer samples.
# ::save-date Wed Feb 24, 2016 ::file pmid_2023_3444_8.txt
(d / detect-01
      :ARG1 (m / mutate-01
            :ARG1 (g / gene :quant 7
                  :ARG1-of (d2 / differ-02)
                  :part (p / position :quant 26
                        :mod (n / nucleotide)
                        :ARG1-of d2
                        :location (d3 / disease :wiki "Colorectal_cancer" :name (n3 / name :op1 "colon" :op2 "cancer")
                              :ARG1-of (s / sample-01
                                    :ARG0 (w / we)))))
            :ARG1-of (i2 / include-91
                  :ARG2 (m2 / mutate-01 :quant 238
                        :ARG1 (g2 / gene :quant 19
                              :ARG1-of (i / interrogate-01
                                    :ARG0 (p2 / panel :name (n2 / name :op1 "OncoCarta"))))
                        :ARG1-of (s2 / share-01
                              :degree (m3 / most))
                        :mod (h / hotspot)))))

# ::id pmid_2023_3444.9 ::date 2015-08-05T00:19:23 ::annotator SDL-AMR-09 ::preferred
# ::snt Twenty-four assays that detected mutations in more than 1% of the samples were reconfigured into a new multiplexed panel, termed here as ColoCarta.
# ::save-date Fri Feb 5, 2016 ::file pmid_2023_3444_9.txt
(c / configure-01
      :ARG1 (a / assay-01 :quant 24
            :ARG0-of (d / detect-01
                  :ARG1 (m / mutate-01)
                  :location (t2 / thing
                        :quant (m2 / more-than
                              :op1 (p / percentage-entity :value 1))
                        :ARG1-of (s / sample-01))))
      :ARG4 (p2 / panel
            :ARG1-of (n / new-01)
            :mod (m3 / multiplex)
            :ARG1-of (t / term-01
                  :ARG3 (p3 / panel :name (n2 / name :op1 "ColoCarta"))
                  :location (h / here)))
      :mod (a2 / again))

# ::id pmid_2023_3444.10 ::date 2015-08-05T00:24:22 ::annotator SDL-AMR-09 ::preferred
# ::snt Mutation profiling was repeated on 32 mutant samples using ColoCarta and the results were identical to results with OncoCarta, demonstrating that this methodology was reproducible.
# ::save-date Sun Jan 17, 2016 ::file pmid_2023_3444_10.txt
(a / and
      :op1 (r4 / repeat-01
            :ARG1 (p2 / profile-01
                  :ARG1 (m2 / mutate-01))
            :ARG3 (m4 / mutate-01 :quant 32
                  :ARG1-of (s / sample-01))
            :manner (u / use-01
                  :ARG1 (p3 / panel :name (n2 / name :op1 "ColoCarta"))))
      :op2 (i / identical-01
            :ARG1 (t / thing
                  :ARG2-of (r / result-01))
            :ARG2 (t2 / thing
                  :ARG2-of (r2 / result-01)
                  :instrument (p / product :name (n / name :op1 "OncoCarta")))
            :ARG0-of (d / demonstrate-01
                  :ARG1 (p4 / possible-01
                        :ARG1 (r3 / reproduce-01
                              :ARG0 (m / methodology
                                    :mod (t3 / this)))))))

# ::id pmid_2023_3444.11 ::date 2015-08-05T00:28:25 ::annotator SDL-AMR-09 ::preferred
# ::snt Further evidence demonstrating the validity of the data was the fact that the mutation frequencies of the most common colon cancer mutations were similar to the COSMIC (Catalog of Somatic Mutations in Cancer) database.
# ::save-date Thu Dec 10, 2015 ::file pmid_2023_3444_11.txt
(e / evidence-01
      :ARG0 (r / resemble-01
            :ARG1 (h / have-frequency-91
                  :ARG1 (m2 / mutate-01
                        :ARG1 (d4 / disease :wiki "Colorectal_cancer" :name (n2 / name :op1 "colon" :op2 "cancer"))
                        :ARG1-of (s / share-01
                              :degree (m3 / most)))
                  :mod (m / mutate-01))
            :ARG2 (m4 / mutate-01
                  :source (d / database :name (n / name :op1 "COSMIC"))))
      :degree (f / further)
      :ARG0-of (d2 / demonstrate-01
            :ARG1 (v / valid-02
                  :ARG1 (d3 / data))))

# ::id pmid_2023_3444.12 ::date 2015-08-04T03:35:45 ::annotator SDL-AMR-09 ::preferred
# ::snt The frequencies were 43.5% for <i>KRAS</i>, 20.1% for <i>PIK3CA</i>, and 12.1% for <i>BRAF</i>.
# ::save-date Thu Aug 6, 2015 ::file pmid_2023_3444_12.txt
(a2 / and
      :op1 (h / have-frequency-91
            :ARG1 (g2 / gene :name (n2 / name :op1 "KRAS"))
            :ARG2 (p / percentage-entity :value 43.5))
      :op2 (h2 / have-frequency-91
            :ARG1 (g / gene :name (n / name :op1 "PIK3CA"))
            :ARG2 (p2 / percentage-entity :value 20.1))
      :op3 (h3 / have-frequency-91
            :ARG1 (g3 / gene :name (n3 / name :op1 "BRAF"))
            :ARG2 (p3 / percentage-entity :value 12.1)))

# ::id pmid_2023_3444.13 ::date 2015-08-03T12:22:30 ::annotator SDL-AMR-09 ::preferred
# ::snt In addition, infrequent mutations in <i>NRAS</i>, <i>AKT1</i>, <i>ABL1</i>, and <i>MET </i>were detected.
# ::save-date Mon Aug 10, 2015 ::file pmid_2023_3444_13.txt
(a / and
      :op2 (d / detect-01
            :ARG1 (m / mutate-01
                  :ARG1 (a2 / and
                        :op1 (g4 / gene :name (n / name :op1 "NRAS"))
                        :op2 (g / gene :name (n2 / name :op1 "AKT1"))
                        :op3 (g2 / gene :name (n3 / name :op1 "ABL1"))
                        :op4 (g3 / gene :name (n4 / name :op1 "MET")))
                  :ARG1-of (f / frequent-02 :polarity -))))

# ::id pmid_2023_3444.14 ::date 2015-08-03T12:26:40 ::annotator SDL-AMR-09 ::preferred
# ::snt Mutation profiling of metastatic lymph nodes and their corresponding primary tumors showed that they were 89.7% concordant.
# ::save-date Mon Aug 10, 2015 ::file pmid_2023_3444_14.txt
(s / show-01
      :ARG0 (a / and
            :op1 (p2 / profile-01
                  :ARG1 (m / mutate-01
                        :ARG1 (n / node
                              :mod (l / lymph
                                    :mod (m2 / metastasis)))))
            :op2 (t / tumor
                  :mod (p3 / primary)
                  :ARG1-of (c / correspond-02
                        :ARG2 n)))
      :ARG1 (c2 / concordant
            :domain a
            :mod (p / percentage-entity :value 89.7)))

# ::id pmid_2023_3444.15 ::date 2015-08-04T08:48:38 ::annotator SDL-AMR-09 ::preferred
# ::snt All mutations found in the lymph nodes were also found in the corresponding primary tumors, but in 4 cases a mutation was present in the primary tumor only.
# ::save-date Sat Jan 30, 2016 ::file pmid_2023_3444_15.txt
(c / contrast-01
      :ARG1 (f2 / find-01
            :ARG1 (m / mutate-01
                  :ARG1-of (f / find-01
                        :location (n / node
                              :mod (l / lymph)))
                  :mod (a / all))
            :location (t / tumor
                  :mod (p / primary)
                  :ARG1-of (c2 / correspond-02))
            :mod (a2 / also))
      :ARG2 (m2 / mutate-01 :quant 1
            :mod (c3 / case-04 :quant 4)
            :location (t2 / tumor
                  :mod p
                  :mod (o / only))))

# ::id pmid_2023_3444.91 ::date 2015-08-03T12:39:57 ::annotator SDL-AMR-09 ::preferred
# ::snt <sec-title level="1">Results</sec-title>
# ::save-date Wed Aug 5, 2015 ::file pmid_2023_3444_91.txt
(t / thing
      :ARG2-of (r / result-01))

# ::id pmid_2023_3444.92 ::date 2015-08-03T13:08:48 ::annotator SDL-AMR-09 ::preferred
# ::snt <sec-title level="2">Mutations were detected in control DNAs from intact and FFPETsamples</sec-title>
# ::save-date Mon Aug 10, 2015 ::file pmid_2023_3444_92.txt
(d / detect-01
      :ARG1 (m / mutate-01)
      :location (n2 / nucleic-acid :wiki "DNA" :name (n3 / name :op1 "DNA")
            :ARG0-of (c / control-01)
            :source (a / and
                  :op1 (t2 / thing
                        :mod (i / intact)
                        :ARG1-of (s / sample-01))
                  :op2 (t3 / thing :name (n / name :op1 "FFPET")
                        :ARG1-of s))))

# ::id pmid_2023_3444.93 ::date 2015-08-03T14:15:02 ::annotator SDL-AMR-09 ::preferred
# ::snt Previously described mutations in control cell lines were detected.
# ::save-date Mon Aug 3, 2015 ::file pmid_2023_3444_93.txt
(d / detect-01
      :ARG1 (m / mutate-01
            :ARG1-of (d2 / describe-01
                  :time (p / previous))
            :location (c / cell-line
                  :ARG0-of (c2 / control-01))))

# ::id pmid_2023_3444.94 ::date 2015-08-03T14:26:58 ::annotator SDL-AMR-09 ::preferred
# ::snt <i>BRAF</i>_V600E, <i>HRAS</i>_G12D, <i>NRAS</i>_Q61L, <i>PIK3CA</i>_E545K, <i>KRAS</i>_G13D, <i>NRAS</i>_Q61K, <i>EGFR</i>1_S125L, and <i>PIK3CA</i>_H1047R were detected in the appropriate cell lines (A2058, HS578T, HL60, MCF7, MDAMB231, NCI-H1299, NCI-H1395, and UACC-893, respectively).
# ::save-date Tue Jan 12, 2016 ::file pmid_2023_3444_94.txt
(d / detect-01
      :ARG1 (a3 / and
            :op1 (g2 / gene :wiki "BRAF_(gene)"
                  :name (n3 / name :op1 "BRAF")
                  :ARG1-of (m2 / mutate-01 :value "V600E"))
            :op2 (g3 / gene :wiki -
                  :name (n4 / name :op1 "HRAS")
                  :ARG1-of (m3 / mutate-01 :value "G12D"))
            :op3 (g4 / gene :wiki -
                  :name (n5 / name :op1 "NRAS")
                  :ARG1-of (m4 / mutate-01 :value "Q61L"))
            :op4 (g5 / gene :wiki -
                  :name (n6 / name :op1 "PIK3CA")
                  :ARG1-of (m5 / mutate-01 :value "E545K"))
            :op5 (g6 / gene :wiki -
                  :name (n7 / name :op1 "KRAS")
                  :ARG1-of (m6 / mutate-01 :value "G13D"))
            :op6 (g7 / gene :wiki -
                  :name (n8 / name :op1 "NRAS")
                  :ARG1-of (m7 / mutate-01 :value "Q61K"))
            :op7 (g / gene :wiki -
                  :name (n2 / name :op1 "EGFR")
                  :ARG1-of (m9 / mutate-01 :value "S125L"))
            :op8 (g8 / gene :wiki -
                  :name (n / name :op1 "PIK3CA")
                  :ARG1-of (m8 / mutate-01 :value "H1047R")))
      :location (c / cell-line
            :ARG1-of (a / appropriate-02)
            :ARG1-of (m / mean-01
                  :ARG2 (a2 / and
                        :op1 (c2 / cell-line :wiki -
                              :name (n9 / name :op1 "A2058"))
                        :op2 (c3 / cell-line :wiki -
                              :name (n16 / name :op1 "HS578T"))
                        :op3 (c4 / cell-line :wiki "HL60"
                              :name (n12 / name :op1 "HL60"))
                        :op4 (c5 / cell-line :wiki "MCF-7"
                              :name (n15 / name :op1 "MCF7"))
                        :op5 (c6 / cell-line :wiki -
                              :name (n13 / name :op1 "MDAMB231"))
                        :op6 (c7 / cell-line :wiki -
                              :name (n11 / name :op1 "NCI-H1299"))
                        :op7 (c8 / cell-line :wiki -
                              :name (n14 / name :op1 "NCI-H1395"))
                        :op8 (c9 / cell-line :wiki -
                              :name (n10 / name :op1 "UACC-893"))))))

# ::id pmid_2023_3444.95 ::date 2015-08-04T07:04:52 ::annotator SDL-AMR-09 ::preferred
# ::snt The appropriate mutation was found in MCF-7 (<i>PIK3CA</i>_E545K) from both intact DNA and DNA isolated from FFPET.
# ::save-date Thu Aug 6, 2015 ::file pmid_2023_3444_95.txt
(f / find-01
      :ARG1 (m / mutate-01
            :ARG1-of (a / appropriate-02))
      :location (c / cell-line :name (n / name :op1 "MCF-7")
            :ARG1-of (m2 / mean-01
                  :ARG2 (g / gene :name (n2 / name :op1 "PIK3CA")
                        :ARG1-of (m3 / mutate-01 :value "E545K")))
            :location (a3 / and
                  :op1 (n3 / nucleic-acid :wiki "DNA" :name (n5 / name :op1 "DNA")
                        :mod (i / intact))
                  :op2 (n6 / nucleic-acid :wiki "DNA" :name (n7 / name :op1 "DNA")
                        :ARG1-of (i2 / isolate-01
                              :ARG2 (t / thing :name (n4 / name :op1 "FFPET")))))))

# ::id pmid_2023_3444.96 ::date 2015-08-04T07:33:58 ::annotator SDL-AMR-09 ::preferred
# ::snt DNAs from clinical samples, control cell lines, and cell lines formalin-fixed, paraffin-embedded cell lines showed the same rates of primer extension and performance on mass spectrometer.
# ::save-date Thu Aug 6, 2015 ::file pmid_2023_3444_96.txt
(s / show-01
      :ARG0 (n / nucleic-acid :wiki "DNA" :name (n2 / name :op1 "DNA")
            :source (a2 / and
                  :op1 (t / thing
                        :mod (c / clinic)
                        :ARG1-of (s4 / sample-01))
                  :op2 (c2 / cell-line
                        :ARG1-of (c3 / control-01))
                  :op3 (c4 / cell-line
                        :ARG0-of (f / fix-01
                              :ARG1 (f2 / formalin)))
                  :op4 (c5 / cell-line
                        :ARG1-of (e2 / embed-01
                              :ARG2 (p3 / paraffin)))))
      :ARG1 (r / rate-entity-91
            :ARG1 (a / and
                  :op1 (e / extend-01
                        :instrument (s3 / spectometer
                              :mod (m / mass))
                        :mod (p / primer))
                  :op2 (p2 / perform-01
                        :instrument s3))
            :ARG1-of (s2 / same-01)))

# ::id pmid_2023_3444.97 ::date 2015-08-05T00:02:09 ::annotator SDL-AMR-09 ::preferred
# ::snt The proportion of the mutated alleles in each cell line, as observed from the area under the mutant peak on the spectra, ranged from 0.4-0.6, as expected for a pure clonal population with a heterozygote mutation.
# ::save-date Thu Aug 6, 2015 ::file pmid_2023_3444_97.txt
(r / range-01
      :ARG1 (p2 / proportion-01
            :ARG1 (a / allele
                  :ARG1-of (m2 / mutate-01)
                  :location (c2 / cell-line
                        :mod (e2 / each)))
            :ARG1-of (o / observe-01
                  :location (a2 / area
                        :location (u / under
                              :op1 (p3 / peak
                                    :ARG0-of (m3 / mutate-01)
                                    :location (s / spectrum))))))
      :ARG3 0.4
      :ARG4 0.6
      :ARG1-of (e / expect-01
            :prep-for (p / population
                  :mod (c / clone)
                  :ARG1-of (m / mutate-01
                        :ARG3 (h / heterozygote))
                  :mod (p4 / pure))))

# ::id pmid_2023_3444.98 ::date 2015-08-04T08:49:31 ::annotator SDL-AMR-09 ::preferred
# ::snt Spectra for cell line UACC-893 had equal fractions of mutant and wt alleles (Fig. <xref ref-type="fig" rid="F2">2A</xref>).
# ::save-date Thu Aug 6, 2015 ::file pmid_2023_3444_98.txt
(h / have-03
      :ARG0 (s / spectrum
            :mod (c / cell-line :name (n / name :op1 "UACC-893")))
      :ARG1 (e / equal-01
            :ARG1 (f / fraction-01
                  :ARG1 (a / allele
                        :ARG1-of (m / mutate-01)))
            :ARG2 (f2 / fraction-01
                  :ARG1 (a2 / allele
                        :mod (w / wild-type))))
      :ARG1-of (d / describe-01
            :ARG0 (f3 / figure :mod "2A")))

# ::id pmid_2023_3444.99 ::date 2015-08-04T09:15:40 ::annotator SDL-AMR-09 ::preferred
# ::snt One exception to this distribution among cell lines was seen in A2058, which showed spectra consistent with 2 copies of the WT allele and one mutant <i>BRAF </i>mutant allele (Fig. <xref ref-type="fig" rid="F2">2B</xref>).
# ::save-date Thu Aug 6, 2015 ::file pmid_2023_3444_99.txt
(s / see-01
      :ARG1 (t / thing
            :ARG1-of (e / except-01
                  :ARG2 (d2 / distribute-01
                        :ARG1 (c2 / cell-line)
                        :mod (t2 / this))))
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod "2B"))
      :location (c / cell-line :name (n / name :op1 "A2058")
            :ARG0-of (s2 / show-01
                  :ARG1 (s3 / spectra
                        :ARG1-of (c3 / consistent-01
                              :ARG2 (a / and
                                    :op1 (c4 / copy-01 :quant 2
                                          :ARG1 (a2 / allele
                                                :mod (w / wild-type)))
                                    :op2 (c5 / copy-01
                                          :ARG1 (a3 / allele
                                                :ARG3-of (m / mutate-01
                                                      :ARG1 (g / gene :name (n2 / name :op1 "BRAF")))))))))))

# ::id pmid_2023_3444.100 ::date 2015-08-04T09:55:13 ::annotator SDL-AMR-09 ::preferred
# ::snt The 3 alleles of <i>BRAF </i>in A2058 are consistent with the observation that there are 3 copies of chromosome 7 in this cell line (COSMIC in the SNP Array Based LOH and Copy Number Analysis data base) [<xref ref-type="bibr" rid="B21">21</xref>].
# ::save-date Mon Aug 10, 2015 ::file pmid_2023_3444_100.txt
(c / consistent-01
      :ARG1 (a / allele :quant 3
            :mod (g / gene :name (n / name :op1 "BRAF"))
            :location (c2 / cell-line :name (n2 / name :op1 "A2058")))
      :ARG2 (o / observe-01
            :ARG1 (b / be-located-at-91
                  :ARG1 (c3 / copy-01 :quant 3
                        :ARG1 (c4 / chromosome :mod 7))
                  :ARG2 (c5 / cell-line
                        :mod (t / this))))
      :ARG1-of (d / describe-01
            :ARG0 (d2 / database :name (n3 / name :op1 "COSMIC")
                  :location (a3 / and
                        :op1 (d5 / database :name (n6 / name :op1 "SNP" :op2 "Array" :op3 "Based" :op4 "LOH"))
                        :op2 (d3 / database :name (n5 / name :op1 "Copy" :op2 "Number" :op3 "Analysis")))))
      :ARG1-of (d4 / describe-01
            :ARG0 (p / publication
                  :ARG0-of (c6 / cite-01
                        :ARG1 21))))

# ::id pmid_2023_3444.101 ::date 2015-08-04T03:40:50 ::annotator SDL-AMR-09 ::preferred
# ::snt <sec-title level="2">The Sequenom platform was sensitive and quantitative</sec-title>
# ::save-date Tue Aug 4, 2015 ::file pmid_2023_3444_101.txt
(a / and
      :op1 (s / sensitive-03
            :ARG0 (p / platform :name (n / name :op1 "Sequenom")))
      :op2 (q / quantitative
            :domain p))

# ::id pmid_2023_3444.102 ::date 2015-08-04T03:44:51 ::annotator SDL-AMR-09 ::preferred
# ::snt Pilot studies demonstrated that the assays worked with as little as 1 ng of DNA (Fig. <xref ref-type="fig" rid="F3">3</xref>).
# ::save-date Thu Aug 6, 2015 ::file pmid_2023_3444_102.txt
(d / demonstrate-01
      :ARG0 (s / study-01
            :mod (p / pilot))
      :ARG1 (w / work-09
            :ARG1 (a / assay-01
                  :mod (c / concentration-quantity :quant 1
                        :unit (n / nanogram)
                        :mod (l / little
                              :compared-to (n2 / nucleic-acid :wiki "DNA" :name (n3 / name :op1 "DNA"))))))
      :ARG1-of (d3 / describe-01
            :ARG0 (f / figure :mod 3)))

# ::id pmid_2023_3444.103 ::date 2015-08-04T03:51:34 ::annotator SDL-AMR-09 ::preferred
# ::snt The fraction of unextended primer was .09 even when the input DNA was between 1-3 ng, When concentrations of the amount of DNA was between 3-14 ng, the fraction of unextended primer was similar, .07.
# ::save-date Mon Aug 10, 2015 ::file pmid_2023_3444_103.txt
(m / multi-sentence
      :snt1 (f4 / fraction :quant 0.09
            :part-of (p / primer
                  :ARG1-of (e / extend-01 :polarity -))
            :condition (n3 / nucleic-acid :wiki "DNA" :name (n4 / name :op1 "DNA")
                  :mod (i / input)
                  :quant (b / between
                        :op1 (c / concentration-quantity :quant 1
                              :unit (n / nanogram))
                        :op2 (c2 / concentration-quantity :quant 3
                              :unit n))))
      :snt2 (f5 / fraction
            :part-of (p2 / primer :quant 0.07
                  :ARG1-of (e2 / extend-01 :polarity -))
            :condition (c3 / concentrate-02
                  :ARG1 (a / amount-01
                        :ARG1 (n5 / nucleic-acid :wiki "DNA" :name (n6 / name :op1 "DNA"))
                        :ARG2 (b2 / between
                              :op1 (c4 / concentration-quantity :quant 3
                                    :unit n2)
                              :op2 (c5 / concentration-quantity :quant 14
                                    :unit (n2 / nanogram)))))
            :ARG1-of (r / resemble-01)))

# ::id pmid_2023_3444.104 ::date 2015-08-04T03:28:08 ::annotator SDL-AMR-09 ::preferred
# ::snt Thus, the assays worked well even when only 1 ng of DNA was used.
# ::save-date Thu Aug 6, 2015 ::file pmid_2023_3444_104.txt
(c3 / cause-01
      :ARG1 (w / work-09
            :ARG1 (a / assay-01)
            :manner (w2 / well)
            :concession (e / even-when
                  :op1 (u / use-01
                        :ARG1 (n2 / nucleic-acid :wiki "DNA" :name (n3 / name :op1 "DNA")
                              :quant (c2 / concentration-quantity :quant 1
                                    :unit (n / nanogram)
                                    :mod (o / only))))))
      :ARG2-of (c / contrast-01))

# ::id pmid_2023_3444.105 ::date 2015-08-04T03:32:50 ::annotator SDL-AMR-09 ::preferred
# ::snt In clinical samples with some assays it was possible to detect mutations that only represented 5% of the total 2 peak areas.
# ::save-date Mon Aug 10, 2015 ::file pmid_2023_3444_105.txt
(p2 / possible-01
      :ARG1 (d / detect-01
            :ARG1 (m / mutate-01
                  :ARG0-of (r / represent-01
                        :ARG1 (p / percentage-entity :value 5
                              :ARG3-of (i / include-91
                                    :ARG1 (a2 / area :quant 2
                                          :mod (t / total)
                                          :mod (p3 / peak))))
                        :mod (o / only)))
            :location (t2 / thing
                  :ARG1-of (s / sample-01
                        :manner (a / assay-01
                              :quant (s2 / some))
                        :mod (c / clinic)))))

# ::id pmid_2023_3444.106 ::date 2015-08-04T05:32:58 ::annotator SDL-AMR-09 ::preferred
# ::snt The spectra in Fig. <xref ref-type="fig" rid="F4">4</xref> show a small but clear peak at the expected size for a <i>PIK3CA </i>1047R mutation in a lymph node.
# ::save-date Tue Nov 17, 2015 ::file pmid_2023_3444_106.txt
(s / show-01
      :ARG0 (s2 / spectra
            :ARG1-of (d / describe-01
                  :ARG0 (f / figure :mod 4)))
      :ARG1 (p / peak
            :mod (s3 / small
                  :ARG1-of (c / contrast-01
                        :ARG2 (p2 / peak
                              :mod (c2 / clear)
                              :ARG0-of (h / have-03
                                    :ARG1 (s4 / size-01
                                          :ARG1 (m / mutate-01 :value "1047R"
                                                :ARG2 (g2 / gene :name (n2 / name :op1 "PIK3CA"))
                                                :location (n4 / node
                                                      :mod (l / lymph)))
                                          :ARG1-of (e / expect-01))))))))

# ::id pmid_2023_3444.107 ::date 2015-08-04T03:54:22 ::annotator SDL-AMR-09 ::preferred
# ::snt We also were able to demonstrate the sensitivity of the platform by performing a cell mixing experiment.
# ::save-date Tue Aug 4, 2015 ::file pmid_2023_3444_107.txt
(p2 / possible-01
      :ARG1 (d / demonstrate-01
            :ARG0 (w / we)
            :ARG1 (s / sensitive-03
                  :ARG0 (p3 / platform))
            :mod (a / also)
            :manner (p / perform-02
                  :ARG0 w
                  :ARG1 (e / experiment-01
                        :ARG1 (m / mix-01
                              :ARG1 (c / cell))))))

# ::id pmid_2023_3444.108 ::date 2015-08-04T04:11:01 ::annotator SDL-AMR-09 ::preferred
# ::snt Mutation analysis was done using MCF-7 cell line DNA alone or mixed with SKBR3 at various percentages.
# ::save-date Wed Aug 5, 2015 ::file pmid_2023_3444_108.txt
(a / analyze-01
      :ARG1 (m / mutate-01)
      :manner (o / or
            :op1 (u / use-01
                  :ARG1 (n3 / nucleic-acid :wiki "DNA" :name (n4 / name :op1 "DNA")
                        :mod (c / cell-line :name (n / name :op1 "MCF-7"))
                        :mod (a2 / alone)))
            :op2 (u2 / use-01
                  :ARG1 (m2 / mix-01
                        :ARG1 n3
                        :ARG2 (c2 / cell-line :name (n2 / name :op1 "SKBR3")))
                  :degree (p / percentage
                        :ARG1-of (v / vary-01)))))

# ::id pmid_2023_3444.109 ::date 2015-08-04T04:19:25 ::annotator SDL-AMR-09 ::preferred
# ::snt MCF-7 cells contain a PIK3CA mutation, and SKBR3 cells do not.
# ::save-date Sun Jan 17, 2016 ::file pmid_2023_3444_109.txt
(a / and
      :op1 (c / contain-01
            :ARG0 (c3 / cell-line :name (n2 / name :op1 "MCF-7"))
            :ARG1 (m / mutate-01
                  :ARG1 (g / gene :name (n / name :op1 "PIK3CA"))))
      :op2 (c2 / contain-01 :polarity -
            :ARG0 (c4 / cell-line :name (n3 / name :op1 "SKBR3"))
            :ARG1 g))

# ::id pmid_2023_3444.110 ::date 2015-08-04T04:23:12 ::annotator SDL-AMR-09 ::preferred
# ::snt Fig. <xref ref-type="fig" rid="F5">5</xref> demonstrates that the mutation was detectable even when the MCF-7 cells represented only 5 to 10% of the total DNA and only 5 to 2.5% of the alleles.
# ::save-date Sun Jan 17, 2016 ::file pmid_2023_3444_110.txt
(d / demonstrate-01
      :ARG0 (f / figure :mod 5)
      :ARG1 (h / have-concession-91
            :ARG1 (p3 / possible-01
                  :ARG1 (d2 / detect-01))
            :ARG2 (r / represent-01
                  :ARG0 (c / cell-line :name (n / name :op1 "MCF-7"))
                  :ARG1 (a / and
                        :op1 (b / between
                              :op1 (p4 / percentage-entity :value 5)
                              :op2 (p / percentage-entity :value 10)
                              :ARG3-of (i / include-91
                                    :ARG2 (n2 / nucleic-acid :wiki "DNA" :name (n3 / name :op1 "DNA")
                                          :mod (t / total))))
                        :op2 (b2 / between
                              :op1 (p6 / percentage-entity :value 5)
                              :op2 (p5 / percentage-entity :value 2.5)
                              :mod (o / only)
                              :ARG3-of (i2 / include-91
                                    :ARG2 (a2 / allele)))))))

# ::id pmid_2023_3444.111 ::date 2015-08-04T04:47:39 ::annotator SDL-AMR-09 ::preferred
# ::snt This sensitivity is important for mutation detection in clinical cancer samples, which usually contain some amount of normal tissue, which dilutes the number of tumor cells.
# ::save-date Thu Dec 10, 2015 ::file pmid_2023_3444_111.txt
(i / important
      :domain (s / sensitive-03
            :mod (t3 / this))
      :purpose (d / detect-01
            :ARG1 (m / mutate-01)
            :location (s2 / sample-01
                  :ARG1 (d2 / disease :wiki "Cancer" :name (n3 / name :op1 "cancer"))
                  :ARG0-of (c / contain-01
                        :ARG1 (a2 / amount
                              :mod (s3 / some)
                              :quant-of (t / tissue)
                              :ARG1-of (n2 / normal-02)
                              :ARG0-of (d3 / dilute-01
                                    :ARG1 (n / number
                                          :quant-of (c2 / cell
                                                :mod (t2 / tumor)))))
                        :manner (u / usual))
                  :mod (c4 / clinic))))

# ::id pmid_2023_3444.112 ::date 2015-08-04T04:25:20 ::annotator SDL-AMR-09 ::preferred
# ::snt This is of particular concern when profiling lymph nodes, which may contain a minority of tumor cells.
# ::save-date Thu Aug 6, 2015 ::file pmid_2023_3444_112.txt
(c / concern-01
      :ARG0 (t2 / this)
      :time (p / profile-01
            :ARG1 (n / node
                  :mod (l / lymph)
                  :ARG0-of (c2 / contain-01
                        :ARG1 (c3 / cell
                              :mod (t / tumor)
                              :quant (m / minority))
                        :ARG1-of (p2 / possible-01))))
      :mod (p3 / particular))

# ::id pmid_2023_3444.113 ::date 2015-08-04T04:46:17 ::annotator SDL-AMR-09 ::preferred
# ::snt <sec-title level="2">Frequencies of C-07 mutations in <i>KRAS</i>, <i>NRAS</i>, <i>PIK3CA</i>, and <i>BRAF </i>detected with OncoCarta and the Sequenom platform were similar to previous reports</sec-title>
# ::save-date Mon Aug 10, 2015 ::file pmid_2023_3444_113.txt
(r2 / resemble-01
      :ARG1 (h / have-frequency-91
            :ARG1 (m / mutate-01
                  :ARG0 (c / cell-line :name (n8 / name :op1 "C-07"))
                  :ARG1 (a2 / and
                        :op1 (g2 / gene :name (n4 / name :op1 "KRAS"))
                        :op2 (g3 / gene :name (n5 / name :op1 "NRAS"))
                        :op3 (g4 / gene :name (n6 / name :op1 "PIK3CA"))
                        :op4 (g5 / gene :name (n7 / name :op1 "BRAF"))))
            :ARG1-of (d / detect-01
                  :ARG2 (a / and
                        :op1 (p2 / platform :name (n / name :op1 "OncoCarta"))
                        :op2 (p3 / platform :name (n3 / name :op1 "Sequenom")))))
      :ARG2 (t / thing
            :ARG1-of (r3 / report-01
                  :time (p / previous))))

# ::id pmid_2023_3444.114 ::date 2015-08-04T07:04:07 ::annotator SDL-AMR-09 ::preferred
# ::snt In this preliminary assessment of the feasibility of using the Sequenom platform to do large-scale mutation profiling of colon cancer samples isolated from FFPET, it was essential to determine if our data yielded frequencies typical of what has been seen previously.
# ::save-date Thu Dec 10, 2015 ::file pmid_2023_3444_114.txt
(e / essential
      :domain (d3 / determine-01
            :ARG1 (y / yield-01 :mode interrogative
                  :ARG0 (d2 / data
                        :poss (w / we))
                  :ARG1 (f / frequency
                        :ARG0-of (t / typify-01
                              :ARG1 (t2 / thing
                                    :ARG1-of (s / see-01
                                          :time (p / previous))))))
            :time (a / assess-01
                  :ARG1 (f2 / feasible
                        :mod (u / use-01
                              :ARG1 (p3 / platform :name (n / name :op1 "Sequenom"))
                              :ARG2 (p4 / profile-01
                                    :ARG0 (m / mutate-01
                                          :mod (l / large-scale))
                                    :ARG1 (s2 / sample-01
                                          :ARG1 (d / disease :wiki "Colorectal_cancer" :name (n3 / name :op1 "colon" :op2 "cancer"))
                                          :ARG1-of (i / isolate-01
                                                :ARG2 (t3 / thing :name (n2 / name :op1 "FFPET")))))))
                  :mod (p2 / preliminary)
                  :mod (t4 / this))))

# ::id pmid_2023_3444.115 ::date 2015-08-04T07:35:03 ::annotator SDL-AMR-09 ::preferred
# ::snt Table <xref ref-type="table" rid="T2">2</xref> shows the mutation frequencies obtained here and from the COSMIC (Catalog of Somatic Mutations in Cancer) database [<xref ref-type="bibr" rid="B21">21</xref>].
# ::save-date Mon Aug 10, 2015 ::file pmid_2023_3444_115.txt
(s / show-01
      :ARG0 (t / table :mod 2)
      :ARG1 (h2 / have-frequency-91
            :ARG1 (m / mutate-01)
            :ARG1-of (o / obtain-01
                  :location (h / here)
                  :source (d2 / database
                        :name (n / name :op1 "COSMIC")
                        :ARG1-of (m2 / mean-01
                              :ARG2 (t2 / thing
                                    :ARG2-of (c2 / catalogue-01
                                          :ARG1 (m3 / mutate-01
                                                :mod (s2 / somatic)
                                                :location (d3 / disease :wiki "Cancer"
                                                      :name (n2 / name :op1 "cancer")))))))))
      :ARG1-of (d / describe-01
            :ARG0 (p / publication
                  :ARG0-of (c / cite-01 :ARG1 21))))

# ::id pmid_2023_3444.116 ::date 2015-08-03T12:36:26 ::annotator SDL-AMR-09 ::preferred
# ::snt The COSMIC frequencies seen in Table <xref ref-type="table" rid="T2">2</xref> are based only on those mutations that are detectable with OncoCarta.
# ::save-date Sun Jan 17, 2016 ::file pmid_2023_3444_116.txt
(b / base-02
      :ARG1 (h / have-frequency-91
            :ARG1-of (s / see-01
                  :location (t / table :mod 2))
            :mod (t4 / thing :name (n / name :op1 "COSMIC")))
      :ARG2 (m / mutate-01
            :mod (t2 / this)
            :ARG1-of (d / detect-01
                  :ARG1-of (p / possible-01)
                  :instrument (p2 / product :name (n2 / name :op1 "OncoCarta"))))
      :mod (o / only))

# ::id pmid_2023_3444.117 ::date 2015-08-03T12:36:37 ::annotator SDL-AMR-09 ::preferred
# ::snt OncoCarta assays interrogate 99%, 98%, and 78% of the known colon cancer mutations in <i>BRAF</i>, <i>KRAS</i>, and <i>PIK3CA</i>, respectively, based on a large number of colon cancer samples that have been sequenced in <i>BRAF </i>(n = 4628), <i>KRAS </i>(n = 858) and <i>PIK3CA </i>(n = 247).
# ::save-date Tue Jan 19, 2016 ::file pmid_2023_3444_117.txt
(i / interrogate-01
      :ARG0 (a / assay-01
            :instrument (p4 / product :name (n / name :op1 "OncoCarta")))
      :ARG1 (m / mutate-01
            :ARG1 (a2 / and
                  :op1 (g / gene :name (n2 / name :op1 "BRAF"))
                  :op2 (g2 / gene :name (n3 / name :op1 "KRAS"))
                  :op3 (g3 / gene :name (n4 / name :op1 "PIK3CA")))
            :manner (r / respective)
            :ARG1-of (k / know-02)
            :ARG2-of (i2 / include-91
                  :ARG1 (m2 / mutate-01
                        :ARG1 a2
                        :ARG1-of k
                        :mod d)
                  :ARG3 (a4 / and
                        :op1 (p / percentage-entity :value 99)
                        :op2 (p2 / percentage-entity :value 98)
                        :op3 (p3 / percentage-entity :value 78)))
            :mod (d / disease :wiki "Colorectal_cancer" :name (n5 / name :op1 "colon" :op2 "cancer")))
      :ARG1-of (b / base-02
            :ARG2 (n8 / number
                  :mod (l / large)
                  :quant-of (a3 / and
                        :op1 (t / thing :quant 4628
                              :ARG1-of (s / sample-01
                                    :ARG2 d)
                              :ARG1-of (s2 / sequence-01
                                    :location g))
                        :op2 (t2 / thing :quant 858
                              :ARG1-of (s3 / sample-01
                                    :ARG2 d)
                              :ARG1-of (s4 / sequence-01
                                    :location g2))
                        :op3 (t3 / thing :quant 247
                              :ARG1-of (s5 / sample-01
                                    :ARG2 d)
                              :ARG1-of (s6 / sequence-01
                                    :location g3))))))

# ::id pmid_2023_3444.118 ::date 2015-08-03T13:22:27 ::annotator SDL-AMR-09 ::preferred
# ::snt The OncoCarta panel found that the most frequent mutations in C-07 were <i>KRAS </i>(43.5%), <i>PIK3CA </i>(20.1%), and <i>BRAF </i>(12.1%), which are similar to what is seen in COSMIC.
# ::save-date Sun Jan 17, 2016 ::file pmid_2023_3444_118.txt
(f / find-01
      :ARG0 (p / panel :name (n / name :op1 "OncoCarta"))
      :ARG1 (f2 / frequent-02
            :ARG1 (a3 / and
                  :op1 (m / mutate-01
                        :ARG1 (g / gene :name (n2 / name :op1 "KRAS")
                              :frequency (p2 / percentage-entity :value 43.5)))
                  :op2 (m3 / mutate-01
                        :ARG1 (g2 / gene :name (n3 / name :op1 "PIK3CA")
                              :frequency (p3 / percentage-entity :value 20.1)))
                  :op3 (m4 / mutate-01
                        :ARG1 (g3 / gene :name (n4 / name :op1 "BRAF")
                              :frequency (p4 / percentage-entity :value 12.1)))
                  :ARG1-of (r / resemble-01
                        :ARG2 (t3 / thing
                              :ARG1-of (s / see-01
                                    :location (t2 / thing :name (n6 / name :op1 "COSMIC")))))
                  :location (c / cell-line :name (n5 / name :op1 "C-07")))
            :degree (m2 / most)))

# ::id pmid_2023_3444.119 ::date 2015-08-03T13:37:40 ::annotator SDL-AMR-09 ::preferred
# ::snt <i>NRAS </i>mutations, while infrequent, were detected in codons 12, 13 and 61 and represent a sizable minority of the C0-7 samples (3.8%).
# ::save-date Tue Jan 12, 2016 ::file pmid_2023_3444_119.txt
(a / and
      :op1 (d / detect-01
            :ARG1 (m / mutate-01
                  :ARG1 (g / gene :wiki -
                        :name (n / name :op1 "NRAS"))
                  :concession (f / frequent-02 :polarity -
                              :ARG1 m))
            :location (a2 / and
                  :op1 (c / codon :mod 12)
                  :op2 (c2 / codon :mod 13)
                  :op3 (c3 / codon :mod 61)))
      :op2 (r / represent-01
            :ARG0 m
            :ARG1 (m2 / minority
                  :mod (s / sizable)
                  :poss (t2 / thing
                        :ARG1-of (s2 / sample-01)
                        :ARG1-of (l / label-01
                              :ARG2 (s3 / string-entity :value "C0-7")))
                  :ARG1-of (m3 / mean-01
                        :ARG2 (p / percentage-entity :value 3.8)))))

# ::id pmid_2023_3444.120 ::date 2015-08-03T13:49:28 ::annotator SDL-AMR-09 ::preferred
# ::snt These data suggest that FFPET samples can be interrogated with the technology described here and yield accurate data.
# ::save-date Mon Aug 10, 2015 ::file pmid_2023_3444_120.txt
(s / suggest-01
      :ARG0 (d / data
            :mod (t / this))
      :ARG1 (a / and
            :op1 (p / possible-01
                  :ARG1 (i / interrogate-01
                        :ARG2 (t3 / thing :name (n / name :op1 "FFPET")
                              :ARG1-of (s2 / sample-01))
                        :instrument (t2 / technology
                              :ARG1-of (d3 / describe-01
                                    :location (h / here)))))
            :op2 (y / yield-01
                  :ARG0 t3
                  :ARG1 (d2 / data
                        :mod (a2 / accurate)))))

# ::id pmid_2023_3444.121 ::date 2015-08-03T13:54:49 ::annotator SDL-AMR-09 ::preferred
# ::snt While most of the specific amino acid mutations mirror what is seen on the COSMIC database, some unique colon cancer gene mutations were found, which include <i>ABL1</i>-F359V, <i>AKT1-</i>E17K, <i>MET-</i>R970C, and <i>MET</i>-T992I.
# ::save-date Thu Dec 10, 2015 ::file pmid_2023_3444_121.txt
(h / have-concession-91
      :ARG1 (f / find-01
            :ARG1 (m / mutate-01
                  :ARG1 (g / gene
                        :mod (d2 / disease :wiki "Colorectal_cancer" :name (n6 / name :op1 "colon" :op2 "cancer")))
                  :mod (u / unique)
                  :ARG2-of (i / include-01
                        :ARG1 (a / and
                              :op1 (g2 / gene :name (n2 / name :op1 "ABL1")
                                    :ARG2-of (m7 / mutate-01 :value "F359V"))
                              :op2 (g3 / gene :name (n3 / name :op1 "AKT1")
                                    :ARG2-of (m2 / mutate-01 :value "E17K"))
                              :op3 (g4 / gene :name (n4 / name :op1 "MET")
                                    :ARG2-of (m3 / mutate-01 :value "R970C"))
                              :op3 (g5 / gene :name (n5 / name :op1 "MET")
                                    :ARG2-of (m8 / mutate-01 :value "T992I"))))
                  :mod (s3 / some)))
      :ARG2 (m4 / mirror-01
            :ARG1 (t / thing
                  :ARG1-of (s2 / see-01
                        :location (d / database :name (n / name :op1 "COSMIC"))))
            :ARG2 (m5 / mutate-01
                  :ARG1 (a4 / amino-acid)
                  :ARG1-of (s / specific-02)
                  :ARG1-of (i2 / include-91
                        :ARG2 (m9 / mutate-01
                              :ARG1 (a2 / amino-acid)
                              :ARG1-of s)
                        :ARG3 (m6 / most)))))

# ::id pmid_2023_3444.122 ::date 2015-08-03T14:09:31 ::annotator SDL-AMR-09 ::preferred
# ::snt Other amino acid changes that were not in the COSMIC database were amino acid changes R88Q, H701P, and C420R in <i>PIK3CA</i>, <i>BRAF</i>-594V/G, and <i>KRAS</i>-Q61R, and several in <i>NRAS</i>, including G12C, G12D, G13R, G13V, Q61H and Q61K (Table <xref ref-type="table" rid="T2">2</xref>).
# ::save-date Mon Aug 10, 2015 ::file pmid_2023_3444_122.txt
(c / change-01
      :ARG1 (a / amino-acid)
      :mod (o / other)
      :ARG1-of (b / be-located-at-91 :polarity -
            :ARG2 (d / database :name (n16 / name :op1 "COSMIC")))
      :ARG1-of (d2 / describe-01
            :ARG0 (t / table :mod 2))
      :domain (a6 / and
            :op1 (c3 / change-01
                  :ARG1 (a7 / amino-acid
                        :part-of (g / gene :name (n4 / name :op1 "PIK3CA")
                              :ARG2-of (m / mutate-01 :value "R88Q"))))
            :op2 (c4 / change-01
                  :ARG1 (a8 / amino-acid
                        :part-of (g5 / gene :name (n / name :op1 "PIK3CA")
                              :ARG2-of (m2 / mutate-01 :value "H701P"))))
            :op3 (c5 / change-01
                  :ARG1 (a9 / amino-acid
                        :part-of (g6 / gene :name (n2 / name :op1 "PIK3CA")
                              :ARG2-of (m3 / mutate-01 :value "C420R"))))
            :op4 (c6 / change-01
                  :ARG1 (a10 / amino-acid
                        :part-of (g2 / gene :name (n6 / name :op1 "BRAF")
                              :ARG2-of (m4 / mutate-01 :value "594V/G"))))
            :op5 (c7 / change-01
                  :ARG1 (a11 / amino-acid
                        :part-of (g3 / gene :name (n8 / name :op1 "KRAS")
                              :ARG2-of (m5 / mutate-01 :value "Q61R"))))
            :op6 (c8 / change-01
                  :ARG1 (a12 / amino-acid
                        :part-of (g4 / gene :name (n9 / name :op1 "NRAS")
                              :ARG2-of (m6 / mutate-01
                                    :ARG2-of (i / include-01
                                          :ARG1 (a4 / and
                                                :op1 (m7 / mutate-01 :value "G12C")
                                                :op2 (m8 / mutate-01 :value "G12D")
                                                :op3 (m9 / mutate-01 :value "G13R")
                                                :op4 (m10 / mutate-01 :value "G13V")
                                                :op5 (m11 / mutate-01 :value "Q61H")
                                                :op6 (m12 / mutate-01 :value "Q61K"))))))
                  :quant (s / several))))

# ::id pmid_2023_3444.123 ::date 2015-08-03T14:25:04 ::annotator SDL-AMR-09 ::preferred
# ::snt <sec-title level="2">MET mutations were found in C0-7 and amplified in sometumors</sec-title>
# ::save-date Sun Jan 17, 2016 ::file pmid_2023_3444_123.txt
(a / and
      :op1 (f / find-01
            :ARG1 (m / mutate-01
                  :ARG1 (p / protein :name (n / name :op1 "MET")))
            :location (t / thing :name (n2 / name :op1 "C0-7")))
      :op2 (a2 / amplify-01
            :ARG1 m
            :location (t2 / tumor
                  :quant (s / some))))

# ::id pmid_2023_3444.124 ::date 2015-08-03T14:28:26 ::annotator SDL-AMR-09 ::preferred
# ::snt <i>MET </i>mutations were found in 3.3% of C-07 samples.
# ::save-date Sun Jan 17, 2016 ::file pmid_2023_3444_124.txt
(f / find-01
      :ARG1 (m / mutate-01
            :ARG1 (g / gene :name (n / name :op1 "MET")))
      :location (t2 / thing
            :ARG1-of (i / include-91
                  :ARG2 (t3 / thing
                        :source c
                        :ARG1-of (s2 / sample-01
                              :source (c / cell-line :name (n2 / name :op1 "C-07"))))
                  :ARG3 (p / percentage-entity :value 3.3))
            :ARG1-of (s / sample-01)))

# ::id pmid_2023_3444.125 ::date 2015-08-03T14:32:27 ::annotator SDL-AMR-09 ::preferred
# ::snt Interestingly, these mutations were not only unexpected in their appearance within the colon cancer population but also the frequency within the samples was unexpected.
# ::save-date Thu Dec 10, 2015 ::file pmid_2023_3444_125.txt
(a2 / and
      :op1 (e / expect-01 :polarity -
            :ARG1 (a / appear-01
                  :ARG1 (m / mutate-01
                        :mod (t / this))
                  :location (p / population
                        :mod (d / disease :wiki "Colorectal_cancer" :name (n / name :op1 "colon" :op2 "cancer")))))
      :op2 (e2 / expect-01 :polarity -
            :ARG1 (f / frequent-02
                  :ARG1 (t2 / thing
                        :ARG1-of (s / sample-01)))
            :mod (a3 / also))
      :ARG2-of (i / interest-01))

# ::id pmid_2023_3444.126 ::date 2015-08-03T14:44:03 ::annotator SDL-AMR-09 ::preferred
# ::snt In four of the eight samples with <i>MET </i>mutations, the mutant alleles were present at 58-70%, suggesting an amplification of the mutant allele or a loss of the wt gene (Fig. <xref ref-type="fig" rid="F6">6</xref>).
# ::save-date Mon Aug 10, 2015 ::file pmid_2023_3444_126.txt
(b / be-located-at-91
      :ARG1 (a / allele
            :ARG2-of (m / mutate-01)
            :quant (v / value-interval
                  :op1 (p / percentage-entity :value 58)
                  :op2 (p2 / percentage-entity :value 70)))
      :ARG2 (s / sample-01 :quant 4
            :ARG1 (m2 / mutate-01
                  :ARG1 (g / gene :name (n / name :op1 "MET")))
            :ARG1-of (i / include-91
                  :ARG2 (s2 / sample-01 :quant 8
                        :ARG1 m2)))
      :ARG0-of (s3 / suggest-01
            :ARG1 (o / or
                  :op1 (a2 / amplify-01
                        :ARG1 (a3 / allele
                              :ARG2-of m))
                  :op2 (l / lose-02
                        :ARG1 (g2 / gene
                              :mod (w / wild-type)))))
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod 6)))

# ::id pmid_2023_3444.127 ::date 2015-08-03T14:52:59 ::annotator SDL-AMR-09 ::preferred
# ::snt Amplification may represent the best explanation, in that amplification of the <i>MET </i>genomic region, 7q31, has been observed in the Progenetix CGH Database in 23% of colorectal cancers [<xref ref-type="bibr" rid="B22">22</xref>]
# ::save-date Thu Feb 4, 2016 ::file pmid_2023_3444_127.txt
(p / possible-01
      :ARG1 (r / represent-01
            :ARG0 (a2 / amplify-01)
            :ARG1 (e / explain-01
                  :ARG2-of (g / good-03
                        :degree (m / most))))
      :ARG0-of (c / cause-01
            :ARG1 (o / observe-01
                  :ARG1 (a / amplify-01
                        :ARG1 (d5 / dna-sequence :name (n5 / name :op1 "7q31" :op2 "region")
                              :mod (g2 / genome)
                              :mod (g3 / gene :name (n / name :op1 "MET"))))
                  :location (d / database :name (n2 / name :op1 "Progenetix" :op2 "CGH"))
                  :location (d4 / disease :wiki "Cancer" :name (n4 / name :op1 "cancer")
                        :ARG1-of (i / include-91
                              :ARG2 (d3 / disease :wiki "Colorectal_cancer" :name (n3 / name :op1 "colorectal" :op2 "cancer"))
                              :ARG3 (p2 / percentage-entity :value 23)))))
      :ARG1-of (d2 / describe-01
            :ARG0 (p3 / publication
                  :ARG1-of (c5 / cite-01
                        :ARG2 22))))

# ::id pmid_2023_3444.128 ::date 2015-08-03T15:13:41 ::annotator SDL-AMR-09 ::preferred
# ::snt <sec-title level="2">Sequenom data was reproducible</sec-title>
# ::save-date Mon Aug 10, 2015 ::file pmid_2023_3444_128.txt
(p / possible-01
      :ARG1 (r / reproduce-01
            :ARG1 (d / data
                  :source (c / company :name (n / name :op1 "Sequenom")))))

# ::id pmid_2023_3444.129 ::date 2015-08-03T15:15:07 ::annotator SDL-AMR-09 ::preferred
# ::snt Most of the assays in the OncoCarta panel did not detect mutations or the frequency of mutations was very low (below 1%) in our colon cancer samples.
# ::save-date Thu Dec 10, 2015 ::file pmid_2023_3444_129.txt
(o / or
      :op1 (d / detect-01 :polarity -
            :ARG0 (a / assay-01
                  :quant (m / most)
                  :ARG1-of (i / include-91
                        :ARG2 (a2 / assay-01
                              :location (p / panel :name (n / name :op1 "OncoCarta")))))
            :ARG1 (m2 / mutate-01))
      :op2 (l / low-04
            :ARG1 (f / frequent-02
                  :ARG1 (m3 / mutate-01
                        :location (s / sample-01
                              :ARG0 (w / we)
                              :ARG1 (d2 / disease :wiki "Colorectal_cancer" :name (n2 / name :op1 "colon" :op2 "cancer")))))
            :ARG3 (b / below
                  :op1 (p2 / percentage-entity :value 1))
            :degree (v / very)))

# ::id pmid_2023_3444.130 ::date 2015-08-04T12:18:44 ::annotator SDL-AMR-09 ::preferred
# ::snt OncoCarta assays interrogate mutations in these 19 genes listed in Table <xref ref-type="table" rid="T1">1</xref>.
# ::save-date Sun Jan 17, 2016 ::file pmid_2023_3444_130.txt
(i / interrogate-01
      :ARG0 (a / assay-01
            :instrument (p / product :name (n / name :op1 "OncoCarta")))
      :ARG1 (m / mutate-01)
      :location (g / gene :quant 19
            :mod (t / this)
            :ARG1-of (l / list-01
                  :ARG2 (t2 / table :mod 1))))

# ::id pmid_2023_3444.131 ::date 2015-08-04T12:23:05 ::annotator SDL-AMR-09 ::preferred
# ::snt To reduce the cost, time and the amount of DNA required for profiling, only 24 assays, which detected mutations at a frequency of 1% or greater in C-07, were selected, resorted in 6 pools and included in a new panel, termed ColoCarta (Table <xref ref-type="table" rid="T3">3</xref>).
# ::save-date Fri Feb 5, 2016 ::file pmid_2023_3444_131.txt
(a / and
      :op1 (s / select-01
            :ARG1 (a2 / assay-01 :quant 24
                  :mod (o / only)
                  :ARG0-of (d / detect-01
                        :ARG1 (m / mutate-01
                              :ARG1-of (h / have-frequency-91
                                    :ARG2 (o2 / or
                                          :op1 (p / percentage-entity :value 1)
                                          :op2 (m2 / more-than
                                                :op1 p))
                                    :location (c / cell-line :name (n / name :op1 "C-07")))))))
      :op2 (r / resort-00
            :ARG1 a2
            :location (p2 / pool :quant 6))
      :op3 (i / include-01
            :ARG1 a2
            :ARG2 (p3 / panel
                  :ARG1-of (n2 / new-01)
                  :ARG1-of (t2 / term-01
                        :ARG3 (t5 / thing :name (n3 / name :op1 "ColoCarta")))))
      :purpose (r2 / reduce-01
            :ARG1 (a3 / and
                  :op1 (c2 / cost)
                  :op2 (t3 / time)
                  :op3 (a4 / amount
                        :quant-of (n4 / nucleic-acid :wiki "DNA" :name (n5 / name :op1 "DNA")))
                  :ARG1-of (r3 / require-01
                        :ARG0 (p4 / profile-01))))
      :ARG1-of (d3 / describe-01
            :ARG0 (t4 / table :mod 3)))

# ::id pmid_2023_3444.132 ::date 2015-08-04T12:47:08 ::annotator SDL-AMR-09 ::preferred
# ::snt Mutation profiles of 32 mutant samples with 41 mutations were repeated with the ColoCarta.
# ::save-date Mon Aug 10, 2015 ::file pmid_2023_3444_132.txt
(r / repeat-01
      :ARG1 (p / profile-01
            :ARG1 (t2 / thing :quant 32
                  :ARG2-of (m / mutate-01)
                  :ARG0-of (h / have-03
                        :ARG1 (m2 / mutate-01 :quant 41))
                  :ARG1-of (s / sample-01))
            :mod m)
      :instrument (t / thing :name (n / name :op1 "ColoCarta")))

# ::id pmid_2023_3444.133 ::date 2015-08-04T12:48:19 ::annotator SDL-AMR-09 ::preferred
# ::snt The mutations detected by the 2 panels (OncoCarta and ColoCarta) were identical, demonstrating the reproducibility of the methodology.
# ::save-date Sun Jan 17, 2016 ::file pmid_2023_3444_133.txt
(i / identical-01
      :ARG1 (m / mutate-01
            :ARG1-of (d / detect-01
                  :ARG0 (p / panel :quant 2
                        :ARG1-of (m3 / mean-01
                              :ARG2 (a / and
                                    :op1 (p3 / panel :name (n / name :op1 "OncoCarta"))
                                    :op2 (p4 / panel :name (n2 / name :op1 "ColoCarta")))))))
      :ARG0-of (d2 / demonstrate-01
            :ARG1 (p2 / possible-01
                  :ARG1 (r / reproduce-01
                        :ARG1 (m2 / methodology)))))

# ::id pmid_2023_3444.134 ::date 2015-08-04T13:17:41 ::annotator SDL-AMR-09 ::preferred
# ::snt <sec-title level="2">Multiple mutation frequencies suggest an order to the acquisition of different mutations</sec-title>
# ::save-date Mon Aug 10, 2015 ::file pmid_2023_3444_134.txt
(s / suggest-01
      :ARG0 (h / have-frequency-91
            :ARG1 (m / mutate-01)
            :mod (m2 / multiple))
      :ARG1 (o / order-03
            :ARG1 (a / acquire-01
                  :ARG1 (m3 / mutate-01
                        :ARG1-of (d / differ-02)))))

# ::id pmid_2023_3444.135 ::date 2015-08-04T13:22:12 ::annotator SDL-AMR-09 ::preferred
# ::snt A majority of the tumors (64%) contained at least one or more mutations in the following genes: <i>BRAF</i>, <i>KRAS</i>, <i>NRAS</i>, <i>MET</i>, or <i>PIK3CA</i>, and 18% had 2 or more mutations.
# ::save-date Mon Aug 10, 2015 ::file pmid_2023_3444_135.txt
(a / and
      :op1 (c / contain-01
            :ARG0 (t / tumor
                  :quant (m / majority
                        :ARG1-of (m2 / mean-01
                              :ARG2 (p / percentage-entity :value 64))))
            :ARG1 (m3 / mutate-01
                  :quant (a2 / at-least
                        :op1 (o / or :op1 1
                              :op2 (m4 / more-than :op1 1))))
            :location (g / gene
                  :ARG1-of (f / follow-04)
                  :ARG1-of (m7 / mean-01
                        :ARG2 (o2 / or
                              :op1 (g2 / gene :name (n / name :op1 "BRAF"))
                              :op2 (g3 / gene :name (n2 / name :op1 "KRAS"))
                              :op3 (g4 / gene :name (n3 / name :op1 "NRAS"))
                              :op4 (g5 / gene :name (n4 / name :op1 "MET"))
                              :op5 (g6 / gene :name (n5 / name :op1 "PIK3CA"))))))
      :op2 (h / have-03
            :ARG0 (t2 / tumor
                  :ARG1-of (i / include-91
                        :ARG2 t
                        :ARG3 (p2 / percentage-entity :value 18)))
            :ARG1 (m5 / mutate-01
                  :quant (o3 / or :op1 2
                        :op2 (m6 / more-than :op1 2)))))

# ::id pmid_2023_3444.136 ::date 2015-08-04T13:34:35 ::annotator SDL-AMR-09 ::preferred
# ::snt The most common double mutation was in <i>KRAS </i>and <i>PIK3CA</i>, followed by <i>PIK3CA </i>and <i>BRAF </i>(Table <xref ref-type="table" rid="T4">4</xref>).
# ::save-date Mon Aug 10, 2015 ::file pmid_2023_3444_136.txt
(m / mutate-01
      :ARG1-of (d / double-01)
      :mod (c / common
            :degree (m2 / most))
      :location (a / and
                  :op1 (g / gene :name (n / name :op1 "KRAS"))
                  :op2 (g2 / gene :name (n2 / name :op1 "PIK3CA"))
                  :ARG2-of (f / follow-01
                        :ARG1 (a2 / and
                              :op1 g2
                              :op2 (g3 / gene :name (n3 / name :op1 "BRAF")))))
      :ARG1-of (d2 / describe-01
            :ARG0 (t / table :mod 4)))

# ::id pmid_2023_3444.137 ::date 2015-08-04T13:39:53 ::annotator SDL-AMR-09 ::preferred
# ::snt Most samples with <i>PIK3CA </i>mutations (80%) also had mutations in other genes, the most frequent of which was <i>KRAS</i>; other mutated genes were <i>BRAF</i>, <i>MET</i>, <i>NRAS</i>, and a second <i>PIK3CA </i>mutation (Table <xref ref-type="table" rid="T2">2</xref>, last column).
# ::save-date Mon Aug 10, 2015 ::file pmid_2023_3444_137.txt
(m / multi-sentence
      :snt1 (h / have-03
            :ARG0 (t2 / thing
                  :ARG1-of (i / include-91
                        :ARG2 (t3 / thing
                              :ARG1-of (s2 / sample-01)
                              :ARG0-of (h2 / have-03
                                    :ARG1 (m3 / mutate-01
                                          :ARG1 (g2 / gene :name (n2 / name :op1 "PIK3CA")))))
                        :ARG3 (m4 / most
                              :ARG1-of (m5 / mean-01
                                    :ARG2 (p / percentage-entity :value 80))))
                  :ARG1-of (s / sample-01))
            :ARG1 (m6 / mutate-01
                  :location (g3 / gene
                        :mod (o / other)
                        :ARG2-of (i2 / include-91
                              :ARG1 (g4 / gene :name (n3 / name :op1 "KRAS")
                                    :ARG1-of (f / frequent-02)))))
            :mod (a / also))
      :snt2 (g5 / gene
            :ARG2-of (m7 / mutate-01)
            :ARG1-of (i3 / include-91
                  :ARG2 (a2 / and
                        :op1 (g6 / gene :name (n4 / name :op1 "BRAF"))
                        :op2 (g7 / gene :name (n5 / name :op1 "MET"))
                        :op3 (g8 / gene :name (n6 / name :op1 "NRAS"))
                        :op4 (g9 / gene :name (n7 / name :op1 "PIK3CA")
                              :ARG1-of (m8 / mutate-01
                                    :ord (o2 / ordinal-entity :value 2)))))
            :mod (o3 / other))
      :ARG1-of (d / describe-01
            :ARG0 (t / table :mod 2
                  :part (c / column
                        :mod (l / last)))))

# ::id pmid_2023_3444.138 ::date 2015-08-04T14:17:59 ::annotator SDL-AMR-09 ::preferred
# ::snt Tumors with <i>MET </i>and <i>NRAS </i>mutations also have an unexpectedly high frequency of co-occurring mutations, which suggests that they occur as a second mutation and perhaps later in the etiology of the tumor.
# ::save-date Mon Dec 21, 2015 ::file pmid_2023_3444_138.txt
(h / have-frequency-91
      :ARG1 (m / mutate-01
            :location (t / tumor
                  :ARG0-of (h3 / have-03
                        :ARG1 (m2 / mutate-01
                              :ARG1 (a / and
                                    :op1 (g / gene :name (n / name :op1 "MET"))
                                    :op2 (g2 / gene :name (n2 / name :op1 "NRAS"))))))
            :ARG1-of (c / cooccur-00))
      :ARG2 (h2 / high
            :ARG1-of (e / expect-01 :polarity -))
      :mod (a2 / also)
      :ARG0-of (s / suggest-01
            :ARG1 (m3 / mutate-01
                  :ord (o / ordinal-entity :value 2)
                  :domain t
                  :ARG1-of (b / be-temporally-at-91
                        :ARG2 (l / late
                              :op1 (e2 / etiology
                                    :poss (t3 / tumor))
                              :degree (m4 / more))
                        :ARG1-of (p / possible-01)))))

# ::id pmid_2023_3444.139 ::date 2015-08-04T14:53:18 ::annotator SDL-AMR-09 ::preferred
# ::snt Many tumors contain only a <i>KRAS </i>or <i>BRAF </i>mutation, which is consistent with previous reports finding these mutations in earlier stages of colon cancer [<xref ref-type="bibr" rid="B23">23</xref>,<xref ref-type="bibr" rid="B24">24</xref>].
# ::save-date Thu Dec 10, 2015 ::file pmid_2023_3444_139.txt
(c / contain-01
      :ARG0 (t / tumor
            :quant (m / many))
      :ARG1 (m2 / mutate-01
            :ARG1 (a / and
                  :op1 (g / gene :name (n / name :op1 "KRAS"))
                  :op2 (g2 / gene :name (n2 / name :op1 "BRAF")))
            :mod (o / only))
      :ARG1-of (c2 / consistent-01
            :ARG2 (r / report
                  :time (p / previous)
                  :ARG0-of (f / find-01
                        :ARG2 m2
                        :time (e / early
                              :op1 (s / stage
                                    :subevent-of (d2 / disease :wiki "Colorectal_cancer" :name (n3 / name :op1 "colon" :op2 "cancer")))
                              :degree (m4 / more)))))
      :ARG1-of (d / describe-01
            :ARG0 (p2 / publication
                  :ARG1-of (c5 / cite-01
                        :ARG2 (a2 / and :op1 23 :op2 24)))))

# ::id pmid_2023_3444.140 ::date 2015-08-04T15:01:42 ::annotator SDL-AMR-09 ::preferred
# ::snt The multiple mutation frequencies for tumors with <i>KRAS </i>and <i>PIK3CA </i>or with <i>PIK3CA </i>and <i>BRAF </i>were slightly higher and lower, respectively, than expected based on their individual frequencies (Table <xref ref-type="table" rid="T4">4</xref>).
# ::save-date Mon Aug 10, 2015 ::file pmid_2023_3444_140.txt
(a / and
      :op1 (h / high-02
            :ARG1 (h3 / have-frequency-91
                  :ARG1 (m / mutate-01
                        :mod (m2 / multiple))
                  :location (t / tumor
                        :ARG0-of (h2 / have-03
                              :ARG1 (a4 / and
                                    :op1 (g / gene :name (n / name :op1 "KRAS"))
                                    :op2 (g2 / gene :name (n2 / name :op1 "PIK3CA")))))
                  :ARG1-of (b / base-02
                        :ARG2 (f2 / frequent-02
                              :ARG1 t
                              :mod (i / individual))))
            :compared-to (e / expect-01))
      :op2 (l / low-04
            :ARG1 (h4 / have-frequency-91
                  :ARG1 (m3 / mutate-01)
                  :location (t3 / tumor
                        :ARG0-of (h5 / have-03
                              :ARG1 (a3 / and
                                    :op1 g2
                                    :op2 (g3 / gene :name (n3 / name :op1 "BRAF")))))
                  :ARG1-of b)
            :compared-to e)
      :mod (r / respective)
      :manner (s / slight)
      :ARG1-of (d / describe-01
            :ARG0 (t2 / table :mod 4)))

# ::id pmid_2023_3444.141 ::date 2015-08-04T15:15:53 ::annotator SDL-AMR-09 ::preferred
# ::snt Conversely, the expected double mutation frequency of <i>BRAF </i>and <i>KRAS </i>would be 5.1%, based on our data, but this combination was not found, also in agreement with previous reports [<xref ref-type="bibr" rid="B24">24</xref>] (Table <xref ref-type="table" rid="T4">4</xref>).
# ::save-date Tue Aug 4, 2015 ::file pmid_2023_3444_141.txt
(h / have-frequency-91
      :ARG1 (m / mutate-01
            :ARG1 (a / and
                  :op1 (g / gene :name (n / name :op1 "BRAF"))
                  :op2 (g2 / gene :name (n2 / name :op1 "KRAS")))
            :ARG1-of (d / double-01)
            :ARG1-of (e / expect-01))
      :ARG2 (p / percentage-entity :value 5.1)
      :ARG1-of (b / base-02
            :ARG2 (d2 / data
                  :poss (w / we)))
      :concession (f / find-01 :polarity -
                  :ARG1 (c / combine-01
                        :mod (t / this))
                  :ARG0-of (a2 / agree-01
                        :ARG2 (r / report
                              :time (p2 / previous))
                        :mod (a3 / also)))
      :ARG1-of (d3 / describe-01
            :ARG0 (p3 / publication
                  :ARG1-of (c2 / cite-01
                        :ARG2 24)))
      :ARG1-of (d4 / describe-01
            :ARG0 (t2 / table :mod 4))
      :manner (c3 / converse))

# ::id pmid_2023_3444.142 ::date 2015-08-04T15:29:47 ::annotator SDL-AMR-09 ::preferred
# ::snt <sec-title level="2">Primary tumors with KRAS and PIK3CA mutations vary with respect to the frequency of these mutant alleles</sec-title>
# ::save-date Mon Aug 10, 2015 ::file pmid_2023_3444_142.txt
(v / vary-01
      :ARG0 (h2 / have-frequency-91
            :ARG1 (a2 / allele
                  :mod (t2 / this)
                  :ARG2-of (m2 / mutate-01)))
      :ARG1 (t / tumor
            :mod (p / primary)
            :ARG0-of (h / have-03
                  :ARG1 (m / mutate-01
                        :ARG1 (a / and
                              :op1 (g / gene :name (n / name :op1 "KRAS"))
                              :op2 (g2 / gene :name (n2 / name :op1 "PIK3CA")))))))

# ::id pmid_2023_3444.143 ::date 2015-08-04T15:34:34 ::annotator SDL-AMR-09 ::preferred
# ::snt In the samples with co-occurring mutations, the ratios of <i>KRAS </i>mutation ratio (<i>KRAS </i>mutation peak area/total peak area) to the <i>PIK3CA </i>mutation ratio (<i>PIK3CA </i>mutation peak area/total peak area) was determined.
# ::save-date Mon Dec 21, 2015 ::file pmid_2023_3444_143.txt
(d / determine-01
      :ARG1 (r / ratio-of
            :op1 (r2 / ratio-of
                  :op1 (m / mutate-01
                        :ARG1 (g / gene :name (n / name :op1 "KRAS")))
                  :ARG1-of (m2 / mean-01
                        :ARG2 (r4 / ratio-of
                              :op1 (a / area
                                    :ARG1-of (p / peak-01)
                                    :mod m)
                              :op2 (a2 / area
                                    :ARG1-of (p2 / peak-01)
                                    :mod (t / total)))))
            :op2 (r3 / ratio-of
                  :op1 (m3 / mutate-01
                        :ARG1 (g2 / gene :name (n2 / name :op1 "PIK3CA")))
                  :ARG1-of (m4 / mean-01
                        :ARG2 (r5 / ratio-of
                              :op1 (a3 / area
                                    :ARG1-of (p3 / peak-01)
                                    :mod m3)
                              :op2 a2))))
      :location (s / sample-01
            :ARG1 (m5 / mutate-01
                  :ARG1-of (c / cooccur-00))))

# ::id pmid_2023_3444.144 ::date 2015-08-04T15:48:15 ::annotator SDL-AMR-09 ::preferred
# ::snt Twenty-two out of 31 samples (71%) had <i>KRAS</i>/<i>PIK3CA </i>ratios above 1.25 (Table <xref ref-type="table" rid="T5">5</xref>).
# ::save-date Mon Aug 10, 2015 ::file pmid_2023_3444_144.txt
(h / have-03
      :ARG0 (t3 / thing :quant 22
            :ARG1-of (i / include-91
                  :ARG2 (t2 / thing :quant 31
                        :ARG1-of (s2 / sample-01))
                  :ARG3 (p / percentage-entity :value 71))
            :ARG1-of (s / sample-01))
      :ARG1 (r / ratio-of
            :op1 (g / gene :name (n / name :op1 "KRAS"))
            :op2 (g2 / gene :name (n2 / name :op1 "PIK3CA"))
            :ARG1-of (e / equal-01
                  :ARG3 (a / above :op1 1.25)))
      :ARG1-of (d / describe-01
            :ARG0 (t / table :mod 5)))

# ::id pmid_2023_3444.145 ::date 2015-08-04T16:03:36 ::annotator SDL-AMR-09 ::preferred
# ::snt <i>PIK3CA </i>mutations were more prevalent in only 2 out of 31 samples.
# ::save-date Mon Aug 10, 2015 ::file pmid_2023_3444_145.txt
(p / prevail-02
      :ARG1 (m2 / mutate-01
            :ARG1 (g / gene :name (n / name :op1 "PIK3CA")))
      :degree (m / more)
      :location (t2 / thing :quant 2
            :ARG1-of (i / include-91
                  :ARG2 (t / thing :quant 31
                        :ARG1-of (s2 / sample-01)))
            :mod (o / only)
            :ARG1-of (s / sample-01)))

# ::id pmid_2023_3444.146 ::date 2015-08-04T16:07:45 ::annotator SDL-AMR-09 ::preferred
# ::snt These differences demonstrate that in a majority of primary tumors with double mutations in <i>KRAS </i>and <i>PIK3CA</i>, the <i>KRAS </i>mutations are more prevalent than the <i>PIK3CA</i>.
# ::save-date Mon Aug 10, 2015 ::file pmid_2023_3444_146.txt
(d / demonstrate-01
      :ARG0 (d2 / differ-02
            :mod (t / this))
      :ARG1 (p / prevail-02
            :ARG1 (m / mutate-01
                  :ARG1 (g / gene :name (n / name :op1 "KRAS")))
            :mod (m2 / more)
            :location (t2 / tumor
                  :quant (m3 / majority)
                  :mod (p2 / primary)
                  :ARG0-of (h / have-03
                        :ARG1 (m4 / mutate-01
                              :ARG1 (a / and
                                    :op1 g
                                    :op2 g2)
                              :ARG1-of (d3 / double-01))))
            :compared-to (g2 / gene :name (n2 / name :op1 "PIK3CA"))))

# ::id pmid_2023_3444.147 ::date 2015-08-03T05:28:53 ::annotator SDL-AMR-09 ::preferred
# ::snt This unequal distribution of mutant alleles within a tumor may be due to the fact that a majority of the tumor cells have only the <i>KRAS </i>mutation, and cells with a <i>PIK3CA </i>mutation are in the minority, or it could be due to copy number variations in the <i>KRAS </i>and <i>PIK3CA </i>loci.
# ::save-date Wed Dec 30, 2015 ::file pmid_2023_3444_147.txt
(p / possible-01
      :ARG1 (d / distribute-01
            :ARG1 (a / allele
                  :ARG2-of (m / mutate-01))
            :mod (e / equal :polarity -)
            :mod (t / this)
            :location (t2 / tumor))
      :ARG1-of (c / cause-01
            :ARG0 (o / or
                  :op1 (a2 / and
                        :op1 (h / have-03
                              :ARG0 (c2 / cell
                                    :mod (t3 / tumor)
                                    :ARG1-of (i / include-91
                                          :ARG2 (c3 / cell)
                                          :ARG3 (m2 / majority)))
                              :ARG1 (m3 / mutate-01
                                    :ARG1 (g2 / gene :name (n / name :op1 "KRAS")))
                              :mod (o2 / only))
                        :op2 (c4 / cell
                              :location-of (m4 / mutate-01
                                    :ARG1 (g / gene :name (n2 / name :op1 "PIK3CA")))
                              :quant (m5 / minority)))
                  :op2 (v / vary-01
                        :ARG1 (n3 / number
                              :quant-of (d2 / dna-sequence
                                    :ARG2-of (c7 / copy-01)))
                        :location (a3 / and
                              :op1 (l / locus
                                    :ARG0-of (c5 / contain-01
                                          :ARG1 g2))
                              :op2 (l2 / locus
                                    :ARG0-of (c6 / contain-01
                                          :ARG1 g)))))))

# ::id pmid_2023_3444.148 ::date 2015-08-03T12:55:36 ::annotator SDL-AMR-09 ::preferred
# ::snt <sec-title level="2">BRAF mutations were correlated with poorly differentiated tumors and with mucinous tumors</sec-title>
# ::save-date Sat Jan 16, 2016 ::file pmid_2023_3444_148.txt
(c / correlate-01
      :ARG1 (m / mutate-01
            :ARG1 (e / enzyme :name (n / name :op1 "BRAF")))
      :ARG2 (a / and
            :op1 (t / tumor
                  :ARG1-of (d / differentiate-101
                        :manner (p / poor)))
            :op2 (t2 / tumor
                  :mod (p2 / protein :name (n2 / name :op1 "mucin")))))

# ::id pmid_2023_3444.149 ::date 2015-08-03T14:28:24 ::annotator SDL-AMR-09 ::preferred
# ::snt The frequency of mutations for <i>KRAS</i>, <i>PIK3CA</i>, and <i>BRAF </i>were tested for correlation to the degree of differentiation and to the prevalence of mucin in the tumor.
# ::save-date Thu Aug 6, 2015 ::file pmid_2023_3444_149.txt
(t / test-01
      :ARG1 (a / and
            :op1 (h / have-frequency-91
                  :ARG1 (m / mutate-01
                        :ARG1 (g / gene :name (n / name :op1 "KRAS"))))
            :op2 (h2 / have-frequency-91
                  :ARG1 (m2 / mutate-01
                        :ARG1 (g2 / gene :name (n2 / name :op1 "PIK3CA"))))
            :op3 (h3 / have-frequency-91
                  :ARG1 (m3 / mutate-01
                        :ARG1 (g3 / gene :name (n3 / name :op1 "BRAF")))))
      :ARG2 (c / correlate-01
            :ARG1 a
            :ARG2 (a2 / and
                  :op1 (d / degree
                        :degree-of (d2 / differentiate-101))
                  :op2 (p / prevail-01
                        :ARG1 (p2 / protein :name (n4 / name :op1 "mucin"))
                        :location (t2 / tumor)))))

# ::id pmid_2023_3444.150 ::date 2015-08-03T21:23:35 ::annotator SDL-AMR-09 ::preferred
# ::snt <i>BRAF </i>mutations were found in 26.2% of the poorly differentiated tumors and in 8.2% of the moderate and well differentiated.
# ::save-date Thu Feb 4, 2016 ::file pmid_2023_3444_150.txt
(f / find-01
      :ARG1 (m / mutate-01
            :ARG1 (g / gene :name (n / name :op1 "BRAF")))
      :location (a / and
            :op1 (t2 / tumor
                  :ARG1-of (i / include-91
                        :ARG2 (t / tumor
                              :ARG1-of (d / differentiate-01
                                    :manner (p / poor)))
                        :ARG3 (p2 / percentage-entity :value 26.2)))
            :op2 (t3 / tumor
                  :ARG1-of (i2 / include-91
                        :ARG2 (a2 / and
                              :op1 (t4 / tumor
                                    :ARG1-of (d2 / differentiate-01
                                          :manner (m2 / moderate)))
                              :op2 (t5 / tumor
                                    :ARG1-of (d3 / differentiate-01
                                          :ARG1-of (w / well-09))))
                        :ARG3 (p3 / percentage-entity :value 8.2)))))

# ::id pmid_2023_3444.151 ::date 2015-08-03T21:46:11 ::annotator SDL-AMR-09 ::preferred
# ::snt These frequencies were significantly different by Chi square test (p value = 0.001).
# ::save-date Mon Dec 14, 2015 ::file pmid_2023_3444_151.txt
(d / differ-02
      :ARG1 (h / have-frequency-91
            :mod (t / this))
      :ARG1-of (s / significant-02)
      :ARG1-of (s3 / statistical-test-91
            :ARG2 0.001
            :ARG4 (t3 / thing :wiki "Chi-squared_test" :name (n / name :op1 "Chi" :op2 "square" :op3 "test"))))

# ::id pmid_2023_3444.152 ::date 2015-08-03T22:00:50 ::annotator SDL-AMR-09 ::preferred
# ::snt <i>BRAF </i>mutations were also associated with mucinous tumors: <i>BRAF </i>mutations occurred in 28% of grade 3 mucinous tumors (>50% mucinous tumor cells) but in only 9.4% of the non-mucinous tumors (grade 1 and 2).
# ::save-date Tue Nov 17, 2015 ::file pmid_2023_3444_152.txt
(a / associate-01
      :ARG1 (m / mutate-01
            :ARG1 (g / gene :name (n / name :op1 "BRAF")))
      :ARG2 (t / tumor
            :mod (p4 / protein :name (n3 / name :op1 "mucin")))
      :mod (a2 / also)
      :ARG1-of (m3 / mean-01
            :ARG2 (b3 / be-located-at-91
                  :ARG1 (m4 / mutate-01
                        :ARG1 g)
                  :ARG2 (a3 / and
                        :op1 (t2 / tumor
                              :ARG1-of (i / include-91
                                    :ARG2 (t3 / tumor
                                          :mod (g3 / grade :mod 3)
                                          :mod p4)
                                    :ARG3 (p2 / percentage-entity :value 28
                                          :ARG1-of (m6 / mean-01
                                                :ARG2 (m2 / more-than
                                                      :op1 (p / percentage-entity :value 50)
                                                      :quant-of (c / cell
                                                            :mod t))))))
                        :op2 (t5 / tumor
                              :ARG1-of (i2 / include-91
                                    :ARG2 (t6 / tumor
                                          :ARG1-of (m9 / mean-01
                                                :ARG2 (a4 / and
                                                      :op1 (g5 / grade :mod 1)
                                                      :op2 (g6 / grade :mod 2)))
                                          :ARG1-of (h / have-mod-91 :polarity -
                                                :ARG2 (p5 / protein :name (n4 / name :op1 "mucin"))))
                                    :ARG3 (p3 / percentage-entity :value 9.4))
                              :mod (o / only))))))

# ::id pmid_2023_3444.153 ::date 2015-08-03T22:40:48 ::annotator SDL-AMR-09 ::preferred
# ::snt This was significant by the Chi square test at p value = 0.006.
# ::save-date Tue Dec 29, 2015 ::file pmid_2023_3444_153.txt
(s / significant-02
      :ARG1 (t / this)
      :ARG1-of (s3 / statistical-test-91
            :ARG2 0.006
            :ARG4 (t2 / thing :wiki "Chi-squared_test" :name (n / name :op1 "Chi" :op2 "square" :op3 "test"))))

# ::id pmid_2023_3444.154 ::date 2015-08-03T22:46:52 ::annotator SDL-AMR-09 ::preferred
# ::snt Similar data have been reported previously [<xref ref-type="bibr" rid="B25">25</xref>,<xref ref-type="bibr" rid="B26">26</xref>].
# ::save-date Mon Aug 3, 2015 ::file pmid_2023_3444_154.txt
(r / report-01
      :ARG1 (d / data
            :ARG1-of (r2 / resemble-01))
      :time (p / previous)
      :ARG1-of (d2 / describe-01
            :ARG0 (p2 / publication
                  :ARG1-of (c / cite-01
                        :ARG2 (a / and :op1 25 :op2 26)))))

# ::id pmid_2023_3444.155 ::date 2015-08-03T23:02:51 ::annotator SDL-AMR-09 ::preferred
# ::snt <i>KRAS </i>and <i>PIK3CA </i>mutations did not correlate with either the degree of differentiation or with prevalence of mucinous cells.
# ::save-date Thu Aug 6, 2015 ::file pmid_2023_3444_155.txt
(c / correlate-01 :polarity -
      :ARG1 (m / mutate-01
            :ARG1 (a / and
                  :op1 (g / gene :name (n / name :op1 "KRAS"))
                  :op2 (g2 / gene :name (n2 / name :op1 "PIK3CA"))))
      :ARG2 (o / or
            :op1 (d / degree
                  :degree-of (d2 / differentiate-01))
            :op2 (p / prevail-01
                  :ARG0 (c2 / cell
                        :mod (p2 / protein :name (n3 / name :op1 "mucin"))))))

# ::id pmid_2023_3444.156 ::date 2015-08-04T08:02:18 ::annotator SDL-AMR-09 ::preferred
# ::snt <sec-title level="2">Mutation profiling demonstrated a majority of primary and lymph node samples were concordant but differences were detected</sec-title>
# ::save-date Thu Aug 6, 2015 ::file pmid_2023_3444_156.txt
(d / demonstrate-01
      :ARG0 (p / profile-01
            :ARG1 (m / mutate-01))
      :ARG1 (c / concordant
            :domain (a / and
                  :op1 (s / sample-01
                        :ARG1 (n / node
                              :mod (p2 / primary))
                        :quant (m2 / majority))
                  :op2 (s2 / sample-01
                        :ARG1 (n2 / node
                              :mod (l / lymph))
                        :quant (m3 / majority))))
      :ARG1-of (c2 / contrast-01
            :ARG2 (d2 / detect-01
                  :ARG1 (d3 / differ-02))))

# ::id pmid_2023_3444.157 ::date 2015-08-04T08:18:41 ::annotator SDL-AMR-09 ::preferred
# ::snt Lymph node metastases were not routinely collected in C-07 but as a pilot study to determine the feasibility of using lymph nodes for mutation profiling was conducted.
# ::save-date Sun Jan 17, 2016 ::file pmid_2023_3444_157.txt
(c2 / contrast-01
      :ARG1 (c / collect-01 :polarity -
            :ARG1 (m / metastasize-101
                  :ARG2 (n / node
                        :mod (l / lymph)))
            :manner (r / routine)
            :location (c4 / cell-line :name (n3 / name :op1 "C-07")))
      :ARG2 (c3 / conduct-01
            :ARG1 (s / study-01
                  :ARG1-of (p / pilot-01))
            :purpose (d / determine-01
                  :ARG1 (f / feasibility
                        :poss (u / use-01
                              :ARG1 (n2 / node
                                    :mod (l2 / lymph))
                              :ARG2 (p2 / profile-01
                                    :ARG1 (m2 / mutate-01)))))))

# ::id pmid_2023_3444.158 ::date 2015-08-04T10:38:36 ::annotator SDL-AMR-09 ::preferred
# ::snt We isolated DNA from 39 lymph nodes containing tumor cells and their corresponding primary tumors.
# ::save-date Thu Aug 6, 2015 ::file pmid_2023_3444_158.txt
(i / isolate-01
      :ARG0 (w / we)
      :ARG1 (n2 / nucleic-acid :wiki "DNA" :name (n3 / name :op1 "DNA"))
      :ARG2 (a / and
            :op1 (n / node :quant 39
                  :mod (l / lymph)
                  :ARG0-of (c / contain-01
                        :ARG1 (c2 / cell
                              :mod (t / tumor))))
            :op2 (t2 / tumor
                  :mod (p / primary)
                  :ARG2-of (c3 / correspond-02
                        :ARG1 n))))

# ::id pmid_2023_3444.159 ::date 2015-08-04T10:56:22 ::annotator SDL-AMR-09 ::preferred
# ::snt These primary and lymph nodes samples were profiled with the entire OncoCarta panel.
# ::save-date Tue Nov 17, 2015 ::file pmid_2023_3444_159.txt
(p / profile-01
      :ARG1 (a / and
            :op1 (s / sample-01
                  :ARG1 (n / node
                        :mod (l / lymph))
                  :mod (t / this))
            :op2 (s2 / sample-01
                  :ARG1 (n2 / node
                        :mod (p2 / primary))
                  :mod t))
      :instrument (p3 / panel :name (n3 / name :op1 "OncoCarta")))

# ::id pmid_2023_3444.160 ::date 2015-08-04T11:08:38 ::annotator SDL-AMR-09 ::preferred
# ::snt The majority of lymph nodes and their corresponding primary tumors (89.7%) were concordant.
# ::save-date Thu Aug 6, 2015 ::file pmid_2023_3444_160.txt
(c2 / concordant
      :domain (a / and
            :op1 (n2 / node
                  :ARG1-of (i / include-91
                        :ARG2 (n / node
                              :mod (l / lymph))
                        :ARG3 (m / majority)))
            :op2 (t / tumor
                  :mod (p / primary)
                  :ARG2-of (c / correspond-02
                        :ARG1 n)
                  :quant (p2 / percentage-entity :value 89.7))))

# ::id pmid_2023_3444.161 ::date 2015-08-04T11:27:56 ::annotator SDL-AMR-09 ::preferred
# ::snt A total of 26 mutations were detected in lymph nodes, including <i>KRAS</i>, <i>BRAF</i>, <i>PIK3CA</i>, and <i>NRAS</i>.
# ::save-date Tue Aug 4, 2015 ::file pmid_2023_3444_161.txt
(d / detect-01
      :ARG1 (m / mutate-01
            :ARG1-of (t / total-01
                  :ARG2 26)
            :ARG2-of (i / include-91
                  :ARG1 (a / and
                        :op1 (g / gene :name (n2 / name :op1 "KRAS"))
                        :op2 (g2 / gene :name (n3 / name :op1 "BRAF"))
                        :op3 (g3 / gene :name (n4 / name :op1 "PIK3CA"))
                        :op4 (g4 / gene :name (n5 / name :op1 "NRAS")))))
      :location (n / node
            :mod (l / lymph)))

# ::id pmid_2023_3444.162 ::date 2015-08-04T11:34:54 ::annotator SDL-AMR-09 ::preferred
# ::snt Thirty-five out of 39 lymph nodes had identical mutation profiles, but in 4 cases mutations in the primary tumors were not found in the corresponding lymph nodes (<i>BRAF </i>[<xref ref-type="bibr" rid="B2">2</xref>], <i>PIK3CA </i>[<xref ref-type="bibr" rid="B1">1</xref>] and <i>KRAS </i>[<xref ref-type="bibr" rid="B1">1</xref>]).
# ::save-date Sat Jan 30, 2016 ::file pmid_2023_3444_162.txt
(c / contrast-01
      :ARG1 (h / have-03
            :ARG0 (n / node :quant 35
                  :mod (l / lymph)
                  :ARG1-of (i / include-91
                        :ARG2 (n2 / node :quant 39
                              :mod l)))
            :ARG1 (p / profile-01
                  :ARG1 (m / mutate-01)
                  :ARG1-of (i2 / identical-01)))
      :ARG2 (f / find-01 :polarity -
            :ARG1 (m2 / mutate-01
                  :location (t / tumor
                        :mod (p2 / primary)))
            :mod (c2 / case-04 :quant 4)
            :location (n3 / node
                  :ARG1-of (m3 / mean-01
                        :ARG2 (a / and
                              :op1 (g / gene :name (n4 / name :op1 "BRAF")
                                    :ARG1-of (d / describe-01
                                          :ARG0 (p3 / publication
                                                :ARG1-of (c3 / cite-01
                                                      :ARG2 2))))
                              :op2 (g2 / gene :name (n5 / name :op1 "PIK3CA")
                                    :ARG1-of (d2 / describe-01
                                          :ARG0 (p4 / publication
                                                :ARG1-of (c4 / cite-01
                                                      :ARG2 1))))
                              :op3 (g3 / gene :name (n6 / name :op1 "KRAS")
                                    :ARG1-of d2)))
                  :ARG2-of (c6 / correspond-02
                        :ARG1 t)
                  :mod l)))

# ::id pmid_2023_3444.163 ::date 2015-08-04T12:01:34 ::annotator SDL-AMR-09 ::preferred
# ::snt <sec-title level="2">Mutation profiles demonstrate that tumor cell populations may be different in lymph nodes and in the primary tumors</sec-title>
# ::save-date Tue Aug 4, 2015 ::file pmid_2023_3444_163.txt
(d / demonstrate-01
      :ARG0 (p / profile-01
            :ARG1 (m / mutate-01))
      :ARG1 (d2 / differ-02
            :ARG1 (p3 / population
                  :mod (c / cell
                        :mod (t / tumor)))
            :ARG1-of (p2 / possible-01)
            :location (a / and
                  :op1 (n / node
                        :mod (l / lymph))
                  :op2 (t2 / tumor
                        :mod (p4 / primary)))))

# ::id pmid_2023_3444.164 ::date 2015-08-04T12:12:36 ::annotator SDL-AMR-09 ::preferred
# ::snt Peak area evaluation of tumors that had 2 mutations and for which a metastatic lymph node was available demonstrated differences between the primary and lymph node samples.
# ::save-date Thu Aug 6, 2015 ::file pmid_2023_3444_164.txt
(d / demonstrate-01
      :ARG0 (e / evaluate-01
            :ARG1 (t / tumor
                  :ARG0-of (h / have-03
                        :ARG1 (m / mutate-01 :quant 2))
                  :ARG1-of (a2 / available-02
                        :ARG2 (n / node
                              :mod (l / lymph)
                              :ARG1-of (m2 / metastasize-101))))
            :location (a / area
                  :mod (p / peak)))
      :ARG1 (d2 / differ-02
            :ARG1 (s / sample-01
                  :ARG1 (n2 / node
                        :mod (p2 / primary)))
            :ARG2 (s2 / sample-01
                  :ARG1 (n3 / node
                        :mod (l2 / lymph)))))

# ::id pmid_2023_3444.165 ::date 2015-08-04T12:37:37 ::annotator SDL-AMR-09 ::preferred
# ::snt Table <xref ref-type="table" rid="T6">6</xref> details the frequency of mutant and wt alleles based on the peak areas for 5 such samples.
# ::save-date Tue Aug 4, 2015 ::file pmid_2023_3444_165.txt
(d / detail-01
      :ARG0 (t / table :mod 6)
      :ARG1 (h / have-frequency-91
            :ARG1 (a / and
                  :op1 (a2 / allele
                        :ARG2-of (m / mutate-01))
                  :op2 (a3 / allele
                        :mod (w / wild-type))))
      :ARG1-of (b / base-02
            :ARG2 (a4 / area
                  :mod (p / peak)))
      :beneficiary (s / sample :quant 5
            :mod (s2 / such)))

# ::id pmid_2023_3444.166 ::date 2015-08-04T12:49:03 ::annotator SDL-AMR-09 ::preferred
# ::snt <i>KRAS </i>to <i>PIK3CA </i>ratios demonstrated that there were more <i>KRAS </i>mutations than <i>PIK3CA </i>mutations in 4 of 4 primary samples, and in 3 of the 4 lymph node samples.
# ::save-date Thu Aug 6, 2015 ::file pmid_2023_3444_166.txt
(d / demonstrate-01
      :ARG0 (r / ratio-of
            :op1 (g / gene :name (n / name :op1 "KRAS"))
            :op2 (g2 / gene :name (n2 / name :op1 "PIK3CA")))
      :ARG1 (m / mutate-01
            :ARG1 g
            :quant (m2 / more-than
                  :op1 (m3 / mutate-01
                        :ARG1 g2))
            :location (a / and
                  :op1 (s / sample-01 :quant 4
                        :ARG1-of (i / include-91
                              :ARG2 (s2 / sample-01 :quant 4
                                    :mod (p2 / primary))))
                  :op2 (s3 / sample-01 :quant 3
                        :ARG1 (n5 / node
                              :mod (l2 / lymph))
                        :ARG1-of (i2 / include-91
                              :ARG2 (s4 / sample-01 :quant 4
                                    :ARG1 n5))))))

# ::id pmid_2023_3444.167 ::date 2015-08-04T13:12:10 ::annotator SDL-AMR-09 ::preferred
# ::snt However, it is also notable that the ratio of <i>KRAS</i>/PIK3A was lower in the lymph node compared to their primary tumor in 3 out of 4 samples.
# ::save-date Thu Aug 6, 2015 ::file pmid_2023_3444_167.txt
(c / contrast-01
      :ARG2 (n / notable-04
            :ARG1 (r / ratio-of
                  :op1 (g / gene :name (n2 / name :op1 "KRAS"))
                  :op2 (g2 / gene :name (n3 / name :op1 "PIK3A")))
            :ARG2 (l / low-04
                  :ARG1 r
                  :location (n4 / node
                        :mod (l2 / lymph))
                  :compared-to (t / tumor
                        :mod (p / primary)
                        :poss n4))
            :location (s / sample :quant 3
                  :ARG1-of (i / include-91
                        :ARG2 (s2 / sample :quant 4)))
            :mod (a / also)))

# ::id pmid_2023_3444.168 ::date 2015-08-04T13:45:09 ::annotator SDL-AMR-09 ::preferred
# ::snt In sample 0940, the <i>KRAS</i>/<i>PIK3CA </i>mutation decreased by almost 1/2 in the lymph node tumor compared to the primary.
# ::save-date Thu Aug 6, 2015 ::file pmid_2023_3444_168.txt
(d / decrease-01
      :ARG1 (m / mutate-01
            :ARG1 (s / slash
                  :op1 (g / gene :name (n / name :op1 "KRAS"))
                  :op2 (g2 / gene :name (n2 / name :op1 "PIK3CA"))))
      :ARG2 (a / almost
            :op1 (p2 / product-of :op1 "1/2"))
      :location (t / tumor
            :mod (n4 / node
                  :mod (l / lymph))
            :compared-to (t2 / tumor
                  :mod (p / primary)))
      :location (s2 / sample :mod 0940))

# ::id pmid_2023_3444.169 ::date 2015-08-04T14:14:56 ::annotator SDL-AMR-09 ::preferred
# ::snt Thus, in these samples there is either a loss of <i>KRAS </i>mutations or an accumulation of <i>PIK3CA </i>mutations, suggesting that <i>PIK3CA </i>mutations may impart a selective advantage in the lymph node.
# ::save-date Thu Aug 6, 2015 ::file pmid_2023_3444_169.txt
(i / infer-01
      :ARG1 (o / or
            :op1 (l / lose-01
                  :ARG1 (m / mutate-01
                        :ARG1 (g / gene :name (n / name :op1 "KRAS")))
                  :location (s / sample
                        :mod (t / this)))
            :op2 (a / accumulate-01
                  :ARG1 (m2 / mutate-01
                        :ARG1 (g2 / gene :name (n2 / name :op1 "PIK3CA")))
                  :location s))
      :ARG0-of (s2 / suggest-01
            :ARG1 (i2 / impart-01
                  :ARG0 m2
                  :ARG1 (a2 / advantage
                        :mod (s3 / selective))
                  :ARG2 (n4 / node
                        :mod (l2 / lymph))
                  :ARG1-of (p / possible-01))))

# ::id pmid_2023_3444.170 ::date 2015-08-04T14:36:55 ::annotator SDL-AMR-09 ::preferred
# ::snt In contrast, two other samples have a less frequent occurrence of their <i>PIK3CA </i>mutation in the lymph node than in the primary tumor.
# ::save-date Tue Nov 17, 2015 ::file pmid_2023_3444_170.txt
(c / contrast-01
      :ARG2 (h / have-frequency-91
            :ARG1 (m / mutate-01
                  :ARG1 (g / gene :name (n / name :op1 "PIK3CA"))
                  :location (s / sample :quant 2
                        :mod (o / other)))
            :ARG2 (l / less)
            :location (n2 / node
                  :mod (l2 / lymph)
                  :compared-to (t / tumor
                        :mod (p / primary)))))

# ::id pmid_2023_3444.171 ::date 2015-08-04T14:52:29 ::annotator SDL-AMR-09 ::preferred
# ::snt In sample 2244, the <i>PIK3CA </i>mutation was undetectable in the lymph node (Table <xref ref-type="table" rid="T6">6</xref>).
# ::save-date Thu Aug 6, 2015 ::file pmid_2023_3444_171.txt
(d / detect-01
      :ARG1 (m / mutate-01
            :ARG1 (g / gene :name (n / name :op1 "PIK3CA")))
      :location (n2 / node
            :mod (l / lymph))
      :location (s / sample :mod 2244)
      :ARG1-of (d2 / describe-01
            :ARG0 (t / table :mod 6))
      :ARG1-of (p / possible-01 :polarity -))

# ::id pmid_2023_3444.172 ::date 2015-08-04T14:57:25 ::annotator SDL-AMR-09 ::preferred
# ::snt In fact, if there was a selection for both mutations in the lymph node, then the <i>PIK3CA </i>mutation frequency would have been the same as that of the <i>KRAS </i>mutation (0.15).
# ::save-date Thu Aug 6, 2015 ::file pmid_2023_3444_172.txt
(h / have-condition-91
      :ARG1 (s2 / same-01
            :ARG1 (h2 / have-frequency-91
                  :ARG1 (m2 / mutate-01
                        :ARG1 (g / gene :name (n2 / name :op1 "PIK3CA")))
                  :ARG2 f3)
            :ARG2 (h3 / have-frequency-91
                  :ARG1 (m3 / mutate-01
                        :ARG1 (g2 / gene :name (n3 / name :op1 "KRAS")))
                  :ARG2 (f3 / frequency-quantity :value 0.15)))
      :ARG2 (s / select-01
            :ARG1 (m / mutate-01
                  :mod (b / both))
            :location (n / node
                  :mod (l / lymph)))
      :mod (i / in-fact))

# ::id pmid_2023_3444.173 ::date 2015-08-04T15:16:02 ::annotator SDL-AMR-09 ::preferred
# ::snt On the other hand, if the <i>PIK3CA</i>/<i>KRAS </i>ratio were the same in the primary and lymph node tumor, then the <i>PIK3CA </i>mutation frequency would have been .08, which is still detectable with this technology (Fig. <xref ref-type="fig" rid="F3">3</xref>).
# ::save-date Thu Aug 6, 2015 ::file pmid_2023_3444_173.txt
(c / contrast-01
      :ARG2 (h / have-condition-91
            :ARG1 (h2 / have-frequency-91
                  :ARG1 (m / mutate-01
                        :ARG1 g)
                  :ARG2 (f2 / frequency-quantity :value 0.08)
                  :ARG1-of (d / detect-01
                        :ARG2 (t3 / technology
                              :mod (t4 / this))
                        :mod (s2 / still)
                        :ARG1-of (p2 / possible-01)))
            :ARG2 (s / same-01
                  :ARG1 (r / ratio-of
                        :op1 (g / gene :name (n / name :op1 "PIK3CA"))
                        :op2 (g2 / gene :name (n2 / name :op1 "KRAS"))
                        :location (t / tumor
                              :mod (n3 / node
                                    :mod (p / primary))))
                  :ARG2 (r2 / ratio-of
                        :op1 g
                        :op2 g2
                        :location (t2 / tumor
                              :mod (n4 / node
                                    :mod (l / lymph))))))
      :ARG1-of (d2 / describe-01
            :ARG0 (f / figure :mod 3)))

# ::id pmid_2023_3444.174 ::date 2015-08-04T15:39:34 ::annotator SDL-AMR-09 ::preferred
# ::snt Thus, in sample 2244 there were fewer <i>PIK3CA </i>mutant alleles in the lymph node than in the primary tumor.
# ::save-date Tue Aug 4, 2015 ::file pmid_2023_3444_174.txt
(i / infer-01
      :ARG1 (f / few
            :quant-of (a / allele
                  :ARG2-of (m / mutate-01
                        :ARG1 (g / gene :name (n / name :op1 "PIK3CA"))))
            :location (n2 / node
                  :mod (l / lymph))
            :compared-to (t / tumor
                  :mod (p / primary))
            :location (s / sample :mod 2244)))

# ::id pmid_2023_3444.175 ::date 2015-08-04T15:57:18 ::annotator SDL-AMR-09 ::preferred
# ::snt In sample 1837, mutations in both <i>BRAF </i>and <i>PIK3CA </i>were detected and the <i>BRAF</i>/<i>PIK3CA </i>ratio was 1.67, but increased to 4.4 in the metastatic lymph node.
# ::save-date Thu Aug 6, 2015 ::file pmid_2023_3444_175.txt
(c / contrast-01
      :ARG1 (a / and
            :op1 (d / detect-01
                  :ARG1 (m / mutate-01
                        :ARG1 (a2 / and
                              :op1 (g / gene :name (n / name :op1 "BRAF"))
                              :op2 (g2 / gene :name (n2 / name :op1 "PIK3CA")))))
            :op2 (e / equal-01
                  :ARG1 (r / ratio-of
                        :op1 g
                        :op2 g2)
                  :ARG2 1.67))
      :ARG2 (i / increase-01
            :ARG1 r
            :ARG4 4.4
            :location (n5 / node
                  :mod (l / lymph)
                  :ARG2-of (m2 / metastasize-101)))
      :location (s / sample :mod 1837))

# ::id pmid_2112_2157.1 ::date 2015-07-18T17:20:13 ::annotator SDL-AMR-09 ::preferred
# ::snt Signal transducer and activator of transcription 3 activation up-regulates interleukin-6 autocrine production: a biochemical and genetic study of established cancer cell lines and clinical isolated human cancer cells (PMID:21122157)
# ::save-date Thu Nov 12, 2015 ::file pmid_2112_2157_1.txt
(u / upregulate-01
      :ARG1 (p / produce-01
            :ARG1 (p2 / protein
                  :name (n / name :op1 "interleukin-6")
                  :mod (a / autocrine)))
      :ARG2 (a2 / activate-01
            :ARG1 (p3 / protein
                  :name (n2 / name :op1 "Signal" :op2 "transducer" :op3 "and" :op4 "activator" :op5 "of" :op6 "transcription-3")))
      :ARG1-of (m / mean-01
            :ARG2 (s / study-01
                  :ARG1 (a3 / and
                        :op1 (c / cell-line
                              :mod (d / disease :wiki "Cancer"
                                    :name (n3 / name :op1 "cancer"))
                              :ARG1-of (e / establish-01))
                        :op2 (c2 / cell
                              :mod d
                              :mod (h / human)
                              :ARG1-of (i / isolate-01
                                    :manner (c3 / clinic))))
                  :mod (b / biochemistry)
                  :mod (g / genetics)))
      :ARG1-of (d2 / describe-01
            :ARG0 (p4 / publication-91 :ARG8 "PMID21122157")))

# ::id pmid_2112_2157.9 ::date 2015-07-18T17:58:16 ::annotator SDL-AMR-09 ::preferred
# ::snt Results
# ::save-date Mon Jul 27, 2015 ::file pmid_2112_2157_9.txt
(t / thing
      :ARG2-of (r / result-01))

# ::id pmid_2112_2157.10 ::date 2015-07-18T17:59:40 ::annotator SDL-AMR-09 ::preferred
# ::snt Inhibitors of Jak2/Stat3, MEK/Erk and PI3-K/Akt pathways down-regulated IL-6 secretion in the lung adenocarcinoma PC14PE6/AS2 (AS2) cells, which spontaneously secreted IL-6 and possessed constitutively activated Stat3.
# ::save-date Thu Dec 10, 2015 ::file pmid_2112_2157_10.txt
(d / downregulate-01
      :ARG1 (s / secrete-01
            :ARG1 (p / protein :name (n / name :op1 "IL-6")))
      :ARG2 (m / molecular-physical-entity
            :ARG0-of (i / inhibit-01
                  :ARG1 (a / and
                        :op1 (p2 / pathway :name (n2 / name :op1 "Jak2/Stat3"))
                        :op2 (p3 / pathway :name (n3 / name :op1 "MEK/Erk"))
                        :op3 (p4 / pathway :name (n4 / name :op1 "PI3-K/Akt")))))
      :location (c / cell :name (n5 / name :op1 "PC14PE6/AS2")
            :part-of (l / lung)
            :ARG0-of (s2 / secrete-01
                  :ARG1 p
                  :manner (s3 / spontaneous))
            :ARG0-of (p5 / possess-01
                  :ARG1 (p6 / protein :name (n6 / name :op1 "Stat3")
                        :ARG1-of (a3 / activate-01
                              :manner (c2 / constitutive))))
            :mod (m2 / medical-condition :name (n7 / name :op1 "adenocarcinoma"))))

# ::id pmid_2112_2157.11 ::date 2015-07-18T18:20:06 ::annotator SDL-AMR-09 ::preferred
# ::snt Transfection with dominant-negative Stat3, Stat3 siRNA, or Stat3 shRNA decreased IL-6 expression in AS2 cells.
# ::save-date Fri Feb 5, 2016 ::file pmid_2112_2157_11.txt
(d / decrease-01
      :ARG0 (t / transfect-01
            :ARG2 (o / or
                  :op1 (p / protein :name (n / name :op1 "Stat3"))
                  :op2 (n6 / nucleic-acid :name (n2 / name :op1 "siRNA")
                        :mod p)
                  :op3 (n7 / nucleic-acid :name (n3 / name :op1 "shRNA")
                        :mod p)
                  :ARG0-of (d2 / dominate-01)
                  :ARG2-of (m / mutate-01 :mod "-/-")))
      :ARG1 (e / express-03
            :ARG2 (p2 / protein :name (n4 / name :op1 "IL-6")))
      :location (c / cell-line :name (n5 / name :op1 "AS2")))

# ::id pmid_2112_2157.12 ::date 2015-07-18T18:31:11 ::annotator SDL-AMR-09 ::preferred
# ::snt Conversely, transfection with constitutively-activated Stat3 increased the production of IL-6.
# ::save-date Sat Jul 18, 2015 ::file pmid_2112_2157_12.txt
(c / contrast-01
      :ARG2 (i / increase-01
            :ARG0 (t / transfect-01
                  :ARG2 (p / protein :name (n / name :op1 "Stat3")
                        :ARG1-of (a / activate-01
                              :manner (c2 / constitutive))))
            :ARG1 (p2 / produce-01
                  :ARG1 (p3 / protein :name (n2 / name :op1 "IL-6")))))

# ::id pmid_2112_2157.13 ::date 2015-07-18T18:36:31 ::annotator SDL-AMR-09 ::preferred
# ::snt In AS2 derived cells, resistance to paclitaxel was positively correlated with Stat3 activation status and the expression of IL-6, which is commonly secreted in drug resistant cancer cells.
# ::save-date Mon Jul 27, 2015 ::file pmid_2112_2157_13.txt
(c / correlate-01
      :ARG1 (r / resist-01
            :ARG1 (s / small-molecule
                  :name (n / name :op1 "paclitaxel")))
      :ARG2 (a / and
            :op1 (s2 / status
                  :mod (a2 / activate-01
                        :ARG1 (p / protein
                              :name (n2 / name :op1 "Stat3"))))
            :op2 (e / express-03
                  :ARG2 (p2 / protein
                        :name (n3 / name :op1 "IL-6")
                        :ARG1-of (s3 / secrete-01
                              :manner (c2 / common)
                              :location (c3 / cell
                                    :mod (d / disease :wiki "Cancer"
                                          :name (n4 / name :op1 "cancer"))
                                    :ARG0-of (r2 / resist-01
                                          :ARG1 (d2 / drug-01)))))))
      :manner (p3 / positive)
      :location (c4 / cell
            :ARG1-of (d3 / derive-01
                  :ARG2 (c5 / cell-line
                        :name (n5 / name :op1 "AS2")))))

# ::id pmid_2112_2157.14 ::date 2015-07-18T18:53:49 ::annotator SDL-AMR-09 ::preferred
# ::snt The pharmacological inhibition of NF-?B, PI3-K/Akt and MEK/Erk and the pharmacological inhibition and genetic inhibition (Stat3 siRNA) of Jak2/Stat3 pathway decreased IL-6 autocrine production in various drug resistant cancer cell lines and similarly decreased IL-6 autocrine production in clinically isolated lung cancer cells.
# ::save-date Mon Dec 21, 2015 ::file pmid_2112_2157_14.txt
(a / and
      :op1 (d / decrease-01
            :ARG0 (a2 / and
                  :op1 (i / inhibit-01
                        :ARG1 (a3 / and
                              :op1 (p / pathway :name (n / name :op1 "NF-κB"))
                              :op2 (p2 / pathway :name (n2 / name :op1 "PI3-K/Akt"))
                              :op3 (p3 / pathway :name (n3 / name :op1 "MEK/Erk")))
                        :mod (p4 / pharmacology))
                  :op2 (a4 / and
                        :op1 (i2 / inhibit-01
                              :ARG1 (p5 / pathway :name (n4 / name :op1 "Jak2/Stat3"))
                              :mod p4)
                        :op2 (i3 / inhibit-01
                              :ARG0 (n9 / nucleic-acid :name (n5 / name :op1 "siRNA")
                                    :mod (p6 / protein :name (n6 / name :op1 "Stat3")))
                              :ARG1 p5
                              :mod (g / genetics))))
            :ARG1 (p7 / produce-01
                  :ARG1 (p8 / protein :name (n7 / name :op1 "IL-6"))
                  :mod (a5 / autocrine))
            :location (c / cell-line
                  :mod (d2 / disease :wiki "Cancer" :name (n8 / name :op1 "cancer"))
                  :ARG0-of (r2 / resist-01
                        :ARG1 (d3 / drug))
                  :quant (v / various)))
      :op2 (d4 / decrease-01
            :ARG0 a2
            :ARG1 p7
            :location (c2 / cell
                  :mod d2
                  :part-of (l / lung)
                  :ARG1-of (i4 / isolate-01
                        :manner (c3 / clinic)))
            :ARG1-of (r3 / resemble-01)))

# ::id pmid_2112_2157.108 ::date 2015-07-19T00:46:12 ::annotator SDL-AMR-09 ::preferred
# ::snt Results
# ::save-date Mon Jul 27, 2015 ::file pmid_2112_2157_108.txt
(t / thing
      :ARG2-of (r / result-01))

# ::id pmid_2112_2157.109 ::date 2015-07-19T00:47:17 ::annotator SDL-AMR-09 ::preferred
# ::snt Autocrine IL-6 induced Stat3 activation and paclitaxel resistance in AS2 cells
# ::save-date Mon Jul 27, 2015 ::file pmid_2112_2157_109.txt
(a / and
      :op1 (a2 / activate-01
            :ARG1 (p / protein :name (n / name :op1 "Stat3"))
            :ARG2-of (i / induce-01
                  :ARG0 (p2 / protein :name (n2 / name :op1 "IL-6")
                        :mod (a3 / autocrine))))
      :op2 (r / resist-01
            :ARG1 (s / small-molecule :name (n4 / name :op1 "paclitaxel")))
      :location (c / cell-line :name (n3 / name :op1 "AS2")))

# ::id pmid_2112_2157.110 ::date 2015-07-19T00:55:40 ::annotator SDL-AMR-09 ::preferred
# ::snt We previously demonstrated that AS2 cells produced autocrine IL-6 and the secreted IL-6 induced Stat3 activation and subsequently promoted tumor progression [2].
# ::save-date Thu Nov 12, 2015 ::file pmid_2112_2157_110.txt
(d / demonstrate-01
      :ARG0 (w / we)
      :ARG1 (a / and
            :op1 (p / produce-01
                  :ARG0 (c / cell-line :name (n / name :op1 "AS2"))
                  :ARG1 (a2 / and
                        :op1 (p2 / protein :name (n2 / name :op1 "IL-6")
                              :mod (a3 / autocrine))
                        :op2 (i / induce-01
                              :ARG0 (p4 / protein :name (n4 / name :op1 "IL-6")
                                    :ARG1-of (s / secrete-01))
                              :ARG2 (a4 / activate-01
                                    :ARG1 (p3 / protein :name (n3 / name :op1 "Stat3"))))))
            :op2 (p5 / promote-01
                  :ARG0 c
                  :ARG1 (p6 / progress-01
                        :ARG1 (t / tumor))
                  :time (s2 / subsequent)))
      :time (p7 / previous)
      :ARG1-of (d2 / describe-01
            :ARG0 (p8 / publication
                  :ARG1-of (c2 / cite-01
                        :ARG2 2))))

# ::id pmid_2112_2157.111 ::date 2015-07-19T01:06:51 ::annotator SDL-AMR-09 ::preferred
# ::snt We used ELISA and Western blot analysis to measure IL-6 secretion and Stat3 activation (phosphorylation) after medium replacement to remove the existing IL-6 in the old medium and make it possible to measure the amount of newly secreted IL-6 time-dependently in AS2 cells, respectively.
# ::save-date Sun Jan 17, 2016 ::file pmid_2112_2157_111.txt
(u / use-01
      :ARG0 (w / we)
      :ARG1 (a / and
            :op1 (a2 / analyze-01
                  :instrument (t2 / thing :name (n / name :op1 "ELISA")))
            :op2 (a3 / analyze-01
                  :manner (i / immunoblot-01
                        :ARG0 w)))
      :ARG2 (m / measure-01
            :ARG0 w
            :ARG1 (a4 / and
                  :op1 (s / secrete-01
                        :ARG1 (p / protein :name (n3 / name :op1 "IL-6")))
                  :op2 (a5 / activate-01
                        :ARG1 (p2 / protein :name (n4 / name :op1 "Stat3"))
                        :ARG1-of (m2 / mean-01
                              :ARG2 (p3 / phosphorylate-01
                                    :ARG1 p2)))))
      :time (a6 / after
            :op1 (r / replace-01
                  :ARG1 (m3 / medium)))
      :purpose (a7 / and
            :op1 (r2 / remove-01
                  :ARG1 (p4 / protein :name (n5 / name :op1 "IL-6")
                        :ARG1-of (e / exist-01))
                  :location (m4 / medium
                        :mod (o / old)))
            :op2 (m5 / make-02
                  :ARG0 w
                  :ARG1 (p5 / possible-01
                        :ARG1 (m6 / measure-01
                              :ARG1 (a8 / amount-01
                                    :ARG1 (p6 / protein :name (n6 / name :op1 "IL-6")
                                          :ARG1-of (s2 / secrete-01
                                                :ARG1-of (n7 / new-01))))
                              :ARG0-of (d / depend-01
                                    :ARG1 (t / time))
                              :location (c / cell-line :name (n8 / name :op1 "AS2")))))
            :mod (r3 / respective)))

# ::id pmid_2112_2157.112 ::date 2015-07-19T01:42:34 ::annotator SDL-AMR-09 ::preferred
# ::snt We found the constitutive secretion of IL-6 at hours 1 to 24 and the activation of Stat3 peaked at hours 3 and 8, confirming the autocrine production of IL-6 and the subsequent activation of Stat3 in AS2 cells (Figure 1A and 1B).
# ::save-date Mon Jul 27, 2015 ::file pmid_2112_2157_112.txt
(f / find-01
      :ARG0 (w / we)
      :ARG1 (a / and
            :op1 (s / secrete-01
                  :ARG1 (p / protein :name (n / name :op1 "IL-6"))
                  :mod (c / constitutive)
                  :time (a2 / after
                        :op1 (t / temporal-quantity
                              :quant (v / value-interval :op1 1 :op2 24)
                              :unit (h / hour))))
            :op2 (p2 / peak-01
                  :ARG1 (a3 / activate-01
                        :ARG1 (p3 / protein :name (n2 / name :op1 "Stat3")))
                  :time (a4 / after
                        :op1 (a5 / and
                              :op1 (t2 / temporal-quantity :quant 3
                                    :unit h)
                              :op2 (t3 / temporal-quantity :quant 8
                                    :unit h))))
            :ARG0-of (c2 / confirm-01
                  :ARG1 (a6 / and
                        :op1 (p4 / produce-01
                              :ARG1 p
                              :mod (a7 / autocrine))
                        :op2 (a8 / activate-01
                              :ARG1 p3
                              :time (s2 / subsequent))
                        :location (c3 / cell-line :name (n3 / name :op1 "AS2")))))
      :ARG1-of (d / describe-01
            :ARG0 (a9 / and
                  :op1 (f2 / figure :mod "1A")
                  :op2 (f3 / figure :mod "1B"))))

# ::id pmid_2112_2157.113 ::date 2015-07-19T01:59:33 ::annotator SDL-AMR-09 ::preferred
# ::snt It has been shown that cancer cells resistant to chemotherapeutic agents express elevated levels of IL-6, and the IL-6 contributes to the drug resistance of cancer cells [30,39].
# ::save-date Mon Jul 27, 2015 ::file pmid_2112_2157_113.txt
(s / show-01
      :ARG1 (a / and
            :op1 (e / express-03
                  :ARG2 (l / level
                        :quant-of (p / protein
                              :name (n / name :op1 "IL-6"))
                        :ARG1-of (e2 / elevate-01))
                  :ARG3 (c / cell
                        :mod (d / disease :wiki "Cancer"
                              :name (n2 / name :op1 "cancer"))
                        :ARG0-of (r / resist-01
                              :ARG1 (a2 / agent
                                    :mod (c2 / chemotherapy)))))
            :op2 (c3 / contribute-01
                  :ARG0 p
                  :ARG2 (r2 / resist-01
                        :ARG0 (c4 / cell
                              :mod d)
                        :ARG1 (d2 / drug))))
      :ARG1-of (d3 / describe-01
            :ARG0 (p2 / publication
                  :ARG1-of (c5 / cite-01
                        :ARG2 (a3 / and :op1 30 :op2 39)))))

# ::id pmid_2112_2157.114 ::date 2015-07-19T02:16:09 ::annotator SDL-AMR-09 ::preferred
# ::snt In our MTT assay of the effect of IL-6 on paclitaxel sensitivity in AS2 cells, we found a significant increase (about 15%) in cell viability in cells pre-treated with exogenous IL-6 and a significant decrease (about 15%) in cell viability in cells treated with anti-IL-6R, compared to the un-pretreated cells (both p < 0.001), indicating that autocrine IL-6 contributed to the paclitaxel resistance in AS2 cells (Figure 1C).
# ::save-date Sat Feb 13, 2016 ::file pmid_2112_2157_114.txt
(f / find-01
      :ARG0 (w / we)
      :ARG1 (a / and
            :op1 (i / increase-01
                  :ARG1 (v / viability
                        :mod (c / cell))
                  :ARG2 (s / significant-02
                        :ARG1-of (m / mean-01
                              :ARG2 (a2 / about
                                    :op1 (p / percentage-entity :value 15))))
                  :location (c2 / cell
                        :ARG1-of (p2 / pretreat-01
                              :ARG3 (p3 / protein :name (n / name :op1 "IL-6")
                                    :mod (e / exogenous)))))
            :op2 (d / decrease-01
                  :ARG1 v
                  :ARG1-of s
                  :location (c3 / cell
                        :ARG1-of (t / treat-04
                              :ARG2 (m2 / molecular-physical-entity
                                    :ARG0-of (c8 / counter-01
                                          :ARG1 p3)))))
            :compared-to (a3 / and
                  :op1 (c4 / cell
                        :ARG1-of (p4 / pretreat-01 :polarity -
                              :ARG3 p3))
                  :op2 (c5 / cell
                        :ARG1-of (t2 / treat-04 :polarity -
                              :ARG2 m2)))
            :ARG1-of (s4 / statistical-test-91
                  :ARG2 (l / less-than :op1 0.001)))
      :ARG0-of (i2 / indicate-01
            :ARG1 (c7 / contribute-01
                  :ARG0 (p6 / protein :name (n6 / name :op1 "IL-6")
                        :mod (a6 / autocrine))
                  :ARG2 (r / resist-01
                        :ARG1 s3)
                  :location c6))
      :ARG1-of (d2 / describe-01
            :ARG0 (f2 / figure :mod "1C"))
      :time (a4 / assay-01
            :ARG0 w
            :ARG1 (a5 / affect-01
                  :ARG0 p3
                  :ARG1 (s2 / sensitive-03
                        :ARG1 (s3 / small-molecule :name (n4 / name :op1 "paclitaxel")))
                  :location (c6 / cell-line :name (n5 / name :op1 "AS2")))
            :instrument (s5 / small-molecule :name (n2 / name :op1 "MTT"))))

# ::id pmid_2112_2157.115 ::date 2015-07-19T15:25:41 ::annotator SDL-AMR-09 ::preferred
# ::snt Jak2/Stat3 pathway positively regulated IL-6 autocrine production in AS2 cells
# ::save-date Mon Jul 27, 2015 ::file pmid_2112_2157_115.txt
(r / regulate-01
      :ARG0 (p / pathway :name (n / name :op1 "Jak2/Stat3"))
      :ARG1 (p2 / produce-01
            :ARG1 (p3 / protein :name (n2 / name :op1 "IL-6"))
            :mod (a / autocrine))
      :location (c / cell-line :name (n3 / name :op1 "AS2"))
      :manner (p4 / positive))

# ::id pmid_2112_2157.116 ::date 2015-07-19T15:32:43 ::annotator SDL-AMR-09 ::preferred
# ::snt To investigate whether Jak2/Stat3 as well as the other three IL-6 downstream pathways (PI3-K/Akt, MEK/Erk, and NF-?B) known to be involved in IL-6 expression in various cells would act as an upstream regulator of IL-6 autocrine production in AS2 cells, we used ELISA to measure IL-6 secretion in one control AS2 group and in four different AS2 treatment groups each with one pathway (Jak2/Stat3, PI3-K/Akt, MEK/Erk, or NF-?B) pharmacologically inhibited by the inhibitors AG490, LY294002, U0126, or BAY11-7082, respectively.
# ::save-date Tue Dec 22, 2015 ::file pmid_2112_2157_116.txt
(u / use-01
      :ARG0 (w / we)
      :ARG1 (t / thing :name (n / name :op1 "ELISA"))
      :ARG2 (m / measure-01
            :ARG0 w
            :ARG1 (s / secrete-01
                  :ARG1 (p / protein :name (n2 / name :op1 "IL-6"))))
      :location (a / and
            :op1 (g / group-01 :quant 1
                  :ARG2 (c / cell-line :name (n3 / name :op1 "AS2"))
                  :ARG2-of (c2 / control-01))
            :op2 (g2 / group-01 :quant 4
                  :mod (t2 / treat-04
                        :ARG1 c)
                  :ARG1-of (d / differ-02)
                  :mod (p2 / pathway :quant 1
                        :ARG1-of (m2 / mean-01
                              :ARG2 (o / or
                                    :op1 (p3 / pathway :name (n4 / name :op1 "Jak2/Stat3")
                                          :ARG1-of (i / inhibit-01
                                                :ARG0 (s2 / small-molecule :name (n5 / name :op1 "AG490"))
                                                :manner (p4 / pharmacology)))
                                    :op2 (p5 / pathway :name (n6 / name :op1 "PI3-K/Akt")
                                          :ARG1-of (i2 / inhibit-01
                                                :ARG0 (s3 / small-molecule :name (n7 / name :op1 "LY294002"))
                                                :manner p4))
                                    :op3 (p6 / pathway :name (n8 / name :op1 "MEK/Erk")
                                          :ARG1-of (i3 / inhibit-01
                                                :ARG0 (s4 / small-molecule :name (n9 / name :op1 "U0126"))
                                                :manner p4))
                                    :op4 (p7 / pathway :name (n10 / name :op1 "NF-κB")
                                          :ARG1-of (i4 / inhibit-01
                                                :ARG0 (s5 / small-molecule :name (n11 / name :op1 "BAY11-7082"))
                                                :manner p4)))))
                  :mod (e / each)))
      :purpose (i5 / investigate-01
            :ARG0 w
            :ARG1 (a2 / act-01 :mode interrogative
                  :ARG0 (a3 / and
                        :op1 p3
                        :op2 (p8 / pathway :quant 3
                              :mod (o2 / other)
                              :direction (d2 / downstream
                                    :mod p)
                              :ARG1-of (m3 / mean-01
                                    :ARG2 (a4 / and
                                          :op1 p5
                                          :op2 p6
                                          :op3 p7)))
                        :ARG1-of (i6 / involve-01
                              :ARG2 (e2 / express-03
                                    :ARG2 p
                                    :ARG3 (c3 / cell
                                          :mod (v / various)))
                              :ARG1-of (k / know-01)))
                  :ARG1 (r / regulate-01
                        :ARG0 a3
                        :ARG1 (p9 / produce-01
                              :ARG1 p
                              :mod (a5 / autocrine))
                        :direction (u2 / upstream))
                  :location c)))

# ::id pmid_2112_2157.117 ::date 2015-07-19T16:31:32 ::annotator SDL-AMR-09 ::preferred
# ::snt We found that, compared to the controls, MEK/Erk inhibitor and PI3-K/Akt inhibitor reduced IL-6 secretion in AS2 cells by about 80% and 90% (both p < 0.01), but NF-?B inhibitor decreased it by only 20% (p < 0.05) (Figure 2A).
# ::save-date Sun Jan 17, 2016 ::file pmid_2112_2157_117.txt
(f / find-01
      :ARG0 (w / we)
      :ARG1 (c / contrast-01
            :ARG1 (r / reduce-01
                  :ARG0 (a / and
                        :op1 (m / molecular-physical-entity
                              :ARG0-of (i / inhibit-01
                                    :ARG1 (p / pathway :name (n / name :op1 "MEK/Erk"))))
                        :op2 (m2 / molecular-physical-entity
                              :ARG0-of (i2 / inhibit-01
                                    :ARG1 (p2 / pathway :name (n2 / name :op1 "PI3-K/Akt")))))
                  :ARG1 (s / secrete-01
                        :ARG1 (p3 / protein :name (n3 / name :op1 "IL-6")))
                  :ARG2 (a2 / about
                        :op1 (a3 / and
                              :op1 (p4 / percentage-entity :value 80)
                              :op2 (p5 / percentage-entity :value 90)))
                  :location (c2 / cell-line :name (n4 / name :op1 "AS2"))
                  :ARG1-of (s2 / statistical-test-91
                        :ARG2 (l / less-than :op1 0.01)))
            :ARG2 (d / decrease-01
                  :ARG0 (m3 / molecular-physical-entity
                        :ARG0-of (i3 / inhibit-01
                              :ARG1 (p7 / pathway :name (n5 / name :op1 "NF-κB"))))
                  :ARG1 s
                  :ARG2 (p8 / percentage-entity :value 20)
                  :mod (o / only)
                  :ARG1-of (s3 / statistical-test-91
                        :ARG2 (l2 / less-than :op1 0.05)))
            :ARG1-of (c3 / compare-01
                  :ARG2 (m4 / molecular-physical-entity
                        :ARG2-of (c4 / control-01))))
      :ARG1-of (d2 / describe-01
            :ARG0 (f2 / figure :mod "2A")))

# ::id pmid_2112_2157.118 ::date 2015-07-19T16:59:11 ::annotator SDL-AMR-09 ::preferred
# ::snt Importantly, Jak2/Stat3 inhibitor also reduced IL-6 secretion by more than 60% (p < 0.01).
# ::save-date Tue Dec 15, 2015 ::file pmid_2112_2157_118.txt
(r / reduce-01
      :ARG0 (m / molecular-physical-entity
            :ARG0-of (i / inhibit-01
                  :ARG1 (p / pathway :name (n / name :op1 "Jak2/Stat3"))))
      :ARG1 (s / secrete-01
            :ARG1 (p2 / protein :name (n2 / name :op1 "IL-6")))
      :ARG2 (m2 / more-than
            :op1 (p3 / percentage-entity :value 60))
      :mod (a / also)
      :mod (i2 / important)
      :ARG1-of (s2 / statistical-test-91
            :ARG2 (l / less-than :op1 0.01)))

# ::id pmid_2112_2157.119 ::date 2015-07-19T17:11:30 ::annotator SDL-AMR-09 ::preferred
# ::snt Though Jak2/Stat3 inhibitor was not the most efficient, Jak2/Stat3 pathway clearly participates in the regulation of IL-6 and should be significant an upstream regulator of IL-6 secretion in AS2 cells (Figure 2A).
# ::save-date Sun Jan 17, 2016 ::file pmid_2112_2157_119.txt
(a / and
      :op1 (p / participate-01
            :ARG0 (p2 / pathway :name (n / name :op1 "Jak2/Stat3"))
            :ARG1 (r / regulate-01
                  :ARG1 (p3 / protein :name (n2 / name :op1 "IL-6")))
            :ARG1-of (c / clear-06))
      :op2 (r2 / recommend-01
            :ARG1 (s / significant-02
                  :ARG1 p2
                  :ARG1-of (c3 / cause-01
                        :ARG0 (r3 / regulate-01
                              :ARG0 p2
                              :ARG1 (s2 / secrete-01
                                    :ARG1 p3)
                              :location (u / upstream))))
            :location (c2 / cell-line :name (n4 / name :op1 "AS2")))
      :concession (e / efficient-01 :polarity -
                  :ARG1 (m / molecular-physical-entity
                        :ARG0-of (i / inhibit-01
                              :ARG1 p2))
                  :degree (m2 / most))
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod "2A")))

# ::id pmid_2112_2157.120 ::date 2015-07-19T17:34:19 ::annotator SDL-AMR-09 ::preferred
# ::snt To exclude the possibility that the reduction of IL-6 secretion was mainly caused by the reduction of cell survival, cell viability was measured by MTT assay after being treated with each one of four inhibitors.
# ::save-date Sat Feb 13, 2016 ::file pmid_2112_2157_120.txt
(m / measure-01
      :ARG1 (v / viability
            :mod (c / cell))
      :manner (a / assay-01
            :instrument (s3 / small-molecule :name (n / name :op1 "MTT")))
      :time (a2 / after
            :op1 (t / treat-04
                  :ARG1 c
                  :ARG2 (m2 / molecular-physical-entity :quant 4
                        :ARG0-of (i / inhibit-01)
                        :mod (e / each))))
      :purpose (e2 / exclude-01
            :ARG1 (p / possible-01
                  :ARG1 (c2 / cause-01
                        :ARG0 (r / reduce-01
                              :ARG1 (s / survive-01
                                    :ARG0 (c3 / cell)))
                        :ARG1 (r2 / reduce-01
                              :ARG1 (s2 / secrete-01
                                    :ARG1 (p2 / protein :name (n2 / name :op1 "IL-6"))))
                        :mod (m3 / main)))))

# ::id pmid_2112_2157.121 ::date 2015-07-19T17:47:34 ::annotator SDL-AMR-09 ::preferred
# ::snt None of these inhibitors compromised the viability of AS2 cells during the treatment period at the indicated doses (Additional file 1, Figure S1A).
# ::save-date Mon Jul 27, 2015 ::file pmid_2112_2157_121.txt
(c / compromise-02 :polarity -
      :ARG0 (m / molecular-physical-entity
            :ARG0-of (i / inhibit-01)
            :mod (t / this)
            :ARG1-of (d / dose-01
                  :ARG1-of (i2 / indicate-01)))
      :ARG1 (v / viability
            :poss (c2 / cell-line :name (n / name :op1 "AS2")))
      :time (p / period
            :mod (t2 / treat-04))
      :ARG1-of (d2 / describe-01
            :ARG0 (a / and
                  :op1 (a2 / add-02
                        :ARG1 (f / file))
                  :op2 (f2 / figure :mod "S1A"))))

# ::id pmid_2112_2157.122 ::date 2015-07-19T17:57:50 ::annotator SDL-AMR-09 ::preferred
# ::snt To confirm our findings, we performed inhibition experiments on AS2 cells using increasing doses of Jak2/Stat3 inhibitor.
# ::save-date Fri Feb 5, 2016 ::file pmid_2112_2157_122.txt
(p / perform-01
      :ARG0 (w / we)
      :ARG1 (e / experiment-01
            :ARG0 w
            :ARG1 (c / cell-line :name (n / name :op1 "AS2"))
            :ARG2 (i / inhibit-01))
      :ARG2 (d / dose-01
            :ARG1 c
            :ARG2 (m / molecular-physical-entity
                  :ARG0-of (i2 / inhibit-01
                        :ARG1 (p2 / pathway :name (n2 / name :op1 "Jak2/Stat3"))))
            :ARG1-of (i3 / increase-01))
      :purpose (c2 / confirm-01
            :ARG0 w
            :ARG1 (t / thing
                  :ARG1-of (f / find-01
                        :ARG0 w))))

# ::id pmid_2112_2157.123 ::date 2015-07-19T18:07:59 ::annotator SDL-AMR-09 ::preferred
# ::snt Decrease in Stat3 phosphorylation was confirmed by Western blot analysis, and IL-6 secretion was measured by ELISA.
# ::save-date Mon Dec 21, 2015 ::file pmid_2112_2157_123.txt
(a / and
      :op1 (c / confirm-01
            :ARG0 (a2 / analyze-01
                  :manner (i / immunoblot-01))
            :ARG1 (d / decrease-01
                  :ARG1 (p / phosphorylate-01
                        :ARG1 (p2 / protein :name (n / name :op1 "Stat3")))))
      :op2 (m / measure-01
            :ARG1 (s / secrete-01
                  :ARG1 (p3 / protein :name (n3 / name :op1 "IL-6")))
            :manner (t / thing :name (n4 / name :op1 "ELISA"))))

# ::id pmid_2112_2157.124 ::date 2015-07-19T18:14:21 ::annotator SDL-AMR-09 ::preferred
# ::snt We found the Jak2/Stat3 inhibitor dose-dependently decreased Stat3 phosphorylation (Figure 2B) and IL-6 secretion (p < 0.05 at doses higher than 20 �M) (Figure 2C).
# ::save-date Wed Feb 24, 2016 ::file pmid_2112_2157_124.txt
(f / find-01
      :ARG0 (w / we)
      :ARG1 (d / decrease-01
            :ARG0 (m / molecular-physical-entity
                  :ARG0-of (i / inhibit-01
                        :ARG1 (p / pathway :name (n / name :op1 "Jak2/Stat3"))))
            :ARG1 (a / and
                  :op1 (p2 / phosphorylate-01
                        :ARG1 (p3 / protein :name (n2 / name :op1 "Stat3"))
                        :ARG1-of (d2 / describe-01
                              :ARG0 (f2 / figure :mod "2B")))
                  :op2 (s / secrete-01
                        :ARG1 (p4 / protein :name (n3 / name :op1 "IL-6"))
                        :ARG1-of (d3 / dose-01
                              :quant (m3 / more-than
                                    :op1 (c / concentration-quantity :quant 20
                                          :unit (m2 / micromolar))))
                        :ARG1-of (d4 / describe-01
                              :ARG0 (f3 / figure :mod "2C"))))
            :ARG0-of (d5 / depend-01
                  :ARG1 d3)
            :ARG1-of (s2 / statistical-test-91
                  :ARG2 (l / less-than :op1 0.05))))

# ::id pmid_2112_2157.125 ::date 2015-07-19T18:32:17 ::annotator SDL-AMR-09 ::preferred
# ::snt We also used MTT assay to analyze the effect of the increasing doses of AG490 on cell viability and showed that only a minor reduction in cell survival (about 15%) was found when cells exposed to 80 �M AG490 (Additional file 1, Figure S1B).
# ::save-date Sat Feb 13, 2016 ::file pmid_2112_2157_125.txt
(a / and
      :op1 (u / use-01
            :ARG0 (w / we)
            :ARG1 (a2 / assay-01
                  :instrument (s5 / small-molecule :name (n / name :op1 "MTT")))
            :ARG2 (a3 / analyze-01
                  :ARG0 w
                  :ARG1 (a4 / affect-01
                        :ARG0 (d / dose-01
                              :ARG1 (s3 / small-molecule :name (n2 / name :op1 "AG490"))
                              :ARG1-of (i / increase-01))
                        :ARG1 (v / viability
                              :mod (c / cell))))
            :mod (a5 / also))
      :op2 (s / show-01
            :ARG0 w
            :ARG1 (f / find-01
                  :ARG0 w
                  :ARG1 (r / reduce-01
                        :ARG1 (s2 / survive-01
                              :ARG0 (c2 / cell))
                        :ARG1-of (m / minor-01
                              :ARG1-of (m3 / mean-01
                                    :ARG2 (a6 / about
                                          :op1 (p / percentage-entity :value 15))))
                        :mod (o / only))
                  :time (e / expose-01
                        :ARG0 w
                        :ARG1 (c3 / cell)
                        :ARG2 (s4 / small-molecule :name (n3 / name :op1 "AG490")
                              :quant (c4 / concentration-quantity :quant 80
                                    :unit (m5 / micromolar))))))
      :ARG1-of (d2 / describe-01
            :ARG0 (a7 / and
                  :op1 (a8 / add-02
                        :ARG1 (f2 / file :mod 1))
                  :op2 (f3 / figure :mod "S1B"))))

# ::id pmid_2112_2157.126 ::date 2015-07-19T22:40:30 ::annotator SDL-AMR-09 ::preferred
# ::snt In addition, we showed that treatment with AG490 (40 �M) significantly decreased IL-6 promoter activity (Figure 2D).
# ::save-date Fri Dec 18, 2015 ::file pmid_2112_2157_126.txt
(a / and
      :op1 (s / show-01
            :ARG0 (w / we)
            :ARG1 (d / decrease-01
                  :ARG0 (t / treat-04
                        :ARG2 (s2 / small-molecule :name (n / name :op1 "AG490")
                              :quant (c / concentration-quantity :quant 40
                                    :unit (m / micromolar))))
                  :ARG1 (a2 / activity-06
                        :ARG0 (m2 / molecular-physical-entity
                              :ARG0-of (p / promote-01
                                    :ARG1 (p2 / protein :name (n2 / name :op1 "IL-6")))))
                  :ARG2 (s3 / significant-02)))
      :ARG1-of (d2 / describe-01
            :ARG0 (f / figure :mod "2D")))

# ::id pmid_2112_2157.127 ::date 2015-07-19T22:48:40 ::annotator SDL-AMR-09 ::preferred
# ::snt Our results suggest that Jak2/Stat3 pathway may regulate the autocrine production of IL-6 in AS2 cells.
# ::save-date Sun Jan 17, 2016 ::file pmid_2112_2157_127.txt
(s / suggest-01
      :ARG0 (t / thing
            :ARG2-of (r / result-01)
            :poss (w / we))
      :ARG1 (p / possible-01
            :ARG1 (r2 / regulate-01
                  :ARG0 (p2 / pathway :name (n / name :op1 "Jak2/Stat3"))
                  :ARG1 (p3 / produce-01
                        :ARG1 (p4 / protein :name (n2 / name :op1 "IL-6"))
                        :mod (a / autocrine)
                        :location (c / cell-line :name (n3 / name :op1 "AS2"))))))

# ::id pmid_2112_2157.128 ::date 2015-07-19T22:54:13 ::annotator SDL-AMR-09 ::preferred
# ::snt Stat3 activation status was positively correlated with IL-6 expression and paclitaxel resistance in AS2-derived cells
# ::save-date Sun Jan 17, 2016 ::file pmid_2112_2157_128.txt
(c / correlate-01
      :ARG1 (s / status
            :mod (a / activate-01
                  :ARG1 (p / protein :name (n / name :op1 "Stat3"))))
      :ARG2 (a2 / and
            :op1 (e / express-03
                  :ARG2 (p2 / protein :name (n2 / name :op1 "IL-6")))
            :op2 (r / resist-01
                  :ARG1 (s2 / small-molecule :name (n4 / name :op1 "paclitaxel"))))
      :location (c2 / cell
            :ARG1-of (d / derive-01
                  :ARG2 (c3 / cell-line :name (n3 / name :op1 "AS2"))))
      :manner (p3 / positive))

# ::id pmid_2112_2157.129 ::date 2015-07-15T23:57:49 ::annotator SDL-AMR-09 ::preferred
# ::snt To clarify the role of Stat3 on IL-6 autocrine production proposed by the biochemical studies, we performed genetic studies to investigate the effect of varying degrees of Stat3 activation and inactivation on the mRNA expression and the secretion of IL-6 using parental AS2 cells and various previously established AS2-derived cell lines with different Stat3 activation status: vector control cells, two AS2/S3C cells, two AS2/S3D cells, and two AS2/S3F cells [2,10].
# ::save-date Fri Feb 5, 2016 ::file pmid_2112_2157_129.txt
(h / have-purpose-91
      :ARG1 (p4 / perform-01
            :ARG0 (w / we)
            :ARG1 (s2 / study-01
                  :mod (g / genetic))
            :purpose (i / investigate-01
                  :ARG0 w
                  :ARG1 (a2 / affect-01
                        :ARG0 (a3 / and
                              :op1 (a4 / activate-01
                                    :ARG1 p)
                              :op2 (a5 / activate-01 :polarity -
                                    :ARG1 p)
                              :degree (d / degree
                                    :ARG1-of (v / vary-01)))
                        :ARG1 (a6 / and
                              :op1 (e2 / express-03
                                    :ARG2 (n / nucleic-acid :name (n3 / name :op1 "mRNA")))
                              :op2 (s3 / secrete-01
                                    :ARG1 (p10 / protein :name (n4 / name :op1 "IL-6"))))
                        :ARG2 (a7 / and
                              :op1 (c2 / cell-line :name (n5 / name :op1 "AS2")
                                    :mod (p5 / parent))
                              :op2 (e4 / establish-01
                                    :ARG1 (c3 / cell-line
                                          :ARG1-of (d2 / derive-01
                                                :ARG2 c2)
                                          :ARG1-of (v2 / vary-01)
                                          :ARG0-of (h3 / have-03
                                                :ARG1 (s4 / status
                                                      :mod (a8 / activate-01
                                                            :ARG1 (p7 / protein :name (n6 / name :op1 "Stat3")))
                                                      :ARG1-of (d3 / differ-02)))
                                          :ARG1-of (m / mean-01
                                                :ARG2 (a9 / and
                                                      :op1 (c4 / cell
                                                            :ARG1-of (c5 / control-01
                                                                  :ARG0 (v3 / vector)))
                                                      :op2 (c6 / cell-line :quant 2 :name (n7 / name :op1 "AS2/S3C"))
                                                      :op3 (c7 / cell-line :quant 2 :name (n8 / name :op1 "AS2/S3D"))
                                                      :op4 (c8 / cell-line :quant 2 :name (n9 / name :op1 "AS2/S3F")))))
                                    :time (p6 / previous))))))
      :ARG2 (c / clarify-10
            :ARG1 (r / role
                  :poss (p / protein :name n6
                        :ARG0-of (p2 / produce-01
                              :ARG1 (p9 / protein :name n4)
                              :mod (a / autocrine))
                        :ARG1-of (p3 / propose-01
                              :ARG0 (s / study-01
                                    :mod (b / biochimic))))))
      :ARG1-of (d4 / describe-01
            :ARG0 (p8 / publication-91
                  :ARG1-of (c9 / cite-01
                        :ARG2 (a10 / and :op1 2 :op2 10)))))

# ::id pmid_2112_2157.130 ::date 2015-07-16T01:10:14 ::annotator SDL-AMR-09 ::preferred
# ::snt In this current study, we used S3C as active form Stat3, and S3D and S3F as inactivated forms of Stat3.
# ::save-date Sat Aug 8, 2015 ::file pmid_2112_2157_130.txt
(u / use-01
      :ARG0 (w / we)
      :ARG1 (a / and
            :op1 (p / protein :name (n / name :op1 "S3C")
                  :mod (c / consider-01
                        :ARG1 (p2 / protein :name (n2 / name :op1 "Stat3")
                              :ARG0-of (a5 / activity-06))))
            :op2 (a3 / and
                  :op1 (p3 / protein :name (n3 / name :op1 "S3D"))
                  :op2 (p4 / protein :name (n4 / name :op1 "S3F"))
                  :mod (c2 / consider-01
                        :ARG1 (p5 / protein :name (n5 / name :op1 "Stat3")
                              :ARG0-of (a2 / activity-06 :polarity -)))))
      :medium (s / study-01
            :mod (c3 / current)
            :mod (t / this)))

# ::id pmid_2112_2157.131 ::date 2015-07-16T01:25:16 ::annotator SDL-AMR-09 ::preferred
# ::snt Western blot analysis showed increased expression of Stat3 protein in all mutant cells, in the AS2/S3C cells (AS2/S3C-A and AS2/S3C-C), in the AS2/S3D cells (AS2/S3D-8 and AS2/S3D-9) and in the AS2/S3F cells (AS2/S3F-3 and AS2/S3F-7), compared to the parental cells (AS2) and vector control cells (AS2/Vec-11) (Figure 3A).
# ::save-date Sun Dec 13, 2015 ::file pmid_2112_2157_131.txt
(s / show-01
      :ARG0 (a / analyze-01
            :manner (i2 / immunoblot-01))
      :ARG1 (e / express-03
            :ARG2 (p / protein :name (n2 / name :op1 "Stat3"))
            :ARG3 (c14 / cell
                  :ARG2-of (m4 / mutate-01)
                  :mod (a7 / all)
                  :ARG1-of (m5 / mean-01
                        :ARG2 (a3 / and
                              :op1 (c5 / cell-line :name (n3 / name :op1 "AS2/S3C")
                                    :ARG1-of (m / mean-01
                                          :ARG2 (a4 / and
                                                :op1 (c6 / cell-line :name (n4 / name :op1 "AS2/S3C-A"))
                                                :op2 (c7 / cell-line :name (n5 / name :op1 "AS2/S3C-C")))))
                              :op2 (c8 / cell-line :name (n6 / name :op1 "AS2/S3D")
                                    :ARG1-of (m2 / mean-01
                                          :ARG2 (a5 / and
                                                :op1 (c9 / cell-line :name (n7 / name :op1 "AS2/S3D-8"))
                                                :op2 (c10 / cell-line :name (n8 / name :op1 "AS2/S3D-9")))))
                              :op3 (c11 / cell-line :name (n9 / name :op1 "AS2/S3F")
                                    :ARG1-of (m3 / mean-01
                                          :ARG2 (a6 / and
                                                :op1 (c12 / cell-line :name (n10 / name :op1 "AS2/S3F-3"))
                                                :op2 (c13 / cell-line :name (n11 / name :op1 "AS2/S3F-7"))))))))
            :ARG1-of (i / increase-01
                  :ARG1-of (c / compare-01
                        :ARG2 (a2 / and
                              :op1 (c2 / cell-line :name (n12 / name :op1 "AS2")
                                    :mod (p2 / parent))
                              :op2 (c3 / cell-line :name (n13 / name :op1 "AS2/Vec-11")
                                    :mod (c4 / control-01
                                          :ARG0 (v / vector)))))))
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod "3A")))

# ::id pmid_2112_2157.132 ::date 2015-07-16T01:38:44 ::annotator SDL-AMR-09 ::preferred
# ::snt However, only AS2/S3F cells but not AS2/S3C or AS2/S3D cells were found to have decreases in Stat3 phosphorylation (Figure 3A).
# ::save-date Sun Jan 17, 2016 ::file pmid_2112_2157_132.txt
(c5 / contrast-01
      :ARG2 (f2 / find-01
            :ARG1 (h / have-03
                  :ARG0 (c2 / cell-line :name (n / name :op1 "AS2/S3F")
                        :mod (o2 / only))
                  :ARG1 (d2 / decrease-01
                        :ARG1 (p / protein :name (n2 / name :op1 "Stat3")
                              :ARG1-of (p2 / phosphorylate-01))))
            :ARG1-of (c3 / contrast-01
                  :ARG2 (o / or
                        :op1 (c4 / cell-line :name (n3 / name :op1 "AS2/S3C"))
                        :op2 (c / cell-line :name (n4 / name :op1 "AS2/S3D"))))
            :ARG1-of (d / describe-01
                  :ARG0 (f / figure :mod "3A"))))

# ::id pmid_2112_2157.133 ::date 2015-07-16T01:45:37 ::annotator SDL-AMR-09 ::preferred
# ::snt RT-PCR showed that the AS2/S3C cells expressed 3 to 4 times more IL-6 mRNA than the parental and vector control cells and that AS2/S3D and AS2/S3F cells expressed 30 to 70 percent less IL-6 mRNA (Figure 3B).
# ::save-date Sun Dec 20, 2015 ::file pmid_2112_2157_133.txt
(s / show-01
      :ARG0 (r / react-01
            :ARG0 (p5 / polymerase)
            :mod (c7 / chain)
            :subevent (t / transcribe-01
                  :ARG1-of (r2 / reverse-01)))
      :ARG1 (a / and
            :op1 (e / express-03
                  :ARG2 (n7 / nucleic-acid :name (n3 / name :op1 "mRNA")
                        :ARG0-of (e2 / encode-01
                              :ARG1 (p4 / protein :name (n4 / name :op1 "IL-6"))))
                  :ARG3 (c / cell-line :name (n2 / name :op1 "AS2/S3C"))
                  :quant (p / product-of
                        :op1 (v2 / value-interval :op1 3 :op2 4))
                  :degree (m / more)
                  :compared-to (a2 / and
                        :op1 (c2 / cell
                              :mod (p2 / parent))
                        :op2 (c3 / cell
                              :mod (c4 / control-01
                                    :ARG0 (v / vector)))))
            :op2 (e3 / express-03
                  :ARG2 n7
                  :ARG3 (a3 / and
                        :op1 (c5 / cell-line :name (n5 / name :op1 "AS2/S3D"))
                        :op2 (c6 / cell-line :name (n6 / name :op1 "AS2/S3F")))
                  :quant (p3 / percentage-entity
                        :op1 (v3 / value-interval :op1 30 :op2 70)
                        :mod (l / less))))
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod "3B")))

# ::id pmid_2112_2157.134 ::date 2015-07-16T02:07:56 ::annotator SDL-AMR-09 ::preferred
# ::snt Similarly, transient transfection with S3C plasmid increased IL-6 promoter luciferase activity by more than 70% and transient transfection with S3F plasmid decreased IL-6 promoter luciferase activity by more than 40% compared with the mock and vector control groups (both p < 0.001) (Figure 3C).
# ::save-date Mon Dec 21, 2015 ::file pmid_2112_2157_134.txt
(c / compare-01
      :ARG1 (a / and
            :op1 (t / transfect-01
                  :ARG2 (p9 / plasmid
                        :mod (p / protein :name (n2 / name :op1 "S3C")))
                  :ARG1-of (t2 / transient-02)
                  :ARG0-of (i / increase-01
                        :ARG1 (m2 / molecular-physical-entity
                              :ARG0-of (p10 / promote-01
                                    :ARG1 (p7 / protein :name (n3 / name :op1 "IL-6")
                                          :ARG0-of (a2 / activity-06
                                                :ARG1 (l / luciferase)))))
                        :ARG2 (m4 / more-than
                              :op1 (p3 / percentage-entity :value 70))))
            :op2 (t3 / transfect-01
                  :ARG2 (p8 / plasmid
                        :mod (p4 / protein :name (n5 / name :op1 "S3F")))
                  :ARG0-of (d / decrease-01
                        :ARG1 p7
                        :ARG2 (m / more-than
                              :op1 (p5 / percentage-entity :value 40)))
                  :ARG1-of t2)
            :ARG1-of (s / statistical-test-91
                  :ARG2 (l2 / less-than :op1 0.001)))
      :ARG2 (a3 / and
            :op1 (g / group
                  :mod (m3 / mock))
            :op2 (g2 / group
                  :mod (c2 / control-01
                        :ARG0 (v / vector))))
      :ARG1-of (d2 / describe-01
            :ARG0 (f / figure :mod "3C"))
      :ARG1-of (r / resemble-01))

# ::id pmid_2112_2157.135 ::date 2015-07-16T02:48:05 ::annotator SDL-AMR-09 ::preferred
# ::snt ELISA showed that AS2/S3C cells secreted 5 to 10 times more IL-6 than the parental and vector control cells (both p < 0.001) (Figure 3D) and AS2/S3D and AS2/S3F cells secreted 40 to 80 percent less IL-6 (both p < 0.01 in AS2/S3D cells and both p < 0.001 in S3F cells) (Figure 3E).
# ::save-date Tue Dec 15, 2015 ::file pmid_2112_2157_135.txt
(s / show-01
      :ARG0 (t / thing :name (n / name :op1 "ELISA"))
      :ARG1 (a / and
            :op1 (s2 / secrete-01
                  :ARG0 (c / cell-line :name (n2 / name :op1 "AS2/S3C"))
                  :ARG1 (p / protein :name (n3 / name :op1 "IL-6"))
                  :quant (p2 / product-of
                        :op1 (v3 / value-interval :op1 5 :op2 10))
                  :degree (m / more)
                  :compared-to (a2 / and
                        :op1 (c2 / cell
                              :mod (p3 / parent))
                        :op2 (c3 / cell
                              :mod (c4 / control-01
                                    :ARG0 (v / vector))))
                  :ARG1-of (d / describe-01
                        :ARG0 (f / figure :mod "3D"))
                  :ARG1-of (s4 / statistical-test-91
                        :ARG2 (l / less-than :op1 0.001)))
            :op2 (s3 / secrete-01
                  :ARG0 (a3 / and
                        :op1 (c5 / cell-line :name (n4 / name :op1 "AS2/S3D"))
                        :op2 (c6 / cell-line :name (n5 / name :op1 "AS2/S3F")))
                  :ARG1 p
                  :quant (p5 / percentage-entity
                        :op1 (v2 / value-interval :op1 40 :op2 80)
                        :mod (l2 / less))
                  :ARG1-of (d2 / describe-01
                        :ARG0 (f2 / figure :mod "3E"))
                  :ARG1-of (s5 / statistical-test-91
                        :ARG2 (a4 / and
                              :op1 (l3 / less-than :op1 0.01
                                    :location c5)
                              :op2 (l4 / less-than :op1 0.001
                                    :location c6))))))

# ::id pmid_2112_2157.136 ::date 2015-07-16T03:28:23 ::annotator SDL-AMR-09 ::preferred
# ::snt These results show that Stat3 may positively regulate the expression of IL-6 mRNA expression and the secretion of IL-6 in AS2 cells.
# ::save-date Sun Jan 17, 2016 ::file pmid_2112_2157_136.txt
(s / show-01
      :ARG0 (t2 / thing
            :ARG2-of (r / result-01)
            :mod (t / this))
      :ARG1 (p / possible-01
            :ARG1 (r2 / regulate-01
                  :ARG0 (p3 / protein :name (n / name :op1 "Stat3"))
                  :ARG1 (a / and
                        :op1 (e / express-03
                              :ARG2 (n5 / nucleic-acid :name (n2 / name :op1 "mRNA")
                                    :mod (p4 / protein :name (n3 / name :op1 "IL-6")))
                              :ARG3 (c / cell-line :name (n4 / name :op1 "AS2")))
                        :op2 (s2 / secrete-01
                              :ARG0 c
                              :ARG1 p4))
                  :mod (p2 / positive))))

# ::id pmid_2112_2157.137 ::date 2015-07-16T03:41:56 ::annotator SDL-AMR-09 ::preferred
# ::snt To evaluate drug resistance, we treated the parental AS2 cells, vector control cells (AS2/Vec-11), the AS2/S3C cells (AS2/S3C-C), the AS2/S3D cells (AS2/S3D-9), and the AS2/S3F cells (AS2/S3F-3) with paclitaxel for 72 hours.
# ::save-date Sat Aug 8, 2015 ::file pmid_2112_2157_137.txt
(h / have-purpose-91
      :ARG1 (t / treat-04
            :ARG0 (w / we)
            :ARG1 (a / and
                  :op1 (c / cell-line :name (n / name :op1 "AS2")
                        :mod (p2 / parent))
                  :op2 (c2 / cell-line :name (n2 / name :op1 "AS2/Vec-11")
                        :mod (c3 / control-01
                              :ARG0 (v / vector)))
                  :op3 (c4 / cell-line :name (n3 / name :op1 "AS2/S3C")
                        :ARG1-of (m / mean-01
                              :ARG2 (c5 / cell-line :name (n4 / name :op1 "AS2/S3C-C"))))
                  :op4 (c6 / cell-line :name (n5 / name :op1 "AS2/S3D")
                        :ARG1-of (m2 / mean-01
                              :ARG2 (c8 / cell-line :name (n7 / name :op1 "AS2/S3D-9"))))
                  :op5 (c7 / cell-line :name (n6 / name :op1 "AS2/S3F")
                        :ARG1-of (m3 / mean-01
                              :ARG2 (c9 / cell-line :name (n8 / name :op1 "AS2/S3F-3")))))
            :ARG2 (s / small-molecule :name (n9 / name :op1 "paclitaxel"))
            :duration (t2 / temporal-quantity :quant 72
                  :unit (h2 / hour)))
      :ARG2 (e / evaluate-01
            :ARG0 w
            :ARG1 (r / resist-01
                  :ARG1 (d / drug))))

# ::id pmid_2112_2157.138 ::date 2015-07-16T03:53:44 ::annotator SDL-AMR-09 ::preferred
# ::snt Using MTT assay to access cell viability, we found AS2 cells with increased Stat3 activity (AS2/S3C-C) to be more resistant to paclitaxel than AS2 and AS2/Vec-11 cells (p < 0.05), and AS2 cells with decreased Stat3 activity (AS2/S3D-9 and AS2/S3F-3) to be less resistant to paclitaxel (p < 0.05) (Figure 3F).
# ::save-date Sat Feb 13, 2016 ::file pmid_2112_2157_138.txt
(f / find-01
      :ARG0 (w / we)
      :ARG1 (a3 / and
            :op1 (r / resist-01
                  :ARG0 (c2 / cell-line :name (n / name :op1 "AS2")
                        :ARG0-of (h / have-03
                              :ARG1 (i / increase-01
                                    :ARG1 (a4 / activity-06
                                          :ARG0 (p / protein :name (n2 / name :op1 "Stat3")))))
                        :ARG1-of (m / mean-01
                              :ARG2 (c3 / cell-line :name (n3 / name :op1 "AS2/S2C-C"))))
                  :ARG1 (s / small-molecule :name (n4 / name :op1 "paclitaxel"))
                  :degree (m2 / more)
                  :compared-to (a5 / and
                        :op1 (c4 / cell :name n)
                        :op2 (c5 / cell-line :name (n5 / name :op1 "AS2/Vec-11")))
                  :ARG1-of (s2 / statistical-test-91
                        :ARG2 (l / less-than :op1 0.05)))
            :op2 (r2 / resist-01
                  :ARG0 (c6 / cell :name n
                        :ARG0-of (h2 / have-03
                              :ARG1 (d / decrease-01
                                    :ARG1 a4))
                        :ARG1-of (m3 / mean-01
                              :ARG2 (a6 / and
                                    :op1 (c7 / cell-line :name (n7 / name :op1 "AS2/S3D-9"))
                                    :op2 (c8 / cell-line :name (n8 / name :op1 "AS2/S3F-3")))))
                  :ARG1 s
                  :degree (l2 / less)
                  :ARG1-of (s3 / statistical-test-91
                        :ARG2 l)))
      :manner (u / use-01
            :ARG0 w
            :ARG1 (a7 / assay-01
                  :instrument (s4 / small-molecule :name (n6 / name :op1 "MTT")))
            :ARG2 (a2 / access-01
                  :ARG0 w
                  :ARG1 (v / viability
                        :mod (c / cell))))
      :ARG1-of (d2 / describe-01
            :ARG0 (f2 / figure :mod "3F")))

# ::id pmid_2112_2157.139 ::date 2015-07-16T04:12:04 ::annotator SDL-AMR-09 ::preferred
# ::snt Together, these findings suggest that the activation of Stat3 may contribute to the regulation of IL-6 autocrine production and resistance to paclitaxel in AS2 cells.
# ::save-date Sun Jan 17, 2016 ::file pmid_2112_2157_139.txt
(s / suggest-01
      :ARG0 (t3 / thing
            :ARG1-of (f / find-01)
            :mod (t / this)
            :mod (t2 / together))
      :ARG1 (p / possible-01
            :ARG1 (c / contribute-01
                  :ARG0 (a / activate-01
                        :ARG1 (p2 / protein :name (n / name :op1 "Stat3")))
                  :ARG2 (a2 / and
                        :op1 (r / regulate-01
                              :ARG1 (p3 / produce-01
                                    :ARG1 (p5 / protein :name (n2 / name :op1 "IL-6"))
                                    :mod (a3 / autocrine)))
                        :op2 (r2 / resist-01
                              :ARG1 (s2 / small-molecule :name (n4 / name :op1 "paclitaxel")))
                        :location (c2 / cell-line :name (n3 / name :op1 "AS2"))))))

# ::id pmid_2112_2157.140 ::date 2015-07-16T05:32:55 ::annotator SDL-AMR-09 ::preferred
# ::snt Knocking-down Stat3 by transient transfection with synthetic siRNA decreased IL-6 expression in AS2 cells
# ::save-date Thu Nov 12, 2015 ::file pmid_2112_2157_140.txt
(d / decrease-01
      :ARG0 (k / knock-down-02
            :ARG1 (p / protein :name (n / name :op1 "Stat3"))
            :ARG5 (t / transfect-01
                  :ARG1 (c / cell-line :name (n4 / name :op1 "AS2"))
                  :ARG2 (n5 / nucleic-acid :name (n2 / name :op1 "siRNA")
                        :mod (s / synthetic))
                  :ARG1-of (t2 / transient-02)))
      :ARG1 (e2 / express-03
            :ARG2 (p2 / protein :name (n3 / name :op1 "IL-6"))
            :ARG3 c))

# ::id pmid_2112_2157.141 ::date 2015-07-16T05:39:42 ::annotator SDL-AMR-09 ::preferred
# ::snt To confirm that Stat3 regulated IL-6 expression in cancer cells, we transiently transfected AS2 cells with Stat3 siRNA to knock-down the expression of Stat3.
# ::save-date Thu Nov 12, 2015 ::file pmid_2112_2157_141.txt
(h / have-purpose-91
      :ARG1 (t / transfect-01
            :ARG0 (w / we)
            :ARG1 (c / cell-line
                  :name (n / name :op1 "AS2"))
            :ARG2 (n6 / nucleic-acid
                  :name (n2 / name :op1 "siRNA")
                  :ARG0-of (e2 / encode-01
                        :ARG1 (p / protein
                              :name (n3 / name :op1 "Stat3"))))
            :ARG1-of (t2 / transient-02)
            :purpose (k / knock-down-02
                        :ARG1 (e / express-03
                              :ARG2 p)))
      :ARG2 (c2 / confirm-01
            :ARG0 w
            :ARG1 (r2 / regulate-01
                  :ARG0 p
                  :ARG1 (p2 / protein
                        :name (n4 / name :op1 "IL-6")
                        :ARG2-of (e3 / express-03
                              :ARG3 (c3 / cell
                                    :mod (d / disease :wiki "Cancer"
                                          :name (n5 / name :op1 "cancer"))))))))

# ::id pmid_2112_2157.142 ::date 2015-07-16T05:58:33 ::annotator SDL-AMR-09 ::preferred
# ::snt Western blot analysis showed transfection with Stat3 siRNA (Stat3#1) dose-dependently decreased the total amount of Stat3 protein and phosphorylated Stat3 (Figure 4A).
# ::save-date Sun Dec 13, 2015 ::file pmid_2112_2157_142.txt
(s / show-01
      :ARG0 (a / analyze-01
            :manner (i / immunoblot-01))
      :ARG1 (t / transfect-01
            :ARG2 (n5 / nucleic-acid :name (n2 / name :op1 "siRNA")
                  :mod (p / protein :name (n3 / name :op1 "Stat3"))
                  :ARG1-of (l / label-01
                        :ARG2 (n7 / name :op1 "Stat3#1")))
            :ARG0-of (d3 / decrease-01
                  :ARG1 (a2 / amount-01
                        :ARG1 (a3 / and
                              :op1 (p2 / protein :name n3)
                              :op2 (p3 / protein :name n3
                                    :ARG3-of (p4 / phosphorylate-01)))
                        :ARG2 (t2 / total))
                  :ARG0-of (d2 / depend-01
                        :ARG1 (d / dose-01
                              :ARG1 n5))))
      :ARG1-of (d4 / describe-01
            :ARG0 (f / figure :mod "4A")))

# ::id pmid_2112_2157.143 ::date 2015-07-16T06:15:56 ::annotator SDL-AMR-09 ::preferred
# ::snt RT-PCR and ELISA showed transfection with Stat3#1 reduced the expression of IL-6 mRNA (Figure 4B) and the secretion of IL-6 at 3, 8, and 24 hours after medium replacement (p < 0.01 in the lower dose and p < 0.001 in the higher doses) (Figure 4C).
# ::save-date Wed Mar 9, 2016 ::file pmid_2112_2157_143.txt
(s / show-01
      :ARG0 (a / and
            :op1 (r3 / react-01
                  :ARG0 (p3 / polymerase)
                  :mod (c / chain)
                  :subevent (t / transcribe-01)
                  :ARG1-of (r / reverse-01))
            :op2 (a9 / assay-01
                  :instrument (i / immunosorbent)
                  :ARG1-of (l4 / link-01
                        :ARG2 (e2 / enzyme))))
      :ARG1 (t3 / transfect-01
            :ARG2 (p / protein :name (n3 / name :op1 "Stat3#1"))
            :ARG0-of (r2 / reduce-01
                  :ARG1 (a2 / and
                        :op1 (e / express-03
                              :ARG2 (n6 / nucleic-acid :name (n4 / name :op1 "mRNA")
                                    :ARG0-of (e3 / encode-01
                                          :ARG1 (p2 / protein :name (n5 / name :op1 "IL-6"))))
                              :ARG1-of (d / describe-01
                                    :ARG0 (f / figure :mod "4B")))
                        :op2 (s2 / secrete-01
                              :ARG1 p2
                              :time (a4 / and
                                    :op1 (a5 / after
                                          :op1 (r4 / replace-01
                                                :ARG1 (m / medium))
                                          :quant (t4 / temporal-quantity :quant 3
                                                :unit (h / hour)))
                                    :op2 (a6 / after
                                          :op1 r4
                                          :quant (t5 / temporal-quantity :quant 8
                                                :unit h))
                                    :op3 (a7 / after
                                          :op1 r4
                                          :quant (t6 / temporal-quantity :quant 24
                                                :unit h)))
                              :ARG1-of (d4 / describe-01
                                    :ARG0 (f2 / figure :mod "4C"))
                              :ARG1-of (s3 / statistical-test-91
                                    :ARG2 (a8 / and
                                          :op1 (l / less-than :op1 0.01
                                                :condition (d2 / dose-01
                                                      :ARG1-of (l2 / low-04
                                                            :degree (m2 / more))))
                                          :op2 (l3 / less-than :op1 0.001
                                                :condition (d3 / dose-01
                                                      :ARG1-of (h2 / high-02
                                                            :degree (m3 / more)))))))))))

# ::id pmid_2112_2157.144 ::date 2015-07-16T06:35:09 ::annotator SDL-AMR-09 ::preferred
# ::snt To make sure our results were not confounded by differences in cell viability, we performed MTT assay of the transfected and untransfected cells, and found that these siRNAs did not affect the viability of AS2 cells (Figure 4D).
# ::save-date Sat Feb 13, 2016 ::file pmid_2112_2157_144.txt
(a / and
      :op1 (p / perform-01
            :ARG0 (w / we)
            :ARG1 (a5 / assay-01
                  :ARG1 (a3 / and
                        :op1 (c5 / cell
                              :ARG1-of (t4 / transfect-01))
                        :op2 (c6 / cell
                              :ARG1-of (t5 / transfect-01 :polarity -)))
                  :instrument (s / small-molecule :name (n3 / name :op1 "MTT")))
            :purpose (e / ensure-01
                  :ARG0 w
                  :ARG1 (c2 / confound-01
                        :ARG0 (d / differ-02
                              :ARG3 (v / viability
                                    :mod (c3 / cell)))
                        :ARG1 (t / thing
                              :ARG2-of (r3 / result-01)
                              :poss w))))
      :op2 (f / find-01
            :ARG0 w
            :ARG1 (a4 / affect-01 :polarity -
                  :ARG0 (n4 / nucleic-acid :name (n / name :op1 "siRNA")
                        :mod (t3 / this))
                  :ARG1 (c / cell-line :name (n2 / name :op1 "AS2")
                        :mod (v2 / viability))))
      :ARG1-of (d2 / describe-01
            :ARG0 (f2 / figure :mod "4D")))

# ::id pmid_2112_2157.145 ::date 2015-07-16T07:27:19 ::annotator SDL-AMR-09 ::preferred
# ::snt The findings suggested that the suppression of IL-6 production by knocking-down Stat3 was not likely a result of a decrease in cell number.
# ::save-date Sun Jan 17, 2016 ::file pmid_2112_2157_145.txt
(s / suggest-01
      :ARG0 (t / thing
            :ARG1-of (f / find-01))
      :ARG1 (l / likely-01 :polarity -
            :ARG1 (r / result-01
                  :ARG1 (d / decrease-01
                        :ARG1 (n / number-01
                              :ARG1 (c / cell)))
                  :ARG2 (s2 / suppress-01
                        :ARG1 (p3 / protein :name (n2 / name :op1 "IL-6")
                              :ARG1-of (p / produce-01))
                        :manner (k / knock-down-02
                              :ARG1 (p2 / protein :name (n3 / name :op1 "Stat3")))))))

# ::id pmid_2112_2157.146 ::date 2015-07-16T07:39:36 ::annotator SDL-AMR-09 ::preferred
# ::snt As can be seen in Figures S2A and S2B in Additional file 2, the other Stat3 siRNA (Stat3#2) with a different targeting sequence also knocked-down Stat3 expression and reduced IL-6 secretion but did not compromise cell proliferation (Additional file 3, Figure S3A), a further confirmation of our findings.
# ::save-date Thu Nov 12, 2015 ::file pmid_2112_2157_146.txt
(c / contrast-01
      :ARG1 (a3 / and
            :op1 (k / knock-down-02
                  :ARG0 (n4 / nucleic-acid :name (n / name :op1 "siRNA")
                        :mod (p / protein :name (n2 / name :op1 "Stat3"))
                        :ARG1-of (m / mean-01
                              :ARG2 (n6 / nucleic-acid :name (n3 / name :op1 "Stat3#2")))
                        :mod (o / other)
                        :ARG0-of (h / have-03
                              :ARG1 (s / sequence
                                    :ARG0-of (t / target-01
                                          :ARG1-of (d2 / differ-02)))))
                  :ARG1 (p2 / protein :name n2
                        :ARG2-of (e / express-03)))
            :op2 (r4 / reduce-01
                  :ARG0 n4
                  :ARG1 (p5 / protein :name (n5 / name :op1 "IL-6")
                        :ARG1-of (s2 / secrete-01)))
            :mod (a / also))
      :ARG2 (c2 / compromise-02 :polarity -
            :ARG0 n4
            :ARG1 (c3 / cell
                  :ARG0-of (p3 / proliferate-01))
            :ARG1-of (d / describe-01
                  :ARG0 (f / figure :mod "S3A"
                        :part-of (f2 / file :mod 3
                              :mod (a2 / additional)))))
      :ARG0-of (c4 / confirm-01
            :ARG1 (t2 / thing
                  :ARG1-of (f3 / find-01
                        :ARG0 (w / we)))
            :ARG1-of (f4 / further-01))
      :ARG1-of (s3 / see-01
            :ARG1-of (p4 / possible-01)
            :location (a5 / and
                  :op1 (f7 / figure :mod "S2A")
                  :op2 (f8 / figure :mod "S2B")
                  :part-of (f6 / file :mod 2
                        :mod (a4 / additional)))))

# ::id pmid_2112_2157.147 ::date 2015-07-16T07:57:23 ::annotator SDL-AMR-09 ::preferred
# ::snt Knocking-down Stat3 by stable transfection with shRNA decreased the expression of IL-6 in AS2 cells
# ::save-date Sun Jan 17, 2016 ::file pmid_2112_2157_147.txt
(d / decrease-01
      :ARG0 (k / knock-down-02
            :ARG1 (p / protein :name (n / name :op1 "Stat3"))
            :manner (t / transfect-01
                  :ARG2 (n5 / nucleic-acid :name (n2 / name :op1 "shRNA"))
                  :ARG1-of (s / stable-03)))
      :ARG1 (e / express-03
            :ARG2 (p2 / protein :name (n3 / name :op1 "IL-6"))
            :ARG3 (c / cell-line :name (n4 / name :op1 "AS2"))))

# ::id pmid_2112_2157.148 ::date 2015-07-16T08:01:23 ::annotator SDL-AMR-09 ::preferred
# ::snt To further investigate the possible role of Stat3 in the regulation of IL-6, we stably transfected AS2 cells with the control vector from which we selected one cell line (AS2/shVec) and the vector expressing Stat3 shRNA from which we selected two cell lines (AS2/shStat3-1 and AS2/shStat3-2).
# ::save-date Thu Nov 12, 2015 ::file pmid_2112_2157_148.txt
(h / have-purpose-91
      :ARG1 (t / transfect-01
            :ARG1 (c / cell-line :name (n / name :op1 "AS2"))
            :ARG2 (a / and
                  :op1 (c2 / control-01
                        :ARG0 (v / vector)
                        :ARG2-of (s / select-01
                              :ARG0 (w / we)
                              :ARG1 (c3 / cell-line :quant 1 :name (n2 / name :op1 "AS2/shVec"))))
                  :op2 (v2 / vector
                        :ARG1-of (e / express-03
                              :ARG2 (n8 / nucleic-acid :name (n3 / name :op1 "shRNA")
                                    :ARG0-of (e2 / encode-01
                                          :ARG1 (p / protein :name (n4 / name :op1 "Stat3")))))
                        :ARG2-of (s2 / select-01
                              :ARG0 w
                              :ARG1 (a2 / and :quant 2
                                    :op1 (c6 / cell-line :name (n5 / name :op1 "AS2/shStat3-1"))
                                    :op2 (c7 / cell-line :name (n7 / name :op1 "AS2/shStat3-2")))))))
      :ARG2 (i / investigate-01
            :ARG0 w
            :ARG1 (r2 / role
                  :ARG1-of (p3 / possible-01)
                  :topic (r3 / regulate-01
                        :ARG1 (p4 / protein :name (n6 / name :op1 "IL-6")))
                  :poss (p2 / protein :name n4))
            :ARG1-of (f / further-01)))

# ::id pmid_2112_2157.149 ::date 2015-07-20T13:30:44 ::annotator SDL-AMR-09 ::preferred
# ::snt Western blot analysis showed a lower expression of Stat3 protein and a lower level of Stat3 phosphorylation in both cell lines expressing Stat3 shRNA than in either the parental cells or the vector control cells (Figure <xref ref-type="fig" rid="F5">5A</xref>).
# ::save-date Sun Dec 13, 2015 ::file pmid_2112_2157_149.txt
(s / show-01
      :ARG0 (a / analyze-01
            :manner (i / immunoblot-01))
      :ARG1 (a2 / and
            :op1 (l / low-04
                  :ARG1 (e / express-03
                        :ARG2 (p / protein :name (n2 / name :op1 "Stat3")))
                  :degree (m / more))
            :op2 (l3 / low-04
                  :ARG1 (l2 / level
                        :quant-of (p2 / phosphorylate-01
                              :ARG3 p))
                  :degree m))
      :location (c / cell-line
            :mod (b / both)
            :ARG3-of (e2 / express-03
                  :ARG2 (n4 / nucleic-acid :name (n3 / name :op1 "shRNA")
                        :mod p))
            :compared-to (o / or
                  :op1 (c2 / cell
                        :mod (p3 / parent)
                        :mod (e3 / either))
                  :op2 (c3 / cell
                        :mod (v / vector)
                        :mod (c4 / control))))
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod "5A")))

# ::id pmid_2112_2157.150 ::date 2015-07-20T13:31:00 ::annotator SDL-AMR-09 ::preferred
# ::snt RT-PCR showed a continuing decrease in the expression of IL-6 mRNA in both cell lines expressing Stat3 shRNA (Figure <xref ref-type="fig" rid="F5">5B</xref>).
# ::save-date Sun Dec 20, 2015 ::file pmid_2112_2157_150.txt
(s / show-01
      :ARG0 (r3 / react-01
            :ARG0 (p3 / polymerase)
            :mod (c3 / chain)
            :subevent (t / transcribe-01
                  :ARG1-of (r / reverse-01)))
      :ARG1 (d / decrease-01
            :ARG1 (e / express-03
                  :ARG2 (n / nucleic-acid :name (n2 / name :op1 "mRNA")
                        :mod (p / protein :name (n3 / name :op1 "IL-6"))))
            :ARG1-of (c / continue-01)
            :location (c2 / cell-line
                  :ARG3-of (e2 / express-03
                        :ARG2 (n6 / nucleic-acid :name (n4 / name :op1 "shRNA")
                              :mod (p2 / protein :name (n5 / name :op1 "Stat3"))))
                  :mod (b / both)))
      :ARG1-of (d2 / describe-01
            :ARG0 (f / figure :mod "5B")))

# ::id pmid_2112_2157.151 ::date 2015-07-20T14:09:37 ::annotator SDL-AMR-09 ::preferred
# ::snt ELISA also showed a continuing decrease IL-6 secretion in both cell lines expressing Stat3 shRNA compared to the parental AS2 (90% in AS2/shStat3-1 and 95% AS2/shStat3-2 at 24 hours) (p < 0.001) (Figure <xref ref-type="fig" rid="F5">5C</xref>).
# ::save-date Sun Dec 20, 2015 ::file pmid_2112_2157_151.txt
(s / show-01
      :ARG0 (t / thing :name (n / name :op1 "ELISA")
            :mod (i / immunosorbent)
            :ARG1-of (l2 / link-01
                  :ARG2 (e2 / enzyme)))
      :ARG1 (d / decrease-01
            :ARG1 (s2 / secrete-01
                  :ARG1 (p / protein :name (n2 / name :op1 "IL-6")))
            :location (c / cell-line
                  :mod (b / both)
                  :ARG3-of (e / express-03
                        :ARG2 (n8 / nucleic-acid :name (n3 / name :op1 "shRNA")
                              :mod (p8 / protein :name (n7 / name :op1 "Stat3"))))
                  :compared-to (c2 / cell-line :name (n4 / name :op1 "AS2")
                        :mod (p2 / parent)))
            :ARG1-of (m / mean-01
                  :ARG2 (a / and
                        :op1 (c3 / cell-line :name (n5 / name :op1 "AS2/shStat3-1")
                              :quant (p4 / percentage-entity :value 90))
                        :op2 (c4 / cell-line :name (n6 / name :op1 "AS2/shStat3-2")
                              :quant (p6 / percentage-entity :value 95))
                        :time (a3 / after
                              :op1 (t2 / temporal-quantity :quant 24
                                    :unit (h / hour)))))
            :ARG1-of (c5 / continue-01)
            :ARG1-of (s3 / statistical-test-91
                  :ARG2 (l / less-than :op1 0.001)))
      :ARG1-of (d2 / describe-01
            :ARG0 (f / figure :mod "5C"))
      :mod (a2 / also))

# ::id pmid_2112_2157.152 ::date 2015-07-20T14:22:09 ::annotator SDL-AMR-09 ::preferred
# ::snt We also analyzed the drug resistance of these cells to paclitaxel by MTT assay.
# ::save-date Sat Feb 13, 2016 ::file pmid_2112_2157_152.txt
(a / analyze-01
      :ARG0 (w / we)
      :ARG1 (r / resist-01
            :ARG0 (c / cell
                  :mod (t / this))
            :ARG1 (s / small-molecule :name (n / name :op1 "paclitaxel"))
            :mod (d / drug))
      :mod (a2 / also)
      :manner (a3 / assay-01
            :instrument (s2 / small-molecule :name (n2 / name :op1 "MTT"))))

# ::id pmid_2112_2157.153 ::date 2015-07-20T14:25:48 ::annotator SDL-AMR-09 ::preferred
# ::snt MTT assay showed that the permanent knock-down of Stat3 in AS2/shStat3-1 and AS2/shStat3-2 cells significantly reduced their resistance to paclitaxel (p < 0.001) (Figure <xref ref-type="fig" rid="F5">5D</xref>).
# ::save-date Sat Feb 13, 2016 ::file pmid_2112_2157_153.txt
(s / show-01
      :ARG0 (a / assay-01
            :instrument (s5 / small-molecule :name (n / name :op1 "MTT")))
      :ARG1 (r / reduce-01
            :ARG0 (k / knock-down-02
                  :ARG1 (p / protein :name (n2 / name :op1 "Stat3"))
                  :location (a2 / and
                        :op1 (c / cell-line :name (n3 / name :op1 "AS2/shStat3-1"))
                        :op2 (c2 / cell-line :name (n4 / name :op1 "AS2/shStat3-2")))
                  :mod (p3 / permanent))
            :ARG1 (r2 / resist-01
                  :ARG0 a2
                  :ARG1 (s3 / small-molecule :name (n5 / name :op1 "paclitaxel")))
            :ARG2 (s2 / significant-02)
            :ARG1-of (s4 / statistical-test-91
                  :ARG2 (l / less-than :op1 0.001)))
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod "5D")))

# ::id pmid_2112_2157.154 ::date 2015-07-20T14:40:15 ::annotator SDL-AMR-09 ::preferred
# ::snt Pretreatment with exogenous IL-6 modestly restored the resistance (p < 0.01) (Figure <xref ref-type="fig" rid="F5">5D</xref>).
# ::save-date Tue Jan 19, 2016 ::file pmid_2112_2157_154.txt
(r / restore-01
      :ARG0 (p / pretreat-01
            :ARG3 (p2 / protein :name (n / name :op1 "IL-6")
                  :mod (e / exogenous)))
      :ARG1 (r2 / resist-01)
      :degree (m / modest)
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod "5D"))
      :ARG1-of (s / statistical-test-91
            :ARG2 (l / less-than :op1 0.01)))

# ::id pmid_2112_2157.155 ::date 2015-07-20T14:44:19 ::annotator SDL-AMR-09 ::preferred
# ::snt These data suggest that the IL-6-induced paclitaxel resistance is mediated by both Stat3-dependent and Stat3-independent pathways.
# ::save-date Thu Nov 12, 2015 ::file pmid_2112_2157_155.txt
(s / suggest-01
      :ARG0 (d / data
            :mod (t / this))
      :ARG1 (m / mediate-01
            :ARG0 (a / and
                  :op1 (p2 / pathway
                        :ARG0-of (d2 / depend-01
                              :ARG1 p5))
                  :op2 (p4 / pathway
                        :ARG0-of (d3 / depend-01 :polarity -
                              :ARG1 (p5 / protein :name (n4 / name :op1 "Stat3")))))
            :ARG1 (r / resist-01
                  :ARG1 (s2 / small-molecule :name (n / name :op1 "paclitaxel"))
                  :ARG2-of (i / induce-01
                        :ARG0 (p / protein :name (n2 / name :op1 "IL-6"))))))

# ::id pmid_2112_2157.156 ::date 2015-07-20T15:05:24 ::annotator SDL-AMR-09 ::preferred
# ::snt <sec-title level="2">Stat3 contributed to the elevation of IL-6 in drug resistant cancer cells</sec-title>
# ::save-date Thu Dec 10, 2015 ::file pmid_2112_2157_156.txt
(c / contribute-01
      :ARG0 (p / protein :name (n / name :op1 "Stat3"))
      :ARG1 (e / elevate-01
            :ARG1 (p2 / protein :name (n2 / name :op1 "IL-6")))
      :ARG2 (c2 / cell
            :mod (d2 / disease :wiki "Cancer" :name (n3 / name :op1 "cancer")
                  :ARG0-of (r / resist-01
                        :ARG1 (d / drug)))))

# ::id pmid_2112_2157.157 ::date 2015-07-20T22:05:22 ::annotator SDL-AMR-09 ::preferred
# ::snt It has been shown that cancer cells resistant to chemotherapeutic agents express elevated levels of IL-6 [<xref ref-type="bibr" rid="B30">30</xref>,<xref ref-type="bibr" rid="B39">39</xref>].
# ::save-date Thu Dec 10, 2015 ::file pmid_2112_2157_157.txt
(s / show-01
      :ARG1 (e / express-03
            :ARG2 (l / level
                  :ARG1-of (e2 / elevate-01)
                  :quant-of (p / protein
                        :name (n / name :op1 "IL-6")))
            :ARG3 (c / cell
                  :mod (d2 / disease :wiki "Cancer"
                        :name (n2 / name :op1 "cancer")
                        :ARG0-of (r / resist-01
                              :ARG1 (a / agent
                                    :mod (c3 / chemotherapy))))))
      :ARG1-of (d / describe-01
            :ARG0 (p2 / publication
                  :ARG1-of (c4 / cite-01
                        :ARG2 (a2 / and :op1 30 :op2 39)))))

# ::id pmid_2112_2157.158 ::date 2015-07-20T22:11:03 ::annotator SDL-AMR-09 ::preferred
# ::snt Thus, drug resistant cancer cells are ideal models for studying IL-6 autocrine production.
# ::save-date Mon Dec 21, 2015 ::file pmid_2112_2157_158.txt
(i / infer-01
      :ARG1 (m / model
            :mod (i2 / ideal)
            :domain (c / cell
                  :mod (d2 / disease :wiki "Cancer" :name (n2 / name :op1 "cancer")
                        :ARG0-of (r / resist-01
                              :ARG1 (d / drug))))
            :purpose (s / study-01
                  :ARG1 (p / produce-01
                        :ARG1 (p2 / protein :name (n / name :op1 "IL-6"))
                        :mod (a / autocrine)))))

# ::id pmid_2112_2157.159 ::date 2015-07-20T22:21:32 ::annotator SDL-AMR-09 ::preferred
# ::snt To find out whether IL-6 would be regulated by Stat3 in cancer cell lines other than AS2, we performed genetic siRNA experiments on two drug resistant cancer cell lines (KB-CPT100 and MCF-7/ADR).
# ::save-date Sun Jan 17, 2016 ::file pmid_2112_2157_159.txt
(p / perform-02
      :ARG0 (w / we)
      :ARG1 (e / experiment-01
            :ARG0 w
            :ARG1 (c / cell-line :quant 2
                  :ARG1-of (m / mean-01
                        :ARG2 (a / and
                              :op1 (c2 / cell-line :name (n2 / name :op1 "KB-CPT100"))
                              :op2 (c4 / cell-line :name (n3 / name :op1 "MCF-7/ADR"))))
                  :mod (d2 / disease :wiki "Cancer" :name (n8 / name :op1 "cancer")
                        :ARG0-of (r / resist-01
                              :ARG1 (d / drug))))
            :mod (g / genetic)
            :mod (n7 / nucleic-acid :name (n / name :op1 "siRNA")))
      :purpose (f / find-out-03
            :ARG0 w
            :ARG1 (r3 / regulate-01 :mode interrogative
                  :ARG0 (p2 / protein :name (n4 / name :op1 "Stat3"))
                  :ARG1 (p3 / protein :name (n5 / name :op1 "IL-6"))
                  :location (c5 / cell-line
                        :ARG2-of (e2 / except-01
                              :ARG1 (c7 / cell-line :name (n6 / name :op1 "AS2")))
                        :mod (d3 / disease :wiki "Cancer" :name (n9 / name :op1 "cancer"))))))

# ::id pmid_2112_2157.160 ::date 2015-07-20T22:30:54 ::annotator SDL-AMR-09 ::preferred
# ::snt MTT assay revealed that KB-CPT100 cells were more resistant to the chemotherapeutic agent camptothecin than the parental KB cells (Figure <xref ref-type="fig" rid="F6">6A</xref>) and MCF-7/ADR cells were much more resistant to the chemotherapeutic agent epirubicin than the parental MCF-7 cells (p < 0.001) (Figure <xref ref-type="fig" rid="F6">6B</xref>).
# ::save-date Sat Feb 13, 2016 ::file pmid_2112_2157_160.txt
(r / reveal-01
      :ARG0 (a / assay-01
            :instrument (s4 / small-molecule :name (n / name :op1 "MTT")))
      :ARG1 (a2 / and
            :op1 (r2 / resist-01
                  :ARG0 (c / cell-line :name (n2 / name :op1 "KB-CPT100")
                        :compared-to (c3 / cell-line :name (n4 / name :op1 "KB")
                              :mod (p / parent)))
                  :ARG1 (s / small-molecule :name (n3 / name :op1 "camptothecin")
                        :ARG1-of (m / mean-01
                              :ARG2 (a3 / agent
                                    :mod (c2 / chemotherapy))))
                  :ARG1-of (d / describe-01
                        :ARG0 (f / figure :mod "6A"))
                  :degree (m2 / more))
            :op2 (r3 / resist-01
                  :ARG0 (c4 / cell-line :name (n5 / name :op1 "MCF-7/ADR")
                        :compared-to (c6 / cell-line :name (n7 / name :op1 "MCF-7")
                              :mod p))
                  :ARG1 (s2 / small-molecule :name (n6 / name :op1 "epirubicin")
                        :ARG1-of (m5 / mean-01
                              :ARG2 a3))
                  :degree (m3 / more
                        :mod (m4 / much))
                  :ARG1-of (d2 / describe-01
                        :ARG0 (f2 / figure :mod "6B"))
                  :ARG1-of (s3 / statistical-test-91
                        :ARG2 (l / less-than :op1 0.001)))))

# ::id pmid_2112_2157.161 ::date 2015-07-20T22:45:06 ::annotator SDL-AMR-09 ::preferred
# ::snt The two drug resistant cell lines were found by ELISA to secrete more IL-6 than their parental cells (Figures <xref ref-type="fig" rid="F6">6C</xref> and <xref ref-type="fig" rid="F6">6D</xref>).
# ::save-date Sun Aug 2, 2015 ::file pmid_2112_2157_161.txt
(f / find-01
      :ARG0 (t / thing :name (n / name :op1 "ELISA"))
      :ARG1 (s / secrete-01
            :ARG0 (c / cell-line :quant 2
                  :ARG0-of (r / resist-01
                        :ARG1 (d / drug)))
            :ARG1 (p / protein :name (n2 / name :op1 "IL-6")
                  :quant (m / more)
                  :compared-to (c2 / cell
                        :mod (p2 / parent)
                        :poss c)))
      :ARG1-of (d2 / describe-01
            :ARG0 (a / and
                  :op1 (f2 / figure :mod "6C")
                  :op2 (f3 / figure :mod "6D"))))

# ::id pmid_2112_2157.162 ::date 2015-07-20T22:49:59 ::annotator SDL-AMR-09 ::preferred
# ::snt We transiently transfected the two drug resistant cells with Stat3#1 to knock-down Stat3.
# ::save-date Sun Aug 2, 2015 ::file pmid_2112_2157_162.txt
(t / transfect-01
      :ARG0 (w / we)
      :ARG1 (c / cell :quant 2
            :ARG0-of (r / resist-01
                  :ARG1 (d / drug)))
      :ARG2 (p / protein :name (n / name :op1 "Stat3#1"))
      :ARG1-of (t2 / transient-02)
      :purpose (k / knock-down-02
            :ARG1 (p2 / protein :name (n2 / name :op1 "Stat3"))))

# ::id pmid_2112_2157.163 ::date 2015-07-20T22:54:51 ::annotator SDL-AMR-09 ::preferred
# ::snt Western blot analysis confirmed that the total amount of Stat3 protein and phosphorylated Stat3 had been knocked-down in both resistant cells (Figures <xref ref-type="fig" rid="F6">6E</xref> and <xref ref-type="fig" rid="F6">6F</xref>).
# ::save-date Sun Dec 13, 2015 ::file pmid_2112_2157_163.txt
(c / confirm-01
      :ARG0 (a / analyze-01
            :manner (i / immunoblot-01))
      :ARG1 (k / knock-down-02
            :ARG1 (a2 / amount
                  :quant-of (a3 / and
                        :op1 (p / protein :wiki "STAT3"
                              :name (n2 / name :op1 "Stat3"))
                        :op2 (p2 / protein :wiki "STAT3"
                              :name (n3 / name :op1 "Stat3")
                              :ARG3-of (p3 / phosphorylate-01)))
                  :mod (t / total))
            :location (c2 / cell
                  :mod (b / both)
                  :ARG0-of (r / resist-01)))
      :ARG1-of (d / describe-01
            :ARG0 (a4 / and
                  :op1 (f / figure :mod "6E")
                  :op2 (f2 / figure :mod "6F"))))

# ::id pmid_2112_2157.164 ::date 2015-07-21T10:15:41 ::annotator SDL-AMR-09 ::preferred
# ::snt MTT assay found no change in cell viability (Additional file <xref ref-type="supplementary-material" rid="S3">3</xref>, Figure S3B and S3C).
# ::save-date Sat Feb 13, 2016 ::file pmid_2112_2157_164.txt
(f / find-01
      :ARG0 (a / assay-01
            :instrument (s / small-molecule :name (n / name :op1 "MTT")))
      :ARG1 (c / change-01 :polarity -
            :ARG1 (v / viability
                  :mod (c2 / cell)))
      :ARG1-of (d / describe-01
            :ARG0 (f2 / file :mod 3
                  :ARG1-of (a3 / add-02)
                  :ARG1-of (m / mean-01
                        :ARG2 (a2 / and
                              :op1 (f3 / figure :mod "S3B")
                              :op2 (f4 / figure :mod "S3C"))))))

# ::id pmid_2112_2157.165 ::date 2015-07-21T10:36:30 ::annotator SDL-AMR-09 ::preferred
# ::snt ELISA revealed that knocking-down Stat3 decreased the secretion of IL-6 in KB-CPT100 cells by one-third (p < 0.001) (Figure <xref ref-type="fig" rid="F6">6G</xref>) and by one-half in MCF-7/ADR cells (p < 0.001) (Figure <xref ref-type="fig" rid="F6">6H</xref>).
# ::save-date Tue Dec 15, 2015 ::file pmid_2112_2157_165.txt
(r / reveal-01
      :ARG0 (t / thing :name (n / name :op1 "ELISA"))
      :ARG1 (a / and
            :op1 (d / decrease-01
                  :ARG0 (k / knock-down-02
                        :ARG1 (p / protein :name (n2 / name :op1 "Stat3")))
                  :ARG1 (s / secrete-01
                        :ARG1 (p2 / protein :name (n3 / name :op1 "IL-6")))
                  :ARG2 (p5 / product-of :op1 "1/3")
                  :location (c / cell-line :name (n4 / name :op1 "KB-CPT100"))
                  :ARG1-of (d4 / describe-01
                        :ARG0 (f2 / figure :mod "6G"))
                  :ARG1-of (s2 / statistical-test-91
                        :ARG2 (l / less-than :op1 0.001)))
            :op2 (d2 / decrease-01
                  :ARG0 k
                  :ARG1 s
                  :ARG2 (p6 / product-of :op1 "1/2")
                  :location (c2 / cell-line :name (n5 / name :op1 "MCF-7/ADR"))
                  :ARG1-of (d3 / describe-01
                        :ARG0 (f / figure :mod "6H"))
                  :ARG1-of (s3 / statistical-test-91
                        :ARG2 l))))

# ::id pmid_2112_2157.166 ::date 2015-07-21T11:10:29 ::annotator SDL-AMR-09 ::preferred
# ::snt These results suggest that the Stat3 also contributes to the elevation of IL-6 in drug resistant cancer cells.
# ::save-date Thu Dec 10, 2015 ::file pmid_2112_2157_166.txt
(s / suggest-01
      :ARG0 (t / thing
            :ARG2-of (r / result-01)
            :mod (t2 / this))
      :ARG1 (c / contribute-01
            :ARG0 (p / protein :name (n / name :op1 "Stat3"))
            :ARG1 (e / elevate-01
                  :ARG0 p
                  :ARG1 (p2 / protein :name (n2 / name :op1 "IL-6")))
            :ARG2 (c2 / cell
                  :mod (d2 / disease :wiki "Cancer" :name (n3 / name :op1 "cancer")
                        :ARG0-of (r2 / resist-01
                              :ARG1 (d / drug))))
            :mod (a / also)))

# ::id pmid_2112_2157.167 ::date 2015-07-21T11:14:31 ::annotator SDL-AMR-09 ::preferred
# ::snt <sec-title level="2">Jak2/Stat3 pathway regulated the expression of IL-6 in cooperation with other IL-6 downstream pathways</sec-title>
# ::save-date Tue Jul 21, 2015 ::file pmid_2112_2157_167.txt
(r / regulate-01
      :ARG0 (p / pathway :name (n / name :op1 "Jak2/Stat3")
            :ARG0-of (c / cooperate-01
                  :ARG1 (p3 / pathway
                        :mod (o / other)
                        :mod (d / downstream)
                        :mod p2)))
      :ARG1 (e / express-03
            :ARG2 (p2 / protein :name (n2 / name :op1 "IL-6"))))

# ::id pmid_2112_2157.168 ::date 2015-07-21T11:18:37 ::annotator SDL-AMR-09 ::preferred
# ::snt To find out whether IL-6 could be regulated by different combinations of its downstream pathways including Jak2/Stat3 in various cancer cells, we pharmacologically inhibited the four IL-6 downstream pathways in six drug resistant cancer cell lines derived from cervical cancer, breast cancer, and lung cancer cells.
# ::save-date Thu Dec 10, 2015 ::file pmid_2112_2157_168.txt
(i / inhibit-01
      :ARG0 (w / we)
      :ARG1 (p2 / pathway :quant 4 :name (n / name :op1 "IL-6")
            :mod (d4 / downstream)
            :mod p4)
      :manner (p / pharmacological)
      :location (c / cell-line :quant 6
            :ARG0-of (r / resist-01
                  :ARG1 (d / drug))
            :ARG1-of (d2 / derive-01
                  :ARG2 (a / and
                        :op1 (c10 / cell
                              :mod (d5 / disease :wiki "Cervical_cancer" :name (n4 / name :op1 "cervical" :op2 "cancer")))
                        :op2 (c11 / cell
                              :mod (d6 / disease :wiki "Breast_cancer" :name (n5 / name :op1 "breast" :op2 "cancer")))
                        :op3 (c5 / cell
                              :mod (d7 / disease :wiki "Lung_cancer" :name (n6 / name :op1 "lung" :op2 "cancer"))))))
      :purpose (f / find-out-03
            :ARG0 w
            :ARG1 (p3 / possible-01 :mode interrogative
                  :ARG1 (r2 / regulate-01
                        :ARG0 (c7 / combine-01
                              :ARG1 (p5 / pathway
                                    :ARG2-of (i2 / include-01
                                          :ARG1 (p6 / pathway :name (n3 / name :op1 "Jak2/Stat3"))
                                          :location (c8 / cell
                                                :mod (v / various)
                                                :mod (d8 / disease :wiki "Cancer" :name (n7 / name :op1 "cancer"))))
                                    :mod d4)
                              :ARG1-of (d3 / differ-02))
                        :ARG1 (p4 / protein :name (n2 / name :op1 "IL-6"))))))

# ::id pmid_2112_2157.169 ::date 2015-07-21T11:52:51 ::annotator SDL-AMR-09 ::preferred
# ::snt ELISA revealed that all drug resistant cells secreted more IL-6 than their parental cells.
# ::save-date Thu Nov 12, 2015 ::file pmid_2112_2157_169.txt
(r / reveal-01
      :ARG0 (t / thing :name (n / name :op1 "ELISA"))
      :ARG1 (s / secrete-01
            :ARG0 (c / cell
                  :ARG0-of (r2 / resist-01
                        :ARG1 (d / drug))
                  :mod (a / all))
            :ARG1 (p / protein :name (n2 / name :op1 "IL-6")
                  :quant (m / more))
            :compared-to (c2 / cell
                  :mod (p2 / parent)
                  :poss c)))

# ::id pmid_2112_2157.170 ::date 2015-07-21T11:56:15 ::annotator SDL-AMR-09 ::preferred
# ::snt Different cells used different combinations of signaling pathways, including Jak2/Stat3, to regulate secretion of IL-6 (Figures <xref ref-type="fig" rid="F7">7A</xref> to <xref ref-type="fig" rid="F7">7F</xref>).
# ::save-date Tue Jul 21, 2015 ::file pmid_2112_2157_170.txt
(u / use-01
      :ARG0 (c / cell
            :ARG1-of (d / differ-02))
      :ARG1 (c2 / combine-01
            :ARG1 (p / pathway
                  :ARG0-of (s / signal-07)
                  :ARG2-of (i / include-01
                        :ARG1 (p2 / pathway :name (n / name :op1 "Jak2/Stat3")))))
      :ARG2 (r / regulate-01
            :ARG0 c
            :ARG1 (s2 / secrete-01
                  :ARG1 (p3 / protein :name (n2 / name :op1 "IL-6"))))
      :ARG1-of (d2 / describe-01
            :ARG0 (a / and
                  :op1 (f / figure :mod "7A")
                  :op2 (f2 / figure :mod "7F"))))

# ::id pmid_2112_2157.171 ::date 2015-07-21T12:03:36 ::annotator SDL-AMR-09 ::preferred
# ::snt To exclude the possibility that the reduction of IL-6 secretion was caused by the reduction of cell survival, we used MTT assay to analyze the effect of these inhibitors on cell viability (Additional file <xref ref-type="supplementary-material" rid="S1">1</xref>, Figure S1C to S1H).
# ::save-date Sat Feb 13, 2016 ::file pmid_2112_2157_171.txt
(u / use-01
      :ARG0 (w / we)
      :ARG1 (a / assay-01
            :instrument (s3 / small-molecule :name (n / name :op1 "MTT")))
      :ARG2 (a2 / analyze-01
            :ARG0 w
            :ARG1 (a3 / affect-01
                  :ARG0 (m / molecular-physical-entity
                        :ARG0-of (i / inhibit-01)
                        :mod (t / this))
                  :ARG1 (v / viability
                        :mod (c / cell))))
      :purpose (e / exclude-01
            :ARG0 w
            :ARG1 (p / possible-01
                  :ARG1 (c2 / cause-01
                        :ARG0 (r / reduce-01
                              :ARG1 (s / survive-01
                                    :ARG0 (c3 / cell)))
                        :ARG1 (r2 / reduce-01
                              :ARG1 (s2 / secrete-01
                                    :ARG1 (p2 / protein :name (n2 / name :op1 "IL-6")))))))
      :ARG1-of (d / describe-01
            :ARG0 (f / file :mod 1
                  :ARG1-of (a5 / add-02)
                  :ARG1-of (m2 / mean-01
                        :ARG2 (v2 / value-interval
                              :op1 (f2 / figure :mod "S1C")
                              :op2 (f3 / figure :mod "S1H"))))))

# ::id pmid_2112_2157.172 ::date 2015-07-21T12:40:35 ::annotator SDL-AMR-09 ::preferred
# ::snt We showed that the majority of inhibitors had only limited suppressive effect on cell viability (below 25%) (Additional file <xref ref-type="supplementary-material" rid="S1">1</xref>, Figure S1C-S1H) except that the PI3-K/Akt pathway inhibitor LY294002 had more suppressive activity on the cellular viability by 30 to 50% (Additional file <xref ref-type="supplementary-material" rid="S1">1</xref>, Figure S1C-S1F).
# ::save-date Sun Aug 2, 2015 ::file pmid_2112_2157_172.txt
(s / show-01
      :ARG0 (w / we)
      :ARG1 (a / affect-01
            :ARG0 (s2 / small-molecule
                  :ARG0-of (i / inhibit-01)
                  :quant (m / majority))
            :ARG1 (v / viability
                  :mod (c / cell)
                  :quant (b / below
                        :op1 (p / percentage-entity :value 25)))
            :ARG2 (s3 / suppress-01)
            :ARG1-of (l / limit-01
                  :mod (o / only))
            :ARG1-of (d / describe-01
                  :ARG0 (f / file :mod 1
                        :ARG1-of (a2 / add-02)
                        :ARG1-of (m2 / mean-01
                              :ARG2 (v2 / value-interval
                                    :op1 (f2 / figure :mod "S1C")
                                    :op2 (f3 / figure :mod "S1F")))))
            :ARG2-of (e / except-01
                  :ARG1 (a3 / activity-06
                        :ARG0 (s4 / small-molecule :name (n / name :op1 "LY294002")
                              :ARG0-of (i2 / inhibit-01
                                    :ARG1 (p2 / pathway :name (n2 / name :op1 "PI3-K/Akt"))))
                        :ARG1 (s5 / suppress-01
                              :ARG1 (v3 / viability
                                    :mod c
                                    :quant (v4 / value-interval
                                          :op1 (p3 / percentage-entity :value 30)
                                          :op2 (p4 / percentage-entity :value 50)))
                              :degree (m3 / more)))
                  :ARG1-of (d2 / describe-01
                        :ARG0 (f4 / file :mod 1
                              :ARG1-of (m4 / mean-01
                                    :ARG2 (v5 / value-interval
                                          :op1 f2
                                          :op2 (f5 / figure :mod "S1F")))
                              :ARG1-of a2)))))

# ::id pmid_2112_2157.173 ::date 2015-07-21T13:15:32 ::annotator SDL-AMR-09 ::preferred
# ::snt However, LY294002 induced much greater (75 to 90%) decrease of IL-6 in these cells (Figure <xref ref-type="fig" rid="F7">7A</xref> to <xref ref-type="fig" rid="F7">7D</xref>).
# ::save-date Mon Aug 3, 2015 ::file pmid_2112_2157_173.txt
(c2 / contrast-01
      :ARG2 (i / induce-01
            :ARG0 (s / small-molecule :name (n / name :op1 "LY294002"))
            :ARG2 (d / decrease-01
                  :ARG1 (p / protein :name (n2 / name :op1 "IL-6"))
                  :ARG2 (v / value-interval
                        :op1 (p2 / percentage-entity :value 75)
                        :op2 (p3 / percentage-entity :value 90))
                  :location (c / cell
                        :mod (t / this))
                  :mod (g / great
                        :degree (m / more
                              :mod (m2 / much)))))
      :ARG1-of (d2 / describe-01
            :ARG0 (v2 / value-interval
                  :op1 (f / figure :mod "7A")
                  :op2 (f2 / figure :mod "7D"))))

# ::id pmid_2112_2157.174 ::date 2015-07-21T13:44:28 ::annotator SDL-AMR-09 ::preferred
# ::snt There is only one exception that the AG490-induced reductions of cell survival and IL-6 secretion were both about 30% in KB-7D cells (Additional file <xref ref-type="supplementary-material" rid="S1">1</xref>, Figure S1F and Figure <xref ref-type="fig" rid="F7">7D</xref>).
# ::save-date Tue Jul 21, 2015 ::file pmid_2112_2157_174.txt
(a / and
      :op1 (r / reduce-01
            :ARG1 (s / survive-01
                  :ARG0 (c / cell))
            :ARG2-of (i / induce-01
                  :ARG0 (s2 / small-molecule :name (n / name :op1 "AG490"))))
      :op2 (s3 / secrete-01
            :ARG1 (p / protein :name (n2 / name :op1 "IL-6")))
      :quant (a2 / about
            :op1 (p2 / percentage-entity :value 30))
      :location (c2 / cell-line :name (n3 / name :op1 "KB-7D"))
      :ARG1-of (e / except-01 :mod 1
            :mod (o / only))
      :ARG1-of (d / describe-01
            :ARG0 (f / file :mod 1
                  :ARG1-of (a3 / add-02)
                  :ARG1-of (m / mean-01
                        :ARG2 (a4 / and
                              :op1 (f2 / figure :mod "S1F")
                              :op2 (f3 / figure :mod "7D"))))))

# ::id pmid_2112_2157.175 ::date 2015-07-21T13:58:05 ::annotator SDL-AMR-09 ::preferred
# ::snt <sec-title level="2">Jak2/Stat3 pathway contributed to IL-6 autocrine production in clinically isolated lung cancer cells</sec-title>
# ::save-date Thu Dec 10, 2015 ::file pmid_2112_2157_175.txt
(c / contribute-01
      :ARG0 (p / pathway :name (n / name :op1 "Jak2/Stat3"))
      :ARG1 (p2 / produce-01
            :ARG1 (p3 / protein :name (n2 / name :op1 "IL-6"))
            :mod (a / autocrine))
      :ARG2 (c2 / cell
            :ARG1-of (i / isolate-01
                  :manner (c4 / clinical))
            :mod (d / disease :wiki "Lung_cancer" :name (n3 / name :op1 "lung" :op2 "cancer"))))

# ::id pmid_2112_2157.176 ::date 2015-07-21T14:07:47 ::annotator SDL-AMR-09 ::preferred
# ::snt Because previous studies suggesting Stat3 on IL-6 were all <i>in vitro </i>cell line studies, not clinical studies, we also wanted to find out whether IL-6 could be regulated by different combinations of pathways including Jak2/Stat3 in not just cell lines but also in the human body.
# ::save-date Mon Aug 3, 2015 ::file pmid_2112_2157_176.txt
(w / want-01
      :ARG0 (w2 / we)
      :ARG1 (f / find-out-03
            :ARG0 w2
            :ARG1 (p4 / possible-01 :mode interrogative
                  :ARG1 (r / regulate-01
                        :ARG0 (c / combine-01
                              :ARG1 (p2 / pathway
                                    :ARG2-of (i / include-01
                                          :ARG1 (p3 / pathway :name (n2 / name :op1 "Jak2/Stat3"))))
                              :ARG1-of (d / differ-02))
                        :ARG1 (p / protein :name (n / name :op1 "IL-6"))
                        :location (a / and
                              :op1 (c2 / cell-line
                                    :mod (j / just :polarity -))
                              :op2 (b / body
                                    :mod (h / human)
                                    :mod (a2 / also))))))
      :ARG1-of (c3 / cause-01
            :ARG0 (s / study-01
                  :ARG1 (c5 / cell-line)
                  :mod (i2 / in-vitro
                        :ARG1-of (c6 / contrast-01
                              :ARG2 (s4 / study-01
                                    :mod (c4 / clinical))))
                  :domain (s2 / study-01
                        :ARG0-of (s3 / suggest-01
                              :ARG1 (r2 / regulate-01
                                    :ARG0 (p5 / protein :name (n3 / name :op1 "Stat3"))
                                    :ARG1 p))
                        :time (p6 / previous)
                        :mod (a3 / all))))
      :mod a2)

# ::id pmid_2112_2157.177 ::date 2015-07-21T14:33:06 ::annotator SDL-AMR-09 ::preferred
# ::snt We had previously found IL-6 levels to be increased in MPE of patients with lung cancer [<xref ref-type="bibr" rid="B2">2</xref>].
# ::save-date Tue Dec 29, 2015 ::file pmid_2112_2157_177.txt
(f / find-01
      :ARG0 (w / we)
      :ARG1 (i / increase-01
            :ARG1 (l / level
                  :quant-of (p / protein :name (n / name :op1 "IL-6")))
            :location (m2 / medical-condition :wiki "Malignant_pleural_effusion" :name (n3 / name :op1 "malignant" :op2 "pleural" :op3 "effusion")
                  :poss (p2 / patient
                        :mod (d / disease :wiki "Lung_cancer" :name (n2 / name :op1 "lung" :op2 "cancer")))))
      :time (p3 / previous))

# ::id pmid_2112_2157.178 ::date 2015-07-21T14:39:50 ::annotator SDL-AMR-09 ::preferred
# ::snt To do this, we pharmacologically inhibited the four IL-6 downstream pathways in 20 clinical samples of human lung cancer obtained from MPE.
# ::save-date Tue Dec 29, 2015 ::file pmid_2112_2157_178.txt
(i / inhibit-01
      :ARG0 (w / we)
      :ARG1 (p2 / pathway :mod 4 :name (n / name :op1 "IL-6")
            :mod (d / downstream))
      :manner (p / pharmacological)
      :location (s / sample-01 :quant 20
            :ARG1 (d3 / disease :wiki "Lung_cancer" :name (n2 / name :op1 "lung" :op2 "cancer")
                  :mod (h / human))
            :mod (c / clinical)
            :ARG1-of (o / obtain-01
                  :ARG2 (m / medical-condition :wiki "Malignant_pleural_effusion" :name (n3 / name :op1 "malignant" :op2 "pleural" :op3 "effusion"))))
      :purpose (d2 / do-02
            :ARG0 w
            :ARG1 (t / this)))

# ::id pmid_2112_2157.179 ::date 2015-07-21T14:48:15 ::annotator SDL-AMR-09 ::preferred
# ::snt ELISA revealed that IL-6 was expressed in the conditioned medium of all samples, ranging from 16.58 ± 0.21 to 1016.47 ± 12.45 pg/ml (Figure <xref ref-type="fig" rid="F8">8A</xref>), with a mean of 393.14 pg/ml.
# ::save-date Thu Feb 4, 2016 ::file pmid_2112_2157_179.txt
(r / reveal-01
      :ARG0 (t / thing :name (n / name :op1 "ELISA"))
      :ARG1 (e / express-03
            :ARG2 (p / protein :name (n2 / name :op1 "IL-6")
                  :ARG1-of (r2 / range-01
                        :ARG3 (c2 / concentration-quantity
                              :quant (v / value-interval
                                    :op1 (a2 / add-02
                                          :ARG1 16.58
                                          :ARG2 0.21)
                                    :op2 (s2 / subtract-01
                                          :ARG1 0.21
                                          :ARG2 16.58))
                              :unit (p3 / picogram-per-milliliter))
                        :ARG4 (c3 / concentration-quantity
                              :quant (v2 / value-interval
                                    :op1 (a3 / add-02
                                          :ARG1 1016.47
                                          :ARG2 12.45)
                                    :op2 (s3 / subtract-01
                                          :ARG1 12.45
                                          :ARG2 1016.47))
                              :unit p3)))
            :ARG3 (m / medium
                  :ARG1-of (c / condition-01)
                  :poss (t2 / thing
                        :mod (a / all)
                        :mod (c4 / concentration-quantity :quant 393.14
                              :unit p3
                              :mod (m2 / mean))
                        :ARG1-of (s / sample-01))))
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod "8A")))

# ::id pmid_2112_2157.180 ::date 2015-07-21T15:25:46 ::annotator SDL-AMR-09 ::preferred
# ::snt The four aforementioned inhibitors significantly decreased IL-6 secretion in the clinically isolated cancer cells differently (U0126, p < 0.01; AG490, LY294002 and BAY11-7082, all p < 0.001) (Figure <xref ref-type="fig" rid="F8">8A</xref>).
# ::save-date Fri Dec 18, 2015 ::file pmid_2112_2157_180.txt
(d / decrease-01
      :ARG0 (s / small-molecule :quant 4
            :ARG1-of (i / inhibit-01)
            :ARG1-of (m / mention-01
                  :time (b / before)))
      :ARG1 (s3 / secrete-01
            :ARG1 (p / protein :name (n / name :op1 "IL-6")))
      :ARG2 (s2 / significant-02)
      :location (c / cell
            :manner (c3 / clinical)
            :mod (d4 / disease :wiki "Cancer" :name (n6 / name :op1 "cancer")
                  :ARG1-of (i2 / isolate-01)))
      :ARG1-of (d2 / differ-02)
      :ARG1-of (m2 / mean-01
            :ARG2 (a / and
                  :op1 (d5 / decrease-01
                        :ARG0 (s7 / small-molecule :name (n2 / name :op1 "U0126"))
                        :ARG1 s3
                        :location c
                        :ARG1-of (s8 / statistical-test-91
                              :ARG2 (l / less-than :op1 0.01))
                        :location c)
                  :op2 (d6 / decrease-01
                        :ARG0 (a2 / and
                              :op1 (s4 / small-molecule :name (n3 / name :op1 "AG490"))
                              :op2 (s5 / small-molecule :name (n4 / name :op1 "LY294002"))
                              :op2 (s6 / small-molecule :name (n5 / name :op1 "BAY11-7082"))
                              :mod (a3 / all))
                        :ARG1 s3
                        :ARG1-of (s9 / statistical-test-91
                              :ARG2 (l2 / less-than :op1 0.001)))))
      :ARG1-of (d3 / describe-01
            :ARG0 (f / figure :mod "8A")))

# ::id pmid_2112_2157.181 ::date 2015-07-21T15:38:17 ::annotator SDL-AMR-09 ::preferred
# ::snt We further analyzed the percent of inhibition by each inhibitor on IL-6 secretion.
# ::save-date Tue Jul 21, 2015 ::file pmid_2112_2157_181.txt
(a / analyze-01
      :ARG0 (w / we)
      :ARG1 (p / percent
            :quant-of (i / inhibit-01
                  :ARG0 (s / small-molecule
                        :ARG1-of i
                        :mod (e / each))
                  :ARG1 (s2 / secrete-01
                        :ARG1 (p2 / protein :name (n / name :op1 "IL-6")))))
      :time (f / further))

# ::id pmid_2112_2157.182 ::date 2015-07-21T15:41:32 ::annotator SDL-AMR-09 ::preferred
# ::snt BAY11-7082 had the greatest inhibitory activity on the autocrine production of IL-6 in the clinical samples (BAY11-7082 > LY294002 > AG490 > U0126) (Figure <xref ref-type="fig" rid="F8">8B</xref>).
# ::save-date Mon Dec 21, 2015 ::file pmid_2112_2157_182.txt
(h / have-03
      :ARG0 (s / small-molecule :name (n / name :op1 "BAY11-7082"))
      :ARG1 (a / activity-06
            :ARG1 (i / inhibit-01
                  :ARG1 (p / produce-01
                        :ARG1 (p2 / protein :name (n2 / name :op1 "IL-6"))
                        :mod (a2 / autocrine)))
            :mod (g / great
                  :degree (m / most)))
      :location (t / thing
            :mod (c / clinical)
            :ARG1-of (s2 / sample-01))
      :ARG1-of (m2 / mean-01
            :ARG2 (s3 / small-molecule :name (n3 / name :op1 "BAY11-7082")
                  :quant (m3 / more-than
                        :op1 (s4 / small-molecule :name (n4 / name :op1 "LY294002")
                              :quant (m4 / more-than
                                    :op1 (s5 / small-molecule :name (n5 / name :op1 "AG490")
                                          :quant (m5 / more-than
                                                :op1 (s6 / small-molecule :name (n6 / name :op1 "U0126")))))))))
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod "8B")))

# ::id pmid_2155_9022.1 ::date 2015-08-06T01:55:21 ::annotator SDL-AMR-09 ::preferred
# ::snt Upregulation of MAPK pathway is associated with survival in castrate-resistant prostate cancer (PMID:21559022)
# ::save-date Thu Dec 10, 2015 ::file pmid_2155_9022_1.txt
(a / associate-01
      :ARG1 (u / upregulate-01
            :ARG1 (p / pathway :name (n / name :op1 "MAPK")))
      :ARG2 (s / survive-01
            :ARG1 (d2 / disease :wiki "Prostate_cancer" :name (n2 / name :op1 "prostate" :op2 "cancer")
                  :ARG0-of (r / resist-01
                        :ARG1 (c2 / castrate-01))))
      :ARG1-of (d / describe-01
            :ARG0 (p3 / publication-91
                  :ARG8 "PMID21559022")))

# ::id pmid_2155_9022.9 ::date 2015-08-06T02:35:09 ::annotator SDL-AMR-09 ::preferred
# ::snt <sec-title level="1" sec-area="abstract">Results:</sec-title>
# ::save-date Thu Aug 6, 2015 ::file pmid_2155_9022_9.txt
(t / thing
      :ARG2-of (r / result-01))

# ::id pmid_2155_9022.10 ::date 2015-08-08T07:15:41 ::annotator SDL-AMR-09 ::preferred
# ::snt Patients whose nuclear expression of MAPK rose with the development of CRPC had a significantly shorter median time to death following biochemical relapse (1.40 <i>vs</i> 3.00 years, <i>P</i>=0.0255) as well as reduced disease-specific survival when compared with those whose expression fell or remained unchanged (1.16 <i>vs</i> 2.62 years, <i>P</i>=0.0005).
# ::save-date Sun Jan 17, 2016 ::file pmid_2155_9022_10.txt
(h / have-03
      :ARG0 (p / person
            :ARG0-of (h2 / have-rel-role-91
                  :ARG2 (p2 / patient))
            :ARG3-of (e / express-03
                  :ARG2 (e2 / enzyme :name (n2 / name :op1 "MAPK"))
                  :mod (n / nucleus)
                  :ARG1-of (r / rise-01
                        :time (d / develop-01
                              :ARG2 (d4 / disease :name (n3 / name :op1 "CRPC")))))
            :ARG1-of (c / compare-01
                  :ARG2 (p3 / person
                        :ARG0-of (h3 / have-rel-role-91
                              :ARG2 (p4 / patient))
                        :poss (o2 / or
                              :op1 (e4 / express-03
                                    :ARG1-of (f2 / fall-01))
                              :op2 (e5 / express-03
                                    :ARG1-of (c3 / change-01 :polarity -))
                              :ARG1-of (m5 / mean-01
                                    :ARG2 (t2 / temporal-quantity :quant 1.16
                                          :compared-to (t3 / temporal-quantity :quant 2.62
                                                :unit y3)
                                          :unit (y3 / year)))
                              :ARG1-of (s6 / statistical-test-91
                                    :ARG2 0.005)))))
      :ARG1 (a / and
            :op1 (t / time
                  :mod (m / median)
                  :ARG1-of (s / short-07
                        :degree (m2 / more)
                        :ARG1-of (s2 / significant-02)
                        :ARG1-of (s5 / statistical-test-91
                              :ARG2 0.0255))
                  :mod (d2 / die-01
                        :ARG1-of (f / follow-01
                              :ARG2 (r2 / relapse-01
                                    :mod (b / biochemistry))))
                  :ARG1-of (m3 / mean-01
                        :ARG2 (t4 / temporal-quantity :quant 1.40
                              :compared-to (t5 / temporal-quantity :quant 3.00
                                    :unit y3)
                              :unit y3)))
            :op2 (s3 / survive-01
                  :ARG1-of (r3 / reduce-01)
                  :ARG1-of (s4 / specific-02
                        :ARG2 (d3 / disease)))))

# ::id pmid_2155_9022.11 ::date 2015-08-12T01:08:14 ::annotator SDL-AMR-09 ::preferred
# ::snt Significant correlations were observed between protein expression of Raf-1 and MAPK with the type 1 receptor tyrosine kinases, Her2 and epidermal growth factor receptor, as well as the transcription factor AP-1 in CRPC tumours.
# ::save-date Mon Jan 4, 2016 ::file pmid_2155_9022_11.txt
(o / observe-01
      :ARG1 (c / correlate-01
            :ARG1 (e / express-03
                  :ARG2 (a / and
                        :op1 (e2 / enzyme :name (n / name :op1 "Raf-1"))
                        :op2 (e3 / enzyme :name (n2 / name :op1 "MAPK")))
                  :location (t3 / tumor
                        :mod (d / disease :name (n7 / name :op1 "CRPC"))))
            :ARG2 (a2 / and
                  :op1 (e4 / enzyme :name (n5 / name :op1 "receptor" :op2 "tyrosine" :op3 "kinase")
                        :mod (t / type :mod 1))
                  :op2 (e5 / enzyme :name (n3 / name :op1 "Her2"))
                  :op3 (e6 / enzyme :name (n4 / name :op1 "epidermal" :op2 "growth" :op3 "factor" :op4 "receptor"))
                  :op4 (p / protein :name (n6 / name :op1 "AP-1")
                        :ARG0-of (t2 / transcribe-01)
                        :mod (f / factor)))
            :ARG1-of (s / significant-02)))

# ::id pmid_2155_9022.73 ::date 2015-08-06T02:36:59 ::annotator SDL-AMR-09 ::preferred
# ::snt <sec-title level="1">Results</sec-title>
# ::save-date Thu Aug 6, 2015 ::file pmid_2155_9022_73.txt
(t / thing
      :ARG2-of (r / result-01))

# ::id pmid_2155_9022.74 ::date 2015-08-06T02:38:01 ::annotator SDL-AMR-09 ::preferred
# ::snt <sec-title level="2">Patient cohort characteristics</sec-title>
# ::save-date Thu Dec 10, 2015 ::file pmid_2155_9022_74.txt
(c / characteristic-02
      :ARG1 (c2 / cohort
            :ARG2-of (i / include-91
                  :ARG1 (p / person
                        :ARG0-of (h / have-rel-role-91
                              :ARG2 (p2 / patient))))))

# ::id pmid_2155_9022.75 ::date 2015-08-14T11:12:36 ::annotator SDL-AMR-09 ::preferred
# ::snt The clinical data collected and recorded for each patient included age (median: 70 years; inter-quartile range: 66–74 years), PSA level at diagnosis (median: 31 ng ml<sup>−1</sup>; inter-quartile range: 7.8–109 ng ml<sup>−1</sup>), PSA level at relapse (median: 10 ng ml<sup>−1</sup>; inter-quartile range: 4–11 ng ml<sup>−1</sup>) and Gleason grade at diagnosis (median: 8, inter-quartile range: 7–9).
# ::save-date Thu Feb 4, 2016 ::file pmid_2155_9022_75.txt
(i / include-91
      :ARG1 (a2 / and
            :op1 (a / age
                  :ARG1-of (m / mean-01
                        :ARG2 (a3 / and
                              :op1 (t / time
                                    :mod (m2 / median)
                                    :ARG1-of (m3 / mean-01
                                          :ARG2 (t2 / temporal-quantity :quant 70
                                                :unit (y / year))))
                              :op2 (r3 / range-01
                                    :ARG3 (t3 / temporal-quantity :quant 66
                                          :unit y)
                                    :ARG4 (t4 / temporal-quantity :quant 74
                                          :unit y)
                                    :mod (i2 / inter-quartile)))))
            :op2 (l / level
                  :degree-of (e2 / enzyme :name (n / name :op1 "PSA"))
                  :time (d2 / diagnose-01)
                  :ARG1-of (m5 / mean-01
                        :ARG2 (a4 / and
                              :op1 (c3 / concentration-quantity :quant 31
                                    :mod m2
                                    :unit (n2 / nanogram-per-milliliter))
                              :op2 (r4 / range-01
                                    :ARG3 (c4 / concentration-quantity :quant 7.8
                                          :unit n2)
                                    :ARG4 (c5 / concentration-quantity :quant 109
                                          :unit n2)
                                    :mod (i3 / inter-quartile)))))
            :op3 (l2 / level
                  :degree-of e2
                  :time (r2 / relapse-01)
                  :ARG1-of (m6 / mean-01
                        :ARG2 (a5 / and
                              :op1 (c6 / concentration-quantity :quant 10
                                    :mod m2
                                    :unit n2)
                              :op2 (r5 / range-01
                                    :ARG3 (c8 / concentration-quantity :quant 4
                                          :unit n2)
                                    :ARG4 (c9 / concentration-quantity :quant 11
                                          :unit n2)
                                    :mod (i4 / inter-quartile)))))
            :op4 (g / grade
                  :time d2
                  :ARG1-of (m7 / mean-01
                        :ARG2 (a6 / and
                              :op1 (c7 / concentration-quantity :quant 8
                                    :unit n2)
                              :op2 (r6 / range-01
                                    :ARG3 (c10 / concentration-quantity :quant 7
                                          :unit n2)
                                    :ARG4 (c11 / concentration-quantity :quant 9
                                          :unit n2)
                                    :mod (i5 / inter-quartile))))
                  :mod (p3 / person :name (n3 / name :op1 "Gleason"))))
      :ARG2 (d / data
            :mod (c / clinic)
            :ARG1-of (c2 / collect-01
                  :topic (p / person
                        :mod (e / each)
                        :ARG0-of (h / have-rel-role-91
                              :ARG2 (p2 / patient))))
            :ARG1-of (r / record-01
                  :topic p)))

# ::id pmid_2155_9022.76 ::date 2015-08-08T08:43:06 ::annotator SDL-AMR-09 ::preferred
# ::snt All patients underwent biochemical relapse (median time to relapse: 2.54 years; inter-quartile range: 1.51–4.62 years).
# ::save-date Thu Dec 10, 2015 ::file pmid_2155_9022_76.txt
(u / undergo-28
      :ARG1 (p / person
            :ARG0-of (h / have-rel-role-91
                  :ARG2 (p2 / patient))
            :mod (a / all))
      :ARG2 (r / relapse-01
            :ARG1 p
            :mod (b / biochemistry)
            :ARG1-of (m / mean-01
                  :ARG2 (a2 / and
                        :op1 (t / time
                              :mod (m2 / median)
                              :mod (r3 / relapse-01)
                              :ARG1-of (m3 / mean-01
                                    :ARG2 (t2 / temporal-quantity :quant 2.54
                                          :unit (y / year))))
                        :op2 (r2 / range-01
                              :ARG3 (t3 / temporal-quantity :quant 1.51
                                    :unit y)
                              :ARG4 (t4 / temporal-quantity :quant 4.62
                                    :unit y)
                              :mod (i / inter-quartile))))))

# ::id pmid_2155_9022.77 ::date 2015-08-12T02:30:59 ::annotator SDL-AMR-09 ::preferred
# ::snt All patients included in this study were deceased (median time to death after relapse: 1.37 years; inter-quartile range: 0.82–2.69).
# ::save-date Thu Dec 10, 2015 ::file pmid_2155_9022_77.txt
(d / decease-01
      :ARG1 (p / person
            :ARG0-of (h / have-rel-role-91
                  :ARG2 (p2 / patient))
            :mod (a / all)
            :ARG1-of (i / include-01
                  :ARG2 (s / study
                        :mod (t / this))))
      :ARG1-of (m / mean-01
            :ARG2 (a2 / and
                  :op1 (t2 / time
                        :mod (m2 / median)
                        :mod (d2 / die-01)
                        :time (a3 / after
                              :op1 (r / relapse-01))
                        :ARG1-of (m3 / mean-01
                              :ARG2 (t3 / temporal-quantity :quant 1.37
                                    :unit (y / year))))
                  :op2 (r2 / range-01
                        :ARG3 (t4 / temporal-quantity :quant 0.82
                              :unit y)
                        :ARG4 (t5 / temporal-quantity :quant 2.69
                              :unit y)
                        :mod (i2 / inter-quartile)))))

# ::id pmid_2155_9022.78 ::date 2015-08-12T02:56:01 ::annotator SDL-AMR-09 ::preferred
# ::snt This resulted in an overall median survival time of 4.5 years (inter-quartile range: 3.00–7.01).
# ::save-date Wed Aug 19, 2015 ::file pmid_2155_9022_78.txt
(r / result-01
      :ARG1 (t / this)
      :ARG2 (t2 / time
            :mod (s / survive-01)
            :mod (o / overall)
            :mod (m / median)
            :duration (t3 / temporal-quantity :quant 4.5
                  :unit (y / year)))
      :ARG1-of (m2 / mean-01
            :ARG2 (r2 / range-01
                  :ARG3 (t4 / temporal-quantity :quant 3.00
                        :unit (y2 / year))
                  :ARG4 (t5 / temporal-quantity :quant 7.01
                        :unit y)
                  :mod (i / inter-quartile))))

# ::id pmid_2155_9022.79 ::date 2015-08-12T22:50:42 ::annotator SDL-AMR-09 ::preferred
# ::snt Patients were diagnosed with locally advanced (46 patients) or metastatic (19 patients) prostate cancer, and at the time of relapse the number of patients presenting with metastatic disease had risen (40 patients).
# ::save-date Wed Dec 30, 2015 ::file pmid_2155_9022_79.txt
(a / and
      :op1 (d / diagnose-01
            :ARG1 p4
            :ARG2 (o / or
                  :op1 (d3 / disease :wiki "Prostate_cancer" :name (n2 / name :op1 "prostate" :op2 "cancer")
                        :ARG1-of (a2 / advanced-02
                              :ARG1-of (l / local-02)
                              :ARG1-of (m2 / mean-01
                                    :ARG2 (p2 / person :quant 46
                                          :ARG0-of (h / have-rel-role-91
                                                :ARG2 (p3 / patient))))))
                  :op2 (d4 / disease :wiki "Cancer" :name (n3 / name :op1 "cancer")
                        :ARG1-of (m / metastasize-101
                              :ARG1-of (m3 / mean-01
                                    :ARG2 (p7 / person :quant 19
                                          :ARG0-of h))))))
      :op2 (r / rise-01
            :ARG1 (n / number
                  :quant-of (p4 / person
                        :ARG0-of (p / present-102
                              :ARG1 (d2 / disease
                                    :ARG1-of m))
                        :ARG0-of h))
            :time (r2 / relapse-01)
            :ARG1-of (m4 / mean-01
                  :ARG2 (p9 / person :quant 40
                        :ARG0-of h))))

# ::id pmid_2155_9022.80 ::date 2015-08-12T23:59:28 ::annotator SDL-AMR-09 ::preferred
# ::snt At diagnosis, patients either underwent surgery (27 orchidectomy) or androgen deprivation therapy (59 GnRH analogue and/or anti-androgen deprivation therapy).
# ::save-date Thu Dec 10, 2015 ::file pmid_2155_9022_80.txt
(u / undergo-28
      :ARG1 (p / person
            :ARG0-of (h / have-rel-role-91
                  :ARG2 (p2 / patient)))
      :ARG2 (o / or
            :op1 (s / surgery-01
                  :ARG1 p
                  :ARG1-of (m / mean-01
                        :ARG2 (o2 / orchidectomy :mod 27)))
            :op2 (t / therapy
                  :ARG0-of (d2 / deprive-01
                        :ARG1 (a / androgen))
                  :ARG1-of (m2 / mean-01
                        :ARG2 (a2 / and-or
                              :op1 (e / enzyme :mod 59 :name (n / name :op1 "GnRH")
                                    :mod (a3 / analogue))
                              :op2 (t2 / therapy
                                    :ARG1-of (d3 / deprive-01)
                                    :ARG0-of (o3 / oppose-01
                                          :ARG1 (a4 / androgen)))))))
      :time (d / diagnose-01))

# ::id pmid_2155_9022.81 ::date 2015-08-09T02:28:32 ::annotator SDL-AMR-09 ::preferred
# ::snt Most patients were deceased during the course of follow-up (46 patients), although some survived beyond follow-up (19 patients).
# ::save-date Thu Dec 10, 2015 ::file pmid_2155_9022_81.txt
(d / decease-01
      :ARG1 (p / person
            :ARG0-of (h / have-rel-role-91
                  :ARG2 (p2 / patient))
            :mod (m / most
                  :ARG1-of (m2 / mean-01
                        :ARG2 (p3 / person :quant 46
                              :ARG0-of h))))
      :time (f / follow-up-03)
      :concession (s / survive-01
            :ARG1 (s2 / some
                  :ARG1-of (m3 / mean-01
                        :ARG2 (p5 / person :quant 19
                              :ARG0-of h)))
            :mod (b / beyond
                  :op1 f)))

# ::id pmid_2155_9022.82 ::date 2015-08-06T03:38:45 ::annotator SDL-AMR-09 ::preferred
# ::snt The presence of metastatic disease at diagnosis was associated with reduced time to biochemical relapse (<i>P</i>=0.037) and a trend in overall patient survival (<i>P</i>=0.06).
# ::save-date Tue Dec 15, 2015 ::file pmid_2155_9022_82.txt
(a / associate-01
      :ARG1 (p / present-02
            :ARG1 (d / disease
                  :ARG1-of (m / metastasize-101))
            :ARG2 (d2 / diagnose-01))
      :ARG2 (a2 / and
            :op1 (t / time
                  :ARG1-of (r / reduce-01)
                  :mod (r2 / relapse-01
                        :mod (b / biochemistry)
                        :ARG1-of (s2 / statistical-test-91
                              :ARG2 0.037)))
            :op2 (t2 / trend-01
                  :ARG1 (s / survive-01
                        :ARG0 (p2 / person
                              :ARG0-of (h / have-rel-role-91
                                    :ARG2 (p3 / patient)))
                        :mod (o / overall))
                  :ARG1-of (s3 / statistical-test-91
                        :ARG2 0.06))))

# ::id pmid_2155_9022.83 ::date 2015-08-13T00:37:57 ::annotator SDL-AMR-09 ::preferred
# ::snt High Gleason scores were associated with more rapid biochemical relapse (<i>P</i>=0.002), time to death after biochemical relapse (<i>P</i>=0.02) and disease-specific survival (<i>P</i>=0.001), confirming the association of these clinical parameters with the progression of prostate cancer.
# ::save-date Tue Dec 15, 2015 ::file pmid_2155_9022_83.txt
(a / associate-01
      :ARG1 (s / score
            :ARG1-of (h / high-02)
            :mod (p6 / person :name (n / name :op1 "Gleason"))
            :ARG1-of (s4 / statistical-test-91
                  :ARG2 0.002))
      :ARG2 (a2 / and
            :op1 (r / relapse-01
                  :mod (r2 / rapid
                        :degree (m / more))
                  :mod (b / biochemistry))
            :op2 (t / time
                  :mod (d / die-01)
                  :time (a3 / after
                        :op1 r)
                  :ARG1-of (s5 / statistical-test-91
                        :ARG2 0.02))
            :op3 (s2 / survive-01
                  :ARG1-of (s3 / specific-02
                        :ARG2 (d2 / disease))
                  :ARG1-of (s6 / statistical-test-91
                        :ARG2 0.001)))
      :ARG0-of (c / confirm-01
            :ARG1 (a4 / associate-01
                  :ARG1 a2
                  :ARG2 (p / progress-01
                        :ARG1 (d3 / disease :wiki "Prostate_cancer" :name (n2 / name :op1 "prostate" :op2 "cancer"))))))

# ::id pmid_2155_9022.84 ::date 2015-08-07T04:02:06 ::annotator SDL-AMR-09 ::preferred
# ::snt <sec-title level="2">Expression and localisation of Raf-1 and MAPK</sec-title>
# ::save-date Sun Jan 17, 2016 ::file pmid_2155_9022_84.txt
(a / and
      :op1 (e / express-03
            :ARG2 (a2 / and
                  :op1 (e2 / enzyme :name (n / name :op1 "Raf-1"))
                  :op2 (e3 / enzyme :name (n2 / name :op1 "MAPK"))))
      :op2 (l / localize-01
            :ARG1 a2))

# ::id pmid_2155_9022.85 ::date 2015-08-14T02:21:34 ::annotator SDL-AMR-09 ::preferred
# ::snt Raf-1 was observed in the cytoplasm and peri-membrane areas (<xref ref-type="fig" rid="fig1">Figure 1A</xref>), and the inactive form of Raf-1 was found only in the peri-membrane region (<xref ref-type="fig" rid="fig1">Figure 1B</xref>); however, the activated form of Raf-1 was observed in the cytoplasm, nucleus and the cell membrane (<xref ref-type="fig" rid="fig1">Figure 1C</xref>).
# ::save-date Sun Aug 23, 2015 ::file pmid_2155_9022_85.txt
(a / and
      :op1 (a2 / and
            :op1 (o / observe-01
                  :ARG1 (e / enzyme :name (n / name :op1 "Raf-1"))
                  :ARG0-of (d / describe-01
                        :ARG1 (f4 / figure :mod "1A"))
                  :location (a8 / and
                        :op1 (a4 / area
                              :part-of (c / cytoplasm))
                        :op2 (a9 / area
                              :part-of (p / peri-membrane))))
            :op2 (f / find-01
                  :ARG1 (e2 / enzyme :name (n2 / name :op1 "Raf-1")
                        :mod (f2 / form
                              :ARG0-of (a3 / activity-06 :polarity -)))
                  :location (r / region
                        :mod (o3 / only)
                        :part-of p)
                  :ARG0-of (d2 / describe-01
                        :ARG1 (f5 / figure :mod "1B"))))
      :op2 (h / have-concession-91
            :ARG1 (o2 / observe-01
                  :ARG1 (e3 / enzyme :name (n3 / name :op1 "Raf-1")
                        :mod (f3 / form
                              :ARG0-of (a5 / activate-01))))
            :location (a7 / and
                  :op1 c
                  :op2 (n4 / nucleus)
                  :op3 (m / membrane
                        :part-of (c3 / cell)))
            :ARG0-of (d3 / describe-01
                  :ARG1 (f6 / figure :mod "1C"))))

# ::id pmid_2155_9022.86 ::date 2015-08-07T03:06:44 ::annotator SDL-AMR-09 ::preferred
# ::snt Mitogen-activated protein kinase and phosphorylated MAPK (pMAPK) (Thr202/204) were observed in the nucleus and cytoplasm (<xref ref-type="fig" rid="fig1">Figure 1D</xref>).
# ::save-date Sun Jan 17, 2016 ::file pmid_2155_9022_86.txt
(o / observe-01
      :ARG1 (a / and
            :op1 (e2 / enzyme :name (n / name :op1 "mitogen-activated" :op2 "protein" :op3 "kinase"))
            :op2 (a2 / amino-acid :name (n2 / name :op1 "threonine")
                  :part-of (e / enzyme :name (n3 / name :op1 "MAPK"))
                  :ARG3-of (p / phosphorylate-01)
                  :mod (s / slash :op1 202 :op2 204)))
      :location (a3 / and
            :op1 (n5 / nucleus)
            :op2 (c / cytoplasm))
      :ARG0-of (d / describe-01
            :ARG1 (f / figure :mod "1D")))

# ::id pmid_2155_9022.87 ::date 2015-08-11T23:11:35 ::annotator SDL-AMR-09 ::preferred
# ::snt Overall, comparison of HNPC tumours and CRPC tumours revealed no differences in total or average expression levels of either Raf-1 (and all phosphorylated forms) (<xref ref-type="table" rid="tbl1">Table 1</xref>) or MAPK (activated or inactivate, nuclear or cytoplasmic) (<xref ref-type="table" rid="tbl2">Table 2</xref>).
# ::save-date Sun Jan 17, 2016 ::file pmid_2155_9022_87.txt
(r / reveal-01
      :ARG0 (c / compare-01
            :ARG1 (t / tumor
                  :mod (d4 / disease :name (n / name :op1 "HNPC")))
            :ARG2 (t2 / tumor
                  :mod (d5 / disease :name (n2 / name :op1 "CRPC"))))
      :ARG1 (d / differ-02 :polarity -
            :ARG1 (l / level
                  :degree-of (e / express-03
                        :ARG2 (o3 / or
                              :op1 (a2 / and
                                    :op1 (e2 / enzyme :name (n3 / name :op1 "Raf-1"))
                                    :op2 (e3 / enzyme :name (n4 / name :op1 "Raf-1")
                                          :ARG3-of (p / phosphorylate-01))
                                    :ARG1-of (d2 / describe-01
                                          :ARG0 (t4 / table :mod 1)))
                              :op2 (o7 / or
                                    :op1 (o8 / or
                                          :op1 (e7 / enzyme :name (n5 / name :op1 "MAPK")
                                                :ARG1-of (d3 / describe-01
                                                      :ARG0 (t5 / table :mod 2))
                                                :ARG0-of (a3 / activate-01))
                                          :op2 (e4 / enzyme :name (n7 / name :op1 "MAPK")
                                                :ARG0-of (a4 / activate-01 :polarity -)))
                                    :op2 (o9 / or
                                          :op1 (e6 / enzyme :name (n8 / name :op1 "MAPK")
                                                :location (n9 / nucleus))
                                          :op2 (e5 / enzyme :name (n10 / name :op1 "MAPK")
                                                :location (c3 / cytoplasm))))))
                  :ARG1-of (t3 / total-01)
                  :ARG1-of (a / average-01)))
      :mod (o / overall))

# ::id pmid_2155_9022.88 ::date 2015-08-10T11:28:33 ::annotator SDL-AMR-09 ::preferred
# ::snt However, analysis of matched pairs revealed a subgroup that showed significant increases in Raf-1 and MAPK levels in CRPC tumours.
# ::save-date Sun Jan 17, 2016 ::file pmid_2155_9022_88.txt
(h / have-concession-91
      :ARG1 (r / reveal-01
            :ARG0 (a / analyze-01
                  :ARG1 (p / pair
                        :ARG1-of (m / match-01)))
            :ARG1 (s / subgroup
                  :ARG0-of (s2 / show-01
                        :ARG1 (i / increase-01
                              :ARG1 (a3 / and
                                    :op1 (l / level
                                          :quant-of (e3 / enzyme :name (n3 / name :op1 "Raf-1")))
                                    :op2 (l2 / level
                                          :quant-of (e / enzyme :name (n2 / name :op1 "MAPK"))))
                              :ARG1-of (s3 / significant-02))
                        :location (t / tumor
                              :mod (d / disease :name (n / name :op1 "CRPC")))))))

# ::id pmid_2155_9022.89 ::date 2015-08-13T02:18:07 ::annotator SDL-AMR-09 ::preferred
# ::snt We have previously reported that patients whose Raf-1 expression rose in this cohort with the development of CRPC had a significantly shorter time to relapse than those patients who had a fall or no change (<i>P</i>=0.0005) (<xref ref-type="bibr" rid="bib31">Mukherjee <i>et al</i>, 2005</xref>).
# ::save-date Tue Dec 15, 2015 ::file pmid_2155_9022_89.txt
(r / report-01
      :ARG0 (w / we)
      :ARG1 (h / have-03
            :ARG0 (p / person
                  :ARG0-of (h2 / have-rel-role-91
                        :ARG2 (p2 / patient))
                  :poss (e / express-03
                        :ARG2 (e2 / enzyme :name (n / name :op1 "Raf-1"))
                        :ARG1-of (r2 / rise-01
                              :location (c / cohort
                                    :mod (t3 / this))
                              :time (d / develop-01
                                    :ARG2 (d4 / disease :name (n2 / name :op1 "CRPC")))))
                  :ARG1-of (c3 / compare-01
                        :ARG2 (p3 / person
                              :ARG0-of (h3 / have-rel-role-91
                                    :ARG2 (p4 / patient))
                              :mod (t2 / that)
                              :ARG0-of (h4 / have-06
                                    :ARG1 (o / or
                                          :op1 (f / fall-01)
                                          :op2 (c4 / change-01 :polarity -))))))
            :ARG1 (t / time
                  :ARG1-of (s / short-07
                        :degree (m / more))
                  :ARG1-of (s2 / significant-02)
                  :mod (r3 / relapse-01))
            :ARG1-of (s3 / statistical-test-91
                  :ARG2 0.0005))
      :ARG1-of (d2 / describe-01
            :ARG0 (p6 / publication-91
                  :ARG0 (a / and
                        :op1 (p7 / person :name (n3 / name :op1 "Mukherjee"))
                        :op2 (p8 / person
                              :mod (o2 / other)))
                  :time (d3 / date-entity :year 2005)))
      :time (p9 / previous))

# ::id pmid_2155_9022.90 ::date 2015-08-14T00:30:22 ::annotator SDL-AMR-09 ::preferred
# ::snt Consistent with this observation, patients with rising levels of nuclear pRaf (Ser338, activated Raf-1) had a significantly shorter time to biochemical relapse (2.2 years; range: 1.84–2.56 years) by 2.4 years when compared with patients who showed a fall in levels (4.6 years; range: 3.4–5.8 years) (<i>P</i>=0.01) (<xref ref-type="fig" rid="fig2">Figure 2</xref>).
# ::save-date Tue Dec 15, 2015 ::file pmid_2155_9022_90.txt
(h / have-03
      :ARG0 (p / person
            :ARG0-of (h2 / have-rel-role-91
                  :ARG2 (p2 / patient))
            :ARG0-of (h4 / have-03
                  :ARG1 (l / level
                        :quant-of (a / amino-acid :mod 338 :name (n / name :op1 "serine")
                              :part-of (e / enzyme :name (n2 / name :op1 "Raf")
                                    :ARG3-of (p3 / phosphorylate-01)
                                    :mod (n3 / nucleus)
                                    :ARG1-of (m2 / mean-01
                                          :ARG2 (e2 / enzyme :name (n4 / name :op1 "Raf-1")
                                                :ARG1-of (a2 / activate-01)))))
                        :ARG1-of (r2 / rise-01))))
      :ARG1 (t5 / time
            :ARG1-of (s / short-07
                  :degree (m / more)
                  :ARG1-of (s2 / significant-02)
                  :ARG1-of (s4 / statistical-test-91
                        :ARG2 0.01))
            :mod (r / relapse-01
                  :mod (b / biochemistry)
                  :duration (t7 / temporal-quantity :quant 2.4
                        :unit (y5 / year)))
            :ARG1-of (m3 / mean-01
                  :ARG2 (a3 / and
                        :op1 (t / temporal-quantity :quant 2.2
                              :unit y5)
                        :op2 (r3 / range-01
                              :ARG3 (t2 / temporal-quantity :quant 1.84
                                    :unit y5)
                              :ARG4 (t3 / temporal-quantity :quant 2.56
                                    :unit y5)))))
      :ARG1-of (c / consistent-01
            :ARG2 (o / observe-01
                  :mod (t6 / this)))
      :ARG1-of (d / describe-01
            :ARG0 (f2 / figure :mod 2))
      :condition (c2 / compare-01
            :ARG1 p
            :ARG2 (p4 / person
                  :ARG0-of (s3 / show-01
                        :ARG1 (f / fall-01
                              :ARG1 (l2 / level
                                    :ARG1-of (m5 / mean-01
                                          :ARG2 (a4 / and
                                                :op1 (t4 / temporal-quantity :quant 4.6
                                                      :unit y5)
                                                :op2 (r4 / range-01
                                                      :ARG3 (t8 / temporal-quantity :quant 3.4
                                                            :unit y5)
                                                      :ARG4 (t9 / temporal-quantity :quant 5.8
                                                            :unit y5)))))))
                  :ARG0-of h2)))

# ::id pmid_2155_9022.91 ::date 2015-08-14T08:54:56 ::annotator SDL-AMR-09 ::preferred
# ::snt Patients whose nuclear MAPK expression rose with the development of CRPC had a significantly shorter time to death from relapse (1.40 (1.20–1.61) years) compared with samples that showed a fall or no change in expression (3.00 (1.43–4.57) years), <i>P</i>=0.0255 (<xref ref-type="fig" rid="fig3">Figure 3A</xref>).
# ::save-date Sun Jan 17, 2016 ::file pmid_2155_9022_91.txt
(h / have-03
      :ARG0 (p / person
            :ARG0-of (h2 / have-rel-role-91
                  :ARG2 (p2 / patient))
            :poss (e / express-03
                  :ARG2 (e2 / enzyme :name (n / name :op1 "MAPK"))
                  :mod (n2 / nucleus)
                  :ARG1-of (r / rise-01
                        :time (d / develop-01
                              :ARG2 (d4 / disease :name (n3 / name :op1 "CRPC")))))
            :ARG1-of (c2 / compare-01
                  :ARG2 (t8 / thing
                        :ARG1-of (s3 / sample-01
                              :ARG0-of (s4 / show-01
                                    :ARG1 (o / or
                                          :op1 (f / fall-01
                                                :ARG1 e3)
                                          :op2 (c3 / change-01 :polarity -
                                                :ARG1 (e3 / express-03))))
                              :ARG1-of (m4 / mean-01
                                    :ARG2 (t5 / temporal-quantity :quant 3.00
                                          :unit y
                                          :ARG1-of (m5 / mean-01
                                                :ARG2 (v2 / value-interval
                                                      :op1 (t6 / temporal-quantity :quant 1.43
                                                            :unit y)
                                                      :op2 (t7 / temporal-quantity :quant 4.57
                                                            :unit y)))))))))
      :ARG1 (t / time
            :ARG1-of (s / short-07
                  :degree (m / more)
                  :ARG1-of (s2 / significant-02)
                  :ARG1-of (s5 / statistical-test-91
                        :ARG2 0.0255))
            :mod (d2 / die-01
                  :time (a / after
                        :op1 (r2 / relapse-01)))
            :ARG1-of (m2 / mean-01
                  :ARG2 (t2 / temporal-quantity :quant 1.40
                        :unit (y / year)
                        :ARG1-of (m3 / mean-01
                              :ARG2 (v / value-interval
                                    :op1 (t3 / temporal-quantity :quant 1.20
                                          :unit y)
                                    :op2 (t4 / temporal-quantity :quant 1.61
                                          :unit y))))))
      :ARG1-of (d3 / describe-01
            :ARG0 (f2 / figure :mod "3A")))

# ::id pmid_2155_9022.92 ::date 2015-08-10T10:06:30 ::annotator SDL-AMR-09 ::preferred
# ::snt This translated into a shorter disease-specific survival of 3.37 (1.58–5.16 ) years compared with 6.89 (5.70–8.08) years, <i>P</i>=0.0068 (<xref ref-type="fig" rid="fig3">Figure 3B</xref>).
# ::save-date Tue Dec 15, 2015 ::file pmid_2155_9022_92.txt
(t / translate-01
      :ARG1 (t2 / this)
      :ARG2 (s / survive-01
            :ARG1-of (s2 / short-07
                  :degree (m / more))
            :ARG1-of (s3 / specific-02
                  :ARG2 (d / disease))
            :duration (t3 / temporal-quantity :quant 3.37
                  :unit (y / year)
                  :compared-to (t4 / temporal-quantity :quant 6.89
                        :unit y
                        :ARG1-of (m3 / mean-01
                              :ARG2 (v2 / value-interval
                                    :op1 (t5 / temporal-quantity :quant 5.70
                                          :unit y)
                                    :op2 (t6 / temporal-quantity :quant 8.08
                                          :unit y))))
                  :ARG1-of (m2 / mean-01
                        :ARG2 (v / value-interval
                              :op1 (t7 / temporal-quantity :quant 1.58
                                    :unit y)
                              :op2 (t8 / temporal-quantity :quant 5.16
                                    :unit y)))))
      :ARG1-of (d2 / describe-01
            :ARG0 (f / figure :mod "3B"))
      :ARG1-of (s4 / statistical-test-91
            :ARG2 0.0068))

# ::id pmid_2155_9022.93 ::date 2015-08-07T04:21:13 ::annotator SDL-AMR-09 ::preferred
# ::snt Interestingly, there was also an association seen between rising cytoplasmic pMAPK (Thr202/204) expression and reduced time to biochemical relapse (<i>P</i>=0.06).
# ::save-date Sun Jan 17, 2016 ::file pmid_2155_9022_93.txt
(s / see-01
      :ARG1 (a / associate-01
            :ARG1 (e / express-03
                  :ARG2 (a2 / amino-acid :name (n / name :op1 "threonine")
                        :mod (s2 / slash :op1 202 :op2 204)
                        :part-of (e2 / enzyme :name (n2 / name :op1 "MAPK"))
                        :ARG3-of (p / phosphorylate-01)
                        :mod (c / cytoplasm))
                  :ARG1-of (r / rise-01))
            :ARG2 (t / time
                  :ARG1-of (r2 / reduce-01)
                  :mod (r3 / relapse-01
                        :mod (b / biochemistry)))
            :mod (a3 / also)
            :ARG1-of (s3 / statistical-test-91
                  :ARG2 0.06))
      :ARG2-of (i / interest-01))

# ::id pmid_2155_9022.94 ::date 2015-08-08T23:30:26 ::annotator SDL-AMR-09 ::preferred
# ::snt <sec-title level="2">Relative protein expression levels in hormone-naïve prostate cancer</sec-title>
# ::save-date Thu Dec 10, 2015 ::file pmid_2155_9022_94.txt
(l / level
      :ARG1-of (r / relative-05)
      :degree-of (e / express-03
            :ARG2 (p / protein))
      :location (d / disease :name (n / name :op1 "hormone-naive" :op2 "prostate" :op3 "cancer")))

# ::id pmid_2155_9022.95 ::date 2015-08-08T09:16:33 ::annotator SDL-AMR-09 ::preferred
# ::snt In HNPC tumours, Raf-1 correlated with the inactive form, pRaf (Ser259), before relapse (<i>P</i>=0.0041, <i>r</i><sup>2</sup>=0.1201).
# ::save-date Tue Dec 15, 2015 ::file pmid_2155_9022_95.txt
(c / correlate-01
      :ARG1 (e / enzyme :name (n / name :op1 "Raf-1"))
      :ARG2 (a / amino-acid :mod 259 :name (n2 / name :op1 "serine")
            :part-of (e2 / enzyme :name (n3 / name :op1 "Raf"))
            :ARG3-of (p / phosphorylate-01)
            :mod (f / form
                  :ARG1-of (a2 / activity-06 :polarity -)))
      :time (b / before
            :op1 (r / relapse-01))
      :location (t / tumor
            :mod (d / disease :name (n4 / name :op1 "HNPC")))
      :ARG1-of (s / statistical-test-91
            :ARG2 0.0041
            :ARG3 0.1201))

# ::id pmid_2155_9022.96 ::date 2015-08-08T10:18:21 ::annotator SDL-AMR-09 ::preferred
# ::snt Nuclear pRaf (Ser338) and cytoplasmic pRaf (Ser338) strongly correlated with each other (<i>P</i>=0.0035, <i>r</i><sup>2</sup>=0.1381).
# ::save-date Tue Dec 15, 2015 ::file pmid_2155_9022_96.txt
(c / correlate-01
      :ARG1 (a2 / amino-acid :mod 338 :name (n / name :op1 "serine")
            :part-of (e / enzyme :name (n2 / name :op1 "Raf")
                  :mod (n3 / nucleus))
            :ARG3-of (p / phosphorylate-01))
      :ARG2 (a / amino-acid :mod 338 :name (n4 / name :op1 "serine")
            :part-of (e2 / enzyme :name (n5 / name :op1 "Raf")
                  :mod (c2 / cytoplasm)
                  :ARG3-of p))
      :ARG1-of (s / strong-02)
      :ARG1-of (s2 / statistical-test-91
            :ARG2 0.0035
            :ARG3 0.1381))

# ::id pmid_2155_9022.97 ::date 2015-08-08T10:55:26 ::annotator SDL-AMR-09 ::preferred
# ::snt No correlations between total Raf-1 and cytoplasmic pRaf (Ser338) or nuclear pRaf (Ser338) expression were evident.
# ::save-date Wed Aug 19, 2015 ::file pmid_2155_9022_97.txt
(e / evidence-01 :polarity -
      :ARG1 (c / correlate-01
            :ARG1 (e2 / enzyme :name (n / name :op1 "Raf-1")
                  :mod (t / total))
            :ARG2 (o / or
                  :op1 (e3 / express-03
                        :ARG2 (a / amino-acid :mod 338 :name (n2 / name :op1 "serine")
                              :part-of (e4 / enzyme :name (n3 / name :op1 "Raf"))
                              :ARG3-of (p / phosphorylate-01)
                              :mod (c2 / cytoplasm)))
                  :op2 (e5 / express-03
                        :ARG2 (a3 / amino-acid :mod 338 :name (n4 / name :op1 "serine")
                              :part-of (e6 / enzyme :name (n6 / name :op1 "Raf")
                                    :ARG3-of p))
                        :mod (n5 / nucleus)))))

# ::id pmid_2155_9022.98 ::date 2015-08-08T10:40:02 ::annotator SDL-AMR-09 ::preferred
# ::snt In addition no correlations were observed between the inactive form of pRaf (Ser259) and nuclear pRaf (Ser338) or cytoplasmic pRaf (Ser338).
# ::save-date Sun Aug 23, 2015 ::file pmid_2155_9022_98.txt
(a / and
      :op2 (o / observe-01 :polarity -
            :ARG1 (c / correlate-01
                  :ARG1 (a4 / amino-acid :mod 259 :name (n / name :op1 "serine")
                        :part-of (e / enzyme :name (n4 / name :op1 "Raf"))
                        :ARG3-of (p / phosphorylate-01)
                        :mod (f / form
                              :ARG0-of (a2 / activity-06 :polarity -)))
                  :ARG2 (o3 / or
                        :op1 (a5 / amino-acid :mod 338 :name (n3 / name :op1 "serine")
                              :part-of (e2 / enzyme :name (n5 / name :op1 "Raf")
                                    :ARG3-of p)
                              :mod (n2 / nucleus))
                        :op2 (a3 / amino-acid :mod 338 :name (n6 / name :op1 "serine")
                              :part-of (e3 / enzyme :name (n7 / name :op1 "Raf")
                                    :ARG3-of p)
                              :mod (c2 / cytoplasm))))))

# ::id pmid_2155_9022.99 ::date 2015-08-11T23:40:09 ::annotator SDL-AMR-09 ::preferred
# ::snt Total cytoplasmic expression of MAPK correlated with total nuclear expression of MAPK (<i>P</i>=0.0126, <i>r</i><sup>2</sup>=0.1009), activated MAPK (Thr202/204) (<i>P</i>=0.0152, <i>r</i><sup>2</sup>=0.1044) and the cytoplasmic expression of MAPK (Thr202/204) (<i>P</i><0.0001, <i>r</i><sup>2</sup>=0.3391).
# ::save-date Sun Jan 17, 2016 ::file pmid_2155_9022_99.txt
(a2 / and
      :op1 (c / correlate-01
            :ARG1 (e / express-03
                  :ARG2 (e2 / enzyme :name (n / name :op1 "MAPK"))
                  :mod (c2 / cytoplasm))
            :ARG2 (e3 / express-03
                  :ARG2 (e5 / enzyme :name (n2 / name :op1 "MAPK")
                        :mod (n3 / nucleus)
                        :mod (t / total)))
            :ARG1-of (s2 / statistical-test-91
                  :ARG2 0.0126
                  :ARG3 0.1009))
      :op2 (c3 / correlate-01
            :ARG1 e
            :ARG2 (a3 / amino-acid :name (n5 / name :op1 "threonine")
                  :part-of (e4 / enzyme :name (n4 / name :op1 "MAPK"))
                  :mod (s / slash :op1 202 :op2 204))
            :ARG1-of (s3 / statistical-test-91
                  :ARG2 0.0152
                  :ARG3 0.1044))
      :op3 (c4 / correlate-01
            :ARG1 e
            :ARG2 (e6 / express-03
                  :ARG2 (a4 / amino-acid :name (n6 / name :op1 "threonine")
                        :mod s
                        :part-of e2)
                  :mod c2)
            :ARG1-of (s4 / statistical-test-91
                  :ARG2 (l / less-than :op1 0.0001)
                  :ARG3 0.3391)))

# ::id pmid_2155_9022.100 ::date 2015-08-11T00:30:06 ::annotator SDL-AMR-09 ::preferred
# ::snt Total nuclear MAPK expression correlated very strongly with the activated form of MAPK (Thr202/204) in the nucleus (<i>P</i><0.0001, <i>r</i><sup>2</sup>=0.3447) and pMAPK (Thr202/204) in the cytoplasm (<i>P</i>=0.0075, <i>r</i><sup>2</sup>=0.1250).
# ::save-date Sun Jan 17, 2016 ::file pmid_2155_9022_100.txt
(a5 / and
      :op1 (c / correlate-01
            :ARG1 (e / express-03
                  :ARG2 (e2 / enzyme :name (n / name :op1 "MAPK")
                        :mod (t / total))
                  :mod (n2 / nucleus))
            :ARG2 (a / amino-acid :name (n3 / name :op1 "threonine")
                  :mod (s2 / slash :op1 202 :op2 204)
                  :part-of (e3 / enzyme :name (n4 / name :op1 "MAPK")
                        :ARG1-of (a2 / activate-01)))
            :location (n5 / nucleus)
            :ARG1-of (s3 / statistical-test-91
                  :ARG2 0.0001
                  :ARG3 0.3447))
      :op2 (c3 / correlate-01
            :ARG1 e
            :ARG2 (a4 / amino-acid :name (n6 / name :op1 "threonine")
                  :part-of (e4 / enzyme :name (n7 / name :op1 "MAPK")
                        :ARG3-of (p / phosphorylate-01))
                  :mod s2)
            :location (c2 / cytoplasm)
            :ARG1-of (s4 / statistical-test-91
                  :ARG2 0.0075
                  :ARG3 0.1250))
      :ARG1-of (s / strong-02
            :degree (v / very)))

# ::id pmid_2155_9022.101 ::date 2015-08-08T09:38:01 ::annotator SDL-AMR-09 ::preferred
# ::snt Activated cytoplasmic MAPK (Thr202/204) also very strongly associated with its activated expression (MAPK pThr202) in the nucleus (<i>P</i><0.0001, <i>r</i><sup>2</sup>=0.5210).
# ::save-date Sun Jan 17, 2016 ::file pmid_2155_9022_101.txt
(a / associate-01
      :ARG1 (a3 / amino-acid :name (n / name :op1 "threonine")
            :part-of (e2 / enzyme :name (n2 / name :op1 "MAPK")
                  :mod (c / cytoplasm)
                  :ARG1-of (a4 / activate-01))
            :mod (s2 / slash :op1 202 :op2 204))
      :ARG2 (a5 / amino-acid :mod 202 :name (n3 / name :op1 "threonine")
            :ARG3-of (p / phosphorylate-01)
            :part-of (e / enzyme :name (n4 / name :op1 "MAPK"))
            :ARG2-of (e3 / express-03
                  :ARG3 (n5 / nucleus)
                  :ARG1-of (a6 / activate-01)))
      :ARG1-of (s / strong-02
            :degree (v / very))
      :mod (a2 / also)
      :ARG1-of (s3 / statistical-test-91
            :ARG2 (l / less-than :op1 0.0001)
            :ARG3 0.5210))

# ::id pmid_2155_9022.102 ::date 2015-08-08T23:42:55 ::annotator SDL-AMR-09 ::preferred
# ::snt In addition, Raf-1 and pRaf (Ser259) both correlated with the cytoplasmic expression of MAPK (<i>P</i><0.0001, <i>r</i><sup>2</sup>=0.2979 and <i>P</i>=0.0005, <i>r</i><sup>2</sup>=0.1879, respectively) and activated cytoplasmic MAPK (Thr202/204) (<i>P</i>=0.0007, <i>r</i><sup>2</sup>=0.1826 and <i>P</i>=0.0069, <i>r</i><sup>2</sup>=0.1214, respectively).
# ::save-date Sun Jan 17, 2016 ::file pmid_2155_9022_102.txt
(a / and
      :op2 (a4 / and
            :op1 (a7 / and
                  :op1 (c / correlate-01
                        :ARG1 (e / enzyme :name (n / name :op1 "Raf-1"))
                        :ARG2 (e14 / express-03
                              :ARG2 (e4 / enzyme :name (n4 / name :op1 "MAPK"))
                              :ARG3 (c2 / cytoplasm))
                        :ARG1-of (s2 / statistical-test-91
                              :ARG2 (l / less-than :op1 0.0001)
                              :ARG3 0.2979))
                  :op2 (c3 / correlate-01
                        :ARG1 (a5 / amino-acid :mod 259 :name (n2 / name :op1 "serine")
                              :part-of (e3 / enzyme :name (n3 / name :op1 "Raf"))
                              :ARG3-of (p / phosphorylate-01))
                        :ARG2 e14
                        :ARG1-of (s3 / statistical-test-91
                              :ARG2 0.0005
                              :ARG3 0.1879)))
            :op2 (a8 / and
                  :op1 (c4 / correlate-01
                        :ARG1 e
                        :ARG2 (a2 / amino-acid :name (n5 / name :op1 "threonine")
                              :mod (s / slash :op1 202 :op2 204)
                              :part-of (e2 / enzyme :name (n6 / name :op1 "MAPK")
                                    :mod c2)
                              :ARG1-of (a3 / activate-01))
                        :ARG1-of (s4 / statistical-test-91
                              :ARG2 0.0007
                              :ARG3 0.1826))
                  :op2 (c5 / correlate-01
                        :ARG1 a5
                        :ARG2 a2
                        :ARG1-of (s5 / statistical-test-91
                              :ARG2 0.0069
                              :ARG3 0.1214)))))

# ::id pmid_2155_9022.103 ::date 2015-08-06T02:45:32 ::annotator SDL-AMR-09 ::preferred
# ::snt Raf-1 also correlated with nuclear activated MAPK (Thr202/204) (<i>P</i>=0.0022, <i>r</i><sup>2</sup>=0.1525).
# ::save-date Sun Jan 17, 2016 ::file pmid_2155_9022_103.txt
(c / correlate-01
      :ARG1 (e / enzyme :name (n / name :op1 "Raf-1"))
      :ARG2 (e2 / enzyme :name (n2 / name :op1 "MAPK")
            :ARG1-of (a / activate-01)
            :mod (n3 / nucleus)
            :part (a2 / amino-acid :name (n4 / name :op1 "threonine")
                  :mod (s / slash :op1 202 :op2 204)))
      :mod (a4 / also)
      :ARG1-of (s2 / statistical-test-91
            :ARG2 0.0022
            :ARG3 0.1525))

# ::id pmid_2155_9022.104 ::date 2015-08-07T01:06:12 ::annotator SDL-AMR-09 ::preferred
# ::snt There were no correlations seen between pRaf (Ser338) and MAPK or pMAPK (Thr202/204).
# ::save-date Sun Jan 17, 2016 ::file pmid_2155_9022_104.txt
(s / see-01 :polarity -
      :ARG1 (c / correlate-01
            :ARG1 (a / amino-acid :mod 338 :name (n / name :op1 "serine")
                  :part-of (e2 / enzyme :name (n2 / name :op1 "Raf")
                        :ARG3-of (p / phosphorylate-01)))
            :ARG2 (o / or
                  :op1 (e3 / enzyme :name (n3 / name :op1 "MAPK"))
                  :op2 (a2 / amino-acid :name (n4 / name :op1 "threonine")
                        :mod (s2 / slash :op1 202 :op2 204)
                        :part-of (e / enzyme :name (n5 / name :op1 "MAPK")
                              :ARG3-of p)))))

# ::id pmid_2155_9022.105 ::date 2015-07-23T06:03:41 ::annotator SDL-AMR-09 ::preferred
# ::snt <sec-title level="2">Relative protein expression levels in CRPC</sec-title>
# ::save-date Thu Feb 4, 2016 ::file pmid_2155_9022_105.txt
(l / level
      :quant-of (p / protein
            :ARG2-of (e / express-03
                  :ARG3 (d2 / disease :name (n2 / name :op1 "castration-resistant" :op2 "prostate" :op3 "cancer"))))
      :ARG2-of (r / relative-05))

# ::id pmid_2155_9022.106 ::date 2015-07-23T10:46:51 ::annotator SDL-AMR-09 ::preferred
# ::snt In CRPC tumours, Raf-1 correlated with pRaf (Ser259) strongly (<i>P</i>=0.0003, <i>r</i><sup>2</sup>=0.1778).
# ::save-date Tue Dec 15, 2015 ::file pmid_2155_9022_106.txt
(c / correlate-01
      :ARG1 (e / enzyme :wiki "C-Raf"
            :name (n / name :op1 "Raf-1"))
      :ARG2 (a2 / amino-acid :mod 259 :wiki "Serine"
            :name (n4 / name :op1 "serine")
            :part-of (e2 / enzyme :wiki "RAF_kinase"
                  :name (n2 / name :op1 "Raf")
                  :ARG3-of (p / phosphorylate-01)))
      :manner (s / strong-02)
      :location (t / tumor
            :mod (d3 / disease :wiki -
                  :name (n5 / name :op1 "castration-resistant" :op2 "prostate" :op3 "cancer")))
      :ARG1-of (s2 / statistical-test-91 :ARG2 0.0003 :ARG3 0.1778))

# ::id pmid_2155_9022.107 ::date 2015-07-23T12:54:26 ::annotator SDL-AMR-09 ::preferred
# ::snt The nuclear and cytoplasmic forms of pRaf (Ser338) also strongly correlated with each other (<i>P</i><0.0001, <i>r</i><sup>2</sup>=0.6009).
# ::save-date Tue Dec 15, 2015 ::file pmid_2155_9022_107.txt
(c / correlate-01
      :ARG1 (a3 / amino-acid :mod 338 :name (n5 / name :op1 "serine")
            :mod (n2 / nucleus)
            :part-of (e / enzyme :name (n / name :op1 "Raf")
                  :ARG3-of (p / phosphorylate-01)))
      :ARG2 (a / amino-acid :mod 338 :name (n3 / name :op1 "serine")
            :mod (c2 / cytoplasm)
            :part-of e)
      :manner (s / strong-02)
      :mod (a2 / also)
      :ARG1-of (s2 / statistical-test-91
            :ARG2 (l / less-than :op1 0.0001)
            :ARG3 0.6009))

# ::id pmid_2155_9022.108 ::date 2015-07-23T13:40:30 ::annotator SDL-AMR-09 ::preferred
# ::snt Similarly to HNPC, protein expression of the inactive form of pRaf (Ser259) and the active forms of pRaf (Ser338) did not correlate in the cell cytoplasm or nucleus.
# ::save-date Wed Aug 5, 2015 ::file pmid_2155_9022_108.txt
(c / correlate-01 :polarity -
      :ARG1 (e / express-03
            :ARG2 (a2 / amino-acid :mod 259 :wiki "Serine"
                  :name (n2 / name :op1 "serine")
                  :part-of (e2 / enzyme :wiki "RAF_kinase"
                        :name (n / name :op1 "Raf")
                        :ARG3-of (p2 / phosphorylate-01))
                  :ARG0-of (a / activity-06 :polarity -)))
      :ARG2 (e3 / express-03
            :ARG2 (a4 / amino-acid :mod 338 :wiki "Serine"
                  :name (n4 / name :op1 "serine")
                  :ARG0-of (a3 / activity-06)
                  :part-of e2))
      :location (o / or
            :op1 (c2 / cytoplasm
                  :part-of (c3 / cell))
            :op2 (n5 / nucleus
                  :part-of c3))
      :ARG1-of (r / resemble-01
            :ARG2 (d / disease :wiki -
                  :name (n3 / name :op1 "hormone-naive" :op2 "prostate" :op3 "cancer"))))

# ::id pmid_2155_9022.109 ::date 2015-07-23T14:38:53 ::annotator SDL-AMR-09 ::preferred
# ::snt After the development of CRPC, cytoplasmic expression of total MAPK became strongly associated with the expression of total MAPK in the nucleus (<i>P</i>=<0.0001, <i>r</i><sup>2</sup>=0.2564) and more weakly with its activated form, pMAPK (Thr202/204), in the nucleus (<i>P</i>=0.0194, <i>r</i><sup>2</sup>=0.0864).
# ::save-date Sun Jan 17, 2016 ::file pmid_2155_9022_109.txt
(a2 / and
      :op1 (a / associate-01
            :ARG1 (e / express-03
                  :ARG2 (e5 / enzyme :name (n / name :op1 "MAPK")
                        :ARG1-of (t / total-01))
                  :ARG3 (c / cytoplasm))
            :ARG2 (e2 / express-03
                  :ARG2 e5
                  :ARG3 (n5 / nucleus))
            :manner (s / strong-02)
            :ARG1-of (s3 / statistical-test-91
                  :ARG2 (o / or :op1 0.0001
                        :op2 (l / less-than :op1 0.0001))
                  :ARG3 0.2564))
      :op2 (a3 / associate-01
            :ARG1 e
            :ARG2 (e3 / express-03
                  :ARG2 (a5 / amino-acid :name (n4 / name :op1 "threonine")
                        :part-of (e4 / enzyme :name (n3 / name :op1 "MAPK"))
                        :ARG1-of (a4 / activate-01)
                        :mod (s2 / slash :op1 202 :op2 204)
                        :ARG3-of (p / phosphorylate-01))
                  :ARG3 n5)
            :manner (w / weak-02)
            :ARG1-of (s4 / statistical-test-91
                  :ARG2 0.0194
                  :ARG3 0.0864))
      :time (a6 / after
            :op1 (d / develop-02
                  :ARG1 (d4 / disease :name (n2 / name :op1 "castration-resistant" :op2 "prostate" :op3 "cancer")))))

# ::id pmid_2155_9022.110 ::date 2015-07-24T03:56:45 ::annotator SDL-AMR-09 ::preferred
# ::snt Cytoplasmic expression of total MAPK continued to show a correlation with its activated form in the cytoplasm (MAPK pThr202/204) (<i>P</i>=0.0004, <i>r</i><sup>2</sup>=0.1861).
# ::save-date Sun Jan 17, 2016 ::file pmid_2155_9022_110.txt
(c / continue-01
      :ARG0 (e / express-03
            :ARG2 (e3 / enzyme :name (n / name :op1 "MAPK")
                  :mod (t / total))
            :ARG3 (c2 / cytoplasm))
      :ARG1 (s / show-01
            :ARG0 e
            :ARG1 (c3 / correlate-01
                  :ARG1 e
                  :ARG2 (e2 / express-03
                        :ARG2 (a2 / amino-acid :name (n3 / name :op1 "threonine")
                              :part-of (e4 / enzyme :name (n2 / name :op1 "MAPK")
                                    :ARG1-of (a / activate-01))
                              :mod (s2 / slash :op1 202 :op2 204))
                        :ARG3 (c4 / cytoplasm))
                  :ARG1-of (s3 / statistical-test-91
                        :ARG2 0.0004
                        :ARG3 0.1861))))

# ::id pmid_2155_9022.111 ::date 2015-07-24T08:58:03 ::annotator SDL-AMR-09 ::preferred
# ::snt Activated cytoplasmic MAPK (Thr202/204) remained strongly associated with activated nuclear MAPK (Thr202/204) (<i>P</i><0.0001, <i>r</i><sup>2</sup>=0.5350).
# ::save-date Sun Jan 17, 2016 ::file pmid_2155_9022_111.txt
(r / remain-01
      :ARG1 (a / amino-acid :name (n / name :op1 "threonine")
            :part-of (e / enzyme :name (n2 / name :op1 "MAPK"))
            :mod (c / cytoplasm)
            :ARG1-of (a2 / activate-01)
            :mod (s2 / slash :op1 202 :op2 204))
      :ARG2 (a3 / associate-01
            :ARG1 a
            :ARG2 (a4 / amino-acid :name (n3 / name :op1 "threonine")
                  :part-of e
                  :mod (n4 / nucleus)
                  :ARG1-of a2
                  :mod (s3 / slash :op1 202 :op2 204))
            :ARG1-of (s / strong-02)
            :ARG1-of (s4 / statistical-test-91
                  :ARG2 (l / less-than :op1 0.0001)
                  :ARG3 0.5350)))

# ::id pmid_2155_9022.112 ::date 2015-07-24T09:15:01 ::annotator SDL-AMR-09 ::preferred
# ::snt Raf-1 showed similar associations with cytoplasmic and nuclear MAPK expression (<i>P</i><0.0001, <i>r</i><sup>2</sup>=0.2141 and <i>P</i>=0.0016, <i>r</i><sup>2</sup>=0.1426, respectively).
# ::save-date Sun Jan 17, 2016 ::file pmid_2155_9022_112.txt
(s / show-01
      :ARG0 (e / enzyme :name (n / name :op1 "Raf-1"))
      :ARG1 (a5 / and
            :op1 (a / associate-01
                  :ARG1 e
                  :ARG2 (e2 / express-03
                        :ARG2 (e4 / enzyme :name (n2 / name :op1 "MAPK"))
                        :ARG3 (c / cytoplasm))
                  :ARG1-of (r / resemble-01)
                  :ARG1-of (s2 / statistical-test-91
                        :ARG2 (l / less-than :op1 0.0001)
                        :ARG3 0.2141))
            :op2 (a6 / associate-01
                  :ARG1 e
                  :ARG2 (e3 / express-03
                        :ARG2 e4
                        :ARG3 (n3 / nucleus))
                  :ARG1-of r
                  :ARG1-of (s3 / statistical-test-91
                        :ARG2 0.0016
                        :ARG3 0.1426))))

# ::id pmid_2155_9022.113 ::date 2015-07-24T09:32:24 ::annotator SDL-AMR-09 ::preferred
# ::snt Cytoplasmic MAPK also correlated with pRaf (Ser259) (<i>P</i>=0.0026, <i>r</i><sup>2</sup>=0.1329).
# ::save-date Sun Jan 17, 2016 ::file pmid_2155_9022_113.txt
(c / correlate-01
      :ARG1 (e / enzyme :name (n / name :op1 "MAPK")
            :mod (c2 / cytoplasm))
      :ARG2 (a2 / amino-acid :mod 259 :name (n2 / name :op1 "serine")
            :part-of (p3 / protein-family :name (n3 / name :op1 "Raf")
                  :ARG3-of (p2 / phosphorylate-01)))
      :mod (a / also)
      :ARG1-of (s / statistical-test-91
            :ARG2 0.0026
            :ARG3 0.1329))

# ::id pmid_2155_9022.114 ::date 2015-07-24T09:40:32 ::annotator SDL-AMR-09 ::preferred
# ::snt Similarly to HNPC tumours, no correlations were noted between pRaf (Ser338) and MAPK in any location or form.
# ::save-date Sun Jan 17, 2016 ::file pmid_2155_9022_114.txt
(n / note-01 :polarity -
      :ARG1 (c / correlate-01
            :ARG1 (a / amino-acid :mod 338 :name (n2 / name :op1 "serine")
                  :part-of (e2 / enzyme :name (n3 / name :op1 "Raf")
                        :ARG3-of (p / phosphorylate-01)))
            :ARG2 (e / enzyme :name (n4 / name :op1 "MAPK"))
            :location (l / location
                  :mod (a2 / any))
            :manner (f / form
                  :mod (a3 / any)))
      :ARG1-of (r / resemble-01
            :ARG2 (t / tumor
                  :mod (d / disease :name (n5 / name :op1 "hormone-naive" :op2 "prostate" :op3 "cancer")))))

# ::id pmid_2155_9022.115 ::date 2015-07-24T09:54:43 ::annotator SDL-AMR-09 ::preferred
# ::snt <sec-title level="2">Relative expression levels of Raf-1 and MAPK compared with upstream and downstream targets in hormone-naïve prostate cancer</sec-title>
# ::save-date Thu Feb 4, 2016 ::file pmid_2155_9022_115.txt
(c / compare-01
      :ARG1 (l / level
            :degree-of (e / express-03
                  :ARG2 (a / and
                        :op1 (e2 / enzyme :name (n / name :op1 "Raf-1"))
                        :op2 (e3 / enzyme :name (n2 / name :op1 "MAPK")))
                  :ARG2-of (r / relative-05)))
      :ARG2 (a3 / and
            :op1 (t / target-01
                  :location (u / upstream))
            :op2 (t2 / target-01
                  :location (d / downstream)))
      :location (d2 / disease :name (n3 / name :op1 "hormone-naïve" :op2 "prostate" :op3 "cancer")))

# ::id pmid_2155_9022.116 ::date 2015-07-24T10:15:56 ::annotator SDL-AMR-09 ::preferred
# ::snt Analysis of the upstream activators EGFR and Her2, as well as the downstream targets AR and AP-1, has previously been carried out on the same cohort of patients (<xref ref-type="bibr" rid="bib16">Edwards <i>et al</i>, 2003a</xref>, <xref ref-type="bibr" rid="bib17">2004</xref>; <xref ref-type="bibr" rid="bib4">Bartlett <i>et al</i>, 2005</xref>).
# ::save-date Sun Jan 17, 2016 ::file pmid_2155_9022_116.txt
(c / carry-out-03
      :ARG1 (a / analyze-01
            :ARG1 (a4 / and
                  :op1 (a2 / activate-01
                        :ARG0 (a3 / and
                              :op1 (e / enzyme :name (n / name :op1 "EGFR"))
                              :op2 (e2 / enzyme :name (n4 / name :op1 "Her2")))
                        :mod (u / upstream))
                  :op2 (t / target-01
                        :ARG1 (a5 / and
                              :op1 (e3 / enzyme :name (n2 / name :op1 "AR"))
                              :op2 (p2 / protein :name (n3 / name :op1 "AP-1")))
                        :mod (d / downstream))))
      :time (p3 / previous)
      :instrument (c2 / cohort
            :consist-of (p4 / person
                  :ARG0-of (h / have-rel-role-91
                        :ARG2 (p5 / patient)))
            :ARG1-of (s / same-01))
      :ARG1-of (d2 / describe-01
            :ARG0 (a6 / and
                  :op1 (p6 / publication-91
                        :ARG0 (a7 / and
                              :op1 (p7 / person :name (n5 / name :op1 "Edwards"))
                              :op2 (p8 / person
                                    :mod (o / other)))
                        :time (a8 / and
                              :op1 (d4 / date-entity :year 2003)
                              :op2 (d5 / date-entity :year 2004)))
                  :op2 (p9 / publication-91
                        :ARG0 (a9 / and
                              :op1 (p10 / person :name (n9 / name :op1 "Bartlett"))
                              :op2 p8)
                        :time (d3 / date-entity :year 2005)))))

# ::id pmid_2155_9022.117 ::date 2015-07-24T10:34:51 ::annotator SDL-AMR-09 ::preferred
# ::snt We therefore correlated Raf-1 and MAPK expression with these previous results, to determine the differences in the entire pathway in the transition from HNPC to CRPC.
# ::save-date Fri Feb 5, 2016 ::file pmid_2155_9022_117.txt
(c / cause-01
      :ARG1 (c2 / correlate-01
            :ARG0 (w / we)
            :ARG1 (a / and
                  :op1 (e / express-03
                        :ARG2 (e2 / enzyme :name (n / name :op1 "Raf-1")))
                  :op2 (e3 / express-03
                        :ARG2 (e5 / enzyme :name (n2 / name :op1 "MAPK"))))
            :ARG2 (t3 / thing
                  :time (p2 / previous)
                  :mod (t / this)
                  :ARG2-of (r / result-01))
            :purpose (d / determine-01
                  :ARG0 w
                  :ARG1 (d2 / differ-02
                        :ARG3 (p3 / pathway
                              :mod (e4 / entire))
                        :time (t2 / transition-01
                              :ARG2 (d4 / disease :name (n3 / name :op1 "castration-resistant" :op2 "prostate" :op3 "cancer"))
                              :ARG3 (d3 / disease :name (n4 / name :op1 "hormone-naive" :op2 "prostate" :op3 "cancer")))))))

# ::id pmid_2155_9022.118 ::date 2015-07-25T08:53:26 ::annotator SDL-AMR-09 ::preferred
# ::snt In hormone-naïve tumours, expression of the putative growth factor receptor Her2 correlated with Raf-1 expression (<i>P</i>=0.0099, <i>r</i><sup>2</sup>=0.1333) and the nuclear and cytoplasmic expression of pMAPK (Thr202/204) (<i>P</i>=0.0150, <i>r</i><sup>2</sup>=0.1300 and <i>P</i>=0.0017, <i>r</i><sup>2</sup>=0.2074, respectively).
# ::save-date Sun Jan 17, 2016 ::file pmid_2155_9022_118.txt
(c / correlate-01
      :ARG1 (e / express-03
            :ARG2 (e10 / enzyme :name (n7 / name :op1 "growth" :op2 "factor" :op3 "receptor" :op4 "Her2")))
      :ARG2 (a / and
            :op1 (e3 / express-03
                  :ARG2 (e4 / enzyme :name (n3 / name :op1 "Raf-1"))
                  :ARG1-of (s2 / statistical-test-91
                        :ARG2 0.0099
                        :ARG3 0.1333))
            :op2 (a2 / and
                  :op1 (e5 / express-03
                        :ARG2 (a3 / amino-acid :name (n5 / name :op1 "threonine")
                              :part-of (e2 / enzyme :name (n6 / name :op1 "MAPK")
                                    :ARG3-of (p3 / phosphorylate-01))
                              :mod (s / slash :op1 202 :op2 204))
                        :ARG3 (n4 / nucleus)
                        :ARG1-of (s3 / statistical-test-91
                              :ARG2 0.0150
                              :ARG3 0.0150))
                  :op2 (e6 / express-03
                        :ARG2 a3
                        :ARG3 (c2 / cytoplasm)
                        :ARG1-of (s4 / statistical-test-91
                              :ARG2 0.0017
                              :ARG3 0.2074))))
      :location (t / tumor
            :mod (h / hormone-naive)))

# ::id pmid_2155_9022.119 ::date 2015-07-25T09:31:20 ::annotator SDL-AMR-09 ::preferred
# ::snt Once activated, the phosphorylated form of Her2 (pHer2) showed moderate correlations with Raf-1 (<i>P</i>=0.0056, <i>r</i><sup>2</sup>=0.1435), pRaf (Ser259) (<i>P</i>=0.0052, <i>r</i><sup>2</sup>=0.1459) and cytoplasmic MAPK expression (<i>P</i>=0.0123, <i>r</i><sup>2</sup>=0.1211) (<xref ref-type="fig" rid="fig4">Figure 4</xref>), but not the activated forms of Raf or MAPK.
# ::save-date Sun Jan 17, 2016 ::file pmid_2155_9022_119.txt
(c3 / contrast-01
      :ARG1 (s / show-01
            :ARG0 (e / enzyme :name (n / name :op1 "Her2")
                  :ARG3-of (p / phosphorylate-01))
            :ARG1 (a6 / and
                  :op1 (c / correlate-01
                        :ARG1 e
                        :ARG2 (e2 / enzyme :name (n2 / name :op1 "Raf-1"))
                        :ARG1-of (m / moderate-03)
                        :ARG1-of (s3 / statistical-test-91
                              :ARG2 0.0056
                              :ARG3 0.1435))
                  :op2 (c6 / correlate-01
                        :ARG1 e
                        :ARG2 (a3 / amino-acid :mod 259 :name (n4 / name :op1 "serine")
                              :part-of (e3 / enzyme :name (n3 / name :op1 "Raf")
                                    :ARG3-of p))
                        :ARG1-of (s4 / statistical-test-91
                              :ARG2 0.0052
                              :ARG3 0.1459))
                  :op3 (c7 / correlate-01
                        :ARG1 e
                        :ARG2 (e4 / express-03
                              :ARG2 (e7 / enzyme :name (n5 / name :op1 "MAPK"))
                              :ARG3 (c2 / cytoplasm))
                        :ARG1-of (s5 / statistical-test-91
                              :ARG2 0.0123
                              :ARG3 0.1211)))
            :ARG1-of (d / describe-01
                  :ARG0 (f / figure :mod 4))
            :time (a / activate-01
                  :ARG1 e))
      :ARG2 (s2 / show-01 :polarity -
            :ARG0 e
            :ARG1 (c4 / correlate-01
                  :ARG1 e
                  :ARG2 (a4 / and
                        :op1 (e5 / enzyme :name (n6 / name :op1 "Raf")
                              :ARG1-of (a5 / activate-01))
                        :op2 (e6 / enzyme :name (n7 / name :op1 "MAPK")
                              :ARG1-of a5)))))

# ::id pmid_2155_9022.120 ::date 2015-07-25T10:05:40 ::annotator SDL-AMR-09 ::preferred
# ::snt No correlations were seen with EGFR in HNPC tumours, except weak correlations with Raf-1 (<i>P</i>=0.0439, <i>r</i><sup>2</sup>=0.06008) and pMAPK (Thr202/204) (nuclear) (<i>P</i>=0.0243, <i>r</i><sup>2</sup>=0.0844).
# ::save-date Sun Jan 17, 2016 ::file pmid_2155_9022_120.txt
(s / see-01
      :ARG1 (c / correlate-01 :polarity -
            :ARG2 (e / enzyme :name (n / name :op1 "EGFR"))
            :ARG2-of (e2 / except-01
                  :ARG1 (a3 / and
                        :op1 (c2 / correlate-01
                              :ARG1 e
                              :ARG2 (e3 / enzyme :name (n2 / name :op1 "Raf-1"))
                              :ARG1-of (s3 / statistical-test-91
                                    :ARG2 0.0439
                                    :ARG3 0.06008))
                        :op2 (c4 / correlate-01
                              :ARG1 e
                              :ARG2 (a2 / amino-acid :name (n3 / name :op1 "threonine")
                                    :part-of (e4 / enzyme :name (n4 / name :op1 "MAPK")
                                          :ARG3-of (p3 / phosphorylate-01))
                                    :mod (n5 / nucleus)
                                    :mod (s2 / slash :op1 202 :op2 204))
                              :ARG1-of (s4 / statistical-test-91
                                    :ARG2 0.0243
                                    :ARG3 0.0844))
                        :ARG1-of (w / weak-02))))
      :location (t / tumor
            :mod (d / disease :name (n6 / name :op1 "hormone-naive" :op2 "prostate" :op3 "cancer"))))

# ::id pmid_2155_9022.121 ::date 2015-07-25T10:30:45 ::annotator SDL-AMR-09 ::preferred
# ::snt However, the mutant variant, EGFR vIII, did correlate strongly with cytoplasmic expression of MAPK (<i>P</i><0.0001, <i>r</i><sup>2</sup>=0.2617) and to a weaker extent with Raf-1 (<i>P</i>=0.025, <i>r</i><sup>2</sup>=0.07965) and pRaf (Ser259) (<i>P</i>=0.0323, <i>r</i><sup>2</sup>=0.07295).
# ::save-date Sun Jan 17, 2016 ::file pmid_2155_9022_121.txt
(c4 / contrast-01
      :ARG2 (a / and
            :op1 (c / correlate-01
                  :ARG1 (v / variant
                        :ARG2-of (m / mutate-01)
                        :ARG1-of (d / describe-01
                              :ARG2 (e / enzyme :name (n / name :op1 "EGFR" :op2 "vIII"))))
                  :ARG2 (e2 / express-03
                        :ARG2 (e6 / enzyme :name (n2 / name :op1 "MAPK"))
                        :ARG3 (c2 / cytoplasm))
                  :manner (s / strong-02)
                  :ARG1-of (s2 / statistical-test-91
                        :ARG2 (l / less-than :op1 0.0001)
                        :ARG3 0.2617))
            :op2 (c3 / correlate-01
                  :ARG1 v
                  :ARG2 (a2 / and
                        :op1 (e4 / enzyme :name (n3 / name :op1 "Raf-1")
                              :ARG1-of (s3 / statistical-test-91
                                    :ARG2 0.025
                                    :ARG3 0.07965))
                        :op2 (a3 / amino-acid :mod 259 :name (n4 / name :op1 "serine")
                              :part-of (e5 / enzyme :name (n5 / name :op1 "Raf")
                                    :ARG3-of (p4 / phosphorylate-01))
                              :ARG1-of (s4 / statistical-test-91
                                    :ARG2 0.0323
                                    :ARG3 0.07295)))
                  :degree (e3 / extent
                        :ARG1-of (w / weak-02)))))

# ::id pmid_2155_9022.122 ::date 2015-07-26T03:19:12 ::annotator SDL-AMR-09 ::preferred
# ::snt Further downstream, activated pRaf (Ser338) in the cytoplasm strongly correlated with phosphorylated c-jun (<i>P</i>=0.0009, <i>r</i><sup>2</sup>=0.2673) and total MAPK (cytoplasmic) correlated weakly with c-Fos (<i>P</i>=0.0453, <i>r</i><sup>2</sup>=0.09418) (<xref ref-type="fig" rid="fig5">Figure 5</xref>).
# ::save-date Tue Dec 15, 2015 ::file pmid_2155_9022_122.txt
(a3 / and
      :op1 (c / correlate-01
            :ARG1 (a / amino-acid :mod 338 :name (n2 / name :op1 "serine")
                  :part-of (e / enzyme :name (n / name :op1 "Raf")
                        :ARG3-of (p / phosphorylate-01)
                        :ARG1-of (a2 / activate-01
                              :location (c2 / cytoplasm))))
            :ARG2 (p2 / protein :name (n3 / name :op1 "c-jun")
                  :ARG3-of p)
            :manner (s / strong-02)
            :ARG1-of (s2 / statistical-test-91
                  :ARG2 0.0009
                  :ARG3 0.2673))
      :op2 (c3 / correlate-01
            :ARG1 (e4 / enzyme :name (n4 / name :op1 "MAPK")
                  :mod (c4 / cytoplasm)
                  :mod (t / total))
            :ARG2 (p5 / protein :name (n5 / name :op1 "c-Fos"))
            :ARG1-of (w / weak-02)
            :ARG1-of (s3 / statistical-test-91
                  :ARG2 0.0453
                  :ARG3 0.09418))
      :location (d / downstream
            :degree (f / further))
      :ARG1-of (d2 / describe-01
            :ARG0 (f2 / figure :mod 5)))

# ::id pmid_2155_9022.123 ::date 2015-07-26T03:44:50 ::annotator SDL-AMR-09 ::preferred
# ::snt There were no correlations seen between MAPK and its activated form with c-jun, phospho c-Jun or c-Fos.
# ::save-date Sun Jan 17, 2016 ::file pmid_2155_9022_123.txt
(s / see-01
      :ARG1 (c / correlate-01 :polarity -
            :ARG1 (a / and
                  :op1 (e / enzyme :name (n / name :op1 "MAPK"))
                  :op2 (e2 / enzyme :name (n2 / name :op1 "MAPK")
                        :ARG1-of (a2 / activate-01)))
            :ARG2 (o / or
                  :op1 (p3 / protein :name (n3 / name :op1 "c-jun"))
                  :op2 (p4 / protein :name (n4 / name :op1 "c-Jun")
                        :ARG3-of (p5 / phosphorylate-01))
                  :op3 (p6 / protein :name (n5 / name :op1 "c-Fos")))))

# ::id pmid_2155_9022.124 ::date 2015-07-26T03:52:13 ::annotator SDL-AMR-09 ::preferred
# ::snt In addition, PSA showed weak correlations with Raf-1 (<i>P</i>=0.0142, <i>r</i><sup>2</sup>=0.09604), pRaf (Ser259) (<i>P</i>=0.043, <i>r</i><sup>2</sup>=0.06547), and showed links to overall MAPK levels, MAPK (nuclear) (<i>P</i>=0.0029, <i>r</i><sup>2</sup>=0.1502) and MAPK (cytoplasmic) (<i>P</i><0.0001, <i>r</i><sup>2</sup>=0.2467), with strong ties to the activated forms, pMAPK (Thr202/204) (cytoplasmic) (<i>P</i><0.0001, <i>r</i><sup>2</sup>=0.2891) and pMAPK (Thr202/204) (nuclear) (<i>P</i>=0.0001, <i>r</i><sup>2</sup>=0.2233) (<xref ref-type="fig" rid="fig6">Figure 6</xref>), whereas AR showed no correlations with Raf, MAPK or any of their forms.
# ::save-date Sun Jan 17, 2016 ::file pmid_2155_9022_124.txt
(a / and
      :op2 (c4 / contrast-01
            :ARG1 (s / show-01
                  :ARG0 (e4 / enzyme :name (n14 / name :op1 "PSA"))
                  :ARG1 (a3 / and
                        :op1 (c / correlate-01
                              :ARG1 e4
                              :ARG2 (a5 / and
                                    :op1 (e / enzyme :name (n / name :op1 "Raf-1")
                                          :ARG1-of (s5 / statistical-test-91
                                                :ARG2 0.0142
                                                :ARG3 0.09604))
                                    :op2 (a6 / amino-acid :mod 259 :name (n2 / name :op1 "serine")
                                          :part-of (e6 / enzyme :name (n3 / name :op1 "Raf")
                                                :ARG3-of (p2 / phosphorylate-01))
                                          :ARG1-of (s6 / statistical-test-91
                                                :ARG2 0.043
                                                :ARG3 0.06547)))
                              :ARG1-of (w / weak-02))
                        :op2 (l / link-01
                              :ARG1 e4
                              :ARG2 (a13 / and
                                    :op1 (l2 / level
                                          :quant-of (e2 / enzyme :name (n4 / name :op1 "MAPK"))
                                          :mod (o / overall))
                                    :op2 (e3 / enzyme :name (n5 / name :op1 "MAPK")
                                          :mod (n6 / nucleus)
                                          :ARG1-of (s7 / statistical-test-91
                                                :ARG2 0.0029
                                                :ARG3 0.1502))
                                    :op3 (e10 / enzyme :name (n7 / name :op1 "MAPK")
                                          :mod (c2 / cytoplasm)
                                          :ARG1-of (s8 / statistical-test-91
                                                :ARG2 (l3 / less-than :op1 0.0001)
                                                :ARG3 0.2467))))
                        :op3 (t / tie-01
                              :ARG1 e4
                              :ARG2 (a8 / and
                                    :op1 (a9 / amino-acid :name (n8 / name :op1 "threonine")
                                          :part-of (e9 / enzyme :quant 0.0001 :name (n9 / name :op1 "MAPK")
                                                :ARG3-of (p11 / phosphorylate-01))
                                          :mod (c3 / cytoplasm)
                                          :mod (s4 / slash :op1 202 :op2 204)
                                          :ARG1-of (s9 / statistical-test-91
                                                :ARG2 (l4 / less-than :op1 0.0001)
                                                :ARG3 0.2891))
                                    :op2 (a10 / amino-acid :name (n10 / name :op1 "threonine")
                                          :part-of e9
                                          :mod (n11 / nucleus)
                                          :mod s4
                                          :ARG1-of (s10 / statistical-test-91
                                                :ARG2 0.0001
                                                :ARG3 0.2233))
                                    :ARG1-of (a7 / activate-01))
                              :ARG1-of (s2 / strong-02)))
                  :ARG1-of (d3 / describe-01
                        :ARG2 (f2 / figure :mod 6)))
            :ARG2 (s3 / show-01
                  :ARG0 (e5 / enzyme :name (n15 / name :op1 "AR"))
                  :ARG2 (c5 / correlate-01 :polarity -
                        :ARG1 e5
                        :ARG2 (o2 / or
                              :op1 (e8 / enzyme :name (n12 / name :op1 "Raf"))
                              :op2 (e7 / enzyme :name (n13 / name :op1 "MAPK"))
                              :op3 (f3 / form
                                    :mod (a11 / any)
                                    :poss (a12 / and
                                          :op1 e8
                                          :op2 e7)))))))

# ::id pmid_2155_9022.125 ::date 2015-07-26T05:33:16 ::annotator SDL-AMR-09 ::preferred
# ::snt <sec-title level="2">Relative expression levels of Raf-1 and MAPK compared with upstream and downstream targets in CRPC</sec-title>
# ::save-date Thu Feb 4, 2016 ::file pmid_2155_9022_125.txt
(c / compare-01
      :ARG1 (l / level
            :ARG2-of (r / relative-05)
            :degree-of (e / express-03
                  :ARG2 (a / and
                        :op1 (e2 / enzyme :name (n / name :op1 "Raf-1"))
                        :op2 (e3 / enzyme :name (n2 / name :op1 "MAPK")))))
      :ARG2 (a2 / and
            :op1 (t / target-01
                  :mod (u / upstream))
            :op2 (t2 / target-01
                  :mod (d / downstream)))
      :location (d2 / disease :name (n3 / name :op1 "castration-resistant" :op2 "prostate" :op3 "cancer")))

# ::id pmid_2155_9022.126 ::date 2015-07-26T05:44:01 ::annotator SDL-AMR-09 ::preferred
# ::snt After the development of CRPC, Her2 no longer showed a correlation with Raf-1 nor a negative association became evident between pRaf (Ser338) both in the cytoplasm (<i>P</i>=0.0035, <i>r</i><sup>2</sup>=0.1854) and nucleus (<i>P</i>=0.0068, <i>r</i><sup>2</sup>=0.1581) with Her2.
# ::save-date Fri Feb 5, 2016 ::file pmid_2155_9022_126.txt
(a / and
      :op1 (s / show-01
            :ARG0 (e / enzyme :name (n / name :op1 "Her2"))
            :ARG1 (c / correlate-01
                  :ARG1 e
                  :ARG2 (e2 / enzyme :name (n3 / name :op1 "Raf-1")))
            :time (n2 / no-longer))
      :op2 (e3 / evident :polarity -
            :domain (a2 / associate-01
                  :ARG1 (a3 / amino-acid :mod 338 :name (n5 / name :op1 "serine")
                        :part-of (e4 / enzyme :name (n6 / name :op1 "Raf")
                              :ARG3-of (p / phosphorylate-01))
                        :location (a4 / and
                              :op1 (c2 / cytoplasm
                                    :ARG1-of (s2 / statistical-test-91
                                          :ARG2 0.0035
                                          :ARG3 0.1854))
                              :op2 (n7 / nucleus
                                    :ARG1-of (s3 / statistical-test-91
                                          :ARG2 0.0068
                                          :ARG3 0.1581))))
                  :ARG2 e
                  :ARG2-of (n4 / negative-01)))
      :time (a5 / after
            :op1 (d / develop-01
                  :ARG2 (d2 / disease :name (n9 / name :op1 "castration-resistant" :op2 "prostate" :op3 "cancer")))))

# ::id pmid_2155_9022.127 ::date 2015-07-26T07:15:42 ::annotator SDL-AMR-09 ::preferred
# ::snt In addition, the activated form (pHer2) correlated with pRaf (Ser259) (<i>P</i>=0.0008, <i>r</i><sup>2</sup>=0.2011).
# ::save-date Tue Dec 15, 2015 ::file pmid_2155_9022_127.txt
(a / and
      :op2 (c / correlate-01
            :ARG1 (f / form
                  :ARG1-of (a2 / activate-01)
                  :ARG1-of (d / describe-01
                        :ARG2 (e / enzyme :name (n / name :op1 "Her2")
                              :ARG3-of (p / phosphorylate-01))))
            :ARG2 (a3 / amino-acid :mod 259 :name (n2 / name :op1 "serine")
                  :part-of (e2 / enzyme :name (n3 / name :op1 "Raf")
                        :ARG3-of p))
            :ARG1-of (s / statistical-test-91
                  :ARG2 0.0008
                  :ARG3 0.02011)))

# ::id pmid_2155_9022.128 ::date 2015-07-26T07:24:29 ::annotator SDL-AMR-09 ::preferred
# ::snt Interestingly, the activated cytoplasmic form of Raf showed a positive weak correlation with the pHer2 (<i>P</i>=0.0363, <i>r</i><sup>2</sup>=0.09376) (<xref ref-type="fig" rid="fig7">Figure 7</xref>).
# ::save-date Tue Dec 15, 2015 ::file pmid_2155_9022_128.txt
(s / show-01
      :ARG0 (e / enzyme :name (n / name :op1 "Raf")
            :mod (c / cytoplasm)
            :ARG1-of (a / activate-01))
      :ARG1 (c2 / correlate-01
            :ARG1 e
            :ARG2 (e2 / enzyme :name (n2 / name :op1 "Her2")
                  :ARG3-of (p2 / phosphorylate-01))
            :mod (p / positive)
            :ARG1-of (w / weak-02)
            :ARG1-of (s2 / statistical-test-91
                  :ARG2 0.0363
                  :ARG3 0.09376))
      :ARG1-of (d / describe-01
            :ARG0 (f2 / figure :mod 7))
      :ARG0-of (i / interest-01))

# ::id pmid_2155_9022.129 ::date 2015-07-26T07:35:47 ::annotator SDL-AMR-09 ::preferred
# ::snt Furthermore, no correlations were evident between Her2 or pHer2 with MAPK in any form.
# ::save-date Sun Jan 17, 2016 ::file pmid_2155_9022_129.txt
(a3 / and
      :op2 (e / evident
            :domain (c / correlate-01 :polarity -
                  :ARG1 (a / and
                        :op1 (e2 / enzyme :name (n / name :op1 "Her2"))
                        :op2 (e3 / enzyme :name (n2 / name :op1 "Her2")
                              :ARG3-of (p / phosphorylate-01)))
                  :ARG2 (f / form
                        :mod (a2 / any)
                        :mod (e4 / enzyme :name (n3 / name :op1 "MAPK"))))))

# ::id pmid_2155_9022.130 ::date 2015-07-26T07:47:00 ::annotator SDL-AMR-09 ::preferred
# ::snt All associations between EGFR and EGFR vIII disappeared after progression to CRPC.
# ::save-date Sun Aug 2, 2015 ::file pmid_2155_9022_130.txt
(d / disappear-01
      :ARG1 (a / associate-01
            :ARG1 (e / enzyme :name (n / name :op1 "EGFR"))
            :ARG2 (e2 / enzyme :name (n2 / name :op1 "EGFR" :op2 "vIII"))
            :mod (a2 / all))
      :time (a3 / after
            :op1 (p / progress-01
                  :ARG4 (d2 / disease :name (n3 / name :op1 "castration-resistant" :op2 "prostate" :op3 "cancer")))))

# ::id pmid_2155_9022.131 ::date 2015-07-26T08:00:19 ::annotator SDL-AMR-09 ::preferred
# ::snt A moderate positive correlation was seen between pRaf (Ser259) and AR (<i>P</i>=0.0035, <i>r</i><sup>2</sup>=0.1154), whereas a negative correlation is evident between nuclear MAPK and AR (<i>P</i>=0.0429, <i>r</i><sup>2</sup>=0.06066).
# ::save-date Fri Feb 5, 2016 ::file pmid_2155_9022_131.txt
(c / contrast-01
      :ARG1 (s / see-01
            :ARG1 (c2 / correlate-01
                  :ARG1 (a / amino-acid :mod 259 :name (n2 / name :op1 "serine")
                        :part-of (e4 / enzyme :name (n / name :op1 "Raf")
                              :ARG3-of (p2 / phosphorylate-01)))
                  :ARG2 (e3 / enzyme :name (n3 / name :op1 "AR"))
                  :ARG1-of (m / moderate-03)
                  :mod (p / positive)
                  :ARG1-of (s2 / statistical-test-91
                        :ARG2 0.0035
                        :ARG3 0.1154)))
      :ARG2 (e2 / evidence-01
            :ARG1 (c3 / correlate-01
                  :ARG1 (e / enzyme :name (n5 / name :op1 "MAPK")
                        :mod (n6 / nucleus))
                  :ARG2 e3
                  :ARG2-of (n4 / negative-01)
                  :ARG1-of (s3 / statistical-test-91
                        :ARG2 0.0429
                        :ARG3 0.06066))))

# ::id pmid_2155_9022.132 ::date 2015-07-26T12:55:49 ::annotator SDL-AMR-09 ::preferred
# ::snt There was no correlation (positive or negative) shown between total Raf-1 expression and AR.
# ::save-date Fri Feb 5, 2016 ::file pmid_2155_9022_132.txt
(s / show-01
      :ARG1 (c / correlate-01 :polarity -
            :ARG1 (e / express-03
                  :ARG2 (e2 / enzyme :name (n2 / name :op1 "Raf-1")
                        :mod (t / total)))
            :ARG2 (e3 / enzyme :name (n3 / name :op1 "AR"))
            :mod (o / or
                  :op1 (p / positive)
                  :op2 (n / negative-01))))

# ::id pmid_2155_9022.133 ::date 2015-07-26T13:03:58 ::annotator SDL-AMR-09 ::preferred
# ::snt In addition, there were no correlations noted between either Raf-1 (any form) or MAPK (any form) and PSA level.
# ::save-date Sun Jan 17, 2016 ::file pmid_2155_9022_133.txt
(a / and
      :op2 (n / note-01
            :ARG1 (c / correlate-01 :polarity -
                  :ARG1 (o / or
                        :op1 (f / form
                              :mod (a2 / any)
                              :mod (e / enzyme :name (n2 / name :op1 "Raf-1")))
                        :op2 (f2 / form
                              :mod (a3 / any)
                              :mod (e3 / enzyme :name (n3 / name :op1 "MAPK"))))
                  :ARG2 (l / level
                        :quant-of (e2 / enzyme :name (n4 / name :op1 "PSA"))))))

# ::id pmid_2155_9022.134 ::date 2015-07-26T13:18:55 ::annotator SDL-AMR-09 ::preferred
# ::snt More correlations were noted with components of the downstream transcription factor AP-1.
# ::save-date Sun Jul 26, 2015 ::file pmid_2155_9022_134.txt
(n / note-01
      :ARG1 (c / correlate-01
            :ARG2 (c2 / component
                  :part-of (p / protein :name (n2 / name :op1 "AP-1")
                        :location (d / downstream)
                        :mod (f / factor)
                        :ARG1-of (t / transcribe-01)))
            :quant (m / more)))

# ::id pmid_2155_9022.135 ::date 2015-07-26T13:30:24 ::annotator SDL-AMR-09 ::preferred
# ::snt Correlations were evident between phosphorylated c-jun and cytoplasmic pRaf (Ser338) (<i>P</i>=0.0026, <i>r</i><sup>2</sup>=0.2192) and pRaf (Ser259) (<i>P</i>=0.0278, <i>r</i><sup>2</sup>=0.1077).
# ::save-date Tue Dec 15, 2015 ::file pmid_2155_9022_135.txt
(e / evidence-01
      :ARG1 (a4 / and
            :op1 (c / correlate-01
                  :ARG1 (p / protein :name (n / name :op1 "c-jun")
                        :ARG3-of (p2 / phosphorylate-01))
                  :ARG2 (a2 / amino-acid :mod 338 :name (n2 / name :op1 "serine")
                        :part-of (e2 / enzyme :name (n3 / name :op1 "Raf")
                              :ARG3-of (p3 / phosphorylate-01))
                        :mod (c2 / cytoplasm))
                  :ARG1-of (s / statistical-test-91
                        :ARG2 0.0026
                        :ARG3 0.2192))
            :op2 (c4 / correlate-01
                  :ARG1 p
                  :ARG2 (a3 / amino-acid :mod 259 :name (n4 / name :op1 "serine")
                        :part-of e2)
                  :ARG1-of (s2 / statistical-test-91
                        :ARG2 0.0278
                        :ARG3 0.1077))))

# ::id pmid_2155_9022.136 ::date 2015-07-26T13:43:33 ::annotator SDL-AMR-09 ::preferred
# ::snt There was also a correlation seen between Raf-1 and c-Fos (<i>P</i>=0.0131, <i>r</i><sup>2</sup>=0.1512), and between the nuclear and cytoplasmic expression of pMAPK (Thr202/204) and c-jun (<i>P</i>=0.0146, <i>r</i><sup>2</sup>=0.1368 and <i>P</i>=0.0178, <i>r</i><sup>2</sup>=0.1295, respectively) (<xref ref-type="fig" rid="fig8">Figure 8</xref>).
# ::save-date Sun Jan 17, 2016 ::file pmid_2155_9022_136.txt
(s / see-01
      :ARG1 (a / and
            :op1 (c / correlate-01
                  :ARG1 (e / enzyme :name (n / name :op1 "Raf-1"))
                  :ARG2 (p / protein :name (n2 / name :op1 "c-Fos"))
                  :ARG1-of (s3 / statistical-test-91
                        :ARG2 0.0131
                        :ARG3 0.1512))
            :op2 (c3 / correlate-01
                  :ARG1 (a2 / and
                        :op1 (e2 / express-03
                              :ARG2 (a3 / amino-acid :name (n3 / name :op1 "threonine")
                                    :part-of (e4 / enzyme :name (n5 / name :op1 "MAPK")
                                          :ARG3-of (p4 / phosphorylate-01))
                                    :mod (s2 / slash :op1 202 :op2 204))
                              :ARG3 (n4 / nucleus)
                              :ARG1-of (s4 / statistical-test-91
                                    :ARG2 0.0146
                                    :ARG3 0.1368))
                        :op2 (e3 / express-03
                              :ARG2 a3
                              :ARG3 (c2 / cytoplasm)
                              :ARG1-of (s5 / statistical-test-91
                                    :ARG2 0.0178
                                    :ARG3 0.1295)))
                  :ARG2 (p5 / protein :name (n6 / name :op1 "c-jun")))
            :ARG1-of (d / describe-01
                  :ARG0 (f / figure :mod 8)))
      :mod (a6 / also))

# ::id pmid_2246_3874.1 ::date 2015-08-05T10:41:21 ::annotator SDL-AMR-09 ::preferred
# ::snt Prognostic value of RKIP and p-ERK in gastric cancer (PMID:22463874)
# ::save-date Sat Jan 16, 2016 ::file pmid_2246_3874_1.txt
(v / value-01
      :ARG1 (a / and
            :op1 (p2 / protein :name (n / name :op1 "RKIP"))
            :op2 (e / enzyme :name (n2 / name :op1 "ERK")
                  :ARG3-of (p3 / phosphorylate-01)))
      :mod (p / prognostic)
      :ARG1-of (d / describe-01
            :ARG0 (p4 / publication-91
                  :ARG8 "PMID22463874"))
      :location (d2 / disease :wiki "Stomach_cancer" :name (n3 / name :op1 "stomach" :op2 "cancer")))

# ::id pmid_2246_3874.8 ::date 2015-08-08T09:55:30 ::annotator SDL-AMR-09 ::preferred
# ::snt <sec-title level="1" sec-area="abstract">Results</sec-title>
# ::save-date Sat Aug 8, 2015 ::file pmid_2246_3874_8.txt
(t / thing
      :ARG2-of (r / result-01))

# ::id pmid_2246_3874.9 ::date 2015-08-08T10:30:48 ::annotator SDL-AMR-09 ::preferred
# ::snt Expression of RKIP, p-MEK, and p-ERK was found in 69 (66%), 54 (51%), and 64 (61%) of all tumours, respectively.
# ::save-date Sat Jan 16, 2016 ::file pmid_2246_3874_9.txt
(f / find-01
      :ARG1 (a2 / and
            :op1 (e / express-03
                  :ARG2 (p / protein :name (n / name :op1 "RKIP"))
                  :ARG3 (t / tumor :quant 69
                        :ARG1-of (i / include-91
                              :ARG2 (t2 / tumor
                                    :mod (a / all))
                              :ARG3 (p2 / percentage-entity :value 66))))
            :op2 (e2 / express-03
                  :ARG2 (e3 / enzyme :name (n2 / name :op1 "MEK")
                        :ARG3-of (p3 / phosphorylate-01))
                  :ARG3 (t3 / tumor :quant 54
                        :ARG1-of (i2 / include-91
                              :ARG2 t2
                              :ARG3 (p4 / percentage-entity :value 51))))
            :op3 (e4 / express-03
                  :ARG2 (e5 / enzyme :name (n3 / name :op1 "ERK")
                        :ARG3-of p3)
                  :ARG3 (t4 / tumor :quant 64
                        :ARG1-of (i3 / include-91
                              :ARG2 t2
                              :ARG3 (p6 / percentage-entity :value 61))))))

# ::id pmid_2246_3874.10 ::date 2015-08-08T10:37:52 ::annotator SDL-AMR-09 ::preferred
# ::snt RKIP expression negatively correlated with the depth of invasion (p < 0.001), lymph node involvement (p = 0.028), and Union for International Cancer Control (UICC) stage (p = 0.007).
# ::save-date Fri Feb 5, 2016 ::file pmid_2246_3874_10.txt
(a2 / and
      :op1 (c / correlate-01
            :ARG1 (e / express-03
                  :ARG2 (p / protein :name (n2 / name :op1 "RKIP")))
            :ARG2 (d / depth
                  :mod (i / invade-01))
            :ARG2-of (n / negative-01)
            :ARG1-of (s / statistical-test-91
                  :ARG2 (l / less-than :value 0.001)))
      :op2 (c2 / correlate-01
            :ARG1 e
            :ARG2 (i2 / involve-01
                  :ARG1 (n3 / node
                        :mod (l2 / lymph)))
            :ARG1-of (s3 / statistical-test-91
                  :ARG2 0.028))
      :op3 (c3 / correlate-01
            :ARG1 e
            :ARG2 (s2 / stage
                  :mod (o / organization :name (n5 / name :op1 "UICC")))
            :ARG1-of (s4 / statistical-test-91
                  :ARG2 0.007)))

# ::id pmid_2246_3874.11 ::date 2015-08-08T10:58:20 ::annotator SDL-AMR-09 ::preferred
# ::snt RKIP expression was associated with significantly longer relapse-free survival (RFS) (p = 0.0033), whereas p-MEK was not (p = 0.79).
# ::save-date Tue Dec 15, 2015 ::file pmid_2246_3874_11.txt
(c / contrast-01
      :ARG1 (a / associate-01
            :ARG1 (e / express-03
                  :ARG2 (p / protein :name (n / name :op1 "RKIP")))
            :ARG2 (s / survive-01
                  :ARG1-of (f / free-04
                        :ARG2 (r / relapse-01))
                  :ARG1-of (l / long-03
                        :degree (m / more)
                        :ARG1-of (s2 / significant-02)))
            :ARG1-of (s3 / statistical-test-91
                  :ARG2 0.0033))
      :ARG2 (a2 / associate-01 :polarity -
            :ARG1 (e2 / enzyme :name (n2 / name :op1 "MEK")
                  :ARG3-of (p4 / phosphorylate-01))
            :ARG2 s
            :ARG1-of (s4 / statistical-test-91
                  :ARG2 0.79)))

# ::id pmid_2246_3874.12 ::date 2015-08-08T11:18:24 ::annotator SDL-AMR-09 ::preferred
# ::snt Patients with p-ERK expression had slightly, but not significantly shorter RFS than those without such expression (p = 0.054).
# ::save-date Sat Jan 16, 2016 ::file pmid_2246_3874_12.txt
(h / have-03
      :ARG0 (p / person
            :ARG0-of (h2 / have-rel-role-91
                  :ARG2 (p2 / patient))
            :ARG3-of (e / express-03
                  :ARG2 (e2 / enzyme :name (n / name :op1 "ERK")
                        :ARG3-of (p3 / phosphorylate-01))))
      :ARG1 (s / survive-01
            :ARG1-of (f / free-04
                  :ARG2 (r / relapse-01))
            :ARG1-of (s2 / short-07
                  :degree (s5 / slight
                        :ARG1-of (c / contrast-01
                              :ARG2 (s4 / significant-02 :polarity -)))
                  :degree (m / more))
            :compared-to (p4 / person
                  :ARG0-of h2
                  :ARG3-of (e3 / express-03 :polarity -
                        :ARG2 e2))
            :ARG1-of (s3 / statistical-test-91
                  :ARG2 0.054)))

# ::id pmid_2246_3874.13 ::date 2015-08-08T11:32:19 ::annotator SDL-AMR-09 ::preferred
# ::snt Patients with positive p-ERK and negative RKIP expression had significantly shorter RFS than the other patients (p < 0.001).
# ::save-date Fri Feb 5, 2016 ::file pmid_2246_3874_13.txt
(h / have-03
      :ARG0 (p / person
            :ARG0-of (h2 / have-rel-role-91
                  :ARG2 (p2 / patient))
            :compared-to (p6 / person
                  :mod (o / other)
                  :ARG0-of h2)
            :ARG3-of (e2 / express-03
                  :ARG2 (e / enzyme :name (n / name :op1 "ERK")
                        :ARG3-of (p3 / phosphorylate-01))
                  :mod (p4 / positive))
            :ARG3-of (e3 / express-03
                  :ARG2 (p5 / protein :name (n2 / name :op1 "RKIP")
                        :ARG2-of (m / mutate-01 :mod "-/-"))))
      :ARG1 (s / survive-01
            :ARG1-of (f / free-04
                  :ARG2 (r / relapse-01))
            :ARG1-of (s2 / short-07
                  :ARG1-of (s3 / significant-02)
                  :ARG1-of (s4 / statistical-test-91
                        :ARG2 (l / less-than :value 0.001)))))

# ::id pmid_2246_3874.14 ::date 2015-08-08T11:41:45 ::annotator SDL-AMR-09 ::preferred
# ::snt The combination of RKIP and p-ERK expression was an independent prognostic factor (hazard ratio, 2.4; 95% confidence interval, 1.3 - 4.6; p = 0.008).
# ::save-date Sat Jan 16, 2016 ::file pmid_2246_3874_14.txt
(f / factor
      :domain (c / combine-01
            :ARG3 (e / express-03
                  :ARG2 (a / and
                        :op1 (p / protein :name (n / name :op1 "RKIP"))
                        :op2 (e2 / enzyme :name (n2 / name :op1 "ERK")
                              :ARG3-of (p2 / phosphorylate-01)))))
      :mod (p3 / prognostic)
      :ARG0-of (d / depend-01 :polarity -)
      :mod (r / ratio :quant 2.4
            :mod (h / hazard))
      :mod (i / interval
            :mod (c2 / confidence)
            :value (v / value-interval :op1 1.3 :op2 4.6)
            :mod (p4 / percentage-entity :value 95))
      :ARG1-of (s / statistical-test-91
            :ARG2 0.008))

# ::id pmid_2246_3874.78 ::date 2015-08-08T11:47:37 ::annotator SDL-AMR-09 ::preferred
# ::snt <sec-title level="1">Results</sec-title>
# ::save-date Sat Aug 8, 2015 ::file pmid_2246_3874_78.txt
(t / thing
      :ARG2-of (r / result-01))

# ::id pmid_2246_3874.79 ::date 2015-08-08T11:48:03 ::annotator SDL-AMR-09 ::preferred
# ::snt RKIP, p-MEK, and p-ERK were respectively expressed by 69 (66%), 54 (51%), and 64 (61%) of all tumours (Figure <xref ref-type="fig" rid="F1">1a-c</xref>).
# ::save-date Sat Jan 16, 2016 ::file pmid_2246_3874_79.txt
(a / and
      :op1 (e / express-03
            :ARG2 (p / protein :name (n / name :op1 "RKIP"))
            :ARG3 (t / tumor :quant 69
                  :ARG1-of (i / include-91
                        :ARG2 (t4 / tumor
                              :mod (a2 / all))
                        :ARG3 (p4 / percentage-entity :value 66))))
      :op2 (e2 / express-03
            :ARG2 (e3 / enzyme :name (n2 / name :op1 "MEK")
                  :ARG3-of (p2 / phosphorylate-01))
            :ARG3 (t2 / tumor :quant 54
                  :ARG1-of (i2 / include-91
                        :ARG2 t4
                        :ARG3 (p5 / percentage-entity :value 51))))
      :op3 (e4 / express-03
            :ARG2 (e5 / enzyme :name (n3 / name :op1 "ERK")
                  :ARG3-of p2)
            :ARG3 (t3 / tumor :quant 64
                  :ARG1-of (i3 / include-91
                        :ARG2 t4
                        :ARG3 (p6 / percentage-entity :value 61))))
      :ARG1-of (d / describe-01
            :ARG0 (a3 / and
                  :op1 (f / figure :mod "1a")
                  :op2 (f2 / figure :mod "1b")
                  :op3 (f3 / figure :mod "1c"))))

# ::id pmid_2246_3874.80 ::date 2015-08-08T11:55:57 ::annotator SDL-AMR-09 ::preferred
# ::snt RKIP expression was mainly observed in the cytoplasm of tumour or non-tumour cells.
# ::save-date Wed Mar 2, 2016 ::file pmid_2246_3874_80.txt
(o / observe-01
      :ARG1 (e / express-03
            :ARG2 (p / protein :name (n / name :op1 "RKIP")))
      :location (c / cytoplasm
            :part-of (o2 / or
                  :op1 (c2 / cell
                        :mod (t / tumor))
                  :op2 (c3 / cell
                        :mod (t2 / tumor :polarity -))))
      :manner (m / main))

# ::id pmid_2246_3874.81 ::date 2015-08-08T11:58:30 ::annotator SDL-AMR-09 ::preferred
# ::snt Expressions of p-MEK and p-ERK were found in both the cytoplasm and nucleus.
# ::save-date Sat Jan 16, 2016 ::file pmid_2246_3874_81.txt
(f / find-01
      :ARG1 (e / express-03
            :ARG2 (a / and
                  :op1 (e2 / enzyme :name (n / name :op1 "MEK")
                        :ARG3-of (p / phosphorylate-01))
                  :op2 (e3 / enzyme :name (n2 / name :op1 "ERK")
                        :ARG3-of p)))
      :location (a2 / and
            :op1 (c / cytoplasm)
            :op2 (n3 / nucleus)
            :mod (b / both)))

# ::id pmid_2246_3874.82 ::date 2015-08-08T12:02:03 ::annotator SDL-AMR-09 ::preferred
# ::snt Expressions of RKIP, p-MEK, and p-ERK were respectively detected in 5 (19%), 9 (35%), and 21 (81%) of 26 metastatic lymph nodes obtained from patients with recurrent disease (Figure <xref ref-type="fig" rid="F1">1d-f</xref>).
# ::save-date Sat Jan 16, 2016 ::file pmid_2246_3874_82.txt
(d / detect-01
      :ARG1 (a / and
            :op1 (e / express-03
                  :ARG2 (p / protein :name (n / name :op1 "RKIP"))
                  :ARG3 (n2 / node :quant 5
                        :ARG1-of (i / include-91
                              :ARG2 (n7 / node :quant 26
                                    :mod (l / lymph)
                                    :mod (m / metastasis)
                                    :ARG1-of (o / obtain-01
                                          :ARG2 (p2 / person
                                                :ARG0-of (h / have-rel-role-91
                                                      :ARG2 (p3 / patient))
                                                :mod (d2 / disease
                                                      :ARG1-of (r / reoccur-01)))))
                              :ARG3 (p5 / percentage-entity :value 19))))
            :op2 (e2 / express-03
                  :ARG2 (e3 / enzyme :name (n3 / name :op1 "MEK")
                        :ARG3-of (p4 / phosphorylate-01))
                  :ARG3 (n4 / node :quant 9
                        :ARG1-of (i2 / include-91
                              :ARG2 n7
                              :ARG3 (p6 / percentage-entity :value 35))))
            :op3 (e5 / express-03
                  :ARG2 (e4 / enzyme :name (n5 / name :op1 "ERK")
                        :ARG3-of p4)
                  :ARG3 (n6 / node :quant 21
                        :ARG1-of (i3 / include-91
                              :ARG2 n7
                              :ARG3 (p7 / percentage-entity :value 81)))))
      :ARG1-of (d3 / describe-01
            :ARG0 (a2 / and
                  :op1 (f / figure :mod "1d")
                  :op2 (f2 / figure :mod "1e")
                  :op3 (f3 / figure :mod "1f"))))

# ::id pmid_2246_3874.83 ::date 2015-08-08T12:14:06 ::annotator SDL-AMR-09 ::preferred
# ::snt Expression of p-ERK was found mainly in the nuclei of metastatic tumour cells.
# ::save-date Sat Jan 16, 2016 ::file pmid_2246_3874_83.txt
(f / find-01
      :ARG1 (e / express-03
            :ARG2 (e2 / enzyme :name (n / name :op1 "ERK")
                  :ARG3-of (p / phosphorylate-01)))
      :manner (m / main)
      :location (n2 / nucleus
            :part-of (c / cell
                  :mod (t / tumor
                        :ARG1-of (m2 / metastasize-101)))))

# ::id pmid_2246_3874.84 ::date 2015-08-08T13:29:32 ::annotator SDL-AMR-09 ::preferred
# ::snt These proteins were also detected in tumour cells associated with venous invasion (Figure <xref ref-type="fig" rid="F1">1g-i</xref>).
# ::save-date Sun Jan 3, 2016 ::file pmid_2246_3874_84.txt
(d / detect-01
      :ARG1 (p / protein
            :mod (t / this))
      :mod (a / also)
      :location (c / cell
            :mod (t2 / tumor)
            :ARG1-of (a2 / associate-01
                  :ARG2 (i / invade-01
                        :ARG1 (v / vein))))
      :ARG1-of (d2 / describe-01
            :ARG0 (a3 / and
                  :op1 (f / figure :mod "1g")
                  :op2 (f2 / figure :mod "1h")
                  :op3 (f3 / figure :mod "1i"))))

# ::id pmid_2246_3874.85 ::date 2015-08-08T13:32:16 ::annotator SDL-AMR-09 ::preferred
# ::snt No p-ERK or p-MEK staining was detected in normal gastric mucosa.
# ::save-date Sat Jan 16, 2016 ::file pmid_2246_3874_85.txt
(d / detect-01
      :ARG1 (s / stain-01 :polarity -
            :ARG2 (o / or
                  :op1 (e / enzyme :name (n / name :op1 "ERK")
                        :ARG3-of (p / phosphorylate-01))
                  :op2 (e2 / enzyme :name (n2 / name :op1 "MEK")
                        :ARG3-of p)))
      :location (m / mucosa
            :mod (s2 / stomach)
            :ARG1-of (n3 / normal-02)))

# ::id pmid_2246_3874.86 ::date 2015-08-08T14:34:35 ::annotator SDL-AMR-09 ::preferred
# ::snt The expression of p-MEK positively correlated with the expressions of RKIP (p = 0.042) and p-ERK (p = 0.007), whereas there was no relation between RKIP and p-ERK expressions (p = 0.98) (Table <xref ref-type="table" rid="T1">1</xref>).
# ::save-date Sat Jan 16, 2016 ::file pmid_2246_3874_86.txt
(c / contrast-01
      :ARG1 (a2 / and
            :op1 (c2 / correlate-01
                  :ARG1 (e / express-03
                        :ARG2 (e2 / enzyme :name (n / name :op1 "MEK")
                              :ARG3-of (p / phosphorylate-01)))
                  :ARG2 (e3 / express-03
                        :ARG2 (p2 / protein :name (n2 / name :op1 "RKIP")))
                  :manner (p6 / positive)
                  :ARG1-of (s / statistical-test-91
                        :ARG2 0.042))
            :op2 (c3 / correlate-01
                  :ARG1 e
                  :ARG2 (e4 / enzyme :name (n3 / name :op1 "ERK")
                        :ARG3-of p)
                  :ARG1-of (s2 / statistical-test-91
                        :ARG2 0.007)))
      :ARG2 (r / relate-01 :polarity -
            :ARG1 (e5 / express-03
                  :ARG2 p2)
            :ARG2 (e6 / express-03
                  :ARG2 e4)
            :ARG1-of (s3 / statistical-test-91
                  :ARG2 0.098))
      :ARG1-of (d / describe-01
            :ARG0 (t / table :mod 1)))

# ::id pmid_2246_3874.87 ::date 2015-08-08T14:42:43 ::annotator SDL-AMR-09 ::preferred
# ::snt RKIP expression negatively correlated with the depth of invasion (p < 0.001), lymph node involvement (p = 0.028), and UICC stage (p = 0.007).
# ::save-date Fri Feb 5, 2016 ::file pmid_2246_3874_87.txt
(a2 / and
      :op1 (c / correlate-01
            :ARG1 (e / express-03
                  :ARG2 (p / protein :name (n / name :op1 "RKIP")))
            :ARG2 (d / depth
                  :mod (i / invade-01))
            :ARG2-of (n3 / negative-01)
            :ARG1-of (s / statistical-test-91
                  :ARG2 (l2 / less-than :op1 0.001)))
      :op2 (c2 / correlate-01
            :ARG1 e
            :ARG2 (i2 / involve-01
                  :ARG1 (n2 / node
                        :mod (l / lymph)))
            :ARG1-of (s3 / statistical-test-91
                  :ARG2 0.028))
      :op3 (c3 / correlate-01
            :ARG1 e
            :ARG2 (s2 / stage
                  :mod (o / organization :name (n5 / name :op1 "UICC")))
            :ARG1-of (s4 / statistical-test-91
                  :ARG2 0.007)))

# ::id pmid_2246_3874.88 ::date 2015-08-08T14:50:15 ::annotator SDL-AMR-09 ::preferred
# ::snt RKIP was more commonly found in differentiated type than in undifferentiated type tumours (p = 0.042).
# ::save-date Tue Dec 15, 2015 ::file pmid_2246_3874_88.txt
(f / find-01
      :ARG1 (p / protein :name (n / name :op1 "RKIP"))
      :location (t / tumor
            :mod (t2 / type
                  :ARG1-of (d / differentiate-01))
            :compared-to (t3 / tumor
                  :mod (t4 / type
                        :ARG1-of (d2 / differentiate-01 :polarity -))))
      :manner (c / common
            :degree (m / more))
      :ARG1-of (s / statistical-test-91
            :ARG2 0.042))

# ::id pmid_2246_3874.89 ::date 2015-08-08T15:04:42 ::annotator SDL-AMR-09 ::preferred
# ::snt The expressions of p-ERK and p-MEK significantly correlated with gender (p = 0.027, p = 0.036, respectively), but were not related to any other clinicopathological factor (Table <xref ref-type="table" rid="T2">2</xref>).
# ::save-date Sat Jan 16, 2016 ::file pmid_2246_3874_89.txt
(c / contrast-01
      :ARG1 (a3 / and
            :op1 (c2 / correlate-01
                  :ARG1 (e / express-03
                        :ARG2 (e2 / enzyme :name (n / name :op1 "ERK")
                              :ARG3-of (p / phosphorylate-01)))
                  :ARG2 (g / gender)
                  :ARG1-of (s / significant-02)
                  :ARG1-of (s2 / statistical-test-91
                        :ARG2 0.027))
            :op2 (c4 / correlate-01
                  :ARG1 (e4 / express-03
                        :ARG2 (e3 / enzyme :name (n2 / name :op1 "MEK")
                              :ARG3-of p))
                  :ARG2 g
                  :ARG1-of (s3 / statistical-test-91
                        :ARG2 0.036)))
      :ARG2 (r / relate-01 :polarity -
            :ARG1 e
            :ARG2 (f / factor
                  :mod (c3 / clinicopathology)
                  :mod (o / other
                        :mod (a2 / any))))
      :ARG1-of (d / describe-01
            :ARG0 (t / table :mod 2)))

# ::id pmid_2246_3874.90 ::date 2015-08-08T15:08:56 ::annotator SDL-AMR-09 ::preferred
# ::snt RKIP expression was associated with significantly longer RFS (p = 0.003), whereas p-MEK was not (p = 0.79).
# ::save-date Tue Dec 15, 2015 ::file pmid_2246_3874_90.txt
(c / contrast-01
      :ARG1 (a / associate-01
            :ARG1 (e / express-03
                  :ARG2 (p / protein :name (n / name :op1 "RKIP")))
            :ARG2 (s / survive-01
                  :ARG1-of (l / long-03
                        :degree (m / more)
                        :ARG1-of (s2 / significant-02))
                  :ARG1-of (f / free-04
                        :ARG2 (r / relapse-01)))
            :ARG1-of (s3 / statistical-test-91
                  :ARG2 0.003))
      :ARG2 (a2 / associate-01 :polarity -
            :ARG1 (e2 / express-03
                  :ARG2 (e3 / enzyme :name (n2 / name :op1 "MEK")
                        :ARG3-of (p3 / phosphorylate-01)))
            :ARG2 s
            :ARG1-of (s4 / statistical-test-91
                  :ARG2 0.79)))

# ::id pmid_2246_3874.91 ::date 2015-08-09T06:11:55 ::annotator SDL-AMR-09 ::preferred
# ::snt The presence of p-ERK expression was associated with slightly, but not significantly shorter RFS than the absence of such expression (p = 0.054) (Table <xref ref-type="table" rid="T3">3</xref>).
# ::save-date Sat Jan 16, 2016 ::file pmid_2246_3874_91.txt
(a / associate-01
      :ARG1 (p / present-02
            :ARG1 (e / express-03
                  :ARG2 (e2 / enzyme :name (n / name :op1 "ERK")
                        :ARG3-of (p2 / phosphorylate-01)))
            :compared-to (a2 / absent-01
                  :ARG1 e))
      :ARG2 (s / survive-01
            :ARG1-of (s2 / short-07
                  :degree (m / more)
                  :degree (s3 / slight
                        :ARG1-of (c / contrast-01
                              :ARG2 (s4 / significant-02 :polarity -))))
            :ARG1-of (f / free-04
                  :ARG2 (r / relapse-01)))
      :ARG1-of (d / describe-01
            :ARG0 (t / table :mod 3))
      :ARG1-of (s5 / statistical-test-91
            :ARG2 0.054))

# ::id pmid_2246_3874.92 ::date 2015-08-09T06:16:56 ::annotator SDL-AMR-09 ::preferred
# ::snt Patients with positive p-ERK and negative RKIP expression had significantly shorter RFS than the other patients (p < 0.001) (Figure <xref ref-type="fig" rid="F2">2</xref>).
# ::save-date Fri Feb 5, 2016 ::file pmid_2246_3874_92.txt
(h / have-03
      :ARG0 (p / person
            :ARG0-of (h2 / have-rel-role-91
                  :ARG2 (p2 / patient))
            :compared-to (p6 / person
                  :mod (o / other)
                  :ARG0-of h2)
            :ARG3-of (e / express-03
                  :ARG2 (e2 / enzyme :name (n / name :op1 "ERK")
                        :ARG3-of (p3 / phosphorylate-01))
                  :mod (p4 / positive))
            :ARG3-of (e3 / express-03
                  :ARG2 (p5 / protein :name (n2 / name :op1 "RKIP")
                        :ARG2-of (m2 / mutate-01 :mod "-/-"))))
      :ARG1 (s / survive-01
            :ARG1-of (s2 / short-07
                  :ARG1-of (s3 / significant-02)
                  :degree (m / more)
                  :ARG1-of (s4 / statistical-test-91
                        :ARG2 (l / less-than :op1 0.001)))
            :ARG1-of (f / free-04
                  :ARG2 (r / relapse-01)))
      :ARG1-of (d / describe-01
            :ARG0 (f2 / figure :mod 2)))

# ::id pmid_2246_3874.93 ::date 2015-08-09T06:23:40 ::annotator SDL-AMR-09 ::preferred
# ::snt The prognostic relevance of positive p-ERK expression combined with negative RKIP expression was therefore assessed using a multivariate proportional-hazards model adjusted for established clinical prognostic factors (i.e., age, gender, histopathology, depth of invasion, lymph node involvement).
# ::save-date Fri Feb 5, 2016 ::file pmid_2246_3874_93.txt
(a / assess-01
      :ARG1 (r / relevant-01
            :ARG1 (e / express-03
                  :ARG2 (e2 / enzyme :name (n / name :op1 "ERK")
                        :ARG3-of (p / phosphorylate-01))
                  :ARG1-of (c / combine-01
                        :ARG2 (e3 / express-03
                              :ARG2 (p2 / protein :name (n2 / name :op1 "RKIP")
                                    :ARG2-of (m3 / mutate-01 :mod "-/-"))))
                  :mod (p3 / positive))
            :mod (p4 / prognostic))
      :instrument (m / model-01
            :ARG1-of (a2 / adjust-01
                  :ARG2 (f / factor
                        :mod (c2 / clinic)
                        :ARG1-of (e4 / establish-01)
                        :mod p4
                        :example (a3 / and
                              :op1 (a4 / age)
                              :op2 (g / gender)
                              :op3 (h / histopathology)
                              :op4 (d / depth
                                    :mod (i2 / invade-01))
                              :op5 (i3 / involve-01
                                    :ARG1 (n4 / node
                                          :mod (l / lymph))))))
            :mod (h2 / hazard
                  :mod (p5 / proportional))
            :mod (m2 / multivariate))
      :ARG1-of (c3 / cause-01))

# ::id pmid_2246_3874.94 ::date 2015-08-09T06:33:02 ::annotator SDL-AMR-09 ::preferred
# ::snt The combination of RKIP and p-ERK expression was found to be an independent prognostic factor (hazard ratio [HR], 2.4; 95% confidence interval [CI], 1.3 - 4.6; p = 0.008).
# ::save-date Sun Jan 17, 2016 ::file pmid_2246_3874_94.txt
(f / find-01
      :ARG1 (f2 / factor
            :mod (p3 / prognostic)
            :ARG0-of (d / depend-01 :polarity -)
            :domain (c / combine-01
                  :ARG1 (e / express-03
                        :ARG2 (a / and
                              :op1 (p / protein :name (n / name :op1 "RKIP"))
                              :op2 (e2 / enzyme :name (n2 / name :op1 "ERK")
                                    :ARG3-of (p2 / phosphorylate-01)))))
            :ARG1-of (s / statistical-test-91
                  :ARG2 0.008))
      :mod (r / ratio :value 2.4
            :mod (h / hazard))
      :mod (i / interval
            :mod (c2 / confidence)
            :mod (p4 / percentage-entity :value 95)
            :value (v / value-interval :op1 1.3 :op2 4.6)))

# ::id pmid_2246_3874.95 ::date 2015-08-09T06:41:27 ::annotator SDL-AMR-09 ::preferred
# ::snt Histopathological type and depth of invasion were also independent prognostic factors (HR, 2.1; 95% CI, 1.0 - 4.2; p = 0.043 and HR, 4.7; 95% CI, 1.0-22; p = 0.048, respectively) (Table <xref ref-type="table" rid="T3">3</xref>).
# ::save-date Tue Dec 15, 2015 ::file pmid_2246_3874_95.txt
(f / factor
      :mod (p / prognostic)
      :ARG0-of (d / depend-01 :polarity -)
      :domain (a / and
            :op1 (t / type
                  :mod (h / histopathological)
                  :mod (r / ratio :value 2.1
                        :mod (h2 / hazard))
                  :mod (i2 / interval
                        :mod (c / confidence)
                        :mod (p2 / percentage-entity :value 95)
                        :value (b / between :op1 1.0 :op2 4.2))
                  :ARG1-of (s / statistical-test-91
                        :ARG2 0.043))
            :op2 (d2 / depth
                  :mod (i / invade-01)
                  :mod (r2 / ratio :value 4.7
                        :mod (h3 / hazard))
                  :mod (i3 / interval
                        :mod (c2 / confidence)
                        :mod (p4 / percentage-entity :value 95)
                        :value (v / value-interval :op1 1.0 :op2 22))
                  :ARG1-of (s2 / statistical-test-91
                        :ARG2 0.048)))
      :ARG1-of (d3 / describe-01
            :ARG0 (t2 / table :mod 3))
      :mod (a2 / also))

# ::id pmid_2247_5322.1 ::date 2015-08-20T00:52:53 ::annotator SDL-AMR-09 ::preferred
# ::snt Comparison of growth factor signalling pathway utilisation in cultured normal melanocytes and melanoma cell lines (PMID:22475322)
# ::save-date Wed Feb 24, 2016 ::file pmid_2247_5322_1.txt
(c / compare-01
      :ARG1 (u / utilize-01
            :ARG1 (p / pathway
                  :mod (g / growth-factor)
                  :ARG0-of (s2 / signal-07))
            :location (a / and
                  :op1 (c2 / cell-line
                        :source (m2 / melanocyte)
                        :ARG1-of (n3 / normal-02))
                  :op2 (c3 / cell-line
                        :source (m / medical-condition :name (n / name :op1 "melanoma")))
                  :ARG1-of (c4 / culture-01)))
      :ARG1-of (d / describe-01
            :ARG0 (p2 / publication-91
                  :ARG8 "PMID22475322")))

# ::id pmid_2247_5322.7 ::date 2015-08-20T02:41:30 ::annotator SDL-AMR-09 ::preferred
# ::snt <sec-title level="1" sec-area="abstract">Results</sec-title>
# ::save-date Thu Aug 20, 2015 ::file pmid_2247_5322_7.txt
(t / thing
      :ARG2-of (r / result-01))

# ::id pmid_2247_5322.8 ::date 2015-08-23T09:36:18 ::annotator SDL-AMR-09 ::preferred
# ::snt Normal melanocytes could not be distinguished from melanoma cells on the basis of pathway utilisation when grown in the presence of serum, but could be distinguished upon serum starvation, where signalling protein phosphorylation was generally abrogated.
# ::save-date Thu Jan 14, 2016 ::file pmid_2247_5322_8.txt
(c / contrast-01
      :ARG1 (p2 / possible-01 :polarity -
            :ARG1 (d / distinguish-01
                  :ARG1 (m / melanocyte
                        :ARG1-of (n / normal-02))
                  :ARG2 (c2 / cell
                        :source (m2 / medical-condition :name (n2 / name :op1 "melanoma")))
                  :instrument (u / utilize-01
                        :ARG1 (p / pathway))
                  :time (g / grow-01
                        :ARG1 m
                        :manner (p3 / present-02
                              :ARG1 (s / serum)))))
      :ARG2 (p4 / possible-01
            :ARG1 (d2 / distinguish-01
                  :ARG1 m
                  :ARG1-of (c3 / cause-01
                        :ARG0 (s2 / starve-01
                              :ARG1 m
                              :ARG2 s))
                  :time (a / abrogate-01
                        :ARG1 (p5 / phosphorylate-01
                              :ARG1 (p6 / protein
                                    :ARG0-of (s3 / signal-07)))
                        :ARG1-of (g2 / general-02)))))

# ::id pmid_2247_5322.9 ::date 2015-08-20T08:07:35 ::annotator SDL-AMR-09 ::preferred
# ::snt Surprisingly, the differential utilisation of individual pathways was not consistently associated with the presence of an oncogenic or tumour suppressor mutation of genes in these pathways.
# ::save-date Mon Feb 1, 2016 ::file pmid_2247_5322_9.txt
(a / associate-01 :polarity -
      :ARG1 (u / utilize-01
            :ARG1 (p / pathway
                  :mod (i / individual))
            :ARG1-of (d / differentiate-01))
      :ARG2 (p2 / present-02
            :ARG1 (o / or
                  :op1 (m / mutate-01
                        :ARG1 (m3 / molecular-physical-entity
                              :ARG0-of (s3 / suppress-01
                                    :ARG1 g))
                        :ARG0-of (c2 / cause-01
                              :ARG1 (d2 / disease :wiki "Cancer" :name (n / name :op1 "cancer"))))
                  :op2 (m2 / mutate-01
                        :ARG1 (m4 / molecular-physical-entity
                              :ARG0-of (s2 / suppress-01
                                    :ARG1 (g / gene))
                              :mod (t / tumor)))
                  :location p))
      :ARG1-of (s / surprise-01)
      :manner (c / consistent-02))

# ::id pmid_2247_5322.68 ::date 2015-08-20T02:45:56 ::annotator SDL-AMR-09 ::preferred
# ::snt <sec-title level="1">Results</sec-title>
# ::save-date Thu Aug 20, 2015 ::file pmid_2247_5322_68.txt
(t / thing
      :ARG2-of (r / result-01))

# ::id pmid_2247_5322.69 ::date 2015-08-20T02:46:30 ::annotator SDL-AMR-09 ::preferred
# ::snt <sec-title level="2">NZM cell line mutations in the PI3K and MAPK pathways</sec-title>
# ::save-date Thu Aug 20, 2015 ::file pmid_2247_5322_69.txt
(m / mutate-01
      :ARG1 (c / cell-line :name (n4 / name :op1 "NZM"))
      :location (a / and
            :op1 (p2 / pathway :name (n2 / name :op1 "PI3K"))
            :op2 (p3 / pathway :name (n3 / name :op1 "MAPK"))))

# ::id pmid_2247_5322.70 ::date 2015-08-23T09:43:06 ::annotator SDL-AMR-09 ::preferred
# ::snt In order to determine whether the presence of activating mutations in the PI3K and MAPK signalling pathways correlated with increased utilisation of downstream signalling pathways, we first determined the mutational status of <i>PIK3CA, PTEN, NRAS </i>and <i>BRAF </i>genes in the NZM cell line collection.
# ::save-date Wed Aug 26, 2015 ::file pmid_2247_5322_70.txt
(d / determine-01
      :ARG0 (w / we)
      :ARG1 (a4 / and
            :op1 (s / status
                  :topic (m / mutate-01
                        :ARG1 (g / gene :name (n2 / name :op1 "PIK3CA"))))
            :op2 (s4 / status
                  :topic (m3 / mutate-01
                        :ARG1 (g2 / gene :name (n3 / name :op1 "PTEN"))))
            :op3 (s5 / status
                  :topic (m4 / mutate-01
                        :ARG1 (g3 / gene :name (n4 / name :op1 "NRAS"))))
            :op4 (s6 / status
                  :topic (m5 / mutate-01
                        :ARG1 (g4 / gene :name (n5 / name :op1 "BRAF"))))
            :location (c / collect-01
                  :ARG1 (c2 / cell-line :name (n / name :op1 "NZM"))))
      :time (f / first)
      :purpose (d2 / determine-01
            :ARG0 w
            :ARG1 (c3 / correlate-01 :mode interrogative
                  :ARG1 (p / present-02
                        :ARG1 (m2 / mutate-01
                              :ARG0-of (a2 / activate-01))
                        :ARG2 (a3 / and
                              :op1 (p2 / pathway :name (n6 / name :op1 "PI3K"))
                              :op2 (p3 / pathway :name (n7 / name :op1 "MAPK"))
                              :ARG0-of (s2 / signal-07)))
                  :ARG2 (u / utilize-01
                        :ARG1 (p4 / pathway
                              :ARG0-of (s3 / signal-07
                                    :direction (d3 / downstream)))
                        :ARG1-of (i / increase-01)))))

# ::id pmid_2247_5322.71 ::date 2015-08-20T12:03:19 ::annotator SDL-AMR-09 ::preferred
# ::snt Representative DNA sequences for <i>PTEN, PIK3CA, BRAF </i>and <i>NRAS </i>are provided in Figure <xref ref-type="fig" rid="F1">1</xref>.
# ::save-date Sun Aug 23, 2015 ::file pmid_2247_5322_71.txt
(p2 / provide-01
      :ARG0 (f / figure :mod 1)
      :ARG1 (d2 / dna-sequence
            :ARG0-of (r / represent-01
                  :ARG1 (a / and
                        :op1 (g4 / gene :name (n / name :op1 "PTEN"))
                        :op2 (g / gene :name (n2 / name :op1 "PIK3CA"))
                        :op3 (g2 / gene :name (n3 / name :op1 "BRAF"))
                        :op4 (g3 / gene :name (n4 / name :op1 "NRAS"))))))

# ::id pmid_2247_5322.72 ::date 2015-08-20T06:23:41 ::annotator SDL-AMR-09 ::preferred
# ::snt As shown in Table <xref ref-type="table" rid="T1">1</xref>, we selected cell lines that were characterised by a number of genetic mutations.
# ::save-date Wed Aug 26, 2015 ::file pmid_2247_5322_72.txt
(s / select-01
      :ARG0 (w / we)
      :ARG1 (c / cell-line
            :ARG1-of (c2 / characterize-01
                  :ARG2 (m / mutate-01
                        :ARG1 (g / gene)
                        :quant (n / number))))
      :ARG1-of (s2 / show-01
            :ARG0 (t / table :mod 1)))

# ::id pmid_2247_5322.73 ::date 2015-08-20T06:27:04 ::annotator SDL-AMR-09 ::preferred
# ::snt All of the selected cell lines harboured either oncogenic V600E or V600K <i>BRAF </i>or Q61H <i>NRAS </i>mutations.
# ::save-date Thu Dec 10, 2015 ::file pmid_2247_5322_73.txt
(h / harbor-01
      :ARG0 (c / cell-line
            :mod (a / all)
            :ARG1-of (i / include-91
                  :ARG2 (c2 / cell-line
                        :ARG1-of (s / select-01))))
      :ARG1 (o / or
            :op1 (g2 / gene :name (n2 / name :op1 "BRAF")
                  :ARG1-of (m / mutate-01 :value "V600E"))
            :op2 (g / gene :name (n / name :op1 "BRAF")
                  :ARG1-of (m3 / mutate-01 :value "V600K"))
            :op3 (g3 / gene :name (n3 / name :op1 "NRAS")
                  :ARG1-of (m2 / mutate-01 :value "Q61H"))
            :ARG0-of (c3 / cause-01
                  :ARG1 (d / disease :wiki "Cancer" :name (n4 / name :op1 "cancer")))))

# ::id pmid_2247_5322.74 ::date 2015-08-23T08:49:31 ::annotator SDL-AMR-09 ::preferred
# ::snt Since the tumour suppressor gene <i>PTEN </i>can be functionally lost during melanoma development through both mutation and epigenetic mechanisms [<xref ref-type="bibr" rid="B32">32</xref>], we measured PTEN protein expression in the NZM cell lines (Figure <xref ref-type="fig" rid="F2">2</xref>).
# ::save-date Thu Jan 14, 2016 ::file pmid_2247_5322_74.txt
(c / cause-01
      :ARG0 (p2 / possible-01
            :ARG1 (l / lose-02
                  :ARG1 (g / gene :name (n3 / name :op1 "PTEN")
                        :ARG0-of (s / suppress-01
                              :ARG1 (t / tumor)))
                  :ARG1-of (f2 / function-01)
                  :time (d2 / develop-01
                        :ARG2 (m2 / medical-condition :name (n4 / name :op1 "melanoma"))
                        :manner (a / and
                              :op1 (m3 / mutate-01)
                              :op2 (m4 / mechanism
                                    :mod (e2 / epigenetic)))))
            :ARG1-of (d3 / describe-01
                  :ARG0 (p3 / publication
                        :ARG0-of (c3 / cite-01
                              :ARG1 32))))
      :ARG1 (m / measure-01
            :ARG0 (w / we)
            :ARG1 (e / express-03
                  :ARG1 (p / protein :name (n / name :op1 "PTEN"))
                  :ARG3 (c2 / cell-line :name (n2 / name :op1 "NZM"))))
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod 2)))

# ::id pmid_2247_5322.75 ::date 2015-08-23T03:50:48 ::annotator SDL-AMR-09 ::preferred
# ::snt Mutation of the <i>PTEN </i>gene led to loss of functional PTEN protein expression, as seen in Figure <xref ref-type="fig" rid="F2">2</xref>.
# ::save-date Sun Aug 30, 2015 ::file pmid_2247_5322_75.txt
(l / lead-03
      :ARG0 (m / mutate-01
            :ARG1 (g / gene :name (n / name :op1 "PTEN")))
      :ARG2 (l2 / lose-02
            :ARG1 (e / express-03
                  :ARG2 (p / protein :name (n2 / name :op1 "PTEN")
                        :ARG0-of (f / function-01))))
      :ARG1-of (s / see-01
            :location (f2 / figure :mod 2)))

# ::id pmid_2247_5322.76 ::date 2015-08-23T03:55:24 ::annotator SDL-AMR-09 ::preferred
# ::snt The cell lines NZM40, NZM46 and NZM52, which all harbour the oncogenic H1047R <i>PIK3CA </i>mutation, had concurrent <i>BRAF </i>or <i>NRAS </i>mutations (Table <xref ref-type="table" rid="T1">1</xref>).
# ::save-date Thu Dec 10, 2015 ::file pmid_2247_5322_76.txt
(h / have-03
      :ARG0 (a / and
            :op1 (c / cell-line :name (n2 / name :op1 "NZM40"))
            :op2 (c2 / cell-line :name (n3 / name :op1 "NZM46"))
            :op3 (c3 / cell-line :name (n4 / name :op1 "NZM52"))
            :ARG0-of (h2 / harbor-01
                  :ARG1 (m / mutate-01 :value "H1047R"
                        :ARG1 (g / gene :name (n / name :op1 "PIK3CA"))
                        :ARG0-of (c5 / cause-01
                              :ARG1 (d2 / disease :wiki "Cancer" :name (n7 / name :op1 "cancer"))))))
      :ARG1 (o / or
            :op1 (m2 / mutate-01
                  :ARG1 (g2 / gene :name (n6 / name :op1 "BRAF")))
            :op2 (m3 / mutate-01
                  :ARG1 (g3 / gene :name (n5 / name :op1 "NRAS")))
            :ARG1-of (c4 / concurrent-02))
      :ARG1-of (d / describe-01
            :ARG0 (t / table :mod 1)))

# ::id pmid_2247_5322.77 ::date 2015-08-23T04:01:13 ::annotator SDL-AMR-09 ::preferred
# ::snt Of particular interest was the high degree of expression of PTEN protein in the NZM46 cell line, compared to other cell lines harbouring the <i>PIK3CA </i>oncogenic mutation.
# ::save-date Thu Dec 10, 2015 ::file pmid_2247_5322_77.txt
(i / interest-01
      :ARG2 (d / degree
            :degree-of (e / express-03
                  :ARG2 (p2 / protein :name (n2 / name :op1 "PTEN"))
                  :ARG3 (c / cell-line :name (n3 / name :op1 "NZM46")))
            :ARG1-of (h / high-02)
            :compared-to (c2 / cell-line
                  :ARG0-of (h2 / harbor-01
                        :ARG1 (m / mutate-01
                              :ARG1 (g / gene :name (n / name :op1 "PIK3CA"))
                              :ARG0-of (c3 / cause-01
                                    :ARG1 (d2 / disease :wiki "Cancer" :name (n4 / name :op1 "cancer")))))
                  :mod (o2 / other)))
      :mod (p / particular))

# ::id pmid_2247_5322.78 ::date 2015-08-23T04:06:06 ::annotator SDL-AMR-09 ::preferred
# ::snt Since the presence of an oncogenic mutation or a loss of tumour suppressor function does not dictate whether the cell uses all of the downstream signalling molecules for pathway activation [<xref ref-type="bibr" rid="B33">33</xref>,<xref ref-type="bibr" rid="B34">34</xref>], we determined the phosphorylation status of the immediate downstream substrates of the PI3K, mTOR and MAPK pathways.
# ::save-date Thu Dec 10, 2015 ::file pmid_2247_5322_78.txt
(c / cause-01
      :ARG0 (d3 / dictate-01 :polarity -
            :ARG0 (o2 / or
                  :op1 (p5 / present-02
                        :ARG1 (m / mutate-01
                              :ARG0-of (c4 / cause-01
                                    :ARG1 (d5 / disease :wiki "Cancer" :name (n4 / name :op1 "cancer")))))
                  :op1 (l / lose-02
                        :ARG1 (f / function-01
                              :ARG1 (s3 / suppress-01
                                    :ARG1 (t / tumor)))))
            :ARG1 (u / use-01
                  :ARG0 (c2 / cell)
                  :ARG1 (m2 / molecule
                        :ARG0-of (s4 / signal-07
                              :mod d2))
                  :ARG2 (a2 / activate-01
                        :ARG0 c2
                        :ARG1 (p6 / pathway)))
            :ARG1-of (d4 / describe-01
                  :ARG0 (p7 / publication
                        :ARG0-of (c3 / cite-01
                              :ARG1 (a3 / and :op1 33 :op2 34)))))
      :ARG1 (d / determine-01
            :ARG0 (w / we)
            :ARG1 (s / status
                  :topic (p / phosphorylate-01)
                  :poss (s2 / substrate
                        :direction (d2 / downstream
                              :mod (i / immediate))
                        :poss (a / and
                              :op1 (p2 / pathway :name (n / name :op1 "PI3K"))
                              :op2 (p3 / pathway :name (n2 / name :op1 "mTOR"))
                              :op3 (p4 / pathway :name (n3 / name :op1 "MAPK")))))))

# ::id pmid_2247_5322.79 ::date 2015-08-20T13:26:35 ::annotator SDL-AMR-09 ::preferred
# ::snt Western blots for phosphorylated molecules were used as surrogate markers for pathway activation.
# ::save-date Sun Dec 13, 2015 ::file pmid_2247_5322_79.txt
(u / use-01
      :ARG1 (i / immunoblot-01
            :ARG1 (m / molecule
                  :ARG1-of (p2 / phosphorylate-01)))
      :ARG2 (a / activate-01
            :ARG1 (p / pathway))
      :manner (t / thing
            :ARG1-of (m2 / mark-02)
            :mod (s / surrogate)))

# ::id pmid_2247_5322.80 ::date 2015-08-20T05:56:46 ::annotator SDL-AMR-09 ::preferred
# ::snt <sec-title level="2">Phosphorylation of PKB in melanoma and melanocytes</sec-title>
# ::save-date Thu Jan 14, 2016 ::file pmid_2247_5322_80.txt
(p2 / phosphorylate-01
      :ARG1 (e / enzyme :name (n / name :op1 "PKB"))
      :location (a / and
            :op1 (m / medical-condition :name (n2 / name :op1 "melanoma"))
            :op2 (m2 / melanocyte)))

# ::id pmid_2247_5322.81 ::date 2015-08-23T08:19:19 ::annotator SDL-AMR-09 ::preferred
# ::snt In order to establish whether <i>PIK3CA, PTEN, NRAS </i>and <i>BRAF </i>mutations resulted in constitutive activation of the downstream signalling pathways, we measured PKB activation by western blotting for phosphorylation at two sites, Ser473 and Thr308.
# ::save-date Sun Aug 30, 2015 ::file pmid_2247_5322_81.txt
(m / measure-01
      :ARG0 (w / we)
      :ARG1 (a / activate-01
            :ARG1 (e2 / enzyme :name (n / name :op1 "PKB")))
      :ARG2 (b / blot
            :purpose (p / phosphorylate-01
                  :ARG1 (s / site :quant 2
                        :ARG1-of (m6 / mean-01
                              :ARG2 (a3 / and
                                    :op1 (a4 / amino-acid :mod 473 :name (n3 / name :op1 "serine"))
                                    :op2 (a5 / amino-acid :mod 308 :name (n4 / name :op1 "threonine"))))))
            :mod (w2 / western))
      :purpose (e / establish-01
            :ARG0 w
            :ARG1 (r / result-01 :mode interrogative
                  :ARG1 (a6 / and
                        :op1 (m2 / mutate-01
                              :ARG1 (g / gene :name (n5 / name :op1 "PIK3CA")))
                        :op2 (m3 / mutate-01
                              :ARG1 (g4 / gene :name (n6 / name :op1 "PTEN")))
                        :op3 (m4 / mutate-01
                              :ARG1 (g2 / gene :name (n7 / name :op1 "NRAS")))
                        :op4 (m5 / mutate-01
                              :ARG1 (g3 / gene :name (n8 / name :op1 "BRAF"))))
                  :ARG2 (a7 / activate-01
                        :ARG1 (p2 / pathway
                              :ARG0-of (s2 / signal-07
                                    :direction (d / downstream)))
                        :manner (c / constitutive)))))

# ::id pmid_2247_5322.82 ::date 2015-08-23T04:27:40 ::annotator SDL-AMR-09 ::preferred
# ::snt Equal amounts of protein from NZM cell lines were loaded onto the same gel, but for clarity, western blots were segmented to show results for individual NZM cell lines.
# ::save-date Sun Dec 13, 2015 ::file pmid_2247_5322_82.txt
(c / contrast-01
      :ARG1 (l / load-01
            :ARG1 (g / gel
                  :ARG1-of (s3 / same-01))
            :ARG2 (a / amount-01
                  :ARG1 (p / protein
                        :source c3)
                  :ARG1-of (e / equal-01)))
      :ARG2 (s / segment-01
            :ARG1 (i2 / immunoblot-01)
            :purpose (c2 / clear-06)
            :purpose (s2 / show-01
                  :ARG0 i2
                  :ARG1 (t / thing
                        :ARG2-of (r / result-01
                              :ARG1 (c3 / cell-line :name (n2 / name :op1 "NZM")
                                    :mod (i / individual)))))))

# ::id pmid_2247_5322.83 ::date 2015-08-23T04:36:09 ::annotator SDL-AMR-09 ::preferred
# ::snt In melanocytes, phosphorylation of PKB on both Ser473 and Thr308 was strongly serum dependent while most of the NZM cell lines in this study showed serum independent phosphorylation.
# ::save-date Sun Aug 30, 2015 ::file pmid_2247_5322_83.txt
(h / have-concession-91
      :ARG1 (d2 / depend-01
            :ARG0 (p / phosphorylate-01
                  :ARG1 (a / and
                        :op1 (a2 / amino-acid :mod 473 :name (n3 / name :op1 "serine")
                              :part-of (e / enzyme :name (n2 / name :op1 "PKB")))
                        :op2 (a3 / amino-acid :mod 308 :name (n4 / name :op1 "threonine")
                              :part-of e)
                        :location (m2 / melanocyte)))
            :ARG1 s2
            :manner s3)
      :ARG2 (s / show-01
            :ARG0 (c / cell-line
                  :ARG1-of (i / include-91
                        :ARG2 (c2 / cell-line :name (n / name :op1 "NZM")
                              :ARG1-of (s4 / study-01
                                    :mod (t / this))))
                  :quant (m / most))
            :ARG1 (p2 / phosphorylate-01
                  :ARG0-of (d / depend-01 :polarity -
                        :ARG1 (s2 / serum)
                        :ARG1-of (s3 / strong-02)))))

# ::id pmid_2247_5322.84 ::date 2015-08-23T08:18:30 ::annotator SDL-AMR-09 ::preferred
# ::snt PKB was phosphorylated independently of serum at the mTORC2 dependent Ser473 site in most of the cell lines, although NZM46 and NZM3 surprisingly had very low levels of phosphorylation even in the presence of serum (Figure <xref ref-type="fig" rid="F3">3</xref>).
# ::save-date Sun Aug 30, 2015 ::file pmid_2247_5322_84.txt
(h / have-concession-91
      :ARG1 (p / phosphorylate-01
            :ARG1 (s3 / site
                  :mod (a2 / amino-acid :mod 473 :name (n4 / name :op1 "serine")
                        :part-of (e / enzyme :name (n3 / name :op1 "PKB")))
                  :ARG0-of (d3 / depend-01
                        :ARG1 (m / macro-molecular-complex :name (n5 / name :op1 "mTORC2"))))
            :ARG0-of (d2 / depend-01 :polarity -
                  :ARG1 s)
            :location (c3 / cell-line
                  :quant (m2 / most)
                  :ARG1-of (i / include-91
                        :ARG2 (c4 / cell-line))))
      :ARG2 (h2 / have-03
            :ARG0 (a / and
                  :op1 (c / cell-line :name (n / name :op1 "NZM46"))
                  :op2 (c2 / cell-line :name (n2 / name :op1 "NZM3")))
            :ARG1 (l / level
                  :ARG1-of (l2 / low-04
                        :degree (v / very))
                  :degree-of (p2 / phosphorylate-01))
            :concession (p3 / present-02
                        :ARG1 (s / serum))
            :ARG0-of (s2 / surprise-01))
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod 3)))

# ::id pmid_2247_5322.85 ::date 2015-08-23T09:19:10 ::annotator SDL-AMR-09 ::preferred
# ::snt In contrast, phosphorylation at the PIP<sub>3</sub>-PDK1 dependent Thr308 site tended to be low in the serum starved state in most cell lines and increased with serum (Figure <xref ref-type="fig" rid="F3">3</xref>).
# ::save-date Sun Aug 30, 2015 ::file pmid_2247_5322_85.txt
(c / contrast-01
      :ARG2 (a / and
            :op1 (t / tend-02
                  :ARG1 (p2 / phosphorylate-01
                        :ARG1 (s / site
                              :mod (a2 / amino-acid :mod 308 :name (n / name :op1 "threonine"))
                              :ARG0-of (d / depend-01
                                    :ARG1 (m / macro-molecular-complex :name (n2 / name :op1 "PIP3-PDK1")))))
                  :ARG2 (l / low-04
                        :ARG1 p2
                        :location (s2 / state
                              :topic (s3 / starve-01
                                    :ARG1 (c2 / cell-line
                                          :quant (m2 / most))
                                    :ARG2 (s4 / serum)))))
            :op2 (i / increase-01
                  :ARG1 p2
                  :ARG1-of (c3 / cause-01
                        :ARG0 s4)))
      :ARG1-of (d2 / describe-01
            :ARG0 (f / figure :mod 3)))

# ::id pmid_2247_5322.86 ::date 2015-08-20T14:39:48 ::annotator SDL-AMR-09 ::preferred
# ::snt The notable exceptions were cell lines NZM12, NZM40 and NZM52 which have comparatively high Thr308 phosphorylation in serum starved cells.
# ::save-date Sun Aug 30, 2015 ::file pmid_2247_5322_86.txt
(e / except-01
      :ARG1 (a / and
            :op1 (c / cell-line :name (n2 / name :op1 "NZM12"))
            :op2 (c2 / cell-line :name (n3 / name :op1 "NZM40"))
            :op3 (c3 / cell-line :name (n4 / name :op1 "NZM52"))
            :ARG0-of (h / have-03
                  :ARG1 (p3 / phosphorylate-01
                        :ARG1 (a2 / amino-acid :mod 308 :name (n5 / name :op1 "threonine")
                              :ARG1-of (h2 / high-02
                                    :ARG1-of (c4 / comparable-03)))
                        :location (c5 / cell
                              :ARG1-of (s / starve-01
                                    :ARG2 (s2 / serum))))))
      :ARG1-of (n / notable-04
            :ARG1-of (p2 / possible-01)))

# ::id pmid_2247_5322.87 ::date 2015-08-23T02:41:47 ::annotator SDL-AMR-09 ::preferred
# ::snt Phosphorylation of Thr308 in the NZM40 and NZM52 cell lines may be explained by the activating <i>PIK3CA </i>mutation in these cells.
# ::save-date Sun Aug 30, 2015 ::file pmid_2247_5322_87.txt
(p2 / possible-01
      :ARG1 (e / explain-01
            :ARG0 (a / activate-01
                  :ARG1 (m / mutate-01
                        :ARG1 (g2 / gene :name (n2 / name :op1 "PIK3CA")))
                  :location a3)
            :ARG1 (p / phosphorylate-01
                  :ARG1 (a2 / amino-acid :mod 308 :name (n3 / name :op1 "threonine"))
                  :location (a3 / and
                        :op1 (c / cell-line :name (n / name :op1 "NZM40"))
                        :op2 (c2 / cell-line :name (n4 / name :op1 "NZM52"))))))

# ::id pmid_2247_5322.88 ::date 2015-08-21T15:47:48 ::annotator SDL-AMR-09 ::preferred
# ::snt These two cell lines also have a very low level of total PKB suggesting some feedback regulation of PKB gene expression in these cells.
# ::save-date Wed Aug 26, 2015 ::file pmid_2247_5322_88.txt
(h / have-03
      :ARG0 (c / cell-line :quant 2
            :mod (t / this))
      :ARG1 (l / level
            :ARG1-of (l2 / low-04
                  :degree (v / very))
            :quant-of (e / enzyme :name (n / name :op1 "PKB")
                  :ARG2-of (t2 / total-01)))
      :mod (a / also)
      :ARG0-of (s / suggest-01
            :ARG1 (r / regulate-01
                  :ARG0 (f / feedback
                        :quant (s2 / some))
                  :ARG1 (e2 / express-03
                        :ARG1 (g / gene :name (n2 / name :op1 "PKB"))
                        :ARG3 c))))

# ::id pmid_2247_5322.89 ::date 2015-08-21T15:57:32 ::annotator SDL-AMR-09 ::preferred
# ::snt In support of this, NZM46, which also has a <i>PIK3CA </i>mutation (Figure <xref ref-type="fig" rid="F3">3</xref>), also has very high PTEN levels (Figure <xref ref-type="fig" rid="F2">2</xref>) which could explain the low Thr308 phosphorylation in these cells and the higher levels of total PKB compared to NZM40 and NZM52, as PIP<sub>3 </sub>levels would be predicted to be low despite the <i>PIK3CA </i>mutation.
# ::save-date Sun Jan 17, 2016 ::file pmid_2247_5322_89.txt
(s / support-01
      :ARG0 (h / have-03
            :ARG0 (c5 / cell-line :name (n7 / name :op1 "NZM46")
                  :ARG0-of (h5 / have-03
                        :ARG1 (m3 / mutate-01
                              :ARG1 g
                              :ARG1-of (d / describe-01
                                    :ARG0 (f / figure :mod 3)))
                        :mod a4))
            :ARG1 (l5 / level
                  :ARG1-of (h4 / high-02
                        :degree (v / very)
                        :ARG1-of (d2 / describe-01
                              :ARG0 (f2 / figure :mod 2)))
                  :quant-of (p5 / protein :name (n8 / name :op1 "PTEN")))
            :ARG0-of (e / explain-01
                  :ARG1 (a / and
                        :op1 (p2 / phosphorylate-01
                              :ARG1 (a2 / amino-acid :mod 308 :name (n / name :op1 "threonine"))
                              :location c5)
                        :op2 (l2 / level
                              :ARG1-of (h2 / high-02
                                    :degree (m / more)
                                    :compared-to (a3 / and
                                          :op1 (c2 / cell-line :name (n3 / name :op1 "NZM40"))
                                          :op2 (c3 / cell-line :name (n4 / name :op1 "NZM52"))))
                              :quant-of (e2 / enzyme :name (n2 / name :op1 "PKB")
                                    :ARG1-of (t2 / total-01))))
                  :ARG1-of (p / possible-01)
                  :ARG1-of (c4 / cause-01
                        :ARG0 (p3 / predict-01
                              :ARG1 (l3 / low-04
                                    :ARG1 (l4 / level
                                          :quant-of (p4 / protein :name (n5 / name :op1 "PIP3")))
                                    :concession (m2 / mutate-01
                                                :ARG1 (g / gene :name (n6 / name :op1 "PIK3CA"))))))
                  :ARG1-of (l / low-04))
            :mod (a4 / also))
      :ARG1 (t / this))

# ::id pmid_2247_5322.90 ::date 2015-08-23T08:57:57 ::annotator SDL-AMR-09 ::preferred
# ::snt NZM46 shows suppression of phosphorylation by serum in the Thr308 site (as with the Ser473 site).
# ::save-date Sun Aug 30, 2015 ::file pmid_2247_5322_90.txt
(s / show-01
      :ARG0 (c / cell-line :name (n2 / name :op1 "NZM46"))
      :ARG1 (s2 / suppress-01
            :ARG1 (p2 / phosphorylate-01
                  :ARG0 (s3 / serum)
                  :ARG1 (s4 / site
                        :mod (a / amino-acid :mod 308 :name (n / name :op1 "threonine")))))
      :ARG1-of (m / mean-01
            :ARG2 (s5 / site
                  :mod (a2 / amino-acid :mod 473 :name (n3 / name :op1 "serine")))))

# ::id pmid_2247_5322.91 ::date 2015-08-23T03:02:23 ::annotator SDL-AMR-09 ::preferred
# ::snt <sec-title level="2">Phosphorylation of components of the mTOR pathway in melanoma cells and melanocytes</sec-title>
# ::save-date Thu Jan 14, 2016 ::file pmid_2247_5322_91.txt
(p2 / phosphorylate-01
      :ARG1 (c / component
            :poss (p / pathway :name (n / name :op1 "mTOR")))
      :location (a / and
            :op1 (c2 / cell
                  :source (m2 / medical-condition :name (n2 / name :op1 "melanoma")))
            :op1 (m / melanocyte)))

# ::id pmid_2247_5322.92 ::date 2015-08-23T03:08:49 ::annotator SDL-AMR-09 ::preferred
# ::snt Activation of components of the protein translation machinery has been observed in a large percentage of melanomas and is predictive of a poor prognosis [<xref ref-type="bibr" rid="B35">35</xref>].
# ::save-date Thu Jan 14, 2016 ::file pmid_2247_5322_92.txt
(a2 / and
      :op1 (o2 / observe-01
            :ARG1 (a / activate-01
                  :ARG1 (c2 / component
                        :poss (m / machinery
                              :ARG0-of (t / translate-02
                                    :ARG2 (p2 / protein)))))
            :location (p3 / percentage
                  :mod (l / large)
                  :quant-of (m2 / medical-condition :name (n / name :op1 "melanoma"))))
      :op2 (p4 / predict-01
            :ARG0 a
            :ARG1 (p5 / prognosis
                  :mod (p6 / poor)))
      :ARG1-of (d / describe-01
            :ARG0 (p / publication
                  :ARG0-of (c / cite-01
                        :ARG1 35))))

# ::id pmid_2247_5322.93 ::date 2015-08-23T03:19:49 ::annotator SDL-AMR-09 ::preferred
# ::snt The PI3K signalling pathway can regulate protein translation machinery through mTORC1 and subsequent activation of p70S6K and phosphorylation of ribosomal protein S6 (rpS6).
# ::save-date Thu Jan 14, 2016 ::file pmid_2247_5322_93.txt
(p2 / possible-01
      :ARG1 (r / regulate-01
            :ARG0 (p6 / pathway :name (n5 / name :op1 "PI3K")
                  :ARG0-of (s / signal-07))
            :ARG1 (m / machinery
                  :ARG0-of (t / translate-02
                        :ARG2 (p3 / protein)))
            :instrument (a / and
                  :op1 (m2 / macro-molecular-complex :name (n2 / name :op1 "mTORC1"))
                  :op2 (a2 / activate-01
                        :ARG1 (e / enzyme :name (n3 / name :op1 "p70S6K"))
                        :time (s2 / subsequent))
                  :op3 (p / phosphorylate-01
                        :ARG1 (p5 / protein :name (n4 / name :op1 "ribosomal" :op2 "protein" :op3 "S6"))))))

# ::id pmid_2247_5322.94 ::date 2015-08-20T13:05:14 ::annotator SDL-AMR-09 ::preferred
# ::snt Therefore we next determined the phosphorylation status of p70S6K (Figure <xref ref-type="fig" rid="F4">4</xref>).
# ::save-date Sun Aug 30, 2015 ::file pmid_2247_5322_94.txt
(c / cause-01
      :ARG1 (d2 / determine-01
            :ARG0 (w / we)
            :ARG1 (s2 / status
                  :mod (p2 / phosphorylate-01
                        :ARG1 (e / enzyme :name (n / name :op1 "p70S6K"))))
            :time (n2 / next))
      :ARG1-of (d3 / describe-01
            :ARG0 (f / figure :mod 4)))

# ::id pmid_2247_5322.95 ::date 2015-08-23T09:01:44 ::annotator SDL-AMR-09 ::preferred
# ::snt The p70S6K was strongly expressed in all cell lines as well as in normal melanocytes but the pattern of phosphorylation of p70S6K and p85S6K at Thr389 did not correlate with the phosphorylation status of PKB nor did it correlate with genotypes (Figure <xref ref-type="fig" rid="F4">4</xref>).
# ::save-date Sun Aug 30, 2015 ::file pmid_2247_5322_95.txt
(c / contrast-01
      :ARG1 (a / and
            :op1 (e / express-03
                  :ARG1 e3
                  :ARG3 (c4 / cell-line
                        :mod (a5 / all))
                  :manner (s / strong-02))
            :op2 (e2 / express-03
                  :ARG3 (m / melanocyte
                        :ARG1-of (n4 / normal-02))))
      :ARG2 (a2 / and
            :op1 (c2 / correlate-01 :polarity -
                  :ARG1 (p / pattern-01
                        :ARG1 (p2 / phosphorylate-01
                              :ARG1 (a3 / and
                                    :op1 (a6 / amino-acid :mod 389 :name (n6 / name :op1 "threonine")
                                          :part-of (e3 / enzyme :name (n / name :op1 "p70S6K")))
                                    :op2 (a4 / amino-acid :mod 389 :name (n3 / name :op1 "threonine")
                                          :part-of (e4 / enzyme :name (n2 / name :op1 "p85S6K"))))))
                  :ARG2 (p3 / phosphorylate-01
                        :ARG1 (e5 / enzyme :name (n5 / name :op1 "PKB"))))
            :op2 (c3 / correlate-01 :polarity -
                  :ARG1 p
                  :ARG2 (g / genotype)))
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod "f4")))

# ::id pmid_2247_5322.96 ::date 2015-08-23T08:37:06 ::annotator SDL-AMR-09 ::preferred
# ::snt In melanocytes, the observed phosphorylation of Ser235/236 was serum dependent while Ser240/244 site, which is phosphorylated by p70S6K, was phosphorylated even in the absence of serum.
# ::save-date Sun Aug 30, 2015 ::file pmid_2247_5322_96.txt
(c / contrast-01
      :ARG1 (d / depend-01
            :ARG0 (p2 / phosphorylate-01
                  :ARG1 (s3 / slash
                        :op1 (a2 / amino-acid :mod 235 :name (n / name :op1 "serine"))
                        :op2 (a3 / amino-acid :mod 236 :name (n4 / name :op1 "serine")))
                  :ARG1-of (o / observe-01
                        :location (m / melanocyte)))
            :ARG1 (s2 / serum))
      :ARG2 (h / have-concession-91
            :ARG1 (p / phosphorylate-01
                  :ARG1 (s / site
                        :ARG1-of (p5 / phosphorylate-01
                              :ARG2 (e / enzyme :name (n3 / name :op1 "p70S6K")))
                        :mod (s4 / slash
                              :op1 (a4 / amino-acid :mod 240 :name (n2 / name :op1 "serine"))
                              :op2 (a5 / amino-acid :mod 244 :name (n5 / name :op1 "serine")))))
            :ARG2 (a / absent-01
                  :ARG1 s2)))

# ::id pmid_2247_5322.97 ::date 2015-08-23T07:20:02 ::annotator SDL-AMR-09 ::preferred
# ::snt In most of the cell lines, we observed serum independent phosphorylation of rpS6 while in NZM43 and to some degree, NZM10 and NZM15 showed serum dependent phosphorylation.
# ::save-date Fri Nov 20, 2015 ::file pmid_2247_5322_97.txt
(c6 / contrast-01
      :ARG1 (o / observe-01
            :ARG0 (w / we)
            :ARG1 (p / phosphorylate-01
                  :ARG1 (p3 / protein :name (n3 / name :op1 "rpS6"))
                  :ARG0-of (d2 / depend-01 :polarity -
                        :ARG1 s2))
            :location (c3 / cell-line
                  :ARG1-of (i / include-91
                        :ARG2 (c4 / cell-line
                              :quant (m / most)))))
      :ARG2 (s / show-01
            :ARG1 (p2 / phosphorylate-01
                  :ARG0-of (d / depend-01
                        :ARG1 (s2 / serum)))
            :location (a2 / and
                  :op1 (c5 / cell-line :name (n4 / name :op1 "NZM43"))
                  :op2 (a3 / and
                        :op1 (c / cell-line :name (n / name :op1 "NZM10"))
                        :op2 (c2 / cell-line :name (n2 / name :op1 "NZM15"))
                        :degree (s3 / some)))))

# ::id pmid_2247_5322.98 ::date 2015-08-23T04:07:01 ::annotator SDL-AMR-09 ::preferred
# ::snt Interestingly, we observed little phosphorylation of rpS6 at both sites in <i>BRAF </i>mutant cell lines, NZM3 and NZM12 (Figure <xref ref-type="fig" rid="F5">5</xref>).
# ::save-date Fri Nov 20, 2015 ::file pmid_2247_5322_98.txt
(o / observe-01
      :ARG0 (w / we)
      :ARG1 (p / phosphorylate-01
            :ARG1 (p2 / protein :name (n / name :op1 "rpS6"))
            :degree (l / little)
            :location (s / site
                  :location (a / and
                        :op1 (c / cell-line :name (n3 / name :op1 "NZM3"))
                        :op2 (c2 / cell-line :name (n4 / name :op1 "NZM12"))
                        :mod (m / mutate-01
                              :ARG3 (g / gene :name (n2 / name :op1 "BRAF"))))
                  :mod (b / both)))
      :ARG2-of (i / interest-01)
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod 5)))

# ::id pmid_2247_5322.99 ::date 2015-08-23T03:34:32 ::annotator SDL-AMR-09 ::preferred
# ::snt Thus, phosphorylation of rpS6 is independent of PI3K pathway activation in these melanoma cell lines.
# ::save-date Thu Jan 14, 2016 ::file pmid_2247_5322_99.txt
(c2 / cause-01
      :ARG1 (d2 / depend-01 :polarity -
            :ARG0 (p / phosphorylate-01
                  :ARG1 (p3 / protein :name (n / name :op1 "rpS6")))
            :ARG1 (a / activate-01
                  :ARG1 (p2 / pathway :name (n2 / name :op1 "PI3K"))
                  :location (c / cell-line
                        :mod (t / this)
                        :source (m / medical-condition :name (n3 / name :op1 "melanoma"))))))

# ::id pmid_2247_5322.100 ::date 2015-08-22T08:20:42 ::annotator SDL-AMR-09 ::preferred
# ::snt In these cells the phosphorylation of rpS6 is likely due to input from the ERK signalling cascade as can be seen in other cell types [<xref ref-type="bibr" rid="B36">36</xref>].
# ::save-date Mon Jan 4, 2016 ::file pmid_2247_5322_100.txt
(l / likely-01
      :ARG1 (c / cause-01
            :ARG0 (i / input
                  :source (p5 / pathway :name (n / name :op1 "ERK")
                        :ARG0-of (s / signal-07)))
            :ARG1 (p3 / phosphorylate-01
                  :ARG1 (p4 / protein :name (n2 / name :op1 "rpS6"))
                  :ARG3 (c2 / cell
                        :mod (t / this))))
      :ARG1-of (d / describe-01
            :ARG0 (p / publication
                  :ARG0-of (c5 / cite-01
                        :ARG1 36)))
      :ARG1-of (s3 / see-01
            :ARG1-of (p2 / possible-01)
            :location (t2 / type-03
                  :ARG2 (c4 / cell)
                  :mod (o / other))))

# ::id pmid_2247_5322.101 ::date 2015-08-22T01:43:07 ::annotator SDL-AMR-09 ::preferred
# ::snt <sec-title level="2">Phosphorylation of components of the ERK pathway in melanoma cells and melanocytes</sec-title>
# ::save-date Thu Jan 14, 2016 ::file pmid_2247_5322_101.txt
(p / phosphorylate-01
      :ARG1 (c / component
            :part-of (p2 / pathway :name (n / name :op1 "ERK")))
      :location (a / and
            :op1 (c2 / cell
                  :mod (m2 / medical-condition :name (n2 / name :op1 "melanoma")))
            :op2 (m / melanocyte)))

# ::id pmid_2247_5322.102 ::date 2015-08-22T02:35:13 ::annotator SDL-AMR-09 ::preferred
# ::snt We also analysed the activation status of the MAPK pathway in NZM cell lines with <i>NRAS </i>or <i>BRAF </i>mutations and cell lines which additionally harbour <i>PTEN </i>or <i>PIK3CA </i>mutations.
# ::save-date Wed Aug 26, 2015 ::file pmid_2247_5322_102.txt
(a / analyze-01
      :ARG0 (w / we)
      :ARG1 (s / status
            :mod (a3 / activate-01
                  :ARG0 (a4 / and
                        :op1 (o / or
                              :op1 (m / mutate-01
                                    :ARG1 (g2 / gene :name (n6 / name :op1 "NRAS")))
                              :op2 (m2 / mutate-01
                                    :ARG1 (g3 / gene :name (n5 / name :op1 "BRAF"))))
                        :op2 (c2 / cell-line
                              :ARG0-of (h / harbor-01
                                    :ARG1 (o2 / or
                                          :op1 (m4 / mutate-01
                                                :ARG1 (g / gene :name (n / name :op1 "PTEN")))
                                          :op2 (m3 / mutate-01
                                                :ARG1 (g4 / gene :name (n2 / name :op1 "PIK3CA"))))
                                    :manner (a5 / additional))))
                  :ARG1 (p2 / pathway :name (n3 / name :op1 "MAPK")
                        :location (c / cell-line :name (n4 / name :op1 "NZM")))))
      :mod (a2 / also))

# ::id pmid_2247_5322.103 ::date 2015-08-22T04:01:56 ::annotator SDL-AMR-09 ::preferred
# ::snt The activation of MEK and then ERK in response to oncogenic <i>NRAS </i>and <i>BRAF </i>mutations is proposed to be the basis of a MAPK pathway addiction by these cells [<xref ref-type="bibr" rid="B37">37</xref>].
# ::save-date Sat Jan 16, 2016 ::file pmid_2247_5322_103.txt
(p4 / propose-01
      :ARG1 (a / and
            :op1 (a2 / activate-01
                  :ARG1 (e / enzyme :name (n / name :op1 "MEK")))
            :op2 (a3 / activate-01
                  :time (t / then)
                  :mod (e2 / enzyme :name (n2 / name :op1 "ERK")))
            :ARG2-of (r / respond-01
                  :ARG1 (a4 / and
                        :op1 (m / mutate-01
                              :ARG1 (g / gene :name (n4 / name :op1 "NRAS")))
                        :op2 (m2 / mutate-01
                              :ARG1 (g2 / gene :name (n5 / name :op1 "BRAF")))
                        :ARG0-of (c3 / cause-01
                              :ARG1 (d2 / disease :wiki "Cancer" :name (n6 / name :op1 "cancer"))))))
      :ARG2 (b / base-02
            :ARG0 (a5 / addictive-02
                  :ARG0 (c / cell
                        :mod (t2 / this))
                  :ARG1 (p3 / pathway :name (n3 / name :op1 "MAPK")))
            :ARG1 a2)
      :ARG1-of (d / describe-01
            :ARG0 (p / publication
                  :ARG0-of (c2 / cite-01
                        :ARG1 37))))

# ::id pmid_2247_5322.104 ::date 2015-08-20T12:14:42 ::annotator SDL-AMR-09 ::preferred
# ::snt Total MEK protein was abundantly expressed in all NZM cell lines as well as melanocytes (Figure <xref ref-type="fig" rid="F6">6</xref>).
# ::save-date Sat Jan 16, 2016 ::file pmid_2247_5322_104.txt
(e / express-03
      :ARG2 (e2 / enzyme :name (n / name :op1 "MEK")
            :mod (t / total))
      :ARG3 (a3 / and
            :op1 (c / cell-line :name (n2 / name :op1 "NZM")
                  :mod (a2 / all))
            :op2 (m / melanocyte))
      :ARG1-of (a / abound-01)
      :ARG1-of (d2 / describe-01
            :ARG0 (f2 / figure :mod 6)))

# ::id pmid_2247_5322.105 ::date 2015-08-20T12:25:21 ::annotator SDL-AMR-09 ::preferred
# ::snt However levels of MEK phosphorylation varied considerably and were not directly related to genotype (Figure <xref ref-type="fig" rid="F6">6</xref>).
# ::save-date Sun Aug 30, 2015 ::file pmid_2247_5322_105.txt
(h / have-concession-91
      :ARG1 (a2 / and
            :op1 (v / vary-01
                  :ARG1 (l / level
                        :degree-of (p / phosphorylate-01
                              :ARG2 (e / enzyme :name (n / name :op1 "MEK"))))
                  :ARG2 (c3 / considerable))
            :op2 (r / relate-01 :polarity -
                  :ARG1 l
                  :ARG2 (g / genotype)
                  :ARG1-of (d2 / direct-02)))
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod 6)))

# ::id pmid_2247_5322.106 ::date 2015-08-20T12:31:58 ::annotator SDL-AMR-09 ::preferred
# ::snt Furthermore, <i>NRAS-</i>only mutant NZM cell lines, NZM10, NZM15 and NZM42 showed very low levels of MEK phosphorylation (Figure <xref ref-type="fig" rid="F6">6</xref>).
# ::save-date Wed Aug 26, 2015 ::file pmid_2247_5322_106.txt
(a2 / and
      :op1 (s2 / show-01
            :ARG0 (c / cell-line :name (n / name :op1 "NZM")
                  :mod (m / mutate-01
                        :ARG1 (g / gene :name (n2 / name :op1 "NRAS")))
                  :ARG1-of (m2 / mean-01
                        :ARG2 (a / and
                              :op1 (c2 / cell-line :name (n3 / name :op1 "NZM10"))
                              :op2 (c3 / cell-line :name (n4 / name :op1 "NZM15"))
                              :op3 (c4 / cell-line :name (n5 / name :op1 "NZM42"))))
                  :mod (o / only))
            :ARG1 (l / level
                  :ARG1-of (l2 / low-04
                        :degree (v / very))
                  :degree-of (p / phosphorylate-01
                        :ARG1 (e / enzyme :name (n6 / name :op1 "MEK")))))
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod 6)))

# ::id pmid_2247_5322.107 ::date 2015-08-23T04:13:43 ::annotator SDL-AMR-09 ::preferred
# ::snt ERK was constitutively phosphorylated in almost all cell lines, and unlike melanocytes, NZM cell lines showed serum independent MEK and ERK phosphorylation patterns (Figures <xref ref-type="fig" rid="F6">6</xref> and <xref ref-type="fig" rid="F7">7</xref>).
# ::save-date Sat Jan 16, 2016 ::file pmid_2247_5322_107.txt
(a / and
      :op1 (p4 / phosphorylate-01
            :ARG1 (e / enzyme :name (n / name :op1 "ERK"))
            :manner (c / constitutive)
            :location (c2 / cell-line
                  :mod (a2 / all
                        :degree (a3 / almost))))
      :op2 (s / show-01
            :ARG0 (c3 / cell-line :name (n3 / name :op1 "NZM"))
            :ARG1 (a4 / and
                  :op1 (p5 / pattern-01
                        :ARG1 (p7 / phosphorylate-01
                              :ARG1 (e2 / enzyme :name (n4 / name :op1 "MEK"))))
                  :op2 (p6 / pattern-01
                        :ARG1 (p8 / phosphorylate-01
                              :ARG1 e))
                  :ARG0-of (d / depend-01 :polarity -
                        :ARG1 (s2 / serum)))
            :ARG1-of (r2 / resemble-01 :polarity -
                  :ARG2 (m / melanocyte)))
      :ARG1-of (d2 / describe-01
            :ARG0 (a5 / and
                  :op1 (f / figure :mod 6)
                  :op2 (f2 / figure :mod 7))))

# ::id pmid_2247_5322.108 ::date 2015-08-20T05:05:24 ::annotator SDL-AMR-09 ::preferred
# ::snt Furthermore, MEK phosphorylation status did not correlate with ERK phosphorylation patterns.
# ::save-date Sat Jan 16, 2016 ::file pmid_2247_5322_108.txt
(a / and
      :op2 (c / correlate-01 :polarity -
            :ARG1 (s / status
                  :mod (p4 / phosphorylate-01
                        :ARG1 (e2 / enzyme :name (n / name :op1 "MEK"))))
            :ARG2 (p5 / pattern-01
                  :ARG1 (p6 / phosphorylate-01
                        :ARG1 (e / enzyme :name (n3 / name :op1 "ERK"))))))

# ::id pmid_2282_9094.1 ::date 2015-07-23T09:21:35 ::annotator SDL-AMR-09 ::preferred
# ::snt The JAK inhibitor AZD1480 regulates proliferation and immunity in Hodgkin lymphoma (PMID:22829094)
# ::save-date Fri Nov 13, 2015 ::file pmid_2282_9094_1.txt
(r / regulate-01
      :ARG0 (s / small-molecule :name (n / name :op1 "AZD1480")
            :ARG0-of (i2 / inhibit-01
                  :ARG1 (e / enzyme :name (n2 / name :op1 "JAK"))))
      :ARG1 (a / and
            :op1 (p / proliferate-01)
            :op2 (i3 / immunity))
      :ARG1-of (d / describe-01
            :ARG0 (p2 / publication-91
                  :ARG8 "PMID22829094"))
      :location (d2 / disease :name (n4 / name :op1 "Hodgkin" :op2 "lymphoma")))

# ::id pmid_2282_9094.72 ::date 2015-07-23T09:26:53 ::annotator SDL-AMR-09 ::preferred
# ::snt <sec-title level="1">Results</sec-title>
# ::save-date Thu Jul 23, 2015 ::file pmid_2282_9094_72.txt
(t / thing
      :ARG2-of (r / result-01))

# ::id pmid_2282_9094.73 ::date 2015-07-23T09:28:28 ::annotator SDL-AMR-09 ::preferred
# ::snt <sec-title level="2">Expression of activated JAK2 in cultured HL cells</sec-title>
# ::save-date Sun Aug 2, 2015 ::file pmid_2282_9094_73.txt
(e / express-03
      :ARG2 (e2 / enzyme :name (n / name :op1 "JAK2")
            :ARG1-of (a / activate-01))
      :ARG3 (c / cell
            :ARG1-of (c2 / culture-01)
            :mod (d / disease :name (n2 / name :op1 "HL"))))

# ::id pmid_2282_9094.74 ::date 2015-07-23T10:10:53 ::annotator SDL-AMR-09 ::preferred
# ::snt To explore the potential therapeutic value of the JAK2 inhibitor AZD1480 in HL, we initially examined the expression pattern of its protein target, the active, phosphorylated form of JAK2 Y1007/1008, in cultured HL cells.
# ::save-date Tue Aug 4, 2015 ::file pmid_2282_9094_74.txt
(e / examine-01
      :ARG0 (w / we)
      :ARG1 (p / pattern-01
            :ARG1 (e2 / express-03
                  :ARG2 (t2 / target-01
                        :ARG0 s
                        :ARG1 (a / amino-acid :mod "1007/1008" :name (n2 / name :op1 "tyrosine")
                              :part-of (e3 / enzyme :name (n / name :op1 "JAK2")
                                    :mod (f / form))
                              :ARG3-of (p3 / phosphorylate-01)
                              :ARG1-of (a2 / activate-01)))
                  :ARG3 (c / cell
                        :ARG1-of (c2 / culture-01)
                        :mod (d / disease :name (n4 / name :op1 "HL")))))
      :time (i2 / initial)
      :purpose (e4 / explore-01
            :ARG0 w
            :ARG1 c
            :ARG2 (v / value-01
                  :ARG1 (s / small-molecule :name (n3 / name :op1 "AZD1480")
                        :ARG0-of (i / inhibit-01
                              :ARG1 e3))
                  :mod (t3 / therapy)
                  :mod (p4 / potential))))

# ::id pmid_2282_9094.75 ::date 2015-07-23T12:05:11 ::annotator SDL-AMR-09 ::preferred
# ::snt We hypothesized that cells with high levels of p-JAK2 would be more sensitive to the antiproliferative effect of AZD1480 than cells with lower levels of p-JAK2.
# ::save-date Sun Aug 2, 2015 ::file pmid_2282_9094_75.txt
(h / hypothesize-01
      :ARG0 (w / we)
      :ARG1 (s / sensitive-03
            :ARG0 (c / cell
                  :ARG0-of (h2 / have-03
                        :ARG1 (l2 / level
                              :quant-of (e2 / enzyme :name (n / name :op1 "JAK2")
                                    :ARG3-of (p / phosphorylate-01))
                              :ARG1-of (h3 / high-02))))
            :ARG1 (a / affect-01
                  :ARG0 (s2 / small-molecule :name (n2 / name :op1 "AZD1480"))
                  :ARG0-of (c2 / counter-01
                        :ARG1 (p2 / proliferate-01)))
            :degree (m2 / more)
            :compared-to (c3 / cell
                  :ARG0-of (h4 / have-03
                        :ARG1 (l3 / level
                              :quant-of e2
                              :ARG1-of (l / low-04
                                    :degree (m / more)))))))

# ::id pmid_2282_9094.76 ::date 2015-07-23T12:13:13 ::annotator SDL-AMR-09 ::preferred
# ::snt We found p-JAK2 to be expressed in two of the four HL cell lines (<xref ref-type="fig" rid="fig1">Figure 1a</xref>).
# ::save-date Sun Aug 2, 2015 ::file pmid_2282_9094_76.txt
(f / find-01
      :ARG0 (w / we)
      :ARG1 (e / express-03
            :ARG2 (e2 / enzyme :name (n / name :op1 "JAK2")
                  :ARG3-of (p / phosphorylate-01))
            :ARG3 (c / cell-line :quant 2
                  :ARG1-of (i / include-91
                        :ARG2 (c2 / cell-line :quant 4
                              :mod (d2 / disease :name (n2 / name :op1 "HL"))))))
      :ARG1-of (d / describe-01
            :ARG0 (f2 / figure :mod "1a")))

# ::id pmid_2282_9094.77 ::date 2015-07-23T12:18:55 ::annotator SDL-AMR-09 ::preferred
# ::snt None of the HL cell lines expressed p-JAK1 Y1022/1023, two cell lines expressed p-TYK2 Y1054/1055, and only one cell line (L-540) expressed p-JAK3 Y980 (<xref ref-type="fig" rid="fig1">Figure 1a</xref>).
# ::save-date Sun Aug 2, 2015 ::file pmid_2282_9094_77.txt
(a / and
      :op1 (e / express-03
            :ARG2 (e2 / enzyme :name (n2 / name :op1 "JAK1")
                  :ARG3-of (p / phosphorylate-01
                        :ARG1 (a2 / amino-acid :mod "1022/1023" :name (n3 / name :op1 "tyrosine"))))
            :ARG3 (c / cell-line
                  :quant (n / none)
                  :mod (d2 / disease :name (n9 / name :op1 "HL"))))
      :op2 (e3 / express-03
            :ARG2 (e4 / enzyme :name (n4 / name :op1 "TYK2")
                  :ARG3-of (p2 / phosphorylate-01
                        :ARG1 (a3 / amino-acid :mod "1054/1055" :name (n5 / name :op1 "tyrosine"))))
            :ARG3 (c2 / cell-line :quant 2))
      :op3 (e5 / express-03
            :ARG2 (e6 / enzyme :name (n7 / name :op1 "JAK3")
                  :ARG3-of (p3 / phosphorylate-01
                        :ARG1 (a4 / amino-acid :mod 980 :name (n8 / name :op1 "tyrosine"))))
            :ARG3 (c3 / cell-line :quant 1
                  :mod (o / only)
                  :ARG1-of (m / mean-01
                        :ARG2 (c4 / cell-line :name (n6 / name :op1 "L-540")))))
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod "1a")))

# ::id pmid_2282_9094.78 ::date 2015-07-23T12:39:42 ::annotator SDL-AMR-09 ::preferred
# ::snt Thus, the activation pattern of the JAK family members is rather heterogeneous in the HL cell lines.
# ::save-date Sun Jan 17, 2016 ::file pmid_2282_9094_78.txt
(c / cause-01
      :ARG1 (h / heterogeneity
            :domain (p / pattern-01
                  :ARG1 (a / activate-01
                        :ARG1 (m / member
                              :ARG1-of (i / include-91
                                    :ARG2 (p2 / protein-family :name (n / name :op1 "JAK")))))
                  :location (c2 / cell-line
                        :mod (d / disease :name (n2 / name :op1 "HL"))))))

# ::id pmid_2282_9094.79 ::date 2015-07-23T12:44:38 ::annotator SDL-AMR-09 ::preferred
# ::snt Next, we investigated the expression pattern of the active phosphorylated form of downstream (p-STATs).
# ::save-date Sun Aug 2, 2015 ::file pmid_2282_9094_79.txt
(i / investigate-01
      :ARG0 (w / we)
      :ARG1 (p / pattern-01
            :ARG1 (e / express-03
                  :ARG2 (d / downstream
                        :mod (f / form)
                        :ARG3-of (p2 / phosphorylate-01)
                        :ARG1-of (a / activate-01)
                        :ARG1-of (m / mean-01
                              :ARG2 (p3 / protein :name (n2 / name :op1 "STAT")
                                    :ARG3-of p2)))))
      :time (n / next))

# ::id pmid_2282_9094.80 ::date 2015-07-23T13:05:30 ::annotator SDL-AMR-09 ::preferred
# ::snt We found p-STAT3, p-STAT5 and p-STAT6 to be expressed in the three cell lines that expressed at least one active phosphorylated member of the JAK family: HD-LM2, L-428 and L-540 (<xref ref-type="fig" rid="fig1">Figure 1a</xref>).
# ::save-date Sun Jan 17, 2016 ::file pmid_2282_9094_80.txt
(f / find-01
      :ARG0 (w / we)
      :ARG1 (e / express-03
            :ARG2 (a3 / and
                  :op1 (p / protein :name (n / name :op1 "STAT3")
                        :ARG3-of (p2 / phosphorylate-01))
                  :op2 (p3 / protein :name (n2 / name :op1 "STAT5")
                        :ARG3-of p2)
                  :op3 (p5 / protein :name (n3 / name :op1 "STAT6")
                        :ARG3-of p2))
            :ARG3 (c / cell-line :quant 3
                  :ARG1-of (e2 / express-03
                        :ARG2 (m / member
                              :ARG1-of (a4 / activate-01)
                              :quant (a / at-least :op1 1)
                              :ARG1-of (i / include-91
                                    :ARG2 (p4 / protein-family :name (n4 / name :op1 "JAK")))
                              :ARG3-of p2))
                  :ARG1-of (m2 / mean-01
                        :ARG2 (a5 / and
                              :op1 (c2 / cell-line :name (n5 / name :op1 "HD-LM2"))
                              :op2 (c3 / cell-line :name (n6 / name :op1 "L-428"))
                              :op3 (c4 / cell-line :name (n7 / name :op1 "L-540"))))))
      :ARG1-of (d / describe-01
            :ARG0 (f3 / figure :mod "1a")))

# ::id pmid_2282_9094.81 ::date 2015-07-23T13:14:15 ::annotator SDL-AMR-09 ::preferred
# ::snt Consistent with a previous report, the KM-H2 cell line did not express p-JAKs or p-STAT3, pSTAT5 or pSTAT6 proteins;<sup><xref ref-type="bibr" rid="bib19">19</xref></sup> neither did the three samples of PBMCs isolated from healthy donors.
# ::save-date Sun Aug 2, 2015 ::file pmid_2282_9094_81.txt
(a / and
      :op1 (e / express-03 :polarity -
            :ARG2 (o / or
                  :op1 (e2 / enzyme :name (n2 / name :op1 "JAK")
                        :ARG3-of (p2 / phosphorylate-01))
                  :op2 (p3 / protein :name (n3 / name :op1 "STAT3")
                        :ARG3-of p2)
                  :op3 (p5 / protein :name (n4 / name :op1 "STAT5")
                        :ARG3-of p2)
                  :op4 (p7 / protein :name (n5 / name :op1 "STAT6")
                        :ARG3-of p2))
            :ARG3 (c / cell-line :name (n / name :op1 "KM-H2"))
            :ARG1-of (d2 / describe-01
                  :ARG0 (p4 / publication
                        :ARG1-of (c4 / cite-01
                              :ARG2 19))))
      :op2 (e3 / express-03 :polarity -
            :ARG3 (c2 / cell :quant 3 :name (n6 / name :op1 "PBMC")
                  :ARG1-of (s / sample-01)
                  :ARG1-of (i / isolate-01
                        :ARG2 (p / person
                              :ARG0-of (d / donate-01)
                              :mod (h / healthy)))))
      :ARG1-of (c3 / consistent-01
            :ARG2 (r / report-01
                  :time (p10 / previous))))

# ::id pmid_2282_9094.82 ::date 2015-07-23T13:35:48 ::annotator SDL-AMR-09 ::preferred
# ::snt We found p-STAT1 to be expressed in all HL cell lines and in only one PBMC sample from a healthy donor.
# ::save-date Fri Nov 13, 2015 ::file pmid_2282_9094_82.txt
(f / find-01
      :ARG0 (w / we)
      :ARG1 (e / express-03
            :ARG2 (p2 / protein :name (n / name :op1 "STAT1")
                  :ARG3-of (p3 / phosphorylate-01))
            :ARG3 (a / and
                  :op1 (c / cell-line
                        :mod (a2 / all)
                        :mod (d2 / disease :name (n3 / name :op1 "Hodgkin's" :op2 "lymphoma")))
                  :op2 (s / sample-01 :quant 1
                        :ARG1 (c2 / cell :name (n2 / name :op1 "PBMC"))
                        :ARG2 (p / person
                              :ARG0-of (d / donate-01)
                              :mod (h2 / healthy))
                        :mod (o / only)))))

# ::id pmid_2282_9094.83 ::date 2015-07-23T13:41:59 ::annotator SDL-AMR-09 ::preferred
# ::snt <sec-title level="2">AZD1480 inhibits STAT3, STAT5 and STAT6 phosphorylation in HL cells</sec-title>
# ::save-date Fri Nov 13, 2015 ::file pmid_2282_9094_83.txt
(i / inhibit-01
      :ARG0 (s / small-molecule :name (n / name :op1 "AZD1480"))
      :ARG1 (a / and
            :op1 (p2 / phosphorylate-01
                  :ARG1 (p3 / protein :name (n2 / name :op1 "STAT3")))
            :op2 (p4 / phosphorylate-01
                  :ARG1 (p5 / protein :name (n3 / name :op1 "STAT5")))
            :op3 (p6 / phosphorylate-01
                  :ARG1 (p7 / protein :name (n4 / name :op1 "STAT6"))))
      :location (c / cell
            :mod (d / disease :name (n5 / name :op1 "Hodgkin's" :op2 "lymphoma"))))

# ::id pmid_2282_9094.84 ::date 2015-07-23T14:15:16 ::annotator SDL-AMR-09 ::preferred
# ::snt The differential expression of JAK/STAT family members in HL cell lines gave us an opportunity to determine the biological effect of AZD1480 in cells that have thee different patterns of expression: HD-LM2 and L-428 (which expressed p-JAK2 and p-TYK2), L-540 (which expressed p-JAK3), and KM-H2 (which lacked p-JAKs expression).
# ::save-date Sun Jan 17, 2016 ::file pmid_2282_9094_84.txt
(g / give-01
      :ARG0 (e / express-03
            :ARG2 (m / member
                  :ARG1-of (i / include-91
                        :ARG2 (s / slash
                              :op1 (p4 / protein-family :name (n2 / name :op1 "JAK"))
                              :op2 (p / protein-family :name (n3 / name :op1 "STAT")))))
            :ARG3 (c2 / cell-line
                  :mod (d3 / disease :name (n / name :op1 "HL")))
            :ARG1-of (d / differ-02))
      :ARG1 (o / opportunity
            :purpose (d2 / determine-01
                  :ARG0 w
                  :ARG1 (a / affect-01
                        :ARG0 (s2 / small-molecule :name (n4 / name :op1 "AZD1480"))
                        :mod (b / biology)
                        :location (c3 / cell
                              :ARG0-of (h2 / have-03
                                    :ARG1 (p2 / pattern-01 :quant 3
                                          :ARG1 (e3 / express-03)
                                          :ARG1-of d))
                              :ARG1-of (m2 / mean-01
                                    :ARG2 (a2 / and
                                          :op1 (a3 / and
                                                :op1 (c4 / cell-line :name (n5 / name :op1 "HD-LM2"))
                                                :op2 (c5 / cell-line :name (n6 / name :op1 "L-428"))
                                                :ARG3-of (e4 / express-03
                                                      :ARG2 (a4 / and
                                                            :op1 (e5 / enzyme :name (n7 / name :op1 "JAK2")
                                                                  :ARG3-of (p3 / phosphorylate-01))
                                                            :op2 (e6 / enzyme :name (n8 / name :op1 "TYK2")
                                                                  :ARG3-of p3))))
                                          :op2 (c6 / cell-line :name (n9 / name :op1 "L-540")
                                                :ARG3-of (e7 / express-03
                                                      :ARG2 (e8 / enzyme :name (n10 / name :op1 "JAK3")
                                                            :ARG3-of p3)))
                                          :op3 (c7 / cell-line :name (n11 / name :op1 "KM-H2")
                                                :ARG0-of (l / lack-01
                                                      :ARG1 (e9 / express-03
                                                            :ARG2 (e10 / enzyme :name (n12 / name :op1 "JAK")
                                                                  :ARG3-of p3))))))))))
      :ARG2 (w / we))

# ::id pmid_2282_9094.85 ::date 2015-07-25T01:42:52 ::annotator SDL-AMR-09 ::preferred
# ::snt Increasing concentrations of AZD1480 (0.1–5 μ) inhibited STAT1, STAT3, STAT5 and STAT6 phosphorylation in all three cell lines that showed evidence of full JAK/STAT activation: HD-LM2, L-428 and L-540 (<xref ref-type="fig" rid="fig1">Figure 1b</xref>).
# ::save-date Mon Dec 21, 2015 ::file pmid_2282_9094_85.txt
(i / inhibit-01
      :ARG0 (c / concentrate-02
            :ARG1 (s / small-molecule :name (n / name :op1 "AZD1480"))
            :ARG1-of (i2 / increase-01
                  :ARG2 (v / value-interval
                        :op1 (c2 / concentration-quantity :quant 0.1
                              :unit (m / micromolar))
                        :op2 (c3 / concentration-quantity :quant 5
                              :unit m))))
      :ARG1 (a / and
            :op1 (p / phosphorylate-01
                  :ARG1 (p2 / protein :name (n2 / name :op1 "STAT1")))
            :op2 (p3 / phosphorylate-01
                  :ARG1 (p4 / protein :name (n3 / name :op1 "STAT3")))
            :op3 (p5 / phosphorylate-01
                  :ARG1 (p6 / protein :name (n4 / name :op1 "STAT5")))
            :op4 (p7 / phosphorylate-01
                  :ARG1 (p8 / protein :name (n5 / name :op1 "STAT6"))))
      :location (c4 / cell-line :quant 3
            :ARG0-of (s2 / show-01
                  :ARG1 (e / evidence-01
                        :ARG1 (a2 / activate-01
                              :ARG1 (a3 / and
                                    :op1 (e2 / enzyme :name (n6 / name :op1 "JAK"))
                                    :op2 (p9 / protein :name (n7 / name :op1 "STAT")))
                              :degree (f2 / full))))
            :ARG1-of (m2 / mean-01
                  :ARG2 (a4 / and
                        :op1 (c5 / cell-line :name (n8 / name :op1 "LM2"))
                        :op2 (c6 / cell-line :name (n9 / name :op1 "L-428"))
                        :op3 (c7 / cell-line :name (n10 / name :op1 "L-540"))))
            :mod (a5 / all))
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod "1b")))

# ::id pmid_2282_9094.86 ::date 2015-07-25T01:59:02 ::annotator SDL-AMR-09 ::preferred
# ::snt These results suggest that in addition to JAK2, AZD1480 may also inhibit JAK3 activity in HL cell lines.
# ::save-date Mon Dec 21, 2015 ::file pmid_2282_9094_86.txt
(s / suggest-01
      :ARG0 (t / thing
            :ARG2-of (r / result-01)
            :mod (t2 / this))
      :ARG1 (p / possible-01
            :ARG1 (i / inhibit-01
                  :ARG0 (s2 / small-molecule :name (n / name :op1 "AZD1480"))
                  :ARG1 (a2 / activity-06
                        :ARG0 (e / enzyme :name (n2 / name :op1 "JAK3")
                              :ARG1-of (a3 / add-02
                                    :ARG2 (e2 / enzyme :name (n3 / name :op1 "JAK2"))))
                        :location (c / cell-line
                              :mod (d / disease :name (n4 / name :op1 "HL"))))
                  :mod (a / also))))

# ::id pmid_2282_9094.87 ::date 2015-07-25T02:17:16 ::annotator SDL-AMR-09 ::preferred
# ::snt Potent inhibition of STAT3 phosphorylation was observed as soon as after 30 min of incubation with AZD1480 and was maintained up to 72 h (<xref ref-type="supplementary-material" rid="sup1">Supplementary Figure S1A and B</xref>).
# ::save-date Sat Jul 25, 2015 ::file pmid_2282_9094_87.txt
(a3 / and
      :op1 (o / observe-01
            :ARG1 (i / inhibit-01
                  :ARG1 (p / phosphorylate-01
                        :ARG1 (p2 / protein :name (n / name :op1 "STAT3")))
                  :mod (p3 / potent))
            :time (a / as-soon-as
                  :op1 (a2 / after
                        :op1 (i2 / incubate-01
                              :ARG1 i
                              :ARG2 (s / small-molecule :name (n2 / name :op1 "AZD1480")))
                        :quant (t / temporal-quantity :quant 30
                              :unit (m / minute)))))
      :op2 (m2 / maintain-01
            :ARG1 i
            :duration (u / up-to
                  :op1 (t2 / temporal-quantity :quant 72
                        :unit (h / hour))))
      :ARG1-of (d / describe-01
            :ARG0 (a4 / and
                  :op1 (f / figure :mod "S1A")
                  :op2 (f2 / figure :mod "S1B")
                  :ARG2-of (s2 / supplement-01))))

# ::id pmid_2282_9094.88 ::date 2015-07-25T02:29:40 ::annotator SDL-AMR-09 ::preferred
# ::snt <sec-title level="2">Antiproliferative effects of AZD1480 in HL cell lines</sec-title>
# ::save-date Sun Dec 20, 2015 ::file pmid_2282_9094_88.txt
(a / affect-01
      :ARG0 (s / small-molecule :name (n / name :op1 "AZD1480"))
      :ARG2 (c2 / counter-01
            :ARG1 (p / proliferate-01))
      :location (c / cell-line
            :mod (d / disease :name (n2 / name :op1 "HL"))))

# ::id pmid_2282_9094.89 ::date 2015-07-25T02:38:42 ::annotator SDL-AMR-09 ::preferred
# ::snt Previous studies have demonstrated that HL cell lines are addicted to the JAK/STAT pathway, and selective inhibition of STAT proteins by RNA interference has been shown to result in antiproliferative effects in HL cell lines.<sup><xref ref-type="bibr" rid="bib2">2</xref></sup>
# ::save-date Sun Dec 20, 2015 ::file pmid_2282_9094_89.txt
(a / and
      :op1 (d / demonstrate-01
            :ARG0 (t / thing
                  :ARG1-of (s / study-01)
                  :time (p / previous))
            :ARG1 (a2 / addict-01
                  :ARG1 (c / cell-line
                        :mod (d3 / disease :name (n4 / name :op1 "HL")))
                  :ARG2 (p2 / pathway :name (n / name :op1 "JAK/STAT"))))
      :op2 (s2 / show-01
            :ARG1 (i / inhibit-01
                  :ARG0 (i3 / interfere-01
                        :ARG1 (n5 / nucleic-acid :name (n2 / name :op1 "RNA")))
                  :ARG1 (p3 / protein :name (n3 / name :op1 "STAT"))
                  :manner (s3 / selective)
                  :ARG1-of (r2 / result-01
                        :ARG2 (a3 / affect-01
                              :ARG2 (c2 / counter-01
                                    :ARG1 (p4 / proliferate-01))
                              :location c))))
      :ARG1-of (d2 / describe-01
            :ARG0 (p5 / publication
                  :ARG1-of (c3 / cite-01
                        :ARG2 2))))

# ::id pmid_2282_9094.90 ::date 2015-07-25T02:49:26 ::annotator SDL-AMR-09 ::preferred
# ::snt Because AZD1480 inhibited p-STAT3, p-STAT5 and p-STAT6, we investigated the antiproliferative effect of AZD1480 in HL cells by using the MTS assay.
# ::save-date Sat Feb 13, 2016 ::file pmid_2282_9094_90.txt
(i2 / investigate-01
      :ARG0 (w / we)
      :ARG1 (a2 / affect-01
            :ARG0 s
            :ARG2 (c3 / counter-01
                  :ARG1 (p7 / proliferate-01))
            :location (c2 / cell
                  :mod (d / disease :name (n5 / name :op1 "HL"))))
      :ARG1-of (c / cause-01
            :ARG0 (i / inhibit-01
                  :ARG0 (s / small-molecule :name (n / name :op1 "AZD1480"))
                  :ARG1 (a / and
                        :op1 (p / protein :name (n2 / name :op1 "STAT3")
                              :ARG3-of (p2 / phosphorylate-01))
                        :op2 (p3 / protein :name (n3 / name :op1 "STAT5")
                              :ARG3-of p2)
                        :op3 (p5 / protein :name (n4 / name :op1 "STAT6")
                              :ARG3-of p2))))
      :manner (u / use-01
            :ARG1 (a3 / assay-01
                  :instrument (s2 / small-molecule :name (n6 / name :op1 "MTS")))))

# ::id pmid_2282_9094.91 ::date 2015-07-25T04:11:11 ::annotator SDL-AMR-09 ::preferred
# ::snt AZD1480 induced antiproliferative effects in a time- and dose-dependent manner (<xref ref-type="fig" rid="fig1">Figure 1c</xref>).
# ::save-date Sun Dec 20, 2015 ::file pmid_2282_9094_91.txt
(i / induce-01
      :ARG0 (s / small-molecule :name (n / name :op1 "AZD1480"))
      :ARG2 (a / affect-01
            :ARG2 (c / counter-01
                  :ARG1 (p / proliferate-01)))
      :manner (d / depend-01
            :ARG1 (a2 / and
                  :op1 (t / time)
                  :op2 (d2 / dose-01)))
      :ARG1-of (d3 / describe-01
            :ARG0 (f / figure :mod "1c")))

# ::id pmid_2282_9094.92 ::date 2015-07-25T04:21:38 ::annotator SDL-AMR-09 ::preferred
# ::snt After 72 h of incubation, the half maximal inhibitory concentration (IC<sub>50</sub>) values for AZD1480 ranged from 1 to 8 μ; L-540 cells were the most sensitive to AZD1480 (<xref ref-type="fig" rid="fig1">Figure 1c and d</xref>).
# ::save-date Sun Jan 3, 2016 ::file pmid_2282_9094_92.txt
(a / and
      :op1 (r / range-01
            :ARG1 (c5 / concentration-quantity
                  :ARG4-of (h3 / have-percentage-maximal-inhibitory-concentration-01
                        :ARG1 (s2 / small-molecule :name (n / name :op1 "AZD1480"))
                        :ARG2 50))
            :ARG3 (c2 / concentration-quantity :quant 1
                  :unit (m2 / micromolar))
            :ARG4 (c3 / concentration-quantity :quant 8
                  :unit m2)
            :time (a2 / after
                  :op1 (i2 / incubate-01)
                  :quant (t / temporal-quantity :quant 72
                        :unit (h2 / hour))))
      :op2 (s / sensitive-03
            :ARG0 (c4 / cell-line :name (n2 / name :op1 "L-540"))
            :ARG1 s2
            :degree (m4 / most))
      :ARG1-of (d / describe-01
            :ARG0 (a3 / and
                  :op1 (f / figure :mod "1c")
                  :op2 (f2 / figure :mod "1d"))))

# ::id pmid_2282_9094.93 ::date 2015-07-25T04:41:53 ::annotator SDL-AMR-09 ::preferred
# ::snt Thus, although submicromolar concentrations of AZD1480 inhibited STAT phosphorylation, these low concentrations were not sufficient to induce a significant antiproliferative activity, especially in the HD-LM2 and L-428 cells.
# ::save-date Sun Dec 20, 2015 ::file pmid_2282_9094_93.txt
(c / cause-01
      :ARG1 (h / have-concession-91
            :ARG1 (s3 / suffice-01 :polarity -
                  :ARG0 (c3 / concentrate-02
                        :ARG1-of (l / low-04)
                        :mod (t / this))
                  :ARG1 (i2 / induce-01
                        :ARG0 c3
                        :ARG2 (a / activity-06
                              :ARG0-of (c4 / counter-01
                                    :ARG1 (p3 / proliferate-01))
                              :ARG1-of (s4 / significant-02))
                        :location (a2 / and
                              :op1 (c5 / cell-line :name (n3 / name :op1 "HD-LM2"))
                              :op2 (c6 / cell-line :name (n4 / name :op1 "L-428"))
                              :mod (e / especially))))
            :ARG2 (i / inhibit-01
                  :ARG0 (c2 / concentrate-01
                        :ARG1 (s / small-molecule :name (n / name :op1 "AZD1480"))
                        :mod (s2 / submicromolar))
                  :ARG1 (p / phosphorylate-01
                        :ARG1 (p2 / protein :name (n2 / name :op1 "STAT"))))))

# ::id pmid_2282_9094.94 ::date 2015-07-25T04:50:30 ::annotator SDL-AMR-09 ::preferred
# ::snt In contrast, at a higher concentration (5 μ), AZD1480 had a stronger effect in all cell lines, including KM-H2, which lacked active JAK/STAT proteins.
# ::save-date Sun Aug 2, 2015 ::file pmid_2282_9094_94.txt
(c / contrast-01
      :ARG2 (h2 / have-condition-91
            :ARG1 (a / affect-01
                  :ARG0 (s2 / small-molecule :name (n / name :op1 "AZD1480"))
                  :ARG1-of (s / strong-02
                        :degree (m2 / more))
                  :location (c2 / cell-line
                        :ARG2-of (i / include-01
                              :ARG1 (c3 / cell-line :name (n2 / name :op1 "KM-H2")
                                    :ARG0-of (l / lack-01
                                          :ARG1 (s3 / slash
                                                :op1 (e / enzyme :name (n3 / name :op1 "JAK"))
                                                :op2 (p / protein :name (n4 / name :op1 "STAT"))
                                                :ARG1-of (a3 / activate-01)))))
                        :mod (a5 / all)))
            :ARG2 (c4 / concentrate-02
                  :ARG1-of (h / high-02
                        :degree (m / more))
                  :quant (c5 / concentration-quantity :quant 5
                        :unit (m3 / micromolar)))))

# ::id pmid_2282_9094.95 ::date 2015-07-25T05:04:30 ::annotator SDL-AMR-09 ::preferred
# ::snt These data suggest that at this higher concentration (5 μ), AZD1480 induced antiproliferative effects in HL cell lines in a JAK/STAT-independent manner.
# ::save-date Sun Dec 20, 2015 ::file pmid_2282_9094_95.txt
(s / suggest-01
      :ARG0 (d / data
            :mod (t / this))
      :ARG1 (i / induce-01
            :ARG0 (s2 / small-molecule :name (n / name :op1 "AZD1480"))
            :ARG2 (a / affect-01
                  :ARG2 (c / counter-01
                        :ARG1 (p / proliferate-01))
                  :location (c2 / cell-line
                        :mod (d3 / disease :name (n4 / name :op1 "HL"))))
            :manner (d2 / depend-01 :polarity -
                  :ARG1 (s3 / slash
                        :op1 (e / enzyme :name (n2 / name :op1 "JAK"))
                        :op2 (p2 / protein :name (n3 / name :op1 "STAT"))))
            :condition (c3 / concentrate-02
                        :ARG1 s2
                        :ARG1-of (h / high-02
                              :degree (m / more))
                        :quant (c4 / concentration-quantity :quant 5
                              :unit (m2 / micromolar)))))

# ::id pmid_2282_9094.96 ::date 2015-07-25T05:09:06 ::annotator SDL-AMR-09 ::preferred
# ::snt To further investigate the mechanisms of the antiproliferative activity of AZD1480, we determined the inhibitor's effect on apoptosis.
# ::save-date Tue Aug 4, 2015 ::file pmid_2282_9094_96.txt
(d / determine-01
      :ARG0 (w / we)
      :ARG1 (a / affect-01
            :ARG0 (m / molecular-physical-entity
                  :ARG0-of (i / inhibit-01))
            :ARG1 (a2 / apoptosis))
      :purpose (i2 / investigate-01
            :ARG0 w
            :ARG1 (m2 / mechanism
                  :poss (a3 / activity-06
                        :ARG0 (s / small-molecule :name (n / name :op1 "AZD1480"))
                        :ARG0-of (c / counter-01
                              :ARG1 (p / proliferate-01))))
            :degree (f / further)))

# ::id pmid_2282_9094.97 ::date 2015-07-25T05:14:50 ::annotator SDL-AMR-09 ::preferred
# ::snt Consistent with the MTS data in <xref ref-type="fig" rid="fig1">Figure 1c</xref>, we found that AZD1480 induced apoptotic cell death in a dose-dependent manner (<xref ref-type="fig" rid="fig2">Figure 2a and b</xref>).
# ::save-date Sat Feb 13, 2016 ::file pmid_2282_9094_97.txt
(f / find-01
      :ARG0 (w / we)
      :ARG1 (i / induce-01
            :ARG0 (s / small-molecule :name (n / name :op1 "AZD1480"))
            :ARG2 (d / die-01
                  :ARG1 (c / cell
                        :mod (a / apoptotic)))
            :manner (d2 / depend-01
                  :ARG1 (d3 / dose-01)))
      :ARG1-of (c2 / consistent-01
            :ARG2 (d4 / data
                  :location (f2 / figure :mod "1c")
                  :source (a3 / assay-01
                        :instrument (s2 / small-molecule :name (n2 / name :op1 "MTS")))))
      :ARG1-of (d5 / describe-01
            :ARG0 (a2 / and
                  :op1 (f3 / figure :mod "2a")
                  :op2 (f4 / figure :mod "2b"))))

# ::id pmid_2282_9094.98 ::date 2015-07-25T05:18:52 ::annotator SDL-AMR-09 ::preferred
# ::snt At the lower concentration of AZD1480 (1 μ), L-540 cells were the most sensitive (43.3% cell death after 72 h of incubation) and L-428 cells were modestly sensitive (27.6% cell death).
# ::save-date Sun Aug 2, 2015 ::file pmid_2282_9094_98.txt
(h / have-condition-91
      :ARG1 (a / and
            :op1 (s / sensitive-03
                  :ARG0 (c / cell-line :name (n / name :op1 "L-540"))
                  :degree (m2 / most)
                  :ARG1-of (m3 / mean-01
                        :ARG2 (d / die-01
                              :ARG1 (c2 / cell
                                    :quant (p / percentage-entity :value 43.3))
                              :time (a2 / after
                                    :op1 (i / incubate-01)
                                    :quant (t / temporal-quantity :quant 72
                                          :unit (h2 / hour))))))
            :op2 (s2 / sensitive-03
                  :ARG0 (c3 / cell-line :name (n2 / name :op1 "L-428"))
                  :ARG1-of (m4 / mean-01
                        :ARG2 (d2 / die-01
                              :ARG1 (c4 / cell
                                    :quant (p2 / percentage-entity :value 27.6))))
                  :degree (m6 / modest)))
      :ARG2 (c5 / concentrate-02
            :ARG1 (s3 / small-molecule :name (n3 / name :op1 "AZD1480"))
            :ARG1-of (l / low-04
                  :degree (m / more))
            :quant (c6 / concentration-quantity :quant 1
                  :unit (m5 / micromolar))))

# ::id pmid_2282_9094.99 ::date 2015-07-25T05:29:00 ::annotator SDL-AMR-09 ::preferred
# ::snt At the higher concentration (5 μ), AZD1480 induced apoptosis in all four cell lines, but L-540 cells remained the most sensitive.
# ::save-date Sun Aug 2, 2015 ::file pmid_2282_9094_99.txt
(c / contrast-01
      :ARG1 (i / induce-01
            :ARG0 (s / small-molecule :name (n / name :op1 "AZD1480"))
            :ARG2 (a / apoptosis)
            :location (c2 / cell-line :quant 4
                  :mod (a2 / all)))
      :ARG2 (r / remain-01
            :ARG1 (c3 / cell-line :name (n2 / name :op1 "L-540"))
            :ARG3 (s2 / sensitive-03
                  :degree (m2 / most)))
      :condition (c4 / concentrate-02
                  :quant (c5 / concentration-quantity :quant 5
                        :unit (m3 / micromolar))
                  :ARG1-of (h / high-02
                        :degree (m / more))))

# ::id pmid_2282_9094.100 ::date 2015-07-25T05:36:45 ::annotator SDL-AMR-09 ::preferred
# ::snt Consistent with induction of apoptosis, AZD1480 activated caspases 9 and 3, and induced poly (adenosine diphosphate ribose) polymerase cleavage.
# ::save-date Sun Jan 17, 2016 ::file pmid_2282_9094_100.txt
(a / and
      :op1 (a2 / activate-01
            :ARG0 (s / small-molecule :name (n / name :op1 "AZD1480"))
            :ARG1 (a3 / and
                  :op1 (p2 / protein :name (n3 / name :op1 "caspase" :op2 "9"))
                  :op2 (p3 / protein :name (n4 / name :op1 "caspase" :op2 "3"))))
      :op2 (i / induce-01
            :ARG0 s
            :ARG2 (c3 / cleave-01
                  :ARG1 (p / protein :name (n2 / name :op1 "poly" :op2 "adenosine" :op3 "diphosphate" :op4 "ribose" :op5 "polymerase"))))
      :ARG1-of (c4 / consistent-01
            :ARG2 (i2 / induce-01
                  :ARG2 (a4 / apoptosis))))

# ::id pmid_2282_9094.101 ::date 2015-07-25T05:41:44 ::annotator SDL-AMR-09 ::preferred
# ::snt (<xref ref-type="fig" rid="fig2">Figure 2c</xref>).
# ::save-date Sat Jul 25, 2015 ::file pmid_2282_9094_101.txt
(f / figure :mod "2c")

# ::id pmid_2282_9094.102 ::date 2015-07-26T11:19:42 ::annotator SDL-AMR-09 ::preferred
# ::snt This was observed as soon as after 24 h of incubation with AZD1480 in all cell lines, when high doses (5 μ) were used (<xref ref-type="supplementary-material" rid="sup1">Supplementary Figure S1C</xref>).
# ::save-date Sun Aug 2, 2015 ::file pmid_2282_9094_102.txt
(o / observe-01
      :ARG1 (t / this)
      :time (a / as-soon-as
            :op1 (a2 / after
                  :op1 (i / incubate-01
                        :ARG2 (s / small-molecule :name (n / name :op1 "AZD1480"))
                        :location (c / cell-line
                              :mod (a3 / all)))
                  :quant (t2 / temporal-quantity :quant 24
                        :unit (h / hour))))
      :time (u / use-01
            :ARG1 (d / dose-01
                  :quant (c2 / concentration-quantity :quant 5
                        :unit (m / micromolar))
                  :ARG1-of (h2 / high-02)))
      :ARG1-of (d2 / describe-01
            :ARG0 (f / figure :mod "S1C"
                  :ARG2-of (s2 / supplement-01))))

# ::id pmid_2282_9094.103 ::date 2015-07-26T11:39:41 ::annotator SDL-AMR-09 ::preferred
# ::snt <sec-title level="2">AZD1480 induces paradoxical hyperphosphorylation of JAK2 and TYK2 at the activation loop in HL cells</sec-title>
# ::save-date Sun Aug 2, 2015 ::file pmid_2282_9094_103.txt
(i / induce-01
      :ARG0 (s / small-molecule :name (n / name :op1 "AZD1480"))
      :ARG2 (h / hyperphosphorylate-01
            :ARG1 (a / and
                  :op1 (e / enzyme :name (n2 / name :op1 "JAK2"))
                  :op2 (e2 / enzyme :name (n3 / name :op1 "TYK2")))
            :manner (p / paradox))
      :location (l / loop
            :ARG0-of (a2 / activate-01)
            :location (c / cell
                  :mod (d / disease :name (n4 / name :op1 "HL")))))

# ::id pmid_2282_9094.104 ::date 2015-07-26T11:44:30 ::annotator SDL-AMR-09 ::preferred
# ::snt Although AZD1480 inhibited phosphorylation of STATs, its effect on the phosphorylation of the JAK family members in HL cells is unknown.
# ::save-date Sun Jan 17, 2016 ::file pmid_2282_9094_104.txt
(h / have-concession-91
      :ARG1 (k / know-01 :polarity -
            :ARG1 (a / affect-01
                  :ARG0 s
                  :ARG1 (p3 / phosphorylate-01
                        :ARG1 (m / member
                              :ARG1-of (i2 / include-91
                                    :ARG2 (p4 / protein-family :name (n3 / name :op1 "JAK")))))
                  :location (c / cell
                        :mod (d / disease :name (n4 / name :op1 "HL")))))
      :ARG2 (i / inhibit-01
            :ARG0 (s / small-molecule :name (n / name :op1 "AZD1480"))
            :ARG1 (p / phosphorylate-01
                  :ARG1 (p2 / protein :name (n2 / name :op1 "STAT")))))

# ::id pmid_2282_9094.105 ::date 2015-07-26T11:50:15 ::annotator SDL-AMR-09 ::preferred
# ::snt Only the Tyr-phosphorylated forms of JAKs are known to exhibit kinase activity, and phosphorylation at two tandem Tyr residues in the activation loop appears to be required for enzymatic activity.<sup><xref ref-type="bibr" rid="bib20">20</xref></sup>
# ::save-date Tue Aug 4, 2015 ::file pmid_2282_9094_105.txt
(a / and
      :op1 (k / know-01
            :ARG1 (e / enzyme :name (n / name :op1 "JAK")
                  :ARG3-of (p / phosphorylate-01
                        :ARG1 (a2 / amino-acid :name (n2 / name :op1 "tyrosine")))
                  :mod (f2 / form)
                  :mod (o / only)
                  :ARG0-of (e2 / exhibit-01
                        :ARG1 (a3 / activity-06
                              :ARG0 (k2 / kinase)))))
      :op2 (a4 / appear-01
            :ARG1 (r2 / require-01
                  :ARG1 (p2 / phosphorylate-01
                        :ARG1 (r / residue
                              :mod (a5 / amino-acid :name (n3 / name :op1 "tyrosine"))
                              :mod (t / tandem :quant 2))
                        :location (l / loop
                              :ARG0-of (a6 / activate-01)))
                  :purpose (a7 / activity-06
                        :ARG0 (e3 / enzyme))))
      :ARG1-of (d / describe-01
            :ARG0 (p3 / publication
                  :ARG1-of (c / cite-01
                        :ARG2 20))))

# ::id pmid_2282_9094.106 ::date 2015-07-26T11:58:38 ::annotator SDL-AMR-09 ::preferred
# ::snt As levels of baseline p-JAK2 expression and p-STATs inhibition did not predict sensitivity to AZD1480 in HD-LM2 and L-428 cells, we investigated the effect of AZD1480 on the phosphorylation status of the JAK family members at the activation loop.
# ::save-date Sun Jan 17, 2016 ::file pmid_2282_9094_106.txt
(i / investigate-01
      :ARG0 (w / we)
      :ARG1 (a / affect-01
            :ARG0 (s / small-molecule :name (n / name :op1 "AZD1480"))
            :ARG1 (s2 / status
                  :poss (m / member
                        :ARG1-of (i3 / include-91
                              :ARG2 (p5 / protein-family :name (n2 / name :op1 "JAK"))))
                  :mod (p / phosphorylate-01))
            :location (l / loop
                  :ARG0-of (a2 / activate-01)))
      :ARG1-of (c3 / cause-01
            :ARG0 (p2 / predict-01 :polarity -
                  :ARG0 (a3 / and
                        :op1 (l2 / level
                              :degree-of (e2 / express-03
                                    :ARG2 (e3 / enzyme :name (n3 / name :op1 "JAK2")
                                          :ARG3-of (p3 / phosphorylate-01)
                                          :mod (b / baseline))))
                        :op2 (l3 / level
                              :degree-of (i2 / inhibit-01
                                    :ARG1 (p4 / protein :name (n4 / name :op1 "STAT")
                                          :ARG3-of p3))))
                  :ARG1 (s3 / sensitive-03
                        :ARG1 s
                        :location (a4 / and
                              :op1 (c / cell-line :name (n6 / name :op1 "HD-LM2"))
                              :op2 (c2 / cell-line :name (n7 / name :op1 "L-428")))))))

# ::id pmid_2282_9094.107 ::date 2015-07-26T12:23:18 ::annotator SDL-AMR-09 ::preferred
# ::snt To determine the effect of AZD1480 on p-JAKs, we focused our experiments on the three cell lines that expressed active JAK/STAT proteins: HD-LM2, L-428 and L-540 (<xref ref-type="fig" rid="fig3">Figure 3a</xref>).
# ::save-date Sun Aug 2, 2015 ::file pmid_2282_9094_107.txt
(f / focus-01
      :ARG0 (w / we)
      :ARG1 (e / experiment-01
            :ARG0 w
            :ARG1 (c / cell-line :quant 3
                  :ARG3-of (e2 / express-03
                        :ARG2 (s / slash
                              :op1 (e3 / enzyme :name (n / name :op1 "JAK"))
                              :op2 (p / protein :name (n2 / name :op1 "STAT"))
                              :ARG1-of (a / activate-01)))
                  :ARG1-of (m / mean-01
                        :ARG2 (a3 / and
                              :op1 (c2 / cell-line :name (n3 / name :op1 "HD-LM2"))
                              :op2 (c3 / cell-line :name (n4 / name :op1 "L-428"))
                              :op3 (c4 / cell-line :name (n5 / name :op1 "L-540"))))))
      :purpose (d / determine-01
            :ARG0 w
            :ARG1 (a4 / affect-01
                  :ARG0 (s2 / small-molecule :name (n6 / name :op1 "AZD1480"))
                  :ARG1 (e4 / enzyme :name (n7 / name :op1 "JAK")
                        :ARG3-of (p2 / phosphorylate-01))))
      :ARG1-of (d2 / describe-01
            :ARG0 (f2 / figure :mod "3a")))

# ::id pmid_2282_9094.108 ::date 2015-07-26T12:30:48 ::annotator SDL-AMR-09 ::preferred
# ::snt In L-540, which was the most sensitive cell line and which expressed only p-JAK3, increasing concentrations of AZD1480 (0.1–5 μ) completely inhibited JAK3 Y980 phosphorylation.
# ::save-date Sun Jan 3, 2016 ::file pmid_2282_9094_108.txt
(i / inhibit-01
      :ARG0 (c / concentrate-02
            :ARG1 (s / small-molecule :name (n / name :op1 "AZD1480"))
            :ARG1-of (i2 / increase-01
                  :ARG2 (v / value-interval
                        :op1 (c2 / concentration-quantity :quant 0.1
                              :unit (m / micromolar))
                        :op2 (c3 / concentration-quantity :quant 5
                              :unit m))))
      :ARG1 (p2 / phosphorylate-01
            :ARG1 (a / amino-acid :mod 980 :name (n2 / name :op1 "tyrosine")
                  :part-of (e / enzyme :name (n3 / name :op1 "JAK3"))))
      :manner (c4 / complete)
      :location (c5 / cell-line :name (n4 / name :op1 "L-540")
            :ARG0-of (s2 / sensitive-03
                  :degree (m3 / most))
            :ARG3-of (e2 / express-03
                  :ARG2 (e3 / enzyme :name (n5 / name :op1 "JAK3")
                        :ARG3-of (p3 / phosphorylate-01))
                  :mod (o / only))))

# ::id pmid_2282_9094.109 ::date 2015-07-26T12:39:58 ::annotator SDL-AMR-09 ::preferred
# ::snt In contrast, when HD-LM2 and L-428 cells were incubated with AZD1480, a paradoxical increase in JAK2 Y1007/1008 and TYK2 Y1054/1055 phosphorylation was observed after 72 h of incubation (<xref ref-type="fig" rid="fig3">Figure 3a</xref>).
# ::save-date Sun Aug 2, 2015 ::file pmid_2282_9094_109.txt
(c / contrast-01
      :ARG2 (o / observe-01
            :ARG1 (a / and
                  :op1 (i / increase-01
                        :ARG1 (a2 / amino-acid :mod "1007/1008" :name (n / name :op1 "tyrosine")
                              :part-of (e / enzyme :name (n2 / name :op1 "JAK2")))
                        :manner (p2 / paradox))
                  :op2 (p / phosphorylate-01
                        :ARG1 (a3 / amino-acid :mod "1054/1055" :name (n3 / name :op1 "tyrosine")
                              :part-of (e2 / enzyme :name (n4 / name :op1 "TYK2")))))
            :time (a4 / after
                  :op1 i3
                  :quant (t / temporal-quantity :quant 72
                        :unit (h / hour)))
            :condition (i3 / incubate-01
                        :ARG1 (a5 / and
                              :op1 (c2 / cell-line :name (n5 / name :op1 "HD-LM2"))
                              :op2 (c3 / cell-line :name (n6 / name :op1 "L-428")))
                        :ARG2 (s / small-molecule :name (n7 / name :op1 "AZD1480"))))
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod "3a")))

# ::id pmid_2282_9094.110 ::date 2015-07-26T12:47:45 ::annotator SDL-AMR-09 ::preferred
# ::snt The hyperphosphorylation of JAK2 at the activation loop was confirmed using two antibodies obtained from different clones.
# ::save-date Sun Aug 2, 2015 ::file pmid_2282_9094_110.txt
(c / confirm-01
      :ARG1 (h / hyperphosphorylate-01
            :ARG1 (e / enzyme :name (n / name :op1 "JAK2"))
            :location (l / loop
                  :ARG0-of (a / activate-01)))
      :manner (u / use-01
            :ARG1 (a2 / antibody :quant 2
                  :ARG1-of (o / obtain-01
                        :ARG2 (c2 / clone-01
                              :ARG1-of (d / differ-02))))))

# ::id pmid_2282_9094.111 ::date 2015-07-26T12:54:04 ::annotator SDL-AMR-09 ::preferred
# ::snt The phosphorylation of the immediate downstream target STAT3 was abrogated at the same time point in all the three cell lines (<xref ref-type="fig" rid="fig1">Figure 1b</xref>), suggesting that the function of the JAKs was effectively inhibited by AZD1480.
# ::save-date Sun Dec 20, 2015 ::file pmid_2282_9094_111.txt
(a / abrogate-01
      :ARG1 (p / phosphorylate-01
            :ARG1 (t2 / target-01
                  :ARG1 (p2 / protein :name (n / name :op1 "STAT3"))
                  :mod (d / downstream)
                  :mod (i / immediacy)))
      :time (p3 / point
            :ARG1-of (s / same-01)
            :mod (t3 / time))
      :location (c / cell-line :quant 3
            :mod (a2 / all))
      :ARG1-of (d2 / describe-01
            :ARG0 (f / figure :mod "1b"))
      :ARG0-of (s3 / suggest-01
            :ARG1 (i2 / inhibit-01
                  :ARG0 (s4 / small-molecule :name (n3 / name :op1 "AZD1480"))
                  :ARG1 (f2 / function-01
                        :ARG0 (e / enzyme :name (n2 / name :op1 "JAK")))
                  :ARG1-of (e2 / effective-04))))

# ::id pmid_2282_9094.112 ::date 2015-07-26T13:13:04 ::annotator SDL-AMR-09 ::preferred
# ::snt When JAKs phosphorylation was analyzed over a shorter time period, a strong increase in JAK2 Y1007/1008 phosphorylation was observed in HD-LM2 and L-428 cells after 30 min of incubation with 1 μ AZD1480 (<xref ref-type="supplementary-material" rid="sup1">Supplementary Figure S1A</xref>), whereas JAK3 Y980 phosphorylation was abrogated in L-540 cells (<xref ref-type="supplementary-material" rid="sup1">Supplementary Figure S1A</xref>).
# ::save-date Wed Mar 9, 2016 ::file pmid_2282_9094_112.txt
(c / contrast-01
      :ARG1 (o / observe-01
            :ARG1 (i / increase-01
                  :ARG1 (p / phosphorylate-01
                        :ARG1 (a / amino-acid :mod "1007/1008" :name (n / name :op1 "tyrosine")
                              :part-of (e / enzyme :name (n2 / name :op1 "JAK2"))))
                  :ARG1-of (s / strong-02))
            :location (a2 / and
                  :op1 (c2 / cell-line :name (n3 / name :op1 "HD-LM2"))
                  :op2 (c3 / cell-line :name (n4 / name :op1 "L-428")))
            :time (a3 / after
                  :op1 (i2 / incubate-01
                        :ARG2 (s2 / small-molecule :name (n5 / name :op1 "AZD1480")
                              :quant (c4 / concentration-quantity :quant 1
                                    :unit (m2 / micromolar))))
                  :quant (t / temporal-quantity :quant 30
                        :unit (m / minute)))
            :ARG1-of (d / describe-01
                  :ARG0 (f / figure :mod "S1A"
                        :ARG2-of (s3 / supplement-01))))
      :ARG2 (a4 / abrogate-01
            :ARG1 (p2 / phosphorylate-01
                  :ARG1 (a5 / amino-acid :mod 980 :name (n6 / name :op1 "tyrosine")
                        :part-of (e2 / enzyme :name (n7 / name :op1 "JAK3"))))
            :location (c5 / cell-line :name (n8 / name :op1 "L-540"))
            :ARG1-of (d2 / describe-01
                  :ARG0 (f2 / figure :mod "S1A"
                        :ARG2-of (s4 / supplement-01))))
      :time (a6 / analyze-01
            :ARG1 (p3 / phosphorylate-01
                  :ARG1 (e3 / enzyme :name (n9 / name :op1 "JAK")))
            :duration (s5 / short-07
                  :degree (m3 / more))))

# ::id pmid_2282_9094.113 ::date 2015-07-26T13:27:46 ::annotator SDL-AMR-09 ::preferred
# ::snt The phosphorylation of the immediate downstream target STAT3 was abrogated at the same time point (30 min) in all the three cell lines, suggesting that the function of the JAKs was effectively inhibited after 30 min of incubation with AZD1480 (<xref ref-type="supplementary-material" rid="sup1">Supplementary Figure S1A</xref>).
# ::save-date Sun Dec 20, 2015 ::file pmid_2282_9094_113.txt
(a / abrogate-01
      :ARG1 (p / phosphorylate-01
            :ARG1 (t2 / target-01
                  :ARG1 (p2 / protein :name (n / name :op1 "STAT3"))
                  :mod (d / downstream)
                  :mod (i / immediacy)))
      :time (p3 / point
            :mod (t3 / time)
            :ARG1-of (s2 / same-01)
            :ARG1-of (m3 / mean-01
                  :ARG2 (t4 / temporal-quantity :quant 30
                        :unit (m / minute))))
      :location (c / cell-line :quant 3
            :mod (a2 / all))
      :ARG0-of (s3 / suggest-01
            :ARG1 (i2 / inhibit-01
                  :ARG1 (f / function-01
                        :ARG0 (e / enzyme :name (n2 / name :op1 "JAK")))
                  :ARG1-of (e2 / effective-04)
                  :time (a3 / after
                        :op1 (i3 / incubate-01
                              :ARG2 (s4 / small-molecule :name (n3 / name :op1 "AZD1480")))
                        :quant t4)))
      :ARG1-of (d2 / describe-01
            :ARG0 (f2 / figure :mod "S1A"
                  :ARG2-of (s5 / supplement-01))))

# ::id pmid_2282_9094.114 ::date 2015-07-26T13:38:16 ::annotator SDL-AMR-09 ::preferred
# ::snt <sec-title level="2">AZD1480 induces a negative-feedback loop involving phosphorylation ERK1/2 and p38</sec-title>
# ::save-date Fri Feb 5, 2016 ::file pmid_2282_9094_114.txt
(i / induce-01
      :ARG0 (s / small-molecule :name (n / name :op1 "AZD1480"))
      :ARG2 (l / loop
            :mod (f / feedback
                  :ARG0-of (n2 / negative-03))
            :ARG2-of (i2 / involve-01
                  :ARG1 (a / and
                        :op1 (p / phosphorylate-01
                              :ARG1 (e / enzyme :name (n3 / name :op1 "ERK1/2")))
                        :op2 (p2 / phosphorylate-01
                              :ARG1 (e2 / enzyme :name (n4 / name :op1 "p38")))))))

# ::id pmid_2282_9094.115 ::date 2015-07-26T13:44:05 ::annotator SDL-AMR-09 ::preferred
# ::snt As AZD1480 inhibition of STATs activity did not translate into antiproliferative activity in two cell lines, we hypothesized that these cells may depend on other signaling pathways to promote their survival.
# ::save-date Mon Dec 21, 2015 ::file pmid_2282_9094_115.txt
(h / hypothesize-01
      :ARG0 (w / we)
      :ARG1 (p / possible-01
            :ARG1 (d2 / depend-01
                  :ARG0 (c / cell
                        :mod (t / this))
                  :ARG1 (p2 / pathway
                        :ARG0-of (s / signal-07)
                        :mod (o / other))
                  :purpose (p3 / promote-01
                        :ARG0 p2
                        :ARG1 (s2 / survive-01
                              :ARG1 c))))
      :ARG1-of (c4 / cause-01
            :ARG0 (t2 / translate-01 :polarity -
                  :ARG1 (i / inhibit-01
                        :ARG0 (s3 / small-molecule :name (n / name :op1 "AZD1480"))
                        :ARG1 (a / activity-06
                              :ARG0 (p4 / protein :name (n2 / name :op1 "STAT"))))
                  :ARG2 (a2 / activity-06
                        :ARG0-of (c2 / counter-01
                              :ARG1 (p5 / proliferate-01)))
                  :location (c3 / cell-line :quant 2))))

# ::id pmid_2282_9094.116 ::date 2015-07-26T13:54:57 ::annotator SDL-AMR-09 ::preferred
# ::snt To test this hypothesis, we examined the effect of AZD1480 on ERK, p38 and phosphatidylinositol-3 kinase/AKT signaling pathways, which are known to promote HL survival.
# ::save-date Sun Aug 2, 2015 ::file pmid_2282_9094_116.txt
(e2 / examine-01
      :ARG0 (w / we)
      :ARG1 (a / affect-01
            :ARG0 (s / small-molecule :name (n2 / name :op1 "AZD1480"))
            :ARG1 (a2 / and
                  :op1 (p / pathway :name (n3 / name :op1 "ERK")
                        :ARG0-of (s2 / signal-07))
                  :op2 (p2 / pathway :name (n4 / name :op1 "p38")
                        :ARG0-of s2)
                  :op3 (p3 / pathway :name (n5 / name :op1 "phosphatidylinositol-3" :op2 "kinase/AKT")
                        :ARG0-of s2)
                  :ARG0-of (p4 / promote-01
                        :ARG1 (s5 / survive-01
                              :ARG1 (d / disease :name (n / name :op1 "HL")))
                        :ARG1-of (k / know-01))))
      :purpose (t2 / test-01
            :ARG0 w
            :ARG1 (t / thing
                  :ARG1-of (h / hypothesize-01)
                  :mod (t3 / this))))

# ::id pmid_2282_9094.117 ::date 2015-07-26T14:02:45 ::annotator SDL-AMR-09 ::preferred
# ::snt We found that AZD1480 had no effect on phosphatidylinositol-3 kinase/AKT signaling in any of these cell lines (data not shown).
# ::save-date Sun Jul 26, 2015 ::file pmid_2282_9094_117.txt
(f / find-01
      :ARG0 (w / we)
      :ARG1 (a / affect-01 :polarity -
            :ARG0 (s / small-molecule :name (n / name :op1 "AZD1480"))
            :ARG1 (s2 / signal-07
                  :ARG0 (p / pathway :name (n2 / name :op1 "phosphatidylinositol-3" :op2 "kinase/AKT")))
            :location (c / cell-line
                  :mod (a2 / any)
                  :mod (t / this)))
      :ARG1-of (d / describe-01
            :ARG0 (d2 / data
                  :ARG1-of (s3 / show-01 :polarity -))))

# ::id pmid_2282_9094.118 ::date 2015-07-26T14:11:49 ::annotator SDL-AMR-09 ::preferred
# ::snt In contrast, AZD1480 increased the levels of ERK and p38 phosphorylation in the resistant HD-LM2 and L-428 cells, whereas it inhibited ERK and p38 phosphorylation in the sensitive L-540 cells (<xref ref-type="fig" rid="fig3">Figure 3b</xref>).
# ::save-date Sat Jan 16, 2016 ::file pmid_2282_9094_118.txt
(c / contrast-01
      :ARG2 (c2 / contrast-01
            :ARG1 (i / increase-01
                  :ARG0 (s / small-molecule :name (n2 / name :op1 "AZD1480"))
                  :ARG1 (a / and
                        :op1 (l / level
                              :degree-of (p / phosphorylate-01
                                    :ARG1 (e / enzyme :name (n / name :op1 "ERK"))))
                        :op2 (l2 / level
                              :degree-of (p2 / phosphorylate-01
                                    :ARG1 (e2 / enzyme :name (n3 / name :op1 "p38")))))
                  :location (a2 / and
                        :op1 (c3 / cell-line :name (n4 / name :op1 "HD-LM2"))
                        :op2 (c4 / cell-line :name (n5 / name :op1 "L-428"))
                        :ARG0-of (r / resist-01)))
            :ARG2 (i2 / inhibit-01
                  :ARG0 s
                  :ARG1 a
                  :location (c5 / cell-line :name (n6 / name :op1 "L-540")
                        :ARG0-of (s2 / sensitive-03))))
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod "3b")))

# ::id pmid_2282_9094.119 ::date 2015-07-26T14:24:54 ::annotator SDL-AMR-09 ::preferred
# ::snt To define the mechanism of ERK and p38 activation in the two resistant cell lines, we first assessed the expression and activation levels of the Src homology 2 domain-containing protein phosphatase 2 (SHP-2) and SOCS-3 (a STAT3 target gene<sup><xref ref-type="bibr" rid="bib21">21</xref></sup>), two known regulators of JAK/STAT and mitogen-activated protein kinase (MAPK) signaling.
# ::save-date Sat Jan 16, 2016 ::file pmid_2282_9094_119.txt
(a / assess-01
      :ARG0 (w / we)
      :ARG1 (a2 / and
            :op1 (l / level
                  :degree-of (e / express-03
                        :ARG2 (a8 / and
                              :op1 (e5 / enzyme :name (n4 / name :op1 "protein" :op2 "phosphatase" :op3 "2"))
                              :op2 (p4 / protein :name (n5 / name :op1 "SOCS-3")
                                    :ARG0-of (t / target-01
                                          :ARG1 (p5 / protein :name (n6 / name :op1 "STAT3"))
                                          :ARG1-of (d / describe-01
                                                :ARG0 (p6 / publication-91 :mod 21))))
                              :ARG0-of (c / contain-01
                                    :ARG1 (p2 / protein-segment :name (n3 / name :op1 "Src" :op2 "homology" :op3 "2" :op4 "domain")))
                              :ARG0-of (r2 / regulate-01
                                    :ARG1 (a5 / and
                                          :op1 (s / signal-07
                                                :ARG0 (p7 / pathway :name (n7 / name :op1 "JAK-STAT")))
                                          :op2 (s2 / signal-07
                                                :ARG0 (p / pathway :name (n8 / name :op1 "mitogen-activated" :op2 "protein" :op3 "kinase"))))
                                    :ARG1-of (k / know-01)))))
            :op2 (l2 / level
                  :ARG1-of (a4 / activate-01)
                  :quant-of p2))
      :time (f / first)
      :purpose (d2 / define-01
            :ARG0 w
            :ARG1 (m / mechanism
                  :poss (a6 / activate-01
                        :ARG1 (a7 / and
                              :op1 (e2 / enzyme :name (n9 / name :op1 "ERK"))
                              :op2 (e4 / enzyme :name (n10 / name :op1 "p38")))
                        :location (c2 / cell-line :quant 2
                              :ARG0-of (r3 / resist-01))))))

# ::id pmid_2282_9094.120 ::date 2015-07-23T07:45:53 ::annotator SDL-AMR-09 ::preferred
# ::snt In fact, SHP-2 has been reported to be a negative regulator of the JAK/STAT activation, whereas having a positive effect on ERK activation.<sup><xref ref-type="bibr" rid="bib22">22</xref>, <xref ref-type="bibr" rid="bib23">23</xref>, <xref ref-type="bibr" rid="bib24">24</xref>, <xref ref-type="bibr" rid="bib25">25</xref></sup>
# ::save-date Sat Jan 16, 2016 ::file pmid_2282_9094_120.txt
(r / report-01
      :ARG1 (d / downregulate-01
            :ARG1 (a / activate-01
                  :ARG1 (p2 / pathway :name (n2 / name :op1 "JAK/STAT")))
            :ARG2 (p / protein :name (n / name :op1 "SHP-2")))
      :manner (i / in-fact)
      :ARG1-of (c / contrast-01
            :ARG2 (a2 / affect-01
                  :ARG0 p
                  :ARG1 (a3 / activate-01
                        :ARG1 (e / enzyme :name (n3 / name :op1 "ERK")))
                  :mod (p3 / positive)))
      :ARG1-of (d2 / describe-01
            :ARG0 (p4 / publication
                  :ARG1-of (c2 / cite-01
                        :ARG0 (a4 / and :op1 22 :op2 23 :op3 24 :op4 25)))))

# ::id pmid_2282_9094.121 ::date 2015-07-24T04:03:11 ::annotator SDL-AMR-09 ::preferred
# ::snt Furthermore, numerous studies have described enhanced SHP-2 and ERK activation after <i>SOCS-3</i> deletion in both <i>in vitro</i> and <i>in vivo</i> models, postulating a negative-feedback loop between SOCS-3 and SHP-2.<sup><xref ref-type="bibr" rid="bib22">22</xref>, <xref ref-type="bibr" rid="bib23">23</xref>, <xref ref-type="bibr" rid="bib26">26</xref></sup>
# ::save-date Fri Feb 5, 2016 ::file pmid_2282_9094_121.txt
(a / and
      :op2 (d / describe-01
            :ARG0 (s / study-01
                  :mod (n4 / numerous)
                  :ARG0-of (p / postulate-01
                        :ARG1 (l / loop-01
                              :ARG2 (b / between
                                    :op1 p4
                                    :op2 (p3 / protein :name (n3 / name :op1 "SHP-2")))
                              :mod (f / feedback
                                    :ARG0-of (n / negative-03)))))
            :ARG1 (a2 / and
                  :op1 (a3 / activate-01
                        :ARG1 p3)
                  :op2 (a4 / activate-01
                        :ARG1 (e / enzyme :name (n5 / name :op1 "ERK"))
                        :time (a5 / after
                              :op1 (d2 / delete-01
                                    :ARG1 (p4 / protein :name (n6 / name :op1 "SOCS-3"))
                                    :ARG2 (a6 / and
                                          :op1 (m / model
                                                :mod (i / in-vivo))
                                          :op2 (m2 / model
                                                :mod (i2 / in-vitro))))))
                  :ARG1-of (e2 / enhance-01)))
      :ARG1-of (d3 / describe-01
            :ARG0 (p5 / publication
                  :ARG0-of (c / cite-01
                        :ARG1 (a7 / and :op1 22 :op2 23 :op3 26)))))

# ::id pmid_2282_9094.122 ::date 2015-07-25T13:33:25 ::annotator SDL-AMR-09 ::preferred
# ::snt Consistent with the described changes in ERK phosphorylation status, after 72 h of incubation with increasing doses of AZD1480 (0.1–5 μ), an increase in SHP-2 phosphorylation on Tyr542 (the major site of SHP-2 activation) coupled with SOCS3 downregulation was observed in the HD-LM2 and L-428 cell lines, but not in the L-540 cells (<xref ref-type="fig" rid="fig3">Figure 3b</xref>).
# ::save-date Sat Jan 16, 2016 ::file pmid_2282_9094_122.txt
(c8 / contrast-01
      :ARG1 (o3 / observe-01
            :ARG1 (i3 / increase-01
                  :ARG1 (p2 / phosphorylate-01
                        :ARG1 (a2 / amino-acid :name (n4 / name :op1 "Tyr542")
                              :ARG1-of (m3 / mean-01
                                    :ARG2 (s2 / site-01
                                          :ARG1 (a3 / activate-01
                                                :ARG1 p3)
                                          :ARG1-of (m4 / major-02))))
                        :ARG2 (p3 / protein :name (n3 / name :op1 "SHP-2"))
                        :ARG1-of (c5 / couple-01
                              :ARG2 (d4 / downregulate-01
                                    :ARG1 (p4 / protein :name (n5 / name :op1 "SOCS3"))))))
            :ARG1-of (c / consistent-01
                  :ARG2 (c2 / change-01
                        :ARG1 (s / status
                              :topic (p / phosphorylate-01
                                    :ARG1 (e / enzyme :name (n / name :op1 "ERK"))))
                        :ARG1-of (d / describe-01)))
            :time (a / after
                  :op1 (i / incubate-01
                        :ARG2 (d2 / dose-01
                              :ARG2 (s3 / small-molecule :name (n2 / name :op1 "AZD1480"))
                              :ARG1-of (i2 / increase-01)
                              :quant (b / between
                                    :op1 (c3 / concentration-quantity :quant 0.1
                                          :unit (m / micromolar))
                                    :op2 (c4 / concentration-quantity :quant 5
                                          :unit m))))
                  :quant (t / temporal-quantity :quant 72
                        :unit (h / hour)))
            :ARG1-of (d3 / describe-01
                  :ARG0 (f / figure :mod "3b"))
            :location (a4 / and
                  :op1 (c6 / cell-line :name (n6 / name :op1 "HD-LM2"))
                  :op2 (c7 / cell-line :name (n7 / name :op1 "L-428"))))
      :ARG2 (o2 / observe-01 :polarity -
            :ARG1 i3
            :location (c9 / cell-line :name (n8 / name :op1 "L-540"))))

# ::id pmid_2282_9094.123 ::date 2015-07-25T05:57:53 ::annotator SDL-AMR-09 ::preferred
# ::snt On the other hand, in the L-540 cells, SOCS3 downregulation was not coupled with SHP-2 hyperphosphorylation, and ERK phosphorylation was in fact inhibited after treatment with AZD1480, suggesting a different model of MAPK activation in this cell line.
# ::save-date Sun Jan 17, 2016 ::file pmid_2282_9094_123.txt
(c / contrast-01
      :ARG2 (a / and
            :op1 (c2 / couple-01 :polarity -
                  :ARG1 (d2 / downregulate-01
                        :ARG1 (p3 / protein :name (n4 / name :op1 "SOCS3"))
                        :location (c3 / cell-line :name (n6 / name :op1 "L-540")))
                  :ARG2 (h / hyperphosphorylate-01
                        :ARG1 (p4 / protein :name (n5 / name :op1 "SHP-2"))))
            :op2 (i / inhibit-01
                  :ARG1 (p / phosphorylate-01
                        :ARG1 (e / enzyme :name (n / name :op1 "ERK")))
                  :time (a2 / after
                        :op1 (t / treat-04
                              :ARG2 (s2 / small-molecule :name (n3 / name :op1 "AZD1480"))))
                  :mod (i2 / in-fact))
            :ARG0-of (s / suggest-01
                  :ARG1 (m / model
                        :ARG1-of (d / differ-02)
                        :mod (a3 / activate-01
                              :ARG1 (p2 / pathway :name (n2 / name :op1 "MAPK"))
                              :location c3)))))

# ::id pmid_2282_9094.124 ::date 2015-07-25T06:29:12 ::annotator SDL-AMR-09 ::preferred
# ::snt The activation of p38 signaling observed in the HD-LM2 and L-428 cell lines after incubation with AZD1480 was probably related to the activity of autocrine and paracrine chemokine and cytokine loops, triggered by SHP-2/ERK activation.
# ::save-date Wed Aug 5, 2015 ::file pmid_2282_9094_124.txt
(r / relate-01
      :ARG1 (a5 / activate-01
            :ARG1 (s / signal-07
                  :ARG0 (e / enzyme :name (n2 / name :op1 "p38"))
                  :ARG1-of (o / observe-01
                        :location (a6 / and
                              :op1 (c3 / cell-line :name (n3 / name :op1 "HD-LM2"))
                              :op2 (c4 / cell-line :name (n4 / name :op1 "L-428")))
                        :time (a7 / after
                              :op1 (i / incubate-01
                                    :ARG2 (s2 / small-molecule :name (n5 / name :op1 "AZD1480")))))))
      :ARG2 (a / activity-06
            :ARG0 (a2 / and
                  :op1 (l3 / loop
                        :mod (c / chemokine
                              :mod (a3 / autocrine)))
                  :op2 (l / loop
                        :mod (c5 / chemokine
                              :mod p2))
                  :op3 (l2 / loop
                        :mod (c6 / cytokine
                              :mod a3))
                  :op4 (l4 / loop
                        :mod (c2 / cytokine
                              :mod (p2 / paracrine)))
                  :ARG1-of (t / trigger-01
                        :ARG2 (a4 / activate-01
                              :ARG1 (p3 / pathway :name (n / name :op1 "SHP-2/ERK"))))))
      :mod (p / probable))

# ::id pmid_2282_9094.125 ::date 2015-07-26T03:40:24 ::annotator SDL-AMR-09 ::preferred
# ::snt Over a shorter time period, we observed a strong correlation between SOCS-3 downregulation and SHP-2/ERK activation in the HD-LM2 cell line after 6 h of incubation with AZD1480, whereas in the L-540 cell line, ERK phosphorylation was inhibited without an increase in SHP-2 phosphorylation or a decrease in SOCS-3 levels (<xref ref-type="supplementary-material" rid="sup1">Supplementary Figure S1D</xref>).
# ::save-date Mon Jan 4, 2016 ::file pmid_2282_9094_125.txt
(c / contrast-01
      :ARG1 (o / observe-01
            :ARG0 (w / we)
            :ARG1 (c2 / correlate-01
                  :ARG1 (d / downregulate-01
                        :ARG1 (p / protein :name (n / name :op1 "SOCS-3")))
                  :ARG2 (a / activate-01
                        :ARG1 (p3 / pathway :name (n2 / name :op1 "SHP-2/ERK")))
                  :ARG1-of (s2 / strong-02))
            :time (o2 / over
                  :op1 (p2 / period
                        :ARG1-of (s / short-07
                              :degree (m / more))))
            :location (c3 / cell-line :name (n3 / name :op1 "HD-LM2"))
            :time (a2 / after
                  :op1 (i / incubate-01
                        :ARG2 (s4 / small-molecule :name (n4 / name :op1 "AZD1480"))
                        :duration (t2 / temporal-quantity :quant 6
                              :unit (h / hour)))))
      :ARG2 (i2 / inhibit-01 :polarity -
            :ARG1 (p4 / phosphorylate-01
                  :ARG1 (p7 / protein-family :name (n5 / name :op1 "ERK")))
            :ARG0-of (i3 / increase-01 :polarity -
                  :ARG1 (o3 / or
                        :op1 (p5 / phosphorylate-01
                              :ARG1 (p6 / protein :name (n6 / name :op1 "SHP-2")))))
            :location (c4 / cell-line :name (n8 / name :op1 "L-540"))
            :ARG0-of (d2 / decrease-01 :polarity -
                  :ARG1 (l / level
                        :quant-of p)))
      :ARG1-of (d3 / describe-01
            :ARG0 (f / figure :mod "S1D"
                  :ARG2-of (s3 / supplement-01))))

# ::id pmid_2282_9094.126 ::date 2015-07-24T14:27:39 ::annotator SDL-AMR-09 ::preferred
# ::snt <sec-title level="2">AZD1480 determines increased production of the chemokines IP-10, IL-8 and RANTES in HL cells</sec-title>
# ::save-date Sun Jan 17, 2016 ::file pmid_2282_9094_126.txt
(d2 / determine-01
      :ARG0 (s / small-molecule :name (n / name :op1 "AZD1480"))
      :ARG1 (p / produce-01
            :ARG1 (a / and
                  :op1 (c / chemokine :name (n3 / name :op1 "IP-10"))
                  :op2 (c2 / chemokine :name (n4 / name :op1 "IL-8"))
                  :op3 (c3 / chemokine :name (n5 / name :op1 "RANTES"))
                  :location (c4 / cell-line
                        :mod (d / disease :name (n2 / name :op1 "HL"))))
            :ARG1-of (i / increase-01)))

# ::id pmid_2282_9094.127 ::date 2015-07-24T14:34:32 ::annotator SDL-AMR-09 ::preferred
# ::snt The interaction between HRS cells and the surrounding reactive infiltrate provides an environment that supports the growth and survival of HRS cells through a complex network of autocrine and paracrine loops involving a variety of cytokines and chemokines.<sup><xref ref-type="bibr" rid="bib1">1</xref>, <xref ref-type="bibr" rid="bib27">27</xref></sup>
# ::save-date Sat Aug 1, 2015 ::file pmid_2282_9094_127.txt
(p / provide-01
      :ARG0 (i / interact-01
            :ARG0 (c / cell-line :name (n / name :op1 "HRS"))
            :ARG1 (i2 / infiltrate
                  :ARG0-of (r / react-01)
                  :ARG1-of (s / surround-01)))
      :ARG1 (e / environment
            :ARG0-of (s2 / support-01
                  :ARG1 (a / and
                        :op1 (g / grow-01
                              :ARG1 c)
                        :op2 (s3 / survive-01
                              :ARG0 c))
                  :manner (n2 / network-01
                        :ARG1 (l / loop-01
                              :ARG1 (a2 / autocrine))
                        :ARG2 (l2 / loop-01
                              :ARG1 (p2 / paracrine))
                        :ARG2-of (i3 / involve-01
                              :ARG1 (a3 / and
                                    :op1 (v / vary-01
                                          :ARG1 (c2 / cytokine))
                                    :op2 (v2 / vary-01
                                          :ARG1 (c3 / chemokine))))
                        :mod (c4 / complex))))
      :ARG1-of (d / describe-01
            :ARG0 (p3 / publication
                  :ARG0-of (c5 / cite-01
                        :ARG1 (a4 / and :op1 1 :op2 27)))))

# ::id pmid_2282_9094.128 ::date 2015-07-25T12:30:33 ::annotator SDL-AMR-09 ::preferred
# ::snt The chemokines IP-10, RANTES and IL-8 are known to be upregulated by MAPK (ERK and p38) activation and have previously been reported to have a role in tumorigenesis and Hodgkin lymphomagenesis by promoting cell proliferation and survival.<sup><xref ref-type="bibr" rid="bib1">1</xref>, <xref ref-type="bibr" rid="bib27">27</xref>, <xref ref-type="bibr" rid="bib28">28</xref>, <xref ref-type="bibr" rid="bib29">29</xref>, <xref ref-type="bibr" rid="bib30">30</xref>, <xref ref-type="bibr" rid="bib31">31</xref></sup>
# ::save-date Sat Jan 16, 2016 ::file pmid_2282_9094_128.txt
(a / and
      :op1 (k / know-01
            :ARG1 (u / upregulate-01
                  :ARG1 (a3 / and
                        :op1 (c2 / chemokine :name (n3 / name :op1 "IP-10"))
                        :op2 (c3 / chemokine :name (n4 / name :op1 "RANTES"))
                        :op3 (c4 / chemokine :name (n5 / name :op1 "IL-8")))
                  :ARG2 (a5 / activate-01
                        :ARG1 (p3 / pathway :name (n6 / name :op1 "MAPK")
                              :ARG1-of (m / mean-01
                                    :ARG2 (a4 / and
                                          :op1 (e / enzyme :name (n / name :op1 "ERK"))
                                          :op2 (e2 / enzyme :name (n2 / name :op1 "p38"))))))))
      :op2 (r / report-01
            :ARG1 (h / have-03
                  :ARG0 a3
                  :ARG1 (r2 / role
                        :prep-in (c6 / create-01
                              :ARG1 (a8 / and
                                    :op1 (t2 / tumor)
                                    :op2 (d2 / disease :name (n8 / name :op1 "Hodgkin" :op2 "lymphoma")))))
                  :manner (p4 / promote-01
                        :ARG0 a3
                        :ARG1 (a7 / and
                              :op1 (p5 / proliferate-01
                                    :ARG0 (c5 / cell))
                              :op2 (s / survive-01
                                    :ARG0 c5))))
            :time (p / previous))
      :ARG1-of (d / describe-01
            :ARG0 (p2 / publication
                  :ARG0-of (c / cite-01
                        :ARG1 (a2 / and :op1 1 :op2 27 :op3 28 :op4 29 :op5 30 :op6 31)))))

# ::id pmid_2282_9094.129 ::date 2015-07-25T05:10:48 ::annotator SDL-AMR-09 ::preferred
# ::snt Consistent with the observed changes in SHP2, ERK and p38 phosphorylation, AZD1480 increased the production of IP-10, RANTES and IL-8 in the supernatants of the resistant HD-LM2 and L-428, and not the sensitive L-540 cells.
# ::save-date Sat Jan 16, 2016 ::file pmid_2282_9094_129.txt
(i / increase-01
      :ARG0 (s3 / small-molecule :name (n / name :op1 "AZD1480"))
      :ARG1 (p / produce-01
            :ARG1 (a2 / and
                  :op1 (p2 / protein :name (n5 / name :op1 "IP-10"))
                  :op2 (p3 / protein :name (n6 / name :op1 "RANTES"))
                  :op3 (p4 / protein :name (n7 / name :op1 "IL-8")))
            :location (s / supernatant
                  :poss (a3 / and
                        :op1 (c3 / cell-line :name (n9 / name :op1 "HD-LM2"))
                        :op2 (c4 / cell-line :name (n10 / name :op1 "L-428"))
                        :ARG0-of (r / resist-01))
                  :ARG1-of (c5 / contrast-01
                        :ARG2 (c6 / cell-line :name (n8 / name :op1 "L-540")
                              :ARG0-of (s2 / sensitive-03)))))
      :ARG1-of (c / consistent-01
            :ARG2 (c2 / change-01
                  :ARG1 (p5 / phosphorylate-01
                        :ARG1 (a / and
                              :op1 (e2 / enzyme :name (n2 / name :op1 "SHP2"))
                              :op2 (e / enzyme :name (n3 / name :op1 "ERK"))
                              :op3 (e4 / enzyme :name (n4 / name :op1 "p38"))))
                  :ARG1-of (o / observe-01))))

# ::id pmid_2282_9094.130 ::date 2015-07-25T05:22:20 ::annotator SDL-AMR-09 ::preferred
# ::snt (<xref ref-type="fig" rid="fig3">Figure 3c</xref>).
# ::save-date Sat Jul 25, 2015 ::file pmid_2282_9094_130.txt
(f / figure :mod "3c")

# ::id pmid_2282_9094.131 ::date 2015-07-25T03:53:53 ::annotator SDL-AMR-09 ::preferred
# ::snt This data suggest that the efficacy of AZD1480 may have been attenuated in the HD-LM2 and L-428 cells by an autocrine negative-feedback loop involving cytokines that activate ERK/p38 survival signaling pathway.
# ::save-date Fri Feb 5, 2016 ::file pmid_2282_9094_131.txt
(s / suggest-01
      :ARG0 (d / data
            :mod (t / this))
      :ARG1 (p / possible-01
            :ARG1 (a / attenuate-01
                  :ARG0 (l2 / loop-01
                        :mod (f / feedback
                              :mod (a3 / autocrine)
                              :ARG0-of (n3 / negative-03)
                              :ARG2-of (i / involve-01
                                    :ARG1 (c3 / cytokine
                                          :ARG0-of (a4 / activate-01
                                                :ARG1 (p2 / pathway :name (n4 / name :op1 "ERK/p38")
                                                      :ARG0-of (s2 / signal-07
                                                            :ARG1 (s3 / survive-01))))))))
                  :ARG1 (e / efficacy
                        :poss (s4 / small-molecule :name (n5 / name :op1 "AZD1480")))
                  :location (a2 / and
                        :op1 (c / cell-line :name (n / name :op1 "HD-LM2"))
                        :op2 (c2 / cell-line :name (n2 / name :op1 "L-428"))))))

# ::id pmid_2282_9094.132 ::date 2015-07-24T14:36:28 ::annotator SDL-AMR-09 ::preferred
# ::snt <sec-title level="2">MEK inhibitors enhance the efficacy of AZD1480 in the HD-LM2 and L-428 cell lines</sec-title>
# ::save-date Sat Jan 16, 2016 ::file pmid_2282_9094_132.txt
(e2 / enhance-01
      :ARG0 (m / molecular-physical-entity
            :ARG0-of (i / inhibit-01
                  :ARG1 (p / protein-family :name (n2 / name :op1 "MEK"))))
      :ARG1 (e / efficacy
            :poss (s / small-molecule :name (n / name :op1 "AZD1480")))
      :location (a / and
            :op1 (c / cell-line :name (n3 / name :op1 "HD-LM2"))
            :op2 (c2 / cell-line :name (n4 / name :op1 "L-428"))))

# ::id pmid_2282_9094.133 ::date 2015-07-24T14:42:28 ::annotator SDL-AMR-09 ::preferred
# ::snt To assess whether the observed activation of the SHP-2/ERK pathway is involved in the resistance to JAK/STAT inhibition, HL cells were treated with 1 μ AZD1480 in combination with two commercially available MEK inhibitors (UO126 and PD98059).
# ::save-date Sun Jan 17, 2016 ::file pmid_2282_9094_133.txt
(t2 / treat-04
      :ARG1 (c2 / cell-line
            :mod (d / disease :name (n / name :op1 "HL")))
      :ARG2 (s / small-molecule :name (n4 / name :op1 "AZD1480")
            :quant (c / concentration-quantity :quant 1
                  :unit (m / micromolar))
            :ARG1-of (c3 / combine-01
                  :ARG2 (m2 / molecular-physical-entity :quant 2
                        :ARG0-of (i / inhibit-01
                              :ARG1 (p / protein-family :name (n5 / name :op1 "MEK")))
                        :ARG2-of (a3 / available-02
                              :manner (c4 / commercial))
                        :ARG1-of (m3 / mean-01
                              :ARG2 (a4 / and
                                    :op1 (s2 / small-molecule :name (n6 / name :op1 "UO126"))
                                    :op2 (s3 / small-molecule :name (n7 / name :op1 "PD98059")))))))
      :purpose (a / assess-01
            :ARG1 (i2 / involve-01 :mode interrogative
                  :ARG1 (a2 / activate-01
                        :ARG1 (p2 / pathway :name (n2 / name :op1 "SHP-2/ERK"))
                        :ARG1-of (o / observe-01))
                  :ARG2 (r / resist-01
                        :ARG1 (i3 / inhibit-01
                              :ARG1 (p3 / pathway :name (n3 / name :op1 "JAK/STAT")))))))

# ::id pmid_2282_9094.134 ::date 2015-07-25T10:41:30 ::annotator SDL-AMR-09 ::preferred
# ::snt Cells were incubated with increasing concentrations of UO126 or PD98059 (10–100 μ), with or without 1 μ AZD1480 for 24, 48 and 72 h, and cell viability was assessed using the MTS assay.
# ::save-date Sat Feb 13, 2016 ::file pmid_2282_9094_134.txt
(a / and
      :op1 (i / incubate-01
            :ARG1 (c2 / cell)
            :ARG2 (c3 / concentrate-01
                  :ARG1 (o / or
                        :op1 (s2 / small-molecule :name (n2 / name :op1 "UO126"))
                        :op2 (s3 / small-molecule :name (n3 / name :op1 "PD98059"))
                        :quant (b / between
                              :op1 (c4 / concentration-quantity :quant 10
                                    :unit (m2 / micromolar))
                              :op2 (c5 / concentration-quantity :quant 100
                                    :unit m2)))
                  :ARG1-of (i2 / increase-01))
            :manner (o2 / or
                  :op1 (s / small-molecule :name (n4 / name :op1 "AZD1480")
                        :quant (c6 / concentration-quantity :quant 1
                              :unit m2))
                  :op2 (s4 / small-molecule :polarity - :name (n5 / name :op1 "AZD1480")))
            :duration (a4 / and
                  :op1 (t2 / temporal-quantity :quant 24
                        :unit (h / hour))
                  :op2 (t3 / temporal-quantity :quant 48
                        :unit (h2 / hour))
                  :op3 (t4 / temporal-quantity :quant 72
                        :unit (h3 / hour))))
      :op2 (a2 / assess-01
            :ARG1 (v2 / viability
                  :poss (c / cell))
            :ARG2-of (u / use-01
                  :ARG1 (a3 / assay-01
                        :instrument (s5 / small-molecule :name (n / name :op1 "MTS"))))))

# ::id pmid_2282_9094.135 ::date 2015-07-25T04:06:42 ::annotator SDL-AMR-09 ::preferred
# ::snt Both UO126 and PD98059 enhanced the effect of AZD1480 in the HD-LM2 and L-428 cells at 72 h (<xref ref-type="fig" rid="fig3">Figure 3d</xref>).
# ::save-date Sat Aug 1, 2015 ::file pmid_2282_9094_135.txt
(e / enhance-01
      :ARG0 (a / and
            :op1 (s / small-molecule :name (n2 / name :op1 "UO126"))
            :op2 (s2 / small-molecule :name (n / name :op1 "PD98059")))
      :ARG1 (a2 / affect-01
            :ARG0 (s3 / small-molecule :name (n3 / name :op1 "AZD1480")))
      :location (a3 / and
            :op1 (c / cell-line :name (n4 / name :op1 "HD-LM2"))
            :op2 (c2 / cell-line :name (n5 / name :op1 "L-428"))
            :time (a4 / after
                  :op1 (t / temporal-quantity :quant 72
                        :unit (h / hour))))
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod "3d")))

# ::id pmid_2282_9094.136 ::date 2015-07-25T04:18:22 ::annotator SDL-AMR-09 ::preferred
# ::snt This effect was associated with inhibition of AZD1480-induced ERK phosphorylation (<xref ref-type="fig" rid="fig3">Figure 3e</xref>).
# ::save-date Sat Jan 16, 2016 ::file pmid_2282_9094_136.txt
(a / associate-01
      :ARG1 (a2 / affect-01
            :mod (t / this))
      :ARG2 (i / inhibit-01
            :ARG1 (p2 / phosphorylate-01
                  :ARG1 (e / enzyme :name (n / name :op1 "ERK"))
                  :ARG2-of (i2 / induce-01
                        :ARG0 (s / small-molecule :name (n2 / name :op1 "AZD1480")))))
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod "3e")))

# ::id pmid_2282_9094.137 ::date 2015-07-24T14:43:54 ::annotator SDL-AMR-09 ::preferred
# ::snt <sec-title level="2">Immunoregulatory effects of AZD1480 in HL cells</sec-title>
# ::save-date Sun Jan 17, 2016 ::file pmid_2282_9094_137.txt
(a / affect-01
      :ARG0 (s / small-molecule :name (n2 / name :op1 "AZD1480"))
      :ARG1 (c / cell-line
            :mod (d / disease :name (n / name :op1 "HL")))
      :ARG2 (i / immunoregulate-00))

# ::id pmid_2282_9094.138 ::date 2015-07-24T14:49:55 ::annotator SDL-AMR-09 ::preferred
# ::snt PD-L1 and PD-L2 are members of the B7 family, which inhibit T-cell function by interacting with the programmed cell death 1 receptor expressed on T cells.
# ::save-date Wed Aug 5, 2015 ::file pmid_2282_9094_138.txt
(m / member
      :ARG1-of (i3 / include-91
            :ARG2 (f / family
                  :mod (p4 / protein :name (n5 / name :op1 "B7"))))
      :domain (a / and
            :op1 (p2 / protein :name (n / name :op1 "PD-L1"))
            :op2 (p3 / protein :name (n2 / name :op1 "PD-L2")))
      :ARG0-of (i / inhibit-01
            :ARG1 (f2 / function-01
                  :ARG0 (c3 / cell :name (n3 / name :op1 "T")))
            :manner (i2 / interact-01
                  :ARG0 a
                  :ARG1 (p / protein :name (n4 / name :op1 "programmed" :op2 "cell" :op3 "death" :op4 "1" :op5 "receptor")
                        :ARG2-of (e / express-03
                              :ARG3 c3)))))

# ::id pmid_2282_9094.139 ::date 2015-07-24T23:32:16 ::annotator SDL-AMR-09 ::preferred
# ::snt PD-L1 and PD-L2 have been reported to be regulated by the JAK/STAT pathway or the MAPK pathway, depending on the cellular context.<sup><xref ref-type="bibr" rid="bib9">9</xref>, <xref ref-type="bibr" rid="bib11">11</xref>, <xref ref-type="bibr" rid="bib13">13</xref></sup>
# ::save-date Fri Jul 24, 2015 ::file pmid_2282_9094_139.txt
(r / report-01
      :ARG1 (r2 / regulate-01
            :ARG0 (o / or
                  :op1 (p4 / pathway :name (n4 / name :op1 "JAK/STAT"))
                  :op2 (p5 / pathway :name (n5 / name :op1 "MAPK")))
            :ARG1 (a / and
                  :op1 (p2 / protein :name (n2 / name :op1 "PD-L1"))
                  :op2 (p3 / protein :name (n3 / name :op1 "PD-L2")))
            :ARG0-of (d / depend-01
                  :ARG1 (c / context
                        :mod (c2 / cell))))
      :ARG1-of (d2 / describe-01
            :ARG0 (p / publication
                  :ARG1-of (c3 / cite-01
                        :ARG0 (a2 / and :op1 9 :op2 11 :op3 13)))))

# ::id pmid_2282_9094.140 ::date 2015-07-24T23:39:14 ::annotator SDL-AMR-09 ::preferred
# ::snt Therefore, we assessed the effect of AZD1480 on PD-L1 and PD-L2 expression in HL cells by flow cytometry.
# ::save-date Sun Jan 17, 2016 ::file pmid_2282_9094_140.txt
(c / cause-01
      :ARG1 (a / assess-01
            :ARG0 (w / we)
            :ARG1 (a2 / and
                  :op1 (a3 / affect-01
                        :ARG0 (s / small-molecule :name (n / name :op1 "AZD1480"))
                        :ARG1 (e2 / express-03
                              :ARG1 (p / protein :name (n2 / name :op1 "PD-L1"))))
                  :op2 (a4 / affect-01
                        :ARG1 (e / express-03
                              :ARG2 (p2 / protein :name (n3 / name :op1 "PD-L2"))
                              :ARG3 (c2 / cell-line
                                    :mod (d / disease :name (n4 / name :op1 "HL"))))))
            :instrument (c3 / cytometry
                  :mod (f / flow))))

# ::id pmid_2282_9094.141 ::date 2015-07-24T23:57:12 ::annotator SDL-AMR-09 ::preferred
# ::snt After incubation with AZD1480 1 μ for 72 h, we observed a significant downregulation of PD-L1 and PD-L2 in the PD-L1/PD-L2-positive HL cell lines HD-LM2 and L-540 (<xref ref-type="fig" rid="fig4">Figure 4a and b</xref>).
# ::save-date Sun Jan 17, 2016 ::file pmid_2282_9094_141.txt
(o / observe-01
      :ARG0 (w / we)
      :ARG1 (d2 / downregulate-01
            :ARG1 (a3 / and
                  :op1 (p / protein :name (n4 / name :op1 "PD-L1"))
                  :op2 (p2 / protein :name (n5 / name :op1 "PD-L2")))
            :ARG1-of (s / significant-02)
            :location (c4 / cell-line
                  :ARG1-of (m2 / mean-01
                        :ARG0 (a4 / and
                              :op1 (c2 / cell-line :name (n2 / name :op1 "HD-LM2"))
                              :op2 (c3 / cell-line :name (n3 / name :op1 "L-540"))))
                  :mod (p4 / positive
                        :topic p2)
                  :mod (d3 / disease :name (n6 / name :op1 "HL"))))
      :ARG1-of (d / describe-01
            :ARG0 (a / and
                  :op1 (f / figure :mod "4a")
                  :op2 (f2 / figure :mod "4b")))
      :time (a2 / after
            :op1 (i / incubate-01
                  :ARG2 (s2 / small-molecule :name (n / name :op1 "AZD1480")
                        :quant (c / concentration-quantity :quant 1
                              :unit (m / micromolar)))
                  :duration (t / temporal-quantity :quant 72
                        :unit (h / hour)))))

# ::id pmid_2282_9094.142 ::date 2015-07-25T02:45:28 ::annotator SDL-AMR-09 ::preferred
# ::snt No significant dowregulation was detected following incubation with MEK inhibitors (UO126 and PD98059 25 μ for 72 h) in the L-540 cell line (data not shown).
# ::save-date Sat Jan 16, 2016 ::file pmid_2282_9094_142.txt
(d / detect-01 :polarity -
      :ARG1 (d2 / downregulate-01
            :ARG1-of (s / significant-02))
      :ARG1-of (f / follow-01
            :ARG2 (i2 / incubate-01
                  :ARG2 (m3 / molecular-physical-entity
                        :ARG0-of (i / inhibit-01
                              :ARG1 (p / protein-family :name (n / name :op1 "MEK")))
                        :location (c / cell-line :name (n2 / name :op1 "L-540"))
                        :ARG1-of (m / mean-01
                              :ARG2 (a / and
                                    :op1 (s3 / small-molecule :name (n3 / name :op1 "UO126"))
                                    :op2 (s4 / small-molecule :name (n4 / name :op1 "PD98059"))
                                    :quant (c2 / concentration-quantity :quant 25
                                          :unit (m2 / micromolar)))))
                  :duration (t2 / temporal-quantity :quant 72
                        :unit (h / hour))))
      :ARG1-of (d3 / describe-01
            :ARG0 (d4 / data
                  :ARG1-of (s2 / show-01 :polarity -))))

# ::id pmid_2282_9094.143 ::date 2015-07-25T03:52:34 ::annotator SDL-AMR-09 ::preferred
# ::snt On the other hand, in the HD-LM2 cell line, an increase in the activation of ERK was observed after incubation with AZD1480, ruling out a role of this pathway in the regulation of PD ligands expression in this cell line (<xref ref-type="fig" rid="fig3">Figure 3b</xref>).
# ::save-date Tue Jan 12, 2016 ::file pmid_2282_9094_143.txt
(c2 / contrast-01
      :ARG2 (o / observe-01
            :ARG1 (i / increase-01
                  :ARG1 (a / activate-01
                        :ARG1 (e / enzyme :wiki "Extracellular_signal-regulated_kinases"
                              :name (n2 / name :op1 "ERK")))
                  :location (c / cell-line :wiki -
                        :name (n3 / name :op1 "HD-LM2")))
            :time (a2 / after
                  :op1 (i2 / incubate-01
                        :ARG2 (s / small-molecule :wiki -
                              :name (n / name :op1 "AZD1480"))))
            :ARG0-of (r / rule-out-02
                  :ARG1 (r2 / role
                        :poss e)
                  :ARG2 (r3 / regulate-01
                        :ARG0 e
                        :ARG1 (e2 / express-03
                              :ARG2 (p / protein :wiki "PD-L1"
                                    :name (n4 / name :op1 "PD-ligand"))
                              :ARG3 c))))
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod "3b")))

# ::id pmid_2282_9094.144 ::date 2015-07-25T11:29:38 ::annotator SDL-AMR-09 ::preferred
# ::snt Given the potent inhibition of STAT proteins phosphorylation observed with low doses AZD1480 (0.1–1 μ), we also assessed the effect of AZD1480 on the expression of STAT-regulated cytokines and chemokines involved in HL cell survival (IL-6) and immune escape (IL-13, TARC), focusing on the three cell lines with baseline JAK/STAT activation.
# ::save-date Sun Jan 17, 2016 ::file pmid_2282_9094_144.txt
(a / assess-01
      :ARG0 (w / we)
      :ARG1 (a4 / and
            :op1 (a5 / affect-01
                  :ARG0 s2
                  :ARG1 (e3 / express-03
                        :ARG2 (a7 / and
                              :op1 (c4 / cytokine)
                              :op2 (c6 / chemokine)
                              :ARG1-of (r / regulate-01
                                    :ARG0 (p4 / protein :name (n3 / name :op1 "STAT")))
                              :ARG1-of (m3 / mean-01
                                    :ARG2 (a9 / and
                                          :op1 (p6 / protein :name (n6 / name :op1 "IL-13"))
                                          :op2 (p7 / protein :name (n7 / name :op1 "TARC"))
                                          :ARG1-of (i4 / involve-01
                                                :ARG2 (e2 / escape-01
                                                      :ARG1 (i3 / immune-02)))))
                              :ARG1-of (m2 / mean-01
                                    :ARG2 (p8 / protein :name (n8 / name :op1 "IL-6")
                                          :ARG1-of (i2 / involve-01
                                                :ARG2 (s / survive-01
                                                      :ARG0 (c5 / cell-line
                                                            :mod (d2 / disease :name (n / name :op1 "HL")))))))))))
      :ARG1-of (c / cause-01
            :ARG0 (i / inhibit-01
                  :ARG0 (s2 / small-molecule :name (n2 / name :op1 "AZD1480")
                        :ARG2-of (d / dose-01
                              :ARG1-of (l / low-04)
                              :quant (a2 / and
                                    :op1 (c2 / concentration-quantity :quant 0.1
                                          :unit (m / micromolar))
                                    :op2 (c3 / concentration-quantity :quant 1
                                          :unit m))))
                  :ARG1 (p / phosphorylate-01
                        :ARG1 p4)
                  :ARG1-of (o / observe-01)
                  :mod (p3 / potent)))
      :mod (a3 / also)
      :ARG1-of (f / focus-01
            :ARG2 (c7 / cell-line :quant 3
                  :mod (a8 / activate-01
                        :ARG1 (p5 / pathway :name (n5 / name :op1 "JAK/STAT"))
                        :mod (b / baseline)))))

# ::id pmid_2282_9094.145 ::date 2015-07-25T12:31:06 ::annotator SDL-AMR-09 ::preferred
# ::snt Following incubation with AZD1480 1 μ for 72 h, cell culture supernatants were analyzed by enzyme-linked immunosorbent assay; consistent with the inhibition of STAT3 and STAT6 phosphorylation, decreased levels of IL-6, IL-13 and TARC were observed in HD-LM2, L-428 and L-540 (<xref ref-type="fig" rid="fig4">Figure 4b</xref>).
# ::save-date Sun Jan 3, 2016 ::file pmid_2282_9094_145.txt
(m / multi-sentence
      :snt1 (a / analyze-01
            :ARG0 (a6 / assay-01
                  :instrument (i / immunosorbent)
                  :ARG1-of (l / link-01
                        :ARG2 (e / enzyme)))
            :ARG1 (s / supernatant
                  :ARG0-of (c / culture-01)
                  :mod (c8 / cell))
            :ARG1-of (f / follow-01
                  :ARG2 (i2 / incubate-01
                        :ARG2 (s2 / small-molecule :name (n / name :op1 "AZD1480")
                              :quant (c3 / concentration-quantity :quant 1
                                    :unit (m2 / micromolar)))
                        :duration (t / temporal-quantity :quant 72
                              :unit (h / hour)))))
      :ARG1-of (d / describe-01
            :ARG0 (f2 / figure :mod "4b"))
      :snt2 (c4 / consistent-01
            :ARG1 (o / observe-01
                  :ARG1 (l2 / level
                        :quant-of (a4 / and
                              :op1 (p4 / protein :name (n4 / name :op1 "IL-6"))
                              :op2 (p5 / protein :name (n5 / name :op1 "IL-13"))
                              :op3 (p6 / protein :name (n6 / name :op1 "TARC")))
                        :ARG1-of (d2 / decrease-01))
                  :location (a5 / and
                        :op1 (c5 / cell-line :name (n7 / name :op1 "HD-LM2"))
                        :op2 (c6 / cell-line :name (n8 / name :op1 "L-428"))
                        :op3 (c7 / cell-line :name (n9 / name :op1 "L-540"))))
            :ARG2 (i3 / inhibit-01
                  :ARG1 (p / phosphorylate-01
                        :ARG1 (a3 / and
                              :op1 (p2 / protein :name (n2 / name :op1 "STAT3"))
                              :op2 (p3 / protein :name (n3 / name :op1 "STAT6")))))))

# ::id pmid_2282_9094.146 ::date 2015-07-24T14:07:19 ::annotator SDL-AMR-09 ::preferred
# ::snt <sec-title level="2">High concentrations of AZD1480 promote early G2/M arrest and cell death in HL cells by inhibiting Aurora kinases</sec-title>
# ::save-date Sun Jan 17, 2016 ::file pmid_2282_9094_146.txt
(p / promote-01
      :ARG0 (c / concentrate-02
            :ARG1 (s / small-molecule :name (n / name :op1 "AZD1480"))
            :ARG1-of (h / high-02))
      :ARG1 (a2 / and
            :op1 (a / arrest-02
                  :time (e / event :name (n4 / name :op1 "G2/M")))
            :op2 (d / die-01
                  :ARG1 (c2 / cell))
            :location (c3 / cell-line
                  :mod (d2 / disease :name (n2 / name :op1 "HL"))))
      :manner (i / inhibit-01
            :ARG0 c
            :ARG1 (k / kinase :name (n3 / name :op1 "Aurora"))))

# ::id pmid_2282_9094.147 ::date 2015-07-24T14:27:09 ::annotator SDL-AMR-09 ::preferred
# ::snt Higher concentrations (5 μ) of AZD1480 promoted a marked increase in the G2/M fraction in all four cell lines after 24 h of incubation, especially pronounced in HD-LM2 and L-428 cells (<xref ref-type="fig" rid="fig5">Figure 5a and b</xref>).
# ::save-date Sun Jan 3, 2016 ::file pmid_2282_9094_147.txt
(p / promote-01
      :ARG0 (c / concentrate-02
            :ARG1 (s / small-molecule :name (n / name :op1 "AZD1480"))
            :ARG1-of (h / high-02
                  :degree (m / more))
            :ARG1-of (m2 / mean-01
                  :ARG2 (c2 / concentration-quantity :quant 5
                        :unit (m3 / micromolar))))
      :ARG1 (i / increase-01
            :ARG1 (f3 / fraction-01
                  :time (e2 / event :name (n2 / name :op1 "G2/M")))
            :location (c3 / cell-line :quant 4)
            :ARG1-of (p3 / pronounced-02
                  :mod (e / especially)
                  :location (a3 / and
                        :op1 (c4 / cell-line :name (n3 / name :op1 "HD-LM2"))
                        :op2 (c5 / cell-line :name (n4 / name :op1 "L-428"))))
            :ARG1-of (m4 / mark-01)
            :time (a2 / after
                  :op1 (i2 / incubate-01
                        :duration (t / temporal-quantity :quant 72
                              :unit (h2 / hour)))))
      :ARG1-of (d / describe-01
            :ARG0 (a / and
                  :op1 (f / figure :mod "5a")
                  :op2 (f2 / figure :mod "5b"))))

# ::id pmid_2282_9094.148 ::date 2015-07-25T05:23:36 ::annotator SDL-AMR-09 ::preferred
# ::snt In contrast, treatment with a lower AZD1480 concentration (1 μ) for 24 h did not significantly affect the cell cycle fractions (<xref ref-type="fig" rid="fig5">Figure 5a and b</xref>).
# ::save-date Sun Jan 3, 2016 ::file pmid_2282_9094_148.txt
(c / contrast-01
      :ARG2 (a / affect-01 :polarity -
            :ARG0 (t / treat-04
                  :ARG2 (c4 / concentrate-02
                        :ARG1 (s2 / small-molecule :name (n / name :op1 "AZD1480"))
                        :ARG1-of (l / low-04
                              :degree (m2 / more))
                        :quant (c5 / concentration-quantity :quant 1
                              :unit (m / micromolar)))
                  :duration (t2 / temporal-quantity :quant 24
                        :unit (h / hour)))
            :ARG1 (f / fraction-01
                  :ARG1 (c2 / cycle-02
                        :ARG1 (c3 / cell)))
            :ARG1-of (s / significant-02))
      :ARG1-of (d / describe-01
            :ARG0 (a2 / and
                  :op1 (f2 / figure :mod "5a")
                  :op2 (f3 / figure :mod "5b"))))

# ::id pmid_2282_9094.149 ::date 2015-07-25T05:51:04 ::annotator SDL-AMR-09 ::preferred
# ::snt As AZD1480 was reported to inhibit Aurora A kinase in enzymatic assays,<sup><xref ref-type="bibr" rid="bib14">14</xref></sup> we assessed whether the significant increase in the G2/M fraction observed in HL cell lines after incubation with 5 μ AZD1480 was related to the inhibition of Aurora A.
# ::save-date Sun Jan 17, 2016 ::file pmid_2282_9094_149.txt
(a / assess-01
      :ARG0 (w / we)
      :ARG1 (r / relate-01 :mode interrogative
            :ARG1 (i / increase-01
                  :ARG1 (f / fraction-01
                        :time (e / event :name (n / name :op1 "G2/M")))
                  :ARG2 (s / significant-02)
                  :ARG1-of (o / observe-01
                        :location (c / cell-line
                              :mod (d / disease :name (n2 / name :op1 "HL")))
                        :time (a2 / after
                              :op1 (i2 / incubate-01
                                    :ARG2 (s2 / small-molecule :name (n3 / name :op1 "AZD1480")
                                          :quant (c2 / concentration-quantity :quant 5
                                                :unit (m / micromolar)))))))
            :ARG2 (i3 / inhibit-01
                  :ARG1 k))
      :ARG0-of (c3 / cause-01
            :ARG1 (r2 / report-01
                  :ARG1 (i4 / inhibit-01
                        :ARG0 s2
                        :ARG1 (k / kinase :name (n5 / name :op1 "Aurora" :op2 "A"))
                        :time (a3 / assay-01
                              :ARG1 (e2 / enzyme))))))

# ::id pmid_2282_9094.150 ::date 2015-07-25T00:30:18 ::annotator SDL-AMR-09 ::preferred
# ::snt First, we analyzed the baseline expression of Aurora A and B kinases in exponentially growing HL cells by western blotting.
# ::save-date Sun Jan 17, 2016 ::file pmid_2282_9094_150.txt
(a / analyze-01
      :ARG0 (w / we)
      :ARG1 (e / express-03
            :ARG2 (a2 / and
                  :op1 (k / kinase :name (n3 / name :op1 "Aurora" :op2 "A"))
                  :op2 (k2 / kinase :name (n4 / name :op1 "Aurora" :op2 "B")))
            :ARG3 (c / cell-line
                  :ARG1-of (g / grow-01
                        :manner (e2 / exponential))
                  :mod (d / disease :name (n / name :op1 "HL")))
            :manner (i / immunoblot-01)
            :mod (b / baseline))
      :ord (o / ordinal-entity :value 1))

# ::id pmid_2282_9094.151 ::date 2015-07-25T00:03:02 ::annotator SDL-AMR-09 ::preferred
# ::snt All four cell lines showed overexpression of Aurora A and B, and histone H3, compared with PBMCs from healthy donors (<xref ref-type="fig" rid="fig5">Figure 5c</xref>).
# ::save-date Sun Jan 17, 2016 ::file pmid_2282_9094_151.txt
(s / show-01
      :ARG0 (c2 / cell-line :quant 4
            :mod (a / all))
      :ARG1 (o / overexpress-01
            :ARG1 (a2 / and
                  :op1 (e / enzyme :name (n / name :op1 "Aurora" :op2 "A"))
                  :op2 (e2 / enzyme :name (n2 / name :op1 "Aurora" :op2 "B"))
                  :op3 (p3 / protein :name (n3 / name :op1 "histone" :op2 "H3"))))
      :ARG1-of (c / compare-01
            :ARG2 (c3 / cell :name (n4 / name :op1 "PBMC")
                  :source (p / person
                        :mod (h / healthy)
                        :ARG0-of (d / donate-01))))
      :ARG1-of (d2 / describe-01
            :ARG0 (f / figure :mod "5c")))

# ::id pmid_2282_9094.152 ::date 2015-07-24T14:50:35 ::annotator SDL-AMR-09 ::preferred
# ::snt Aurora A kinase activity depends on autophosphorylation at Thr288 in the activation loop.
# ::save-date Thu Aug 6, 2015 ::file pmid_2282_9094_152.txt
(d / depend-01
      :ARG0 (a / activity-06
            :ARG0 (k / kinase :name (n / name :op1 "Aurora")))
      :ARG1 (p2 / phosphorylate-01
            :ARG1 (a3 / amino-acid :mod 288 :name (n2 / name :op1 "threonine")
                  :part-of k)
            :ARG2 k
            :location (l / loop-01
                  :ARG0-of (a4 / activate-01
                        :ARG1 k))))

# ::id pmid_2282_9094.153 ::date 2015-07-24T14:54:27 ::annotator SDL-AMR-09 ::preferred
# ::snt Thus, to determine the effect of AZD1480 on Aurora A kinase, we evaluated the levels of autophosphorylation at Thr288 by western blotting.
# ::save-date Sun Jan 3, 2016 ::file pmid_2282_9094_153.txt
(c / cause-01
      :ARG1 (e2 / evaluate-01
            :ARG0 (w / we)
            :ARG2 (l / level
                  :degree-of (p2 / phosphorylate-01
                        :ARG1 (a2 / amino-acid :mod 288 :name (n / name :op1 "threonine")
                              :part-of k)
                        :ARG2 k))
            :manner (i / immunoblot-01))
      :purpose (d / determine-01
            :ARG0 w
            :ARG1 (a3 / affect-01
                  :ARG0 (s / small-molecule :name (n3 / name :op1 "AZD1480"))
                  :ARG1 (k / kinase :name (n4 / name :op1 "Aurora" :op2 "A")))))

# ::id pmid_2282_9094.154 ::date 2015-07-24T23:31:16 ::annotator SDL-AMR-09 ::preferred
# ::snt Cells were pretreated with nocodazole (400 ng/ml) for 18 h, to achieve a mitotic block, and then exposed to AZD1480 (1 or 5 μ) with or without the proteasome inhibitor MG132 (20 μ; to prevent a potential override of the nocodazole-induced mitotic block by proteasome-dependent mechanisms) for 3 h (<xref ref-type="fig" rid="fig5">Figure 5d</xref>).
# ::save-date Fri Feb 5, 2016 ::file pmid_2282_9094_154.txt
(a / and
      :op1 (p / pretreat-01
            :ARG1 (c / cell)
            :ARG3 (s2 / small-molecule :name (n / name :op1 "nocodazole")
                  :quant (c2 / concentration-quantity :quant 400
                        :unit (n2 / nanogram-per-milliliter)))
            :duration (t / temporal-quantity :quant 18
                  :unit (h / hour))
            :purpose (a2 / achieve-01
                  :ARG0 c
                  :ARG1 (b / block
                        :mod (m / mitosis))))
      :op2 (e / expose-01
            :ARG1 c
            :ARG2 (s / small-molecule :name (n3 / name :op1 "AZD1480")
                  :quant (o / or
                        :op1 (c3 / concentration-quantity :quant 1
                              :unit (m2 / micromolar))
                        :op2 (c4 / concentration-quantity :quant 5
                              :unit m2))
                  :accompanier (o2 / or
                        :op1 (s3 / small-molecule :name (n4 / name :op1 "MG132")
                              :mod (c5 / concentration-quantity :quant 20
                                    :unit m2)
                              :ARG0-of (i / inhibit-01
                                    :ARG1 (p2 / proteasome))
                              :purpose (p3 / prevent-01
                                    :ARG1 (o3 / override-01
                                          :ARG0 (m7 / mechanism
                                                :ARG0-of (d2 / depend-01
                                                      :ARG1 (m3 / macro-molecular-complex :name (n6 / name :op1 "proteasome"))))
                                          :ARG1 (b2 / block
                                                :mod (m8 / mitosis)
                                                :ARG2-of (i2 / induce-01
                                                      :ARG0 s2))
                                          :mod (p5 / potential))))
                        :op2 (s4 / small-molecule :polarity - :name (n5 / name :op1 "MG132"))))
            :time (t2 / then)
            :duration (t3 / temporal-quantity :quant 3
                  :unit (h2 / hour)))
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod "5d")))

# ::id pmid_2282_9094.155 ::date 2015-07-25T01:10:07 ::annotator SDL-AMR-09 ::preferred
# ::snt Dose-dependent inhibition of Aurora A was detected after 3 h of incubation in all the four cell lines, and Thr288 autophosphorylation was abrogated when a higher dose of AZD1480 (5 μ) was used (<xref ref-type="fig" rid="fig5">Figure 5d</xref>).
# ::save-date Sun Jan 3, 2016 ::file pmid_2282_9094_155.txt
(a / and
      :op1 (d2 / detect-01
            :ARG1 (i / inhibit-01
                  :ARG1 (e / enzyme :name (n2 / name :op1 "Aurora" :op2 "A"))
                  :ARG0-of (d4 / depend-01
                        :ARG1 (d5 / dose-01)))
            :time (a3 / after
                  :op1 (i2 / incubate-01
                        :location (c2 / cell-line :quant 4
                              :mod (a4 / all)))
                  :quant (t / temporal-quantity :quant 3
                        :unit (h2 / hour))))
      :op2 (a2 / abrogate-01
            :ARG1 (p / phosphorylate-01
                  :ARG1 (a6 / amino-acid :mod 288 :name (n3 / name :op1 "Threonine")
                        :part-of e)
                  :ARG2 e)
            :time (u / use-01
                  :ARG1 (d3 / dose-01
                        :ARG2 (s / small-molecule :name (n / name :op1 "AZD1480"))
                        :ARG1-of (h / high-02
                              :degree (m / more))
                        :quant (c / concentration-quantity :quant 5
                              :unit (m2 / micromolar)))))
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod "5d")))

# ::id pmid_2282_9094.156 ::date 2015-07-25T00:41:13 ::annotator SDL-AMR-09 ::preferred
# ::snt These findings are consistent with the analysis of the cell cycle fractions, showing major dose-dependent changes in the cell cycle after incubation with AZD1480.
# ::save-date Mon Dec 21, 2015 ::file pmid_2282_9094_156.txt
(c / consistent-01
      :ARG1 (t / thing
            :ARG1-of (f / find-01)
            :mod (t2 / this)
            :ARG0-of (s / show-01
                  :ARG1 (c4 / change-01
                        :ARG1 (c5 / cycle-02
                              :ARG1 (c6 / cell))
                        :ARG0-of (d / depend-01
                              :ARG1 (d2 / dose))
                        :ARG1-of (m / major-02)
                        :time (a2 / after
                              :op1 (i / incubate-01
                                    :ARG1 c6
                                    :ARG2 (s2 / small-molecule :name (n / name :op1 "AZD1480")))))))
      :ARG2 (a / analyze-01
            :ARG1 (f2 / fraction
                  :mod c5)))

# ::id pmid_2282_9094.157 ::date 2015-07-25T00:56:01 ::annotator SDL-AMR-09 ::preferred
# ::snt In L-428 and L-540 cells, a dose-dependent inhibition of the phosphorylation of histone H3 at Ser10 was observed, suggesting a dual inhibition of Aurora A and B in these cell lines.
# ::save-date Thu Aug 6, 2015 ::file pmid_2282_9094_157.txt
(o / observe-01
      :ARG1 (i2 / inhibit-01
            :ARG1 (p / phosphorylate-01
                  :ARG1 (a2 / amino-acid :mod 10 :name (n4 / name :op1 "Serine")
                        :part-of (p4 / protein :name (n3 / name :op1 "histone" :op2 "H3"))))
            :ARG0-of (d2 / depend-01
                  :ARG1 (d3 / dose)))
      :ARG0-of (s / suggest-01
            :ARG1 (i / inhibit-01
                  :ARG1 (a / and
                        :op1 (e / enzyme :name (n / name :op1 "Aurora" :op2 "A"))
                        :op2 (e2 / enzyme :name (n2 / name :op1 "Aurora" :op2 "B")))
                  :location a3
                  :mod (d / dual)))
      :location (a3 / and
            :op1 (c / cell-line :name (n5 / name :op1 "L-428"))
            :op2 (c2 / cell-line :name (n6 / name :op1 "L-540"))))

# ::id pmid_2290_9976.1 ::date 2015-08-24T01:18:14 ::annotator SDL-AMR-09 ::preferred
# ::snt K-Ras gene mutation status as a prognostic and predictive factor in patients with colorectal cancer undergoing irinotecan- or oxaliplatin-based chemotherapy (PMID:22909976)
# ::save-date Thu Dec 10, 2015 ::file pmid_2290_9976_1.txt
(s / status
      :mod (m / mutate-01
            :ARG1 (g / gene :name (n / name :op1 "K-Ras")))
      :condition (f / factor
            :mod (p / prognostic)
            :ARG0-of (p2 / predict-01)
            :location (p3 / person
                  :ARG0-of (h / have-rel-role-91
                        :ARG2 (p4 / patient))
                  :ARG0-of (h2 / have-03
                        :ARG1 (d2 / disease :wiki "Colorectal_cancer" :name (n2 / name :op1 "colorectal" :op2 "cancer")))
                  :ARG1-of (u / undergo-28
                        :ARG2 (c3 / chemotherapy
                              :ARG1-of (b / base-02
                                    :ARG2 (o / or
                                          :op1 (s2 / small-molecule :name (n3 / name :op1 "irinotecan"))
                                          :op2 (s3 / small-molecule :name (n4 / name :op1 "oxaliplatin"))))))))
      :ARG1-of (d / describe-01
            :ARG0 (p5 / publication-91
                  :ARG8 "PMID2909976")))

# ::id pmid_2290_9976.28 ::date 2015-08-24T02:14:26 ::annotator SDL-AMR-09 ::preferred
# ::snt <sec-title level="1">Results</sec-title>
# ::save-date Mon Aug 24, 2015 ::file pmid_2290_9976_28.txt
(t / thing
      :ARG2-of (r / result-01))

# ::id pmid_2290_9976.29 ::date 2015-08-24T02:14:55 ::annotator SDL-AMR-09 ::preferred
# ::snt <sec-title level="2">Patient characteristics</sec-title>
# ::save-date Thu Dec 10, 2015 ::file pmid_2290_9976_29.txt
(t / thing
      :ARG2-of (c / characteristic-02
            :ARG1 (p / person
                  :ARG0-of (h / have-rel-role-91
                        :ARG2 (p2 / patient)))))

# ::id pmid_2290_9976.30 ::date 2015-08-24T02:16:46 ::annotator SDL-AMR-09 ::preferred
# ::snt Patient characteristics are summarized in <xref ref-type="table" rid="T1">Table 1</xref>.
# ::save-date Thu Dec 10, 2015 ::file pmid_2290_9976_30.txt
(s / summarize-01
      :ARG1 (t / thing
            :ARG2-of (c / characteristic-02
                  :ARG1 (p / person
                        :ARG0-of (h / have-rel-role-91
                              :ARG2 (p2 / patient)))))
      :ARG2 (t2 / table :mod 1))

# ::id pmid_2290_9976.31 ::date 2015-08-24T02:19:16 ::annotator SDL-AMR-09 ::preferred
# ::snt The median age of the patients included in this study was 65 y (181 women, 92 men).
# ::save-date Thu Dec 10, 2015 ::file pmid_2290_9976_31.txt
(a / age-01
      :ARG1 (p / person
            :ARG0-of (h / have-rel-role-91
                  :ARG2 (p2 / patient))
            :ARG1-of (i / include-01
                  :ARG2 (s / study-01
                        :mod (t2 / this)))
            :ARG1-of (m2 / mean-01
                  :ARG2 (a2 / and
                        :op1 (w / woman :quant 181)
                        :op2 (m3 / man :quant 92))))
      :ARG2 (t / temporal-quantity :quant 65
            :unit (y / year))
      :mod (m / median))

# ::id pmid_2290_9976.32 ::date 2015-08-24T02:23:03 ::annotator SDL-AMR-09 ::preferred
# ::snt Most underwent primary tumor resection (260/273 patients, 95.2%), while secondary metastatic disease was diagnosed in 194 patients (71.1%), of whom 70 (36.1%) underwent resection and 22 (11.3%) underwent thermoablation.
# ::save-date Thu Dec 10, 2015 ::file pmid_2290_9976_32.txt
(c / contrast-01
      :ARG1 (u / undergo-28
            :ARG1 (p5 / person
                  :ARG0-of (h / have-rel-role-91
                        :ARG2 (p6 / patient))
                  :quant (m / most)
                  :ARG1-of (m2 / mean-01
                        :ARG2 (i / include-91
                              :ARG1 (p8 / person :quant 260
                                    :ARG0-of h)
                              :ARG2 (p9 / person :quant 273
                                    :ARG0-of h)
                              :ARG3 (p / percentage-entity :value 95.2))))
            :ARG2 (r / resection
                  :mod (t / tumor
                        :mod (p7 / primary))))
      :ARG2 (d / diagnose-01
            :ARG1 (p10 / person :quant 194
                  :ARG0-of h
                  :ARG1-of (m4 / mean-01
                        :ARG2 (p2 / percentage-entity :value 71.1))
                  :ARG2-of (i2 / include-91
                        :ARG1 (a / and
                              :op1 (p11 / person :quant 70
                                    :ARG0-of h
                                    :ARG1-of (m5 / mean-01
                                          :ARG2 (p3 / percentage-entity :value 36.1))
                                    :ARG1-of (u2 / undergo-28
                                          :ARG2 (r2 / resection)))
                              :op2 (p12 / person :quant 22
                                    :ARG0-of h
                                    :ARG1-of (u3 / undergo-28
                                          :ARG2 (t2 / thermoablation))
                                    :ARG1-of (m6 / mean-01
                                          :ARG2 (p4 / percentage-entity :value 11.3))))))
            :ARG2 (d2 / disease
                  :mod (s / secondary)
                  :ARG1-of (m3 / metastasize-101))))

# ::id pmid_2290_9976.33 ::date 2015-08-24T02:30:42 ::annotator SDL-AMR-09 ::preferred
# ::snt The primary tumor was located in the colon in 112 patients (41.1%), sigmoid colon in 100 patients (36.6%) and rectum in 61 patients (22.3%).
# ::save-date Thu Dec 10, 2015 ::file pmid_2290_9976_33.txt
(a / and
      :op1 (b / be-located-at-91
            :ARG1 (t / tumor
                  :mod (p4 / primary))
            :ARG2 (c / colon)
            :location (p5 / person :quant 112
                  :ARG0-of (h / have-rel-role-91
                        :ARG2 (p6 / patient))
                  :ARG1-of (m / mean-01
                        :ARG2 (p / percentage-entity :value 41.1))))
      :op2 (b2 / be-located-at-91
            :ARG1 t
            :ARG2 (c2 / colon
                  :mod (s / sigmoid))
            :location (p7 / person :quant 100
                  :ARG0-of h
                  :ARG1-of (m2 / mean-01
                        :ARG2 (p2 / percentage-entity :value 36.6))))
      :op3 (b3 / be-located-at-91
            :ARG1 t
            :ARG2 (r / rectum)
            :location (p8 / person :quant 61
                  :ARG0-of h
                  :ARG1-of (m3 / mean-01
                        :ARG2 (p3 / percentage-entity :value 22.3)))))

# ::id pmid_2290_9976.34 ::date 2015-08-24T02:36:18 ::annotator SDL-AMR-09 ::preferred
# ::snt The metastases were located in the liver in 129 (66.5% of patients with metastases), in the lungs in 39 (20.1%), and in other organs in 126 patients (64.9%).
# ::save-date Thu Dec 10, 2015 ::file pmid_2290_9976_34.txt
(a / and
      :op1 (b / be-located-at-91
            :ARG1 (m / metastasize-101)
            :ARG2 (l2 / liver)
            :location (p4 / person :quant 129
                  :ARG0-of (h / have-rel-role-91
                        :ARG2 (p5 / patient))
                  :ARG1-of (m2 / mean-01
                        :ARG2 (p / percentage-entity :value 66.5
                              :ARG3-of (i / include-91
                                    :ARG2 (p6 / person
                                          :ARG0-of h
                                          :ARG0-of (h2 / have-03
                                                :ARG1 m)))))))
      :op2 (b2 / be-located-at-91
            :ARG1 m
            :ARG2 (l4 / lung)
            :location (p7 / person :quant 39
                  :ARG0-of h
                  :ARG1-of (m5 / mean-01
                        :ARG2 (p2 / percentage-entity :value 20.1))))
      :op3 (b3 / be-located-at-91
            :ARG1 m
            :ARG2 (o / organ
                  :mod (o2 / other))
            :location (p8 / person :quant 126
                  :ARG0-of h
                  :ARG1-of (m7 / mean-01
                        :ARG2 (p3 / percentage-entity :value 64.9)))))

# ::id pmid_2290_9976.35 ::date 2015-08-24T02:41:35 ::annotator SDL-AMR-09 ::preferred
# ::snt Pretreatment carcinoembryonic antigen (CEA) levels were elevated above the normal range in 89 patients (32.6%).
# ::save-date Thu Dec 10, 2015 ::file pmid_2290_9976_35.txt
(e / elevate-01
      :ARG1 (l / level
            :quant-of (p2 / protein :name (n / name :op1 "carcinoembryonic" :op2 "antigen"))
            :time (b / before
                  :op1 (t / treat-04)))
      :ARG2 (a / above
            :op1 (r / range
                  :ARG1-of (n2 / normal-02)))
      :location (p3 / person :quant 89
            :ARG0-of (h / have-rel-role-91
                  :ARG2 (p4 / patient))
            :ARG1-of (m / mean-01
                  :ARG2 (p / percentage-entity :value 32.6))))

# ::id pmid_2290_9976.36 ::date 2015-08-24T02:45:20 ::annotator SDL-AMR-09 ::preferred
# ::snt <sec-title level="2"><bold>Table 1.</bold> Patient and tumor characteristics</sec-title>
# ::save-date Thu Dec 10, 2015 ::file pmid_2290_9976_36.txt
(d / describe-01
      :ARG0 (t / table :mod 1)
      :ARG1 (a / and
            :op1 (c / characteristic-02
                  :ARG1 (p / person
                        :ARG0-of (h / have-rel-role-91
                              :ARG2 (p2 / patient))))
            :op2 (c2 / characteristic-02
                  :ARG1 (t2 / tumor))))

# ::id pmid_2290_9976.37 ::date 2015-08-24T02:49:12 ::annotator SDL-AMR-09 ::preferred
# ::snt <sec-title level="2"><i>K-Ras</i> and <i>B-Raf</i> gene mutation status</sec-title>
# ::save-date Mon Aug 31, 2015 ::file pmid_2290_9976_37.txt
(a / and
      :op1 (s / status
            :mod (m / mutate-01
                  :ARG1 (g / gene :name (n / name :op1 "K-Ras"))))
      :op2 (s2 / status
            :mod (m2 / mutate-01
                  :ARG1 (g2 / gene :name (n3 / name :op1 "B-Raf")))))

# ::id pmid_2290_9976.38 ::date 2015-08-24T02:50:26 ::annotator SDL-AMR-09 ::preferred
# ::snt <i>K-Ras</i> gene mutations were present in 89 patients (32.6%), of whom 76 (85.4%) had mutations in codon 12 and 10 (11.2%) had mutations in codon 13.
# ::save-date Thu Dec 10, 2015 ::file pmid_2290_9976_38.txt
(p4 / present-102
      :ARG0 (p5 / person :quant 89
            :ARG0-of (h / have-rel-role-91
                  :ARG2 (p6 / patient))
            :ARG1-of (m2 / mean-01
                  :ARG2 (p / percentage-entity :value 32.6))
            :ARG2-of (i / include-91
                  :ARG1 (a / and
                        :op1 (p7 / person :quant 76
                              :ARG0-of h
                              :ARG1-of (m3 / mean-01
                                    :ARG2 (p2 / percentage-entity :value 85.4))
                              :ARG0-of (h2 / have-03
                                    :ARG1 (m4 / mutate-01
                                          :ARG1 (c / codon :mod 12))))
                        :op2 (p8 / person :quant 10
                              :ARG0-of h
                              :ARG1-of (m5 / mean-01
                                    :ARG2 (p3 / percentage-entity :value 11.2))
                              :ARG0-of (h3 / have-03
                                    :ARG1 (m6 / mutate-01
                                          :ARG1 (c2 / codon :mod 13)))))))
      :ARG1 (m / mutate-01
            :ARG1 (g / gene :name (n / name :op1 "K-Ras"))))

# ::id pmid_2290_9976.39 ::date 2015-08-24T02:57:07 ::annotator SDL-AMR-09 ::preferred
# ::snt Women showed a higher incidence of <i>K-Ras</i> gene mutations relative to men (p = 0.0290).
# ::save-date Tue Dec 15, 2015 ::file pmid_2290_9976_39.txt
(s / show-01
      :ARG0 (w / woman)
      :ARG1 (i / incidence
            :ARG1-of (h / high-02
                  :degree (m / more)
                  :compared-to (m3 / man)
                  :ARG1-of (s2 / statistical-test-91
                        :ARG2 0.0290))
            :frequency-of (m2 / mutate-01
                  :ARG1 (g / gene :name (n / name :op1 "K-Ras")))))

# ::id pmid_2290_9976.40 ::date 2015-08-24T04:25:35 ::annotator SDL-AMR-09 ::preferred
# ::snt No significant differences were observed with respect to tumor size, lymph node involvement grade, histological grade, histopathological type, primary tumor localization, performance status, age, or pretreatment CEA level.
# ::save-date Mon Aug 31, 2015 ::file pmid_2290_9976_40.txt
(o / observe-01
      :ARG1 (d / differ-02 :polarity -
            :ARG3 (o2 / or
                  :op1 (s2 / size
                        :poss (t / tumor))
                  :op2 (g / grade
                        :extent-of (i / involve-01
                              :ARG1 (n / node
                                    :mod (l / lymph))))
                  :op3 (g2 / grade
                        :mod (h / histology))
                  :op4 (t2 / type
                        :mod (h2 / histopathology))
                  :op5 (b2 / be-located-at-91
                        :ARG1 (t3 / tumor
                              :mod (p / primary)))
                  :op6 (s3 / status
                        :mod (p2 / perform-02))
                  :op7 (a / age-01)
                  :op8 (l3 / level
                        :quant-of (p3 / protein :name (n2 / name :op1 "CEA"))
                        :time (b / before
                              :op1 (t4 / treat-03))))
            :ARG1-of (s / significant-02)))

# ::id pmid_2290_9976.41 ::date 2015-08-24T04:32:41 ::annotator SDL-AMR-09 ::preferred
# ::snt <i>B-Raf</i> gene mutations were present in 17 patients (6.9%), of whom 6 (35.3%) had mutations in exon 15.
# ::save-date Sun Jan 3, 2016 ::file pmid_2290_9976_41.txt
(p3 / present-102
      :ARG0 (p4 / person :quant 17
            :ARG0-of (h / have-rel-role-91
                  :ARG2 (p5 / patient))
            :ARG1-of (m2 / mean-01
                  :ARG2 (p / percentage-entity :value 6.9))
            :ARG2-of (i / include-91
                  :ARG1 (p6 / person :quant 6
                        :ARG0-of h
                        :ARG0-of (h2 / have-03
                              :ARG1 (m4 / mutate-01
                                    :ARG1 (e / exon :mod 15))))
                  :ARG3 (p2 / percentage-entity :value 35.3)))
      :ARG1 (m / mutate-01
            :ARG1 (g / gene :name (n2 / name :op1 "B-Raf"))))

# ::id pmid_2290_9976.42 ::date 2015-08-24T04:35:32 ::annotator SDL-AMR-09 ::preferred
# ::snt One patient had a mutation in exon 11, while mutation status was not determined in 10 patients (58.8%).
# ::save-date Sun Jan 3, 2016 ::file pmid_2290_9976_42.txt
(c / contrast-01
      :ARG1 (h / have-03
            :ARG0 (p2 / person :quant 1
                  :ARG0-of (h2 / have-rel-role-91
                        :ARG2 (p3 / patient)))
            :ARG1 (m / mutate-01
                  :ARG1 (e / exon :mod 11)))
      :ARG2 (d2 / determine-01 :polarity -
            :ARG1 (s / status
                  :mod (m2 / mutate-01))
            :location (p4 / person :quant 10
                  :ARG0-of h2
                  :ARG1-of (m3 / mean-01
                        :ARG2 (p / percentage-entity :value 58.8)))))

# ::id pmid_2290_9976.43 ::date 2015-08-24T04:37:58 ::annotator SDL-AMR-09 ::preferred
# ::snt A higher incidence of <i>B-Raf</i> gene mutations was detected in patients with low-grade neoplasm (p < 0.0001), primary tumor localization outside the sigmoid colon (p = 0.0467) and with non-tubular neoplasms (p = 0.0468).
# ::save-date Tue Dec 15, 2015 ::file pmid_2290_9976_43.txt
(d / detect-01
      :ARG1 (i / incidence
            :ARG1-of (h / high-02
                  :degree (m / more))
            :frequency-of (m2 / mutate-01
                  :ARG1 (g / gene :name (n / name :op1 "B-Raf"))))
      :location (a / and
            :op1 (p / person
                  :ARG0-of (h2 / have-rel-role-91
                        :ARG2 (p2 / patient))
                  :ARG0-of (h3 / have-03
                        :ARG1 (n2 / neoplasm
                              :mod (g2 / grade
                                    :ARG1-of (l / low-04))
                              :ARG1-of (s2 / statistical-test-91
                                    :ARG2 (l2 / less-than :op1 0.0001)))))
            :op2 (p4 / person
                  :ARG0-of h2
                  :ARG0-of (h4 / have-03
                        :ARG1 (b / be-located-at-91
                              :ARG1 (t / tumor
                                    :mod (p5 / primary)
                                    :ARG1-of (s3 / statistical-test-91
                                          :ARG2 0.0467))
                              :ARG2 (o / outside
                                    :op1 (c / colon
                                          :mod (s / sigmoid))))))
            :op3 (p7 / person
                  :ARG0-of h2
                  :ARG0-of (h5 / have-03
                        :ARG1 (n3 / neoplasm
                              :mod (t2 / tubular :polarity -)
                              :ARG1-of (s4 / statistical-test-91
                                    :ARG2 0.0468))))))

# ::id pmid_2290_9976.44 ::date 2015-08-24T04:46:49 ::annotator SDL-AMR-09 ::preferred
# ::snt Other parameters assessed were not statistically different.
# ::save-date Mon Aug 24, 2015 ::file pmid_2290_9976_44.txt
(d / differ-02 :polarity -
      :ARG1 (p / parameter
            :mod (o / other)
            :ARG1-of (a / assess-01))
      :manner (s / statistic))

# ::id pmid_2290_9976.45 ::date 2015-08-24T04:48:31 ::annotator SDL-AMR-09 ::preferred
# ::snt <sec-title level="2">Prognostic significance of <i>K-Ras</i> and <i>B-Raf</i> gene mutation status</sec-title>
# ::save-date Mon Aug 24, 2015 ::file pmid_2290_9976_45.txt
(s / signify-01
      :ARG0 (a / and
            :op1 (s2 / status
                  :mod (m / mutate-01
                        :ARG1 (g / gene :name (n / name :op1 "K-Ras"))))
            :op2 (s3 / status
                  :mod (m2 / mutate-01
                        :ARG1 (g2 / gene :name (n2 / name :op1 "B-Raf")))))
      :mod (p / prognostic))

# ::id pmid_2290_9976.46 ::date 2015-08-24T04:51:02 ::annotator SDL-AMR-09 ::preferred
# ::snt There were no significant differences in OS rates between patients with <i>K-Ras</i> mutations and wild-type <i>K-Ras</i> genes (p = 0.6869; <xref ref-type="fig" rid="F1">Fig. 1</xref>).
# ::save-date Tue Dec 15, 2015 ::file pmid_2290_9976_46.txt
(d / differ-02 :polarity -
      :ARG1 (r / rate
            :mod (s2 / survive-01
                  :ARG0 (p / person
                        :ARG0-of (h / have-rel-role-91
                              :ARG2 (p2 / patient))
                        :ARG0-of (h2 / have-03
                              :ARG1 (m / mutate-01
                                    :ARG1 (g / gene :name (n / name :op1 "K-Ras")))))
                  :mod (o2 / overall)))
      :ARG2 (r2 / rate
            :mod (s3 / survive-01
                  :ARG1 (p3 / person
                        :ARG0-of h
                        :ARG0-of (h3 / have-03
                              :ARG1 (g2 / gene :name (n2 / name :op1 "K-Ras")
                                    :mod (w / wild-type))))
                  :mod o2))
      :ARG1-of (s / significant-02)
      :ARG1-of (d2 / describe-01
            :ARG0 (f / figure :mod 1))
      :ARG1-of (s4 / statistical-test-91
            :ARG2 0.6869))

# ::id pmid_2290_9976.47 ::date 2015-08-24T04:55:59 ::annotator SDL-AMR-09 ::preferred
# ::snt A perceptible trend to prolongation of OS was apparent when <i>K-Ras</i> mutations were present in codon 13 relative to codon 12 (p = 0.0830; <xref ref-type="fig" rid="F2">Fig. 2</xref>).
# ::save-date Tue Dec 15, 2015 ::file pmid_2290_9976_47.txt
(a / appear-02
      :ARG1 (t / trend-01
            :ARG1 (p / prolong-01
                  :ARG1 (s / survive-01
                        :mod (o2 / overall)))
            :ARG1-of (p2 / perceptive-02
                  :ARG1-of (p5 / possible-01)))
      :time (p3 / present-102
            :ARG1 (m / mutate-01
                  :ARG1 (c / codon :mod 13
                        :part-of (g / gene :name (n3 / name :op1 "K-Ras"))))
            :ARG1-of (r / relative-05
                  :ARG3 (p4 / present-102
                        :ARG1 (m2 / mutate-01
                              :ARG1 (c2 / codon :mod 12
                                    :part-of g)))))
      :ARG1-of (d3 / describe-01
            :ARG0 (f / figure :mod 2))
      :ARG1-of (s2 / statistical-test-91
            :ARG2 0.0830))

# ::id pmid_2290_9976.48 ::date 2015-08-24T05:02:20 ::annotator SDL-AMR-09 ::preferred
# ::snt Similarly, mutations in the <i>B-Raf</i> gene showed no prognostic significance (<xref ref-type="fig" rid="F3">Fig. 3</xref>).
# ::save-date Wed Aug 26, 2015 ::file pmid_2290_9976_48.txt
(s / show-01
      :ARG0 (m / mutate-01
            :ARG1 (g / gene :name (n2 / name :op1 "B-Raf")))
      :ARG1 (s2 / significant-02 :polarity -
            :ARG1 m
            :mod (p / prognostic))
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod 3))
      :ARG1-of (r / resemble-01))

# ::id pmid_2290_9976.49 ::date 2015-08-24T05:04:05 ::annotator SDL-AMR-09 ::preferred
# ::snt Patients with disseminated CRC (M+) and <i>B-Raf</i> gene mutations tended toward shorter OS relative to those with wild-type <i>B-Raf</i> genes (p = 0.06723).
# ::save-date Sun Jan 3, 2016 ::file pmid_2290_9976_49.txt
(t / tend-02
      :ARG1 (p / person
            :ARG0-of (h / have-rel-role-91
                  :ARG2 (p2 / patient))
            :ARG0-of (h2 / have-03
                  :ARG1 (a / and
                        :op1 (d / disease :wiki "Colorectal_cancer" :name (n3 / name :op1 "colorectal" :op2 "cancer")
                              :ARG1-of (d2 / disseminate-01)
                              :ARG1-of (l / label-01
                                    :ARG2 (s4 / string-entity :value "M+")))
                        :op2 (m2 / mutate-01
                              :ARG1 (g / gene :name (n2 / name :op1 "B-Raf"))))))
      :ARG2 (s / short-07
            :ARG1 (s2 / survive-01
                  :ARG0 p
                  :mod (o2 / overall))
            :degree (m3 / more)
            :ARG1-of (r / relative-05
                  :ARG3 (p3 / person
                        :ARG0-of h
                        :ARG0-of (h4 / have-03
                              :ARG1 (g2 / gene :name (n / name :op1 "B-Raf")
                                    :mod (w / wild-type))))))
      :ARG1-of (s3 / statistical-test-91
            :ARG2 0.06723))

# ::id pmid_2290_9976.50 ::date 2015-08-24T05:10:17 ::annotator SDL-AMR-09 ::preferred
# ::snt <sec-title level="2">Clinical and pathological variables identified by univariate analysis as potential prognostic factors for OS rate</sec-title>
# ::save-date Mon Aug 31, 2015 ::file pmid_2290_9976_50.txt
(a / and
      :op1 (v / variable
            :mod (c / clinic))
      :op2 (v2 / variable
            :mod (p / pathology))
      :ARG1-of (i / identify-01
            :ARG0 (a2 / analyze-01
                  :mod (u / univariate))
            :ARG2 (f / factor
                  :mod (p2 / prognostic)
                  :mod (p3 / potential)
                  :topic (r / rate
                        :mod (s / survive-01
                              :mod (o2 / overall))))))

# ::id pmid_2290_9976.51 ::date 2015-08-24T05:16:05 ::annotator SDL-AMR-09 ::preferred
# ::snt These results are summarized in <xref ref-type="table" rid="T2">Table 2</xref>.
# ::save-date Mon Aug 24, 2015 ::file pmid_2290_9976_51.txt
(s / summarize-01
      :ARG1 (t / thing
            :ARG2-of (r / result-01)
            :mod (t2 / this))
      :ARG2 (t3 / table :mod 2))

# ::id pmid_2290_9976.52 ::date 2015-08-26T01:05:51 ::annotator SDL-AMR-09 ::preferred
# ::snt Univariate analysis identified the following prognostic factors as influencing OS rate in this patient cohort: Age, patients 75 y and older lived for 36.7 mo relative to those younger than 75 (58.9 mo) (p = 0.0472); Gender, female patients lived for 62.7 mo relative to 42.6 mo for male patients (p = 0.0328); Primary tumor localization, patients with primary tumors in the sigmoid colon lived for 68.0 mo compared with 43.5 mo in patients with primary tumors located in the colon or rectum (p = 0.0039); Performance status, patients with a good performance score e.g., WHO 0–1 (58.4 mo) and Karnofsky status 81–100% (58.1 mo) lived longer relative to those with poor performance status (19.0 and 19.4 mo for patients with WHO 2–3 and Karnofsky status ≤ 80%, respectively) (p = 0.0027 and p = 0.0036, respectively); Lymph node involvement grade, survival in patients without lymph node metastases was 65.3 mo relative to 46.3 mo in patients presenting with metastases (p = 0.0031); Pretreatment CEA level, median time to progression in patients with normal pretreatment CEA level ≤ 5 ng/ml was 76.3 mo relative to 25.6 mo in patients with increased pretreatment CEA level (p < 0.0001; <xref ref-type="table" rid="T2">Table 2</xref>).
# ::save-date Sun Jan 3, 2016 ::file pmid_2290_9976_52.txt
(i / identify-01
      :ARG0 (a / analyze-01
            :mod (u / univariate))
      :ARG1 (f / factor
            :ARG1-of (f2 / follow-04)
            :mod (p / prognostic)
            :ARG0-of (i2 / influence-01
                  :ARG1 (r / rate
                        :mod (s11 / survive-01
                              :mod (o6 / overall)))
                  :location (c / cohort
                        :mod (t / this)
                        :consist-of (p2 / person
                              :ARG0-of (h / have-rel-role-91
                                    :ARG2 (p3 / patient)))))
            :ARG1-of (m / mean-01
                  :ARG2 (a2 / and
                        :op1 (a3 / age-01
                              :ARG1-of (m2 / mean-01
                                    :ARG2 (l / live-01
                                          :ARG0 (p4 / person
                                                :ARG0-of h
                                                :age (a5 / and
                                                            :op1 (t2 / temporal-quantity :quant 75
                                                                  :unit (y / year))
                                                            :op2 (m3 / more-than
                                                                  :op1 t2)))
                                          :duration (t3 / temporal-quantity :quant 36.7
                                                :unit (m4 / month)
                                                :ARG1-of (r2 / relative-05
                                                      :ARG3 (p5 / person
                                                            :ARG0-of h
                                                            :age (l2 / less-than
                                                                        :op1 t2)
                                                            :ARG0-of (l3 / live-01
                                                                  :duration (t4 / temporal-quantity :quant 58.9
                                                                        :unit m4)))))))
                              :ARG1-of (s12 / statistical-test-91
                                    :ARG2 0.0472))
                        :op2 (g / gender
                              :ARG1-of (m5 / mean-01
                                    :ARG2 (l4 / live-01
                                          :ARG0 (p7 / person
                                                :mod (f3 / female)
                                                :ARG0-of h)
                                          :duration (t5 / temporal-quantity :quant 62.7
                                                :unit m4
                                                :ARG1-of (r3 / relative-05
                                                      :ARG3 (t6 / temporal-quantity :quant 42.6
                                                            :unit m4
                                                            :duration-of (l5 / live-01
                                                                  :ARG0 (p8 / person
                                                                        :mod (m6 / male)
                                                                        :ARG0-of h)))))))
                              :ARG1-of (s13 / statistical-test-91
                                    :ARG2 0.0328))
                        :op3 (b6 / be-located-at-91
                              :ARG1 (t7 / tumor
                                    :mod (p10 / primary))
                              :ARG1-of (m7 / mean-01
                                    :ARG2 (l7 / live-01
                                          :ARG0 (p11 / person
                                                :ARG0-of h
                                                :ARG0-of (h2 / have-03
                                                      :ARG1 t7
                                                      :location (c2 / colon
                                                            :mod (s / sigmoid))))
                                          :duration (t8 / temporal-quantity :quant 68.0
                                                :unit m4
                                                :compared-to (t9 / temporal-quantity :quant 43.5
                                                      :unit m4
                                                      :duration-of (l8 / live-01
                                                            :ARG0 (p12 / person
                                                                  :ARG0-of h
                                                                  :ARG0-of (h3 / have-03
                                                                        :ARG1 t7
                                                                        :location (o2 / or
                                                                              :op1 (c3 / colon)
                                                                              :op2 (r4 / rectum)))))))))
                              :ARG1-of (s14 / statistical-test-91
                                    :ARG2 0.0039))
                        :op4 (s2 / status
                              :mod (p14 / perform-01)
                              :ARG1-of (m8 / mean-01
                                    :ARG2 (l9 / live-01
                                          :ARG0 (p15 / person
                                                :ARG0-of h
                                                :ARG1-of (s3 / score-01
                                                      :ARG2 (a7 / and
                                                            :op1 (s4 / status
                                                                  :value (b / between :op1 0 :op2 1)
                                                                  :mod (o / organization :wiki "World_Health_Organization" :name (n6 / name :op1 "World" :op2 "Health" :op3 "Organization")))
                                                            :op2 (s5 / status
                                                                  :value (b2 / between
                                                                        :op1 (p16 / percentage-entity :value 81)
                                                                        :op2 (p17 / percentage-entity :value 100))
                                                                  :mod (p34 / person :name (n / name :op1 "Karnofsky"))))
                                                      :ARG3 p14
                                                      :ARG1-of (g2 / good-02)))
                                          :ARG1-of (l10 / long-03
                                                :ARG2 (m9 / more)
                                                :ARG1-of (r5 / relative-05
                                                      :ARG3 (p18 / person
                                                            :ARG0-of h
                                                            :ARG0-of (h4 / have-03
                                                                  :ARG1 (s6 / status
                                                                        :mod p14
                                                                        :mod (p19 / poor)))
                                                            :ARG1-of (m10 / mean-01
                                                                  :ARG2 (a8 / and
                                                                        :op1 (t12 / temporal-quantity :quant 19.0
                                                                              :unit m4
                                                                              :duration-of (l11 / live-01
                                                                                    :ARG0 (p20 / person
                                                                                          :ARG0-of h
                                                                                          :ARG0-of (h5 / have-03
                                                                                                :ARG1 (s7 / status
                                                                                                      :value (b3 / between :op1 2 :op2 3)
                                                                                                      :mod o))))
                                                                              :ARG1-of (s15 / statistical-test-91
                                                                                    :ARG2 0.0027))
                                                                        :op2 (t13 / temporal-quantity :quant 19.4
                                                                              :unit m4
                                                                              :duration-of (l12 / live-01
                                                                                    :ARG0 (p21 / person
                                                                                          :ARG0-of h
                                                                                          :ARG0-of (h6 / have-03
                                                                                                :ARG1 (s8 / status
                                                                                                      :value (o4 / or
                                                                                                            :op1 (l13 / less-than
                                                                                                                  :op1 (p22 / percentage-entity :value 80))
                                                                                                            :op2 p22)
                                                                                                      :mod p34))))
                                                                              :ARG1-of (s16 / statistical-test-91
                                                                                    :ARG2 0.0036))))))
                                                :ARG1-of (m15 / mean-01
                                                      :ARG2 (a9 / and
                                                            :op1 (t10 / temporal-quantity :quant 58.4
                                                                  :unit m4
                                                                  :condition s4)
                                                            :op2 (t11 / temporal-quantity :quant 58.1
                                                                  :unit m4
                                                                  :condition s5)))))))
                        :op5 (g3 / grade
                              :degree-of (i3 / involve-01
                                    :ARG1 (n2 / node
                                          :mod (l14 / lymph)))
                              :ARG1-of (m11 / mean-01
                                    :ARG2 (s9 / survive-01
                                          :ARG0 (p25 / person
                                                :ARG0-of h
                                                :ARG0-of (h7 / have-03 :polarity -
                                                      :ARG1 (m12 / metastasize-101
                                                            :ARG2 n2)))
                                          :duration (t14 / temporal-quantity :quant 65.3
                                                :unit m4
                                                :ARG1-of (r6 / relative-05
                                                      :ARG3 (t15 / temporal-quantity :quant 46.3
                                                            :unit m4
                                                            :duration-of (s10 / survive-01
                                                                  :ARG0 (p26 / person
                                                                        :ARG0-of h
                                                                        :ARG0-of (p27 / present-102
                                                                              :ARG1 m12))))))))
                              :ARG1-of (s17 / statistical-test-91
                                    :ARG2 0.0031))
                        :op6 (l15 / level
                              :time (b4 / before
                                    :op1 (t16 / treat-03))
                              :quant-of (p29 / protein :name (n3 / name :op1 "CEA"))
                              :ARG1-of (m13 / mean-01
                                    :ARG2 (t17 / time
                                          :time (b5 / before
                                                :op1 (p30 / progress-01))
                                          :mod (m14 / median)
                                          :location (p31 / person
                                                :ARG0-of h
                                                :ARG0-of (h8 / have-03
                                                      :ARG1 (l16 / level
                                                            :ARG1-of (n4 / normal-02)
                                                            :time b4
                                                            :quant (o5 / or
                                                                  :op1 (c4 / concentration-quantity :quant 5
                                                                        :unit (n5 / nanogram-per-milliliter))
                                                                  :op2 (l17 / less-than
                                                                        :op1 c4))
                                                            :quant-of p29)))
                                          :duration (t18 / temporal-quantity :quant 76.3
                                                :unit m4
                                                :ARG1-of (r7 / relative-05
                                                      :ARG3 (t19 / temporal-quantity :quant 25.6
                                                            :unit m4
                                                            :duration-of (t20 / time
                                                                  :location (p32 / person
                                                                        :ARG0-of h
                                                                        :ARG0-of (h9 / have-03
                                                                              :ARG1 (l18 / level
                                                                                    :ARG1-of (i4 / increase-01)
                                                                                    :quant-of p29
                                                                                    :time b4)))
                                                                  :mod m14
                                                                  :time b5))))))
                              :ARG1-of (d / describe-01
                                    :ARG0 (t21 / table :mod 2))
                              :ARG1-of (s18 / statistical-test-91
                                    :ARG2 0.0001))))))

# ::id pmid_2290_9976.53 ::date 2015-08-24T05:18:34 ::annotator SDL-AMR-09 ::preferred
# ::snt <sec-title level="2"><bold>Table 2.</bold> Univariate and multivariate analysis of OS rate (log-rank test)</sec-title>
# ::save-date Mon Aug 31, 2015 ::file pmid_2290_9976_53.txt
(d / describe-01
      :ARG0 (t / table :mod 2)
      :ARG1 (a / and
            :op1 (a2 / analyze-01
                  :ARG1 (r / rate
                        :mod (s / survive-01
                              :mod (o2 / overall)))
                  :mod (u / univariate))
            :op2 (a3 / analyze-01
                  :ARG1 r
                  :mod (m / multivariate))
            :ARG1-of (m2 / mean-01
                  :ARG2 (t2 / test-01
                        :mod (l / log-rank)))))

# ::id pmid_2290_9976.54 ::date 2015-08-24T05:20:26 ::annotator SDL-AMR-09 ::preferred
# ::snt Other clinical parameters such as histological differentiation grade and primary tumor size showed no significant differences between groups.
# ::save-date Wed Aug 26, 2015 ::file pmid_2290_9976_54.txt
(s / show-01
      :ARG0 (p / parameter
            :mod (o / other)
            :mod (c / clinic)
            :example (a / and
                        :op1 (g / grade
                              :degree-of (d / differentiate-01
                                    :mod (h / histology)))
                        :op2 (s2 / size
                              :poss (t / tumor
                                    :mod (p2 / primary)))))
      :ARG1 (d2 / differ-02 :polarity -
            :ARG1 (g2 / group)
            :ARG3 p
            :ARG1-of (s3 / significant-02)))

# ::id pmid_2290_9976.55 ::date 2015-08-24T05:24:10 ::annotator SDL-AMR-09 ::preferred
# ::snt <sec-title level="2">Clinical and pathological variables identified by multivariate analysis as potential prognostic factors for OS rate</sec-title>
# ::save-date Mon Aug 31, 2015 ::file pmid_2290_9976_55.txt
(a / and
      :op1 (v / variable
            :mod (c / clinic))
      :op2 (v2 / variable
            :mod (p / pathology))
      :ARG1-of (i / identify-01
            :ARG0 (a2 / analyze-01
                  :mod (m / multivariate))
            :ARG2 (f / factor
                  :mod (p2 / potential)
                  :mod (p3 / prognostic)
                  :topic (r / rate
                        :mod (s / survive-01
                              :mod (o2 / overall))))))

# ::id pmid_2290_9976.56 ::date 2015-08-24T05:26:02 ::annotator SDL-AMR-09 ::preferred
# ::snt These results are summarized in <xref ref-type="table" rid="T2">Table 2</xref>.
# ::save-date Mon Aug 24, 2015 ::file pmid_2290_9976_56.txt
(s / summarize-01
      :ARG1 (t / thing
            :mod (t2 / this)
            :ARG2-of (r / result-01))
      :ARG2 (t3 / table :mod 2))

# ::id pmid_2290_9976.57 ::date 2015-08-26T00:29:29 ::annotator SDL-AMR-09 ::preferred
# ::snt Multivariate analysis identified the following independent prognostic factors affecting OS rates: Primary tumor localization (HR 0.53; p = 0.0032); Pretreatment CEA level (HR 2.68; p < 0.0001); WHO performance status (HR 0.34; p = 0.0008); Lymph node involvement grade (HR 1.94; p = 0.0107).
# ::save-date Tue Dec 15, 2015 ::file pmid_2290_9976_57.txt
(i / identify-01
      :ARG0 (a / analyze-01
            :mod (m / multivariate))
      :ARG1 (f / factor
            :ARG1-of (f2 / follow-04)
            :ARG0-of (d / depend-01 :polarity -)
            :mod (p / prognostic)
            :ARG0-of (a2 / affect-01
                  :ARG1 (r / rate
                        :mod (s2 / survive-01
                              :mod (o3 / overall))))
            :ARG1-of (m2 / mean-01
                  :ARG2 (a3 / and
                        :op1 (b2 / be-located-at-91
                              :ARG1 (t / tumor
                                    :mod (p2 / primary))
                              :ARG1-of (m3 / mean-01
                                    :ARG2 (r2 / ratio-of :quant 0.53
                                          :op1 (h / hazard)))
                              :ARG1-of (s3 / statistical-test-91
                                    :ARG2 0.0032))
                        :op2 (l2 / level
                              :quant-of (p4 / protein :name (n / name :op1 "CEA"))
                              :time (b / before
                                    :op1 (t2 / treat-03))
                              :ARG1-of (m4 / mean-01
                                    :ARG2 (r3 / ratio-of :quant 2.68
                                          :op1 h))
                              :ARG1-of (s4 / statistical-test-91
                                    :ARG2 (l3 / less-than :op1 0.0001)))
                        :op3 (s / status
                              :mod (p6 / perform-02
                                    :ARG2 (o2 / organization :wiki "World_Health_Organization" :name (n2 / name :op1 "World" :op2 "Health" :op3 "Organization")))
                              :ARG1-of (m5 / mean-01
                                    :ARG2 (r4 / ratio-of :quant 0.34
                                          :op1 h))
                              :ARG1-of (s5 / statistical-test-91
                                    :ARG2 0.0008))
                        :op4 (g / grade
                              :degree-of (i2 / involve-01
                                    :ARG1 (n3 / node
                                          :mod (l4 / lymph)))
                              :ARG1-of (m6 / mean-01
                                    :ARG2 (r5 / ratio-of :quant 1.94
                                          :op1 h))
                              :ARG1-of (s6 / statistical-test-91
                                    :ARG2 0.01077))))))

# ::id pmid_2290_9976.58 ::date 2015-08-24T05:27:22 ::annotator SDL-AMR-09 ::preferred
# ::snt Other clinical parameters such as age, gender, and Karnofsky performance status showed no significant differences in this analysis.
# ::save-date Mon Sep 14, 2015 ::file pmid_2290_9976_58.txt
(s / show-01
      :ARG0 (p / parameter
            :mod (o / other)
            :mod (c / clinic)
            :example (a / and
                        :op1 (a2 / age-01)
                        :op2 (g / gender)
                        :op3 (s2 / status
                              :mod (p2 / perform-02)
                              :mod (p3 / person :name (n / name :op1 "Karnofsky")))))
      :ARG1 (d / differ-02 :polarity -
            :ARG1 p
            :time (a3 / analyze-01
                  :mod (t / this))
            :ARG1-of (s3 / significant-02)))

# ::id pmid_2290_9976.59 ::date 2015-08-25T07:37:22 ::annotator SDL-AMR-09 ::preferred
# ::snt <sec-title level="2">Predictive roles of <i>K-Ras</i> and <i>B-Raf</i> mutations on time to progression in CRC patients treated with irinotecan-based first-line palliative chemotherapy on the basis of univariate analysis</sec-title>
# ::save-date Thu Dec 10, 2015 ::file pmid_2290_9976_59.txt
(p / play-02
      :ARG0 (a / and
            :op1 (m / mutate-01
                  :ARG1 (g / gene :name (n / name :op1 "K-Ras")))
            :op2 (m2 / mutate-01
                  :ARG1 (g2 / gene :name (n3 / name :op1 "B-Raf"))))
      :ARG1 (p2 / predict-01
            :ARG0 a
            :ARG1 (t2 / time
                  :time (b2 / before
                        :op1 (p6 / progress-01
                              :ARG1 (d / disease)))))
      :location (p3 / person
            :ARG0-of (h / have-rel-role-91
                  :ARG2 (p4 / patient))
            :ARG1-of (t / treat-03
                  :ARG2 (d2 / disease :wiki "Colorectal_cancer" :name (n2 / name :op1 "colorectal" :op2 "cancer"))
                  :ARG3 (c / chemotherapy
                        :mod (p5 / palliative)
                        :ARG1-of (b / base-02
                              :ARG2 (s / small-molecule :name (n4 / name :op1 "irinotecan")))
                        :mod (l / line
                              :ord (o / ordinal-entity :value 1)))))
      :ARG1-of (b3 / base-02
            :ARG2 (a2 / analyze-01
                  :mod (u / univariate))))

# ::id pmid_2290_9976.60 ::date 2015-08-25T07:51:16 ::annotator SDL-AMR-09 ::preferred
# ::snt These results are summarized in <xref ref-type="table" rid="T3">Table 3</xref>.
# ::save-date Tue Aug 25, 2015 ::file pmid_2290_9976_60.txt
(s / summarize-01
      :ARG1 (t / thing
            :mod (t2 / this)
            :ARG2-of (r / result-01))
      :ARG2 (t3 / table :mod 3))

# ::id pmid_2290_9976.61 ::date 2015-08-25T07:54:08 ::annotator SDL-AMR-09 ::preferred
# ::snt Patients with higher pretreatment levels of CEA (> 5 ng/ml) showed a median time to progression of 9.0 mo relative to 13.0 mo in patients with normal levels (≤ 5 ng/ml, p = 0.0085).
# ::save-date Tue Dec 15, 2015 ::file pmid_2290_9976_61.txt
(s / show-01
      :ARG0 (p / person
            :ARG0-of (h / have-rel-role-91
                  :ARG2 (p2 / patient))
            :ARG0-of (h2 / have-03
                  :ARG1 (l / level
                        :ARG1-of (h3 / high-02
                              :degree (m / more))
                        :quant-of (p3 / protein :name (n / name :op1 "CEA"))
                        :ARG1-of (m2 / mean-01
                              :ARG2 (m3 / more-than
                                    :op1 (c / concentration-quantity :quant 5
                                          :unit (n2 / nanogram-per-milliliter))))
                        :time (b / before
                              :op1 (t / treat-03)))))
      :ARG1 (t2 / time
            :time (b2 / before
                  :op1 (p4 / progress-01))
            :mod (m4 / median)
            :ARG1-of (r / relative-05
                  :ARG3 (t4 / time
                        :ARG1-of (s2 / show-01
                              :ARG0 (p5 / person
                                    :ARG0-of h
                                    :ARG0-of (h4 / have-03
                                          :ARG1 (l2 / level
                                                :ARG1-of (n3 / normal-02)
                                                :ARG1-of (m6 / mean-01
                                                      :ARG2 (o / or
                                                            :op1 (l3 / less-than
                                                                  :op1 c)
                                                            :op2 c))
                                                :ARG1-of (s3 / statistical-test-91
                                                      :ARG2 0.0085)))))
                        :duration (t5 / temporal-quantity :quant 13
                              :unit m5)
                        :time b2))
            :duration (t3 / temporal-quantity :quant 9
                  :unit (m5 / month))))

# ::id pmid_2290_9976.62 ::date 2015-08-25T08:11:40 ::annotator SDL-AMR-09 ::preferred
# ::snt Patients without resection of metastases showed a median time to progression of 9.0 mo relative to 14.0 mo in patients who underwent resection (p = 0.0131).
# ::save-date Tue Dec 15, 2015 ::file pmid_2290_9976_62.txt
(s / show-01
      :ARG0 (p / person
            :ARG0-of (h / have-rel-role-91
                  :ARG2 (p2 / patient))
            :ARG1-of (u / undergo-28 :polarity -
                  :ARG2 (r / resection
                        :mod (m / metastasize-101))))
      :ARG1 (t / time
            :mod (m2 / median)
            :time (b / before
                  :op1 (p3 / progress-01))
            :ARG1-of (r2 / relative-05
                  :ARG3 (t3 / time
                        :ARG1-of (s2 / show-01
                              :ARG0 (p4 / person
                                    :ARG0-of h
                                    :ARG1-of (u2 / undergo-28
                                          :ARG2 r)))
                        :duration (t4 / temporal-quantity :quant 14
                              :unit m3)
                        :time b))
            :duration (t2 / temporal-quantity :quant 9
                  :unit (m3 / month)))
      :ARG1-of (s3 / statistical-test-91
            :ARG2 0.0131))

# ::id pmid_2290_9976.63 ::date 2015-08-25T08:19:47 ::annotator SDL-AMR-09 ::preferred
# ::snt Patients with <i>K-Ras</i> gene mutations showed a median time to progression of 9.0 mo relative to 11.0 mo in those with the wild-type <i>K-Ras</i> gene (p = 0.05883).
# ::save-date Tue Dec 15, 2015 ::file pmid_2290_9976_63.txt
(s / show-01
      :ARG0 (p / person
            :ARG0-of (h / have-rel-role-91
                  :ARG2 (p2 / patient))
            :ARG0-of (h2 / have-03
                  :ARG1 (m / mutate-01
                        :ARG1 (g / gene :name (n / name :op1 "K-Ras")))))
      :ARG1 (t / time
            :mod (m2 / median)
            :time (b / before
                  :op1 (p3 / progress-01))
            :ARG1-of (r / relative-05
                  :ARG3 (t3 / time
                        :ARG1-of (s2 / show-01
                              :ARG0 (p4 / person
                                    :ARG0-of h
                                    :ARG0-of (h3 / have-03
                                          :ARG1 (g2 / gene :name (n2 / name :op1 "K-Ras")
                                                :mod (w / wild-type)))))
                        :duration (t4 / temporal-quantity :quant 11
                              :unit m3)
                        :time b))
            :duration (t2 / temporal-quantity :quant 9
                  :unit (m3 / month)))
      :ARG1-of (s3 / statistical-test-91
            :ARG2 0.05883))

# ::id pmid_2290_9976.64 ::date 2015-08-25T08:24:18 ::annotator SDL-AMR-09 ::preferred
# ::snt Other clinical parameters including histological differentiation grade, primary tumor location and size, lymph node involvement grade, and <i>B-Raf</i> gene mutation status showed no predictive significance in this analysis.
# ::save-date Mon Aug 31, 2015 ::file pmid_2290_9976_64.txt
(s / show-01
      :ARG0 (p / parameter
            :mod (o / other)
            :mod (c / clinic)
            :ARG2-of (i / include-91
                  :ARG1 (a / and
                        :op1 (g / grade
                              :degree-of (d / differentiate-01
                                    :mod (h / histology)))
                        :op2 (b / be-located-at-91
                              :ARG1 (t / tumor
                                    :mod (p2 / primary)))
                        :op3 (s2 / size
                              :poss t)
                        :op4 (g2 / grade
                              :degree-of (i2 / involve-01
                                    :ARG1 (n3 / node
                                          :mod (l2 / lymph))))
                        :op5 (s3 / status
                              :mod (m / mutate-01
                                    :ARG1 (g3 / gene :name (n2 / name :op1 "B-Raf")))))))
      :ARG1 (s4 / significant-02 :polarity -
            :ARG1 p
            :ARG0-of (p3 / predict-01))
      :time (a2 / analyze-01
            :mod (t2 / this)))

# ::id pmid_2290_9976.65 ::date 2015-08-25T08:34:33 ::annotator SDL-AMR-09 ::preferred
# ::snt <sec-title level="2"><bold>Table 3.</bold> Univariate and multivariate analysis of time to progression (log-rank test) for irinotecan-based chemotherapy</sec-title>
# ::save-date Tue Aug 25, 2015 ::file pmid_2290_9976_65.txt
(d / describe-01
      :ARG0 (t / table :mod 3)
      :ARG1 (a / and
            :op1 (a2 / analyze-01
                  :ARG1 (t2 / time
                        :time (b / before
                              :op1 (p / progress-01)))
                  :mod (u / univariate))
            :op2 (a3 / analyze-01
                  :ARG1 t2
                  :mod (m / multivariate))
            :ARG1-of (m2 / mean-01
                  :ARG2 (t3 / test-01
                        :mod (l / log-rank)))
            :condition (c / chemotherapy
                  :ARG1-of (b2 / base-02
                        :ARG2 (s / small-molecule :name (n / name :op1 "irinotecan"))))))

# ::id pmid_2290_9976.66 ::date 2015-08-25T08:38:35 ::annotator SDL-AMR-09 ::preferred
# ::snt <sec-title level="2">Predictive roles of <i>K-Ras</i> and <i>B-Raf</i> mutations on time to progression in CRC patients treated with irinotecan-based first-line palliative chemotherapy on the basis of multivariate analysis</sec-title>
# ::save-date Thu Dec 10, 2015 ::file pmid_2290_9976_66.txt
(p / play-02
      :ARG0 (a / and
            :op1 (m / mutate-01
                  :ARG1 (g / gene :name (n / name :op1 "K-Ras")))
            :op2 (m2 / mutate-01
                  :ARG1 (g2 / gene :name (n3 / name :op1 "B-Raf"))))
      :ARG1 (p2 / predict-01
            :ARG0 a
            :ARG1 (t / time
                  :time (b / before
                        :op1 (p3 / progress-01
                              :ARG1 (d / disease)))))
      :location (p4 / person
            :ARG0-of (h / have-rel-role-91
                  :ARG2 (p5 / patient))
            :ARG0-of (h2 / have-03
                  :ARG1 (d2 / disease :wiki "Colorectal_cancer" :name (n2 / name :op1 "colorectal" :op2 "cancer")))
            :ARG1-of (t2 / treat-03
                  :ARG2 (c / chemotherapy
                        :ARG1-of (b2 / base-02
                              :ARG2 (s / small-molecule :name (n4 / name :op1 "irinotecan")))
                        :mod (p6 / palliative)
                        :mod (l / line
                              :ord (o / ordinal-entity :value 1)))))
      :ARG1-of (b3 / base-02
            :ARG2 (a2 / analyze-01
                  :mod (m3 / multivariate))))

# ::id pmid_2290_9976.67 ::date 2015-08-25T08:52:20 ::annotator SDL-AMR-09 ::preferred
# ::snt These results are summarized in <xref ref-type="table" rid="T3">Table 3</xref>.
# ::save-date Tue Aug 25, 2015 ::file pmid_2290_9976_67.txt
(s / summarize-01
      :ARG1 (t / thing
            :mod (t2 / this)
            :ARG2-of (r / result-01))
      :ARG2 (t3 / table :mod 3))

# ::id pmid_2290_9976.68 ::date 2015-08-25T08:57:13 ::annotator SDL-AMR-09 ::preferred
# ::snt Multivariate analysis identified the following independent favorable predictive factors in patients with disseminated CRC treated with irinotecan-based first-line palliative chemotherapy: Wild-type <i>K-Ras</i> gene (HR 0.59; p = 0.0459) and normal pretreatment CEA levels (HR 0.52; p = 0.0065).
# ::save-date Sun Jan 3, 2016 ::file pmid_2290_9976_68.txt
(i / identify-01
      :ARG0 (a / analyze-01
            :mod (m / multivariate))
      :ARG1 (f / factor
            :ARG1-of (f2 / follow-04)
            :ARG0-of (d / depend-01 :polarity -)
            :ARG0-of (p / predict-01)
            :ARG1-of (m2 / mean-01
                  :ARG2 (a2 / and
                        :op1 (g / gene :name (n3 / name :op1 "K-Ras")
                              :mod (w / wild-type)
                              :ARG1-of (m3 / mean-01
                                    :ARG2 (r / ratio-of :quant 0.59
                                          :op1 (h3 / hazard)))
                              :ARG1-of (s2 / statistical-test-91
                                    :ARG2 0.0459))
                        :op2 (l2 / level
                              :ARG1-of (n4 / normal-02)
                              :time (b2 / before
                                    :op1 (t2 / treat-03))
                              :quant-of (p6 / protein :name (n5 / name :op1 "CEA"))
                              :ARG1-of (m4 / mean-01
                                    :ARG2 (r2 / ratio-of :quant 0.52
                                          :op1 h3))
                              :ARG1-of (s3 / statistical-test-91
                                    :ARG2 0.065))))
            :mod (f3 / favorable))
      :location (p2 / person
            :ARG0-of (h / have-rel-role-91
                  :ARG2 (p3 / patient))
            :ARG0-of (h2 / have-03
                  :ARG1 (d2 / disease :wiki "Colorectal_cancer" :name (n / name :op1 "colorectal" :op2 "cancer")
                        :ARG1-of (d3 / disseminate-01)))
            :ARG1-of (t / treat-03
                  :ARG2 (c / chemotherapy
                        :ARG1-of (b / base-02
                              :ARG2 (s / small-molecule :name (n2 / name :op1 "irinotecan")))
                        :mod (l / line
                              :ord (o / ordinal-entity :value 1))
                        :mod (p4 / palliative)))))

# ::id pmid_2290_9976.69 ::date 2015-08-25T08:57:38 ::annotator SDL-AMR-09 ::preferred
# ::snt However, this analysis did not reveal any significant differences between patients with and without resection of metastases, with different histological types of neoplasms and <i>B-Raf</i> gene mutation status.
# ::save-date Thu Dec 10, 2015 ::file pmid_2290_9976_69.txt
(c / contrast-01
      :ARG2 (r / reveal-01 :polarity -
            :ARG0 (a / analyze-01
                  :mod (t2 / this))
            :ARG1 (d / differ-02
                  :ARG1 (a2 / and
                        :op1 (p / person
                              :ARG0-of (h2 / have-rel-role-91
                                    :ARG2 (p2 / patient))
                              :ARG0-of (h3 / have-03
                                    :ARG1 (r2 / resection
                                          :mod (m / metastasize-101))))
                        :op2 (p3 / person
                              :ARG0-of h2
                              :ARG0-of (h4 / have-03 :polarity -
                                    :ARG1 r2)))
                  :ARG2 (a3 / and
                        :op1 (p4 / person
                              :ARG0-of h2
                              :ARG0-of (h5 / have-03
                                    :ARG1 (t / type
                                          :mod (n3 / neoplasm)
                                          :mod (h6 / histology)
                                          :ARG1-of (d2 / differ-02))))
                        :op2 (p5 / person
                              :ARG0-of h2
                              :ARG0-of (h7 / have-03
                                    :ARG1 (s2 / status
                                          :ARG1-of d2
                                          :mod (m2 / mutate-01
                                                :ARG1 (g / gene :name (n2 / name :op1 "B-Raf")))))))
                  :ARG1-of (s / significant-02))))

# ::id pmid_2290_9976.70 ::date 2015-08-25T09:08:09 ::annotator SDL-AMR-09 ::preferred
# ::snt <sec-title level="2">Predictive roles of <i>K-Ras</i> and <i>B-Raf</i> mutations on time to progression in CRC patients treated with oxaliplatin-based first-line palliative chemotherapy on the basis of univariate analysis</sec-title>
# ::save-date Thu Dec 10, 2015 ::file pmid_2290_9976_70.txt
(p / play-02
      :ARG0 (a / and
            :op1 (m / mutate-01
                  :ARG1 (g / gene :wiki -
                        :name (n / name :op1 "K-Ras")))
            :op2 (m2 / mutate-01
                  :ARG2 (g2 / gene :wiki "BRAF_(gene)"
                        :name (n3 / name :op1 "B-Raf"))))
      :ARG1 (p2 / predict-01
            :ARG0 a
            :ARG1 (t / time
                  :time (b / before
                        :op1 (p3 / progress-01
                              :ARG1 (d / disease)))))
      :location (p4 / person
            :ARG0-of (h / have-rel-role-91
                  :ARG2 (p5 / patient))
            :ARG0-of (h2 / have-03
                  :ARG1 (d2 / disease :wiki "Colorectal_cancer"
                        :name (n2 / name :op1 "colorectal" :op2 "cancer")))
            :ARG1-of (t2 / treat-03
                  :ARG2 (c / chemotherapy
                        :mod (p6 / palliative)
                        :ARG1-of (b2 / base-02
                              :ARG2 (s / small-molecule :wiki "Oxaliplatin"
                                    :name (n4 / name :op1 "oxaliplatin")))
                        :mod (l / line
                              :ord (o / ordinal-entity :value 1)))))
      :ARG1-of (b3 / base-02
            :ARG2 (a2 / analyze-01
                  :mod (u / univariate))))

# ::id pmid_2290_9976.71 ::date 2015-08-25T09:11:40 ::annotator SDL-AMR-09 ::preferred
# ::snt These results are summarized in <xref ref-type="table" rid="T4">Table 4</xref>.
# ::save-date Tue Aug 25, 2015 ::file pmid_2290_9976_71.txt
(s / summarize-01
      :ARG1 (t / thing
            :mod (t2 / this)
            :ARG2-of (r / result-01))
      :ARG2 (t3 / table :mod 4))

# ::id pmid_2290_9976.72 ::date 2015-08-25T09:12:43 ::annotator SDL-AMR-09 ::preferred
# ::snt Univariate analysis of time to progression in patients treated with oxaliplatin-based first-line chemotherapy regimens reveals that increased CEA levels and resection of metastases exerted significant influences on median time to progression.
# ::save-date Thu Dec 10, 2015 ::file pmid_2290_9976_72.txt
(r / reveal-01
      :ARG0 (a / analyze-01
            :ARG1 (t / time
                  :time (b / before
                        :op1 (p / progress-01)))
            :mod (u / univariate))
      :ARG1 (e / exert-01
            :ARG0 (a2 / and
                  :op1 (l2 / level
                        :quant-of (p4 / protein :name (n2 / name :op1 "CEA"))
                        :ARG1-of (i / increase-01))
                  :op2 (r3 / resection
                        :mod (m / metastasize-101)))
            :ARG1 (i2 / influence-01
                  :ARG1-of (s2 / significant-02))
            :ARG2 (t3 / time
                  :time b
                  :mod (m2 / median)))
      :location (p2 / person
            :ARG0-of (h / have-rel-role-91
                  :ARG2 (p3 / patient))
            :ARG1-of (t2 / treat-03
                  :ARG2 (r2 / regimen
                        :mod (c / chemotherapy
                              :ARG1-of (b2 / base-02
                                    :ARG2 (s / small-molecule :name (n / name :op1 "oxaliplatin")))
                              :mod (l / line
                                    :ord (o / ordinal-entity :value 1)))))))

# ::id pmid_2290_9976.73 ::date 2015-08-25T09:17:59 ::annotator SDL-AMR-09 ::preferred
# ::snt Patients with increased pretreatment CEA levels had a time to progression of 8.0 mo compared with 13.0 mo in patients with normal CEA levels (p = 0.0084).
# ::save-date Tue Dec 15, 2015 ::file pmid_2290_9976_73.txt
(h / have-03
      :ARG0 (p / person
            :ARG0-of (h2 / have-rel-role-91
                  :ARG2 (p2 / patient))
            :ARG0-of (h3 / have-03
                  :ARG1 (l / level
                        :quant-of (p3 / protein :name (n / name :op1 "CEA"))
                        :ARG1-of (i / increase-01)
                        :time (b / before
                              :op1 (t / treat-03)))))
      :ARG1 (t2 / time
            :time (b2 / before
                  :op1 (p4 / progress-01))
            :duration (t3 / temporal-quantity :quant 8
                  :unit (m / month))
            :compared-to (t4 / time
                  :time b2
                  :duration (t5 / temporal-quantity :quant 13
                        :unit m)
                  :ARG1-of (h4 / have-03
                        :ARG0 (p5 / person
                              :ARG0-of h2
                              :ARG0-of (h5 / have-03
                                    :ARG1 (l2 / level
                                          :ARG1-of (n2 / normal-02)
                                          :quant-of p3))))))
      :ARG1-of (s / statistical-test-91
            :ARG2 0.0084))

# ::id pmid_2290_9976.74 ::date 2015-08-25T09:27:02 ::annotator SDL-AMR-09 ::preferred
# ::snt Patients without resection of metastases had a time to progression of 9.0 mo relative to 16.0 mo in patients who underwent resection (p = 0.0226).
# ::save-date Tue Dec 15, 2015 ::file pmid_2290_9976_74.txt
(h / have-03
      :ARG0 (p / person
            :ARG0-of (h2 / have-rel-role-91
                  :ARG2 (p2 / patient))
            :ARG1-of (u / undergo-28 :polarity -
                  :ARG2 (r / resection
                        :mod (m / metastasize-101))))
      :ARG1 (t / time
            :time (b / before
                  :op1 (p3 / progress-01))
            :duration (t2 / temporal-quantity :quant 9
                  :unit (m2 / month))
            :ARG1-of (r2 / relative-05
                  :ARG3 (t3 / time
                        :time b
                        :duration (t4 / temporal-quantity :quant 16
                              :unit m2)
                        :ARG1-of (h3 / have-03
                              :ARG0 (p4 / person
                                    :ARG0-of h2
                                    :ARG1-of (u2 / undergo-28
                                          :ARG2 r))))))
      :ARG1-of (s / statistical-test-91
            :ARG2 0.0226))

# ::id pmid_2290_9976.75 ::date 2015-08-25T09:37:34 ::annotator SDL-AMR-09 ::preferred
# ::snt Patients with tubular tumors showed a time to progression of 9.0 mo compared with 13.0 mo in those with other histological types (p = 0.0462).
# ::save-date Tue Dec 15, 2015 ::file pmid_2290_9976_75.txt
(s / show-01
      :ARG0 (p / person
            :ARG0-of (h / have-rel-role-91
                  :ARG2 (p2 / patient))
            :ARG0-of (h2 / have-03
                  :ARG1 (t / tumor
                        :mod (t2 / tubular))))
      :ARG1 (t3 / time
            :time (b / before
                  :op1 (p3 / progress-01))
            :duration (t4 / temporal-quantity :quant 9
                  :unit (m / month))
            :compared-to (t5 / time
                  :time b
                  :duration (t6 / temporal-quantity :quant 13
                        :unit m)
                  :ARG1-of (s2 / show-01
                        :ARG0 (p4 / person
                              :ARG0-of h
                              :mod (t7 / type
                                    :mod (h3 / histology)
                                    :mod (o / other))))))
      :ARG1-of (s3 / statistical-test-91
            :ARG2 0.0462))

# ::id pmid_2290_9976.76 ::date 2015-08-25T09:41:49 ::annotator SDL-AMR-09 ::preferred
# ::snt Patients with <i>K-Ras</i> gene mutations did not show a significant difference in time to progression when treated with oxaliplatin chemotherapy, when compared with those with the wild-type <i>K-Ras</i> gene (<xref ref-type="fig" rid="F4">Fig. 4</xref>).
# ::save-date Thu Dec 10, 2015 ::file pmid_2290_9976_76.txt
(s / show-01 :polarity -
      :ARG0 (p / person
            :ARG0-of (h / have-rel-role-91
                  :ARG2 (p2 / patient))
            :ARG0-of (h2 / have-03
                  :ARG1 (m / mutate-01
                        :ARG1 (g / gene :name (n / name :op1 "K-Ras")))))
      :ARG1 (d / differ-02
            :ARG1 (t / time
                  :time (b / before
                        :op1 (p3 / progress-01)))
            :ARG1-of (s2 / significant-02))
      :time (t2 / treat-03
            :ARG1 p
            :ARG2 (c / chemotherapy
                  :mod (s3 / small-molecule :name (n2 / name :op1 "oxaliplatin"))))
      :compared-to (p4 / person
            :ARG0-of h
            :mod (g2 / gene :name (n3 / name :op1 "K-Ras")
                  :mod (w / wild-type)))
      :ARG1-of (d2 / describe-01
            :ARG0 (f / figure :mod 4)))

# ::id pmid_2290_9976.77 ::date 2015-08-25T09:46:40 ::annotator SDL-AMR-09 ::preferred
# ::snt The significance of <i>B-Raf</i> gene status, WHO performance status, and Karnofsky performance status could not be assessed.
# ::save-date Fri Nov 20, 2015 ::file pmid_2290_9976_77.txt
(p2 / possible-01 :polarity -
      :ARG1 (a / assess-01
            :ARG1 (s / signify-01
                  :ARG0 (a2 / and
                        :op1 (s2 / status
                              :mod (g / gene
                                    :name (n / name :op1 "B-RAF")))
                        :op2 (s3 / status
                              :mod (p3 / perform-02)
                              :mod (o / organization :wiki "World_Health_Organization"
                                    :name (n2 / name :op1 "World" :op2 "Health" :op3 "Organization")))
                        :op3 (s4 / status
                              :mod (p4 / perform-02)
                              :mod (p / person
                                    :name (n3 / name :op1 "Karnofsky")))))))

# ::id pmid_2290_9976.78 ::date 2015-08-25T09:49:45 ::annotator SDL-AMR-09 ::preferred
# ::snt <sec-title level="2"><bold>Table 4.</bold> Univariate and multivariate analysis of time to progression (log-rank test) for oxaliplatin-based chemotherapy</sec-title>
# ::save-date Tue Aug 25, 2015 ::file pmid_2290_9976_78.txt
(d / describe-01
      :ARG0 (t / table :mod 4)
      :ARG1 (a / and
            :op1 (a2 / analyze-01
                  :ARG1 (t2 / time
                        :time (b / before
                              :op1 (p / progress-01)))
                  :mod (u / univariate))
            :op2 (a3 / analyze-01
                  :ARG1 t2
                  :mod (m / multivariate))
            :ARG1-of (m2 / mean-01
                  :ARG2 (t3 / test-01
                        :mod (l / log-rank)))
            :condition (c / chemotherapy
                  :ARG1-of (b2 / base-02
                        :ARG2 (s / small-molecule :name (n / name :op1 "oxaliplatin"))))))

# ::id pmid_2290_9976.79 ::date 2015-08-25T09:52:58 ::annotator SDL-AMR-09 ::preferred
# ::snt <sec-title level="2">Predictive roles of <i>K-Ras</i> and <i>B-Raf</i> mutations on time to progression in CRC patients treated with oxaliplatin-based first-line palliative chemotherapy on the basis of multivariate analysis</sec-title>
# ::save-date Thu Dec 10, 2015 ::file pmid_2290_9976_79.txt
(p / play-02
      :ARG0 (a / and
            :op1 (m / mutate-01
                  :ARG1 (g / gene :name (n / name :op1 "K-Ras")))
            :op2 (m2 / mutate-01
                  :ARG1 (g2 / gene :name (n3 / name :op1 "B-Raf"))))
      :ARG1 (p2 / predict-01
            :ARG0 a
            :ARG1 (t / time
                  :time (b / before
                        :op1 (p3 / progress-01
                              :ARG1 (d / disease)))))
      :location (p4 / person
            :ARG0-of (h / have-rel-role-91
                  :ARG2 (p5 / patient))
            :ARG0-of (h2 / have-03
                  :ARG1 (d2 / disease :wiki "Colorectal_cancer" :name (n2 / name :op1 "colorectal" :op2 "cancer")))
            :ARG1-of (t2 / treat-03
                  :ARG2 (c / chemotherapy
                        :mod (p6 / palliative)
                        :ARG1-of (b2 / base-02
                              :ARG2 (s / small-molecule :name (n4 / name :op1 "oxaliplatin")))
                        :mod (l / line
                              :ord (o / ordinal-entity :value 1)))))
      :ARG1-of (b3 / base-02
            :ARG2 (a2 / analyze-01
                  :mod (m3 / multivariate))))

# ::id pmid_2290_9976.80 ::date 2015-08-25T10:00:53 ::annotator SDL-AMR-09 ::preferred
# ::snt These results are summarized in <xref ref-type="table" rid="T4">Table 4</xref>.
# ::save-date Tue Aug 25, 2015 ::file pmid_2290_9976_80.txt
(s / summarize-01
      :ARG1 (t / thing
            :mod (t2 / this)
            :ARG2-of (r / result-01))
      :ARG2 (t3 / table :mod 4))

# ::id pmid_2290_9976.81 ::date 2015-08-25T10:01:37 ::annotator SDL-AMR-09 ::preferred
# ::snt Multivariate analysis identified resection of metastases (HR 0.43; p = 0.0249) and wild-type <i>K-Ras</i> gene (HR 0.49; p = 0.0451) as independent favorable predictive factors in patients with disseminated CRC who were treated with oxaliplatin-based first-line palliative chemotherapy regimens.
# ::save-date Tue Dec 15, 2015 ::file pmid_2290_9976_81.txt
(i / identify-01
      :ARG0 (a / analyze-01
            :mod (m / multivariate))
      :ARG1 (a2 / and
            :op1 (r / resection
                  :mod (m2 / metastasize-101)
                  :ARG1-of (m3 / mean-01
                        :ARG2 (r2 / ratio-of :quant 0.43
                              :op1 (h / hazard)))
                  :ARG1-of (s2 / statistical-test-91
                        :ARG2 0.0249))
            :op2 (g / gene :name (n / name :op1 "K-Ras")
                  :mod (w / wild-type)
                  :ARG1-of (m4 / mean-01
                        :ARG2 (r3 / ratio-of :quant 0.49
                              :op1 h))
                  :ARG1-of (s3 / statistical-test-91
                        :ARG2 0.0451)))
      :ARG2 (f / factor
            :ARG0-of (d / depend-01 :polarity -)
            :ARG0-of (p3 / predict-01)
            :mod (f3 / favorable))
      :location (p4 / person
            :ARG0-of (h2 / have-rel-role-91
                  :ARG2 (p5 / patient))
            :ARG0-of (h3 / have-03
                  :ARG1 (d2 / disease :wiki "Colorectal_cancer" :name (n2 / name :op1 "colorectal" :op2 "cancer")
                        :ARG1-of (d3 / disseminate-01)))
            :ARG1-of (t / treat-03
                  :ARG2 (r4 / regimen
                        :mod (c / chemotherapy
                              :ARG1-of (b / base-02
                                    :ARG2 (s / small-molecule :name (n3 / name :op1 "oxaliplatin")))
                              :mod (l / line
                                    :ord (o / ordinal-entity :value 1))
                              :mod (p6 / palliative))))))

# ::id pmid_2290_9976.82 ::date 2015-08-25T10:01:56 ::annotator SDL-AMR-09 ::preferred
# ::snt However, no statistically significant effects of CEA levels and types of neoplasm could be seen.
# ::save-date Tue Aug 25, 2015 ::file pmid_2290_9976_82.txt
(h / have-concession-91
      :ARG1 (p / possible-01
            :ARG1 (s / see-01
                  :ARG1 (a / affect-01 :polarity -
                        :ARG0 (a2 / and
                              :op1 (l / level
                                    :quant-of (p2 / protein :name (n / name :op1 "CEA")))
                              :op2 (t / type
                                    :mod (n2 / neoplasm)))
                        :ARG1-of (s2 / significant-02
                              :manner (s3 / statistic))))))

# ::id pmid_2290_9976.83 ::date 2015-08-25T10:04:26 ::annotator SDL-AMR-09 ::preferred
# ::snt The significance of <i>B-Raf</i> gene status, WHO performance status, and Karnofsky performance status could not be assessed due to the small number of patients.
# ::save-date Thu Dec 10, 2015 ::file pmid_2290_9976_83.txt
(p2 / possible-01 :polarity -
      :ARG1 (a / assess-01
            :ARG1 (s2 / signify-01
                  :ARG0 (a2 / and
                        :op1 (s / status
                              :mod (g / gene :name (n2 / name :op1 "B-Raf")))
                        :op2 (s3 / status
                              :mod (p3 / perform-02)
                              :mod (o / organization :wiki "World_Health_Organization" :name (n3 / name :op1 "World" :op2 "Health" :op3 "Organization")))
                        :op3 (s4 / status
                              :mod (p4 / perform-02)
                              :mod (p / person :name (n4 / name :op1 "Karnofsky"))))))
      :ARG1-of (c / cause-01
            :ARG0 (n / number
                  :mod (s5 / small)
                  :quant-of (p5 / person
                        :ARG0-of (h / have-rel-role-91
                              :ARG2 (p6 / patient))))))

# ::id pmid_2303_9341.1 ::date 2015-06-23T00:51:05 ::annotator SDL-AMR-09 ::preferred
# ::snt Sensitivity to the MEK inhibitor E6201 in melanoma cells is associated with mutant <i>BRAF</i> and wildtype <i>PTEN</i> status (PMID:23039341)
# ::save-date Sat Jan 16, 2016 ::file pmid_2303_9341_1.txt
(a / associate-01
      :ARG1 (s / sensitive-03
            :ARG0 (c / cell
                  :mod (m2 / medical-condition :wiki "Melanoma" :name (n3 / name :op1 "melanoma")))
            :ARG1 (s4 / small-molecule :wiki - :name (n / name :op1 "E6201")
                  :ARG0-of (i / inhibit-01
                        :ARG1 (p2 / protein-family :wiki "Mitogen-activated_protein_kinase_kinase" :name (n2 / name :op1 "MEK")))))
      :ARG2 (a2 / and
            :op1 (s2 / status
                  :mod (g / gene :wiki "BRAF_(gene)" :name (n4 / name :op1 "BRAF")
                        :ARG2-of (m / mutate-01)))
            :op2 (s3 / status
                  :mod (g2 / gene :wiki "PTEN_(gene)" :name (n5 / name :op1 "PTEN")
                        :mod (w / wild-type))))
      :ARG1-of (d2 / describe-01
            :ARG0 (p / publication-91
                  :ARG8 "PMID23039341")))

# ::id pmid_2303_9341.8 ::date 2015-06-23T01:05:59 ::annotator SDL-AMR-09 ::preferred
# ::snt <sec-title level="1" sec-area="abstract">Results</sec-title>
# ::save-date Tue Jun 23, 2015 ::file pmid_2303_9341_8.txt
(t / thing
      :ARG2-of (r / result-01))

# ::id pmid_2303_9341.9 ::date 2015-06-23T01:06:58 ::annotator SDL-AMR-09 ::preferred
# ::snt The majority of melanoma cell lines were either sensitive (IC50 < 500 nM, 24/31) or hypersensitive (IC50 < 100 nM, 18/31) to E6201.
# ::save-date Tue Dec 15, 2015 ::file pmid_2303_9341_9.txt
(o / or
      :op1 (s / sensitive-03
            :ARG0 (c / cell-line :quant 24
                  :quant (m / majority)
                  :ARG1-of (i / include-91
                        :ARG2 (c3 / cell-line :quant 31
                              :mod (m2 / medical-condition :name (n / name :op1 "melanoma"))))
                  :ARG0-of (h2 / have-03
                        :ARG1 (c6 / concentrate-02
                              :mod (i3 / inhibit-01
                                    :degree (p / percentage-entity :degree 50))
                              :quant (l3 / less-than
                                    :op1 (c2 / concentration-quantity :quant 500
                                          :unit (n3 / nanomolar))))))
            :ARG1 (s3 / small-molecule :name (n2 / name :op1 "E6201")))
      :op2 (s2 / sensitive-03
            :ARG0 (c4 / cell-line :quant 18
                  :ARG1-of (i2 / include-91
                        :ARG2 c3)
                  :ARG0-of (h3 / have-03
                        :ARG1 (c7 / concentrate-02
                              :mod i3
                              :quant (l / less-than
                                    :op1 (c5 / concentration-quantity :quant 100
                                          :unit n3))))
                  :quant (m3 / majority)
                  :mod m2)
            :ARG1 s3
            :degree (h / hyper)))

# ::id pmid_2303_9341.10 ::date 2015-06-23T01:34:19 ::annotator SDL-AMR-09 ::preferred
# ::snt This sensitivity correlated with wildtype <i>PTEN</i> and mutant <i>BRAF</i> status, whereas mutant <i>RAS</i> and PI3K pathway activation were associated with resistance.
# ::save-date Sat Jan 16, 2016 ::file pmid_2303_9341_10.txt
(c / contrast-01
      :ARG1 (c2 / correlate-01
            :ARG1 (s / sensitive-03
                  :mod (t / this))
            :ARG2 (a / and
                  :op1 (s2 / status
                        :mod (g / gene :name (n2 / name :op1 "PTEN")
                              :mod (w / wild-type)))
                  :op2 (s3 / status
                        :mod (g2 / gene :name (n / name :op1 "BRAF")
                              :ARG2-of (m / mutate-01)))))
      :ARG2 (a2 / associate-01
            :ARG1 (a6 / and
                  :op1 (g3 / gene :name (n3 / name :op1 "RAS")
                        :ARG2-of (m2 / mutate-01))
                  :op2 (p / pathway :name (n4 / name :op1 "PI3K")
                        :ARG1-of (a7 / activate-01)))
            :ARG2 (r / resist-01)))

# ::id pmid_2303_9341.11 ::date 2015-06-23T01:42:45 ::annotator SDL-AMR-09 ::preferred
# ::snt Although MEK inhibitors predominantly exert a cytostatic effect, E6201 elicited a potent cytocidal effect on most of the sensitive lines studied, as evidenced by Annexin positivity and cell death ELISA.
# ::save-date Sat Jan 16, 2016 ::file pmid_2303_9341_11.txt
(e2 / elicit-01
      :ARG0 (s4 / small-molecule :name (n2 / name :op1 "E6201"))
      :ARG1 (a / affect-01
            :ARG0 s4
            :ARG1 (l / line
                  :ARG0-of (s / sensitive-03)
                  :quant (m / most)
                  :ARG1-of (i2 / include-91
                        :ARG2 (l2 / line
                              :ARG0-of (s2 / sensitive-03)
                              :ARG1-of (s3 / study-01))))
            :ARG2 (c / cytocide
                  :mod (p / potent)))
      :concession (e3 / exert-01
                  :ARG0 (m2 / molecular-physical-entity
                        :ARG0-of (i3 / inhibit-01
                              :ARG1 (p5 / protein-family :name (n3 / name :op1 "MEK"))))
                  :ARG2 (a2 / affect-01
                        :ARG0 m2
                        :ARG2 (c2 / cytostatic)
                        :ARG1-of (p4 / predominate-01)))
      :ARG1-of (e5 / evidence-01
            :ARG0 (a3 / and
                  :op1 (p2 / positive
                        :domain (p3 / protein :name (n4 / name :op1 "Annexin")))
                  :op2 (c3 / cell
                        :ARG1-of (d / die-01)))
            :instrument (t / thing :name (n / name :op1 "ELISA"))))

# ::id pmid_2303_9341.12 ::date 2015-06-23T02:02:29 ::annotator SDL-AMR-09 ::preferred
# ::snt Conversely, E6201 did not induce cell death in the two resistant melanoma cell lines tested.
# ::save-date Sun Jan 3, 2016 ::file pmid_2303_9341_12.txt
(c3 / contrast-01
      :ARG2 (i / induce-01 :polarity -
            :ARG0 (s / small-molecule :name (n / name :op1 "E6201"))
            :ARG1 (c / cell-line :quant 2
                  :mod (m / medical-condition :name (n2 / name :op1 "melanoma"))
                  :ARG0-of (r / resist-01)
                  :ARG1-of (t2 / test-01))
            :ARG2 (d2 / die-01
                  :ARG1 (c2 / cell))))

# ::id pmid_2303_9341.13 ::date 2015-06-23T04:24:49 ::annotator SDL-AMR-09 ::preferred
# ::snt E6201 inhibited xenograft tumour growth in all four melanoma cell lines studied to varying degrees, but a more pronounced anti-tumour effect was observed for cell lines that previously demonstrated a cytocidal response <i>in vitro</i>.
# ::save-date Sun Dec 20, 2015 ::file pmid_2303_9341_13.txt
(c / contrast-01
      :ARG1 (i / inhibit-01
            :ARG0 (s2 / small-molecule :name (n / name :op1 "E6201"))
            :ARG1 (g / grow-01
                  :ARG1 (t2 / tumor
                        :mod (x / xenograft)))
            :location (c2 / cell-line :quant 4
                  :mod (m2 / medical-condition :name (n2 / name :op1 "melanoma"))
                  :mod (a / all)
                  :ARG1-of (s / study-01))
            :degree (d3 / degree
                  :ARG1-of (v / vary-01)))
      :ARG2 (o / observe-01
            :ARG1 (a2 / affect-01
                  :ARG1 (c3 / cell-line
                        :ARG0-of (d2 / demonstrate-01
                              :ARG1 (r / respond-01
                                    :ARG0 c3
                                    :ARG2 (c4 / cytocide))
                              :manner (i2 / in-vitro)
                              :time (p2 / previous)))
                  :ARG2 (c5 / counter-01
                        :ARG1 (t3 / tumor))
                  :ARG1-of (p / pronounce-01
                        :degree (m / more)))))

# ::id pmid_2303_9341.14 ::date 2015-06-23T04:50:20 ::annotator SDL-AMR-09 ::preferred
# ::snt <i>In vitro</i> combination studies of E6201 and LY294002 showed synergism in all six melanoma cell lines tested, as defined by a mean combination index < 1.
# ::save-date Thu Dec 10, 2015 ::file pmid_2303_9341_14.txt
(s / show-01
      :ARG0 (c / combine-01
            :ARG1 (a2 / and
                  :op1 (s4 / study-01
                        :ARG1 (s2 / small-molecule :name (n / name :op1 "E6201")))
                  :op2 (s5 / study-01
                        :ARG1 (s6 / small-molecule :name (n2 / name :op1 "LY294002"))))
            :manner (i3 / in-vitro)
            :ARG1-of (d2 / define-01
                  :ARG0 (i / index
                        :mod (c3 / combine-01
                              :mod (m / mean))
                        :value (l / less-than :op1 1))))
      :ARG1 (s3 / synergism)
      :location (c2 / cell-line :quant 6
            :mod (m2 / medical-condition :name (n4 / name :op1 "melanoma"))
            :ARG1-of (t3 / test-01)
            :mod (a / all)))

# ::id pmid_2303_9341.44 ::date 2015-06-23T05:14:58 ::annotator SDL-AMR-09 ::preferred
# ::snt <sec-title level="1">Results</sec-title>
# ::save-date Tue Jun 23, 2015 ::file pmid_2303_9341_44.txt
(t / thing
      :ARG1-of (r / result-01))

# ::id pmid_2303_9341.45 ::date 2015-06-23T05:15:43 ::annotator SDL-AMR-09 ::preferred
# ::snt <sec-title level="2">Sensitivity to E6201 in a melanoma cell line panel</sec-title>
# ::save-date Thu Dec 10, 2015 ::file pmid_2303_9341_45.txt
(s / sensitive-03
      :ARG0 (p / panel
            :consist-of (c / cell-line
                  :mod (m / medical-condition :name (n2 / name :op1 "melanoma"))))
      :ARG1 (s2 / small-molecule :name (n / name :op1 "E6201")))

# ::id pmid_2303_9341.46 ::date 2015-06-23T05:17:12 ::annotator SDL-AMR-09 ::preferred
# ::snt Sensitivity to E6201 was assessed in a panel of 31 cell lines for which the mutation status of common melanoma genes was known (Table <xref ref-type="table" rid="T1">1</xref>).
# ::save-date Thu Dec 10, 2015 ::file pmid_2303_9341_46.txt
(a / assess-01
      :ARG1 (s / sensitive-03
            :ARG1 (s3 / small-molecule :name (n / name :op1 "E6201")))
      :location (p / panel
            :consist-of (c / cell-line :quant 31
                  :mod (k / know-01
                        :ARG1 (s2 / status
                              :mod (m / mutate-01
                                    :ARG1 (g / gene
                                          :mod (m2 / medical-condition :name (n2 / name :op1 "melanoma"))
                                          :mod (c2 / common)))))))
      :ARG1-of (d2 / describe-01
            :ARG0 (t2 / table :mod 1)))

# ::id pmid_2303_9341.47 ::date 2015-06-23T05:31:03 ::annotator SDL-AMR-09 ::preferred
# ::snt These lines were chosen to represent different mutational profiles from a larger panel of more than one hundred melanoma cell lines.
# ::save-date Thu Dec 10, 2015 ::file pmid_2303_9341_47.txt
(c / choose-01
      :ARG1 (l / line
            :mod (t / this))
      :ARG2 (p2 / panel
            :mod (l2 / large
                  :degree (m3 / more))
            :consist-of (c2 / cell-line
                  :mod (m2 / medical-condition :name (n / name :op1 "melanoma"))
                  :quant (m4 / more-than :op1 100)))
      :ARG4 (r / represent-01
            :ARG0 l
            :ARG1 (p / profile
                  :mod (m / mutate-01)
                  :ARG1-of (d / differ-02))))

# ::id pmid_2303_9341.48 ::date 2015-06-23T05:41:06 ::annotator SDL-AMR-09 ::preferred
# ::snt Western blots in <xref ref-type="supplementary-material" rid="S1">Additional file 1: Figure S1</xref> confirm that E6201 efficiently inhibits MEK1/2 activity by virtue of its ability to abrogate phosphorylation of ERK1/2 in our entire panel of melanoma cell lines.
# ::save-date Sun Jan 3, 2016 ::file pmid_2303_9341_48.txt
(c / confirm-01
      :ARG0 (i2 / immunoblot-01
            :ARG1-of (d / describe-01
                  :ARG0 (f / figure :mod "S1"
                        :location (f2 / file :mod 1
                              :mod (a / additional)))))
      :ARG1 (i / inhibit-01
            :ARG0 (s / small-molecule :name (n3 / name :op1 "E6201"))
            :ARG1 (a2 / activity-06
                  :ARG0 (e2 / enzyme :name (n4 / name :op1 "MEK1/2")))
            :ARG2-of (e / efficient-01
                  :ARG1 s)
            :ARG1-of (c4 / cause-01
                  :ARG0 (c3 / capable-01
                        :ARG1 s
                        :ARG2 (a4 / abrogate-01
                              :ARG0 s
                              :ARG1 (p2 / phosphorylate-01
                                    :ARG1 (e3 / enzyme :name (n5 / name :op1 "ERK1/2")))
                              :location (p3 / panel
                                    :consist-of (c2 / cell-line
                                          :mod (m / medical-condition :name (n6 / name :op1 "melanoma")))
                                    :mod (e4 / entire)
                                    :poss (w2 / we)))))))

# ::id pmid_2303_9341.49 ::date 2015-06-23T05:53:27 ::annotator SDL-AMR-09 ::preferred
# ::snt The majority (24/31) of the melanoma cell lines were sensitive to E6201 (IC50 <500 nM) (Figure <xref ref-type="fig" rid="F1">1</xref>).
# ::save-date Tue Dec 15, 2015 ::file pmid_2303_9341_49.txt
(s / sensitive-03
      :ARG0 (c / cell-line :quant 24
            :ARG1-of (i / include-91
                  :ARG2 (c2 / cell-line :quant 31
                        :mod (m2 / medical-condition :name (n / name :op1 "melanoma")))
                  :ARG3 (m / majority))
            :mod (c4 / concentrate-02
                  :mod (i2 / inhibit-01
                        :degree (p / percentage-entity :value 50))
                  :quant (l2 / less-than
                        :op1 (c3 / concentration-quantity :quant 500
                              :unit (n3 / nanomolar)))))
      :ARG1 (s2 / small-molecule :name (n2 / name :op1 "E6201"))
      :ARG1-of (d2 / describe-01
            :ARG0 (f / figure :mod 1)))

# ::id pmid_2303_9341.50 ::date 2015-06-23T05:58:14 ::annotator SDL-AMR-09 ::preferred
# ::snt MAPK activation due to mutations in <i>BRAF</i> and <i>NRAS</i> was not significantly associated with increased sensitivity to E6201.
# ::save-date Wed Jun 24, 2015 ::file pmid_2303_9341_50.txt
(a / associate-01
      :ARG1 (a2 / activate-01
            :ARG1 (p2 / pathway :name (n2 / name :op1 "MAPK"))
            :ARG1-of (c / cause-01
                  :ARG0 (m / mutate-01
                        :ARG1 (a3 / and
                              :op1 (g / gene :name (n3 / name :op1 "BRAF"))
                              :op2 (g2 / gene :name (n4 / name :op1 "NRAS"))))))
      :ARG2 (s2 / sensitive-03
            :ARG1 (s3 / small-molecule :name (n5 / name :op1 "E6201"))
            :ARG1-of (i / increase-01))
      :ARG1-of (s / significant-02 :polarity -))

# ::id pmid_2303_9341.51 ::date 2015-06-23T06:07:34 ::annotator SDL-AMR-09 ::preferred
# ::snt In the 26 cell lines carrying mutations in <i>BRAF</i>, <i>NRAS</i>, or <i>HRAS</i>, sensitivity to E6201 was statistically associated with wildtype <i>PTEN</i> status (p = 0.02).
# ::save-date Sun Jan 3, 2016 ::file pmid_2303_9341_51.txt
(a / associate-01
      :ARG1 (s / sensitive-03
            :ARG1 (s4 / small-molecule :name (n / name :op1 "E6201")))
      :ARG2 (s3 / status
            :mod (g / gene :name (n2 / name :op1 "PTEN")
                  :mod (w / wild-type)))
      :mod (s2 / statistic)
      :location (c / cell-line :quant 26
            :ARG0-of (c2 / carry-01
                  :ARG1 (m / mutate-01
                        :ARG1 (o / or
                              :op1 (g2 / gene :name (n3 / name :op1 "BRAF"))
                              :op2 (g3 / gene :name (n4 / name :op1 "NRAS"))
                              :op3 (g4 / gene :name (n5 / name :op1 "HRAS"))))))
      :ARG1-of (s5 / statistical-test-91
            :ARG2 0.02))

# ::id pmid_2303_9341.52 ::date 2015-06-23T06:14:43 ::annotator SDL-AMR-09 ::preferred
# ::snt Specifically, of the 18 cell lines with wildtype <i>PTEN</i>, 17 were sensitive whereas in the 8 cell lines with mutant <i>PTEN</i>, only 4 were sensitive.
# ::save-date Sun Jan 17, 2016 ::file pmid_2303_9341_52.txt
(c / contrast-01
      :ARG1 (s / sensitive-03
            :ARG0 (c2 / cell-line :quant 17
                  :ARG1-of (i / include-91
                        :ARG2 (c3 / cell-line :quant 18
                              :ARG0-of (h / have-03
                                    :ARG1 (g / gene :name (n / name :op1 "PTEN")
                                          :mod (w / wild-type)))))))
      :ARG2 (s2 / sensitive-03
            :ARG0 (c4 / cell-line :quant 4
                  :ARG1-of (i2 / include-91
                        :ARG2 (c5 / cell-line :quant 8
                              :ARG0-of (h2 / have-03
                                    :ARG1 (g2 / gene :name (n2 / name :op1 "PTEN")
                                          :ARG2-of (m / mutate-01)))))
                  :mod (o / only)))
      :ARG1-of (s3 / specific-02))

# ::id pmid_2303_9341.53 ::date 2015-06-23T06:28:29 ::annotator SDL-AMR-09 ::preferred
# ::snt Moreover, even if <i>PTEN</i> status alone is examined, E6201 sensitivity is associated, albeit non-significantly, with wildtype <i>PTEN</i> status; 23/31 cell lines are wildtype for <i>PTEN</i> and of these 20 are sensitive (whereas only 4/8 cell lines with mutant <i>PTEN</i> are sensitive) (p = 0.053).
# ::save-date Sun Jan 3, 2016 ::file pmid_2303_9341_53.txt
(m / multi-sentence
      :snt1 (a / and
            :op2 (a2 / associate-01
                  :ARG1 (s / sensitive-03
                        :ARG1 (s7 / small-molecule :name (n / name :op1 "E6201")))
                  :ARG2 (s2 / status
                        :mod (g4 / gene :name (n2 / name :op1 "PTEN")
                              :mod (w / wild-type)))
                  :ARG1-of (s3 / significant-02 :polarity -
                        :concession-of a2)
                  :concession (e2 / even-if
                        :op1 (e3 / examine-01
                              :ARG1 (s4 / status
                                    :mod (g3 / gene :name (n3 / name :op1 "PTEN"))
                                    :mod (a3 / alone))))))
      :snt2 (c / contrast-01
            :ARG1 (a4 / and
                  :op1 (c2 / cell-line :quant 23
                        :mod (g2 / gene :name (n4 / name :op1 "PTEN")
                              :mod (w2 / wild-type))
                        :ARG1-of (i / include-91
                              :ARG2 (c3 / cell-line :quant 31)))
                  :op2 (s5 / sensitive-03
                        :ARG0 (c4 / cell-line :quant 20
                              :ARG1-of (i2 / include-91
                                    :ARG2 c2))))
            :ARG2 (s6 / sensitive-03
                  :ARG0 (c5 / cell-line :quant 4
                        :ARG1-of (i3 / include-91
                              :ARG2 (c6 / cell-line :quant 8
                                    :ARG0-of (h2 / have-03
                                          :ARG1 (m2 / mutate-01
                                                :ARG2 (g / gene :name (n5 / name :op1 "PTEN"))))))
                        :mod (o / only)))
            :ARG1-of (s8 / statistical-test-91
                  :ARG2 0.053)))

# ::id pmid_2303_9341.54 ::date 2015-06-23T06:53:58 ::annotator SDL-AMR-09 ::preferred
# ::snt Interestingly, 18 of the 24 sensitive cell lines also demonstrated hypersensitivity to E6201, with an IC50 < 100 nM.
# ::save-date Tue Dec 15, 2015 ::file pmid_2303_9341_54.txt
(d / demonstrate-01
      :ARG0 (c / cell-line :quant 18
            :ARG1-of (i / include-91
                  :ARG2 (c2 / cell-line :quant 24
                        :ARG0-of (s2 / sensitive-03)))
            :ARG0-of (h2 / have-03
                  :ARG1 (c4 / concentrate-02
                        :mod (i3 / inhibit-01
                              :degree (p / percentage-entity :value 50))
                        :mod (l2 / less-than
                              :op1 (c3 / concentration-quantity :quant 100
                                    :unit (n2 / nanomolar))))))
      :ARG1 (s3 / sensitive-03
            :ARG0 c
            :ARG1 (s4 / small-molecule :name (n / name :op1 "E6201"))
            :degree (h / hyper))
      :mod (a / also)
      :ARG0-of (i2 / interest-01))

# ::id pmid_2303_9341.55 ::date 2015-06-23T06:59:57 ::annotator SDL-AMR-09 ::preferred
# ::snt Using this criterion, <i>BRAF</i> mutation status correlated with E6201 hypersensitivity (p < 0.03), with 15 out of the 18 hypersensitive cell lines possessing a <i>BRAF</i> mutation.
# ::save-date Sun Jan 3, 2016 ::file pmid_2303_9341_55.txt
(c / correlate-01
      :ARG1 (s / status
            :mod (g / gene :name (n / name :op1 "BRAF")
                  :ARG1-of (m / mutate-01)))
      :ARG2 (s2 / sensitive-03
            :ARG1 (s5 / small-molecule :name (n2 / name :op1 "E6201"))
            :degree (h / hyper))
      :condition (u / use-01
            :ARG1 (c2 / criterion
                  :mod (t2 / this)))
      :prep-with (c3 / cell-line :quant 15
            :ARG0-of (p2 / possess-01
                  :ARG1 g)
            :ARG1-of (i / include-91
                  :ARG2 (c4 / cell-line :quant 18
                        :ARG0-of (s4 / sensitive-03
                              :degree (h3 / hyper)))))
      :ARG1-of (s3 / statistical-test-91
            :ARG2 (l / less-than :op1 0.03)))

# ::id pmid_2303_9341.56 ::date 2015-06-23T07:30:16 ::annotator SDL-AMR-09 ::preferred
# ::snt In contrast, of the 11 cell lines with wildtype <i>BRAF</i>, only 3 were hypersensitive.
# ::save-date Wed Jun 24, 2015 ::file pmid_2303_9341_56.txt
(c / contrast-01
      :ARG2 (c2 / cell-line :quant 3
            :ARG0-of (s / sensitive-03
                  :degree (h / hyper))
            :ARG1-of (i / include-91
                  :ARG2 (c3 / cell-line :quant 11
                        :ARG0-of (h2 / have-03
                              :ARG1 (g / gene :name (n / name :op1 "BRAF")
                                    :mod (w / wild-type)))))
            :mod (o / only)))

# ::id pmid_2303_9341.57 ::date 2015-06-23T07:34:35 ::annotator SDL-AMR-09 ::preferred
# ::snt In those cell lines carrying mutations in <i>BRAF</i> (21 cell lines), sensitivity to E6201 was not statistically associated with wildtype <i>PTEN</i> status.
# ::save-date Sun Jan 3, 2016 ::file pmid_2303_9341_57.txt
(a / associate-01 :polarity -
      :ARG1 (s / sensitive-03
            :ARG1 (s4 / small-molecule :name (n / name :op1 "E6201")))
      :ARG2 (s2 / status
            :mod (g2 / gene :name (n2 / name :op1 "PTEN")
                  :mod (w / wild-type)))
      :mod (s3 / statistic)
      :location (c / cell-line :quant 21
            :ARG0-of (c2 / carry-01
                  :ARG1 (m / mutate-01
                        :ARG1 (g / gene :name (n3 / name :op1 "BRAF"))))
            :mod (t / that)))

# ::id pmid_2303_9341.58 ::date 2015-06-23T07:42:00 ::annotator SDL-AMR-09 ::preferred
# ::snt <i>NRAS/HRAS</i> mutation status correlated with E6201 resistance, where none of the 5 <i>NRAS</i>/<i>HRAS</i> mutant cell lines were hypersensitive to E6201 and 18 of the 26 <i>NRAS/HRAS</i> wildtype cell lines were hypersensitive (p < 0.01).
# ::save-date Sun Jan 3, 2016 ::file pmid_2303_9341_58.txt
(c / correlate-01
      :ARG1 (s / status
            :mod (m / mutate-01
                  :ARG1 (s2 / slash
                        :op1 (g5 / gene :name (n2 / name :op1 "NRAS"))
                        :op2 (g6 / gene :name (n3 / name :op1 "HRAS")))))
      :ARG2 (r / resist-01
            :ARG1 (s8 / small-molecule :name (n / name :op1 "E6201")))
      :example (a / and
                  :op1 (c2 / cell-line :quant 0
                        :ARG1-of (i / include-91
                              :ARG2 (c3 / cell-line :quant 5
                                    :mod (m2 / mutate-01
                                          :ARG2 (s3 / slash
                                                :op1 g5
                                                :op2 g6))))
                        :ARG0-of (s4 / sensitive-03
                              :ARG1 s8
                              :degree (h / hyper)))
                  :op2 (c4 / cell-line :quant 18
                        :ARG1-of (i2 / include-91
                              :ARG2 (c5 / cell-line :quant 26
                                    :mod (s5 / slash
                                          :op1 g5
                                          :op2 g6
                                          :mod (w / wild-type))))
                        :ARG0-of s4))
      :ARG1-of (s6 / statistical-test-91
            :ARG2 (l / less-than :op1 0.01)))

# ::id pmid_2303_9341.59 ::date 2015-06-23T08:00:55 ::annotator SDL-AMR-09 ::preferred
# ::snt Neither <i>CDKN2A</i>, <i>CDK4</i> or <i>TP53</i> mutational status in our panel of melanoma cell lines, irrespective of their <i>BRAF</i> and <i>RAS</i> mutational status, was associated with E6201 sensitivity.
# ::save-date Thu Jan 7, 2016 ::file pmid_2303_9341_59.txt
(a / associate-01
      :ARG1 (s / status
            :mod (m / mutate-01
                  :ARG1 (o / or
                        :op1 (g / gene :name (n3 / name :op1 "CDKN2A"))
                        :op2 (g2 / gene :name (n4 / name :op1 "CDK4"))
                        :op3 (g3 / gene :name (n5 / name :op1 "TP53"))))
            :mod (n6 / neither)
            :location (p / panel
                  :poss (w / we)
                  :consist-of (c / cell-line
                        :mod (m3 / medical-condition :name (n7 / name :op1 "melanoma")))))
      :ARG2 (s2 / sensitive-03
            :ARG1 (s4 / small-molecule :name (n2 / name :op1 "E6201")))
      :ARG1-of (r / regardless-91
            :ARG2 (s3 / status
                  :mod (m2 / mutate-01
                        :ARG1 (a2 / and
                              :op1 (g4 / gene :name (n8 / name :op1 "BRAF"))
                              :op2 (g5 / gene :name (n9 / name :op1 "RAS"))))
                  :poss c)))

# ::id pmid_2303_9341.60 ::date 2015-06-23T08:15:10 ::annotator SDL-AMR-09 ::preferred
# ::snt <sec-title level="2">E6201 sensitivity and downstream pathway activation</sec-title>
# ::save-date Wed Jun 24, 2015 ::file pmid_2303_9341_60.txt
(a / and
      :op1 (s2 / small-molecule :name (n / name :op1 "E6201")
            :ARG1-of (s / sensitive-03))
      :op2 (a2 / activate-01
            :ARG1 (p / pathway
                  :mod (d / downstream))))

# ::id pmid_2303_9341.61 ::date 2015-06-23T08:16:54 ::annotator SDL-AMR-09 ::preferred
# ::snt To determine whether E6201 responsiveness correlated with direct Akt or ERK1/2 activation, the phosphorylation status of Akt and ERK1/2 proteins was evaluated following serum starvation (Figure <xref ref-type="fig" rid="F2">2</xref>).
# ::save-date Mon Dec 21, 2015 ::file pmid_2303_9341_61.txt
(e / evaluate-01
      :ARG1 (a / and
            :op1 (s / status
                  :mod (p / phosphorylate-01
                        :ARG1 (e3 / enzyme :name (n / name :op1 "Akt"))))
            :op2 (s2 / status
                  :mod (p3 / phosphorylate-01
                        :ARG1 (e2 / enzyme :name (n2 / name :op1 "ERK1/2")))))
      :ARG1-of (f / follow-01
            :ARG2 (s3 / starve-01
                  :ARG2 (s4 / serum)))
      :purpose (d / determine-01
            :ARG1 (c / correlate-01 :mode interrogative
                  :ARG1 (r / respond-01
                        :ARG1 (s5 / small-molecule :name (n3 / name :op1 "E6201")))
                  :ARG2 (a2 / activate-01
                        :ARG1 (a3 / and
                              :op1 e3
                              :op2 e2)
                        :ARG1-of (d2 / direct-02))))
      :ARG1-of (d3 / describe-01
            :ARG0 (f2 / figure :mod 2)))

# ::id pmid_2303_9341.62 ::date 2015-06-23T08:33:20 ::annotator SDL-AMR-09 ::preferred
# ::snt Phosphorylated (p) Akt (Ser473) was detectable in 7/7 cell lines with mutant PTEN.
# ::save-date Sun Jan 17, 2016 ::file pmid_2303_9341_62.txt
(d / detect-01
      :ARG1 (a / amino-acid :mod 473 :name (n2 / name :op1 "serine")
            :part-of (e / enzyme :name (n4 / name :op1 "Akt")
                  :ARG3-of (p / phosphorylate-01)))
      :location (c / cell-line :quant 7
            :ARG1-of (i / include-91
                  :ARG2 (c2 / cell-line :quant 7
                        :ARG0-of (h / have-03
                              :ARG1 (m2 / mutate-01
                                    :ARG2 (p3 / protein :name (n3 / name :op1 "PTEN")))))))
      :ARG1-of (p2 / possible-01))

# ::id pmid_2303_9341.63 ::date 2015-06-23T08:39:33 ::annotator SDL-AMR-09 ::preferred
# ::snt In addition, pAkt was present in 5/23 cell lines with wildtype <i>PTEN</i> although the mechanism responsible for phosphorylation of Akt in these cell lines is unknown.
# ::save-date Mon Dec 21, 2015 ::file pmid_2303_9341_63.txt
(a / and
      :op2 (h2 / have-concession-91
            :ARG1 (p / present-02
                  :ARG1 (e / enzyme :name (n / name :op1 "Akt")
                        :ARG3-of (p3 / phosphorylate-01))
                  :ARG2 (c2 / cell-line :quant 5
                        :ARG1-of (i / include-91
                              :ARG2 (c3 / cell-line :quant 23
                                    :ARG0-of (h / have-03
                                          :ARG1 (g / gene :name (n2 / name :op1 "PTEN")
                                                :mod (w / wild-type)))))))
            :ARG2 (k / know-01 :polarity -
                  :ARG1 (m / mechanism
                        :ARG0-of (r / responsible-01
                              :ARG1 (p5 / phosphorylate-01
                                    :ARG1 (p4 / protein)
                                    :location c3))))))

# ::id pmid_2303_9341.64 ::date 2015-06-23T08:50:06 ::annotator SDL-AMR-09 ::preferred
# ::snt Phosphorylated (p) ERK1/2 was detected in all cell lines with mutant <i>BRAF</i> (20/20).
# ::save-date Mon Jul 6, 2015 ::file pmid_2303_9341_64.txt
(d / detect-01
      :ARG1 (e / enzyme :name (n / name :op1 "ERK1/2")
            :ARG3-of (p / phosphorylate-01))
      :location (c / cell-line :quant 20
            :ARG1-of (i / include-91
                  :ARG2 (c2 / cell-line :quant 20
                        :ARG0-of (h / have-03
                              :ARG1 (m / mutate-01
                                    :ARG2 (g / gene :name (n2 / name :op1 "BRAF"))))))
            :mod (a / all)))

# ::id pmid_2303_9341.65 ::date 2015-06-23T08:56:33 ::annotator SDL-AMR-09 ::preferred
# ::snt Consistent with previous reports [<xref ref-type="bibr" rid="B13">13</xref>,<xref ref-type="bibr" rid="B26">26</xref>], elevated pERK1/2 was detected in 3/5 cell lines with mutant <i>NRAS</i> or <i>HRAS</i>.
# ::save-date Wed Jul 15, 2015 ::file pmid_2303_9341_65.txt
(d / detect-01
      :ARG1 (e / enzyme :name (n / name :op1 "ERK1/2")
            :ARG3-of (p / phosphorylate-01)
            :ARG1-of (e2 / elevate-01))
      :location (c / cell-line :quant 3
            :ARG1-of (i / include-91
                  :ARG2 (c2 / cell-line :quant 5
                        :ARG0-of (h / have-03
                              :ARG1 (m / mutate-01
                                    :ARG2 (o / or
                                          :op1 (g2 / gene :name (n2 / name :op1 "NRAS"))
                                          :op2 (g / gene :name (n3 / name :op1 "HRAS"))))))))
      :ARG1-of (c3 / consistent-01
            :ARG2 (r / report-01
                  :time (p2 / previous))
            :ARG1-of (d2 / describe-01
                  :ARG0 (p3 / publication
                        :ARG1-of (c4 / cite-01
                              :ARG2 (a / and :op1 13 :op2 26))))))

# ::id pmid_2303_9341.66 ::date 2015-06-23T09:09:28 ::annotator SDL-AMR-09 ::preferred
# ::snt All five cell lines with wildtype <i>BRAF</i> and <i>NRAS</i> also had elevated ERK1/2 phosphorylation, as reported previously [<xref ref-type="bibr" rid="B26">26</xref>,<xref ref-type="bibr" rid="B27">27</xref>], although the mechanism responsible for ERK1/2 activation in these cell lines is unknown.
# ::save-date Mon Jul 6, 2015 ::file pmid_2303_9341_66.txt
(h3 / have-concession-91
      :ARG1 (c2 / cell-line :quant 5
            :ARG0-of (h / have-03
                  :ARG1 (a / and
                        :op1 (g / gene :name (n / name :op1 "BRAF"))
                        :op2 (g2 / gene :name (n2 / name :op1 "NRAS"))
                        :mod (w / wild-type))
                  :mod (a3 / also))
            :ARG0-of (h2 / have-03
                  :ARG1 (p3 / phosphorylate-01
                        :ARG1 (e3 / enzyme :name (n3 / name :op1 "ERK1/2"))
                        :ARG1-of (e4 / elevate-01)))
            :mod (a2 / all)
            :ARG1-of (r / report-01
                  :time (p2 / previous)
                  :ARG1-of (d / describe-01
                        :ARG0 (p4 / publication
                              :ARG1-of (c3 / cite-01
                                    :ARG2 (a4 / and :op1 26 :op2 27))))))
      :ARG2 (k / know-01 :polarity -
            :ARG1 (m / mechanism
                  :ARG0-of (r2 / responsible-01
                        :ARG1 (a5 / activate-01
                              :ARG1 e3))
                  :location (c4 / cell-line
                        :mod (t / this)))))

# ::id pmid_2303_9341.67 ::date 2015-06-23T09:20:39 ::annotator SDL-AMR-09 ::preferred
# ::snt When the cell lines were classified based on phospho-ERK levels rather than <i>BRAF</i> mutation status, there was no correlation with the degree of cell growth inhibition.
# ::save-date Sat Jan 16, 2016 ::file pmid_2303_9341_67.txt
(c / correlate-01 :polarity -
      :ARG2 (d / degree
            :degree-of (i / inhibit-01
                  :ARG1 (g / grow-01
                        :ARG1 (c2 / cell))))
      :condition (c3 / classify-01
            :ARG1 (c4 / cell-line)
            :ARG1-of (b / base-02
                  :ARG2 (l / level
                        :quant-of (p / phosphorylate-01
                              :ARG2 (e / enzyme :name (n / name :op1 "ERK")))
                        :ARG1-of (i2 / instead-of-91
                              :ARG2 (s / status
                                    :mod (g2 / gene :name (n2 / name :op1 "BRAF")
                                          :ARG1-of (m / mutate-01))))))))

# ::id pmid_2303_9341.68 ::date 2015-06-23T09:32:31 ::annotator SDL-AMR-09 ::preferred
# ::snt In contrast, high levels of pAkt (3+) in <i>BRAF/RAS</i> mutant cell lines were strongly suggestive of insensitivity to E6201 (p = 0.057).
# ::save-date Sun Jan 3, 2016 ::file pmid_2303_9341_68.txt
(c / contrast-01
      :ARG2 (s / suggest-01
            :ARG0 (l / level
                  :ARG1-of (h / high-02)
                  :quant-of (p / phosphorylate-01
                        :ARG2 (e / enzyme :name (n / name :op1 "Akt")))
                  :location (c2 / cell-line
                        :mod (m / mutate-01
                              :ARG2 (a / and
                                    :op1 (g / gene :name (n2 / name :op1 "BRAF"))
                                    :op2 (g2 / gene :name (n3 / name :op1 "RAS")))))
                  :value (m2 / more-than :op1 3))
            :ARG1 (s4 / sensitive-03 :polarity -
                  :ARG1 (s3 / small-molecule :name (n4 / name :op1 "E6201")))
            :ARG1-of (s2 / strong-02)
            :ARG1-of (s5 / statistical-test-91
                  :ARG2 0.057)))

# ::id pmid_2303_9341.69 ::date 2015-06-24T00:19:27 ::annotator SDL-AMR-09 ::preferred
# ::snt Furthermore, high levels of pAkt (3+) significantly correlated with E6201 insensitivity independent of <i>BRAF</i> or <i>PTEN</i> status (p < 0.02).
# ::save-date Sun Jan 3, 2016 ::file pmid_2303_9341_69.txt
(a / and
      :op2 (c / correlate-01
            :ARG1 (l / level
                  :quant-of (p / phosphorylate-01
                        :ARG2 (e / enzyme :name (n / name :op1 "Akt")))
                  :ARG1-of (h / high-02)
                  :value (m / more-than :op1 3))
            :ARG2 (s5 / sensitive-03 :polarity -
                  :ARG1 (s4 / small-molecule :name (n2 / name :op1 "E6201")))
            :ARG0-of (d / depend-01 :polarity -
                  :ARG1 (a2 / and
                        :op1 (s2 / status
                              :mod (g / gene :name (n3 / name :op1 "BRAF")))
                        :op2 (s3 / status
                              :mod (g2 / gene :name (n4 / name :op1 "PTEN")))))
            :ARG1-of (s / significant-02)
            :ARG1-of (s6 / statistical-test-91
                  :ARG2 (l2 / less-than :op1 0.02))))

# ::id pmid_2303_9341.70 ::date 2015-06-24T00:34:02 ::annotator SDL-AMR-09 ::preferred
# ::snt PTEN protein was present in 20 of the melanoma cell lines tested with a lack of the tumour suppressor being suggestive of resistance to E6201 in not only <i>BRAF/RAS</i> mutant lines (p = 0.12) but also if all lines are considered (p = 0.14).
# ::save-date Sun Jan 3, 2016 ::file pmid_2303_9341_70.txt
(a3 / and
      :op1 (p4 / present-02
            :ARG1 (p2 / protein :name (n / name :op1 "PTEN"))
            :ARG2 (c / cell-line :quant 20
                  :mod (m3 / medical-condition :name (n2 / name :op1 "melanoma"))
                  :ARG1-of (i / include-91
                        :ARG2 (c2 / cell-line
                              :ARG1-of (t / test-01)))))
      :op2 (s / suggest-01
            :ARG0 (l / lack-01
                  :ARG1 (m2 / molecular-physical-entity
                        :ARG0-of (s5 / suppress-01
                              :ARG1 (t3 / tumor))))
            :ARG1 (r / resist-01
                  :ARG0 (a4 / and
                        :op1 (l2 / line
                              :mod (m / mutate-01
                                    :ARG2 (s3 / slash
                                          :op1 (g / gene :name (n4 / name :op1 "BRAF"))
                                          :op2 (g2 / gene :name (n5 / name :op1 "RAS"))))
                              :ARG1-of (s2 / statistical-test-91
                                    :ARG2 0.12))
                        :op2 (l3 / line
                              :ARG1-of (c3 / consider-01)
                              :mod (a5 / all)
                              :mod (a / also)
                              :ARG1-of (s6 / statistical-test-91
                                    :ARG2 0.14)))
                  :ARG1 (s4 / small-molecule :name (n3 / name :op1 "E3201")))))

# ::id pmid_2303_9341.71 ::date 2015-06-25T13:29:16 ::annotator SDL-AMR-09 ::preferred
# ::snt <sec-title level="2">Characterization of E6201 response <i>in vitro</i></sec-title>
# ::save-date Wed Jul 1, 2015 ::file pmid_2303_9341_71.txt
(c / characterize-01
      :ARG1 (r / respond-01
            :ARG1 (s / small-molecule :name (n / name :op1 "E6201"))
            :manner (i / in-vitro)))

# ::id pmid_2303_9341.72 ::date 2015-06-25T14:15:20 ::annotator SDL-AMR-09 ::preferred
# ::snt MEK inhibitors have been previously shown to have a predominantly cytostatic effect on melanoma cells, although some clinically relevant inhibitors, such as CI-1040, PD0325901 and AZD6244, have been shown to induce cell death [<xref ref-type="bibr" rid="B10">10</xref>,<xref ref-type="bibr" rid="B12">12</xref>,<xref ref-type="bibr" rid="B13">13</xref>].
# ::save-date Sat Jan 16, 2016 ::file pmid_2303_9341_72.txt
(c / contrast-01
      :ARG1 (s5 / show-01
            :ARG1 (a3 / affect-01
                  :ARG0 (m2 / molecular-physical-entity
                        :ARG0-of (i3 / inhibit-01
                              :ARG1 (p4 / protein-family :name (n4 / name :op1 "MEK"))))
                  :ARG1 (c5 / cell
                        :source (m / medical-condition :name (n5 / name :op1 "melanoma")))
                  :ARG2 (c6 / cytostasis)
                  :ARG1-of (p2 / predominate-01))
            :time (p3 / previous))
      :ARG2 (s / show-01
            :ARG1 (i / induce-01
                  :ARG0 (m3 / molecular-physical-entity
                        :ARG1-of (r / relevant-01
                              :manner (c4 / clinical))
                        :mod (s6 / some)
                        :ARG0-of i3
                        :example (a2 / and
                              :op1 (s2 / small-molecule :name (n / name :op1 "CI-1040"))
                              :op2 (s3 / small-molecule :name (n2 / name :op1 "PD0325901"))
                              :op3 (s4 / small-molecule :name (n3 / name :op1 "AZD6244"))))
                  :ARG2 (d2 / die-01
                        :ARG1 (c3 / cell))))
      :ARG1-of (d / describe-01
            :ARG0 (p / publication-91
                  :ARG1-of (c2 / cite-01
                        :ARG2 (a / and :op1 10 :op2 12 :op3 13)))))

# ::id pmid_2303_9341.73 ::date 2015-06-25T16:05:00 ::annotator SDL-AMR-09 ::preferred
# ::snt We sought to further evaluate the mechanism of sensitivity to E6201, as an equivocal cytocidal response <i>in vitro</i> may equate to the poor clinical response observed with current MEK inhibitors.
# ::save-date Sat Jan 16, 2016 ::file pmid_2303_9341_73.txt
(c / cause-01
      :ARG0 (p / possible-01
            :ARG1 (e3 / equate-01
                  :ARG1 (t2 / thing
                        :ARG2-of (r / respond-01
                              :manner (i2 / in-vitro))
                        :mod (c2 / cytocidal))
                  :ARG2 (t3 / thing
                        :ARG2-of (r2 / respond-01
                              :ARG1-of (o / observe-01
                                    :prep-with (m3 / molecular-physical-entity
                                          :ARG0-of (i3 / inhibit-01
                                                :ARG1 (p3 / protein-family :name (n / name :op1 "MEK")))
                                          :time (c4 / current))))
                        :mod (p2 / poor)
                        :mod (c3 / clinic)
                        :mod (e4 / equivocal))))
      :ARG1 (s / seek-01
            :ARG0 (w / we)
            :ARG1 (e2 / evaluate-01
                  :ARG0 w
                  :ARG1 (m / mechanism
                        :ARG0-of (s2 / sensitive-03
                              :ARG1 (s3 / small-molecule :name (n2 / name :op1 "E6201"))))
                  :degree (f / further))))

# ::id pmid_2303_9341.74 ::date 2015-06-25T14:16:10 ::annotator SDL-AMR-09 ::preferred
# ::snt Fifteen melanoma cell lines were selected such that 13 cell lines demonstrated sensitivity to E6201 and 2 cell lines were insensitive to E6201.
# ::save-date Thu Jan 14, 2016 ::file pmid_2303_9341_74.txt
(s / select-01
      :ARG1 (c / cell-line :quant 15
            :source (m / medical-condition :name (n2 / name :op1 "melanoma")))
      :purpose (a / and
            :op1 (d / demonstrate-01
                  :ARG0 (c2 / cell-line :quant 13)
                  :ARG1 (s3 / sensitive-03
                        :ARG0 c2
                        :ARG1 (s4 / small-molecule :name (n / name :op1 "E6201"))))
            :op2 (s2 / sensitive-03 :polarity -
                  :ARG0 (c3 / cell-line :quant 2)
                  :ARG1 s4)))

# ::id pmid_2303_9341.75 ::date 2015-06-25T14:26:51 ::annotator SDL-AMR-09 ::preferred
# ::snt Of these cell lines, seven were mutant for <i>BRAF</i> but wildtype for <i>PTEN</i>, five were mutant for both <i>BRAF</i>/<i>NRAS</i> and <i>PTEN</i>, and three were wildtype for both <i>BRAF</i> and <i>PTEN</i>.
# ::save-date Sat Jan 16, 2016 ::file pmid_2303_9341_75.txt
(a / and
      :op1 (c / cell-line :quant 7
            :mod (g4 / gene :name (n / name :op1 "BRAF")
                  :ARG2-of (m2 / mutate-01)
                  :ARG1-of (c5 / contrast-01
                        :ARG2 (g5 / gene :name (n2 / name :op1 "PTEN")
                              :mod (w / wild-type)))))
      :op2 (c2 / cell-line :quant 5
            :mod (s / slash
                  :op1 (g / gene :name (n4 / name :op1 "BRAF"))
                  :op2 (g2 / gene :name (n3 / name :op1 "NRAS"))
                  :op3 (g3 / gene :name (n5 / name :op1 "PTEN"))
                  :ARG2-of (m / mutate-01)))
      :op3 (c3 / cell-line :quant 3
            :mod (e3 / enzyme :name (n6 / name :op1 "BRAF")
                  :mod (w2 / wild-type))
            :mod g5)
      :ARG1-of (i / include-91
            :ARG2 (c4 / cell-line
                  :mod (t / this))))

# ::id pmid_2303_9341.76 ::date 2015-06-25T15:29:41 ::annotator SDL-AMR-09 ::preferred
# ::snt E6201 treatment induced G1 arrest in all of the sensitive cell lines and had little to no effect on cell cycle progression in the two insensitive cell lines (Figure <xref ref-type="fig" rid="F3">3</xref>A).
# ::save-date Sun Jan 3, 2016 ::file pmid_2303_9341_76.txt
(a / and
      :op1 (i / induce-01
            :ARG0 (t / treat-04
                  :ARG2 (s3 / small-molecule :name (n / name :op1 "E6201")))
            :ARG2 (a2 / arrest-02
                  :time (e / event :name (n2 / name :op1 "G1")))
            :location (c / cell-line
                  :mod (a3 / all)
                  :ARG0-of (s / sensitive-03)))
      :op2 (o2 / or
            :op1 (a4 / affect-01
                  :ARG0 t
                  :ARG1 (p3 / progress-01
                        :ARG1 (c2 / cycle-02
                              :ARG1 (c3 / cell))
                        :location (c4 / cell-line :quant 2
                              :ARG0-of (s2 / sensitive-03 :polarity -)))
                  :degree (l / little))
            :op2 (a5 / affect-01 :polarity -
                  :ARG0 t
                  :ARG1 p3))
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod "3A")))

# ::id pmid_2303_9341.77 ::date 2015-06-25T14:56:45 ::annotator SDL-AMR-09 ::preferred
# ::snt E6201 treatment resulted in a greater than 2-fold increase in Annexin-positive staining in eleven out of fifteen cell lines, including eleven out of thirteen sensitive cell lines (Figure <xref ref-type="fig" rid="F3">3</xref>B).
# ::save-date Mon Dec 21, 2015 ::file pmid_2303_9341_77.txt
(r / result-01
      :ARG1 (t / treat-04
            :ARG2 (s3 / small-molecule :name (n / name :op1 "E6201")))
      :ARG2 (i2 / increase-01
            :ARG1 (s / stain-01
                  :ARG2 (p / protein :name (n2 / name :op1 "Annexin"))
                  :mod (p2 / positive))
            :ARG2 (m / more-than
                  :op1 (p3 / product-of :op1 2))
            :location (c / cell-line :quant 11
                  :ARG1-of (i3 / include-91
                        :ARG2 (c2 / cell-line :quant 15)
                        :ARG2-of (i4 / include-91
                              :ARG1 (c3 / cell-line :quant 11
                                    :ARG1-of (i5 / include-91
                                          :ARG2 (c4 / cell-line :quant 13
                                                :ARG0-of (s2 / sensitive-03))))))))
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod "3B")))

# ::id pmid_2303_9341.78 ::date 2015-06-25T15:03:23 ::annotator SDL-AMR-09 ::preferred
# ::snt Two sensitive cell lines, SKMEL13 and BL, did not demonstrate E6201-induced Annexin staining although both of these cell lines underwent cell cycle arrest with E6201 treatment and were hypersensitive to E6201 (IC50 < 100 nM).
# ::save-date Mon Dec 21, 2015 ::file pmid_2303_9341_78.txt
(h2 / have-concession-91
      :ARG1 (d / demonstrate-01 :polarity -
            :ARG0 (c2 / cell-line :quant 2
                  :ARG0-of (s2 / sensitive-03)
                  :ARG1-of (m2 / mean-01
                        :ARG2 (a2 / and
                              :op1 (c3 / cell-line :name (n2 / name :op1 "SKMEL13"))
                              :op2 (c4 / cell-line :name (n3 / name :op1 "BL")))))
            :ARG1 (s3 / stain-01
                  :ARG2 (p / protein :name (n4 / name :op1 "Annexin"))
                  :ARG2-of (i / induce-01
                        :ARG0 s4)))
      :ARG2 (a / and
            :op1 (u / undergo-28
                  :ARG1 a2
                  :ARG2 (a3 / arrest-02
                        :ARG0 (t / treat-04
                              :ARG2 s4)
                        :ARG1 (c5 / cycle-02
                              :ARG1 (c6 / cell))))
            :op2 (s / sensitive-03
                  :ARG0 a2
                  :ARG1 (s4 / small-molecule :name (n / name :op1 "E6201"))
                  :degree (h / hyper)
                  :mod (c7 / concentrate-02
                        :quant (l / less-than
                              :op1 (c / concentration-quantity :quant 100
                                    :unit (n5 / nanomolar)))
                        :mod (i2 / inhibit-01
                              :degree (p2 / percentage-entity :value 50))))))

# ::id pmid_2303_9341.79 ::date 2015-06-25T14:27:32 ::annotator SDL-AMR-09 ::preferred
# ::snt These experiments were repeated in duplicate to confirm this finding.
# ::save-date Thu Jun 25, 2015 ::file pmid_2303_9341_79.txt
(r / repeat-01
      :ARG1 (e / experiment-01
            :mod (t / this))
      :ARG3 (d / duplicate-01
            :ARG1 e)
      :purpose (c / confirm-01
            :ARG0 r
            :ARG1 (t2 / thing
                  :ARG1-of (f / find-01))))

# ::id pmid_2303_9341.80 ::date 2015-06-25T14:35:57 ::annotator SDL-AMR-09 ::preferred
# ::snt E6201 induced a less than two-fold increase in Annexin staining in the E6201-insensitive cell lines (IC50 > 500 nM) (Figure <xref ref-type="fig" rid="F3">3</xref>B).
# ::save-date Tue Dec 15, 2015 ::file pmid_2303_9341_80.txt
(i / induce-01
      :ARG0 (s3 / small-molecule :name (n / name :op1 "E6201"))
      :ARG2 (i2 / increase-01
            :ARG1 (s / stain-01
                  :ARG2 (p2 / protein :name (n2 / name :op1 "Annexin")))
            :ARG2 (l / less-than
                  :op1 (p / product-of :op1 2))
            :location (c / cell-line
                  :ARG0-of (s2 / sensitive-03 :polarity -
                        :ARG1 s3)
                  :ARG1-of (m2 / mean-01
                        :ARG2 (c3 / concentrate-02
                              :quant (m / more-than
                                    :op1 (c2 / concentration-quantity :quant 500
                                          :unit (n3 / nanomolar)))
                              :mod (i3 / inhibit-01
                                    :degree (p3 / percentage-entity :value 50))))))
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod "3B")))

# ::id pmid_2303_9341.81 ::date 2015-06-25T14:36:59 ::annotator SDL-AMR-09 ::preferred
# ::snt Three of the five <i>PTEN</i>-mutant cell lines exhibited a cytocidal response to E6201, demonstrating that <i>PTEN</i> mutation does not preclude a cytocidal response to E6201.
# ::save-date Sun Jan 17, 2016 ::file pmid_2303_9341_81.txt
(c / cause-01
      :ARG0 (e / exhibit-01
            :ARG0 (c2 / cell-line :quant 3
                  :ARG1-of (i / include-91
                        :ARG2 (c3 / cell-line :quant 5
                              :mod (g / gene :name (n / name :op1 "PTEN")
                                    :ARG2-of (m / mutate-01)))))
            :ARG1 (t / thing
                  :mod (c4 / cytocidal)
                  :ARG2-of (r / respond-01
                        :ARG0 c2
                        :ARG1 (s / small-molecule :name (n2 / name :op1 "E6201")))))
      :ARG1 (d / demonstrate-01
            :ARG0 c2
            :ARG1 (p2 / preclude-01 :polarity -
                  :ARG0 g
                  :ARG1 t)))

# ::id pmid_2303_9341.82 ::date 2015-06-25T14:45:07 ::annotator SDL-AMR-09 ::preferred
# ::snt E6201 also induced cell cycle arrest and cell death in cell lines with constitutively active Akt, suggesting that although high pAkt correlates with E6201 insensitivity, cell lines with high pAkt can still undergo a cytocidal response to E6201.
# ::save-date Mon Dec 21, 2015 ::file pmid_2303_9341_82.txt
(i / induce-01
      :ARG0 (s4 / small-molecule :name (n / name :op1 "E6201"))
      :ARG2 (a2 / and
            :op1 (a3 / arrest-02
                  :ARG1 (c / cycle-02
                        :ARG1 (c2 / cell)))
            :op2 (d / die-01
                  :ARG1 c)
            :location (c3 / cell-line
                  :mod (e / enzyme :name (n2 / name :op1 "Akt")
                        :ARG0-of (a4 / activity-06
                              :manner (c4 / constitutive)))))
      :ARG0-of (s / suggest-01
            :ARG1 (h2 / have-concession-91
                  :ARG1 (p / possible-01
                        :ARG1 (u / undergo-28
                              :ARG1 (c7 / cell-line
                                    :mod e2)
                              :ARG2 (t / thing
                                    :ARG2-of (r / respond-01
                                          :ARG0 c7
                                          :ARG1 s4
                                          :mod (c5 / cytocidal)))
                              :mod (s3 / still)))
                  :ARG2 (c6 / correlate-01
                        :ARG1 (e2 / enzyme :name n2
                              :ARG3-of (p2 / phosphorylate-01)
                              :ARG1-of (h / high-02))
                        :ARG2 (s2 / sensitive-03 :polarity -
                              :ARG1 s4))))
      :mod (a / also))

# ::id pmid_2303_9341.83 ::date 2015-06-26T01:13:24 ::annotator SDL-AMR-09 ::preferred
# ::snt To confirm our Annexin V results we also performed an enzyme-linked immunosorbent assay (ELISA) to determine the degree of DNA fragmentation as an indicator of cell death with E6201 treatment (Figure <xref ref-type="fig" rid="F3">3</xref>C).
# ::save-date Sun Dec 20, 2015 ::file pmid_2303_9341_83.txt
(p / perform-01
      :ARG0 (w / we)
      :ARG1 (a2 / assay-01
            :purpose (d / determine-01
                  :ARG0 w
                  :ARG1 (d2 / degree
                        :degree-of (f / fragment-01
                              :ARG1 (n4 / nucleic-acid :wiki "DNA" :name (n5 / name :op1 "DNA")))
                        :ARG0-of (i / indicate-01
                              :ARG1 (d4 / die-01
                                    :ARG1 (c2 / cell)
                                    :ARG0-of (c3 / cause-01
                                          :ARG1 (t3 / treat-04
                                                :ARG2 (s / small-molecule :name (n3 / name :op1 "E6201"))))))))
            :instrument (i2 / immunosorbent
                  :ARG1-of (l / link-01
                        :ARG2 (e / enzyme)))
            :ARG1-of (d3 / describe-01
                  :ARG2 (t / thing :name (n2 / name :op1 "ELISA"))))
      :purpose (c / confirm-01
            :ARG0 w
            :ARG1 (t2 / thing
                  :ARG2-of (r / result-01
                        :ARG1 (p2 / protein :name (n / name :op1 "Annexin" :op2 "V")))))
      :mod (a / also)
      :ARG1-of (d5 / describe-01
            :ARG0 (f2 / figure :mod "3C")))

# ::id pmid_2303_9341.84 ::date 2015-06-26T01:37:39 ::annotator SDL-AMR-09 ::preferred
# ::snt The results from the cell death ELISA were very similar to that obtained from the Annexin studies with 10 out of 13 sensitive melanoma lines demonstrating a greater than two-fold increase in DNA fragmentation with E6201.
# ::save-date Thu Jan 14, 2016 ::file pmid_2303_9341_84.txt
(r2 / resemble-01
      :ARG1 (t / thing
            :ARG2-of (r / result-01
                  :ARG1 (d / die-01
                        :ARG1 (c / cell)
                        :mod (a / assay-01
                              :mod (t2 / thing :name (n / name :op1 "ELISA"))))))
      :ARG2 (t3 / thing
            :ARG2-of (r3 / result-01
                  :ARG1-of (o / obtain-01
                        :ARG2 (s / study-01
                              :ARG1 (p / protein :name (n2 / name :op1 "Annexin")
                                    :prep-with (c2 / cell-line :quant 10
                                          :ARG1-of (i / include-91
                                                :ARG2 (c3 / cell-line :quant 13
                                                      :ARG0-of (s2 / sensitive-03)
                                                      :source (m / medical-condition :name (n6 / name :op1 "melanoma"))))))))))
      :degree (v / very)
      :ARG0-of (d2 / demonstrate-01
            :ARG1 (i2 / increase-01
                  :ARG1 (f / fragment-01
                        :ARG0 (s3 / small-molecule :name (n3 / name :op1 "E6201"))
                        :ARG1 (n4 / nucleic-acid :wiki "DNA" :name (n5 / name :op1 "DNA")))
                  :ARG2 (m2 / more-than
                        :op1 (p2 / product-of :op1 2)))))

# ::id pmid_2303_9341.85 ::date 2015-06-26T01:46:00 ::annotator SDL-AMR-09 ::preferred
# ::snt Of the three sensitive lines that did not exhibit a cytocidal response by ELISA, SKMEL13 and BL also demonstrated no induction of cell death with E6201 by Annexin positivity, as stated previously.
# ::save-date Sun Dec 20, 2015 ::file pmid_2303_9341_85.txt
(d3 / demonstrate-01
      :ARG0 (a4 / and
            :op1 (c2 / cell-line :name (n2 / name :op1 "SKMEL13"))
            :op2 (c3 / cell-line :name (n3 / name :op1 "BL"))
            :ARG1-of (i / include-91
                  :ARG2 (c4 / cell-line :quant 3
                        :ARG0-of (s2 / sensitive-03)
                        :ARG0-of (e / exhibit-01 :polarity -
                              :ARG1 (r / respond-01
                                    :ARG0 c4
                                    :mod (c5 / cytocidal))
                              :manner (a / assay-01
                                    :mod (t / thing :name (n / name :op1 "ELISA")))))))
      :ARG1 (i2 / induce-01 :polarity -
            :ARG0 (s3 / small-molecule :name (n4 / name :op1 "E6201"))
            :ARG2 (d2 / die-01
                  :ARG1 (c6 / cell)))
      :manner (p2 / positive
            :domain (p3 / protein :name (n5 / name :op1 "Annexin")))
      :ARG1-of (s / state-01
            :time (p / previous))
      :mod (a3 / also))

# ::id pmid_2303_9341.86 ::date 2015-06-25T14:45:42 ::annotator SDL-AMR-09 ::preferred
# ::snt There was no significant induction of DNA fragmentation in any of the E6201-resistant melanoma cell lines.
# ::save-date Thu Jan 14, 2016 ::file pmid_2303_9341_86.txt
(i / induce-01
      :ARG2 (f / fragment-01
            :ARG1 (n2 / nucleic-acid :wiki "DNA" :name (n3 / name :op1 "DNA")))
      :location (c / cell-line
            :mod (a / any)
            :ARG0-of (r / resist-01
                  :ARG1 (s2 / small-molecule :name (n / name :op1 "E6201")))
            :source (m / medical-condition :name (n4 / name :op1 "melanoma")))
      :ARG1-of (s / significant-02 :polarity -))

# ::id pmid_2303_9341.87 ::date 2015-06-25T14:52:44 ::annotator SDL-AMR-09 ::preferred
# ::snt <sec-title level="2">Characterization of E6201 response <i>in vivo</i> in melanoma xenografts</sec-title>
# ::save-date Thu Jan 14, 2016 ::file pmid_2303_9341_87.txt
(c / characterize-01
      :ARG1 (r / respond-01
            :ARG1 (s / small-molecule :name (n / name :op1 "E6201"))
            :location (x / xenograft
                  :source (m / medical-condition :name (n2 / name :op1 "melanoma")))
            :manner (i / in-vivo)))

# ::id pmid_2303_9341.88 ::date 2015-06-25T14:55:55 ::annotator SDL-AMR-09 ::preferred
# ::snt We evaluated the <i>in vivo</i> activity of E6201 in two melanoma cell lines that exhibited a cytocidal response (MM540, MM604) and two melanoma cell lines that exhibited a cytostatic response (SKMEL13, BL) to E6201 <i>in vitro</i> (Figure <xref ref-type="fig" rid="F4">4</xref>).
# ::save-date Thu Jan 14, 2016 ::file pmid_2303_9341_88.txt
(e / evaluate-01
      :ARG0 (w / we)
      :ARG1 (a2 / activity-06
            :ARG0 (s / small-molecule :name (n / name :op1 "E6201"))
            :manner (i / in-vivo)
            :location (a5 / and
                  :op1 (c / cell-line :quant 2
                        :ARG0-of (e2 / exhibit-01
                              :ARG1 (t / thing
                                    :ARG2-of (r / respond-01
                                          :ARG1 s
                                          :mod (c2 / cytocidal))))
                        :ARG1-of (m3 / mean-01
                              :ARG2 (a3 / and
                                    :op1 (c3 / cell-line :name (n2 / name :op1 "MM540"))
                                    :op2 (c4 / cell-line :name (n3 / name :op1 "MM604"))))
                        :source (m / medical-condition :name (n6 / name :op1 "melanoma")))
                  :op2 (c5 / cell-line :quant 2
                        :source (m2 / melanoma)
                        :ARG0-of (e3 / exhibit-01
                              :ARG1 (r2 / respond-01
                                    :ARG1 s
                                    :ARG2 (c6 / cytostasis)
                                    :manner (i2 / in-vitro)))
                        :ARG1-of (m4 / mean-01
                              :ARG2 (a4 / and
                                    :op1 (c7 / cell-line :name (n4 / name :op1 "SKMEL13"))
                                    :op2 (c8 / cell-line :name (n5 / name :op1 "BL")))))))
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod 4)))

# ::id pmid_2303_9341.89 ::date 2015-06-26T02:17:34 ::annotator SDL-AMR-09 ::preferred
# ::snt Given that the majority of sensitive melanoma cell lines in our cell line panel exhibited a cytocidal response to E6201 <i>in vitro</i>, we hypothesized that E6201 would induce tumour regression in a xenograft model of these cell lines as well, and to a greater extent in those cell lines that demonstrated a cytocidal response to E6201 <i>in vitro</i> compared to those with a cytostatic response.
# ::save-date Thu Jan 14, 2016 ::file pmid_2303_9341_89.txt
(h / hypothesize-01
      :ARG0 w
      :ARG1 (a / and
            :op1 (i2 / induce-01
                  :ARG0 s2
                  :ARG2 (r2 / regress-01
                        :ARG1 (t2 / tumor))
                  :manner (a2 / as-well)
                  :location (m4 / model
                        :mod (x / xenograft)
                        :source c2))
            :op2 (i3 / induce-01
                  :ARG0 s2
                  :degree (e2 / extent
                        :mod (g / great
                              :degree (m5 / more)))
                  :location (c3 / cell-line
                        :mod (t3 / that)
                        :ARG0-of (d / demonstrate-01
                              :ARG1 (r3 / respond-01
                                    :ARG0 c2
                                    :ARG1 s2
                                    :mod (c4 / cytocidal)
                                    :manner i))
                        :compared-to (c5 / cell-line
                              :ARG0-of (r4 / respond-01
                                    :ARG2 (c6 / cytostasis))))))
      :ARG1-of (c / cause-01
            :ARG0 (e / exhibit-01
                  :ARG0 (c2 / cell-line
                        :ARG1-of (i4 / include-91
                              :ARG2 (c7 / cell-line
                                    :location (p / panel
                                          :mod c2
                                          :poss (w / we))
                                    :ARG0-of (s / sensitive-03)
                                    :source (m / medical-condition :name (n2 / name :op1 "melanoma")))
                              :ARG3 (m2 / majority)))
                  :ARG1 (t / thing
                        :ARG2-of (r / respond-01
                              :ARG1 (s2 / small-molecule :name (n / name :op1 "E6201"))
                              :manner (i / in-vitro))
                        :mod c4))))

# ::id pmid_2303_9341.90 ::date 2015-06-26T02:55:10 ::annotator SDL-AMR-09 ::preferred
# ::snt Administration of E6201 at all doses (10, 20 and 40 mg/kg) to MM540 tumour-bearing mice completely abrogated tumour growth and caused transient, partial tumour regression for the two weeks of drug treatment, although tumour growth recommenced following drug withdrawal, indicating not all cells were killed in this two week period (Figure <xref ref-type="fig" rid="F4">4</xref>A).
# ::save-date Mon Dec 21, 2015 ::file pmid_2303_9341_90.txt
(a / and
      :op1 (a2 / abrogate-01
            :ARG0 (a4 / administer-01
                  :ARG1 (s / small-molecule :name (n / name :op1 "E6201")
                        :ARG2-of (d3 / dose-01
                              :mod (a5 / all))
                        :quant (c6 / concentration-quantity
                              :quant (a6 / and :op1 10 :op2 20 :op3 40)
                              :unit (m / milligram-per-kilogram)))
                  :ARG2 (m2 / mouse
                        :ARG0-of (b / bear-01
                              :ARG1 (t4 / tumor
                                    :mod (c5 / cell-line :name (n2 / name :op1 "MM540"))))))
            :ARG1 g
            :degree (c4 / complete))
      :op2 (c2 / cause-01
            :ARG0 a4
            :ARG1 (r2 / regress-01
                  :ARG1 t
                  :ARG1-of (t2 / transient-02)
                  :degree (p / part)
                  :duration (t3 / temporal-quantity :quant 2
                        :unit (w2 / week)
                        :time-of (t5 / treat-04
                              :ARG2 d2)))
            :concession (r / recommence-01
                        :ARG1 (g / grow-01
                              :ARG1 (t / tumor))
                        :ARG0-of (i / indicate-01
                              :ARG1 (k / kill-01
                                    :ARG1 (c3 / cell
                                          :mod (a3 / all :polarity -))))
                        :ARG1-of (f2 / follow-01
                              :ARG2 (w / withdraw-01
                                    :ARG1 (d2 / drug)))))
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod "4A")))

# ::id pmid_2303_9341.91 ::date 2015-06-26T04:10:38 ::annotator SDL-AMR-09 ::preferred
# ::snt E6201 at 40 mg/kg in MM604 and SKMEL13 xenografts prevented tumour progression for the two weeks of drug treatment, with tumour growth recommencing following drug removal, while lower doses of drug (10 and 20 mg/kg) only attenuated, rather than prevented, tumour growth <i>in vivo</i> (Figure <xref ref-type="fig" rid="F4">4</xref>B and C).
# ::save-date Mon Dec 21, 2015 ::file pmid_2303_9341_91.txt
(c / contrast-01
      :ARG1 (a4 / and
            :op1 (p / prevent-01
                  :ARG0 (s / small-molecule :name (n / name :op1 "E6201")
                        :quant (c2 / concentration-quantity :quant 40
                              :unit (m2 / milligram-per-kilogram))
                        :location (a / and
                              :op1 (x / xenograft
                                    :mod (c3 / cell-line :name (n2 / name :op1 "MM604")))
                              :op2 (x2 / xenograft
                                    :mod (c4 / cell-line :name (n3 / name :op1 "SKMEL13")))))
                  :ARG1 (p2 / progress-01
                        :ARG1 t3)
                  :time (t2 / treat-04
                        :ARG2 (d / drug)
                        :duration (t / temporal-quantity :quant 2
                              :unit (w / week))))
            :op2 (r / recommence-01
                  :ARG1 (g / grow-01
                        :ARG1 (t3 / tumor))
                  :ARG1-of (f / follow-01
                        :ARG2 (r2 / remove-01
                              :ARG1 d))))
      :ARG2 (i2 / instead-of-91
            :ARG1 (a2 / attenuate-01
                  :ARG0 (d2 / dose-01
                        :ARG2 d
                        :ARG1-of (l / low-04
                              :degree (m / more))
                        :quant (a5 / and
                              :op1 (c5 / concentration-quantity :quant 10
                                    :unit (m3 / milligram-per-kilogram))
                              :op2 (c6 / concentration-quantity :quant 20
                                    :unit (m4 / milligram-per-kilogram))))
                  :mod (o / only))
            :ARG2 (p3 / prevent-01
                  :ARG0 d2
                  :ARG1 (g2 / grow-01
                        :ARG1 t3
                        :manner (i / in-vivo))))
      :ARG1-of (d3 / describe-01
            :ARG0 (a3 / and
                  :op1 (f2 / figure :mod "4B")
                  :op2 (f3 / figure :mod "4C"))))

# ::id pmid_2303_9341.92 ::date 2015-06-26T04:32:02 ::annotator SDL-AMR-09 ::preferred
# ::snt Only the highest dose of E6201 (40 mg/kg) had any significant inhibitory effect on tumour growth in BL tumour-bearing mice, while lower drug doses had little or no effect on tumour progression (Figure <xref ref-type="fig" rid="F4">4</xref>D).
# ::save-date Fri Dec 18, 2015 ::file pmid_2303_9341_92.txt
(c / contrast-01
      :ARG1 (a / affect-01
            :ARG0 (d4 / dose-01
                  :ARG2 (s3 / small-molecule :name (n / name :op1 "E6201")
                        :quant (c3 / concentration-quantity :quant 40
                              :unit (m3 / milligram-per-kilogram)))
                  :ARG1-of (h / high-02
                        :degree (m2 / most))
                  :mod (o2 / only))
            :ARG2 (i / inhibit-01
                  :ARG1 (g / grow-01
                        :ARG1 t
                        :location (m4 / mouse
                              :ARG0-of (b / bear-01
                                    :ARG1 (t2 / tumor
                                          :mod (c2 / cell-line :name (n2 / name :op1 "BL")))))))
            :ARG1-of (s2 / significant-02)
            :mod (a4 / any))
      :ARG2 (o / or
            :op1 (a2 / affect-01
                  :ARG0 (d2 / dose-01
                        :ARG1 (d3 / drug)
                        :ARG1-of (l2 / low-04
                              :degree (m / more)))
                  :ARG1 (p / progress-01
                        :ARG1 (t / tumor))
                  :mod (l / little))
            :op2 (a3 / affect-01 :polarity -
                  :ARG0 d2
                  :ARG1 p))
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod "4D")))

# ::id pmid_2303_9341.93 ::date 2015-06-26T04:44:08 ::annotator SDL-AMR-09 ::preferred
# ::snt As such our hypothesis was confirmed, with E6201 inhibiting xenograft tumour growth in all four melanoma cell lines studied, and enhanced <i>in vivo</i> activity observed for those cell lines that demonstrated a cytocidal response <i>in vitro</i>.
# ::save-date Thu Jan 14, 2016 ::file pmid_2303_9341_93.txt
(c / confirm-01
      :ARG0 (a2 / and
            :op1 (i / inhibit-01
                  :ARG0 (s2 / small-molecule :name (n / name :op1 "E6201"))
                  :ARG1 (g / grow-01
                        :ARG1 (t2 / tumor
                              :mod (x / xenograft)))
                  :location (c2 / cell-line :quant 4
                        :mod (a3 / all)
                        :ARG1-of (s / study-01)
                        :mod (t4 / that)
                        :source (m / medical-condition :name (n2 / name :op1 "melanoma"))))
            :op2 (e / enhance-01
                  :ARG1 (a4 / activity-06
                        :manner (i2 / in-vivo)
                        :ARG1-of (o / observe-01
                              :location (c3 / cell-line
                                    :ARG0-of (d / demonstrate-01
                                          :ARG1 (t3 / thing
                                                :ARG2-of (r / respond-01
                                                      :mod (c4 / cytocidal)
                                                      :manner (i3 / in-vitro))))
                                    :mod (t5 / that))))))
      :ARG1 (t / thing
            :ARG1-of (h / hypothesize-01
                  :ARG0 (w / we)))
      :mod (a / as-such))

# ::id pmid_2303_9341.94 ::date 2015-06-24T05:45:08 ::annotator SDL-AMR-09 ::preferred
# ::snt <sec-title level="2">E6201 and LY294002</sec-title>
# ::save-date Thu Jul 2, 2015 ::file pmid_2303_9341_94.txt
(a / and
      :op1 (s / small-molecule :name (n / name :op1 "E6201"))
      :op2 (s2 / small-molecule :name (n2 / name :op1 "LY294002")))

# ::id pmid_2303_9341.95 ::date 2015-06-24T06:29:32 ::annotator SDL-AMR-09 ::preferred
# ::snt Given our previous data suggesting that E6201 resistance is associated with mutation of <i>PTEN</i> and high levels of pAkt, we hypothesized that combining E6201 with an inhibitor of the PI3K pathway in these cell lines might result in either an additive or synergistic effect.
# ::save-date Tue Feb 2, 2016 ::file pmid_2303_9341_95.txt
(h3 / hypothesize-01
      :ARG0 (w2 / we)
      :ARG1 (r2 / result-01
            :ARG1 (c / combine-01
                  :ARG1 (s3 / small-molecule :name (n4 / name :op1 "E6201"))
                  :ARG2 (m / molecular-physical-entity
                        :ARG0-of (i2 / inhibit-01
                              :ARG1 (p4 / pathway :name (n5 / name :op1 "PI3K"))))
                  :location (c2 / cell-line
                        :mod (t / this)))
            :ARG2 (a3 / affect-01
                  :ARG2 (o / or
                        :op1 (a4 / add-02)
                        :op2 (s2 / synergize-01)))
            :ARG1-of (p5 / possible-01))
      :ARG1-of (i / infer-01
            :ARG2 (d / data
                  :poss (w / we)
                  :time (p / previous)
                  :ARG0-of (s / suggest-01
                        :ARG1 (r / resist-01
                              :ARG0 s3
                              :ARG1-of (a / associate-01
                                    :ARG2 (a2 / and
                                          :op1 (m2 / mutate-01
                                                :ARG1 (g / gene :name (n2 / name :op1 "PTEN")))
                                          :op2 (l / level
                                                :ARG1-of (h / high-02)
                                                :quant-of (e / enzyme :name (n3 / name :op1 "Akt")
                                                      :ARG3-of (p6 / phosphorylate-01))))))))))

# ::id pmid_2303_9341.96 ::date 2015-06-24T06:32:09 ::annotator SDL-AMR-09 ::preferred
# ::snt <xref ref-type="supplementary-material" rid="S2">Additional file 2: Figure S2</xref> demonstrates that LY294002 effectively inhibits PI3K by evidence of reduced phosphorylated AKT protein levels in the four <i>PTEN</i>-mutant melanoma cell lines that normally express high levels of pAKT (UACC647, UACC558, UACC903 and MM622).
# ::save-date Sun Jan 17, 2016 ::file pmid_2303_9341_96.txt
(d / demonstrate-01
      :ARG0 (a2 / and
            :op1 (f / file :mod 2
                  :mod (a3 / additional))
            :op2 (f2 / figure :mod 2))
      :ARG1 (i / inhibit-01
            :ARG0 (s / small-molecule :name (n / name :op1 "LY294002"))
            :ARG1 (e6 / enzyme :name (n2 / name :op1 "PI3K"))
            :ARG1-of (e / effective-04))
      :ARG1-of (e2 / evidence-01
            :ARG0 (l / level
                  :mod (e7 / enzyme :name (n3 / name :op1 "AKT")
                        :ARG3-of (p3 / phosphorylate-01))
                  :ARG1-of (r / reduce-01))
            :location (c / cell-line :quant 4
                  :ARG3-of (e3 / express-03
                        :ARG2 (l2 / level
                              :ARG1-of (h / high-02)
                              :quant-of e7)
                        :ARG1-of (n5 / normal-02))
                  :example (a / and
                              :op1 (c2 / cell-line :name (n7 / name :op1 "UACC647"))
                              :op2 (c3 / cell-line :name (n8 / name :op1 "UACC558"))
                              :op3 (c4 / cell-line :name (n9 / name :op1 "UACC903"))
                              :op4 (c5 / cell-line :name (n10 / name :op1 "MM622")))
                  :source (m / medical-condition :name (n6 / name :op1 "melanoma")
                        :mod (g / gene :name (n4 / name :op1 "PTEN")
                              :ARG2-of (m4 / mutate-01))))))

# ::id pmid_2303_9341.97 ::date 2015-06-24T06:32:41 ::annotator SDL-AMR-09 ::preferred
# ::snt In addition, <xref ref-type="supplementary-material" rid="S3">Additional file 3: Figures S3</xref> and <xref ref-type="supplementary-material" rid="S4">Additional file 4: Figure S4</xref> show the concentration-effect curves for single-agent LY294002 and E6201 respectively, where both drugs were added 24 hours following plating.
# ::save-date Mon Dec 21, 2015 ::file pmid_2303_9341_97.txt
(a / and
      :op2 (s / show-01
            :ARG0 (a2 / and
                  :op1 (f / figure :mod "S3"
                        :location (f3 / file :mod 3
                              :mod (a7 / additional)))
                  :op2 (f2 / figure :mod "S4"
                        :location (f4 / file :mod 4
                              :mod a7)))
            :ARG1 (a8 / and
                  :op1 (c / curve
                        :beneficiary (a4 / agent
                              :ARG1-of (s2 / single-02)
                              :mod (s3 / small-molecule :name (n / name :op1 "LY294002")))
                        :topic (a3 / affect-01
                              :ARG0 (c2 / concentrate-02)))
                  :op2 (c3 / curve
                        :beneficiary (a5 / agent
                              :mod (s5 / small-molecule :name (n2 / name :op1 "E6201")))
                        :topic a3)
                  :location-of (a6 / add-on-05
                        :ARG1 (a10 / and
                              :op1 s3
                              :op2 s5)
                        :ARG1-of (f5 / follow-01
                              :ARG2 (p / plate-00)
                              :quant (t / temporal-quantity :quant 24
                                    :unit (h / hour)))))))

# ::id pmid_2303_9341.98 ::date 2015-06-24T06:33:01 ::annotator SDL-AMR-09 ::preferred
# ::snt The six melanoma cell lines tested displayed similar trends in E6201 sensitivity compared to our previous experiments, with MM622, MM540, UACC903, and WM35 being the most sensitive (IC50 = 40-61 nM) and UACC558 and UACC647 being less sensitive (302 and 2310 nM, respectively).
# ::save-date Mon Dec 21, 2015 ::file pmid_2303_9341_98.txt
(d / display-01
      :ARG0 (c / cell-line :quant 6
            :ARG1-of (t / test-01)
            :mod (m / medical-condition :name (n12 / name :op1 "melanoma")))
      :ARG1 (t2 / trend-01
            :ARG2 (s / sensitive-03
                  :ARG0 (a / and
                        :op1 (c4 / cell-line :name (n2 / name :op1 "MM622"))
                        :op2 (c5 / cell-line :name (n3 / name :op1 "MM540"))
                        :op3 (c6 / cell-line :name (n4 / name :op1 "UACC903"))
                        :op4 (c9 / cell-line :name (n5 / name :op1 "WM35"))
                        :ARG1-of (c3 / contrast-01
                              :ARG2 (a2 / and
                                    :op1 (c8 / cell-line :name (n6 / name :op1 "UACC558"))
                                    :op1 (c7 / cell-line :name (n7 / name :op1 "UACC647"))
                                    :ARG1-of (s2 / sensitive-03
                                          :degree (l / less))
                                    :mod (c12 / concentrate-02
                                          :ARG1-of (e3 / equal-01
                                                :ARG2 (c11 / concentration-quantity
                                                      :unit (n9 / nanomolar)
                                                      :quant (a3 / and :op1 302 :op2 2310)))
                                          :mod (i / inhibit-01
                                                :degree (p2 / percentage-entity :value 50)))))
                        :ARG1-of (h / have-percentage-maximal-inhibitory-concentration-01
                              :ARG2 50
                              :ARG4 (c10 / concentration-quantity
                                    :quant (v / value-interval :op1 40 :op2 61)
                                    :unit (n8 / nanomolar))))
                  :ARG1 (s3 / small-molecule :name (n / name :op1 "E6201")))
            :ARG1-of (r / resemble-01)
            :ARG1-of (c2 / compare-01
                  :ARG2 (e / experiment-01
                        :ARG0 (w / we)
                        :time (p / previous))))
      :degree (m2 / most))

# ::id pmid_2303_9341.99 ::date 2015-06-24T22:33:34 ::annotator SDL-AMR-09 ::preferred
# ::snt Surprisingly, all cell lines showed similar sensitivity to LY294002, with IC50 ranging from 11 μM to 17 μM.
# ::save-date Tue Dec 15, 2015 ::file pmid_2303_9341_99.txt
(s / show-01
      :ARG0 (c / cell-line
            :mod (a / all)
            :ARG0-of (h / have-03
                  :ARG1 (c4 / concentrate-02
                        :ARG1-of (r2 / range-01
                              :ARG3 (c2 / concentration-quantity :quant 11
                                    :unit (m / micromolar))
                              :ARG4 (c3 / concentration-quantity :quant 17
                                    :unit m))
                        :mod (i / inhibit-01
                              :degree (p / percentage-entity :value 50)))))
      :ARG1 (s2 / sensitive-03
            :ARG0 c
            :ARG1 (s4 / small-molecule :name (n / name :op1 "LY294002"))
            :ARG1-of (r / resemble-01))
      :ARG0-of (s3 / surprise-01))

# ::id pmid_2303_9341.100 ::date 2015-06-24T22:52:13 ::annotator SDL-AMR-09 ::preferred
# ::snt This was unexpected, as one would predict MM540 and WM35 cells to be relatively resistant to PI3K inhibition given the lack of detectable levels of pAkt indicating no constitutive PI3K activation in these cell lines.
# ::save-date Wed Nov 4, 2015 ::file pmid_2303_9341_100.txt
(e / expect-01 :polarity -
      :ARG1 (t / this)
      :ARG0-of (c / cause-01
            :ARG1 (p / predict-01
                  :ARG0 (p2 / person)
                  :ARG1 (r / resist-01
                        :ARG0 (a / and
                              :op1 (c2 / cell-line :name (n / name :op1 "MM540"))
                              :op2 (c3 / cell-line :name (n2 / name :op1 "WM35")))
                        :ARG1 (i / inhibit-01
                              :ARG1 (e2 / enzyme :name (n3 / name :op1 "PI3K")))
                        :ARG2-of (r2 / relative-05)
                        :ARG1-of (c4 / cause-01
                              :ARG0 (l / lack-01
                                    :ARG1 (l2 / level
                                          :ARG1-of (d / detect-01
                                                :ARG1-of (p4 / possible-01))
                                          :quant-of (e3 / enzyme :name (n4 / name :op1 "Akt")
                                                :ARG3-of (p3 / phosphorylate-01)))
                                    :ARG0-of (i2 / indicate-01
                                          :ARG1 (a2 / activate-01 :polarity -
                                                :ARG1 e2
                                                :manner (c5 / constitutive)
                                                :location a))))))))

# ::id pmid_2303_9341.101 ::date 2015-06-25T07:34:37 ::annotator SDL-AMR-09 ::preferred
# ::snt A previous study by Smalley and others [<xref ref-type="bibr" rid="B26">26</xref>], however, reported a similar sensitivity of WM35 cells to LY294002.
# ::save-date Tue Jul 14, 2015 ::file pmid_2303_9341_101.txt
(r / report-01
      :ARG0 (s / study-01
            :ARG0 (a / and
                  :op1 (p2 / person :name (n / name :op1 "Smalley"))
                  :op2 (p4 / person
                        :mod (o / other)))
            :time (p / previous)
            :ARG1-of (d / describe-01
                  :ARG0 (p3 / publication-91
                        :ARG0-of (c / cite-01
                              :ARG2 26))))
      :ARG1 (s2 / sensitive-03
            :ARG0 (c2 / cell-line :name (n2 / name :op1 "WM35"))
            :ARG1 (s3 / small-molecule :name (n3 / name :op1 "LY294002"))
            :ARG1-of (r2 / resemble-01))
      :ARG2-of (c3 / contrast-01))

# ::id pmid_2303_9341.102 ::date 2015-06-25T10:02:39 ::annotator SDL-AMR-09 ::preferred
# ::snt The concentration response curves for E6201 and LY294002 combinations, normalized to a dimethyl sulfoxide (DMSO) control are given in <xref ref-type="supplementary-material" rid="S4">Additional file 4: Figure S4</xref>.
# ::save-date Sun Jan 17, 2016 ::file pmid_2303_9341_102.txt
(g / give-01
      :ARG1 (c / curve
            :mod (r / respond-01
                  :ARG1 (c2 / concentrate-02
                        :ARG1 (c3 / combine-01
                              :ARG1 (s / small-molecule :name (n / name :op1 "E6201"))
                              :ARG2 (s2 / small-molecule :name (n2 / name :op1 "LY294002")))))
            :ARG1-of (n3 / normalize-01
                  :topic (c4 / control-01
                        :ARG2 (s3 / small-molecule :name (n4 / name :op1 "DMSO")))))
      :location (f / figure :mod "S4"
            :location (f2 / file :mod 4
                  :mod (a / additional))))

# ::id pmid_2303_9341.103 ::date 2015-06-25T11:35:00 ::annotator SDL-AMR-09 ::preferred
# ::snt As differences in synergy may exist at different drug effect levels, we graphed individual combination index values for LY294002 with increasing concentrations of E6201 for each cell line (Figure <xref ref-type="fig" rid="F5">5</xref>A).
# ::save-date Tue Feb 2, 2016 ::file pmid_2303_9341_103.txt
(c / cause-01
      :ARG0 (p / possible-01
            :ARG1 (e / exist-01
                  :ARG1 (d / differ-02
                        :ARG2 (s / synergize-01))
                  :location (l / level
                        :ARG1-of (d2 / differ-02)
                        :degree-of (a / affect-01
                              :ARG0 (d3 / drug)))))
      :ARG1 (g / graph-00
            :ARG0 (w / we)
            :ARG1 (v / value
                  :mod (i / individual)
                  :mod (c2 / combine-01)
                  :mod (i2 / index))
            :value-of (s2 / small-molecule :name (n / name :op1 "LY294002"))
            :accompanier (c3 / concentrate-02
                  :ARG1 (s3 / small-molecule :name (n2 / name :op1 "E6201"))
                  :ARG1-of (i3 / increase-01))
            :location (c4 / cell-line
                  :mod (e2 / each))
            :ARG1-of (d4 / describe-01
                  :ARG0 (f / figure :mod "5A"))))

# ::id pmid_2303_9341.104 ::date 2015-06-25T12:30:04 ::annotator SDL-AMR-09 ::preferred
# ::snt As shown in Figure <xref ref-type="fig" rid="F5">5</xref>A, evaluating the individual combination index for all combinations tested revealed that E6201 and LY294002 exhibit synergistic activity in all six melanoma cell lines, irrespective of E6201 sensitivity or <i>PTEN</i> or pAkt status.
# ::save-date Tue Feb 2, 2016 ::file pmid_2303_9341_104.txt
(r / reveal-01
      :ARG0 (e / evaluate-01
            :ARG1 (i / index
                  :mod (c / combine-01
                        :manner (i2 / individual))
                  :beneficiary (c2 / combine-01
                        :mod (a / all)
                        :ARG1-of (t / test-01))))
      :ARG1 (e2 / exhibit-01
            :ARG0 (a2 / and
                  :op1 (s5 / small-molecule :name (n / name :op1 "E6201"))
                  :op2 (s6 / small-molecule :name (n2 / name :op1 "LY294002")))
            :ARG1 (a3 / activity-06
                  :ARG1 (s / synergize-01)
                  :location (c3 / cell-line :quant 6
                        :mod (m / medical-condition :name (n3 / name :op1 "melanoma"))
                        :mod (a4 / all))
                  :ARG1-of (r2 / regardless-91
                        :ARG2 (o / or
                              :op1 (s2 / sensitive-03
                                    :ARG1 s5)
                              :op2 (s3 / status
                                    :poss (a5 / and
                                          :op1 (p / protein :name (n5 / name :op1 "PTEN"))
                                          :op2 (e3 / enzyme :name (n6 / name :op1 "Akt")
                                                :ARG3-of (p2 / phosphorylate-01))))))))
      :ARG1-of (s4 / show-01
            :ARG0 (f / figure :mod "5A")))

# ::id pmid_2303_9341.105 ::date 2015-06-25T13:16:21 ::annotator SDL-AMR-09 ::preferred
# ::snt Interestingly, different patterns of synergy were observed among the groups of cell lines tested.
# ::save-date Tue Feb 2, 2016 ::file pmid_2303_9341_105.txt
(o / observe-01
      :ARG1 (p / pattern-01
            :ARG1 (s / synergize-01)
            :ARG1-of (d / differ-02)
            :ARG1-of (i / include-91
                  :ARG2 (g / group
                        :consist-of (c / cell-line
                              :ARG1-of (t / test-01)))))
      :ARG2-of (i2 / interest-01))

# ::id pmid_2303_9341.106 ::date 2015-06-25T13:27:52 ::annotator SDL-AMR-09 ::preferred
# ::snt While most (4/6) of the cell lines showed an increasing combination index (and thus decreasing synergy) at higher concentrations of E6201, UACC647 and UACC558 cells showed a decreasing combination index or enhanced synergy with increasing concentrations of E6201.
# ::save-date Tue Feb 2, 2016 ::file pmid_2303_9341_106.txt
(c / contrast-01
      :ARG1 (s / show-01
            :ARG0 (c2 / cell-line :quant 4
                  :ARG1-of (i5 / include-91
                        :ARG2 (c8 / cell-line :quant 6)
                        :ARG3 (m / most)))
            :ARG1 (i / index
                  :mod (c3 / combine-01
                        :ARG1-of (i2 / increase-01)))
            :ARG0-of (c4 / cause-01
                  :ARG1 (d2 / decrease-01
                        :ARG1 (s2 / synergize-01)))
            :condition (c5 / concentrate-02
                  :ARG1 (s5 / small-molecule :name (n / name :op1 "E6201"))
                  :ARG1-of (h / high-02)))
      :ARG2 (s3 / show-01
            :ARG0 (a / and
                  :op1 (c9 / cell-line :name (n2 / name :op1 "UACC647"))
                  :op2 (c10 / cell-line :name (n3 / name :op1 "UACC558")))
            :ARG1 (o / or
                  :op1 (i3 / index
                        :mod (c6 / combine-01
                              :ARG1-of (d / decrease-01)))
                  :op2 (s4 / synergize-01
                        :ARG1-of (e / enhance-01)
                        :condition (c7 / concentrate-02
                              :ARG1 s5
                              :ARG1-of (i4 / increase-01))))))

# ::id pmid_2303_9341.107 ::date 2015-06-25T21:58:06 ::annotator SDL-AMR-09 ::preferred
# ::snt Notably, this pattern observed for UACC647 and UACC558 cells occurs within the context of high pAkt and relative resistance to E6201, supporting the hypothesis that administration of a PI3K inhibitor can sensitize E6201-resistant cells with high pAkt levels to E6201.
# ::save-date Sun Jan 17, 2016 ::file pmid_2303_9341_107.txt
(p3 / pattern
      :ARG1-of (n6 / notable-04)
      :mod (t / this)
      :ARG1-of (o2 / observe-01)
      :topic (a / and
            :op1 (c3 / cell-line :name (n / name :op1 "UACC647"))
            :op2 (c4 / cell-line :name (n2 / name :op1 "UACC558")))
      :time (c / context
            :poss (a2 / and
                  :op1 (e / enzyme :name (n3 / name :op1 "Akt")
                        :ARG3-of (p6 / phosphorylate-01)
                        :ARG1-of (h2 / high-02))
                  :op2 (r / resist-01
                        :ARG1 (s3 / small-molecule :name (n4 / name :op1 "E6201"))
                        :ARG2-of (r2 / relative-05))))
      :ARG0-of (s / support-01
            :ARG1 (h / hypothesize-01
                  :ARG1 (s2 / sensitize-01
                        :ARG0 (a3 / administer-01
                              :ARG1 (m / molecular-physical-entity
                                    :ARG0-of (i / inhibit-01
                                          :ARG1 (p / protein-family :name (n5 / name :op1 "PI3K")))))
                        :ARG1 (c2 / cell
                              :ARG0-of (r3 / resist-01
                                    :ARG1 s3)
                              :mod (l / level
                                    :quant-of e
                                    :degree h2))
                        :ARG2 s3
                        :ARG1-of (p4 / possible-01)))))

# ::id pmid_2303_9341.108 ::date 2015-06-25T23:17:47 ::annotator SDL-AMR-09 ::preferred
# ::snt In summary, the combination of E6201 and LY294002 resulted in synergistic activity in all six melanoma cell lines tested, as defined by a combination index < 1.
# ::save-date Tue Feb 2, 2016 ::file pmid_2303_9341_108.txt
(r / result-01
      :ARG1 (c / combine-01
            :ARG1 (s2 / small-molecule :name (n / name :op1 "E6201"))
            :ARG2 (s3 / small-molecule :name (n2 / name :op1 "LY294002")))
      :ARG2 (a / activity-06
            :ARG1 (s / synergize-01))
      :location (c2 / cell-line :quant 6
            :mod (a2 / all)
            :ARG1-of (t / test-01)
            :mod (m / medical-condition :name (n3 / name :op1 "melanoma")))
      :ARG1-of (d / define-01
            :ARG0 (i / index
                  :mod (c3 / combine-01)
                  :value (l / less-than :op1 1)))
      :ARG2-of (s4 / summarize-01))

# ::id pmid_2303_9341.109 ::date 2015-06-28T11:07:11 ::annotator SDL-AMR-09 ::preferred
# ::snt Interestingly, enhanced synergy of E6201 with LY294002 treatment in the E6201-resistant cell lines UACC647 and UACC558 was observed at high concentrations of E6201.
# ::save-date Tue Feb 2, 2016 ::file pmid_2303_9341_109.txt
(o / observe-01
      :ARG1 (s / synergize-01
            :ARG0 (t / treat-04
                  :ARG2 (s2 / small-molecule :name (n2 / name :op1 "LY294002")))
            :ARG1 (t2 / treat-04
                  :ARG2 (s3 / small-molecule :name (n3 / name :op1 "E6201")))
            :ARG1-of (e / enhance-01)
            :location (c / cell-line
                  :ARG0-of (r / resist-01)
                  :ARG2-of (i / include-91
                        :ARG1 (a / and
                              :op1 (c3 / cell-line :name (n4 / name :op1 "UACC647"))
                              :op2 (c4 / cell-line :name (n5 / name :op1 "UACC558"))))))
      :condition (c2 / concentrate-02
            :ARG1 s3
            :ARG1-of (h / high-02))
      :ARG2-of (i2 / interest-01))

# ::id pmid_2325_9591.1 ::date 2015-08-22T01:09:11 ::annotator SDL-AMR-09 ::preferred
# ::snt Alternative dosing of dual PI3K and MEK inhibition in cancer therapy (PMID:23259591)
# ::save-date Sat Jan 16, 2016 ::file pmid_2325_9591_1.txt
(d2 / dose-01
      :ARG1 (i / inhibit-01
            :ARG1 (a3 / and
                  :op1 (e / enzyme :name (n3 / name :op1 "PI3K"))
                  :op2 (e2 / enzyme :name (n / name :op1 "MEK")))
            :mod (d3 / dual))
      :mod (a / alternative)
      :location (t / therapy
            :mod (d / disease :wiki "Cancer" :name (n2 / name :op1 "cancer")))
      :ARG1-of (d4 / describe-01
            :ARG0 (p3 / publication-91
                  :ARG8 "PMID23259591")))

# ::id pmid_2325_9591.10 ::date 2015-08-22T01:15:00 ::annotator SDL-AMR-09 ::preferred
# ::snt <sec-title level="1" sec-area="abstract">Results</sec-title>
# ::save-date Sat Aug 22, 2015 ::file pmid_2325_9591_10.txt
(t / thing
      :ARG2-of (r / result-01))

# ::id pmid_2325_9591.11 ::date 2015-08-22T01:15:38 ::annotator SDL-AMR-09 ::preferred
# ::snt Two of the 12 NSCLC cell lines tested, H3122 (ALK translocated) and H1437 (triple-negative), showed increased cytotoxicity upon dual MEK and PI3K inhibition.
# ::save-date Fri Feb 5, 2016 ::file pmid_2325_9591_11.txt
(s / show-01
      :ARG0 (c / cell-line :quant 2
            :ARG1-of (i / include-91
                  :ARG2 (c2 / cell-line :quant 12
                        :ARG1-of (t / test-01)
                        :mod (d2 / disease :name (n2 / name :op1 "NSCLC"))))
            :ARG1-of (m / mean-01
                  :ARG2 (a / and
                        :op1 (c3 / cell-line :name (n4 / name :op1 "H3122")
                              :ARG2-of (t2 / translocate-01
                                    :ARG1 (e / enzyme :name (n5 / name :op1 "ALK"))))
                        :op2 (c4 / cell-line :name (n6 / name :op1 "H1437")
                              :ARG1-of (n3 / negative-01
                                    :ARG1-of (t3 / triple-01))))))
      :ARG1 (c5 / cytotoxicity
            :ARG1-of (i2 / increase-01
                  :time (a2 / after
                        :op1 (i3 / inhibit-01
                              :ARG1 (a3 / and
                                    :op1 (e2 / enzyme :name (n / name :op1 "MEK"))
                                    :op2 (e3 / enzyme :name (n8 / name :op1 "PI3K")))
                              :mod (d / dual))))))

# ::id pmid_2325_9591.12 ::date 2015-08-22T01:08:49 ::annotator SDL-AMR-09 ::preferred
# ::snt Furthermore, MDA-MB231 (breast) and HCT116 (colon), showed increased cytotoxicity upon dual inhibition, as in previous studies.
# ::save-date Wed Aug 26, 2015 ::file pmid_2325_9591_12.txt
(a / and
      :op2 (s / show-01
            :ARG0 (a2 / and
                  :op1 (c / cell-line :name (n / name :op1 "MDA-MB231")
                        :mod (b / breast))
                  :op2 (c2 / cell-line :name (n2 / name :op1 "HCT116")
                        :mod (c3 / colon)))
            :ARG1 (c4 / cytotoxicity
                  :ARG1-of (i / increase-01
                        :ARG1-of (r / resemble-01
                              :ARG2 (s2 / study-01
                                    :time (p / previous)))
                        :time (a3 / after
                              :op1 (i2 / inhibit-01
                                    :mod (d / dual)))))))

# ::id pmid_2325_9591.13 ::date 2015-08-22T02:25:46 ::annotator SDL-AMR-09 ::preferred
# ::snt Activation of parallel pathways in the dual inhibition-sensitive lines was also noted in response to single inhibitor treatment.
# ::save-date Sat Aug 22, 2015 ::file pmid_2325_9591_13.txt
(n / note-01
      :ARG1 (a2 / activate-01
            :ARG1 (p / pathway
                  :ARG1-of (p2 / parallel-01))
            :location (c / cell-line
                  :ARG0-of (s / sensitive-03
                        :ARG1 (i2 / inhibit-01
                              :mod (d / dual)))))
      :mod (a / also)
      :ARG2-of (r / respond-01
            :ARG1 (t2 / treat-04
                  :ARG2 (s2 / small-molecule
                        :ARG0-of (i / inhibit-01)
                        :ARG1-of (s3 / single-02)))))

# ::id pmid_2325_9591.14 ::date 2015-08-22T02:30:54 ::annotator SDL-AMR-09 ::preferred
# ::snt Otherwise, no significant differences in downstream intracellular pathway activity (S6 and 4E-BPI) were noted between PI3K alone and dual inhibition other than the increased cytotoxicity of the latter.
# ::save-date Fri Nov 20, 2015 ::file pmid_2325_9591_14.txt
(h2 / have-condition-91
      :ARG1 (n / note-01
            :ARG1 (d / differ-02 :polarity -
                  :ARG1 (p4 / protein-family :name (n4 / name :op1 "PI3K")
                        :mod (a3 / alone))
                  :ARG2 (i2 / inhibit-01
                        :mod (d3 / dual))
                  :ARG3 (a / activity-06
                        :ARG0 (p / pathway
                              :mod (i / intracellular)
                              :location (d2 / downstream)
                              :ARG1-of (m / mean-01
                                    :ARG2 (a4 / activity-06
                                          :ARG0 (a2 / and
                                                :op1 (p2 / protein :name (n2 / name :op1 "S6"))
                                                :op2 (p3 / protein :name (n3 / name :op1 "4E-BPI")))))))
                  :ARG1-of (s / significant-02)
                  :ARG2-of (e2 / except-01
                        :ARG1 (c / cytotoxicity
                              :ARG1-of (i3 / increase-01)
                              :topic i2)))))

# ::id pmid_2325_9591.15 ::date 2015-08-22T02:48:35 ::annotator SDL-AMR-09 ::preferred
# ::snt In the alternative dosing schedules two out of the four dual inhibition-sensitive cell lines showed similar cytotoxicity to continuous PI3K and short (15min) MEK inhibition treatment.
# ::save-date Sun Aug 23, 2015 ::file pmid_2325_9591_15.txt
(s / show-01
      :ARG0 (c / cell-line :quant 2
            :ARG1-of (i / include-91
                  :ARG2 (c2 / cell-line :quant 4
                        :ARG0-of (s2 / sensitive-03
                              :ARG1 (i2 / inhibit-01
                                    :mod (d / dual))))))
      :ARG1 (c3 / cytotoxicity
            :ARG1-of (r2 / resemble-01))
      :ARG2 (t / treat-04
            :ARG2 (a2 / and
                  :op1 (s4 / small-molecule
                        :ARG0-of (i3 / inhibit-01
                              :ARG1 (p2 / protein-family :name (n2 / name :op1 "PI3K"))
                              :mod (c4 / continuity)))
                  :op2 (s6 / small-molecule
                        :ARG0-of (i4 / inhibit-01
                              :ARG1 (p / protein-family :name (n / name :op1 "MEK"))
                              :ARG1-of (s5 / short-07
                                    :duration (t2 / temporal-quantity :quant 15
                                          :unit (m / minute)))))))
      :location (s3 / schedule-01
            :ARG1 (d2 / dose-01
                  :mod (a / alternative))))

# ::id pmid_2325_9591.79 ::date 2015-08-22T03:49:06 ::annotator SDL-AMR-09 ::preferred
# ::snt <sec-title level="1">Results</sec-title>
# ::save-date Sat Aug 22, 2015 ::file pmid_2325_9591_79.txt
(t / thing
      :ARG2-of (r / result-01))

# ::id pmid_2325_9591.80 ::date 2015-08-22T03:50:45 ::annotator SDL-AMR-09 ::preferred
# ::snt <sec-title level="2">Dual inhibition of PI3K and MEK in cancer cell lines</sec-title>
# ::save-date Sat Jan 16, 2016 ::file pmid_2325_9591_80.txt
(i / inhibit-01
      :ARG1 (a / and
            :op1 (e / enzyme :name (n3 / name :op1 "PI3K"))
            :op2 (e2 / enzyme :name (n4 / name :op1 "MEK")))
      :mod (d2 / dual)
      :location (c / cell-line
            :mod (d / disease :wiki "Cancer" :name (n / name :op1 "cancer"))))

# ::id pmid_2325_9591.81 ::date 2015-08-22T03:52:47 ::annotator SDL-AMR-09 ::preferred
# ::snt The inhibitors used were ZSTK474 (PI3K inhibitor) and PI-103 (PI3K and mTOR inhibitor) and CI-1040 (MEK inhibitor).
# ::save-date Sat Aug 22, 2015 ::file pmid_2325_9591_81.txt
(u / use-01
      :ARG1 (s / small-molecule
            :ARG0-of (i2 / inhibit-01)
            :ARG1-of (m / mean-01
                  :ARG2 (a / and
                        :op1 (s2 / small-molecule :name (n2 / name :op1 "ZSTK474")
                              :ARG0-of (i3 / inhibit-01
                                    :ARG1 (p2 / protein-family :name (n3 / name :op1 "PI3K"))))
                        :op2 (s3 / small-molecule :name (n4 / name :op1 "PI-103")
                              :ARG0-of (i4 / inhibit-01
                                    :ARG1 (a2 / and
                                          :op1 p2
                                          :op2 (p3 / protein :name (n5 / name :op1 "mTOR")))))
                        :op3 (s4 / small-molecule :name (n6 / name :op1 "CI-1040")
                              :ARG0-of (i5 / inhibit-01
                                    :ARG1 (p / protein-family :name (n / name :op1 "MEK"))))))))

# ::id pmid_2325_9591.82 ::date 2015-08-22T04:02:16 ::annotator SDL-AMR-09 ::preferred
# ::snt We first addressed the effects of these inhibitors alone in the NSCLC lines A549 (<i>K</i>-<i>Ras</i> mutant), HCC827 (<i>EGFR</i> mutant) and H3122 (<i>EML4</i>-<i>ALK</i> translocated), representing the three most frequent oncogenic genotypes of the disease, to establish concentration frames for the target inhibition.
# ::save-date Thu Dec 10, 2015 ::file pmid_2325_9591_82.txt
(a / address-02
      :ARG0 (w / we)
      :ARG1 (a2 / affect-01
            :ARG0 (s / small-molecule
                  :mod (t2 / this)
                  :mod (a3 / alone)
                  :ARG0-of (i2 / inhibit-01))
            :location (c / cell-line
                  :ARG1-of (m / mean-01
                        :ARG2 (a4 / and
                              :op1 (c3 / cell-line :name (n5 / name :op1 "A549")
                                    :mod (g / gene :name (n4 / name :op1 "K-Ras")
                                          :ARG2-of (m2 / mutate-01)))
                              :op2 (c2 / cell-line :name (n6 / name :op1 "HCC827")
                                    :mod (g2 / gene :name (n7 / name :op1 "EGFR")
                                          :ARG2-of (m3 / mutate-01)))
                              :op3 (c4 / cell-line :name (n8 / name :op1 "H3122")
                                    :ARG2-of (t3 / translocate-01
                                          :ARG1 (e2 / enzyme :name (n9 / name :op1 "EML4-ALK"))))
                              :ARG1-of (r / represent-01
                                    :ARG2 (g3 / genotype :quant 3
                                          :ARG1-of (i3 / include-91
                                                :ARG2 (g4 / genotype
                                                      :ARG1-of (f2 / frequent-02
                                                            :degree (m4 / most))
                                                      :poss (d / disease)
                                                      :ARG0-of (c6 / cause-01
                                                            :ARG1 (d3 / disease :wiki "Cancer" :name (n2 / name :op1 "cancer")))))))))
                  :mod (d2 / disease :name (n / name :op1 "NSCLC"))))
      :time (f / first)
      :purpose (e3 / establish-01
            :ARG0 w
            :ARG1 (f3 / frame
                  :mod (c5 / concentrate-02))
            :ARG3 (i4 / inhibit-01
                  :ARG1-of (t4 / target-01))))

# ::id pmid_2325_9591.83 ::date 2015-08-22T04:21:32 ::annotator SDL-AMR-09 ::preferred
# ::snt In the Western blots ZSTK474 at a 3.3μM concentration induced complete downregulation of pAKT, an immediate downstream target of PI3K, while PI-103 induced a similar inhibition at concentrations of 1 to 3.3 μM (Figure <xref ref-type="fig" rid="F1">1A</xref>).
# ::save-date Sun Dec 13, 2015 ::file pmid_2325_9591_83.txt
(c / contrast-01
      :ARG1 (i / induce-01
            :ARG0 (c3 / concentrate-02
                  :ARG1 (s / small-molecule :name (n / name :op1 "ZSTK474"))
                  :quant (c2 / concentration-quantity :quant 3.3
                        :unit (m / micromolar)))
            :ARG2 (d / downregulate-01
                  :ARG1 (e / enzyme :name (n3 / name :op1 "AKT")
                        :ARG3-of (p / phosphorylate-01))
                  :ARG1-of (c4 / complete-02)
                  :ARG1-of (t2 / target-01
                        :ARG0 (p2 / protein-family :name (n4 / name :op1 "PI3K"))
                        :location (d2 / downstream)
                        :time (i2 / immediate)))
            :location (i5 / immunoblot-01))
      :ARG2 (i3 / induce-01
            :ARG0 (s2 / small-molecule :name (n5 / name :op1 "PI-103"))
            :ARG2 (i4 / inhibit-01
                  :ARG1-of (r / resemble-01))
            :condition (c5 / concentrate-02
                        :ARG1 s2
                        :quant (v / value-interval
                              :op1 (c6 / concentration-quantity :quant 1
                                    :unit m)
                              :op2 c2)))
      :ARG1-of (d3 / describe-01
            :ARG0 (f / figure :mod "1A")))

# ::id pmid_2325_9591.84 ::date 2015-08-22T04:38:54 ::annotator SDL-AMR-09 ::preferred
# ::snt pS6 downregulation correlated highly with pAKT downregulation (Figure <xref ref-type="fig" rid="F1">1A</xref>).
# ::save-date Sun Jan 17, 2016 ::file pmid_2325_9591_84.txt
(c / correlate-01
      :ARG1 (d / downregulate-01
            :ARG1 (p / protein :name (n / name :op1 "S6")
                  :ARG3-of (p2 / phosphorylate-01)))
      :ARG2 (d2 / downregulate-01
            :ARG1 (e / enzyme :name (n2 / name :op1 "AKT")
                  :ARG3-of p2))
      :ARG1-of (h / high-02)
      :ARG1-of (d3 / describe-01
            :ARG0 (f / figure :mod "1A")))

# ::id pmid_2325_9591.85 ::date 2015-08-22T04:56:44 ::annotator SDL-AMR-09 ::preferred
# ::snt The MTS cytotoxicity assay showed a major reduction in the number of viable cells in all the cell lines with similar concentrations of both inhibitors, which were closely correlated with the concentrations inducing complete inhibition of pAKT in Western blot analysis (Figure <xref ref-type="fig" rid="F1">1A</xref>,C).
# ::save-date Sat Feb 13, 2016 ::file pmid_2325_9591_85.txt
(s / show-01
      :ARG0 (a / assay-01
            :ARG1 (c / cytotoxicity)
            :mod (s3 / small-molecule :name (n2 / name :op1 "MTS")))
      :ARG1 (r2 / reduce-01
            :ARG1 (n / number
                  :quant-of (c2 / cell
                        :mod (v / viable)))
            :ARG1-of (m / major-02)
            :location (c3 / cell-line
                  :ARG0-of (h / have-03
                        :ARG1 (c4 / concentrate-02
                              :ARG1 (s2 / small-molecule
                                    :ARG0-of (i2 / inhibit-01)
                                    :mod (b / both))
                              :ARG1-of (r3 / resemble-01)
                              :ARG1-of (c5 / correlate-01
                                    :ARG2 (c6 / concentrate-02
                                          :ARG0-of (i3 / induce-01
                                                :ARG2 (i4 / inhibit-01
                                                      :ARG1 (e / enzyme :name (n4 / name :op1 "AKT")
                                                            :ARG3-of (p / phosphorylate-01))
                                                      :ARG1-of (c7 / complete-02))
                                                :time (a2 / analyze-01
                                                      :manner (i / immunoblot-01))))
                                    :ARG1-of (c8 / close-10))))
                  :mod (a4 / all)))
      :ARG1-of (d / describe-01
            :ARG0 (a3 / and
                  :op1 (f / figure :mod "1A")
                  :op2 (f2 / figure :mod "1C"))))

# ::id pmid_2325_9591.86 ::date 2015-08-22T05:24:22 ::annotator SDL-AMR-09 ::preferred
# ::snt CI-1040 induced complete inhibition of ERK1/2, an immediate downstream target of MEK, at a 1 μM concentration (Figure <xref ref-type="fig" rid="F1">1B</xref>).
# ::save-date Sat Jan 16, 2016 ::file pmid_2325_9591_86.txt
(i / induce-01
      :ARG0 (s / small-molecule :name (n2 / name :op1 "CI-1040")
            :ARG1-of (c2 / concentrate-02
                  :quant (c3 / concentration-quantity :quant 1
                        :unit (m / micromolar))))
      :ARG2 (i2 / inhibit-01
            :ARG1 (e / enzyme :name (n3 / name :op1 "ERK1/2")
                  :ARG1-of (t / target-01
                        :ARG0 (e2 / enzyme :name (n / name :op1 "MEK"))
                        :location (d / downstream)
                        :time (i3 / immediate)))
            :ARG1-of (c / complete-02))
      :ARG1-of (d2 / describe-01
            :ARG0 (f / figure :mod "1B")))

# ::id pmid_2325_9591.87 ::date 2015-08-22T05:37:16 ::annotator SDL-AMR-09 ::preferred
# ::snt Only the H3122 line showed any marked reduction in cell viability in the MTS assays in response to increasing concentrations of the inhibitor, correlating with maximal target inhibition, while the other lines displayed minor changes in viability, except for the 10 μM treatment in HCC827, despite the achieving of complete inhibition of pERK1/2 in all the lines tested at 1 μM (Figure <xref ref-type="fig" rid="F1">1C</xref>).
# ::save-date Sat Feb 13, 2016 ::file pmid_2325_9591_87.txt
(c13 / contrast-01
      :ARG1 (s / show-01
            :ARG0 (c / cell-line :name (n / name :op1 "H3122")
                  :mod (o / only))
            :ARG1 (r / reduce-01
                  :ARG1 (v / viable
                        :mod (c2 / cell)
                        :location (a / assay-01
                              :mod (s4 / small-molecule :name (n2 / name :op1 "MTS"))))
                  :manner (m / marked)
                  :mod (a2 / any)
                  :ARG2-of (r2 / respond-01
                        :ARG1 (c3 / concentrate-02
                              :ARG1 (s2 / small-molecule
                                    :ARG0-of (i3 / inhibit-01))
                              :ARG1-of (i2 / increase-01)
                              :ARG1-of (c4 / correlate-01
                                    :ARG2 (i4 / inhibit-01
                                          :ARG1-of (t3 / target-01)
                                          :degree (m2 / maximum)))))))
      :ARG2 (d / display-01
            :ARG0 (c6 / cell-line
                  :mod (o2 / other)
                  :ARG2-of (e / except-01
                        :ARG1 (t4 / treat-04
                              :ARG1 (c8 / cell-line :name (n3 / name :op1 "HCC827"))
                              :ARG2 (s3 / small-molecule
                                    :quant (c9 / concentration-quantity :quant 10
                                          :unit (m4 / micromolar))))))
            :ARG1 (c7 / change-01
                  :ARG1 (v2 / viability)
                  :ARG1-of (m3 / minor-01))
            :concession (a3 / achieve-01
                  :ARG1 (i5 / inhibit-01
                        :ARG1 (e2 / enzyme :name (n4 / name :op1 "ERK1/2")
                              :ARG3-of (p / phosphorylate-01))
                        :ARG1-of (c10 / complete-02)
                        :location (c11 / cell-line
                              :mod (a4 / all)
                              :ARG1-of (t5 / test-01
                                    :manner (c12 / concentration-quantity :quant 1
                                          :unit (m5 / micromolar)))))))
      :ARG1-of (d2 / describe-01
            :ARG0 (f / figure :mod "1C")))

# ::id pmid_2325_9591.88 ::date 2015-08-22T06:16:49 ::annotator SDL-AMR-09 ::preferred
# ::snt Dual inhibition of PI3K and MEK was tested in a panel of NSCLC lines (n=12) with the <i>K</i>-<i>Ras</i> (n=3), <i>EGFR</i> (n=3), <i>ALK</i> (n=3), or triple-negative (n=3) oncogenic genotypes.
# ::save-date Fri Feb 5, 2016 ::file pmid_2325_9591_88.txt
(t / test-01
      :ARG1 (i / inhibit-01
            :ARG1 (a / and
                  :op1 (e / enzyme :name (n4 / name :op1 "PI3K"))
                  :op2 (e2 / enzyme :name (n / name :op1 "MEK")))
            :mod (d / dual))
      :location (p4 / panel
            :consist-of (c / cell-line
                  :ARG0-of (h / have-03
                        :ARG1 (o / or
                              :op1 (g4 / genotype
                                    :mod (g / gene :name (n6 / name :op1 "K-Ras"))
                                    :ARG1-of (n3 / number-01
                                          :ARG2 3))
                              :op2 (g5 / genotype
                                    :mod (g2 / gene :name (n7 / name :op1 "EGFR"))
                                    :ARG1-of (n10 / number-01
                                          :ARG2 3))
                              :op3 (g6 / genotype
                                    :mod (g3 / gene :name (n8 / name :op1 "ALK"))
                                    :ARG1-of (n11 / number-01
                                          :ARG2 3))
                              :op4 (g7 / genotype
                                    :ARG1-of (n9 / negative-01
                                          :ARG1-of (t2 / triple-01))
                                    :ARG1-of (n12 / number-01
                                          :ARG2 3))
                              :ARG0-of (c2 / cause-01
                                    :ARG1 (d3 / disease :wiki "Cancer" :name (n5 / name :op1 "cancer")))))
                  :ARG1-of (n2 / number-01
                        :ARG2 12)
                  :mod (d2 / disease :name (n13 / name :op1 "NSCLC")))))

# ::id pmid_2325_9591.89 ::date 2015-08-22T06:38:01 ::annotator SDL-AMR-09 ::preferred
# ::snt Analogously to the cell lines in the preliminary experiments, all the cell lines tested here showed a major reduction in cell growth in response to the PI3K inhibitors alone, with no significant differences between ZSTK474 or PI-103 (Figure <xref ref-type="fig" rid="F2">2A</xref>, eight of the twelve lines presented graphically).
# ::save-date Wed Aug 26, 2015 ::file pmid_2325_9591_89.txt
(s / show-01
      :ARG0 (c / cell-line
            :mod (a / all)
            :ARG1-of (t2 / test-01
                  :location (h / here))
            :ARG1-of (r3 / resemble-01
                  :ARG2 (c3 / cell-line
                        :location (e / experiment-01
                              :mod (p2 / preliminary)))))
      :ARG1 (a3 / and
            :op1 (r / reduce-01
                  :ARG1 (g / grow-01
                        :ARG1 (c2 / cell))
                  :ARG1-of (m / major-02)
                  :ARG2-of (r2 / respond-01
                        :ARG1 (s2 / small-molecule
                              :mod (a2 / alone)
                              :ARG0-of (i2 / inhibit-01
                                    :ARG1 (p / protein-family :name (n / name :op1 "PI3K"))))))
            :op2 (d / differ-02 :polarity -
                  :ARG1 (s4 / small-molecule :name (n2 / name :op1 "ZSTK474"))
                  :ARG2 (s5 / small-molecule :name (n3 / name :op1 "PI-103"))
                  :ARG1-of (s3 / significant-02)))
      :ARG1-of (d2 / describe-01
            :ARG0 (a4 / and
                  :op1 (f / figure :mod "2A")
                  :op2 (c4 / cell-line :quant 8
                        :ARG1-of (i3 / include-01
                              :ARG2 (c5 / cell-line :quant 12
                                    :ARG1-of (p3 / present-02
                                          :manner (g2 / graphic))))))))

# ::id pmid_2325_9591.90 ::date 2015-08-22T08:27:49 ::annotator SDL-AMR-09 ::preferred
# ::snt The MEK inhibitor CI-1040 elicited variable responses with the majority of cell lines, showing only minor inhibition of growth or none at all.
# ::save-date Wed Jan 20, 2016 ::file pmid_2325_9591_90.txt
(e / elicit-01
      :ARG0 (s / small-molecule :name (n2 / name :op1 "CI-1040")
            :ARG0-of (i2 / inhibit-01
                  :ARG1 (p / protein-family :name (n / name :op1 "MEK"))))
      :ARG1 (r / respond-01
            :ARG1 (c / cell-line
                  :ARG1-of (i3 / include-91
                        :ARG2 (c2 / cell-line))
                  :quant (m / majority))
            :ARG1-of (v2 / vary-01))
      :ARG0-of (s2 / show-01
            :ARG1 (o / or
                  :op1 (i4 / inhibit-01
                        :ARG1-of (m2 / minor-01)
                        :mod (o2 / only))
                  :op2 (i5 / inhibit-01 :polarity -
                        :mod (a / at-all)))))

# ::id pmid_2325_9591.91 ::date 2015-08-22T10:06:00 ::annotator SDL-AMR-09 ::preferred
# ::snt When the cell lines were exposed to dual, concurrent inhibition of PI3K and MEK, two out of 12 tested cell lines, H3122 and H1437, showed marked additional cytotoxicity compared with treatment with a single agent (Figure <xref ref-type="fig" rid="F2">2A</xref>).
# ::save-date Sat Jan 16, 2016 ::file pmid_2325_9591_91.txt
(s / show-01
      :ARG0 (c / cell-line :quant 2
            :ARG1-of (i / include-91
                  :ARG2 (c2 / cell-line :quant 12
                        :ARG1-of (t / test-01)))
            :ARG1-of (m / mean-01
                  :ARG2 (a / and
                        :op1 (c3 / cell-line :name (n2 / name :op1 "H3122"))
                        :op2 (c4 / cell-line :name (n3 / name :op1 "H1437")))))
      :ARG1 (c5 / cytotoxicity
            :ARG1-of (a2 / add-02)
            :mod (m2 / marked)
            :compared-to (t2 / treat-04
                  :ARG2 (a3 / agent
                        :ARG1-of (s2 / single-02))))
      :time (e / expose-01
            :ARG1 c2
            :ARG2 (i2 / inhibit-01
                  :ARG1 (a4 / and
                        :op1 (e2 / enzyme :name (n4 / name :op1 "PI3K"))
                        :op2 (e3 / enzyme :name (n / name :op1 "MEK")))
                  :ARG1-of (c6 / concurrent-02)
                  :mod (d / dual)))
      :ARG1-of (d2 / describe-01
            :ARG0 (f / figure :mod "2A")))

# ::id pmid_2325_9591.92 ::date 2015-08-22T10:18:55 ::annotator SDL-AMR-09 ::preferred
# ::snt The results were submitted to combination index (CI) analysis and average CI values were calculated based on combinations of ZSTK474 and PI-103.
# ::save-date Sun Aug 23, 2015 ::file pmid_2325_9591_92.txt
(a / and
      :op1 (s / submit-01
            :ARG1 (t / thing
                  :ARG2-of (r / result-01))
            :ARG2 (a2 / analyze-01
                  :ARG1 (i / index-01
                        :mod (c / combine-01))))
      :op2 (c2 / calculate-01
            :ARG1 (a3 / average-01
                  :ARG1 (v / value-01
                        :ARG1 i))
            :ARG1-of (b / base-02
                  :ARG2 (c3 / combine-01
                        :ARG1 (s2 / small-molecule :name (n / name :op1 "ZSTK474"))
                        :ARG2 (s3 / small-molecule :name (n2 / name :op1 "PI-103"))))))

# ::id pmid_2325_9591.93 ::date 2015-08-22T10:26:43 ::annotator SDL-AMR-09 ::preferred
# ::snt This analysis grouped the cell lines into three categories: antagonism (n=5, CI 1.10-3.3), nearly additive or slight synergy (n=5, CI 0.7-1.10), and synergy or strong synergy (n=2, CI <0.7) (Table <xref ref-type="table" rid="T1">1</xref>).
# ::save-date Tue Feb 2, 2016 ::file pmid_2325_9591_93.txt
(g / group-01
      :ARG0 (a / analyze-01
            :mod (t / this))
      :ARG1 (c / cell-line)
      :ARG2 (c2 / category :quant 3
            :ARG1-of (m / mean-01
                  :ARG2 (a2 / and
                        :op1 (a3 / antagonize-01
                              :ARG1-of (n / number-01
                                    :ARG2 5)
                              :ARG1-of (i / index-01
                                    :ARG2 (b / between :op1 1.10 :op2 3.3)
                                    :mod (c3 / combine-01)))
                        :op2 (o / or
                              :op1 (a4 / additive
                                    :mod (n2 / near))
                              :op2 (s / synergize-01
                                    :mod (s2 / slight))
                              :ARG1-of (n3 / number-01
                                    :ARG2 5)
                              :ARG1-of (i2 / index-01
                                    :ARG2 (b2 / between :op1 0.7 :op2 1.10)))
                        :op2 (o2 / or
                              :op1 (s3 / synergize-01)
                              :op2 (s4 / synergize-01
                                    :ARG1-of (s5 / strong-02))
                              :ARG1-of (n4 / number-01
                                    :ARG2 2)
                              :ARG1-of (i3 / index-01
                                    :ARG2 (l / less-than :op1 0.7))))))
      :ARG1-of (d / describe-01
            :ARG0 (t2 / table :mod 1)))

# ::id pmid_2325_9591.94 ::date 2015-08-22T10:51:19 ::annotator SDL-AMR-09 ::preferred
# ::snt Visual assessment of the dual inhibition in MTS curves did not suggest any major antagonism of treatment in any of the lines tested, however, since the combination treatment curves in the cell lines with antagonistic CI values closely followed the single PI3K inhibitor treatment curves (Figure <xref ref-type="fig" rid="F2">2A</xref>).
# ::save-date Thu Feb 4, 2016 ::file pmid_2325_9591_94.txt
(h / have-concession-91
      :ARG1 (s / suggest-01 :polarity -
            :ARG0 (a / assess-01
                  :ARG1 (i2 / inhibit-01
                        :mod (d / dual)
                        :location (c / curve-01
                              :mod (t2 / thing :name (n / name :op1 "MTS"))))
                  :mod (v / visual))
            :ARG1 (a2 / antagonize-01
                  :ARG1 (t3 / treat-04)
                  :location (c2 / cell-line
                        :mod (a3 / any)
                        :ARG1-of (t4 / test-01))
                  :ARG1-of (m / major-02)))
      :ARG2 (f / follow-01
            :ARG1 (c4 / curve-01
                  :location (c5 / cell-line)
                  :ARG0-of (h2 / have-03
                        :ARG1 (v2 / value-01
                              :mod (i3 / index-01
                                    :mod (c6 / combine-01)
                                    :ARG0-of (a4 / antagonize-01))))
                  :ARG1-of (t5 / treat-04
                        :mod (c3 / combine-01)))
            :ARG2 (c7 / curve-01
                  :ARG1-of (t6 / treat-04
                        :ARG2 (s2 / small-molecule
                              :ARG0-of (i4 / inhibit-01
                                    :ARG1 (p / protein-family :name (n2 / name :op1 "PI3K")))
                              :ARG1-of (s3 / single-02))))
            :ARG1-of (c8 / close-10))
      :ARG1-of (d2 / describe-01
            :ARG0 (f2 / figure :mod "2A")))

# ::id pmid_2325_9591.95 ::date 2015-08-22T11:30:04 ::annotator SDL-AMR-09 ::preferred
# ::snt There was no correlation between the cancer genotypes in responsiveness to the dual inhibition, since an <i>ALK</i> translocated line (H3122) and a triple-negative negative line (H1437) showed synergistic responses to dual inhibition (Figure <xref ref-type="fig" rid="F2">2A</xref>, Table <xref ref-type="table" rid="T1">1</xref>).
# ::save-date Fri Feb 5, 2016 ::file pmid_2325_9591_95.txt
(c / correlate-01 :polarity -
      :ARG1 (g / genotype
            :mod (d / disease :wiki "Cancer" :name (n / name :op1 "cancer")))
      :ARG2-of (r / respond-01
            :ARG1 (i / inhibit-01
                  :mod (d2 / dual)))
      :ARG1-of (d3 / describe-01
            :ARG0 (a2 / and
                  :op1 (f / figure :mod "2A")
                  :op2 (t4 / table :mod 1)))
      :ARG1-of (c7 / cause-01
            :ARG0 (s / show-01
                  :ARG0 (a / and
                        :op1 (c3 / cell-line
                              :ARG2-of (t / translocate-01
                                    :ARG1 (g2 / gene :name (n2 / name :op1 "ALK")))
                              :ARG1-of (m / mean-01
                                    :ARG2 (c4 / cell-line :name (n3 / name :op1 "H3122"))))
                        :op2 (c5 / cell-line
                              :ARG1-of (n4 / negative-01
                                    :ARG1-of (t2 / triple-01))
                              :ARG1-of (m2 / mean-01
                                    :ARG2 (c6 / cell-line :name (n5 / name :op1 "H1437")))))
                  :ARG1 (t3 / thing
                        :ARG2-of (r2 / respond-01
                              :ARG1 i)
                        :ARG0-of (s2 / synergize-01)))))

# ::id pmid_2325_9591.96 ::date 2015-08-22T23:02:38 ::annotator SDL-AMR-09 ::preferred
# ::snt The NSCLC lines showing synergistic responses to dual inhibition seemed to be more responsive to low concentrations (<1 μM) of the MEK inhibitor alone (Figure <xref ref-type="fig" rid="F2">2A</xref>).
# ::save-date Wed Mar 2, 2016 ::file pmid_2325_9591_96.txt
(s / seem-01
      :ARG1 (r2 / responsive-02
            :ARG0 (c / cell-line
                  :ARG0-of (s2 / show-01
                        :ARG1 (t2 / thing
                              :ARG2-of (r / respond-01
                                    :ARG1 (i2 / inhibit-01
                                          :mod (d / dual)))
                              :ARG0-of (s3 / synergize-01)))
                  :mod (d3 / disease :name (n3 / name :op1 "NSCLC")))
            :ARG1 (c2 / concentrate-02
                  :ARG1 (s4 / small-molecule
                        :ARG0-of (i3 / inhibit-01
                              :ARG1 (p / protein-family :name (n / name :op1 "MEK")))
                        :mod (a / alone))
                  :ARG1-of (l / low-04)
                  :quant (l2 / less-than
                        :op1 (c3 / concentration-quantity :quant 1
                              :unit (m / micromolar)))))
      :ARG1-of (d2 / describe-01
            :ARG0 (f / figure :mod "2A")))

# ::id pmid_2325_9591.97 ::date 2015-08-23T03:48:22 ::annotator SDL-AMR-09 ::preferred
# ::snt Analogously to the single inhibitor results, the lines sensitive to dual inhibition showed only a minor difference between the activities of the different PI3K inhibitors in combination with the MEK inhibitor.
# ::save-date Wed Jan 20, 2016 ::file pmid_2325_9591_97.txt
(s / show-01
      :ARG0 (c / cell-line
            :ARG0-of (s2 / sensitive-03
                  :ARG1 (i2 / inhibit-01
                        :mod (d / dual))))
      :ARG1 (d2 / differ-02
            :ARG1 (a / activity-06
                  :ARG0 (s3 / small-molecule
                        :ARG0-of (i3 / inhibit-01
                              :ARG1 (p2 / protein-family :name (n2 / name :op1 "PI3K")))
                        :ARG1-of (d3 / differ-02)
                        :ARG1-of (c2 / combine-01
                              :ARG2 (s4 / small-molecule
                                    :ARG0-of (i4 / inhibit-01
                                          :ARG1 (p / protein-family :name (n / name :op1 "MEK")))))))
            :ARG1-of (m / minor-01))
      :ARG1-of (r / resemble-01
            :ARG2 (t / thing
                  :ARG2-of (r2 / result-01
                        :ARG1 (s5 / small-molecule
                              :ARG0-of (i / inhibit-01)
                              :ARG1-of (s6 / single-02))))))

# ::id pmid_2325_9591.98 ::date 2015-08-23T03:55:07 ::annotator SDL-AMR-09 ::preferred
# ::snt Based on a literature search [<xref ref-type="bibr" rid="B4">4</xref>,<xref ref-type="bibr" rid="B7">7</xref>], additional cell lines known to be responsive to dual PI3K and MEK inhibition were studied.
# ::save-date Sat Jan 16, 2016 ::file pmid_2325_9591_98.txt
(s / study-01
      :ARG1 (c / cell-line
            :ARG1-of (a / add-02)
            :ARG0-of (r / responsive-02
                  :ARG1 (i / inhibit-01
                        :ARG1 (a2 / and
                              :op1 (e / enzyme :name (n2 / name :op1 "PI3K"))
                              :op2 (e2 / enzyme :name (n / name :op1 "MEK")))
                        :mod (d / dual))
                  :ARG1-of (k / know-01)))
      :ARG1-of (b / base-02
            :ARG2 (s2 / search-01
                  :ARG1 (l / literature)
                  :ARG1-of (d2 / describe-01
                        :ARG0 (p3 / publication
                              :ARG1-of (c2 / cite-01
                                    :ARG2 (a3 / and :op1 4 :op2 7)))))))

# ::id pmid_2325_9591.99 ::date 2015-08-23T04:00:16 ::annotator SDL-AMR-09 ::preferred
# ::snt MDA-MB231, a basal-like breast cancer line, and HCT116, a <i>K</i><i>Ras</i> mutant colorectal line, were exposed to single inhibitors or dual inhibition and analyzed with the MTS assay.
# ::save-date Sat Feb 13, 2016 ::file pmid_2325_9591_99.txt
(a2 / and
      :op1 (e / expose-01
            :ARG1 (a / and
                  :op1 (c / cell-line :name (n3 / name :op1 "MDA-MB231")
                        :ARG1-of (r / resemble-01
                              :ARG2 (c3 / cell-line
                                    :mod (b2 / basal)
                                    :mod (d / disease :wiki "Breast_cancer" :name (n2 / name :op1 "breast" :op2 "cancer")))))
                  :op2 (c4 / cell-line :name (n4 / name :op1 "HCT116")
                        :ARG1-of (m / mean-01
                              :ARG2 (c5 / cell-line
                                    :mod (c6 / colon)
                                    :mod (g / gene :name (n5 / name :op1 "KRas")
                                          :ARG2-of (m2 / mutate-01))))))
            :ARG2 (o / or
                  :op1 (s / small-molecule
                        :ARG1-of (s2 / single-02)
                        :ARG0-of (i2 / inhibit-01))
                  :op2 (i3 / inhibit-01
                        :mod (d2 / dual))))
      :op2 (a3 / analyze-01
            :ARG1 a
            :instrument (a4 / assay-01
                  :mod (s3 / small-molecule :name (n / name :op1 "MTS")))))

# ::id pmid_2325_9591.100 ::date 2015-08-23T04:19:32 ::annotator SDL-AMR-09 ::preferred
# ::snt As in the previous work, both the cell lines showed synergistic responses to dual inhibition (Figure <xref ref-type="fig" rid="F2">2B</xref>, Table <xref ref-type="table" rid="T1">1</xref>).
# ::save-date Tue Feb 2, 2016 ::file pmid_2325_9591_100.txt
(s / show-01
      :ARG0 (c / cell-line
            :mod (b / both))
      :ARG1 (t / thing
            :ARG2-of (r / respond-01
                  :ARG1 (i / inhibit-01
                        :mod (d / dual)))
            :ARG0-of (s2 / synergize-01))
      :ARG1-of (r2 / resemble-01
            :ARG2 (w / work-01
                  :time (p / previous)))
      :ARG1-of (d2 / describe-01
            :ARG0 (a / and
                  :op1 (f / figure :mod "2B")
                  :op2 (t2 / table :mod 1))))

# ::id pmid_2325_9591.101 ::date 2015-08-23T04:28:30 ::annotator SDL-AMR-09 ::preferred
# ::snt PI-103 was markedly less effective than ZSTK474 in the HCT116 cell line, while, like all the NSCLC cell lines, MDA-MB231 responded similarly to both PI3K inhibitors (Figure <xref ref-type="fig" rid="F2">2B</xref>, Table <xref ref-type="table" rid="T1">1</xref>).
# ::save-date Wed Aug 26, 2015 ::file pmid_2325_9591_101.txt
(c / contrast-01
      :ARG1 (a / affect-01
            :ARG0 (s / small-molecule :name (n / name :op1 "PI-103"))
            :degree (l / less)
            :manner (m / marked)
            :compared-to (s2 / small-molecule :name (n2 / name :op1 "ZSTK474"))
            :location (c2 / cell-line :name (n3 / name :op1 "HCT116")))
      :ARG2 (r / respond-01
            :ARG1 (c3 / cell-line :name (n4 / name :op1 "MDA-MB231")
                  :ARG1-of (r2 / resemble-01
                        :ARG2 (c4 / cell-line
                              :mod (a2 / all)
                              :mod (d2 / disease :name (n7 / name :op1 "NSCLC")))))
            :ARG2 (s3 / small-molecule
                  :ARG0-of (i2 / inhibit-01
                        :ARG1 (p / protein-family :name (n6 / name :op1 "PI3K")))
                  :mod (b / both))
            :ARG1-of (r3 / resemble-01))
      :ARG1-of (d / describe-01
            :ARG0 (a3 / and
                  :op1 (f / figure :mod "2B")
                  :op2 (t2 / table :mod 1))))

# ::id pmid_2325_9591.102 ::date 2015-08-23T04:42:59 ::annotator SDL-AMR-09 ::preferred
# ::snt Interestingly, we did not see any differences in target inhibition between ZSTK474 and PI-103 in the HCT116 line (Figure <xref ref-type="fig" rid="F3">3A</xref>), so that the mechanism of differential efficiency remains unknown.
# ::save-date Wed Aug 26, 2015 ::file pmid_2325_9591_102.txt
(s / see-01 :polarity -
      :ARG0 (w / we)
      :ARG1 (d / differ-02
            :ARG1 (s2 / small-molecule :name (n / name :op1 "ZSTK474"))
            :ARG2 (s3 / small-molecule :name (n2 / name :op1 "PI-103"))
            :ARG3 (i / inhibit-01
                  :ARG1-of (t / target-01))
            :mod (a / any)
            :location (c / cell-line :name (n3 / name :op1 "HCT116")))
      :ARG1-of (d2 / describe-01
            :ARG0 (f / figure :mod "3A"))
      :ARG2-of (i3 / interest-01)
      :ARG0-of (c2 / cause-01
            :ARG1 (r / remain-01
                  :ARG1 (m / mechanism
                        :ARG1-of (e / efficient-01
                              :mod (d3 / differential)))
                  :ARG3 (k / know-01 :polarity -
                        :ARG1 m))))

# ::id pmid_2325_9591.103 ::date 2015-08-23T05:02:06 ::annotator SDL-AMR-09 ::preferred
# ::snt The lines H3122, H1437, MDA-MB231, and HCT116, which were sensitive to dual inhibition, were further analyzed with Western blot analysis for cleaved PARP, a well-characterized marker of apoptosis.
# ::save-date Sun Jan 17, 2016 ::file pmid_2325_9591_103.txt
(a / analyze-01
      :ARG1 (a2 / and
            :op1 (c / cell-line :name (n2 / name :op1 "H3122"))
            :op2 (c2 / cell-line :name (n3 / name :op1 "H1437"))
            :op3 (c3 / cell-line :name (n4 / name :op1 "MDA-MB231"))
            :op4 (c4 / cell-line :name (n5 / name :op1 "HCT116"))
            :ARG0-of (s / sensitive-03
                  :ARG1 (i / inhibit-01
                        :mod (d / dual))))
      :degree (f / further)
      :manner (i2 / immunoblot-01
            :ARG1 (p / protein :name (n7 / name :op1 "PARP")
                  :ARG1-of (c5 / cleave-01)
                  :ARG0-of (m / mark-02
                        :ARG1 (a4 / apoptosis)
                        :ARG1-of (c6 / characterize-01)
                        :ARG1-of (w / well-09)))
            :ARG2 a2))

# ::id pmid_2325_9591.104 ::date 2015-08-23T05:45:54 ::annotator SDL-AMR-09 ::preferred
# ::snt No cleaved PARP was detected in any of the cell lines following the single agent treatments (Figure <xref ref-type="fig" rid="F4">4A</xref>), but when dual inhibition with either ZSTK474 or PI-103 was administered, marked PARP cleavage was seen in the H3122 line but not in the other lines tested (Figure <xref ref-type="fig" rid="F4">4A</xref>).
# ::save-date Sun Jan 17, 2016 ::file pmid_2325_9591_104.txt
(c / contrast-01
      :ARG1 (d / detect-01 :polarity -
            :ARG1 (p / protein :name (n / name :op1 "PARP")
                  :ARG1-of (c2 / cleave-01))
            :location (c3 / cell-line
                  :mod (a / any))
            :ARG1-of (d2 / describe-01
                  :ARG0 (f2 / figure :mod "4A"))
            :ARG1-of (f / follow-01
                  :ARG2 (t / treat-04
                        :ARG2 (a2 / agent
                              :ARG1-of (s / single-02)))))
      :ARG2 (s2 / see-01
            :ARG1 (p2 / protein :name (n2 / name :op1 "PARP")
                  :ARG1-of (c4 / cleave-01
                        :ARG1-of (m / mark-01)))
            :location (c5 / cell-line :name (n3 / name :op1 "H3122"))
            :ARG1-of (c6 / contrast-01
                  :ARG2 (s3 / see-01 :polarity -
                        :ARG1 p2
                        :location (c7 / cell-line
                              :mod (o / other)
                              :ARG1-of (t2 / test-01))))
            :time (a3 / administer-01
                  :ARG1 (i / inhibit-01
                        :ARG0 (o2 / or
                              :op1 (s4 / small-molecule :name (n4 / name :op1 "ZSTK474"))
                              :op2 (s5 / small-molecule :name (n5 / name :op1 "PI-103")))
                        :mod (d3 / dual)))
            :ARG1-of d2))

# ::id pmid_2325_9591.105 ::date 2015-08-23T06:54:57 ::annotator SDL-AMR-09 ::preferred
# ::snt <sec-title level="2">Effect of dual inhibition on cell signaling</sec-title>
# ::save-date Sun Aug 23, 2015 ::file pmid_2325_9591_105.txt
(a / affect-01
      :ARG0 (i / inhibit-01
            :mod (d / dual))
      :ARG1 (s / signal-07
            :ARG1 (c / cell)))

# ::id pmid_2325_9591.106 ::date 2015-08-23T06:58:06 ::annotator SDL-AMR-09 ::preferred
# ::snt The NSCLC (H3122 and H1437), breast cancer (MDA-MB231) and colon cancer (HCT116) lines, which showing major synergy upon dual inhibition, were further studied for cell signaling in response to the inhibitors.
# ::save-date Tue Feb 2, 2016 ::file pmid_2325_9591_106.txt
(s / study-01
      :ARG1 (a / and
            :op1 (c / cell-line
                  :ARG1-of (m / mean-01
                        :ARG2 (a2 / and
                              :op1 (c2 / cell-line :name (n3 / name :op1 "H3122"))
                              :op2 (c3 / cell-line :name (n4 / name :op1 "H1437"))))
                  :mod (d / disease :name (n / name :op1 "NSCLC")))
            :op2 (c4 / cell-line
                  :ARG1-of (m2 / mean-01
                        :ARG2 (c6 / cell-line :name (n5 / name :op1 "MDA-MB231")))
                  :mod (d3 / disease :wiki "Breast_cancer" :name (n2 / name :op1 "breast" :op2 "cancer")))
            :op3 (c7 / cell-line
                  :ARG1-of (m3 / mean-01
                        :ARG2 (c10 / cell-line :name (n6 / name :op1 "HCT116")))
                  :mod (d4 / disease :wiki "Colorectal_cancer" :name (n7 / name :op1 "colon" :op2 "cancer")))
            :ARG0-of (s2 / show-01
                  :ARG1 (s3 / synergize-01
                        :ARG1-of (m4 / major-02))
                  :time (a3 / after
                        :op1 (i2 / inhibit-01
                              :mod (d2 / dual)))))
      :degree (f / further)
      :purpose (s4 / signal-07
            :ARG1 (c11 / cell)
            :ARG2-of (r / respond-01
                  :ARG1 (s5 / small-molecule
                        :ARG0-of (i3 / inhibit-01)))))

# ::id pmid_2325_9591.107 ::date 2015-08-23T07:03:47 ::annotator SDL-AMR-09 ::preferred
# ::snt All the cell lines downregulated pAKT and its downstream target pS6 completely in response to 6h of treatment with the PI3K inhibitor ZSTK474 or PI-103 (3.3 μM) (Figure <xref ref-type="fig" rid="F3">3A</xref>).
# ::save-date Sun Jan 17, 2016 ::file pmid_2325_9591_107.txt
(d / downregulate-01
      :ARG0 (c / cell-line
            :mod (a / all))
      :ARG1 (a2 / and
            :op1 (e / enzyme :name (n / name :op1 "AKT")
                  :ARG3-of (p / phosphorylate-01))
            :op2 (p3 / protein :name (n2 / name :op1 "S6")
                  :ARG3-of p
                  :ARG1-of (t2 / target-01
                        :ARG0 e
                        :location (d2 / downstream))))
      :ARG2-of (r / respond-01
            :ARG1 (t3 / treat-04
                  :ARG2 (o / or
                        :op1 (s / small-molecule :name (n3 / name :op1 "ZSTK474")
                              :quant (c3 / concentration-quantity :quant 3.3
                                    :unit (m / micromolar)))
                        :op2 (s2 / small-molecule :name (n4 / name :op1 "PI-103")
                              :quant c3)
                        :ARG0-of (i2 / inhibit-01
                              :ARG1 (p2 / protein-family :name (n5 / name :op1 "PI3K"))))
                  :duration (t4 / temporal-quantity :quant 6
                        :unit (h / hour)))
            :ARG1-of (c2 / complete-02))
      :ARG1-of (d3 / describe-01
            :ARG0 (f / figure :mod "3A")))

# ::id pmid_2325_9591.108 ::date 2015-08-23T07:38:50 ::annotator SDL-AMR-09 ::preferred
# ::snt Downregulation of p4E-BP1 was also noted with all the cell lines tested, but it was complete only in the H3122 cell line (Figure <xref ref-type="fig" rid="F3">3A</xref>).
# ::save-date Wed Aug 26, 2015 ::file pmid_2325_9591_108.txt
(c2 / contrast-01
      :ARG1 (n / note-01
            :ARG1 (d / downregulate-01
                  :ARG1 (p / protein :name (n2 / name :op1 "4E-BP1")
                        :ARG3-of (p2 / phosphorylate-01))
                  :location (c / cell-line
                        :ARG1-of (t / test-01))))
      :ARG2 (c3 / complete-02
            :ARG1 d
            :location (c4 / cell-line :name (n3 / name :op1 "H3122")
                  :mod (o / only)))
      :ARG1-of (d2 / describe-01
            :ARG0 (f / figure :mod "3A")))

# ::id pmid_2325_9591.109 ::date 2015-08-23T07:45:17 ::annotator SDL-AMR-09 ::preferred
# ::snt Furthermore, concurrent activation of pERK1/2 was recognized in the H3122, MDA-MB231 and HCT116 cell lines during PI3K inhibitor treatment (Figure <xref ref-type="fig" rid="F3">3A</xref>).
# ::save-date Sun Aug 23, 2015 ::file pmid_2325_9591_109.txt
(a / and
      :op2 (r / recognize-01
            :ARG1 (a2 / activate-01
                  :ARG1 (e / enzyme :name (n / name :op1 "ERK1/2")
                        :ARG3-of (p / phosphorylate-01))
                  :ARG1-of (c / concurrent-02))
            :location (a3 / and
                  :op1 (c2 / cell-line :name (n2 / name :op1 "H3122"))
                  :op2 (c3 / cell-line :name (n3 / name :op1 "MDA-MB231"))
                  :op3 (c4 / cell-line :name (n4 / name :op1 "HCT116")))
            :time (t2 / treat-04
                  :ARG2 (s / small-molecule
                        :ARG0-of (i2 / inhibit-01
                              :ARG1 (p2 / protein-family :name (n5 / name :op1 "PI3K"))))))
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod "3A")))

# ::id pmid_2325_9591.110 ::date 2015-08-23T08:05:45 ::annotator SDL-AMR-09 ::preferred
# ::snt When the cell lines were treated with the MEK inhibitor CI-1040 (1 μM, 6 h), complete (H3122, H1437) or marked (MDA-MB231, HCT116) downregulation of pERK1/2 was seen (Figure <xref ref-type="fig" rid="F3">3A</xref>).
# ::save-date Wed Aug 26, 2015 ::file pmid_2325_9591_110.txt
(s / see-01
      :ARG1 (o / or
            :op1 (d / downregulate-01
                  :ARG1 (e / enzyme :name (n2 / name :op1 "ERK1/2")
                        :ARG3-of (p2 / phosphorylate-01))
                  :ARG1-of (c3 / complete-02)
                  :location (a / and
                        :op1 (c4 / cell-line :name (n4 / name :op1 "H3122"))
                        :op2 (c5 / cell-line :name (n5 / name :op1 "H1437"))))
            :op2 (d2 / downregulate-01
                  :ARG1 e
                  :location (a2 / and
                        :op1 (c6 / cell-line :name (n6 / name :op1 "MDA-MB231"))
                        :op2 (c7 / cell-line :name (n7 / name :op1 "HCT116")))
                  :degree (m3 / marked)))
      :time (t2 / treat-04
            :ARG1 (c / cell-line)
            :ARG2 (s2 / small-molecule :name (n3 / name :op1 "CI-1040")
                  :ARG0-of (i2 / inhibit-01
                        :ARG1 (p / protein-family :name (n / name :op1 "MEK")))
                  :quant (c2 / concentration-quantity :quant 1
                        :unit (m / micromolar)))
            :duration (t3 / temporal-quantity :quant 6
                  :unit (h / hour)))
      :ARG1-of (d3 / describe-01
            :ARG0 (f / figure :mod "3A")))

# ::id pmid_2325_9591.111 ::date 2015-08-23T08:15:41 ::annotator SDL-AMR-09 ::preferred
# ::snt This was accompanied by upregulation of pAKT in the H3122 and MDA-MB231 lines, but not by upregulation of pS6 or p4E-BP1 (H3122) (Figure <xref ref-type="fig" rid="F3">3A</xref>).
# ::save-date Sun Jan 17, 2016 ::file pmid_2325_9591_111.txt
(c / contrast-01
      :ARG1 (a / accompany-01
            :ARG0 (u / upregulate-01
                  :ARG1 (e / enzyme :name (n / name :op1 "AKT")
                        :ARG3-of (p / phosphorylate-01))
                  :location (a2 / and
                        :op1 (c2 / cell-line :name (n2 / name :op1 "H3122"))
                        :op2 (c3 / cell-line :name (n3 / name :op1 "MDA-MB231"))))
            :ARG1 (t / this))
      :ARG2 (a3 / accompany-01 :polarity -
            :ARG0 (u2 / upregulate-01
                  :ARG1 (o / or
                        :op1 (p3 / protein :name (n4 / name :op1 "S6")
                              :ARG3-of p)
                        :op2 (p2 / protein :name (n5 / name :op1 "4E-BP1")
                              :ARG3-of p))
                  :location c2)
            :ARG1 t)
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod "3A")))

# ::id pmid_2325_9591.112 ::date 2015-08-23T08:21:01 ::annotator SDL-AMR-09 ::preferred
# ::snt p4E-BP1 was markedly upregulated in the MDA-MB231 line in response to CI-1040 treatment (Figure <xref ref-type="fig" rid="F3">3A</xref>).
# ::save-date Sun Aug 23, 2015 ::file pmid_2325_9591_112.txt
(u / upregulate-01
      :ARG1 (p / protein :name (n / name :op1 "4E-BP1")
            :ARG3-of (p2 / phosphorylate-01))
      :manner (m / marked)
      :location (c / cell-line :name (n2 / name :op1 "MDA-MB231"))
      :ARG2-of (r / respond-01
            :ARG1 (t / treat-04
                  :ARG2 (s / small-molecule :name (n3 / name :op1 "CI-1040"))))
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod "3A")))

# ::id pmid_2325_9591.113 ::date 2015-08-23T08:40:22 ::annotator SDL-AMR-09 ::preferred
# ::snt When the PI3K and MEK inhibitors were administered simultaneously the inhibition of the targets was similar to that seen with single inhibitor treatment (Figure <xref ref-type="fig" rid="F3">3A</xref>).
# ::save-date Wed Aug 26, 2015 ::file pmid_2325_9591_113.txt
(r2 / resemble-01
      :ARG1 (i2 / inhibit-01
            :ARG1 (t / thing
                  :ARG1-of (t2 / target-01)))
      :ARG2 (i3 / inhibit-01
            :ARG1-of (s / see-01)
            :time (t3 / treat-04
                  :ARG2 (s2 / small-molecule
                        :ARG0-of (i4 / inhibit-01)
                        :ARG1-of (s3 / single-02))))
      :time (a / administer-01
            :ARG1 (a2 / and
                  :op1 (s5 / small-molecule
                        :ARG0-of (i5 / inhibit-01
                              :ARG1 (p2 / protein-family :name (n2 / name :op1 "PI3K"))))
                  :op2 (s6 / small-molecule
                        :ARG0-of (i6 / inhibit-01
                              :ARG1 (p / protein-family :name (n / name :op1 "MEK")))))
            :manner (s4 / simultaneous))
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod "3A")))

# ::id pmid_2325_9591.114 ::date 2015-08-23T08:46:57 ::annotator SDL-AMR-09 ::preferred
# ::snt Dual inhibition was able to overcome the single inhibitor-induced stimulation of parallel pathway activation (Figure <xref ref-type="fig" rid="F3">3A</xref>).
# ::save-date Wed Aug 26, 2015 ::file pmid_2325_9591_114.txt
(c / capable-01
      :ARG1 (i / inhibit-01
            :mod (d / dual))
      :ARG2 (o / overcome-01
            :ARG0 i
            :ARG1 (s3 / stimulate-01
                  :ARG1 (a / activate-01
                        :ARG1 (p2 / pathway
                              :ARG1-of (p3 / parallel-01)))
                  :ARG2-of (i3 / induce-01
                        :ARG0 (s / small-molecule
                              :ARG1-of (s2 / single-02)
                              :ARG0-of (i2 / inhibit-01)))))
      :ARG1-of (d2 / describe-01
            :ARG0 (f / figure :mod "3A")))

# ::id pmid_2325_9591.115 ::date 2015-08-23T08:58:04 ::annotator SDL-AMR-09 ::preferred
# ::snt We were not able to detect any significant difference in the activity of either pS6 or p4E-BP1 following dual inhibitor treatment as compared with the single PI3K inhibitor treatments (Figure <xref ref-type="fig" rid="F3">3A</xref>).
# ::save-date Sun Jan 17, 2016 ::file pmid_2325_9591_115.txt
(c / capable-01 :polarity -
      :ARG1 (w / we)
      :ARG2 (d / detect-01
            :ARG0 w
            :ARG1 (d2 / differ-02
                  :ARG3 (a2 / activity-06
                        :ARG0 (o / or
                              :op1 (p / protein :name (n / name :op1 "S6")
                                    :ARG3-of (p2 / phosphorylate-01))
                              :op2 (p3 / protein :name (n2 / name :op1 "4E-BP1")
                                    :ARG3-of p2))
                        :ARG1-of (f / follow-01
                              :ARG2 (t2 / treat-04
                                    :ARG2 (s2 / small-molecule
                                          :ARG0-of (i2 / inhibit-01
                                                :mod (d3 / dual)))
                                    :compared-to (t3 / treat-04
                                          :ARG2 (s3 / small-molecule
                                                :ARG1-of (s4 / single-02)
                                                :ARG0-of (i3 / inhibit-01
                                                      :ARG1 (p4 / protein-family :name (n3 / name :op1 "PI3K"))))))))
                  :mod (a / any)
                  :ARG1-of (s / significant-02)))
      :ARG1-of (d4 / describe-01
            :ARG0 (f2 / figure :mod "3A")))

# ::id pmid_2325_9591.116 ::date 2015-08-23T09:05:22 ::annotator SDL-AMR-09 ::preferred
# ::snt Further analysis of the dual inhibition of the central RTKs and signaling nodes was carried out with the PathScan Antibody Array, which investigates the phosphorylation status of 28 RTKs and 11 signaling nodes concurrently.
# ::save-date Sun Jan 17, 2016 ::file pmid_2325_9591_116.txt
(c / carry-out-03
      :ARG0 (p3 / product :name (n3 / name :op1 "PathScan" :op2 "Antibody" :op3 "Array")
            :ARG0-of (i2 / investigate-01
                  :ARG1 (s2 / status
                        :mod (p4 / phosphorylate-01
                              :ARG1 (a4 / and
                                    :op1 (p5 / protein :quant 28
                                          :ARG1-of (i3 / include-91
                                                :ARG2 (p6 / protein-family :name (n4 / name :op1 "RTK"))))
                                    :op2 (n5 / node :quant 11
                                          :ARG0-of (s3 / signal-07)))))
                  :ARG1-of (c3 / concurrent-02)))
      :ARG1 (a / and
            :op1 (a2 / analyze-01
                  :ARG1 (a3 / and
                        :op1 (i / inhibit-01
                              :ARG1 (p / protein :name (n / name :op1 "RTK")
                                    :mod (c2 / central))
                              :mod (d / dual))
                        :op2 (n2 / node
                              :ARG0-of s3))
                  :degree (f / further))))

# ::id pmid_2325_9591.117 ::date 2015-08-23T09:15:57 ::annotator SDL-AMR-09 ::preferred
# ::snt Attention was focused on the dual inhibition-sensitive H1437 and MDA-MB231 lines.
# ::save-date Sun Aug 23, 2015 ::file pmid_2325_9591_117.txt
(f / focus-01
      :ARG1 (a / attend-02
            :ARG1 a2)
      :ARG2 (a2 / and
            :op1 (c / cell-line :name (n / name :op1 "H1437")
                  :ARG0-of (s / sensitive-03
                        :ARG1 (i / inhibit-01
                              :mod (d / dual))))
            :op2 (c2 / cell-line :name (n2 / name :op1 "MDA-MB231")
                  :ARG0-of s)))

# ::id pmid_2325_9591.118 ::date 2015-08-25T23:59:57 ::annotator SDL-AMR-09 ::preferred
# ::snt A low level of RTK activation was noted in untreated cells of both cell lines, H1437 showing some activity with c-MET (Figure <xref ref-type="fig" rid="F5">5</xref>), while in the signaling nodes, pAKT, S6 and ERK1/2 showed activity in both cell lines and Src activity was also noted in H1437.
# ::save-date Sun Jan 17, 2016 ::file pmid_2325_9591_118.txt
(c3 / contrast-01
      :ARG1 (n / note-02
            :ARG1 (l / level
                  :ARG1-of (l2 / low-04)
                  :degree-of (a2 / activate-01
                        :ARG1 (e / enzyme :name (n2 / name :op1 "RKT"))))
            :location (c / cell-line
                  :ARG1-of (t / treat-04 :polarity -)
                  :mod (b / both)
                  :ARG1-of (m / mean-01
                        :ARG2 (c2 / cell-line :name (n3 / name :op1 "H1437")
                              :ARG0-of (s / show-01
                                    :ARG1 (a / activity-06
                                          :condition (t2 / treat-04
                                                :ARG1 c2
                                                :ARG2 (p / protein :name (n4 / name :op1 "c-MET")))
                                          :mod (s5 / some))
                                    :ARG1-of (d / describe-01
                                          :ARG0 (f / figure :mod 5)))))))
      :ARG2 (a5 / and
            :op1 (s2 / show-01
                  :ARG0 (a4 / and
                        :op1 (e2 / enzyme :name (n5 / name :op1 "AKT")
                              :ARG3-of (p2 / phosphorylate-01))
                        :op2 (p4 / protein :name (n6 / name :op1 "S6"))
                        :op3 (s3 / slash
                              :op1 (e4 / enzyme :name (n7 / name :op1 "ERK1"))
                              :op2 (e5 / enzyme :name (n8 / name :op1 "ERK2"))))
                  :ARG1 (a3 / activity-06
                        :location c)
                  :location (n9 / node
                        :ARG0-of (s4 / signal-07)))
            :op2 (n10 / note-02
                  :ARG1 (a6 / activity-06
                        :ARG0 (p3 / protein :name (n11 / name :op1 "Src")))
                  :location c2
                  :mod (a7 / also))))

# ::id pmid_2325_9591.119 ::date 2015-08-26T00:31:17 ::annotator SDL-AMR-09 ::preferred
# ::snt In the drug-treated cells, ZSTK474 (24 h) was able to inhibit both AKT and S6 phosphorylation, S6 showing a more pronounced effect (Figure <xref ref-type="fig" rid="F5">5</xref>).
# ::save-date Sun Jan 17, 2016 ::file pmid_2325_9591_119.txt
(c / capable-01
      :ARG1 (s2 / small-molecule :name (n / name :op1 "ZSTK474"))
      :ARG2 (i / inhibit-01
            :ARG1 (p2 / phosphorylate-01
                  :ARG1 (a / and
                        :op1 (e2 / enzyme :name (n2 / name :op1 "AKT"))
                        :op2 (p / protein :name (n3 / name :op1 "S6")
                              :ARG0-of (s / show-01
                                    :ARG1 (a2 / affect-01
                                          :ARG1-of (p3 / pronounced-02))
                                    :ARG1-of (d2 / describe-01
                                          :ARG0 (f / figure :mod 5))))))
            :time (a3 / after
                  :op1 (t / temporal-quantity :quant 24
                        :unit (h / hour))))
      :location (c2 / cell
            :ARG1-of (t2 / treat-04
                  :ARG2 (d / drug))))

# ::id pmid_2325_9591.120 ::date 2015-08-26T00:46:10 ::annotator SDL-AMR-09 ::preferred
# ::snt Furthermore, ZSTK474 induced a marked broad feedback RTK activation in the H1437 cell line (Figure <xref ref-type="fig" rid="F5">5</xref>).
# ::save-date Mon Aug 31, 2015 ::file pmid_2325_9591_120.txt
(a / and
      :op2 (i / induce-01
            :ARG0 (s / small-molecule :name (n / name :op1 "ZSTK474"))
            :ARG2 (a2 / activate-01
                  :ARG1 (e2 / enzyme :name (n2 / name :op1 "RTK"))
                  :mod (f / feedback)
                  :mod (b / broad)
                  :ARG1-of (m / mark-01))
            :location (c / cell-line :name (n3 / name :op1 "H1437"))
            :ARG1-of (d / describe-01
                  :ARG0 (f2 / figure :mod 5))))

# ::id pmid_2325_9591.121 ::date 2015-08-26T00:49:57 ::annotator SDL-AMR-09 ::preferred
# ::snt CI-1040 (24 h) effects were limited to the inhibition of ERK1/2 activity.
# ::save-date Wed Aug 26, 2015 ::file pmid_2325_9591_121.txt
(l / limit-01
      :ARG1 (a / affect-01
            :ARG0 (s2 / small-molecule :name (n3 / name :op1 "CI-1040"))
            :time (a3 / after
                  :op1 (t / temporal-quantity :quant 24
                        :unit (h / hour))))
      :ARG2 (i / inhibit-01
            :ARG1 (a2 / activity-06
                  :ARG0 (s / slash
                        :op1 (e / enzyme :name (n / name :op1 "ERK1"))
                        :op2 (e2 / enzyme :name (n2 / name :op1 "ERK2"))))))

# ::id pmid_2325_9591.122 ::date 2015-08-26T00:54:29 ::annotator SDL-AMR-09 ::preferred
# ::snt When dual inhibition with ZSTK474 and CI-1040 was administered, downregulation of both pAKT/S6 and ERK1/2 was noted, but otherwise no marked difference was evident relative to the single agent treatments (Figure <xref ref-type="fig" rid="F5">5</xref>).
# ::save-date Sun Jan 17, 2016 ::file pmid_2325_9591_122.txt
(c / contrast-01
      :ARG1 (n / note-02
            :ARG1 (d / downregulate-01
                  :ARG1 (a / and
                        :op1 (s / slash
                              :op1 (e / enzyme :name (n2 / name :op1 "AKT")
                                    :ARG3-of (p / phosphorylate-01))
                              :op2 (p2 / protein :name (n3 / name :op1 "S6")))
                        :op2 (s2 / slash
                              :op1 (e3 / enzyme :name (n4 / name :op1 "ERK1"))
                              :op2 (e4 / enzyme :name (n5 / name :op1 "ERK2")))))
            :condition (a2 / administer-01
                  :ARG1 (i / inhibit-01
                        :ARG0 (a3 / and
                              :op1 (s3 / small-molecule :name (n6 / name :op1 "ZSTK474"))
                              :op2 (s4 / small-molecule :name (n7 / name :op1 "CI-1040"))))))
      :ARG2 (e7 / evidence-01 :polarity -
            :ARG1 (d2 / differ-02
                  :ARG1-of (m / mark-01))
            :ARG1-of (r / relative-05
                  :ARG3 (t / treat-04
                        :ARG2 (o / or
                              :op1 s3
                              :op2 s4))))
      :ARG1-of (d3 / describe-01
            :ARG0 (f / figure :mod 5)))

# ::id pmid_2325_9591.123 ::date 2015-08-26T01:02:47 ::annotator SDL-AMR-09 ::preferred
# ::snt The results suggest specificity of the inhibitors for their targets and the existence of broad feedback activation.
# ::save-date Mon Aug 31, 2015 ::file pmid_2325_9591_123.txt
(s2 / suggest-01
      :ARG0 (t2 / thing
            :ARG2-of (r / result-01))
      :ARG1 (a / and
            :op1 (s / specific-02
                  :ARG1 (m / molecular-physical-entity
                        :ARG0-of (i / inhibit-01))
                  :ARG2 (m2 / molecular-physical-entity
                        :ARG1-of (t / target-01
                              :ARG0 m)))
            :op2 (a2 / activate-01
                  :mod (f / feedback)
                  :mod (b / broad))))

# ::id pmid_2325_9591.124 ::date 2015-08-26T01:07:04 ::annotator SDL-AMR-09 ::preferred
# ::snt <sec-title level="2">Alternative dosing of dual inhibition</sec-title>
# ::save-date Wed Aug 26, 2015 ::file pmid_2325_9591_124.txt
(d / dose-01
      :ARG1 (i / inhibit-01
            :mod (d2 / dual))
      :mod (a / alternative))

# ::id pmid_2325_9591.125 ::date 2015-08-26T01:08:08 ::annotator SDL-AMR-09 ::preferred
# ::snt Even though dual inhibition of PI3K and MEK was identified as an effective form of cancer therapy based on the <i>in vitro</i> models, administration of both drugs at doses inducing major downregulation of the target for long periods of time may be too toxic in a clinical setting.
# ::save-date Mon Aug 31, 2015 ::file pmid_2325_9591_125.txt
(h / have-concession-91
      :ARG1 (p2 / possible-01
            :ARG1 (t2 / toxic
                  :degree (t3 / too)
                  :domain (a3 / administer-01
                        :ARG1 (d3 / drug
                              :mod (b2 / both)
                              :ARG1-of (d4 / dose-01
                                    :ARG0-of (i4 / induce-01
                                          :ARG2 (d5 / downregulate-01
                                                :ARG1 (m3 / molecular-physical-entity
                                                      :ARG1-of (t4 / target-01))
                                                :time (p3 / period
                                                      :ARG1-of (l / long-03))
                                                :ARG1-of (m2 / major-02))))))
                  :condition (s / setting
                        :mod (c / clinical))))
      :ARG2 (i / identify-01
            :ARG1 (i2 / inhibit-01
                  :ARG1 (a2 / and
                        :op1 (e / enzyme :name (n3 / name :op1 "PI3K"))
                        :op2 (e2 / enzyme :name (n4 / name :op1 "MEK"))))
            :ARG2 (f / form
                  :topic (t / therapy
                        :mod (d2 / disease :wiki "Cancer" :name (n2 / name :op1 "cancer")))
                  :ARG0-of (e3 / effective-04))
            :ARG1-of (b / base-02
                  :ARG2 (m / model
                        :mod (i3 / in-vitro)))))

# ::id pmid_2325_9591.126 ::date 2015-08-26T01:49:39 ::annotator SDL-AMR-09 ::preferred
# ::snt We therefore set out to investigate concurrent administration of PI3K and MEK inhibitors to cell lines sensitive to dual inhibition with alternative dosing schedules.
# ::save-date Sat Jan 16, 2016 ::file pmid_2325_9591_126.txt
(s / set-out-07
      :ARG0 (w / we)
      :ARG1 (i2 / investigate-01
            :ARG0 w
            :ARG1 (a2 / administer-01
                  :ARG1 (a3 / and
                        :op1 (m / molecular-physical-entity
                              :ARG0-of (i / inhibit-01
                                    :ARG1 (p2 / protein-family :name (n2 / name :op1 "PI3K"))))
                        :op2 (m2 / molecular-physical-entity
                              :ARG0-of (i3 / inhibit-01
                                    :ARG1 (p / protein-family :name (n3 / name :op1 "MEK")))))
                  :ARG2 (c3 / cell-line
                        :ARG0-of (s2 / sensitive-03
                              :ARG1 (i4 / inhibit-01
                                    :ARG0 (s3 / schedule-01
                                          :ARG1 (d2 / dose-01)
                                          :ARG1-of (a4 / alternate-01))
                                    :mod (d / dual))))
                  :ARG1-of (c2 / concurrent-02)))
      :ARG1-of (c / cause-01))

# ::id pmid_2325_9591.127 ::date 2015-08-26T02:00:30 ::annotator SDL-AMR-09 ::preferred
# ::snt The MTS assays showed that for maximal reduction in the number of living cells in all the lines, dual inhibition needed to be administered for longer periods of time.
# ::save-date Sat Feb 13, 2016 ::file pmid_2325_9591_127.txt
(s / show-01
      :ARG0 (a / assay-01
            :instrument (s2 / small-molecule :name (n3 / name :op1 "MTS")))
      :ARG1 (n / need-01
            :ARG0 (r / reduce-01
                  :ARG1 (n2 / number
                        :quant-of (c / cell
                              :ARG0-of (l2 / live-01)
                              :part-of (c2 / cell-line
                                    :mod (a3 / all))))
                  :ARG2 (m3 / maximum))
            :ARG1 (a2 / administer-01
                  :ARG1 (i / inhibit-01
                        :mod (d / dual))
                  :duration (p / period
                        :ARG1-of (l / long-03
                              :degree (m2 / more))))))

# ::id pmid_2325_9591.128 ::date 2015-08-26T02:06:10 ::annotator SDL-AMR-09 ::preferred
# ::snt The therapy was significantly more effective when it was administered throughout the 72 h experiment as compared with 15 min, 4 h or 24 h periods (Figure <xref ref-type="fig" rid="F6">6</xref>).
# ::save-date Mon Aug 31, 2015 ::file pmid_2325_9591_128.txt
(e / effective-04
      :ARG0 (t / therapy)
      :ARG1-of (s / significant-02)
      :condition (a / administer-01
            :ARG1 t
            :time (e2 / experiment-01
                  :duration (t2 / temporal-quantity :quant 72
                        :unit (h / hour)
                        :compared-to (o / or
                              :op1 (p / period
                                    :consist-of (t3 / temporal-quantity :quant 15
                                          :unit (m2 / minute)))
                              :op2 (p2 / period
                                    :consist-of (t4 / temporal-quantity :quant 4
                                          :unit (h2 / hour)))
                              :op3 (p3 / period
                                    :consist-of (t5 / temporal-quantity :quant 24
                                          :unit (h3 / hour)))))))
      :degree (m / more)
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod 6)))

# ::id pmid_2325_9591.129 ::date 2015-08-26T02:12:31 ::annotator SDL-AMR-09 ::preferred
# ::snt Interestingly, maximal cytotoxicity was seen in the <i>ALK</i> translocated H3122 line even with short courses of ALK inhibition (15 min), while similar cytotoxicity was seen with 72 h inhibition of PI3K and MEK concurrently (Figure <xref ref-type="fig" rid="F6">6</xref>), even though both approaches induced major inhibition of phosphorylated AKT and ERK in Western blots after 6 h treatments (Figure <xref ref-type="fig" rid="F3">3A</xref>).
# ::save-date Sat Jan 16, 2016 ::file pmid_2325_9591_129.txt
(h2 / have-concession-91
      :ARG1 (c3 / contrast-01
            :ARG1 (s / see-01
                  :ARG1 (c4 / cytotoxic
                        :degree (m / maximal)
                        :condition (c2 / course-01
                              :ARG1-of (s2 / short-07)
                              :consist-of (i2 / inhibit-01
                                    :ARG1 e5)
                              :ARG1-of (m2 / mean-01
                                    :ARG2 (t3 / temporal-quantity :quant 15
                                          :unit (m3 / minute)))))
                  :ARG2-of (i / interest-01)
                  :location (c / cell-line :name (n4 / name :op1 "H3122")
                        :ARG1-of (t2 / translocate-01
                              :ARG0 (e5 / enzyme :name (n5 / name :op1 "ALK")))))
            :ARG2 (s3 / see-01
                  :ARG1 (c5 / cytotoxic
                        :ARG1-of (r2 / resemble-01
                              :ARG2 c4))
                  :concession (i3 / inhibit-01
                        :ARG1 (a / and
                              :op1 (e / enzyme :name (n6 / name :op1 "PI3K"))
                              :op2 (e2 / enzyme :name (n7 / name :op1 "MEK"))
                              :ARG1-of (c6 / concurrent-02))
                        :duration (t / temporal-quantity :quant 72
                              :unit (h / hour)))
                  :ARG1-of (d / describe-01
                        :ARG0 (f / figure :mod 6))))
      :ARG2 (i4 / induce-01
            :ARG0 (a2 / approach-02
                  :mod (b / both))
            :ARG2 (i5 / inhibit-01
                  :ARG1 (a3 / and
                        :op1 (e3 / enzyme :name (n8 / name :op1 "AKT")
                              :ARG3-of (p3 / phosphorylate-01))
                        :op2 (e4 / enzyme :name (n9 / name :op1 "ERK")
                              :ARG3-of p3))
                  :ARG1-of (m4 / major-02))
            :time (a4 / after
                  :op1 (t4 / treat-04
                        :duration (t5 / temporal-quantity :quant 6
                              :unit (h3 / hour))))
            :ARG1-of (d2 / describe-01
                  :ARG0 (f2 / figure :mod "3A"))
            :location (i6 / immunoblot-01)))

# ::id pmid_2325_9591.130 ::date 2015-08-26T03:28:52 ::annotator SDL-AMR-09 ::preferred
# ::snt Since the results showed that dual inhibition needed to be administered for longer periods of time for maximal cytotoxicity, we turned next to investigating whether both inhibitors are required throughout the period of exposure.
# ::save-date Mon Sep 14, 2015 ::file pmid_2325_9591_130.txt
(c / cause-01
      :ARG0 (s / show-01
            :ARG0 (t2 / thing
                  :ARG2-of (r / result-01))
            :ARG1 (n / need-01
                  :ARG0 (i / inhibit-01
                        :mod (d / dual))
                  :ARG1 (a / administer-01
                        :ARG1 i
                        :duration (p / period
                              :consist-of (t3 / time)
                              :ARG1-of (l / long-03
                                    :degree (m / more))))
                  :purpose (c2 / cytotoxic
                        :degree (m2 / maximal))))
      :ARG1 (t / turn-02
            :ARG1 (w / we)
            :ARG2 (i2 / investigate-01
                  :ARG0 w
                  :ARG1 (r2 / require-01 :mode interrogative
                        :ARG1 (m3 / molecular-physical-entity
                              :ARG0-of (i3 / inhibit-01)
                              :mod (b / both))
                        :time (p2 / period
                              :duration-of (e / expose-01))))
            :time (n2 / next)))

# ::id pmid_2325_9591.131 ::date 2015-08-26T03:37:33 ::annotator SDL-AMR-09 ::preferred
# ::snt The dual inhibition-sensitive cell lines were exposed to one inhibitor throughout the treatment period (72 h) while the other inhibitor was administered concurrently for 15 min, 4 h or 24 h at the beginning of the drug exposure.
# ::save-date Mon Aug 31, 2015 ::file pmid_2325_9591_131.txt
(c2 / contrast-01
      :ARG1 (e / expose-01
            :ARG1 (c / cell-line
                  :ARG0-of (s / sensitive-03
                        :ARG1 (i2 / inhibit-01
                              :mod (d / dual))))
            :ARG2 (m / molecular-physical-entity :quant 1
                  :ARG0-of (i / inhibit-01))
            :duration (t2 / treat-04
                  :ARG1-of (m2 / mean-01
                        :ARG2 (t3 / temporal-quantity :quant 72
                              :unit (h / hour)))))
      :ARG2 (a / administer-01
            :ARG1 (m3 / molecular-physical-entity
                  :ARG0-of i)
            :ARG1-of (c3 / concurrent-02)
            :duration (o / or
                  :op1 (t4 / temporal-quantity :quant 15
                        :unit (m4 / minute))
                  :op2 (t5 / temporal-quantity :quant 4
                        :unit (h2 / hour))
                  :op3 (t6 / temporal-quantity :quant 24
                        :unit (h3 / hour)))
            :time (b / begin-01
                  :ARG1 (e2 / expose-01
                        :ARG2 (d2 / drug)))))

# ::id pmid_2325_9591.132 ::date 2015-08-27T02:55:02 ::annotator SDL-AMR-09 ::preferred
# ::snt The results varied significantly between the cell lines tested.
# ::save-date Thu Aug 27, 2015 ::file pmid_2325_9591_132.txt
(v / vary-01
      :ARG1 (t / thing
            :ARG2-of (r / result-01))
      :ARG5 (c / cell-line
            :ARG1-of (t2 / test-01))
      :ARG1-of (s / significant-02))

# ::id pmid_2325_9591.133 ::date 2015-08-27T03:01:13 ::annotator SDL-AMR-09 ::preferred
# ::snt In the H1437 and MDA-MB231 lines concurrent inhibition of PI3K and MEK for 15 min with continued PI3K inhibition for 72 h achieved similar cytotoxicity to concurrent inhibition for 72 h (Figure <xref ref-type="fig" rid="F6">6</xref>).
# ::save-date Mon Sep 14, 2015 ::file pmid_2325_9591_133.txt
(a / achieve-01
      :ARG0 (a2 / and
            :op1 (i / inhibit-01
                  :ARG1 (a3 / and
                        :op1 (e / enzyme :name (n2 / name :op1 "PI3K"))
                        :op2 (e2 / enzyme :name (n3 / name :op1 "MEK")))
                  :ARG1-of (c / concurrent-02)
                  :duration (t / temporal-quantity :quant 15
                        :unit (m / minute))
                  :location (a4 / and
                        :op1 (c2 / cell-line :name (n4 / name :op1 "H1437"))
                        :op2 (c3 / cell-line :name (n5 / name :op1 "MDA-MB231"))))
            :op2 (i2 / inhibit-01
                  :ARG1 e
                  :duration (t2 / temporal-quantity :quant 72
                        :unit (h / hour))
                  :ARG1-of (c4 / continue-01)))
      :ARG1 (c5 / cytotoxic
            :ARG1-of (r / resemble-01
                  :ARG2 (i3 / inhibit-01
                        :ARG1-of c
                        :duration (t3 / temporal-quantity :quant 72
                              :unit (h2 / hour)))))
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod 6)))

# ::id pmid_2325_9591.134 ::date 2015-08-27T03:13:55 ::annotator SDL-AMR-09 ::preferred
# ::snt Conversely, when these lines were exposed to the MEK inhibitor throughout the treatment period, short concurrent exposures (15 min, 4 h or 24 h) to PI3K inhibitors did not induce any comparable cytotoxicity (Figure <xref ref-type="fig" rid="F6">6</xref>).
# ::save-date Sat Jan 16, 2016 ::file pmid_2325_9591_134.txt
(c / contrast-01
      :ARG2 (i2 / induce-01 :polarity -
            :ARG0 (e / expose-01
                  :ARG2 (m2 / molecular-physical-entity
                        :ARG0-of (i / inhibit-01
                              :ARG1 (p3 / protein-family :name (n2 / name :op1 "PI3K"))))
                  :ARG1-of (c2 / concurrent-02)
                  :ARG1-of (s / short-07)
                  :duration (o / or
                        :op1 (t2 / temporal-quantity :quant 15
                              :unit (m / minute))
                        :op2 (t3 / temporal-quantity :quant 4
                              :unit (h / hour))
                        :op3 (t4 / temporal-quantity :quant 24
                              :unit h)))
            :ARG2 (c3 / cytotoxic
                  :ARG1-of (c4 / comparable-03)
                  :mod (a / any)))
      :time (e3 / expose-01
            :ARG1 (c5 / cell-line
                  :mod (t5 / this))
            :ARG2 (m3 / molecular-physical-entity
                  :ARG0-of (i3 / inhibit-01
                        :ARG1 (p / protein-family :name (n3 / name :op1 "MEK"))))
            :duration (p2 / period
                  :duration-of (t7 / treat-04)))
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod 6)))

# ::id pmid_2325_9591.135 ::date 2015-08-27T03:35:24 ::annotator SDL-AMR-09 ::preferred
# ::snt On the other hand, the effects of dual inhibition with PI-103 occurred faster in the H1437 line than with ZSTK474, since shorter exposures to the drug (24 h) seemed to be sufficient for maximal cytotoxicity as compared with 72h of ZSTK474 (Figure <xref ref-type="fig" rid="F6">6</xref>).
# ::save-date Wed Jan 20, 2016 ::file pmid_2325_9591_135.txt
(c / contrast-01
      :ARG2 (a / affect-01
            :ARG0 (i / inhibit-01
                  :ARG0 (s / small-molecule :name (n / name :op1 "PI-103"))
                  :mod (d / dual))
            :location (c2 / cell-line :name (n2 / name :op1 "H1437"))
            :ARG1-of (f / fast-02
                  :degree (m / more)
                  :compared-to (i2 / inhibit-01
                        :ARG0 (s2 / small-molecule :name (n3 / name :op1 "ZSTK474")))))
      :ARG1-of (c3 / cause-01
            :ARG0 (s5 / seem-01
                  :ARG1 (s3 / suffice-01
                        :ARG0 (e / expose-01
                              :ARG2 s
                              :ARG1-of (s4 / short-07
                                    :degree (m2 / more))
                              :ARG1-of (m3 / mean-01
                                    :ARG2 (t / temporal-quantity :quant 24
                                          :unit (h / hour)))
                              :compared-to (e2 / expose-01
                                    :ARG2 s2
                                    :duration (t2 / temporal-quantity :quant 72
                                          :unit (h2 / hour))))
                        :ARG1 (c4 / cytotoxic
                              :mod (m4 / maximal)))))
      :ARG1-of (d2 / describe-01
            :ARG0 (f2 / figure :mod 6)))

# ::id pmid_2325_9591.136 ::date 2015-08-27T03:49:23 ::annotator SDL-AMR-09 ::preferred
# ::snt In the case of the H3122 and HCT116 lines, both the PI3K and MEK inhibitors needed to be administered throughout the treatment period for maximal cytotoxicity (Figure <xref ref-type="fig" rid="F6">6</xref>).
# ::save-date Sat Jan 16, 2016 ::file pmid_2325_9591_136.txt
(n2 / need-01
      :ARG0 (c / cytotoxicity
            :mod (m3 / maximal))
      :ARG1 (a2 / administer-01
            :ARG1 (a / and
                  :op1 (m / molecular-physical-entity
                        :ARG0-of (i / inhibit-01
                              :ARG1 (p3 / protein-family :name (n3 / name :op1 "PI3K"))))
                  :op2 (m2 / molecular-physical-entity
                        :ARG0-of (i2 / inhibit-01
                              :ARG1 (p / protein-family :name (n4 / name :op1 "MEK")))))
            :duration (p2 / period
                  :duration-of (t2 / treat-04)))
      :location (a3 / and
            :op1 (c2 / cell-line :name (n5 / name :op1 "H3122"))
            :op2 (c3 / cell-line :name (n6 / name :op1 "HCT116")))
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod 6)))

# ::id pmid_2325_9591.137 ::date 2015-08-27T03:57:54 ::annotator SDL-AMR-09 ::preferred
# ::snt We next investigated alternative dosing of the dual inhibition of cell signaling.
# ::save-date Thu Aug 27, 2015 ::file pmid_2325_9591_137.txt
(i / investigate-01
      :ARG0 (w / we)
      :ARG1 (d / dose-01
            :ARG1 (i2 / inhibit-01
                  :ARG1 (s / signal-07
                        :ARG0 (c / cell))
                  :mod (d2 / dual))
            :ARG1-of (a / alternate-01))
      :time (n / next))

# ::id pmid_2325_9591.138 ::date 2015-08-27T04:02:57 ::annotator SDL-AMR-09 ::preferred
# ::snt The dual inhibition-sensitive lines were exposed to the PI3K inhibitors and MEK inhibitor concurrently for 15 min, after which treatment was continued with a single inhibitor for the remainder of the 6 h period.
# ::save-date Sat Jan 16, 2016 ::file pmid_2325_9591_138.txt
(c3 / continue-01
      :ARG1 (t3 / treat-04
            :ARG2 (m4 / molecular-physical-entity
                  :ARG1-of (s2 / single-02)
                  :ARG0-of (i4 / inhibit-01)))
      :duration (p / period
            :ARG1-of (r / remain-01)
            :ARG1-of (m5 / mean-01
                  :ARG2 (t4 / temporal-quantity :quant 6
                        :unit (h / hour))))
      :time (a2 / after
            :op1 (e / expose-01
                  :ARG1 (c / cell-line
                        :ARG0-of (s / sensitive-03
                              :ARG1 (i2 / inhibit-01
                                    :mod (d / dual))))
                  :ARG2 (a / and
                        :op1 (m / molecular-physical-entity
                              :ARG0-of (i / inhibit-01
                                    :ARG1 (p2 / protein-family :name (n2 / name :op1 "PI3K"))))
                        :op2 (m2 / molecular-physical-entity
                              :ARG0-of (i3 / inhibit-01
                                    :ARG1 (p3 / protein-family :name (n3 / name :op1 "MEK")))))
                  :ARG1-of (c2 / concurrent-02)
                  :duration (t2 / temporal-quantity :quant 15
                        :unit (m3 / minute)))))

# ::id pmid_2325_9591.139 ::date 2015-08-27T04:39:59 ::annotator SDL-AMR-09 ::preferred
# ::snt pAKT downregulation was complete or nearly complete when the cells were treated for only 15 min and with PI3K inhibitors for 6 h (Figure <xref ref-type="fig" rid="F3">3B</xref>), while conversely, pERK1/2 recovered completely in 6 h when the cells were treated with the MEK inhibitor for 15 min (Figure <xref ref-type="fig" rid="F3">3B</xref>).
# ::save-date Sat Jan 16, 2016 ::file pmid_2325_9591_139.txt
(c4 / contrast-01
      :ARG1 (o / or
            :op1 (c / complete-02
                  :ARG1 (d / downregulate-01
                        :ARG1 (e / enzyme :name (n2 / name :op1 "AKT")
                              :ARG3-of (p2 / phosphorylate-01)))
                  :condition (a / and
                        :op1 (t2 / treat-04
                              :ARG1 (c3 / cell)
                              :duration (t3 / temporal-quantity :quant 15
                                    :unit (m / minute)
                                    :mod (o2 / only)))
                        :op2 (t4 / treat-04
                              :ARG1 c3
                              :ARG2 (m2 / molecular-physical-entity
                                    :ARG0-of (i / inhibit-01
                                          :ARG1 (p / protein-family :name (n4 / name :op1 "PI3K"))))
                              :duration (t5 / temporal-quantity :quant 6
                                    :unit (h / hour)))))
            :op2 (c2 / complete-02
                  :ARG1 d
                  :ARG1-of (n3 / near-01)
                  :condition a)
            :ARG1-of (d2 / describe-01
                  :ARG0 (f / figure :mod "3B")))
      :ARG2 (r / recover-01
            :ARG1 (s / slash
                  :op1 (e3 / enzyme :name (n5 / name :op1 "ERK1")
                        :ARG3-of (p3 / phosphorylate-01))
                  :op2 (e4 / enzyme :name (n6 / name :op1 "ERK2")
                        :ARG3-of p3))
            :ARG1-of (c5 / complete-02)
            :time (a2 / after
                  :op1 t5)
            :condition (t6 / treat-04
                  :ARG1 (c6 / cell)
                  :ARG2 (m3 / molecular-physical-entity
                        :ARG0-of (i2 / inhibit-01
                              :ARG1 (p4 / protein-family :name (n7 / name :op1 "MEK"))))
                  :duration t3)
            :ARG1-of (d3 / describe-01
                  :ARG0 (f2 / figure :mod "3B"))))

# ::id pmid_2325_9591.140 ::date 2015-08-27T04:52:47 ::annotator SDL-AMR-09 ::preferred
# ::snt Interestingly, we were able to see some recovery in the activity of the downstream targets of AKT when the PI3K inhibitors were administered for 15min despite the remaining pAKT downregulation.
# ::save-date Sun Jan 17, 2016 ::file pmid_2325_9591_140.txt
(c2 / capable-01
      :ARG1 (w / we)
      :ARG2 (s / see-01
            :ARG0 w
            :ARG1 (r / recover-02
                  :ARG1 (a / activity-06
                        :ARG0 (m3 / molecular-physical-entity
                              :ARG1-of (t2 / target-01
                                    :ARG0 (e / enzyme :name (n / name :op1 "AKT")))
                              :mod (d / downstream)))
                  :mod (s2 / some))
            :condition (a2 / administer-01
                  :ARG1 (m / molecular-physical-entity
                        :ARG0-of (i / inhibit-01
                              :ARG1 (p / protein-family :name (n2 / name :op1 "PI3K"))))
                  :duration (t3 / temporal-quantity :quant 15
                        :unit (m2 / minute))))
      :concession (d2 / downregulate-01
            :ARG1 (e3 / enzyme :name (n3 / name :op1 "AKT")
                  :ARG3-of (p2 / phosphorylate-01))
            :ARG1-of (r2 / remain-01))
      :ARG2-of (i2 / interest-01))

# ::id pmid_2325_9591.141 ::date 2015-08-27T04:59:57 ::annotator SDL-AMR-09 ::preferred
# ::snt The pS6 signal was able to recovery in the MDA-MB231 (with ZSTK474) and HCT116 (with both PI3K inhibitors) lines after short PI3K administration (Figure <xref ref-type="fig" rid="F3">3B</xref>).
# ::save-date Sun Jan 17, 2016 ::file pmid_2325_9591_141.txt
(a2 / and
      :op1 (c / capable-01
            :ARG1 (s / signal-07
                  :ARG0 (p3 / protein :name (n / name :op1 "S6")
                        :ARG3-of (p2 / phosphorylate-01)))
            :ARG2 (r / recover-01
                  :ARG1 s
                  :location (c2 / cell-line :name (n2 / name :op1 "MDA-MB231"))
                  :condition (t2 / treat-04
                        :ARG2 (s2 / small-molecule :name (n3 / name :op1 "ZSTK474")))))
      :op2 (c3 / capable-01
            :ARG1 s
            :ARG2 (r2 / recover-01
                  :location (c4 / cell-line :name (n4 / name :op1 "HCT116"))
                  :condition (t3 / treat-04
                        :ARG2 (m / molecular-physical-entity
                              :ARG0-of (i / inhibit-01
                                    :ARG1 (p / protein-family :name (n5 / name :op1 "PI3K")))
                              :mod (b / both)))))
      :time (a3 / after
            :op1 (a4 / administer-01
                  :ARG1 p
                  :ARG1-of (s3 / short-07)))
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod "3B")))

# ::id pmid_2325_9591.142 ::date 2015-08-27T05:08:03 ::annotator SDL-AMR-09 ::preferred
# ::snt Furthermore, p4E-BP1 recovery was noted in the H3122 (with ZSTK474), MDA-MB231 (with ZSTK474), and HCT116 (with both PI3K inhibitors) lines (Figure <xref ref-type="fig" rid="F3">3B</xref>).
# ::save-date Sun Jan 17, 2016 ::file pmid_2325_9591_142.txt
(a / and
      :op2 (n / note-02
            :ARG1 (a2 / and
                  :op1 (r / recover-01
                        :ARG1 (p2 / protein :name (n2 / name :op1 "4E-BP1")
                              :ARG3-of (p / phosphorylate-01))
                        :location (c / cell-line :name (n3 / name :op1 "H3122"))
                        :condition (t2 / treat-04
                              :ARG2 (s / small-molecule :name (n4 / name :op1 "ZSTK474"))))
                  :op2 (r2 / recover-01
                        :ARG1 p2
                        :location (c2 / cell-line :name (n5 / name :op1 "MDA-MB231"))
                        :condition t2)
                  :op3 (r3 / recover-01
                        :ARG1 p2
                        :location (c3 / cell-line :name (n6 / name :op1 "HCT116"))
                        :condition (t3 / treat-04
                              :ARG2 (m / molecular-physical-entity
                                    :ARG0-of (i / inhibit-01
                                          :ARG1 (p3 / protein-family :name (n7 / name :op1 "PI3K")))
                                    :mod (b / both)))))
            :ARG1-of (d / describe-01
                  :ARG0 (f / figure :mod "3B"))))

# ::id pmid_2325_9591.143 ::date 2015-08-27T05:15:29 ::annotator SDL-AMR-09 ::preferred
# ::snt Interestingly, MEK inhibitor treatment induced upregulation of p4E-BP1 in the MDA-MB231 line (Figure <xref ref-type="fig" rid="F3">3A</xref>), and marked downregulation p4E-BP1 was noted only with PI-103 (PI3K and mTOR inhibitor) in the alternative dosing experiments, but not with ZSTK474 (with a PI3K inhibitor alone) (Figure <xref ref-type="fig" rid="F5">5</xref>), suggesting mTOR-mediated activation of 4E-BP1 in response to MEK inhibition.
# ::save-date Sun Jan 17, 2016 ::file pmid_2325_9591_143.txt
(a / and
      :op1 (i2 / induce-01
            :ARG0 (t2 / treat-04
                  :ARG2 (m / molecular-physical-entity
                        :ARG0-of (i / inhibit-01
                              :ARG1 (e / enzyme :name (n2 / name :op1 "MEK")))))
            :ARG2 (u / upregulate-01
                  :ARG1 (p4 / protein :name (n3 / name :op1 "4E-BP1")
                        :ARG3-of (p2 / phosphorylate-01))
                  :location (c / cell-line :name (n4 / name :op1 "MDA-MB231")))
            :ARG2-of (i3 / interest-01)
            :ARG1-of (d / describe-01
                  :ARG0 (f / figure :mod "3A"))
            :location (e4 / experiment-01
                  :ARG2 (d3 / dose-01
                        :ARG1-of (a3 / alternate-01))))
      :op2 (c2 / contrast-01
            :ARG1 (n5 / note-02
                  :ARG1 (d2 / downregulate-01
                        :ARG1 p4
                        :ARG1-of (m2 / mark-01))
                  :condition (t3 / treat-04
                        :ARG2 (s / small-molecule :name (n6 / name :op1 "PI-103")
                              :ARG0-of (i4 / inhibit-01
                                    :ARG1 (a2 / and
                                          :op1 (p5 / protein-family :name (n7 / name :op1 "PI3K"))
                                          :op2 (p3 / protein :name (n8 / name :op1 "mTOR")))))
                        :mod (o / only))
                  :location e4)
            :ARG2 (n9 / note-02 :polarity -
                  :ARG1 d2
                  :condition (t4 / treat-04
                        :ARG2 (s2 / small-molecule :name (n10 / name :op1 "ZSTK474")
                              :ARG1-of (m3 / mean-01
                                    :ARG2 (m4 / molecular-physical-entity
                                          :ARG0-of (i5 / inhibit-01
                                                :ARG1 p5)
                                          :mod (a4 / alone))))))
            :ARG1-of (d4 / describe-01
                  :ARG0 (f2 / figure :mod 5)))
      :ARG0-of (s3 / suggest-01
            :ARG1 (a5 / activate-01
                  :ARG1 (p / protein :name (n11 / name :op1 "4E-BP1"))
                  :ARG1-of (m5 / mediate-01
                        :ARG0 p3)
                  :ARG2-of (r / respond-01
                        :ARG1 i))))

# ::id pmid_2325_9591.144 ::date 2015-08-27T05:48:36 ::annotator SDL-AMR-09 ::preferred
# ::snt TAE684, an ALK inhibitor, treatment was also included in the experiments conducted with the H3122 line, and this induced comparable pAKT, pERK1/2, and pS6 downregulation to that achieved with dual inhibition, whereas no change in p4E-BPI was noted (Figure <xref ref-type="fig" rid="F3">3B</xref>).
# ::save-date Sun Jan 17, 2016 ::file pmid_2325_9591_144.txt
(c4 / contrast-01
      :ARG1 (a / and
            :op1 (i2 / include-01
                  :ARG1 (t2 / treat-04
                        :ARG2 (s / small-molecule :name (n / name :op1 "TAE684")
                              :ARG0-of (i / inhibit-01
                                    :ARG1 (e6 / enzyme :name (n2 / name :op1 "ALK"))))
                        :mod (a4 / also))
                  :ARG2 (e / experiment-01
                        :ARG1 (c2 / cell-line :name (n3 / name :op1 "H3122"))
                        :ARG1-of (c / conduct-01)))
            :op2 (i3 / induce-01
                  :ARG0 i2
                  :ARG2 (d / downregulate-01
                        :ARG1 (a2 / and
                              :op1 (e2 / enzyme :name (n4 / name :op1 "AKT")
                                    :ARG3-of (p / phosphorylate-01))
                              :op2 (s2 / slash
                                    :op1 (e3 / enzyme :name (n5 / name :op1 "ERK1")
                                          :ARG3-of p)
                                    :op2 (e4 / enzyme :name (n6 / name :op1 "ERK2")
                                          :ARG3-of p))
                              :op3 (p3 / protein :name (n7 / name :op1 "S6")
                                    :ARG3-of p))
                        :ARG1-of (c3 / comparable-03
                              :ARG2 (d2 / downregulate-01
                                    :ARG1 a2
                                    :ARG1-of (a3 / achieve-01
                                          :ARG0 (i4 / inhibit-01
                                                :mod (d3 / dual))))))))
      :ARG2 (n8 / note-02 :polarity -
            :ARG1 (c5 / change-01
                  :ARG1 (p2 / protein :name (n9 / name :op1 "4E-BPI")
                        :ARG3-of p)))
      :ARG1-of (d4 / describe-01
            :ARG0 (f / figure :mod "3B")))

# ::id pmid_2325_9591.145 ::date 2015-08-27T09:02:39 ::annotator SDL-AMR-09 ::preferred
# ::snt Some recovery of pAKT and pS6 was seen after a short treatment with TAE684 (Figure <xref ref-type="fig" rid="F3">3B</xref>).
# ::save-date Sun Jan 17, 2016 ::file pmid_2325_9591_145.txt
(s / see-01
      :ARG1 (r / recover-02
            :ARG1 (a / and
                  :op1 (e / enzyme :name (n / name :op1 "AKT")
                        :ARG3-of (p / phosphorylate-01))
                  :op2 (p2 / protein :name (n2 / name :op1 "S6")
                        :ARG3-of p))
            :degree (s4 / some))
      :time (a2 / after
            :op1 (t / treat-04
                  :ARG2 (s3 / small-molecule :name (n3 / name :op1 "TAE684"))
                  :ARG1-of (s2 / short-07)))
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod "3B")))

# ::id pmid_2325_9591.146 ::date 2015-08-27T09:21:34 ::annotator SDL-AMR-09 ::preferred
# ::snt We went on further to analyze whether the alternative dosing could also result in apoptosis in the H3122 cell line, the only line identified as inducing apoptosis in response to dual inhibition.
# ::save-date Mon Aug 31, 2015 ::file pmid_2325_9591_146.txt
(g / go-06
      :ARG0 (w / we)
      :ARG1 (a / analyze-01
            :ARG0 w
            :ARG1 (p2 / possible-01 :mode interrogative
                  :ARG1 (r / result-01
                        :ARG1 (d / dose-01
                              :ARG1-of (a2 / alternate-01))
                        :ARG2 (a3 / apoptosis)
                        :location (c / cell-line :name (n / name :op1 "H3122")
                              :ARG1-of (i / identify-01
                                    :ARG2 (i2 / induce-01
                                          :ARG0 c
                                          :ARG2 a3
                                          :ARG2-of (r2 / respond-01
                                                :ARG1 (i3 / inhibit-01
                                                      :mod (d2 / dual)))))
                              :mod (o / only))
                        :mod (a4 / also))))
      :ARG2 (f / further))

# ::id pmid_2325_9591.147 ::date 2015-08-27T23:28:08 ::annotator SDL-AMR-09 ::preferred
# ::snt When the cells was treated for 15 min with dual inhibition and treatment with either the PI3K inhibitors or the MEK inhibitor was continued for 48 h, marked PARP cleavage was seen in all the treatments (Figure <xref ref-type="fig" rid="F4">4B</xref>).
# ::save-date Sat Jan 16, 2016 ::file pmid_2325_9591_147.txt
(s / see-01
      :ARG1 (c / cleave-01
            :ARG1 (p2 / protein :name (n2 / name :op1 "PARP"))
            :ARG1-of (m / mark-01)
            :location (t3 / treat-04
                  :mod (a / all)))
      :condition (a2 / and
            :op1 (t2 / treat-04
                  :ARG1 (c2 / cell)
                  :ARG2 (i2 / inhibit-01
                        :mod (d / dual))
                  :duration (t4 / temporal-quantity :quant 15
                        :unit (m2 / minute)))
            :op2 (c3 / continue-01
                  :ARG1 (t5 / treat-04
                        :ARG2 (o / or
                              :op1 (m3 / molecular-physical-entity
                                    :ARG0-of (i3 / inhibit-01
                                          :ARG1 (p / protein-family :name (n3 / name :op1 "PI3K"))))
                              :op2 (m4 / molecular-physical-entity
                                    :ARG0-of (i4 / inhibit-01
                                          :ARG1 (p3 / protein-family :name (n4 / name :op1 "MEK"))))))
                  :duration (t6 / temporal-quantity :quant 48
                        :unit (h / hour))))
      :ARG1-of (d2 / describe-01
            :ARG0 (f / figure :mod "4B")))

# ::id pmid_2325_9591.148 ::date 2015-08-27T23:45:35 ::annotator SDL-AMR-09 ::preferred
# ::snt Furthermore, 15 min treatment with an ALK inhibitor resulted in marked PARP cleavage (Figure <xref ref-type="fig" rid="F4">4B</xref>).
# ::save-date Fri Aug 28, 2015 ::file pmid_2325_9591_148.txt
(a / and
      :op2 (r / result-01
            :ARG1 (t2 / treat-04
                  :ARG2 (m / molecular-physical-entity
                        :ARG0-of (i / inhibit-01
                              :ARG1 (e / enzyme :name (n / name :op1 "ALK"))))
                  :duration (t3 / temporal-quantity :quant 15
                        :unit (m2 / minute)))
            :ARG2 (c / cleave-01
                  :ARG1 (p / protein :name (n2 / name :op1 "PARP"))
                  :ARG1-of (m3 / mark-01))
            :ARG1-of (d / describe-01
                  :ARG0 (f / figure :mod "4B"))))

# ::id pmid_2325_9591.149 ::date 2015-08-27T23:50:24 ::annotator SDL-AMR-09 ::preferred
# ::snt Cleaved PARP results were further verified with western blot analysis for cleaved caspase-3, another marker for apoptosis.
# ::save-date Sun Dec 13, 2015 ::file pmid_2325_9591_149.txt
(v / verify-01
      :ARG1 (r / result-01
            :ARG1 (p / protein :name (n2 / name :op1 "PARP")
                  :ARG1-of (c / cleave-01)))
      :mod (f / further)
      :purpose (f2 / find-01
            :ARG1 (p2 / protein :name (n3 / name :op1 "caspase-3")
                  :ARG1-of (c2 / cleave-01)
                  :ARG1-of (m2 / mean-01
                        :ARG2 (t / thing
                              :ARG0-of (m / mark-01
                                    :ARG1 (a2 / apoptosis))
                              :mod (a3 / another)))))
      :instrument (a / analyze-01
            :manner (i / immunoblot-01)))

# ::id pmid_2325_9591.150 ::date 2015-08-27T23:56:19 ::annotator SDL-AMR-09 ::preferred
# ::snt Cleaved caspase-3 was detected with concurrent PI3K and MEK, or ALK inhibition while no signal was seen in PI3K or MEK inhibitor treatments.
# ::save-date Sat Jan 16, 2016 ::file pmid_2325_9591_150.txt
(c2 / contrast-01
      :ARG1 (d / detect-01
            :ARG1 (p2 / protein :name (n2 / name :op1 "caspase-3")
                  :ARG1-of (c / cleave-01))
            :condition (t2 / treat-04
                  :ARG2 (o / or
                        :op1 (a / and
                              :op1 (m / molecular-physical-entity
                                    :ARG0-of (i / inhibit-01
                                          :ARG1 (p3 / protein-family :name (n3 / name :op1 "PI3K"))))
                              :op2 (m2 / molecular-physical-entity
                                    :ARG0-of (i2 / inhibit-01
                                          :ARG1 (p / protein-family :name (n4 / name :op1 "MEK")))))
                        :op2 (m3 / molecular-physical-entity
                              :ARG0-of (i3 / inhibit-01
                                    :ARG1 (e3 / enzyme :name (n5 / name :op1 "ALK")))))
                  :ARG1-of (c3 / concurrent-02)))
      :ARG2 (s / see-01 :polarity -
            :ARG1 (s2 / signal-07)
            :condition (t3 / treat-04
                  :ARG2 (o2 / or
                        :op1 m
                        :op2 m2))))

# ::id pmid_2325_9591.151 ::date 2015-08-28T00:08:26 ::annotator SDL-AMR-09 ::preferred
# ::snt Conversely to cleaved PARP, the cleaved caspase-3 signal was much lower in alternative dosing schedules compared to continuous, concurrent PI3K and MEK inhibition (Figure <xref ref-type="fig" rid="F4">4C</xref>).
# ::save-date Mon Aug 31, 2015 ::file pmid_2325_9591_151.txt
(c / contrast-01
      :ARG1 (l2 / low-04
            :ARG1 (s / signal-07
                  :ARG0 (p3 / protein :name (n3 / name :op1 "caspase-3")
                        :ARG1-of (c3 / cleave-01)))
            :degree (m2 / more
                  :mod (m3 / much))
            :location (s2 / schedule-01
                  :mod (d / dose-01
                        :ARG1-of (a / alternate-01)))
            :compared-to (i / inhibit-01
                  :ARG1 (a2 / and
                        :op1 (e / enzyme :name (n4 / name :op1 "PI3K"))
                        :op2 (e2 / enzyme :name (n5 / name :op1 "MEK")))
                  :ARG1-of (c4 / continue-01)
                  :ARG1-of (c5 / concurrent-02)))
      :ARG2 (p2 / protein :name (n2 / name :op1 "PARP")
            :ARG1-of (c2 / cleave-01))
      :ARG1-of (d2 / describe-01
            :ARG0 (f / figure :mod "4C")))

# ::id pmid_2337_4602.1 ::date 2015-08-04T00:48:12 ::annotator SDL-AMR-09 ::preferred
# ::snt Biomarkers of benefit from cetuximab-based therapy in metastatic colorectal cancer: interaction of EGFR ligand expression with RAS/RAF, PIK3CA genotypes (PMID:23374602)
# ::save-date Sun Jan 17, 2016 ::file pmid_2337_4602_1.txt
(b4 / biomarker
      :ARG0-of (b / benefit-01)
      :topic (t / therapy
            :ARG1-of (b3 / base-02
                  :ARG2 (s / small-molecule :name (n / name :op1 "cetuximab"))))
      :ARG1-of (m2 / mean-01
            :ARG2 (i / interact-01
                  :ARG0 (e2 / express-03
                        :ARG2 (l / ligand :name (n2 / name :op1 "EGFR")))
                  :ARG1 (a / and
                        :op1 (g2 / genotype
                              :mod (p2 / pathway :name (n4 / name :op1 "RAS/RAF")))
                        :op2 (g4 / genotype
                              :mod (g / gene :name (n3 / name :op1 "PIK3CA"))))))
      :ARG1-of (d / describe-01
            :ARG0 (p / publication-91
                  :ARG8 "PMID23374602"))
      :location (d2 / disease :wiki "Colorectal_cancer" :name (n5 / name :op1 "colorectal" :op2 "cancer")
            :ARG1-of (m / metastasize-101)))

# ::id pmid_2337_4602.8 ::date 2015-08-04T01:14:14 ::annotator SDL-AMR-09 ::preferred
# ::snt <sec-title level="1" sec-area="abstract">Results</sec-title>
# ::save-date Tue Aug 4, 2015 ::file pmid_2337_4602_8.txt
(t / thing
      :ARG2-of (r / result-01))

# ::id pmid_2337_4602.9 ::date 2015-08-04T01:15:22 ::annotator SDL-AMR-09 ::preferred
# ::snt Only PIK3CA mutations occasionally coexisted with other gene mutations.
# ::save-date Mon Aug 10, 2015 ::file pmid_2337_4602_9.txt
(c / coexist-01
      :ARG1 (m / mutate-01
            :ARG1 (g / gene :name (n / name :op1 "PIK3CA"))
            :mod (o / only))
      :ARG2 (m2 / mutate-01
            :ARG2 (g2 / gene
                  :mod (o3 / other)))
      :frequency (o2 / occasional))

# ::id pmid_2337_4602.10 ::date 2015-08-04T01:17:18 ::annotator SDL-AMR-09 ::preferred
# ::snt In univariate analysis, prognostic significance for survival ( from metastases until death) was seen for BRAF mutations (Hazard Ratio HR 8.1, 95% CI 3.4-19), codon 12-only KRAS mutations (HR 1.62, 95% CI 1.1-2.4), high AREG mRNA expression only in KRAS wild type CRC (HR 0.47, 95% CI 0.3-0.7) and high EREG mRNA expression irrespective of KRAS mutation status (HR 0.45, 95% CI 0.28-0.7).
# ::save-date Sat Jan 16, 2016 ::file pmid_2337_4602_10.txt
(s / see-01
      :ARG1 (s2 / signify-01
            :ARG0 (a / and
                  :op1 (m2 / mutate-01
                        :ARG1 (e5 / enzyme :name (n / name :op1 "BRAF"))
                        :ARG1-of (m5 / mean-01
                              :ARG2 (a2 / and
                                    :op1 (r4 / ratio-of :quant 8.1
                                          :op1 (h2 / hazard))
                                    :op2 (i / interval
                                          :value (b / between :op1 3.4 :op2 19)
                                          :quant (p / percentage-entity :value 95)
                                          :mod (c2 / confidence)))))
                  :op2 (m3 / mutate-01
                        :ARG1 (c / codon :mod 12
                              :mod (o / only)
                              :part-of (e6 / enzyme :name (n3 / name :op1 "KRAS")))
                        :ARG1-of (m6 / mean-01
                              :ARG2 (a3 / and
                                    :op1 (r5 / ratio-of :quant 1.62
                                          :op1 h2)
                                    :op2 (i2 / interval
                                          :value (b2 / between :op1 1.1 :op2 2.4)
                                          :quant p
                                          :mod c2))))
                  :op3 (e / express-03
                        :ARG2 (n10 / nucleic-acid :name (n4 / name :op1 "mRNA")
                              :ARG0-of (e2 / encode-01
                                    :ARG1 (p3 / protein :name (n5 / name :op1 "AREG"))))
                        :ARG3 (d / disease :name (n6 / name :op1 "CRC")
                              :mod o
                              :mod (e7 / enzyme :name (n7 / name :op1 "KRAS")
                                    :mod (w / wild-type)))
                        :ARG1-of (h / high-02)
                        :ARG1-of (m7 / mean-01
                              :ARG2 (a4 / and
                                    :op1 (r6 / ratio-of :quant 0.47
                                          :op1 h2)
                                    :op2 (i3 / interval
                                          :value (b3 / between :op1 0.3 :op2 0.7)
                                          :quant p
                                          :mod c2))))
                  :op4 (e3 / express-03
                        :ARG2 (n11 / nucleic-acid :name (n8 / name :op1 "mRNA")
                              :ARG0-of (e4 / encode-01
                                    :ARG1 (p4 / protein :name (n9 / name :op1 "EREG"))))
                        :ARG1-of (m8 / mean-01
                              :ARG2 (a5 / and
                                    :op1 (r7 / ratio-of :quant 0.45
                                          :op1 h2)
                                    :op2 (i4 / interval
                                          :value (b4 / between :op1 0.28 :op2 0.7)
                                          :quant p
                                          :mod c2)))
                        :ARG1-of h
                        :ARG1-of (r / regardless-91
                              :ARG2 (s4 / status
                                    :mod (m4 / mutate-01
                                          :ARG2 e6)))))
            :ARG1 (s3 / survive-01
                  :time (a6 / after
                        :op1 (m / metastasize-101))
                  :time (u2 / until
                        :op1 (d2 / die-01)))
            :mod (p2 / prognostic))
      :time (a7 / analyze-01
            :mod (u / univariate)))

# ::id pmid_2337_4602.11 ::date 2015-08-04T01:53:43 ::annotator SDL-AMR-09 ::preferred
# ::snt EREG tumoural mRNA expression was significantly associated with a 2.26-fold increased likelihood of objective response to cetuximab therapy (RECIST 1.1).
# ::save-date Wed Aug 5, 2015 ::file pmid_2337_4602_11.txt
(a / associate-01
      :ARG1 (e / express-03
            :ARG2 (n5 / nucleic-acid :name (n / name :op1 "mRNA")
                  :ARG0-of (e2 / encode-01
                        :ARG1 (p / protein :name (n2 / name :op1 "EREG"))))
            :ARG0-of (c / cause-01
                  :ARG1 (t / tumor)))
      :ARG2 (l / likely-01
            :ARG1 (t2 / thing
                  :ARG2-of (r2 / respond-01
                        :ARG1 (t3 / therapy
                              :mod (s / small-molecule :name (n3 / name :op1 "cetuximab"))))
                  :mod (o / objective))
            :ARG1-of (i / increase-01
                  :ARG2 (p2 / product-of :op1 2.26))
            :ARG1-of (m / mean-01
                  :ARG2 (t4 / thing :value 1.1 :name (n4 / name :op1 "RECIST"))))
      :ARG1-of (s2 / significant-02))

# ::id pmid_2337_4602.12 ::date 2015-08-04T02:07:44 ::annotator SDL-AMR-09 ::preferred
# ::snt In multivariate analysis, favourable predictive factors were high AREG mRNA in KRAS wild type tumours, high EREG mRNA, low Ephrin A2 receptor mRNA.
# ::save-date Mon Aug 10, 2015 ::file pmid_2337_4602_12.txt
(a / and
      :op1 (n8 / nucleic-acid :name (n / name :op1 "mRNA")
            :ARG0-of (e / encode-01
                  :ARG1 (p / protein :name (n2 / name :op1 "AREG")))
            :ARG1-of (h / high-02)
            :location (t / tumor
                  :mod (g / gene :name (n3 / name :op1 "KRAS")
                        :mod (w / wild-type))))
      :op2 (n9 / nucleic-acid :name (n4 / name :op1 "mRNA")
            :ARG0-of (e3 / encode-01
                  :ARG1 (p2 / protein :name (n5 / name :op1 "EREG")))
            :ARG1-of h)
      :op3 (n10 / nucleic-acid :name (n6 / name :op1 "mRNA")
            :ARG0-of (e4 / encode-01
                  :ARG1 (p3 / protein :name (n7 / name :op1 "Ephrin" :op2 "A2" :op3 "receptor")))
            :ARG1-of (l / low-04))
      :domain (f / factor
            :ARG0-of (p4 / predict-01)
            :ARG0-of (f2 / favor-01))
      :time (a2 / analyze-01
            :mod (m / multivariate)))

# ::id pmid_2337_4602.13 ::date 2015-08-04T02:21:44 ::annotator SDL-AMR-09 ::preferred
# ::snt Cetuximab-treated patients with AREG-low KRAS wild type CRC fared very poorly, their survival being similar to KRAS mutant CRC.
# ::save-date Thu Dec 10, 2015 ::file pmid_2337_4602_13.txt
(f / fare-01
      :ARG0 (p / person
            :ARG0-of (h / have-rel-role-91
                  :ARG2 (p2 / patient))
            :ARG1-of (t / treat-03
                  :ARG3 (s / small-molecule :name (n / name :op1 "cetuximab")))
            :ARG0-of (h2 / have-03
                  :ARG1 (d / disease :name (n2 / name :op1 "CRC")
                        :mod (g / gene :name (n3 / name :op1 "KRAS")
                              :mod (w / wild-type))
                        :ARG1-of (l / low-04
                              :ARG2 (p3 / protein :name (n4 / name :op1 "AREG"))))))
      :manner (p4 / poor
            :degree (v / very))
      :ARG1-of (c / cause-01
            :ARG0 (r / resemble-01
                  :ARG1 (s2 / survive-01
                        :ARG0 p)
                  :ARG2 (s3 / survive-01
                        :ARG1 (d2 / disease :name (n5 / name :op1 "CRC")
                              :mod (g2 / gene :name (n6 / name :op1 "KRAS")
                                    :ARG2-of (m / mutate-01)))))))

# ::id pmid_2337_4602.14 ::date 2015-08-04T02:30:20 ::annotator SDL-AMR-09 ::preferred
# ::snt Patients with KRAS codon 13 or other non-codon 12 mutations had a median survival (30 months, 95% CI 20–35) similar to that of patients with KRAS wild-type (median survival 29 months, 95% CI 25–35), in contrast to patients with KRAS codon 12 mutations who fared worse (median survival 19 months, 95% CI 15–26).
# ::save-date Sun Jan 3, 2016 ::file pmid_2337_4602_14.txt
(h3 / have-03
      :ARG0 (p2 / person
            :ARG0-of (h / have-rel-role-91
                  :ARG2 (p3 / patient))
            :ARG0-of (h2 / have-03
                  :ARG1 (o / or
                        :op1 (m / mutate-01
                              :ARG1 (c2 / codon :mod 13
                                    :part-of (g / gene :name (n3 / name :op1 "KRAS"))))
                        :op2 (m2 / mutate-01
                              :ARG1 (c4 / codon :mod 12 :polarity -
                                    :part-of g)
                              :mod (o2 / other)))))
      :ARG1 (s / survive-01
            :ARG0 p2
            :mod (m3 / median)
            :ARG1-of (r / resemble-01
                  :ARG2 (s2 / survive-01
                        :ARG0 (p4 / person
                              :ARG0-of h
                              :ARG0-of (h4 / have-03
                                    :ARG1 (g2 / gene :name (n4 / name :op1 "KRAS")
                                          :mod (w / wild-type))))
                        :ARG1-of (m6 / mean-01
                              :ARG2 (a2 / and
                                    :op1 (s3 / survive-01
                                          :duration (t2 / temporal-quantity :quant 29
                                                :unit m5)
                                          :mod m3)
                                    :op2 (i / interval
                                          :value (b3 / between
                                                :op1 (t6 / temporal-quantity :quant 25
                                                      :unit m5)
                                                :op2 t5)
                                          :quant p
                                          :mod (c3 / confidence)))))))
      :ARG1-of (m4 / mean-01
            :ARG2 (a / and
                  :op1 (t / temporal-quantity :quant 30
                        :unit (m5 / month))
                  :op2 (i2 / interval
                        :value (b2 / between
                              :op1 (t4 / temporal-quantity :quant 20
                                    :unit m5)
                              :op2 (t5 / temporal-quantity :quant 35
                                    :unit m5))
                        :quant (p / percentage-entity :value 95)
                        :mod c3)))
      :ARG1-of (c / contrast-01
            :ARG2 (p5 / person
                  :ARG0-of h
                  :ARG0-of (h5 / have-03
                        :ARG1 (m8 / mutate-01
                              :ARG1 (c5 / codon :mod 12
                                    :part-of g)))
                  :ARG0-of (f / fare-01
                        :ARG1-of (b / bad-07
                              :degree (m9 / more)
                              :ARG1-of (m10 / mean-01
                                    :ARG2 (a3 / and
                                          :op1 (s4 / survive-01
                                                :duration (t3 / temporal-quantity :quant 19
                                                      :unit m5)
                                                :mod m3)
                                          :op2 (i3 / interval
                                                :value (b4 / between
                                                      :op1 (t7 / temporal-quantity :quant 15
                                                            :unit m5)
                                                      :op2 (t8 / temporal-quantity :quant 26
                                                            :unit m5))
                                                :quant p
                                                :mod c3))))))))

# ::id pmid_2337_4602.81 ::date 2015-08-04T02:59:40 ::annotator SDL-AMR-09 ::preferred
# ::snt <sec-title level="1">Results</sec-title>
# ::save-date Tue Aug 4, 2015 ::file pmid_2337_4602_81.txt
(t / thing
      :ARG2-of (r / result-01))

# ::id pmid_2337_4602.82 ::date 2015-08-04T04:52:38 ::annotator SDL-AMR-09 ::preferred
# ::snt <sec-title level="2">Patient and tumour demographics</sec-title>
# ::save-date Thu Dec 10, 2015 ::file pmid_2337_4602_82.txt
(a / and
      :op1 (d / demographic
            :mod (p / person
                  :ARG0-of (h / have-rel-role-91
                        :ARG2 (p2 / patient))))
      :op2 (d2 / demographic
            :mod (t / tumor)))

# ::id pmid_2337_4602.83 ::date 2015-08-04T04:53:58 ::annotator SDL-AMR-09 ::preferred
# ::snt A total of 226 patients of a median age of 62.6 years (range 26–85) underwent excisional or incisional biopsy of colorectal adenocarcinoma, of whom 83 (36.8%) were diagnosed with localised (stage I-III) colon cancer and 137 (60.6%) with metastatic disease (Table  <xref ref-type="table" rid="T1">1</xref>).
# ::save-date Thu Dec 10, 2015 ::file pmid_2337_4602_83.txt
(u / undergo-28
      :ARG1 (p3 / person
            :ARG0-of (h / have-rel-role-91
                  :ARG2 (p4 / patient))
            :ARG1-of (t / total-01
                  :ARG2 226)
            :ARG1-of (a / age-01
                  :ARG2 (t2 / temporal-quantity :quant 62.6
                        :unit (y / year))
                  :mod (m / median)
                  :ARG1-of (r / range-01
                        :ARG3 (t3 / temporal-quantity :quant 26
                              :unit y)
                        :ARG4 (t4 / temporal-quantity :quant 85
                              :unit y)))
            :ARG2-of (i2 / include-91
                  :ARG1 (a3 / and
                        :op1 (p5 / person :quant 83
                              :ARG0-of h
                              :ARG1-of (m2 / mean-01
                                    :ARG2 (p / percentage-entity :value 36.8))
                              :ARG1-of (d2 / diagnose-01
                                    :ARG2 (d5 / disease :wiki "Cancer" :name (n / name :op1 "cancer")
                                          :ARG1-of (l / local-02
                                                :ARG2 (c3 / colon))
                                          :ARG1-of (r2 / range-01
                                                :ARG3 (s / stage
                                                      :ord (o / ordinal-entity :value 1))
                                                :ARG4 (s2 / stage
                                                      :ord (o3 / ordinal-entity :value 3))))))
                        :op2 (p6 / person :quant 137
                              :ARG0-of h
                              :ARG1-of (m3 / mean-01
                                    :ARG2 (p2 / percentage-entity :value 60.6))
                              :ARG1-of (d3 / diagnose-01
                                    :ARG2 (d4 / disease
                                          :ARG1-of (m4 / metastasize-101)))))))
      :ARG2 (o2 / or
            :op1 (b / biopsy-101
                  :ARG1 (m5 / medical-condition :name (n2 / name :op1 "adenocarcinoma")
                        :mod (c / colorectal))
                  :ARG0-of (e / excise-01))
            :op2 (b2 / biopsy-101
                  :ARG1 (a2 / adenocarcinoma)
                  :ARG0-of (i / incise-01)))
      :ARG1-of (d / describe-01
            :ARG0 (t5 / table :mod 1)))

# ::id pmid_2337_4602.84 ::date 2015-08-04T05:10:55 ::annotator SDL-AMR-09 ::preferred
# ::snt The primary tumour was located in the left colon (distal transverse to rectum) in 165 (73.0%) of cases and in the right colon (caecum to proximal transverse) in 60 (26.6%).
# ::save-date Sat Jan 30, 2016 ::file pmid_2337_4602_84.txt
(a / and
      :op1 (l / locate-02
            :ARG1 (t / tumor
                  :mod (p3 / primary))
            :location (c / colon
                  :ARG1-of (l2 / left-20)
                  :ARG1-of (m / mean-01
                        :ARG2 (b / between
                              :op1 (t2 / transverse
                                    :mod (d / distal))
                              :op2 (r / rectum))))
            :location (c2 / case-04 :quant 165
                  :ARG1-of (m3 / mean-01
                        :ARG2 (p / percentage-entity :value 73.0))))
      :op2 (l3 / locate-02
            :ARG1 t
            :location (c3 / colon
                  :ARG1-of (m2 / mean-01
                        :ARG2 (b2 / between
                              :op1 (c4 / caecum)
                              :op2 (t3 / transverse
                                    :mod (p4 / proximal))))
                  :ARG1-of (r2 / right-04))
            :location (c5 / case-04 :quant 60
                  :ARG1-of (m4 / mean-01
                        :ARG2 (p2 / percentage-entity :value 26.6)))))

# ::id pmid_2337_4602.85 ::date 2015-08-04T05:20:07 ::annotator SDL-AMR-09 ::preferred
# ::snt Rectal tumours accounted for 71 cases (31%).
# ::save-date Sat Jan 30, 2016 ::file pmid_2337_4602_85.txt
(a / account-01
      :ARG0 (t / tumor
            :mod (r / rectum))
      :ARG1 (c / case-04 :quant 71
            :ARG1-of (m / mean-01
                  :ARG2 (p / percentage-entity :value 31))))

# ::id pmid_2337_4602.86 ::date 2015-08-04T05:22:11 ::annotator SDL-AMR-09 ::preferred
# ::snt From May 2004 until December 2008, cetuximab had been administered as an intravenous infusion according to standard regimens (loading dose 400 mg/m2 followed by weekly 250 mg/m2) as monotherapy (42, 13.4%) or with regimes based on irinotecan (153, 48.7%), oxaliplatin (84, 26.7%) or both agents (29, 9.2%).
# ::save-date Sat Jan 30, 2016 ::file pmid_2337_4602_86.txt
(o / or
      :op1 (a / administer-01
            :ARG1 (s / small-molecule :name (n / name :op1 "cetuximab"))
            :ARG2 (c3 / case-04 :quant 42
                  :ARG1-of (m4 / mean-01
                        :ARG2 (p / percentage-entity :value 13.4)))
            :ARG1-of (i / infuse-01
                  :mod (i2 / intravenous))
            :ARG1-of (a2 / accord-02
                  :ARG2 (r / regimen
                        :ARG1-of (s2 / standard-02)
                        :ARG1-of (m / mean-01
                              :ARG2 (d3 / dose-01
                                    :ARG2-of (l / load-01)
                                    :quant (c / concentration-quantity :quant 400
                                          :unit (m2 / milligram-per-square-meter))
                                    :ARG2-of (f / follow-01
                                          :ARG1 (d4 / dose-01
                                                :frequency (w / week)
                                                :quant (c2 / concentration-quantity :quant 250
                                                      :unit m2)))))))
            :manner (m3 / monotherapy))
      :op2 (a3 / administer-01
            :ARG1 s
            :ARG2 (c4 / case-04 :quant 153
                  :ARG1-of (m5 / mean-01
                        :ARG2 (p2 / percentage-entity :value 48.7)))
            :ARG1-of i
            :prep-with (r2 / regimen
                  :ARG1-of (b / base-02
                        :ARG2 (s3 / small-molecule :name (n2 / name :op1 "irinotecan"))))
            :ARG1-of a2)
      :op3 (a4 / administer-01
            :ARG1 s
            :ARG2 (c5 / case-04 :quant 84
                  :ARG1-of (m6 / mean-01
                        :ARG2 (p3 / percentage-entity :value 26.7)))
            :ARG1-of i
            :prep-with (r3 / regimen
                  :ARG1-of (b2 / base-02
                        :ARG2 (s4 / small-molecule :name (n3 / name :op1 "oxaliplatin"))))
            :ARG1-of a2)
      :op4 (a5 / administer-01
            :ARG1 s
            :ARG2 (c6 / case-04 :quant 29
                  :ARG1-of (m7 / mean-01
                        :ARG2 (p4 / percentage-entity :value 9.2)))
            :ARG1-of i
            :prep-with (r4 / regimen
                  :ARG1-of (b3 / base-02
                        :ARG2 (a6 / and
                              :op1 s3
                              :op2 s4)))
            :ARG1-of a2)
      :time (d5 / date-interval
            :op1 (d / date-entity :month 5 :year 2004)
            :op2 (d2 / date-entity :month 12 :year 2008)))

# ::id pmid_2337_4602.87 ::date 2015-08-04T05:45:23 ::annotator SDL-AMR-09 ::preferred
# ::snt The lines of therapy during which cetuximab was administered were 1st line in 38 (16.8%), 2nd line in 108 (47.8%), 3rd and beyond in 80 (35.4%) (Table  <xref ref-type="table" rid="T1">1</xref>).
# ::save-date Sat Jan 30, 2016 ::file pmid_2337_4602_87.txt
(a / and
      :op1 (l2 / line
            :ord (o / ordinal-entity :value 1)
            :location (c / case-04 :quant 38
                  :ARG1-of (m / mean-01
                        :ARG2 (p / percentage-entity :value 16.8))))
      :op2 (l3 / line
            :ord (o2 / ordinal-entity :value 2)
            :location (c2 / case-04 :quant 108
                  :ARG1-of (m2 / mean-01
                        :ARG2 (p2 / percentage-entity :value 47.8))))
      :op3 (a3 / and
            :op1 (l4 / line
                  :ord (o3 / ordinal-entity :value 3))
            :op2 (l5 / line
                  :mod (b / beyond
                        :op1 l4))
            :location (c3 / case-04 :quant 80
                  :ARG1-of (m3 / mean-01
                        :ARG2 (p3 / percentage-entity :value 35.4))))
      :domain (l / line
            :mod (t / therapy)
            :time-of (a2 / administer-01
                  :ARG1 (s / small-molecule :name (n / name :op1 "cetuximab"))))
      :ARG1-of (d / describe-01
            :ARG0 (t2 / table :mod 1)))

# ::id pmid_2337_4602.88 ::date 2015-08-04T05:52:55 ::annotator SDL-AMR-09 ::preferred
# ::snt Of note, as the period of therapy extended from 2004 until December 2008, an unselected patient population received cetuximab-based therapies, irrespective of KRAS mutational status.
# ::save-date Thu Jan 7, 2016 ::file pmid_2337_4602_88.txt
(r / receive-01
      :ARG0 (p / population
            :consist-of (p2 / person
                  :ARG0-of (h / have-rel-role-91
                        :ARG2 (p3 / patient))
                  :ARG1-of (s / select-01 :polarity -)))
      :ARG1 (t / therapy
            :ARG1-of (b / base-02
                  :ARG2 (s2 / small-molecule :name (n / name :op1 "cetuximab"))))
      :ARG1-of (n3 / note-02)
      :ARG1-of (c / cause-01
            :ARG0 (e2 / extend-01
                  :ARG1 (p4 / period
                        :duration-of t)
                  :ARG3 (d / date-entity :year 2004)
                  :ARG4 (d2 / date-entity :month 12 :year 2008)))
      :ARG1-of (r2 / regardless-91
            :ARG2 (s3 / status
                  :mod (m / mutate-01
                        :ARG2 (g / gene :name (n2 / name :op1 "KRAS"))))))

# ::id pmid_2337_4602.89 ::date 2015-08-04T05:59:19 ::annotator SDL-AMR-09 ::preferred
# ::snt <sec-title level="2">mRNA markers and somatic genotypes</sec-title>
# ::save-date Tue Aug 4, 2015 ::file pmid_2337_4602_89.txt
(a / and
      :op1 (m / marker
            :mod (n2 / nucleic-acid :name (n / name :op1 "mRNA")))
      :op2 (g / genotype
            :mod (s / somatic)))

# ::id pmid_2337_4602.90 ::date 2015-08-04T06:07:58 ::annotator SDL-AMR-09 ::preferred
# ::snt Out of the 199 samples tested for mRNA expression, three were found not eligible for all targets.
# ::save-date Mon Aug 10, 2015 ::file pmid_2337_4602_90.txt
(f / find-02
      :ARG1 (t / thing :quant 3
            :ARG1-of (s / sample-01)
            :ARG1-of (q / qualify-02 :polarity -
                  :ARG2 (t3 / thing
                        :ARG1-of (t2 / target-01)
                        :mod (a / all)))
            :ARG1-of (i / include-91
                  :ARG2 (t4 / thing :quant 199
                        :ARG1-of s
                        :ARG1-of (t5 / test-01
                              :ARG2 (e2 / express-03
                                    :ARG2 (n2 / nucleic-acid :name (n / name :op1 "mRNA"))))))))

# ::id pmid_2337_4602.91 ::date 2015-08-04T06:25:07 ::annotator SDL-AMR-09 ::preferred
# ::snt In total, 84.4% of samples were eligible for AREG analysis; 83.9% for EGF; 84.4% for EGFR; 80.4% for EREG; and 81.4% for TGFa.
# ::save-date Sun Jan 17, 2016 ::file pmid_2337_4602_91.txt
(p7 / possible-01
      :ARG1 (a / and
            :op1 (q / qualify-02
                  :ARG1 (t / thing
                        :ARG1-of (s / sample-01)
                        :ARG1-of (i / include-91
                              :ARG2 (t7 / thing
                                    :ARG1-of s)
                              :ARG3 (p / percentage-entity :value 84.4)))
                  :ARG2 (a2 / analyze-01
                        :ARG1 (p6 / protein :name (n2 / name :op1 "AREG"))))
            :op2 (q2 / qualify-02
                  :ARG1 (t2 / thing
                        :ARG1-of s
                        :ARG1-of (i2 / include-91
                              :ARG2 t7
                              :ARG3 (p2 / percentage-entity :value 83.9)))
                  :ARG2 (a3 / analyze-01
                        :ARG1 (p9 / protein :name (n3 / name :op1 "EGF"))))
            :op3 (q3 / qualify-02
                  :ARG1 t
                  :ARG2 (a4 / analyze-01
                        :ARG1 (e / enzyme :name (n / name :op1 "EGFR"))))
            :op4 (q4 / qualify-02
                  :ARG1 (t4 / thing
                        :ARG1-of s
                        :ARG1-of (i3 / include-91
                              :ARG2 t7
                              :ARG3 (p4 / percentage-entity :value 80.4)))
                  :ARG2 (a5 / analyze-01
                        :ARG1 (p3 / protein :name (n4 / name :op1 "EREG"))))
            :op5 (q5 / qualify-02
                  :ARG1 (t5 / thing
                        :ARG1-of s
                        :ARG1-of (i4 / include-91
                              :ARG2 t7
                              :ARG3 (p5 / percentage-entity :value 81.4)))
                  :ARG2 (a6 / analyze-01
                        :ARG1 (p8 / protein :name (n5 / name :op1 "TGFa")))))
      :ARG1-of (t6 / total-01))

# ::id pmid_2337_4602.92 ::date 2015-08-04T06:35:32 ::annotator SDL-AMR-09 ::preferred
# ::snt Out of the 226 DNA samples screened for the presence of mutations, genotyping was successful in 205 samples for KRAS (90.8%), 159 (70.4%) for NRAS, 220 for BRAF and 220 for PIK3CA (97.3% in each case) (Table  <xref ref-type="table" rid="T2">2</xref>).
# ::save-date Sun Jan 17, 2016 ::file pmid_2337_4602_92.txt
(a2 / and
      :op1 (s / succeed-01
            :ARG0 (g5 / genotyping)
            :ARG1 (e4 / enzyme :name (n3 / name :op1 "KRAS"))
            :location (s7 / sample-01 :quant 205
                  :ARG2 n2
                  :ARG1-of (i / include-91
                        :ARG2 (s6 / sample-01 :quant 226
                              :ARG1 (n2 / nucleic-acid :wiki "DNA" :name (n6 / name :op1 "DNA"))
                              :ARG1-of (s8 / screen-01
                                    :ARG2 (p4 / present-02
                                          :ARG1 (m / mutate-01))))
                        :ARG3 (p / percentage-entity :value 90.8))))
      :op2 (s3 / succeed-01
            :ARG0 g5
            :ARG1 (e / enzyme :name (n4 / name :op1 "NRAS"))
            :location (s9 / sample-01 :quant 159
                  :ARG2 n2
                  :ARG1-of (i2 / include-91
                        :ARG2 s6
                        :ARG3 (p2 / percentage-entity :value 70.4))))
      :op3 (s4 / succeed-01
            :ARG0 g5
            :ARG1 (e3 / enzyme :name (n5 / name :op1 "BRAF"))
            :location (s10 / sample-01 :quant 220
                  :ARG2 n2
                  :ARG1-of (i3 / include-91
                        :ARG2 s6
                        :ARG3 (p3 / percentage-entity :value 97.3))))
      :op4 (s5 / succeed-01
            :ARG0 g5
            :ARG1 (g / gene :name (n / name :op1 "PIK3CA"))
            :location (s2 / sample-01 :quant 220
                  :ARG2 n2
                  :ARG1-of i3))
      :ARG1-of (d / describe-01
            :ARG0 (t6 / table :mod 2)))

# ::id pmid_2337_4602.93 ::date 2015-08-04T06:46:24 ::annotator SDL-AMR-09 ::preferred
# ::snt KRAS mutations were detected in 72 tumours (31.9%), mostly in exon 2, in codon 12 in 45 cases (20.0%) and in codon 13 in 16 cases (7.0%), while BRAF V600E mutations were found in 6 cases (2.6%).
# ::save-date Sat Jan 30, 2016 ::file pmid_2337_4602_93.txt
(c / contrast-01
      :ARG1 (d / detect-01
            :ARG1 (m / mutate-01
                  :ARG2 (e / exon :mod 2
                        :part-of (g / gene :name (n / name :op1 "KRAS"))
                        :degree (m2 / most)))
            :location (t / tumor :quant 72
                  :ARG1-of (m6 / mean-01
                        :ARG2 (p / percentage-entity :value 31.9))
                  :ARG2-of (i / include-91
                        :ARG1 (a2 / and
                              :op1 (c2 / case-04 :quant 45
                                    :ARG1-of (m7 / mean-01
                                          :ARG2 (p2 / percentage-entity :value 20.0))
                                    :ARG0-of (h / have-03
                                          :ARG1 (m3 / mutate-01
                                                :ARG2 (c5 / codon :mod 12
                                                      :part-of g))))
                              :op2 (c3 / case-04 :quant 16
                                    :ARG1-of (m8 / mean-01
                                          :ARG2 (p3 / percentage-entity :value 7.0))
                                    :ARG0-of (h2 / have-03
                                          :ARG1 (m4 / mutate-01
                                                :ARG2 (c6 / codon :mod 13))))))))
      :ARG2 (f / find-01
            :ARG1 (m5 / mutate-01 :value "V600E"
                  :ARG2 (e2 / enzyme :name (n5 / name :op1 "BRAF")))
            :location (c4 / case-04 :quant 6
                  :ARG1-of (m9 / mean-01
                        :ARG2 (p4 / percentage-entity :value 2.6)))))

# ::id pmid_2337_4602.94 ::date 2015-08-04T06:58:07 ::annotator SDL-AMR-09 ::preferred
# ::snt NRAS mutations were also quite rare, found only in 7 cases (3.1%).
# ::save-date Sat Jan 30, 2016 ::file pmid_2337_4602_94.txt
(r / rare-02
      :ARG1 (m / mutate-01
            :ARG1 (e / enzyme :name (n / name :op1 "NRAS"))
            :mod (a / also))
      :degree (q / quite)
      :ARG1-of (i / infer-01
            :ARG2 (f / find-01
                  :ARG1 m
                  :mod (o / only)
                  :location (c / case-04 :quant 7
                        :ARG1-of (m2 / mean-01
                              :ARG2 (p / percentage-entity :value 3.1))))))

# ::id pmid_2337_4602.95 ::date 2015-08-04T07:01:49 ::annotator SDL-AMR-09 ::preferred
# ::snt PIK3CA mutations were detected in 37 tumours (16.4%), 20 in exon 9 (8.8%) and only five in exon 20 (2.2%).
# ::save-date Sun Jan 3, 2016 ::file pmid_2337_4602_95.txt
(d2 / detect-01
      :ARG1 (m / mutate-01
            :ARG1 (g / gene :name (n / name :op1 "PIK3CA")))
      :location (t / tumor :quant 37
            :ARG1-of (m2 / mean-01
                  :ARG2 (p / percentage-entity :value 16.4))
            :ARG2-of (i / include-91
                  :ARG1 (a / and
                        :op1 (t2 / tumor :quant 20
                              :ARG0-of (h / have-03
                                    :ARG1 (m3 / mutate-01
                                          :ARG1 (e / exon :mod 9)))
                              :ARG1-of (m4 / mean-01
                                    :ARG2 (p2 / percentage-entity :value 8.8)))
                        :op2 (t3 / tumor :quant 5
                              :mod (o / only)
                              :ARG0-of (h2 / have-03
                                    :ARG1 (m5 / mutate-01
                                          :ARG1 (e2 / exon :mod 20)))
                              :ARG1-of (m6 / mean-01
                                    :ARG2 (p3 / percentage-entity :value 2.2)))))))

# ::id pmid_2337_4602.96 ::date 2015-08-04T07:07:42 ::annotator SDL-AMR-09 ::preferred
# ::snt This genotypic analysis was included in a previous publication [<xref ref-type="bibr" rid="B8">8</xref>].
# ::save-date Mon Aug 10, 2015 ::file pmid_2337_4602_96.txt
(i / include-01
      :ARG1 (a / analyze-01
            :ARG1 (g / genotype)
            :mod (t / this))
      :ARG2 (t2 / thing
            :time (p2 / previous)
            :ARG1-of (d / describe-01
                  :ARG0 (p3 / publication
                        :ARG1-of (c / cite-01
                              :ARG2 8)))
            :ARG1-of (p / publish-01)))

# ::id pmid_2337_4602.97 ::date 2015-08-04T07:09:02 ::annotator SDL-AMR-09 ::preferred
# ::snt Correlation analysis revealed that mutations in KRAS, BRAF, NRAS genes were mutually exclusive in all evaluable cases.
# ::save-date Sat Jan 30, 2016 ::file pmid_2337_4602_97.txt
(r / reveal-01
      :ARG0 (a / analyze-01
            :ARG1 (c / correlate-01))
      :ARG1 (e / exclude-01
            :ARG1 (a2 / and
                  :op1 (m / mutate-01
                        :ARG1 (g / gene :name (n / name :op1 "KRAS")))
                  :op2 (m2 / mutate-01
                        :ARG1 (g2 / gene :name (n2 / name :op1 "BRAF")))
                  :op3 (m3 / mutate-01
                        :ARG1 (g3 / gene :name (n3 / name :op1 "NRAS"))))
            :manner (m4 / mutual)
            :location (c2 / case-04
                  :ARG1-of (e2 / evaluate-101
                        :ARG1-of (p / possible-01))
                  :mod (a3 / all))))

# ::id pmid_2337_4602.98 ::date 2015-08-04T07:12:53 ::annotator SDL-AMR-09 ::preferred
# ::snt On the contrary, mutations in the PIK3CA gene co-existed with KRAS mutations in 17 cases and with NRAS mutations in two.
# ::save-date Sat Jan 30, 2016 ::file pmid_2337_4602_98.txt
(c / contrast-01
      :ARG2 (a / and
            :op1 (c2 / coexist-01
                  :ARG1 (m / mutate-01
                        :ARG1 (g / gene :name (n / name :op1 "PIK3CA")))
                  :ARG2 (m2 / mutate-01
                        :ARG1 (g2 / gene :name (n2 / name :op1 "KRAS")))
                  :location (t / thing
                        :ARG1-of (c3 / case-04 :quant 17)))
            :op2 (c4 / coexist-01
                  :ARG1 m
                  :ARG2 (m3 / mutate-01
                        :ARG1 (g3 / gene :name (n3 / name :op1 "NRAS")))
                  :location (t2 / thing
                        :ARG1-of (c5 / case-04 :quant 2)))))

# ::id pmid_2337_4602.99 ::date 2015-08-04T07:16:30 ::annotator SDL-AMR-09 ::preferred
# ::snt Statistically significant associations at the 2-sided p<0.05 level were seen between wild type status of KRAS, BRAF genes and high AREG, EREG, EGFR mRNA levels.
# ::save-date Tue Dec 15, 2015 ::file pmid_2337_4602_99.txt
(s / see-01
      :ARG1 (a / associate-01
            :ARG1 (a2 / and
                  :op1 (g / gene :name (n2 / name :op1 "KRAS"))
                  :op2 (g2 / gene :name (n3 / name :op1 "BRAF"))
                  :mod (w / wild-type))
            :ARG1-of (s2 / significant-02
                  :manner (s3 / statistic)))
      :ARG2 (a4 / and
            :op1 (l / level
                  :quant-of (n9 / nucleic-acid :name (n4 / name :op1 "mRNA")
                        :ARG0-of (e2 / encode-01
                              :ARG1 (p / protein :name (n7 / name :op1 "AREG")))))
            :op2 (l4 / level
                  :quant-of (n10 / nucleic-acid :name (n5 / name :op1 "mRNA")
                        :ARG0-of (e3 / encode-01
                              :ARG1 (p2 / protein :name (n8 / name :op1 "EREG")))))
            :op3 (l5 / level
                  :quant-of (n11 / nucleic-acid :name (n6 / name :op1 "mRNA")
                        :ARG0-of (e4 / encode-01
                              :ARG1 (e / enzyme :name (n / name :op1 "EGFR")))))
            :ARG1-of (h / high-02))
      :condition (s5 / statistical-test-91
            :ARG2 (l3 / less-than :op1 0.05)
            :mod (s4 / side :quant 2)))

# ::id pmid_2337_4602.100 ::date 2015-08-04T07:18:16 ::annotator SDL-AMR-09 ::preferred
# ::snt Among KRAS-wild type cases, 81.4% were seen in AREG-high and 57.4% in EREG-high tumours, while of KRAS-mutated cases only 63.9% were observed in AREG-high and only 35.7% in EREG-high tumours.
# ::save-date Sat Jan 30, 2016 ::file pmid_2337_4602_100.txt
(c / contrast-01
      :ARG1 (a / and
            :op1 (s / see-01
                  :ARG1 (c2 / case-04
                        :ARG1-of (i / include-91
                              :ARG2 (c4 / case-04
                                    :ARG1 (g / gene :name (n3 / name :op1 "KRAS")
                                          :mod (w / wild-type)))
                              :ARG3 (p / percentage-entity :value 81.4)))
                  :location (t / tumor
                        :ARG1-of (h / high-02
                              :ARG2 (p5 / protein :name (n / name :op1 "AREG")))))
            :op2 (s2 / see-01
                  :ARG1 (c3 / case-04
                        :ARG1-of (i3 / include-91
                              :ARG2 c4
                              :ARG3 (p2 / percentage-entity :value 57.4)))
                  :location (t2 / tumor
                        :ARG1-of (h2 / high-02
                              :ARG2 (p6 / protein :name (n2 / name :op1 "EREG"))))))
      :ARG2 (a2 / and
            :op1 (o / observe-01
                  :ARG1 (c5 / case-04
                        :ARG1-of (i2 / include-91
                              :ARG2 (c6 / case-04
                                    :ARG1 (g2 / gene :name (n4 / name :op1 "KRAS")
                                          :ARG2-of (m / mutate-01)))
                              :ARG3 (p3 / percentage-entity :value 63.9
                                    :mod (o2 / only))))
                  :location t)
            :op2 (o3 / observe-01
                  :ARG1 (c7 / case-04
                        :ARG1-of (i4 / include-91
                              :ARG2 c6
                              :ARG3 (p4 / percentage-entity :value 35.7
                                    :mod o2)))
                  :location t2)))

# ::id pmid_2337_4602.101 ::date 2015-08-04T07:27:06 ::annotator SDL-AMR-09 ::preferred
# ::snt Similarly, among BRAF-wild type cases, 76.1% were seen in AREG-high and 50.7% in EREG-high tumours, while of BRAF-mutated cases only two out of six (33.3%) were observed in AREG-high and none in EREG-high tumours.
# ::save-date Sat Jan 30, 2016 ::file pmid_2337_4602_101.txt
(c / contrast-01
      :ARG1 (a / and
            :op1 (s / see-01
                  :ARG1 (c2 / case-04
                        :ARG1-of (i / include-91
                              :ARG2 (c3 / case-04
                                    :ARG1 (e / enzyme :name (n / name :op1 "BRAF")
                                          :mod (w / wild-type)))
                              :ARG3 (p / percentage-entity :value 76.1)))
                  :location (t / tumor
                        :ARG1-of (h / high-02
                              :ARG2 (p4 / protein :name (n2 / name :op1 "AREG")))))
            :op2 (s2 / see-01
                  :ARG1 (c4 / case-04
                        :ARG1-of (i3 / include-91
                              :ARG2 c3
                              :ARG3 (p2 / percentage-entity :value 50.7)))
                  :location (t2 / tumor
                        :ARG1-of (h2 / high-02
                              :ARG2 (p5 / protein :name (n3 / name :op1 "EREG"))))))
      :ARG2 (a2 / and
            :op1 (o / observe-01
                  :ARG1 (c5 / case-04 :quant 2
                        :ARG1-of (i2 / include-91
                              :ARG2 (c6 / case-04 :quant 6
                                    :ARG1 (e2 / enzyme :name (n4 / name :op1 "BRAF")
                                          :ARG2-of (m / mutate-01)))
                              :ARG3 (p3 / percentage-entity :value 33.3))
                        :mod (o2 / only))
                  :location t)
            :op2 (o3 / observe-01
                  :ARG1 (c7 / case-04 :polarity -
                        :ARG1-of i2)
                  :location t2))
      :ARG1-of (r / resemble-01))

# ::id pmid_2337_4602.102 ::date 2015-08-04T07:34:54 ::annotator SDL-AMR-09 ::preferred
# ::snt Regarding the primary location, 64.8% of KRAS mutations (p=0.07) and 58% of PIK3CA mutations (p=0.036) occurred in left-sided colorectal tumours, whereas four (66.7%) of BRAF mutations in right-sided colon carcinomas (p=0.024).
# ::save-date Sat Jan 30, 2016 ::file pmid_2337_4602_102.txt
(c / contrast-01
      :ARG1 (a2 / and
            :op1 (m2 / mutate-01
                  :ARG1-of (i / include-91
                        :ARG2 (m / mutate-01
                              :ARG1 (e / enzyme :name (n2 / name :op1 "KRAS")))
                        :ARG3 (p / percentage-entity :value 64.8))
                  :ARG1-of (s3 / statistical-test-91
                        :ARG2 0.07))
            :op2 (m9 / mutate-01
                  :ARG1-of (i2 / include-91
                        :ARG2 (m3 / mutate-01
                              :ARG1 (g / gene :name (n / name :op1 "PIK3CA")))
                        :ARG3 (p2 / percentage-entity :value 58))
                  :ARG1-of (s4 / statistical-test-91
                        :ARG2 0.036))
            :location (t / tumor
                  :mod (c2 / colorectal)
                  :location (s / side
                        :ARG1-of (l / left-20))))
      :ARG2 (m7 / mutate-01 :quant 4
            :location (c3 / carcinoma
                  :location (s2 / side
                        :poss (c4 / colon)
                        :ARG1-of (r / right-04)))
            :ARG1-of (i3 / include-91
                  :ARG2 (m6 / mutate-01
                        :ARG1 (e2 / enzyme :name (n3 / name :op1 "BRAF")))
                  :ARG3 (p3 / percentage-entity :value 66.7))
            :ARG1-of (s5 / statistical-test-91
                  :ARG2 0.024))
      :topic (l2 / location
            :mod (p7 / primary)))

# ::id pmid_2337_4602.103 ::date 2015-08-04T07:51:06 ::annotator SDL-AMR-09 ::preferred
# ::snt mRNA RQ values were examined as continuous variables and significant correlations at Spearmann’s R>0.4 were found between AREG and EREG mRNA (R=0.63, 95% CI 0.53-0.72, p=0.0005).
# ::save-date Mon Jan 4, 2016 ::file pmid_2337_4602_103.txt
(a / and
      :op1 (e / examination-02
            :ARG1 (v / value
                  :ARG2-of (r / result-01
                        :ARG1 (q / quantify-01
                              :ARG1-of (r6 / relative-05)))
                  :quant-of (n7 / nucleic-acid :name (n2 / name :op1 "mRNA")))
            :manner (v2 / variable
                  :ARG1-of (c / continue-01)))
      :op2 (f / find-01
            :ARG1 (c2 / correlate-01
                  :ARG1 (n8 / nucleic-acid :name (n3 / name :op1 "mRNA")
                        :ARG0-of (e2 / encode-01
                              :ARG1 (p2 / protein :name (n5 / name :op1 "AREG"))))
                  :ARG2 (n9 / nucleic-acid :name (n4 / name :op1 "mRNA")
                        :ARG0-of (e3 / encode-01
                              :ARG1 (p3 / protein :name (n6 / name :op1 "EREG"))))
                  :ARG1-of (s / significant-02)
                  :ARG1-of (m / mean-01
                        :ARG2 (a2 / and
                              :op1 (r5 / rho :value 0.63)
                              :op2 (i / interval
                                    :value (b2 / between :op1 0.53 :op2 0.72)
                                    :quant (p / percentage-entity :value 95)
                                    :mod (c3 / confidence)))))
            :manner (v3 / value
                  :mod (p5 / person :name (n / name :op1 "Spearmann"))
                  :value (m2 / more-than :op1 0.4)
                  :mod (s3 / string-entity :value "R")))
      :ARG1-of (s2 / statistical-test-91
            :ARG2 0.0005))

# ::id pmid_2337_4602.104 ::date 2015-08-04T07:58:14 ::annotator SDL-AMR-09 ::preferred
# ::snt <sec-title level="2">Factors with predictive significance at univariate analysis</sec-title>
# ::save-date Mon Aug 10, 2015 ::file pmid_2337_4602_104.txt
(f / factor
      :ARG1-of (s / significant-02
            :ARG0-of (p / predict-01)
            :time (a / analyze-01
                  :mod (u / univariate))))

# ::id pmid_2337_4602.105 ::date 2015-08-04T08:02:19 ::annotator SDL-AMR-09 ::preferred
# ::snt At a median follow-up of 73.6 months, 215 patients (95.1%) had experienced disease progression and 163 (93.1%) had died.
# ::save-date Thu Dec 10, 2015 ::file pmid_2337_4602_105.txt
(a / and
      :op1 (e / experience-01
            :ARG0 (p3 / person :quant 215
                  :ARG0-of (h / have-rel-role-91
                        :ARG2 (p4 / patient))
                  :ARG1-of (m3 / mean-01
                        :ARG2 (p / percentage-entity :value 95.1)))
            :ARG1 (p5 / progress-01
                  :ARG1 (d / disease)))
      :op2 (d2 / die-01
            :ARG1 (p6 / person :quant 163
                  :ARG0-of h
                  :ARG1-of (m4 / mean-01
                        :ARG2 (p2 / percentage-entity :value 93.1))))
      :time (f / follow-up-03
            :mod (m / median)
            :time (a2 / after
                  :op1 (t / temporal-quantity :quant 73.6
                        :unit (m2 / month)))))

# ::id pmid_2337_4602.106 ::date 2015-08-04T08:07:20 ::annotator SDL-AMR-09 ::preferred
# ::snt The median survival was was 27 months (95% CI 25–31).
# ::save-date Mon Aug 10, 2015 ::file pmid_2337_4602_106.txt
(t2 / temporal-quantity :quant 27
      :unit (m / month)
      :domain (s / survive-01
            :mod (m2 / median))
      :condition (i / interval
            :value (b / between
                  :op1 (t / temporal-quantity :quant 25
                        :unit m)
                  :op2 (t3 / temporal-quantity :quant 31
                        :unit m))
            :quant (p / percentage-entity :value 95)
            :mod (c / confidence)))

# ::id pmid_2337_4602.107 ::date 2015-08-04T08:09:31 ::annotator SDL-AMR-09 ::preferred
# ::snt At univariate analysis, in the present cohort of patients treated with cetuximab the presence of BRAF mutations was significantly associated with an 8.1-fold increased risk of death compared to patients harbouring BRAF-wild type tumours.
# ::save-date Sat Jan 16, 2016 ::file pmid_2337_4602_107.txt
(a / associate-01
      :ARG1 (p / present-02
            :ARG1 (m / mutate-01
                  :ARG1 (e2 / enzyme :name (n / name :op1 "BRAF")))
            :ARG2 (c / cohort
                  :ARG1-of (p2 / present-02)
                  :consist-of (p3 / person
                        :ARG0-of (h / have-rel-role-91
                              :ARG2 (p4 / patient))
                        :ARG1-of (t / treat-03
                              :ARG3 (s2 / small-molecule :name (n2 / name :op1 "cetuximab"))))))
      :ARG2 (r / risk-01
            :ARG1 (d / die-01)
            :ARG1-of (i / increase-01
                  :ARG2 (p5 / product-of :op1 8.1)))
      :ARG1-of (s / significant-02)
      :compared-to (p6 / person
            :ARG0-of h
            :ARG0-of (h2 / harbor-01
                  :ARG1 (t2 / tumor
                        :mod (e / enzyme :name (n3 / name :op1 "BRAF")
                              :mod (w / wild-type)))))
      :time (a2 / analyze-01
            :mod (u / univariate)))

# ::id pmid_2337_4602.108 ::date 2015-08-05T05:55:36 ::annotator SDL-AMR-09 ::preferred
# ::snt When all types of mutations were pooled for each gene, KRAS (HR 1.28, p=0.14), NRAS (HR 1.43, p=0.36) and PIK3CA (HR 1.27, p=0.25) mutations did not have prognostic/predictive utility.
# ::save-date Sun Jan 17, 2016 ::file pmid_2337_4602_108.txt
(h / have-03 :polarity -
      :ARG0 (a2 / and
            :op1 (m / mutate-01
                  :ARG2 (e2 / enzyme :name (n / name :op1 "KRAS")
                        :mod (r / ratio-of :quant 1.28
                              :op1 (h2 / hazard)))
                  :ARG1-of (s / statistical-test-91
                        :ARG2 0.14))
            :op2 (m3 / mutate-01
                  :ARG2 (e3 / enzyme :name (n2 / name :op1 "NRAS"))
                  :mod (r2 / ratio-of :quant 1.43
                        :op1 h2)
                  :ARG1-of (s2 / statistical-test-91
                        :ARG2 0.36))
            :op3 (m4 / mutate-01
                  :ARG2 (g2 / gene :name (n3 / name :op1 "PIK3CA"))
                  :mod (r3 / ratio-of :quant 1.27
                        :op1 h2)
                  :ARG1-of (s3 / statistical-test-91
                        :ARG2 0.25)))
      :ARG1 (u / utility
            :mod (p / prognostic)
            :ARG0-of (p2 / predict-01))
      :time (p3 / pool-01
            :ARG1 (m2 / mutate-01
                  :mod (t / type
                        :mod (a / all)))
            :topic (g / gene
                  :mod (e / each))))

# ::id pmid_2337_4602.109 ::date 2015-08-05T07:23:09 ::annotator SDL-AMR-09 ::preferred
# ::snt However, when types of mutations were analysed separately for each gene, KRAS codon 12 mutations were predictive for increased risk of death (HR 1.62, p=0.014).
# ::save-date Sun Jan 3, 2016 ::file pmid_2337_4602_109.txt
(c / contrast-01
      :ARG2 (p / predict-01
            :ARG0 (m / mutate-01
                  :ARG1 (c2 / codon :mod 12
                        :part-of (e / enzyme :name (n / name :op1 "KRAS")))
                  :mod (r2 / ratio-of :quant 1.62
                        :op1 (h / hazard)))
            :ARG1 (r / risk-01
                  :ARG2 (d / die-01))
            :time (a / analyze-01
                  :ARG1 (m2 / mutate-01
                        :mod (t / type))
                  :manner (s / separate-02
                        :ARG1 (g / gene
                              :mod (e2 / each))))
            :ARG1-of (s2 / statistical-test-91
                  :ARG2 0.014)))

# ::id pmid_2337_4602.110 ::date 2015-08-05T07:34:05 ::annotator SDL-AMR-09 ::preferred
# ::snt Among parameters studied for gene expression, only the 25th percentile of AREG mRNA values and the 75th percentile of EREG mRNA values dichotomized cases into groups with different outcome and were selected as optimal cut-offs.
# ::save-date Sat Jan 30, 2016 ::file pmid_2337_4602_110.txt
(a / and
      :op1 (d / dichotomize-00
            :ARG0 (a2 / and
                  :op1 (v / value
                        :mod (p / percentile
                              :ARG3-of (i / include-91
                                    :ARG2 (n5 / nucleic-acid :name (n / name :op1 "mRNA")
                                          :ARG0-of (e2 / encode-01
                                                :ARG1 (p5 / protein :name (n3 / name :op1 "AREG")))))
                              :mod (o2 / only)
                              :ord (o5 / ordinal-entity :value 25)))
                  :op2 (v2 / value
                        :mod (p2 / percentile
                              :ARG3-of (i2 / include-91
                                    :ARG2 (n6 / nucleic-acid :name (n2 / name :op1 "mRNA")
                                          :ARG0-of (e3 / encode-01
                                                :ARG1 (p4 / protein :name (n4 / name :op1 "EREG")))))
                              :mod (o3 / only)
                              :ord (o6 / ordinal-entity :value 75)))
                  :ARG1-of (i3 / include-91
                        :ARG2 (p3 / parameter
                              :ARG1-of (s2 / study-01
                                    :purpose (e / express-03
                                          :ARG1 (g2 / gene))))))
            :ARG1 (c / case-04)
            :ARG2 (g / group
                  :ARG0-of (h / have-03
                        :ARG1 (o / outcome
                              :ARG1-of (d2 / differ-02)))))
      :op2 (s / select-01
            :ARG1 a2
            :ARG3 (t / thing
                  :mod (o4 / optimal)
                  :ARG3-of (c2 / cut-off-04))))

# ::id pmid_2337_4602.111 ::date 2015-08-06T03:41:49 ::annotator SDL-AMR-09 ::preferred
# ::snt None of EGF, TGFa, EGFR mRNA levels disclosed cut-off points of prognostic significance.
# ::save-date Sun Jan 17, 2016 ::file pmid_2337_4602_111.txt
(d / disclose-01
      :ARG0 (a / and
            :op1 (l / level
                  :quant-of (n / nucleic-acid :name (n2 / name :op1 "mRNA")
                        :ARG0-of (e2 / encode-01
                              :ARG1 (p / protein :name (n3 / name :op1 "EGF")))))
            :op2 (l2 / level
                  :quant-of (n9 / nucleic-acid :name (n4 / name :op1 "mRNA")
                        :ARG0-of (e3 / encode-01
                              :ARG1 (p2 / protein :name (n5 / name :op1 "TGFa")))))
            :op3 (l3 / level
                  :quant-of (n10 / nucleic-acid :name (n6 / name :op1 "mRNA")
                        :ARG0-of (e4 / encode-01
                              :ARG1 (e / enzyme :name (n7 / name :op1 "EGFR")))))
            :quant (n8 / none))
      :ARG1 (p4 / point
            :mod (c / cut-off-04)
            :ARG0-of (h / have-03
                  :ARG1 (t / thing
                        :mod (p5 / prognostic)
                        :ARG1-of (s / significant-02)))))

# ::id pmid_2337_4602.112 ::date 2015-08-06T03:42:10 ::annotator SDL-AMR-09 ::preferred
# ::snt Cetuximab therapy in patients harbouring AREG-high (HR 0.47, p=0.0002) or EREG-high (HR 0.45, p=0.0009) tumours resulted in reduced risk of death.
# ::save-date Tue Jan 5, 2016 ::file pmid_2337_4602_112.txt
(r / result-01
      :ARG1 (t / therapy
            :mod (s / small-molecule :name (n / name :op1 "Cetuximab"))
            :location (p / person
                  :ARG0-of (h / harbor-01
                        :ARG1 (o / or
                              :op1 (t2 / tumor
                                    :ARG1-of (h2 / high-02
                                          :ARG2 (p2 / protein :name (n2 / name :op1 "AREG")))
                                    :mod (r4 / ratio-of :quant 0.47
                                          :op1 (h5 / hazard))
                                    :ARG1-of (s2 / statistical-test-91
                                          :ARG2 0.0002))
                              :op2 (t3 / tumor
                                    :ARG1-of (h3 / high-02
                                          :ARG2 (p3 / protein :name (n3 / name :op1 "EREG")))
                                    :mod (r5 / ratio-of :quant 0.45
                                          :op1 (h6 / hazard))
                                    :ARG1-of (s3 / statistical-test-91
                                          :ARG2 0.0009))))
                  :ARG0-of (h4 / have-rel-role-91
                        :ARG2 (p6 / patient))))
      :ARG2 (r2 / risk-01
            :ARG2 (d / die-01)
            :ARG1-of (r3 / reduce-01)))

# ::id pmid_2337_4602.113 ::date 2015-08-06T07:19:05 ::annotator SDL-AMR-09 ::preferred
# ::snt EGFR, EGF, TGFa mRNA expression had no significant prognostic/predictive value, either in the entire cohort or in the KRAS-wild type versus KRAS mutant cases.
# ::save-date Sun Jan 17, 2016 ::file pmid_2337_4602_113.txt
(h / have-03 :polarity -
      :ARG0 (e2 / express-03
            :ARG1 (n / nucleic-acid :name (n2 / name :op1 "mRNA")
                  :ARG0-of (e3 / encode-01
                        :ARG1 (a / and
                              :op1 (e / enzyme :name (n3 / name :op1 "EGFR"))
                              :op2 (p4 / protein :name (n4 / name :op1 "EGF"))
                              :op3 (p5 / protein :name (n5 / name :op1 "TGFa"))))))
      :ARG1 (v / value
            :ARG1-of (s / significant-02)
            :mod (p / prognostic)
            :ARG0-of (p2 / predict-01))
      :location (o2 / or
            :op1 (c / cohort
                  :mod (e4 / entire))
            :op2 (c2 / compare-01
                  :ARG1 (e5 / enzyme :name (n6 / name :op1 "KRAS")
                        :mod (w / wild-type))
                  :ARG2 (e6 / enzyme :name (n7 / name :op1 "KRAS")
                        :ARG2-of (m / mutate-01)))))

# ::id pmid_2337_4602.114 ::date 2015-08-06T07:34:32 ::annotator SDL-AMR-09 ::preferred
# ::snt Regarding objective tumour response to any line of cetuximab-based therapy, tumoural AREG and EREG mRNA expression levels were associated with tumour shrinkage as continuous variables.
# ::save-date Fri Oct 16, 2015 ::file pmid_2337_4602_114.txt
(a / associate-01
      :ARG1 (l / level
            :quant-of (e / express-03
                  :ARG1 (a2 / and
                        :op1 (n6 / nucleic-acid :name (n / name :op1 "mRNA")
                              :ARG0-of (e2 / encode-01
                                    :ARG1 (p / protein :name (n2 / name :op1 "AREG"))))
                        :op2 (n7 / nucleic-acid :name (n3 / name :op1 "mRNA")
                              :ARG0-of (e3 / encode-01
                                    :ARG1 (p2 / protein :name (n4 / name :op1 "EREG"))))))
            :location (t / tumor))
      :ARG2 (s / shrink-01
            :ARG1 t)
      :purpose (v / variable
            :ARG1-of (c / continue-01))
      :topic (r3 / respond-01
            :ARG0 t
            :ARG1 (l2 / line
                  :mod (a3 / any)
                  :part-of (t2 / therapy
                        :ARG1-of (b / base-02
                              :ARG2 (s2 / small-molecule :name (n5 / name :op1 "cetuximab")))))
            :mod (o / objective)))

# ::id pmid_2337_4602.115 ::date 2015-08-06T08:22:39 ::annotator SDL-AMR-09 ::preferred
# ::snt AREG was not statistically significant as categorical variable but EREG mRNA at the 75th percentile was associated with a 2.26-fold increased likelihood of tumour response to cetuximab compared to tumours with lower EREG mRNA expression.
# ::save-date Fri Oct 16, 2015 ::file pmid_2337_4602_115.txt
(c / contrast-01
      :ARG1 (p / protein :name (n2 / name :op1 "AREG")
            :ARG1-of (s / significant-02 :polarity -
                  :mod (s2 / statistic)
                  :purpose (v / variable
                        :mod (c2 / categorical))))
      :ARG2 (n7 / nucleic-acid :name (n3 / name :op1 "mRNA")
            :ARG0-of (e2 / encode-01
                  :ARG1 (p2 / protein :name (n4 / name :op1 "EREG")))
            :location (p3 / percentile
                  :ord (o / ordinal-entity :value 75))
            :ARG1-of (a / associate-01
                  :ARG2 (l / likely-01
                        :ARG1 (r / respond-01
                              :ARG0 (t / tumor)
                              :ARG1 (s3 / small-molecule :name (n / name :op1 "cetuximab")))
                        :ARG1-of (i / increase-01
                              :ARG2 (p4 / product-of :op1 2.26))
                        :compared-to (t2 / tumor
                              :ARG3-of (e / express-03
                                    :ARG1 (n8 / nucleic-acid :name (n5 / name :op1 "mRNA"))
                                    :ARG2 (p5 / protein :name (n6 / name :op1 "EREG"))
                                    :ARG2-of (l2 / low-04
                                          :degree (m / more))))))))

# ::id pmid_2337_4602.116 ::date 2015-08-06T09:13:58 ::annotator SDL-AMR-09 ::preferred
# ::snt AREG failed to predict response in either KRAS wild type or mutated cases.
# ::save-date Sat Jan 30, 2016 ::file pmid_2337_4602_116.txt
(f / fail-01
      :ARG1 (p / protein :name (n / name :op1 "AREG"))
      :ARG2 (p2 / predict-01
            :ARG0 p
            :ARG1 (r / respond-01
                  :prep-in (o / or
                        :op1 (c / case-04
                              :ARG1 (e / enzyme :name (n2 / name :op1 "KRAS")
                                    :mod (w / wild-type)))
                        :op2 (c2 / case-04
                              :ARG1 (e2 / enzyme :name (n3 / name :op1 "KRAS")
                                    :ARG2-of (m / mutate-01)))))))

# ::id pmid_2337_4602.117 ::date 2015-08-06T09:20:34 ::annotator SDL-AMR-09 ::preferred
# ::snt The expression levels of EREG in the tumours of responding and non-responding patients by KRAS gene status is depicted in a waterfall plot (Figure  <xref ref-type="fig" rid="F1">1</xref>).
# ::save-date Thu Dec 10, 2015 ::file pmid_2337_4602_117.txt
(d / depict-01
      :ARG1 (l / level
            :quant-of (e / express-03
                  :ARG2 (p / protein :name (n / name :op1 "EREG"))
                  :ARG3 (t / tumor
                        :source (a / and
                              :op1 (p2 / person
                                    :ARG0-of (r / respond-01)
                                    :ARG0-of (h / have-rel-role-91
                                          :ARG2 (p5 / patient)))
                              :op2 (p3 / person
                                    :ARG0-of (r2 / respond-01 :polarity -)
                                    :ARG0-of h)
                              :ARG1-of (s / say-01
                                    :ARG0 (s2 / status
                                          :poss (g / gene :name (n2 / name :op1 "KRAS"))))))))
      :location (p4 / plot
            :mod (w / waterfall))
      :ARG1-of (d2 / describe-01
            :ARG0 (f / figure :mod 1)))

# ::id pmid_2337_4602.118 ::date 2015-08-06T10:01:23 ::annotator SDL-AMR-09 ::preferred
# ::snt Of note, in an exploratory analysis, the predictive significance for objective response was maintained only in KRAS mutated CRC, in which EREG had an odds ratio for response of 5.4 (95% CI 1.2-23.8, p=0.024).
# ::save-date Sun Jan 3, 2016 ::file pmid_2337_4602_118.txt
(n / note-02
      :ARG1 (m / maintain-01
            :ARG1 (s / significant-02
                  :ARG1 (r / respond-01
                        :mod (o / objective))
                  :ARG0-of (p2 / predict-01))
            :location (d / disease :name (n2 / name :op1 "CRC")
                  :mod (m2 / mutate-01
                        :ARG1 (e / enzyme :name (n3 / name :op1 "KRAS")))
                  :location-of (h / have-03
                        :ARG0 (p3 / protein :name (n4 / name :op1 "EREG"))
                        :ARG1 (e3 / equal-01
                              :ARG1 (r2 / ratio
                                    :mod (o2 / odds)
                                    :prep-for (r3 / respond-01))
                              :ARG2 (r4 / ratio-of :op1 5.4)
                              :mod (i / interval
                                    :quant (v / value-interval :op1 1.2 :op2 23.8)
                                    :mod (p4 / percentage-entity :quant 95)
                                    :mod (c / confidence))))
                  :mod (o3 / only))
            :time (a / analyze-01 :quant 1
                  :ARG0-of (e2 / explore-01))
            :ARG1-of (s2 / statistical-test-91
                  :ARG2 0.024)))

# ::id pmid_2337_4602.119 ::date 2015-08-06T10:36:10 ::annotator SDL-AMR-09 ::preferred
# ::snt By contrast, in KRAS-wild type tumours EREG failed to significantly predict for response to therapy (OR 2.2, 95% CI 0.83-5.86, p=0.11).
# ::save-date Sun Jan 3, 2016 ::file pmid_2337_4602_119.txt
(c / contrast-01
      :ARG2 (f / fail-01
            :ARG1 (p2 / protein :name (n / name :op1 "EREG"))
            :ARG2 (p3 / predict-01
                  :ARG0 p2
                  :ARG1 (r / respond-01
                        :ARG1 (t / therapy))
                  :ARG1-of (s / significant-02))
            :location (t2 / tumor
                  :mod (e / enzyme :name (n2 / name :op1 "KRAS")
                        :mod (w / wild-type)))
            :mod (i / interval
                  :mod (p4 / percentage-entity :quant 95)
                  :quant (v / value-interval :op1 0.83 :op2 5.86)
                  :mod (c2 / confidence))
            :mod (r2 / ratio :quant 2.2
                  :mod (o / odds))
            :ARG1-of (s2 / statistical-test-91
                  :ARG2 0.11)))

# ::id pmid_2337_4602.120 ::date 2015-08-06T10:51:53 ::annotator SDL-AMR-09 ::preferred
# ::snt EGF, TGFa and EGFR mRNA expression had no predictive utility for response to cetuximab in the whole cohort, neither in KRAS wild-type or KRAS mutated cases.
# ::save-date Sat Jan 30, 2016 ::file pmid_2337_4602_120.txt
(h / have-03 :polarity -
      :ARG0 (e2 / express-03
            :ARG1 (n / nucleic-acid :name (n2 / name :op1 "mRNA")
                  :ARG0-of (e3 / encode-01
                        :ARG1 (a / and
                              :op1 (p / protein :name (n3 / name :op1 "EGF"))
                              :op2 (p2 / protein :name (n4 / name :op1 "TGFa"))
                              :op2 (e / enzyme :name (n5 / name :op1 "EGFR"))))))
      :ARG1 (u / utility
            :ARG0-of (p4 / predict-01
                  :ARG1 (r2 / respond-01
                        :ARG1 (s / small-molecule :name (n6 / name :op1 "cetuximab")))))
      :location (c2 / cohort
            :mod (w / whole))
      :topic (o / or
            :op1 (c / case-04
                  :ARG1 (e4 / enzyme :name (n7 / name :op1 "KRAS")
                        :mod (w2 / wild-type)))
            :op2 (c3 / case-04
                  :ARG1 (e5 / enzyme :name (n8 / name :op1 "KRAS")
                        :ARG2-of (m / mutate-01)))))

# ::id pmid_2337_4602.121 ::date 2015-08-06T11:27:36 ::annotator SDL-AMR-09 ::preferred
# ::snt All factors with potential predictive utility for cetuximab benefit are summarized in Table  <xref ref-type="table" rid="T3">3</xref>.
# ::save-date Wed Oct 14, 2015 ::file pmid_2337_4602_121.txt
(s / summarize-01
      :ARG1 (f / factor
            :mod (a / all)
            :poss (u / utility
                  :ARG0-of (p / predict-01
                        :ARG1 (b / benefit-01
                              :ARG0 (s2 / small-molecule :name (n / name :op1 "cetuximab"))))))
      :ARG1-of (d / describe-01
            :ARG0 (t / table :mod 3)))

# ::id pmid_2337_4602.122 ::date 2015-08-06T13:00:11 ::annotator SDL-AMR-09 ::preferred
# ::snt <sec-title level="2">Interactions and factors with predictive utility at multivariate analysis</sec-title>
# ::save-date Thu Aug 6, 2015 ::file pmid_2337_4602_122.txt
(h / have-03
      :ARG0 (a / and
            :op1 (i / interact-01)
            :op2 (f / factor))
      :ARG1 (u / utility
            :ARG0-of (p / predict-01))
      :location (a2 / analyze-01
            :mod (m / multivariate)))

# ::id pmid_2337_4602.123 ::date 2015-08-06T13:07:39 ::annotator SDL-AMR-09 ::preferred
# ::snt Significant interactions (at the 1% significance level) between study variables for prognostic/predictive utility (survival, ORR) were sought.
# ::save-date Wed Nov 18, 2015 ::file pmid_2337_4602_123.txt
(s / seek-01
      :ARG1 (i / interact-01
            :ARG0 (v / variable
                  :mod (s4 / study-01))
            :ARG1-of (s2 / significant-02)
            :prep-at (l / level
                  :ARG1-of (s3 / significant-02)
                  :mod (p / percentage-entity :value 1))
            :purpose (u / utility
                  :ARG0-of (p2 / predict-01)
                  :mod (p3 / prognostic)
                  :ARG1-of (m / mean-01
                        :ARG2 (a / and
                              :op1 (s5 / survive-01)
                              :op2 (r / rate
                                    :mod (r2 / respond-01)
                                    :mod (o / overall)))))))

# ::id pmid_2337_4602.124 ::date 2015-08-06T13:57:22 ::annotator SDL-AMR-09 ::preferred
# ::snt In terms of impact on survival, significant interactions were found between AREG mRNA levels and mutational status of the KRAS gene (p=0.0033).
# ::save-date Tue Dec 15, 2015 ::file pmid_2337_4602_124.txt
(f / find-01
      :ARG1 (i / interact-01
            :ARG0 (l / level
                  :quant-of (n4 / nucleic-acid :name (n / name :op1 "mRNA")
                        :ARG0-of (e / encode-01
                              :ARG1 (p / protein :name (n2 / name :op1 "AREG")))))
            :ARG1 (s2 / status
                  :mod (m / mutate-01)
                  :poss (g / gene :name (n3 / name :op1 "KRAS")))
            :ARG1-of (s / significant-02))
      :topic (i2 / impact-01
            :ARG1 (s3 / survive-01))
      :ARG1-of (s4 / statistical-test-91
            :ARG2 0.0033))

# ::id pmid_2337_4602.125 ::date 2015-08-06T13:57:35 ::annotator SDL-AMR-09 ::preferred
# ::snt High mRNA levels of AREG predicted for longer survival in patients with KRAS wild-type (median survival 33 vs. 15 months, p=0.0005, Figure  <xref ref-type="fig" rid="F2">2</xref>), but not in KRAS mutant tumours (median survival 22 vs. 17 months, p=0.64).
# ::save-date Tue Dec 15, 2015 ::file pmid_2337_4602_125.txt
(c / contrast-01
      :ARG1 (p / predict-01
            :ARG0 (l / level
                  :quant-of (n5 / nucleic-acid :name (n / name :op1 "mRNA")
                        :ARG0-of (e3 / encode-01
                              :ARG1 (p2 / protein :name (n2 / name :op1 "AREG"))))
                  :ARG1-of (h / high-02))
            :ARG1 (s / survive-01
                  :ARG0 (p3 / person
                        :poss (t / tumor
                              :mod (e / enzyme :name (n3 / name :op1 "KRAS")
                                    :mod (w / wild-type)))
                        :ARG0-of (h2 / have-rel-role-91
                              :ARG2 (p8 / patient)))
                  :ARG1-of (l2 / long-03
                        :degree (m / more))
                  :mod (c2 / contrast-01
                        :ARG1 (s3 / survive-01
                              :mod (m3 / median)
                              :duration (t3 / temporal-quantity :quant 33
                                    :unit (m5 / month)))
                        :ARG2 (s4 / survive-01
                              :duration (t4 / temporal-quantity :quant 15
                                    :unit m5)
                              :mod m3)
                        :ARG1-of (d / describe-01
                              :ARG0 (f / figure :mod 2)))
                  :ARG1-of (s7 / statistical-test-91
                        :ARG2 0.0005)))
      :ARG2 (p4 / predict-01 :polarity -
            :ARG0 l
            :ARG1 (s2 / survive-01
                  :ARG0 (p5 / person
                        :poss (t2 / tumor
                              :mod (m2 / mutate-01
                                    :ARG2 (e2 / enzyme :name (n4 / name :op1 "KRAS"))))
                        :ARG0-of h2)
                  :mod (c3 / contrast-01
                        :ARG1 (s5 / survive-01
                              :duration (t5 / temporal-quantity :quant 22
                                    :unit m5)
                              :mod m3)
                        :ARG2 (s6 / survive-01
                              :mod m3
                              :duration (t6 / temporal-quantity :quant 17
                                    :unit m5)))
                  :ARG1-of (s8 / statistical-test-91
                        :ARG2 0.64))))

# ::id pmid_2337_4602.126 ::date 2015-08-07T04:43:40 ::annotator SDL-AMR-09 ::preferred
# ::snt In contrast, high mRNA levels of EREG were associated with favourable prognosis irrespective of KRAS mutational status.
# ::save-date Thu Jan 7, 2016 ::file pmid_2337_4602_126.txt
(c / contrast-01
      :ARG2 (a / associate-01
            :ARG1 (l / level
                  :quant-of (n4 / nucleic-acid :name (n / name :op1 "mRNA")
                        :ARG0-of (e2 / encode-01
                              :ARG1 (p / protein :name (n2 / name :op1 "EREG"))))
                  :ARG1-of (h / high-02))
            :ARG2 (p2 / prognosis
                  :mod (f / favourable))
            :ARG1-of (r / regardless-91
                  :ARG2 (s / status
                        :mod (m / mutate-01
                              :ARG1 (e / enzyme :name (n3 / name :op1 "KRAS")))))))

# ::id pmid_2337_4602.127 ::date 2015-08-07T04:44:15 ::annotator SDL-AMR-09 ::preferred
# ::snt In KRAS wild type cases, the median survival was 37 months for EREG-high as compared to 23 months for EREG-low expressing tumours (p=0.01), while in KRAS mutated tumours median survival was 33 versus 19 months (p=0.02) in EREG-high vs. low cases (Figure  <xref ref-type="fig" rid="F3">3</xref>).
# ::save-date Sat Jan 30, 2016 ::file pmid_2337_4602_127.txt
(c / contrast-01
      :ARG1 (c2 / compare-01
            :ARG1 (s / survive-01
                  :condition (t / tumor
                        :ARG3-of (e / express-03
                              :ARG2 (p / protein :wiki "Epiregulin" :name (n / name :op1 "EREG")
                                    :ARG1-of (h / high-02))))
                  :mod (m / median)
                  :duration (t2 / temporal-quantity :quant 37
                        :unit (m2 / month))
                  :ARG1-of (s5 / statistical-test-91
                        :ARG2 0.01))
            :ARG2 (s2 / survive-01
                  :condition (t3 / tumor
                        :ARG3-of (e2 / express-03
                              :ARG2 (p2 / protein :wiki "Epiregulin" :name (n2 / name :op1 "EREG")
                                    :ARG1-of (l / low-04))))
                  :mod m
                  :duration (t4 / temporal-quantity :quant 23
                        :unit m2))
            :topic (c3 / case-04
                  :ARG1 (e3 / enzyme :wiki "KRAS" :name (n3 / name :op1 "KRAS")
                        :mod (w / wild-type))))
      :ARG2 (c4 / compare-01
            :ARG1 (s3 / survive-01
                  :mod m
                  :duration (t6 / temporal-quantity :quant 33
                        :unit m2)
                  :condition (c5 / case-04
                        :ARG1 p)
                  :ARG1-of (s6 / statistical-test-91
                        :ARG2 0.02))
            :ARG2 (s4 / survive-01
                  :mod m
                  :duration (t7 / temporal-quantity :quant 19
                        :unit m2)
                  :condition (c6 / case-04
                        :ARG1 p2))
            :condition (t5 / tumor
                  :mod (e4 / enzyme :wiki "KRAS" :name (n4 / name :op1 "KRAS")
                        :ARG2-of (m3 / mutate-01))))
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod 3)))

# ::id pmid_2337_4602.128 ::date 2015-08-07T04:46:09 ::annotator SDL-AMR-09 ::preferred
# ::snt Similar findings for EREG high vs. low were seen when we examined complex cancer genotypes: a) KRAS+BRAF, both wild type vs. any mutant, b) KRAS+BRAF+PIK3CA+NRAS, all wild type vs. any mutant.
# ::save-date Sun Jan 17, 2016 ::file pmid_2337_4602_128.txt
(s / see-01
      :ARG1 (t / thing
            :ARG1-of (f / find-01)
            :topic (c / compare-01
                  :ARG1 (p / protein :name (n2 / name :op1 "EREG")
                        :ARG1-of (h / high-02))
                  :ARG2 (p2 / protein :name (n3 / name :op1 "EREG")
                        :ARG1-of (l / low-04)))
            :ARG1-of (r / resemble-01))
      :time (e / examine-01
            :ARG0 (w / we)
            :ARG1 (g / genotype
                  :mod (c3 / complex)
                  :ARG1-of (m / mean-01
                        :ARG2 (a3 / and
                              :op1 (c4 / compare-01 :li "a"
                                    :ARG1 (a / and
                                          :op1 (g5 / gene :name (n4 / name :op1 "KRAS")
                                                :mod (w2 / wild-type))
                                          :op2 (g4 / gene :name (n5 / name :op1 "BRAF")
                                                :mod w2))
                                    :ARG2 (m2 / molecular-physical-entity
                                          :ARG2-of (m3 / mutate-01)
                                          :mod (a2 / any)))
                              :op2 (c5 / compare-01 :li "b"
                                    :ARG1 (a5 / and
                                          :op1 g5
                                          :op2 g4
                                          :op3 (g2 / gene :name (n8 / name :op1 "PIK3CA")
                                                :mod w2)
                                          :op4 (g3 / gene :name (n9 / name :op1 "NRAS")
                                                :mod w2))
                                    :ARG2 m2)))
                  :mod (d / disease :wiki "Cancer" :name (n / name :op1 "cancer")))))

# ::id pmid_2337_4602.129 ::date 2015-08-07T04:49:01 ::annotator SDL-AMR-09 ::preferred
# ::snt AREG mRNA had a favourable predictive significance in wild type cases only, whereas EREG mRNA preserved its significance in wild type as well as in mutant cases.
# ::save-date Sat Jan 30, 2016 ::file pmid_2337_4602_129.txt
(c / contrast-01
      :ARG1 (n5 / nucleic-acid :name (n / name :op1 "mRNA")
            :ARG0-of (e / encode-01
                  :ARG1 (p / protein :name (n2 / name :op1 "AREG")))
            :ARG1-of (s / significant-02
                  :mod (f / favourable)
                  :ARG0-of (p2 / predict-01)
                  :topic (c2 / case-04
                        :mod (w / wild-type)
                        :mod (o / only))))
      :ARG2 (n6 / nucleic-acid :name (n3 / name :op1 "mRNA")
            :ARG0-of (e2 / encode-01
                  :ARG1 (p3 / protein :name (n4 / name :op1 "EREG")))
            :ARG0-of (p4 / preserve-01
                  :ARG1 (s2 / significant-02
                        :ARG1 n6)
                  :topic (a / and
                        :op1 (c3 / case-04
                              :mod w)
                        :op2 (c4 / case-04
                              :ARG2-of (m / mutate-01))))))

# ::id pmid_2337_4602.130 ::date 2015-08-07T04:50:36 ::annotator SDL-AMR-09 ::preferred
# ::snt A multivariate analysis was performed in the context of a broader mRNA profiling project of several biomarkers (IGFBP2, IGF1R, cMET, EGFR, TGFa, EphA2, HER2, HER3, HER4, Table  <xref ref-type="table" rid="T4">4</xref>).
# ::save-date Sun Jan 17, 2016 ::file pmid_2337_4602_130.txt
(p / perform-02
      :ARG1 (a / analyze-01
            :mod (m / multivariate))
      :ARG1-of (d / describe-01
            :ARG0 (t / table :mod 4))
      :time (p2 / project
            :ARG0-of (p3 / profile-01
                  :ARG1 (b2 / biomarker
                        :ARG1-of (m2 / mean-01
                              :ARG2 (a2 / and
                                    :op1 (p4 / protein :name (n5 / name :op1 "IGFBP2"))
                                    :op2 (p5 / protein :name (n6 / name :op1 "IGF1R"))
                                    :op3 (p6 / protein :name (n7 / name :op1 "cMET"))
                                    :op4 (e / enzyme :name (n / name :op1 "EGFR"))
                                    :op5 (p8 / protein :name (n9 / name :op1 "TGFa"))
                                    :op6 (p9 / protein :name (n10 / name :op1 "EphA2"))
                                    :op7 (e2 / enzyme :name (n11 / name :op1 "HER2"))
                                    :op8 (e3 / enzyme :name (n12 / name :op1 "HER3"))
                                    :op9 (e4 / enzyme :name (n13 / name :op1 "HER4"))))
                        :quant (s / several))
                  :instrument (n2 / nucleic-acid :name (n4 / name :op1 "mRNA")))
            :ARG1-of (b / broad-02
                  :degree (m3 / more))))

# ::id pmid_2337_4602.131 ::date 2015-08-09T13:32:22 ::annotator SDL-AMR-09 ::preferred
# ::snt In the presence of wild-type KRAS, high AREG mRNA levels were independently associated with 83.0% reduction in the risk of death compared to patients with AREG-low tumours.
# ::save-date Thu Dec 10, 2015 ::file pmid_2337_4602_131.txt
(a / associate-01
      :ARG1 (l / level
            :quant-of (n3 / nucleic-acid :name (n / name :op1 "mRNA")
                  :ARG0-of (e / encode-01
                        :ARG1 (p2 / protein :name (n2 / name :op1 "AREG"))))
            :ARG1-of (h / high-02))
      :ARG2 (r2 / reduce-01
            :ARG1 (r3 / risk-01
                  :ARG2 (d / die-01))
            :ARG2 (p3 / percentage-entity :value 83)
            :compared-to (p4 / person
                  :poss (t / tumor
                        :ARG1-of (l2 / low-04
                              :ARG2 p2))
                  :ARG0-of (h2 / have-rel-role-91
                        :ARG2 (p / patient))))
      :ARG0-of (d2 / depend-01 :polarity -)
      :condition (p5 / present-02
            :ARG1 (e2 / enzyme :name (n4 / name :op1 "KRAS")
                  :mod (w / wild-type))))

# ::id pmid_2337_4602.132 ::date 2015-08-09T14:32:03 ::annotator SDL-AMR-09 ::preferred
# ::snt High EREG tumoural mRNA was a favourable outcome predictor for cetuximab-treated patients, irrespective of KRAS mutation status.
# ::save-date Thu Jan 7, 2016 ::file pmid_2337_4602_132.txt
(t / thing
      :ARG0-of (p / predict-01
            :ARG1 (o / outcome))
      :domain (n5 / nucleic-acid :name (n / name :op1 "mRNA")
            :ARG0-of (e / encode-01
                  :ARG1 (p2 / protein :name (n2 / name :op1 "EREG")))
            :mod (h / high))
      :mod (f / favourable)
      :topic (p3 / patient
            :ARG1-of (t2 / treat-03
                  :ARG3 (s / small-molecule :name (n3 / name :op1 "cetuximab"))))
      :ARG1-of (r / regardless-91
            :ARG2 (s2 / status
                  :mod (m / mutate-01
                        :ARG2 (e2 / enzyme :name (n4 / name :op1 "KRAS"))))))

# ::id pmid_2337_4602.133 ::date 2015-08-09T15:13:08 ::annotator SDL-AMR-09 ::preferred
# ::snt High Ephrin A2 (EphA2) mRNA and advanced age were adverse independent prognosticators.
# ::save-date Wed Oct 14, 2015 ::file pmid_2337_4602_133.txt
(p / prognosticator
      :domain (a / and
            :op1 (n3 / nucleic-acid :name (n / name :op1 "mRNA")
                  :ARG0-of (e / encode-01
                        :ARG1 (p2 / protein :name (n2 / name :op1 "Ephrin" :op2 "A2")
                              :ARG1-of (h / high-02))))
            :op2 (a2 / age
                  :ARG1-of (a3 / advance-01)))
      :ARG0-of (d / depend-01 :polarity -)
      :mod (a4 / adverse))

# ::id pmid_2337_4602.134 ::date 2015-08-09T15:17:22 ::annotator SDL-AMR-09 ::preferred
# ::snt Finally, among cetuximab-treated patients with AREG-low tumours, those with mutant KRAS fared significantly better than patients harbouring colon cancer with KRAS wild type (81% decreased risk of death).
# ::save-date Thu Dec 10, 2015 ::file pmid_2337_4602_134.txt
(f / fare-01
      :ARG0 (p6 / person
            :ARG1-of (i / include-91
                  :ARG2 (p / person
                        :ARG1-of (t2 / treat-03
                              :ARG3 (s2 / small-molecule :name (n3 / name :op1 "cetuximab")))
                        :poss (t / tumor
                              :mod (p5 / protein :name (n4 / name :op1 "AREG")
                                    :ARG1-of (l / low-04)))
                        :ARG0-of (h2 / have-rel-role-91
                              :ARG2 (p4 / patient))))
            :mod (e2 / enzyme :name (n / name :op1 "KRAS")
                  :ARG2-of (m4 / mutate-01)))
      :ARG1-of (w2 / well-09
            :mod (m2 / more)
            :ARG1-of (s / significant-02)
            :ARG1-of (m3 / mean-01
                  :ARG2 (r / risk-01
                        :ARG2 (d2 / die-01)
                        :ARG1-of (d3 / decrease-01
                              :ARG2 (p3 / percentage-entity :value 81))))
            :degree (m / more))
      :compared-to (p2 / person
            :ARG0-of (h / harbor-01
                  :ARG1 (d / disease :wiki "Colorectal_cancer" :name (n5 / name :op1 "colon" :op2 "cancer")
                        :mod (e / enzyme :name (n2 / name :op1 "KRAS")
                              :mod (w / wild-type))))
            :ARG0-of h2)
      :time (f2 / final))

# ::id pmid_2337_4602.135 ::date 2015-08-09T15:29:57 ::annotator SDL-AMR-09 ::preferred
# ::snt <sec-title level="2">Impact of distinct types of KRAS and PIK3CA mutations on outcome of cetuximab-treated patients</sec-title>
# ::save-date Thu Dec 10, 2015 ::file pmid_2337_4602_135.txt
(i / impact-01
      :ARG0 (t / type
            :mod (d / distinct)
            :mod (m / mutate-01
                  :ARG1 (a / and
                        :op1 (g2 / gene :name (n2 / name :op1 "KRAS"))
                        :op2 (g3 / gene :name (n3 / name :op1 "PIK3CA")))))
      :ARG1 (o / outcome
            :topic (p / person
                  :ARG1-of (t2 / treat-03
                        :ARG3 (s / small-molecule :name (n4 / name :op1 "cetuximab")))
                  :ARG0-of (h / have-rel-role-91
                        :ARG2 (p2 / patient)))))

# ::id pmid_2337_4602.136 ::date 2015-08-09T23:28:02 ::annotator SDL-AMR-09 ::preferred
# ::snt We examined different types of KRAS and PIK3CA mutations for potentially distinct impact on patient survival.
# ::save-date Thu Dec 10, 2015 ::file pmid_2337_4602_136.txt
(e / examine-01
      :ARG0 (w / we)
      :ARG1 (t / type
            :mod (m / mutate-01
                  :ARG2 (a / and
                        :op1 (g2 / gene :name (n2 / name :op1 "KRAS"))
                        :op2 (g3 / gene :name (n3 / name :op1 "PIK3CA"))))
            :ARG1-of (d / differ-02))
      :ARG2 (i / impact-01
            :ARG0 t
            :ARG1 (s / survive-01
                  :ARG0 (p / person
                        :ARG0-of (h / have-rel-role-91
                              :ARG2 (p3 / patient))))
            :mod (d2 / distinct
                  :mod (p2 / potential))))

# ::id pmid_2337_4602.137 ::date 2015-08-09T23:33:11 ::annotator SDL-AMR-09 ::preferred
# ::snt Regarding KRAS, cetuximab-treated patients with codon 12 mutations had a median survival of 19 months (95% CI 15–26), significantly lower (p=0.033) than the median survival of patients with other KRAS mutations (30 months, 95% CI 20–35) and that of patients with wild-type KRAS (29 months, 95% CI 25–35).
# ::save-date Sun Jan 3, 2016 ::file pmid_2337_4602_137.txt
(h / have-03
      :ARG0 (p / person
            :ARG1-of (t / treat-03
                  :ARG3 (s / small-molecule :name (n2 / name :op1 "cetuximab")))
            :poss (m2 / mutate-01
                  :ARG1 (c / codon :mod 12))
            :ARG0-of (h2 / have-rel-role-91
                  :ARG2 (p2 / patient)))
      :ARG1 (s2 / survive-01
            :mod (m3 / median)
            :duration (t2 / temporal-quantity :quant 19
                  :unit (m4 / month))
            :ARG1-of (m5 / mean-01
                  :ARG2 (i / interval
                        :mod (p3 / percentage-entity :value 95)
                        :mod (v / value-interval :op1 15 :op2 26)
                        :mod (c2 / confidence)))
            :ARG1-of (l / low-04
                  :degree (m6 / more)
                  :ARG1-of (s3 / significant-02)
                  :compared-to (a / and
                        :op1 (s4 / survive-01
                              :ARG0 (p5 / person
                                    :poss (m8 / mutate-01
                                          :ARG1 g
                                          :mod (o / other))
                                    :ARG0-of h2)
                              :mod m3
                              :ARG1-of (m9 / mean-01
                                    :ARG2 (i2 / interval
                                          :mod (v2 / value-interval :op1 20 :op2 35)
                                          :mod p3
                                          :mod c2)
                                    :duration (t3 / temporal-quantity :quant 30
                                          :unit m4)))
                        :op2 (s5 / survive-01
                              :ARG0 (p6 / person
                                    :poss (g2 / gene :name (n3 / name :op1 "KRAS")
                                          :mod (w / wild-type))
                                    :ARG0-of h2)
                              :ARG1-of (m10 / mean-01
                                    :ARG2 (i3 / interval
                                          :mod (v3 / value-interval :op1 25 :op2 35)
                                          :mod c2)
                                    :duration (t4 / temporal-quantity :quant 29
                                          :unit m4))))
                  :ARG1-of (s6 / statistical-test-91
                        :ARG2 0.033)))
      :topic (g / gene :name (n / name :op1 "KRAS")))

# ::id pmid_2337_4602.138 ::date 2015-08-10T00:18:36 ::annotator SDL-AMR-09 ::preferred
# ::snt Further subgroup analyses showed that the median survival in patients with codon 12 KRAS mutations was also lower than the median survival of all other patient subgroups (other KRAS mutations or KRAS wild-type).
# ::save-date Thu Dec 10, 2015 ::file pmid_2337_4602_138.txt
(s / show-01
      :ARG0 (a / analyze-01
            :ARG1 (s2 / subgroup)
            :degree (f / further))
      :ARG1 (s3 / survive-01
            :ARG0 (p / person
                  :poss (m3 / mutate-01
                        :ARG1 (c / codon :mod 12
                              :part-of (g / gene :name (n / name :op1 "KRAS"))))
                  :ARG0-of (h / have-rel-role-91
                        :ARG2 (p2 / patient)))
            :mod (m2 / median)
            :ARG1-of (l / low-04
                  :degree (m4 / more)
                  :compared-to (s4 / survive-01
                        :ARG0 (s5 / subgroup
                              :mod (o / other)
                              :mod (a2 / all)
                              :ARG1-of (m5 / mean-01
                                    :ARG2 (o2 / or
                                          :op1 (m6 / mutate-01
                                                :ARG2 g
                                                :mod (o3 / other))
                                          :op2 (g2 / gene :name (n2 / name :op1 "KRAS")
                                                :mod (w / wild-type))))
                              :consist-of (p3 / person
                                    :ARG0-of h))
                        :mod m2)
                  :mod (a3 / also))))

# ::id pmid_2337_4602.139 ::date 2015-08-10T00:49:50 ::annotator SDL-AMR-09 ::preferred
# ::snt Specifically, patients with codon 13 mutations reached a median survival of 28 months (95% CI 16–39), those with other rarer KRAS mutations a median survival of 33 months (95% CI 16–42) and patients with KRAS wild-type tumours a median survival of 29 months (95% CI 25–35).
# ::save-date Sat Jan 30, 2016 ::file pmid_2337_4602_139.txt
(a / and
      :op1 (p / person
            :poss (m / mutate-01
                  :ARG1 (c / codon :mod 13))
            :ARG0-of (r / reach-01
                  :ARG1 (s2 / survive-01
                        :mod (m2 / median)
                        :duration (t / temporal-quantity :quant 28
                              :unit (m3 / month))
                        :ARG1-of (m4 / mean-01
                              :ARG2 (i / interval
                                    :mod (p3 / percentage-entity :value 95)
                                    :mod (v / value-interval :op1 16 :op2 39)
                                    :mod (c2 / confidence)))))
            :ARG0-of (h / have-rel-role-91
                  :ARG2 (p5 / patient)))
      :op2 (p2 / person
            :poss (m5 / mutate-01
                  :ARG1 (g / gene :name (n / name :op1 "KRAS"))
                  :mod (o / other)
                  :ARG1-of (r4 / rare-02
                        :degree (m8 / more)))
            :ARG0-of (r2 / reach-01
                  :ARG1 (s3 / survive-01
                        :mod m2
                        :duration (t2 / temporal-quantity :quant 33
                              :unit m3)
                        :ARG1-of (m6 / mean-01
                              :ARG2 (i2 / interval
                                    :mod (v2 / value-interval :op1 16 :op2 42)
                                    :mod p3
                                    :mod c2))))
            :ARG0-of h)
      :op3 (p4 / person
            :poss (t3 / tumor
                  :mod (g2 / gene :name (n2 / name :op1 "KRAS")
                        :mod (w / wild-type)))
            :ARG0-of (r3 / reach-01
                  :ARG1 (s4 / survive-01
                        :mod m2
                        :duration (t4 / temporal-quantity :quant 29
                              :unit m3)
                        :ARG1-of (m7 / mean-01
                              :ARG2 (i3 / interval
                                    :mod (v3 / value-interval :op1 25 :op2 35)
                                    :mod p3
                                    :mod c2))))
            :ARG0-of h)
      :ARG1-of (s / specific-02))

# ::id pmid_2337_4602.140 ::date 2015-08-10T01:00:58 ::annotator SDL-AMR-09 ::preferred
# ::snt Despite the rather small size of compared subgroups, a trend for statistical significance was evident (p=0.068, Figure  <xref ref-type="fig" rid="F4">4</xref>).
# ::save-date Tue Dec 15, 2015 ::file pmid_2337_4602_140.txt
(e / evidence-01
      :ARG1 (t / trend-01
            :ARG2 (s / signify-01
                  :mod (s2 / statistic)))
      :concession (s3 / size-01
            :ARG1 (s5 / subgroup
                  :ARG1-of (c / compare-01))
            :ARG2 (s4 / small
                  :degree (r / rather)))
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod 4))
      :ARG1-of (s6 / statistical-test-91
            :ARG2 0.068))

# ::id pmid_2337_4602.141 ::date 2015-08-10T01:07:42 ::annotator SDL-AMR-09 ::preferred
# ::snt No difference in patient outcomes was found when we compared tumours with PIK3CA exon 9 versus exon 20 mutations versus PIK3CA wild-type status, as survival times clustered from 25 to 29 months (p=0.31).
# ::save-date Tue Dec 15, 2015 ::file pmid_2337_4602_141.txt
(f / find-01 :polarity -
      :ARG1 (d / differ-02
            :ARG1 (o / outcome
                  :poss-of (p / person
                        :ARG0-of (h / have-rel-role-91
                              :ARG2 (p3 / patient)))))
      :time (c / compare-01
            :ARG0 (w / we)
            :ARG1 (t / tumor
                  :poss (a / and
                        :op1 (m / mutate-01
                              :ARG2 (e / exon :mod 9
                                    :part-of (g2 / gene :name (n2 / name :op1 "PIK3CA"))))
                        :op2 (m2 / mutate-01
                              :ARG2 (e2 / exon :mod 20
                                    :part-of g2))
                        :op3 (g3 / gene :name (n3 / name :op1 "PIK3CA")
                              :poss (s / status
                                    :mod (w2 / wild-type))))))
      :ARG1-of (c2 / cause-01
            :ARG0 (t2 / time
                  :duration-of (s2 / survive-01)
                  :ARG1-of (c3 / cluster-01
                        :duration (v / value-interval
                              :op1 (t3 / temporal-quantity :quant 25
                                    :unit (m3 / month))
                              :op2 (t4 / temporal-quantity :quant 29
                                    :unit m3)))))
      :ARG1-of (s3 / statistical-test-91
            :ARG2 0.31))

# ::id pmid_2337_4602.142 ::date 2015-08-10T01:33:42 ::annotator SDL-AMR-09 ::preferred
# ::snt The only complex genotype that harboured significance for cetuximab benefit was CG3 (p=0.019): Patients with tumours wild-type for all PIK3CA, KRAS, BRAF reached a median survival of 32 months (95% CI 25–36), those with a PIK3CA mutation along with KRAS or BRAF mutation had a median survival of 26 months (95% CI 16–32) while patients with any single mutation in KRAS, BRAF or PIK3CA genes had a median survival of 22 months (95% CI 19–28).
# ::save-date Sun Jan 17, 2016 ::file pmid_2337_4602_142.txt
(m / multi-sentence
      :snt1 (h / harbor-01
            :ARG0 (g2 / genotype
                  :mod (c / complex)
                  :mod (o / only)
                  :domain (d / dna-sequence :name (n / name :op1 "CG3")))
            :ARG1 (s / significant-02
                  :ARG1 (b / benefit-01
                        :ARG0 (s2 / small-molecule :name (n2 / name :op1 "cetuximab")))
                  :ARG1-of (s7 / statistical-test-91
                        :ARG2 0.019)))
      :snt2 (a / and
            :op1 (r / reach-01
                  :ARG0 (p / person
                        :poss (t / tumor
                              :mod (g / gene :name (n3 / name :op1 "PIK3CA")
                                    :mod (w / wild-type)))
                        :ARG0-of (h4 / have-rel-role-91
                              :ARG2 (p5 / patient))
                        :poss (t6 / tumor
                              :mod (e2 / enzyme :name (n4 / name :op1 "KRAS")
                                    :mod w))
                        :poss (t7 / tumor
                              :mod (e3 / enzyme :name (n5 / name :op1 "BRAF")
                                    :mod w)))
                  :ARG1 (s3 / survive-01
                        :ARG0 p
                        :mod (m2 / median)
                        :duration (t2 / temporal-quantity :quant 32
                              :unit (m3 / month))
                        :ARG1-of (m4 / mean-01
                              :ARG2 (i / interval
                                    :mod (p4 / percentage-entity :value 95)
                                    :mod (v / value-interval :op1 25 :op2 36)
                                    :mod (c2 / confidence)))))
            :op2 (h2 / have-03
                  :ARG0 (p7 / person
                        :poss (a4 / and
                              :op1 (m5 / mutate-01
                                    :ARG2 g)
                              :op2 (o2 / or
                                    :op1 (m6 / mutate-01
                                          :ARG2 e2)
                                    :op2 (m7 / mutate-01
                                          :ARG2 e3)))
                        :ARG0-of h4)
                  :ARG1 (s4 / survive-01
                        :ARG0 p7
                        :mod m2
                        :duration (t3 / temporal-quantity :quant 26
                              :unit m3)
                        :ARG1-of (m8 / mean-01
                              :ARG2 (i2 / interval
                                    :mod (v2 / value-interval :op1 16 :op2 32)
                                    :mod p4
                                    :mod c2))))
            :op3 (h3 / have-03
                  :ARG0 (p3 / person
                        :poss (m9 / mutate-01
                              :ARG2 (o3 / or
                                    :op1 g
                                    :op2 e2
                                    :op3 e3)
                              :ARG1-of (s5 / single-02))
                        :ARG0-of h4)
                  :ARG1 (s6 / survive-01
                        :ARG0 p3
                        :mod m2
                        :duration (t5 / temporal-quantity :quant 22
                              :unit m3)
                        :ARG1-of (m10 / mean-01
                              :ARG2 (i3 / interval
                                    :mod (v3 / value-interval :op1 19 :op2 28)
                                    :mod p4
                                    :mod c2))))))

# ::id pmid_2337_4602.143 ::date 2015-08-10T02:09:16 ::annotator SDL-AMR-09 ::preferred
# ::snt Apparently, concurrent mutations in PIK3CA along with KRAS or BRAF mutations carried rather weak additional adverse prediction.
# ::save-date Sat Jan 16, 2016 ::file pmid_2337_4602_143.txt
(c / carry-01
      :ARG0 (a4 / and
            :op1 (m / mutate-01
                  :ARG2 (e3 / enzyme :name (n2 / name :op1 "PIK3CA"))
                  :ARG1-of (c2 / concurrent-02))
            :op2 (m2 / mutate-01
                  :ARG2 (o / or
                        :op1 (e / enzyme :name (n3 / name :op1 "KRAS"))
                        :op2 (e2 / enzyme :name (n4 / name :op1 "BRAF")))))
      :ARG1 (p / predict-01
            :mod (a2 / adverse)
            :mod (a3 / additional)
            :ARG1-of (w / weak-02
                  :degree (r / rather)))
      :manner (a / apparent))

# ::id pmid_2352_4590.1 ::date 2015-07-23T06:02:47 ::annotator SDL-AMR-09 ::preferred
# ::snt MEK inhibitors as a chemotherapeutic intervention in multiple myeloma (PMID:23524590)
# ::save-date Sat Jan 16, 2016 ::file pmid_2352_4590_1.txt
(i / inhibit-01
      :ARG0 (m / molecular-physical-entity
            :prep-as (i2 / intervene-01
                  :ARG1 (d / disease :name (n2 / name :op1 "multiple" :op2 "myeloma"))
                  :mod (c / chemotherapy)))
      :ARG1 (p2 / protein-family :name (n / name :op1 "MEK"))
      :ARG1-of (d2 / describe-01
            :ARG0 (p / publication-91
                  :ARG8 "PMID23524590")))

# ::id pmid_2352_4590.2 ::date 2015-07-23T23:15:50 ::annotator SDL-AMR-09 ::preferred
# ::snt The Ras/Raf/MEK/extracellular signal regulated kinase (ERK) (Ras/mitogen-activated protein kinases (MAPK)) signal transduction pathway is a crucial mediator of many fundamental biological processes, including cellular proliferation, survival, angiogenesis and migration.
# ::save-date Tue Jan 19, 2016 ::file pmid_2352_4590_2.txt
(m / mediate-01
      :ARG0 (p3 / pathway :name (n / name :op1 "MAPK")
            :ARG0-of (t / transduce-01
                  :ARG1 (s2 / signal-07))
            :mod (c2 / crucial))
      :ARG1 (p / process-02
            :ARG1 (b / biology)
            :mod (f / fundamental)
            :mod (m2 / many)
            :ARG2-of (i / include-91
                  :ARG1 (a / and
                        :op1 (p2 / proliferate-01
                              :ARG0 (c / cell))
                        :op2 (s / survive-01
                              :ARG0 c)
                        :op3 (a2 / angiogenesis
                              :mod c)
                        :op4 (m3 / migrate-01
                              :ARG0 c)))))

# ::id pmid_2352_4590.3 ::date 2015-07-23T23:31:20 ::annotator SDL-AMR-09 ::preferred
# ::snt Aberrant signalling through the Ras/MAPK cascade is common in a wide array of malignancies, including multiple myeloma (MM), making it an appealing candidate for the development of novel targeted therapies.
# ::save-date Fri Jan 1, 2016 ::file pmid_2352_4590_3.txt
(c / common
      :domain (s / signal-07
            :ARG0 (p / pathway :name (n / name :op1 "Ras/MAPK"))
            :mod (a / aberrant))
      :location (a2 / array
            :ARG1-of (w / wide-02)
            :consist-of (m / malignancy
                  :ARG2-of (i / include-91
                        :ARG1 (d / disease :name (n2 / name :op1 "multiple" :op2 "myeloma")))))
      :ARG0-of (m2 / make-02
            :ARG1 (c3 / candidate
                  :ARG0-of (a3 / appeal-03)
                  :purpose (d2 / develop-02
                        :ARG1 (t / therapy
                              :ARG0-of (t2 / target-01)
                              :mod (n3 / novel)))
                  :domain s)))

# ::id pmid_2352_4590.4 ::date 2015-07-23T23:44:37 ::annotator SDL-AMR-09 ::preferred
# ::snt In this review, we explore our current understanding of the Ras/MAPK pathway and its role in MM.
# ::save-date Tue Aug 4, 2015 ::file pmid_2352_4590_4.txt
(e / explore-01
      :ARG0 (w / we)
      :ARG1 (u / understand-01
            :ARG0 w
            :ARG1 (a / and
                  :op1 (p / pathway :name (n / name :op1 "Ras/MAPK"))
                  :op2 (r / role
                        :topic (d / disease :name (n2 / name :op1 "multiple" :op2 "myeloma"))
                        :poss p))
            :mod (c / current))
      :medium (r2 / review
            :mod (t / this)))

# ::id pmid_2352_4590.5 ::date 2015-07-23T23:48:15 ::annotator SDL-AMR-09 ::preferred
# ::snt Additionally, we summarise the current status of small molecule inhibitors of MEK under clinical evaluation, and discuss future approaches required to optimise their use.
# ::save-date Sat Jan 16, 2016 ::file pmid_2352_4590_5.txt
(a / and
      :op1 (s / summarize-01
            :ARG0 (w / we)
            :ARG2 (s2 / status
                  :mod (c / current)
                  :mod (s4 / small-molecule
                        :ARG0-of (i / inhibit-01
                              :ARG1 (p / protein-family :name (n / name :op1 "MEK")))
                        :mod (m2 / molecule
                              :mod (s3 / small))
                        :ARG1-of (e2 / evaluate-01
                              :mod (c2 / clinic)))))
      :op2 (d / discuss-01
            :ARG0 w
            :ARG1 (a2 / approach-02
                  :mod (f / future)
                  :ARG1-of (r / require-01
                        :ARG0 (o / optimize-01
                              :ARG1 (u / use-01
                                    :ARG1 s4)))))
      :manner (a3 / additional))

# ::id pmid_2352_4590.6 ::date 2015-07-23T23:58:30 ::annotator SDL-AMR-09 ::preferred
# ::snt <sec-title level="1">Introduction</sec-title>
# ::save-date Tue Aug 4, 2015 ::file pmid_2352_4590_6.txt
(i / introduce-01)

# ::id pmid_2352_4590.7 ::date 2015-07-23T23:59:32 ::annotator SDL-AMR-09 ::preferred
# ::snt Mitogen-activated protein kinases (MAPKs) are a family of ubiquitously expressed serine/threonine kinases that transmit diverse cell surface signals throughout the cell.
# ::save-date Mon Jan 4, 2016 ::file pmid_2352_4590_7.txt
(p / protein-family
      :mod (o / or
            :op1 (e2 / enzyme :name (n2 / name :op1 "serine" :op2 "kinase"))
            :op2 (e3 / enzyme :name (n3 / name :op1 "threonine" :op2 "kinase"))
            :ARG2-of (e / express-03
                  :manner (u / ubiquitous))
            :ARG0-of (t2 / transmit-01
                  :ARG1 (s2 / signal-07
                        :mod (s3 / surface
                              :mod (c / cell))
                        :mod (d / diverse))
                  :ARG2 (t3 / throughout
                        :op1 (c2 / cell))))
      :domain (e4 / enzyme :name (n4 / name :op1 "Mitogen-activated" :op2 "protein" :op3 "kinase")))

# ::id pmid_2352_4590.8 ::date 2015-07-24T00:08:59 ::annotator SDL-AMR-09 ::preferred
# ::snt MAPK pathways consist of a three-tiered signalling module activated via a phosphorylation cascade.
# ::save-date Fri Jul 24, 2015 ::file pmid_2352_4590_8.txt
(c / consist-01
      :ARG1 (p / pathway :name (n / name :op1 "MAPK"))
      :ARG2 (m / module
            :ARG0-of (s / signal-07)
            :ARG1-of (a / activate-01
                  :instrument (c2 / cascade
                        :mod (p2 / phosphorylate-01)))
            :mod (t / tier :quant 3)))

# ::id pmid_2352_4590.9 ::date 2015-07-24T00:14:02 ::annotator SDL-AMR-09 ::preferred
# ::snt The most proximal kinase in these pathways, the MAPK kinase kinase (MAPKKK or MAP3k), engaged by extracellular signals, phosphorylates a dual specificity MAPK kinase (MAPKK or MAP2K), which in turn phosphorylates and actives the distil effector MAPK.
# ::save-date Mon Jan 4, 2016 ::file pmid_2352_4590_9.txt
(p / phosphorylate-01
      :ARG1 (e6 / enzyme :name (n2 / name :op1 "MAPK")
            :mod (s2 / specificity
                  :mod (d / dual))
            :ARG1-of (m2 / mean-01
                  :ARG2 (e4 / enzyme :name (n3 / name :op1 "MAPK" :op2 "kinase" :op3 "kinase")))
            :ARG2-of (p8 / phosphorylate-01
                  :ARG1 (e7 / effector
                        :mod (d2 / distal)
                        :mod (e3 / enzyme :name (n / name :op1 "MAPK")))
                  :mod (i3 / in-turn))
            :ARG0-of (a / activate-01
                  :ARG1 e7
                  :manner i3))
      :ARG2 (e5 / enzyme :name (n4 / name :op1 "MAPK" :op2 "kinase" :op3 "kinase")
            :ARG1-of (i / include-91
                  :ARG2 (p3 / pathway
                        :mod (t / this)))
            :ARG1-of (e / engage-01
                  :ARG0 (s / signal-07
                        :mod (e2 / extracellular)))
            :mod (p4 / proximal
                  :degree (m / most))))

# ::id pmid_2352_4590.10 ::date 2015-07-24T00:33:32 ::annotator SDL-AMR-09 ::preferred
# ::snt Mammalian MAPK pathways are represented by the Extracellular Signal Regulated Kinase (ERK), c-Jun N-terminal kinase, p38, ERK 5, ERK 3/4 and ERK 7/8 pathways.<sup><xref ref-type="bibr" rid="bib1">1</xref></sup>
# ::save-date Fri Jul 24, 2015 ::file pmid_2352_4590_10.txt
(r / represent-01
      :ARG0 (a / and
            :op1 (p2 / pathway :name (n2 / name :op1 "ERK"))
            :op2 (p3 / pathway :name (n3 / name :op1 "c-Jun" :op2 "N-terminal" :op3 "kinase"))
            :op3 (p4 / pathway :name (n4 / name :op1 "p38"))
            :op4 (p5 / pathway :name (n5 / name :op1 "ERK5"))
            :op5 (p6 / pathway :name (n6 / name :op1 "ERK3/4"))
            :op6 (p7 / pathway :name (n7 / name :op1 "ERK7/8")))
      :ARG1 (p / pathway :name (n / name :op1 "MAPK")
            :mod (m / mammal))
      :ARG1-of (d / describe-01
            :ARG0 (p8 / publication-91
                  :ARG1-of (c / cite-01
                        :ARG2 1))))

# ::id pmid_2352_4590.11 ::date 2015-07-23T06:04:41 ::annotator SDL-AMR-09 ::preferred
# ::snt The Ras/MAPK pathway is the best characterised of the mammalian MAPK signal transduction networks, consisting of the Ras proteins, a family of small G-coupled molecules, the Raf kinases (MAP3K), the MAP2K kinases (MEK1 and MEK2) and the pathway distil kinases ERK1 and ERK2.
# ::save-date Tue Jan 19, 2016 ::file pmid_2352_4590_11.txt
(c / characterize-01
      :ARG1 (p / pathway :name (n / name :op1 "Ras/MAPK")
            :ARG1-of (i / include-91
                  :ARG2 (n2 / network
                        :ARG2-of (t / transduce-01
                              :ARG1 (s / signal-07))
                        :mod (p2 / pathway :name (n3 / name :op1 "MAPK"))
                        :mod (m2 / mammal)
                        :ARG1-of (c2 / consist-01
                              :ARG2 (a / and
                                    :op1 (p3 / protein-family :name (n4 / name :op1 "Ras"))
                                    :op2 (f / family
                                          :ARG2-of (i3 / include-91
                                                :ARG1 (m3 / molecule
                                                      :mod (s2 / small)
                                                      :ARG1-of (c3 / couple-01
                                                            :ARG2 (p4 / protein :name (n5 / name :op1 "G"))))))
                                    :op3 (p6 / protein-family :name (n6 / name :op1 "Raf")
                                          :ARG2-of (i4 / include-91
                                                :ARG1 (k7 / kinase :name (n12 / name :op1 "MAP3K"))))
                                    :op4 (k2 / kinase :name (n7 / name :op1 "MAP2K")
                                          :ARG2-of (i2 / include-91
                                                :ARG1 (a2 / and
                                                      :op1 (k3 / kinase :name (n8 / name :op1 "MEK1"))
                                                      :op2 (k4 / kinase :name (n9 / name :op1 "MEK2")))))
                                    :op5 (a3 / and
                                          :op1 (k5 / kinase :name (n10 / name :op1 "ERK1")
                                                :mod (d / distal)
                                                :mod (p5 / pathway))
                                          :op2 (k6 / kinase :name (n11 / name :op1 "ERK2")
                                                :mod d
                                                :mod p5)))))))
      :ARG1-of (g / good-02
            :degree (m / most)))

# ::id pmid_2352_4590.12 ::date 2015-07-24T00:59:06 ::annotator SDL-AMR-09 ::preferred
# ::snt The Ras/MAPK network is frequently deregulated in malignancy and contributes to many of the hallmarks of oncogenesis, including abnormal cellular proliferation, impaired apoptosis, enhanced angiogenesis, metastasis and the development of drug resistance.<sup><xref ref-type="bibr" rid="bib2">2</xref></sup>
# ::save-date Sun Dec 20, 2015 ::file pmid_2352_4590_12.txt
(a / and
      :op1 (d / deregulate-01
            :ARG1 (p3 / pathway :name (n2 / name :op1 "Ras/MAPK"))
            :ARG1-of (f / frequent-02)
            :location (m / malignancy))
      :op2 (c / contribute-01
            :ARG0 p3
            :ARG2 (h / hallmark
                  :quant (m2 / many)
                  :ARG2-of (i / include-91
                        :ARG1 (a2 / and
                              :op1 (p / proliferate-01
                                    :ARG0 (c3 / cell)
                                    :mod (a3 / abnormal))
                              :op2 (a4 / apoptosis
                                    :ARG1-of (i2 / impair-01))
                              :op3 (a5 / angiogenesis
                                    :ARG1-of (e / enhance-01))
                              :op4 (m3 / metastasis)
                              :op5 (d2 / develop-01
                                    :ARG2 (r / resist-01
                                          :ARG1 (d3 / drug)))))
                  :mod (d5 / disease :wiki "Cancer" :name (n3 / name :op1 "cancer")
                        :ARG1-of (o / originate-01))))
      :ARG1-of (d4 / describe-01
            :ARG0 (p2 / publication-91
                  :ARG1-of (c4 / cite-01
                        :ARG2 2))))

# ::id pmid_2352_4590.13 ::date 2015-07-24T01:08:33 ::annotator SDL-AMR-09 ::preferred
# ::snt MEK lies at a critical juncture within the Ras/MAPK pathway, having a limited number of direct upstream MAP3K activators and ERK1/2 as its only known cellular targets, thereby making it an attractive target for cancer therapy.
# ::save-date Tue Dec 22, 2015 ::file pmid_2352_4590_13.txt
(l / lie-07
      :ARG1 (e / enzyme :name (n / name :op1 "MEK")
            :ARG0-of (h / have-03
                  :ARG1 (a2 / and
                        :op1 (n3 / number
                              :ARG1-of (l2 / limit-01)
                              :quant-of (m / molecular-physical-entity
                                    :ARG0-of (a / activate-01
                                          :ARG1 (e2 / enzyme :name (n4 / name :op1 "MAP3K")))
                                    :ARG1-of (d / direct-02)
                                    :mod (u / upstream)))
                        :op2 (e3 / enzyme :name (n5 / name :op1 "ERK1/2"))
                        :ARG1-of (t / target-01
                              :ARG1-of (k / know-01)
                              :mod (o / only)
                              :mod (c2 / cell)))))
      :ARG2 (j / juncture
            :ARG1-of (c / critical-02)
            :location (p / pathway :name (n2 / name :op1 "Ras/MAPK")))
      :ARG0-of (m2 / make-02
            :ARG1 (t2 / target-01
                  :ARG0 (t4 / therapy
                        :mod (d2 / disease :wiki "Cancer" :name (n6 / name :op1 "cancer")))
                  :ARG1 e
                  :ARG0-of (a3 / attract-01))))

# ::id pmid_2352_4590.14 ::date 2015-07-24T01:26:56 ::annotator SDL-AMR-09 ::preferred
# ::snt Several MEK inhibitors have been developed and investigated in preclinical and clinical models.
# ::save-date Sat Jan 16, 2016 ::file pmid_2352_4590_14.txt
(a / and
      :op1 (d / develop-02
            :ARG1 (m / molecular-physical-entity
                  :ARG0-of (i / inhibit-01
                        :ARG1 (p2 / protein-family :name (n / name :op1 "MEK")))
                  :quant (s / several)))
      :op2 (i2 / investigate-01
            :ARG1 m)
      :location (a2 / and
            :op1 (m2 / model
                  :mod (p / preclinical))
            :op2 (m3 / model
                  :mod (c / clinic))))

# ::id pmid_2352_4590.15 ::date 2015-07-24T01:30:47 ::annotator SDL-AMR-09 ::preferred
# ::snt Results from these studies have been promising and suggest that MEK inhibitors, whether alone or in combination with other anticancer therapies, may have a significant role to play in the future management of malignancy.
# ::save-date Sat Jan 16, 2016 ::file pmid_2352_4590_15.txt
(a / and
      :op1 (p / promise-01
            :ARG0 (t / thing
                  :ARG2-of (r / result-01
                        :ARG1 (s / study-01
                              :mod (t2 / this)))))
      :op2 (s2 / suggest-01
            :ARG0 t
            :ARG1 (p2 / possible-01
                  :ARG1 (p3 / play-08
                        :ARG0 (m / molecular-physical-entity
                              :ARG0-of (i / inhibit-01
                                    :ARG1 (p4 / protein-family :name (n / name :op1 "MEK"))))
                        :ARG1 (m2 / manage-01
                              :ARG1 (m3 / malignancy)
                              :mod (f / future))
                        :ARG1-of (s3 / significant-02)
                        :manner (o / or
                              :op1 (a2 / alone)
                              :op2 (c / combine-01
                                    :ARG1 m
                                    :ARG2 (t3 / therapy
                                          :ARG0-of (c2 / counter-01
                                                :ARG1 (d / disease :wiki "Cancer" :name (n2 / name :op1 "cancer")))
                                          :mod (o2 / other))))))))

# ::id pmid_2352_4590.16 ::date 2015-07-24T01:43:42 ::annotator SDL-AMR-09 ::preferred
# ::snt Current management strategies for multiple myeloma (MM) involve conventional chemotherapeutics and novel anti-MM agents (thalidomide, lenalidomide and bortezomib), with or without subsequent autologous stem cell transplantation.<sup><xref ref-type="bibr" rid="bib3">3</xref></sup>
# ::save-date Mon Nov 16, 2015 ::file pmid_2352_4590_16.txt
(i / involve-01
      :ARG1 (a / and
            :op1 (t / thing
                  :mod (c2 / chemotherapy)
                  :mod (c3 / conventional))
            :op2 (a2 / agent
                  :mod (n2 / novel)
                  :ARG0-of (c4 / counter-01
                        :ARG1 d)
                  :ARG2-of (i2 / include-91
                        :ARG1 (a3 / and
                              :op1 (s4 / small-molecule :name (n3 / name :op1 "thalidomide"))
                              :op2 (s5 / small-molecule :name (n4 / name :op1 "lenalidomide"))
                              :op3 (s6 / small-molecule :name (n5 / name :op1 "bortezomib"))))))
      :ARG2 (s / strategy
            :mod (m / manage-01)
            :mod (c / current)
            :prep-for (d / disease :name (n / name :op1 "multiple" :op2 "myeloma")))
      :ARG1-of (d2 / describe-01
            :ARG0 (p / publication-91
                  :ARG1-of (c6 / cite-01
                        :ARG2 3)))
      :manner (o / or
            :op1 (a4 / accompany-01
                  :ARG0 (t3 / transplant-01
                        :ARG1 (c5 / cell
                              :mod (s2 / stem))
                        :mod (a5 / autologous))
                  :ARG1 a
                  :mod (s3 / subsequent))
            :op2 (a6 / accompany-01 :polarity -
                  :ARG0 t3
                  :ARG1 a)))

# ::id pmid_2352_4590.17 ::date 2015-07-24T01:54:22 ::annotator SDL-AMR-09 ::preferred
# ::snt Although these anticancer therapies are typically effective initially, MM remains a fatal and largely incurable disease.
# ::save-date Fri Jan 1, 2016 ::file pmid_2352_4590_17.txt
(h / have-concession-91
      :ARG1 (r / remain-01
            :ARG1 (d / disease :name (n / name :op1 "multiple" :op2 "myeloma"))
            :ARG3 (a / and
                  :op1 (d2 / disease
                        :mod (f / fatal))
                  :op2 (d3 / disease
                        :ARG2-of (c3 / cure-01
                              :manner (l / large)
                              :ARG1-of (p / possible-01 :polarity -)))))
      :ARG2 (e / effective-04
            :ARG0 (t / therapy
                  :ARG0-of (c / counter-01
                        :ARG1 (d4 / disease :wiki "Cancer" :name (n2 / name :op1 "cancer")))
                  :mod (t2 / this))
            :time (i / initial)
            :ARG1-of (t3 / typical-02)))

# ::id pmid_2352_4590.18 ::date 2015-07-24T02:00:59 ::annotator SDL-AMR-09 ::preferred
# ::snt This is due to the high frequency of relapse and the eventual development of drug resistance.
# ::save-date Mon Dec 21, 2015 ::file pmid_2352_4590_18.txt
(c / cause-01
      :ARG0 (a / and
            :op1 (f / frequent-02
                  :ARG1 (r / relapse-01)
                  :ARG1-of (h / high-02))
            :op2 (d / develop-01
                  :ARG2 (r2 / resist-01
                        :ARG1 (d2 / drug))
                  :mod (e / eventual)))
      :ARG1 (t / this))

# ::id pmid_2352_4590.19 ::date 2015-07-24T04:09:09 ::annotator SDL-AMR-09 ::preferred
# ::snt Accumulative genetic changes within malignant plasma cells, together with MM interplay with the bone marrow microenvironment (BMME), potentiate disease progression by promoting the deregulation of multiple signal transduction networks, one of which is the Ras/MAPK pathway.<sup><xref ref-type="bibr" rid="bib4">4</xref>, <xref ref-type="bibr" rid="bib5">5</xref></sup>
# ::save-date Tue Jan 19, 2016 ::file pmid_2352_4590_19.txt
(p / potentiate-01
      :ARG1 (p3 / progress-01
            :ARG1 (d2 / disease))
      :ARG2 (a / and
            :op1 (c / change-01
                  :ARG1-of (a2 / accumulate-01)
                  :mod (g / genetics)
                  :location (c2 / cell
                        :mod (p2 / plasma)
                        :ARG1-of (m / malignant-02)))
            :op2 (i / interplay-00
                  :mod (d / disease :name (n / name :op1 "multiple" :op2 "myeloma"))
                  :prep-with (m2 / microenvironment
                        :mod (m3 / marrow
                              :mod (b / bone)))))
      :manner (p4 / promote-01
            :ARG0 a
            :ARG1 (d3 / deregulate-01
                  :ARG1 (n2 / network
                        :quant (m4 / multiple)
                        :ARG2-of (t / transduce-01
                              :ARG1 (s / signal-07))
                        :ARG2-of (i2 / include-91
                              :ARG1 (p5 / pathway :name (n3 / name :op1 "Ras/MAPK"))))))
      :ARG1-of (d4 / describe-01
            :ARG0 (p6 / publication-91
                  :ARG1-of (c3 / cite-01
                        :ARG2 (a3 / and :op1 4 :op2 5)))))

# ::id pmid_2352_4590.20 ::date 2015-07-24T04:23:20 ::annotator SDL-AMR-09 ::preferred
# ::snt This suggests that MM patients may benefit from the abrogation of this kinase network through the administration of a MEK inhibitor.
# ::save-date Thu Feb 4, 2016 ::file pmid_2352_4590_20.txt
(p / possible-01
      :ARG1 (b / benefit-01
            :ARG0 (a / abrogate-01
                  :ARG1 (n2 / network
                        :mod (k / kinase)
                        :mod (t / this))
                  :manner (a2 / administer-01
                        :ARG1 (m / molecular-physical-entity
                              :ARG0-of (i / inhibit-01
                                    :ARG1 (p4 / protein-family :name (n3 / name :op1 "MEK"))))))
            :ARG1 (p2 / person
                  :ARG0-of (h / have-rel-role-91
                        :ARG2 (p3 / patient))
                  :mod (d / disease :name (n / name :op1 "multiple" :op2 "myeloma"))))
      :ARG1-of (s / suggest-01
            :ARG0 (t2 / this)))

# ::id pmid_2352_4590.21 ::date 2015-07-24T04:32:59 ::annotator SDL-AMR-09 ::preferred
# ::snt Here, we discuss the Ras/MAPK pathway, its involvement in MM and the role of MEK inhibitors in the future management of the disease.
# ::save-date Thu Feb 4, 2016 ::file pmid_2352_4590_21.txt
(d / discuss-01
      :ARG0 (w / we)
      :ARG1 (a / and
            :op1 (p / pathway :name (n / name :op1 "Ras/MAPK"))
            :op2 (i / involve-01
                  :ARG1 p
                  :ARG2 (d2 / disease :name (n4 / name :op1 "multiple" :op2 "myeloma")))
            :op3 (r / role
                  :poss (m / molecular-physical-entity
                        :ARG0-of (i2 / inhibit-01
                              :ARG1 (p2 / protein-family :name (n3 / name :op1 "MEK"))))
                  :purpose (m2 / manage-01
                        :ARG1 d2
                        :mod (f / future))))
      :medium (h / here))

# ::id pmid_2352_4590.22 ::date 2015-07-24T04:39:27 ::annotator SDL-AMR-09 ::preferred
# ::snt <sec-title level="2">Overview of the Ras/Raf/MEK/ERK pathway</sec-title>
# ::save-date Fri Jul 24, 2015 ::file pmid_2352_4590_22.txt
(o / overview
      :poss (p / pathway :name (n / name :op1 "Ras/Raf/MEK/ERK")))

# ::id pmid_2352_4590.23 ::date 2015-07-24T04:40:21 ::annotator SDL-AMR-09 ::preferred
# ::snt Members of the Ras protein subfamily (H-, K- and N-Ras) function as molecular switches in cellular signal transduction.
# ::save-date Tue Jan 19, 2016 ::file pmid_2352_4590_23.txt
(f / function-01
      :ARG0 (m / member
            :ARG1-of (i2 / include-91
                  :ARG2 (p / protein-family :name (n / name :op1 "Ras")))
            :ARG1-of (m3 / mean-01
                  :ARG2 (a / and
                        :op1 (e / enzyme :name (n2 / name :op1 "H-Ras"))
                        :op2 (e2 / enzyme :name (n3 / name :op1 "K-Ras"))
                        :op3 (e3 / enzyme :name (n4 / name :op1 "N-Ras")))))
      :ARG1 (s2 / switch-01
            :mod (m2 / molecule))
      :time (t / transduce-01
            :ARG1 (s3 / signal-07
                  :location (c / cell))))

# ::id pmid_2352_4590.24 ::date 2015-07-24T04:54:43 ::annotator SDL-AMR-09 ::preferred
# ::snt Diverse growth factor, mitogen and cytokine engagement of cognate receptors leads to the recruitment of the GDP/GTP exchange factors, growth-factor-receptor bound protein 2 (Grp2) and Sons of Sevenless (SOS) to the plasma membrane where Ras resides.
# ::save-date Wed Feb 24, 2016 ::file pmid_2352_4590_24.txt
(l / lead-03
      :ARG0 (e / engage-01
            :ARG0 (a / and
                  :op1 (g / growth-factor)
                  :op2 (m / mitogen)
                  :op3 (c / cytokine))
            :ARG1 (r / receptor
                  :mod (c2 / cognate))
            :mod (d / diverse))
      :ARG2 (r2 / recruit-01
            :ARG1 (a2 / and
                  :op1 (f / factor
                        :ARG0-of (e3 / exchange-01
                              :ARG1 (s / small-molecule :name (n2 / name :op1 "GDP"))
                              :ARG3 (s2 / small-molecule :name (n6 / name :op1 "GTP"))))
                  :op2 (p / protein :name (n3 / name :op1 "growth-factor-receptor" :op2 "bound" :op3 "protein2"))
                  :op3 (p3 / protein :name (n4 / name :op1 "Sons" :op2 "of" :op3 "Sevenless")))
            :ARG2 (m2 / membrane
                  :mod (p2 / plasma)
                  :ARG1-of (r3 / reside-01
                        :ARG0 (e4 / enzyme :name (n5 / name :op1 "Ras"))))))

# ::id pmid_2352_4590.25 ::date 2015-07-24T05:17:19 ::annotator SDL-AMR-09 ::preferred
# ::snt The grp2/SOS complex then promotes inactive Ras to exchange GDP with GTP and enters an activated state.<sup><xref ref-type="bibr" rid="bib6">6</xref></sup>
# ::save-date Tue Aug 4, 2015 ::file pmid_2352_4590_25.txt
(p / promote-01
      :ARG0 (m / macro-molecular-complex
            :part (p3 / protein :name (n / name :op1 "grp2"))
            :part (p4 / protein :name (n5 / name :op1 "SOS")))
      :ARG1 (e / enzyme :name (n2 / name :op1 "Ras")
            :ARG1-of (a2 / activate-01 :polarity -))
      :ARG2 (a / and
            :op1 (e2 / exchange-01
                  :ARG1 (s / small-molecule :name (n3 / name :op1 "GDP"))
                  :ARG3 (s2 / small-molecule :name (n4 / name :op1 "GTP")))
            :op2 (e3 / enter-01
                  :ARG0 e
                  :ARG1 (s3 / state
                        :ARG1-of (a3 / activate-01))))
      :time (t / then)
      :ARG1-of (d / describe-01
            :ARG0 (p2 / publication-91
                  :ARG1-of (c / cite-01
                        :ARG2 6))))

# ::id pmid_2352_4590.26 ::date 2015-07-24T05:30:21 ::annotator SDL-AMR-09 ::preferred
# ::snt Activated Ras then recruits Raf to the cell membrane, where it is activated by phosphorylation.
# ::save-date Fri Jul 24, 2015 ::file pmid_2352_4590_26.txt
(r / recruit-01
      :ARG0 (e / enzyme :name (n / name :op1 "Ras")
            :ARG1-of (a / activate-01))
      :ARG1 (e2 / enzyme :name (n2 / name :op1 "Raf"))
      :ARG2 (m / membrane
            :mod (c / cell)
            :location-of (a2 / activate-01
                  :ARG1 e2
                  :manner (p / phosphorylate-01)))
      :time (t / then))

# ::id pmid_2352_4590.27 ::date 2015-07-24T05:35:25 ::annotator SDL-AMR-09 ::preferred
# ::snt This process is antagonised by GTPase-activating proteins, which promote GTP hydrolysis and the formation of inactive Ras-GDP complexes.<sup><xref ref-type="bibr" rid="bib7">7</xref></sup>
# ::save-date Mon Jan 4, 2016 ::file pmid_2352_4590_27.txt
(a / antagonize-02
      :ARG1 (p2 / protein
            :ARG0-of (a2 / activate-01
                  :ARG1 (e / enzyme :name (n / name :op1 "GTPase")))
            :ARG0-of (p3 / promote-01
                  :ARG1 (a3 / and
                        :op1 (h / hydrolyze-01
                              :ARG1 (s / small-molecule :name (n2 / name :op1 "GTP")))
                        :op2 (f / form-01
                              :ARG1 (m / macro-molecular-complex
                                    :ARG1-of (a4 / activate-01 :polarity -)
                                    :part (e2 / enzyme :name (n3 / name :op1 "Ras"))
                                    :part (s2 / small-molecule :name (n4 / name :op1 "GDP")))))))
      :ARG2 (p / process-02
            :mod (t / this))
      :ARG1-of (d / describe-01
            :ARG0 (p4 / publication
                  :ARG1-of (c / cite-01
                        :ARG2 7))))

# ::id pmid_2352_4590.28 ::date 2015-07-24T05:41:23 ::annotator SDL-AMR-09 ::preferred
# ::snt Approximately 30% of malignancies contain activating mutations in a Ras proto-oncogene, with pancreatic (90%), colon (50%) and thyroid (50%) carcinomas demonstrating the highest prevalence.
# ::save-date Wed Mar 2, 2016 ::file pmid_2352_4590_28.txt
(c / contain-01
      :ARG0 (m / malignancy
            :ARG2-of (i2 / include-91
                  :ARG1 (a2 / and
                        :op1 (c5 / carcinoma
                              :value (p4 / percentage-entity :value 90)
                              :mod (p3 / pancreas))
                        :op2 (c4 / carcinoma
                              :value (p5 / percentage-entity :value 50)
                              :mod (c6 / colon))
                        :op3 (c7 / carcinoma
                              :value (p6 / percentage-entity :value 50)
                              :mod (t2 / thyroid))
                        :ARG0-of (d / demonstrate-01
                              :ARG1 (p7 / prevalence
                                    :ARG1-of (h / high-02
                                          :degree (m3 / most))))))
            :ARG1-of (i3 / include-91
                  :ARG2 (m4 / malignancy)
                  :ARG3 (a3 / approximately
                        :op1 (p / percentage-entity :value 30))))
      :ARG1 (m2 / mutate-01
            :ARG1 (p8 / proto-oncogene
                  :ARG1-of (i / include-91
                        :ARG2 (p2 / protein-family :name (n / name :op1 "Ras"))))
            :ARG0-of (a / activate-01)))

# ::id pmid_2352_4590.29 ::date 2015-07-24T05:52:02 ::annotator SDL-AMR-09 ::preferred
# ::snt Mutations typically affect K-Ras and N-Ras, but rarely H-Ras, and occur in a mutually exclusive manner.<sup><xref ref-type="bibr" rid="bib8">8</xref></sup>
# ::save-date Mon Dec 21, 2015 ::file pmid_2352_4590_29.txt
(a / and
      :op1 (a2 / affect-01
            :ARG0 (m / mutate-01)
            :ARG1 (a3 / and
                  :op1 (e / enzyme :wiki "KRAS"
                        :name (n / name :op1 "K-Ras"))
                  :op2 (e2 / enzyme :wiki "Neuroblastoma_RAS_viral_oncogene_homolog"
                        :name (n2 / name :op1 "N-Ras"))
                  :ARG1-of (c / contrast-01
                        :ARG2 (e3 / enzyme :wiki "HRAS"
                              :name (n3 / name :op1 "H-Ras")
                              :ARG1-of (a4 / affect-01
                                    :ARG0 m
                                    :ARG1-of (r / rare-02)))))
            :ARG1-of (t / typical-02))
      :op2 (e4 / exclude-01
            :manner (m2 / mutual)
            :manner-of m)
      :ARG1-of (d / describe-01
            :ARG0 (p / publication-91
                  :ARG1-of (c2 / cite-01 :ARG2 8))))

# ::id pmid_2352_4590.30 ::date 2015-07-24T06:03:21 ::annotator SDL-AMR-09 ::preferred
# ::snt The Raf family of serine/threonine kinases (A-, B- and c-Raf (Raf-1)) lie at the apex of the MEK/ERK pathway.
# ::save-date Fri Jan 1, 2016 ::file pmid_2352_4590_30.txt
(l / lie-07
      :ARG1 (p2 / protein-family :name (n / name :op1 "Raf")
            :ARG2-of (i2 / include-91
                  :ARG1 (o / or
                        :op1 (e7 / enzyme :name (n2 / name :op1 "serine" :op2 "kinase"))
                        :op2 (e2 / enzyme :name (n3 / name :op1 "threonine" :op2 "kinase"))
                        :ARG2-of (i / include-91
                              :ARG1 (a / and
                                    :op1 (e4 / enzyme :name (n4 / name :op1 "A-Raf"))
                                    :op2 (e5 / enzyme :name (n5 / name :op1 "B-Raf"))
                                    :op3 (e6 / enzyme :name (n6 / name :op1 "c-Raf")))))))
      :ARG2 (a2 / apex
            :poss (p / pathway :name (n7 / name :op1 "MEK/ERK"))))

# ::id pmid_2352_4590.31 ::date 2015-07-24T06:11:10 ::annotator SDL-AMR-09 ::preferred
# ::snt All three Raf isoforms share similar structural characteristics.
# ::save-date Thu Feb 4, 2016 ::file pmid_2352_4590_31.txt
(s / share-01
      :ARG0 (i / isoform
            :quant (t / three)
            :mod (a / all)
            :mod (e / enzyme :name (n / name :op1 "Raf")))
      :ARG1 (t2 / thing
            :ARG2-of (c / characteristic-02
                  :ARG1 (s2 / structure))
            :ARG1-of (r / resemble-01)))

# ::id pmid_2352_4590.32 ::date 2015-07-23T20:40:07 ::annotator SDL-AMR-09 ::preferred
# ::snt However, they differ in their ability to phosphorylate and activate MEK, with B-Raf demonstrating higher basal kinase activity compared with Raf-1 and A-Raf.<sup><xref ref-type="bibr" rid="bib9">9</xref>, <xref ref-type="bibr" rid="bib10">10</xref></sup>
# ::save-date Mon Dec 21, 2015 ::file pmid_2352_4590_32.txt
(c3 / contrast-01
      :ARG2 (d / differ-02
            :ARG1 (t / they)
            :ARG3 (c / capable-01
                  :ARG1 t
                  :ARG2 (a / and
                        :op1 (p / phosphorylate-01
                              :ARG1 (e4 / enzyme :name (n4 / name :op1 "MEK")))
                        :op2 (a2 / activate-01
                              :ARG1 e4)))
            :manner (d2 / demonstrate-01
                  :ARG0 (e / enzyme :name (n / name :op1 "B-Raf"))
                  :ARG1 (a3 / activity-06
                        :ARG0 (k / kinase
                              :mod (b / basal))
                        :ARG1-of (h / high-02
                              :degree (m / more))
                        :compared-to (a4 / and
                              :op1 (e2 / enzyme :name (n2 / name :op1 "Raf-1"))
                              :op2 (e3 / enzyme :name (n3 / name :op1 "A-Raf"))))))
      :ARG1-of (d3 / describe-01
            :ARG0 (p2 / publication
                  :ARG1-of (c2 / cite-01
                        :ARG2 (a5 / and :op1 9 :op2 10)))))

# ::id pmid_2352_4590.33 ::date 2015-07-23T20:57:07 ::annotator SDL-AMR-09 ::preferred
# ::snt Activating B-Raf mutations have been described in 66% of melanomas and to a lesser degree in other solid tumours.<sup><xref ref-type="bibr" rid="bib11">11</xref></sup>
# ::save-date Thu Jan 14, 2016 ::file pmid_2352_4590_33.txt
(d / describe-01
      :ARG1 (m / mutate-01
            :ARG1 (e / enzyme :name (n / name :op1 "B-Raf"))
            :ARG0-of (a / activate-01))
      :ARG1-of (d3 / describe-01
            :ARG0 (p2 / publication
                  :ARG1-of (c / cite-01
                        :ARG2 11)))
      :location (a2 / and
            :op1 (m5 / medical-condition :name (n2 / name :op1 "melanoma")
                  :ARG1-of (i / include-91
                        :ARG3 (p / percentage-entity :value 66)))
            :op2 (t / tumor
                  :mod (o / other)
                  :ARG1-of (s / solid-02)
                  :quant (d2 / degree
                        :mod (l / less
                              :degree (m4 / more))
                        :compared-to p))))

# ::id pmid_2352_4590.34 ::date 2015-07-23T21:08:06 ::annotator SDL-AMR-09 ::preferred
# ::snt The clinical relevance of this association is reinforced by the exquisite sensitivity of these B-Raf mutated tumours to MEK inhibition.<sup><xref ref-type="bibr" rid="bib12">12</xref></sup>
# ::save-date Thu Jul 30, 2015 ::file pmid_2352_4590_34.txt
(r / reinforce-01
      :ARG1 (r2 / relevance
            :mod (c / clinical)
            :poss (a / associate-01
                  :mod (t / this)))
      :ARG2 (s / sensitive-03
            :ARG0 (t2 / tumor
                  :ARG2-of (m / mutate-01
                        :ARG1 (e2 / enzyme :name (n / name :op1 "B-Raf")))
                  :mod t)
            :ARG1 (i / inhibit-01
                  :ARG1 (e3 / enzyme :name (n2 / name :op1 "MEK")))
            :mod (e / exquisite))
      :ARG1-of (d / describe-01
            :ARG0 (p / publication
                  :ARG1-of (c2 / cite-01
                        :ARG2 12))))

# ::id pmid_2352_4590.35 ::date 2015-07-23T21:20:50 ::annotator SDL-AMR-09 ::preferred
# ::snt Despite a high prevalence of activating B-Raf mutations in melanoma and solid tumours, these mutations are infrequent in MM.<sup><xref ref-type="bibr" rid="bib13">13</xref></sup>
# ::save-date Thu Jan 14, 2016 ::file pmid_2352_4590_35.txt
(h / have-concession-91
      :ARG1 (f2 / frequent-02 :polarity -
            :ARG1 m
            :location (d3 / disease :name (n3 / name :op1 "multiple" :op2 "myeloma")))
      :ARG2 (p / prevail-02
            :ARG1 (m / mutate-01
                  :ARG1 (e / enzyme :name (n / name :op1 "B-Raf"))
                  :ARG0-of (a / activate-01)
                  :mod (t2 / this))
            :ARG1-of (h2 / high-02)
            :location (a2 / and
                  :op1 (m2 / medical-condition :name (n2 / name :op1 "melanoma"))
                  :op2 (t / tumor
                        :ARG1-of (s / solid-02))))
      :ARG1-of (d / describe-01
            :ARG0 (p2 / publication
                  :ARG1-of (c / cite-01
                        :ARG2 13))))

# ::id pmid_2352_4590.36 ::date 2015-07-23T21:40:30 ::annotator SDL-AMR-09 ::preferred
# ::snt This suggests that molecules other than B-Raf or alternative kinase pathways may have a crucial role in MM tumourigenesis.
# ::save-date Thu Jul 30, 2015 ::file pmid_2352_4590_36.txt
(s / suggest-01
      :ARG0 (t / this)
      :ARG1 (p / possible-01
            :ARG1 (h / have-03
                  :ARG0 (m / molecule
                        :ARG2-of (e2 / except-01
                              :ARG1 (o / or
                                    :op1 (e / enzyme :name (n / name :op1 "B-Raf"))
                                    :op2 (p2 / pathway
                                          :mod (k / kinase)
                                          :mod (a / alternative)))))
                  :ARG1 (r / role
                        :mod (c / crucial)
                        :topic (t3 / tumourigenesis
                              :mod (d2 / disease :name (n3 / name :op1 "multiple" :op2 "myeloma")))))))

# ::id pmid_2352_4590.37 ::date 2015-07-24T10:59:24 ::annotator SDL-AMR-09 ::preferred
# ::snt MEK is a unique dual specificity kinase that phosphorylates both serine/threonine and tyrosine residues.<sup><xref ref-type="bibr" rid="bib14">14</xref></sup>
# ::save-date Thu Jul 30, 2015 ::file pmid_2352_4590_37.txt
(k / kinase
      :mod (s / specificity
            :mod (d / dual)
            :mod (u / unique))
      :domain (e / enzyme :name (n / name :op1 "MEK"))
      :ARG2-of (p / phosphorylate-01
            :ARG1 (a / and
                  :op1 (s2 / slash
                        :op1 (a2 / amino-acid :name (n2 / name :op1 "serine"))
                        :op2 (a3 / amino-acid :name (n3 / name :op1 "threonine")))
                  :op2 (r / residue
                        :mod (a4 / amino-acid :name (n4 / name :op1 "tyrosine")))
                  :mod (b / both)))
      :ARG1-of (d2 / describe-01
            :ARG0 (p2 / publication
                  :ARG1-of (c / cite-01
                        :ARG2 14))))

# ::id pmid_2352_4590.38 ::date 2015-07-24T11:09:53 ::annotator SDL-AMR-09 ::preferred
# ::snt MEK consists of two isoforms, MEK1 and MEK2, which in turn phosphorylate ERK1 and ERK2.<sup><xref ref-type="bibr" rid="bib15">15</xref></sup>
# ::save-date Sat Jan 16, 2016 ::file pmid_2352_4590_38.txt
(c / consist-01
      :ARG1 (p4 / protein-family :name (n / name :op1 "MEK"))
      :ARG2 (i / isoform :quant 2
            :mod (i2 / in-turn)
            :ARG1-of (m / mean-01
                  :ARG2 (a / and
                        :op1 (e3 / enzyme :name (n2 / name :op1 "MEK1")
                              :ARG2-of (p2 / phosphorylate-01
                                    :ARG1 (e5 / enzyme :name (n4 / name :op1 "ERK1"))))
                        :op2 (e4 / enzyme :name (n3 / name :op1 "MEK2")
                              :ARG1-of (p3 / phosphorylate-01
                                    :ARG2 (e6 / enzyme :name (n5 / name :op1 "ERK2")))))))
      :ARG1-of (d / describe-01
            :ARG0 (p / publication
                  :ARG1-of (c2 / cite-01
                        :ARG2 15))))

# ::id pmid_2352_4590.39 ::date 2015-07-24T11:24:03 ::annotator SDL-AMR-09 ::preferred
# ::snt Activated ERK1/2 control a diverse range of cellular processes through their many substrates (>160) that are located in cellular membranes, the cytoplasm and nucleus.
# ::save-date Fri Jan 1, 2016 ::file pmid_2352_4590_39.txt
(c / control-01
      :ARG0 (a / and
            :op1 (e / enzyme :name (n / name :op1 "ERK1"))
            :op2 (e2 / enzyme :name (n2 / name :op1 "ERK2"))
            :ARG1-of (a2 / activate-01))
      :ARG1 (r / range-01
            :ARG1 (p / process
                  :mod (c2 / cell))
            :mod (d / diverse))
      :ARG2 (s / substrate
            :poss a
            :quant (m2 / many)
            :ARG1-of (l / locate-01
                  :location (a4 / and
                        :op1 (m4 / membrane
                              :mod (c3 / cell))
                        :op2 (c4 / cytoplasm)
                        :op3 (n4 / nucleus)))
            :quant (m3 / more-than :op1 160)))

# ::id pmid_2352_4590.40 ::date 2015-07-24T11:44:30 ::annotator SDL-AMR-09 ::preferred
# ::snt Many of these are transcription factors that are important in cellular proliferation, differentiation, survival, angiogenesis and migration.<sup><xref ref-type="bibr" rid="bib16">16</xref></sup>
# ::save-date Thu Jul 30, 2015 ::file pmid_2352_4590_40.txt
(f / factor
      :ARG0-of (t / transcribe-01)
      :mod (i / important
            :topic (a / and
                  :op1 (p / proliferate-01
                        :ARG0 (c / cell))
                  :op2 (d / differentiate-01
                        :ARG1 c)
                  :op3 (s / survive-01
                        :ARG0 c)
                  :op4 (a2 / angiogenesis)
                  :op5 (m2 / migrate-01
                        :ARG0 c)))
      :ARG1-of (d2 / describe-01
            :ARG0 (p2 / publication
                  :ARG1-of (c2 / cite-01
                        :ARG2 16)))
      :ARG1-of (i2 / include-91
            :ARG2 (t3 / this))
      :quant (m / many))

# ::id pmid_2352_4590.41 ::date 2015-07-24T14:41:56 ::annotator SDL-AMR-09 ::preferred
# ::snt Physiological activation of the Ras/MAPK pathway is also influenced by multiple mechanisms.
# ::save-date Thu Jul 30, 2015 ::file pmid_2352_4590_41.txt
(i / influence-01
      :ARG0 (m / mechanism
            :quant (m2 / multiple))
      :ARG1 (a / activate-01
            :ARG1 (p2 / pathway :name (n / name :op1 "Ras/MAPK"))
            :mod (p / physiology))
      :mod (a2 / also))

# ::id pmid_2352_4590.42 ::date 2015-07-24T14:46:30 ::annotator SDL-AMR-09 ::preferred
# ::snt Inhibitory molecules, such as Sprouty proteins (SPRY) and MAPK phosphatases (MKP or DUSPs), engage the pathway at different points to negatively regulate signalling.<sup><xref ref-type="bibr" rid="bib17">17</xref>, <xref ref-type="bibr" rid="bib18">18</xref></sup>
# ::save-date Fri Feb 5, 2016 ::file pmid_2352_4590_42.txt
(e / engage-01
      :ARG0 (m / molecule
            :ARG0-of (i / inhibit-01)
            :example (a / and
                  :op1 (p5 / protein :name (n5 / name :op1 "Sprouty"))
                  :op2 (e6 / enzyme :name (n2 / name :op1 "phosphatase")
                        :mod (e4 / enzyme :name (n6 / name :op1 "MAPK"))
                        :ARG1-of (m3 / mean-01
                              :ARG0 (o / or
                                    :op1 (e3 / enzyme :name (n / name :op1 "MKP"))
                                    :op2 (e5 / enzyme :name (n7 / name :op1 "DUSP")))))))
      :ARG1 (p3 / pathway
            :location (p4 / point)
            :ARG1-of (d / differ-02))
      :ARG2 (d3 / downregulate-01
            :ARG1 (s3 / signal-07)
            :ARG2 p3)
      :ARG1-of (d2 / describe-01
            :ARG0 (p / publication
                  :ARG1-of (c / cite-01
                        :ARG2 (a3 / and :op1 17 :op2 18)))))

# ::id pmid_2352_4590.43 ::date 2015-07-25T12:54:55 ::annotator SDL-AMR-09 ::preferred
# ::snt Activated ERK induces the expression of these inhibitory factors.
# ::save-date Sat Jul 25, 2015 ::file pmid_2352_4590_43.txt
(i / induce-01
      :ARG0 (e / enzyme :name (n / name :op1 "ERK")
            :ARG1-of (a / activate-01))
      :ARG2 (e2 / express-03
            :ARG1 (f / factor
                  :ARG1-of (i2 / inhibit-01)
                  :mod (t / this))))

# ::id pmid_2352_4590.44 ::date 2015-07-25T12:58:39 ::annotator SDL-AMR-09 ::preferred
# ::snt For example, certain DUSPs, induced by ERK-regulated transcription factors, dephosphorylate ERK.<sup><xref ref-type="bibr" rid="bib19">19</xref></sup>
# ::save-date Sun Dec 20, 2015 ::file pmid_2352_4590_44.txt
(e / exemplify-01
      :ARG0 (d / dephosphorylate-01
            :ARG1 (e2 / enzyme :name (n / name :op1 "ERK"))
            :ARG2 (e3 / enzyme :name (n3 / name :op1 "DUSP")
                  :mod (c / certain)
                  :ARG2-of (i / induce-01
                        :ARG0 (f / factor
                              :ARG0-of (t / transcribe-01)
                              :ARG1-of (r / regulate-01
                                    :ARG0 e2)))))
      :ARG1-of (d2 / describe-01
            :ARG0 (p / publication
                  :ARG1-of (c2 / cite-01
                        :ARG2 19))))

# ::id pmid_2352_4590.45 ::date 2015-07-25T13:10:05 ::annotator SDL-AMR-09 ::preferred
# ::snt Downstream signalling from B-Raf, Raf-1 and MEK1 may also be diminished following ERK-mediated phosphorylation.<sup><xref ref-type="bibr" rid="bib20">20</xref>, <xref ref-type="bibr" rid="bib21">21</xref></sup>
# ::save-date Thu Jul 30, 2015 ::file pmid_2352_4590_45.txt
(p / possible-01
      :ARG1 (d / diminish-01
            :ARG1 (s / signal-07
                  :ARG0 (a2 / and
                        :op1 (e / enzyme :name (n / name :op1 "B-Raf"))
                        :op2 (e2 / enzyme :name (n2 / name :op1 "Raf-1"))
                        :op3 (e3 / enzyme :name (n3 / name :op1 "MEK1")))
                  :direction (d2 / downstream)))
      :mod (a / also)
      :ARG1-of (d3 / describe-01
            :ARG0 (p3 / publication
                  :ARG1-of (c / cite-01
                        :ARG2 (a3 / and :op1 20 :op2 21))))
      :ARG1-of (f / follow-01
            :ARG2 (p2 / phosphorylate-01
                  :ARG1-of (m / mediate-01
                        :ARG0 (e4 / enzyme :name (n4 / name :op1 "ERK"))))))

# ::id pmid_2352_4590.46 ::date 2015-07-25T13:54:36 ::annotator SDL-AMR-09 ::preferred
# ::snt These various mechanisms fine tune the activity of the Ras/MAPK cascade through the creation of a negative-feedback loop.
# ::save-date Fri Feb 5, 2016 ::file pmid_2352_4590_46.txt
(f / finetune-01
      :ARG0 (m / mechanism
            :mod (v / various)
            :mod (t / this))
      :ARG1 (a / activity-06
            :ARG0 (c / cascade-01
                  :ARG1 (p / pathway :name (n3 / name :op1 "Ras/MAPK")))
            :manner (c2 / create-01
                  :ARG1 (l / loop-01
                        :mod (f2 / feedback
                              :ARG0-of (n / negative-03))))))

# ::id pmid_2352_4590.47 ::date 2015-07-25T14:23:55 ::annotator SDL-AMR-09 ::preferred
# ::snt As will be discussed later, this mode of regulation has implications for inhibitors targeting the pathway.
# ::save-date Thu Jul 30, 2015 ::file pmid_2352_4590_47.txt
(d / discuss-01
      :ARG1 (i / implicate-01
            :ARG0 (r / regulate-01
                  :mod (m2 / mode
                        :mod (t / this)))
            :ARG1 (m3 / molecular-physical-entity
                  :ARG0-of (i2 / inhibit-01)
                  :ARG0-of (t3 / target-01
                        :ARG1 (p / pathway))))
      :time (l / late
            :degree (m / more)))

# ::id pmid_2352_4590.48 ::date 2015-07-25T14:33:49 ::annotator SDL-AMR-09 ::preferred
# ::snt <sec-title level="2">The Ras/MAPK pathway and MM</sec-title>
# ::save-date Thu Jul 30, 2015 ::file pmid_2352_4590_48.txt
(a / and
      :op1 (p / pathway :name (n / name :op1 "Ras/MAPK"))
      :op2 (d2 / disease :name (n2 / name :op1 "multiple" :op2 "myeloma")))

# ::id pmid_2352_4590.49 ::date 2015-07-25T23:20:13 ::annotator SDL-AMR-09 ::preferred
# ::snt The genetic changes associated with MM are complex and heterogeneous.
# ::save-date Thu Jul 30, 2015 ::file pmid_2352_4590_49.txt
(a / and
      :op1 (c / complex)
      :op2 (h / heterogeneous)
      :domain (c2 / change-01
            :ARG1-of (a2 / associate-01
                  :ARG2 (d2 / disease :name (n / name :op1 "multiple" :op2 "myeloma")))
            :mod (g2 / genetic)))

# ::id pmid_2352_4590.50 ::date 2015-07-25T23:28:40 ::annotator SDL-AMR-09 ::preferred
# ::snt Increasing evidence suggests that the disease evolves through a multistep transformation process, involving the gain or loss of whole chromosomes, nonrandom chromosomal translocations involving the IgH locus and point mutations.<sup><xref ref-type="bibr" rid="bib4">4</xref></sup>
# ::save-date Mon Dec 21, 2015 ::file pmid_2352_4590_50.txt
(s / suggest-01
      :ARG0 (e / evidence
            :ARG1-of (i / increase-01))
      :ARG1 (e2 / evolve-01
            :ARG1 (d / disease)
            :manner (p / process-01
                  :ARG1 (t / transform-01
                        :mod (m / multistep))
                  :ARG0-of (i2 / involve-01
                        :ARG1 (a / and
                              :op1 (o / or
                                    :op1 (g / gain-02
                                          :ARG1 (c / chromosome
                                                :mod (w / whole)))
                                    :op2 (l / lose-02
                                          :ARG1 c))
                              :op2 (t2 / translocate-01
                                    :ARG1 (c2 / chromosome)
                                    :mod (r / random :polarity -)
                                    :ARG0-of (i3 / involve-01
                                          :ARG1 (a2 / and
                                                :op1 (l3 / locus
                                                      :location-of (g2 / gene :name (n2 / name :op1 "IgH")))
                                                :op2 (m2 / mutate-01
                                                      :ARG1 (p2 / point)))))))))
      :ARG1-of (d2 / describe-01
            :ARG0 (p3 / publication
                  :ARG1-of (c3 / cite-01
                        :ARG2 4))))

# ::id pmid_2352_4590.51 ::date 2015-07-25T23:51:41 ::annotator SDL-AMR-09 ::preferred
# ::snt These aberrations, which influence the clinical and pathological features of MM are manifest in variable disease progression and therapeutic outcomes.
# ::save-date Thu Jul 30, 2015 ::file pmid_2352_4590_51.txt
(m / manifest-01
      :ARG1 (a / aberration
            :mod (t / this)
            :ARG0-of (i / influence-01
                  :ARG1 (f / feature-01
                        :ARG1 (d3 / disease :name (n2 / name :op1 "multiple" :op2 "myeloma"))
                        :mod (c2 / clinic)
                        :mod (p2 / pathology))))
      :ARG3 (a2 / and
            :op1 (p / progress-01
                  :ARG1 (d / disease
                        :mod (v / variable)))
            :op2 (o / outcome
                  :mod (t2 / therapy))))

# ::id pmid_2352_4590.52 ::date 2015-07-26T00:24:34 ::annotator SDL-AMR-09 ::preferred
# ::snt Several of these molecular alterations lead to deregulated activation of the Ras/MAPK pathway.
# ::save-date Thu Jul 30, 2015 ::file pmid_2352_4590_52.txt
(l / lead-03
      :ARG0 (a / alter-01
            :quant (s / several)
            :ARG1-of (i / include-91
                  :ARG2 (a3 / alter-01
                        :ARG1 (m / molecule)
                        :mod (t2 / this))))
      :ARG2 (a2 / activate-01
            :ARG1 (p / pathway :name (n / name :op1 "Ras/MAPK"))
            :ARG1-of (d / deregulate-01)))

# ::id pmid_2352_4590.53 ::date 2015-07-26T00:44:29 ::annotator SDL-AMR-09 ::preferred
# ::snt The t(4;14) translocation that juxtaposes the fibroblast growth factor receptor 3 gene and a strong IgH enhancer, resulting in fibroblast growth factor receptor 3 overexpression, stimulates the Ras/MAPK pathway, an outcome typically associated with abnormal cellular proliferation and apoptosis.<sup><xref ref-type="bibr" rid="bib22">22</xref></sup>
# ::save-date Thu Jul 30, 2015 ::file pmid_2352_4590_53.txt
(s / stimulate-01
      :ARG0 (t / translocate-01
            :ARG2 14
            :ARG3 4
            :ARG0-of (j / juxtapose-01
                  :ARG1 (a / and
                        :op1 (g / gene :name (n / name :op1 "fibroblast" :op2 "growth" :op3 "factor" :op4 "receptor" :op5 "3"))
                        :op2 (t3 / thing
                              :ARG0-of (e / enhance-01
                                    :ARG1 (g2 / gene :name (n5 / name :op1 "IgH"))
                                    :ARG1-of (s2 / strong-02))))
                  :ARG1-of (r / result-01
                        :ARG2 (o / overexpress-01
                              :ARG1 g))))
      :ARG1 (p / pathway :name (n3 / name :op1 "Ras/MAPK")
            :ARG1-of (m2 / mean-01
                  :ARG2 (o2 / outcome
                        :ARG1-of (a2 / associate-01
                              :ARG2 (a3 / and
                                    :op1 (p2 / proliferate-01
                                          :ARG0 (c / cell)
                                          :ARG1-of (n4 / normal-02 :polarity -))
                                    :op2 (a4 / apoptosis))
                              :ARG1-of (t2 / typical-02)))))
      :ARG1-of (d2 / describe-01
            :ARG0 (p3 / publication
                  :ARG1-of (c2 / cite-01
                        :ARG2 22))))

# ::id pmid_2352_4590.54 ::date 2015-07-26T01:14:13 ::annotator SDL-AMR-09 ::preferred
# ::snt Activating Ras mutations, which have a reported incidence varying between 32–50% in MM, are also thought to deregulate this pathway.<sup><xref ref-type="bibr" rid="bib23">23</xref>, <xref ref-type="bibr" rid="bib24">24</xref>, <xref ref-type="bibr" rid="bib25">25</xref></sup>
# ::save-date Sun Dec 20, 2015 ::file pmid_2352_4590_54.txt
(t / think-01
      :ARG1 (d3 / deregulate-01
            :ARG0 (m / mutate-01
                  :ARG1 (e / enzyme :name (n / name :op1 "Ras")
                        :ARG0-of (a2 / activate-01))
                  :ARG0-of (h / have-03
                        :ARG1 (i / incidence
                              :ARG1-of (r / report-01)
                              :ARG1-of (v / vary-01
                                    :ARG3 (p2 / percentage-entity :value 32)
                                    :ARG4 (p3 / percentage-entity :value 50)
                                    :location (d / disease :name (n2 / name :op1 "multiple" :op2 "myeloma"))))))
            :ARG1 (p / pathway
                  :mod (t2 / this)))
      :mod (a / also)
      :ARG1-of (d2 / describe-01
            :ARG0 (p4 / publication
                  :ARG1-of (c / cite-01
                        :ARG2 (a3 / and :op1 23 :op2 24 :op3 25)))))

# ::id pmid_2352_4590.55 ::date 2015-07-26T01:34:15 ::annotator SDL-AMR-09 ::preferred
# ::snt K-Ras and N- Ras are the most frequently mutated, with oncogenic H-Ras being a rare phenomenon.<sup><xref ref-type="bibr" rid="bib25">25</xref></sup>
# ::save-date Thu Dec 10, 2015 ::file pmid_2352_4590_55.txt
(m / mutate-01
      :ARG1 (a / and
            :op1 (e / enzyme :name (n / name :op1 "K-Ras"))
            :op2 (e2 / enzyme :name (n2 / name :op1 "N-Ras")))
      :manner (p / phenomenon
            :domain (e3 / enzyme :name (n3 / name :op1 "H-Ras")
                  :ARG0-of (c3 / cause-01
                        :ARG1 (d2 / disease :wiki "Cancer" :name (n4 / name :op1 "cancer"))))
            :ARG1-of (r / rare-02))
      :ARG1-of (d / describe-01
            :ARG0 (p2 / publication
                  :ARG1-of (c / cite-01
                        :ARG2 25)))
      :ARG1-of (f2 / frequent-02
            :degree (m2 / most)))

# ::id pmid_2352_4590.56 ::date 2015-07-26T01:50:17 ::annotator SDL-AMR-09 ::preferred
# ::snt While certain genetic lesions common to MM (for example, t(14;16), t(4;14) and hyperdiploidy) are also present in the asymptomatic precursor to MM, monoclonal gammopathy of unknown significance,<sup><xref ref-type="bibr" rid="bib26">26</xref></sup> Ras mutations occur almost exclusively in MM.
# ::save-date Thu Feb 4, 2016 ::file pmid_2352_4590_56.txt
(h / have-concession-91
      :ARG1 (m3 / mutate-01
            :ARG1 (e / enzyme :name (n / name :op1 "Ras"))
            :location (d / disease :name (n3 / name :op1 "multiple" :op2 "myeloma"))
            :ARG0-of (e4 / exclusive-02
                  :mod (a / almost)))
      :ARG2 (p / present-02
            :ARG1 (l / lesion
                  :mod (g / genetics)
                  :mod (c2 / certain)
                  :ARG1-of (s / share-01
                        :ARG2 d)
                  :example (a3 / and
                        :op1 (t / translocate-01
                              :ARG2 16
                              :ARG3 14)
                        :op2 (t2 / translocate-01
                              :ARG2 14
                              :ARG3 4)
                        :op3 (h3 / hyperdiploidy)))
            :ARG2 (p2 / precursor
                  :mod (s2 / symptom :polarity -)
                  :location d)
            :mod (a2 / also)
            :ARG1-of (m2 / mean-01
                  :ARG2 (g2 / gammopathy
                        :ARG0-of (s3 / signify-01
                              :ARG1-of (k / know-01 :polarity -))
                        :mod (m4 / monoclone)))
            :ARG1-of (d2 / describe-01
                  :ARG0 (p3 / publication
                        :ARG1-of (c6 / cite-01
                              :ARG2 26)))))

# ::id pmid_2352_4590.57 ::date 2015-07-26T03:06:23 ::annotator SDL-AMR-09 ::preferred
# ::snt This indicates that Ras mutations are likely to contribute to the transition of the disease from a premalignant state.<sup><xref ref-type="bibr" rid="bib27">27</xref></sup>
# ::save-date Thu Jul 30, 2015 ::file pmid_2352_4590_57.txt
(i / indicate-01
      :ARG0 (t / this)
      :ARG1 (l / likely-01
            :ARG1-of (c / contribute-01
                  :ARG0 (m / mutate-01
                        :ARG1 (e / enzyme :name (n / name :op1 "Ras")))
                  :ARG2 (t2 / transition-01
                        :ARG1 (d / disease)
                        :ARG3 (s / state
                              :mod (p / premalignant)))))
      :ARG1-of (d2 / describe-01
            :ARG0 (p2 / publication
                  :ARG1-of (c2 / cite-01
                        :ARG2 27))))

# ::id pmid_2352_4590.58 ::date 2015-07-26T03:47:40 ::annotator SDL-AMR-09 ::preferred
# ::snt In the case of the t(4:14) lesion that can activate the Ras/MAPK pathway, this raises the interesting possibility that deregulation of the Ras/MAPK pathway in monoclonal gammopathy of unknown significance precedes constitutive MAPK activation associated with Ras mutations.
# ::save-date Tue Dec 22, 2015 ::file pmid_2352_4590_58.txt
(r / raise-01
      :ARG0 (t2 / this)
      :ARG1 (p / possible-01
            :ARG1 (p4 / precede-01
                  :ARG1 (d / deregulate-01
                        :ARG1 p3
                        :location (g / gammopathy
                              :mod (m / monoclonal)
                              :ARG0-of (s / signify-01
                                    :ARG1-of (k / know-01 :polarity -))))
                  :ARG2 (a2 / activate-01
                        :ARG1 (p5 / pathway :name (n3 / name :op1 "MAPK"))
                        :ARG1-of (a3 / associate-01
                              :ARG2 (m2 / mutate-01
                                    :ARG1 (e3 / enzyme :name (n4 / name :op1 "Ras"))))
                        :mod (c2 / constitutive)))
            :ARG2-of (i / interest-01))
      :condition (l / lesion
            :mod (t / translocate-01
                  :ARG2 14
                  :ARG3 4)
            :ARG0-of (a / activate-01
                  :ARG1 (p3 / pathway :name (n / name :op1 "Ras/MAPK"))
                  :ARG1-of (p2 / possible-01))))

# ::id pmid_2352_4590.59 ::date 2015-07-26T04:07:18 ::annotator SDL-AMR-09 ::preferred
# ::snt Patients with MM harbouring oncogenic K-Ras often have a worse clinical outcomes compared with those with N-Ras mutations or wild-type Ras <sup><xref ref-type="bibr" rid="bib24">24</xref></sup> This link is exemplified by Ras mutations being associated with the evolution of MM from an intermedullary disease to a more advanced extramedullary phenotype.<sup><xref ref-type="bibr" rid="bib28">28</xref></sup>
# ::save-date Thu Feb 4, 2016 ::file pmid_2352_4590_59.txt
(m3 / multi-sentence
      :snt1 (h / have-03
            :ARG0 (p / person
                  :ARG0-of (h2 / have-rel-role-91
                        :ARG2 (p2 / patient))
                  :ARG0-of (h3 / have-03
                        :ARG1 (d6 / disease :name (n7 / name :op1 "multiple" :op2 "myeloma")
                              :ARG0-of (h5 / harbor-01
                                    :ARG1 (e / enzyme :name (n / name :op1 "K-Ras")
                                          :ARG0-of (c6 / cause-01
                                                :ARG1 (d3 / disease :wiki "Cancer" :name (n6 / name :op1 "cancer"))))))))
            :ARG1 (o / outcome
                  :mod (c2 / clinical)
                  :ARG1-of (b / bad-07
                        :degree (m / more))
                  :ARG1-of (c3 / compare-01
                        :ARG2 (p3 / person
                              :ARG0-of (h6 / have-03
                                    :ARG1 (o3 / or
                                          :op1 (m2 / mutate-01
                                                :ARG1 (e2 / enzyme :name (n3 / name :op1 "N-Ras")))
                                          :op2 (e3 / enzyme :name (n4 / name :op1 "Ras")
                                                :mod (w / wild-type))))
                              :ARG0-of (h7 / have-rel-role-91
                                    :ARG2 (p4 / patient)))))
            :frequency (o2 / often)
            :ARG1-of (d2 / describe-01
                  :ARG0 (p7 / publication
                        :ARG1-of (c4 / cite-01
                              :ARG2 24))))
      :snt2 (e4 / exemplify-01
            :ARG0 (m4 / mutate-01
                  :ARG1 (e5 / enzyme :name (n5 / name :op1 "Ras"))
                  :ARG1-of (a / associate-01
                        :ARG2 (e6 / evolve-01
                              :ARG1 (d / disease :name (n2 / name :op1 "multiple" :op2 "myeloma"))
                              :ARG2 (p5 / phenotype
                                    :mod (e7 / extramedullary)
                                    :ARG1-of (a2 / advance-01
                                          :degree (m5 / more)))
                              :ARG3 (d4 / disease
                                    :mod (i / intermedullary)))))
            :ARG1 (l / link-01
                  :mod (t / this))
            :ARG1-of (d5 / describe-01
                  :ARG0 (p6 / publication
                        :ARG1-of (c5 / cite-01
                              :ARG2 28)))))

# ::id pmid_2352_4590.60 ::date 2015-07-26T04:56:01 ::annotator SDL-AMR-09 ::preferred
# ::snt These observations suggest that aberrant MEK/ERK signalling has an important role in MM disease progression and prognosis.
# ::save-date Thu Jul 30, 2015 ::file pmid_2352_4590_60.txt
(s / suggest-01
      :ARG0 (o / observe-01
            :mod (t / this))
      :ARG1 (h / have-03
            :ARG0 (p / pathway :name (n / name :op1 "MEK/ERK")
                  :ARG0-of (s2 / signal-07
                        :manner (a / aberrant)))
            :ARG1 (r / role
                  :mod (i / important)
                  :topic (a2 / and
                        :op1 (p2 / progress-01
                              :ARG1 (d2 / disease :name (n3 / name :op1 "multiple" :op2 "myeloma")))
                        :op2 (p3 / prognosis
                              :mod d2)))))

# ::id pmid_2352_4590.61 ::date 2015-07-26T05:06:28 ::annotator SDL-AMR-09 ::preferred
# ::snt Malignant plasma cell and BMME interactions are thought to contribute to disease progression through the induction of various cytokines and growth factors, a number of which mediate their effects through the Ras/MAPK cascade.<sup><xref ref-type="bibr" rid="bib5">5</xref>, <xref ref-type="bibr" rid="bib29">29</xref>, <xref ref-type="bibr" rid="bib30">30</xref></sup>
# ::save-date Sun Dec 20, 2015 ::file pmid_2352_4590_61.txt
(t / think-01
      :ARG1 (c / contribute-01
            :ARG0 (a / and
                  :op1 (c2 / cell
                        :mod (p / plasma)
                        :ARG1-of (m / malignant-02))
                  :op2 (i / interact-01
                        :ARG0 (m2 / microenvironment
                              :mod (m4 / marrow
                                    :part-of (b / bone)))))
            :ARG2 (p2 / progress-01
                  :ARG1 (d / disease)
                  :manner (i2 / induce-01
                        :ARG2 (a2 / and
                              :op1 (c3 / cytokine
                                    :mod (v / various))
                              :op2 (f / factor
                                    :mod (g / growth))
                              :quant (n2 / number
                                    :ARG0-of (m3 / mediate-01
                                          :ARG1 (a3 / affect-01
                                                :ARG0 a2
                                                :ARG2 (c4 / cascade-01
                                                      :ARG1 (p3 / pathway :name (n3 / name :op1 "Ras/MAPK"))))))))))
      :ARG1-of (d2 / describe-01
            :ARG0 (p4 / publication
                  :ARG1-of (c5 / cite-01
                        :ARG2 (a4 / and :op1 5 :op2 29 :op3 30)))))

# ::id pmid_2352_4590.62 ::date 2015-07-26T10:27:01 ::annotator SDL-AMR-09 ::preferred
# ::snt In addition to a number of these cytokines being able to activate MEK/ERK via the classical Ras/Raf link, another MAP3K, Tpl2 (Cot, MAP3K8), a known oncogene, has emerged as being important in the cytokine-induced activation of ERK in various cell types, in particular hemopoietic cells.<sup><xref ref-type="bibr" rid="bib31">31</xref></sup>
# ::save-date Tue Dec 22, 2015 ::file pmid_2352_4590_62.txt
(a / add-02
      :ARG1 (g / gene :name (n6 / name :op1 "MAP3K")
            :mod (a3 / another)
            :domain (o / oncogene
                  :ARG1-of (k / know-01))
            :ARG1-of (m / mean-01
                  :ARG2 (g2 / gene :name (n8 / name :op1 "Tpl2")))
            :ARG0-of (e4 / emerge-02
                  :ARG1 (i / important
                        :topic (a4 / activate-01
                              :ARG1 (e5 / enzyme :name (n7 / name :op1 "ERK"))
                              :location (c4 / cell
                                    :ARG1-of (t2 / type-03
                                          :mod (v / various)))
                              :manner (p3 / particular
                                    :location (c5 / cell
                                          :mod (h / hematopoiesis)))
                              :ARG2-of (i2 / induce-01
                                    :ARG0 (c3 / cytokine)))
                        :domain g)))
      :ARG2 (n5 / number-01
            :ARG1 (c / cytokine
                  :mod (t / this)
                  :ARG0-of (a2 / activate-01
                        :ARG1 (p2 / pathway :name (n / name :op1 "MEK/ERK"))
                        :manner (l / link-01
                              :ARG1 (e / enzyme :name (n3 / name :op1 "Ras"))
                              :ARG2 (e2 / enzyme :name (n4 / name :op1 "Raf"))
                              :mod (c2 / classical))
                        :ARG1-of (p / possible-01))))
      :ARG1-of (d / describe-01
            :ARG0 (p4 / publication
                  :ARG1-of (c6 / cite-01
                        :ARG2 31))))

# ::id pmid_2352_4590.63 ::date 2015-07-28T02:20:52 ::annotator SDL-AMR-09 ::preferred
# ::snt The observation that the tumour necrosis factor receptor superfamily cytokines (tumour necrosis factor-α, BAFF), CD40 and RANK ligands, all of which have been implicate in MM, activate MEK/ERK via Tpl2 raises the likelihood that the MEK/ERK arm of this MAPK pathway can be activated through different MAP3K.<sup><xref ref-type="bibr" rid="bib32">32</xref></sup>
# ::save-date Fri Jan 1, 2016 ::file pmid_2352_4590_63.txt
(r / raise-01
      :ARG0 (o / observe-02
            :ARG1 (a3 / activate-01
                  :ARG0 (a4 / and
                        :op1 (p4 / protein-family :name (n6 / name :op1 "tumour" :op2 "necrosis" :op3 "factor" :op4 "receptor")
                              :ARG2-of (i2 / include-91
                                    :ARG1 (a5 / and
                                          :op1 (c4 / cytokine :name (n7 / name :op1 "tumour" :op2 "necrosis" :op3 "factor-α"))
                                          :op2 (c5 / cytokine :name (n8 / name :op1 "BAFF")))))
                        :op2 (l2 / ligand :name (n9 / name :op1 "CD40"))
                        :op3 (l3 / ligand :name (n10 / name :op1 "RANK"))
                        :mod (a6 / all
                              :ARG1-of (i / implicate-01
                                    :ARG2 (d4 / disease :name (n13 / name :op1 "multiple" :op2 "myeloma")))))
                  :ARG1 (p / pathway :name (n / name :op1 "MEK/ERK"))
                  :instrument (e4 / enzyme :name (n12 / name :op1 "Tpl2"))))
      :ARG1 (l / likely-01
            :ARG1 (p3 / possible-01
                  :ARG1 (a2 / activate-01
                        :ARG0 (e3 / enzyme :name (n5 / name :op1 "MAP3K")
                              :ARG1-of (d / differ-02))
                        :ARG1 (a / arm
                              :consist-of (s / slash
                                    :op1 (e / enzyme :name (n3 / name :op1 "MEK"))
                                    :op2 (e2 / enzyme :name (n4 / name :op1 "ERK")))
                              :part-of p))))
      :ARG1-of (d3 / describe-01
            :ARG0 (p6 / publication
                  :ARG1-of (c2 / cite-01
                        :ARG2 32))))

# ::id pmid_2352_4590.64 ::date 2015-07-28T02:46:09 ::annotator SDL-AMR-09 ::preferred
# ::snt With aberrant MEK/ERK signalling thought to be important in regulating the growth, survival, migration and drug resistance of MM, it will be interesting to determine if specific MAP3Ks differentially control these particular features of the disease.
# ::save-date Fri Jan 1, 2016 ::file pmid_2352_4590_64.txt
(i / interest-01
      :ARG0 (t2 / think-01
            :ARG1 (i2 / important
                  :domain (s2 / signal-07
                        :ARG0 (p / pathway :name (n / name :op1 "MEK/ERK"))
                        :mod (a / aberrant))
                  :purpose (r / regulate-01
                        :ARG1 (a2 / and
                              :op1 (g / grow-01
                                    :ARG1 (d3 / disease :name (n4 / name :op1 "multiple" :op2 "myeloma")))
                              :op2 (s3 / survive-01
                                    :ARG0 d3)
                              :op3 (m / migrate-01
                                    :ARG0 d3)
                              :op3 (r2 / resist-01
                                    :ARG0 d3
                                    :ARG1 (d5 / drug))))))
      :ARG2 (d / determine-01
            :ARG1 (c / control-01 :mode interrogative
                  :ARG0 (e / enzyme :name (n2 / name :op1 "MAP3K")
                        :ARG1-of (s / specific-02))
                  :ARG1 (f / feature
                        :mod (t / this)
                        :mod (p2 / particular)
                        :poss d3)
                  :manner (d2 / differential))))

# ::id pmid_2352_4590.65 ::date 2015-07-28T03:05:56 ::annotator SDL-AMR-09 ::preferred
# ::snt Interactions between Bcl-2-like prosurvival and BH3-only pro-apoptotic family members play an integral role in controlling the balance between cell survival and death though the intrinsic apoptosis pathway.
# ::save-date Mon Nov 16, 2015 ::file pmid_2352_4590_65.txt
(p / play-08
      :ARG0 (i / interact-01
            :ARG0 (m / member
                  :ARG0-of (f2 / favor-01
                        :ARG1 (s / survive-01))
                  :part-of (f4 / family
                        :ARG1-of (r / resemble-01
                              :ARG2 (p2 / protein :name (n / name :op1 "Bcl-2")))))
            :ARG1 (m2 / member
                  :part-of (p4 / protein-family :name (n2 / name :op1 "BH3")
                        :mod (o / only))
                  :ARG0-of (f3 / favor-01
                        :ARG1 (a2 / apoptosis))))
      :ARG1 (c / control-01
            :ARG0 i
            :ARG1 (b2 / balance-01
                  :ARG1 (s2 / survive-01
                        :ARG0 (c2 / cell))
                  :ARG2 (d / die-01
                        :ARG1 c2))
            :ARG2 (p3 / pathway
                  :mod (i3 / intrinsic)
                  :mod a2))
      :mod (i2 / integral))

# ::id pmid_2352_4590.66 ::date 2015-07-28T03:51:41 ::annotator SDL-AMR-09 ::preferred
# ::snt Aberrant expression of these apoptotic regulatory molecules in diverse cancers, including MM, contributes to drug resistance.
# ::save-date Thu Dec 10, 2015 ::file pmid_2352_4590_66.txt
(c / contribute-01
      :ARG0 (e / express-03
            :ARG2 (m / molecule
                  :mod (t / this)
                  :ARG0-of (r / regulate-01
                        :ARG1 (a2 / apoptosis)))
            :ARG3 (d2 / disease :wiki "Cancer" :name (n / name :op1 "cancer")
                  :mod (d / diverse)
                  :ARG2-of (i / include-01
                        :ARG1 (d4 / disease :name (n2 / name :op1 "multiple" :op2 "myeloma"))))
            :mod (a / aberrant))
      :ARG2 (r2 / resist-01
            :ARG1 (d3 / drug)))

# ::id pmid_2352_4590.67 ::date 2015-07-28T03:55:05 ::annotator SDL-AMR-09 ::preferred
# ::snt Importantly, the activity of a number of these proteins is modulated by MEK/ERK signalling.
# ::save-date Tue Aug 4, 2015 ::file pmid_2352_4590_67.txt
(m / modulate-01
      :ARG0 (s / signal-07
            :ARG0 (p / pathway :name (n / name :op1 "MEK/ERK")))
      :ARG1 (a / activity-06
            :ARG0 (n2 / number
                  :quant-of (p2 / protein
                        :mod (t / this))))
      :mod (i / important))

# ::id pmid_2352_4590.68 ::date 2015-07-28T03:59:46 ::annotator SDL-AMR-09 ::preferred
# ::snt For example, ERK-mediated phosphorylation of the antiapoptotic molecule, Mcl-1, decreases its degradation, thereby promoting cell survival.<sup><xref ref-type="bibr" rid="bib33">33</xref></sup>
# ::save-date Wed Jul 29, 2015 ::file pmid_2352_4590_68.txt
(d / decrease-01
      :ARG0 (p2 / phosphorylate-01
            :ARG1 (p4 / protein :name (n2 / name :op1 "Mcl-1")
                  :ARG0-of (c / counter-01
                        :ARG1 (a / apoptosis)))
            :ARG1-of (m / mediate-01
                  :ARG0 (e2 / enzyme :name (n / name :op1 "ERK"))))
      :ARG1 (d2 / degrade-01
            :ARG1 p4)
      :ARG0-of (c2 / cause-01
            :ARG1 (p3 / promote-02
                  :ARG0 p2
                  :ARG1 (s / survive-01
                        :ARG0 (c3 / cell))))
      :ARG0-of (e / exemplify-01)
      :ARG1-of (d3 / describe-01
            :ARG0 (p / publication
                  :ARG1-of (c4 / cite-01
                        :ARG2 33))))

# ::id pmid_2352_4590.69 ::date 2015-07-28T04:08:14 ::annotator SDL-AMR-09 ::preferred
# ::snt With the overexpression of Mcl-1, a common feature of MM associated with greater relapse and shorter survival,<sup><xref ref-type="bibr" rid="bib34">34</xref></sup> constitutive MEK/ERK activity almost certainly contributes to elevated Mcl-1 expression in those MM with lesions in the Ras/ERK pathway.
# ::save-date Sun Jan 17, 2016 ::file pmid_2352_4590_69.txt
(c / contribute-01
      :ARG0 (a2 / activity-06
            :ARG0 (p / pathway :name (n / name :op1 "MEK/ERK"))
            :mod (c3 / constitutive))
      :ARG1 (o / overexpress-01
            :ARG1 p2
            :mod (f / feature
                  :mod (c4 / common)
                  :ARG1-of (a3 / associate-01
                        :ARG2 (a4 / and
                              :op1 (r / relapse-01
                                    :mod (g2 / great
                                          :degree (m2 / more)))
                              :op2 (s / survive-01
                                    :ARG1-of (s2 / short-07
                                          :degree (m3 / more)))))
                  :ARG1-of (d2 / describe-01
                        :ARG0 (p4 / publication
                              :ARG1-of (c5 / cite-01
                                    :ARG2 34)))
                  :poss d3))
      :ARG2 (e / express-03
            :ARG1 (p2 / protein :name (n2 / name :op1 "Mcl-1"))
            :ARG3 (d3 / disease :name (n5 / name :op1 "multiple" :op2 "myeloma")
                  :mod (t / that)
                  :mod (l / lesion
                        :mod (p3 / pathway :name (n4 / name :op1 "Ras/ERK"))))
            :ARG1-of (e2 / elevate-01))
      :manner (c2 / certain
            :degree (a / almost)))

# ::id pmid_2352_4590.70 ::date 2015-07-28T04:16:58 ::annotator SDL-AMR-09 ::preferred
# ::snt In contrast, Bim, a proapoptotic Bcl-2 family member that can bind to and neutralize Mcl-1, is targeted by ERK phosphorylation for proteasome-dependent degradation.<sup><xref ref-type="bibr" rid="bib35">35</xref></sup>
# ::save-date Wed Jan 13, 2016 ::file pmid_2352_4590_70.txt
(c / contrast-01
      :ARG2 (t / target-01
            :ARG0 (p / phosphorylate-01
                  :ARG1 (e / enzyme :name (n / name :op1 "ERK")))
            :ARG1 (p2 / protein :name (n2 / name :op1 "Bim")
                  :ARG0-of (f2 / favor-01
                        :ARG1 (a / apoptosis))
                  :ARG1-of (b / bind-01
                        :ARG2 (p5 / protein :name (n5 / name :op1 "Mcl-1"))
                        :ARG1-of (p6 / possible-01))
                  :ARG0-of (n6 / neutralize-01
                        :ARG1 p5
                        :ARG1-of p6)
                  :ARG1-of (i / include-91
                        :ARG2 (p4 / protein-family :name (n4 / name :op1 "Bcl-2"))))
            :purpose (d / degrade-01
                  :ARG0-of (d2 / depend-01
                        :ARG1 (m / macro-molecular-complex :name (n3 / name :op1 "proteasome")))))
      :ARG1-of (d3 / describe-01
            :ARG0 (p7 / publication
                  :ARG1-of (c2 / cite-01
                        :ARG2 35))))

# ::id pmid_2352_4590.71 ::date 2015-07-28T04:27:07 ::annotator SDL-AMR-09 ::preferred
# ::snt Hence, constitutive ERK signalling is likely to contribute significantly to MM survival by stabilising Mcl-1 and diminishing Bim expression.
# ::save-date Mon Nov 16, 2015 ::file pmid_2352_4590_71.txt
(i / infer-01
      :ARG1 (l / likely-01
            :ARG1 (c / contribute-01
                  :ARG0 (s / signal-07
                        :ARG0 (e / enzyme :name (n / name :op1 "ERK"))
                        :mod (c2 / constitutive))
                  :ARG1 (a / and
                        :op1 (s4 / stabilize-01
                              :ARG0 s
                              :ARG1 (p / protein :name (n3 / name :op1 "Mcl-1")))
                        :op2 (d2 / diminish-01
                              :ARG0 s
                              :ARG1 (e2 / express-03
                                    :ARG2 (p2 / protein :name (n4 / name :op1 "Bim")))))
                  :ARG2 (s2 / survive-01
                        :ARG0 (d3 / disease :name (n5 / name :op1 "multiple" :op2 "myeloma")))
                  :ARG1-of (s3 / significant-02))))

# ::id pmid_2352_4590.72 ::date 2015-07-28T04:32:26 ::annotator SDL-AMR-09 ::preferred
# ::snt The activity of other prosurvival (Bcl-2 and Bcl-xL) and proapoptotic (Bad) Bcl-2-like proteins, that are also known to be regulated by ERK signalling, represent additional candidates that may contribute to the enhanced survival of MM cells.
# ::save-date Tue Dec 22, 2015 ::file pmid_2352_4590_72.txt
(r / represent-01
      :ARG0 (a / activity-06
            :ARG0 (a2 / and
                  :op1 (p / protein
                        :ARG0-of (f / favor-01
                              :ARG1 (s / survive-01))
                        :ARG1-of (m / mean-01
                              :ARG2 (a3 / and
                                    :op1 (p2 / protein :name (n2 / name :op1 "Bcl-2"))
                                    :op2 (p3 / protein :name (n3 / name :op1 "Bcl-xL")))))
                  :op2 (p4 / protein
                        :ARG0-of (f2 / favor-01
                              :ARG1 (a4 / apoptosis))
                        :ARG1-of (m2 / mean-01
                              :ARG2 (p5 / protein :name (n4 / name :op1 "Bad")))
                        :ARG1-of (r2 / resemble-01
                              :ARG2 p2))
                  :mod (o / other)
                  :ARG1-of (r3 / regulate-01
                        :ARG0 (s2 / signal-07
                              :ARG0 (e / enzyme :name (n / name :op1 "ERK")))
                        :ARG1-of (k / know-01
                              :mod (a5 / also)))))
      :ARG1 (c / candidate
            :mod (a6 / additional)
            :ARG0-of (c2 / contribute-01
                  :ARG2 (s3 / survive-01
                        :ARG0 (c3 / cell
                              :mod (d / disease :name (n6 / name :op1 "multiple" :op2 "myeloma")))
                        :ARG1-of (e2 / enhance-01))
                  :ARG1-of (p6 / possible-01))))

# ::id pmid_2352_4590.73 ::date 2015-07-28T04:42:51 ::annotator SDL-AMR-09 ::preferred
# ::snt <sec-title level="2">MEK inhibitors</sec-title>
# ::save-date Sat Jan 16, 2016 ::file pmid_2352_4590_73.txt
(m / molecular-physical-entity
      :ARG0-of (i / inhibit-01
            :ARG1 (p / protein-family :name (n / name :op1 "MEK"))))

# ::id pmid_2352_4590.74 ::date 2015-07-28T04:44:13 ::annotator SDL-AMR-09 ::preferred
# ::snt MEK1 and MEK2 are homologous dual specificity kinases that share ERK as their only known catalytic substrate,<sup><xref ref-type="bibr" rid="bib15">15</xref></sup> making MEK an appealing target for cancer drug development.
# ::save-date Wed Mar 2, 2016 ::file pmid_2352_4590_74.txt
(k / kinase
      :mod (h / homologous)
      :domain (a / and
            :op1 (k2 / kinase :name (n5 / name :op1 "MEK1"))
            :op2 (k3 / kinase :name (n6 / name :op1 "MEK2")))
      :ARG0-of (s / share-01
            :ARG1 (e / enzyme :name (n / name :op1 "ERK")
                  :ARG0-of (h2 / have-rel-role-91
                        :ARG2 (s2 / substrate
                              :ARG0-of (c / catalyze-01)
                              :ARG1-of (k4 / know-01)
                              :mod (o / only)
                              :poss a)))
            :ARG1-of (d3 / describe-01
                  :ARG0 (p / publication
                        :ARG1-of (c2 / cite-01
                              :ARG2 15)))
            :ARG0-of (m / make-02
                  :ARG1 (e2 / enzyme :name (n2 / name :op1 "MEK")
                        :ARG1-of (t / target-01
                              :ARG0-of (a2 / appeal-03
                                    :ARG1 (d4 / develop-02
                                          :ARG1 (d5 / drug
                                                :mod (d2 / disease :wiki "Cancer" :name (n3 / name :op1 "cancer")))))))))
      :mod (s3 / specificity
            :mod (d / dual)))

# ::id pmid_2352_4590.75 ::date 2015-07-28T04:56:03 ::annotator SDL-AMR-09 ::preferred
# ::snt Although many kinase inhibitors target the ATP-binding region of an enzyme, MEK contains a hydrophobic allosteric pocket adjacent to the ATP-binding site that is not shared with other kinases.<sup><xref ref-type="bibr" rid="bib36">36</xref></sup>
# ::save-date Tue Aug 4, 2015 ::file pmid_2352_4590_75.txt
(h / have-concession-91
      :ARG1 (c / contain-01
            :ARG0 (e / enzyme :name (n / name :op1 "MEK"))
            :ARG1 (p / pocket
                  :mod (a / allosteric)
                  :mod (h2 / hydrophobic)
                  :ARG1-of (s3 / share-01 :polarity -
                        :ARG0 e
                        :ARG2 (k2 / kinase
                              :mod (o / other)))
                  :ARG1-of (b2 / border-01
                        :ARG2 (s2 / site
                              :ARG2-of b))))
      :ARG2 (t2 / target-01
            :ARG0 (m / molecular-physical-entity
                  :ARG0-of (i / inhibit-01
                        :ARG1 (k / kinase))
                  :quant (m2 / many))
            :ARG1 (r / region
                  :ARG2-of (b / bind-01
                        :ARG1 (s / small-molecule :name (n2 / name :op1 "ATP")))
                  :part-of (e2 / enzyme)))
      :ARG1-of (d2 / describe-01
            :ARG0 (p2 / publication
                  :ARG1-of (c2 / cite-01
                        :ARG2 36))))

# ::id pmid_2352_4590.76 ::date 2015-07-28T05:10:34 ::annotator SDL-AMR-09 ::preferred
# ::snt This offers the opportunity to design highly selective inhibitors of MEK that do not simply target the conserved ATP region of the kinase.
# ::save-date Sat Jan 16, 2016 ::file pmid_2352_4590_76.txt
(o / offer-01
      :ARG0 (t2 / this)
      :ARG1 (o2 / opportunity
            :topic (d / design-01
                  :ARG1 (m / molecular-physical-entity
                        :ARG0-of (i / inhibit-01
                              :ARG1 (p / protein-family :name (n / name :op1 "MEK")))
                        :ARG0-of (s / select-01
                              :ARG1-of (h / high-02))
                        :ARG0-of (t / target-01 :polarity -
                              :ARG1 (r / region
                                    :part-of (k / kinase)
                                    :mod (s3 / small-molecule :name (n2 / name :op1 "ATP"))
                                    :ARG1-of (c / conserve-01))
                              :ARG1-of (s2 / simple-02))))))

# ::id pmid_2352_4590.77 ::date 2015-07-28T05:41:09 ::annotator SDL-AMR-09 ::preferred
# ::snt In the remainder of the review, we describe some of the various MEK inhibitors currently being investigated and their future role in cancer therapy.
# ::save-date Sat Jan 16, 2016 ::file pmid_2352_4590_77.txt
(d2 / describe-01
      :ARG0 (w / we)
      :ARG1 (a / and
            :op1 (m / molecular-physical-entity
                  :ARG0-of (i / inhibit-01
                        :ARG1 (p2 / protein-family :name (n / name :op1 "MEK")))
                  :ARG1-of (i2 / include-91
                        :ARG2 (m2 / molecular-physical-entity
                              :ARG0-of i
                              :mod (v / various)
                              :ARG1-of (i3 / investigate-01
                                    :time (c / current)))
                        :ARG3 (s / some)))
            :op2 (p / play-08
                  :ARG0 m
                  :ARG1 (t / therapy
                        :mod (d / disease :wiki "Cancer" :name (n2 / name :op1 "cancer")))
                  :time (f / future)))
      :medium (r / remainder
            :part-of (r2 / review)))

# ::id pmid_2352_4590.78 ::date 2015-07-28T05:48:17 ::annotator SDL-AMR-09 ::preferred
# ::snt <sec-title level="2">Prototypic MEK inhibitors</sec-title>
# ::save-date Sat Jan 16, 2016 ::file pmid_2352_4590_78.txt
(m / molecular-physical-entity
      :ARG0-of (i / inhibit-01
            :ARG1 (p2 / protein-family :name (n / name :op1 "MEK")))
      :mod (p / prototype))

# ::id pmid_2352_4590.79 ::date 2015-07-28T06:14:28 ::annotator SDL-AMR-09 ::preferred
# ::snt Despite demonstrating <i>in vitro</i> activity, major <i>in vivo</i> limitations were identified for the early first generation MEK inhibitors, PD098059<sup><xref ref-type="bibr" rid="bib37">37</xref></sup> and U0126.<sup><xref ref-type="bibr" rid="bib38">38</xref></sup>
# ::save-date Sat Jan 16, 2016 ::file pmid_2352_4590_79.txt
(i2 / identify-01
      :ARG1 (l / limit-01
            :manner (i3 / in-vivo)
            :ARG1-of (m / major-02))
      :location (m2 / molecular-physical-entity
            :ARG0-of (i / inhibit-01
                  :ARG1 (p3 / protein-family :name (n / name :op1 "MEK")))
            :time (e2 / early)
            :mod (g / generation
                  :ord (o2 / ordinal-entity :value 1))
            :ARG1-of (m3 / mean-01
                  :ARG2 (a / and
                        :op1 (s / small-molecule :name (n2 / name :op1 "PD098059")
                              :ARG1-of (d / describe-01
                                    :ARG0 (p / publication
                                          :ARG1-of (c / cite-01
                                                :ARG2 37))))
                        :op2 (s2 / small-molecule :name (n3 / name :op1 "U0126")
                              :ARG1-of (d2 / describe-01
                                    :ARG0 (p2 / publication
                                          :ARG1-of (c2 / cite-01
                                                :ARG2 38)))))))
      :concession (d3 / demonstrate-01
                  :ARG0 a
                  :ARG1 (a2 / activity-06
                        :ARG0 a
                        :manner (i4 / in-vitro))))

# ::id pmid_2352_4590.80 ::date 2015-07-28T06:20:56 ::annotator SDL-AMR-09 ::preferred
# ::snt Although both compounds were deemed unsuitable for clinical consideration they have proven to be invaluable tools for investigating the Ras/MAPK pathway.
# ::save-date Tue Aug 4, 2015 ::file pmid_2352_4590_80.txt
(h / have-concession-91
      :ARG1 (p / prove-01
            :ARG0 c
            :ARG1 (t / tool
                  :domain c
                  :ARG1-of (v / value-02
                        :degree (e / extreme)
                        :purpose (i / investigate-01
                              :ARG1 (p2 / pathway :name (n / name :op1 "Ras/MAPK"))))))
      :ARG2 (d / deem-01
            :ARG1 (s / suitable-04 :polarity -
                  :ARG1 (c / compound
                        :mod (b / both))
                  :ARG2 (c2 / consider-02
                        :ARG1 c
                        :manner (c3 / clinic)))))

# ::id pmid_2352_4590.81 ::date 2015-07-28T06:30:07 ::annotator SDL-AMR-09 ::preferred
# ::snt CI-1040 (PD184352) was the first MEK inhibitor to demonstrate tumour inhibitory activity <i>in vivo</i>.<sup><xref ref-type="bibr" rid="bib39">39</xref></sup>
# ::save-date Sat Jan 16, 2016 ::file pmid_2352_4590_81.txt
(m / molecular-physical-entity
      :ARG0-of (i / inhibit-01
            :ARG1 (p2 / protein-family :name (n / name :op1 "MEK")))
      :ord (o / ordinal-entity :value 1)
      :domain (s / small-molecule :name (n2 / name :op1 "CI-1040")
            :ARG1-of (m3 / mean-01
                  :ARG2 (s2 / small-molecule :name (n3 / name :op1 "PD184352"))))
      :ARG0-of (d / demonstrate-01
            :ARG1 (a / activity-06
                  :ARG0 m
                  :ARG1 (i2 / inhibit-01
                        :ARG0 m
                        :ARG1 (t / tumor)))
            :manner (i3 / in-vivo))
      :ARG1-of (d2 / describe-01
            :ARG0 (p / publication
                  :ARG1-of (c / cite-01
                        :ARG2 39))))

# ::id pmid_2352_4590.82 ::date 2015-07-28T06:36:43 ::annotator SDL-AMR-09 ::preferred
# ::snt Encouraging phase I results in advanced cancer patients, where one patient with pancreatic cancer achieved a partial response (PR) lasting 12 months, prompted a phase II study of CI-1040 in patients with advanced solid tumours.<sup><xref ref-type="bibr" rid="bib40">40</xref></sup>
# ::save-date Thu Feb 4, 2016 ::file pmid_2352_4590_82.txt
(p / prompt-01
      :ARG0 (t2 / thing
            :ARG2-of (r / result-01
                  :ARG1 (p2 / phase
                        :ord (o / ordinal-entity :value 1)))
            :ARG0-of (e / encourage-02)
            :topic (p3 / person
                  :ARG0-of (h / have-rel-role-91
                        :ARG2 (p4 / patient))
                  :ARG2-of (i / include-91
                        :ARG1 (p7 / person
                              :ARG0-of h
                              :ARG0-of (a2 / achieve-01
                                    :ARG1 (t4 / thing
                                          :ARG2-of (r2 / respond-01
                                                :degree (p9 / part)
                                                :duration (t / temporal-quantity :quant 12
                                                            :unit (m / month)))))
                              :mod (d3 / disease :wiki "Pancreatic_cancer" :name (n3 / name :op1 "pancreatic" :op2 "cancer"))))
                  :mod (d2 / disease :wiki "Cancer" :name (n / name :op1 "cancer")
                        :ARG1-of (a / advance-01))))
      :ARG1 (s / study-01
            :ARG1 (s3 / small-molecule :name (n2 / name :op1 "CI-1040"))
            :mod (p5 / phase
                  :ord (o2 / ordinal-entity :value 2))
            :location (p6 / person
                  :ARG0-of h
                  :ARG0-of (h2 / have-03
                        :ARG1 (t3 / tumor
                              :ARG1-of (s2 / solid-02)
                              :ARG1-of a))))
      :ARG1-of (d / describe-01
            :ARG0 (p11 / publication
                  :ARG1-of (c3 / cite-01
                        :ARG2 40))))

# ::id pmid_2352_4590.83 ::date 2015-07-28T06:52:25 ::annotator SDL-AMR-09 ::preferred
# ::snt However, in contrast to the phase I trial, no PR was observed.<sup><xref ref-type="bibr" rid="bib41">41</xref></sup>
# ::save-date Mon Nov 16, 2015 ::file pmid_2352_4590_83.txt
(c3 / contrast-01
      :ARG1 (t / trial-06
            :mod (p2 / phase
                  :ord (o2 / ordinal-entity :value 1)))
      :ARG2 (o / observe-02 :polarity -
            :ARG1 (t2 / thing
                  :ARG2-of (r / respond-01
                        :degree (p / part)))
            :ARG1-of (c / contrast-01))
      :ARG1-of (d / describe-01
            :ARG0 (p3 / publication
                  :ARG1-of (c2 / cite-01
                        :ARG2 41))))

# ::id pmid_2352_4590.84 ::date 2015-07-28T06:58:45 ::annotator SDL-AMR-09 ::preferred
# ::snt As a result of its weak antitumour activity, development of CI-1040 was terminated in favour of the more potent PD0325901.
# ::save-date Tue Aug 4, 2015 ::file pmid_2352_4590_84.txt
(t / terminate-01
      :ARG1 (d / develop-02
            :ARG1 (s / small-molecule :name (n / name :op1 "CI-1040")))
      :purpose (f / favor-01
            :ARG1 (s2 / small-molecule :name (n2 / name :op1 "PD0325901")
                  :mod (p / potent
                        :degree (m3 / more))))
      :ARG2-of (r / result-01
            :ARG1 (a / activity-06
                  :ARG0 s
                  :ARG1-of (w / weak-02)
                  :ARG0-of (c2 / counter-01
                        :ARG1 (t2 / tumor)))))

# ::id pmid_2352_4590.85 ::date 2015-07-28T07:05:02 ::annotator SDL-AMR-09 ::preferred
# ::snt Compared with CI-1040, PD0325901 demonstrates significantly improved potency in cell-based assays (100-fold), oral bioavailability and metabolic stability.<sup><xref ref-type="bibr" rid="bib42">42</xref></sup>
# ::save-date Wed Jul 29, 2015 ::file pmid_2352_4590_85.txt
(d / demonstrate-01
      :ARG0 (s3 / small-molecule :name (n / name :op1 "PD0325901"))
      :ARG1 (a / and
            :op1 (p / potency
                  :ARG1-of (i / improve-02
                        :ARG2 (p2 / product-of :op1 100)
                        :ARG1-of (s / significant-02))
                  :condition (a2 / assay-01
                        :ARG1-of (b / base-02
                              :ARG2 (c / cell))))
            :op2 (b2 / bioavailability
                  :mod (o / oral))
            :op3 (s2 / stability
                  :mod (m2 / metabolize-01)))
      :compared-to (s4 / small-molecule :name (n2 / name :op1 "CI-1040"))
      :ARG1-of (d2 / describe-01
            :ARG0 (p3 / publication
                  :ARG1-of (c2 / cite-01
                        :ARG2 42))))

# ::id pmid_2352_4590.86 ::date 2015-07-28T07:11:43 ::annotator SDL-AMR-09 ::preferred
# ::snt Phase I investigation of PD0325901 was conducted in 66 advanced cancer patients.
# ::save-date Thu Feb 4, 2016 ::file pmid_2352_4590_86.txt
(c / conduct-01
      :ARG1 (i / investigate-01
            :ARG1 (s / small-molecule :name (n2 / name :op1 "PD0325901"))
            :mod (p / phase
                  :ord (o / ordinal-entity :value 1)))
      :location (p2 / person :quant 66
            :ARG0-of (h / have-rel-role-91
                  :ARG2 (p3 / patient))
            :mod (d / disease :wiki "Cancer" :name (n / name :op1 "cancer")
                  :ARG1-of (a / advance-01))))

# ::id pmid_2352_4590.87 ::date 2015-07-28T07:15:45 ::annotator SDL-AMR-09 ::preferred
# ::snt Three of 48 evaluable patients with melanoma achieved PR, while 10 had stable disease (s.d.) for ≥4 months.
# ::save-date Sun Dec 20, 2015 ::file pmid_2352_4590_87.txt
(c / contrast-01
      :ARG1 (a / achieve-01
            :ARG0 (p / person :quant 3
                  :ARG0-of (h / have-rel-role-91
                        :ARG2 (p2 / patient))
                  :ARG1-of (i / include-91
                        :ARG2 (p3 / person :quant 48
                              :ARG0-of h
                              :ARG1-of (e / evaluate-01
                                    :ARG1-of (p6 / possible-01))
                              :mod (m3 / medical-condition :name (n / name :op1 "melanoma")))))
            :ARG1 (t2 / thing
                  :ARG2-of (r / respond-01
                        :degree (p4 / part))))
      :ARG2 (h2 / have-03
            :ARG0 (p5 / person :quant 10
                  :ARG0-of h
                  :ARG1-of i)
            :ARG1 (d2 / disease
                  :ARG1-of (s / stable-03))
            :duration (o / or
                  :op1 (t / temporal-quantity :quant 4
                        :unit (m / month))
                  :op2 (m2 / more-than
                        :op1 t))))

# ::id pmid_2352_4590.88 ::date 2015-07-28T07:22:39 ::annotator SDL-AMR-09 ::preferred
# ::snt A subset of these patients developed retinal vein occlusion.<sup><xref ref-type="bibr" rid="bib43">43</xref></sup>
# ::save-date Tue Feb 2, 2016 ::file pmid_2352_4590_88.txt
(d / develop-01
      :ARG1 (s / subset
            :ARG1-of (i / include-91
                  :ARG2 (p / person
                        :ARG0-of (h / have-rel-role-91
                              :ARG2 (p2 / patient))
                        :mod (t / this))))
      :ARG2 (o / occlude-01
            :ARG1 (v / vein
                  :mod (r / retina)))
      :ARG1-of (d2 / describe-01
            :ARG0 (p3 / publication
                  :ARG1-of (c / cite-01
                        :ARG2 43))))

# ::id pmid_2352_4590.89 ::date 2015-07-28T07:26:30 ::annotator SDL-AMR-09 ::preferred
# ::snt A phase II study of PD0325901 was assessed in 34 advanced non-small cell lung carcinoma patients, but was eventually terminated owing to lack of objective responses and increasing concerns about ocular function and neurotoxicity at therapeutic doses.<sup><xref ref-type="bibr" rid="bib44">44</xref></sup>
# ::save-date Thu Feb 4, 2016 ::file pmid_2352_4590_89.txt
(c / contrast-01
      :ARG1 (a / assess-01
            :ARG1 (s / study-01
                  :ARG1 (s3 / small-molecule :name (n / name :op1 "PD0325901"))
                  :mod (p / phase
                        :ord (o / ordinal-entity :value 2)))
            :location (p2 / person :quant 34
                  :ARG0-of (h / have-rel-role-91
                        :ARG2 (p3 / patient))
                  :mod (c2 / carcinoma
                        :mod (l / lung)
                        :mod (c3 / cell
                              :mod (s2 / small :polarity -))
                        :ARG1-of (a2 / advance-01))))
      :ARG2 (t / terminate-01
            :ARG1 s
            :time (e / eventual)
            :ARG1-of (c4 / cause-01
                  :ARG0 (a3 / and
                        :op1 (l2 / lack-01
                              :ARG1 (t2 / thing
                                    :ARG2-of (r / respond-01)
                                    :mod (o2 / objective)))
                        :op2 (c5 / concern-01
                              :ARG0 (a4 / and
                                    :op1 (f / function-01
                                          :ARG0 (e2 / eye))
                                    :op2 (n2 / neurotoxicity))
                              :ARG1-of (i / increase-01)
                              :condition (d / dose-01
                                    :mod (t3 / therapy))))))
      :ARG1-of (d2 / describe-01
            :ARG0 (p4 / publication
                  :ARG1-of (c6 / cite-01
                        :ARG2 44))))

# ::id pmid_2352_4590.90 ::date 2015-07-28T07:38:44 ::annotator SDL-AMR-09 ::preferred
# ::snt Investigation of these treatment-related toxicities was conducted in animal models, where PD0325901 was found to cause retinal vein occlusion in rabbits.
# ::save-date Tue Feb 2, 2016 ::file pmid_2352_4590_90.txt
(c / conduct-01
      :ARG1 (i / investigate-01
            :ARG1 (t / toxicity
                  :mod (t2 / this)
                  :ARG1-of (r / relate-01
                        :ARG2 (t3 / treat-04))))
      :location (m / model
            :mod (a / animal)
            :location-of (f / find-01
                  :ARG1 (o / occlude-01
                        :ARG0 (s / small-molecule :name (n / name :op1 "PD0325901"))
                        :ARG1 (v / vein
                              :mod (r2 / retina))
                        :location (r3 / rabbit)))))

# ::id pmid_2352_4590.91 ::date 2015-07-28T07:43:38 ::annotator SDL-AMR-09 ::preferred
# ::snt This adverse effect was attributed to the abrogation of phosphorylated-ERK (p-ERK) within the brain.<sup><xref ref-type="bibr" rid="bib45">45</xref></sup>
# ::save-date Mon Nov 16, 2015 ::file pmid_2352_4590_91.txt
(a / attribute-01
      :ARG1 (a2 / affect-01
            :mod (a3 / adverse)
            :mod (t / this))
      :ARG2 (a4 / abrogate-01
            :ARG1 (e / enzyme :name (n / name :op1 "ERK")
                  :ARG3-of (p / phosphorylate-01))
            :location (b / brain))
      :ARG1-of (d / describe-01
            :ARG0 (p3 / publication
                  :ARG1-of (c / cite-01
                        :ARG2 45))))

# ::id pmid_2352_4590.92 ::date 2015-07-28T07:46:09 ::annotator SDL-AMR-09 ::preferred
# ::snt In light of these observations, development of PD0325901 has been suspended.
# ::save-date Wed Jul 29, 2015 ::file pmid_2352_4590_92.txt
(s / suspend-01
      :ARG1 (d / develop-02
            :ARG1 (s2 / small-molecule :name (n / name :op1 "PD0325901")))
      :ARG1-of (c / cause-01
            :ARG0 (t / thing
                  :mod (t2 / this)
                  :ARG1-of (o / observe-01))))

# ::id pmid_2352_4590.93 ::date 2015-07-28T07:47:41 ::annotator SDL-AMR-09 ::preferred
# ::snt <sec-title level="2">MEK inhibitors in development</sec-title>
# ::save-date Sat Jan 16, 2016 ::file pmid_2352_4590_93.txt
(d / develop-02
      :ARG1 (m / molecular-physical-entity
            :ARG0-of (i / inhibit-01
                  :ARG1 (p / protein-family :name (n / name :op1 "MEK")))))

# ::id pmid_2352_4590.94 ::date 2015-07-28T07:48:36 ::annotator SDL-AMR-09 ::preferred
# ::snt AZD6244/ARRY-142886 (selumetinib) is a potent MEK inhibitor that has demonstrated significant tumour suppressive activity in a number of preclinical solid tumour models.<sup><xref ref-type="bibr" rid="bib46">46</xref>, <xref ref-type="bibr" rid="bib47">47</xref>, <xref ref-type="bibr" rid="bib48">48</xref></sup>
# ::save-date Sat Jan 16, 2016 ::file pmid_2352_4590_94.txt
(m / molecular-physical-entity
      :ARG0-of (i / inhibit-01
            :ARG1 (p6 / protein-family :name (n / name :op1 "MEK")))
      :domain (s5 / small-molecule :name (n2 / name :op1 "AZD6244/ARRY-142886")
            :ARG1-of (m3 / mean-01
                  :ARG2 (s / small-molecule :name (n3 / name :op1 "selumetinib"))))
      :mod (p / potent)
      :ARG1-of (d2 / describe-01
            :ARG0 (a2 / and
                  :op1 (p3 / publication
                        :ARG1-of (c / cite-01
                              :ARG2 46))
                  :op2 (p4 / publication
                        :ARG1-of (c2 / cite-01
                              :ARG2 47))
                  :op3 (p5 / publication
                        :ARG1-of (c3 / cite-01
                              :ARG2 48))))
      :ARG0-of (d / demonstrate-01
            :ARG1 (a / activity-06
                  :ARG0 m
                  :ARG1 (s2 / suppress-01
                        :ARG0 m
                        :ARG1 (t / tumor))
                  :ARG1-of (s3 / significant-02))
            :location (n4 / number
                  :quant-of (m4 / model
                        :mod (t2 / tumor
                              :ARG1-of (s4 / solid-02))
                        :mod (p2 / preclinical)))))

# ::id pmid_2352_4590.95 ::date 2015-07-28T07:54:32 ::annotator SDL-AMR-09 ::preferred
# ::snt In cell-based enzymatic assays, AZD6244 inhibited purified MEK at an IC<sub>50</sub> of 14.1±0.79 nM, with no inhibition observed at 10 μℳ against 40 other kinases.
# ::save-date Sun Dec 20, 2015 ::file pmid_2352_4590_95.txt
(a2 / and
      :op1 (i / inhibit-01
            :ARG0 (s / small-molecule :name (n / name :op1 "AZD6244")
                  :ARG1-of (h / have-percentage-maximal-inhibitory-concentration-01
                        :ARG2 50
                        :ARG4 (c / concentration-quantity
                              :quant (v / value-interval
                                    :op1 (a3 / add-02
                                          :ARG1 0.79
                                          :ARG2 14.1)
                                    :op2 (s2 / subtract-01
                                          :ARG1 0.79
                                          :ARG2 14.1))
                              :unit (n3 / nanomolar))))
            :ARG1 (e / enzyme :name (n2 / name :op1 "MEK")
                  :ARG1-of (p / purify-01))
            :condition (a / assay-01
                  :ARG1 (e2 / enzyme)
                  :ARG1-of (b / base-02
                        :ARG2 (c2 / cell))))
      :op2 (o / observe-02 :polarity -
            :ARG1 (i3 / inhibit-01)
            :ARG1-of (c4 / contrast-01
                  :ARG2 (k / kinase :quant 40
                        :mod (o3 / other)))
            :condition (h2 / have-percentage-maximal-inhibitory-concentration-01
                  :ARG2 50
                  :ARG4 (c3 / concentration-quantity :quant 10
                        :unit (m / micromolar)))))

# ::id pmid_2352_4590.96 ::date 2015-07-28T08:06:36 ::annotator SDL-AMR-09 ::preferred
# ::snt Cell lines harbouring oncogenic B-Raf and N-Ras mutations displayed enhanced sensitivity to AZD6244, whereas K-Ras mutated tumours showed variable responsiveness.<sup><xref ref-type="bibr" rid="bib47">47</xref></sup>
# ::save-date Thu Dec 10, 2015 ::file pmid_2352_4590_96.txt
(c / contrast-01
      :ARG1 (d / display-01
            :ARG0 (c2 / cell-line
                  :ARG0-of (h / harbor-01
                        :ARG1 (m / mutate-01
                              :ARG2 (a / and
                                    :op1 (e4 / enzyme :name (n5 / name :op1 "B-Raf"))
                                    :op2 (e5 / enzyme :name (n6 / name :op1 "N-Ras")))
                              :ARG0-of (c3 / cause-01
                                    :ARG1 (d3 / disease :wiki "Cancer" :name (n / name :op1 "cancer"))))))
            :ARG1 (s2 / sensitive-03
                  :ARG0 c2
                  :ARG1 (s / small-molecule :name (n3 / name :op1 "AZD6244"))
                  :ARG1-of (e6 / enhance-01)))
      :ARG2 (s3 / show-01
            :ARG0 (t / tumor
                  :mod (e3 / enzyme :name (n4 / name :op1 "K-Ras")
                        :ARG2-of (m2 / mutate-01)))
            :ARG1 (r / responsiveness
                  :ARG1-of (v / vary-01)))
      :ARG1-of (d2 / describe-01
            :ARG0 (p / publication
                  :ARG1-of (c5 / cite-01
                        :ARG2 47))))

# ::id pmid_2352_4590.97 ::date 2015-07-28T08:13:24 ::annotator SDL-AMR-09 ::preferred
# ::snt In 2004, a total of 57 patients with advanced cancer were treated in a phase I evaluation of AZD6244.
# ::save-date Thu Dec 10, 2015 ::file pmid_2352_4590_97.txt
(t / treat-03
      :ARG1 (p / person
            :ARG0-of (h / have-rel-role-91
                  :ARG2 (p2 / patient))
            :ARG1-of (t2 / total-01
                  :ARG2 57)
            :ARG0-of (h2 / have-03
                  :ARG1 (d2 / disease :wiki "Cancer" :name (n / name :op1 "cancer")
                        :ARG1-of (a / advance-01))))
      :time (d / date-entity :year 2004)
      :time (e / evaluate-01
            :ARG1 (s / small-molecule :name (n2 / name :op1 "AZD6244"))
            :mod (p3 / phase
                  :ord (o / ordinal-entity :value 1))))

# ::id pmid_2352_4590.98 ::date 2015-07-28T08:18:58 ::annotator SDL-AMR-09 ::preferred
# ::snt The best clinical response achieved was s.d. ≥ for 5 months in 9 patients, with 2 patients maintaining s.d. for 19 and 22 months.
# ::save-date Fri Jan 1, 2016 ::file pmid_2352_4590_98.txt
(t2 / thing
      :ARG2-of (r / respond-01)
      :ARG1-of (g / good-02
            :degree (m2 / most))
      :mod (c / clinic)
      :ARG1-of (a / achieve-01)
      :domain (d / disease
            :duration (o2 / or
                  :op1 (t3 / temporal-quantity :quant 5
                        :unit (m3 / month))
                  :op2 (m5 / more-than
                        :op1 t3))
            :location (p / person :quant 9
                  :ARG0-of (h / have-rel-role-91
                        :ARG2 (p2 / patient))
                  :ARG2-of (i / include-91
                        :ARG1 (a2 / and
                              :op1 (p3 / person
                                    :ARG0-of h
                                    :ARG0-of (m6 / maintain-01
                                          :ARG1 d2)
                                    :duration (t4 / temporal-quantity :quant 19
                                          :unit (m4 / month)))
                              :op2 (p4 / person
                                    :ARG0-of h
                                    :ARG0-of (m7 / maintain-01
                                          :ARG1 (d2 / disease
                                                :ARG1-of s)
                                          :duration (t5 / temporal-quantity :quant 22
                                                :unit (m / month)))))))
            :ARG1-of (s / stable-03)))

# ::id pmid_2352_4590.99 ::date 2015-07-28T08:26:08 ::annotator SDL-AMR-09 ::preferred
# ::snt Similar to PD0325901, blurred vision was reported in 7 patients; however, neurotoxicity was not observed.<sup><xref ref-type="bibr" rid="bib49">49</xref></sup>
# ::save-date Thu Feb 4, 2016 ::file pmid_2352_4590_99.txt
(r2 / report-01
      :ARG1 (s2 / see-01
            :ARG1-of (b / blur-01))
      :location (p / person :quant 7
            :ARG0-of (h / have-rel-role-91
                  :ARG2 (p2 / patient)))
      :ARG1-of (r / resemble-01
            :ARG2 (s / small-molecule :name (n2 / name :op1 "PD0325901")))
      :ARG1-of (d / describe-01
            :ARG0 (p3 / publication
                  :ARG1-of (c / cite-01
                        :ARG2 49)))
      :concession-of (o / observe-01 :polarity -
                  :ARG1 (n / neurotoxicity)))

# ::id pmid_2352_4590.100 ::date 2015-07-28T08:32:04 ::annotator SDL-AMR-09 ::preferred
# ::snt Several phase II trials have since examined the effectiveness of AZD6244 in a diverse range of solid tumours.<sup><xref ref-type="bibr" rid="bib50">50</xref>, <xref ref-type="bibr" rid="bib51">51</xref>, <xref ref-type="bibr" rid="bib52">52</xref></sup>
# ::save-date Mon Dec 21, 2015 ::file pmid_2352_4590_100.txt
(e / examine-01
      :ARG0 (t2 / trial-06
            :mod (p / phase
                  :ord (o / ordinal-entity :value 2))
            :quant (s3 / several))
      :ARG1 (e2 / effective-04
            :ARG0 (s / small-molecule :name (n / name :op1 "AZD6244"))
            :ARG1 (r / range-01
                  :ARG1 (t / tumor
                        :ARG1-of (s2 / solid-02))
                  :mod (d / diverse)))
      :time (s4 / since)
      :ARG1-of (d2 / describe-01
            :ARG0 (a / and
                  :op1 (p2 / publication
                        :ARG1-of (c / cite-01
                              :ARG2 50))
                  :op2 (p3 / publication
                        :ARG1-of (c2 / cite-01
                              :ARG2 51))
                  :op3 (p4 / publication
                        :ARG1-of (c3 / cite-01
                              :ARG2 52)))))

# ::id pmid_2352_4590.101 ::date 2015-07-28T08:36:40 ::annotator SDL-AMR-09 ::preferred
# ::snt In each of these studies, the efficacy and tolerability of AZD6244 was compared with a conventional chemotherapeutic agent.
# ::save-date Tue Aug 4, 2015 ::file pmid_2352_4590_101.txt
(c / compare-01
      :ARG1 (a / and
            :op1 (e / effective-04
                  :ARG0 (s / small-molecule :name (n / name :op1 "AZD6244")))
            :op2 (t / tolerate-01
                  :ARG1 s
                  :ARG1-of (p / possible-01)))
      :ARG2 (a2 / agent
            :mod (c2 / conventional)
            :mod (c3 / chemotherapy))
      :manner (s2 / study-01
            :mod (e2 / each)
            :mod (t2 / this)))

# ::id pmid_2352_4590.102 ::date 2015-07-28T05:41:33 ::annotator SDL-AMR-09 ::preferred
# ::snt However, even though some objective responses were observed, AZD6244 failed to demonstrate superior clinical responses over established treatment modalities.
# ::save-date Tue Jul 28, 2015 ::file pmid_2352_4590_102.txt
(h / have-concession-91
      :ARG2 (f / fail-01
            :ARG1 (s / small-molecule :name (n / name :op1 "AZD6244"))
            :ARG2 (d / demonstrate-01
                  :ARG0 s
                  :ARG1 (r / respond-01
                        :ARG1-of (s2 / superior-01
                              :compared-to (m / modality
                                    :mod (t / treat-04)
                                    :ARG1-of (e / establish-01)))
                        :mod (c / clinic)))
            :concession (o / observe-01
                        :ARG1 (r2 / respond-01
                              :mod (o2 / objective)
                              :quant (s3 / some)))))

# ::id pmid_2352_4590.103 ::date 2015-07-28T09:33:39 ::annotator SDL-AMR-09 ::preferred
# ::snt As a result of these studies there has not been an advocacy for AZD6244 as a monotherapy.
# ::save-date Sun Aug 9, 2015 ::file pmid_2352_4590_103.txt
(a / advocate-01 :polarity -
      :ARG1 (s / small-molecule :name (n / name :op1 "AZD6244")
            :mod (m / monotherapy))
      :ARG2-of (r / result-01
            :ARG1 (t / thing
                  :ARG1-of (s2 / study-01)
                  :mod (t2 / this))))

# ::id pmid_2352_4590.104 ::date 2015-07-28T09:54:00 ::annotator SDL-AMR-09 ::preferred
# ::snt AS703026/MSC1935369 demonstrates IC<sub>50</sub> values in the subnanomolar range and potently inhibits tumour growth <i>in vivo.</i><sup><xref ref-type="bibr" rid="bib53">53</xref></sup> Eighty-five advanced cancer patients were recruited for the phase I trial of AS703026.
# ::save-date Fri Jan 1, 2016 ::file pmid_2352_4590_104.txt
(m / multi-sentence
      :snt1 (a / and
            :op1 (d / demonstrate-01
                  :ARG0 (s / small-molecule
                        :name (n / name :op1 "AS703026/MSC1935369"))
                  :ARG1 (c / concentration-quantity
                        :ARG4-of (h2 / have-percentage-maximal-inhibitory-concentration-01 :ARG2 50
                              :ARG1 s)
                        :ARG1-of (r / range-01
                              :ARG2 (s2 / subnanomolar))))
            :op2 (i / inhibit-01
                  :ARG0 s
                  :ARG1 (g / grow-01
                        :ARG1 (t2 / tumor))
                  :manner (p / potent)
                  :manner (i2 / in-vivo))
            :ARG1-of (d2 / describe-01
                  :ARG0 (p5 / publication
                        :ARG1-of (c2 / cite-01 :ARG2 53))))
      :snt2 (r2 / recruit-01
            :ARG1 (p2 / person :quant 85
                  :ARG0-of (h / have-org-role-91
                        :ARG2 (p4 / patient))
                  :mod (d3 / disease :wiki "Cancer"
                        :name (n4 / name :op1 "cancer")
                        :ARG1-of (a2 / advance-01)))
            :purpose (t3 / trial-06
                  :ARG2 (s3 / small-molecule
                        :name (n3 / name :op1 "AS703026"))
                  :mod (p3 / phase
                        :ord (o / ordinal-entity :value 1)))))

# ::id pmid_2352_4590.105 ::date 2015-07-28T10:10:43 ::annotator SDL-AMR-09 ::preferred
# ::snt Visual disturbances were reported in a subset of patients, including some cases of serous macular detachment.
# ::save-date Sat Jan 30, 2016 ::file pmid_2352_4590_105.txt
(r / report-01
      :ARG1 (d / disturb-01
            :mod (v / visual)
            :location (s / subset
                  :ARG2-of (i2 / include-91
                        :ARG1 (p / person
                              :ARG0-of (h / have-org-role-91
                                    :ARG2 (p2 / patient)))))
            :ARG2-of (i / include-01
                  :ARG1 (c / case-04
                        :ARG1 (d2 / detach-01
                              :mod (s2 / serum)
                              :mod (m / macular))
                        :quant (s3 / some)))))

# ::id pmid_2352_4590.106 ::date 2015-07-28T10:16:36 ::annotator SDL-AMR-09 ::preferred
# ::snt Tumour shrinkage was witnessed in four melanoma patients, three of whom (all bearing B-Raf mutations) demonstrated PR.<sup><xref ref-type="bibr" rid="bib54">54</xref></sup>
# ::save-date Thu Feb 4, 2016 ::file pmid_2352_4590_106.txt
(w / witness-01
      :ARG1 (s / shrink-01
            :ARG1 (t / tumor))
      :location (p / person :quant 4
            :ARG2-of (i / include-91
                  :ARG1 (p2 / person :quant 3
                        :ARG0-of (d / demonstrate-01
                              :ARG1 (r / respond-01
                                    :degree (p3 / part)))
                        :ARG0-of (b / bear-01
                              :ARG1 (e / enzyme :name (n / name :op1 "B-Raf")
                                    :ARG2-of (m2 / mutate-01))
                              :mod (a / all))
                        :ARG0-of (h / have-org-role-91
                              :ARG2 (p5 / patient))))
            :mod (m / medical-condition :name (n2 / name :op1 "melanoma")))
      :ARG1-of (d2 / describe-01
            :ARG0 (p4 / publication
                  :ARG1-of (c / cite-01
                        :ARG2 54))))

# ::id pmid_2352_4590.107 ::date 2015-07-28T10:28:53 ::annotator SDL-AMR-09 ::preferred
# ::snt XL-518/GDC-0973 is a potent, orally bioavailable inhibitor that blocks MEK1 function with an IC<sub>50</sub><1 nℳ in enzymatic assays measuring ERK phosphorylation.
# ::save-date Wed Mar 2, 2016 ::file pmid_2352_4590_107.txt
(m3 / molecular-physical-entity
      :ARG0-of (i / inhibit-01)
      :domain (s / small-molecule :name (n / name :op1 "XL-518/GDC-0973"))
      :mod (p / potent)
      :mod (b / bioavailable
            :manner (o / oral))
      :ARG0-of (b2 / block-01
            :ARG1 (f / function-01
                  :ARG0 (e / enzyme :name (n2 / name :op1 "MEK1"))))
      :ARG1-of (h2 / have-percentage-maximal-inhibitory-concentration-01
            :ARG2 50
            :ARG4 (l / less-than
                  :op1 (c / concentration-quantity :quant 1
                        :unit (n4 / nanomolar))))
      :time (a / assay-01
            :ARG1 (e2 / enzyme)
            :ARG0-of (m2 / measure-01
                  :manner (p2 / phosphorylate-01
                        :ARG2 (e3 / enzyme :name (n5 / name :op1 "ERK"))))))

# ::id pmid_2352_4590.108 ::date 2015-07-28T10:42:50 ::annotator SDL-AMR-09 ::preferred
# ::snt Pharmacodynamic studies have demonstrated that a single dose of GDC-0973 inhibits p-ERK in xenograft tumours for up to 48 h.
# ::save-date Sun Aug 9, 2015 ::file pmid_2352_4590_108.txt
(d / demonstrate-01
      :ARG0 (s / study-01
            :mod (p / pharmacodynamic))
      :ARG1 (i / inhibit-01
            :ARG0 (d2 / dose-01
                  :ARG2 (s3 / small-molecule :name (n / name :op1 "GDC-0973"))
                  :ARG1-of (s2 / single-02))
            :ARG1 (e / enzyme :name (n2 / name :op1 "ERK")
                  :ARG3-of (p2 / phosphorylate-01))
            :location (t2 / tumor
                  :mod (x / xenograft))
            :duration (u / up-to
                  :op1 (t / temporal-quantity :quant 48
                        :unit (h / hour)))))

# ::id pmid_2352_4590.109 ::date 2015-07-28T11:13:57 ::annotator SDL-AMR-09 ::preferred
# ::snt In contrast to PD0325901, p-ERK levels in mouse brain tissue were not significantly suppressed following the administration of GDC-0973, suggesting reduced potential for adverse CNS events.<sup><xref ref-type="bibr" rid="bib55">55</xref></sup>
# ::save-date Thu Feb 4, 2016 ::file pmid_2352_4590_109.txt
(s / suppress-01 :polarity -
      :ARG1 (l / level
            :quant-of (e / enzyme :name (n / name :op1 "ERK")
                  :ARG3-of (p / phosphorylate-01))
            :location (t / tissue
                  :mod (b / brain
                        :mod (m / mouse))))
      :ARG1-of (s2 / significant-02)
      :ARG2-of (f / follow-01
            :ARG1 (a / administer-01
                  :ARG1 (s3 / small-molecule :name (n2 / name :op1 "GDC-0973"))))
      :ARG0-of (s4 / suggest-01
            :ARG1 (p2 / potential
                  :ARG1-of (r / reduce-01)
                  :beneficiary (e2 / event
                        :mod (s6 / system
                              :mod (n4 / nerve)
                              :mod (c / central))
                        :mod (a2 / adverse))))
      :ARG1-of (c2 / contrast-01
            :ARG2 (s5 / small-molecule :name (n3 / name :op1 "PD0325901")))
      :ARG1-of (d / describe-01
            :ARG0 (p3 / publication
                  :ARG1-of (c3 / cite-01
                        :ARG2 55))))

# ::id pmid_2352_4590.110 ::date 2015-07-28T11:27:35 ::annotator SDL-AMR-09 ::preferred
# ::snt A phase I study of GDC-0972 in patients with solid tumour was initiated in 2007.
# ::save-date Thu Dec 10, 2015 ::file pmid_2352_4590_110.txt
(i / initiate-01
      :ARG1 (s / study-01
            :ARG1 (s2 / small-molecule :name (n / name :op1 "GDC-0972"))
            :mod (p / phase
                  :ord (o / ordinal-entity :value 1))
            :location (p2 / person
                  :ARG0-of (h / have-03
                        :ARG1 (t / tumor
                              :ARG1-of (s3 / solid-02)))
                  :ARG0-of (h2 / have-org-role-91
                        :ARG2 (p3 / patient))))
      :time (d / date-entity :year 2007))

# ::id pmid_2352_4590.111 ::date 2015-07-28T11:37:04 ::annotator SDL-AMR-09 ::preferred
# ::snt Confirmed PR were witnessed in three melanoma patients, two of which harboured B-Raf V600E mutations.
# ::save-date Thu Jan 14, 2016 ::file pmid_2352_4590_111.txt
(w / witness-01
      :ARG1 (r / respond-01
            :ARG1-of (c / confirm-01)
            :degree (p / part))
      :location (p2 / person :quant 3
            :ARG2-of (i / include-91
                  :ARG1 (p3 / patient :quant 2
                        :ARG0-of (h / harbor-01
                              :ARG1 (m2 / mutate-01 :value "V600E"
                                    :ARG1 (e / enzyme :name (n / name :op1 "B-Raf"))))))
            :ARG0-of (h2 / have-org-role-91
                  :ARG2 (p4 / patient))
            :mod (m / medical-condition :name (n2 / name :op1 "melanoma"))))

# ::id pmid_2352_4590.112 ::date 2015-07-28T11:40:57 ::annotator SDL-AMR-09 ::preferred
# ::snt Six patients with prolonged s.d. (≥5 months) have been observed to date.<sup><xref ref-type="bibr" rid="bib56">56</xref></sup>
# ::save-date Wed Mar 2, 2016 ::file pmid_2352_4590_112.txt
(o / observe-01
      :ARG1 (p / patient :quant 6
            :ARG0-of (h / have-03
                  :ARG1 (d / disease
                        :ARG1-of (s / stable-03)
                        :ARG1-of (p2 / prolong-01
                              :ARG1-of (m / mean-01
                                    :ARG2 (o2 / or
                                          :op1 (e / equal-01
                                                :ARG1 (t2 / temporal-quantity :quant 5
                                                      :unit (m2 / month)))
                                          :op2 (m3 / more-than
                                                :op1 (t3 / temporal-quantity :quant 5
                                                      :unit m2))))))))
      :time (t / to-date)
      :ARG1-of (d2 / describe-01
            :ARG0 (p3 / publication
                  :ARG1-of (c / cite-01
                        :ARG2 56))))

# ::id pmid_2352_4590.113 ::date 2015-07-28T11:50:29 ::annotator SDL-AMR-09 ::preferred
# ::snt The MEK inhibitor, BAY869766/RDEA119, specifically inhibits MEK1 (IC<sub>50</sub>=19 nℳ) and MEK2 (IC<sub>50</sub>=47 nℳ) when compared with 205 other kinases.
# ::save-date Sat Jan 16, 2016 ::file pmid_2352_4590_113.txt
(a2 / and
      :op1 (i4 / inhibit-01
            :ARG0 (s / small-molecule :name (n / name :op1 "BAY869766/RDEA119")
                  :ARG0-of (i2 / inhibit-01
                        :ARG1 (p / protein-family :name (n2 / name :op1 "MEK")))
                  :ARG1-of (h / have-percentage-maximal-inhibitory-concentration-01
                        :ARG2 50
                        :ARG4 (c2 / concentration-quantity :quant 19
                              :unit (n5 / nanomolar))))
            :ARG1 (e2 / enzyme :name (n3 / name :op1 "MEK1")))
      :op2 (i / inhibit-01
            :ARG0 (s3 / small-molecule :name (n6 / name :op1 "BAY869766/RDEA119")
                  :ARG1-of (h2 / have-percentage-maximal-inhibitory-concentration-01
                        :ARG2 50
                        :ARG4 (c3 / concentration-quantity :quant 47
                              :unit (n7 / nanomolar))))
            :ARG1 (e3 / enzyme :name (n4 / name :op1 "MEK2")))
      :ARG1-of (s2 / specific-02)
      :condition (c / compare-01
            :ARG1 s
            :ARG2 (k / kinase :quant 205
                  :mod (o / other))))

# ::id pmid_2352_4590.114 ::date 2015-07-28T12:13:39 ::annotator SDL-AMR-09 ::preferred
# ::snt The antitumour effect of BAY8697655 has been established in mouse xenograft models, with potent growth inhibition observed during drug treatment.<sup><xref ref-type="bibr" rid="bib57">57</xref></sup>
# ::save-date Fri Jan 1, 2016 ::file pmid_2352_4590_114.txt
(e / establish-01
      :ARG1 (a / affect-01
            :ARG0 (s / small-molecule :name (n / name :op1 "BAY8697655"))
            :ARG2 (c2 / counter-01
                  :ARG1 (t / tumor)))
      :location (m / model
            :mod (x / xenograft)
            :mod (m2 / mouse)
            :ARG0-of (h / have-03
                  :ARG1 (i / inhibit-01
                        :ARG1 (g / grow-01
                              :mod (p / potent))
                        :ARG1-of (o2 / observe-01
                              :time (t2 / treat-03
                                    :ARG3 (d / drug))))))
      :ARG1-of (d2 / describe-01
            :ARG0 (p2 / publication
                  :ARG1-of (c / cite-01
                        :ARG2 57))))

# ::id pmid_2352_4590.115 ::date 2015-07-28T12:32:28 ::annotator SDL-AMR-09 ::preferred
# ::snt Early data from the BAY8679655 phase I trial demonstrates good drug tolerability, with rash being the most prevalent treatment-related adverse effect.
# ::save-date Fri Dec 18, 2015 ::file pmid_2352_4590_115.txt
(d / demonstrate-01
      :ARG0 (d2 / data
            :time (e / early)
            :source (t / trial-06
                  :ARG2 (s / small-molecule :name (n / name :op1 "BAY8679655"))
                  :mod (p / phase
                        :ord (o / ordinal-entity :value 1))))
      :ARG1 (a3 / and
            :op1 (t2 / tolerate-01
                  :ARG1 (d3 / drug)
                  :ARG1-of (g / good-02)
                  :ARG2-of (e2 / except-01))
            :op2 (r / rash
                  :domain (a / affect-01
                        :mod (a2 / adverse)
                        :ARG1-of (p2 / prevail-02
                              :degree (m / most))
                        :ARG1-of (r2 / relate-01
                              :ARG2 (t3 / treat-03))))))

# ::id pmid_2352_4590.116 ::date 2015-07-28T12:37:34 ::annotator SDL-AMR-09 ::preferred
# ::snt Among the 69 advanced cancer patients enroled in the trial, 10 achieved s.d. with a mean duration of 10 months.
# ::save-date Thu Feb 4, 2016 ::file pmid_2352_4590_116.txt
(a2 / achieve-01
      :ARG0 (p2 / person :quant 10
            :ARG0-of (h / have-org-role-91
                  :ARG2 (p3 / patient))
            :ARG1-of (i / include-91
                  :ARG2 (p / person :quant 69
                        :ARG1-of (e / enroll-01
                              :ARG2 (t / trial-06))
                        :ARG0-of h
                        :mod (d2 / disease :wiki "Cancer" :name (n / name :op1 "cancer")
                              :ARG1-of (a / advance-01)))))
      :ARG1 (d / disease
            :duration (t2 / temporal-quantity :quant 10
                  :unit (m / month)
                  :mod (m2 / mean))
            :ARG1-of (s / stable-03)))

# ::id pmid_2352_4590.117 ::date 2015-07-28T12:44:24 ::annotator SDL-AMR-09 ::preferred
# ::snt Phase II development of BAY867966 is currently being pursued in light of these findings.<sup><xref ref-type="bibr" rid="bib58">58</xref></sup>
# ::save-date Sun Aug 9, 2015 ::file pmid_2352_4590_117.txt
(p / pursue-01
      :ARG1 (d / develop-01
            :ARG2 (s / small-molecule :name (n / name :op1 "BAY867966"))
            :mod (p2 / phase
                  :ord (o / ordinal-entity :value 2)))
      :time (c / current)
      :ARG1-of (c2 / cause-01
            :ARG0 (t / thing
                  :ARG1-of (f / find-01)
                  :mod (t2 / this)))
      :ARG1-of (d2 / describe-01
            :ARG0 (p3 / publication
                  :ARG1-of (c3 / cite-01
                        :ARG2 58))))

# ::id pmid_2352_4590.118 ::date 2015-07-28T12:49:35 ::annotator SDL-AMR-09 ::preferred
# ::snt GSK1120212 is a structurally novel allosteric MEK inhibitor with an <i>in vitro</i> IC<sub>50</sub> of 0.4±00.1 nℳ for MEK1 activation by B-Raf and 10±2 nℳ for p-MEK1 activity.
# ::save-date Sat Jan 16, 2016 ::file pmid_2352_4590_118.txt
(s / small-molecule :name (n / name :op1 "GSK1120212")
      :mod (a / allosteric)
      :mod (n3 / novel)
      :mod (s2 / structural)
      :ARG0-of (i / inhibit-01
            :ARG1 (p2 / protein-family :name (n2 / name :op1 "MEK")))
      :ARG1-of (h2 / have-percentage-maximal-inhibitory-concentration-01
            :ARG2 50
            :ARG3 (a4 / activate-01
                  :ARG0 (e3 / enzyme :name (n5 / name :op1 "B-Raf"))
                  :ARG1 (e4 / enzyme :name (n6 / name :op1 "MEK1")))
            :ARG4 (c / concentration-quantity
                  :quant (v / value-interval
                        :op1 (s3 / subtract-01
                              :ARG1 0.001
                              :ARG2 0.4)
                        :op2 (a3 / add-02
                              :ARG1 0.001
                              :ARG2 0.4))
                  :unit (n9 / nanomolar))
            :manner i2)
      :ARG1-of (h3 / have-percentage-maximal-inhibitory-concentration-01
            :ARG2 50
            :ARG3 (a6 / activity-06
                  :ARG0 (e6 / enzyme :name (n8 / name :op1 "MEK1")
                        :ARG3-of (p / phosphorylate-01)))
            :ARG4 (c2 / concentration-quantity
                  :quant (v2 / value-interval
                        :op1 (s4 / subtract-01
                              :ARG1 2
                              :ARG2 10)
                        :op2 (a5 / add-02
                              :ARG1 2
                              :ARG2 10))
                  :unit (n4 / nanomolar))
            :manner (i2 / in-vitro)))

# ::id pmid_2352_4590.119 ::date 2015-07-29T12:21:05 ::annotator SDL-AMR-09 ::preferred
# ::snt In cell lines harbouring activating Ras or B-Raf mutations, GSK1120212 inhibited cell proliferation at IC<sub>50</sub> values <50 nℳ, but demonstrated decreased activity against those cells with wild-type Ras or wild-type-B-Raf.<sup><xref ref-type="bibr" rid="bib59">59</xref></sup>
# ::save-date Tue Dec 15, 2015 ::file pmid_2352_4590_119.txt
(i / inhibit-01
      :ARG0 (s / small-molecule :name (n / name :op1 "GSK1120212")
            :ARG1-of (h2 / have-percentage-maximal-inhibitory-concentration-01
                  :ARG2 50
                  :ARG4 (l / less-than
                        :op1 (c2 / concentration-quantity :quant 50
                              :unit (n3 / nanomolar)))))
      :ARG1 (p / proliferate-01
            :ARG0 (c / cell))
      :ARG1-of (c6 / contrast-01
            :ARG2 (d / demonstrate-01
                  :ARG0 s
                  :ARG1 (a / activity-06
                        :ARG0 s
                        :ARG1 (c3 / cell
                              :mod (t2 / that)
                              :ARG0-of (h3 / have-03
                                    :ARG1 (a2 / and
                                          :op1 (e2 / enzyme :name (n4 / name :op1 "Ras")
                                                :mod (w / wild-type))
                                          :op2 (e3 / enzyme :name (n5 / name :op1 "B-Raf")
                                                :mod w))))
                        :ARG1-of (d2 / decrease-01))))
      :location (c4 / cell-line
            :ARG0-of (h4 / harbor-01
                  :ARG1 (o / or
                        :op1 (m / mutate-01
                              :ARG1 (e4 / enzyme :name (n6 / name :op1 "Ras"))
                              :ARG0-of (a3 / activate-01))
                        :op2 (m2 / mutate-01
                              :ARG1 (e5 / enzyme :name (n7 / name :op1 "B-Raf"))
                              :ARG0-of a3))))
      :ARG1-of (d3 / describe-01
            :ARG0 (p2 / publication
                  :ARG1-of (c5 / cite-01
                        :ARG2 59))))

# ::id pmid_2352_4590.120 ::date 2015-07-29T12:47:50 ::annotator SDL-AMR-09 ::preferred
# ::snt These results are consistent with other MEK inhibitors, where cells with constitutively active Ras/MAPK signalling demonstrate a reliance on these oncogenic pathways, thereby making them hypersensitive to MEK inhibition.
# ::save-date Sat Jan 16, 2016 ::file pmid_2352_4590_120.txt
(c / consistent-01
      :ARG1 (t / thing
            :ARG2-of (r / result-01))
      :ARG2 (m2 / molecular-physical-entity
            :ARG0-of (i / inhibit-01
                  :ARG1 (p3 / protein-family :name (n / name :op1 "MEK")))
            :mod (o / other)
            :location-of (d / demonstrate-01
                  :ARG0 (c2 / cell
                        :location-of (s / signal-07
                              :ARG1 (p2 / pathway :name (n2 / name :op1 "Ras/MAPK"))
                              :ARG0-of (a / activity-06
                                    :manner (c3 / constitutive))))
                  :ARG1 (r2 / rely-01
                        :ARG1 (p / pathway
                              :mod (t3 / this)
                              :ARG0-of (c5 / cause-01
                                    :ARG1 (d2 / disease :wiki "Cancer" :name (n3 / name :op1 "cancer"))))
                        :ARG0-of (c4 / cause-01
                              :ARG1 (m / make-02
                                    :ARG0 p
                                    :ARG1 (s2 / sensitive-03
                                          :ARG0 p
                                          :ARG1 (i2 / inhibit-01
                                                :ARG1 p3)
                                          :degree (h / hyper))))))))

# ::id pmid_2352_4590.121 ::date 2015-07-29T13:15:18 ::annotator SDL-AMR-09 ::preferred
# ::snt In melanoma xenografted mouse models, GSK1120212 administered orally once daily demonstrated an effective t<sub>1/2</sub> of 36 h with sustained suppression of p-ERK for >24 h.<sup><xref ref-type="bibr" rid="bib60">60</xref></sup>
# ::save-date Thu Jan 14, 2016 ::file pmid_2352_4590_121.txt
(d / demonstrate-01
      :ARG1 (a2 / and
            :op1 (h3 / have-half-life-01
                  :ARG1 s
                  :ARG2 (t3 / temporal-quantity :quant 36
                        :unit (h / hour))
                  :ARG1-of (e / effective-04))
            :op2 (s2 / suppress-01
                  :ARG0 s
                  :ARG1 (e3 / enzyme :name (n3 / name :op1 "ERK")
                        :ARG3-of (p / phosphorylate-01))
                  :ARG1-of (s3 / sustain-01)
                  :duration (m / more-than
                        :op1 (t4 / temporal-quantity :quant 24
                              :unit h))))
      :location (m2 / model
            :mod (m3 / mouse)
            :ARG1-of (x / xenograft-00)
            :mod (m4 / medical-condition :name (n2 / name :op1 "melanoma")))
      :ARG1-of (d3 / describe-01
            :ARG0 (p2 / publication
                  :ARG1-of (c / cite-01
                        :ARG2 60)))
      :condition (a / administer-01
            :ARG1 (s / small-molecule :name (n / name :op1 "GSK1120212"))
            :frequency (r / rate-entity-91
                  :ARG1 1
                  :ARG2 (t / temporal-quantity :quant 1
                        :unit (d2 / day)))
            :manner (o / oral)))

# ::id pmid_2352_4590.122 ::date 2015-07-29T13:33:33 ::annotator SDL-AMR-09 ::preferred
# ::snt Notably, inhibition of p-ERK was not observed within brain samples.
# ::save-date Sun Aug 9, 2015 ::file pmid_2352_4590_122.txt
(o / observe-01 :polarity -
      :ARG1 (i / inhibit-01
            :ARG1 (e / enzyme :wiki "Extracellular_signal-regulated_kinases"
                  :name (n / name :op1 "ERK")
                  :ARG3-of (p / phosphorylate-01)))
      :location (s / sample-01
            :ARG1 (b / brain))
      :ARG1-of (n2 / notable-04))

# ::id pmid_2352_4590.123 ::date 2015-07-29T13:38:49 ::annotator SDL-AMR-09 ::preferred
# ::snt Phase I results of this compound have recently been presented by Gordon <i>et al.</i><sup><xref ref-type="bibr" rid="bib61">61</xref></sup> For 22 patients with B-Raf mutant melanoma, 1 CR and 9 PR were observed.
# ::save-date Thu Jan 14, 2016 ::file pmid_2352_4590_123.txt
(m / multi-sentence
      :snt1 (p / present-01
            :ARG0 (p3 / publication-91
                  :ARG0 (a / and
                        :op1 (p4 / person :name (n / name :op1 "Gordon"))
                        :op2 (p5 / person
                              :mod (o / other))))
            :ARG1 (t / thing
                  :ARG2-of (r / result-01
                        :ARG1 (c / compound-01
                              :mod (t2 / this)))
                  :mod (p2 / phase
                        :ord (o3 / ordinal-entity :value 1)))
            :time (r2 / recent)
            :ARG1-of (d / describe-01
                  :ARG0 (p6 / publication
                        :ARG1-of (c2 / cite-01
                              :ARG2 61))))
      :snt2 (o2 / observe-01
            :ARG1 (a2 / and
                  :op1 (r3 / respond-01 :quant 1
                        :ARG1-of (c3 / complete-01))
                  :op2 (r4 / respond-01 :quant 9
                        :degree (p9 / part)))
            :location (p7 / person :quant 22
                  :ARG0-of (h / have-03
                        :ARG1 (m4 / medical-condition :name (n3 / name :op1 "melanoma")
                              :mod (e / enzyme :name (n2 / name :op1 "B-Raf")
                                    :ARG2-of (m3 / mutate-01))))
                  :ARG0-of (h2 / have-org-role-91
                        :ARG2 (p8 / patient)))))

# ::id pmid_2352_4590.124 ::date 2015-07-29T13:50:54 ::annotator SDL-AMR-09 ::preferred
# ::snt For 22 patients with pancreatic cancer, 1 PR and 9 s.d. were reported.
# ::save-date Thu Dec 10, 2015 ::file pmid_2352_4590_124.txt
(r / report-01
      :ARG1 (a / and
            :op1 (r2 / respond-01 :quant 1
                  :degree (p / part))
            :op2 (d / disease :quant 9
                  :ARG1-of (s / stable-03)))
      :location (p2 / patient :quant 22
            :ARG0-of (h / have-03
                  :ARG1 (d2 / disease :wiki "Pancreatic_cancer" :name (n / name :op1 "pancreatic" :op2 "cancer")))))

# ::id pmid_2352_4590.125 ::date 2015-07-29T13:55:50 ::annotator SDL-AMR-09 ::preferred
# ::snt Early data from a phase I/II trial examining GSK1120212 in patients with relapsed/refractory myeloid malignancies harbouring Ras mutations has also recently been reported.
# ::save-date Thu Dec 10, 2015 ::file pmid_2352_4590_125.txt
(r / report-01
      :ARG1 (d / data
            :time (e / early)
            :source (t / trial-06
                  :mod (s / slash
                        :op1 (p / phase
                              :ord (o / ordinal-entity :value 1))
                        :op2 (p2 / phase
                              :ord (o2 / ordinal-entity :value 2)))
                  :ARG0-of (e2 / examine-01
                        :ARG1 (s2 / small-molecule :name (n / name :op1 "GSK1120212"))
                        :location (p3 / person
                              :ARG0-of (h / have-03
                                    :ARG1 (s3 / slash
                                          :op1 (m / malignancy
                                                :mod (m2 / myeloid)
                                                :ARG1-of (r2 / relapse-01))
                                          :op2 (m3 / malignancy
                                                :mod (r3 / refractory)
                                                :mod m2)
                                          :ARG0-of (h2 / harbor-01
                                                :ARG1 (e3 / enzyme :name (n2 / name :op1 "Ras")
                                                      :ARG2-of (m4 / mutate-01)))))
                              :ARG0-of (h3 / have-org-role-91
                                    :ARG2 (p4 / patient))))))
      :time (r4 / recent)
      :mod (a / also))

# ::id pmid_2352_4590.126 ::date 2015-07-29T14:04:52 ::annotator SDL-AMR-09 ::preferred
# ::snt Patients were prospectively screened for K- and N-Ras mutations before receiving daily treatment with GSK1120212.
# ::save-date Thu Dec 10, 2015 ::file pmid_2352_4590_126.txt
(s / screen-01
      :ARG1 (p / person
            :ARG0-of (h / have-org-role-91
                  :ARG2 (p3 / patient)))
      :ARG2 (a / and
            :op1 (m / mutate-01
                  :ARG1 (e / enzyme :name (n / name :op1 "K-Ras")))
            :op2 (m2 / mutate-01
                  :ARG1 (e2 / enzyme :name (n2 / name :op1 "N-Ras"))))
      :time (b / before
            :op1 (r / receive-01
                  :ARG0 p
                  :ARG1 (t / treat-03
                        :ARG3 (s2 / small-molecule :name (n3 / name :op1 "GSK1120212")))
                  :frequency (d / day)))
      :manner (p2 / prospective))

# ::id pmid_2352_4590.127 ::date 2015-07-29T14:10:15 ::annotator SDL-AMR-09 ::preferred
# ::snt Encouraging signs of clinical activity with manageable adverse effects have been observed.<sup><xref ref-type="bibr" rid="bib62">62</xref></sup>
# ::save-date Fri Dec 18, 2015 ::file pmid_2352_4590_127.txt
(o / observe-01
      :ARG1 (s / signal-07
            :ARG1 (a / activity-06
                  :mod (c / clinic)
                  :ARG0-of (a2 / affect-01
                        :mod (a3 / adverse)
                        :ARG1-of (m / manage-01
                              :ARG1-of (p / possible-01))))
            :ARG0-of (e / encourage-01))
      :ARG1-of (d / describe-01
            :ARG0 (p2 / publication
                  :ARG1-of (c2 / cite-01
                        :ARG2 62))))

# ::id pmid_2352_4590.128 ::date 2015-07-29T14:18:39 ::annotator SDL-AMR-09 ::preferred
# ::snt <sec-title level="2">Enhancing effectiveness with combination therapies</sec-title>
# ::save-date Sun Aug 9, 2015 ::file pmid_2352_4590_128.txt
(e / enhance-01
      :ARG1 (e2 / effective-04)
      :ARG2 (c / combine-01
            :ARG1 (t / therapy)))

# ::id pmid_2352_4590.129 ::date 2015-07-29T14:20:20 ::annotator SDL-AMR-09 ::preferred
# ::snt Despite improvements in clinical potency and pharmacokinetics, MEK inhibitors have generally shown limited effectiveness as monotherapeutic agents.
# ::save-date Sat Jan 16, 2016 ::file pmid_2352_4590_129.txt
(h / have-concession-91
      :ARG1 (s / show-01
            :ARG0 (m2 / molecular-physical-entity
                  :ARG0-of (i / inhibit-01
                        :ARG1 (p3 / protein-family :name (n / name :op1 "MEK"))))
            :ARG1 (e2 / effective-04
                  :ARG1 (a / agent
                        :mod (m / monotherapeutic))
                  :ARG1-of (l / limit-01))
            :ARG1-of (g / general-02))
      :ARG2 (i2 / improve-01
            :ARG1 (a2 / and
                  :op2 (p / potency
                        :mod (c / clinic))
                  :op2 (p2 / pharmacokinetics))))

# ::id pmid_2352_4590.130 ::date 2015-07-29T14:30:11 ::annotator SDL-AMR-09 ::preferred
# ::snt Several reasons may account for this observation.
# ::save-date Sun Aug 9, 2015 ::file pmid_2352_4590_130.txt
(p / possible-01
      :ARG1 (a / account-01
            :ARG0 (r / reason
                  :quant (s / several))
            :ARG1 (o / observe-01
                  :mod (t / this))))

# ::id pmid_2352_4590.131 ::date 2015-07-29T14:33:39 ::annotator SDL-AMR-09 ::preferred
# ::snt Abrogation of Ras/MAPK signalling appears to be mainly cytostatic, and suggests that an additional therapeutic modality is required to maximise the antitumour effectiveness of MEK inhibitors.
# ::save-date Sat Jan 16, 2016 ::file pmid_2352_4590_131.txt
(a / and
      :op1 (a2 / appear-02
            :ARG1 (c / cytostatic
                  :mod (m / main)
                  :domain (a3 / abrogate-01
                        :ARG1 (s2 / signal-07
                              :ARG0 (p / pathway :name (n / name :op1 "Ras/MAPK"))))))
      :op2 (s / suggest-01
            :ARG0 a3
            :ARG1 (r / require-01
                  :ARG0 (m3 / maximize-01
                        :ARG1 (e / effective-04
                              :ARG0 (m4 / molecular-physical-entity
                                    :ARG0-of (i / inhibit-01
                                          :ARG1 (p2 / protein-family :name (n2 / name :op1 "MEK"))))
                              :ARG1 (o / oppose-01
                                    :ARG0 i
                                    :ARG1 (t3 / tumor))))
                  :ARG1 (m2 / modality
                        :mod (t / therapy)
                        :ARG1-of (a4 / add-02)))))

# ::id pmid_2352_4590.132 ::date 2015-07-29T14:46:33 ::annotator SDL-AMR-09 ::preferred
# ::snt In hepatocellular carcinoma xenograft models, AZD6244 in conjunction with doxorubicin demonstrated enhanced growth suppression (76%±7), compared with AZD6244 (52±15%) and doxorubicin (12±9%) alone.
# ::save-date Fri Jan 1, 2016 ::file pmid_2352_4590_132.txt
(d / demonstrate-01
      :ARG0 (a / and
            :op1 (s / small-molecule :name (n / name :op1 "AZD6244"))
            :op2 (s2 / small-molecule :name (n2 / name :op1 "doxorubicin")))
      :ARG1 (s3 / suppress-01
            :ARG1 (g / grow-01)
            :ARG1-of (e / enhance-01
                  :compared-to (a3 / and
                        :op1 (s5 / small-molecule :name (n3 / name :op1 "AZD6244")
                              :quant (p3 / percentage-entity :value 52
                                    :ARG2-of (a4 / add-02
                                          :ARG1 (p4 / percentage-entity :value 15))
                                    :ARG2-of (s7 / subtract-01
                                          :ARG1 p4)))
                        :op2 (s6 / small-molecule :name (n4 / name :op1 "doxorubicin")
                              :quant (p5 / percentage-entity :value 12
                                    :ARG2-of (a5 / add-02
                                          :ARG1 (p6 / percentage-entity :value 9))
                                    :ARG2-of (s8 / subtract-01
                                          :ARG1 p6)))
                        :mod (a6 / alone)))
            :ARG1-of (m / mean-01
                  :ARG2 (p / percentage-entity :value 76
                        :ARG2-of (a2 / add-02
                              :ARG1 (p2 / percentage-entity :value 7))
                        :ARG2-of (s4 / subtract-01
                              :ARG1 p2))))
      :location (m2 / model
            :mod (x / xenograft)
            :mod (h / hepatocellular)
            :mod (m3 / medical-condition :name (n5 / name :op1 "carcinoma"))))

# ::id pmid_2352_4590.133 ::date 2015-07-29T15:14:31 ::annotator SDL-AMR-09 ::preferred
# ::snt This synergy was associated with increased apoptosis.<sup><xref ref-type="bibr" rid="bib63">63</xref></sup>
# ::save-date Tue Feb 2, 2016 ::file pmid_2352_4590_133.txt
(a / associate-01
      :ARG1 (s / synergize-01
            :mod (t / this))
      :ARG2 (a2 / apoptosis
            :ARG1-of (i / increase-01))
      :ARG1-of (d / describe-01
            :ARG0 (p / publication
                  :ARG1-of (c / cite-01
                        :ARG2 63))))

# ::id pmid_2352_4590.134 ::date 2015-07-29T15:17:30 ::annotator SDL-AMR-09 ::preferred
# ::snt Similar effects have been observed with AZD6244 and docetaxel in malignant melanoma,<sup><xref ref-type="bibr" rid="bib64">64</xref></sup> and AZD6244 and cytarabine in acute myelogenous leukaemia.<sup><xref ref-type="bibr" rid="bib65">65</xref></sup>
# ::save-date Thu Jan 14, 2016 ::file pmid_2352_4590_134.txt
(o / observe-01
      :ARG1 (a / and
            :op1 (a2 / affect-01
                  :ARG0 (a3 / and
                        :op1 (s / small-molecule :name (n / name :op1 "AZD6244"))
                        :op2 (s2 / small-molecule :name (n2 / name :op1 "docetaxel")))
                  :ARG1 (m4 / medical-condition :name (n5 / name :op1 "melanoma")
                        :ARG2-of (m2 / malignant-02))
                  :ARG1-of (d / describe-01
                        :ARG0 (p / publication
                              :ARG1-of (c / cite-01
                                    :ARG2 64)))
                  :ARG1-of (r / resemble-01))
            :op2 (a4 / affect-01
                  :ARG0 (a5 / and
                        :op1 s
                        :op2 (s3 / small-molecule :name (n3 / name :op1 "cytarabine")))
                  :ARG1 (d3 / disease :name (n4 / name :op1 "leukaemia")
                        :mod (m3 / myelogenous)
                        :mod (a6 / acute))
                  :ARG1-of (d2 / describe-01
                        :ARG0 (p2 / publication
                              :ARG1-of (c2 / cite-01
                                    :ARG2 65)))
                  :mod r)))

# ::id pmid_2352_4590.135 ::date 2015-07-29T15:28:23 ::annotator SDL-AMR-09 ::preferred
# ::snt The mechanism by which these agents cooperate is not entirely clear, but the available evidence suggests that many of these drugs can activate the Ras/MAPK pathway through diverse processes, thereby increasing the effectiveness of MEK inhibitors.<sup><xref ref-type="bibr" rid="bib66">66</xref></sup>
# ::save-date Sat Jan 16, 2016 ::file pmid_2352_4590_135.txt
(h / have-concession-91
      :ARG1 (c / clear-06 :polarity -
            :ARG1 (m / mechanism
                  :instrument-of (c2 / cooperate-01
                        :ARG0 (a / agent
                              :mod (t / this))))
            :mod (e / entire))
      :ARG2 (s / suggest-01
            :ARG0 (e2 / evidence
                  :ARG2-of (a2 / available-02))
            :ARG1 (p / possible-01
                  :ARG1 (a4 / activate-01
                        :ARG0 (d / drug
                              :mod t
                              :quant (m2 / many))
                        :ARG1 (p2 / pathway :name (n / name :op1 "Ras/MAPK"))
                        :instrument (p3 / process-02
                              :mod (d2 / diverse))
                        :ARG0-of (c3 / cause-01
                              :ARG1 (i / increase-01
                                    :ARG1 (e3 / effective-04
                                          :ARG0 (m3 / molecular-physical-entity
                                                :ARG0-of (i2 / inhibit-01
                                                      :ARG1 (p5 / protein-family :name (n2 / name :op1 "MEK"))))))))))
      :ARG1-of (d3 / describe-01
            :ARG0 (p4 / publication
                  :ARG1-of (c4 / cite-01
                        :ARG2 66))))

# ::id pmid_2352_4590.136 ::date 2015-07-29T15:39:30 ::annotator SDL-AMR-09 ::preferred
# ::snt However, the inhibitory effects of MEK on cell cycle progression may potentially reduce the effectiveness of many standard chemotherapeutic agents in combination therapy, due to the reliance of these agents on killing malignant cells that are rapidly dividing.
# ::save-date Sun Aug 9, 2015 ::file pmid_2352_4590_136.txt
(h / have-concession-91
      :ARG2 (p / possible-01
            :ARG1 (r / reduce-01
                  :ARG0 (a / affect-01
                        :ARG0 (e / enzyme :name (n / name :op1 "MEK"))
                        :ARG1 (p2 / progress-01
                              :ARG1 (c / cycle-02
                                    :ARG1 (c2 / cell)))
                        :ARG2 (i / inhibit-01))
                  :ARG1 (e2 / effective-04
                        :ARG0 (a2 / agent
                              :mod (c3 / chemotherapy)
                              :ARG1-of (s / standard-02)
                              :quant (m / many))
                        :ARG1 (t / therapy
                              :ARG1-of (c4 / combine-01)))
                  :manner (p3 / potential)
                  :ARG1-of (c5 / cause-01
                        :ARG0 (r2 / rely-01
                              :ARG0 a2
                              :ARG1 (k / kill-01
                                    :ARG1 (c6 / cell
                                          :ARG1-of (m2 / malignant-02)
                                          :ARG1-of (d / divide-02
                                                :manner (r3 / rapid)))))))))

# ::id pmid_2352_4590.137 ::date 2015-07-29T15:48:22 ::annotator SDL-AMR-09 ::preferred
# ::snt Therefore, drug scheduling may have a critical role in the optimal utilisation of MEK inhibitors when combined with traditional chemotherapeutic drugs.
# ::save-date Sat Jan 16, 2016 ::file pmid_2352_4590_137.txt
(c / cause-01
      :ARG1 (p / possible-01
            :ARG1 (h / have-03
                  :ARG0 (s / schedule-01
                        :ARG1 (d / drug))
                  :ARG1 (r / role
                        :ARG1-of (c2 / critical-02
                              :ARG2 (u / utilize-01
                                    :ARG1 (m / molecular-physical-entity
                                          :ARG0-of (i / inhibit-01
                                                :ARG1 (p2 / protein-family :name (n / name :op1 "MEK"))))
                                    :mod (o / optimal))
                              :condition (c3 / combine-01
                                          :ARG1 m
                                          :ARG2 (d2 / drug
                                                :mod (t2 / traditional)
                                                :mod (c4 / chemotherapy))))))))

# ::id pmid_2352_4590.138 ::date 2015-07-29T15:59:18 ::annotator SDL-AMR-09 ::preferred
# ::snt In this regard, Yu <i>et al.</i><sup><xref ref-type="bibr" rid="bib67">67</xref></sup> have demonstrated that incubating leukaemic cells with paclitaxel before PD98059 exposure significantly increased cell death.
# ::save-date Fri Dec 18, 2015 ::file pmid_2352_4590_138.txt
(d / demonstrate-01
      :ARG0 (a / and
            :op1 (p / person :name (n / name :op1 "Yu"))
            :op2 (p2 / person
                  :mod (o / other)))
      :ARG1 (i / increase-01
            :ARG0 (i2 / incubate-01
                  :ARG1 (c2 / cell
                        :mod (l / leukaemic))
                  :ARG2 (s2 / small-molecule :name (n2 / name :op1 "paclitaxel"))
                  :time (b / before
                        :op1 (e / expose-01
                              :ARG1 c2
                              :ARG2 (s3 / small-molecule :name (n3 / name :op1 "PD98059")))))
            :ARG1 (d2 / die-01
                  :ARG1 (c3 / cell))
            :ARG2 (s / significant-02))
      :purpose (t / this)
      :ARG1-of (d3 / describe-01
            :ARG0 (p3 / publication
                  :ARG1-of (c / cite-01
                        :ARG2 67))))

# ::id pmid_2352_4590.139 ::date 2015-07-29T16:09:40 ::annotator SDL-AMR-09 ::preferred
# ::snt In contrast, pretreatment with the MEK inhibitor reduced the susceptibility of cells to paclitaxel-induced apoptosis.
# ::save-date Tue Jan 19, 2016 ::file pmid_2352_4590_139.txt
(c / contrast-01
      :ARG2 (r / reduce-01
            :ARG0 (p / pretreat-01
                  :ARG3 (m / molecular-physical-entity
                        :ARG0-of (i / inhibit-01
                              :ARG1 (p2 / protein-family :name (n / name :op1 "MEK")))))
            :ARG1 (s / susceptibility
                  :poss (c2 / cell)
                  :prep-to (a / apoptosis
                        :ARG2-of (i2 / induce-01
                              :ARG0 (s2 / small-molecule :name (n2 / name :op1 "paclitaxel")))))))

# ::id pmid_2352_4590.140 ::date 2015-07-29T16:17:55 ::annotator SDL-AMR-09 ::preferred
# ::snt Activating mutations within the Ras/MAPK network also contribute to the mechanisms of resistance to MEK inhibitors.
# ::save-date Sat Jan 16, 2016 ::file pmid_2352_4590_140.txt
(c / contribute-01
      :ARG0 (m / mutate-01
            :ARG0-of (a / activate-01
                  :location (p / pathway :name (n2 / name :op1 "Ras/MAPK"))))
      :ARG1 (m2 / mechanism
            :mod (r / resist-01
                  :ARG1 (m3 / molecular-physical-entity
                        :ARG0-of (i / inhibit-01
                              :ARG1 (p2 / protein-family :name (n3 / name :op1 "MEK"))))))
      :mod (a2 / also))

# ::id pmid_2352_4590.141 ::date 2015-07-29T16:22:01 ::annotator SDL-AMR-09 ::preferred
# ::snt A number of studies have demonstrated that oncogenic amplification of K-Ras and B-Raf confers decreased susceptibility to AZD6244.<sup><xref ref-type="bibr" rid="bib68">68</xref>, <xref ref-type="bibr" rid="bib69">69</xref></sup>
# ::save-date Thu Dec 10, 2015 ::file pmid_2352_4590_141.txt
(d / demonstrate-01
      :ARG0 (n / number
            :quant-of (t / thing
                  :ARG1-of (s / study-01)))
      :ARG1 (c / confer-01
            :ARG0 (a / amplify-01
                  :ARG1 (a2 / and
                        :op1 (e / enzyme :name (n2 / name :op1 "K-Ras"))
                        :op2 (e2 / enzyme :name (n3 / name :op1 "B-Raf")))
                  :ARG0-of (c3 / cause-01
                        :ARG1 (d4 / disease :wiki "Cancer" :name (n5 / name :op1 "cancer"))))
            :ARG1 (s2 / susceptibility
                  :ARG1-of (d2 / decrease-01)
                  :prep-to (s3 / small-molecule :name (n4 / name :op1 "AZD6244"))))
      :ARG1-of (d3 / describe-01
            :ARG0 (p / publication
                  :ARG1-of (c2 / cite-01
                        :ARG0 (a3 / and :op1 68 :op2 69)))))

# ::id pmid_2352_4590.142 ::date 2015-07-29T16:27:35 ::annotator SDL-AMR-09 ::preferred
# ::snt Point mutations within MEK1 may also significantly attenuate the ability of MEK inhibitors to block ERK signalling in B-Raf V600E mutated tumours.<sup><xref ref-type="bibr" rid="bib70">70</xref></sup>
# ::save-date Sat Jan 16, 2016 ::file pmid_2352_4590_142.txt
(p2 / possible-01
      :ARG1 (a / attenuate-01
            :ARG0 (m / mutate-01
                  :ARG1 (e / enzyme :name (n / name :op1 "MEK1"))
                  :mod (p / point))
            :ARG1 (c / capable-01
                  :ARG1 (m3 / molecular-physical-entity
                        :ARG0-of (i / inhibit-01
                              :ARG1 (p3 / protein-family :name (n2 / name :op1 "MEK"))))
                  :ARG2 (b / block-01
                        :ARG0 m3
                        :ARG1 (s2 / signal-07
                              :ARG0 (e3 / enzyme :name (n3 / name :op1 "ERK")))
                        :ARG2 (t / tumor
                              :mod (e4 / enzyme :name (n4 / name :op1 "B-Raf")
                                    :ARG2-of (m2 / mutate-01 :value "V600E")))))
            :ARG1-of (s / significant-02))
      :ARG1-of (d / describe-01
            :ARG0 (p4 / publication
                  :ARG1-of (c2 / cite-01
                        :ARG2 70)))
      :mod (a2 / also))

# ::id pmid_2352_4590.143 ::date 2015-07-30T08:01:09 ::annotator SDL-AMR-09 ::preferred
# ::snt These oncogenic events result in constitutive ERK pathway activation.
# ::save-date Thu Dec 10, 2015 ::file pmid_2352_4590_143.txt
(r / result-01
      :ARG1 (e / event
            :ARG0-of (c / cause-01
                  :ARG1 (d / disease :wiki "Cancer" :name (n2 / name :op1 "cancer")))
            :mod (t / this))
      :ARG2 (a / activate-01
            :ARG1 (p / pathway :name (n / name :op1 "ERK"))
            :mod (c3 / constitutive)))

# ::id pmid_2352_4590.144 ::date 2015-07-30T08:14:05 ::annotator SDL-AMR-09 ::preferred
# ::snt In the absence of oncogenic Ras and Raf mutations, other oncogenic events that engage the Ras/MAPK pathway are also likely to stimulate normal feedback mechanisms that may increase the activity of various intermediaries in the Ras/MAPK signalling module, thereby promoting the ongoing activation of ERK kinase signalling.<sup><xref ref-type="bibr" rid="bib71">71</xref></sup>
# ::save-date Fri Jan 1, 2016 ::file pmid_2352_4590_144.txt
(l / likely-01
      :ARG1 (s / stimulate-01
            :ARG0 (e / event
                  :ARG0-of (c / cause-01
                        :ARG1 (d2 / disease :wiki "Cancer" :name (n6 / name :op1 "cancer")))
                  :mod (o / other)
                  :ARG0-of (e2 / engage-01
                        :ARG1 (p / pathway :name (n2 / name :op1 "Ras/MAPK"))))
            :ARG1 (m / mechanism
                  :mod (f / feedback)
                  :ARG1-of (n / normal-02)
                  :ARG0-of (i / increase-01
                        :ARG1 (a / activity-06
                              :ARG0 (i2 / intermediary
                                    :mod (v / various))
                              :ARG1 (m2 / module
                                    :ARG0-of (s2 / signal-07
                                          :ARG1 p)))
                        :ARG1-of (p2 / possible-01))))
      :condition (a2 / absent-01
            :ARG1 (a3 / and
                  :op1 (m3 / mutate-01
                        :ARG1 (e3 / enzyme :name (n3 / name :op1 "Ras")))
                  :op2 (m4 / mutate-01
                        :ARG1 (e4 / enzyme :name (n4 / name :op1 "Raf")))
                  :ARG0-of c))
      :ARG0-of (p3 / promote-01
            :ARG1 (a4 / activate-01
                  :ARG1 (s3 / signal-07
                        :ARG1 (e5 / enzyme :name (n5 / name :op1 "ERK")))
                  :ARG1-of (g / go-on-15)))
      :ARG1-of (d / describe-01
            :ARG0 (p4 / publication
                  :ARG1-of (c3 / cite-01
                        :ARG2 71)))
      :mod (a5 / also))

# ::id pmid_2352_4590.145 ::date 2015-07-30T08:16:00 ::annotator SDL-AMR-09 ::preferred
# ::snt For either scenario, the activity of ERK and its target substrates may be maintained at levels that are sufficient to drive key cellular functions even in the presence of a MEK inhibitor.
# ::save-date Sat Jan 16, 2016 ::file pmid_2352_4590_145.txt
(p / possible-01
      :ARG1 (m / maintain-01
            :ARG1 (a / activity-06
                  :ARG0 (a2 / and
                        :op1 (e3 / enzyme :name (n3 / name :op1 "ERK"))
                        :op2 (s / substrate
                              :ARG1-of (t2 / target-01)
                              :poss e3)))
            :ARG2 (l / level
                  :ARG0-of (s2 / suffice-01
                        :ARG1 (d2 / drive-02
                              :ARG0 l
                              :ARG1 (f / function-01
                                    :ARG0 (c / cell)
                                    :ARG1-of (k / key-02))
                              :concession (p2 / present-02
                                    :ARG1 (s4 / small-molecule
                                          :ARG0-of (i2 / inhibit-01
                                                :ARG1 (p3 / protein-family :name (n4 / name :op1 "MEK")))))))))
      :topic (s3 / scenario
            :mod (e / either)))

# ::id pmid_2352_4590.146 ::date 2015-07-30T09:37:05 ::annotator SDL-AMR-09 ::preferred
# ::snt These observations suggest that targeting multiple nodes within the Ras/MAPK network may be a more efficacious clinical strategy than single target therapy.
# ::save-date Thu Jul 30, 2015 ::file pmid_2352_4590_146.txt
(s / suggest-01
      :ARG0 (o / observe-01
            :mod (t / this))
      :ARG1 (p / possible-01
            :ARG1 (s2 / strategy
                  :mod (c / clinic)
                  :mod (e / efficacious
                        :degree (m2 / more))
                  :compared-to (t3 / therapy
                        :mod (t4 / target
                              :ARG1-of (s3 / single-02)))
                  :domain (t2 / target-01
                        :ARG1 (n / node
                              :quant (m / multiple))
                        :location (p2 / pathway :name (n2 / name :op1 "Ras/MAPK"))))))

# ::id pmid_2352_4590.147 ::date 2015-07-30T11:28:37 ::annotator SDL-AMR-09 ::preferred
# ::snt The contribution of multiple signalling networks to tumorigenesis also accounts for the limited responses seen with MEK inhibitors alone.
# ::save-date Sat Jan 16, 2016 ::file pmid_2352_4590_147.txt
(a / account-01
      :ARG0 (c / contribute-01
            :ARG0 (n2 / network
                  :ARG0-of (s / signal-07)
                  :quant (m / multiple))
            :ARG2 (c2 / create-01
                  :ARG1 (t2 / tumor)))
      :ARG1 (r / respond-01
            :ARG1-of (l / limit-01)
            :ARG1-of (s2 / see-01
                  :condition (s3 / small-molecule
                        :ARG0-of (i2 / inhibit-01
                              :ARG1 (p / protein-family :name (n3 / name :op1 "MEK")))
                        :mod (a3 / alone))))
      :mod (a2 / also))

# ::id pmid_2352_4590.148 ::date 2015-07-30T12:13:32 ::annotator SDL-AMR-09 ::preferred
# ::snt For example, the phosphatidylinositol 3-kinase (PI3K/Akt/mTOR) and MAPK pathways share Ras as a common upstream effector.<sup><xref ref-type="bibr" rid="bib72">72</xref></sup>
# ::save-date Fri Aug 14, 2015 ::file pmid_2352_4590_148.txt
(s / share-01
      :ARG0 (a / and
            :op1 (e3 / enzyme :name (n3 / name :op1 "phosphatidylinositol" :op2 "3-kinase")
                  :ARG1-of (m / mean-01
                        :ARG2 (p2 / pathway :name (n4 / name :op1 "PI3K/Akt/mTOR"))))
            :op2 (p3 / pathway :name (n5 / name :op1 "MAPK")))
      :ARG1 (e4 / enzyme :name (n6 / name :op1 "Ras")
            :ARG1-of (m2 / mean-01
                  :ARG2 (e5 / effector
                        :direction (u / upstream))))
      :ARG1-of (d / describe-01
            :ARG0 (p4 / publication
                  :ARG1-of (c / cite-01
                        :ARG2 72)))
      :ARG0-of (e / exemplify-01))

# ::id pmid_2352_4590.149 ::date 2015-07-30T12:14:07 ::annotator SDL-AMR-09 ::preferred
# ::snt Consequently, activation of Ras, despite the downregulation of ERK activity by MKPs and SPRYs, could lead to compensatory signalling through this parallel network.
# ::save-date Fri Jul 31, 2015 ::file pmid_2352_4590_149.txt
(c2 / cause-01
      :ARG1 (p2 / possible-01
            :ARG1 (l / lead-03
                  :ARG0 (a / activate-01
                        :ARG1 (e3 / enzyme :name (n3 / name :op1 "Ras"))
                        :concession (d / downregulate-01
                              :ARG1 (a2 / activity-06
                                    :ARG0 (e4 / enzyme :name (n5 / name :op1 "ERK")))
                              :ARG2 (a3 / and
                                    :op1 (e5 / enzyme :name (n6 / name :op1 "MKP"))
                                    :op2 (p4 / protein :name (n7 / name :op1 "SPRY")))))
                  :ARG2 (s / signal-07
                        :ARG0-of (c / compensate-01)
                        :instrument (n4 / network
                              :mod (p3 / parallel)
                              :mod (t / this))))))

# ::id pmid_2352_4590.150 ::date 2015-07-30T12:14:29 ::annotator SDL-AMR-09 ::preferred
# ::snt Alternatively, oncogenic mutations within the PI3K/Akt axis may enhance MEK/ERK signal transduction.
# ::save-date Tue Jan 19, 2016 ::file pmid_2352_4590_150.txt
(p2 / possible-01
      :ARG1 (e / enhance-01
            :ARG0 (m / mutate-01
                  :ARG0-of (c / cause-01
                        :ARG1 (d / disease :wiki "Cancer" :name (n3 / name :op1 "cancer")))
                  :location (a2 / axis
                        :mod (p / pathway :name (n / name :op1 "PI3K/Akt"))))
            :ARG1 (t / transduce-01
                  :ARG1 (s / signal-07
                        :ARG0 (p3 / pathway :name (n2 / name :op1 "MEK/ERK")))))
      :manner (a / alternative))

# ::id pmid_2352_4590.151 ::date 2015-07-30T12:14:47 ::annotator SDL-AMR-09 ::preferred
# ::snt Indeed, dysregulation of the PI3K/Akt pathway has been shown to correlate with the decreased sensitivity to MEK inhibition.<sup><xref ref-type="bibr" rid="bib73">73</xref></sup>
# ::save-date Thu Jul 30, 2015 ::file pmid_2352_4590_151.txt
(s / show-01
      :ARG1 (c / correlate-01
            :ARG1 (d / dysregulate-01
                  :ARG1 (p2 / pathway :name (n3 / name :op1 "PI3K/Akt")))
            :ARG2 (s2 / sensitive-03
                  :ARG1 (i / inhibit-01
                        :ARG1 (e2 / enzyme :name (n4 / name :op1 "MEK")))
                  :ARG1-of (d2 / decrease-01)))
      :mod (i2 / indeed)
      :ARG1-of (d3 / describe-01
            :ARG0 (p / publication
                  :ARG1-of (c2 / cite-01
                        :ARG2 73))))

# ::id pmid_2352_4590.152 ::date 2015-07-30T12:15:06 ::annotator SDL-AMR-09 ::preferred
# ::snt Predictably targeting both pathways simultaneously has proven effective in several studies.
# ::save-date Thu Oct 15, 2015 ::file pmid_2352_4590_152.txt
(p / prove-01
      :ARG1 (e / effective-04
            :ARG0 (t / target-01
                  :ARG1 (p2 / pathway
                        :mod (b / both))
                  :manner (s / simultaneous)))
      :medium (t2 / thing
            :ARG1-of (s2 / study-01)
            :quant (s3 / several))
      :ARG1-of (p3 / predict-01
            :ARG1-of (p4 / possible-01)))

# ::id pmid_2352_4590.153 ::date 2015-07-30T12:15:39 ::annotator SDL-AMR-09 ::preferred
# ::snt In AZD6244-resistant gastric cancer cell lines, activation of Akt through the EGFR/PI3K/Akt pathway was still observed following MEK inhibition.
# ::save-date Thu Dec 10, 2015 ::file pmid_2352_4590_153.txt
(o / observe-01
      :ARG1 (a / activate-01
            :ARG1 (e2 / enzyme :name (n3 / name :op1 "Akt"))
            :instrument (p / pathway :name (n4 / name :op1 "EGFR/PI3K/Akt")))
      :mod (s / still)
      :ARG1-of (f / follow-01
            :ARG2 (i / inhibit-01
                  :ARG1 (e3 / enzyme :name (n5 / name :op1 "MEK"))))
      :location (c / cell-line
            :ARG0-of (r / resist-01
                  :ARG1 (s3 / small-molecule :name (n6 / name :op1 "AZD6244")))
            :source (d / disease :wiki "Stomach_cancer" :name (n / name :op1 "stomach" :op2 "cancer"))))

# ::id pmid_2352_4590.154 ::date 2015-07-30T12:15:55 ::annotator SDL-AMR-09 ::preferred
# ::snt Blockade of this pathway using the EGFR inhibitor, gefitinib, synergistically enhanced tumour apoptosis <i>in vitro</i> and <i>in vivo</i>.<sup><xref ref-type="bibr" rid="bib74">74</xref></sup>
# ::save-date Tue Feb 2, 2016 ::file pmid_2352_4590_154.txt
(e2 / enhance-01
      :ARG0 (b / blockade-01
            :ARG1 (p / pathway
                  :mod (t2 / this))
            :ARG2 (s3 / small-molecule
                  :ARG0-of (i2 / inhibit-01
                        :ARG1 (e3 / enzyme :name (n2 / name :op1 "EGFR")))
                  :ARG1-of (m2 / mean-01
                        :ARG2 (s / small-molecule :name (n3 / name :op1 "gefitinib")))))
      :ARG1 (a / apoptosis
            :poss (t / tumor))
      :manner (s2 / synergize-01)
      :manner (a2 / and
            :op1 (i3 / in-vitro)
            :op2 (i4 / in-vivo))
      :ARG1-of (d / describe-01
            :ARG0 (p2 / publication
                  :ARG1-of (c / cite-01
                        :ARG2 74))))

# ::id pmid_2352_4590.155 ::date 2015-07-30T12:16:15 ::annotator SDL-AMR-09 ::preferred
# ::snt Treatment of mutant murine lung cancers with the dual PI3K/mTOR inhibitor, NVP-BEZ235 and AZD6244 produced similar results.<sup><xref ref-type="bibr" rid="bib75">75</xref></sup>
# ::save-date Thu Dec 10, 2015 ::file pmid_2352_4590_155.txt
(p / produce-01
      :ARG0 (t3 / treat-04
            :ARG1 (d3 / disease :wiki "Lung_cancer" :name (n / name :op1 "lung" :op2 "cancer")
                  :mod (o / organism :name (n5 / name :op1 "Muridae"))
                  :ARG2-of (m2 / mutate-01))
            :ARG2 (s2 / small-molecule
                  :ARG0-of (i2 / inhibit-01
                        :ARG1 (p2 / pathway :name (n2 / name :op1 "PI3K/mTOR")))
                  :ARG1-of (m / mean-01
                        :ARG2 (a / and
                              :op1 (s3 / small-molecule :name (n3 / name :op1 "NVP-BEZ235"))
                              :op2 (s4 / small-molecule :name (n4 / name :op1 "AZD6244"))))
                  :mod (d2 / dual)))
      :ARG1 (t2 / thing
            :ARG2-of (r2 / result-01)
            :ARG1-of (r3 / resemble-01))
      :ARG1-of (d / describe-01
            :ARG0 (p3 / publication
                  :ARG1-of (c2 / cite-01
                        :ARG2 75))))

# ::id pmid_2352_4590.156 ::date 2015-07-30T12:16:34 ::annotator SDL-AMR-09 ::preferred
# ::snt Recently, preliminary results from a phase I trial evaluating the combined activity of GDC-0973/XL-518 and the Akt inhibitor, GDC-0941, found that in a cohort of 27 advanced solid tumour patients, three patients achieved prolonged s.d. ≥6 months when treated with both agents.<sup><xref ref-type="bibr" rid="bib76">76</xref></sup>
# ::save-date Sun Jan 17, 2016 ::file pmid_2352_4590_156.txt
(f / find-01
      :ARG0 (t3 / thing
            :ARG2-of (r / result-01
                  :ARG1 (t4 / trial-06
                        :mod (p2 / phase
                              :ord (o / ordinal-entity :value 1))
                        :ARG0-of (e / evaluate-01
                              :ARG1 (a / activity-06
                                    :ARG0 (a2 / and
                                          :op1 (s / small-molecule :name (n / name :op1 "GDC-0973/XL-518"))
                                          :op2 (s2 / small-molecule
                                                :ARG0-of (i2 / inhibit-01
                                                      :ARG1 (p6 / protein-family :name (n3 / name :op1 "Akt")))
                                                :ARG1-of (m2 / mean-01
                                                      :ARG2 (s3 / small-molecule :name (n2 / name :op1 "GDC-0941")))))
                                    :ARG3-of (c3 / combine-01)))))
            :mod (p / preliminary))
      :ARG1 (a3 / achieve-01
            :ARG0 (p3 / person :quant 3
                  :part-of (c / cohort
                        :consist-of (p7 / person :quant 27
                              :mod (t / tumor
                                    :ARG1-of (s5 / solid-02)
                                    :ARG1-of (a5 / advance-01))
                              :ARG0-of h))
                  :ARG0-of (h / have-rel-role-91
                        :ARG2 (p5 / patient)))
            :ARG1 (d2 / disease
                  :ARG1-of (p4 / prolong-01)
                  :ARG1-of (s4 / stable-03)
                  :duration (o2 / or
                        :op1 (t2 / temporal-quantity :quant 6
                              :unit (m / month))
                        :op2 (m3 / more-than
                              :op1 t2)))
            :condition (t6 / treat-03
                  :ARG1 p3
                  :ARG3 (a4 / agent
                        :mod (b / both))))
      :time (r2 / recent)
      :ARG1-of (d / describe-01
            :ARG0 (p8 / publication
                  :ARG1-of (c2 / cite-01
                        :ARG2 76))))

# ::id pmid_2352_4590.157 ::date 2015-07-30T12:16:51 ::annotator SDL-AMR-09 ::preferred
# ::snt Promising clinical activity has also been observed in the phase I trial of GSK1120212 in conjunction with the Akt inhibitor, GSK2141795.<sup><xref ref-type="bibr" rid="bib77">77</xref></sup>
# ::save-date Sun Jan 17, 2016 ::file pmid_2352_4590_157.txt
(o / observe-01
      :ARG1 (a / activity-06
            :mod (c / clinic)
            :ARG2-of (p / promise-01))
      :location (t / trial-06
            :ARG2 (a3 / and
                  :op1 (s / small-molecule :name (n / name :op1 "GSK1120212"))
                  :op2 (s2 / small-molecule
                        :ARG0-of (i / inhibit-01
                              :ARG1 (p4 / protein-family :name (n2 / name :op1 "Akt")))
                        :ARG1-of (m / mean-01
                              :ARG2 (s3 / small-molecule :name (n3 / name :op1 "GSK2141795")))))
            :mod (p2 / phase
                  :ord (o2 / ordinal-entity :value 1))
            :manner (c2 / conjunction))
      :mod (a2 / also)
      :ARG1-of (d / describe-01
            :ARG0 (p3 / publication
                  :ARG1-of (c3 / cite-01
                        :ARG2 77))))

# ::id pmid_2352_4590.158 ::date 2015-07-30T12:22:39 ::annotator SDL-AMR-09 ::preferred
# ::snt The number of preclinical and clinical studies investigating dual Ras/MAPK and PI3K/Akt inhibition indicates a growing trend to using these combinations to maximise antitumour response.
# ::save-date Thu Oct 15, 2015 ::file pmid_2352_4590_158.txt
(i / indicate-01
      :ARG0 (n2 / number
            :quant-of (a3 / and
                  :op1 (s / study-01
                        :mod (p2 / preclinical))
                  :op2 (s2 / study-01
                        :mod (c / clinical))
                  :ARG0-of (i2 / investigate-01
                        :ARG1 (i3 / inhibit-01
                              :ARG1 (a2 / and
                                    :op1 (p3 / pathway :name (n3 / name :op1 "Ras/MAPK"))
                                    :op2 (p4 / pathway :name (n4 / name :op1 "PI3K/Akt")))
                              :mod (d / dual)))))
      :ARG1 (t2 / trend-01
            :ARG2 (u / use-01
                  :ARG1 (c2 / combine-01
                        :mod (t3 / this))
                  :ARG2 (m / maximize-01
                        :ARG1 (r / respond-01
                              :ARG2 (c3 / counter-01
                                    :ARG1 (t4 / tumor)))))
            :ARG1-of (g / grow-01)))

# ::id pmid_2352_4590.159 ::date 2015-07-30T12:22:56 ::annotator SDL-AMR-09 ::preferred
# ::snt Aberrant signalling through additional kinase pathways may also contribute to MEK inhibitor resistance.
# ::save-date Sat Jan 16, 2016 ::file pmid_2352_4590_159.txt
(p / possible-01
      :ARG1 (c / contribute-01
            :ARG0 (s / signal-07
                  :manner (p2 / pathway
                        :mod (k / kinase)
                        :mod (a2 / additional))
                  :manner (a / aberrant))
            :ARG2 (r / resist-01
                  :ARG1 (s2 / small-molecule
                        :ARG0-of (i2 / inhibit-01
                              :ARG1 (p3 / protein-family :name (n2 / name :op1 "MEK")))))
            :mod (a3 / also)))

# ::id pmid_2352_4590.160 ::date 2015-07-31T01:39:05 ::annotator SDL-AMR-09 ::preferred
# ::snt For example, although non-small cell lung carcinomas carry both K-Ras and PTEN mutations, resistance of these cell lines to AZD6244 coincides with activation of the Janus kinase/signal transducer and activator of transcription pathway (JAK/STAT) following MEK inhibition.<sup><xref ref-type="bibr" rid="bib78">78</xref></sup>
# ::save-date Wed Mar 2, 2016 ::file pmid_2352_4590_160.txt
(c / coincide-01
      :ARG1 (r / resist-01
            :ARG0 (c2 / cell-line
                  :mod (t2 / this))
            :ARG1 (s2 / small-molecule :name (n4 / name :op1 "AZD6244")))
      :ARG2 (a2 / activate-01
            :ARG1 (p / pathway :name (n5 / name :op1 "Janus" :op2 "kinase/signal" :op3 "transducer" :op4 "and" :op5 "activator" :op6 "of" :op7 "transcription"))
            :ARG1-of (f / follow-01
                  :ARG2 (i / inhibit-01
                        :ARG1 (e5 / enzyme :name (n6 / name :op1 "MEK")))))
      :ARG0-of (e4 / exemplify-01)
      :concession (c3 / carry-01
            :ARG0 (c4 / carcinoma
                  :mod (l / lung)
                  :mod (c6 / cell :polarity -
                        :mod (s / small)))
            :ARG1 (a3 / and
                  :op1 (m / mutate-01
                        :ARG1 (e6 / enzyme :name (n7 / name :op1 "K-Ras")))
                  :op2 (m2 / mutate-01
                        :ARG1 (p3 / protein :name (n8 / name :op1 "PTEN")))))
      :ARG1-of (d / describe-01
            :ARG0 (p2 / publication
                  :ARG1-of (c5 / cite-01
                        :ARG2 78))))

# ::id pmid_2352_4590.161 ::date 2015-07-31T02:03:21 ::annotator SDL-AMR-09 ::preferred
# ::snt AZD6244 combined with STAT3 inhibition synergistically induced apoptosis in these cells.
# ::save-date Tue Feb 2, 2016 ::file pmid_2352_4590_161.txt
(i / induce-01
      :ARG0 (s2 / small-molecule :name (n2 / name :op1 "AZD6244")
            :ARG1-of (c / combine-01
                  :ARG2 (i2 / inhibit-01
                        :ARG1 (p / protein :name (n3 / name :op1 "STAT3")))))
      :ARG2 (a2 / apoptosis
            :location (c2 / cell
                  :mod (t / this)))
      :manner (s / synergize-01))

# ::id pmid_2352_4590.162 ::date 2015-07-31T02:08:52 ::annotator SDL-AMR-09 ::preferred
# ::snt This effect can be explained by STAT3 suppressing the proapoptotic protein Bim through upregulation of miRNA-17, which antagonises the Bim expression induced by AZD6244.<sup><xref ref-type="bibr" rid="bib79">79</xref></sup>
# ::save-date Sun Dec 20, 2015 ::file pmid_2352_4590_162.txt
(p / possible-01
      :ARG1 (e / explain-01
            :ARG0 (p2 / protein :wiki "STAT3"
                  :name (n / name :op1 "STAT3")
                  :ARG0-of (s / suppress-01
                        :ARG1 (p3 / protein :wiki "BCL2L11"
                              :name (n2 / name :op1 "Bim")
                              :ARG0-of (f / favor-01
                                    :ARG1 (a2 / apoptosis)))
                        :instrument (u / upregulate-01
                              :ARG1 (n5 / nucleic-acid :wiki "Mir-17_microRNA_precursor_family"
                                    :name (n3 / name :op1 "miRNA-17"))
                              :ARG1-of (a3 / antagonize-02
                                    :ARG2 (e2 / express-03
                                          :ARG2 p3
                                          :ARG2-of (i / induce-01
                                                :ARG0 (s2 / small-molecule :wiki "Selumetinib"
                                                      :name (n4 / name :op1 "AZD6244"))))))))
            :ARG1 (a / affect-01
                  :mod (t / this)))
      :ARG1-of (d / describe-01
            :ARG0 (p4 / publication
                  :ARG1-of (c / cite-01 :ARG2 79))))

# ::id pmid_2352_4590.163 ::date 2015-07-31T02:27:12 ::annotator SDL-AMR-09 ::preferred
# ::snt Collectively, these results provide a rationale for combining inhibitors of the JAK/STAT pathway and MEK inhibitors to reduce the potential impact of drug resistance.
# ::save-date Sat Jan 16, 2016 ::file pmid_2352_4590_163.txt
(p / provide-01
      :ARG0 (t2 / thing
            :ARG2-of (r / result-01)
            :mod (t / this))
      :ARG1 (r2 / rationale)
      :ARG2 (c2 / combine-01
            :ARG1 (s / small-molecule
                  :ARG0-of (i2 / inhibit-01
                        :ARG1 (p2 / pathway :name (n2 / name :op1 "JAK/STAT"))))
            :ARG2 (s2 / small-molecule
                  :ARG0-of (i3 / inhibit-01
                        :ARG1 (p4 / protein-family :name (n3 / name :op1 "MEK"))))
            :purpose (r3 / reduce-01
                  :ARG1 (i4 / impact-01
                        :ARG0 (r4 / resist-01
                              :ARG1 (d / drug))
                        :mod (p3 / potential))))
      :manner (c / collective))

# ::id pmid_2352_4590.164 ::date 2015-07-31T02:35:14 ::annotator SDL-AMR-09 ::preferred
# ::snt Information about the use of MEK inhibitors and other kinase pathway inhibitors is unknown.
# ::save-date Sat Jan 16, 2016 ::file pmid_2352_4590_164.txt
(k / know-01 :polarity -
      :ARG1 (i2 / information
            :topic (u / use-01
                  :ARG1 (a / and
                        :op1 (s / small-molecule
                              :ARG0-of (i3 / inhibit-01
                                    :ARG1 (p2 / protein-family :name (n2 / name :op1 "MEK"))))
                        :op2 (s2 / small-molecule
                              :ARG0-of (i4 / inhibit-01
                                    :ARG1 (p / pathway
                                          :mod (k2 / kinase)
                                          :mod (o / other))))))))

# ::id pmid_2352_4590.165 ::date 2015-07-31T02:39:57 ::annotator SDL-AMR-09 ::preferred
# ::snt <sec-title level="2">The role of MEK inhibitors in MM</sec-title>
# ::save-date Sat Jan 16, 2016 ::file pmid_2352_4590_165.txt
(r / role
      :poss (s / small-molecule
            :ARG0-of (i2 / inhibit-01
                  :ARG1 (p / protein-family :name (n2 / name :op1 "MEK"))))
      :topic (d / disease :name (n / name :op1 "multiple" :op2 "myeloma")))

# ::id pmid_2352_4590.166 ::date 2015-07-31T02:45:26 ::annotator SDL-AMR-09 ::preferred
# ::snt The advent of novel anti-MM agents has improved the management and prognosis of MM.
# ::save-date Fri Oct 16, 2015 ::file pmid_2352_4590_166.txt
(i / improve-01
      :ARG0 (a / advent
            :mod (a2 / agent
                  :ARG0-of (c / counter-01
                        :ARG1 (d / disease :name (n2 / name :op1 "multiple" :op2 "myeloma")))
                  :mod (n / novel)))
      :ARG1 (a3 / and
            :op1 (m2 / manage-01
                  :ARG1 d)
            :op2 (p / prognosis
                  :topic d)))

# ::id pmid_2352_4590.167 ::date 2015-07-31T02:52:04 ::annotator SDL-AMR-09 ::preferred
# ::snt With the immunomodulatory drugs, thalidomide and lenalidomide, and the proteasome inhibitor, bortezomib, able to abrogate the survival advantage created by the BMME, current research has focussed on combining these novel therapies to improve patient outcomes.<sup><xref ref-type="bibr" rid="bib80">80</xref></sup>
# ::save-date Thu Feb 4, 2016 ::file pmid_2352_4590_167.txt
(f / focus-01
      :ARG0 (r / research-01
            :mod (c / current))
      :ARG2 (c2 / combine-01
            :ARG1 (t2 / therapy
                  :mod (n / novel)
                  :mod (t / this)))
      :ARG1-of (d2 / describe-01
            :ARG0 (p3 / publication
                  :ARG1-of (c5 / cite-01
                        :ARG2 80)))
      :ARG1-of (c6 / cause-01
            :ARG0 (a / and
                  :op1 (d / drug
                        :ARG1-of (m2 / mean-01
                              :ARG2 (a2 / and
                                    :op1 (s3 / small-molecule :name (n3 / name :op1 "thalidomide"))
                                    :op2 (s4 / small-molecule :name (n4 / name :op1 "lenalidomide"))))
                        :ARG0-of (i / immunomodulate-00))
                  :op2 (s / small-molecule
                        :ARG0-of (i4 / inhibit-01
                              :ARG1 (m3 / macro-molecular-complex :name (n2 / name :op1 "proteasome")))
                        :ARG1-of (m4 / mean-01
                              :ARG2 (s5 / small-molecule :name (n5 / name :op1 "bortezomib"))))
                  :ARG1-of (c3 / capable-01
                        :ARG2 (a3 / abrogate-01
                              :ARG1 (a4 / advantage
                                    :mod (s2 / survive-01)
                                    :ARG1-of (c4 / create-01
                                          :ARG0 (m / microenvironment
                                                :mod (m5 / marrow
                                                      :part-of (b / bone)))))))))
      :purpose (i2 / improve-01
            :ARG0 r
            :ARG1 (o / outcome
                  :poss (p / person
                        :ARG0-of (h / have-rel-role-91
                              :ARG2 (p2 / patient))))))

# ::id pmid_2352_4590.168 ::date 2015-07-31T03:31:18 ::annotator SDL-AMR-09 ::preferred
# ::snt To date, promising results have been obtained in several clinical trials.<sup><xref ref-type="bibr" rid="bib81">81</xref>, <xref ref-type="bibr" rid="bib82">82</xref></sup>
# ::save-date Fri Dec 18, 2015 ::file pmid_2352_4590_168.txt
(o / obtain-01
      :ARG1 (t / thing
            :ARG2-of (r / result-01)
            :ARG2-of (p / promise-01))
      :ARG2 (t2 / trial-06
            :mod (c / clinic)
            :quant (s / several))
      :time (t3 / to-date)
      :ARG1-of (d / describe-01
            :ARG0 (p2 / publication
                  :ARG1-of (c2 / cite-01
                        :ARG2 (a / and :op1 81 :op2 82)))))

# ::id pmid_2352_4590.169 ::date 2015-07-31T03:35:45 ::annotator SDL-AMR-09 ::preferred
# ::snt However, despite the clinical success of thalidomide, lenalidomide and bortezomib, a subset of patients do not initially respond to or ultimately become refractory to these agents.<sup><xref ref-type="bibr" rid="bib83">83</xref></sup>
# ::save-date Thu Dec 10, 2015 ::file pmid_2352_4590_169.txt
(h / have-concession-91
      :ARG1 (o / or
            :op1 (r / respond-01 :polarity -
                  :ARG0 (p / person
                        :ARG1-of (i2 / include-91
                              :ARG2 (s / subset))
                        :ARG0-of (h2 / have-rel-role-91
                              :ARG2 (p3 / patient)))
                  :ARG1 a
                  :time (i / initial))
            :op2 (b / become-01
                  :ARG1 p
                  :ARG2 (r2 / refractory
                        :prep-to (a / agent
                              :mod (t / this)
                              :ARG1-of (m / mean-01
                                    :ARG2 a2)))
                  :manner (u / ultimate)))
      :ARG2 (s2 / succeed-01
            :ARG0 (a2 / and
                  :op1 (s3 / small-molecule :name (n / name :op1 "thalidomide"))
                  :op2 (s4 / small-molecule :name (n2 / name :op1 "lenalidomide"))
                  :op3 (s5 / small-molecule :name (n3 / name :op1 "bortezomib")))
            :mod (c / clinic))
      :ARG1-of (d / describe-01
            :ARG0 (p2 / publication
                  :ARG1-of (c2 / cite-01
                        :ARG2 83))))

# ::id pmid_2352_4590.170 ::date 2015-07-31T04:05:20 ::annotator SDL-AMR-09 ::preferred
# ::snt This emphasises the need for innovative anti-MM therapies.
# ::save-date Fri Oct 16, 2015 ::file pmid_2352_4590_170.txt
(e / emphasize-01
      :ARG0 (t / this)
      :ARG1 (n / need-01
            :ARG1 (t2 / therapy
                  :ARG1-of (i / innovate-01)
                  :ARG0-of (c / counter-01
                        :ARG1 (d / disease :name (n2 / name :op1 "multiple" :op2 "myeloma"))))))

# ::id pmid_2352_4590.171 ::date 2015-07-31T04:09:13 ::annotator SDL-AMR-09 ::preferred
# ::snt The impact of AZD6244 has been investigated in MM cells within the BMME.<sup><xref ref-type="bibr" rid="bib84">84</xref></sup>
# ::save-date Mon Nov 16, 2015 ::file pmid_2352_4590_171.txt
(i / investigate-01
      :ARG1 (i2 / impact-01
            :ARG0 (s2 / small-molecule :name (n2 / name :op1 "AZD6244")))
      :location (c / cell
            :part-of (m / microenvironment
                  :mod (m2 / marrow
                        :part-of (b / bone)))
            :source (d2 / disease :name (n / name :op1 "multiple" :op2 "myeloma")))
      :ARG1-of (d / describe-01
            :ARG0 (p / publication
                  :ARG1-of (c2 / cite-01
                        :ARG2 84))))

# ::id pmid_2352_4590.172 ::date 2015-07-31T04:12:34 ::annotator SDL-AMR-09 ::preferred
# ::snt This compound specifically abrogated constitutive and cytokine-stimulated ERK phosphorylation and induced cytotoxicity in a panel of human myeloma cell lines (HMCL).
# ::save-date Fri Jan 1, 2016 ::file pmid_2352_4590_172.txt
(a / and
      :op1 (a2 / abrogate-01
            :ARG0 (c3 / compound
                  :mod (t / this))
            :ARG1 (a3 / and
                  :op1 (p2 / phosphorylate-01
                        :ARG1 (e2 / enzyme :name (n2 / name :op1 "ERK"))
                        :mod (c / constitutive))
                  :op2 (p3 / phosphorylate-01
                        :ARG1 e2
                        :ARG1-of (s / stimulate-01
                              :ARG0 (c5 / cytokine))))
            :ARG1-of (s2 / specific-02))
      :op2 (i / induce-01
            :ARG0 c3
            :ARG2 (c2 / cytotoxicity))
      :location (p5 / panel
            :consist-of (c4 / cell-line
                  :mod (d / disease :name (n / name :op1 "myeloma")
                        :mod (h / human)))))

# ::id pmid_2352_4590.173 ::date 2015-07-31T04:30:45 ::annotator SDL-AMR-09 ::preferred
# ::snt Responses to AZD6244 were also witnessed in tumour cells derived from MM patients with advanced disease.
# ::save-date Thu Dec 10, 2015 ::file pmid_2352_4590_173.txt
(w / witness-01
      :ARG1 (t / thing
            :ARG2-of (r / respond-01
                  :ARG1 (s2 / small-molecule :name (n2 / name :op1 "AZD6244"))))
      :mod (a / also)
      :location (c / cell
            :mod (t2 / tumor)
            :ARG1-of (d / derive-01
                  :ARG2 (p / patient
                        :mod (d3 / disease :name (n / name :op1 "multiple" :op2 "myeloma")
                              :ARG1-of (a2 / advance-01))))))

# ::id pmid_2352_4590.174 ::date 2015-07-30T10:46:07 ::annotator SDL-AMR-09 ::preferred
# ::snt These results suggest that AZD6244 is effective at advanced stages of disease, where MM cells are less reliant on the growth factors produced by the BMME.
# ::save-date Wed Feb 24, 2016 ::file pmid_2352_4590_174.txt
(s / suggest-01
      :ARG0 (t / thing
            :ARG2-of (r / result-01)
            :mod (t2 / this))
      :ARG1 (e / effective-04
            :ARG0 (s2 / small-molecule :name (n / name :op1 "AZD6244"))
            :time (s3 / stage-02
                  :ARG1 (d / disease)
                  :ARG1-of (a / advance-01)
                  :time-of (r2 / rely-01
                        :ARG0 (c / cell
                              :mod (d2 / disease :name (n4 / name :op1 "multiple" :op2 "myeloma")))
                        :ARG2 (g / growth-factor
                              :ARG1-of (p / produce-01
                                    :ARG0 (m / microenvironment
                                          :mod (m2 / marrow
                                                :mod (b / bone)))))
                        :degree (l / less)))))

# ::id pmid_2352_4590.175 ::date 2015-07-30T11:01:57 ::annotator SDL-AMR-09 ::preferred
# ::snt Furthermore, culturing of HMCL and patient-derived samples in the presence of exogenous interleukin-6 or bone marrow stromal cells did not protect against AZD6244-induced apoptosis.
# ::save-date Thu Feb 4, 2016 ::file pmid_2352_4590_175.txt
(a / and
      :op2 (p / protect-01 :polarity -
            :ARG0 (c / culture-01
                  :ARG1 (a2 / and
                        :op1 (c2 / cell-line
                              :mod (d3 / disease :name (n4 / name :op1 "myeloma")
                                    :mod (h / human)))
                        :op2 (t / thing
                              :ARG1-of (d2 / derive-01
                                    :ARG2 (p2 / person
                                          :ARG0-of (h2 / have-rel-role-91
                                                :ARG2 (p4 / patient))))
                              :ARG1-of (s / sample-01)))
                  :condition (p5 / present-02
                        :ARG1 (o / or
                              :op1 (p6 / protein :name (n / name :op1 "interleukin-6")
                                    :mod (e / exogenous))
                              :op2 (c3 / cell
                                    :mod (s2 / stroma
                                          :mod (m / marrow
                                                :mod (b / bone)))))))
            :ARG2 (a3 / apoptosis
                  :ARG2-of (i / induce-01
                        :ARG0 (s3 / small-molecule :name (n3 / name :op1 "AZD6244"))))))

# ::id pmid_2352_4590.176 ::date 2015-07-30T11:10:54 ::annotator SDL-AMR-09 ::preferred
# ::snt Synergistically enhanced cell death was noted in combinations of AZD6244 with conventional (dexamethasone) and novel (bortezomib, lenalidomide, perifisone) anti-MM agents.
# ::save-date Thu Feb 4, 2016 ::file pmid_2352_4590_176.txt
(n / note-01
      :ARG1 (d / die-01
            :ARG1 (c / cell)
            :ARG1-of (e / enhance-01
                  :manner (s / synergize-01)))
      :location (c2 / combine-01
            :ARG1 (s2 / small-molecule :name (n2 / name :op1 "AZD6244"))
            :ARG2 (a / and
                  :op1 (a2 / agent
                        :ARG0-of (c3 / counter-01
                              :ARG1 (d2 / disease :name (n3 / name :op1 "multiple" :op2 "myeloma")))
                        :mod (c4 / conventional)
                        :ARG2-of (i / include-91
                              :ARG1 (d3 / dexamethasone)))
                  :op2 (a3 / agent
                        :ARG0-of c3
                        :mod (n4 / novel)
                        :ARG2-of (i2 / include-91
                              :ARG1 (a4 / and
                                    :op1 (s3 / small-molecule :name (n5 / name :op1 "bortezomib"))
                                    :op2 (s4 / small-molecule :name (n6 / name :op1 "lenalidomide"))
                                    :op3 (s5 / small-molecule :name (n7 / name :op1 "perifisone"))))))))

# ::id pmid_2352_4590.177 ::date 2015-07-30T11:22:25 ::annotator SDL-AMR-09 ::preferred
# ::snt AZD6244 as a single agent was also examined in an <i>in vivo</i> human plasmocytoma xenograft model and demonstrated prolonged survival when compared with control animals.
# ::save-date Mon Aug 10, 2015 ::file pmid_2352_4590_177.txt
(a / and
      :op1 (e / examine-01
            :ARG1 (s / small-molecule :name (n / name :op1 "AZD6244"))
            :manner (a2 / agent
                  :ARG1-of (s2 / single-02))
            :mod (a3 / also)
            :location (x2 / xenograft
                  :manner (i / in-vivo)
                  :mod (m / model)
                  :mod (p2 / plasmocytoma)
                  :mod (h / human)))
      :op2 (d / demonstrate-01
            :ARG0 s
            :ARG1 (s3 / survive-01
                  :ARG1-of (p / prolong-01)
                  :compared-to (a4 / animal
                        :mod (c / control)))))

# ::id pmid_2352_4590.178 ::date 2015-07-30T11:30:32 ::annotator SDL-AMR-09 ::preferred
# ::snt Breitkreutz <i>et al.</i><sup><xref ref-type="bibr" rid="bib85">85</xref></sup> have also investigated the consequences of AZD6244 administration on osteoclast differentiation, function and cytokine secretion in MM.
# ::save-date Thu Feb 4, 2016 ::file pmid_2352_4590_178.txt
(i / investigate-01
      :ARG0 (p / publication-91
            :ARG0 (a / and
                  :op1 (p2 / person :name (n / name :op1 "Breitkreutz"))
                  :op2 (p3 / person
                        :mod (o / other)))
            :ARG1-of (d3 / describe-01
                  :ARG0 (p5 / publication
                        :ARG1-of (c / cite-01
                              :ARG2 85))))
      :ARG1 (c2 / consequence
            :poss (a3 / administer-01
                  :ARG1 (s / small-molecule :name (n2 / name :op1 "AZD6244")))
            :prep-on (a4 / and
                  :op1 (d / differentiate-01
                        :mod (o2 / osteoclast))
                  :op2 (f / function-01
                        :mod o2)
                  :op3 (s2 / secrete-01
                        :ARG1 (p4 / protein :name (n3 / name :op1 "cytokine"))
                        :mod o2))
            :location (m / multiple :name (n4 / name :op1 "myeloma")))
      :mod (a2 / also))

# ::id pmid_2352_4590.179 ::date 2015-07-30T11:47:02 ::annotator SDL-AMR-09 ::preferred
# ::snt AZD6244 blocked osteoclast differentiation and bone reabsorption in a dose-dependent manner.
# ::save-date Thu Dec 17, 2015 ::file pmid_2352_4590_179.txt
(b / block-01
      :ARG0 (s / small-molecule :name (n / name :op1 "AZD6244"))
      :ARG1 (a / and
            :op1 (d / differentiate-01
                  :ARG1 (o / osteoclast))
            :op2 (r / reabsorb-00
                  :ARG1 (b2 / bone)))
      :manner (d2 / depend-01
            :ARG1 (d3 / dose)))

# ::id pmid_2352_4590.180 ::date 2015-07-30T11:52:34 ::annotator SDL-AMR-09 ::preferred
# ::snt Furthermore, critical MM growth factors produced by the BMME, including interleukin-6, BAFF, APRIL and MIP-1α were all significantly reduced following AZD6244 treatment.
# ::save-date Wed Feb 24, 2016 ::file pmid_2352_4590_180.txt
(a / and
      :op2 (r / reduce-01
            :ARG1 (g / growth-factor
                  :mod (d / disease :name (n9 / name :op1 "multiple" :op2 "myeloma"))
                  :ARG1-of (c / critical-02)
                  :ARG1-of (p / produce-01
                        :ARG0 (m / microenvironment
                              :mod (m2 / marrow
                                    :mod (b / bone))))
                  :mod (a3 / all)
                  :ARG2-of (i / include-91
                        :ARG1 (a2 / and
                              :op1 (p2 / pritein :name (n / name :op1 "interleukin-6"))
                              :op2 (p3 / protein :name (n4 / name :op1 "BAFF"))
                              :op3 (p4 / protein :name (n5 / name :op1 "APRIL"))
                              :op4 (p5 / protein :name (n6 / name :op1 "MIP-1α")))))
            :ARG2 (s2 / significant-02)
            :time (a4 / after
                  :op1 (t / treat-04
                        :ARG1 g
                        :ARG2 (s3 / small-molecule :name (n7 / name :op1 "AZD6244"))))))

# ::id pmid_2352_4590.181 ::date 2015-07-30T12:03:53 ::annotator SDL-AMR-09 ::preferred
# ::snt Taken together, these results indicate that AZD6244 is able to abrogate paracrine signal dependent MM cell survival within the bone marrow niche.
# ::save-date Thu Feb 4, 2016 ::file pmid_2352_4590_181.txt
(i2 / indicate-01
      :ARG0 (t / thing
            :ARG2-of (r / result-01)
            :mod (t2 / this)
            :ARG1-of (t3 / take-01
                  :manner (t4 / together)))
      :ARG1 (p / possible-01
            :ARG1 (a / abrogate-01
                  :ARG1 (s2 / survive-01
                        :ARG0 (c / cell
                              :mod (d / disease :name (n2 / name :op1 "multiple" :op2 "myeloma")))
                        :ARG0-of (d2 / depend-01
                              :ARG1 (s3 / signal-07
                                    :ARG0 (p2 / paracrine))))
                  :ARG2 (s / small-molecule :name (n / name :op1 "AZD6244"))
                  :location (n3 / niche
                        :mod (m / marrow
                              :mod (b / bone))))))

# ::id pmid_2352_4590.182 ::date 2015-07-30T12:12:55 ::annotator SDL-AMR-09 ::preferred
# ::snt Both these studies provide a preclinical rationale for the further evaluation of AZD6244.
# ::save-date Thu Jul 30, 2015 ::file pmid_2352_4590_182.txt
(p / provide-01
      :ARG0 (s / study-01
            :mod (t / this)
            :mod (b / both))
      :ARG1 (r / rationale
            :mod (p2 / preclinical)
            :purpose (e / evaluate-01
                  :ARG1 (s2 / small-molecule :name (n / name :op1 "AZD6244"))
                  :degree (f / further))))

# ::id pmid_2352_4590.183 ::date 2015-07-30T12:16:14 ::annotator SDL-AMR-09 ::preferred
# ::snt A phase II trial examining the compound in MM is presently ongoing.
# ::save-date Thu Feb 4, 2016 ::file pmid_2352_4590_183.txt
(g / go-on-15
      :ARG1 (t / trial-06
            :ARG2 (e / examine-01
                  :ARG1 (c / compound)
                  :location (d / disease :name (n / name :op1 "multiple" :op2 "myeloma")))
            :mod (p / phase
                  :ord (o / ordinal-entity :value 2)))
      :time (p2 / present))

# ::id pmid_2352_4590.184 ::date 2015-07-30T12:21:00 ::annotator SDL-AMR-09 ::preferred
# ::snt Treatment with AS703026 has also been explored in MM.<sup><xref ref-type="bibr" rid="bib86">86</xref></sup>
# ::save-date Thu Feb 4, 2016 ::file pmid_2352_4590_184.txt
(e / explore-01
      :ARG1 (t / treat-04
            :ARG2 (s / small-molecule :name (n / name :op1 "AS703026")))
      :ARG1-of (d2 / describe-01
            :ARG0 (p / publication
                  :ARG1-of (c / cite-01
                        :ARG2 86)))
      :mod (a / also)
      :location (d / disease :name (n2 / name :op1 "multiple" :op2 "myeloma")))

# ::id pmid_2352_4590.185 ::date 2015-07-30T12:24:13 ::annotator SDL-AMR-09 ::preferred
# ::snt AS703026 inhibits HMCL and cytokine-induced osteoclast differentiation more potently (9- to 10-fold) than AZD6244, with an IC<sub>50</sub> ranging from 0.005–2 μℳ.
# ::save-date Thu Feb 4, 2016 ::file pmid_2352_4590_185.txt
(i / inhibit-01
      :ARG0 (s2 / small-molecule :name (n / name :op1 "AS703026")
            :ARG1-of (h2 / have-percentage-maximal-inhibitory-concentration-01
                  :ARG2 50
                  :ARG4 (v / value-interval
                        :op1 (c2 / concentration-quantity :quant 0.005
                              :unit (n5 / nanomolar))
                        :op2 (c4 / concentration-quantity :quant 2
                              :unit (n6 / nanomolar)))))
      :ARG1 (a / and
            :op1 (c / cell-line
                  :mod (d / disease :name (n2 / name :op1 "multiple" :op2 "myeloma")
                        :mod (h / human)))
            :op2 (d2 / differentiate-01
                  :ARG1 (o / osteoclast)
                  :ARG2-of (i2 / induce-01
                        :ARG0 (p / protein :name (n3 / name :op1 "cytokine")))))
      :manner (p2 / potent
            :degree (m2 / more))
      :quant (b / between
            :op1 (p3 / product-of :op1 9)
            :op2 (p4 / product-of :op1 10))
      :ARG1-of (c3 / compare-01
            :ARG2 (s / small-molecule :name (n4 / name :op1 "AZD6244"))))

# ::id pmid_2352_4590.186 ::date 2015-07-30T12:38:51 ::annotator SDL-AMR-09 ::preferred
# ::snt No discernable relationship between Ras or Raf mutational status and the sensitivity of HMCL to AS703026 was observed.
# ::save-date Thu Feb 4, 2016 ::file pmid_2352_4590_186.txt
(o / observe-01 :polarity -
      :ARG1 (r / relation-03
            :ARG0 (o2 / or
                  :op1 (s / status
                        :mod (m / mutate-01
                              :ARG1 (e / enzyme :name (n / name :op1 "Ras"))))
                  :op2 (s2 / status
                        :mod (m2 / mutate-01
                              :ARG1 (e2 / enzyme :name (n2 / name :op1 "Raf")))))
            :ARG2 (s3 / sensitive-03
                  :ARG0 (c / cell-line
                        :mod (d2 / disease :name (n3 / name :op1 "multiple" :op2 "myeloma")
                              :mod (h / human)))
                  :ARG1 (s4 / small-molecule :name (n4 / name :op1 "AS703026")))
            :ARG1-of (d / discern-01
                  :ARG1-of (p2 / possible-01))))

# ::id pmid_2352_4590.187 ::date 2015-07-30T12:44:45 ::annotator SDL-AMR-09 ::preferred
# ::snt This compound also induced apoptosis in HMCL cultured in the presence of bone marrow stromal cells.
# ::save-date Thu Feb 4, 2016 ::file pmid_2352_4590_187.txt
(i / induce-01
      :ARG0 (c / compound
            :mod (t / this))
      :ARG2 (a / apoptosis)
      :mod (a2 / also)
      :condition (p / present-02
            :ARG1 (c2 / cell-line
                  :ARG1-of (c4 / culture-01
                        :condition (c3 / cell
                              :mod (s / stroma
                                    :mod (m / marrow
                                          :mod (b / bone)))))
                  :mod (d / disease :name (n / name :op1 "multiple" :op2 "myeloma")
                        :mod (h / human)))))

# ::id pmid_2352_4590.188 ::date 2015-07-30T12:46:51 ::annotator SDL-AMR-09 ::preferred
# ::snt Further evaluation of AS703026 in conjunction with conventional (dexamethasone, melphalan) and novel (lenalidomide, bortezomib, perifisone, rapamycin) anti-MM therapies revealed synergistic cytotoxicity against HMCL and patient samples.
# ::save-date Thu Feb 4, 2016 ::file pmid_2352_4590_188.txt
(r / reveal-01
      :ARG0 (e / evaluate-01
            :ARG1 (s9 / small-molecule :name (n / name :op1 "AS703026"))
            :degree (f / further)
            :ARG1-of (a2 / accompany-01
                  :ARG0 (a3 / and
                        :op1 (t / therapy
                              :ARG0-of (c3 / counter-01
                                    :ARG1 (d2 / disease :name (n3 / name :op1 "multiple" :op2 "myeloma")))
                              :mod (c4 / conventional)
                              :ARG2-of (i / include-91
                                    :ARG1 (a4 / and
                                          :op1 (s3 / small-molecule :name (n5 / name :op1 "dexamethasone"))
                                          :op2 (s4 / small-molecule :name (n6 / name :op1 "melphalan")))))
                        :op2 (t2 / therapy
                              :ARG0-of c3
                              :mod (n4 / novel)
                              :ARG2-of (i2 / include-91
                                    :ARG1 (a5 / and
                                          :op1 (s5 / small-molecule :name (n7 / name :op1 "lenalidomide"))
                                          :op2 (s6 / small-molecule :name (n8 / name :op1 "bortezomib"))
                                          :op3 (s7 / small-molecule :name (n9 / name :op1 "perifisone"))
                                          :op4 (s8 / small-molecule :name (n10 / name :op1 "rapamycin"))))))))
      :ARG1 (c / cytotoxicity
            :ARG0-of (s / synergize-01)
            :prep-against (a / and
                  :op1 (c2 / cell-line
                        :mod (d / disease :name (n2 / name :op1 "myeloma")
                              :mod (h / human)))
                  :op2 (t3 / thing
                        :ARG1-of (s2 / sample-01
                              :ARG2 (p / person
                                    :ARG0-of (h2 / have-rel-role-91
                                          :ARG2 (p2 / patient))))))))

# ::id pmid_2352_4590.189 ::date 2015-07-30T12:56:06 ::annotator SDL-AMR-09 ::preferred
# ::snt Lastly, for tumour cells isolated from patients with relapsed/refractory MM treated with AS703026 at concentrations below 200 nℳ, dose-dependent cytotoxicity was observed for 15 of 18 patient MM samples.
# ::save-date Wed Mar 2, 2016 ::file pmid_2352_4590_189.txt
(o / observe-01
      :ARG1 (c / cytotoxicity
            :ARG0-of (d / depend-01
                  :ARG1 (d2 / dose)))
      :condition (c3 / cell
            :source (p2 / person
                  :ARG1-of (t2 / treat-03
                        :ARG3 (s2 / small-molecule :name (n2 / name :op1 "AS703026")
                              :quant (b / below
                                    :op1 (c2 / concentration-quantity :quant 200
                                          :unit (n3 / nanomolar)))))
                  :ARG0-of (h2 / have-rel-role-91
                        :ARG2 (p4 / patient))
                  :ARG0-of (h3 / have-03
                        :ARG1 (o2 / or
                              :op1 (d5 / disease :name (n6 / name :op1 "multiple" :op2 "myeloma")
                                    :ARG1-of (r / relapse-01))
                              :op2 (d4 / disease :name (n4 / name :op1 "multiple" :op2 "myeloma")
                                    :mod (r2 / refract)))))
            :mod (t / tumor)
            :ARG1-of (i2 / isolate-01))
      :time (l / last)
      :location (d6 / disease :name (n5 / name :op1 "multiple" :op2 "myeloma")
            :ARG1-of (s3 / sample-01 :quant 15
                  :ARG2 (p / person
                        :ARG0-of (h / have-rel-role-91
                              :ARG2 (p3 / patient)))
                  :ARG1-of (i / include-91
                        :ARG2 (t3 / thing :quant 18
                              :ARG1-of (s / sample-01))))))

# ::id pmid_2352_4590.190 ::date 2015-07-30T13:10:53 ::annotator SDL-AMR-09 ::preferred
# ::snt In this cohort of MM patient samples, while six and two of the patient samples harboured K-Ras/N-Ras and B-Raf mutations, respectively, the presence or absence of Ras or B-Raf mutations did not correlate with the sensitivity to MEK inhibition by AS703026.
# ::save-date Thu Feb 4, 2016 ::file pmid_2352_4590_190.txt
(c / contrast-01
      :ARG1 (a / and
            :op1 (h / harbor-01
                  :ARG0 (t3 / thing :quant 6
                        :ARG1-of (s / sample-01
                              :ARG2 p2))
                  :ARG1 (o / or
                        :op1 (m / mutate-01
                              :ARG1 (e / enzyme :name (n / name :op1 "K-Ras")))
                        :op2 (m2 / mutate-01
                              :ARG1 (e2 / enzyme :name (n2 / name :op1 "N-Ras")))))
            :op2 (h2 / harbor-01
                  :ARG0 (t2 / thing :quant 2
                        :ARG1-of (s2 / sample-01))
                  :ARG1 (m3 / mutate-01
                        :ARG1 (e3 / enzyme :name (n3 / name :op1 "B-Raf")))))
      :ARG2 (c2 / correlate-01 :polarity -
            :ARG1 (o2 / or
                  :op1 (p / present-02
                        :ARG1 (o3 / or
                              :op1 (m4 / mutate-01
                                    :ARG1 (e4 / enzyme :name (n4 / name :op1 "Ras")))
                              :op2 m3))
                  :op2 (a2 / absent-01
                        :ARG1 o3))
            :ARG2 (s3 / sensitive-03
                  :ARG1 (i / inhibit-01
                        :ARG0 (s5 / small-molecule :name (n6 / name :op1 "AS703026"))
                        :ARG1 (e5 / enzyme :name (n5 / name :op1 "MEK")))))
      :location (c3 / cohort
            :mod (t / this)
            :consist-of (d / disease :name (n8 / name :op1 "multiple" :op2 "myeloma")
                  :ARG1-of (s4 / sample-01
                        :ARG2 (p2 / person
                              :ARG0-of (h3 / have-rel-role-91
                                    :ARG2 (p3 / patient)))))))

# ::id pmid_2352_4590.191 ::date 2015-07-30T14:28:14 ::annotator SDL-AMR-09 ::preferred
# ::snt Despite these encouraging findings, outcomes from solid tumour models suggest that combination regimes are required to maximise the effectiveness of MEK inhibitors in MM.
# ::save-date Thu Feb 4, 2016 ::file pmid_2352_4590_191.txt
(h / have-concession-91
      :ARG1 (s / suggest-01
            :ARG0 (o / outcome
                  :source (t3 / tumor
                        :mod (m / model
                              :ARG1-of (s2 / solid-02))))
            :ARG1 (r / require-01
                  :ARG0 (m2 / maximize-01
                        :ARG1 (e2 / effective-04
                              :ARG0 (m3 / molecular-physical-entity
                                    :ARG0-of (i / inhibit-01
                                          :ARG1 (p / protein-family :name (n / name :op1 "MEK"))))
                              :ARG1 (d / disease :name (n2 / name :op1 "multiple" :op2 "myeloma"))))
                  :ARG1 (r2 / regime
                        :ARG3-of (c / combine-01))))
      :ARG2 (f / find-01
            :ARG0-of (e / encourage-02)
            :mod (t / this)))

# ::id pmid_2352_4590.192 ::date 2015-07-30T14:36:31 ::annotator SDL-AMR-09 ::preferred
# ::snt AZD6244 and AS703026 have demonstrated improved potency when used in combination with other anti-MM agents.<sup><xref ref-type="bibr" rid="bib84">84</xref>, <xref ref-type="bibr" rid="bib85">85</xref>, <xref ref-type="bibr" rid="bib86">86</xref></sup>
# ::save-date Thu Feb 4, 2016 ::file pmid_2352_4590_192.txt
(d / demonstrate-01
      :ARG0 (a / and
            :op1 (s / small-molecule :name (n / name :op1 "AZD6244"))
            :op2 (s2 / small-molecule :name (n2 / name :op1 "AS703026")))
      :ARG1 (p3 / potency
            :ARG1-of (i / improve-01))
      :condition (u / use-01
            :ARG0 a
            :manner (c / combine-01
                  :ARG1 a
                  :ARG2 (a2 / agent
                        :ARG0-of (c2 / counter-01
                              :ARG1 (d2 / disease :name (n3 / name :op1 "multiple" :op2 "myeloma")))
                        :mod (o / other))))
      :ARG1-of (d3 / describe-01
            :ARG0 (p / publication
                  :ARG1-of (c3 / cite-01
                        :ARG2 (a3 / and :op1 84 :op2 85 :op3 86)))))

# ::id pmid_2352_4590.193 ::date 2015-07-30T14:40:00 ::annotator SDL-AMR-09 ::preferred
# ::snt The contribution of additional signalling pathways to MM tumorigenesis also offers the opportunity to target MEK in conjunction with the inhibition of these biochemical networks.
# ::save-date Mon Aug 10, 2015 ::file pmid_2352_4590_193.txt
(o / offer-01
      :ARG0 (c / contribute-01
            :ARG0 (p / pathway
                  :ARG0-of (s / signal-07)
                  :mod (a / additional))
            :ARG2 (c2 / create-01
                  :ARG1 (t / tumor
                        :mod (d / disease :name (n3 / name :op1 "multiple" :op2 "myeloma")))))
      :ARG1 (o2 / opportunity
            :purpose (t2 / target-01
                  :ARG1 (e / enzyme :name (n / name :op1 "MEK"))
                  :manner (a2 / accompany-01
                        :ARG1 (i / inhibit-01
                              :ARG0 (n2 / network
                                    :mod (b / biochemistry)
                                    :mod (t3 / this))))))
      :mod (a3 / also))

# ::id pmid_2352_4590.194 ::date 2015-07-30T14:46:09 ::annotator SDL-AMR-09 ::preferred
# ::snt Chatterjee <i>et al.</i><sup><xref ref-type="bibr" rid="bib30">30</xref></sup> have determined that the combined disruption of the Ras/MAPK and JAK/STAT pathway is required to induce MM apoptosis in the presence of bone marrow stromal cells.
# ::save-date Thu Feb 4, 2016 ::file pmid_2352_4590_194.txt
(d / determine-01
      :ARG0 (p4 / publication-91
            :ARG0 (a3 / and
                  :op1 (p5 / person :name (n4 / name :op1 "Chatterjee"))
                  :op2 (p6 / person
                        :mod (o / other)))
            :ARG1-of (d4 / describe-01
                  :ARG0 (p7 / publication
                        :ARG1-of (c2 / cite-01
                              :ARG2 30))))
      :ARG1 (r / require-01
            :ARG0 (i / induce-01
                  :ARG2 (a2 / apoptosis
                        :mod (d3 / disease :name (n3 / name :op1 "multiple" :op2 "myeloma"))))
            :ARG1 (d2 / disrupt-01
                  :ARG1 (a / and
                        :op1 (p / pathway :name (n / name :op1 "Ras/MAPK"))
                        :op2 (p2 / pathway :name (n2 / name :op1 "JAK/STAT")))
                  :ARG1-of (c3 / combine-01))
            :condition (p3 / present-02
                  :ARG1 (c / cell
                        :mod (s / stroma
                              :mod (m / marrow
                                    :mod (b / bone)))))))

# ::id pmid_2352_4590.195 ::date 2015-07-30T14:53:51 ::annotator SDL-AMR-09 ::preferred
# ::snt Similarly, the contribution PI3K/Akt and nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB) pathway deregulation exerts on MM and drug resistance also makes these pathways attractive targets for co-inhibition with MEK specific agents.<sup><xref ref-type="bibr" rid="bib5">5</xref>, <xref ref-type="bibr" rid="bib29">29</xref></sup>
# ::save-date Thu Feb 4, 2016 ::file pmid_2352_4590_195.txt
(m / make-02
      :ARG0 (e / exert-01
            :ARG0 (d / deregulate-01
                  :ARG1 (a3 / and
                        :op1 (p / pathway :name (n / name :op1 "PI3K/Akt"))
                        :op2 (p2 / pathway :name (n2 / name :op1 "NFκB"))))
            :ARG1 (c / contribute-01)
            :ARG2 (a / and
                  :op1 (d2 / disease :name (n3 / name :op1 "multiple" :op2 "myeloma"))
                  :op2 (r / resist-01
                        :ARG1 (d3 / drug))))
      :ARG1 (t / target-01
            :ARG0 (c2 / coinhibit-00
                  :instrument (a5 / agent
                        :ARG1-of (s / specific-02
                              :ARG2 (p3 / protein-family :name (n4 / name :op1 "MEK")))))
            :ARG1 a3
            :ARG0-of (a4 / attract-01))
      :ARG1-of (d4 / describe-01
            :ARG0 (p4 / publication
                  :ARG1-of (c3 / cite-01
                        :ARG2 (a6 / and :op1 5 :op2 29))))
      :mod (a7 / also)
      :ARG1-of (r2 / resemble-01))

# ::id pmid_2352_4590.196 ::date 2015-07-30T15:11:00 ::annotator SDL-AMR-09 ::preferred
# ::snt Several other small molecule inhibitors have also recently emerged as promising therapies in MM.
# ::save-date Thu Feb 4, 2016 ::file pmid_2352_4590_196.txt
(e / emerge-02
      :ARG0 (s3 / small-molecule
            :ARG0-of (i / inhibit-01)
            :mod (o / other)
            :quant (s2 / several))
      :ARG1 (t / therapy
            :ARG0-of (p / promise-01)
            :location (d / disease :name (n / name :op1 "multiple" :op2 "myeloma")))
      :mod (a / also)
      :time (r / recent))

# ::id pmid_2352_4590.197 ::date 2015-07-30T15:14:53 ::annotator SDL-AMR-09 ::preferred
# ::snt Histone deacetylases (HDAC) represent a family of enzymes that control transcription by modifying histones.
# ::save-date Thu Feb 4, 2016 ::file pmid_2352_4590_197.txt
(r / represent-01
      :ARG0 (e2 / enzyme :name (n / name :op1 "histone" :op2 "deacetylase"))
      :ARG1 (f / family
            :consist-of (e / enzyme)
            :ARG0-of (c / control-01
                  :ARG1 (t / transcribe-01)
                  :ARG2 (m / modify-01
                        :ARG0 f
                        :ARG1 (p / protein :name (n2 / name :op1 "histone"))))))

# ::id pmid_2352_4590.198 ::date 2015-07-30T15:18:51 ::annotator SDL-AMR-09 ::preferred
# ::snt Overexpression of HDAC in MM prevents the transcription of various tumour-suppressor genes, which in turn enhances cellular proliferation and represses cell death.<sup><xref ref-type="bibr" rid="bib87">87</xref></sup>
# ::save-date Thu Feb 4, 2016 ::file pmid_2352_4590_198.txt
(p / prevent-01
      :ARG0 (o / overexpress-01
            :ARG1 (e / enzyme :name (n / name :op1 "HDAC"))
            :location (d / disease :name (n2 / name :op1 "multiple" :op2 "myeloma")))
      :ARG1 (t / transcribe-01
            :ARG1 (g / gene
                  :ARG0-of (s / suppress-01
                        :ARG1 (t2 / tumor))
                  :mod (v / various)))
      :ARG1-of (d3 / describe-01
            :ARG0 (p3 / publication
                  :ARG1-of (c2 / cite-01
                        :ARG2 87)))
      :ARG0-of (e2 / enhance-01
            :ARG1 (p2 / proliferate-01
                  :ARG0 (c / cell)))
      :ARG0-of (r / repress-01
            :ARG1 (d2 / die-01
                  :ARG1 c))
      :manner (i2 / in-turn))

# ::id pmid_2352_4590.199 ::date 2015-07-30T15:26:17 ::annotator SDL-AMR-09 ::preferred
# ::snt Inhibition of HDAC activity reverses these outcomes, culminating in the accumulation of acetylated histones that promote the apoptosis of malignant cells.<sup><xref ref-type="bibr" rid="bib88">88</xref></sup>
# ::save-date Thu Feb 4, 2016 ::file pmid_2352_4590_199.txt
(r / reverse-01
      :ARG0 (i / inhibit-01
            :ARG1 (a / activity-06
                  :ARG0 (e / enzyme :name (n / name :op1 "HDAC"))))
      :ARG1 (o / outcome
            :mod (t / this))
      :ARG2 (c / culminate-01
            :ARG2 (a2 / accumulate-01
                  :ARG1 (p3 / protein :name (n3 / name :op1 "histone")
                        :ARG3-of (a3 / acetylate-01)
                        :ARG0-of (p / promote-01
                              :ARG1 (a4 / apoptosis
                                    :poss (c2 / cell
                                          :ARG1-of (m / malignant-02)))))))
      :ARG1-of (d / describe-01
            :ARG0 (p2 / publication
                  :ARG1-of (c3 / cite-01
                        :ARG2 88))))

# ::id pmid_2352_4590.200 ::date 2015-07-30T15:35:05 ::annotator SDL-AMR-09 ::preferred
# ::snt Clinical evaluation of the HDAC inhibitors as single agents in relapsed/refractory MM patients has yielded modest response rates.<sup><xref ref-type="bibr" rid="bib89">89</xref>, <xref ref-type="bibr" rid="bib90">90</xref></sup>
# ::save-date Thu Feb 4, 2016 ::file pmid_2352_4590_200.txt
(y / yield-01
      :ARG0 (e / evaluate-01
            :ARG1 (m / molecular-physical-entity
                  :ARG0-of (i / inhibit-01
                        :ARG1 (e2 / enzyme :name (n / name :op1 "HDAC")))
                  :manner (a / agent
                        :ARG2-of (s / single-02)))
            :mod (c / clinical)
            :location (o / or
                  :op1 (p / person
                        :ARG0-of (h / have-rel-role-91
                              :ARG2 (p4 / patient))
                        :ARG0-of (h3 / have-03
                              :ARG1 (d / disease :name (n4 / name :op1 "multiple" :op2 "myeloma")
                                    :ARG1-of (r / relapse-01))))
                  :op2 (p2 / person
                        :ARG0-of (h2 / have-rel-role-91
                              :ARG2 (p5 / patient))
                        :ARG0-of (h4 / have-03
                              :ARG1 (d2 / disease :name (n2 / name :op1 "multiple" :op2 "myeloma")
                                    :mod (r2 / refract))))))
      :ARG1 (r3 / rate
            :mod (r4 / respond-01)
            :quant (m2 / modest))
      :ARG1-of (d3 / describe-01
            :ARG0 (p3 / publication
                  :ARG1-of (c2 / cite-01
                        :ARG2 (a2 / and :op1 89 :op2 90)))))

# ::id pmid_2352_4590.201 ::date 2015-07-30T22:59:21 ::annotator SDL-AMR-09 ::preferred
# ::snt Nevertheless, several studies have reported a significant increase in the anti-MM effect of these agents, when used in conjunction with conventional anti-MM chemotherapeutics,<sup><xref ref-type="bibr" rid="bib91">91</xref></sup> lenalidomide and bortezomib.<sup><xref ref-type="bibr" rid="bib92">92</xref></sup>
# ::save-date Sun Dec 20, 2015 ::file pmid_2352_4590_201.txt
(h / have-concession-91
      :ARG1 (r / report-01
            :ARG0 (s / study-01
                  :quant (s2 / several))
            :ARG1 (i / increase-01
                  :ARG1 (a / affect-01
                        :ARG0 (a2 / agent
                              :mod (t / this))
                        :ARG2 (c / counter-01
                              :ARG1 (d / disease :name (n / name :op1 "multiple" :op2 "myeloma"))))
                  :ARG2 (s3 / significant-02)
                  :condition (u / use-01
                        :ARG1 a2
                        :manner (a3 / accompany-01
                              :ARG0 (c2 / chemotherapy
                                    :ARG0-of c
                                    :mod (c3 / conventional)
                                    :ARG2-of (i2 / include-91
                                          :ARG1 (a4 / and
                                                :op1 (s4 / small-molecule :name (n2 / name :op1 "lenalidomide"))
                                                :op2 (s5 / small-molecule :name (n3 / name :op1 "bortezomib"))
                                                :ARG1-of (d3 / describe-01
                                                      :ARG0 (p2 / publication
                                                            :ARG1-of (c5 / cite-01
                                                                  :ARG2 92))))))
                              :ARG1-of (d2 / describe-01
                                    :ARG0 (p / publication
                                          :ARG1-of (c4 / cite-01
                                                :ARG2 91))))))))

# ::id pmid_2352_4590.202 ::date 2015-07-30T23:07:42 ::annotator SDL-AMR-09 ::preferred
# ::snt Combinations of MEK and HDAC inhibitors have been limited to preclinical studies involving chronic myelogenous leukaemia and non-small cell lung carcinoma cell lines, but preliminary results have been promising.<sup><xref ref-type="bibr" rid="bib93">93</xref>, <xref ref-type="bibr" rid="bib94">94</xref></sup>
# ::save-date Mon Aug 10, 2015 ::file pmid_2352_4590_202.txt
(c / contrast-01
      :ARG1 (l / limit-01
            :ARG1 (c2 / combine-01
                  :ARG1 (m / molecular-physical-entity
                        :ARG0-of (i / inhibit-01
                              :ARG1 (e / enzyme :name (n / name :op1 "MEK"))))
                  :ARG2 (m2 / molecular-physical-entity
                        :ARG0-of (i2 / inhibit-01
                              :ARG1 (e2 / enzyme :name (n2 / name :op1 "HDAC")))))
            :ARG2 (s / study-01
                  :mod (p / preclinical)
                  :ARG0-of (i3 / involve-01
                        :ARG1 (a / and
                              :op1 (d / disease :name (n3 / name :op1 "myelogenous" :op2 "leukaemia")
                                    :mod (c3 / chronic))
                              :op2 (c4 / cell-line
                                    :source (c5 / carcinoma
                                          :mod (l2 / lung)
                                          :mod (c6 / cell
                                                :mod (s2 / small :polarity -))))))))
      :ARG2 (p2 / promise-01
            :ARG0 (t / thing
                  :ARG2-of (r / result-01)
                  :mod (p3 / preliminary))
            :ARG1-of (d2 / describe-01
                  :ARG0 (p4 / publication
                        :ARG1-of (c7 / cite-01
                              :ARG2 (a2 / and :op1 93 :op2 94))))))

# ::id pmid_2352_4590.203 ::date 2015-07-30T23:18:20 ::annotator SDL-AMR-09 ::preferred
# ::snt Heat shock protein 90 (HSP90) is a molecular chaperone that regulates many of the proteins involved in Ras/MAPK, PI3K/Akt, JAK/STAT and NFκB signalling, as well other biochemical pathways that control apoptosis and cell cycle progression.<sup><xref ref-type="bibr" rid="bib95">95</xref></sup>
# ::save-date Mon Dec 21, 2015 ::file pmid_2352_4590_203.txt
(c6 / chaperone
      :ARG1-of (d / describe-01
            :ARG0 (p10 / publication
                  :ARG1-of (c5 / cite-01
                        :ARG2 95)))
      :mod (m / molecule)
      :ARG0-of (r / regulate-01
            :ARG1 (p2 / protein
                  :quant (m2 / many)
                  :ARG1-of (i / include-91
                        :ARG2 (p3 / protein
                              :ARG1-of (i2 / involve-01
                                    :ARG2 (a / and
                                          :op1 (a2 / and
                                                :op1 (s / signal-07
                                                      :ARG0 (p4 / pathway :name (n2 / name :op1 "Ras/MAPK")))
                                                :op2 (s2 / signal-07
                                                      :ARG0 (p5 / pathway :name (n3 / name :op1 "PI3K/Akt")))
                                                :op3 (s3 / signal-07
                                                      :ARG0 (p6 / pathway :name (n4 / name :op1 "JAK/STAT")))
                                                :op4 (s4 / signal-07
                                                      :ARG0 (p7 / pathway :name (n5 / name :op1 "NFκB"))))
                                          :op2 (p8 / pathway
                                                :ARG0-of (c2 / control-01
                                                      :ARG1 (a3 / and
                                                            :op1 (a4 / apoptosis)
                                                            :op2 (p9 / progress-01
                                                                  :ARG1 (c / cycle-02
                                                                        :ARG1 (c4 / cell)))))
                                                :mod (b / biochemistry)
                                                :mod (o / other))))))))
      :domain (p / protein :mod 90 :name (n / name :op1 "Heat" :op2 "shock" :op3 "protein")))

# ::id pmid_2352_4590.204 ::date 2015-07-30T23:27:56 ::annotator SDL-AMR-09 ::preferred
# ::snt Consistent with these properties, inhibition of HSP90 has been shown to disrupt multiple pathways crucial to MM survival.<sup><xref ref-type="bibr" rid="bib96">96</xref>, <xref ref-type="bibr" rid="bib97">97</xref></sup>
# ::save-date Mon Aug 10, 2015 ::file pmid_2352_4590_204.txt
(s / show-01
      :ARG1 (d4 / disrupt-01
            :ARG0 (i / inhibit-01
                  :ARG1 (p / protein :name (n / name :op1 "HSP90")))
            :ARG1 (p2 / pathway
                  :quant (m / multiple)
                  :mod (c / crucial
                        :purpose (s2 / survive-01
                              :ARG0 (d2 / disease :name (n2 / name :op1 "multiple" :op2 "myeloma"))))))
      :ARG1-of (c2 / consistent-01
            :ARG2 (p3 / property
                  :mod (t / this)))
      :ARG1-of (d3 / describe-01
            :ARG0 (p4 / publication
                  :ARG1-of (c3 / cite-01
                        :ARG2 (a / and :op1 96 :op2 97)))))

# ::id pmid_2352_4590.205 ::date 2015-07-30T23:33:59 ::annotator SDL-AMR-09 ::preferred
# ::snt While co-treatment of MM cells with a MEK and HSP90 inhibitors might serve as a means of attenuating the feedback mechanisms that promote resistance to MEK inhibitors, the clinical efficacy of these approaches is dependent upon how selective and active these combination regimes are <i>in vivo</i>.
# ::save-date Thu Feb 4, 2016 ::file pmid_2352_4590_205.txt
(c5 / contrast-01
      :ARG1 (d2 / depend-01
            :ARG0 (e2 / efficient-01
                  :ARG1 (a3 / approach-02
                        :mod (t / this))
                  :mod (c4 / clinic))
            :ARG1 (a4 / and
                  :op1 (t2 / thing
                        :degree-of (s2 / selective))
                  :op2 (t3 / thing
                        :degree-of (a5 / activity-06))
                  :domain (r2 / regime
                        :ARG3-of (c3 / combine-01))
                  :manner (i3 / in-vivo)))
      :ARG2 (p / possible-01
            :ARG1 (s / serve-01
                  :ARG0 (t4 / treat-04
                        :ARG1 (c2 / cell
                              :mod (d / disease :name (n / name :op1 "multiple" :op2 "myeloma")))
                        :ARG2 (m / molecular-physical-entity
                              :ARG0-of (i / inhibit-01
                                    :ARG1 (a / and
                                          :op1 (e / enzyme :name (n2 / name :op1 "MEK"))
                                          :op2 (p2 / protein :name (n3 / name :op1 "HSP90"))))))
                  :ARG1 (m2 / mean
                        :ARG0-of (a2 / attenuate-01
                              :ARG1 (m3 / mechanism
                                    :mod (f / feedback)
                                    :ARG0-of (p3 / promote-01
                                          :ARG1 (r / resist-01
                                                :ARG1 (m4 / molecular-physical-entity
                                                      :ARG0-of (i2 / inhibit-01
                                                            :ARG1 e))))))))))

# ::id pmid_2352_4590.206 ::date 2015-07-30T02:15:05 ::annotator SDL-AMR-09 ::preferred
# ::snt In particular, the potential interrupting multiple kinase networks has for increasing the likelihood of adverse effects and drug toxicity is likely to be an important factor in determining the optimal use of these agents.
# ::save-date Wed Aug 5, 2015 ::file pmid_2352_4590_206.txt
(l / likely-01
      :ARG1 (f / factor
            :domain (i / interrupt-01
                  :ARG1 (n / network-01
                        :ARG1 (k / kinase)
                        :quant (m / multiple))
                  :ARG0-of (h / have-03
                        :ARG1 (p / potential)
                        :purpose (i2 / increase-01
                              :ARG1 (l2 / likely-01
                                    :ARG1 (a / and
                                          :op1 (a2 / affect-01
                                                :mod (a3 / adverse))
                                          :op2 (t / toxicity
                                                :mod (d / drug)))))))
            :purpose (d2 / determine-01
                  :ARG1 (u / use-01
                        :ARG1 (a4 / agent
                              :mod (t2 / this))
                        :mod (o / optimal)))
            :mod (i3 / important))
      :mod (p2 / particular))

# ::id pmid_2352_4590.207 ::date 2015-07-30T15:34:46 ::annotator SDL-AMR-09 ::preferred
# ::snt <sec-title level="2">Predicting patient responses to MEK inhibitors: identification of relevant biomarkers</sec-title>
# ::save-date Sat Jan 16, 2016 ::file pmid_2352_4590_207.txt
(p / predict-01
      :ARG1 (t / thing
            :ARG2-of (r / respond-01
                  :ARG0 (p2 / person
                        :ARG0-of (h / have-rel-role-91
                              :ARG2 (p3 / patient)))
                  :ARG1 (m / molecular-physical-entity
                        :ARG0-of (i / inhibit-01
                              :ARG1 (p4 / protein-family :name (n / name :op1 "MEK"))))))
      :ARG1-of (m2 / mean-01
            :ARG2 (i2 / identify-01
                  :ARG1 (b / biomarker
                        :ARG1-of (r2 / relevant-01)))))

# ::id pmid_2352_4590.208 ::date 2015-07-30T15:43:20 ::annotator SDL-AMR-09 ::preferred
# ::snt As all MEK inhibitors tested to date demonstrate potent and selective activity against MEK1/2, toxicity profiles and drug exposure are likely to be the key criteria that refine these drugs for therapeutic use.
# ::save-date Sat Jan 16, 2016 ::file pmid_2352_4590_208.txt
(l / likely-01
      :ARG1 (r / refine-01
            :ARG0 (a / and
                  :op1 (p / profile-01
                        :ARG1 (t / toxicity))
                  :op2 (e / expose-01
                        :ARG2 (d / drug))
                  :mod (c / criteria
                        :ARG1-of (k / key-02)))
            :ARG1 (d2 / drug
                  :mod (t2 / this))
            :purpose (u / use-01
                  :mod (t3 / therapy)))
      :ARG1-of (c2 / cause-01
            :ARG0 (d3 / demonstrate-01
                  :ARG0 (m / molecular-physical-entity
                        :ARG0-of (i / inhibit-01
                              :ARG1 (p3 / protein-family :name (n / name :op1 "MEK")))
                        :ARG1-of (t4 / test-01
                              :time (t5 / to-date))
                        :mod (a2 / all))
                  :ARG1 (a3 / activity-06
                        :ARG0 m
                        :ARG0-of (c3 / counter-01
                              :ARG1 (e3 / enzyme :name (n2 / name :op1 "MEK1/2")))
                        :mod (p2 / potent)
                        :mod (s / selective)))))

# ::id pmid_2352_4590.209 ::date 2015-07-30T16:03:34 ::annotator SDL-AMR-09 ::preferred
# ::snt Furthermore, it has become clear that certain genetic sub-types in solid tumours are associated with increased susceptibility or resistance to MEK inhibitors.
# ::save-date Wed Mar 2, 2016 ::file pmid_2352_4590_209.txt
(a / and
      :op2 (b / become-01
            :ARG2 (c / clear-06
                  :ARG1 (a2 / associate-01
                        :ARG1 (s / subtype
                              :mod (g / genetics)
                              :mod (c2 / certain)
                              :location (t / tumor
                                    :ARG1-of (s2 / solid-02)))
                        :ARG2 (o / or
                              :op1 (s3 / susceptible
                                    :ARG1-of (i / increase-01)
                                    :domain s
                                    :topic (m / molecular-physical-entity
                                          :ARG0-of (i2 / inhibit-01
                                                :ARG1 (p / protein-family :name (n / name :op1 "MEK")))))
                              :op2 (r / resist-01
                                    :ARG0 s
                                    :ARG1 m))))))

# ::id pmid_2352_4590.210 ::date 2015-07-30T16:26:02 ::annotator SDL-AMR-09 ::preferred
# ::snt This observation highlights the need for a reliable marker of responsiveness to MEK inhibitors, allowing tailoring of individualised therapies and reducing the occurrence of adverse events.
# ::save-date Thu Jan 28, 2016 ::file pmid_2352_4590_210.txt
(h / highlight-01
      :ARG0 (o / observe-01
            :mod (t / this))
      :ARG1 (n / need-01
            :ARG1 (m3 / molecular-physical-entity
                  :ARG0-of (m / mark-01
                        :ARG1 (r / responsive-02
                              :ARG1 (m2 / molecular-physical-entity
                                    :ARG0-of (i / inhibit-01
                                          :ARG1 (p2 / protein-family :name (n2 / name :op1 "MEK"))))))
                  :ARG1-of (r2 / rely-01
                        :ARG1-of (p / possible-01))))
      :ARG0-of (a / allow-01
            :ARG1 (a2 / and
                  :op1 (t2 / tailor-01
                        :ARG1 (t3 / therapy
                              :ARG1-of (i2 / individualize-02)))
                  :op2 (r3 / reduce-01
                        :ARG1 (e2 / event
                              :mod (a3 / adverse))))))

# ::id pmid_2352_4590.211 ::date 2015-07-30T16:41:04 ::annotator SDL-AMR-09 ::preferred
# ::snt Currently it remains difficult to determine which patients will benefit most from MEK inhibitor treatment.
# ::save-date Sat Jan 16, 2016 ::file pmid_2352_4590_211.txt
(r / remain-01
      :ARG1 (d / difficult
            :domain (d2 / determine-01
                  :ARG1 (b / benefit-01
                        :ARG0 (t / treat-04
                              :ARG2 (m / molecular-physical-entity
                                    :ARG0-of (i / inhibit-01
                                          :ARG1 (p3 / protein-family :name (n / name :op1 "MEK")))))
                        :ARG1 (p / person
                              :ARG0-of (h / have-rel-role-91
                                    :ARG2 (p2 / patient))
                              :mod (a / amr-unknown))
                        :degree (m2 / most))))
      :time (c / current))

# ::id pmid_2352_4590.212 ::date 2015-07-30T16:53:00 ::annotator SDL-AMR-09 ::preferred
# ::snt Whilst activating B-Raf mutations are associated with exquisite sensitivity against these agents, other biochemical markers demonstrate less predictability.
# ::save-date Wed Aug 5, 2015 ::file pmid_2352_4590_212.txt
(c / contrast-01
      :ARG1 (a / associate-01
            :ARG1 (m / mutate-01
                  :ARG2 (e / enzyme :name (n / name :op1 "B-Raf"))
                  :ARG0-of (a2 / activate-01))
            :ARG2 (s / sensitive-03
                  :ARG0 m
                  :ARG1 (a3 / agent
                        :mod (t / this))
                  :degree (e2 / exquisite)))
      :ARG2 (d / demonstrate-01
            :ARG0 (m2 / marker
                  :mod (b / biochemistry)
                  :mod (o / other))
            :ARG1 (p / possible-01
                  :ARG1 (p2 / predict-01)
                  :quant (l / less))))

# ::id pmid_2352_4590.213 ::date 2015-07-30T17:07:23 ::annotator SDL-AMR-09 ::preferred
# ::snt For example, the poor correlation between MEK inhibitor susceptibility Ras genotypes and p-ERK expression is well documented.<sup><xref ref-type="bibr" rid="bib12">12</xref>, <xref ref-type="bibr" rid="bib41">41</xref>, <xref ref-type="bibr" rid="bib46">46</xref>, <xref ref-type="bibr" rid="bib47">47</xref>, <xref ref-type="bibr" rid="bib48">48</xref>, <xref ref-type="bibr" rid="bib60">60</xref></sup>
# ::save-date Sat Jan 16, 2016 ::file pmid_2352_4590_213.txt
(e / exemplify-01
      :ARG0 (d / document-01
            :ARG1 (c / correlate-01
                  :ARG1 (s / susceptible
                        :domain (g / genotype
                              :mod (e2 / enzyme :name (n / name :op1 "Ras")))
                        :mod (m / molecular-physical-entity
                              :ARG0-of (i / inhibit-01
                                    :ARG1 (p4 / protein-family :name (n2 / name :op1 "MEK")))))
                  :ARG2 (e4 / express-03
                        :ARG2 (e5 / enzyme :name (n3 / name :op1 "ERK")
                              :ARG3-of (p / phosphorylate-01)))
                  :degree (p2 / poor))
            :ARG1-of (w / well-09))
      :ARG1-of (d2 / describe-01
            :ARG0 (p3 / publication
                  :ARG1-of (c2 / cite-01
                        :ARG2 (a / and :op1 12 :op2 41 :op3 46 :op4 47 :op5 48 :op6 60)))))

# ::id pmid_2352_4590.214 ::date 2015-07-30T17:23:53 ::annotator SDL-AMR-09 ::preferred
# ::snt In one study, analysis of transcriptional pathway signatures in various solid tumours, identified a panel of 18 genes, the expression of which correlated with responsiveness to AZD6244.<sup><xref ref-type="bibr" rid="bib98">98</xref></sup>
# ::save-date Fri Jan 1, 2016 ::file pmid_2352_4590_214.txt
(i / identify-01
      :ARG0 (a / analyze-01
            :ARG1 (s / signature
                  :mod (p / pathway
                        :ARG1-of (t / transcribe-01)))
            :location (t2 / tumor
                  :ARG1-of (s2 / solid-02)
                  :mod (v / various)))
      :ARG1 (p2 / panel
            :consist-of (g / gene :quant 18
                  :ARG1-of (e / express-03
                        :ARG1-of (c / correlate-01
                              :ARG2 (r / responsive-02
                                    :ARG1 (s3 / small-molecule :name (n / name :op1 "AZD6244")))))))
      :medium (s4 / study :quant 1)
      :ARG1-of (d / describe-01
            :ARG0 (p3 / publication
                  :ARG1-of (c2 / cite-01
                        :ARG2 98))))

# ::id pmid_2352_4590.215 ::date 2015-07-30T17:35:07 ::annotator SDL-AMR-09 ::preferred
# ::snt This signature contained transcriptional targets of ERK involved in negative-feedback regulation (DUSP4/6 and SPRY2), members of the Ets family of transcription factors (ETV4, ETV5 and ELF1) and other genes associated with MAPK signalling, cell cycle progression and tumour prognosis.
# ::save-date Fri Feb 5, 2016 ::file pmid_2352_4590_215.txt
(c / contain-01
      :ARG0 (s / signature
            :mod (t / this))
      :ARG1 (a / and
            :op1 (a2 / and
                  :op1 (p8 / protein :name (n / name :op1 "DUSP4/6"))
                  :op2 (p9 / protein :name (n2 / name :op1 "SPRY2"))
                  :ARG1-of (t2 / target-01
                        :ARG0 (e / enzyme :name (n3 / name :op1 "ERK"))
                        :ARG1-of (t3 / transcribe-01)
                        :ARG1-of (i / involve-01
                              :ARG2 (r / regulate-01
                                    :ARG1 (f / feedback
                                          :ARG0-of (n4 / negative-03))))))
            :op2 (m / member
                  :ARG1-of (i2 / include-91
                        :ARG2 (p / protein-family :name (n5 / name :op1 "Ets")))
                  :ARG1-of (m2 / mean-01
                        :ARG2 (a3 / and
                              :op1 (p5 / protein :name (n6 / name :op1 "ETV4"))
                              :op2 (p6 / protein :name (n7 / name :op1 "ETV5"))
                              :op3 (p7 / protein :name (n8 / name :op1 "ELF1")))))
            :op3 (g6 / gene
                  :ARG1-of (a4 / associate-01
                        :ARG2 (a5 / and
                              :op1 (s2 / signal-07
                                    :ARG0 (p2 / pathway :name (n9 / name :op1 "MAPK")))
                              :op2 (p3 / progress-01
                                    :ARG1 (c2 / cycle-02
                                          :ARG1 (c3 / cell)))
                              :op3 (p4 / prognosis
                                    :mod (t4 / tumor))))
                  :mod (o / other))))

# ::id pmid_2352_4590.216 ::date 2015-07-30T17:55:56 ::annotator SDL-AMR-09 ::preferred
# ::snt A 13-gene signature was also identified that was predictive of resistance to AZD6244.
# ::save-date Thu Jul 30, 2015 ::file pmid_2352_4590_216.txt
(i / identify-01
      :ARG1 (s / signature
            :mod (g / gene :quant 13))
      :mod (a / also)
      :ARG0-of (p / predict-01
            :ARG1 (r / resist-01
                  :ARG1 (s2 / small-molecule :name (n / name :op1 "AZD6244")))))

# ::id pmid_2352_4590.217 ::date 2015-07-30T18:02:47 ::annotator SDL-AMR-09 ::preferred
# ::snt This diverse set of genes shared common links with transforming growth factor-β (TGF-β), tumour necrosis factor-α and NFκB signalling.
# ::save-date Wed Aug 5, 2015 ::file pmid_2352_4590_217.txt
(s / share-01
      :ARG0 (s2 / set
            :consist-of (g / gene)
            :mod (d / diverse)
            :mod (t / this))
      :ARG1 (l / link-01
            :mod (c / common))
      :ARG2 (s3 / signal-07
            :ARG0 (a / and
                  :op1 (p / protein :name (n / name :op1 "transforming" :op2 "growth" :op3 "factor-β"))
                  :op2 (p2 / protein :name (n2 / name :op1 "tumour" :op2 "necrosis" :op3 "factor-α"))
                  :op3 (p3 / protein :name (n3 / name :op1 "NFκB")))))

# ::id pmid_2352_4590.218 ::date 2015-07-30T18:11:08 ::annotator SDL-AMR-09 ::preferred
# ::snt The role of these genes in MM and their potential predictive value for MEK inhibitor responsiveness has not been appraised.
# ::save-date Sat Jan 16, 2016 ::file pmid_2352_4590_218.txt
(a / appraise-02 :polarity -
      :ARG1 (a2 / and
            :op1 (r / role
                  :poss (g / gene
                        :mod (t / this))
                  :topic (d / disease :name (n / name :op1 "multiple" :op2 "myeloma")))
            :op2 (v / value
                  :mod (p / predict-01
                        :ARG0 g
                        :ARG1 (r2 / responsive-02
                              :ARG1 (m / molecular-physical-entity
                                    :ARG0-of (i / inhibit-01
                                          :ARG1 (p3 / protein-family :name (n2 / name :op1 "MEK"))))))
                  :mod (p2 / potential)
                  :poss g)))

# ::id pmid_2352_4590.219 ::date 2015-07-30T18:24:48 ::annotator SDL-AMR-09 ::preferred
# ::snt Recent data published by Annuziata <i>et al.</i><sup><xref ref-type="bibr" rid="bib99">99</xref></sup> has reported the use of the musculoaponeurotic fibrosarcoma (MAF) oncogene as a potential biomarker for MEK inhibitor responses in MM.
# ::save-date Sat Jan 16, 2016 ::file pmid_2352_4590_219.txt
(r / report-01
      :ARG0 (d / data
            :time (r2 / recent)
            :ARG1-of (p / publish-01
                  :ARG0 (p2 / publication-91
                        :ARG0 (a / and
                              :op1 (p3 / person :name (n / name :op1 "Annuziata"))
                              :op2 (p4 / person
                                    :mod (o / other)))
                        :ARG1-of (c / cite-01
                              :ARG2 99))))
      :ARG1 (u / use-01
            :ARG0 (g / gene :name (n5 / name :op1 "musculoaponeurotic" :op2 "fibrosarcoma")
                  :ARG0-of (c2 / cause-01
                        :ARG1 (d3 / disease :wiki "Cancer" :name (n6 / name :op1 "cancer"))))
            :ARG2 (b / biomarker
                  :mod (p5 / potential)
                  :purpose (t / thing
                        :ARG2-of (r3 / respond-01
                              :ARG0 (m / molecular-physical-entity
                                    :ARG0-of (i / inhibit-01
                                          :ARG1 (p6 / protein-family :name (n3 / name :op1 "MEK"))))
                              :location (d2 / disease :name (n4 / name :op1 "multiple" :op2 "myeloma")))))))

# ::id pmid_2352_4590.220 ::date 2015-07-30T18:36:58 ::annotator SDL-AMR-09 ::preferred
# ::snt In approximately 10% of cases, aberrant MAF expression is due to a (14;16) translocation.
# ::save-date Sat Jan 30, 2016 ::file pmid_2352_4590_220.txt
(c / cause-01
      :ARG0 (t / translocate-01
            :ARG1 (a / and
                  :op1 (c2 / chromosome :mod 14)
                  :op2 (c3 / chromosome :mod 16)))
      :ARG1 (e / express-03
            :ARG2 (p / protein :name (n3 / name :op1 "MAF"))
            :mod (a2 / aberrant))
      :ARG1-of (i / include-91
            :ARG2 (c4 / case-04)
            :ARG3 (p2 / percentage-entity :value 10
                  :ARG1-of (a3 / approximate-01))))

# ::id pmid_2352_4590.221 ::date 2015-07-30T18:52:39 ::annotator SDL-AMR-09 ::preferred
# ::snt High levels of MAF were also observed in patient samples with t(4;14) translocations.
# ::save-date Thu Dec 10, 2015 ::file pmid_2352_4590_221.txt
(o / observe-01
      :ARG1 (l / level
            :quant-of (p / protein :name (n / name :op1 "MAF"))
            :ARG1-of (h / high-02))
      :location (s / sample-01
            :ARG2 (p2 / person
                  :ARG0-of (h2 / have-rel-role-91
                        :ARG2 (p3 / patient)))
            :location-of (t / translocate-01
                  :ARG1 (a / and
                        :op1 (c / chromosome :mod 4)
                        :op2 (c2 / chromosome :mod 14))))
      :mod (a2 / also))

# ::id pmid_2352_4590.222 ::date 2015-07-30T18:59:00 ::annotator SDL-AMR-09 ::preferred
# ::snt Both t(4:16) and t(4;14) translocations correlate with disease progression and worse overall survival.
# ::save-date Fri Dec 18, 2015 ::file pmid_2352_4590_222.txt
(c / correlate-01
      :ARG1 (a / and
            :op1 (t / translocate-01
                  :ARG1 (a2 / and
                        :op1 (c2 / chromosome :mod 4)
                        :op2 (c3 / chromosome :mod 16)))
            :op2 (t2 / translocate-01
                  :ARG1 (a3 / and
                        :op1 c2
                        :op2 (c4 / chromosome :mod 14))))
      :ARG2 (a4 / and
            :op1 (p / progress-01
                  :ARG1 (d / disease))
            :op2 (s / survive-01
                  :mod (o / overall)
                  :ARG1-of (b / bad-07
                        :degree (m / more)))))

# ::id pmid_2352_4590.223 ::date 2015-07-30T19:06:23 ::annotator SDL-AMR-09 ::preferred
# ::snt The MEK/ERK pathway was found to regulate transcription of the MAF proto-oncogene through ERK activation of FOS, a finding consistent with MAF protein and mRNA levels being downregulated following MEK inhibition.
# ::save-date Sat Jan 16, 2016 ::file pmid_2352_4590_223.txt
(f / find-01
      :ARG1 (r / regulate-01
            :ARG0 (p / pathway :name (n / name :op1 "MEK/ERK"))
            :ARG1 (t / transcribe-01
                  :ARG1 (p2 / proto-oncogene
                        :mod p3))
            :manner (a / activate-01
                  :ARG0 (e / enzyme :name (n3 / name :op1 "ERK"))
                  :ARG1 (e3 / enzyme :name (n4 / name :op1 "FOS"))))
      :ARG1-of (c / consistent-01
            :ARG2 (d / downregulate-01
                  :ARG1 (a2 / and
                        :op1 (l / level
                              :quant-of (p3 / protein :name (n5 / name :op1 "MAF")))
                        :op2 (l2 / level
                              :quant-of (n8 / nucleic-acid :name (n6 / name :op1 "mRNA"))))
                  :ARG1-of (f2 / follow-01
                        :ARG2 (i / inhibit-01
                              :ARG1 (e2 / enzyme :name (n7 / name :op1 "MEK")))))))

# ::id pmid_2352_4590.224 ::date 2015-07-30T19:18:35 ::annotator SDL-AMR-09 ::preferred
# ::snt To examine the dependence of MM cells on MEK/ERK signalling, U0126 was administered to 16 HMCL that represented the heterogeneous onco-genetics of the disease.
# ::save-date Wed Mar 2, 2016 ::file pmid_2352_4590_224.txt
(a / administer-01
      :ARG1 (s / small-molecule :name (n / name :op1 "U0126"))
      :ARG2 (c / cell-line :quant 16 :name (n2 / name :op1 "HMCL")
            :ARG0-of (r / represent-01
                  :ARG1 (o / oncogenetics
                        :mod (h / heterogeneity)
                        :poss (d / disease))))
      :purpose (e / examine-01
            :ARG1 (d2 / depend-01
                  :ARG0 (c2 / cell
                        :mod (d4 / disease :name (n3 / name :op1 "multiple" :op2 "myeloma")))
                  :ARG1 (s2 / signal-07
                        :ARG0 (p / pathway :name (n5 / name :op1 "MEK/ERK"))))))

# ::id pmid_2352_4590.225 ::date 2015-07-30T19:26:45 ::annotator SDL-AMR-09 ::preferred
# ::snt Of the 10 HMCL killed by this MEK inhibitor in a dose-dependent manner, 9 cell lines exhibited a t(4;16) or t(4;14) translocation and over expressed MAF.
# ::save-date Sun Jan 17, 2016 ::file pmid_2352_4590_225.txt
(a / and
      :op1 (e / exhibit-01
            :ARG0 (c / cell-line :quant 9)
            :ARG1 (o / or
                  :op1 (t / translocate-01
                        :value (a2 / and :op1 4 :op2 16))
                  :op2 (t2 / translocate-01
                        :value (a3 / and :op1 4 :op2 14))))
      :op2 (o2 / overexpress-01
            :ARG1 (p2 / protein :name (n / name :op1 "MAF"))
            :location c)
      :ARG1-of (i / include-91
            :ARG2 (c2 / cell-line :quant 10
                  :ARG1-of (k / kill-01
                        :ARG0 (m / molecular-physical-entity
                              :ARG0-of (i2 / inhibit-01
                                    :ARG1 (p / protein-family :name (n3 / name :op1 "MEK")))
                              :mod (t3 / this))
                        :ARG0-of (d / depend-01
                              :ARG1 (d2 / dose-01)))
                  :mod (d3 / disease :name (n2 / name :op1 "myeloma")
                        :mod (h / human)))))

# ::id pmid_2352_4590.226 ::date 2015-07-30T19:40:31 ::annotator SDL-AMR-09 ::preferred
# ::snt Moreover, the cytotoxic effect of U0126 was not neutralised by the presence of bone marrow stromal cells and remarkably, the impact of MEK inhibition on MM viability could be rescued by exogenous MAF expression.
# ::save-date Fri Jan 1, 2016 ::file pmid_2352_4590_226.txt
(a / and
      :op2 (a2 / and
            :op1 (n / neutralize-01 :polarity -
                  :ARG0 (p / present-02
                        :ARG1 (c / cell
                              :mod (s / stromal)
                              :part-of (m / marrow
                                    :mod (b / bone))))
                  :ARG1 (a3 / affect-01
                        :ARG0 (s2 / small-molecule :name (n2 / name :op1 "U0126"))
                        :ARG2 (c2 / cytotoxicity)))
            :op2 (p2 / possible-01
                  :ARG1 (r / rescue-01
                        :ARG0 (e / express-03
                              :ARG2 (p3 / protein :name (n3 / name :op1 "MAF"))
                              :mod (e2 / exogenous))
                        :ARG1 (i / impact-01
                              :ARG0 (i2 / inhibit-01
                                    :ARG1 (e3 / enzyme :name (n4 / name :op1 "MEK")))
                              :ARG1 (v / viability
                                    :mod (d2 / disease :name (n6 / name :op1 "multiple" :op2 "myeloma")))))
                  :ARG1-of (r2 / remarkable-02))))

# ::id pmid_2352_4590.227 ::date 2015-07-30T19:50:59 ::annotator SDL-AMR-09 ::preferred
# ::snt Importantly, this study provides a mechanistic rationale for using MEK inhibitor therapy in MM patients that overexpress c-MAF.
# ::save-date Sat Jan 16, 2016 ::file pmid_2352_4590_227.txt
(p / provide-01
      :ARG0 (s / study-01
            :mod (t / this))
      :ARG1 (r / rationale
            :mod (m / mechanism))
      :ARG2 (u / use-01
            :ARG1 (t2 / therapy
                  :mod (m2 / molecular-physical-entity
                        :ARG0-of (i / inhibit-01
                              :ARG1 (p5 / protein-family :name (n / name :op1 "MEK")))))
            :location (p2 / person
                  :ARG0-of (h / have-rel-role-91
                        :ARG2 (p3 / patient))
                  :location-of (o / overexpress-01
                        :ARG1 (p4 / protein :name (n3 / name :op1 "c-MAF")))
                  :mod (d2 / disease :name (n4 / name :op1 "multiple" :op2 "myeloma"))))
      :mod (i2 / important))

# ::id pmid_2352_4590.228 ::date 2015-07-30T20:03:04 ::annotator SDL-AMR-09 ::preferred
# ::snt These findings emphasise the potential benefit of genetic profiling to identify patients with MAF-expressing MM who may benefit from this class of agents.
# ::save-date Thu Dec 10, 2015 ::file pmid_2352_4590_228.txt
(e / emphasize-01
      :ARG0 (t / thing
            :ARG1-of (f / find-01)
            :mod (t2 / this))
      :ARG1 (b / benefit-01
            :ARG0 (p / profile-01
                  :mod (g / genetics)
                  :ARG0-of (i / identify-01
                        :ARG1 (p3 / person
                              :ARG0-of (h / have-rel-role-91
                                    :ARG2 (p4 / patient))
                              :ARG0-of (h2 / have-03
                                    :ARG1 (c / cell
                                          :ARG3-of (e2 / express-03
                                                :ARG2 (p5 / protein :name (n2 / name :op1 "MAF")))
                                          :mod (d2 / disease :name (n3 / name :op1 "multiple" :op2 "myeloma"))))
                              :ARG1-of (b2 / benefit-01
                                    :ARG0 (c2 / class
                                          :mod (a / agent)
                                          :mod (t3 / this))
                                    :ARG1-of (p6 / possible-01)))))
            :mod (p2 / potential)))

# ::id pmid_2352_4590.229 ::date 2015-07-30T20:14:05 ::annotator SDL-AMR-09 ::preferred
# ::snt As part of the phase II trial of AZD6244 in relapsed/refractory MM, extensive molecular profiling of a subset of patients was conducted to correlate the genetic characteristics of MM with clinical outcomes.
# ::save-date Thu Dec 10, 2015 ::file pmid_2352_4590_229.txt
(c / conduct-01
      :ARG1 (p / profile-01
            :ARG1 (s / subset
                  :consist-of (p2 / person
                        :ARG0-of (h / have-rel-role-91
                              :ARG2 (p3 / patient))))
            :mod (m / molecule)
            :ARG1-of (e / extensive-03))
      :purpose (c2 / correlate-01
            :ARG1 (c3 / characteristic-02
                  :ARG1 (d4 / disease :name (n5 / name :op1 "multiple" :op2 "myeloma"))
                  :ARG2 (g / genetics))
            :ARG2 (o / outcome
                  :mod (c4 / clinic)))
      :part-of (t / trial-06
            :ARG2 (s2 / small-molecule :name (n2 / name :op1 "AZD6244"))
            :mod (p4 / phase :value 2)
            :condition (s3 / slash
                  :op1 (d / disease :name (n / name :op1 "multiple" :op2 "myeloma")
                        :ARG1-of (r2 / relapse-01))
                  :op2 (d2 / disease :name (n3 / name :op1 "multiple" :op2 "myeloma")
                        :mod (r / refractory)))))

# ::id pmid_2352_4590.230 ::date 2015-07-30T20:26:39 ::annotator SDL-AMR-09 ::preferred
# ::snt To date, detailed clinical data from eight patients has been analysed, four of whom overexpress c-MAF or MAF-B.
# ::save-date Fri Jan 1, 2016 ::file pmid_2352_4590_230.txt
(a / analyze-01
      :ARG1 (d / data
            :mod (c / clinic)
            :ARG1-of (d2 / detail-01)
            :source (p / person :quant 8
                  :ARG0-of (h / have-rel-role-91
                        :ARG2 (p2 / patient))
                  :ARG2-of (i / include-91
                        :ARG1 (p3 / person :quant 4
                              :ARG0-of h
                              :location-of (o / overexpress-01
                                    :ARG1 (o2 / or
                                          :op1 (p4 / protein :name (n / name :op1 "c-MAF"))
                                          :op2 (p5 / protein :name (n2 / name :op1 "MAF-B"))))))))
      :time (t / to-date))

# ::id pmid_2352_4590.231 ::date 2015-07-30T20:33:09 ::annotator SDL-AMR-09 ::preferred
# ::snt One patient (fibroblast growth factor receptor 3) had a very good PR lasting 8 months.
# ::save-date Fri Jan 1, 2016 ::file pmid_2352_4590_231.txt
(h / have-03
      :ARG0 (p / person :quant 1
            :ARG0-of (h2 / have-rel-role-91
                  :ARG2 (p2 / patient))
            :mod (p3 / protein :name (n / name :op1 "fibroblast" :op2 "growth" :op3 "factor" :op4 "receptor-3")))
      :ARG1 (t / thing
            :ARG2-of (r / respond-01
                  :degree (p4 / part))
            :ARG1-of (g / good-02
                  :degree (v / very))
            :duration (t2 / temporal-quantity :quant 8
                        :unit (m / month))))

# ::id pmid_2352_4590.232 ::date 2015-07-30T20:39:59 ::annotator SDL-AMR-09 ::preferred
# ::snt Another patient (MAF-B) had a PR of 6 months.
# ::save-date Thu Dec 10, 2015 ::file pmid_2352_4590_232.txt
(h / have-03
      :ARG0 (p / person
            :ARG0-of (h2 / have-rel-role-91
                  :ARG2 (p2 / patient))
            :mod (p3 / protein :name (n / name :op1 "MAF-B"))
            :mod (a / another))
      :ARG1 (t / thing
            :ARG2-of (r / respond-01
                  :duration (t2 / temporal-quantity :quant 6
                        :unit (m / month))
                  :degree (p4 / part))))

# ::id pmid_2352_4590.233 ::date 2015-07-30T20:44:09 ::annotator SDL-AMR-09 ::preferred
# ::snt Finally, two patients (one MAF-B, one pending results) demonstrated s.d. of >5 and 13 months, respectively.<sup><xref ref-type="bibr" rid="bib100">100</xref></sup>
# ::save-date Thu Dec 10, 2015 ::file pmid_2352_4590_233.txt
(a3 / and
      :op1 (d / demonstrate-01
            :ARG0 (p / person :quant 1
                  :ARG0-of (h / have-rel-role-91
                        :ARG2 (p2 / patient))
                  :mod (p4 / protein :name (n / name :op1 "MAF-B")))
            :ARG1 (d4 / disease
                  :duration (m2 / more-than
                        :op1 (t4 / temporal-quantity :quant 5
                              :unit m3))
                  :ARG1-of (s / stable-03)))
      :op2 (d3 / demonstrate-01
            :ARG0 (p5 / person :quant 1
                  :ARG0-of h
                  :mod (t / thing
                        :ARG2-of (r / result-01)
                        :ARG1-of (p6 / pend-01)))
            :ARG1 (d5 / disease
                  :duration (t3 / temporal-quantity :quant 13
                        :unit (m3 / month))
                  :ARG1-of (s2 / stable-03)))
      :ARG1-of (d2 / describe-01
            :ARG0 (p7 / publication
                  :ARG1-of (c / cite-01
                        :ARG2 100)))
      :mod (f / final))

# ::id pmid_2352_4590.234 ::date 2015-07-30T20:56:36 ::annotator SDL-AMR-09 ::preferred
# ::snt Additional studies with larger sample sizes are required to support or refute MAF expression as a reliable biomarker for MEK inhibition.
# ::save-date Sun Dec 20, 2015 ::file pmid_2352_4590_234.txt
(r / require-01
      :ARG0 (o / or
            :op1 (s / support-01
                  :ARG0 (s2 / study-01
                        :ARG1-of (a / add-02)
                        :mod (s3 / size-01
                              :ARG1 (t / thing
                                    :ARG1-of (s4 / sample-01))
                              :ARG2 (l / large
                                    :degree (m / more))))
                  :ARG1 (e / express-03
                        :ARG2 (p / protein :name (n / name :op1 "MAF"))
                        :mod (b / biomarker
                              :ARG1-of (r2 / rely-01
                                    :ARG1-of (p2 / possible-01))
                              :purpose (i / inhibit-01
                                    :ARG1 (e2 / enzyme :name (n2 / name :op1 "MEK"))))))
            :op2 (r3 / refute-01
                  :ARG0 s2
                  :ARG1 e))
      :ARG1 s2)

# ::id pmid_2352_4590.235 ::date 2015-07-30T21:13:04 ::annotator SDL-AMR-09 ::preferred
# ::snt <sec-title level="1">Conclusion</sec-title>
# ::save-date Thu Jul 30, 2015 ::file pmid_2352_4590_235.txt
(t / thing
      :ARG1-of (c / conclude-01))

# ::id pmid_2352_4590.236 ::date 2015-07-30T21:15:20 ::annotator SDL-AMR-09 ::preferred
# ::snt The Ras/Raf/MEK/ERK pathway has an established role in the various neoplastic phenotypes observed in many malignancies.
# ::save-date Wed Aug 5, 2015 ::file pmid_2352_4590_236.txt
(h / have-03
      :ARG0 (p / pathway :name (n / name :op1 "Ras/Raf/MEK/ERK"))
      :ARG1 (r / role
            :topic (p2 / phenotype
                  :mod (n2 / neoplasm)
                  :mod (v / various)
                  :ARG1-of (o / observe-01
                        :location (m / malignancy
                              :quant (m2 / many))))
            :ARG1-of (e / establish-01)))

# ::id pmid_2352_4590.237 ::date 2015-07-30T21:20:22 ::annotator SDL-AMR-09 ::preferred
# ::snt Deregulation of this pathway is also a common feature of MM, and contributes to the relapsing and refractory nature of the disease.
# ::save-date Tue Nov 17, 2015 ::file pmid_2352_4590_237.txt
(a / and
      :op1 (f / feature
            :domain (d / deregulate-01
                  :ARG1 (p / pathway
                        :mod (t / this)))
            :mod (c / common)
            :mod (a2 / also)
            :mod (d3 / disease :name (n4 / name :op1 "multiple" :op2 "myeloma")))
      :op2 (c2 / contribute-01
            :ARG0 f
            :ARG2 (a3 / and
                  :op1 (r / relapse-01
                        :ARG1 d3)
                  :op2 (r2 / refractory
                        :domain d3))))

# ::id pmid_2352_4590.238 ::date 2015-07-30T21:31:21 ::annotator SDL-AMR-09 ::preferred
# ::snt These observations make this pathway an attractive target for pharmaceutical investigation, with a number of MEK inhibitors having been developed and evaluated clinically.
# ::save-date Sat Jan 16, 2016 ::file pmid_2352_4590_238.txt
(m / make-02
      :ARG0 (o / observe-01
            :mod (t / this))
      :ARG1 (t2 / target-01
            :ARG0 (i / investigate-01
                  :mod (p / pharmaceutical))
            :ARG1 (p2 / pathway
                  :mod t)
            :ARG2-of (a / attract-01))
      :accompanier (a2 / and
            :op1 (d / develop-02
                  :ARG1 (n / number
                        :quant-of (m2 / molecular-physical-entity
                              :ARG0-of (i2 / inhibit-01
                                    :ARG1 (p3 / protein-family :name (n2 / name :op1 "MEK"))))))
            :op2 (e2 / evaluate-01
                  :ARG1 n)
            :manner (c / clinical)))

# ::id pmid_2352_4590.239 ::date 2015-07-30T21:44:35 ::annotator SDL-AMR-09 ::preferred
# ::snt Although preclinical studies of MEK inhibitors in MM have demonstrated a capacity to induce MM apoptosis by overcoming the prosurvival effects of the BMME, solid tumour studies indicate that the therapeutic benefit of MEK inhibitors alone are likely to be of limited benefit.
# ::save-date Sat Jan 16, 2016 ::file pmid_2352_4590_239.txt
(h / have-concession-91
      :ARG1 (i / indicate-01
            :ARG0 (s / study-01
                  :ARG1 (t / tumor
                        :ARG1-of (s2 / solid-02)))
            :ARG1 (l / likely-01
                  :ARG1 (b / benefit-01
                        :ARG0 (b2 / benefit-01
                              :ARG0 (m / molecular-physical-entity
                                    :ARG0-of (i2 / inhibit-01
                                          :ARG1 (p2 / protein-family :name (n / name :op1 "MEK"))))
                              :mod (t2 / therapy)
                              :mod (a / alone))
                        :ARG1-of (l2 / limit-01))))
      :ARG2 (d / demonstrate-01
            :ARG0 (s3 / study-01
                  :ARG1 m
                  :mod (p / preclinical)
                  :location (d3 / disease :name (n4 / name :op1 "multiple" :op2 "myeloma")))
            :ARG1 (c / capable-01
                  :ARG1 m
                  :ARG2 (i3 / induce-01
                        :ARG0 m
                        :ARG2 (a2 / apoptosis
                              :mod (c2 / cell
                                    :mod d3))
                        :manner (o / overcome-01
                              :ARG1 (a3 / affect-01
                                    :ARG0 (m2 / microenvironment
                                          :mod (m3 / marrow
                                                :part-of (b3 / bone)))
                                    :ARG2 (f / favor-01
                                          :ARG1 (s4 / survive-01))))))))

# ::id pmid_2352_4590.240 ::date 2015-07-30T22:05:21 ::annotator SDL-AMR-09 ::preferred
# ::snt Therefore, future clinical approaches require a shift towards using MEK inhibitors in combination with current anti-MM compounds and other novel small molecule inhibitors.
# ::save-date Sat Jan 16, 2016 ::file pmid_2352_4590_240.txt
(c / cause-01
      :ARG1 (r / require-01
            :ARG0 (a / approach-01
                  :mod (c2 / clinic)
                  :time (f / future))
            :ARG1 (s / shift-01
                  :ARG1 a
                  :ARG2 (u / use-01
                        :ARG1 (m / molecular-physical-entity
                              :ARG0-of (i / inhibit-01
                                    :ARG1 (p / protein-family :name (n / name :op1 "MEK")))
                              :ARG1-of (c3 / combine-01
                                    :ARG2 (a2 / and
                                          :op1 (c4 / compound
                                                :ARG0-of (c5 / counter-01
                                                      :ARG1 (d2 / disease :name (n4 / name :op1 "multiple" :op2 "myeloma")))
                                                :mod (c6 / current))
                                          :op2 (s2 / small-molecule
                                                :ARG0-of (i2 / inhibit-01)
                                                :mod (n3 / novel)
                                                :mod (o / other)))))))))

# ::id pmid_2352_4590.241 ::date 2015-07-30T22:13:11 ::annotator SDL-AMR-09 ::preferred
# ::snt The identification of relevant biomarkers of MEK inhibitor responses remains a high priority that can be used to predict patient sensitivity and to tailor individualised therapies.
# ::save-date Thu Feb 4, 2016 ::file pmid_2352_4590_241.txt
(r / remain-01
      :ARG1 (i / identify-01
            :ARG1 (b / biomarker
                  :ARG1-of (r2 / relevant-01)
                  :mod (t / thing
                        :ARG2-of (r3 / respond-01
                              :ARG0 (m / molecular-physical-entity
                                    :ARG0-of (i2 / inhibit-01
                                          :ARG1 (p6 / protein-family :name (n / name :op1 "MEK"))))))))
      :ARG3 (p / priority
            :ARG1-of (h / high-02)
            :ARG1-of (u / use-01
                  :ARG2 (a / and
                        :op1 (p2 / predict-01
                              :ARG1 (s / sensitive-03
                                    :ARG0 (p3 / person
                                          :ARG0-of (h2 / have-rel-role-91
                                                :ARG2 (p4 / patient)))))
                        :op2 (t2 / tailor-01
                              :ARG1 (t3 / therapy
                                    :ARG1-of (i3 / individualize-02))))
                  :ARG1-of (p5 / possible-01))))

# ::id pmid_2354_8132.1 ::date 2015-08-25T17:18:50 ::annotator SDL-AMR-09 ::preferred
# ::snt High resolution melting analysis of <i>KRAS</i>, <i>BRAF</i> and <i>PIK3CA</i> in <i>KRAS</i> exon 2 wild-type metastatic colorectal cancer (PMID:23548132)
# ::save-date Sun Jan 3, 2016 ::file pmid_2354_8132_1.txt
(a / analyze-01
      :ARG1 (a2 / and
            :op1 (g / gene :name (n / name :op1 "KRAS"))
            :op2 (g2 / gene :name (n2 / name :op1 "BRAF"))
            :op3 (g3 / gene :name (n3 / name :op1 "PIK3CA")))
      :manner (m2 / melt-01
            :mod (r / resolution
                  :ARG1-of (h / high-02)))
      :ARG1-of (d3 / describe-01
            :ARG0 (p / publication-91
                  :ARG8 "PMID23548132"))
      :location (d4 / disease :wiki "Colorectal_cancer" :name (n4 / name :op1 "colorectal" :op2 "cancer")
            :ARG1-of (m / metastasize-101)
            :mod (w / wild-type)
            :mod (e / exon :mod 2
                  :part-of g)))

# ::id pmid_2354_8132.9 ::date 2015-08-25T19:01:11 ::annotator SDL-AMR-09 ::preferred
# ::snt <sec-title level="1" sec-area="abstract">Results</sec-title>
# ::save-date Tue Aug 25, 2015 ::file pmid_2354_8132_9.txt
(t / thing
      :ARG2-of (r / result-01))

# ::id pmid_2354_8132.10 ::date 2015-08-25T19:28:11 ::annotator SDL-AMR-09 ::preferred
# ::snt One mutation was present in 23.4% (47/201) of the cases and 3.0% additional cases (6/201) had two concomitant mutations.
# ::save-date Sat Jan 30, 2016 ::file pmid_2354_8132_10.txt
(a / and
      :op1 (p / present-02
            :ARG1 (m / mutate-01 :quant 1)
            :ARG2 (c / case-04 :quant 47
                  :ARG1-of (i / include-91
                        :ARG2 (c2 / case-04 :quant 201)
                        :ARG3 (p2 / percentage-entity :value 23.4))))
      :op2 (h / have-03
            :ARG0 (c3 / case-04 :quant 6
                  :ARG1-of (i2 / include-91
                        :ARG2 c2
                        :ARG3 (p3 / percentage-entity :value 3.0))
                  :ARG1-of (a2 / add-02))
            :ARG1 (m2 / mutate-01 :quant 2
                  :mod (c4 / concomitant))))

# ::id pmid_2354_8132.11 ::date 2015-08-26T02:51:01 ::annotator SDL-AMR-09 ::preferred
# ::snt A total of 53 cases showed 59 mutations, with the following distribution: 44.1% (26/59) in <i>KRAS</i> (13 in exon 3 and 13 in exon 4), 18.6% (11/59) in <i>BRAF</i> (two in exon 11 and nine in exon 15) and 37.3% (22/59) in <i>PIK3CA</i> (16 in exon 9 and six in exon 20).
# ::save-date Sat Jan 30, 2016 ::file pmid_2354_8132_11.txt
(s / show-01
      :ARG0 (c / case-04 :quant 53
            :ARG1-of (t / total-01))
      :ARG1 (m / mutate-01 :quant 59
            :ARG1-of (d / distribute-01
                  :ARG2 (a / and
                        :op1 (m2 / mutate-01 :quant 26
                              :ARG1 (g / gene :name (n / name :op1 "KRAS"))
                              :ARG1-of (i / include-91
                                    :ARG2 m
                                    :ARG3 (p / percentage-entity :value 44.1))
                              :ARG1-of (m3 / mean-01
                                    :ARG2 (a2 / and
                                          :op1 (m4 / mutate-01 :quant 13
                                                :location (e6 / exon :mod 3))
                                          :op2 (m5 / mutate-01 :quant 13
                                                :location (e5 / exon :mod 4)))))
                        :op2 (m6 / mutate-01 :quant 11
                              :ARG1 (g2 / gene :name (n4 / name :op1 "BRAF"))
                              :ARG1-of (i2 / include-91
                                    :ARG2 m
                                    :ARG3 (p2 / percentage-entity :value 18.6))
                              :ARG1-of (m7 / mean-01
                                    :ARG2 (a3 / and
                                          :op1 (m8 / mutate-01 :quant 2
                                                :location (e3 / exon :mod 11))
                                          :op2 (m9 / mutate-01 :quant 9
                                                :location (e4 / exon :mod 15)))))
                        :op3 (m10 / mutate-01 :quant 22
                              :ARG1 (g3 / gene :name (n7 / name :op1 "PIK3CA"))
                              :ARG1-of (i3 / include-91
                                    :ARG2 m
                                    :ARG3 (p3 / percentage-entity :value 37.3))
                              :ARG1-of (m11 / mean-01
                                    :ARG2 (a4 / and
                                          :op1 (m12 / mutate-01 :quant 16
                                                :location (e / exon :mod 9))
                                          :op2 (m13 / mutate-01 :quant 6
                                                :location (e2 / exon :mod 20))))))
                  :ARG1-of (f / follow-01))))

# ::id pmid_2354_8132.12 ::date 2015-08-26T15:50:30 ::annotator SDL-AMR-09 ::preferred
# ::snt In total, 26.4% (53/201) of the cases had at least one mutation and the remaining 73.6% (148/201) were wild-type for all regions studied.
# ::save-date Sat Jan 30, 2016 ::file pmid_2354_8132_12.txt
(a / and
      :op1 (h / have-03
            :ARG0 (c / case-04 :quant 53
                  :ARG1-of (i / include-91
                        :ARG2 (c2 / case-04 :quant 201)
                        :ARG3 (p / percentage-entity :value 26.4)))
            :ARG1 (m / mutate-01
                  :quant (a2 / at-least :op1 1)))
      :op2 (w / wild-type
            :domain (c3 / case-04 :quant 148
                  :ARG1-of (i2 / include-91
                        :ARG2 c2
                        :ARG3 (p2 / percentage-entity :value 73.6))
                  :ARG1-of (r / remain-01))
            :location (r2 / region
                  :mod (a3 / all)
                  :ARG1-of (s / study-01)))
      :ARG1-of (t / total-01))

# ::id pmid_2354_8132.13 ::date 2015-08-27T11:54:07 ::annotator SDL-AMR-09 ::preferred
# ::snt Five of the mutations we report, four in <i>KRAS</i> and one in <i>BRAF</i>, have not previously been described in CRC.
# ::save-date Sat Sep 12, 2015 ::file pmid_2354_8132_13.txt
(d / describe-01 :polarity -
      :ARG1 (m / mutate-01 :quant 5
            :ARG1-of (i / include-91
                  :ARG2 (m2 / mutate-01
                        :ARG1-of (r / report-01
                              :ARG0 (w / we))))
            :ARG2-of (i2 / include-91
                  :ARG1 (a / and
                        :op1 (m3 / mutate-01 :quant 4
                              :ARG1 (g / gene :name (n / name :op1 "KRAS")))
                        :op2 (m4 / mutate-01 :quant 1
                              :ARG1 (g2 / gene :name (n2 / name :op1 "BRAF"))))))
      :time (p / previous)
      :location (d2 / disease :name (n3 / name :op1 "CRC")))

# ::id pmid_2354_8132.14 ::date 2015-08-27T12:05:21 ::annotator SDL-AMR-09 ::preferred
# ::snt <i>BRAF</i> and <i>PIK3CA</i> mutations were more frequent in the colon than in the sigmoid or rectum: 20.8% <i>vs.</i> 1.6% <i>vs.</i> 0.0% (<i>P=</i>0.000) for <i>BRAF</i> and 23.4% <i>vs.</i> 12.1% <i>vs.</i> 5.4% (<i>P</i>=0.011) for <i>PIK3CA</i> mutations.
# ::save-date Tue Dec 15, 2015 ::file pmid_2354_8132_14.txt
(f / frequent-02
      :ARG1 (a / and
            :op1 (m / mutate-01
                  :ARG1 (g / gene :name (n / name :op1 "BRAF")))
            :op2 (m2 / mutate-01
                  :ARG1 (g2 / gene :name (n2 / name :op1 "PIK3CA"))))
      :degree (m3 / more)
      :location (c / colon)
      :compared-to (o / or
            :op1 (s / sigmoid)
            :op2 (r / rectum))
      :ARG1-of (m4 / mean-01
            :ARG2 (a2 / and
                  :op1 (m5 / mutate-01
                        :ARG1 g
                        :quant (p / percentage-entity :value 20.8)
                        :location c
                        :compared-to (m6 / mutate-01
                              :ARG1 g
                              :quant (p2 / percentage-entity :value 1.6)
                              :location s)
                        :compared-to (m7 / mutate-01
                              :ARG1 g
                              :quant (p3 / percentage-entity :value 0.0)
                              :location r)
                        :ARG1-of (s2 / statistical-test-91
                              :ARG2 0.000))
                  :op2 (m8 / mutate-01
                        :ARG1 g2
                        :quant (p5 / percentage-entity :value 23.4)
                        :location c
                        :compared-to (m9 / mutate-01
                              :ARG1 g2
                              :quant (p6 / percentage-entity :value 12.1)
                              :location s)
                        :compared-to (m10 / mutate-01
                              :ARG1 g2
                              :quant (p7 / percentage-entity :value 5.4)
                              :location r)
                        :ARG1-of (s3 / statistical-test-91
                              :ARG2 0.011)))))

# ::id pmid_2354_8132.74 ::date 2015-08-27T12:33:07 ::annotator SDL-AMR-09 ::preferred
# ::snt <sec-title level="1">Results</sec-title>
# ::save-date Thu Aug 27, 2015 ::file pmid_2354_8132_74.txt
(t / thing
      :ARG2-of (r / result-01))

# ::id pmid_2354_8132.75 ::date 2015-08-27T12:34:49 ::annotator SDL-AMR-09 ::preferred
# ::snt <sec-title level="2">Mutation frequencies</sec-title>
# ::save-date Thu Aug 27, 2015 ::file pmid_2354_8132_75.txt
(f / frequent-02
      :ARG1 (m / mutate-01))

# ::id pmid_2354_8132.76 ::date 2015-08-27T12:36:42 ::annotator SDL-AMR-09 ::preferred
# ::snt A total of 201 <i>KRAS</i> exon 2 wild-type mCRC samples were screened by HRM for mutations in exons 3 and 4 of <i>KRAS</i>, exons 11 and 15 of <i>BRAF,</i> and exons 9 and 20 of <i>PIK3CA</i> (Figure <xref ref-type="fig" rid="F1">1</xref>).
# ::save-date Sun Jan 3, 2016 ::file pmid_2354_8132_76.txt
(s / screen-01
      :ARG1 (s2 / sample-01
            :ARG1 (d / disease :name (n / name :op1 "mCRC")
                  :mod (w / wild-type)
                  :mod (e / exon :mod 2
                        :part-of (g / gene :name (n3 / name :op1 "KRAS"))))
            :ARG1-of (t / total-01
                  :ARG2 201))
      :manner (t2 / thing :name (n4 / name :op1 "HRM"))
      :purpose (a / and
            :op1 (m / mutate-01
                  :location (a2 / and
                        :op1 (e2 / exon :mod 3)
                        :op2 (e3 / exon :mod 4)
                        :part-of g))
            :op2 (m2 / mutate-01
                  :location (a3 / and
                        :op1 (e4 / exon :mod 11)
                        :op2 (e5 / exon :mod 15)
                        :part-of (g2 / gene :name (n9 / name :op1 "BRAF"))))
            :op3 (m3 / mutate-01
                  :location (a4 / and
                        :op1 (e6 / exon :mod 9)
                        :op2 (e7 / exon :mod 20)
                        :part-of (g3 / gene :name (n12 / name :op1 "PIK3CA")))))
      :ARG1-of (d9 / describe-01
            :ARG0 (f / figure :mod 1)))

# ::id pmid_2354_8132.77 ::date 2015-08-27T12:56:55 ::annotator SDL-AMR-09 ::preferred
# ::snt Subsequent automated sequencing of HRM positive cases confirmed the presence of 59 mutations in 53 cases, with the following distribution: 44.1% (26/59) in <i>KRAS</i> (13 in exon 3 and 13 in exon 4), 18.6% (11/59) in <i>BRAF</i> (two in exon 11 and nine in exon 15) and 37.3% (22/59) in <i>PIK3CA</i> (16 in exon 9 and six in exon 20).
# ::save-date Sat Jan 30, 2016 ::file pmid_2354_8132_77.txt
(c / confirm-01
      :ARG0 (s / sequence-01
            :ARG1 (c2 / case-04
                  :ARG1 (t / thing :name (n / name :op1 "HRM"))
                  :mod (p / positive))
            :ARG1-of (a / automate-01)
            :time (s2 / subsequent))
      :ARG1 (p2 / present-02
            :ARG1 (m / mutate-01 :quant 59)
            :ARG2 (c3 / case-04 :quant 53)
            :ARG1-of (d / distribute-01
                  :ARG2 (a2 / and
                        :op1 (m2 / mutate-01 :quant 26
                              :ARG1 (g / gene :name (n2 / name :op1 "KRAS"))
                              :ARG1-of (i / include-91
                                    :ARG2 m
                                    :ARG3 (p3 / percentage-entity :value 44.1))
                              :ARG1-of (m3 / mean-01
                                    :ARG2 (a3 / and
                                          :op1 (m4 / mutate-01 :quant 13
                                                :location (e / exon :mod 3))
                                          :op2 (m5 / mutate-01 :quant 13
                                                :location (e2 / exon :mod 4)))))
                        :op2 (m6 / mutate-01 :quant 11
                              :ARG1 (g2 / gene :name (n5 / name :op1 "BRAF"))
                              :ARG1-of (i2 / include-91
                                    :ARG2 m
                                    :ARG3 (p4 / percentage-entity :value 18.6))
                              :ARG1-of (m7 / mean-01
                                    :ARG2 (a4 / and
                                          :op1 (m8 / mutate-01 :quant 2
                                                :location (e3 / exon :mod 11))
                                          :op2 (m9 / mutate-01 :quant 9
                                                :location (e4 / exon :mod 15)))))
                        :op3 (m10 / mutate-01 :quant 22
                              :ARG1 (g3 / gene :name (n8 / name :op1 "PIK3CA"))
                              :ARG1-of (i3 / include-91
                                    :ARG2 m
                                    :ARG3 (p5 / percentage-entity :value 37.3))
                              :ARG1-of (m11 / mean-01
                                    :ARG2 (a5 / and
                                          :op1 (m12 / mutate-01 :quant 16
                                                :location (e5 / exon :mod 9))
                                          :op2 (m13 / mutate-01 :quant 6
                                                :location (e6 / exon :mod 20))))))
                  :ARG1-of (f / follow-01))))

# ::id pmid_2354_8132.78 ::date 2015-08-27T13:30:31 ::annotator SDL-AMR-09 ::preferred
# ::snt One mutation was present in 23.4% (47/201) of the cases and 3.0% additional cases (6/201) had two concomitant mutations.
# ::save-date Sat Jan 30, 2016 ::file pmid_2354_8132_78.txt
(a / and
      :op1 (p / present-02
            :ARG1 (m / mutate-01 :quant 1)
            :ARG2 (c / case-04 :quant 47
                  :ARG1-of (i / include-91
                        :ARG2 (c2 / case-04 :quant 201)
                        :ARG3 (p2 / percentage-entity :value 23.4))))
      :op2 (h / have-03
            :ARG0 (c3 / case-04 :quant 6
                  :ARG1-of (i2 / include-91
                        :ARG2 c2
                        :ARG3 (p3 / percentage-entity :value 3.0))
                  :ARG1-of (a2 / add-02))
            :ARG1 (m2 / mutate-01 :quant 2
                  :mod (c4 / concomitant))))

# ::id pmid_2354_8132.79 ::date 2015-08-27T14:55:59 ::annotator SDL-AMR-09 ::preferred
# ::snt In total, 26.4% (53/201) of the cases had at least one mutation and the remaining 73.6% (148/201) were wild-type for all regions studied.
# ::save-date Sat Jan 30, 2016 ::file pmid_2354_8132_79.txt
(a / and
      :op1 (h / have-03
            :ARG0 (c / case-04 :quant 53
                  :ARG1-of (i / include-91
                        :ARG2 (c2 / case-04 :quant 201)
                        :ARG3 (p / percentage-entity :value 26.4)))
            :ARG1 (m / mutate-01
                  :quant (a2 / at-least :op1 1)))
      :op2 (w / wild-type
            :domain (c3 / case-04 :quant 148
                  :ARG1-of (i2 / include-91
                        :ARG2 c2
                        :ARG3 (p2 / percentage-entity :value 73.6))
                  :ARG1-of (r / remain-01))
            :location (r2 / region
                  :mod (a3 / all)
                  :ARG1-of (s / study-01)))
      :ARG1-of (t / total-01))

# ::id pmid_2354_8132.80 ::date 2015-08-27T15:05:50 ::annotator SDL-AMR-09 ::preferred
# ::snt All mutations were found in heterozygosity and were confirmed in a second HRM and DNA sequence analysis.
# ::save-date Tue Jan 12, 2016 ::file pmid_2354_8132_80.txt
(a / and
      :op1 (f / find-01
            :ARG1 (m / mutate-01
                  :mod (a2 / all))
            :manner (h / heterozygosity))
      :op2 (c / confirm-01
            :ARG0 (a3 / and
                  :op1 (a4 / analyze-01
                        :ARG1 m
                        :manner (m2 / melt-01
                              :mod (r / resolution
                                    :ARG1-of (h2 / high-02))))
                  :op2 (a5 / analyze-01
                        :ARG1 m
                        :mod (d / dna-sequence))
                  :ord (o / ordinal-entity :value 2))
            :ARG1 m))

# ::id pmid_2354_8132.81 ::date 2015-08-30T17:47:13 ::annotator SDL-AMR-09 ::preferred
# ::snt Samples with single mutations were distributed as follows: 10.0% (20/201) were <i>KRAS</i> mutated, 5.0% (10/201) in exon 3 and 5.0% (10/201) in exon 4; 5.0% (10/201) had one <i>BRAF</i> mutation, 0.5% (1/201) in exon 11 and 4.5% (9/201) in exon 15; 8.5% (17/201) were <i>PIK3CA</i> mutated, 7.0% (14/201) in exon 9 and 1.5% (3/201) in exon 20 (Table <xref ref-type="table" rid="T1">1</xref>).
# ::save-date Sun Jan 3, 2016 ::file pmid_2354_8132_81.txt
(d / distribute-01
      :ARG1 (t / thing
            :ARG1-of (s / sample-01)
            :ARG0-of (h / have-03
                  :ARG1 (m / mutate-01
                        :ARG1-of (s2 / single-02))))
      :ARG2 (a / and
            :op1 (t3 / thing :quant 20
                  :ARG1-of (i / include-91
                        :ARG2 (t4 / thing :quant 201
                              :ARG1-of (s4 / sample-01))
                        :ARG3 (p / percentage-entity :value 10.0
                              :ARG1-of (m2 / mean-01
                                    :ARG2 (a2 / and
                                          :op1 (t5 / thing :quant 10
                                                :ARG1-of (i2 / include-91
                                                      :ARG2 t4
                                                      :ARG3 (p2 / percentage-entity :value 5.0))
                                                :ARG2-of (m3 / mutate-01
                                                      :location (e / exon :mod 3)))
                                          :op2 (t6 / thing :quant 10
                                                :ARG1-of i2
                                                :ARG2-of (m4 / mutate-01
                                                      :location (e2 / exon :mod 4)))))))
                  :location-of (m5 / mutate-01
                        :ARG1 (g / gene :name (n3 / name :op1 "KRAS"))))
            :op2 (t7 / thing :quant 10
                  :ARG1-of (i3 / include-91
                        :ARG2 t4
                        :ARG3 (p3 / percentage-entity :value 5.0
                              :ARG1-of (m6 / mean-01
                                    :ARG2 (a3 / and
                                          :op1 (t8 / thing :quant 1
                                                :ARG1-of (i4 / include-91
                                                      :ARG2 t4
                                                      :ARG3 (p4 / percentage-entity :value 0.5))
                                                :ARG2-of (m7 / mutate-01
                                                      :location (e3 / exon :mod 11)))
                                          :op2 (t9 / thing :quant 9
                                                :ARG1-of (i5 / include-91
                                                      :ARG2 t4
                                                      :ARG3 (p5 / percentage-entity :value 4.5))
                                                :ARG2-of (m8 / mutate-01
                                                      :location (e4 / exon :mod 15)))))))
                  :ARG0-of (h2 / have-03
                        :ARG1 (m9 / mutate-01 :quant 1
                              :ARG1 (g2 / gene :name (n6 / name :op1 "BRAF")))))
            :op3 (t10 / thing :quant 17
                  :ARG1-of (i6 / include-91
                        :ARG2 t4
                        :ARG3 (p6 / percentage-entity :value 8.5
                              :ARG1-of (m10 / mean-01
                                    :ARG2 (a4 / and
                                          :op1 (t11 / thing :quant 14
                                                :ARG1-of (i7 / include-91
                                                      :ARG2 t4
                                                      :ARG3 (p7 / percentage-entity :value 7.0))
                                                :ARG2-of (m11 / mutate-01
                                                      :location (e5 / exon :mod 9)))
                                          :op2 (t12 / thing :quant 3
                                                :ARG1-of (i8 / include-91
                                                      :ARG2 t4
                                                      :ARG3 (p8 / percentage-entity :value 1.5))
                                                :ARG2-of (m12 / mutate-01
                                                      :location (e6 / exon :mod 20)))))))
                  :location-of (m13 / mutate-01
                        :ARG1 (g3 / gene :name (n9 / name :op1 "PIK3CA")))))
      :ARG1-of (f / follow-01)
      :ARG1-of (d8 / describe-01
            :ARG0 (t2 / table :mod 1)))

# ::id pmid_2354_8132.82 ::date 2015-08-27T16:34:18 ::annotator SDL-AMR-09 ::preferred
# ::snt Concomitant mutations were found with the following distribution: 2.0% (4/201) of cases had simultaneous mutations in <i>PIK3CA</i> and <i>KRAS</i>, 0.5% (1/201) in <i>PIK3CA</i> and <i>BRAF</i>, and 0.5% (1/201) two mutations in <i>KRAS</i> (Table <xref ref-type="table" rid="T2">2</xref>).
# ::save-date Sat Jan 30, 2016 ::file pmid_2354_8132_82.txt
(f / find-01
      :ARG1 (m / mutate-01
            :mod (c / concomitant)
            :ARG1-of (d / distribute-01
                  :ARG2 (a / and
                        :op1 (h / have-03
                              :ARG0 (c2 / case-04 :quant 4
                                    :ARG1-of (i / include-91
                                          :ARG2 (c3 / case-04 :quant 201)
                                          :ARG3 (p / percentage-entity :value 2.0)))
                              :ARG1 (m2 / mutate-01
                                    :ARG1 (a2 / and
                                          :op1 (g / gene :name (n / name :op1 "PIK3CA"))
                                          :op2 (g2 / gene :name (n2 / name :op1 "KRAS")))
                                    :mod (s / simultaneous)))
                        :op2 (h2 / have-03
                              :ARG0 (c4 / case-04 :quant 1
                                    :ARG1-of (i2 / include-91
                                          :ARG2 c3
                                          :ARG3 (p2 / percentage-entity :value 0.5)))
                              :ARG1 (m3 / mutate-01
                                    :ARG1 (a3 / and
                                          :op1 g
                                          :op2 (g3 / gene :name (n3 / name :op1 "BRAF")))))
                        :op3 (h3 / have-03
                              :ARG0 c4
                              :ARG1 (m4 / mutate-01 :quant 2
                                    :ARG1 g2)))
                  :ARG1-of (f2 / follow-01)))
      :ARG1-of (d2 / describe-01
            :ARG0 (t / table :mod 2)))

# ::id pmid_2354_8132.83 ::date 2015-08-27T17:12:25 ::annotator SDL-AMR-09 ::preferred
# ::snt Of all mutations here reported, five have not been previously described in colorectal cancer [<xref ref-type="bibr" rid="B23">23</xref>-<xref ref-type="bibr" rid="B25">25</xref>]: two duplications, one deletion, and one point mutation in <i>KRAS</i> and one point mutation in <i>BRAF</i> (Figure <xref ref-type="fig" rid="F2">2</xref>).
# ::save-date Sun Sep 13, 2015 ::file pmid_2354_8132_83.txt
(d / describe-01 :polarity -
      :ARG1 (m / mutate-01 :quant 5
            :ARG1-of (i / include-91
                  :ARG2 (m2 / mutate-01
                        :mod (a / all)
                        :ARG1-of (r / report-01
                              :location (h / here))))
            :ARG1-of (m3 / mean-01
                  :ARG2 (a2 / and
                        :op1 (d2 / duplicate-01 :quant 2)
                        :op2 (d3 / delete-01 :quant 1)
                        :op3 (a3 / and
                              :op1 (m4 / mutate-01
                                    :ARG1 (g / gene :name (n / name :op1 "KRAS"))
                                    :degree (p / point :quant 1))
                              :op2 (m5 / mutate-01
                                    :ARG1 (g2 / gene :name (n2 / name :op1 "BRAF"))
                                    :degree p)))))
      :time (p2 / previous)
      :location (d4 / disease :name (n3 / name :op1 "colorectal" :op2 "cancer"))
      :ARG1-of (d5 / describe-01
            :ARG0 (p3 / publication
                  :ARG1-of (c / cite-01
                        :ARG2 (v / value-interval :op1 23 :op2 25))))
      :ARG1-of (d6 / describe-01
            :ARG0 (f / figure :mod 2)))

# ::id pmid_2354_8132.84 ::date 2015-08-27T17:25:27 ::annotator SDL-AMR-09 ::preferred
# ::snt <sec-title level="2">KRAS mutations</sec-title>
# ::save-date Sun Sep 13, 2015 ::file pmid_2354_8132_84.txt
(m / mutate-01
      :ARG1 (g / gene :name (n / name :op1 "KRAS")))

# ::id pmid_2354_8132.85 ::date 2015-08-27T17:27:13 ::annotator SDL-AMR-09 ::preferred
# ::snt The eight <i>KRAS</i> codon 61 mutations present in our series result in four different amino acid substitutions (p.Gln61His, p.Gln61Lys, p.Gln61Leu, and p.Gln61Arg), with the p.Gln61Leu being the most frequent codon 61 mutation in this series (37.5%; 3/8).
# ::save-date Sun Jan 3, 2016 ::file pmid_2354_8132_85.txt
(r / result-01
      :ARG1 (m / mutate-01 :quant 8
            :ARG1 (g / gene :name (n / name :op1 "KRAS"))
            :location (c / codon :mod 61)
            :ARG1-of (p / present-02
                  :ARG2 (s / series
                        :poss (w / we))))
      :ARG2 (s2 / substitute-01 :quant 4
            :ARG2 (a / amino-acid)
            :ARG1-of (d2 / differ-02)
            :ARG1-of (m2 / mean-01
                  :ARG2 (a2 / and
                        :op1 (s3 / substitute-01
                              :ARG1 (a3 / amino-acid :name (n3 / name :op1 "histidine"))
                              :ARG2 (a4 / amino-acid :mod 61 :name (n4 / name :op1 "glutamine")))
                        :op2 (s4 / substitute-01
                              :ARG1 (a5 / amino-acid :name (n5 / name :op1 "lysine"))
                              :ARG2 a4)
                        :op3 (s5 / substitute-01
                              :ARG1 (a6 / amino-acid :name (n6 / name :op1 "leucine"))
                              :ARG2 a4
                              :ARG1-of (f / frequent-02
                                    :degree (m3 / most)
                                    :location (s6 / series
                                          :mod (t / this))
                                    :ARG1-of (m5 / mean-01
                                          :ARG2 (m6 / mutate-01 :quant 3
                                                :location c
                                                :ARG1-of (i / include-91
                                                      :ARG2 m
                                                      :ARG3 (p2 / percentage-entity :value 37.5))))))
                        :op4 (s7 / substitute-01
                              :ARG1 (a7 / amino-acid :name (n7 / name :op1 "arginine"))
                              :ARG2 a4)))))

# ::id pmid_2354_8132.86 ::date 2015-08-29T04:21:32 ::annotator SDL-AMR-09 ::preferred
# ::snt Mutations found in codon 146 were restricted to the p.Ala146Thr substitution.
# ::save-date Sun Jan 3, 2016 ::file pmid_2354_8132_86.txt
(r / restrict-01
      :ARG1 (f / find-01
            :ARG1 (m / mutate-01)
            :location (c / codon :mod 146))
      :ARG2 (s / substitute-01
            :ARG1 (a / amino-acid :name (n2 / name :op1 "threonine"))
            :ARG2 (a2 / amino-acid :mod 146 :name (n3 / name :op1 "alanine"))))

# ::id pmid_2354_8132.87 ::date 2015-08-29T04:28:03 ::annotator SDL-AMR-09 ::preferred
# ::snt Besides those in codons 61 and 146, other <i>KRAS</i> exon 3 mutations represented 19% (5/26) of all <i>KRAS</i> changes, including one deletion (p.Ala59del), two point mutations (p.Glu49Lys and p.Gly60Val) and two large in frame duplications (p.Cys51_Ser65dup and p.Thr58_Met72dup).
# ::save-date Sun Jan 3, 2016 ::file pmid_2354_8132_87.txt
(r / represent-01
      :ARG0 (a / and
            :op1 (m / mutate-01
                  :location (a2 / and
                        :op1 (c4 / codon :mod 61)
                        :op2 (c5 / codon :mod 146)))
            :op2 (m2 / mutate-01
                  :ARG1 (g / gene :name (n3 / name :op1 "KRAS"))
                  :location (e / exon :mod 3)
                  :mod (o / other)))
      :ARG1 (c / change-01 :quant 5
            :ARG1-of (i / include-91
                  :ARG2 (c2 / change-01 :quant 26)
                  :ARG3 (p / percentage-entity :value 19))
            :ARG1-of (i2 / include-91
                  :ARG2 (c3 / change-01
                        :ARG1 g
                        :mod (a3 / all)))
            :ARG2-of (i3 / include-01
                  :ARG1 (a4 / and
                        :op1 (d4 / delete-01 :quant 1
                              :ARG1 (a5 / amino-acid :mod 59 :name (n5 / name :op1 "alanine")))
                        :op2 (m3 / mutate-01 :quant 2
                              :ARG1-of (m4 / mean-01
                                    :ARG2 (a6 / and
                                          :op1 (m5 / mutate-01
                                                :ARG2 (a7 / amino-acid :name (n6 / name :op1 "lysine"))
                                                :ARG3 (a8 / amino-acid :mod 49 :name (n7 / name :op1 "glutamic" :op2 "acid")))
                                          :op2 (m6 / mutate-01
                                                :ARG2 (a9 / amino-acid :name (n8 / name :op1 "valine"))
                                                :ARG3 (a10 / amino-acid :mod 60 :name (n9 / name :op1 "glycine")))))
                              :degree (p2 / point))
                        :op3 (d5 / duplicate-01 :quant 2
                              :ARG1-of (m7 / mean-01
                                    :ARG2 (a11 / and
                                          :op1 (d6 / duplicate-01
                                                :ARG0 (a12 / amino-acid :mod 51 :name (n10 / name :op1 "cysteine"))
                                                :ARG1 (a13 / amino-acid :mod 65 :name (n11 / name :op1 "serine")))
                                          :op2 (d7 / duplicate-01
                                                :ARG0 (a14 / amino-acid :mod 58 :name (n12 / name :op1 "threonine"))
                                                :ARG1 (a15 / amino-acid :mod 72 :name (n13 / name :op1 "methionine")))))
                              :mod (l / large)
                              :mod (i4 / in-frame))))))

# ::id pmid_2354_8132.88 ::date 2015-08-30T04:22:04 ::annotator SDL-AMR-09 ::preferred
# ::snt Of these five mutations, only p.Gly60Val has been recently reported in CRC [<xref ref-type="bibr" rid="B26">26</xref>], whereas the other four are novel mutations in CRC [<xref ref-type="bibr" rid="B23">23</xref>].
# ::save-date Sun Sep 13, 2015 ::file pmid_2354_8132_88.txt
(c / contrast-01
      :ARG1 (r / report-01
            :ARG1 (m / mutate-01
                  :ARG2 (a / amino-acid :name (n / name :op1 "valine"))
                  :ARG3 (a2 / amino-acid :mod 60 :name (n2 / name :op1 "glycine"))
                  :mod (o / only)
                  :ARG1-of (i / include-91
                        :ARG2 (m2 / mutate-01 :quant 5
                              :mod (t / this))))
            :time (r2 / recent)
            :location (d / disease :name (n3 / name :op1 "CRC"))
            :ARG1-of (d2 / describe-01
                  :ARG0 (p / publication
                        :ARG1-of (c2 / cite-01
                              :ARG2 26))))
      :ARG2 (m3 / mutate-01 :quant 4
            :mod (n4 / novel)
            :mod (o2 / other)
            :location d
            :ARG1-of (d3 / describe-01
                  :ARG0 (p2 / publication
                        :ARG1-of (c3 / cite-01
                              :ARG2 23)))))

# ::id pmid_2354_8132.89 ::date 2015-08-30T04:29:42 ::annotator SDL-AMR-09 ::preferred
# ::snt One of the cases carrying a <i>KRAS</i> p.Gln61His mutation had a concomitant <i>PIK3CA</i> p.Glu542Lys substitution.
# ::save-date Sat Jan 30, 2016 ::file pmid_2354_8132_89.txt
(h / have-03
      :ARG0 (c / case-04 :quant 1
            :ARG0-of (c2 / carry-01
                  :ARG1 (m / mutate-01
                        :ARG1 (g / gene :name (n / name :op1 "KRAS"))
                        :ARG2 (a / amino-acid :name (n2 / name :op1 "histidine"))
                        :ARG3 (a2 / amino-acid :mod 61 :name (n3 / name :op1 "glutamine"))))
            :ARG1-of (i / include-91
                  :ARG2 (c3 / case-04
                        :ARG0-of c2)))
      :ARG1 (s / substitute-01
            :ARG1 (a3 / amino-acid :name (n4 / name :op1 "lysine"))
            :ARG2 (a4 / amino-acid :mod 542 :name (n5 / name :op1 "glutamic" :op2 "acid"))
            :ARG3 (g2 / gene :name (n6 / name :op1 "PIK3CA"))
            :mod (c4 / concomitant)))

# ::id pmid_2354_8132.90 ::date 2015-08-30T04:39:32 ::annotator SDL-AMR-09 ::preferred
# ::snt The p.Thr58_Met72dup duplication occurred in one tumor carrying a <i>PIK3CA</i> p.His1047Tyr substitution.
# ::save-date Fri Nov 20, 2015 ::file pmid_2354_8132_90.txt
(d / duplicate-01
      :ARG0 (a / amino-acid :mod 58 :name (n / name :op1 "threonine"))
      :ARG1 (a2 / amino-acid :mod 72 :name (n2 / name :op1 "methionine"))
      :location (t / tumor :quant 1
            :ARG0-of (c / carry-01
                  :ARG1 (s / substitute-01
                        :ARG1 (a3 / amino-acid :name (n3 / name :op1 "tyrosine"))
                        :ARG2 (a4 / amino-acid :mod 1047 :name (n4 / name :op1 "histidine"))
                        :ARG3 (g / gene :name (n5 / name :op1 "PIK3CA"))))))

# ::id pmid_2354_8132.91 ::date 2015-08-30T04:56:54 ::annotator SDL-AMR-09 ::preferred
# ::snt Two tumors with <i>KRAS</i> Ala146Thr mutations also had a <i>PIK3CA</i> mutation, either p.Glu545Lys or p.His1046Arg.
# ::save-date Fri Nov 20, 2015 ::file pmid_2354_8132_91.txt
(h / have-03
      :ARG0 (t / tumor :quant 2
            :poss (m / mutate-01
                  :ARG1 (g / gene :name (n / name :op1 "KRAS"))
                  :ARG2 (a / amino-acid :name (n2 / name :op1 "threonine"))
                  :ARG3 (a2 / amino-acid :mod 146 :name (n3 / name :op1 "alanine"))))
      :ARG1 (o / or
            :op1 (m2 / mutate-01
                  :ARG1 (g2 / gene :name (n8 / name :op1 "PIK3CA"))
                  :ARG2 (a3 / amino-acid :name (n4 / name :op1 "lysine"))
                  :ARG3 (a4 / amino-acid :mod 545 :name (n5 / name :op1 "glutamic" :op2 "acid")))
            :op2 (m3 / mutate-01
                  :ARG1 g2
                  :ARG2 (a5 / amino-acid :name (n6 / name :op1 "arginine"))
                  :ARG3 (a6 / amino-acid :mod 1046 :name (n7 / name :op1 "histidine")))
            :mod (e / either))
      :mod (a7 / also))

# ::id pmid_2354_8132.92 ::date 2015-08-30T05:04:01 ::annotator SDL-AMR-09 ::preferred
# ::snt In addition, one case harbored two <i>KRAS</i> mutations, namely p.Glu49Lys and p.Ala146Thr.
# ::save-date Sat Jan 30, 2016 ::file pmid_2354_8132_92.txt
(a / and
      :op2 (h / harbor-01
            :ARG0 (c / case-04 :quant 1)
            :ARG1 (m / mutate-01 :quant 2
                  :ARG1 (a2 / and
                        :op1 (m2 / mutate-01
                              :ARG2 (a3 / amino-acid :name (n2 / name :op1 "lysine"))
                              :ARG3 (a4 / amino-acid :mod 49 :name (n3 / name :op1 "glutamic" :op2 "acid")))
                        :op2 (m3 / mutate-01
                              :ARG2 (a5 / amino-acid :name (n4 / name :op1 "threonine"))
                              :ARG3 (a6 / amino-acid :mod 146 :name (n5 / name :op1 "alanine")))
                        :mod (n6 / namely))
                  :ARG2 (g / gene :name (n / name :op1 "KRAS")))))

# ::id pmid_2354_8132.93 ::date 2015-08-30T05:10:03 ::annotator SDL-AMR-09 ::preferred
# ::snt <sec-title level="2">BRAF mutations</sec-title>
# ::save-date Sat Jan 16, 2016 ::file pmid_2354_8132_93.txt
(m / mutate-01
      :ARG1 (e / enzyme :name (n / name :op1 "BRAF")))

# ::id pmid_2354_8132.94 ::date 2015-08-30T05:13:03 ::annotator SDL-AMR-09 ::preferred
# ::snt The frequency of <i>BRAF</i> p.Val600Glu mutations found in this series was 4.0% (8/201).
# ::save-date Sun Sep 13, 2015 ::file pmid_2354_8132_94.txt
(f / frequent-02
      :ARG1 (m / mutate-01
            :ARG1 (g / gene :name (n / name :op1 "BRAF"))
            :ARG2 (a / amino-acid :name (n2 / name :op1 "glutamic" :op2 "acid"))
            :ARG3 (a2 / amino-acid :mod 600 :name (n3 / name :op1 "valine"))
            :ARG1-of (f2 / find-01
                  :location (s / series
                        :mod (t / this))))
      :quant (p / percentage-entity :value 4.0
            :ARG1-of (m2 / mean-01
                  :ARG2 (m3 / mutate-01 :quant 8
                        :ARG1 g
                        :ARG2 a
                        :ARG3 a2
                        :ARG1-of (i / include-91
                              :ARG2 (m4 / mutate-01 :quant 201))))))

# ::id pmid_2354_8132.95 ::date 2015-08-30T05:23:48 ::annotator SDL-AMR-09 ::preferred
# ::snt This mutation represented 89% (8/9) of exon 15 mutations and 73% (8/11) of all <i>BRAF</i> mutations.
# ::save-date Sun Jan 3, 2016 ::file pmid_2354_8132_95.txt
(r / represent-01
      :ARG0 (m / mutate-01
            :mod (t / this))
      :ARG1 (a / and
            :op1 (m2 / mutate-01 :quant 8
                  :mod t
                  :ARG1-of (i / include-91
                        :ARG2 (m3 / mutate-01 :quant 9)
                        :ARG3 (p / percentage-entity :value 89))
                  :location (e / exon :mod 15))
            :op2 (m4 / mutate-01 :quant 8
                  :mod t
                  :ARG1-of (i2 / include-91
                        :ARG2 (m5 / mutate-01 :quant 11
                              :ARG1 (g / gene :name (n2 / name :op1 "BRAF"))
                              :mod (a2 / all))
                        :ARG3 (p2 / percentage-entity :value 73)))))

# ::id pmid_2354_8132.96 ::date 2015-08-30T05:41:42 ::annotator SDL-AMR-09 ::preferred
# ::snt We also found mutations in codons 601 (p.Lys601Glu), 466 (p.Gly466Glu), and 471 (p.Val471Ala) of <i>BRAF</i>, the latter not previously described in mCRC [<xref ref-type="bibr" rid="B23">23</xref>].
# ::save-date Sun Jan 3, 2016 ::file pmid_2354_8132_96.txt
(f / find-01
      :ARG0 (w / we)
      :ARG1 (a / and
            :op1 (m / mutate-01
                  :ARG1 (g / gene :name (n / name :op1 "BRAF"))
                  :ARG2 (a8 / amino-acid :name (n2 / name :op1 "glutamic" :op2 "acid"))
                  :ARG3 (a3 / amino-acid :mod 601 :name (n3 / name :op1 "lysine"))
                  :location (c2 / codon :mod 601))
            :op2 (m2 / mutate-01
                  :ARG1 g
                  :ARG2 a8
                  :ARG3 (a4 / amino-acid :mod 466 :name (n5 / name :op1 "glycine"))
                  :location (c3 / codon :mod 466))
            :op3 (m3 / mutate-01
                  :ARG1 g
                  :ARG2 (a5 / amino-acid :name (n6 / name :op1 "alanine"))
                  :ARG3 (a6 / amino-acid :mod 471 :name (n7 / name :op1 "valine"))
                  :location (c4 / codon :mod 471)
                  :ARG1-of (d4 / describe-01 :polarity -
                        :ARG0 (d5 / disease :name (n10 / name :op1 "mCRC"))
                        :time (p / previous))))
      :mod (a7 / also)
      :ARG1-of (d6 / describe-01
            :ARG0 (p2 / publication
                  :ARG1-of (c / cite-01
                        :ARG2 23))))

# ::id pmid_2354_8132.97 ::date 2015-08-30T05:54:05 ::annotator SDL-AMR-09 ::preferred
# ::snt One <i>BRAF</i> mutation, p.Val471Ala, occurred in a tumor also carrying a <i>PIK3CA</i> p.His1047Arg mutation.
# ::save-date Sun Sep 13, 2015 ::file pmid_2354_8132_97.txt
(m / mutate-01 :quant 1
      :ARG1 (g / gene :name (n / name :op1 "BRAF"))
      :ARG2 (a / amino-acid :name (n2 / name :op1 "alanine"))
      :ARG3 (a2 / amino-acid :mod 471 :name (n3 / name :op1 "valine"))
      :location (t / tumor
            :ARG0-of (c / carry-01
                  :ARG1 (m2 / mutate-01
                        :ARG1 (g2 / gene :name (n4 / name :op1 "PIK3CA"))
                        :ARG2 (a3 / amino-acid :name (n5 / name :op1 "arginine"))
                        :ARG3 (a4 / amino-acid :mod 1047 :name (n6 / name :op1 "histidine")))
                  :mod (a5 / also))))

# ::id pmid_2354_8132.98 ::date 2015-08-30T05:58:36 ::annotator SDL-AMR-09 ::preferred
# ::snt <sec-title level="2">PIK3CA</sec-title>
# ::save-date Sun Aug 30, 2015 ::file pmid_2354_8132_98.txt
(g / gene :name (n / name :op1 "PIK3CA"))

# ::id pmid_2354_8132.99 ::date 2015-08-30T06:12:00 ::annotator SDL-AMR-09 ::preferred
# ::snt <i>PIK3CA</i> mutations were present in 10.9% (22/201) of the tumors, unequally distributed between exons 9 and 20: 73% (16/22) were helical domain mutants (p.Glu542Lys, p.Glu545Lys, p.Glu545Asp, and p.Gln546Lys) and 27% (6/22) kinase domain mutants (p.Met1043Ile, p.His1047Arg, p.His1047Leu, and p.His1047Tyr).
# ::save-date Sun Jan 3, 2016 ::file pmid_2354_8132_99.txt
(p / present-02
      :ARG1 (m / mutate-01
            :ARG1 (g / gene :name (n / name :op1 "PIK3CA"))
            :ARG1-of (d / distribute-01
                  :ARG2 (b / between
                        :op1 (e2 / exon :mod 9)
                        :op2 (e3 / exon :mod 20))
                  :manner (e / equal-01 :polarity -)
                  :ARG1-of (m2 / mean-01
                        :ARG2 (a / and
                              :op1 (m3 / mutate-01 :quant 16
                                    :ARG1 (d4 / domain
                                          :mod (h / helical))
                                    :ARG1-of (i / include-91
                                          :ARG2 (m4 / mutate-01 :quant 22)
                                          :ARG3 (p2 / percentage-entity :value 73))
                                    :ARG1-of (m5 / mean-01
                                          :ARG2 (a2 / and
                                                :op1 (m6 / mutate-01
                                                      :ARG2 (a3 / amino-acid :name (n4 / name :op1 "lysine"))
                                                      :ARG3 (a4 / amino-acid :mod 542 :name (n5 / name :op1 "glutamic" :op2 "acid")))
                                                :op2 (m7 / mutate-01
                                                      :ARG2 a3
                                                      :ARG3 (a5 / amino-acid :mod 545 :name (n6 / name :op1 "glutamic" :op2 "acid")))
                                                :op3 (m8 / mutate-01
                                                      :ARG2 (a6 / amino-acid :name (n7 / name :op1 "aspartic" :op2 "acid"))
                                                      :ARG3 a5)
                                                :op4 (m9 / mutate-01
                                                      :ARG2 a3
                                                      :ARG3 (a7 / amino-acid :mod 546 :name (n8 / name :op1 "glutamine"))))))
                              :op2 (m10 / mutate-01 :quant 6
                                    :ARG1 (d5 / domain
                                          :mod (k / kinase))
                                    :ARG1-of (i2 / include-91
                                          :ARG2 m4
                                          :ARG3 (p3 / percentage-entity :value 27))
                                    :ARG1-of (m11 / mean-01
                                          :ARG2 (a8 / and
                                                :op1 (m12 / mutate-01
                                                      :ARG2 (a9 / amino-acid :name (n9 / name :op1 "isoleucine"))
                                                      :ARG3 (a10 / amino-acid :mod 1043 :name (n10 / name :op1 "methionine")))
                                                :op2 (m13 / mutate-01
                                                      :ARG2 (a11 / amino-acid :name (n11 / name :op1 "arginine"))
                                                      :ARG3 (a12 / amino-acid :mod 1047 :name (n12 / name :op1 "histidine")))
                                                :op3 (m14 / mutate-01
                                                      :ARG2 (a13 / amino-acid :name (n13 / name :op1 "leucine"))
                                                      :ARG3 a12)
                                                :op4 (m15 / mutate-01
                                                      :ARG2 (a14 / amino-acid :name (n14 / name :op1 "tyrosine"))
                                                      :ARG3 a12))))))))
      :ARG2 (t / tumor :quant 22
            :ARG1-of (i3 / include-91
                  :ARG2 (t2 / tumor :quant 201)
                  :ARG3 (p4 / percentage-entity :value 10.9))))

# ::id pmid_2354_8132.100 ::date 2015-08-30T07:12:42 ::annotator SDL-AMR-09 ::preferred
# ::snt Five of the <i>PIK3CA</i> mutants also contained another mutation in either <i>KRAS</i> or <i>BRAF</i>.
# ::save-date Sun Sep 13, 2015 ::file pmid_2354_8132_100.txt
(c / contain-01
      :ARG0 (m / mutate-01 :quant 5
            :ARG2 (g / gene :name (n / name :op1 "PIK3CA"))
            :ARG1-of (i / include-91
                  :ARG2 (m2 / mutate-01
                        :ARG2 g)))
      :ARG1 (m3 / mutate-01
            :ARG1 (o / or
                  :op1 (g2 / gene :name (n2 / name :op1 "KRAS"))
                  :op2 (g3 / gene :name (n3 / name :op1 "BRAF")))
            :mod (a / another))
      :mod (a2 / also))

# ::id pmid_2354_8132.101 ::date 2015-08-30T07:17:46 ::annotator SDL-AMR-09 ::preferred
# ::snt <sec-title level="2">Clinicopathological associations</sec-title>
# ::save-date Sun Aug 30, 2015 ::file pmid_2354_8132_101.txt
(a / associate-01
      :mod (c / clinicopathological))

# ::id pmid_2354_8132.102 ::date 2015-08-30T07:20:16 ::annotator SDL-AMR-09 ::preferred
# ::snt <i>KRAS</i> mutations were more frequent in patients older than the median age of diagnosis (21.5% <i>vs.</i> 8.2%; <i>P</i>=0.034), whereas no statistically significant differences were found for <i>BRAF</i> or <i>PIK3CA</i> mutations regarding this parameter.
# ::save-date Tue Dec 15, 2015 ::file pmid_2354_8132_102.txt
(c / contrast-01
      :ARG1 (f / frequent-02
            :ARG1 (m / mutate-01
                  :ARG1 (g / gene :name (n / name :op1 "KRAS")))
            :location (p / person
                  :ARG0-of (h / have-rel-role-91
                        :ARG2 (p2 / patient))
                  :mod (o / old
                        :degree (m2 / more)
                        :compared-to (a / age
                              :mod (d / diagnose-01)
                              :mod (m3 / median))))
            :degree (m4 / more)
            :ARG1-of (m5 / mean-01
                  :ARG2 (c2 / contrast-01
                        :ARG1 (p3 / percentage-entity :value 21.5)
                        :ARG2 (p4 / percentage-entity :value 8.2)))
            :ARG1-of (s3 / statistical-test-91
                  :ARG2 0.034))
      :ARG2 (f2 / find-01 :polarity -
            :ARG1 (d2 / differ-02
                  :ARG1 (o2 / or
                        :op1 (m6 / mutate-01
                              :ARG1 (g2 / gene :name (n2 / name :op1 "BRAF")))
                        :op2 (m7 / mutate-01
                              :ARG1 (g3 / gene :name (n3 / name :op1 "PIK3CA"))))
                  :ARG3 (p6 / parameter
                        :mod (t / this))
                  :ARG1-of (s / significant-02
                        :manner (s2 / statistics)))
            :ARG0-of (r / regard-01)))

# ::id pmid_2354_8132.103 ::date 2015-08-30T13:14:08 ::annotator SDL-AMR-09 ::preferred
# ::snt <i>BRAF</i> and <i>PIK3CA</i> mutations were more frequent in the colon than in the sigmoid or rectum: 20.8% <i>vs.</i> 1.6% <i>vs.</i> 0.0% (<i>P=</i>0.000) for <i>BRAF</i> and 23.4% <i>vs.</i> 12.1% <i>vs.</i> 5.4% (<i>P</i>=0.011) for <i>PIK3CA</i> mutations (Figure <xref ref-type="fig" rid="F3">3</xref>).
# ::save-date Tue Dec 15, 2015 ::file pmid_2354_8132_103.txt
(f / frequent-02
      :ARG1 (a / and
            :op1 (m / mutate-01
                  :ARG1 (g / gene :name (n / name :op1 "BRAF")))
            :op2 (m2 / mutate-01
                  :ARG1 (g2 / gene :name (n2 / name :op1 "PIK3CA"))))
      :degree (m3 / more)
      :location (c / colon)
      :compared-to (o / or
            :op1 (s / sigmoid)
            :op2 (r / rectum))
      :ARG1-of (m4 / mean-01
            :ARG2 (a2 / and
                  :op1 (m5 / mutate-01
                        :ARG1 g
                        :quant (p / percentage-entity :value 20.8)
                        :location c
                        :compared-to (m6 / mutate-01
                              :ARG1 g
                              :quant (p2 / percentage-entity :value 1.6)
                              :location s)
                        :compared-to (m7 / mutate-01
                              :ARG1 g
                              :quant (p3 / percentage-entity :value 0.0)
                              :location r)
                        :ARG1-of (s2 / statistical-test-91
                              :ARG2 0.000))
                  :op2 (m8 / mutate-01
                        :ARG1 g2
                        :quant (p5 / percentage-entity :value 23.4)
                        :location c
                        :compared-to (m9 / mutate-01
                              :ARG1 2
                              :quant (p6 / percentage-entity :value 12.1)
                              :location s)
                        :compared-to (m10 / mutate-01
                              :ARG1 g2
                              :quant (p7 / percentage-entity :value 5.4)
                              :location r)
                        :ARG1-of (s3 / statistical-test-91
                              :ARG2 0.011))))
      :ARG1-of (d / describe-01
            :ARG0 (f2 / figure :mod 3)))

# ::id pmid_2354_8132.104 ::date 2015-08-30T13:31:52 ::annotator SDL-AMR-09 ::preferred
# ::snt Although the frequency of <i>KRAS</i> mutations is higher in sigmoid and rectum, the difference is not statistically significant.
# ::save-date Sun Sep 13, 2015 ::file pmid_2354_8132_104.txt
(s / significant-02 :polarity -
      :ARG1 (d / differ-02)
      :manner (s2 / statistics)
      :concession (h / high-02
            :ARG1 (f / frequent-02
                  :ARG1 (m / mutate-01
                        :ARG1 (g / gene :name (n / name :op1 "KRAS"))))
            :location (a / and
                  :op1 (s3 / sigmoid)
                  :op2 (r / rectum))
            :degree (m2 / more)))

# ::id pmid_2354_8132.105 ::date 2015-08-30T13:44:03 ::annotator SDL-AMR-09 ::preferred
# ::snt No significant differences were found between genders regarding <i>KRAS</i>, <i>BRAF</i>, or <i>PIK3CA</i> mutation frequencies.
# ::save-date Sun Sep 13, 2015 ::file pmid_2354_8132_105.txt
(f / find-01 :polarity -
      :ARG1 (d / differ-02
            :ARG1 (g / gender)
            :ARG3 (f2 / frequent-02
                  :ARG1 (o / or
                        :op1 (m / mutate-01
                              :ARG1 (g2 / gene :name (n / name :op1 "KRAS")))
                        :op2 (m2 / mutate-01
                              :ARG1 (g3 / gene :name (n2 / name :op1 "BRAF")))
                        :op3 (m3 / mutate-01
                              :ARG1 (g4 / gene :name (n3 / name :op1 "PIK3CA")))))
            :ARG1-of (s / significant-02)))

# ::id pmid_2384_5441.1 ::date 2015-06-24T12:39:12 ::annotator SDL-AMR-09 ::preferred
# ::snt A Genetic Progression Model of Braf<sup>V600E</sup>-Induced Intestinal Tumorigenesis Reveals Targets for Therapeutic Intervention (PMID:23845441)
# ::save-date Mon Nov 2, 2015 ::file pmid_2384_5441_1.txt
(r / reveal-01
      :ARG0 (m / model
            :mod (p / progress-01
                  :mod (g / genetic))
            :topic (c / create-01
                  :ARG1 (t3 / tumor
                        :mod (i2 / intestine))
                  :ARG2-of (i3 / induce-01
                        :ARG0 (e / enzyme :name (n / name :op1 "Braf")
                              :ARG2-of (m2 / mutate-01 :value "V600E")))))
      :ARG1 (t / target-01
            :purpose (i / intervene-01
                  :ARG1 (t2 / therapy)))
      :ARG1-of (d / describe-01
            :ARG0 (p3 / publication-91
                  :ARG8 "PMID23845441")))

# ::id pmid_2384_5441.52 ::date 2015-06-24T12:41:09 ::annotator SDL-AMR-09 ::preferred
# ::snt <sec-title level="1">Results</sec-title>
# ::save-date Thu Jun 25, 2015 ::file pmid_2384_5441_52.txt
(t / thing
      :ARG2-of (r / result-01))

# ::id pmid_2384_5441.53 ::date 2015-06-24T12:53:56 ::annotator SDL-AMR-09 ::preferred
# ::snt <sec-title level="2">BRAF<sup>V600E</sup> Initiates a Serrated Pathway to Intestinal Tumorigenesis</sec-title>
# ::save-date Tue Jan 19, 2016 ::file pmid_2384_5441_53.txt
(i / initiate-01
      :ARG0 (e / enzyme :name (n / name :op1 "BRAF")
            :ARG2-of (m / mutate-01 :value "V600E"))
      :ARG1 (p / pathway
            :ARG1-of (s / serrate-01)
            :destination (c / create-01
                  :ARG1 (t / tumor
                        :mod (i2 / intestine)))))

# ::id pmid_2384_5441.54 ::date 2015-06-24T13:04:20 ::annotator SDL-AMR-09 ::preferred
# ::snt To examine the effect of <i>Braf</i><sup><i>V600E</i></sup> in the intestine, we created a <i>Braf</i> knockin allele, which can be activated by Cre, leading to the production of the V637E mutant Braf protein.
# ::save-date Sat Jan 16, 2016 ::file pmid_2384_5441_54.txt
(c / create-01
      :ARG0 (w / we)
      :ARG1 (a / allele
            :mod (g / gene :name (n / name :op1 "Braf"))
            :ARG1-of (k / knock-in-00)
            :ARG1-of (a2 / activate-01
                  :ARG0 (e3 / enzyme :name (n2 / name :op1 "Cre"))
                  :ARG1-of (p / possible-01)
                  :ARG0-of (l / lead-03
                        :ARG2 (p3 / produce-01
                              :ARG0 a2
                              :ARG1 (e4 / enzyme :name (n3 / name :op1 "Braf")
                                    :ARG2-of (m / mutate-01 :value "V637E"))))))
      :purpose (e / examine-01
            :ARG0 w
            :ARG1 (a3 / affect-01
                  :ARG0 (g2 / gene :name (n4 / name :op1 "Braf")
                        :ARG2-of (m2 / mutate-01 :value "V600E"))
                  :ARG1 (i / intestine))))

# ::id pmid_2384_5441.55 ::date 2015-06-24T14:14:39 ::annotator SDL-AMR-09 ::preferred
# ::snt <i>Braf</i><sup><i>V637E</i></sup> in mouse exon 18 is at the orthologous position of the human <i>BRAF</i><sup><i>V600E</i></sup> mutation affecting exon 15.
# ::save-date Sat Jan 16, 2016 ::file pmid_2384_5441_55.txt
(b / be-located-at-91
      :ARG1 (g / gene :name (n / name :op1 "Braf")
            :ARG2-of (m / mutate-01 :value "V637E")
            :location (e / exon :mod 18
                  :mod (m2 / mouse)))
      :ARG2 (p / position
            :mod (o / orthologous)
            :compared-to (g2 / gene :name (n2 / name :op1 "Braf")
                  :ARG2-of (m3 / mutate-01 :value "V600E")
                  :mod (h / human)
                  :ARG0-of (a / affect-01
                        :ARG1 (e2 / exon :mod 15)))))

# ::id pmid_2384_5441.56 ::date 2015-06-24T14:22:21 ::annotator SDL-AMR-09 ::preferred
# ::snt In the absence of Cre, a Lox-Stop-Lox cassette located in intron 17 prevents expression of the mutant allele (<xref ref-type="fig" rid="fig1">Figures 1</xref>A–1D).
# ::save-date Thu Jul 2, 2015 ::file pmid_2384_5441_56.txt
(p / prevent-01
      :ARG0 (c3 / cassette :name (n / name :op1 "Lox-Stop-Lox")
            :location (i / intron :mod 17))
      :ARG1 (e / express-03
            :ARG1 (a / allele
                  :ARG2-of (m / mutate-01)))
      :ARG1-of (c2 / cause-01
            :ARG0 (a2 / absent-01
                  :ARG1 (e2 / enzyme :name (n2 / name :op1 "Cre"))))
      :ARG1-of (d / describe-01
            :ARG0 (v / value-interval
                  :op1 (f / figure :mod "1A")
                  :op2 (f2 / figure :mod "1D"))))

# ::id pmid_2384_5441.57 ::date 2015-06-24T14:29:24 ::annotator SDL-AMR-09 ::preferred
# ::snt To direct mutant Braf expression to the intestine, we used <i>Villin-Cre</i> (<i>Vil-Cre</i>) mice in which Cre is broadly expressed in epithelia of the small and large intestine (<xref ref-type="bibr" rid="bib26">Madison et al., 2002</xref>).
# ::save-date Sat Jan 16, 2016 ::file pmid_2384_5441_57.txt
(u / use-01
      :ARG0 (w / we)
      :ARG1 (m / mouse
            :mod (m3 / macro-molecular-complex
                  :part (p5 / protein :name (n / name :op1 "Villin"))
                  :part (e4 / enzyme :name (n5 / name :op1 "Cre")))
            :location-of (e / express-03
                  :ARG2 e4
                  :ARG3 (e2 / epithelium
                        :part-of (a / and
                              :op1 (i / intestine
                                    :mod (s / small))
                              :op2 (i2 / intestine
                                    :mod (l / large))))
                  :ARG1-of (b / broad-02)))
      :ARG2 (d / direct-01
            :ARG0 w
            :ARG1 (e3 / express-03
                  :ARG2 (e5 / enzyme :name (n3 / name :op1 "Braf")
                        :ARG2-of (m2 / mutate-01)))
            :ARG2 (i3 / intestine))
      :ARG1-of (d2 / describe-01
            :ARG0 (p2 / publication-91
                  :ARG0 (a2 / and
                        :op1 (p3 / person :name (n4 / name :op1 "Madison"))
                        :op2 (p4 / person
                              :mod (o / other))
                        :time (d3 / date-entity :year 2002)))))

# ::id pmid_2384_5441.58 ::date 2015-06-25T10:29:56 ::annotator SDL-AMR-09 ::preferred
# ::snt In <i>Vil-Cre;Braf</i><sup><i>LSL-V637E/+</i></sup> mice the stop cassette at the <i>Braf</i> locus is excised specifically in the intestine but not in other organs (<xref ref-type="fig" rid="fig1">Figure 1</xref>E).
# ::save-date Sat Jan 16, 2016 ::file pmid_2384_5441_58.txt
(c3 / contrast-01
      :ARG1 (e / excise-01
            :ARG1 (c / cassette
                  :ARG2-of (s / stop-01))
            :ARG2 (l / locus
                  :mod (g / gene :name (n / name :op1 "Braf")))
            :location (i / intestine)
            :ARG1-of (s2 / specific-02))
      :ARG2 (e2 / excise-01 :polarity -
            :ARG1 c
            :ARG2 l
            :location (o / organ
                  :mod (o2 / other)))
      :location (m / mouse
            :mod (m3 / macro-molecular-complex
                  :part (p / protein :name (n2 / name :op1 "Villin"))
                  :part (e4 / enzyme :name (n4 / name :op1 "Cre")))
            :mod (g2 / gene :name (n3 / name :op1 "Braf")
                  :ARG2-of (m2 / mutate-01 :value "LSL-V637E/+")))
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod "1E")))

# ::id pmid_2384_5441.59 ::date 2015-06-25T10:44:45 ::annotator SDL-AMR-09 ::preferred
# ::snt The murine <i>Braf</i><sup><i>LSL-V637E</i></sup> allele is a knockin allele and is thus expressed from the endogenous <i>Braf</i> locus at physiologic levels.
# ::save-date Sat Jan 16, 2016 ::file pmid_2384_5441_59.txt
(a / allele
      :mod (g / gene :name (n / name :op1 "Braf")
            :ARG2-of (m / mutate-01 :value "LSL-V637E"))
      :domain (a2 / allele
            :ARG1-of (k / knock-in-00)
            :ARG0-of (c / cause-01
                  :ARG1 (e / express-03
                        :ARG1 a
                        :ARG3 (l / locus
                              :mod (g2 / gene :name (n2 / name :op1 "Braf"))
                              :mod (e2 / endogenous))
                        :location (l2 / level
                              :mod (p / physiologic)))))
      :mod (o / organism :name (n3 / name :op1 "Muridae")))

# ::id pmid_2384_5441.60 ::date 2015-06-25T11:04:52 ::annotator SDL-AMR-09 ::preferred
# ::snt All <i>Vil-Cre;Braf</i><sup><i>LSL-V637E</i>/+</sup> animals developed lifelong persistent generalized crypt hyperplasia affecting nearly every crypt, leading to significantly elongated and thickened small and large intestines (<xref ref-type="fig" rid="fig1">Figures 1</xref>F–1P; <xref ref-type="sec" rid="app3">Figure S1</xref>A available online).
# ::save-date Sat Jan 16, 2016 ::file pmid_2384_5441_60.txt
(d / develop-01
      :ARG1 (a / animal
            :mod (a2 / all)
            :mod (m2 / macro-molecular-complex
                  :part (p / protein :name (n / name :op1 "Villin"))
                  :part (e4 / enzyme :name (n4 / name :op1 "Cre")))
            :mod (g / gene :name (n2 / name :op1 "Braf")
                  :ARG2-of (m / mutate-01 :value "LSL-V637E/+")))
      :ARG2 (h / hyperplasia
            :mod (c / crypt)
            :ARG1-of (g2 / generalize-01)
            :duration (l / lifelong)
            :ARG0-of (a3 / affect-01
                  :ARG1 (c2 / crypt
                        :mod (e / every
                              :mod (n3 / near))))
            :ARG0-of (l2 / lead-03
                  :ARG2 (a4 / and
                        :op1 (e2 / elongate-01
                              :ARG1 (a5 / and
                                    :op1 (i / intestine
                                          :mod (s / small))
                                    :op2 (i2 / intestine
                                          :mod (l3 / large))))
                        :op2 (t / thicken-01
                              :ARG1 a5)
                        :ARG1-of (s2 / significant-02)))
            :ARG1-of (p2 / persist-01))
      :ARG1-of (d2 / describe-01
            :ARG0 (a6 / and
                  :op1 (v / value-interval
                        :op1 (f / figure :mod "1F")
                        :op2 (f2 / figure :mod "1P"))
                  :op2 (f3 / figure :mod "S1A"
                        :ARG2-of (a7 / available-02
                              :medium (o / online))))))

# ::id pmid_2384_5441.61 ::date 2015-06-25T11:31:52 ::annotator SDL-AMR-09 ::preferred
# ::snt Endoscopically and histologically, villi in the small intestine (SI) had a thickened and deformed appearance and were often branched (<xref ref-type="fig" rid="fig1">Figures 1</xref>I–1L).
# ::save-date Thu Jul 2, 2015 ::file pmid_2384_5441_61.txt
(a / and
      :op1 (h / have-03
            :ARG0 (v / villus
                  :part-of (i / intestine
                        :mod (s / small)))
            :ARG1 (a2 / appear-01
                  :ARG1 (a3 / and
                        :op1 (t / thicken-01)
                        :op2 (d / deform-01))))
      :op2 (b / branch-01
            :frequency (o / often))
      :mod (e / endoscopic)
      :mod (h2 / histologic)
      :ARG1-of (d2 / describe-01
            :ARG0 (v2 / value-interval
                  :op1 (f / figure :mod "1I")
                  :op2 (f2 / figure :mod "1L"))))

# ::id pmid_2384_5441.62 ::date 2015-06-25T11:44:49 ::annotator SDL-AMR-09 ::preferred
# ::snt Changes in the large intestine (LI) included crypt hyperplasia and mucosal protrusions resembling villous structures that replaced the normal crypt pattern (<xref ref-type="fig" rid="fig1">Figures 1</xref>M–1P).
# ::save-date Mon Dec 21, 2015 ::file pmid_2384_5441_62.txt
(i / include-01
      :ARG1 (a / and
            :op1 (h / hyperplasia
                  :mod (c2 / crypt))
            :op2 (p / protrude-01
                  :ARG2 (m / mucus)
                  :ARG1-of (r / resemble-01
                        :ARG2 (s / structure
                              :mod (v / villus)
                              :ARG2-of (r2 / replace-01
                                    :ARG1 (p2 / pattern-01
                                          :ARG1 (c3 / crypt
                                                :ARG1-of (n / normal-02))))))))
      :ARG2 (c / change-01
            :ARG1 (i2 / intestine
                  :mod (l / large)))
      :ARG1-of (d / describe-01
            :ARG0 (v2 / value-interval
                  :op1 (f / figure :mod "1M")
                  :op2 (f2 / figure :mod "1P"))))

# ::id pmid_2384_5441.63 ::date 2015-06-27T03:51:45 ::annotator SDL-AMR-09 ::preferred
# ::snt This generalized hyperplasia was characterized by focal serrated epithelial formations, which had cytomorphologic features of human microvesicular or goblet cell-rich hyperplastic (serrated) polyps (<xref ref-type="fig" rid="fig1">Figures 1</xref>Q–1T and <xref ref-type="sec" rid="app3">S1</xref>B).
# ::save-date Tue Jan 19, 2016 ::file pmid_2384_5441_63.txt
(c / characterize-01
      :ARG1 (h / hyperplasia
            :mod (t / this)
            :ARG1-of (g / generalize-01))
      :ARG2 (f / form-01
            :ARG1 (e / epithelium
                  :ARG1-of (s / serrate-01
                        :ARG2 (f2 / focus)))
            :ARG0-of (h2 / have-03
                  :ARG1 (f3 / feature
                        :mod (c2 / cytomorphologic)
                        :poss (o / or
                              :op1 (p / polyp
                                    :mod (m / microvesicular)
                                    :mod (h3 / human))
                              :op2 (p3 / polyp
                                    :mod (h5 / hyperplastic)
                                    :mod (r / rich
                                          :mod (c3 / cell :name (n / name :op1 "goblet" :op2 "cell"))))))))
      :ARG1-of (d / describe-01
            :ARG0 (a / and
                  :op1 (v / value-interval
                        :op1 (f4 / figure :mod "1Q")
                        :op2 (f5 / figure :mod "1T"))
                  :op2 (f6 / figure :mod "S1B"))))

# ::id pmid_2384_5441.64 ::date 2015-06-27T05:24:21 ::annotator SDL-AMR-09 ::preferred
# ::snt Both types were present in the LI, whereas microvesicular hyperplasia was predominant in the SI.
# ::save-date Mon Dec 21, 2015 ::file pmid_2384_5441_64.txt
(c / contrast-01
      :ARG1 (p / present-02
            :ARG1 (t / type-03
                  :mod (b / both))
            :ARG2 (i / intestine
                  :mod (l / large)))
      :ARG2 (p2 / predominate-01
            :ARG1 (h / hyperplasia
                  :mod (m / microvesicular))
            :location (i2 / intestine
                  :mod (s / small))))

# ::id pmid_2384_5441.65 ::date 2015-06-27T05:29:40 ::annotator SDL-AMR-09 ::preferred
# ::snt Because of this resemblance to human serrated hyperplasia (<xref ref-type="sec" rid="app3">Figure S1</xref>B), we refer to the histology in the mouse as murine serrated hyperplasia (mSH).
# ::save-date Tue Jan 19, 2016 ::file pmid_2384_5441_65.txt
(r / refer-01
      :ARG0 (w / we)
      :ARG1 (h / histology
            :location (m / mouse))
      :ARG2 (m2 / medical-condition :name (n2 / name :op1 "hyperplasia")
            :ARG1-of (s / serrate-01)
            :mod (o / organism :name (n / name :op1 "Muridae")))
      :ARG0-of (c / cause-01
            :ARG1 (r2 / resemble-01
                  :ARG2 (m3 / medical-condition :name (n3 / name :op1 "hyperplasia")
                        :mod (h4 / human)
                        :ARG1-of s)
                  :mod (t / this))))

# ::id pmid_2384_5441.66 ::date 2015-06-27T05:57:20 ::annotator SDL-AMR-09 ::preferred
# ::snt Like in human serrated hyperplastic polyps, there was a mild increase in the number of proliferating cells in mSH as compared to wild-type mucosa (<xref ref-type="sec" rid="app3">Figures S1</xref>C and S1D).
# ::save-date Tue Jan 19, 2016 ::file pmid_2384_5441_66.txt
(i / increase-01
      :ARG1 (n / number
            :quant-of (c / cell
                  :ARG0-of (p / proliferate-01)
                  :location (m4 / medical-condition :name (n2 / name :op1 "mSH"))))
      :degree (m / mild)
      :ARG1-of (d / describe-01
            :ARG0 (a / and
                  :op1 (f / figure :mod "S1C")
                  :op2 (f2 / figure :mod "S1D")))
      :ARG1-of (r / resemble-01
            :ARG2 (p2 / polyp
                  :mod (h / hyperplastic)
                  :ARG1-of (s / serrate-01)
                  :mod (h2 / human)))
      :ARG1-of (c2 / compare-01
            :ARG2 (m3 / mucosa
                  :mod (w / wild-type))))

# ::id pmid_2384_5441.67 ::date 2015-06-27T06:18:51 ::annotator SDL-AMR-09 ::preferred
# ::snt Ki67-positive cells were present in the mid and/or upper crypt in <i>Vil-Cre;Braf</i><sup><i>LSL-V637E</i>/+</sup> intestines but were restricted to the lower crypt in wild-type intestines (<xref ref-type="sec" rid="app3">Figure S1</xref>C).
# ::save-date Sat Jan 16, 2016 ::file pmid_2384_5441_67.txt
(c / contrast-01
      :ARG1 (p4 / present-02
            :ARG1 (c2 / cell
                  :mod (p / protein :name (n / name :op1 "Ki67"))
                  :mod (p2 / positive))
            :ARG2 (a / and-or
                  :op1 (c3 / crypt
                        :mod (m / mid))
                  :op2 (c4 / crypt
                        :mod (u / upper))
                  :part-of (i / intestine
                        :mod (g / gene :name (n3 / name :op1 "Braf")
                              :ARG2-of (m2 / mutate-01 :value "LSL-V637E"))
                        :mod (m4 / macro-molecular-complex
                              :part (p3 / protein :name (n2 / name :op1 "Villin"))
                              :part (e2 / enzyme :name (n4 / name :op1 "Cre"))))))
      :ARG2 (r / restrict-01
            :ARG1 c2
            :location (c5 / crypt
                  :ARG1-of (l / low-04
                        :degree (m3 / more))
                  :part-of (i2 / intestine
                        :mod (w / wild-type))))
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod "S1C")))

# ::id pmid_2384_5441.68 ::date 2015-06-27T07:22:54 ::annotator SDL-AMR-09 ::preferred
# ::snt Hyperproliferation seems to be the underlying mechanism of the hyperplastic changes because apoptosis was not reduced in <i>Vil-Cre;Braf</i><sup><i>LSL-V637E</i>/+</sup> intestines as compared to wild-type mucosa (<xref ref-type="sec" rid="app3">Figures S1</xref>E and S1F).
# ::save-date Tue Feb 2, 2016 ::file pmid_2384_5441_68.txt
(s / seem-01
      :ARG1 (m / mechanism
            :ARG0-of (u / underlie-01
                  :ARG1 (c / change-01
                        :mod (h2 / hyperplastic)))
            :domain (h / hyperproliferate-01))
      :ARG1-of (c2 / cause-01
            :ARG0 (r / reduce-01 :polarity -
                  :ARG1 (a / apoptosis)
                  :location (i / intestine
                        :mod (m4 / macro-molecular-complex
                              :part (p / protein :name (n / name :op1 "Villin"))
                              :part (e2 / enzyme :name (n3 / name :op1 "Cre")))
                        :mod (g / gene :name (n2 / name :op1 "Braf")
                              :ARG2-of (m2 / mutate-01 :value "LSL-V637E")))
                  :ARG1-of (c3 / compare-01
                        :ARG2 (m3 / mucosa
                              :mod (w / wild-type)))))
      :ARG1-of (d / describe-01
            :ARG0 (a2 / and
                  :op1 (f / figure :mod "S1E")
                  :op2 (f2 / figure :mod "S1F"))))

# ::id pmid_2384_5441.69 ::date 2015-06-27T07:51:34 ::annotator SDL-AMR-09 ::preferred
# ::snt We also intercrossed <i>LSL-Braf</i><sup><i>V600E</i></sup> mice with <i>Lgr5-EGFP-IRES-CreERT2</i> knockin mice.
# ::save-date Sat Jan 16, 2016 ::file pmid_2384_5441_69.txt
(i / intercross-00
      :ARG0 (w / we)
      :ARG1 (m / mouse
            :mod (m5 / molecular-physical-entity :name (n / name :op1 "LSL"))
            :mod (g / gene :name (n2 / name :op1 "Braf")
                  :ARG2-of (m2 / mutate-01 :value "V600E")))
      :ARG2 (m3 / mouse
            :ARG1-of (k / knock-in-00)
            :mod (m4 / molecular-physical-entity :name (n3 / name :op1 "Lgr5-EGFP-IRES-CreERT2")))
      :mod (a / also))

# ::id pmid_2384_5441.70 ::date 2015-06-27T09:01:35 ::annotator SDL-AMR-09 ::preferred
# ::snt Tamoxifen-inducible Lgr5-Cre allowed stochastic activation of mutant Braf in a part of the intestinal stem cells, thereby inducing hyperplastic polyps in nonhyperplastic surrounding mucosa (<xref ref-type="sec" rid="app3">Figure S1</xref>G).
# ::save-date Sun Jan 17, 2016 ::file pmid_2384_5441_70.txt
(a / allow-01
      :ARG0 (m / macro-molecular-complex
            :part (p / protein :name (n / name :op1 "Lgr5"))
            :part (e2 / enzyme :name (n2 / name :op1 "Cre"))
            :ARG2-of (i / induce-01
                  :ARG0 (s / small-molecule :name (n3 / name :op1 "tamoxifen"))
                  :ARG1-of (p3 / possible-01)))
      :ARG1 (a2 / activate-01
            :ARG1 (e / enzyme :name (n4 / name :op1 "Braf")
                  :ARG1-of (m2 / mutate-01))
            :mod (s2 / stochastic))
      :location (p4 / part
            :part-of (c / cell
                  :mod (s3 / stem)
                  :source (i2 / intestine)))
      :ARG0-of (c2 / cause-01
            :ARG1 (i3 / induce-01
                  :ARG2 (p5 / polyp
                        :mod (h / hyperplastic))
                  :location (m3 / mucosa
                        :ARG1-of (s4 / surround-01)
                        :mod (h2 / hyperplastic :polarity -))))
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod "S1G")))

# ::id pmid_2384_5441.71 ::date 2015-06-27T09:22:48 ::annotator SDL-AMR-09 ::preferred
# ::snt <i>BRAF</i> mutations have been observed in human serrated polyps occurring sporadically or in serrated polyposis syndrome and we show here that BRAF<sup>V600E</sup> is indeed the underlying initiating event that is sufficient to induce lifelong sustained hyperplasia.
# ::save-date Tue Jan 19, 2016 ::file pmid_2384_5441_71.txt
(a / and
      :op1 (o / observe-01
            :ARG1 (m / mutate-01
                  :ARG1 (g / gene :name (n / name :op1 "BRAF")))
            :location (o2 / or
                  :op1 (p / polyp
                        :mod (h / human)
                        :ARG1-of (s / serrate-01)
                        :frequency (s2 / sporadic))
                  :op2 (s3 / syndrome
                        :mod (p2 / polyposis
                              :ARG1-of s))))
      :op2 (s4 / show-01
            :ARG0 (w / we)
            :ARG1 (e / event
                  :ARG0-of (i / initiate-01)
                  :ARG0-of (u / underlie-01)
                  :domain (e2 / enzyme :name (n2 / name :op1 "BRAF")
                        :ARG2-of (m2 / mutate-01 :value "V600E"))
                  :ARG0-of (s5 / suffice-01
                        :ARG1 (i2 / induce-01
                              :ARG2 (h2 / hyperplasia
                                    :duration (l / lifelong)
                                    :ARG1-of (s6 / sustain-01))))
                  :mod (i3 / indeed))
            :location (h3 / here)))

# ::id pmid_2384_5441.72 ::date 2015-06-27T09:42:14 ::annotator SDL-AMR-09 ::preferred
# ::snt <sec-title level="2">BRAF<sup>V600E</sup> Induced Serrated Tumorigenesis Progresses through a Hyperplasia/Adenoma/Carcinoma Sequence</sec-title>
# ::save-date Tue Jan 19, 2016 ::file pmid_2384_5441_72.txt
(p / progress-01
      :ARG1 (c2 / create-01
            :ARG1 (t / tumor)
            :ARG1-of (s / serrate-01)
            :ARG2-of (i / induce-01
                  :ARG0 (e / enzyme :name (n / name :op1 "BRAF")
                        :ARG2-of (m / mutate-01 :value "V600E"))))
      :instrument (s2 / slash
            :op1 (s3 / sequence
                  :mod (m3 / medical-condition :name (n3 / name :op1 "hyperplasia")))
            :op2 (s4 / sequence
                  :mod (m2 / medical-condition :name (n2 / name :op1 "adenoma")))
            :op3 (s5 / sequence
                  :mod (c / carcinoma))))

# ::id pmid_2384_5441.73 ::date 2015-06-27T09:52:06 ::annotator SDL-AMR-09 ::preferred
# ::snt To investigate whether mSH progresses to dysplasia, we aged <i>Vil-Cre;Braf</i><sup><i>LSL-V637E</i>/+</sup>mice up to 18 months and sacrificed them at various time points.
# ::save-date Sat Jan 16, 2016 ::file pmid_2384_5441_73.txt
(a / and
      :op1 (a2 / age-01
            :ARG0 (w / we)
            :ARG1 (m / mice
                  :mod (m2 / macro-molecular-complex
                        :part (p / protein :name (n / name :op1 "Villin"))
                        :part (e2 / enzyme :name (n2 / name :op1 "Cre")))
                  :mod (g / gene :name (n3 / name :op1 "Braf")
                        :ARG2-of (m3 / mutate-01 :value "LSL-V637E")))
            :time (u / up-to
                  :op1 (t / temporal-quantity :quant 18
                        :unit (m4 / month))))
      :op2 (s / sacrifice-01
            :ARG0 w
            :ARG1 m
            :time (p3 / point
                  :mod (t2 / time)
                  :mod (v / various)))
      :purpose (i / investigate-01
            :ARG0 w
            :ARG1 (p4 / progress-01 :mode interrogative
                  :ARG1 (m6 / medical-condition :name (n4 / name :op1 "mSH"))
                  :ARG4 (m7 / medical-condition :name (n5 / name :op1 "dysplasia")))))

# ::id pmid_2384_5441.74 ::date 2015-06-27T10:07:10 ::annotator SDL-AMR-09 ::preferred
# ::snt Hyperplasia to dysplasia progression was often observed at a young age (2–3 months), at which time some animals already developed macroscopic tumors (>2 mm) with dysplasia.
# ::save-date Sat Jul 4, 2015 ::file pmid_2384_5441_74.txt
(o / observe-01
      :ARG1 (p / progress-01
            :ARG3 (h / hyperplasia)
            :ARG4 (d / dysplasia))
      :time (a / age-01
            :ARG2 (y / young)
            :ARG1-of (m / mean-01
                  :ARG2 (t / temporal-quantity
                        :quant (v / value-interval :op1 2 :op2 3)
                        :unit (m2 / month)))
            :time-of (d2 / develop-01
                  :ARG1 (a2 / animal
                        :mod (s / some))
                  :ARG2 (t2 / tumor
                        :mod (m3 / macroscopic)
                        :quant (m4 / more-than
                              :op1 (a3 / area-quantity :quant 2
                                    :unit (m5 / millimeter)))
                        :accompanier d)
                  :time (a4 / already)))
      :frequency (o2 / often))

# ::id pmid_2384_5441.75 ::date 2015-06-27T10:38:58 ::annotator SDL-AMR-09 ::preferred
# ::snt At 10 months, virtually all mice had such dysplastic lesions, often large numbers (<xref ref-type="fig" rid="fig2">Figure 2</xref>A).
# ::save-date Sat Jul 4, 2015 ::file pmid_2384_5441_75.txt
(h / have-03
      :ARG0 (m / mouse
            :mod (a / all)
            :mod (v / virtual))
      :ARG1 (l / lesion
            :mod (d / dysplastic)
            :quant (n / number
                  :mod (l2 / large))
            :frequency (o / often)
            :mod (s / such))
      :age (t / temporal-quantity :quant 10
                  :unit (m2 / month))
      :ARG1-of (d2 / describe-01
            :ARG0 (f / figure :mod "2A")))

# ::id pmid_2384_5441.76 ::date 2015-06-27T10:48:33 ::annotator SDL-AMR-09 ::preferred
# ::snt Histologically, Braf<sup>V637E</sup>-induced dysplastic lesions had features of human traditional serrated adenomas (TSAs), including crypt elongation and a serrated eosinophilic adenomatous epithelium (<xref ref-type="fig" rid="fig2">Figures 2</xref>B–2E and <xref ref-type="sec" rid="app3">S1</xref>B).
# ::save-date Tue Jan 19, 2016 ::file pmid_2384_5441_76.txt
(h / have-03
      :ARG0 (l / lesion
            :mod (d / dysplastic)
            :ARG2-of (i / induce-01
                  :ARG0 (e4 / enzyme :name (n / name :op1 "Braf")
                        :ARG2-of (m / mutate-01 :value "V637E"))))
      :ARG1 (f / feature
            :ARG2-of (i2 / include-91
                  :ARG1 (a2 / and
                        :op1 (e / elongate-01
                              :ARG1 (c / crypt))
                        :op2 (e2 / epithelium
                              :mod (e3 / eosinophilic)
                              :ARG1-of s
                              :mod (m2 / medical-condition :name (n2 / name :op1 "adenoma")))))
            :poss (m3 / medical-condition :name (n3 / name :op1 "adenoma")
                  :ARG1-of (s / serrate-01)
                  :mod (t / traditional)
                  :mod (h2 / human)))
      :manner (h3 / histologic)
      :ARG1-of (d2 / describe-01
            :ARG0 (a4 / and
                  :op1 (v / value-interval
                        :op1 (f2 / figure :mod "2B")
                        :op2 (f3 / figure :mod "2E"))
                  :op2 (f4 / figure :mod "S1B"))))

# ::id pmid_2384_5441.77 ::date 2015-06-27T12:48:12 ::annotator SDL-AMR-09 ::preferred
# ::snt Although both TSAs and SSAs are associated with mutant <i>BRAF</i> in humans, we did not observe SSA in our model.
# ::save-date Wed Dec 9, 2015 ::file pmid_2384_5441_77.txt
(h / have-concession-91
      :ARG1 (o / observe-01 :polarity -
            :ARG0 (w / we)
            :ARG1 (m4 / medical-condition :name (n3 / name :op1 "sessile" :op2 "serrated" :op3 "adenoma"))
            :location (m / model
                  :poss w))
      :ARG2 (a / associate-01
            :ARG1 (a2 / and
                  :op1 (m3 / medical-condition :name (n2 / name :op1 "traditional" :op2 "serrated" :op3 "adenoma"))
                  :op2 m4)
            :ARG2 (g / gene :name (n4 / name :op1 "BRAF")
                  :ARG1-of (m2 / mutate-01))
            :location (h2 / human)))

# ::id pmid_2384_5441.78 ::date 2015-06-27T12:54:43 ::annotator SDL-AMR-09 ::preferred
# ::snt A possible reason is that mouse tumors were predominantly in the SI (only five of 95 tumors were in the large intestine), where the specific morphologic features of human colonic SSAs might not develop.
# ::save-date Mon Dec 21, 2015 ::file pmid_2384_5441_78.txt
(c / cause-01
      :ARG0 (b / be-located-at-91
            :ARG1 (t / tumor
                  :mod (m / mouse))
            :ARG2 (i / intestine
                  :mod (s / small)
                  :ARG1-of (d / develop-01 :polarity -
                        :ARG2 (f / feature
                              :ARG1-of (s2 / specific-02)
                              :mod (m3 / morphologic)
                              :poss (m4 / medical-condition :name (n2 / name :op1 "sessile" :op2 "serrated" :op3 "adenoma")
                                    :mod (h / human)
                                    :mod (c2 / colon)))
                        :ARG1-of (p3 / possible-01)))
            :ARG1-of (p2 / predominate-01)
            :ARG1-of (m2 / mean-01
                  :ARG2 (b2 / be-located-at-91
                        :ARG1 (t2 / tumor :quant 5
                              :ARG1-of (i3 / include-91
                                    :ARG2 (t3 / tumor :quant 95))
                              :mod (o / only))
                        :ARG2 (i2 / intestine
                              :mod (l / large)))))
      :ARG1-of (p / possible-01))

# ::id pmid_2384_5441.79 ::date 2015-06-27T13:23:40 ::annotator SDL-AMR-09 ::preferred
# ::snt To avoid misleading nomenclature by drawing inadequate morphologic parallels between murine SI lesions and human LI tumors, we refer to dysplastic lesions as “murine serrated adenoma with dysplasia” (mSA) or more specifically as mSA with low-grade dysplasia (mSA-LGD) or high-grade dysplasia (mSA-HGD).
# ::save-date Tue Jan 19, 2016 ::file pmid_2384_5441_79.txt
(r / refer-01
      :ARG0 (w / we)
      :ARG1 (l / lesion
            :mod (d / dysplastic))
      :ARG2 (o / or
            :op1 (m / medical-condition :name (n3 / name :op1 "adenoma")
                  :ARG1-of (s / serrate-01)
                  :mod (o3 / organism :name (n2 / name :op1 "Muridae"))
                  :prep-with (d2 / dysplasia))
            :op2 (o2 / or
                  :op1 (m2 / medical-condition :name (n4 / name :op1 "adenoma")
                        :ARG0-of (h4 / have-03
                              :ARG1 (d3 / dysplasia
                                    :degree (g / grade
                                          :ARG1-of (l2 / low-04)))))
                  :op2 (m3 / medical-condition :name (n5 / name :op1 "adenoma")
                        :ARG0-of (h3 / have-03
                              :ARG1 (d4 / dysplasia
                                    :degree (g2 / grade
                                          :ARG1-of (h / high-02))))
                        :ARG1-of (s3 / specific-02
                              :degree (m8 / more)))))
      :purpose (a2 / avoid-01
            :ARG0 w
            :ARG1 (n / nomenclature
                  :ARG0-of (m7 / mislead-02))
            :manner (d5 / draw-01
                  :ARG1 (p / parallel-01
                        :ARG1 (a4 / and
                              :op1 (l3 / lesion
                                    :mod (i / intestine
                                          :mod (s2 / small))
                                    :mod o3))
                        :mod (m6 / morphologic)
                        :mod (a3 / adequate :polarity -
                              :op2 (t / tumor
                                    :mod (h2 / human)
                                    :mod (i2 / intestine
                                          :mod (l4 / large))))))))

# ::id pmid_2384_5441.80 ::date 2015-06-27T13:55:24 ::annotator SDL-AMR-09 ::preferred
# ::snt Macroscopically, Braf<sup>V6<i>37</i>E</sup>-induced neoplasia resembled human <i>BRAF</i> mutant colonic tumors, which frequently show a nonpolypoid sessile growth pattern (<xref ref-type="sec" rid="app3">Figure S2</xref>A).
# ::save-date Sat Jan 16, 2016 ::file pmid_2384_5441_80.txt
(r / resemble-01
      :ARG1 (n4 / neoplasia
            :ARG2-of (i / induce-01
                  :ARG0 (e2 / enzyme :name (n / name :op1 "Braf")
                        :ARG2-of (m / mutate-01 :value "V637E"))))
      :ARG2 (t2 / tumor
            :mod (h / human)
            :mod (g / gene :name (n2 / name :op1 "BRAF")
                  :ARG1-of (m2 / mutate-01))
            :mod (c / colon)
            :ARG0-of (s / show-01
                  :ARG1 (p / pattern
                        :mod (g3 / grow-01
                              :ARG1 (s2 / sessile
                                    :mod (p2 / polypoid :polarity -))))
                  :ARG1-of (f2 / frequent-02)))
      :manner (m3 / macroscopic)
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod "S2A")))

# ::id pmid_2384_5441.81 ::date 2015-06-27T14:05:26 ::annotator SDL-AMR-09 ::preferred
# ::snt Proliferation rates were increased on average 2.4-fold in mSA-LGD and 9.1-fold in mSA-HGD as compared to hyperplasia (<xref ref-type="sec" rid="app3">Figures S2</xref>B–2D).
# ::save-date Tue Nov 3, 2015 ::file pmid_2384_5441_81.txt
(i / increase-01
      :ARG1 (r / rate
            :degree-of (p / proliferate-01))
      :ARG2 (a / and
            :op1 (p2 / product-of :op1 2.4
                  :location (d2 / disease :name (n / name :op1 "mSA-LGD")))
            :op1 (p3 / product-of :op1 9.1
                  :location (d3 / disease :name (n2 / name :op1 "mSA-HGD")))
            :ARG2-of (a2 / average-01))
      :ARG1-of (d / describe-01
            :ARG0 (v / value-interval
                  :op1 (f / figure :mod "S2B")
                  :op2 (f2 / figure :mod "2D")))
      :ARG1-of (c / compare-01
            :ARG2 (h / hyperplasia)))

# ::id pmid_2384_5441.82 ::date 2015-06-27T14:19:12 ::annotator SDL-AMR-09 ::preferred
# ::snt Like human <i>BRAF</i> mutant tumors, mouse mSAs frequently showed abundant mucin production and stained positive for Alcian blue (<xref ref-type="sec" rid="app3">Figure S2</xref>E).
# ::save-date Mon Dec 21, 2015 ::file pmid_2384_5441_82.txt
(a / and
      :op1 (s / show-01
            :ARG0 (d2 / disease :name (n3 / name :op1 "mSA")
                  :mod (m3 / mouse))
            :ARG1 (p / produce-01
                  :ARG1 (m2 / mucin)
                  :mod (a2 / abundant))
            :ARG1-of (f2 / frequent-02))
      :op2 (s2 / stain-01
            :ARG1 d2
            :ARG2 (s3 / small-molecule :name (n / name :op1 "Alcian" :op2 "blue"))
            :mod (p2 / positive))
      :ARG1-of (r / resemble-01
            :ARG2 (t / tumor
                  :mod (g / gene :name (n2 / name :op1 "BRAF")
                        :ARG2-of (m4 / mutate-01))
                  :mod (h / human)))
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod "S2E")))

# ::id pmid_2384_5441.83 ::date 2015-06-27T14:26:59 ::annotator SDL-AMR-09 ::preferred
# ::snt In a subset of mice (n = 5) dysplasia progressed to invasive carcinomas: 8.3% (1/12) of <i>Vil-Cre;Braf</i><sup><i>LSL-V637E</i>/+</sup> mice younger than 10 months and 13.8% (4/29) of mice older 10 months had cancers (<xref ref-type="fig" rid="fig2">Figure 2</xref>A).
# ::save-date Sat Jan 16, 2016 ::file pmid_2384_5441_83.txt
(p / progress-01
      :ARG1 (d / dysplasia)
      :ARG4 (c / carcinoma
            :ARG0-of (i / invade-01))
      :location (s / subset
                  :ARG1-of (i2 / include-91
                        :ARG2 (m / mouse))
                  :ord (o / ordinal-entity :value 5))
      :ARG1-of (m2 / mean-01
            :ARG2 (h / have-03
                  :ARG0 (a / and
                        :op1 (m3 / mouse :quant 1
                              :ARG1-of (i3 / include-91
                                    :ARG2 (m4 / mouse :quant 12
                                          :mod (g / gene :name (n3 / name :op1 "Braf")
                                                :ARG2-of (m6 / mutate-01 :value "LSL-V637E"))
                                          :mod (y / young
                                                :degree (m7 / more)
                                                :compared-to (t / temporal-quantity :quant 10
                                                      :unit (m9 / month)))
                                          :mod (m11 / macro-molecular-complex
                                                :part (p3 / protein :name (n / name :op1 "Villin"))
                                                :part (e2 / enzyme :name (n2 / name :op1 "Cre"))))
                                    :ARG3 (p2 / percentage-entity :value 8.3)))
                        :op2 (m8 / mouse :quant 4
                              :ARG1-of (i4 / include-91
                                    :ARG2 (m10 / mouse :quant 29
                                          :mod g
                                          :mod (o2 / old
                                                :degree m7
                                                :compared-to t)
                                          :mod m11)
                                    :ARG3 (p5 / percentage-entity :value 13.8))))
                  :ARG1 (d3 / disease :wiki "Cancer" :name (n4 / name :op1 "cancer"))))
      :ARG1-of (d2 / describe-01
            :ARG0 (f / figure :mod "2A")))

# ::id pmid_2384_5441.84 ::date 2015-06-28T07:03:52 ::annotator SDL-AMR-09 ::preferred
# ::snt Two of these cancers were low-grade tumors (well and moderately differentiated), and three were high-grade cancers (poorly or undifferentiated; glandular structures in less than 50% of the tumor).
# ::save-date Sun Dec 20, 2015 ::file pmid_2384_5441_84.txt
(a / and
      :op1 (t / tumor
            :mod (g / grade
                  :ARG1-of (l / low-04))
            :ARG1-of (m / mean-01
                  :ARG2 (a2 / and
                        :op1 (d / differentiate-01
                              :ARG1 t
                              :ARG1-of (g2 / good-02))
                        :op2 (d2 / differentiate-01
                              :ARG1 t
                              :ARG1-of (m2 / moderate-03))))
            :domain (d5 / disease :quant 2 :wiki "Cancer" :name (n / name :op1 "cancer")
                  :ARG1-of (i / include-91
                        :ARG2 (d6 / disease :wiki "Cancer" :name (n2 / name :op1 "cancer")))
                  :mod (t4 / this)))
      :op2 (d7 / disease :wiki "Cancer" :name (n3 / name :op1 "cancer")
            :domain (d8 / disease :quant 3 :wiki "Cancer" :name (n4 / name :op1 "cancer")
                  :ARG1-of i)
            :mod (g3 / grade
                  :ARG1-of (h / high-02))
            :ARG1-of (m3 / mean-01
                  :ARG2 (o / or
                        :op1 (d3 / differentiate-01
                              :ARG1 d7
                              :manner (p / poor))
                        :op2 (d4 / differentiate-01 :polarity -
                              :ARG1 d7
                              :ARG1-of (m4 / mean-01
                                    :ARG2 (s / structure
                                          :mod (g4 / gland)
                                          :poss (t2 / tumor
                                                :quant (l2 / less-than
                                                      :op1 (p2 / percentage-entity :value 50))
                                                :ARG1-of (i2 / include-91
                                                      :ARG2 (t3 / tumor))))))))))

# ::id pmid_2384_5441.85 ::date 2015-06-28T07:04:52 ::annotator SDL-AMR-09 ::preferred
# ::snt Examples are shown in <xref ref-type="fig" rid="fig2">Figures 2</xref>F–2I.
# ::save-date Thu Jul 2, 2015 ::file pmid_2384_5441_85.txt
(s / show-01
      :ARG1 (e / exemplify-01)
      :location (v / value-interval
            :op1 (f / figure :mod "2F")
            :op2 (f2 / figure :mod "2I")))

# ::id pmid_2384_5441.86 ::date 2015-06-28T08:14:43 ::annotator SDL-AMR-09 ::preferred
# ::snt Across a larger set of Braf<sup>V637E</sup>-induced cancers in <i>p53</i> or <i>p16</i> mutant backgrounds (<xref ref-type="sec" rid="app3">Table S1</xref> and detailed below), we found that 30% of tumors were high grade.
# ::save-date Sun Jan 17, 2016 ::file pmid_2384_5441_86.txt
(f / find-01
      :ARG0 (w / we)
      :ARG1 (t / tumor
            :mod (g / grade
                  :ARG1-of (h / high-02))
            :ARG1-of (i / include-91
                  :ARG2 (t2 / tumor)
                  :ARG3 (p / percentage-entity :value 30)))
      :location (a / across
            :op1 (s / set
                  :mod (l / large
                        :degree (m / more))
                  :ARG2-of (i2 / include-91
                        :ARG1 (d3 / disease :wiki "Cancer" :name (n4 / name :op1 "cancer")
                              :ARG2-of (i3 / induce-01
                                    :ARG0 (e / enzyme :name (n / name :op1 "Braf")
                                          :ARG2-of (m2 / mutate-01 :value "V637E")))
                              :location (a2 / and
                                    :op1 (b / background
                                          :mod (g3 / gene :name (n2 / name :op1 "p53")
                                                :ARG2-of (m3 / mutate-01)))
                                    :op2 (b2 / background
                                          :mod (g2 / gene :name (n3 / name :op1 "p16")
                                                :ARG2-of m3))))))
            :ARG1-of (d / describe-01
                  :ARG0 (t3 / table :mod "S1"))
            :ARG1-of (d2 / detail-01
                  :location (b3 / below))))

# ::id pmid_2384_5441.87 ::date 2015-06-28T08:33:36 ::annotator SDL-AMR-09 ::preferred
# ::snt Collectively these results describe a mouse model of serrated intestinal cancer, which provides functional evidence for the key role of mutant <i>Braf</i> in tumor initiation.
# ::save-date Tue Jan 19, 2016 ::file pmid_2384_5441_87.txt
(d / describe-01
      :ARG0 (t / thing
            :ARG2-of (r / result-01)
            :mod (t3 / this))
      :ARG1 (m / model
            :mod (m2 / mouse)
            :mod (d2 / disease :wiki "Cancer" :name (n2 / name :op1 "cancer")
                  :mod (i / intestine)
                  :ARG1-of (s / serrate-01)))
      :ARG0-of (p / provide-01
            :ARG1 (e / evidence-01
                  :ARG1 (r2 / role
                        :ARG1-of (k / key-01)
                        :poss (g / gene :name (n / name :op1 "Braf")
                              :ARG2-of (m3 / mutate-01))
                        :topic (i2 / initiate-01
                              :ARG0 g
                              :ARG1 (t2 / tumor)))
                  :ARG0-of (f / function-01)))
      :manner (c2 / collective))

# ::id pmid_2384_5441.88 ::date 2015-06-28T08:45:17 ::annotator SDL-AMR-09 ::preferred
# ::snt <sec-title level="2">Braf<sup>V637E</sup>-Induced Murine Intestinal Tumors Are Frequently Microsatellite-Unstable</sec-title>
# ::save-date Mon Dec 21, 2015 ::file pmid_2384_5441_88.txt
(s / stable-03 :polarity -
      :ARG1 (t / tumor
            :mod (i / intestine)
            :ARG2-of (i2 / induce-01
                  :ARG0 (e / enzyme :name (n / name :op1 "Braf")
                        :ARG2-of (m2 / mutate-01 :value "V637E")))
            :mod (o / organism :name (n2 / name :op1 "Muridae")))
      :ARG1-of (f / frequent-02)
      :mod (m3 / microsatellite))

# ::id pmid_2384_5441.89 ::date 2015-06-28T08:54:59 ::annotator SDL-AMR-09 ::preferred
# ::snt High level microsatellite instability (MSI-H) occurs in 50% of human <i>BRAF</i> mutant cancers (<xref ref-type="bibr" rid="bib38">Rajagopalan et al., 2002</xref>).
# ::save-date Thu Dec 10, 2015 ::file pmid_2384_5441_89.txt
(b / be-located-at-91
      :ARG1 (s / stable-03 :polarity -
            :degree (l / level
                  :ARG1-of (h2 / high-02))
            :mod (m2 / microsatellite))
      :ARG2 (d4 / disease :wiki "Cancer"
            :name (n4 / name :op1 "cancer")
            :mod (h / human)
            :mod (g / gene
                  :name (n2 / name :op1 "Braf")
                  :ARG2-of (m / mutate-01))
            :ARG1-of (i / include-91
                  :ARG2 (d3 / disease :wiki "Cancer"
                        :name (n / name :op1 "cancer")
                        :mod h
                        :mod g)
                  :ARG3 (p / percentage-entity :value 50)))
      :ARG1-of (d / describe-01
            :ARG0 (p2 / publication-91
                  :ARG0 (a / and
                        :op1 (p3 / person
                              :name (n3 / name :op1 "Rajagopalan"))
                        :op2 (p4 / person
                              :mod (o2 / other)))
                  :time (d2 / date-entity :year 2002))))

# ::id pmid_2384_5441.90 ::date 2015-06-28T09:10:04 ::annotator SDL-AMR-09 ::preferred
# ::snt It is however not understood at which stage MSI develops and whether <i>BRAF</i> mutations are cause or consequence of MSI.
# ::save-date Mon Nov 2, 2015 ::file pmid_2384_5441_90.txt
(c / contrast-01
      :ARG2 (u / understand-01 :polarity -
            :ARG1 (a / and
                  :op1 (s / stage
                        :time-of (d / develop-01
                              :ARG1 (s2 / stable-03 :polarity -
                                    :mod (m2 / microsatellite))))
                  :op2 (o / or :mode interrogative
                        :op1 (c2 / cause-01
                              :ARG0 (m / mutate-01
                                    :ARG2 (g / gene :name (n2 / name :op1 "Braf")))
                              :ARG1 s2)
                        :op2 (c3 / cause-01
                              :ARG0 s2
                              :ARG1 m)))))

# ::id pmid_2384_5441.91 ::date 2015-06-28T09:25:00 ::annotator SDL-AMR-09 ::preferred
# ::snt To address this question, we assessed the MSI status in Braf<sup>V6<i>37</i>E</sup>-induced serrated hyperplasia and neoplasia as well as in <i>Msh2</i><sup>−<i>/</i>−</sup> and <i>Apc</i><sup><i>min</i></sup> control tumors.
# ::save-date Tue Jan 19, 2016 ::file pmid_2384_5441_91.txt
(a / assess-01
      :ARG0 (w / we)
      :ARG1 (s / status
            :ARG1-of (s3 / stable-03 :polarity -
                  :mod (m5 / microsatellite))
            :location (a2 / and
                  :op1 (m6 / medical-condition :name (n / name :op1 "hyperplasia")
                        :ARG1-of (s2 / serrate-01)
                        :ARG2-of (i / induce-01
                              :ARG0 (e / enzyme :name (n2 / name :op1 "Braf")
                                    :ARG2-of (m / mutate-01 :value "V637E"))))
                  :op2 (m7 / medical-condition :name (n6 / name :op1 "neoplasia")
                        :ARG1-of s2
                        :ARG1-of i)
                  :op3 (t2 / tumor
                        :mod (c / control)
                        :mod (p / protein :name (n4 / name :op1 "Msh2")
                              :ARG2-of (m2 / mutate-01 :mod "-/-")))
                  :op4 (t3 / tumor
                        :mod c
                        :mod (p2 / protein :name (n5 / name :op1 "Apc")
                              :ARG2-of (m3 / mutate-01 :mod "-/+"
                                    :mod (m4 / min))))))
      :purpose (a3 / address-02
            :ARG0 w
            :ARG1 (t / thing
                  :mod (t4 / this)
                  :ARG1-of (q / question-01))))

# ::id pmid_2384_5441.92 ::date 2015-06-28T09:47:46 ::annotator SDL-AMR-09 ::preferred
# ::snt A panel of eight microsatellite repeats was used for MSI typing (<xref ref-type="fig" rid="fig2">Figure 2</xref>J; <xref ref-type="sec" rid="app3">Supplemental Experimental Procedures</xref>).
# ::save-date Mon Nov 2, 2015 ::file pmid_2384_5441_92.txt
(u / use-01
      :ARG1 (p / panel
            :consist-of (m3 / molecular-physical-entity :quant 8
                  :ARG1-of (r2 / repeat-01)
                  :part-of (m / microsatellite)))
      :ARG2 (t / type-03
            :ARG1 (s2 / stable-03 :polarity -
                  :mod (m2 / microsatellite)))
      :ARG1-of (d / describe-01
            :ARG0 (a / and
                  :op1 (f / figure :mod "2J")
                  :op2 (p2 / procedure
                        :mod (e / experiment-01)
                        :ARG2-of (s / supplement-01)))))

# ::id pmid_2384_5441.93 ::date 2015-06-28T09:56:26 ::annotator SDL-AMR-09 ::preferred
# ::snt We found that all Braf<sup>V6<i>37</i>E</sup>-induced hyperplastic polyps (13/13) were microsatellite stable (MSS) or MSI-low (MSI-L).
# ::save-date Sun Dec 20, 2015 ::file pmid_2384_5441_93.txt
(f / find-01
      :ARG0 (w / we)
      :ARG1 (s / stable-03
            :ARG1 (p / polyp :quant 13
                  :mod (h / hyperplastic)
                  :ARG2-of (i / induce-01
                        :ARG0 (e / enzyme :name (n / name :op1 "Braf")
                              :ARG2-of (m2 / mutate-01 :value "V637E")))
                  :mod (a2 / all)
                  :ARG1-of (i2 / include-91
                        :ARG2 (p2 / polyp)))
            :mod (m / microsatellite)))

# ::id pmid_2384_5441.94 ::date 2015-06-28T10:06:14 ::annotator SDL-AMR-09 ::preferred
# ::snt Contrarily, 39.4% (13/33) of Braf<sup>V6<i>37</i>E</sup>-induced mSAs and carcinomas were MSI-H and only 6% (2/32) were MSS (<xref ref-type="fig" rid="fig2">Figure 2</xref>J).
# ::save-date Tue Jan 19, 2016 ::file pmid_2384_5441_94.txt
(c / contrast-01
      :ARG2 (a / and
            :op1 (h / high-02
                  :ARG1 (a2 / and :quant 13
                        :op1 (m / medical-condition :name (n3 / name :op1 "adenoma")
                              :ARG1-of (s2 / serrate-01)
                              :mod (o2 / organism :name (n / name :op1 "Muridae")))
                        :op2 (m5 / medical-condition :name (n5 / name :op1 "carcinoma"))
                        :ARG1-of (i2 / include-91
                              :ARG2 (a4 / and :quant 33
                                    :op1 (m4 / medical-condition :name (n4 / name :op1 "adenoma"))
                                    :op2 m5
                                    :ARG2-of (i / induce-01
                                          :ARG0 (e / enzyme :name (n2 / name :op1 "Braf")
                                                :ARG2-of (m2 / mutate-01 :value "V637E"))))
                              :ARG3 (p / percentage-entity :value 39.4)))
                  :ARG2 (s / stable-03 :polarity -
                        :mod (m3 / microsatellite)))
            :op2 (s3 / stable-03
                  :ARG1 (a3 / and :quant 2
                        :op1 m4
                        :op2 m5
                        :ARG1-of (i4 / include-91
                              :ARG2 (a5 / and :quant 32
                                    :op1 m4
                                    :op2 m5
                                    :ARG2-of i)
                              :ARG3 (p2 / percentage-entity :value 6
                                    :mod (o / only))))
                  :mod m3))
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod "2J")))

# ::id pmid_2384_5441.95 ::date 2015-06-28T10:40:21 ::annotator SDL-AMR-09 ::preferred
# ::snt MSI-H was observed at similar frequencies in mSAs (10/25; 40%) and carcinomas (3/8; 37.5%).
# ::save-date Tue Jan 19, 2016 ::file pmid_2384_5441_95.txt
(o / observe-01
      :ARG1 (h / high-02
            :ARG2 (s / stable-03 :polarity -
                  :mod (m3 / microsatellite))
            :frequency (f / frequency
                  :ARG1-of (r / resemble-01)))
      :location (a / and
            :op1 (m / medical-condition :quant 10 :name (n2 / name :op1 "adenoma")
                  :ARG1-of (i / include-91
                        :ARG2 (m2 / medical-condition :quant 25 :name (n3 / name :op1 "adenoma"))
                        :ARG3 (p / percentage-entity :value 40))
                  :ARG1-of (s2 / serrate-01)
                  :mod (o2 / organism :name (n / name :op1 "Muridae")))
            :op2 (c / carcinoma :quant 3
                  :ARG1-of (i2 / include-91
                        :ARG2 (m4 / medical-condition :quant 8 :name (n4 / name :op1 "carcinoma"))
                        :ARG3 (p2 / percentage-entity :value 37.5)))))

# ::id pmid_2384_5441.96 ::date 2015-06-28T10:46:54 ::annotator SDL-AMR-09 ::preferred
# ::snt <i>Apc</i><sup><i>min</i></sup>-induced adenomas were all (9/9; 100%) MSS or MSI-L.
# ::save-date Thu Dec 10, 2015 ::file pmid_2384_5441_96.txt
(s / stable-03
      :ARG1 (m3 / medical-condition :quant 9 :name (n / name :op1 "adenoma")
            :ARG2-of (i / induce-01
                  :ARG0 (g / gene :name (n3 / name :op1 "Apc")
                        :ARG2-of (m / mutate-01 :mod "-/+"
                              :value (m2 / min))))
            :mod (a3 / all)
            :ARG1-of (i2 / include-91
                  :ARG2 (m4 / medical-condition :quant 9 :name (n2 / name :op1 "adenoma"))
                  :ARG3 (p / percentage-entity :value 100)))
      :mod (m5 / microsatellite))

# ::id pmid_2384_5441.97 ::date 2015-06-28T11:06:45 ::annotator SDL-AMR-09 ::preferred
# ::snt The lack of MSI-H in mSH, but its presence in all subsequent stages of tumorigenesis (mSA-LGD, mSA-HGD and carcinoma) suggests its early development during Braf<sup>V6<i>37</i>E</sup>-initiated transformation.
# ::save-date Sun Jan 17, 2016 ::file pmid_2384_5441_97.txt
(s / suggest-01
      :ARG0 (c / contrast-01
            :ARG1 (l / lack-01
                  :ARG0 (m3 / medical-condition :name (n / name :op1 "mSH"))
                  :ARG1 (s4 / stable-03 :polarity -
                        :mod (m5 / microsatellite)
                        :ARG2-of (h / high-02)))
            :ARG2 (b / be-temporally-at-91
                  :ARG1 s4
                  :ARG2 (t2 / thing
                        :ARG2-of (s2 / stage-02
                              :ARG1 (c2 / create-01
                                    :ARG1 (t / tumor))
                              :ARG1-of (m / mean-01
                                    :ARG2 (a / and
                                          :op1 (m6 / medical-condition :name (n2 / name :op1 "mSA-LGD"))
                                          :op2 (m7 / medical-condition :name (n4 / name :op1 "mSA-HGD"))
                                          :op3 (m2 / medical-condition :name (n5 / name :op1 "carcinoma"))))
                              :time (s3 / subsequent)))))
      :ARG1 (d / develop-01
            :ARG2 s4
            :time (e / early)
            :time (t4 / transform-01
                  :ARG1-of (i / initiate-01
                        :ARG0 (e2 / enzyme :name (n3 / name :op1 "Braf")
                              :ARG2-of (m4 / mutate-01 :value "V637E"))))))

# ::id pmid_2384_5441.98 ::date 2015-06-28T11:18:33 ::annotator SDL-AMR-09 ::preferred
# ::snt <sec-title level="2">P53 Tumor Suppression Inhibits Invasion and Metastasis but Does Not Affect Tumor Initiation in Braf<sup><i>V637E</i></sup>-Induced Tumorigenesis</sec-title>
# ::save-date Tue Nov 3, 2015 ::file pmid_2384_5441_98.txt
(h / have-concession-91
      :ARG1 (i / inhibit-01
            :ARG0 (s / suppress-01
                  :ARG0 (p / protein :name (n / name :op1 "p53"))
                  :ARG1 (t / tumor))
            :ARG1 (a2 / and
                  :op2 (i2 / invade-01)
                  :op2 (m / metastasize-101)))
      :ARG2 (a / affect-01 :polarity -
            :ARG0 s
            :ARG2 (i3 / initiate-01
                  :ARG1 (c / create-01
                        :ARG1 (t2 / tumor)
                        :ARG2-of (i4 / induce-01
                              :ARG0 (e / enzyme :name (n2 / name :op1 "Braf")
                                    :ARG2-of (m2 / mutate-01 :value "V637E")))))))

# ::id pmid_2384_5441.99 ::date 2015-06-28T11:27:15 ::annotator SDL-AMR-09 ::preferred
# ::snt The long latency and low penetrance of cancer development might be explained by the ability of constitutive MAPK signaling to activate anti-oncogenic programs, most notably the <i>p16</i><sup><i>INK4a</i></sup>/Rb and <i>p19</i><sup><i>ARF</i></sup>/p53 pathways (<xref ref-type="bibr" rid="bib33 bib25">Palmero et al., 1998; Lin et al., 1998</xref>).
# ::save-date Mon Dec 21, 2015 ::file pmid_2384_5441_99.txt
(p / possible-01
      :ARG1 (e / explain-01
            :ARG0 (c / capable-01
                  :ARG1 (p3 / pathway :name (n2 / name :op1 "MAPK")
                        :ARG0-of (s / signal-07)
                        :mod (c2 / constitutive))
                  :ARG2 (a / activate-01
                        :ARG0 p3
                        :ARG1 (p4 / program
                              :ARG0-of (o / oppose-01
                                    :ARG1 (o2 / oncogene))
                              :ARG2-of (i / include-91
                                    :ARG1 (a2 / and
                                          :op1 (p5 / pathway :name (n3 / name :op1 "p16INK4a/Rb"))
                                          :op2 (p6 / pathway :name (n4 / name :op1 "p19ARF/p53")))
                                    :ARG1-of (n5 / notable-04
                                          :degree (m / most))))))
            :ARG1 (d / develop-01
                  :ARG1 (d2 / disease :wiki "Cancer" :name (n / name :op1 "cancer"))
                  :mod (l / latent
                        :ARG1-of (l2 / long-03))
                  :ARG1-of (p2 / penetrate-01
                        :ARG1-of (l3 / low-04))))
      :ARG1-of (d3 / describe-01
            :ARG0 (a3 / and
                  :op1 (p7 / publication-91
                        :ARG0 (a4 / and
                              :op1 (p8 / person :name (n6 / name :op1 "Palmero"))
                              :op2 (p9 / person
                                    :mod (o3 / other)))
                        :time (d4 / date-entity :year 1998))
                  :op1 (p10 / publication-91
                        :ARG0 (a5 / and
                              :op1 (p11 / person :name (n7 / name :op1 "Lin"))
                              :op2 p9)
                        :time d4))))

# ::id pmid_2384_5441.100 ::date 2015-06-26T01:28:13 ::annotator SDL-AMR-09 ::preferred
# ::snt To investigate the role of <i>p53</i> in Braf<sup>V6<i>37</i>E</sup>-induced intestinal tumorigenesis, we used <i>p53</i><sup><i>LSL-R172H/+</i></sup> knockin mice, expressing the equivalent of the dominant-negative human <i>TP53</i><sup><i>R175H</i></sup> conditionally (<xref ref-type="bibr" rid="bib32">Olive et al., 2004</xref>).
# ::save-date Fri Feb 5, 2016 ::file pmid_2384_5441_100.txt
(u / use-01
      :ARG0 (w / we)
      :ARG1 (m / mouse
            :location-of (k / knock-in-00
                  :ARG1 (p / protein :name (n / name :op1 "p53")
                        :ARG2-of (m2 / mutate-01 :value "LSL-R172H")))
            :ARG3-of (e / express-03
                  :ARG2 (e2 / equal-01
                        :ARG1 (g / gene :name (n4 / name :op1 "TP53")
                              :ARG2-of (m3 / mutate-01 :value "R175H" :mod "-/-")
                              :mod (h / human)
                              :ARG0-of (d3 / dominate-01)))
                  :manner (c / conditional)))
      :ARG2 (i / investigate-01
            :ARG0 w
            :ARG1 (r / role
                  :poss (p3 / protein :name (n3 / name :op1 "p53"))
                  :topic (c2 / create-01
                        :ARG1 (t / tumor
                              :mod (i2 / intestine))
                        :ARG2-of (i3 / induce-01
                              :ARG0 (e3 / enzyme :name (n5 / name :op1 "Braf")
                                    :ARG2-of (m4 / mutate-01 :value "V637E"))))))
      :ARG1-of (d / describe-01
            :ARG0 (p4 / publication-91
                  :ARG0 (a / and
                        :op1 (p5 / person :name (n6 / name :op1 "Olive"))
                        :op2 (p6 / person
                              :mod (o / other)))
                  :time (d2 / date-entity :year 2004))))

# ::id pmid_2384_5441.101 ::date 2015-06-26T02:48:09 ::annotator SDL-AMR-09 ::preferred
# ::snt We intercrossed them with <i>Vil-Cre;Braf</i><sup><i>LSL-V637E</i>/+</sup> mice, aged the different double- and triple-transgenic cohorts, and monitored mice for tumor development (<xref ref-type="fig" rid="fig3">Figure 3</xref>A).
# ::save-date Wed Jul 1, 2015 ::file pmid_2384_5441_101.txt
(a / and
      :op1 (i / intercross-00
            :ARG0 (w / we)
            :ARG1 (a2 / and
                  :op1 (t / they)
                  :op2 (m / mouse
                        :mod (e / enzyme :name (n / name :op1 "Braf")
                              :ARG2-of (m2 / mutate-01 :value "LSL-V637E"))
                        :mod (e2 / enzyme :name (n2 / name :op1 "Cre")
                              :ARG2-of (e3 / express-03
                                    :ARG1 (g / gene :name (n3 / name :op1 "Villin")))))))
      :op2 (a3 / age-01
            :ARG0 w
            :ARG1 (a4 / and
                  :op1 (c / cohort
                        :mod (p / product-of :op1 2
                              :op2 (t2 / transgenesis)))
                  :op2 (c2 / cohort
                        :mod (p2 / product-of :op1 3
                              :op2 t2))
                  :ARG1-of (d / differ-02)))
      :op2 (m3 / monitor-01
            :ARG0 w
            :ARG1 a2
            :ARG2 (d2 / develop-02
                  :ARG1 (t3 / tumor)))
      :ARG1-of (d3 / describe-01
            :ARG0 (f / figure :mod "3A")))

# ::id pmid_2384_5441.102 ::date 2015-06-26T05:05:05 ::annotator SDL-AMR-09 ::preferred
# ::snt We found that the average number of mSAs per mouse was similar in <i>Vil-Cre;Braf</i><sup><i>LSL-V637E</i>/+</sup> and <i>Vil-Cre;Braf</i><sup><i>LSL-V637E</i>/+</sup><i>;p53</i><sup><i>LSL-R172H/+</i></sup> animals (2.3 and 1.8, respectively; <xref ref-type="fig" rid="fig3">Figure 3</xref>B; <xref ref-type="sec" rid="app3">Table S2</xref>).
# ::save-date Wed Jul 1, 2015 ::file pmid_2384_5441_102.txt
(f / find-01
      :ARG0 (w / we)
      :ARG1 (r / resemble-01
            :ARG1 (r2 / rate-entity-91
                  :ARG1 (n / number-01
                        :ARG1 (d / disease :name (n2 / name :op1 "mSA"))
                        :ARG2 2.3
                        :ARG1-of (a / average-01))
                  :ARG2 (m / mouse)
                  :location (a2 / animal
                        :mod (e / enzyme :name (n3 / name :op1 "Braf")
                              :ARG2-of (m2 / mutate-01 :value "LSL-V637E"))
                        :mod (e2 / enzyme :name (n4 / name :op1 "Cre")
                              :ARG2-of (e3 / express-03
                                    :ARG1 (g / gene :name (n5 / name :op1 "Villin"))))))
            :ARG2 (r3 / rate-entity-91
                  :ARG1 (n6 / number-01
                        :ARG1 d
                        :ARG2 1.8
                        :ARG1-of a)
                  :ARG2 m
                  :location (a3 / animal
                        :mod e2
                        :mod e
                        :mod (p / protein :name (n7 / name :op1 "p53")
                              :ARG2-of (m3 / mutate-01 :value "LSL-R172H")))))
      :ARG1-of (d2 / describe-01
            :ARG0 (a4 / and
                  :op1 (f2 / figure :mod "3B")
                  :op2 (t / table :mod "S2"))))

# ::id pmid_2384_5441.103 ::date 2015-06-26T09:08:32 ::annotator SDL-AMR-09 ::preferred
# ::snt Likewise, the proportion of mice developing mSAs did not differ between groups (82.9% and 82.8%, respectively, <xref ref-type="sec" rid="app3">Table S2</xref>), suggesting that the p53 pathway does not restrain dysplasia initiation.
# ::save-date Fri Dec 18, 2015 ::file pmid_2384_5441_103.txt
(d / differ-02 :polarity -
      :ARG1 (p / proportion-01
            :ARG1 (m / mouse
                  :ARG1-of (d2 / develop-01
                        :ARG2 (d3 / disease :name (n / name :op1 "mSA")))))
      :quant (a / and
            :op1 (p2 / percentage-entity :value 82.9)
            :op2 (p3 / percentage-entity :value 82.8))
      :ARG1-of (d4 / describe-01
            :ARG0 (t / table :mod "S2"))
      :ARG0-of (s / suggest-01
            :ARG1 (r / restrain-01 :polarity -
                  :ARG0 (p4 / pathway :name (n2 / name :op1 "p53"))
                  :ARG1 (i / initiate-01
                        :ARG1 (d5 / dysplasia))))
      :ARG1-of (r2 / resemble-01)
      :location (g / group))

# ::id pmid_2384_5441.104 ::date 2015-06-26T09:36:21 ::annotator SDL-AMR-09 ::preferred
# ::snt In sharp contrast, invasive cancers were found considerably more frequently in <i>Vil-Cre;Braf</i><sup><i>V637E</i>/+</sup><i>;p53</i><sup><i>LSL-R172H/+</i></sup> mice (<xref ref-type="fig" rid="fig3">Figure 3</xref>B; <xref ref-type="sec" rid="app3">Table S3</xref>).
# ::save-date Mon Dec 21, 2015 ::file pmid_2384_5441_104.txt
(c / contrast-01
      :ARG2 (f / find-01
            :ARG1 (d / disease :wiki "Cancer" :name (n / name :op1 "cancer")
                  :ARG0-of (i / invade-01))
            :location (m / mouse
                  :mod (e / enzyme :name (n2 / name :op1 "Cre")
                        :ARG2-of (e2 / express-03
                              :ARG1 (g / gene :name (n3 / name :op1 "Villin"))))
                  :mod (e3 / enzyme :name (n4 / name :op1 "Braf")
                        :ARG2-of (m2 / mutate-01 :value "V637E"))
                  :mod (p / protein :name (n5 / name :op1 "p53")
                        :ARG2-of (m3 / mutate-01 :value "LSL-R172H")))
            :ARG1-of (f2 / frequent-02
                  :degree (m4 / more
                        :degree (c2 / considerable))))
      :degree (s / sharp)
      :ARG1-of (d2 / describe-01
            :ARG0 (a / and
                  :op1 (f3 / figure :mod "3B")
                  :op2 (t / table :mod "S3"))))

# ::id pmid_2384_5441.105 ::date 2015-06-26T09:55:51 ::annotator SDL-AMR-09 ::preferred
# ::snt Fifty-six percent of <i>Vil-Cre;Braf</i><sup><i>LSL-V637E</i>/+</sup><i>; p53</i><sup><i>LSL-R172H/+</i></sup> animals at an age of 10–20 months had carcinomas, as compared to 13.8% of mice in the <i>Vil-Cre;Braf</i><sup><i>LSL-V637E</i>/+</sup> cohort (p = 0.002, χ<sup>2</sup> test).
# ::save-date Sun Dec 20, 2015 ::file pmid_2384_5441_105.txt
(h / have-03
      :ARG0 (a / animal
            :mod (e / enzyme :name (n / name :op1 "Cre")
                  :ARG2-of (e2 / express-03
                        :ARG1 (g / gene :name (n2 / name :op1 "Villin"))))
            :mod (e3 / enzyme :name (n3 / name :op1 "Braf")
                  :ARG2-of (m / mutate-01 :value "LSL-V637E"))
            :mod (p / protein :name (n4 / name :op1 "p53")
                  :ARG2-of (m2 / mutate-01 :value "LSL-R172H"))
            :ARG1-of (i / include-91
                  :ARG2 (a2 / animal
                        :mod e
                        :mod e3
                        :mod p)
                  :ARG3 (p2 / percentage-entity :value 56))
            :age (t / temporal-quantity
                        :quant (v / value-interval :op1 10 :op2 20)
                        :unit (m3 / month)))
      :ARG1 (c / carcinoma)
      :compared-to (h2 / have-03
            :ARG0 (m4 / mouse
                  :location (c2 / cohort
                        :mod e
                        :mod e3)
                  :ARG1-of (i2 / include-91
                        :ARG2 (m5 / mouse
                              :location c2)
                        :ARG3 (p3 / percentage-entity :value 13.8)))
            :ARG1 c)
      :ARG1-of (s / statistical-test-91
            :ARG2 0.002
            :ARG4 (t2 / test :name (n5 / name :op1 "χ2"))))

# ::id pmid_2384_5441.106 ::date 2015-06-26T14:00:30 ::annotator SDL-AMR-09 ::preferred
# ::snt The average number of cancers was 5.2 times higher in the <i>Vil-Cre;Braf</i><sup><i>LSL-V637E</i>/+</sup><i>;p53</i><sup><i>LSL-R172H/+</i></sup> cohort (p = 0.007; Mann-Whitney rank sum test).
# ::save-date Mon Dec 21, 2015 ::file pmid_2384_5441_106.txt
(n / number-01
      :ARG1 (d / disease :wiki "Cancer" :name (n2 / name :op1 "cancer"))
      :ARG1-of (a / average-01)
      :ARG1-of (h / high-02
            :degree (m / more)
            :degree (p / product-of :op1 5.2))
      :location (c / cohort
            :mod (e / enzyme :name (n3 / name :op1 "Cre")
                  :ARG2-of (e2 / express-03
                        :ARG1 (g / gene :name (n4 / name :op1 "Villin"))))
            :mod (e3 / enzyme :name (n5 / name :op1 "Braf")
                  :ARG2-of (m2 / mutate-01 :value "LSL-V637"))
            :mod (p2 / protein :name (n6 / name :op1 "p53")
                  :ARG2-of (m3 / mutate-01 :value "LSL-R172H")))
      :ARG1-of (s / statistical-test-91
            :ARG2 0.007
            :ARG4 (t / test :name (n7 / name :op1 "Mann-Whitney" :op2 "rank" :op3 "sum" :op4 "test"))))

# ::id pmid_2384_5441.107 ::date 2015-06-26T14:28:15 ::annotator SDL-AMR-09 ::preferred
# ::snt Some animals had more than one synchronous cancer and 25% (3/12) of mice with cancer had metastases to local lymph nodes, pancreas, or lungs (<xref ref-type="fig" rid="fig3">Figures 3</xref>C and 3D).
# ::save-date Mon Dec 21, 2015 ::file pmid_2384_5441_107.txt
(a / and
      :op1 (h / have-03
            :ARG0 (a2 / animal
                  :quant (s / some))
            :ARG1 (d / disease :wiki "Cancer" :name (n / name :op1 "cancer")
                  :mod (s2 / synchrony)
                  :quant (m / more-than :op1 1)))
      :op2 (h2 / have-03
            :ARG0 (m2 / mouse :quant 3
                  :ARG1-of (i / include-91
                        :ARG2 (m3 / mouse :quant 12)
                        :ARG3 (p / percentage-entity :value 25))
                  :ARG0-of (h3 / have-03
                        :ARG1 d))
            :ARG1 (m4 / metastasize-101
                  :ARG1 d
                  :ARG2 (o / or
                        :op1 (n2 / node
                              :mod (l / lymph)
                              :ARG1-of (l2 / local-02))
                        :op2 (p2 / pancreas)
                        :op3 (l3 / lung))))
      :ARG1-of (d2 / describe-01
            :ARG0 (a3 / and
                  :op1 (f / figure :mod "3C")
                  :op2 (f2 / figure :mod "3D"))))

# ::id pmid_2384_5441.108 ::date 2015-06-26T14:55:24 ::annotator SDL-AMR-09 ::preferred
# ::snt All together, these data show that p53 does not affect early stages of Braf<sup>V6<i>37</i>E</sup>-induced tumorigenesis but plays an important role in invasiveness control.
# ::save-date Sun Jan 3, 2016 ::file pmid_2384_5441_108.txt
(s / show-01
      :ARG0 (d / data
            :mod (t / this))
      :ARG1 (c / contrast-01
            :ARG1 (a / affect-01 :polarity -
                  :ARG0 (p / protein :name (n / name :op1 "p53"))
                  :ARG1 (t3 / thing
                        :ARG2-of (s2 / stage-02
                              :ARG1 (c3 / create-01
                                    :ARG1 (t2 / tumor)
                                    :ARG2-of (i / induce-01
                                          :ARG0 (e / enzyme :name (n2 / name :op1 "Braf")
                                                :ARG2-of (m / mutate-01 :value "V637E"))))
                              :time (e2 / early))))
            :ARG2 (p2 / play-02
                  :ARG0 p
                  :ARG1 (c2 / control-01
                        :ARG1 (i2 / invade-01)
                        :mod (i3 / important))))
      :ARG2-of (s3 / sum-up-01))

# ::id pmid_2384_5441.109 ::date 2015-06-26T15:06:03 ::annotator SDL-AMR-09 ::preferred
# ::snt <sec-title level="2">Activation of p53 Tumor Suppression during Advanced, but Not Early Tumorigenesis</sec-title>
# ::save-date Tue Nov 3, 2015 ::file pmid_2384_5441_109.txt
(a / activate-01
      :ARG1 (s / suppress-01
            :ARG1 (t / tumor
                  :mod (p / protein :name (n / name :op1 "p53"))))
      :time (c / contrast-01
            :ARG1 (c2 / create-01
                  :ARG1 (t2 / tumor)
                  :ARG1-of (a2 / advance-01))
            :ARG2 (c3 / create-01
                  :ARG1 (t3 / tumor)
                  :time (e / early :polarity -))))

# ::id pmid_2384_5441.110 ::date 2015-06-26T15:10:42 ::annotator SDL-AMR-09 ::preferred
# ::snt We next examined at which stage of tumorigenesis the p53 pathway becomes activated (<xref ref-type="fig" rid="fig3">Figures 3</xref>E–3N).
# ::save-date Tue Dec 22, 2015 ::file pmid_2384_5441_110.txt
(e / examine-01
      :ARG0 (w / we)
      :ARG1 (t2 / thing
            :ARG2-of (s / stage-02
                  :ARG1 (c / create-01
                        :ARG1 (t / tumor)))
            :time-of (b / become-01
                  :ARG1 (p / pathway :name (n / name :op1 "p53"))
                  :ARG2 (a / activate-01
                        :ARG1 p)))
      :time (n2 / next)
      :ARG1-of (d / describe-01
            :ARG0 (v / value-interval
                  :op1 (f / figure :mod "3E")
                  :op2 (f2 / figure :mod "3N"))))

# ::id pmid_2384_5441.111 ::date 2015-06-26T15:19:24 ::annotator SDL-AMR-09 ::preferred
# ::snt We performed immunohistochemistry for p53 and its target gene p21 in wild-type as well as <i>Braf</i> mutant hyperplasia and neoplasia.
# ::save-date Sat Jan 16, 2016 ::file pmid_2384_5441_111.txt
(p / perform-01
      :ARG0 (w / we)
      :ARG1 (i / immunohistochemistry)
      :beneficiary (a / and
            :op1 (p2 / protein :name (n / name :op1 "p53"))
            :op2 (g / gene :name (n2 / name :op1 "p21")
                  :ARG1-of (t / target-01)
                  :poss p2))
      :location (a2 / and
            :op1 (h / hyperplasia
                  :mod (w2 / wild-type))
            :op2 (h2 / hyperplasia
                  :ARG2-of (m / mutate-01
                        :ARG0 (g2 / gene :name (n3 / name :op1 "Braf"))))
            :op3 (n4 / neoplasia
                  :mod w2)
            :op4 (n5 / neoplasia
                  :ARG2-of m)))

# ::id pmid_2384_5441.112 ::date 2015-06-26T15:30:42 ::annotator SDL-AMR-09 ::preferred
# ::snt Immunoreactivity for p53 was negative in all wild-type intestines (n = 21), all Braf<sup>V637E</sup>-induced mSHs (n = 43), and most mSAs-LGD (<xref ref-type="fig" rid="fig3">Figures 3</xref>F–3H and 3N).
# ::save-date Fri Feb 5, 2016 ::file pmid_2384_5441_112.txt
(n / negative-01
      :ARG1 (a / and
            :op1 (i2 / intestine
                  :mod (w / wild-type)
                  :mod (a2 / all)
                  :ARG1-of (n3 / number-01
                        :ARG2 21))
            :op2 (m / medical-condition :name (n4 / name :op1 "mSH")
                  :ARG2-of (i3 / induce-01
                        :ARG0 (e / enzyme :name (n5 / name :op1 "Braf")
                              :ARG2-of (m2 / mutate-01 :value "V637E")))
                  :ARG1-of (n6 / number-01
                        :ARG2 43)
                  :mod a2)
            :op3 (d2 / disease :name (n7 / name :op1 "mSA-LGD")
                  :quant (m4 / most)))
      :ARG2 (i / immunoreact-00
            :ARG1 (p / protein :name (n2 / name :op1 "p53")))
      :ARG1-of (d3 / describe-01
            :ARG0 (a3 / and
                  :op1 (v / value-interval
                        :op1 (f / figure :mod "3F")
                        :op2 (f2 / figure :mod "3H"))
                  :op2 (f3 / figure :mod "3N"))))

# ::id pmid_2384_5441.113 ::date 2015-06-26T15:52:49 ::annotator SDL-AMR-09 ::preferred
# ::snt Only 5/37 mSAs-LGD were p53-positive (example in <xref ref-type="fig" rid="fig3">Figure 3</xref>I).
# ::save-date Wed Jul 1, 2015 ::file pmid_2384_5441_113.txt
(p / positive
      :topic (p2 / protein :name (n / name :op1 "p53"))
      :domain (d / disease :quant 5 :name (n2 / name :op1 "mSA-LGD")
            :ARG1-of (i / include-91
                  :ARG2 (d2 / disease :quant 37 :name (n3 / name :op1 "mSA-LGD"))))
      :mod (o / only)
      :ARG0-of (e / exemplify-01
            :location (f / figure :mod "3I")))

# ::id pmid_2384_5441.114 ::date 2015-06-26T15:57:40 ::annotator SDL-AMR-09 ::preferred
# ::snt We detected however marked p53 expression in 97% (28/29) of mSAs-HGD (<xref ref-type="fig" rid="fig3">Figures 3</xref>L and 3N).
# ::save-date Wed Jul 1, 2015 ::file pmid_2384_5441_114.txt
(h / have-concession-91
      :ARG2 (d / detect-01
            :ARG0 (w / we)
            :ARG1 (e / express-03
                  :ARG2 (p / protein :name (n / name :op1 "p53"))
                  :degree (m / mark-01))
            :location (d2 / disease :quant 28 :name (n2 / name :op1 "mSA-HGD")
                  :ARG1-of (i / include-91
                        :ARG2 (d3 / disease :quant 29 :name (n3 / name :op1 "mSA-HGD"))
                        :ARG3 (p2 / percentage-entity :value 97))))
      :ARG1-of (d4 / describe-01
            :ARG0 (a / and
                  :op1 (f / figure :mod "3L")
                  :op2 (f2 / figure :mod "3N"))))

# ::id pmid_2384_5441.115 ::date 2015-06-26T16:05:44 ::annotator SDL-AMR-09 ::preferred
# ::snt There was a strong concordance of p53 and p21 immunoreactivity in all samples.
# ::save-date Fri Jan 29, 2016 ::file pmid_2384_5441_115.txt
(r / resemble-01
      :ARG1 (i / immunoreact-00
            :ARG1 (p / protein :name (n / name :op1 "p53")))
      :ARG2 (i2 / immunoreact-00
            :ARG1 (p2 / protein :name (n2 / name :op1 "p21")))
      :location (t / thing
            :mod (a / all)
            :ARG1-of (s / sample-01))
      :degree (s2 / strong))

# ::id pmid_2384_5441.116 ::date 2015-06-26T16:17:20 ::annotator SDL-AMR-09 ::preferred
# ::snt Similar to p53, p21 IHC was negative in all wild-type intestines (n = 21), all Braf<sup>V637E</sup>-induced mSHs (n = 15), and most (10/11) mSAs-LGD but was present in the majority (8/9; 89%) of mSAs-HGD (<xref ref-type="fig" rid="fig3">Figures 3</xref>G, 3J, 3M, and 3N).
# ::save-date Fri Feb 5, 2016 ::file pmid_2384_5441_116.txt
(c / contrast-01
      :ARG1 (n / negative-01
            :ARG1 (a / and
                  :op1 (i2 / intestine
                        :mod (w / wild-type)
                        :mod (a2 / all)
                        :ARG1-of (n3 / number-01
                              :ARG2 21))
                  :op2 (d / disease :name (n4 / name :op1 "mSH")
                        :ARG2-of (i3 / induce-01
                              :ARG0 (e / enzyme :name (n5 / name :op1 "Braf")
                                    :ARG2-of (m / mutate-01 :value "V637E")))
                        :ARG1-of (n6 / number-01
                              :ARG2 15)
                        :mod a2)
                  :op3 (m4 / medical-condition :quant 10 :name (n7 / name :op1 "mSA-LGD")
                        :ARG1-of (i4 / include-91
                              :ARG2 (m5 / medical-condition :quant 11 :name (n8 / name :op1 "mSA-LGD"))
                              :ARG3 (m2 / most))))
            :ARG2 (i / immunohistochemistry
                  :mod (p / protein :name (n2 / name :op1 "p21"))))
      :ARG2 (p4 / present-02
            :ARG1 i
            :ARG2 (m6 / medical-condition :quant 8 :name (n9 / name :op1 "mSA-HGD")
                  :ARG1-of (i5 / include-91
                        :ARG2 (m7 / medical-condition :quant 9 :name (n10 / name :op1 "mSA-HGD"))
                        :ARG3 (a3 / and
                              :op1 (m3 / majority)
                              :op2 (p2 / percentage-entity :value 89)))))
      :ARG1-of (r / resemble-01
            :ARG2 (p3 / protein :name (n11 / name :op1 "p53")))
      :ARG1-of (d6 / describe-01
            :ARG0 (a4 / and
                  :op1 (f / figure :mod "3G")
                  :op2 (f2 / figure :mod "3J")
                  :op3 (f3 / figure :mod "3M")
                  :op4 (f4 / figure :mod "3N"))))

# ::id pmid_2384_5441.117 ::date 2015-06-26T16:40:12 ::annotator SDL-AMR-09 ::preferred
# ::snt These data suggest selective activation of p53 tumor suppression during advanced but not early stages of tumor evolution.
# ::save-date Sun Jan 3, 2016 ::file pmid_2384_5441_117.txt
(s / suggest-01
      :ARG0 (d / data
            :mod (t / this))
      :ARG1 (a / activate-01
            :ARG1 (s2 / suppress-01
                  :ARG1 (t2 / tumor
                        :mod (p / protein :name (n / name :op1 "p53"))))
            :ARG0-of (s3 / select-01)
            :time (c / contrast-01
                  :ARG1 (t3 / thing
                        :ARG2-of (s4 / stage-02
                              :ARG1 (e / evolve-01
                                    :ARG1 t2)
                              :ARG1-of (a2 / advance-01)))
                  :ARG2 (t4 / thing
                        :ARG2-of (s5 / stage-02
                              :ARG1 e
                              :time (e2 / early :polarity -))))))

# ::id pmid_2384_5441.118 ::date 2015-06-26T16:47:50 ::annotator SDL-AMR-09 ::preferred
# ::snt To investigate the mechanism of p53 activation, we first stained for the DNA damage marker γH2AX.
# ::save-date Mon Nov 2, 2015 ::file pmid_2384_5441_118.txt
(s / stain-01
      :ARG0 (w / we)
      :purpose (m / marker :name (n / name :op1 "γH2AX")
            :mod (d / damage-01
                  :ARG1 (n2 / nucleic-acid :name (n4 / name :op1 "DNA"))))
      :time (f / first)
      :purpose (i / investigate-01
            :ARG0 w
            :ARG1 (m2 / mechanism
                  :poss (a / activate-01
                        :ARG1 (p / protein :name (n3 / name :op1 "p53"))))))

# ::id pmid_2384_5441.119 ::date 2015-06-26T17:34:07 ::annotator SDL-AMR-09 ::preferred
# ::snt Oncogene-induced DNA damage can activate p53 via ARF-independent pathways (<xref ref-type="bibr" rid="bib44">Sherr and McCormick, 2002</xref>).
# ::save-date Mon Nov 2, 2015 ::file pmid_2384_5441_119.txt
(p / possible-01
      :ARG1 (a / activate-01
            :ARG0 (d / damage-01
                  :ARG1 (n5 / nucleic-acid :name (n6 / name :op1 "DNA"))
                  :ARG2-of (i / induce-01
                        :ARG0 (o / oncogene)))
            :ARG1 (p2 / protein :name (n / name :op1 "p53"))
            :instrument (p3 / pathway
                  :ARG0-of (d3 / depend-01 :polarity -
                        :ARG1 (p4 / protein :name (n2 / name :op1 "ARF")))))
      :ARG1-of (d4 / describe-01
            :ARG0 (p5 / publication-91
                  :ARG0 (a2 / and
                        :op1 (p6 / person :name (n3 / name :op1 "Sherr"))
                        :op2 (p7 / person :name (n4 / name :op1 "McCormick")))
                  :time (d5 / date-entity :year 2002))))

# ::id pmid_2384_5441.120 ::date 2015-06-26T17:42:20 ::annotator SDL-AMR-09 ::preferred
# ::snt All mSHs (n = 20) or mSAs-LGD (n = 12) were γH2AX-negative (<xref ref-type="fig" rid="fig3">Figure 3</xref>K), and only three of 17 mSAs-HGD (all p53/p21-positive) showed evidence for activation of the DNA damage response.
# ::save-date Fri Feb 5, 2016 ::file pmid_2384_5441_120.txt
(a / and
      :op1 (n / negative-01
            :ARG1 (o / or
                  :op1 (m / medical-condition :name (n3 / name :op1 "mSH")
                        :ARG1-of (n4 / number-01
                              :ARG2 20))
                  :op2 (m4 / medical-condition :name (n5 / name :op1 "mSA-LGD")
                        :ARG1-of (n6 / number-01
                              :ARG2 12))
                  :mod (a2 / all))
            :ARG2 (p4 / protein :name (n2 / name :op1 "γH2AX"))
            :ARG1-of (d3 / describe-01
                  :ARG0 (f / figure :mod "3K")))
      :op2 (s / show-01
            :ARG0 (m3 / medical-condition :quant 3 :name (n7 / name :op1 "mSA-HGD")
                  :ARG1-of (i / include-91
                        :ARG2 (m2 / medical-condition :quant 17 :name (n8 / name :op1 "mSA-HGD")
                              :mod (p / positive
                                    :topic (s2 / slash
                                          :op1 (p2 / protein :name (n9 / name :op1 "p53"))
                                          :op2 (p3 / protein :name (n10 / name :op1 "p21"))))
                              :mod a2))
                  :mod (o2 / only))
            :ARG1 (e / evidence-01
                  :ARG1 (a3 / activate-01
                        :ARG1 (r / respond-01
                              :ARG2 (d6 / damage-01
                                    :ARG1 (n11 / nucleic-acid :name (n12 / name :op1 "DNA"))))))))

# ::id pmid_2384_5441.121 ::date 2015-06-26T17:55:25 ::annotator SDL-AMR-09 ::preferred
# ::snt In contrast, p19<sup>Arf</sup> expression increased substantially during tumor progression: average normalized p19<sup>Arf</sup> mRNA levels were similar in Braf<sup>V6<i>37</i>E</sup>-induced mSHs (0.7) and wild-type mucosa (1.0), but were increased 9.9-, 32.3-, and 39.4-fold in mSAs-LGD, mSAs-HGD, and carcinomas, respectively (<xref ref-type="fig" rid="fig3">Figure 3</xref>E).
# ::save-date Sun Jan 17, 2016 ::file pmid_2384_5441_121.txt
(c / contrast-01
      :ARG2 (i / increase-01
            :ARG1 (e / express-03
                  :ARG2 (p / protein :name (n / name :op1 "p19Arf")))
            :degree (s / substantial)
            :time (p2 / progress-01
                  :ARG1 (t / tumor))
            :ARG1-of (m / mean-01
                  :ARG2 (c2 / contrast-01
                        :ARG1 (r / resemble-01
                              :ARG1 (l / level
                                    :quant-of (n8 / nucleic-acid :name (n2 / name :op1 "mRNA"))
                                    :mod p
                                    :ARG1-of (n3 / normalize-01)
                                    :ARG1-of (a / average-04))
                              :location (a2 / and
                                    :op1 (m6 / medical-condition :quant 0.7 :name (n4 / name :op1 "mSH")
                                          :ARG2-of (i2 / induce-01
                                                :ARG0 (e2 / enzyme :name (n5 / name :op1 "Braf")
                                                      :ARG2-of (m2 / mutate-01 :value "V637E"))))
                                    :op2 (m3 / mucosa :quant 1.0
                                          :mod (w / wild-type))))
                        :ARG2 (a3 / and
                              :op1 (i3 / increase-01
                                    :ARG1 l
                                    :ARG2 (p3 / product-of :op1 9.9)
                                    :location (m4 / medical-condition :name (n6 / name :op1 "mSA-LGD")))
                              :op2 (i4 / increase-01
                                    :ARG1 l
                                    :ARG2 (p4 / product-of :op1 32.3)
                                    :location (m5 / medical-condition :name (n7 / name :op1 "mSA-HGD")))
                              :op3 (i5 / increase-01
                                    :ARG1 l
                                    :ARG2 (p5 / product-of :op1 39.4)
                                    :location (c3 / carcinoma))))))
      :ARG1-of (d4 / describe-01
            :ARG0 (f / figure :mod "3E")))

# ::id pmid_2384_5441.122 ::date 2015-06-26T21:39:48 ::annotator SDL-AMR-09 ::preferred
# ::snt We conclude that p53 is activated mainly via p19<sup>Arf</sup> in advanced Braf<sup>V637E</sup>-iduced tumorigenesis, explaining its late stage specific function.
# ::save-date Tue Dec 22, 2015 ::file pmid_2384_5441_122.txt
(c / conclude-01
      :ARG0 (w / we)
      :ARG1 (a / activate-01
            :ARG0 (p / protein :name (n / name :op1 "p19Arf"))
            :ARG1 (p2 / protein :name (n3 / name :op1 "p53"))
            :mod (m / main)
            :time (c2 / create-01
                  :ARG1 (t / tumor)
                  :ARG2-of (i / induce-01
                        :ARG0 (e / enzyme :name (n4 / name :op1 "Braf")
                              :ARG2-of (m2 / mutate-01 :value "V637E")))
                  :ARG1-of (a2 / advance-01))
            :ARG0-of (e2 / explain-01
                  :ARG1 (f / function-01
                        :ARG0 p2
                        :ARG1-of (s / specific-02
                              :ARG2 (t2 / thing
                                    :ARG2-of (s2 / stage-02
                                          :ARG1 c2)))
                        :time (l / late)))))

# ::id pmid_2384_5441.123 ::date 2015-06-26T21:49:50 ::annotator SDL-AMR-09 ::preferred
# ::snt <sec-title level="2">Selective Pressure for p53 Inactivation Develops at Advanced Stages of Tumor Evolution</sec-title>
# ::save-date Wed Jul 1, 2015 ::file pmid_2384_5441_123.txt
(d / develop-01
      :ARG2 (p / pressure-01
            :ARG1 (a / activate-01 :polarity -
                  :ARG1 (p2 / protein :name (n / name :op1 "p53")))
            :ARG0-of (s / select-01))
      :time (s2 / stage
            :subevent-of (e / evolve-01
                  :ARG1 (t / tumor))
            :ARG1-of (a2 / advance-01)))

# ::id pmid_2384_5441.124 ::date 2015-06-26T21:54:23 ::annotator SDL-AMR-09 ::preferred
# ::snt To examine whether <i>p53</i> mutations occur spontaneously during Braf<sup>V637E</sup>-induced intestinal tumorigenesis, we next sequenced <i>p53</i> in <i>Braf</i> mutant tumors.
# ::save-date Tue Jan 19, 2016 ::file pmid_2384_5441_124.txt
(s / sequence-01
      :ARG0 (w / we)
      :ARG1 (p / protein :name (n / name :op1 "p53"))
      :location (t / tumor
            :ARG0-of (m / mutate-01
                  :ARG2 (e / enzyme :name (n2 / name :op1 "Braf"))))
      :time (n3 / next)
      :purpose (e2 / examine-01
            :ARG0 w
            :ARG1 (m2 / mutate-01 :mode interrogative
                  :ARG1 p
                  :manner (s2 / spontaneous)
                  :time (c / create-01
                        :ARG1 (t2 / tumor
                              :mod (i / intestine))
                        :ARG2-of (i2 / induce-01
                              :ARG0 (e3 / enzyme :name (n4 / name :op1 "Braf")
                                    :ARG2-of (m3 / mutate-01 :value "V637E")))))))

# ::id pmid_2384_5441.125 ::date 2015-06-26T22:01:37 ::annotator SDL-AMR-09 ::preferred
# ::snt Whereas mSAs (n = 17) did not have <i>p53</i> mutations, we identified a missense mutation (S152R; equivalent of human T155A) in one of the two carcinomas.
# ::save-date Wed Jul 1, 2015 ::file pmid_2384_5441_125.txt
(i / identify-01
      :ARG0 (w / we)
      :ARG1 (m / mutate-01 :value "S152R"
            :mod (m2 / missense)
            :ARG1-of (e / equal-01
                  :ARG2 (m3 / mutate-01 :value "T155A"
                        :mod (h / human))))
      :location (c / carcinoma :quant 1
            :ARG1-of (i2 / include-91
                  :ARG2 (c2 / carcinoma :quant 2)))
      :ARG1-of (c3 / contrast-01
            :ARG2 (h2 / have-03 :polarity -
                  :ARG0 (d / disease :name (n / name :op1 "mSA")
                        :ARG1-of (n2 / number-01
                              :ARG2 17))
                  :ARG1 (m4 / mutate-01
                        :ARG1 (p / protein :name (n3 / name :op1 "p53"))))))

# ::id pmid_2384_5441.126 ::date 2015-06-26T22:09:26 ::annotator SDL-AMR-09 ::preferred
# ::snt S152R leads to stabilization of nonfunctional p53, as evidenced by loss of p21 expression in cancer cells (<xref ref-type="fig" rid="fig3">Figures 3</xref>O–3Q).
# ::save-date Thu Jul 2, 2015 ::file pmid_2384_5441_126.txt
(l / lead-03
      :ARG0 (m / mutate-01 :value "S152R")
      :ARG2 (s / stabilize-01
            :ARG1 (p / protein
                  :name (n / name :op1 "p53")
                  :ARG0-of (f / function-01 :polarity -)))
      :ARG1-of (e / evidence-01
            :ARG0 (l2 / lose-02
                  :ARG1 (e2 / express-03
                        :ARG2 (p2 / protein
                              :name (n2 / name :op1 "p21"))
                        :ARG3 (c / cell
                              :mod (d / disease :wiki "Cancer"
                                    :name (n3 / name :op1 "cancer"))))))
      :ARG1-of (d2 / describe-01
            :ARG0 (v / value-interval
                  :op1 (f2 / figure :mod "3O")
                  :op2 (f3 / figure :mod "3Q"))))

# ::id pmid_2384_5441.127 ::date 2015-06-26T22:15:08 ::annotator SDL-AMR-09 ::preferred
# ::snt In the second cancer, p53 expression was lost whereas the surrounding dysplasia, which gave rise to the cancer, was p53-positive (<xref ref-type="fig" rid="fig3">Figures 3</xref>R and 3S).
# ::save-date Wed Jul 1, 2015 ::file pmid_2384_5441_127.txt
(c / contrast-01
      :ARG1 (l / lose-02
            :ARG1 (e / express-03
                  :ARG2 (p / protein
                        :name (n / name :op1 "p53"))))
      :ARG2 (p2 / positive
            :topic p
            :domain (d / dysplasia
                  :ARG1-of (s / surround-01)
                  :ARG0-of (g / give-01
                        :ARG1 (a / arise-02
                              :ARG1 (d2 / disease :wiki "Cancer"
                                    :name (n2 / name :op1 "cancer"))))))
      :location (d3 / disease :wiki "Cancer"
            :name (n3 / name :op1 "cancer")
            :ord (o / ordinal-entity :value 2))
      :ARG1-of (d4 / describe-01
            :ARG0 (a2 / and
                  :op1 (f / figure :mod "3R")
                  :op2 (f2 / figure :mod "3S"))))

# ::id pmid_2384_5441.128 ::date 2015-06-26T22:23:49 ::annotator SDL-AMR-09 ::preferred
# ::snt These results suggest late stage specific selective pressure to inactivate p53, further supporting the importance of p53 for invasiveness control.
# ::save-date Mon Dec 21, 2015 ::file pmid_2384_5441_128.txt
(s / suggest-01
      :ARG0 (t / thing
            :ARG2-of (r / result-01)
            :mod (t2 / this))
      :ARG1 (p / pressure-01
            :ARG2 (a / activate-01 :polarity -
                  :ARG1 (p2 / protein :name (n / name :op1 "p53")))
            :ARG0-of (s2 / select-01)
            :ARG1-of (s3 / specific-02)
            :time (s4 / stage
                  :mod (l / late)))
      :ARG0-of (s5 / support-01
            :ARG1 (i / important
                  :domain p2
                  :purpose (c / control-01
                        :ARG1 (i2 / invade-01)))
            :mod (f / further)))

# ::id pmid_2384_5441.129 ::date 2015-06-26T22:30:17 ::annotator SDL-AMR-09 ::preferred
# ::snt <sec-title level="2">Inactivation of p16 Promotes Advanced Phases of Braf<sup>V637E</sup>-Induced Intestinal Tumorigenesis</sec-title>
# ::save-date Tue Nov 3, 2015 ::file pmid_2384_5441_129.txt
(p / promote-01
      :ARG0 (a / activate-01 :polarity -
            :ARG1 (p2 / protein :name (n / name :op1 "p16")))
      :ARG1 (p3 / phase
            :subevent-of (c / create-01
                  :ARG1 (t / tumor
                        :mod (i / intestine))
                  :ARG2-of (i2 / induce-01
                        :ARG0 (e / enzyme :name (n2 / name :op1 "Braf")
                              :ARG2-of (m / mutate-01 :value "V637E"))))
            :ARG1-of (a2 / advance-01)))

# ::id pmid_2384_5441.130 ::date 2015-06-26T22:42:10 ::annotator SDL-AMR-09 ::preferred
# ::snt To examine the role of <i>p16</i><sup><i>Ink4a</i></sup>, we first analyzed <i>p16</i><sup><i>Ink4a</i></sup> expression in <i>Braf</i> mutant healthy and neoplastic intestines (<xref ref-type="fig" rid="fig4">Figure 4</xref>A).
# ::save-date Wed Jan 13, 2016 ::file pmid_2384_5441_130.txt
(a / analyze-01
      :ARG0 (w / we)
      :ARG1 (e / express-03
            :ARG2 (g / gene :name (n / name :op1 "p16Ink4a"))
            :ARG3 (a2 / and
                  :op1 (i / intestine
                        :mod (n2 / neoplasm))
                  :op2 (i2 / intestine
                        :mod (h / health))
                  :ARG0-of (m / mutate-01
                        :ARG2 (g2 / gene :name (n3 / name :op1 "Braf")))))
      :time (f / first)
      :purpose (e3 / examine-01
            :ARG0 w
            :ARG1 (r / role
                  :poss g))
      :ARG1-of (d / describe-01
            :ARG0 (f2 / figure :mod "4A")))

# ::id pmid_2384_5441.131 ::date 2015-06-26T22:47:42 ::annotator SDL-AMR-09 ::preferred
# ::snt Whereas <i>p16</i><sup><i>Ink4a</i></sup> expression was similar in <i>Braf</i> mutant mSH and WT mucosa, there was a marked upregulation of <i>p16</i><sup><i>Ink4a</i></sup> expression in <i>Braf</i> mutant neoplasia.
# ::save-date Sun Jan 17, 2016 ::file pmid_2384_5441_131.txt
(u / upregulate-01
      :ARG1 (e / express-03
            :ARG2 (g / gene :name (n / name :op1 "p16Ink4a")))
      :location (n2 / neoplasia
            :ARG0-of (m / mutate-01
                  :ARG2 (g2 / gene :name (n3 / name :op1 "Braf"))))
      :degree (m2 / marked)
      :ARG1-of (c / contrast-01
            :ARG2 (r / resemble-01
                  :ARG1 e
                  :location (a / and
                        :op1 (m4 / medical-condition :name (n4 / name :op1 "mSH")
                              :ARG0-of m)
                        :op2 (m3 / mucosa
                              :mod (w / wild-type))))))

# ::id pmid_2384_5441.132 ::date 2015-06-26T22:56:52 ::annotator SDL-AMR-09 ::preferred
# ::snt This effect was less pronounced in mSAs-LGD than in mSAs-HGD, in which <i>p16</i><sup><i>Ink4a</i></sup> was induced on average 100-fold (<xref ref-type="fig" rid="fig4">Figure 4</xref>A).
# ::save-date Wed Jan 13, 2016 ::file pmid_2384_5441_132.txt
(p / pronounced-02
      :ARG1 (t / thing
            :ARG2-of (a / affect-01)
            :mod (t2 / this))
      :location (d / disease :name (n / name :op1 "mSA-LGD"))
      :degree (l / less)
      :compared-to (d2 / disease :name (n2 / name :op1 "mSA-HGD")
            :location-of (p2 / pronounced-02
                  :ARG1 t)
            :location-of (i / induce-01
                  :ARG2 (g / gene :name (n3 / name :op1 "p16Ink4a"))
                  :quant (p4 / product-of :op1 100
                        :ARG1-of (a2 / average-01))))
      :ARG1-of (d3 / describe-01
            :ARG0 (f / figure :mod "4A")))

# ::id pmid_2384_5441.133 ::date 2015-06-30T00:26:23 ::annotator SDL-AMR-09 ::preferred
# ::snt Thus, similarly to Braf<sup>V6<i>37</i>E</sup>-induced Arf/p53 activation, substantial p16<sup>Ink4a</sup> activation is only triggered at advanced stages of tumorigenesis.
# ::save-date Tue Dec 22, 2015 ::file pmid_2384_5441_133.txt
(i / infer-01
      :ARG1 (t / trigger-01
            :ARG1 (a / activate-01
                  :ARG1 (p / protein :name (n / name :op1 "p16Ink4a"))
                  :mod (s / substantial))
            :mod (o / only)
            :ARG1-of (r / resemble-01
                  :ARG2 (a3 / activate-01
                        :ARG1 (p2 / pathway :name (n2 / name :op1 "Arf/p53"))
                        :ARG2-of (i2 / induce-01
                              :ARG0 (e / enzyme :name (n3 / name :op1 "Braf")
                                    :ARG2-of (m / mutate-01 :value "V637E")))))
            :time (t3 / thing
                  :ARG2-of (s2 / stage-02
                        :ARG1 (c / create-01
                              :ARG1 (t2 / tumor))
                        :ARG1-of (a2 / advance-01)))))

# ::id pmid_2384_5441.134 ::date 2015-06-30T00:50:25 ::annotator SDL-AMR-09 ::preferred
# ::snt This is consistent with observations in humans, where <i>p16</i> was upregulated in <i>BRAF</i> mutant premalignant lesions (SSAs and TSAs) but not in hyperplasia (<xref ref-type="bibr" rid="bib23">Kriegl et al., 2011</xref>).
# ::save-date Wed Dec 9, 2015 ::file pmid_2384_5441_134.txt
(c / consistent-01
      :ARG1 (t / this)
      :ARG2 (o / observe-01
            :location (h / human
                  :location-of (c2 / contrast-01
                        :ARG1 (u / upregulate-01
                              :ARG1 (g / gene :name (n / name :op1 "p16"))
                              :condition (l / lesion
                                    :mod (p / premalignant)
                                    :mod (g2 / gene :name (n2 / name :op1 "BRAF")
                                          :ARG2-of (m / mutate-01))
                                    :ARG1-of (m2 / mean-01
                                          :ARG2 (a / and
                                                :op1 (m4 / medical-condition :name (n4 / name :op1 "sessile" :op2 "serrated" :op3 "adenoma"))
                                                :op2 (m3 / medical-condition :name (n5 / name :op1 "traditional" :op2 "serrated" :op3 "adenoma"))))))
                        :ARG2 (u2 / upregulate-01 :polarity -
                              :ARG1 g
                              :condition (h2 / hyperplasia)))))
      :ARG1-of (d2 / describe-01
            :ARG0 (p2 / publication-91
                  :ARG0 (a2 / and
                        :op1 (p3 / person :name (n3 / name :op1 "Kriegl"))
                        :op2 (p4 / person
                              :mod (o2 / other)))
                  :time (d / date-entity :year 2011))))

# ::id pmid_2384_5441.135 ::date 2015-06-30T01:01:26 ::annotator SDL-AMR-09 ::preferred
# ::snt To investigate whether <i>p16</i><sup><i>Ink4a</i></sup> inactivation occurs spontaneously in Braf<sup>V6<i>37</i>E</sup>-induced tumors, we performed comparative genomic hybridization, sequencing, and methylation analysis of the <i>cdkn2a</i> locus.
# ::save-date Tue Nov 3, 2015 ::file pmid_2384_5441_135.txt
(p / perform-01
      :ARG0 (w / we)
      :ARG1 (a / and
            :op1 (h / hybridize-01
                  :ARG1 (l / locus
                        :ARG0-of (c2 / contain-01
                              :ARG1 (g2 / gene :name (n / name :op1 "CDKN2A"))))
                  :mod (g / genome)
                  :ARG0-of (c / compare-01))
            :op2 (s / sequence
                  :mod g2)
            :op3 (a2 / analyze-01
                  :ARG1 g2
                  :mod (m / methylate-01)))
      :purpose (i / investigate-01
            :ARG0 w
            :ARG1 (a3 / activate-01 :polarity - :mode interrogative
                  :ARG1 (g4 / gene :name (n2 / name :op1 "p16Ink4a"))
                  :mod (s2 / spontaneous)
                  :location (t / tumor
                        :ARG2-of (i2 / induce-01
                              :ARG0 (e / enzyme :name (n3 / name :op1 "Braf")
                                    :ARG2-of (m2 / mutate-01 :value "V637E")))))))

# ::id pmid_2384_5441.136 ::date 2015-06-30T01:13:43 ::annotator SDL-AMR-09 ::preferred
# ::snt We did not identify <i>Cdkn2a</i> mutations or copy number alterations in any of the 12 TSAs and eight carcinomas analyzed (data not shown).
# ::save-date Wed Dec 9, 2015 ::file pmid_2384_5441_136.txt
(i / identify-01 :polarity -
      :ARG0 (w / we)
      :ARG1 (o / or
            :op1 (m / mutate-01
                  :ARG2 (g / gene :name (n / name :op1 "Cdkn2a")))
            :op2 (a / alter-01
                  :ARG1 (n2 / number
                        :quant-of (t2 / thing
                              :ARG2-of (c / copy-01)))))
      :location (a2 / and
            :op1 (m2 / medical-condition :name (n3 / name :op1 "traditional" :op2 "serrated" :op3 "adenoma"))
            :op2 (c2 / carcinoma :quant 8)
            :mod (a3 / any)
            :ARG1-of (a4 / analyze-01))
      :ARG1-of (d / describe-01
            :ARG0 (d2 / data
                  :ARG1-of (s / show-01 :polarity -))))

# ::id pmid_2384_5441.137 ::date 2015-06-30T01:19:31 ::annotator SDL-AMR-09 ::preferred
# ::snt In a subset of Braf<sup>V637E</sup>-induced mSAs-HGD and carcinomas, however, we found partial CpG island methylation in the <i>p16</i><sup><i>Ink4a</i></sup> (but not <i>p19</i><sup><i>Arf</i></sup>) promoter (<xref ref-type="sec" rid="app3">Figure S3</xref>), similar to observations in humans (<xref ref-type="bibr" rid="bib23">Kriegl et al., 2011</xref>).
# ::save-date Tue Nov 3, 2015 ::file pmid_2384_5441_137.txt
(h / have-concession-91
      :ARG1 (c2 / contrast-01
            :ARG1 (f / find-01
                  :ARG0 (w / we)
                  :ARG1 (m / methylate-01
                        :ARG1 (d2 / dna-sequence :name (n / name :op1 "CpG" :op2 "island")
                              :part-of (m2 / molecular-physical-entity
                                    :ARG0-of (p2 / promote-01
                                          :ARG1 (g2 / gene :name (n2 / name :op1 "p16Ink4a")))))
                        :degree (p / part)))
            :ARG2 (f2 / find-01 :polarity -
                  :ARG0 w
                  :ARG1 (m4 / methylate-01
                        :ARG1 (d3 / dna-sequence :name (n4 / name :op1 "CpG" :op2 "island")
                              :part-of (m3 / molecular-physical-entity
                                    :ARG0-of (p4 / promote-01
                                          :ARG1 (g3 / gene :name (n3 / name :op1 "p19Arf")))))
                        :degree p))
            :ARG1-of (d4 / describe-01
                  :ARG0 (f3 / figure :mod "S3"))
            :location (s / subset
                  :ARG1-of (i2 / include-91
                        :ARG2 (a / and
                              :op1 (d6 / disease :name (n7 / name :op1 "mSA-HGD"))
                              :op2 (c3 / carcinoma)
                              :ARG2-of (i / induce-01
                                    :ARG0 (e / enzyme :name (n5 / name :op1 "Braf")
                                          :ARG2-of (m6 / mutate-01 :value "V637E"))))))
            :ARG2-of (r2 / resemble-01
                  :ARG1 (o / observe-01
                        :location (h2 / human))))
      :ARG1-of (d5 / describe-01
            :ARG0 (p6 / publication-91
                  :ARG0 (a2 / and
                        :op1 (p7 / person :name (n6 / name :op1 "Kriegl"))
                        :op2 (p8 / person
                              :mod (o2 / other)))
                  :time (d / date-entity :year 2011))))

# ::id pmid_2384_5441.138 ::date 2015-06-30T01:42:46 ::annotator SDL-AMR-09 ::preferred
# ::snt To study the effect of <i>p16</i><sup><i>Ink4a</i></sup> inactivation in vivo, we used <i>p16</i><sup><i>Ink4a<sup>∗</sup></i></sup> mice, which have a point mutation that is silent in the <i>p19</i><sup><i>Arf</i></sup> reading frame but introduces a stop codon in <i>p16</i><sup><i>Ink4a</i></sup> (<xref ref-type="bibr" rid="bib24">Krimpenfort et al., 2001</xref>).
# ::save-date Sun Jan 3, 2016 ::file pmid_2384_5441_138.txt
(u2 / use-01
      :ARG0 (w / we)
      :ARG1 (m / mouse
            :mod (g / gene :name (n / name :op1 "p16Ink4a*"))
            :location-of (m2 / mutate-01
                  :mod (p / point)
                  :mod (s / silent)
                  :location (f / frame
                        :topic (r / read-01)
                        :mod (g3 / gene :name (n2 / name :op1 "p19Arf")))
                  :ARG1-of (c / contrast-01
                        :ARG2 (i / introduce-02
                              :ARG0 m2
                              :ARG1 (c2 / codon
                                    :mod (s2 / stop))
                              :ARG2 g2))))
      :ARG2 (s3 / study-01
            :ARG0 w
            :ARG1 (a / affect-01
                  :ARG0 (a2 / activate-01 :polarity -
                        :ARG1 (g2 / gene :name (n5 / name :op1 "p16Ink4a")))
                  :manner (i2 / in-vivo)))
      :ARG1-of (d3 / describe-01
            :ARG0 (p3 / publication-91
                  :ARG0 (a3 / and
                        :op1 (p4 / person :name (n4 / name :op1 "Krimpenfort"))
                        :op2 (p5 / person
                              :mod (o / other)))
                  :time (d / date-entity :year 2001))))

# ::id pmid_2384_5441.139 ::date 2015-06-30T02:36:36 ::annotator SDL-AMR-09 ::preferred
# ::snt <i>Vil-Cre;Braf</i><sup><i>LSL-V637E</i>/+</sup> mice with heterozygous or homozygous mutation of <i>p16</i><sup><i>Ink4a</i></sup><i>(Vil-Cre;Braf</i><sup><i>LSL-V637E</i>/+</sup><i>;p16</i><sup><i>Ink4a<sup>∗</sup></i></sup><i>)</i> were aged and sacrificed at different time points to assess tumor incidence and latency (<xref ref-type="fig" rid="fig4">Figure 4</xref>B).
# ::save-date Wed Jan 13, 2016 ::file pmid_2384_5441_139.txt
(a / and
      :op1 (a2 / age-01
            :ARG1 (m / mouse
                  :location-of (o / or
                        :op1 (m2 / mutate-01
                              :ARG2 (g2 / gene :name (n / name :op1 "p16Ink4a"))
                              :mod (h / heterozygous))
                        :op2 (m3 / mutate-01
                              :ARG2 g2
                              :mod (h2 / homozygous)))
                  :mod (g / gene :name (n2 / name :op1 "Braf")
                        :ARG2-of (m4 / mutate-01 :value "LSL-V637E/+"))
                  :ARG1-of (d3 / describe-01
                        :ARG2 (m5 / mouse
                              :mod g
                              :mod (g3 / gene :name (n4 / name :op1 "p16Ink4a")
                                    :ARG2-of (m6 / mutate-01))
                              :mod e))
                  :mod (e / enzyme :name (n3 / name :op1 "Cre")
                        :ARG2-of (e2 / express-03
                              :ARG1 (g4 / gene :name (n5 / name :op1 "Vil"))))))
      :op2 (s / sacrifice-01
            :ARG1 m
            :time (p2 / point
                  :ARG1-of (d / differ-02))
            :purpose (a3 / assess-01
                  :ARG1 (a4 / and
                        :op1 (i / incidence)
                        :op2 (l / latency)
                        :mod (t / tumor))))
      :ARG1-of (d2 / describe-01
            :ARG0 (f / figure :mod "4B")))

# ::id pmid_2384_5441.140 ::date 2015-06-30T02:53:37 ::annotator SDL-AMR-09 ::preferred
# ::snt We observed 1.3-fold increased numbers of mSAs in <i>Vil-Cre;Braf</i><sup><i>LSL-V637E</i>/+</sup><i>;p16</i><sup><i>Ink4a<sup>∗</sup></i></sup> animals as compared to <i>Vil-Cre;Braf</i><sup><i>LSL-V637E</i>/+</sup> mice, but this was statistically not significant (<xref ref-type="fig" rid="fig4">Figure 4</xref>C; <xref ref-type="sec" rid="app3">Table S4</xref>).
# ::save-date Wed Jan 13, 2016 ::file pmid_2384_5441_140.txt
(c / contrast-01
      :ARG1 (o / observe-01
            :ARG0 (w / we)
            :ARG1 (n / number
                  :quant-of (d2 / disease :name (n6 / name :op1 "mSA"))
                  :ARG1-of (i / increase-01
                        :ARG2 (p / product-of :op1 1.3)
                        :location (a / animal
                              :mod g
                              :mod (g2 / gene :name (n4 / name :op1 "p16Ink4a")
                                    :ARG2-of (m4 / mutate-01))
                              :mod (e / enzyme :name (n3 / name :op1 "Cre")
                                    :ARG2-of (e2 / express-03
                                          :ARG1 (g3 / gene :name (n5 / name :op1 "Vil")))))
                        :compared-to (m2 / mouse
                              :mod (g / gene :name (n2 / name :op1 "Braf")
                                    :ARG2-of (m3 / mutate-01 :value "LSL-V637E/+"))
                              :mod e))))
      :ARG2 (s / significant-02 :polarity -
            :ARG1 n
            :manner (s2 / statistic))
      :ARG1-of (d / describe-01
            :ARG0 (a2 / and
                  :op1 (t / table :mod "S4")
                  :op2 (f / figure :mod "4C"))))

# ::id pmid_2384_5441.141 ::date 2015-06-30T03:05:03 ::annotator SDL-AMR-09 ::preferred
# ::snt In contrast, carcinoma development was significantly increased in <i>Vil-Cre;Braf</i><sup><i>LSL-V637E</i>/+</sup><i>;p16</i><sup><i>Ink4<sup>∗</sup></i></sup> mice, which had on average 6.4 times as many cancers as <i>Vil-Cre;Braf</i><sup><i>LSL-V637E</i>/+</sup><i>;p16</i><sup><i>Ink4a+/+</i></sup> mice (p < 0.001; <xref ref-type="fig" rid="fig4">Figure 4</xref>C; <xref ref-type="sec" rid="app3">Table S5</xref>).
# ::save-date Wed Jan 13, 2016 ::file pmid_2384_5441_141.txt
(c / contrast-01
      :ARG2 (i / increase-01
            :ARG1 (d / develop-01
                  :ARG2 (c2 / carcinoma))
            :ARG2 (s / significant-02)
            :location (m / mouse
                  :mod (g / gene :name (n / name :op1 "Braf")
                        :ARG2-of (m3 / mutate-01 :value "LSL-V637E/+"))
                  :ARG0-of (h / have-03
                        :ARG1 (d3 / disease :wiki "Cancer" :name (n6 / name :op1 "cancer")
                              :quant (p / product-of :op1 6.4
                                    :ARG1-of (a / average-01))
                              :compared-to (m2 / mouse
                                    :mod g
                                    :mod (g2 / gene :name (n3 / name :op1 "p16Ink4a")
                                          :mod (w / wild-type))
                                    :mod e)))
                  :mod (g3 / gene :name (n4 / name :op1 "p16Ink4a")
                        :ARG2-of (m5 / mutate-01))
                  :mod (e / enzyme :name (n2 / name :op1 "Cre")
                        :ARG2-of (e2 / express-03
                              :ARG1 (g4 / gene :name (n5 / name :op1 "Vil")))))
            :ARG1-of (s2 / statistical-test-91
                  :ARG2 (l / less-than :op1 0.001)))
      :ARG1-of (d2 / describe-01
            :ARG0 (a2 / and
                  :op1 (t / table :mod "S5")
                  :op2 (f / figure :mod "4C"))))

# ::id pmid_2384_5441.142 ::date 2015-06-30T03:13:11 ::annotator SDL-AMR-09 ::preferred
# ::snt Many of the mice developed multiple synchronous carcinomas and, in some animals (3/24), these tumors were metastatic.
# ::save-date Thu Jul 16, 2015 ::file pmid_2384_5441_142.txt
(a / and
      :op1 (d / develop-01
            :ARG1 (m / mouse
                  :quant (m2 / many))
            :ARG2 (c / carcinoma
                  :quant (m3 / multiple)
                  :ARG1-of (s / synchronous-02)))
      :op2 (m4 / metastasize-101
            :ARG1 (t / tumor
                  :mod (t2 / this))
            :location (a2 / animal
                  :quant (s2 / some
                        :ARG1-of (m5 / mean-01
                              :ARG2 (a3 / animal :quant 3
                                    :ARG1-of (i / include-91
                                          :ARG2 (a4 / animal :quant 24))))))))

# ::id pmid_2384_5441.143 ::date 2015-06-30T03:21:04 ::annotator SDL-AMR-09 ::preferred
# ::snt All together, these results show that Arf/p53 and p16 exert independent critical tumor-suppressive effects, which are mainly operative at advanced stages of Braf<sup>V637E</sup>-induced intestinal tumorigenesis.
# ::save-date Wed Mar 9, 2016 ::file pmid_2384_5441_143.txt
(s / show-01
      :ARG0 (t / thing
            :ARG2-of (r / result-01)
            :mod (t2 / this))
      :ARG1 (e / exert-01
            :ARG0 (a / and
                  :op1 (p / pathway :name (n / name :op1 "Arf/p53"))
                  :op2 (p2 / protein :name (n2 / name :op1 "p16")))
            :ARG1 (a2 / affect-01
                  :ARG0 a
                  :ARG2 (s2 / suppress-01
                        :ARG1 (t3 / tumor))
                  :ARG1-of (c / critical-02)
                  :ARG0-of (d / depend-01 :polarity -)
                  :ARG0-of (o / operate-01
                        :manner (m / main)
                        :time (t5 / thing
                              :ARG2-of (s3 / stage-02
                                    :ARG1 (c2 / create-01
                                          :ARG1 (t4 / tumor
                                                :mod (i / intestine))
                                          :ARG2-of (i2 / induce-01
                                                :ARG0 (e2 / enzyme :name (n3 / name :op1 "Braf")
                                                      :ARG2-of (m2 / mutate-01 :value "V637E"))))
                                    :ARG1-of (a3 / advance-01))))))
      :manner (t6 / together
            :mod (a4 / all)))

# ::id pmid_2384_5441.144 ::date 2015-06-30T04:00:06 ::annotator SDL-AMR-09 ::preferred
# ::snt <sec-title level="2">Intensification of Map Kinase Signaling during Dysplasia Progression</sec-title>
# ::save-date Sun Jan 17, 2016 ::file pmid_2384_5441_144.txt
(i / intensify-01
      :ARG1 (s / signal-07
            :ARG0 (p2 / pathway :name (n / name :op1 "Map" :op2 "Kinase")))
      :time (p / progress-01
            :ARG1 (m / medical-condition :name (n2 / name :op1 "dysplasia"))))

# ::id pmid_2384_5441.145 ::date 2015-06-30T04:04:54 ::annotator SDL-AMR-09 ::preferred
# ::snt Because Braf-induced Mapk signaling does not seem to engage intrinsic tumor suppression in early tumorigenesis, we next assessed the MAPK pathway activity at different stages of tumor evolution.
# ::save-date Tue Dec 22, 2015 ::file pmid_2384_5441_145.txt
(a / assess-01
      :ARG0 (w / we)
      :ARG1 (a2 / activity-06
            :ARG0 (p2 / pathway :name (n3 / name :op1 "Mapk")))
      :time (n2 / next)
      :ARG1-of (c / cause-01
            :ARG0 (s2 / seem-01 :polarity -
                  :ARG1 (e2 / engage-01
                        :ARG0 (s3 / signal-07
                              :ARG0 p2
                              :ARG2-of (i / induce-01
                                    :ARG0 (e4 / enzyme :name (n / name :op1 "Braf"))))
                        :ARG1 (s4 / suppress-01
                              :ARG1 t
                              :mod (i2 / intrinsic))
                        :ARG2 (c2 / create-01
                              :ARG1 t
                              :time (e3 / early)))))
      :time (t2 / thing
            :ARG2-of (s / stage-02
                  :ARG1 (e / evolve-01
                        :ARG1 (t / tumor))
                  :ARG1-of (d / differ-02))))

# ::id pmid_2384_5441.146 ::date 2015-06-30T04:11:43 ::annotator SDL-AMR-09 ::preferred
# ::snt Unexpectedly, phospho-p42/p44 MAPK (pErk) protein levels were only slightly increased in Braf<sup>V6<i>37</i>E</sup>-induced mSH as compared to wild-type mucosa but were highly induced in mSAs and carcinomas (<xref ref-type="fig" rid="fig5">Figure 5</xref>A).
# ::save-date Sun Jan 17, 2016 ::file pmid_2384_5441_146.txt
(c / contrast-01
      :ARG1 (i / increase-01
            :ARG1 (l / level
                  :quant-of (e3 / enzyme :name (n2 / name :op1 "p42/p44" :op2 "MAPK")
                        :ARG3-of (p3 / phosphorylate-01)
                        :ARG1-of (m5 / mean-01
                              :ARG2 (e4 / enzyme :name (n3 / name :op1 "Erk")
                                    :ARG3-of p3))))
            :ARG2 (s / slight
                  :mod (o / only))
            :location (d2 / disease :name (n4 / name :op1 "mSH")
                  :ARG2-of (i2 / induce-01
                        :ARG0 (e2 / enzyme :name (n / name :op1 "Braf")
                              :ARG2-of (m2 / mutate-01 :value "V637E"))))
            :compared-to (m3 / mucosa
                  :mod (w / wild-type)))
      :ARG2 (i3 / induce-01
            :ARG2 l
            :ARG1-of (h / high-02)
            :location (a / and
                  :op1 (m / medical-condition :name (n5 / name :op1 "mSA"))
                  :op2 (c2 / carcinoma)))
      :ARG1-of (e / expect-01 :polarity -)
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod "5A")))

# ::id pmid_2384_5441.147 ::date 2015-06-30T04:20:54 ::annotator SDL-AMR-09 ::preferred
# ::snt Immunohistochemistry revealed that in wild-type mucosa and Braf<sup>V6<i>37</i>E</sup>-induced mSH, pErk reactivity was mostly confined to the lower parts of the crypts (<xref ref-type="fig" rid="fig5">Figures 5</xref>B and 5C).
# ::save-date Sun Jan 17, 2016 ::file pmid_2384_5441_147.txt
(r2 / reveal-01
      :ARG0 (i / immunohistochemistry)
      :ARG1 (c / confine-01
            :ARG1 (r / react-01
                  :ARG0 (e / enzyme :name (n / name :op1 "Erk")
                        :ARG3-of (p2 / phosphorylate-01)))
            :ARG2 (p3 / part
                  :ARG1-of (l / low-04
                        :ARG2 (c2 / crypt)
                        :degree (m / more)))
            :degree (m2 / most)
            :location (a / and
                  :op1 (m3 / mucosa
                        :mod (w / wild-type))
                  :op2 (m4 / medical-condition :name (n3 / name :op1 "mSH")
                        :ARG2-of (i2 / induce-01
                              :ARG0 (e2 / enzyme :name (n2 / name :op1 "Braf")
                                    :ARG2-of (m5 / mutate-01 :value "V637E"))))))
      :ARG1-of (d / describe-01
            :ARG0 (a2 / and
                  :op1 (f / figure :mod "5B")
                  :op2 (f2 / figure :mod "5C"))))

# ::id pmid_2384_5441.148 ::date 2015-06-30T04:27:57 ::annotator SDL-AMR-09 ::preferred
# ::snt In mSAs-LGD, few scattered pERK-positive cells were occasionally additionally detected in dysplastic areas (<xref ref-type="fig" rid="fig5">Figure 5</xref>D).
# ::save-date Sat Jan 16, 2016 ::file pmid_2384_5441_148.txt
(d / detect-01
      :ARG1 (c / cell
            :quant (f / few)
            :ARG1-of (s / scatter-01)
            :mod (p / positive
                  :topic (e / enzyme :name (n / name :op1 "ERK")
                        :ARG3-of (p3 / phosphorylate-01))))
      :time (o / occasional)
      :manner (a / additional)
      :location (a2 / area
            :mod (m2 / medical-condition :name (n2 / name :op1 "dysplasia")))
      :ARG1-of (d3 / describe-01
            :ARG0 (f2 / figure :mod "5D"))
      :condition (m3 / medical-condition :name (n3 / name :op1 "mSAs-LGD")))

# ::id pmid_2384_5441.149 ::date 2015-06-30T04:32:11 ::annotator SDL-AMR-09 ::preferred
# ::snt mSAs-HGD and carcinomas, however, stained uniformly positive for pErk (<xref ref-type="fig" rid="fig5">Figures 5</xref>E–5G).
# ::save-date Sat Jan 16, 2016 ::file pmid_2384_5441_149.txt
(h / have-concession-91
      :ARG1 (s / stain-01
            :ARG1 (a / and
                  :op1 (d2 / disease :name (n2 / name :op1 "mSA-HGD"))
                  :op2 (m / medical-condition :name (n3 / name :op1 "carcinoma")))
            :manner (p / positive
                  :ARG1-of (u / uniform-02)
                  :topic (e / enzyme :name (n / name :op1 "Erk")
                        :ARG3-of (p3 / phosphorylate-01))))
      :ARG1-of (d / describe-01
            :ARG0 (a2 / and
                  :op1 (f / figure :mod "5E")
                  :op2 (f2 / figure :mod "5F")
                  :op3 (f3 / figure :mod "5G"))))

# ::id pmid_2384_5441.150 ::date 2015-06-30T04:42:42 ::annotator SDL-AMR-09 ::preferred
# ::snt Compared to wild-type mucosa, the number of pERK-positive cells per gland was increased 1.4-, 2.4-, and 6.6-fold in mSH, mSAs-LGD, and mSAs-HGD, respectively (<xref ref-type="sec" rid="app3">Figure S4</xref>A).
# ::save-date Sun Jan 17, 2016 ::file pmid_2384_5441_150.txt
(a3 / and
      :op1 (i / increase-01
            :ARG1 (r / rate-entity-91
                  :ARG1 (n / number
                        :quant-of (c / cell
                              :mod (p / positive
                                    :topic (e / enzyme :name (n2 / name :op1 "ERK")
                                          :ARG3-of (p3 / phosphorylate-01)))))
                  :ARG2 (g / gland))
            :ARG2 (p4 / product-of :op1 1.4)
            :location (m2 / medical-condition :name (n3 / name :op1 "mSH")))
      :op2 (i2 / increase-01
            :ARG1 r
            :ARG2 (p5 / product-of :op1 2.4)
            :location (m / medical-condition :name (n4 / name :op1 "mSAs-LGD")))
      :op3 (i3 / increase-01
            :ARG1 r
            :ARG2 (p6 / product-of :op1 6.6)
            :location (m3 / medical-condition :name (n5 / name :op1 "mSAs-HGD")))
      :compared-to (m4 / mucosa
            :mod (w / wild-type))
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod "S4A"))
      :manner (r2 / respective))

# ::id pmid_2384_5441.151 ::date 2015-06-30T04:53:46 ::annotator SDL-AMR-09 ::preferred
# ::snt To assess the functional relevance of these observations, we examined expression of a panel of 15 Erk target genes (<xref ref-type="bibr" rid="bib35">Pratilas et al., 2009</xref>) using qRT-PCR (<xref ref-type="fig" rid="fig5">Figure 5</xref>H) or immunohistochemistry (<xref ref-type="sec" rid="app3">Figure S4</xref>).
# ::save-date Mon Jan 4, 2016 ::file pmid_2384_5441_151.txt
(e2 / examine-01
      :ARG0 (w / we)
      :ARG1 (e3 / express-03
            :ARG1 (p / panel
                  :consist-of (g / gene :quant 15
                        :ARG1-of (t / target-01
                              :ARG0 (p6 / protein-family :name (n / name :op1 "Erk"))))
                  :ARG1-of (d2 / describe-01
                        :ARG0 (p2 / publication-91
                              :ARG0 (a / and
                                    :op1 (p3 / person :name (n2 / name :op1 "Pratilas"))
                                    :op2 (p4 / person
                                          :mod (o / other)))
                              :time (d / date-entity :year 2009)))))
      :manner (u / use-01
            :ARG1 (o2 / or
                  :op1 (r2 / react-01
                        :ARG0 (p5 / polymerase)
                        :ARG1-of (d3 / describe-01
                              :ARG0 (f / figure :mod "5H"))
                        :mod (c / chain)
                        :mod (r3 / real-time)
                        :mod (q / quantitative)
                        :subevent (t3 / transcribe-01
                              :ARG1-of (r4 / reverse-01)))
                  :op2 (i / immunohistochemistry
                        :ARG1-of (d4 / describe-01
                              :ARG0 (f2 / figure :mod "S4")))))
      :purpose (a2 / assess-01
            :ARG0 w
            :ARG1 (r / relevance
                  :mod (f3 / function)
                  :poss (o3 / observe-01
                        :mod (t2 / this)))))

# ::id pmid_2384_5441.152 ::date 2015-06-30T05:14:01 ::annotator SDL-AMR-09 ::preferred
# ::snt The panel of markers includes a number of effectors of Ras/Raf-induced transformation, such as the ETS family members <i>Etv4</i> and <i>Etv5</i> or <i>cMyc</i> and <i>Ccnd1</i>, and genes involved in the feedback regulation of Mek/Erk signaling, such as <i>Dusp4</i>, <i>Dusp6</i>, <i>Spry2</i>, and <i>Spry4</i>.
# ::save-date Sun Jan 17, 2016 ::file pmid_2384_5441_152.txt
(i / include-91
      :ARG1 (a / and
            :op1 (n2 / number
                  :quant-of (e / effector
                        :ARG0-of (t / transform-01
                              :ARG2-of (i2 / induce-01
                                    :ARG0 (s / slash
                                          :op1 (e2 / enzyme :name (n3 / name :op1 "Ras"))
                                          :op2 (e3 / enzyme :name (n4 / name :op1 "Raf")))))
                        :example (o / or
                              :op1 (a2 / and
                                    :op1 (g8 / gene :name (n5 / name :op1 "Etv4"))
                                    :op2 (g9 / gene :name (n6 / name :op1 "Etv5"))
                                    :mod (m2 / member
                                          :ARG1-of (i4 / include-91
                                                :ARG2 (p3 / protein-family :name (n9 / name :op1 "ETS")))))
                              :op2 (g / gene :name (n7 / name :op1 "cMyc"))
                              :op3 (g2 / gene :name (n8 / name :op1 "Ccnd1")))))
            :op2 (g3 / gene
                  :ARG1-of (i3 / involve-01
                        :ARG2 (r / regulate-01
                              :ARG1 (s2 / signal-07
                                    :ARG0 (p / pathway :name (n / name :op1 "Mek/Erk")))
                              :mod (f2 / feedback)))
                  :example (a3 / and
                        :op1 (g4 / gene :name (n10 / name :op1 "Dusp4"))
                        :op2 (g5 / gene :name (n11 / name :op1 "Dusp6"))
                        :op3 (g6 / gene :name (n12 / name :op1 "Spry2"))
                        :op4 (g7 / gene :name (n13 / name :op1 "Spry4")))))
      :ARG2 (p2 / panel
            :consist-of (m / marker)))

# ::id pmid_2384_5441.153 ::date 2015-06-30T05:28:47 ::annotator SDL-AMR-09 ::preferred
# ::snt We found that the transcriptional output of the Erk pathway was only slightly induced in Braf<sup>V6<i>37</i>E</sup>-dependent mSH and mSAs-LGD (average fold-change across target genes: 1.1 and 3.4, respectively) but was strongly upregulated in mSAs-HGD and carcinomas (average fold-change across target genes: 13.0 and 12.6, respectively).
# ::save-date Sun Jan 3, 2016 ::file pmid_2384_5441_153.txt
(f / find-01
      :ARG0 (w / we)
      :ARG1 (c / contrast-01
            :ARG1 (i / induce-01
                  :ARG2 (o2 / output
                        :ARG1-of (t / transcribe-01
                              :ARG0 (p / pathway :name (n / name :op1 "Erk"))))
                  :degree (s / slight
                        :mod (o / only)
                        :ARG1-of (m5 / mean-01
                              :ARG2 (c3 / change-01
                                    :ARG1 (g2 / gene
                                          :ARG1-of (t2 / target-01))
                                    :ARG1-of (a3 / average-04)
                                    :mod (f2 / fold)
                                    :quant (a4 / and
                                          :op1 (p2 / product-of :op1 1.1)
                                          :op2 (p4 / product-of :op1 3.4)
                                          :mod (r / respective)))))
                  :location (a / and
                        :op1 (m7 / medical-condition :name (n3 / name :op1 "mSH"))
                        :op2 (m / medical-condition :name (n4 / name :op1 "mSAs-LGD"))
                        :ARG0-of (d / depend-01
                              :ARG1 (e / enzyme :name (n2 / name :op1 "Braf")
                                    :ARG2-of (m3 / mutate-01 :value "V637E")))))
            :ARG2 (u / upregulate-01
                  :ARG1 o2
                  :degree (s2 / strong
                        :ARG1-of (m6 / mean-01
                              :ARG2 (c4 / change-01
                                    :ARG1 g2
                                    :ARG1-of a3
                                    :mod f2
                                    :quant (a5 / and
                                          :op1 (p3 / product-of :op1 13.0)
                                          :op2 (p5 / product-of :op1 12.6)
                                          :mod r))))
                  :location (a2 / and
                        :op1 (m2 / medical-condition :name (n5 / name :op1 "mSAs-HGD"))
                        :op2 (m8 / medical-condition :name (n6 / name :op1 "carcinoma"))))))

# ::id pmid_2384_5441.154 ::date 2015-06-30T05:39:08 ::annotator SDL-AMR-09 ::preferred
# ::snt The extent of induction varied between markers and was highest for Fosl1 (60-fold induction in Braf<sup>V6<i>37</i>E</sup>-induced mSAs-HGD).
# ::save-date Sun Jan 3, 2016 ::file pmid_2384_5441_154.txt
(a / and
      :op1 (v / vary-01
            :ARG1 (e / extent
                  :extent-of (i / induce-01))
            :ARG0-of (d / depend-01
                  :ARG1 (m2 / marker)))
      :op2 (h / high-02
            :ARG1 e
            :degree (m / most)
            :condition (p / protein :name (n / name :op1 "Fosl1"))
            :ARG1-of (m3 / mean-01
                  :ARG2 (i2 / induce-01
                        :degree (p2 / product-of :op1 60)
                        :location (m6 / medical-condition :name (n3 / name :op1 "mSAs-HGD")
                              :ARG2-of (i3 / induce-01
                                    :ARG0 (e2 / enzyme :name (n2 / name :op1 "Braf")
                                          :ARG2-of (m5 / mutate-01 :value "V637E"))))))))

# ::id pmid_2384_5441.155 ::date 2015-06-30T05:44:29 ::annotator SDL-AMR-09 ::preferred
# ::snt <sec-title level="2">Wnt Pathway Activation during Dysplasia Progression</sec-title>
# ::save-date Sun Jan 17, 2016 ::file pmid_2384_5441_155.txt
(a / activate-01
      :ARG1 (p / pathway :name (n / name :op1 "Wnt"))
      :time (p2 / progress-01
            :ARG1 (m / medical-condition :name (n2 / name :op1 "dysplasia"))))

# ::id pmid_2384_5441.156 ::date 2015-06-30T05:46:00 ::annotator SDL-AMR-09 ::preferred
# ::snt To examine the role of the Wnt pathway in Braf<sup>V6<i>37</i>E</sup>-induced tumorigenesis, we first analyzed the expression of ten different Wnt target genes in a total of 78 samples (<xref ref-type="fig" rid="fig6">Figures 6</xref>A and <xref ref-type="sec" rid="app3">S5</xref>).
# ::save-date Sun Jul 19, 2015 ::file pmid_2384_5441_156.txt
(a / analyze-01
      :ARG0 (w / we)
      :ARG1 (e / express-03
            :ARG1 (g / gene :quant 10
                  :ARG1-of (d / differ-02)
                  :ARG0-of (t / target-01
                        :ARG1 (p / pathway :name (n / name :op1 "Wnt"))))
            :ARG3 (t4 / thing
                  :ARG1-of (s / sample-01)
                  :ARG1-of (t2 / total-01
                        :ARG2 78)))
      :time (f / first)
      :purpose (e2 / examine-01
            :ARG0 w
            :ARG1 (p2 / play-08
                  :ARG0 p
                  :ARG1 (c / create-01
                        :ARG1 (t3 / tumor)
                        :ARG2-of (i / induce-01
                              :ARG0 (e3 / enzyme :name (n2 / name :op1 "Braf")
                                    :ARG2-of (m / mutate-01 :value "V637E"))))))
      :ARG1-of (d2 / describe-01
            :ARG0 (a2 / and
                  :op1 (f2 / figure :mod "6A")
                  :op2 (f3 / figure :mod "S5"))))

# ::id pmid_2384_5441.157 ::date 2015-06-30T05:51:07 ::annotator SDL-AMR-09 ::preferred
# ::snt We found that Wnt target gene expression was similar in wild-type mucosa and Braf<sup>V6<i>37</i>E</sup>-induced mSH but was upregulated in a large number of Braf<sup>V6<i>37</i>E</sup>-induced mSAs-HGD (and occasionally in mSAs-LGD) to similar levels as in <i>Apc</i><sup><i>min</i></sup>-induced tumors.
# ::save-date Sun Jan 3, 2016 ::file pmid_2384_5441_157.txt
(f / find-01
      :ARG0 (w / we)
      :ARG1 (c / contrast-01
            :ARG1 (r2 / resemble-01
                  :ARG1 (e / express-03
                        :ARG1 (g / gene
                              :ARG0-of (t / target-01
                                    :ARG1 (p / protein :name (n2 / name :op1 "Wnt"))))
                        :ARG3 (m / mucosa
                              :mod (w2 / wild-type)))
                  :ARG2 (e2 / express-03
                        :ARG1 g
                        :ARG3 (m6 / medical-condition :name (n5 / name :op1 "mSH")
                              :ARG2-of (i / induce-01
                                    :ARG0 (e3 / enzyme :name (n3 / name :op1 "Braf")
                                          :ARG2-of (m3 / mutate-01 :value "V637E"))))))
            :ARG2 (u / upregulate-01
                  :ARG1 e
                  :location (a / and
                        :op1 (n / number
                              :mod (l / large)
                              :quant-of (m2 / medical-condition :name (n6 / name :op1 "mSAs-HGD")
                                    :ARG2-of i))
                        :op2 (m4 / medical-condition :name (n7 / name :op1 "mSAs-LGD")
                              :manner (o / occasional)))
                  :degree (l2 / level
                        :ARG1-of (r3 / resemble-01
                              :ARG2 (l3 / level
                                    :location (t2 / tumor
                                          :ARG2-of (i2 / induce-01
                                                :ARG0 (g3 / gene :name (n4 / name :op1 "Apcmin"))))))))))

# ::id pmid_2384_5441.158 ::date 2015-06-30T06:12:11 ::annotator SDL-AMR-09 ::preferred
# ::snt Immunohistochemical staining of beta-catenin (<i>Ctnnb1</i>), a key effector of Wnt pathway activation, was performed to further confirm these observations.
# ::save-date Sun Dec 20, 2015 ::file pmid_2384_5441_158.txt
(p / perform-01
      :ARG1 (s / stain-01
            :ARG1 (p2 / protein :name (n / name :op1 "beta-catenin")
                  :ARG1-of (e2 / encode-01
                        :ARG0 (g / gene :name (n3 / name :op1 "Ctnnb1")))
                  :mod (e / effector
                        :ARG1-of (k / key-02)
                        :ARG0-of (a / activate-01
                              :ARG1 (p3 / pathway :name (n2 / name :op1 "Wnt")))))
            :mod (i / immunohistochemistry))
      :purpose (c2 / confirm-01
            :ARG1 (o / observe-01
                  :mod (t / this))
            :degree (f / further)))

# ::id pmid_2384_5441.159 ::date 2015-06-30T06:16:59 ::annotator SDL-AMR-09 ::preferred
# ::snt As in wild-type mucosa, there was no evidence for nuclear β-catenin accumulation in mSHs (n = 42) and the majority of mSAs-LGD (14/15).
# ::save-date Wed Mar 2, 2016 ::file pmid_2384_5441_159.txt
(e3 / evidence-01 :polarity -
      :ARG1 (a / accumulate-01
            :ARG0 (n2 / nucleus)
            :ARG1 (p / protein :name (n / name :op1 "β-catenin")))
      :location (a2 / and
            :op1 (m9 / medical-condition :name (n3 / name :op1 "mSH")
                  :ARG1-of (m7 / mean-01
                        :ARG2 (e2 / equal-01
                              :ARG1 m9
                              :ARG2 42)))
            :op2 (m / medical-condition :name (n4 / name :op1 "mSAs-LGD")
                  :quant (m2 / majority
                        :ARG1-of (m4 / mean-01
                              :ARG2 (m3 / medical-condition :quant 14 :name (n5 / name :op1 "mSAs-LGD")
                                    :ARG1-of (i / include-91
                                          :ARG2 (m5 / medical-condition :quant 15 :name (n6 / name :op1 "mSAs-LGD"))))))))
      :ARG1-of (s2 / same-01
            :ARG2 (m6 / mucosa
                  :mod (w / wild-type))))

# ::id pmid_2384_5441.160 ::date 2015-06-30T06:28:05 ::annotator SDL-AMR-09 ::preferred
# ::snt In contrast, there was diffuse or focal nuclear β-catenin accumulation in a substantial part of mSAs-HGD (8/14) and carcinomas (2/4) (<xref ref-type="fig" rid="fig6">Figures 6</xref>B–6F).
# ::save-date Sun Jan 3, 2016 ::file pmid_2384_5441_160.txt
(c / contrast-01
      :ARG2 (a / accumulate-01
            :ARG0 (n / nucleus)
            :ARG1 (p / protein :name (n2 / name :op1 "β-catenin"))
            :mod (o / or
                  :op1 (d / diffuse-01)
                  :op2 (f / focus))
            :location (a2 / and
                  :op1 (p2 / part
                        :ARG1-of (m2 / mean-01
                              :ARG2 (m / medical-condition :quant 8 :name (n4 / name :op1 "mSAs-HGD")
                                    :ARG1-of (i / include-91
                                          :ARG2 (m3 / medical-condition :quant 14 :name (n5 / name :op1 "mSAs-HGD")))))
                        :quant-of (m6 / medical-condition :name (n3 / name :op1 "mSAs-HGD")))
                  :op2 (p3 / part
                        :quant-of (c2 / carcinoma)
                        :ARG1-of (m5 / mean-01
                              :ARG2 (c3 / carcinoma :quant 2
                                    :ARG1-of (i2 / include-91
                                          :ARG2 (c4 / carcinoma :quant 4)))))
                  :mod (s / substantial)))
      :ARG1-of (d2 / describe-01
            :ARG0 (a3 / and
                  :op1 (f2 / figure :mod "6B")
                  :op2 (f3 / figure :mod "6C")
                  :op3 (f4 / figure :mod "6D")
                  :op4 (f5 / figure :mod "6E")
                  :op5 (f6 / figure :mod "6F"))))

# ::id pmid_2384_5441.161 ::date 2015-06-30T06:34:28 ::annotator SDL-AMR-09 ::preferred
# ::snt To analyze the mechanisms of Wnt pathway activation, we performed whole-exome sequencing of 20 <i>Braf</i> mutant tumors.
# ::save-date Thu Jul 16, 2015 ::file pmid_2384_5441_161.txt
(p / perform-01
      :ARG0 (w / we)
      :ARG1 (s / sequence
            :mod (e / exome
                  :mod (w2 / whole)))
      :location (t / tumor :quant 20
            :mod (g / gene :name (n / name :op1 "Braf")
                  :ARG2-of (m / mutate-01)))
      :purpose (a / analyze-01
            :ARG0 w
            :ARG1 (m2 / mechanism
                  :ARG0-of (a2 / activate-01
                        :ARG1 (p2 / pathway :name (n2 / name :op1 "Wnt"))))))

# ::id pmid_2384_5441.162 ::date 2015-06-30T06:38:41 ::annotator SDL-AMR-09 ::preferred
# ::snt We identified a number of mutations in known Wnt pathway genes (<xref ref-type="sec" rid="app3">Table S6</xref>), including intracellular components of the Wnt pathway (e.g., <i>Apc</i>, <i>Ctnnb1</i>, <i>Gsk3b</i>, and <i>Axin2</i>), Wnt receptors (e.g., <i>Lrp8</i> and <i>Fzd9</i>), or negative regulators of Wnt signaling (e.g., <i>Lrp1b</i> and <i>Lrp4</i>).
# ::save-date Wed Jan 13, 2016 ::file pmid_2384_5441_162.txt
(i / identify-01
      :ARG0 (w / we)
      :ARG1 (n / number
            :quant-of (m / mutate-01
                  :ARG1 (g / gene
                        :ARG1-of (k / know-01)
                        :mod (p / pathway :name (n2 / name :op1 "Wnt"))
                        :ARG1-of (d / describe-01
                              :ARG0 (t / table :mod "S6"))
                        :ARG2-of (i2 / include-01
                              :ARG1 (o2 / or
                                    :op1 (c / component
                                          :mod (i3 / intracellular)
                                          :part-of p
                                          :example (a2 / and
                                                :op1 (p2 / protein :name (n3 / name :op1 "Apc"))
                                                :op2 (p3 / protein :name (n4 / name :op1 "Ctnnb1"))
                                                :op3 (e / enzyme :name (n5 / name :op1 "Gsk3b"))
                                                :op4 (p4 / protein :name (n6 / name :op1 "Axin2"))))
                                    :op2 (r2 / receptor
                                          :mod p
                                          :example (a3 / and
                                                :op1 (p5 / protein :name (n7 / name :op1 "Lrp8"))
                                                :op2 (p6 / protein :name (n8 / name :op1 "Fzd9"))))
                                    :op3 (g10 / gene
                                          :example (a / and
                                                :op1 (p7 / protein :name (n10 / name :op1 "Lrp1b"))
                                                :op2 (p8 / protein :name (n11 / name :op1 "Lrp4")))
                                          :ARG2-of (d2 / downregulate-01
                                                :ARG1 (s / signal-07
                                                      :ARG0 p)))))))))

# ::id pmid_2384_5441.163 ::date 2015-06-30T06:45:35 ::annotator SDL-AMR-09 ::preferred
# ::snt We then further analyzed the most frequently altered genes <i>(Apc, Ctnnb1</i>, and <i>Lrp1b)</i> in another 46 tumors and found mutations in these three genes in 21/66 samples: <i>Apc</i> (n = 6), <i>Ctnnb1</i> (n = 9), and <i>Lrp1b</i> (n = 6).
# ::save-date Mon Dec 21, 2015 ::file pmid_2384_5441_163.txt
(a / and
      :op1 (a2 / analyze-01
            :ARG0 (w / we)
            :ARG1 (g / gene
                  :ARG1-of (a3 / alter-01
                        :ARG1-of (f3 / frequent-02
                              :degree (m / most)))
                  :ARG1-of (m2 / mean-01
                        :ARG2 (a4 / and
                              :op1 (g2 / gene :name (n / name :op1 "Apc"))
                              :op2 (g3 / gene :name (n2 / name :op1 "Ctnnb1"))
                              :op3 (g4 / gene :name (n3 / name :op1 "Lrp1b")))))
            :time (t / then)
            :degree (f / further)
            :location (t2 / tumor :quant 46
                  :mod (a5 / another)))
      :op2 (f2 / find-01
            :ARG0 w
            :ARG1 (m3 / mutate-01
                  :ARG1 (a7 / and
                        :op1 g2
                        :op2 g3
                        :op3 g4
                        :ARG1-of (s / sample-01 :quant 21
                              :ARG1-of (i / include-91
                                    :ARG2 (t3 / thing :quant 66
                                          :ARG1-of (s2 / sample-01)))
                              :ARG1-of (m4 / mean-01
                                    :ARG2 (a6 / and
                                          :op1 (s3 / sample-01 :quant 6
                                                :ARG1 g2)
                                          :op2 (s4 / sample-01 :quant 9
                                                :ARG1 g3)
                                          :op3 (s5 / sample-01 :quant 6
                                                :ARG1 g4))))))))

# ::id pmid_2384_5441.164 ::date 2015-06-30T08:45:39 ::annotator SDL-AMR-09 ::preferred
# ::snt Wnt pathway mutations frequently occurred in high-grade dysplasia, suggesting an early requirement during tumorigenesis.
# ::save-date Mon Dec 21, 2015 ::file pmid_2384_5441_164.txt
(f / frequent-02
      :ARG1 (m / mutate-01
            :ARG1 (p / pathway :name (n / name :op1 "Wnt")))
      :location (m2 / medical-condition :name (n2 / name :op1 "dysplasia")
            :mod (g / grade
                  :ARG1-of (h / high-02)))
      :ARG0-of (s / suggest-01
            :ARG1 (r / require-01
                  :ARG1 m
                  :time (e / early)
                  :time (c / create-01
                        :ARG1 (t / tumor)))))

# ::id pmid_2384_5441.165 ::date 2015-06-30T08:52:04 ::annotator SDL-AMR-09 ::preferred
# ::snt Only missense, nonsense, essential splice site mutations or frameshift-causing indels were observed (no silent mutations), suggesting a strong enrichment for functionally relevant events.
# ::save-date Thu Jul 16, 2015 ::file pmid_2384_5441_165.txt
(o / observe-01
      :ARG1 (o2 / or
            :op1 (m / mutate-01
                  :mod (m2 / missense))
            :op2 (m3 / mutate-01
                  :mod (n / nonsense))
            :op3 (m4 / mutate-01
                  :ARG0-of (s / splice-01
                        :ARG1 (s2 / site))
                  :mod (e / essential))
            :op4 (i / indel
                  :ARG0-of (c / cause-01
                        :ARG1 (f / frameshift)))
            :ARG1-of (m5 / mean-01
                  :ARG2 (m6 / mutate-01 :polarity -
                        :mod (s3 / silent))))
      :mod (o3 / only)
      :ARG0-of (s4 / suggest-01
            :ARG1 (e2 / enrich-01
                  :ARG1 (e3 / event
                        :ARG1-of (r / relevant-01
                              :manner (f2 / functional)))
                  :ARG1-of (s5 / strong-02))))

# ::id pmid_2384_5441.166 ::date 2015-06-30T10:07:51 ::annotator SDL-AMR-09 ::preferred
# ::snt For example, <i>Apc</i> mutations were mostly nonsense or frameshift mutations, whereas <i>Ctnnb1</i> mutations were recurrent activating mutations at specific positions that have also been described in humans (e.g., T141I).
# ::save-date Mon Dec 21, 2015 ::file pmid_2384_5441_166.txt
(c / contrast-01
      :ARG1 (o / or
            :op1 (m / mutate-01
                  :mod (n / nonsense))
            :op2 (m2 / mutate-01
                  :mod (f / frameshift))
            :quant (m3 / most)
            :domain (m4 / mutate-01
                  :ARG1 (g / gene :name (n2 / name :op1 "Apc"))))
      :ARG2 (m6 / mutate-01
            :location (p / position
                  :ARG1-of (s / specific-02))
            :ARG0-of (a / activate-01
                  :frequency (r / recurrent))
            :domain (m5 / mutate-01
                  :ARG1 (g2 / gene :name (n3 / name :op1 "Ctnnb1")))
            :example (m7 / mutate-01 :value "T141I")
            :ARG1-of (d / describe-01
                  :mod (a2 / also)
                  :condition (h / human)))
      :ARG0-of (e / exemplify-01))

# ::id pmid_2384_5441.167 ::date 2015-06-30T10:14:37 ::annotator SDL-AMR-09 ::preferred
# ::snt Missense mutations in <i>Lrp1b</i>, a negative regulator of Wnt signaling, have been found earlier in <i>Braf</i> mutant human melanoma (<xref ref-type="bibr" rid="bib30">Nikolaev et al., 2012</xref>).
# ::save-date Thu Jan 14, 2016 ::file pmid_2384_5441_167.txt
(f / find-01
      :ARG1 (m2 / mutate-01
            :ARG1 (g / gene :name (n / name :op1 "Lrp1b")
                  :ARG2-of (d2 / downregulate-01
                        :ARG1 (s / signal-07
                              :ARG0 (p / pathway :name (n2 / name :op1 "Wnt")))))
            :mod (m3 / missense))
      :time (e / early
            :degree (m / more))
      :ARG1-of (d3 / describe-01
            :ARG0 (p4 / publication-91
                  :ARG0 (a / and
                        :op1 (p2 / person :name (n4 / name :op1 "Nikolaev"))
                        :op2 (p3 / person
                              :mod (o / other)))
                  :time (d / date-entity :year 2012)))
      :location (m6 / medical-condition :name (n5 / name :op1 "melanoma")
            :mod (h / human)
            :mod (g2 / gene :name (n3 / name :op1 "Braf")
                  :ARG2-of (m5 / mutate-01))))

# ::id pmid_2384_5441.168 ::date 2015-06-30T10:18:55 ::annotator SDL-AMR-09 ::preferred
# ::snt All together, these results provide strong evidence for an important role of Wnt pathway activation during early dysplasia progression.
# ::save-date Wed Mar 9, 2016 ::file pmid_2384_5441_168.txt
(p / provide-01
      :ARG0 (t / thing
            :mod (t2 / this)
            :ARG2-of (r / result-01))
      :ARG1 (e / evidence-01
            :ARG1 (r2 / role
                  :poss (a / activate-01
                        :ARG1 (p2 / pathway :name (n / name :op1 "Wnt")))
                  :mod (i / important)
                  :time (p3 / progress-01
                        :ARG1 (m / medical-condition :name (n2 / name :op1 "dysplasia"))
                        :time (e2 / early)))
            :ARG1-of (s / strong-02))
      :manner (t3 / together
            :mod (a2 / all)))

# ::id pmid_2384_5441.169 ::date 2015-06-30T10:24:37 ::annotator SDL-AMR-09 ::preferred
# ::snt It is worth noting that in some tumors with strong Wnt target gene expression, no mutations in Wnt pathway genes were found, suggesting additional unidentified mechanisms.
# ::save-date Wed Jan 20, 2016 ::file pmid_2384_5441_169.txt
(w / worth-02
      :ARG2 (n2 / note-01
            :ARG1 (f / find-01 :polarity -
                  :ARG1 (m / mutate-01
                        :ARG2 g)
                  :location (t / tumor
                        :quant (s / some)
                        :mod (e / express-03
                              :ARG1 (g / gene
                                    :ARG0-of (t2 / target-01
                                          :ARG1 (p / pathway :name (n / name :op1 "Wnt"))))
                              :ARG1-of (s2 / strong-02)))
                  :ARG0-of (s3 / suggest-01
                        :ARG1 (m2 / mechanism
                              :mod (a / additional)
                              :ARG1-of (i / identify-01 :polarity -))))))

# ::id pmid_2384_5441.170 ::date 2015-06-30T10:25:12 ::annotator SDL-AMR-09 ::preferred
# ::snt <sec-title level="2">Large-Scale Drug Screening Identifies Targetable Nodes in Braf-Induced Tumorigenesis</sec-title>
# ::save-date Thu Jul 16, 2015 ::file pmid_2384_5441_170.txt
(i / identify-01
      :ARG0 (s / screen-01
            :ARG1 (d / drug)
            :mod (s2 / scale
                  :mod (l / large)))
      :ARG1 (n / node
            :ARG1-of (t / target-01
                  :ARG1-of (p / possible-01)))
      :location (c / create-01
            :ARG1 (t2 / tumor)
            :ARG2-of (i2 / induce-01
                  :ARG0 (e / enzyme :name (n2 / name :op1 "Braf")))))

# ::id pmid_2384_5441.171 ::date 2015-06-29T14:06:12 ::annotator SDL-AMR-09 ::preferred
# ::snt To test the sensitivity of <i>Braf</i><sup><i>LSL-V637E</i>/+</sup>-induced intestinal cancer cell lines to Braf inhibition we performed short-term proliferation assays.
# ::save-date Sat Jan 16, 2016 ::file pmid_2384_5441_171.txt
(p / perform-01
      :ARG0 (w / we)
      :ARG1 (a / assay-01
            :ARG1 (p2 / proliferate-01
                  :ARG1-of (s3 / short-07)))
      :purpose (t / test-01
            :ARG0 w
            :ARG1 (s2 / sensitive-03
                  :ARG0 (c / cell-line
                        :ARG2-of (i / induce-01
                              :ARG0 (i3 / inhibit-01
                                    :ARG1 (e2 / enzyme :name (n3 / name :op1 "Braf"))))
                        :mod (d / disease :wiki "Cancer" :name (n / name :op1 "Cancer")
                              :mod (i2 / intestine)))
                  :ARG1 (g / gene :name (n2 / name :op1 "Braf")
                        :ARG2-of (m / mutate-01 :value "LSL-V637E/+")))))

# ::id pmid_2384_5441.172 ::date 2015-06-29T14:19:17 ::annotator SDL-AMR-09 ::preferred
# ::snt Overall, only minor growth inhibition was observed for <i>Braf</i> mutant mouse and human colorectal cancer cell lines treated with 5 μM PLX4720, a selective inhibitor of mutant Braf (<xref ref-type="fig" rid="fig7">Figures 7</xref>A and 7B).
# ::save-date Wed Jan 20, 2016 ::file pmid_2384_5441_172.txt
(o / observe-01
      :ARG1 (i2 / inhibit-01
            :ARG1 (g / grow-01)
            :mod (o2 / only)
            :beneficiary (a / and
                  :op1 (m2 / mouse
                        :mod (e / enzyme :name (n2 / name :op1 "Braf")
                              :ARG2-of (m3 / mutate-01)))
                  :op2 (c / cell-line
                        :mod (h / human)
                        :ARG1-of (t2 / treat-04
                              :ARG2 (s / small-molecule :name (n3 / name :op1 "PLX4720")
                                    :quant (c4 / concentration-quantity :quant 5
                                          :unit (m4 / micromolar))
                                    :ARG0-of (i3 / inhibit-01
                                          :ARG1 e
                                          :mod (s2 / selective))))
                        :mod (d / disease :wiki "Colorectal_cancer" :name (n / name :op1 "colorectal" :op2 "cancer"))))
            :ARG1-of (m / minor-01))
      :mod (o3 / overall)
      :ARG1-of (d2 / describe-01
            :ARG0 (a2 / and
                  :op1 (f / figure :mod "7A")
                  :op2 (f2 / figure :mod "7B"))))

# ::id pmid_2384_5441.173 ::date 2015-06-29T14:30:09 ::annotator SDL-AMR-09 ::preferred
# ::snt Braf inhibition was proposed to cause feedback activation of the epidermal growth factor receptor (EGFR) in human <i>BRAF</i> mutant CRCs (<xref ref-type="bibr" rid="bib34">Prahallad et al., 2012</xref>).
# ::save-date Sat Jan 16, 2016 ::file pmid_2384_5441_173.txt
(p / propose-01
      :ARG1 (c / cause-01
            :ARG0 (i / inhibit-01
                  :ARG1 (e2 / enzyme :name (n3 / name :op1 "Braf")))
            :ARG1 (a / activate-01
                  :ARG1 (e3 / enzyme :name (n4 / name :op1 "epidermal" :op2 "growth" :op3 "factor" :op4 "receptor"))
                  :destination-of (f / feedback)
                  :location (d / disease :name (n / name :op1 "colorectal" :op2 "cancer")
                        :mod (h / human)
                        :mod (g / gene :name (n6 / name :op1 "BRAF")
                              :ARG2-of (m / mutate-01)))))
      :ARG1-of (d2 / describe-01
            :ARG0 (p2 / publication-91
                  :ARG0 (a2 / and
                        :op1 (p3 / person :name (n7 / name :op1 "Prahallad"))
                        :op2 (p4 / person
                              :mod (o / other)))
                  :time (d3 / date-entity :year 2012))))

# ::id pmid_2384_5441.174 ::date 2015-06-29T14:38:11 ::annotator SDL-AMR-09 ::preferred
# ::snt We therefore treated mouse and human <i>BRAF</i> mutant cell lines with the EGFR small molecule kinase inhibitor, Gefitinib, alone or in combination with PLX4720.
# ::save-date Sat Jan 16, 2016 ::file pmid_2384_5441_174.txt
(t2 / treat-04
      :ARG0 (w / we)
      :ARG1 (a / and
            :op1 (c / cell-line
                  :mod (m / mouse)
                  :mod (g / gene :name (n2 / name :op1 "BRAF")
                        :ARG2-of (m2 / mutate-01)))
            :op2 (c2 / cell-line
                  :mod (h / human)
                  :mod g))
      :ARG2 (a2 / and
            :op1 (s / small-molecule :name (n3 / name :op1 "Gefitinib")
                  :ARG0-of (i2 / inhibit-01
                        :ARG1 (k / kinase :name (n6 / name :op1 "EGFR")))
                  :mod (a4 / alone))
            :op2 (c3 / combine-01
                  :ARG1 s
                  :ARG2 (s2 / small-molecule :name (n4 / name :op1 "PLX4720"))))
      :ARG1-of (c4 / cause-01))

# ::id pmid_2384_5441.175 ::date 2015-06-29T14:45:49 ::annotator SDL-AMR-09 ::preferred
# ::snt As expected, Gefitinib and PLX4720 synergized in-growth inhibition (<xref ref-type="fig" rid="fig7">Figures 7</xref>A and 7B).
# ::save-date Wed Mar 9, 2016 ::file pmid_2384_5441_175.txt
(s / synergize-01
      :ARG0 (a / and
            :op1 (s2 / small-molecule :name (n / name :op1 "Gefitinib"))
            :op2 (s3 / small-molecule :name (n2 / name :op1 "PLX4720")))
      :ARG2 (i / inhibit-01
            :ARG1 (g / grow-in-00))
      :ARG1-of (e / expect-01)
      :ARG1-of (d / describe-01
            :ARG0 (a2 / and
                  :op1 (f / figure :mod "7A")
                  :op2 (f2 / figure :mod "7B"))))

# ::id pmid_2384_5441.176 ::date 2015-06-29T14:49:37 ::annotator SDL-AMR-09 ::preferred
# ::snt The murine intestinal cancer cell line MouseT1 (from a <i>Vil-Cre;Braf</i><sup><i>LSL-V637E</i>/+</sup><i>;p53</i><sup><i>LSL-R172H/+</i></sup> mouse), had similar sensitivity to combinatorial PLX4720/Gefitinib treatment as HT-29 (WiDr), one of the three human cell lines tested by Prahallad and colleagues (<xref ref-type="fig" rid="fig7">Figures 7</xref>A and 7B; inhibition of proliferation by 60%–70%).
# ::save-date Sun Jan 17, 2016 ::file pmid_2384_5441_176.txt
(h / have-03
      :ARG0 (c / cell-line :wiki -
            :name (n2 / name :op1 "MouseT1")
            :mod (o / organism :wiki "Muridae"
                  :name (n / name :op1 "Muridae"))
            :source (m / mouse
                  :mod (m2 / macro-molecular-complex
                        :part (p3 / protein :wiki "Villin"
                              :name (n3 / name :op1 "Vil"))
                        :part (e2 / enzyme :wiki "Cre_recombinase"
                              :name (n4 / name :op1 "Cre")))
                  :mod (e / enzyme :wiki -
                        :name (n5 / name :op1 "Braf")
                        :ARG2-of (m3 / mutate-01 :value "LSL-V637E/+"))
                  :mod (p5 / protein :wiki "P53"
                        :name (n6 / name :op1 "p53")
                        :ARG2-of (m4 / mutate-01 :value "LSL-R172H/+")))
            :mod (d / disease :wiki "Cancer"
                  :name (n12 / name :op1 "cancer")
                  :mod (i / intestine)))
      :ARG1 (s / sensitive-03
            :ARG0 c
            :ARG1 (t / treat-04
                  :ARG2 (c3 / combine-01
                        :ARG1 (s2 / small-molecule :wiki -
                              :name (n7 / name :op1 "PLX4720"))
                        :ARG2 (s3 / small-molecule :wiki "Gefitinib"
                              :name (n8 / name :op1 "Gefitinib"))))
            :ARG1-of (r2 / resemble-01
                  :ARG2 (c4 / cell-line :wiki -
                        :name (n9 / name :op1 "HT-29")
                        :ARG2-of (i4 / include-91
                              :ARG1 (c7 / cell-line :wiki -
                                    :name (n11 / name :op1 "WiDr")))
                        :ARG1-of (i2 / include-91
                              :ARG2 (c5 / cell-line :quant 3
                                    :mod (h2 / human)
                                    :ARG1-of (t2 / test-01
                                          :ARG0 (a2 / and
                                                :op1 (p6 / person :wiki -
                                                      :name (n10 / name :op1 "Prahallad"))
                                                :op2 (c6 / colleague))))))))
      :ARG1-of (d2 / describe-01
            :ARG0 (a3 / and
                  :op1 (f / figure :mod "7A")
                  :op2 (f2 / figure :mod "7B")
                  :op3 (i3 / inhibit-01
                        :ARG1 (p7 / proliferate-01)))
            :ARG2 (v / value-interval
                  :op1 (p / percentage-entity :value 60)
                  :op2 (p2 / percentage-entity :value 70))))

# ::id pmid_2384_5441.177 ::date 2015-06-29T14:53:29 ::annotator SDL-AMR-09 ::preferred
# ::snt It seems, however, that the effectiveness of PLX4720/Gefitinib varies considerably among human cancers: in three of five tested human cell lines the effects were rather modest (growth inhibition by 25%–40%; <xref ref-type="fig" rid="fig7">Figure 7</xref>A and data not shown).
# ::save-date Sun Jan 3, 2016 ::file pmid_2384_5441_177.txt
(h / have-concession-91
      :ARG1 (s3 / seem-01
            :ARG1 (v / vary-01
                  :ARG1 (e / effective-04
                        :ARG0 (a / and
                              :op1 (s / small-molecule
                                    :name (n / name :op1 "PLX4720"))
                              :op2 (s2 / small-molecule
                                    :name (n2 / name :op1 "Gefitinib"))))
                  :manner (c / considerable)
                  :ARG1-of (m2 / mean-01
                        :ARG2 (m / modest
                              :domain (a3 / affect-01)
                              :location (c3 / cell-line :quant 3
                                    :ARG1-of (i2 / include-91
                                          :ARG2 (c4 / cell-line :quant 5
                                                :ARG1-of (t2 / test-01)
                                                :mod (h2 / human))))
                              :degree (r / rather)))
                  :location (d3 / disease :wiki "Cancer"
                        :name (n3 / name :op1 "cancer")
                        :mod h2)))
      :ARG1-of (d / describe-01
            :ARG0 (a4 / and
                  :op1 (i3 / inhibit-01
                        :ARG1 (g / grow-01))
                  :op2 (f / figure :mod "7A")
                  :op3 (d2 / data
                        :ARG1-of (s4 / show-01 :polarity -)))
            :ARG2 (v2 / value-interval
                  :op1 (p / percentage-entity :value 25)
                  :op2 (p2 / percentage-entity :value 40))))

# ::id pmid_2384_5441.178 ::date 2015-06-30T02:54:09 ::annotator SDL-AMR-09 ::preferred
# ::snt We next performed long-term (14 days) clonogenic assays and again found that although PLX4720 and Gefitinib synergized in-growth inhibition, most of the treated cell lines retained variable levels of colony-forming capacity (<xref ref-type="fig" rid="fig7">Figure 7</xref>C).
# ::save-date Wed Mar 9, 2016 ::file pmid_2384_5441_178.txt
(a / and
      :op1 (p / perform-01
            :ARG0 (w / we)
            :ARG1 (a2 / assay-01
                  :ARG1 (c / clonogenic)
                  :duration (l / long-03
                        :ARG1-of (m2 / mean-01
                              :ARG2 (t / temporal-quantity :quant 14
                                    :unit (d / day)))))
            :time (n / next))
      :op2 (f / find-01
            :ARG0 w
            :ARG1 (h / have-concession-91
                  :ARG1 (r / retain-01
                        :ARG0 (c2 / cell-line
                              :quant (m / most)
                              :ARG1-of (i3 / include-91
                                    :ARG2 (c3 / cell-line
                                          :ARG1-of (t2 / treat-04))))
                        :ARG1 (l2 / level
                              :ARG1-of (v / vary-01)
                              :degree-of (c4 / capable-01
                                    :ARG1 c2
                                    :ARG2 (f2 / form-01
                                          :ARG1 (c5 / colony)))))
                  :ARG2 (s / synergize-01
                        :ARG0 (a4 / and
                              :op1 (s2 / small-molecule :name (n2 / name :op1 "PLX4720"))
                              :op2 (s3 / small-molecule :name (n3 / name :op1 "Gefitinib")))
                        :ARG2 (i / inhibit-01
                              :ARG1 (g / grow-in-00))))
            :mod (a3 / again))
      :ARG1-of (d2 / describe-01
            :ARG0 (f3 / figure :mod "7C")))

# ::id pmid_2384_5441.179 ::date 2015-06-30T03:12:17 ::annotator SDL-AMR-09 ::preferred
# ::snt To identify alternative drugs with effectiveness across cell lines, we performed high-throughput drug screening.
# ::save-date Wed Mar 2, 2016 ::file pmid_2384_5441_179.txt
(p / perform-01
      :ARG0 (w / we)
      :ARG1 (s / screen-01
            :ARG1 (d / drug)
            :manner (t / throughput
                  :ARG1-of (h / high-02)))
      :purpose (i / identify-01
            :ARG0 w
            :ARG1 (d2 / drug
                  :mod (a / alternative)
                  :ARG0-of (e / effective-04
                        :ARG1 (a2 / across
                              :op1 (c / cell-line))))))

# ::id pmid_2384_5441.180 ::date 2015-06-30T03:15:42 ::annotator SDL-AMR-09 ::preferred
# ::snt We tested a large set of compounds inhibiting a broad range of molecules, pathways, and biologic processes (<xref ref-type="fig" rid="fig7">Figure 7</xref>B; <xref ref-type="sec" rid="app3">Table S7</xref>).
# ::save-date Mon Dec 21, 2015 ::file pmid_2384_5441_180.txt
(t / test-01
      :ARG0 (w / we)
      :ARG1 (s / set
            :mod (l / large)
            :consist-of (c / compound)
            :ARG0-of (i / inhibit-01
                  :ARG1 (a / and
                        :op1 (m / molecule)
                        :op2 (p / pathway)
                        :op3 (p2 / process-01
                              :ARG1 (b2 / biology))
                        :ARG1-of (r / range-01
                              :ARG1-of (b / broad-02)))))
      :ARG1-of (d / describe-01
            :ARG0 (a2 / and
                  :op1 (f / figure :mod "7B")
                  :op2 (t2 / table :mod "S7"))))

# ::id pmid_2384_5441.181 ::date 2015-06-30T03:39:19 ::annotator SDL-AMR-09 ::preferred
# ::snt All compounds were tested alone or in combination with PLX4720 and for each cell line we performed 100 different short-term (6 day) sensitivity assays.
# ::save-date Fri Dec 18, 2015 ::file pmid_2384_5441_181.txt
(a / and
      :op1 (t2 / test-01
            :ARG1 (c / compound
                  :mod (a2 / all))
            :manner (o / or
                  :op1 (a3 / alone)
                  :op2 (c2 / combine-01
                        :ARG1 c
                        :ARG2 (s / small-molecule :name (n / name :op1 "PLX4720")))))
      :op2 (p / perform-01
            :ARG0 (w / we)
            :ARG1 (a4 / assay-01 :quant 100
                  :ARG1 (s2 / sensitive-03)
                  :ARG1-of (d2 / differ-02)
                  :ARG1-of (s4 / short-07
                        :ARG1-of (m / mean-01
                              :ARG2 (t / temporal-quantity :quant 6
                                    :unit (d / day)))))
            :beneficiary (c3 / cell-line
                  :mod (e / each))))

# ::id pmid_2384_5441.182 ::date 2015-06-30T04:07:04 ::annotator SDL-AMR-09 ::preferred
# ::snt These screens revealed several treatment approaches that were highly effective (<xref ref-type="fig" rid="fig7">Figure 7</xref>B).
# ::save-date Mon Dec 21, 2015 ::file pmid_2384_5441_182.txt
(r / reveal-01
      :ARG0 (s / screen-01
            :mod (t / this))
      :ARG1 (a / approach-02
            :ARG2 (t2 / treat-04)
            :quant (s2 / several)
            :ARG1-of (e / effective-04
                  :ARG1-of (h / high-02)))
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod "7B")))

# ::id pmid_2384_5441.183 ::date 2015-06-30T04:11:23 ::annotator SDL-AMR-09 ::preferred
# ::snt PD0325901, a Mek inhibitor, was the most effective single compound across cell lines in the short-term assays (<xref ref-type="fig" rid="fig7">Figure 7</xref>B).
# ::save-date Sat Jan 16, 2016 ::file pmid_2384_5441_183.txt
(c / compound
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod "7B"))
      :ARG1-of (s4 / single-02)
      :ARG1-of (e2 / effective-04
            :mod (m / most)
            :time (a / assay-01
                  :ARG1-of (s2 / short-07))
            :location (a2 / across
                  :op1 (c2 / cell-line)))
      :domain (s / small-molecule :name (n2 / name :op1 "PD0325901")
            :ARG0-of (i2 / inhibit-01
                  :ARG1 (p / protein-family :name (n / name :op1 "MEK")))))

# ::id pmid_2384_5441.184 ::date 2015-06-30T04:18:37 ::annotator SDL-AMR-09 ::preferred
# ::snt In the long-term clonogenic assay, it induced complete inhibition of colony-forming capacity in five of six cell lines and partial inhibition in the remaining line RKO (<xref ref-type="fig" rid="fig7">Figure 7</xref>C).
# ::save-date Sun Dec 20, 2015 ::file pmid_2384_5441_184.txt
(i / induce-01
      :ARG0 (i3 / it)
      :ARG2 (a / and
            :op1 (i2 / inhibit-01
                  :ARG1 (c / capable-01
                        :ARG2 (f / form-01
                              :ARG1 (c2 / colony)))
                  :ARG1-of (c3 / complete-01)
                  :location (c4 / cell-line :quant 5
                        :ARG1-of (i4 / include-91
                              :ARG2 (c5 / cell-line :quant 6))))
            :op2 (i5 / inhibit-01
                  :location (c6 / cell-line :name (n / name :op1 "RKO")
                        :ARG1-of (r / remain-01))
                  :degree (p / part)))
      :ARG1-of (d / describe-01
            :ARG0 (f2 / figure :mod "7C"))
      :time (a2 / assay-01
            :ARG1 (c7 / clonogenic)
            :duration (l / long-03)))

# ::id pmid_2384_5441.185 ::date 2015-06-30T04:25:17 ::annotator SDL-AMR-09 ::preferred
# ::snt The PI3K inhibitor GDC0941 was not effective as a single agent, but induced potent inhibition in combination with PLX4720 across cell lines (<xref ref-type="fig" rid="fig7">Figures 7</xref>B and 7C).
# ::save-date Sun Jan 17, 2016 ::file pmid_2384_5441_185.txt
(c / contrast-01
      :ARG1 (e / effective-04 :polarity -
            :ARG0 (s / small-molecule :name (n / name :op1 "GDC0941")
                  :ARG0-of (i2 / inhibit-01
                        :ARG1 (p2 / protein-family :name (n2 / name :op1 "PI3K"))))
            :manner (a / agent
                  :ARG1-of (s2 / single-02)))
      :ARG2 (i3 / induce-01
            :ARG0 s
            :ARG2 (i4 / inhibit-01
                  :mod (p / potent))
            :manner (c2 / combine-01
                  :ARG1 s
                  :ARG2 (s3 / small-molecule :name (n3 / name :op1 "PLX4720")))
            :location (a2 / across
                  :op1 (c3 / cell-line)))
      :ARG1-of (d / describe-01
            :ARG0 (a3 / and
                  :op1 (f / figure :mod "7B")
                  :op2 (f2 / figure :mod "7C"))))

# ::id pmid_2384_5441.186 ::date 2015-06-30T04:30:36 ::annotator SDL-AMR-09 ::preferred
# ::snt Some other drug combinations strongly inhibited selected cell lines, although they were not broadly effective across tumors.
# ::save-date Mon Dec 21, 2015 ::file pmid_2384_5441_186.txt
(h / have-concession-91
      :ARG1 (i / inhibit-01
            :ARG0 (c / combine-01
                  :ARG1 (d / drug)
                  :mod (s / some)
                  :mod (o / other))
            :ARG1 (c2 / cell-line
                  :ARG1-of (s3 / select-01))
            :ARG1-of (s2 / strong-02))
      :ARG2 (e / effective-04 :polarity -
            :ARG0 c
            :ARG1 (a / across
                  :op1 (t / tumor))
            :ARG1-of (b / broad-02)))

# ::id pmid_2384_5441.187 ::date 2015-06-30T04:34:51 ::annotator SDL-AMR-09 ::preferred
# ::snt For example, the combination of PLX4720 plus the kinase inhibitor VX-680 was the most potent drug combination for the treatment of RKO, a highly resistant cell line to most other drugs.
# ::save-date Mon Dec 21, 2015 ::file pmid_2384_5441_187.txt
(c2 / combine-01
      :ARG1 (s / small-molecule :name (n / name :op1 "PLX4720"))
      :ARG2 (s2 / small-molecule :name (n2 / name :op1 "VX-680")
            :ARG0-of (i / inhibit-01
                  :ARG1 (k / kinase)))
      :domain (c / combine-01
            :mod (d / drug)
            :mod (p / potent
                  :degree (m / most))
            :ARG2-of (t2 / treat-04
                  :ARG1 (c3 / cell-line :name (n3 / name :op1 "RKO")
                        :ARG0-of (r / resist-01
                              :ARG1 (d2 / drug
                                    :mod (o / other)
                                    :mod m)
                              :ARG1-of (h / high-02)))))
      :ARG1-of (e / exemplify-01))

# ::id pmid_2384_5441.188 ::date 2015-06-30T05:16:25 ::annotator SDL-AMR-09 ::preferred
# ::snt This shows the power of systematic drug screening to identify patient-specific treatment approaches even for highly resistant tumors.
# ::save-date Mon Dec 21, 2015 ::file pmid_2384_5441_188.txt
(s / show-01
      :ARG0 (t / this)
      :ARG1 (p / power
            :poss (s3 / screen-01
                  :ARG1 (d / drug
                        :mod (s2 / systematic))
                  :ARG2 (i / identify-01
                        :ARG1 (a / approach-02
                              :ARG1-of (s4 / specific-02
                                    :ARG2 (t2 / treat-04
                                          :ARG1 (p2 / patient))))
                        :beneficiary (t3 / tumor
                              :ARG0-of (r / resist-01
                                    :ARG1-of (h / high-02))
                              :mod (e / even))))))

# ::id pmid_2384_5441.189 ::date 2015-06-30T05:22:53 ::annotator SDL-AMR-09 ::preferred
# ::snt Another example is the combination of the Chk1/2 inhibitor AZD-7762 plus PLX4720, which was very effective in MouseT1, HT-29, LS411N, and COLO-205 and could potentially be a broadly effective alternative first-line or second-line combination.
# ::save-date Wed Mar 2, 2016 ::file pmid_2384_5441_189.txt
(a / and
      :op1 (c / combine-01
            :ARG1 (s / small-molecule :name (n / name :op1 "AZD-7762")
                  :ARG0-of (i2 / inhibit-01
                        :ARG1 (e2 / enzyme :name (n2 / name :op1 "Chk1/2"))))
            :ARG2 (s2 / small-molecule :name (n3 / name :op1 "PLX4720"))
            :ARG1-of (e3 / exemplify-01
                  :mod (a2 / another))
            :ARG0-of (e / effective-04
                  :ARG1 (a3 / and
                        :op1 (c2 / cell-line :name (n4 / name :op1 "MouseT1"))
                        :op2 (c3 / cell-line :name (n5 / name :op1 "HT-29"))
                        :op3 (c4 / cell-line :name (n6 / name :op1 "LS411N"))
                        :op4 (c5 / cell-line :name (n7 / name :op1 "COLO-205")))
                  :degree (v / very)))
      :op2 (p2 / possible-01
            :ARG1 (o / or
                  :op1 (c6 / combine-01
                        :mod (a4 / alternative)
                        :mod (l / line
                              :ord (o2 / ordinal-entity :value 1)))
                  :op2 (c7 / combine-01
                        :mod a4
                        :mod (l2 / line
                              :ord (o3 / ordinal-entity :value 2)))
                  :ARG1-of (e4 / effective-04
                        :ARG1-of (b / broad-02))
                  :domain c)
            :mod (p3 / potential)))

# ::id pmid_2384_5441.190 ::date 2015-06-30T05:34:36 ::annotator SDL-AMR-09 ::preferred
# ::snt <sec-title level="2">In Vivo Validation of Mek and Combinatorial Braf/PI3K Inhibition</sec-title>
# ::save-date Tue Jun 30, 2015 ::file pmid_2384_5441_190.txt
(a / and
      :op1 (v / validate-01
            :ARG1 (e / enzyme :name (n / name :op1 "MEK"))
            :manner (i / in-vivo))
      :op2 (i4 / inhibit-01
            :ARG1 (c / combine-01
                  :ARG1 (e2 / enzyme :name (n2 / name :op1 "Braf"))
                  :ARG2 (e3 / enzyme :name (n3 / name :op1 "PI3K")))))

# ::id pmid_2384_5441.191 ::date 2015-06-30T05:38:16 ::annotator SDL-AMR-09 ::preferred
# ::snt To study the effectiveness of broadly effective drug combinations in vivo, we first transplanted mouse and human cell lines subcutaneously (s.c.) into immunodeficient Nod Scid IL12R-gamma null (NSG) mice and assessed their response to PD0325901.
# ::save-date Sat Feb 13, 2016 ::file pmid_2384_5441_191.txt
(a / and
      :op1 (t / transplant-01
            :ARG0 (w / we)
            :ARG1 (a2 / and
                  :op1 (c / cell-line
                        :mod (m / mouse))
                  :op2 (c2 / cell-line
                        :mod (h / human)))
            :ARG2 (o / organism :name (n / name :op1 "NSG" :op2 "mouse")
                  :mod (i / immunodeficient))
            :time (f / first)
            :manner (s / subcutaneous))
      :op2 (a3 / assess-01
            :ARG0 w
            :ARG1 (r / respond-01
                  :ARG0 a2
                  :ARG1 (s2 / small-molecule :name (n2 / name :op1 "PD0325901"))))
      :purpose (s3 / study-01
            :ARG0 w
            :ARG1 (e / effective-04
                  :ARG0 (c3 / combine-01
                        :mod (d / drug)
                        :manner (i2 / in-vivo)
                        :ARG0-of (e2 / effective-04
                              :ARG1-of (b / broad-02))))))

# ::id pmid_2384_5441.192 ::date 2015-06-30T06:09:30 ::annotator SDL-AMR-09 ::preferred
# ::snt Treatment was started 7–14 days after s.c. injection of cells as soon as tumors were palpable.
# ::save-date Tue Jun 30, 2015 ::file pmid_2384_5441_192.txt
(s / start-01
      :ARG1 (t2 / treat-04)
      :time (a / after
            :op1 (i / inject-01
                  :ARG1 (c / cell)
                  :manner (s2 / subcutaneous)
                  :time (a2 / as-soon-as
                        :op1 (p / palpable
                              :domain (t4 / tumor))))
            :quant (v / value-interval
                  :op1 (t3 / temporal-quantity :quant 7
                        :unit (d2 / day))
                  :op2 (t / temporal-quantity :quant 14
                        :unit (d / day)))))

# ::id pmid_2384_5441.193 ::date 2015-06-30T06:16:30 ::annotator SDL-AMR-09 ::preferred
# ::snt Animals were given PD0325901 or vehicle by oral gavage for 13–15 days.
# ::save-date Tue Jun 30, 2015 ::file pmid_2384_5441_193.txt
(g / give-01
      :ARG1 (o / or
            :op1 (s / small-molecule :name (n / name :op1 "PD0325901"))
            :op2 (v / vehicle))
      :ARG2 (a / animal)
      :manner (g2 / gavage
            :mod (o2 / oral))
      :duration (v2 / value-interval
            :op1 (t2 / temporal-quantity :quant 13
                  :unit (d2 / day))
            :op2 (t / temporal-quantity :quant 15
                  :unit (d / day))))

# ::id pmid_2384_5441.194 ::date 2015-06-30T06:23:23 ::annotator SDL-AMR-09 ::preferred
# ::snt PD0325901 was highly effective, causing regression of tumors from all tested cell lines (<xref ref-type="fig" rid="fig7">Figure 7</xref>D).
# ::save-date Mon Dec 21, 2015 ::file pmid_2384_5441_194.txt
(e / effective-04
      :ARG0 (s / small-molecule :name (n / name :op1 "PD0325901"))
      :ARG1-of (h / high-02)
      :ARG0-of (c / cause-01
            :ARG1 (r / regress-01
                  :ARG1 (t / tumor
                        :source (c2 / cell-line
                              :ARG1-of (t2 / test-01)
                              :mod (a / all)))))
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod "7D")))

# ::id pmid_2384_5441.195 ::date 2015-06-30T06:25:48 ::annotator SDL-AMR-09 ::preferred
# ::snt <xref ref-type="sec" rid="app3">Figures S6</xref>A and S6B show that after 13–15 days of PD0325901 treatment there was complete inhibition of ERK phosphorylation in surviving tumor cells and that only very few scattered Ki67-positive cancer cells could still be observed in the necrotic tumor mass.
# ::save-date Sat Jan 16, 2016 ::file pmid_2384_5441_195.txt
(s / show-01
      :ARG0 (a / and
            :op1 (f / figure :mod "S6A")
            :op2 (f2 / figure :mod "S6B"))
      :ARG1 (a2 / and
            :op1 (i / inhibit-01
                  :ARG1 (p / phosphorylate-01
                        :ARG1 (e / enzyme :name (n / name :op1 "ERK")))
                  :ARG1-of (c / complete-01)
                  :time (a3 / after
                        :op1 (t2 / treat-04
                              :ARG2 (s2 / small-molecule :name (n3 / name :op1 "PD0325901")))
                        :quant (v / value-interval
                              :op1 (t3 / temporal-quantity :quant 13
                                    :unit (d3 / day))
                              :op2 (t / temporal-quantity :quant 15
                                    :unit (d / day))))
                  :location (c2 / cell
                        :mod (t4 / tumor)
                        :ARG0-of (s3 / survive-01)))
            :op2 (p3 / possible-01
                  :ARG1 (o / observe-01
                        :ARG1 (c3 / cell
                              :mod (p4 / protein :name (n4 / name :op1 "Ki67")
                                    :mod (p2 / positive))
                              :ARG1-of (s4 / scatter-01)
                              :quant (f3 / few
                                    :mod (o2 / only))
                              :mod (d2 / disease :wiki "Cancer" :name (n2 / name :op1 "cancer")))
                        :location (m / mass-01
                              :ARG0 (t5 / tumor)
                              :mod (n5 / necrosis))
                        :mod (s5 / still)))))

# ::id pmid_2384_5441.196 ::date 2015-06-30T06:26:09 ::annotator SDL-AMR-09 ::preferred
# ::snt We next performed orthotopic transplantation of mouse and human <i>Braf</i> mutant cancer cell lines into the cecum of NSG mice.
# ::save-date Sat Feb 13, 2016 ::file pmid_2384_5441_196.txt
(p / perform-01
      :ARG0 (w / we)
      :ARG1 (t / transplant-01
            :ARG0 w
            :ARG1 (a / and
                  :op1 (c / cell-line
                        :mod (g / gene :name (n4 / name :op1 "Braf")
                              :ARG2-of (m / mutate-01))
                        :mod (m2 / mouse)
                        :mod (d / disease :wiki "Cancer" :name (n / name :op1 "cancer")))
                  :op2 (c3 / cell-line
                        :mod g
                        :mod (h / human)
                        :mod d))
            :ARG2 (c4 / cecum
                  :part-of (o / organism :name (n2 / name :op1 "NSG" :op2 "mouse")))
            :mod (o2 / orthotopic))
      :time (n3 / next))

# ::id pmid_2384_5441.197 ::date 2015-06-30T06:30:19 ::annotator SDL-AMR-09 ::preferred
# ::snt Fourteen days later, treatment was started with either vehicle or PD0325901.
# ::save-date Mon Jul 6, 2015 ::file pmid_2384_5441_197.txt
(s / start-01
      :ARG1 (t2 / treat-04
            :ARG2 (o / or
                  :op1 (v / vehicle)
                  :op2 (s2 / small-molecule :name (n / name :op1 "PD0325901"))))
      :time (l3 / late
            :degree (m3 / more
                  :quant (t / temporal-quantity :quant 14
                        :unit (d / day)))))

# ::id pmid_2384_5441.198 ::date 2015-06-30T06:33:31 ::annotator SDL-AMR-09 ::preferred
# ::snt Mice were sacrificed after 17 days of treatment.
# ::save-date Mon Jul 6, 2015 ::file pmid_2384_5441_198.txt
(s / sacrifice-01
      :ARG1 (m / mouse)
      :time (a / after
            :op1 (t2 / treat-01)
            :quant (t / temporal-quantity :quant 17
                  :unit (d / day))))

# ::id pmid_2384_5441.199 ::date 2015-06-30T06:34:40 ::annotator SDL-AMR-09 ::preferred
# ::snt <xref ref-type="sec" rid="app3">Figures S6</xref>C–S6E show that vehicle-treated mice developed large tumors, which metastasized to local lymph nodes and the peritoneum, causing hemorrhagic ascites.
# ::save-date Mon Dec 21, 2015 ::file pmid_2384_5441_199.txt
(s / show-01
      :ARG0 (v / value-interval
            :op1 (f / figure :mod "S6C")
            :op2 (f2 / figure :mod "S6E"))
      :ARG1 (d / develop-01
            :ARG1 (m / mouse
                  :ARG1-of (t / treat-04
                        :ARG2 (v2 / vehicle)))
            :ARG2 (t2 / tumor
                  :mod (l / large)
                  :ARG1-of (m2 / metastasize-101
                        :ARG2 (a / and
                              :op1 (n / node
                                    :mod (l2 / lymph)
                                    :ARG1-of (l3 / local-02))
                              :op2 (p / peritoneum))
                        :ARG0-of (c / cause-01
                              :ARG1 (a2 / ascite
                                    :mod (h / hemorrhagic)))))))

# ::id pmid_2384_5441.200 ::date 2015-06-30T06:41:12 ::annotator SDL-AMR-09 ::preferred
# ::snt In contrast, in the PD0325901-treated group, tumors were either not detectable or small (maximum 0.01 cm<sup>3</sup>).
# ::save-date Mon Jul 6, 2015 ::file pmid_2384_5441_200.txt
(c / contrast-01
      :ARG2 (o / or
            :op1 (d / detect-01
                  :ARG1 (t / tumor)
                  :ARG1-of (p / possible-01 :polarity -))
            :op2 (s / small
                  :domain (t2 / tumor
                        :ARG1-of (m / mean-01
                              :ARG2 (m2 / maximum
                                    :op1 (v / volume-quantity :quant 0.01
                                          :unit (c2 / cubic-centimeter))))))
            :location (g / group
                  :ARG1-of (t3 / treat-04
                        :ARG2 (s2 / small-molecule :name (n / name :op1 "PD0325901"))))))

# ::id pmid_2384_5441.201 ::date 2015-06-30T06:51:27 ::annotator SDL-AMR-09 ::preferred
# ::snt To examine the effect of PD0325901 on proliferation in endogenous Braf<sup>V637E</sup>-induced tumors, we performed short-term treatments (5 days) of <i>Vil-Cre;Braf</i><sup><i>LSL-V637E</i>/+</sup> mice.
# ::save-date Sun Jan 17, 2016 ::file pmid_2384_5441_201.txt
(p / perform-01
      :ARG0 (w / we)
      :ARG1 (t2 / treat-04
            :ARG1 (m7 / mouse
                  :mod (m / macro-molecular-complex
                        :part (p2 / protein :name (n / name :op1 "Vil"))
                        :part (e4 / enzyme :name (n2 / name :op1 "Cre")))
                  :mod (e / enzyme :name (n3 / name :op1 "Braf")
                        :ARG2-of (m3 / mutate-01 :value "LSL-V637E/+")))
            :ARG1-of (s3 / short-07
                  :ARG1-of (m2 / mean-01
                        :ARG2 (t / temporal-quantity :quant 5
                              :unit (d / day)))))
      :purpose (e2 / examine-01
            :ARG0 w
            :ARG1 (a2 / affect-01
                  :ARG0 (s2 / small-molecule :name (n4 / name :op1 "PD0325901"))
                  :ARG1 (p4 / proliferate-01
                        :ARG0 (t3 / tumor
                              :ARG2-of (i / induce-01
                                    :ARG0 (e3 / enzyme :name (n5 / name :op1 "Braf")
                                          :ARG2-of (m4 / mutate-01 :value "V637E")))
                              :mod (m5 / monocot))))))

# ::id pmid_2384_5441.202 ::date 2015-06-30T07:00:07 ::annotator SDL-AMR-09 ::preferred
# ::snt We used animals that were more than 1 year of age and were expected to have tumors.
# ::save-date Tue Jun 30, 2015 ::file pmid_2384_5441_202.txt
(u / use-01
      :ARG0 (w / we)
      :ARG1 (a3 / and
            :op1 (a / animal
                  :age (m2 / more-than
                              :op1 (t / temporal-quantity :quant 1
                                    :unit (y / year))))
            :op2 (e / expect-01
                  :ARG1 (h / have-03
                        :ARG0 a
                        :ARG1 (t2 / tumor)))))

# ::id pmid_2384_5441.203 ::date 2015-06-30T07:04:03 ::annotator SDL-AMR-09 ::preferred
# ::snt <xref ref-type="sec" rid="app3">Figures S6</xref>F and S6G show that Ki67 immunoreactivity was weak in the majority of dysplastic cells in PD0325901-treated mice but was strong in tumors of vehicle-treated animals.
# ::save-date Thu Dec 17, 2015 ::file pmid_2384_5441_203.txt
(s / show-01
      :ARG0 (v / value-interval
            :op1 (f / figure :mod "S6F")
            :op2 (f2 / figure :mod "S6G"))
      :ARG1 (c / contrast-01
            :ARG1 (w / weak-02
                  :ARG1 (i / immunoreact-00
                        :ARG1 (p / protein :name (n / name :op1 "Ki67")))
                  :location (m2 / mouse
                        :ARG1-of (t / treat-04
                              :ARG2 (s2 / small-molecule :name (n2 / name :op1 "PD0325901"))))
                  :location (c2 / cell
                        :quant (m / majority)
                        :mod (d / dysplastic)))
            :ARG2 (s3 / strong-02
                  :ARG1 i
                  :location (a / animal
                        :ARG1-of (t2 / treat-01
                              :ARG2 (v2 / vehicle))))))

# ::id pmid_2384_5441.204 ::date 2015-06-30T07:25:24 ::annotator SDL-AMR-09 ::preferred
# ::snt All together, these data show that Mek inhibition is effective in the treatment of Braf-induced intestinal tumors in vivo.
# ::save-date Mon Jul 6, 2015 ::file pmid_2384_5441_204.txt
(s / show-01
      :ARG0 (d / data
            :mod (t / this))
      :ARG1 (e2 / effective-04
            :ARG0 (i / inhibit-01
                  :ARG1 (e / enzyme :name (n / name :op1 "MEK")))
            :ARG1 (t2 / treat-04
                  :ARG1 (t3 / tumor
                        :mod (i2 / intestine)
                        :ARG2-of (i3 / induce-01
                              :ARG0 (e3 / enzyme :name (n2 / name :op1 "Braf"))))
                  :manner (i4 / in-vivo)))
      :mod (t4 / together
            :mod (a / all)))

# ::id pmid_2384_5441.205 ::date 2015-06-30T07:29:14 ::annotator SDL-AMR-09 ::preferred
# ::snt To examine the effectiveness of combinatorial Braf/PI3K inhibition in vivo we treated s.c. transplanted murine and human cell lines with a combination of PLX4720 and GDC0941 or vehicle.
# ::save-date Mon Jul 6, 2015 ::file pmid_2384_5441_205.txt
(t / treat-04
      :ARG0 (w / we)
      :ARG1 (a / and
            :op1 (c / cell-line
                  :ARG1-of (t2 / transplant-01
                        :manner (s / subcutaneous))
                  :mod (o2 / organism :name (n5 / name :op1 "Muridae")))
            :op2 (c2 / cell-line
                  :mod (h / human)
                  :ARG1-of t2))
      :ARG2 (c3 / combine-01
            :ARG1 (s2 / small-molecule :name (n / name :op1 "PLX4720"))
            :ARG2 (o / or
                  :op1 (s3 / small-molecule :name (n2 / name :op1 "GDC0941"))
                  :op2 (v / vehicle)))
      :purpose (e / examine-01
            :ARG0 w
            :ARG1 (e2 / effective-04
                  :ARG0 (i / inhibit-01
                        :ARG1 (c4 / combine-01
                              :ARG1 (e3 / enzyme :name (n3 / name :op1 "Braf"))
                              :ARG2 (e4 / enzyme :name (n4 / name :op1 "PI3K")))
                        :manner (i2 / in-vivo)))))

# ::id pmid_2384_5441.206 ::date 2015-06-30T07:34:20 ::annotator SDL-AMR-09 ::preferred
# ::snt <xref ref-type="fig" rid="fig7">Figures 7</xref>E, <xref ref-type="sec" rid="app3">S6</xref>H, and S6I show that combined Braf/PI3K inhibition elicited potent growth inhibition in both models.
# ::save-date Tue Jun 30, 2015 ::file pmid_2384_5441_206.txt
(s / show-01
      :ARG0 (a / and
            :op1 (f / figure :mod "7E")
            :op2 (f2 / figure :mod "S6H")
            :op3 (f3 / figure :mod "S6I"))
      :ARG1 (e / elicit-01
            :ARG0 (i / inhibit-01
                  :ARG1 (c / combine-01
                        :ARG1 (e2 / enzyme :name (n / name :op1 "Braf"))
                        :ARG2 (e3 / enzyme :name (n2 / name :op1 "PI3K"))))
            :ARG1 (i2 / inhibit-01
                  :ARG1 (g / grow-01)
                  :mod (p / potent))
            :location (m / model
                  :mod (b / both))))

# ::id pmid_2384_5441.207 ::date 2015-06-30T07:37:10 ::annotator SDL-AMR-09 ::preferred
# ::snt Immunohistochemical staining revealed that proliferation was substantially inhibited in the PLX4720/GDC0941-treated group, with only few Ki67-positive cells being detectable in regressed tumor masses (<xref ref-type="sec" rid="app3">Figure S6</xref>I).
# ::save-date Mon Jul 6, 2015 ::file pmid_2384_5441_207.txt
(r / reveal-01
      :ARG0 (s / stain-01
            :mod (i / immunohistochemical))
      :ARG1 (a2 / and
            :op1 (i2 / inhibit-01
                  :ARG1 (p / proliferate-01)
                  :degree (s2 / substantial)
                  :location (g / group
                        :ARG1-of (t / treat-04
                              :ARG2 (a / and
                                    :op1 (s3 / small-molecule :name (n / name :op1 "PLX4720"))
                                    :op2 (s4 / small-molecule :name (n2 / name :op1 "GDC0941"))))))
            :op2 (p2 / possible-01
                  :ARG1 (d / detect-01
                        :ARG1 (c2 / cell
                              :quant (f2 / few
                                    :mod (o / only))
                              :mod (p4 / protein :name (n3 / name :op1 "Ki67")
                                    :mod (p3 / positive)))
                        :location (m / mass-01
                              :ARG0 (t2 / tumor)
                              :ARG1-of (r2 / regress-01)))))
      :ARG1-of (d2 / describe-01
            :ARG0 (f / figure :mod "S6I")))

# ::id pmid_2384_5441.208 ::date 2015-06-30T07:43:50 ::annotator SDL-AMR-09 ::preferred
# ::snt These data mirror the in vitro effectiveness of these treatments in vivo.
# ::save-date Mon Jul 6, 2015 ::file pmid_2384_5441_208.txt
(m / mirror-01
      :ARG1 (d / data
            :mod (t / this))
      :ARG2 (e / effective-04
            :ARG0 (t2 / treat-04
                  :manner (i2 / in-vivo)
                  :mod t)
            :manner (i / in-vitro)))

# ::id pmid_2423_8212.1 ::date 2015-08-25T08:45:27 ::annotator SDL-AMR-09 ::preferred
# ::snt Mek inhibition results in marked antitumor activity against metastatic melanoma patient-derived melanospheres and in melanosphere-generated xenografts (PMID:24238212)
# ::save-date Thu Feb 4, 2016 ::file pmid_2423_8212_1.txt
(r / result-01
      :ARG1 (i / inhibit-01
            :ARG1 (e / enzyme :name (n / name :op1 "Mek")))
      :ARG2 (a3 / and
            :op1 (a / activity-06
                  :ARG1-of (m / mark-01)
                  :ARG0-of (o / oppose-01
                        :ARG1 (m4 / melanosphere
                              :ARG1-of (d / derive-01
                                    :ARG2 (p / person
                                          :ARG1-of (h / have-org-role-91
                                                :ARG2 (p2 / patient))))
                              :mod (m6 / medical-condition :name (n2 / name :op1 "melanoma")
                                    :ARG1-of (m3 / metastasize-101))))
                  :ARG0-of (c / counter-01
                        :ARG1 (t / tumor)))
            :op2 (x / xenograft
                  :ARG1-of (g / generate-01
                        :ARG0 (m5 / melanosphere))))
      :ARG1-of (d2 / describe-01
            :ARG0 (p3 / publication-91
                  :ARG8 "PMID24238212")))

# ::id pmid_2423_8212.94 ::date 2015-08-25T08:47:15 ::annotator SDL-AMR-09 ::preferred
# ::snt <sec-title level="1">Results</sec-title>
# ::save-date Tue Aug 25, 2015 ::file pmid_2423_8212_94.txt
(t / thing
      :ARG2-of (r / result-01))

# ::id pmid_2423_8212.95 ::date 2015-08-25T08:48:26 ::annotator SDL-AMR-09 ::preferred
# ::snt <sec-title level="2">Melanospheres isolated from metastatic melanoma tumors possess stem cell properties, are highly tumorigenic in vivo and recapitulate the patient tumor</sec-title>
# ::save-date Thu Feb 4, 2016 ::file pmid_2423_8212_95.txt
(a / and
      :op1 (p / possess-01
            :ARG0 (m3 / melanosphere
                  :ARG1-of (i / isolate-01
                        :ARG2 (t / tumor
                              :ARG1-of (m2 / metastasize-101)
                              :mod (m / medical-condition :name (n / name :op1 "melanoma")))))
            :ARG1 (p2 / property
                  :mod (c2 / cell
                        :mod (s / stem))))
      :op2 (c3 / cause-01
            :ARG0 m3
            :ARG1 (t2 / tumor)
            :degree (h / high)
            :manner (i2 / in-vivo))
      :op3 (r / recapitulate-01
            :ARG0 m3
            :ARG1 (t3 / tumor
                  :mod (p3 / person
                        :ARG1-of (h2 / have-org-role-91
                              :ARG2 (p4 / patient))))))

# ::id pmid_2423_8212.96 ::date 2015-08-25T09:11:20 ::annotator SDL-AMR-09 ::preferred
# ::snt Ten patient-derived metastatic melanoma specimens were enzymatically dissociated and tumor cells were cultured in selective conditions for CSC (tumor spheres), as previously described [<xref ref-type="bibr" rid="B41">41</xref>-<xref ref-type="bibr" rid="B44">44</xref>].
# ::save-date Thu Feb 4, 2016 ::file pmid_2423_8212_96.txt
(a / and
      :op1 (d / dissociate-01
            :ARG1 (s / specimen :quant 10
                  :ARG1-of (m2 / metastasize-101)
                  :ARG1-of (d2 / derive-01
                        :ARG2 (p / person
                              :ARG1-of (h / have-org-role-91
                                    :ARG2 (p2 / patient))))
                  :mod (m4 / medical-condition :name (n2 / name :op1 "melanoma")))
            :manner (e / enzyme))
      :op2 (c / culture-01
            :ARG1 (c2 / cell
                  :mod (t / tumor))
            :manner (c3 / condition
                  :ARG0-of (s2 / select-01))
            :purpose (c4 / cell
                        :mod (s3 / stem)
                        :ARG1-of (m3 / mean-01
                              :ARG2 (s4 / sphere
                                    :mod t))
                        :mod (d5 / disease :wiki "Cancer" :name (n / name :op1 "cancer"))))
      :ARG1-of (d3 / describe-01
            :time (p3 / previous))
      :ARG1-of (d4 / describe-01
            :ARG0 (p4 / publication
                  :ARG1-of (c6 / cite-01
                        :ARG2 (v / value-interval :op1 41 :op2 44)))))

# ::id pmid_2423_8212.97 ::date 2015-08-25T09:34:20 ::annotator SDL-AMR-09 ::preferred
# ::snt Following prolonged culture, we obtained exponentially growing “melanospheres” with efficiency of 80% (Figure <xref ref-type="fig" rid="F1">1</xref>A left).
# ::save-date Sat Jan 30, 2016 ::file pmid_2423_8212_97.txt
(o / obtain-01
      :ARG0 (w / we)
      :ARG1 (m / melanosphere
            :ARG1-of (g / grow-01
                  :manner (e / exponential))
            :ARG1-of (e2 / efficient-01
                  :degree (p / percentage-entity :value 80)))
      :ARG1-of (f / follow-01
            :ARG2 (c2 / culture-01
                  :ARG1-of (p2 / prolong-01)))
      :ARG1-of (d / describe-01
            :ARG0 (f2 / figure :mod "1A"
                  :ARG1-of (l / left-20))))

# ::id pmid_2423_8212.98 ::date 2015-08-25T09:54:23 ::annotator SDL-AMR-09 ::preferred
# ::snt The same cells cultured in conditions specific for the growth of melanocytes generated monolayers of tumor cells whose morphology resembled differentiated cells, suggesting the capacity of melanospheres to differentiate <i>in vitro</i> (Figure <xref ref-type="fig" rid="F1">1</xref>A right).
# ::save-date Sun Aug 30, 2015 ::file pmid_2423_8212_98.txt
(g / generate-01
      :ARG0 (c / cell
            :ARG1-of (c2 / culture-01
                  :manner (c3 / condition
                        :ARG1-of (s2 / specific-02
                              :ARG2 (g2 / grow-01
                                    :ARG1 (m4 / melanocyte)))))
            :ARG1-of (s4 / same-01))
      :ARG1 (m / monolayer
            :consist-of (c5 / cell
                  :ARG0-of (h / have-03
                        :ARG1 (m2 / morphology
                              :ARG1-of (r / resemble-01
                                    :ARG2 (c6 / cell
                                          :ARG1-of (d / differentiate-101)))))
                  :mod (t / tumor)))
      :ARG0-of (s3 / suggest-01
            :ARG1 (c7 / capable-01
                  :ARG1 (m3 / melanosphere)
                  :ARG2 (d2 / differentiate-101
                        :manner (i / in-vitro))))
      :ARG1-of (d3 / describe-01
            :ARG0 (f / figure :mod "1A"
                  :ARG1-of (r2 / right-04))))

# ::id pmid_2423_8212.99 ::date 2015-08-25T10:10:12 ::annotator SDL-AMR-09 ::preferred
# ::snt We next investigated the expression of antigens that have been previously associated with MIC.
# ::save-date Thu Jan 14, 2016 ::file pmid_2423_8212_99.txt
(i / investigate-01
      :ARG0 (w / we)
      :ARG1 (e / express-03
            :ARG2 (a / antigen
                  :ARG1-of (a2 / associate-01
                        :ARG2 (c / cell
                              :ARG0-of (i2 / initiate-01
                                    :ARG1 (m / medical-condition :name (n2 / name :op1 "melanoma"))))
                        :time (p / previous))))
      :time (n / next))

# ::id pmid_2423_8212.100 ::date 2015-08-25T10:17:06 ::annotator SDL-AMR-09 ::preferred
# ::snt Melanospheres did not express CD133, CD20, CD24, ABCB5 or CD271 (Additional file <xref ref-type="supplementary-material" rid="S1">1</xref>: Figure S1A-B), while p-glycoprotein was detectable at low levels.
# ::save-date Sun Jan 3, 2016 ::file pmid_2423_8212_100.txt
(c / contrast-01
      :ARG1 (e / express-03 :polarity -
            :ARG2 (o / or
                  :op1 (p / protein :name (n / name :op1 "CD133"))
                  :op2 (p2 / protein :name (n2 / name :op1 "CD20"))
                  :op3 (p3 / protein :name (n3 / name :op1 "CD24"))
                  :op4 (p4 / protein :name (n4 / name :op1 "ABCB5"))
                  :op5 (p5 / protein :name (n5 / name :op1 "CD271")))
            :ARG3 (m / melanosphere)
            :ARG1-of (d / describe-01
                  :ARG0 (f / file :mod 1
                        :ARG1-of (a / add-02)
                        :ARG1-of (m2 / mean-01
                              :ARG2 (a2 / and
                                    :op1 (f2 / figure :mod "S1A")
                                    :op2 (f3 / figure :mod "S1B"))))))
      :ARG2 (d2 / detect-01
            :ARG1 (g / glycoprotein
                  :ARG3-of (p8 / phosphorylate-01)
                  :quant (l / level
                        :ARG1-of (l2 / low-04)))
            :ARG1-of (p6 / possible-01)))

# ::id pmid_2423_8212.101 ::date 2015-08-25T10:37:58 ::annotator SDL-AMR-09 ::preferred
# ::snt They expressed stem cell-related markers as c-Kit, Cripto, CD146, CD44 and CD166 (Additional file <xref ref-type="supplementary-material" rid="S1">1</xref>: Figure S1A) in agreement with previous reports on cell line-derived melanospheres [<xref ref-type="bibr" rid="B38">38</xref>].
# ::save-date Sun Jan 17, 2016 ::file pmid_2423_8212_101.txt
(e / express-03
      :ARG2 (m / marker
            :ARG1-of (r / relate-01
                  :ARG2 (c / cell
                        :mod (s / stem)))
            :ARG1-of (e2 / exemplify-01
                  :ARG0 (a / and
                        :op1 (e3 / enzyme :name (n / name :op1 "c-Kit"))
                        :op2 (p2 / protein :name (n2 / name :op1 "Cripto"))
                        :op3 (p3 / protein :name (n3 / name :op1 "CD146"))
                        :op4 (p4 / protein :name (n4 / name :op1 "CD44"))
                        :op5 (p5 / protein :name (n5 / name :op1 "CD166")))
                  :ARG1-of (d3 / describe-01
                        :ARG0 (f / file :mod 1
                              :ARG1-of (a3 / add-02)
                              :ARG1-of (m2 / mean-01
                                    :ARG2 (f2 / figure :mod "S1A"))))))
      :ARG3 (t / they)
      :ARG0-of (a2 / agree-01
            :ARG2 (t2 / thing
                  :time (p6 / previous)
                  :ARG1-of (r2 / report-01
                        :topic (m3 / melanosphere
                              :ARG1-of (d / derive-01
                                    :ARG2 (c3 / cell-line))))))
      :ARG1-of (d2 / describe-01
            :ARG0 (p7 / publication
                  :ARG1-of (c4 / cite-01
                        :ARG2 38))))

# ::id pmid_2423_8212.102 ::date 2015-08-25T10:50:08 ::annotator SDL-AMR-09 ::preferred
# ::snt Finally, embryonic stem cell markers Nanog and Oct-4 were detected at the RNA level in all samples analyzed (Additional file <xref ref-type="supplementary-material" rid="S1">1</xref>: Figure S1C).
# ::save-date Mon Nov 23, 2015 ::file pmid_2423_8212_102.txt
(d / detect-01
      :ARG1 (a / and
            :op1 (m / marker :wiki "Homeobox_protein_NANOG"
                  :name (n / name :op1 "Nanog")
                  :mod (c / cell
                        :mod (s / stem))
                  :mod (e / embryo))
            :op2 (m2 / marker :wiki "Oct-4"
                  :name (n2 / name :op1 "Oct-4")
                  :mod c
                  :mod e))
      :location (t / thing
            :mod (a2 / all)
            :ARG1-of (a3 / analyze-01)
            :ARG1-of (s2 / sample-01))
      :location (l / level
            :mod (n3 / nucleic-acid :wiki "RNA"
                  :name (n4 / name :op1 "RNA")))
      :ARG1-of (d2 / describe-01
            :ARG0 (f / file :mod 1
                  :ARG1-of (a4 / add-02)
                  :ARG1-of (m3 / mean-01
                        :ARG2 (f2 / figure :mod "S1C"))))
      :time (f3 / final))

# ::id pmid_2423_8212.103 ::date 2015-08-25T10:58:38 ::annotator SDL-AMR-09 ::preferred
# ::snt The CD44 isoform V6 was specifically restricted to melanospheres, being not expressed in differentiated cells, nor in tumor cells freshly isolated from melanosphere-derived xenografts nor in melanocytes (Additional file <xref ref-type="supplementary-material" rid="S1">1</xref>: Figure S1D).
# ::save-date Sun Aug 30, 2015 ::file pmid_2423_8212_103.txt
(r / restrict-01
      :ARG1 (i / isoform :name (n / name :op1 "V6")
            :mod (p / protein :name (n2 / name :op1 "CD44"))
            :ARG1-of (e / express-03 :polarity -
                  :ARG3 (o / or
                        :op1 (c2 / cell
                              :ARG1-of (d / differentiate-101))
                        :op2 (c3 / cell
                              :mod (t / tumor)
                              :ARG1-of (i2 / isolate-01
                                    :ARG2 (x / xenograft
                                          :ARG1-of (d2 / derive-01
                                                :ARG2 m3))
                                    :ARG1-of (f / fresh-04)))
                        :op3 (m2 / melanocyte))))
      :ARG2 (m3 / melanosphere)
      :manner (s / specific-02)
      :ARG1-of (d3 / describe-01
            :ARG0 (f2 / file :mod 1
                  :ARG1-of (a / add-02)
                  :ARG1-of (m / mean-01
                        :ARG2 (f3 / figure :mod "S1D")))))

# ::id pmid_2423_8212.104 ::date 2015-08-25T11:07:49 ::annotator SDL-AMR-09 ::preferred
# ::snt Melanospheres could be expanded <i>in vitro</i> for several months and their proliferation rate was not lost with time (Additional file <xref ref-type="supplementary-material" rid="S2">2</xref>: Figure S2A).
# ::save-date Mon Aug 31, 2015 ::file pmid_2423_8212_104.txt
(a / and
      :op1 (p2 / possible-01
            :ARG1 (e / expand-01
                  :ARG1 (m3 / melanosphere)
                  :manner (i / in-vitro)
                  :duration (s / several
                        :op1 (t2 / temporal-quantity :quant 1
                              :unit (m / month)))))
      :op2 (l / lose-02
            :ARG0 m3
            :ARG1 (r / rate
                  :degree-of (p / proliferate-01
                        :ARG0 m3))
            :condition (t / time))
      :ARG1-of (d / describe-01
            :ARG0 (f / file :mod 2
                  :ARG1-of (a2 / add-02)
                  :ARG1-of (m2 / mean-01
                        :ARG2 (f2 / figure :mod "S2A")))))

# ::id pmid_2423_8212.105 ::date 2015-08-25T11:35:04 ::annotator SDL-AMR-09 ::preferred
# ::snt They were composed by a large (mean 42% ± 8 in all examined samples) fraction of self-renewing sphere-reforming cells (Additional file <xref ref-type="supplementary-material" rid="S2">2</xref>: Figure S2B upper left).
# ::save-date Sat Jan 30, 2016 ::file pmid_2423_8212_105.txt
(c / compose-01
      :ARG1 (t / they)
      :ARG2 (f / fraction-01
            :ARG1 (c2 / cell
                  :ARG0-of (r / renew-01
                        :ARG1 c2)
                  :ARG0-of (r2 / reform-01
                        :ARG2 (s / sphere)))
            :mod (l / large)
            :ARG1-of (a2 / average-01
                  :ARG2 (o / or
                        :op1 (p / percentage-entity :value 42
                              :ARG2-of (a3 / add-02
                                    :ARG1 (p2 / percentage-entity :value 8)))
                        :op2 (p3 / percentage-entity :value 42
                              :ARG2-of (s2 / subtract-01
                                    :ARG1 p2)))
                  :location (t2 / thing
                        :mod (a4 / all)
                        :ARG1-of (e / examine-01)
                        :ARG1-of (s3 / sample-01))))
      :ARG1-of (d / describe-01
            :ARG0 (f2 / file :mod 2
                  :ARG1-of (a / add-02)
                  :ARG1-of (m / mean-01
                        :ARG2 (f3 / figure :mod "S2B"
                              :ARG1-of (l2 / left-20
                                    :mod (u / upper)))))))

# ::id pmid_2423_8212.106 ::date 2015-08-25T11:58:25 ::annotator SDL-AMR-09 ::preferred
# ::snt Finally, secondary and tertiary spheres were formed with a similar frequency and tertiary spheres were able to proliferate indefinitely, indicating that the fraction of self-renewing cells did not decrease with passages (Additional file <xref ref-type="supplementary-material" rid="S2">2</xref>: Figure S2B upper right panel).
# ::save-date Sun Aug 30, 2015 ::file pmid_2423_8212_106.txt
(a2 / and
      :op1 (f / form-01
            :ARG1 (a / and
                  :op1 (s / sphere
                        :mod (s2 / secondary))
                  :op2 (s3 / sphere
                        :mod (t / tertiary)))
            :manner (f2 / frequency
                  :ARG1-of (r / resemble-01)))
      :op2 (p / possible-01
            :ARG1 (p2 / proliferate-01
                  :ARG0 s3
                  :duration (d / definite :polarity -)))
      :ARG0-of (i / indicate-01
            :ARG1 (d2 / decrease-01 :polarity -
                  :ARG0 (f3 / fraction-01
                        :ARG1 (c / cell
                              :ARG0-of (r2 / renew-01
                                    :ARG1 c)))
                  :condition (p3 / pass-08)))
      :time (f4 / final)
      :ARG1-of (d3 / describe-01
            :ARG0 (f5 / file :mod 2
                  :ARG1-of (a3 / add-02)
                  :ARG1-of (m / mean-01
                        :ARG2 (f6 / figure :mod "S2B"
                              :part (p4 / panel
                                    :ARG1-of (r3 / right-04
                                          :mod (u / upper))))))))

# ::id pmid_2423_8212.107 ::date 2015-08-25T12:15:04 ::annotator SDL-AMR-09 ::preferred
# ::snt The clonogenic activity was higher in melanospheres than in their differentiated counterpart (Additional file <xref ref-type="supplementary-material" rid="S2">2</xref>: Figure S2B lower panels).
# ::save-date Sun Aug 30, 2015 ::file pmid_2423_8212_107.txt
(h / high-02
      :ARG1 (a / activity-06
            :ARG0 (m2 / melanosphere)
            :mod (c / clonogenic))
      :compared-to (c3 / counterpart
            :ARG1-of (d / differentiate-101)
            :poss m2)
      :ARG1-of (d2 / describe-01
            :ARG0 (f / file :mod 2
                  :ARG1-of (a2 / add-02)
                  :ARG1-of (m / mean-01
                        :ARG2 (f2 / figure :mod "S2B"
                              :part (p / panel
                                    :ARG1-of (l / low-04))))))
      :degree (m3 / more))

# ::id pmid_2423_8212.108 ::date 2015-08-25T12:22:39 ::annotator SDL-AMR-09 ::preferred
# ::snt Under appropriate conditions, melanospheres generated a progeny of cells with morphology and phenotype of melanocytic, adipogenic or osteogenic cells, demonstrating multiple differentiation ability and recapitulating the plasticity of neural crest cells (Additional file <xref ref-type="supplementary-material" rid="S2">2</xref>:Figure S2C).
# ::save-date Sun Aug 30, 2015 ::file pmid_2423_8212_108.txt
(g / generate-01
      :ARG0 (m5 / melanosphere)
      :ARG1 (p / progeny
            :poss (c2 / cell
                  :ARG0-of (h / have-03
                        :ARG1 (a / and
                              :op1 (m / morphology)
                              :op2 (p2 / phenotype)
                              :poss (o / or
                                    :op1 (c3 / cell
                                          :mod (m2 / melanocyte))
                                    :op2 (c4 / cell
                                          :mod (a2 / adipogenesis))
                                    :op3 (c5 / cell
                                          :mod (o2 / osteogenesis)))))))
      :ARG0-of (d / demonstrate-01
            :ARG1 (c6 / capable-01
                  :ARG1 m5
                  :ARG2 (d2 / differentiate-101
                        :mod (m3 / multiple))))
      :ARG0-of (r / recapitulate-01
            :ARG1 (p3 / plasticity
                  :poss (c7 / cell
                        :mod (c8 / crest)
                        :mod (n2 / neural))))
      :ARG1-of (d3 / describe-01
            :ARG0 (f / file :mod 2
                  :ARG1-of (a3 / add-02)
                  :ARG1-of (m4 / mean-01
                        :ARG2 (f2 / figure :mod "S2C"))))
      :condition (c9 / condition
            :ARG1-of (a4 / appropriate-02)))

# ::id pmid_2423_8212.109 ::date 2015-08-25T12:45:10 ::annotator SDL-AMR-09 ::preferred
# ::snt Melanospheres were highly tumorigenic when injected subcutaneously in NOD Scid or Nude mice and all samples displayed tumor take of 100% down to 25000 cells.
# ::save-date Mon Nov 23, 2015 ::file pmid_2423_8212_109.txt
(a / and
      :op1 (c / cause-01
            :ARG0 (m4 / melanosphere)
            :ARG1 (t / tumor)
            :degree (h / high)
            :condition (i / inject-01
                  :ARG1 m4
                  :ARG2 (o / or
                        :op1 (m5 / mouse :name (n / name :op1 "NOD-Scid"))
                        :op2 (m2 / mouse
                              :mod (n3 / nude)))
                  :manner (s / subcutaneous)))
      :op2 (d / display-01
            :ARG0 (t2 / thing
                  :ARG1-of (s2 / sample-01)
                  :mod (a2 / all))
            :ARG1 (t3 / take-01
                  :ARG1 t
                  :quant (p / percentage-entity :value 100
                        :ARG1-of (m3 / mean-01
                              :ARG2 (c4 / cell
                                    :quant (d2 / down-to :quant 25000))))
                  :mod t)))

# ::id pmid_2423_8212.110 ::date 2015-08-25T13:10:19 ::annotator SDL-AMR-09 ::preferred
# ::snt For one sample we performed a limiting dilution experiment and even as low as 5 cells readily generated a tumor within 8 weeks (Figure <xref ref-type="fig" rid="F1">1</xref>B and C).
# ::save-date Sun Aug 30, 2015 ::file pmid_2423_8212_110.txt
(a / and
      :op1 (p / perform-02
            :ARG0 (w / we)
            :ARG1 (e / experiment-01
                  :ARG0 w
                  :ARG1 (t3 / thing :quant 1
                        :ARG1-of (s / sample-01))
                  :ARG2 (d / dilute-01
                        :ARG0-of (l / limit-01))))
      :op2 (g / generate-01
            :ARG0 (c / cell
                  :ARG1-of (l2 / low-04
                        :ARG3 5)
                  :mod (e2 / even))
            :ARG1 (t / tumor)
            :manner (r / ready)
            :time (u / up-to
                  :op1 (t2 / temporal-quantity :quant 8
                        :unit (w2 / week))))
      :ARG1-of (d2 / describe-01
            :ARG0 (a2 / and
                  :op1 (f / figure :mod "1B")
                  :op2 (f2 / figure :mod "1C"))))

# ::id pmid_2423_8212.111 ::date 2015-08-25T13:20:04 ::annotator SDL-AMR-09 ::preferred
# ::snt In contrast, melanosphere-derived differentiated cells displayed a decreased and delayed tumor growth <i>in vivo</i>, and as many as 5x10<sup>4</sup> differentiated cells generated a slowly growing tumor with a 10-week delay post-injection (Figure <xref ref-type="fig" rid="F1">1</xref>B).
# ::save-date Sun Aug 30, 2015 ::file pmid_2423_8212_111.txt
(c / contrast-01
      :ARG2 (a / and
            :op1 (d / display-01
                  :ARG0 (c3 / cell
                        :ARG1-of (d4 / differentiate-101)
                        :ARG1-of (d5 / derive-01
                              :ARG2 (m / melanosphere)))
                  :ARG1 (g / grow-01
                        :ARG1 (t / tumor)
                        :ARG1-of (d2 / decrease-01)
                        :ARG1-of (d3 / delay-01))
                  :manner (i / in-vivo))
            :op2 (g2 / generate-01
                  :ARG0 (c2 / cell
                        :ARG1-of d4
                        :quant (a3 / as-many-as :op1 50000))
                  :ARG1 (t2 / tumor
                        :ARG1-of (g3 / grow-01
                              :ARG1-of (s / slow-05)))
                  :ARG0-of (h / have-03
                        :ARG1 (d6 / delay-01
                              :ARG2 (t3 / temporal-quantity :quant 10
                                    :unit (w / week))
                              :time (a2 / after
                                    :op1 (i2 / inject-01)))))
            :ARG1-of (d7 / describe-01
                  :ARG0 (f / figure :mod "1B"))))

# ::id pmid_2423_8212.112 ::date 2015-08-25T13:35:24 ::annotator SDL-AMR-09 ::preferred
# ::snt Immunohistochemical analysis of melanosphere-derived xenografts, performed for all samples, revealed a high similarity between the xenograft and the original patient tumor in terms of morphology and expression of the melanoma-associated diagnostic antigens MART1 and S100 (Figure <xref ref-type="fig" rid="F1">1</xref>D is a representative image).
# ::save-date Thu Feb 4, 2016 ::file pmid_2423_8212_112.txt
(r / reveal-01
      :ARG0 (a / analyze-01
            :ARG1 (x / xenograft
                  :ARG1-of (d / derive-01
                        :ARG2 (m3 / melanosphere)))
            :ARG1-of (p / perform-02)
            :beneficiary (t / thing
                  :ARG1-of (s / sample-01)
                  :mod (a2 / all))
            :mod (i / immunohistochemical))
      :ARG1 (r2 / resemble-01
            :ARG1 x
            :ARG2 (t2 / tumor
                  :mod (o / original)
                  :mod (p2 / person
                        :ARG0-of (h2 / have-org-role-91
                              :ARG2 (p3 / patient))))
            :ARG1-of (h / high-02)
            :topic (a3 / and
                  :op1 (m / morphology)
                  :op2 (e / express-03
                        :ARG2 (a4 / and
                              :op1 (a5 / antigen :name (n2 / name :op1 "MART1")
                                    :ARG1-of (a7 / associate-01
                                          :ARG2 (m2 / medical-condition :name (n / name :op1 "melanoma")))
                                    :mod (d2 / diagnose-01))
                              :op2 (a6 / antigen :name (n3 / name :op1 "S100")
                                    :ARG1-of a7
                                    :mod d2)))))
      :ARG1-of (d3 / describe-01
            :ARG0 (f / figure :mod "1D"
                  :ARG1-of (r3 / represent-01
                        :ARG0 (i2 / image)))))

# ::id pmid_2423_8212.113 ::date 2015-08-25T13:53:32 ::annotator SDL-AMR-09 ::preferred
# ::snt Following xenograft dissociation and re-injection we easily obtained secondary and tertiary tumors, suggesting that tumorigenic potential was not lost with passages in mice, in fact these results proved the ability of tumorigenic cells to self-renew <i>in vivo</i> (results not shown).
# ::save-date Mon Dec 21, 2015 ::file pmid_2423_8212_113.txt
(m2 / multi-sentence
      :snt1 (o / obtain-01
            :ARG0 (w / we)
            :ARG1 (a / and
                  :op1 (t / tumor
                        :mod (s / secondary))
                  :op2 (t2 / tumor
                        :mod (t3 / tertiary)))
            :ARG1-of (e / easy-05)
            :ARG0-of (s2 / suggest-01
                  :ARG1 (l / lose-02 :polarity -
                        :ARG1 (c / capable-01
                              :ARG1 (c2 / cause-01
                                    :ARG1 (t4 / tumor)))
                        :condition (p / pass-03
                              :location (m / mouse))))
            :ARG1-of (f / follow-01
                  :ARG2 (a2 / and
                        :op1 (d / dissociate-01
                              :ARG1 (x / xenograft))
                        :op2 (r / reinject-00
                              :ARG1 x))))
      :snt2 (p2 / prove-01
            :ARG0 (t5 / thing
                  :ARG2-of (r2 / result-01)
                  :ARG1-of (s3 / show-01 :polarity -)
                  :mod (t6 / this))
            :ARG1 (c3 / capable-01
                  :ARG1 (c4 / cell
                        :ARG0-of (c5 / cause-01
                              :ARG1 (t7 / tumor)))
                  :ARG2 (r3 / renew-01
                        :ARG0 c4
                        :ARG1 c4
                        :manner (i / in-vivo)))
            :mod (i2 / in-fact)))

# ::id pmid_2423_8212.114 ::date 2015-08-25T14:15:06 ::annotator SDL-AMR-09 ::preferred
# ::snt Based on these <i>in vitro</i> and <i>in vivo</i> results, we considered melanospheres as surrogate of melanoma-initiating cells (MIC) exploitable for pre-clinical experimentation.
# ::save-date Thu Jan 14, 2016 ::file pmid_2423_8212_114.txt
(c / consider-02
      :ARG0 (w / we)
      :ARG1 (m2 / melanosphere)
      :ARG2 (s / surrogate
            :poss (c3 / cell
                  :ARG0-of (i / initiate-01
                        :ARG1 (m / medical-condition :name (n / name :op1 "melanoma")))
                  :ARG1-of (e / exploit-01
                        :ARG2 (e2 / experiment-01
                              :time (b / before
                                    :op1 (c4 / clinic)))
                        :ARG1-of (p / possible-01))))
      :ARG2-of (b2 / base-02
            :ARG1 (t / thing
                  :ARG2-of (r / result-01)
                  :manner (i2 / in-vivo)
                  :manner (i3 / in-vitro)
                  :mod (t2 / this))))

# ::id pmid_2423_8212.115 ::date 2015-08-25T14:24:59 ::annotator SDL-AMR-09 ::preferred
# ::snt <sec-title level="2">Melanospheres are resistant to chemotherapeutic drugs and to most pathway inhibitors</sec-title>
# ::save-date Sun Aug 30, 2015 ::file pmid_2423_8212_115.txt
(r / resist-01
      :ARG0 (m3 / melanosphere)
      :ARG1 (a / and
            :op1 (d / drug
                  :mod (c2 / chemotherapy))
            :op2 (m / molecular-physical-entity
                  :ARG0-of (i / inhibit-01
                        :ARG1 (p / pathway))
                  :quant (m2 / most))))

# ::id pmid_2423_8212.116 ::date 2015-08-25T14:29:29 ::annotator SDL-AMR-09 ::preferred
# ::snt We investigated the response of melaospheres to chemotherapeutic agents currently used in the treatment of melanoma patients.
# ::save-date Sat Jan 30, 2016 ::file pmid_2423_8212_116.txt
(i / investigate-01
      :ARG0 (w / we)
      :ARG1 (r / respond-01
            :ARG0 (m2 / melanosphere)
            :ARG1 (a / agent
                  :mod (c2 / chemotherapy)
                  :ARG1-of (u / use-01
                        :ARG2 (t / treat-03
                              :ARG1 (p / person
                                    :ARG0-of (h / have-org-role-91
                                          :ARG2 (p2 / patient)))
                              :ARG2 (m / medical-condition :name (n / name :op1 "melanoma")))
                        :time (c3 / current)))))

# ::id pmid_2423_8212.117 ::date 2015-08-25T14:33:04 ::annotator SDL-AMR-09 ::preferred
# ::snt Melanospheres were exposed to cisplatin, temozolomide, dacarbazine and paclitaxel for 48 hours and cell viability was assessed by MTT assay.
# ::save-date Sat Feb 13, 2016 ::file pmid_2423_8212_117.txt
(a / and
      :op1 (e / expose-01
            :ARG1 (m / melanosphere)
            :ARG2 (a2 / and
                  :op1 (s / small-molecule :name (n2 / name :op1 "cisplatin"))
                  :op2 (s2 / small-molecule :name (n3 / name :op1 "temozolomide"))
                  :op3 (s3 / small-molecule :name (n4 / name :op1 "dacarbazine"))
                  :op4 (s4 / small-molecule :name (n5 / name :op1 "paclitaxel")))
            :duration (t / temporal-quantity :quant 48
                  :unit (h / hour)))
      :op1 (a3 / assess-01
            :ARG0 (a4 / assay-01
                  :instrument (s5 / small-molecule :name (n / name :op1 "MTT")))
            :ARG1 (v / viability
                  :mod (c2 / cell))))

# ::id pmid_2423_8212.118 ::date 2015-08-25T14:39:15 ::annotator SDL-AMR-09 ::preferred
# ::snt Overall a weak cytotoxic effect (<40% in all samples and with all drugs) was observed with no therapeutic window as compared to normal melanocytes (Figure <xref ref-type="fig" rid="F2">2</xref>A).
# ::save-date Sun Aug 30, 2015 ::file pmid_2423_8212_118.txt
(o / observe-01
      :ARG1 (a / affect-01
            :ARG1 (t2 / thing
                  :ARG1-of (s / sample-01)
                  :mod (a2 / all))
            :ARG2 (d2 / drug
                  :mod a2)
            :ARG1-of (w / weak-02)
            :mod (c / cytotoxic)
            :ARG0-of (h / have-03 :polarity -
                  :ARG1 (w2 / window
                        :mod (t / therapy)))
            :degree (l / less-than
                  :op1 (p / percentage-entity :value 40)))
      :compared-to (m / melanocyte
            :ARG1-of (n2 / normal-02))
      :mod (o2 / overall)
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod "2A")))

# ::id pmid_2423_8212.119 ::date 2015-08-25T14:47:35 ::annotator SDL-AMR-09 ::preferred
# ::snt Conversely, differentiated cells were extremely sensitive to cisplatin, in 3 out of 3 samples assessed (Figure <xref ref-type="fig" rid="F2">2</xref>B is a representative sample).
# ::save-date Tue Aug 25, 2015 ::file pmid_2423_8212_119.txt
(s / sensitive-03
      :ARG0 (c / cell
            :ARG1-of (d / differentiate-101))
      :ARG1 (s2 / small-molecule :name (n / name :op1 "cisplatin"))
      :degree (e / extreme)
      :location (t / thing :quant 3
            :ARG1-of (a / assess-01)
            :ARG1-of (s3 / sample-01)
            :ARG1-of (i / include-91
                  :ARG2 (t2 / thing :quant 3
                        :ARG1-of s3)))
      :ARG1-of (d2 / describe-01
            :ARG0 (f / figure :mod "2B"
                  :ARG0-of (r / represent-01
                        :ARG1 (t3 / thing
                              :ARG1-of s3))))
      :manner (c2 / converse))

# ::id pmid_2423_8212.120 ::date 2015-08-25T14:55:50 ::annotator SDL-AMR-09 ::preferred
# ::snt We next investigated the cytotoxic potential of a panel of 80 signaling pathway inhibitors on melanospheres derived from patient #1 and #2 and #3 encompassing inhibitors of RAS/RAF/MEK and PI3K/AKT pathways as well as tyrosine kinase receptors.
# ::save-date Thu Feb 4, 2016 ::file pmid_2423_8212_120.txt
(i / investigate-01
      :ARG0 (w / we)
      :ARG1 (c / capable-01
            :ARG1 (p / panel
                  :consist-of (m / molecular-physical-entity :quant 80
                        :ARG0-of (i2 / inhibit-01
                              :ARG1 (p2 / pathway
                                    :ARG0-of (s / signal-07))))
                  :ARG0-of (e / encompass-01
                        :ARG1 (a3 / and
                              :op1 (m3 / molecular-physical-entity
                                    :ARG0-of (i3 / inhibit-01
                                          :ARG1 (a2 / and
                                                :op1 (p7 / pathway :name (n2 / name :op1 "RAS/RAF/MEK"))
                                                :op2 (p8 / pathway :name (n3 / name :op1 "PI3K/AKT")))))
                              :op2 (p9 / protein :name (n4 / name :op1 "tyrosine" :op2 "kinase" :op3 "receptor")))))
            :ARG2 (c2 / cytotoxic)
            :beneficiary (m2 / melanosphere
                  :ARG1-of (d / derive-01
                        :ARG2 (a / and
                              :op1 (p3 / person
                                    :ARG1-of (h / have-org-role-91
                                          :ARG2 (p4 / patient))
                                    :ord (o / ordinal-entity :value 1))
                              :op2 (p5 / person
                                    :ARG1-of h
                                    :ord (o2 / ordinal-entity :value 2))
                              :op3 (p6 / person
                                    :ARG1-of h
                                    :ord (o3 / ordinal-entity :value 3))))))
      :time (n / next))

# ::id pmid_2423_8212.121 ::date 2015-08-25T15:11:30 ::annotator SDL-AMR-09 ::preferred
# ::snt Only inhibitors of the RAS/RAF/MEK pathway (including the MEK inhibitors PD098059 and U0126 and the Erk2 inhibitor 5-iodotubercidin) showed promising antitumor activity in terms of reduced cell viability, as measured by MTT assay.
# ::save-date Sat Feb 13, 2016 ::file pmid_2423_8212_121.txt
(s / show-01
      :ARG0 (m / molecular-physical-entity
            :ARG0-of (i / inhibit-01
                  :ARG1 (p / pathway :name (n / name :op1 "RAS/RAF/MEK")))
            :ARG2-of (i2 / include-01
                  :ARG1 (a / and
                        :op1 (s2 / small-molecule :name (n2 / name :op1 "PD098059")
                              :ARG0-of (i3 / inhibit-01
                                    :ARG1 (p3 / protein-family :name (n5 / name :op1 "MEK"))))
                        :op2 (s3 / small-molecule :name (n3 / name :op1 "U0126")
                              :ARG0-of i3)
                        :op3 (s4 / small-molecule :name (n4 / name :op1 "5-iodotubercidin")
                              :ARG0-of (i4 / inhibit-01
                                    :ARG1 (e / enzyme :name (n6 / name :op1 "Erk2"))))))
            :mod (o / only))
      :ARG1 (a2 / activity-06
            :ARG1 (o2 / oppose-01
                  :ARG1 (t / tumor))
            :ARG0-of (p2 / promise-01)
            :topic (v / viability
                  :mod (c / cell)
                  :ARG0-of (r / reduce-01)
                  :ARG1-of (m2 / measure-01
                        :ARG0 (a3 / assay-01
                              :instrument (s5 / small-molecule :name (n7 / name :op1 "MTT")))))))

# ::id pmid_2423_8212.122 ::date 2015-08-25T15:24:24 ::annotator SDL-AMR-09 ::preferred
# ::snt The other drugs, except for the broadly toxic compound staurosporin used as positive control, were nearly unable to reduce cell viability/proliferation, although all compounds were used at doses higher than the described IC<sub>50</sub> in order to enhance their activity.
# ::save-date Sun Aug 30, 2015 ::file pmid_2423_8212_122.txt
(p / possible-01 :polarity -
      :ARG1 (r / reduce-01
            :ARG0 (d / drug
                  :mod (o / other)
                  :ARG2-of (e / except-01
                        :ARG1 (c / compound :name (n / name :op1 "staurosporin")
                              :mod (t / toxic
                                    :ARG1-of (b / broad-02))
                              :ARG1-of (u / use-01
                                    :ARG2 (c2 / control
                                          :mod (p2 / positive))))))
            :ARG1 (s / slash
                  :op1 (v / viability
                        :mod (c3 / cell))
                  :op2 (p3 / proliferate-01
                        :ARG0 c3)))
      :concession (u2 / use-01
                  :ARG1 (c4 / compound
                        :mod (a / all)
                        :ARG2-of (d2 / dose-01
                              :ARG1-of (h2 / high-02
                                    :degree (m / more)
                                    :compared-to (t2 / thing :name (n2 / name :op1 "IC50")
                                          :ARG1-of (d3 / describe-01)))))
                  :ARG2 (e2 / enhance-01
                        :ARG1 (a2 / activity-06
                              :ARG0 c4)))
      :mod (n3 / near))

# ::id pmid_2423_8212.123 ::date 2015-08-25T15:36:12 ::annotator SDL-AMR-09 ::preferred
# ::snt A similar drug response was observed for the different samples (Figure <xref ref-type="fig" rid="F2">2</xref>C shows a representative one).
# ::save-date Tue Aug 25, 2015 ::file pmid_2423_8212_123.txt
(o / observe-01
      :ARG1 (r / respond-01
            :ARG0 (d / drug)
            :ARG1-of (r2 / resemble-01))
      :location (t / thing
            :ARG1-of (s / sample-01)
            :ARG1-of (d2 / differ-02))
      :ARG1-of (d3 / describe-01
            :ARG0 (f / figure :mod "2C"
                  :ARG0-of (s2 / show-01
                        :ARG1 (t2 / thing
                              :ARG1-of (s3 / sample-01
                                    :ARG0-of (r3 / represent-01)))))))

# ::id pmid_2423_8212.124 ::date 2015-08-30T05:03:36 ::annotator SDL-AMR-09 ::preferred
# ::snt In line with the melanosphere sensitivity to compounds targeting the MAPK pathways, we observed the activation of this signaling pathway with high levels of phosphorylation of Erk and downstream S6 (Figure <xref ref-type="fig" rid="F2">2</xref>D).
# ::save-date Sat Jan 16, 2016 ::file pmid_2423_8212_124.txt
(o / observe-01
      :ARG0 (w / we)
      :ARG1 (a / activate-01
            :ARG1 (p / pathway
                  :ARG0-of (s / signal-07)
                  :mod (t / this))
            :mod (l / level
                  :ARG1-of (h / high-02
                        :ARG2 (p2 / phosphorylate-01
                              :ARG1 (a2 / and
                                    :op1 (e / enzyme :name (n / name :op1 "Erk"))
                                    :op2 (p4 / protein :name (n2 / name :op1 "S6")
                                          :location (d / downstream)))))))
      :ARG1-of (a3 / align-01
            :ARG2 (s2 / sensitive-03
                  :ARG0 (c / cell :name (n3 / name :op1 "melanosphere"))
                  :ARG1 (c2 / compound
                        :ARG0-of (t2 / target-01
                              :ARG1 (p5 / pathway :name (n4 / name :op1 "MAPK"))))))
      :ARG1-of (d2 / describe-01
            :ARG0 (f / figure :mod "2D")))

# ::id pmid_2423_8212.125 ::date 2015-08-30T05:25:39 ::annotator SDL-AMR-09 ::preferred
# ::snt We also found high levels of Cyclin-D and undetectable p16 (Figure <xref ref-type="fig" rid="F2">2</xref>D).
# ::save-date Sun Aug 30, 2015 ::file pmid_2423_8212_125.txt
(f / find-01
      :ARG0 (w / we)
      :ARG1 (l / level
            :ARG1-of (h / high-02
                  :ARG2 (a2 / and
                        :op1 (p / protein :name (n / name :op1 "Cyclin-D"))
                        :op2 (p2 / protein :name (n2 / name :op1 "p16")
                              :ARG1-of (d / detect-01
                                    :ARG1-of (p3 / possible-01 :polarity -))))))
      :mod (a / also)
      :ARG1-of (d2 / describe-01
            :ARG0 (f2 / figure :mod "2D")))

# ::id pmid_2423_8212.126 ::date 2015-08-30T05:31:28 ::annotator SDL-AMR-09 ::preferred
# ::snt These results are in agreement with the frequent alteration of the RAS/RAF/MEK pathway and cell cycle deregulation found in melanomas.
# ::save-date Thu Jan 14, 2016 ::file pmid_2423_8212_126.txt
(a / agree-01
      :ARG0 (t / thing
            :ARG2-of (r / result-01)
            :mod (t2 / this))
      :ARG2 (a3 / and
            :op1 (a2 / alter-01
                  :ARG1 (p / pathway :name (n / name :op1 "RAS/RAF/MEK"))
                  :ARG1-of (f2 / frequent-02))
            :op1 (d / deregulate-01
                  :ARG1 (c / cycle
                        :mod (c2 / cell)))
            :ARG1-of (f / find-01
                  :location (m / medical-condition :name (n2 / name :op1 "melanoma")))))

# ::id pmid_2423_8212.127 ::date 2015-08-30T05:46:59 ::annotator SDL-AMR-09 ::preferred
# ::snt Next, we analyzed DNA sequences of genes whose alterations may contribute to the abnormal pathway activation.
# ::save-date Sat Sep 12, 2015 ::file pmid_2423_8212_127.txt
(a / analyze-01
      :ARG0 (w / we)
      :ARG1 (d / dna-sequence
            :part-of (g / gene
                  :poss-of (a2 / alter-01
                        :ARG0-of (c / contribute-01
                              :ARG2 (a3 / activate-01
                                    :ARG1 (p2 / pathway)
                                    :ARG1-of (n / normal-02 :polarity -))
                              :ARG1-of (p3 / possible-01)))))
      :time (n2 / next))

# ::id pmid_2423_8212.128 ::date 2015-08-30T05:55:22 ::annotator SDL-AMR-09 ::preferred
# ::snt As reported in the Additional file <xref ref-type="supplementary-material" rid="S3">3</xref>: Table S1, NRAS was never mutated in the analyzed samples.
# ::save-date Sat Sep 12, 2015 ::file pmid_2423_8212_128.txt
(m / mutate-01 :polarity -
      :ARG1 (e / enzyme :name (n / name :op1 "NRAS"))
      :location (t2 / thing
            :ARG1-of (a / analyze-01)
            :ARG1-of (s / sample-01))
      :ARG1-of (r / report-01
            :medium (t / table :mod "S1"
                  :part-of (f / file :mod 3
                        :mod (a2 / additional))))
      :time (e2 / ever))

# ::id pmid_2423_8212.129 ::date 2015-08-30T06:00:34 ::annotator SDL-AMR-09 ::preferred
# ::snt Instead, despite the ubiquitous Erk phosphorylation found in melanospheres, the BRAF-V600E mutation was detected in samples 1, 2 and 4, BRAF-V600K mutation was found in samples 5 and 8, while samples 3, 6 and 7 displayed wild type BRAF.
# ::save-date Sat Jan 16, 2016 ::file pmid_2423_8212_129.txt
(h / have-concession-91
      :ARG1 (a / and
            :op1 (d / detect-01
                  :ARG1 (m / mutate-01 :value "V600E"
                        :ARG2 (e / enzyme :name (n3 / name :op1 "BRAF")))
                  :location (a2 / and
                        :op1 (t / thing :mod 1
                              :ARG1-of (s / sample-01))
                        :op2 (t2 / thing :mod 2
                              :ARG1-of s)
                        :op3 (t3 / thing :mod 4
                              :ARG1-of s)))
            :op2 (f2 / find-01
                  :ARG1 (m2 / mutate-01 :value "V600K"
                        :ARG1 e)
                  :location (a3 / and
                        :op1 (t4 / thing :mod 5
                              :ARG1-of s)
                        :op2 (t5 / thing :mod 8
                              :ARG1-of s)))
            :op3 (d2 / display-01
                  :ARG0 (a4 / and
                        :op1 (t6 / thing :mod 3
                              :ARG1-of s)
                        :op2 (t7 / thing :mod 6
                              :ARG1-of s)
                        :op3 (t8 / thing :mod 7
                              :ARG1-of s))
                  :ARG1 (e2 / enzyme :name (n4 / name :op1 "BRAF")
                        :mod (w / wild-type))))
      :ARG2 (p / phosphorylate-01
            :ARG1 (e3 / enzyme :name (n / name :op1 "Erk"))
            :mod (u / ubiquity)
            :ARG1-of (f / find-01
                  :location (c / cell :name (n2 / name :op1 "melanosphere"))))
      :ARG1-of (i / instead-of-91))

# ::id pmid_2423_8212.130 ::date 2015-08-30T06:14:45 ::annotator SDL-AMR-09 ::preferred
# ::snt All samples displayed wild type PTEN.
# ::save-date Sat Sep 12, 2015 ::file pmid_2423_8212_130.txt
(d / display-01
      :ARG0 (t / thing
            :mod (a / all)
            :ARG1-of (s / sample-01))
      :ARG1 (p / protein :name (n / name :op1 "PTEN")
            :mod (w / wild-type)))

# ::id pmid_2423_8212.131 ::date 2015-08-30T06:16:26 ::annotator SDL-AMR-09 ::preferred
# ::snt Finally, sequence analysis of the exon 4 and 5 of GNAQ gene, whose mutations have been associated with wild type BRAF and NRAS melanomas, revealed wild type status in all samples (Additional file <xref ref-type="supplementary-material" rid="S3">3</xref>: Table S1 and Additional file <xref ref-type="supplementary-material" rid="S4">4</xref>) [<xref ref-type="bibr" rid="B45">45</xref>].
# ::save-date Sat Jan 16, 2016 ::file pmid_2423_8212_131.txt
(r / reveal-01
      :ARG0 (a / analyze-01
            :ARG1 (a2 / and
                  :op1 (e / exon :mod 4)
                  :op2 (e2 / exon :mod 5)
                  :part-of (g / gene :name (n / name :op1 "GNAQ")
                        :poss-of (m / mutate-01
                              :ARG1-of (a3 / associate-01
                                    :ARG2 (a4 / and
                                          :op1 (m2 / medical-condition :name (n2 / name :op1 "melanoma")
                                                :mod (e3 / enzyme :name (n3 / name :op1 "BRAF")
                                                      :mod (w / wild-type)))
                                          :op2 (m3 / medical-condition :name (n4 / name :op1 "melanoma")
                                                :mod (e4 / enzyme :name (n5 / name :op1 "NRAS")
                                                      :mod w)))))))
            :mod (s / sequence))
      :ARG1 (s2 / status
            :location (t2 / thing
                  :mod (a5 / all)
                  :ARG1-of (s3 / sample-01))
            :mod w)
      :ARG1-of (d3 / describe-01
            :ARG0 (a6 / and
                  :op1 (t / table :mod "S1"
                        :part-of (f / file :mod 3
                              :mod (a7 / additional)))
                  :op2 (f2 / file :mod 4
                        :mod (a8 / additional))
                  :op3 (p / publication
                        :ARG1-of (c / cite-01
                              :ARG2 45))))
      :time (f3 / final))

# ::id pmid_2423_8212.132 ::date 2015-08-30T06:25:58 ::annotator SDL-AMR-09 ::preferred
# ::snt <sec-title level="2">Treatment with MEK inhibitor PD0325901 results in strong antitumor activity against melanospheres</sec-title>
# ::save-date Sat Sep 12, 2015 ::file pmid_2423_8212_132.txt
(r / result-01
      :ARG1 (t / treat-04
            :ARG2 (s / small-molecule :name (n / name :op1 "PD0325901")
                  :ARG0-of (i / inhibit-01
                        :ARG1 (p / protein-family :name (n2 / name :op1 "MEK")))))
      :ARG2 (a / activity-06
            :ARG1 (c2 / counter-01
                  :ARG1 (c3 / cell :name (n3 / name :op1 "melanosphere")))
            :ARG0-of (c / counter-01
                  :ARG1 (t2 / tumor))
            :ARG1-of (s2 / strong-02)))

# ::id pmid_2423_8212.133 ::date 2015-08-30T06:34:52 ::annotator SDL-AMR-09 ::preferred
# ::snt The encouraging activity of the MEK inhibitors used in the pathway inhibitor screening (see above) prompted us to study the antitumor effect of the MEK inhibitor PD0325901 on the melanospheres, based on its antitumor activity described in clinical studies [<xref ref-type="bibr" rid="B16">16</xref>].
# ::save-date Sat Sep 12, 2015 ::file pmid_2423_8212_133.txt
(p / prompt-01
      :ARG0 (a / activity-06
            :ARG0 (s / small-molecule
                  :ARG0-of (i / inhibit-01
                        :ARG1 (p2 / protein-family :name (n / name :op1 "MEK")))
                  :ARG1-of (u / use-01
                        :ARG2 (s2 / screen-01
                              :ARG1 (s3 / small-molecule
                                    :ARG0-of (i2 / inhibit-01
                                          :ARG1 (p3 / pathway))))))
            :ARG0-of (e / encourage-01)
            :ARG1-of (d / describe-01
                  :location (a2 / above)))
      :ARG1 (s4 / study-01
            :ARG0 (w / we)
            :ARG1 (a3 / affect-01
                  :ARG0 (s5 / small-molecule :name (n2 / name :op1 "PD0325901")
                        :ARG0-of (i3 / inhibit-01
                              :ARG1 p2))
                  :ARG1 (c / cell :name (n3 / name :op1 "melanosphere"))
                  :ARG2 (c2 / counter-01
                        :ARG1 (t / tumor)))
            :ARG1-of (b / base-02
                  :ARG2 (a4 / activity-06
                        :ARG0 s5
                        :ARG1 c2
                        :ARG1-of (d2 / describe-01
                              :medium (s6 / study-01
                                    :mod (c3 / clinic)
                                    :ARG1-of (d3 / describe-01
                                          :ARG0 (p4 / publication
                                                :ARG1-of (c4 / cite-01
                                                      :ARG2 16)))))))))

# ::id pmid_2423_8212.134 ::date 2015-08-30T06:48:29 ::annotator SDL-AMR-09 ::preferred
# ::snt Following 3 day-exposure to PD0325901, at doses comparable with those achieved <i>in vivo,</i> both wild type and mutated-BRAF cells displayed decreased proliferation/viability, with mutated-BRAF samples being more sensitive to the drug (Figure <xref ref-type="fig" rid="F3">3</xref>A).
# ::save-date Sat Jan 16, 2016 ::file pmid_2423_8212_134.txt
(d / display-01
      :ARG0 (a / and
            :op1 (c / cell
                  :mod (e2 / enzyme :name (n / name :op1 "BRAF")
                        :mod (w / wild-type)))
            :op2 (c2 / cell
                  :mod (e3 / enzyme :name (n2 / name :op1 "BRAF")
                        :ARG2-of (m / mutate-01))))
      :ARG1 (a4 / and
            :op1 (o / or
                  :op1 (p / proliferate-01)
                  :op2 (v / viability)
                  :ARG1-of (d2 / decrease-01))
            :op2 (s2 / sensitive-03
                  :ARG0 (s3 / sample-01
                        :mod e3)
                  :ARG1 s
                  :degree (m2 / more)))
      :time (a2 / after
            :op1 (e / expose-01
                  :ARG1 a
                  :ARG2 (s / small-molecule :name (n3 / name :op1 "PD0325901")
                        :quant (d4 / dose
                              :ARG1-of (c3 / comparable-03
                                    :ARG2 (d5 / dose
                                          :ARG1-of (a3 / achieve-01
                                                :manner (i / in-vivo)))))
                        :ARG2-of (d8 / dose-01))
                  :duration (t / temporal-quantity :quant 3
                        :unit (d3 / day))))
      :ARG1-of (d7 / describe-01
            :ARG0 (f / figure :mod "3A")))

# ::id pmid_2423_8212.135 ::date 2015-08-30T06:58:03 ::annotator SDL-AMR-09 ::preferred
# ::snt In order to distinguish the cytostatic from the cytotoxic effect and to unravel the molecular mechanisms of PD0325901 antitumor activity against malenospheres, we first performed cell cycle analysis of control and treated samples.
# ::save-date Sun Sep 13, 2015 ::file pmid_2423_8212_135.txt
(p / perform-02
      :ARG0 (w / we)
      :ARG1 (a / analyze-01
            :ARG1 (a2 / and
                  :op1 (t3 / thing
                        :mod (c3 / control)
                        :ARG1-of (s2 / sample-01))
                  :op2 (t4 / thing
                        :ARG1-of (t / treat-04)
                        :ARG1-of s2))
            :mod (c / cycle
                  :mod (c2 / cell)))
      :purpose (a3 / and
            :op1 (d / distinguish-01
                  :ARG0 w
                  :ARG1 (a4 / affect-01
                        :ARG2 (c4 / cytostasis))
                  :ARG2 (a5 / affect-01
                        :ARG2 (c5 / cytotoxicity)))
            :op2 (u / unravel-01
                  :ARG0 w
                  :ARG1 (m / mechanism
                        :mod (m2 / molecule)
                        :poss (a6 / activity-06
                              :ARG0 (s3 / small-molecule :name (n / name :op1 "PD0325901"))
                              :ARG1 (c6 / counter-01
                                    :ARG1 (t2 / tumor))
                              :ARG0-of (c7 / counter-01
                                    :ARG1 (c8 / cell :name (n2 / name :op1 "melanosphere")))))))
      :time (f / first))

# ::id pmid_2423_8212.136 ::date 2015-08-30T09:42:21 ::annotator SDL-AMR-09 ::preferred
# ::snt After short exposure (2 days), PD0325901 greatly affected cell cycle progression by determining accumulation of cells in the G1 phase, both in the wild type and mutated-BRAF samples (Figure <xref ref-type="fig" rid="F3">3</xref>B).
# ::save-date Sat Jan 16, 2016 ::file pmid_2423_8212_136.txt
(a / affect-01
      :ARG0 (s / small-molecule :name (n / name :op1 "PD0325901"))
      :ARG1 (p / progress-01
            :ARG1 (c / cycle
                  :mod (c2 / cell)))
      :ARG2 (d / determine-01
            :ARG0 s
            :ARG1 (a2 / accumulate-01
                  :ARG1 (c3 / cell)
                  :time (e2 / event :name (n4 / name :op1 "G1" :op2 "phase")))
            :location (a3 / and
                  :op1 (t2 / thing
                        :mod (e3 / enzyme :name (n2 / name :op1 "BRAF")
                              :mod (w / wild-type))
                        :ARG1-of (s2 / sample-01))
                  :op2 (t3 / thing
                        :mod (e4 / enzyme :name (n3 / name :op1 "BRAF")
                              :ARG2-of (m / mutate-01))
                        :ARG1-of s2)))
      :manner (g / great)
      :ARG1-of (d2 / describe-01
            :ARG0 (f / figure :mod "3B"))
      :time (a4 / after
            :op1 (e / expose-01
                  :ARG1-of (s4 / short-07))
            :duration (t / temporal-quantity :quant 2
                  :unit (d3 / day))))

# ::id pmid_2423_8212.137 ::date 2015-08-30T09:54:58 ::annotator SDL-AMR-09 ::preferred
# ::snt At the molecular level, together with a striking decrease in Cyclin D levels which is in line with the observed cell cycle arrest, treated samples displayed a decline in Erk and S6 phosphorylation, thus, proving MEK signaling inhibition by PD0325901 (Figure <xref ref-type="fig" rid="F3">3</xref>C).
# ::save-date Sat Jan 16, 2016 ::file pmid_2423_8212_137.txt
(d / display-01
      :ARG0 (t2 / thing
            :ARG1-of (t / treat-04)
            :ARG1-of (s / sample-01))
      :ARG1 (a5 / and
            :op1 (d2 / decline-01
                  :ARG1 (p / phosphorylate-01
                        :ARG1 (a / and
                              :op1 (e / enzyme :name (n / name :op1 "Erk"))
                              :op2 (p3 / protein :name (n2 / name :op1 "S6")))))
            :op2 (d3 / decrease-01
                  :ARG1 (l2 / level
                        :quant-of (p6 / protein :name (n5 / name :op1 "Cyclin" :op2 "D")))
                  :ARG1-of (s4 / strike-04)
                  :ARG1-of (a3 / align-01
                        :ARG2 (a4 / arrest-02
                              :ARG1 (c2 / cycle
                                    :mod (c3 / cell))
                              :ARG1-of (o / observe-01)))))
      :ARG0-of (c / cause-01
            :ARG1 (p4 / prove-01
                  :ARG1 (i / inhibit-01
                        :ARG0 (s2 / small-molecule :name (n3 / name :op1 "PD0325901"))
                        :ARG1 (s3 / signal-07
                              :ARG0 (p5 / pathway :name (n4 / name :op1 "MEK"))))))
      :location (l / level
            :mod (m / molecule))
      :ARG1-of (d4 / describe-01
            :ARG0 (f / figure :mod "3C")))

# ::id pmid_2423_8212.138 ::date 2015-08-30T10:07:11 ::annotator SDL-AMR-09 ::preferred
# ::snt Given that PD0325901 may induce apoptosis in melanoma cell lines, we investigated whether a similar mechanism could account for the reduced number of viable cells in PD0325901-treated melanosphere samples [<xref ref-type="bibr" rid="B17">17</xref>].
# ::save-date Thu Jan 14, 2016 ::file pmid_2423_8212_138.txt
(i / investigate-01
      :ARG0 (w / we)
      :ARG1 (p3 / possible-01 :mode interrogative
            :ARG1 (a / account-01
                  :ARG0 (m / mechanism
                        :ARG1-of (r / resemble-01))
                  :ARG1 (n / number-01
                        :ARG1 (c / cell
                              :mod (v / viable))
                        :ARG1-of (r2 / reduce-01)
                        :location (s / sample-01
                              :ARG1 (c2 / cell :name (n2 / name :op1 "melanosphere"))
                              :ARG1-of (t / treat-04
                                    :ARG2 (s2 / small-molecule :name (n3 / name :op1 "PD0325901")))))))
      :ARG1-of (c3 / cause-01
            :ARG0 (p / possible-01
                  :ARG1 (i2 / induce-01
                        :ARG0 s2
                        :ARG2 (a2 / apoptosis)
                        :location (c4 / cell-line
                              :mod (m2 / medical-condition :name (n4 / name :op1 "melanoma"))))))
      :ARG1-of (d2 / describe-01
            :ARG0 (p2 / publication
                  :ARG1-of (c5 / cite-01
                        :ARG2 17))))

# ::id pmid_2423_8212.139 ::date 2015-08-30T10:14:34 ::annotator SDL-AMR-09 ::preferred
# ::snt Indeed, PD0325901-treated mutant-BRAF melanospheres contained a high fraction of apoptotic annexin V-positive cells compared to control samples.
# ::save-date Sat Jan 16, 2016 ::file pmid_2423_8212_139.txt
(c / contain-01
      :ARG0 (c2 / cell :name (n / name :op1 "melanosphere")
            :mod (e / enzyme :name (n2 / name :op1 "BRAF")
                  :ARG2-of (m / mutate-01))
            :ARG1-of (t / treat-04
                  :ARG2 (s / small-molecule :name (n3 / name :op1 "PD0335901"))))
      :ARG1 (f / fraction
            :ARG1-of (h / high-02)
            :quant-of (c3 / cell
                  :mod (p / positive
                        :mod (p2 / protein :name (n4 / name :op1 "annexin" :op2 "V")))
                  :mod (a / apoptosis))
            :compared-to (t2 / thing
                  :mod (c4 / control)
                  :ARG1-of (s2 / sample-01)))
      :mod (i / indeed))

# ::id pmid_2423_8212.140 ::date 2015-08-30T10:21:09 ::annotator SDL-AMR-09 ::preferred
# ::snt In contrast, PD0325901 treated wild type-BRAF melanospheres did not show such a dramatic increase (Figure <xref ref-type="fig" rid="F3">3</xref>D).
# ::save-date Sat Jan 16, 2016 ::file pmid_2423_8212_140.txt
(c3 / contrast-01
      :ARG2 (s / show-01 :polarity -
            :ARG0 (c / cell :name (n / name :op1 "melanosphere")
                  :ARG1-of (t / treat-04
                        :ARG2 (s2 / small-molecule :name (n2 / name :op1 "PD0325901")))
                  :mod (e / enzyme :name (n3 / name :op1 "BRAF")
                        :mod (w / wild-type)))
            :ARG1 (i / increase-01
                  :ARG2 (d / dramatic)))
      :ARG1-of (d2 / describe-01
            :ARG0 (f / figure :mod "3D")))

# ::id pmid_2423_8212.141 ::date 2015-08-30T10:24:42 ::annotator SDL-AMR-09 ::preferred
# ::snt Importantly, we found that both wild type and mutated-BRAF melanoma differentiated cells, were exquisitely sensitive to the drug, as indicated by the high fraction of sub-diploid cells detected in treated samples stained with Propidium Iodide (Figure <xref ref-type="fig" rid="F3">3</xref>E).
# ::save-date Sat Jan 16, 2016 ::file pmid_2423_8212_141.txt
(f / find-01
      :ARG0 (w / we)
      :ARG1 (s / sensitive-03
            :ARG0 (a / and
                  :op1 (c / cell
                        :ARG1-of (d / differentiate-01)
                        :mod (m2 / medical-condition :name (n / name :op1 "melanoma"))
                        :mod (e2 / enzyme :name (n2 / name :op1 "BRAF")
                              :ARG2-of (m / mutate-01)))
                  :op2 (c2 / cell
                        :ARG1-of d
                        :mod m2
                        :mod (w2 / wild-type)))
            :ARG1 (d3 / drug)
            :manner (e / exquisite)
            :ARG1-of (i / indicate-01
                  :ARG0 (f2 / fraction
                        :ARG1-of (h / high-02)
                        :quant-of (c3 / cell
                              :mod (s2 / sub-diploid)
                              :ARG1-of (d4 / detect-01
                                    :location (t2 / thing
                                          :ARG1-of (t / treat-04)
                                          :ARG1-of (s4 / stain-01
                                                :ARG2 (s5 / small-molecule :name (n3 / name :op1 "Propidium" :op2 "Iodide")))
                                          :ARG1-of (s3 / sample-01)))))))
      :mod (i2 / important)
      :ARG1-of (d5 / describe-01
            :ARG0 (f3 / figure :mod "3E")))

# ::id pmid_2423_8212.142 ::date 2015-08-30T10:33:51 ::annotator SDL-AMR-09 ::preferred
# ::snt This additional apoptosis assay confirmed that, at the level of melanospheres, only mutated-BRAF cells rapidly underwent PD0325901-induced apoptosis, while apoptotic hypodiploid DNA-cells were almost absent in the treated wild type-BRAF cells (Figure <xref ref-type="fig" rid="F3">3</xref>E).
# ::save-date Sat Jan 16, 2016 ::file pmid_2423_8212_142.txt
(c / confirm-01
      :ARG0 (a / assay-01
            :ARG1 (a2 / apoptosis)
            :mod (a3 / additional)
            :mod (t / this))
      :ARG1 (c3 / contrast-01
            :ARG1 (u / undergo-28
                  :ARG1 (c2 / cell
                        :mod (e2 / enzyme :name (n / name :op1 "BRAF")
                              :ARG2-of (m / mutate-01))
                        :mod (o / only))
                  :ARG2 (a4 / apoptosis
                        :ARG2-of (i / induce-01
                              :ARG0 (s / small-molecule :name (n2 / name :op1 "PD0325901"))))
                  :manner (r / rapid))
            :ARG2 (a5 / absent-01
                  :ARG1 (c4 / cell
                        :mod (h / hypodiploid)
                        :mod (a6 / apoptosis)
                        :mod (n5 / nucleic-acid :name (n6 / name :op1 "DNA")))
                  :ARG2 (c5 / cell
                        :mod (e / enzyme :name (n3 / name :op1 "BRAF")
                              :mod (w / wild-type))
                        :ARG1-of (t2 / treat-04))
                  :degree (a7 / almost))
            :location (l / level
                  :mod (c6 / cell :name (n4 / name :op1 "melanosphere"))))
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod "3E")))

# ::id pmid_2423_8212.143 ::date 2015-08-30T10:41:43 ::annotator SDL-AMR-09 ::preferred
# ::snt These results indicate that PD0325901 exerted strong cytotoxic activity against mutant-BRAF melanospheres, and a strong cytostatic activity against wild type-BRAF melanospheres, where cytotoxicity played a minor role.
# ::save-date Wed Jan 20, 2016 ::file pmid_2423_8212_143.txt
(i / indicate-01
      :ARG0 (t / thing
            :ARG2-of (r / result-01)
            :mod (t2 / this))
      :ARG1 (e / exert-01
            :ARG0 (s / small-molecule :name (n / name :op1 "PD0325901"))
            :ARG1 (a / and
                  :op1 (a2 / activity-06
                        :ARG1 (c / cytotoxicity)
                        :ARG1-of (s2 / strong-02)
                        :ARG0-of (c3 / counter-01
                              :ARG1 (c2 / cell :name (n2 / name :op1 "melanosphere")
                                    :mod (e2 / enzyme :name (n3 / name :op1 "BRAF")
                                          :ARG2-of (m / mutate-01)))))
                  :op2 (a3 / activity-06
                        :ARG1 (c4 / cytostasis)
                        :ARG0-of (c5 / counter-01
                              :ARG1 (c6 / cell :name (n4 / name :op1 "melanosphere")
                                    :mod (e3 / enzyme :name (n5 / name :op1 "BRAF")
                                          :mod (w / wild-type))
                                    :location-of (p / play-02
                                          :ARG0 (c7 / cytotoxicity)
                                          :ARG1 (r2 / role
                                                :ARG1-of (m2 / minor-01)))))
                        :ARG1-of s2))))

# ::id pmid_2423_8212.144 ::date 2015-08-30T10:48:50 ::annotator SDL-AMR-09 ::preferred
# ::snt In contrast, differentiated melanoma cells were efficiently killed by PD0325901, regardless BRAF status (Figure <xref ref-type="fig" rid="F3">3</xref>E).
# ::save-date Sat Jan 16, 2016 ::file pmid_2423_8212_144.txt
(c3 / contrast-01
      :ARG2 (k / kill-01
            :ARG0 (s / small-molecule :name (n2 / name :op1 "PD0325901"))
            :ARG1 (c / cell
                  :ARG1-of (d / differentiate-01)
                  :mod (m / medical-condition :name (n / name :op1 "melanoma")))
            :ARG2-of (e / efficient-01)
            :concession (s2 / status
                  :mod (e2 / enzyme :name (n3 / name :op1 "BRAF"))))
      :ARG1-of (d3 / describe-01
            :ARG0 (f / figure :mod "3E")))

# ::id pmid_2423_8212.145 ::date 2015-08-30T10:55:28 ::annotator SDL-AMR-09 ::preferred
# ::snt <sec-title level="2">Treatment with MEK inhibitor PD0325901 results in strong antitumor activity in melanosphere-derived xenografts</sec-title>
# ::save-date Sun Aug 30, 2015 ::file pmid_2423_8212_145.txt
(r / result-01
      :ARG1 (t / treat-04
            :ARG2 (s / small-molecule :name (n / name :op1 "PD0325901")
                  :ARG0-of (i / inhibit-01
                        :ARG1 (p / protein-family :name (n2 / name :op1 "MEK")))))
      :ARG2 (a / activity-06
            :ARG1 (c / counter-01
                  :ARG1 (t2 / tumor))
            :ARG1-of (s2 / strong-02)
            :location (x / xenograft
                  :ARG1-of (d / derive-01
                        :ARG2 (c2 / cell :name (n3 / name :op1 "melanosphere"))))))

# ::id pmid_2423_8212.146 ::date 2015-08-30T10:58:12 ::annotator SDL-AMR-09 ::preferred
# ::snt We investigated the activity of PD0325901 against melanosphere-generated subcutaneous xenografts.
# ::save-date Sun Aug 30, 2015 ::file pmid_2423_8212_146.txt
(i / investigate-01
      :ARG0 (w / we)
      :ARG1 (a / activity-06
            :ARG0 (s / small-molecule :name (n / name :op1 "PD0325901"))
            :ARG0-of (c / counter-01
                  :ARG1 (x / xenograft
                        :mod (s2 / subcutaneous)
                        :ARG1-of (g / generate-01
                              :ARG2 (c2 / cell :name (n2 / name :op1 "melanosphere")))))))

# ::id pmid_2423_8212.147 ::date 2015-08-30T13:05:46 ::annotator SDL-AMR-09 ::preferred
# ::snt Doses of 25 or 12.5 mg/Kg were investigated in order to define a well tolerated dose with reduced toxicity and maximum antitumor activity, as the optimal doses and schedules for antitumor activity in the absence of toxicity was not previously determined in cancer patients.
# ::save-date Thu Feb 4, 2016 ::file pmid_2423_8212_147.txt
(i / investigate-01
      :ARG1 (d / dose
            :quant (c / concentration-quantity
                  :quant (o / or :op1 25 :op2 12.5)
                  :unit (m / milligram-per-kilogram)))
      :purpose (d2 / define-01
            :ARG1 (d3 / dose
                  :ARG1-of (t / tolerate-01
                        :ARG1-of (w / well-09))
                  :ARG0-of (h2 / have-03
                        :ARG1 (a5 / and
                              :op1 (t2 / toxicity
                                    :ARG1-of (r / reduce-01))
                              :op2 (a / activity-06
                                    :ARG1 (c2 / counter-01
                                          :ARG1 (t3 / tumor))
                                    :degree (m2 / maximum))))))
      :ARG1-of (c3 / cause-01
            :ARG0 (d4 / determine-01 :polarity -
                  :ARG1 (a2 / and
                        :op1 (d5 / dose
                              :mod (o2 / optimal))
                        :op2 (s / schedule
                              :mod o2)
                        :beneficiary (a3 / activity-06
                              :ARG1 c2))
                  :time (p / previous)
                  :condition (a4 / absent-01
                        :ARG1 (t5 / toxicity))
                  :location (p2 / person
                        :ARG0-of (h / have-rel-role-91
                              :ARG2 (p3 / patient))
                        :mod (c5 / cancer)))))

# ::id pmid_2423_8212.148 ::date 2015-08-30T13:16:43 ::annotator SDL-AMR-09 ::preferred
# ::snt We chose the bi-weekly treatment schedule for drug administration based on previously published results showing high systemic toxicity occurring during daily drug administration [<xref ref-type="bibr" rid="B46">46</xref>] and as we previously experienced similar results in mice (results not shown).
# ::save-date Sat Sep 12, 2015 ::file pmid_2423_8212_148.txt
(c / choose-01
      :ARG0 (w / we)
      :ARG1 (s / schedule-01
            :ARG0 w
            :ARG1 (t / treat-04)
            :ARG2 (a / administer-01
                  :ARG1 (d / drug))
            :ARG3 (r / rate-entity-91
                  :ARG1 1
                  :ARG2 (t2 / temporal-quantity :quant 2
                        :unit (w2 / week))))
      :ARG1-of (b / base-02
            :ARG2 (a3 / and
                  :op1 (t3 / thing
                        :ARG2-of (r2 / result-01)
                        :ARG1-of (p4 / publish-01
                              :time (p / previous))
                        :ARG0-of (s2 / show-01
                              :ARG1 (t4 / toxicity
                                    :mod (s3 / systemic)
                                    :time (a2 / administer-01
                                          :ARG1 d
                                          :frequency (r3 / rate-entity-91
                                                :ARG3 (t5 / temporal-quantity :quant 1
                                                      :unit (d2 / day))))))
                        :ARG1-of (h / high-02)
                        :ARG1-of (d3 / describe-01
                              :ARG0 (p2 / publication
                                    :ARG1-of (c2 / cite-01
                                          :ARG2 46))))
                  :op2 (e2 / experience-01
                        :ARG0 w
                        :ARG1 (t6 / thing
                              :ARG2-of (r4 / result-01)
                              :ARG1-of (r5 / resemble-01)
                              :location (m / mouse)
                              :ARG1-of (s4 / show-01 :polarity -))
                        :time p))))

# ::id pmid_2423_8212.149 ::date 2015-08-30T13:32:39 ::annotator SDL-AMR-09 ::preferred
# ::snt PD0325901 administration, by oral gavage, caused a striking reduction in tumor growth at both drug doses, displaying stronger activity for the higher dose (Figure <xref ref-type="fig" rid="F4">4</xref>A and Additional file <xref ref-type="supplementary-material" rid="S5">5</xref>: Figure S3A).
# ::save-date Sat Sep 12, 2015 ::file pmid_2423_8212_149.txt
(c / cause-01
      :ARG0 (a / administer-01
            :ARG1 (s / small-molecule :name (n / name :op1 "PD0325901"))
            :medium (m / mouth)
            :ARG0-of (d3 / display-01
                  :ARG1 (a2 / activity-06
                        :ARG0 (d4 / dose
                              :ARG1-of (h / high-02
                                    :degree m2))
                        :ARG1-of (s3 / strong-02
                              :degree (m2 / more)))))
      :ARG1 (r / reduce-01
            :ARG1 (g / grow-01
                  :ARG1 (t / tumor)
                  :condition (d / dose-01
                        :ARG1 (d2 / drug)
                        :mod (b / both)))
            :ARG1-of (s2 / strike-04))
      :ARG1-of (d5 / describe-01
            :ARG0 (a3 / and
                  :op1 (f / figure :mod "4A")
                  :op2 (f2 / figure :mod "S3A"
                        :part-of (f3 / file :mod 5
                              :mod (a4 / additional))))))

# ::id pmid_2423_8212.150 ::date 2015-08-30T13:42:57 ::annotator SDL-AMR-09 ::preferred
# ::snt Importantly, treated mice did not exhibit signs of toxicity under this treatment schedule.
# ::save-date Sat Sep 12, 2015 ::file pmid_2423_8212_150.txt
(e / exhibit-01 :polarity -
      :ARG0 (m / mouse
            :ARG1-of (t / treat-04))
      :ARG1 (s / signal-07
            :ARG1 (t2 / toxicity))
      :condition (s2 / schedule-01
            :ARG1 (t3 / treat-04)
            :mod (t4 / this))
      :mod (i / important))

# ::id pmid_2423_8212.151 ::date 2015-08-30T13:44:41 ::annotator SDL-AMR-09 ::preferred
# ::snt Immunoblot analysis of xenografts displayed markedly reduced levels of Erk and downstream S6 phosphorylation in treated tumors, indicating that PD0325901 levels reached <i>in vivo</i> were sufficient to achieve almost complete Erk inactivation and that the effects observed on tumors were caused by specific PD0325901 activity (Additional file <xref ref-type="supplementary-material" rid="S5">5</xref>: Figure S3B).
# ::save-date Sat Jan 16, 2016 ::file pmid_2423_8212_151.txt
(d / display-01
      :ARG0 (a / analyze-01
            :ARG1 (x / xenograft)
            :mod (i / immunoblot-01))
      :ARG1 (l / level
            :degree-of (p2 / phosphorylate-01
                  :ARG1 (a3 / and
                        :op1 (e / enzyme :name (n / name :op1 "Erk"))
                        :op2 (p3 / protein :name (n2 / name :op1 "S6")
                              :location (d2 / downstream))))
            :ARG1-of (r / reduce-01
                  :ARG2 (m / marked))
            :location (t / tumor
                  :ARG1-of (t2 / treat-04)))
      :ARG0-of (i2 / indicate-01
            :ARG1 (a6 / and
                  :op1 (s2 / suffice-01
                        :ARG0 (l2 / level
                              :quant-of (s / small-molecule :name (n3 / name :op1 "PD0325901"))
                              :ARG1-of (r2 / reach-01
                                    :manner (i3 / in-vivo)))
                        :ARG1 (a2 / achieve-01
                              :ARG0 l2
                              :ARG1 (a4 / activate-01 :polarity -
                                    :ARG1 e
                                    :ARG1-of (c / complete-02
                                          :degree (a5 / almost)))))
                  :op2 (c2 / cause-01
                        :ARG0 (a8 / activity-06
                              :ARG0 s
                              :ARG1-of (s3 / specific-02))
                        :ARG1 (a7 / affect-01
                              :ARG1-of (o / observe-01
                                    :location (t3 / tumor))))))
      :ARG1-of (d3 / describe-01
            :ARG0 (f / figure :mod "S3B"
                  :part-of (f2 / file :mod 5
                        :mod (a9 / additional)))))

# ::id pmid_2423_8212.152 ::date 2015-08-30T13:56:51 ::annotator SDL-AMR-09 ::preferred
# ::snt Immunohistochemistry analysis of xenografts revealed decreased proliferation rates for treated tumors (lower Ki-67 expression in comparison with control tumors) and reduced activation of the Mek/Erk pathway (lower Erk phosphorylation) (Figure <xref ref-type="fig" rid="F4">4</xref>B).
# ::save-date Sat Jan 16, 2016 ::file pmid_2423_8212_152.txt
(r / reveal-01
      :ARG0 (a / analyze-01
            :ARG1 (x / xenograft)
            :mod (i / immunohistochemistry))
      :ARG1 (a2 / and
            :op1 (r2 / rate
                  :degree-of (p / proliferate-01
                        :ARG0 (t / tumor
                              :ARG1-of (t2 / treat-04)))
                  :ARG1-of (d / decrease-01)
                  :ARG1-of (m2 / mean-01
                        :ARG2 (e / express-03
                              :ARG2 (p2 / protein :name (n / name :op1 "Ki-67"))
                              :ARG1-of (l / low-04
                                    :degree (m / more)
                                    :ARG1-of (c / compare-01
                                          :ARG2 (t3 / tumor
                                                :mod (c2 / control)))))))
            :op2 (a3 / activate-01
                  :ARG1 (p3 / pathway :name (n2 / name :op1 "Mek/Erk"))
                  :ARG1-of (r3 / reduce-01)
                  :ARG1-of (m3 / mean-01
                        :ARG2 (p4 / phosphorylate-01
                              :ARG1 (e2 / enzyme :name (n3 / name :op1 "Erk"))
                              :ARG1-of (l2 / low-04
                                    :degree m)))))
      :ARG1-of (d2 / describe-01
            :ARG0 (f / figure :mod "4B")))

# ::id pmid_2423_8212.153 ::date 2015-08-30T15:22:02 ::annotator SDL-AMR-09 ::preferred
# ::snt In addition, staining with murine CD34 antibody demonstrated a strong inhibitory effect of PD0325901 on tumor vascularization, as control tumors contained large vessels, while treated tumors displayed drastically compromised vasculature composed by minuscule vessels (Figure <xref ref-type="fig" rid="F4">4</xref>B).
# ::save-date Tue Feb 2, 2016 ::file pmid_2423_8212_153.txt
(a2 / and
      :op2 (d / demonstrate-01
            :ARG0 (s / stain-01
                  :ARG2 (a3 / antibody
                        :ARG0-of (c2 / counter-01
                              :ARG1 (p / protein :name (n / name :op1 "CD34")
                                    :mod (o / organism :name (n3 / name :op1 "Muridae"))))))
            :ARG1 (a / affect-01
                  :ARG0 (s2 / small-molecule :name (n2 / name :op1 "PD0325901"))
                  :ARG1 (v / vascularize-01
                        :ARG1 (t / tumor))
                  :ARG2 (i / inhibit-01)
                  :ARG1-of (s3 / strong-02)
                  :ARG1-of (c / cause-01
                        :ARG0 (c7 / contrast-01
                              :ARG1 (c3 / contain-01
                                    :ARG0 (t2 / tumor
                                          :mod (c4 / control))
                                    :ARG1 (v2 / vessel
                                          :mod (l / large)))
                              :ARG2 (d2 / display-01
                                    :ARG0 (t3 / tumor
                                          :ARG1-of (t4 / treat-04))
                                    :ARG1 (v3 / vasculature
                                          :ARG1-of (c5 / compromise-02
                                                :manner (d3 / drastic))
                                          :ARG1-of (c6 / compose-01
                                                :ARG2 (v4 / vessel
                                                      :mod (m / minuscule)))))))))
      :ARG1-of (d4 / describe-01
            :ARG0 (f / figure :mod "4B")))

# ::id pmid_2423_8212.154 ::date 2015-08-30T15:35:30 ::annotator SDL-AMR-09 ::preferred
# ::snt A decrease of tumor vascularization appeared also by macroscopic observation of the tumors (Additional file <xref ref-type="supplementary-material" rid="S5">5</xref>: Figure S3A).
# ::save-date Tue Feb 2, 2016 ::file pmid_2423_8212_154.txt
(a / appear-01
      :ARG1 (d / decrease-01
            :ARG1 (v / vascularize-01
                  :ARG1 (t / tumor)))
      :mod (a2 / also)
      :manner (o / observe-01
            :ARG1 t
            :mod (m / macroscopy))
      :ARG1-of (d2 / describe-01
            :ARG0 (f / figure :mod "S3A"
                  :part-of (f2 / file :mod 5
                        :mod (a3 / additional)))))

# ::id pmid_2423_8212.155 ::date 2015-08-30T15:38:14 ::annotator SDL-AMR-09 ::preferred
# ::snt Importantly, similar results were obtained when xenografts were generated by wild type-BRAF melanospheres indicating that this strategy might constitute a potentially exploitable therapeutic approach both for mutated-BRAF and wild type-BRAF melanoma patients (Figure <xref ref-type="fig" rid="F4">4</xref>C and D).
# ::save-date Thu Feb 4, 2016 ::file pmid_2423_8212_155.txt
(o / obtain-01
      :ARG1 (t / thing
            :ARG2-of (r / result-01)
            :ARG1-of (r2 / resemble-01))
      :time (g / generate-01
            :ARG0 (c / cell :wiki - :name (n / name :op1 "melanosphere")
                  :mod (e3 / enzyme :wiki - :name (n2 / name :op1 "BRAF")
                        :mod (w / wild-type)))
            :ARG1 (x / xenograft))
      :ARG0-of (i / indicate-01
            :ARG1 (p / possible-01
                  :ARG1 (c2 / constitute-01
                        :ARG0 (s / strategy
                              :mod (t2 / this))
                        :ARG1 (a / approach-02
                              :ARG1-of (e / exploit-01
                                    :ARG1-of (p2 / possible-01)
                                    :manner (p5 / potential))
                              :mod (t3 / therapy)
                              :beneficiary (a4 / and
                                    :op1 (p3 / person
                                          :ARG0-of (h2 / have-rel-role-91
                                                :ARG2 (p6 / patient))
                                          :mod (m2 / medical-condition :wiki "Melanoma" :name (n3 / name :op1 "melanoma")
                                                :mod (e2 / enzyme :wiki - :name (n4 / name :op1 "BRAF")
                                                      :ARG2-of (m / mutate-01))))
                                    :op2 (p4 / person
                                          :ARG0-of (h3 / have-rel-role-91
                                                :ARG2 p6)
                                          :mod (m3 / medical-condition :wiki "Melanoma" :name (n5 / name :op1 "melanoma")
                                                :mod e3)))))))
      :mod (i2 / important)
      :ARG1-of (d3 / describe-01
            :ARG0 (a2 / and
                  :op1 (f2 / figure :mod "4C")
                  :op2 (f3 / figure :mod "4D"))))

# ::id pmid_2423_8212.156 ::date 2015-08-30T15:46:34 ::annotator SDL-AMR-09 ::preferred
# ::snt Immunoblot analysis showed that VEGF levels were lower in treated-melanospheres (Figure <xref ref-type="fig" rid="F4">4</xref>E) and immunohistochemistry analysis showed that PD0325901-treated xenografts expressed reduced levels of VEGF in comparison with control tumors (Figure <xref ref-type="fig" rid="F4">4</xref>F).
# ::save-date Sat Sep 12, 2015 ::file pmid_2423_8212_156.txt
(a / and
      :op1 (s / show-01
            :ARG0 (a2 / analyze-01
                  :mod (i / immunoblot-01))
            :ARG1 (l / level
                  :quant-of (p / protein :name (n / name :op1 "VEGF"))
                  :ARG1-of (l2 / low-04
                        :degree (m / more))
                  :location (c / cell :name (n2 / name :op1 "melanosphere")
                        :ARG1-of (t / treat-04))
                  :ARG1-of (d / describe-01
                        :ARG0 (f / figure :mod "4E"))))
      :op2 (s2 / show-01
            :ARG0 (a3 / analyze-01
                  :mod (i2 / immunohistochemistry))
            :ARG1 (e / express-03
                  :ARG2 (l3 / level
                        :quant-of p
                        :ARG1-of (r / reduce-01)
                        :ARG1-of (c2 / compare-01
                              :ARG2 (t3 / tumor
                                    :mod (c3 / control))))
                  :ARG3 (x / xenograft
                        :ARG1-of (t2 / treat-04
                              :ARG2 (s3 / small-molecule :name (n3 / name :op1 "PD0325901"))))
                  :ARG1-of (d2 / describe-01
                        :ARG0 (f2 / figure :mod "4F")))))

# ::id pmid_2423_8212.157 ::date 2015-08-30T16:36:39 ::annotator SDL-AMR-09 ::preferred
# ::snt These results were obtained both for mutated BRAF and wild type BRAF melanospheres and xenografts and suggest that Mek inhibition might determine, together with a direct cytotoxic/cytostatic effect on tumor cells, a reduction of the tumor cell-dependent pro-angiogenic activity <i>in vivo.</i>
# ::save-date Sat Jan 16, 2016 ::file pmid_2423_8212_157.txt
(a / and
      :op1 (o / obtain-01
            :ARG1 (t / thing
                  :ARG2-of (r / result-01)
                  :mod (t2 / this))
            :beneficiary (a2 / and
                  :op1 (a3 / and
                        :op1 (c / cell :name (n / name :op1 "melanosphere")
                              :mod (e2 / enzyme :name (n2 / name :op1 "BRAF")
                                    :ARG2-of (m / mutate-01)))
                        :op2 (c2 / cell :name (n3 / name :op1 "melanosphere")
                              :mod (e / enzyme :name (n4 / name :op1 "BRAF")
                                    :mod (w / wild-type))))
                  :op2 (x / xenograft)))
      :op2 (s / suggest-01
            :ARG0 t
            :ARG1 (p / possible-01
                  :ARG1 (d / determine-01
                        :ARG0 (i / inhibit-01
                              :ARG1 (e3 / enzyme :name (n5 / name :op1 "Mek"))
                              :ARG1-of (a4 / accompany-01
                                    :ARG0 (a5 / affect-01
                                          :ARG1 (c5 / cell
                                                :mod (t3 / tumor))
                                          :ARG2 (o2 / or
                                                :op1 (c3 / cytotoxicity)
                                                :op2 (c4 / cytostasis))
                                          :ARG1-of (d2 / direct-02))))
                        :ARG1 (r2 / reduce-01
                              :ARG1 (a6 / activity-06
                                    :ARG0-of (d3 / depend-01
                                          :ARG1 c5)
                                    :manner (i2 / in-vivo)
                                    :ARG0-of (f / favor-01
                                          :ARG1 (a7 / angiogenesis))))))))

# ::id pmid_2456_8222.1 ::date 2015-08-25T10:59:34 ::annotator SDL-AMR-09 ::preferred
# ::snt Targeting the prohibitin scaffold-CRAF kinase interaction in RAS-ERK-driven pancreatic ductal adenocarcinoma (PMID:24568222)
# ::save-date Mon Nov 23, 2015 ::file pmid_2456_8222_1.txt
(t / target-01
      :ARG1 (i / interact-01
            :ARG0 (p5 / protein :name (n3 / name :op1 "prohibitin")
                  :mod (s / scaffold))
            :ARG1 (k / kinase :name (n / name :op1 "CRAF"))
            :location (a / adenocarcinoma
                  :ARG1-of (d2 / drive-02
                        :ARG0 (p / pathway :name (n4 / name :op1 "RAS-ERK")))
                  :mod (d4 / duct
                        :part-of (p2 / pancreas))))
      :ARG1-of (d3 / describe-01
            :ARG0 (p3 / publication-91
                  :ARG8 "PMID24568222")))

# ::id pmid_2456_8222.9 ::date 2015-08-25T11:25:48 ::annotator SDL-AMR-09 ::preferred
# ::snt <sec-title level="1" sec-area="abstract">Results</sec-title>
# ::save-date Tue Aug 25, 2015 ::file pmid_2456_8222_9.txt
(t / thing
      :ARG2-of (r / result-01))

# ::id pmid_2456_8222.10 ::date 2015-08-25T11:28:27 ::annotator SDL-AMR-09 ::preferred
# ::snt The level of PHB expression was crucial for maintenance of oncogenic ERK-driven pancreatic tumorigenesis.
# ::save-date Sun Jan 17, 2016 ::file pmid_2456_8222_10.txt
(c / crucial
      :domain (l / level
            :mod (e / express-03
                  :ARG2 (p2 / protein :name (n / name :op1 "PHB"))))
      :purpose (m / maintain-01
            :ARG1 (c4 / create-01
                  :ARG1 (t / tumor
                        :mod (p / pancreas))
                  :ARG1-of (d / drive-02
                        :ARG0 (e2 / enzyme :name (n2 / name :op1 "ERK")
                              :ARG0-of (c2 / cause-01
                                    :ARG1 (c3 / cancer)))))))

# ::id pmid_2456_8222.11 ::date 2015-08-25T11:40:48 ::annotator SDL-AMR-09 ::preferred
# ::snt Additionally, rocaglamide (RocA), a small molecular inhibitor, selectively bound to PHB with nanomolar affinity to disrupt the PHB-CRAF interaction by altering its localization to the plasma membrane.
# ::save-date Tue Sep 15, 2015 ::file pmid_2456_8222_11.txt
(a / and
      :op2 (b / bind-01
            :ARG1 (s3 / small-molecule :name (n2 / name :op1 "rocaglamide")
                  :ARG1-of (m2 / mean-01
                        :ARG2 (s4 / small-molecule
                              :ARG0-of (i / inhibit-01))))
            :ARG2 (p2 / protein :name (n / name :op1 "PHB"))
            :mod (s / selective)
            :manner (a2 / affinity
                  :prep-to (d / disrupt-01
                        :ARG0 (r / rocaglamide)
                        :ARG1 (i2 / interact-01
                              :ARG0 p2
                              :ARG1 (e / enzyme :name (n4 / name :op1 "CRAF")))
                        :manner (a3 / alter-01
                              :ARG0 s3
                              :ARG1 (b2 / be-located-at-91
                                    :ARG1 i2
                                    :ARG2 (m3 / membrane
                                          :mod (p / plasma)))))
                  :mod (n3 / nanomolar))))

# ::id pmid_2456_8222.12 ::date 2015-08-25T12:07:46 ::annotator SDL-AMR-09 ::preferred
# ::snt Consequently, there was an impairment of oncogenic RAS-ERK signaling, thereby blocking <i>in vitro</i> and <i>in vivo</i> growth and metastasis of pancreatic cancer cells that were addicted to RAS-ERK signaling.
# ::save-date Wed Aug 26, 2015 ::file pmid_2456_8222_12.txt
(c / cause-01
      :ARG1 (i / impair-01
            :ARG1 (s / signal-07
                  :ARG0 (p2 / pathway :name (n / name :op1 "RAS-ERK")
                        :ARG0-of (c2 / cause-01
                              :ARG1 (c3 / cancer)))
                  :ARG0-of (c4 / cause-01
                        :ARG1 (b / block-01
                              :ARG1 (a / and
                                    :op1 (g / grow-01
                                          :ARG1 (c5 / cell
                                                :mod (c6 / cancer)
                                                :mod (p / pancreas)
                                                :ARG1-of (a3 / addict-01
                                                      :ARG2 s))
                                          :manner (a2 / and
                                                :op1 (i2 / in-vitro)
                                                :op2 (i3 / in-vivo)))
                                    :op2 (m / metastasize-101
                                          :ARG1 c5)))))))

# ::id pmid_2456_8222.13 ::date 2015-08-25T12:31:03 ::annotator SDL-AMR-09 ::preferred
# ::snt More importantly, RocA treatment resulted in a significant increase of the lifespan of tumor-bearing mice without any detectable toxicity.
# ::save-date Tue Sep 15, 2015 ::file pmid_2456_8222_13.txt
(r / result-01
      :ARG1 (t / treat-04
            :ARG2 (s2 / small-molecule :name (n / name :op1 "rocaglamide")))
      :ARG2 (i / increase-01
            :ARG1 (l / lifespan
                  :duration-of (l3 / live-01
                        :ARG0 (m / mouse
                              :ARG0-of (b / bear-01
                                    :ARG1 (t3 / tumor)))))
            :ARG1-of (s / significant-02))
      :mod (i2 / important
            :degree (m2 / more))
      :manner (t2 / toxicity :polarity -
            :ARG1-of (d3 / detect-01
                  :ARG1-of (p / possible-01))))

# ::id pmid_2456_8222.39 ::date 2015-08-25T12:45:48 ::annotator SDL-AMR-09 ::preferred
# ::snt <sec-title level="1">Results</sec-title>
# ::save-date Tue Aug 25, 2015 ::file pmid_2456_8222_39.txt
(t / thing
      :ARG2-of (r / result-01))

# ::id pmid_2456_8222.40 ::date 2015-08-25T12:57:36 ::annotator SDL-AMR-09 ::preferred
# ::snt <sec-title level="2">Expression and localization of PHB in pancreatic cancer cells and tissue</sec-title>
# ::save-date Mon Aug 31, 2015 ::file pmid_2456_8222_40.txt
(a / and
      :op1 (e / express-03
            :ARG2 (p2 / protein :name (n / name :op1 "PHB")))
      :op2 (b / be-located-at-91
            :ARG1 p2
            :ARG2 (a2 / and
                  :op1 (c / cell
                        :mod (p / pancreas)
                        :mod (c2 / cancer))
                  :op2 (t / tissue
                        :mod p
                        :mod c2))))

# ::id pmid_2456_8222.41 ::date 2015-08-25T13:04:03 ::annotator SDL-AMR-09 ::preferred
# ::snt To investigate the role of PHB in pancreatic cancer cells, we first chose two human pancreatic cancer cell lines, AsPC-1 (high malignancy) and Capan-2 (low malignancy).
# ::save-date Mon Aug 31, 2015 ::file pmid_2456_8222_41.txt
(c / choose-01
      :ARG0 (w / we)
      :ARG1 (c2 / cell-line :quant 2
            :mod (c3 / cancer)
            :mod (p / pancreas)
            :ARG1-of (m / mean-01
                  :ARG2 (a / and
                        :op1 (c4 / cell-line :name (n / name :op1 "AsPC-1")
                              :ARG0-of (h3 / have-03
                                    :ARG1 (m2 / malignancy
                                          :ARG1-of (h2 / high-02))))
                        :op1 (c5 / cell-line :name (n2 / name :op1 "Capan-2")
                              :ARG0-of (h4 / have-03
                                    :ARG1 (m3 / malignancy
                                          :ARG1-of (l / low-04))))))
            :part-of (h / human))
      :purpose (i / investigate-01
            :ARG0 w
            :ARG1 (r / role
                  :poss (p2 / protein :name (n3 / name :op1 "PHB"))
                  :location (c6 / cell
                        :mod (p3 / pancreas)
                        :mod (c7 / cancer))))
      :ord (o2 / ordinal-entity :value 1))

# ::id pmid_2456_8222.42 ::date 2015-08-25T20:29:15 ::annotator SDL-AMR-09 ::preferred
# ::snt Interestingly, AsPC-1 cells grew as single cells (Figure <xref ref-type="fig" rid="F1">1</xref>A, left), whereas Capan-2 cells exhibited tiny islands of densely packed cells (Figure <xref ref-type="fig" rid="F1">1</xref>A, right).
# ::save-date Sat Jan 30, 2016 ::file pmid_2456_8222_42.txt
(c / contrast-01
      :ARG1 (g / grow-01
            :ARG1 (c2 / cell-line :name (n / name :op1 "AsPC-1"))
            :ARG4 (c3 / cell
                  :ARG1-of (s / single-02))
            :ARG1-of (d / describe-01
                  :ARG0 (f / figure :mod "1A"
                        :ARG1-of (l / left-20))))
      :ARG2 (e / exhibit-01
            :ARG0 (c4 / cell-line :name (n2 / name :op1 "Capan-2"))
            :ARG1 (i / island
                  :mod (t / tiny)
                  :consist-of (c6 / cell
                        :ARG2-of (p / pack-01
                              :manner (d2 / dense))))
            :ARG1-of (d3 / describe-01
                  :ARG0 (f2 / figure :mod "1A"
                        :ARG1-of (r / right-04))))
      :ARG2-of (i2 / interest-01))

# ::id pmid_2456_8222.43 ::date 2015-08-25T20:37:43 ::annotator SDL-AMR-09 ::preferred
# ::snt Additionally, AsPC-1 cells exhibited much higher growth and migration capacities than those of Capan-2 cells (Additional file <xref ref-type="supplementary-material" rid="S1">1</xref>: Figure S1A,B).
# ::save-date Tue Sep 15, 2015 ::file pmid_2456_8222_43.txt
(a / and
      :op2 (e / exhibit-01
            :ARG0 (c / cell-line :name (n / name :op1 "AsPC-1"))
            :ARG1 (a2 / and
                  :op1 (g / grow-01
                        :ARG1-of (h / high-02
                              :degree (m / more
                                    :quant (m2 / much))))
                  :op2 (c2 / capable-01
                        :ARG2 (m3 / migrate-01)
                        :ARG1-of (h2 / high-02)))
            :compared-to (c3 / cell-line :name (n2 / name :op1 "Capan-2")))
      :ARG1-of (d / describe-01
            :ARG0 (f / file :mod 1
                  :mod (a3 / additional)
                  :part (a4 / and
                        :op1 (f2 / figure :mod "S1A")
                        :op2 (f3 / figure :mod "S1B")))))

# ::id pmid_2456_8222.44 ::date 2015-08-25T20:49:06 ::annotator SDL-AMR-09 ::preferred
# ::snt RT-PCR showed a difference in PHB mRNA expression levels, revealing higher expression in AsPC-1 cells than that in Capan-2 cells (Figure <xref ref-type="fig" rid="F1">1</xref>B and Additional file <xref ref-type="supplementary-material" rid="S1">1</xref>: Figure S2A).
# ::save-date Sun Jan 3, 2016 ::file pmid_2456_8222_44.txt
(s / show-01
      :ARG0 (t / thing :name (n / name :op1 "RT-PCR"))
      :ARG1 (d / differ-02
            :ARG1 (l / level
                  :degree-of (e / express-03
                        :ARG2 (n4 / nucleic-acid :name (n6 / name :op1 "RNA")
                              :ARG0-of (e4 / encode-01
                                    :ARG1 (p / protein :name (n2 / name :op1 "PHB")))))))
      :ARG0-of (r2 / reveal-01
            :ARG1 (e2 / express-03
                  :ARG3 (c / cell-line :name (n3 / name :op1 "AsPC-1"))
                  :ARG1-of (h / high-02
                        :degree (m2 / more)
                        :compared-to (e3 / express-03
                              :ARG3 (c2 / cell-line :name (n5 / name :op1 "Capan-2"))))))
      :ARG1-of (d2 / describe-01
            :ARG0 (a / and
                  :op1 (f / figure :mod "1B")
                  :op2 (f2 / file
                        :mod (a2 / additional)
                        :part (f3 / figure :mod "S2A")))))

# ::id pmid_2456_8222.45 ::date 2015-08-25T21:03:16 ::annotator SDL-AMR-09 ::preferred
# ::snt In agreement with RT-PCR data, immunoblot analysis also demonstrated high expression of PHB protein in AsPC-1 cells, but little expression in Capan-2 cells (Figure <xref ref-type="fig" rid="F1">1</xref>C and Additional file <xref ref-type="supplementary-material" rid="S1">1</xref>: Figure S2B).
# ::save-date Tue Sep 15, 2015 ::file pmid_2456_8222_45.txt
(d / demonstrate-01
      :ARG0 (a / analyze-01
            :mod (i / immunoblot-01))
      :ARG1 (c2 / contrast-01
            :ARG1 (e / express-03
                  :ARG2 (p / protein :name (n / name :op1 "PHB"))
                  :ARG3 (c / cell-line :name (n2 / name :op1 "AsPC-1"))
                  :ARG1-of (h / high-02))
            :ARG2 (e2 / express-03
                  :ARG3 (c3 / cell-line :name (n3 / name :op1 "Capan-2"))
                  :mod (l / little)))
      :mod (a2 / also)
      :ARG1-of (a3 / agree-01
            :ARG2 (d2 / data
                  :mod (t / thing :name (n4 / name :op1 "RT-PCR"))))
      :ARG1-of (d3 / describe-01
            :ARG0 (a4 / and
                  :op1 (f / figure :mod "1C")
                  :op2 (f2 / file
                        :mod (a5 / additional)
                        :part (f3 / figure :mod "S2B")))))

# ::id pmid_2456_8222.46 ::date 2015-08-25T21:13:36 ::annotator SDL-AMR-09 ::preferred
# ::snt Intriguingly, localization of PHB in AsPC-1 cells was mainly in the plasma membrane and cytosol, whereas its localization was in Capan-2 cells (Figure <xref ref-type="fig" rid="F1">1</xref>D,E).
# ::save-date Tue Sep 15, 2015 ::file pmid_2456_8222_46.txt
(c2 / contrast-01
      :ARG1 (b / be-located-at-91
            :ARG1 p2
            :ARG2 (a / and
                  :op1 (m / membrane
                        :mod (p / plasma))
                  :op2 (c / cytosol)
                  :part-of (c3 / cell-line :name (n2 / name :op1 "AsPC-1")))
            :mod (m2 / main)
            :ARG0-of (i / intrigue-01)
            :ARG1-of (d / describe-01
                  :ARG0 (a2 / and
                        :op1 (f / figure :mod "1D")
                        :op2 (f2 / figure :mod "1E"))))
      :ARG2 (b3 / be-located-at-91
            :ARG1 (p2 / protein :name (n / name :op1 "PHB"))
            :ARG2 (c4 / cell-line :name (n3 / name :op1 "Capan-2"))))

# ::id pmid_2456_8222.47 ::date 2015-08-25T21:23:22 ::annotator SDL-AMR-09 ::preferred
# ::snt This result indicated that the observed phenotypes may correlate with the expression and localization of PHB protein.
# ::save-date Tue Sep 1, 2015 ::file pmid_2456_8222_47.txt
(i / indicate-01
      :ARG0 (t / thing
            :ARG2-of (r / result-01)
            :mod (t2 / this))
      :ARG1 (p / possible-01
            :ARG1 (c / correlate-01
                  :ARG1 (p2 / phenotype
                        :ARG1-of (o / observe-01))
                  :ARG2 (a / and
                        :op1 (e / express-03
                              :ARG2 (p3 / protein :name (n / name :op1 "PHB")))
                        :op2 (b / be-located-at-91
                              :ARG1 p3)))))

# ::id pmid_2456_8222.48 ::date 2015-08-25T21:27:03 ::annotator SDL-AMR-09 ::preferred
# ::snt Therefore, AsPC-1 cells were chosen to investigate the biological properties of PHB in pancreatic cancer both <i>in vitro</i> and <i>in vivo</i>.
# ::save-date Tue Sep 1, 2015 ::file pmid_2456_8222_48.txt
(c / cause-01
      :ARG1 (c2 / choose-01
            :ARG1 (c3 / cell-line :name (n / name :op1 "AsPC-1"))
            :purpose (i / investigate-01
                  :ARG1 (p / property
                        :mod (b / biological)
                        :poss (p2 / protein :name (n2 / name :op1 "PHB")
                              :topic (c4 / cancer
                                    :mod (p3 / pancreas))))
                  :manner (a / and
                        :op1 (i2 / in-vitro)
                        :op2 (i3 / in-vivo)
                        :mod (b2 / both)))))

# ::id pmid_2456_8222.49 ::date 2015-08-25T21:41:35 ::annotator SDL-AMR-09 ::preferred
# ::snt We next assessed PHB expression in pancreatic tissue.
# ::save-date Wed Aug 26, 2015 ::file pmid_2456_8222_49.txt
(a / assess-01
      :ARG0 (w / we)
      :ARG1 (e / express-03
            :ARG2 (p / protein :name (n2 / name :op1 "PHB"))
            :ARG3 (t / tissue
                  :mod (p2 / pancreas)))
      :time (n / next))

# ::id pmid_2456_8222.50 ::date 2015-08-26T09:48:50 ::annotator SDL-AMR-09 ::preferred
# ::snt PHB protein was weakly expressed in 63.6% of normal pancreas samples (n = 11) (Figure <xref ref-type="fig" rid="F1">1</xref>F,G).
# ::save-date Sat Jan 30, 2016 ::file pmid_2456_8222_50.txt
(e / express-03
      :ARG2 (p2 / protein :name (n / name :op1 "PHB"))
      :ARG3 (s / sample
            :ARG1-of (i / include-91
                  :ARG2 (s2 / sample :quant 11
                        :mod (p3 / pancreas)
                        :ARG1-of (n2 / normal-02))
                  :ARG3 (p / percentage-entity :value 63.6)))
      :degree (w / weak-02)
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod "1F" :mod "1G")))

# ::id pmid_2456_8222.51 ::date 2015-08-26T09:58:17 ::annotator SDL-AMR-09 ::preferred
# ::snt However, PHB protein was strongly expressed in 58.7% of PDAC samples (n = 46) (Figure <xref ref-type="fig" rid="F1">1</xref>F,G and Additional file <xref ref-type="supplementary-material" rid="S1">1</xref>: Figure S3).
# ::save-date Tue Sep 15, 2015 ::file pmid_2456_8222_51.txt
(c / contrast-01
      :ARG2 (e / express-03
            :ARG2 (p2 / protein :name (n / name :op1 "PHB"))
            :ARG3 (s2 / sample
                  :ARG1-of (i / include-91
                        :ARG2 (s3 / sample :quant 46
                              :mod (a / adenocarcinoma
                                    :mod (d3 / duct
                                          :part-of (p3 / pancreas))))
                        :ARG3 (p / percentage-entity :value 58.7)))
            :ARG1-of (s / strong-02))
      :ARG1-of (d2 / describe-01
            :ARG0 (a2 / and
                  :op1 (f / figure :mod "1F" :mod "1G")
                  :op2 (f2 / file :mod 1
                        :mod (a3 / additional)
                        :part (f3 / figure :mod "S3")))))

# ::id pmid_2456_8222.52 ::date 2015-08-26T10:06:49 ::annotator SDL-AMR-09 ::preferred
# ::snt Taken together, these results show that PHB, which becomes more pronounced with pancreatic cancer malignancy, may serve as a therapeutic target in pancreatic cancer.
# ::save-date Tue Sep 1, 2015 ::file pmid_2456_8222_52.txt
(s / show-01
      :ARG0 (t / thing
            :ARG2-of (r / result-01)
            :ARG1-of (t2 / take-04
                  :mod (t3 / together))
            :mod (t6 / this))
      :ARG1 (p / possible-01
            :ARG1 (s2 / serve-01
                  :ARG0 (p2 / protein :name (n2 / name :op1 "PHB")
                        :ARG1-of (b / become-01
                              :ARG2 (p4 / pronounced-02
                                    :degree (m2 / more)
                                    :condition (m3 / malignant-02
                                          :ARG1 (p5 / pancreas)
                                          :ARG2 (c2 / cancer)))))
                  :ARG2 (t4 / target-01
                        :ARG1 p2
                        :mod (t5 / therapy)
                        :condition (c / cancer
                              :mod (p3 / pancreas))))))

# ::id pmid_2456_8222.53 ::date 2015-08-26T10:18:51 ::annotator SDL-AMR-09 ::preferred
# ::snt <sec-title level="2">PHB is indispensable for EGF-induced ERK activation in pancreatic cancer cells</sec-title>
# ::save-date Sun Jan 17, 2016 ::file pmid_2456_8222_53.txt
(i / indispensable-01
      :ARG1 (p2 / protein :name (n3 / name :op1 "PHB"))
      :ARG2 (a / activate-01
            :ARG1 (e / enzyme :name (n / name :op1 "ERK")
                  :ARG2-of (i2 / induce-01
                        :ARG0 (p4 / protein :name (n4 / name :op1 "EGF"))))
            :location (c / cell
                  :mod (c2 / cancer
                        :mod (p3 / pancreas)))))

# ::id pmid_2456_8222.54 ::date 2015-08-26T10:25:01 ::annotator SDL-AMR-09 ::preferred
# ::snt The duration of ERK activity is a crucial factor in diverse biological processes that determine cell fate decisions [<xref ref-type="bibr" rid="B18">18</xref>].
# ::save-date Sun Jan 17, 2016 ::file pmid_2456_8222_54.txt
(f / factor
      :mod (c / crucial)
      :domain (d / duration
            :duration-of (a / activity-06
                  :ARG0 (e / enzyme :name (n / name :op1 "ERK"))))
      :topic (p2 / process-01
            :mod (b / biological)
            :mod (d2 / diverse)
            :ARG0-of (d3 / determine-01
                  :ARG1 (d4 / decide-01
                        :ARG1 (f2 / fate-01
                              :ARG1 (c2 / cell)))))
      :ARG1-of (d5 / describe-01
            :ARG0 (p3 / publication
                  :ARG1-of (c3 / cite-01
                        :ARG2 18))))

# ::id pmid_2456_8222.55 ::date 2015-08-26T10:33:57 ::annotator SDL-AMR-09 ::preferred
# ::snt ERK is phosphorylated and activated by MEK in response to growth factor stimulation, and then activated ERK phosphorylates and activates nuclear targets to up-regulate immediate-early genes [<xref ref-type="bibr" rid="B19">19</xref>].
# ::save-date Sun Jan 17, 2016 ::file pmid_2456_8222_55.txt
(a6 / and
      :op1 (a / and
            :op1 (p3 / phosphorylate-01
                  :ARG1 (e3 / enzyme :name (n / name :op1 "ERK"))
                  :ARG2 (e / enzyme :name (n4 / name :op1 "MEK")))
            :op2 (a2 / activate-01
                  :ARG0 e
                  :ARG1 e3)
            :ARG2-of (r / respond-01
                  :ARG1 (s / stimulate-01
                        :ARG0 (p / protein :name (n5 / name :op1 "growth-factor")))))
      :op2 (a4 / and
            :op1 (p2 / phosphorylate-01
                  :ARG1 (m / molecular-physical-entity
                        :ARG1-of (t / target-01)
                        :mod (n3 / nucleus))
                  :ARG2 (e4 / enzyme :name (n2 / name :op1 "ERK")
                        :ARG1-of (a3 / activate-01)))
            :op2 (a5 / activate-01
                  :ARG0 e4
                  :ARG1 m)
            :purpose (u2 / upregulate-01
                  :ARG1 (g2 / gene
                        :mod (e2 / early
                              :mod (i / immediate)))
                  :ARG2 e4)
            :time (t2 / then))
      :ARG1-of (d / describe-01
            :ARG0 (p5 / publication
                  :ARG1-of (c / cite-01
                        :ARG2 19))))

# ::id pmid_2456_8222.56 ::date 2015-08-26T11:10:16 ::annotator SDL-AMR-09 ::preferred
# ::snt Therefore, we determined the expression levels of p-ERK1/2 in AsPC-1 and Capan-2 cells.
# ::save-date Tue Sep 1, 2015 ::file pmid_2456_8222_56.txt
(c / cause-01
      :ARG1 (d / determine-01
            :ARG0 (w / we)
            :ARG1 (l / level
                  :degree-of (e / express-03
                        :ARG2 (e2 / enzyme :name (n4 / name :op1 "ERK1/2")
                              :ARG3-of (p2 / phosphorylate-01))
                        :ARG3 (a / and
                              :op1 (c2 / cell-line :name (n2 / name :op1 "AsPC-1"))
                              :op2 (c3 / cell-line :name (n3 / name :op1 "Capan-2")))))))

# ::id pmid_2456_8222.57 ::date 2015-08-26T11:19:44 ::annotator SDL-AMR-09 ::preferred
# ::snt Intriguingly, the phosphorylation status of ERK2 was much higher than that of ERK1 in AsPC-1 cells, and this phenomenon was completely converse in Capan-2 cells (Figure <xref ref-type="fig" rid="F2">2</xref>A).
# ::save-date Tue Sep 15, 2015 ::file pmid_2456_8222_57.txt
(a / and
      :op1 (h / high-02
            :ARG1 (s / status
                  :mod (p / phosphorylate-01
                        :ARG1 (e / enzyme :name (n5 / name :op1 "ERK2"))))
            :degree (m / more
                  :quant (m2 / much))
            :compared-to (s2 / status
                  :location (c / cell-line :name (n3 / name :op1 "AsPC-1"))
                  :mod (p2 / phosphorylate-01
                        :ARG1 (e2 / enzyme :name (n / name :op1 "ERK1")))))
      :op2 (c5 / converse
            :domain (p3 / phenomenon
                  :mod (t / this))
            :ARG1-of (c3 / complete-02)
            :location (c4 / cell-line :name (n4 / name :op1 "Capan-2")))
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod "2A"))
      :ARG0-of (i / intrigue-01))

# ::id pmid_2456_8222.58 ::date 2015-08-26T11:30:03 ::annotator SDL-AMR-09 ::preferred
# ::snt This observation suggests distinct roles of ERK1 and ERK2 in the regulation of cell behavior in AsPC-1 and Capan-2 cells.
# ::save-date Tue Sep 1, 2015 ::file pmid_2456_8222_58.txt
(s / suggest-01
      :ARG0 (o / observe-01
            :mod (t / this))
      :ARG1 (r / roles
            :mod (d / distinct)
            :topic (r2 / regulate-01
                  :ARG1 (b / behave-01
                        :ARG0 (c / cell)
                        :location (a2 / and
                              :op1 (c2 / cell-line :name (n3 / name :op1 "AsPC-1"))
                              :op2 (c3 / cell-line :name (n4 / name :op1 "Capan-2")))))
            :poss (a / and
                  :op1 (e / enzyme :name (n / name :op1 "ERK1"))
                  :op2 (e2 / enzyme :name (n2 / name :op1 "ERK2")))))

# ::id pmid_2456_8222.59 ::date 2015-08-26T11:35:06 ::annotator SDL-AMR-09 ::preferred
# ::snt To test whether PHB is required for the ERK pathway, we validated a siRNA against PHB (siPHB) in AsPC-1 and Panc-1 cells by quantitative real-time PCR.
# ::save-date Sun Jan 17, 2016 ::file pmid_2456_8222_59.txt
(v / validate-01
      :ARG0 (w / we)
      :ARG1 (n3 / nucleic-acid :name (n2 / name :op1 "siRNA")
            :ARG0-of (o / oppose-01
                  :ARG1 p))
      :location (a / and
            :op1 (c / cell-line :name (n4 / name :op1 "AsPC-1"))
            :op2 (c2 / cell-line :name (n5 / name :op1 "Panc-1")))
      :manner (r / react-01
            :ARG0 (p2 / polymerase)
            :mod (q / quantitative)
            :mod (r2 / real-time)
            :ARG1-of (c3 / chain-01))
      :purpose (t2 / test-01
            :ARG0 w
            :ARG1 (r3 / require-01 :mode interrogative
                  :ARG0 (p3 / pathway :name (n7 / name :op1 "ERK"))
                  :ARG1 (p / protein :name (n / name :op1 "PHB")))))

# ::id pmid_2456_8222.60 ::date 2015-08-26T12:32:44 ::annotator SDL-AMR-09 ::preferred
# ::snt The results showed that siPHB reduced the PHB mRNA level by about 80% compared with that using control siRNA (siCon) (Additional file <xref ref-type="supplementary-material" rid="S1">1</xref>: Figure S4A,B).
# ::save-date Mon Dec 21, 2015 ::file pmid_2456_8222_60.txt
(s / show-01
      :ARG0 (t / thing
            :ARG2-of (r / result-01))
      :ARG1 (r2 / reduce-01
            :ARG0 (n4 / nucleic-acid :name (n6 / name :op1 "siRNA")
                  :mod p2)
            :ARG1 (l / level
                  :quant-of (n2 / nucleic-acid :name (n5 / name :op1 "mRNA")
                        :mod (p2 / protein :name (n / name :op1 "PHB"))))
            :ARG2 (a / about
                  :quant (p / percentage-entity :value 80
                        :compared-to (l2 / level
                              :condition (u / use-01
                                    :ARG1 (n7 / nucleic-acid :name (n3 / name :op1 "siRNA")
                                          :ARG0-of (c / control-01)))))))
      :ARG1-of (d / describe-01
            :ARG0 (f / file
                  :mod (a2 / additional)
                  :part (f2 / figure :mod "S4A" :mod "S4B"))))

# ::id pmid_2456_8222.61 ::date 2015-08-26T12:42:57 ::annotator SDL-AMR-09 ::preferred
# ::snt Furthermore, we checked the phosphorylation status of ERK1/2 in siPHB-transfected AsPC-1 and Panc-1 cells.
# ::save-date Mon Nov 23, 2015 ::file pmid_2456_8222_61.txt
(a2 / and
      :op2 (c / check-01
            :ARG0 (w / we)
            :ARG1 (s / status
                  :mod (p / phosphorylate-01
                        :ARG1 (e / enzyme :name (n / name :op1 "ERK1/2"))
                        :location (a / and
                              :op1 (c2 / cell-line :name (n2 / name :op1 "AsPC-1")
                                    :ARG1-of (t / transfect-01
                                          :ARG2 (n5 / nucleic-acid :name (n6 / name :op1 "siRNA")
                                                :mod (p3 / protein :name (n4 / name :op1 "PHB")))))
                              :op2 (c3 / cell-line :name (n3 / name :op1 "Panc-1")
                                    :ARG1-of t))))))

# ::id pmid_2456_8222.62 ::date 2015-08-26T12:57:26 ::annotator SDL-AMR-09 ::preferred
# ::snt As expected, stimulation of AsPC-1 cells with epidermal growth factor (EGF) caused an increase of ERK1/2 phosphorylation (Figure <xref ref-type="fig" rid="F2">2</xref>B,C), whereas silencing of PHB expression strongly suppressed the EGF-induced phosphorylation of ERK (Figure <xref ref-type="fig" rid="F2">2</xref>B,C).
# ::save-date Sun Jan 17, 2016 ::file pmid_2456_8222_62.txt
(c3 / contrast-01
      :ARG1 (c / cause-01
            :ARG0 (s / stimulate-01
                  :ARG1 (c2 / cell-line :name (n / name :op1 "AsPC-1"))
                  :ARG2 (p / protein :name (n2 / name :op1 "epidermal" :op2 "growth" :op3 "factor")))
            :ARG1 (i / increase-01
                  :ARG1 (p2 / phosphorylate-01
                        :ARG1 (e3 / enzyme :name (n3 / name :op1 "ERK1/2"))))
            :ARG1-of (d / describe-01
                  :ARG0 (f / figure :mod "2B" :mod "2C")))
      :ARG2 (s2 / suppress-01
            :ARG0 (s3 / silence-01
                  :ARG1 (e / express-03
                        :ARG2 (p4 / protein :name (n4 / name :op1 "PHB"))))
            :ARG1 (p5 / phosphorylate-01
                  :ARG1 (e4 / enzyme :name (n5 / name :op1 "ERK"))
                  :ARG2-of (i2 / induce-01
                        :ARG0 p))
            :ARG1-of (d2 / describe-01
                  :ARG0 (f2 / figure :mod "2B" :mod "2C"))
            :ARG1-of (s4 / strong-02))
      :ARG1-of (e2 / expect-01))

# ::id pmid_2456_8222.63 ::date 2015-08-26T13:11:40 ::annotator SDL-AMR-09 ::preferred
# ::snt This finding suggested specific involvement of PHB in the RAS-RAF-ERK pathway.
# ::save-date Wed Aug 26, 2015 ::file pmid_2456_8222_63.txt
(s / suggest-01
      :ARG0 (t / thing
            :ARG1-of (f / find-01)
            :mod (t2 / this))
      :ARG1 (i / involve-01
            :ARG1 (p / protein :name (n / name :op1 "PHB"))
            :ARG2 (p2 / pathway :name (n2 / name :op1 "RAS-RAF-ERK"))
            :ARG1-of (s2 / specific-02)))

# ::id pmid_2456_8222.64 ::date 2015-08-26T08:19:14 ::annotator SDL-AMR-09 ::preferred
# ::snt Moreover, a similar result was obtained in Panc-1 cells (Figure <xref ref-type="fig" rid="F2">2</xref>B), indicating general inhibition of ERK activation by PHB depletion.
# ::save-date Sun Jan 17, 2016 ::file pmid_2456_8222_64.txt
(a / and
      :op2 (o / obtain-01
            :ARG1 (t / thing
                  :ARG2-of (r / result-01)
                  :ARG1-of (r2 / resemble-01))
            :location (c / cell-line :name (n / name :op1 "Panc-1"))
            :ARG1-of (d / describe-01
                  :ARG0 (f / figure :mod "2B"))
            :ARG0-of (i / indicate-01
                  :ARG1 (i2 / inhibit-01
                        :ARG0 (d2 / deplete-01
                              :ARG2 (p2 / protein :name (n3 / name :op1 "PHB")))
                        :ARG1 (a2 / activate-01
                              :ARG1 (e / enzyme :name (n2 / name :op1 "ERK")))
                        :ARG1-of (g / general-02)))))

# ::id pmid_2456_8222.65 ::date 2015-08-26T08:28:51 ::annotator SDL-AMR-09 ::preferred
# ::snt Thus, these results clearly indicate that PHB is required for EGF-induced ERK1/2 activation in pancreatic cancer cells.
# ::save-date Tue Sep 1, 2015 ::file pmid_2456_8222_65.txt
(c / cause-01
      :ARG1 (i / indicate-01
            :ARG0 (t / thing
                  :ARG2-of (r / result-01)
                  :mod (t2 / this))
            :ARG1 (r2 / require-01
                  :ARG0 (a / activate-01
                        :ARG1 (e / enzyme :name (n2 / name :op1 "ERK1/2")
                              :ARG2-of (i2 / induce-01
                                    :ARG0 (p2 / protein :name (n3 / name :op1 "EGF"))))
                        :location (c2 / cell
                              :mod (c4 / cancer
                                    :mod (p3 / pancreas))))
                  :ARG1 (p / protein :name (n / name :op1 "PHB")))
            :ARG1-of (c3 / clear-06)))

# ::id pmid_2456_8222.66 ::date 2015-08-26T08:33:22 ::annotator SDL-AMR-09 ::preferred
# ::snt <sec-title level="2">RocA disrupts the ERK pathway by targeting the CRAF-PHB interaction in AsPC-1 cells</sec-title>
# ::save-date Fri Aug 28, 2015 ::file pmid_2456_8222_66.txt
(d / disrupt-01
      :ARG0 (s / small-molecule :name (n / name :op1 "RocA"))
      :ARG1 (p / pathway :name (n2 / name :op1 "ERK"))
      :manner (t / target-01
            :ARG0 s
            :ARG1 (i / interact-01
                  :ARG0 (e / enzyme :name (n3 / name :op1 "CRAF"))
                  :ARG1 (p2 / protein :name (n4 / name :op1 "PHB"))
                  :location (c / cell-line :name (n5 / name :op1 "AsPC-1")))))

# ::id pmid_2456_8222.67 ::date 2015-08-26T09:12:55 ::annotator SDL-AMR-09 ::preferred
# ::snt The oncogenic RAS-ERK pathway is a key node for cellular proliferation signals and has been the focus of substantial drug discovery efforts in many cancers [<xref ref-type="bibr" rid="B20">20</xref>-<xref ref-type="bibr" rid="B23">23</xref>].
# ::save-date Thu Jan 21, 2016 ::file pmid_2456_8222_67.txt
(a / and
      :op1 (k / key-02
            :ARG1 (n / node
                  :domain (p / pathway :name (n2 / name :op1 "RAS-ERK")
                        :ARG0-of (c / cause-01
                              :ARG1 (c2 / cancer))))
            :ARG2 (s / signal-07
                  :ARG1 (p2 / proliferate-01
                        :ARG0 (c3 / cell))))
      :op2 (f / focus-01
            :ARG1 (e / effort-01
                  :ARG1 (d / discover-01
                        :ARG1 (d2 / drug))
                  :degree (s2 / substantial))
            :ARG2 p
            :location (c4 / cancer
                  :quant (m / many)))
      :ARG1-of (d3 / describe-01
            :ARG0 (p3 / publication
                  :ARG1-of (c5 / cite-01
                        :ARG2 (v / value-interval :op1 20 :op2 23)))))

# ::id pmid_2456_8222.68 ::date 2015-08-26T09:31:03 ::annotator SDL-AMR-09 ::preferred
# ::snt A previous study has indicated that RocA suppresses the ERK pathway in leukemic cells [<xref ref-type="bibr" rid="B24">24</xref>].
# ::save-date Tue Sep 1, 2015 ::file pmid_2456_8222_68.txt
(i / indicate-01
      :ARG0 (s / study-01
            :time (p2 / previous))
      :ARG1 (s2 / suppress-01
            :ARG0 (s3 / small-molecule :name (n2 / name :op1 "RocA"))
            :ARG1 (p3 / pathway :name (n3 / name :op1 "ERK"))
            :location (c / cell
                  :mod (l / leukemia)))
      :ARG1-of (d / describe-01
            :ARG0 (p / publication
                  :ARG1-of (c2 / cite-01
                        :ARG2 24))))

# ::id pmid_2456_8222.69 ::date 2015-08-26T09:40:36 ::annotator SDL-AMR-09 ::preferred
# ::snt To confirm that the anti-tumor effect of RocA is indeed caused by suppression of the ERK pathway, we examined the effect of RocA on ERK activity in AsPC-1 cells (Figure <xref ref-type="fig" rid="F3">3</xref>E).
# ::save-date Sun Jan 17, 2016 ::file pmid_2456_8222_69.txt
(e / examine-01
      :ARG0 (w / we)
      :ARG1 (a / affect-01
            :ARG0 (s2 / small-molecule :name (n2 / name :op1 "RocA"))
            :ARG1 (a2 / activity-06
                  :ARG0 (e2 / enzyme :name (n / name :op1 "ERK")))
            :location (c / cell-line :name (n3 / name :op1 "AsPC-1")))
      :purpose (c2 / confirm-01
            :ARG0 w
            :ARG1 (c3 / cause-01
                  :ARG0 (s / suppress-01
                        :ARG1 (p2 / pathway :name (n4 / name :op1 "ERK")))
                  :ARG1 (a3 / affect-01
                        :ARG0 s2
                        :ARG2 (t / tumor
                              :ARG1-of (c4 / counter-01
                                    :ARG0 s2)))
                  :mod (i / indeed)))
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod "3E")))

# ::id pmid_2456_8222.70 ::date 2015-08-26T09:52:55 ::annotator SDL-AMR-09 ::preferred
# ::snt The results showed significant dose-dependent inhibition of the phosphorylation status of ERK1/2 (Figure <xref ref-type="fig" rid="F3">3</xref>B).
# ::save-date Wed Aug 26, 2015 ::file pmid_2456_8222_70.txt
(s / show-01
      :ARG0 (t / thing
            :ARG2-of (r / result-01))
      :ARG1 (i / inhibit-01
            :ARG1 (s3 / status
                  :mod (p / phosphorylate-01
                        :ARG1 (e / enzyme :name (n / name :op1 "ERK1/2"))))
            :ARG0-of (d / depend-01
                  :ARG1 (d2 / dose-01))
            :ARG1-of (s2 / significant-02))
      :ARG1-of (d3 / describe-01
            :ARG0 (f / figure :mod "3B")))

# ::id pmid_2456_8222.71 ::date 2015-08-26T10:03:35 ::annotator SDL-AMR-09 ::preferred
# ::snt Importantly, RocA showed very strong time-dependent suppression of ERK1/2 activities (Figure <xref ref-type="fig" rid="F3">3</xref>B).
# ::save-date Fri Aug 28, 2015 ::file pmid_2456_8222_71.txt
(s / show-01
      :ARG0 (s4 / small-molecule :name (n / name :op1 "RocA"))
      :ARG1 (s2 / suppress-01
            :ARG1 (a / activity-06
                  :ARG1 (e / enzyme :name (n2 / name :op1 "ERK1/2")))
            :ARG0-of (d / depend-01
                  :ARG1 (t / time))
            :ARG1-of (s3 / strong-02
                  :degree (v / very)))
      :mod (i / important)
      :ARG1-of (d2 / describe-01
            :ARG0 (f / figure :mod "3B")))

# ::id pmid_2456_8222.72 ::date 2015-08-26T10:16:11 ::annotator SDL-AMR-09 ::preferred
# ::snt PHB was previously shown to be required for membrane association and activation of CRAF [<xref ref-type="bibr" rid="B15">15</xref>].
# ::save-date Tue Sep 1, 2015 ::file pmid_2456_8222_72.txt
(s / show-01
      :ARG1 (p / protein :name (n / name :op1 "PHB")
            :ARG1-of (r / require-01
                  :ARG0 (a / and
                        :op1 (a2 / associate-01
                              :ARG1 (m / membrane))
                        :op2 (a3 / activate-01
                              :ARG1 (e / enzyme :name (n2 / name :op1 "CRAF"))))))
      :ARG1-of (d / describe-01
            :ARG0 (p2 / publication
                  :ARG1-of (c / cite-01
                        :ARG2 15)))
      :time (p3 / previous))

# ::id pmid_2456_8222.73 ::date 2015-08-26T10:19:57 ::annotator SDL-AMR-09 ::preferred
# ::snt Therefore, we examined whether RocA affects PHB-CRAF membrane association in AsPC-1 cells.
# ::save-date Tue Sep 1, 2015 ::file pmid_2456_8222_73.txt
(c / cause-01
      :ARG1 (e / examine-01
            :ARG0 (w / we)
            :ARG1 (a / affect-01 :mode interrogative
                  :ARG0 (s / small-molecule :name (n / name :op1 "RocA"))
                  :ARG1 (a2 / associate-01
                        :ARG1 (m2 / membrane)
                        :ARG2 (m3 / macro-molecular-complex
                              :part (p / protein :name (n2 / name :op1 "PHB"))
                              :part (e2 / enzyme :name (n3 / name :op1 "CRAF")))
                        :location (c2 / cell-line :name (n4 / name :op1 "AsPC-1"))))))

# ::id pmid_2456_8222.74 ::date 2015-08-26T10:32:39 ::annotator SDL-AMR-09 ::preferred
# ::snt To this end, cell membrane and cytosol fractions were prepared from AsPC-1 cells treated with Roc-A or DMSO to analyze the localization of PHB and CRAF.
# ::save-date Tue Sep 1, 2015 ::file pmid_2456_8222_74.txt
(p / prepare-01
      :ARG1 (a / and
            :op1 (m / membrane
                  :mod (c / cell))
            :op2 (f / fraction-01
                  :location (c2 / cytosol)))
      :ARG2 (c3 / cell-line :name (n / name :op1 "AsPC-1")
            :ARG1-of (t / treat-04
                  :ARG2 (o / or
                        :op1 (s / small-molecule :name (n2 / name :op1 "Roc-A"))
                        :op2 (s2 / small-molecule :name (n3 / name :op1 "DMSO")))))
      :purpose (a2 / analyze-01
            :ARG1 (b / be-located-at-91
                  :ARG1 (a3 / and
                        :op1 (p2 / protein :name (n4 / name :op1 "PHB"))
                        :op2 (e / enzyme :name (n5 / name :op1 "CRAF")))))
      :purpose (t2 / this))

# ::id pmid_2456_8222.75 ::date 2015-08-26T11:02:18 ::annotator SDL-AMR-09 ::preferred
# ::snt Immunoblot analysis showed significant reduction of CRAF, particularly phosphorylated CRAF (pSer338), in the membrane fraction after RocA treatment (Figure <xref ref-type="fig" rid="F3">3</xref>C).
# ::save-date Tue Sep 1, 2015 ::file pmid_2456_8222_75.txt
(s / show-01
      :ARG0 (a / analyze-01
            :ARG1 (i / immunoblot-01))
      :ARG1 (r / reduce-01
            :ARG1 (e / enzyme :name (n / name :op1 "CRAF")
                  :ARG2-of (i2 / include-01
                        :ARG1 (a2 / amino-acid :mod 338 :name (n2 / name :op1 "serine")
                              :ARG3-of (p / phosphorylate-01)
                              :mod (p2 / particular)
                              :part-of e)))
            :ARG1-of (s2 / significant-02)
            :location (f / fraction-01
                  :ARG1 (m / membrane)))
      :time (a3 / after
            :op1 (t / treat-04
                  :ARG2 (s3 / small-molecule :name (n3 / name :op1 "RocA"))))
      :ARG1-of (d / describe-01
            :ARG0 (f2 / figure :mod "3C")))

# ::id pmid_2456_8222.76 ::date 2015-08-26T11:10:43 ::annotator SDL-AMR-09 ::preferred
# ::snt Notably, RocA also significantly reduced the levels of PHB in the membrane fraction, indicating that binding of RocA to PHB may also interfere with PHB membrane association.
# ::save-date Tue Sep 1, 2015 ::file pmid_2456_8222_76.txt
(r / reduce-01
      :ARG0 (s / small-molecule :name (n / name :op1 "RocA"))
      :ARG1 (l / level
            :quant-of (p / protein :name (n2 / name :op1 "PHB")))
      :mod (a / also)
      :ARG1-of (s2 / significant-02)
      :location (f / fraction-01
            :ARG1 (m / membrane))
      :ARG0-of (i / indicate-01
            :ARG1 (p2 / possible-01
                  :ARG1 (i2 / interfere-01
                        :ARG0 (b / bind-01
                              :ARG1 s
                              :ARG2 p)
                        :ARG1 (a2 / associate-01
                              :ARG1 (m2 / membrane)
                              :ARG2 p)
                        :mod a)))
      :ARG1-of (n3 / notable-04))

# ::id pmid_2456_8222.77 ::date 2015-08-26T11:24:03 ::annotator SDL-AMR-09 ::preferred
# ::snt However, RocA did not influence membrane localization of RAS (Figure <xref ref-type="fig" rid="F3">3</xref>C).
# ::save-date Tue Sep 15, 2015 ::file pmid_2456_8222_77.txt
(c / contrast-01
      :ARG2 (i / influence-01 :polarity -
            :ARG0 (s / small-molecule :name (n2 / name :op1 "RocA"))
            :ARG1 (b / be-located-at-91
                  :ARG1 (p2 / protein-family :name (n3 / name :op1 "RAS"))
                  :ARG2 (m / membrane)))
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod "3C")))

# ::id pmid_2456_8222.78 ::date 2015-08-26T11:53:04 ::annotator SDL-AMR-09 ::preferred
# ::snt Indeed, immunoprecipitation analysis suggested that RocA substantially decreased the amounts of total CRAF bound to PHB in AsPC-1 cells (Figure <xref ref-type="fig" rid="F3">3</xref>D).
# ::save-date Wed Aug 26, 2015 ::file pmid_2456_8222_78.txt
(s / suggest-01
      :ARG0 (a / analyze-01
            :ARG1 (i / immunoprecipitate-01))
      :ARG1 (d / decrease-01
            :ARG0 (s2 / small-molecule :name (n / name :op1 "RocA"))
            :ARG1 (a2 / amount-01
                  :ARG1 (e / enzyme :name (n2 / name :op1 "CRAF")
                        :mod (t / total)
                        :ARG1-of (b / bind-01
                              :ARG2 (p / protein :name (n3 / name :op1 "PHB"))
                              :location (c / cell-line :name (n4 / name :op1 "AsPC-1")))))
            :manner (s3 / substantial))
      :mod (i2 / indeed)
      :ARG1-of (d2 / describe-01
            :ARG0 (f / figure :mod "3D")))

# ::id pmid_2456_8222.79 ::date 2015-08-26T12:11:01 ::annotator SDL-AMR-09 ::preferred
# ::snt Notably, confocal microscopic analysis showed that treatment of AsPC-1 cells with 100 nM RocA for 4 h led to a loss of plasma membrane localization and random redistribution of PHB (Figure <xref ref-type="fig" rid="F3">3</xref>E).
# ::save-date Tue Sep 15, 2015 ::file pmid_2456_8222_79.txt
(s / show-01
      :ARG0 (a / analyze-01
            :mod (m / microscopy
                  :mod (c / confocal)))
      :ARG1 (l / lead-03
            :ARG0 (t / treat-04
                  :ARG1 (c2 / cell-line :name (n / name :op1 "AsPC-1"))
                  :ARG2 (s2 / small-molecule :name (n2 / name :op1 "RocA")
                        :quant (c3 / concentration-quantity :quant 100
                              :unit (n3 / nanomolar)))
                  :duration (t2 / temporal-quantity :quant 4
                        :unit (h / hour)))
            :ARG1 (a2 / and
                  :op1 (l2 / lose-02
                        :ARG1 (b / be-located-at-91
                              :ARG1 p2
                              :ARG2 (m2 / membrane
                                    :mod (p / plasma))))
                  :op2 (r / redistribute-01
                        :ARG1 (p2 / protein :name (n4 / name :op1 "PHB"))
                        :manner (r2 / random))))
      :ARG1-of (n5 / notable-04)
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod "3E")))

# ::id pmid_2456_8222.80 ::date 2015-08-26T12:59:34 ::annotator SDL-AMR-09 ::preferred
# ::snt This observation indicates that inhibition of the PHB-CRAF interaction by RocA leads to the loss of spatial organization of PHB in AsPC-1 cells.
# ::save-date Wed Aug 26, 2015 ::file pmid_2456_8222_80.txt
(i / indicate-01
      :ARG0 (o / observe-01
            :mod (t / this))
      :ARG1 (l / lead-03
            :ARG0 (i2 / inhibit-01
                  :ARG0 (s / small-molecule :name (n3 / name :op1 "RocA"))
                  :ARG1 (i3 / interact-01
                        :ARG0 (p / protein :name (n / name :op1 "PHB"))
                        :ARG1 (e / enzyme :name (n2 / name :op1 "CRAF"))))
            :ARG1 (l2 / lose-02
                  :ARG1 (o2 / organize-01
                        :ARG1 p
                        :mod (s2 / space)
                        :location (c / cell-line :name (n4 / name :op1 "AsPC-1"))))))

# ::id pmid_2456_8222.81 ::date 2015-08-26T13:04:26 ::annotator SDL-AMR-09 ::preferred
# ::snt Collectively, these results further demonstrate that RocA blocks the RAS-CRAF-ERK signaling pathway by disruption of the PHB-CRAF interaction in pancreatic cancer.
# ::save-date Wed Aug 26, 2015 ::file pmid_2456_8222_81.txt
(d2 / demonstrate-01
      :ARG0 (r / result-01
            :mod (t / this))
      :ARG1 (b / block-01
            :ARG0 (s / small-molecule :name (n2 / name :op1 "RocA"))
            :ARG1 (p / pathway :name (n3 / name :op1 "RAS-CRAF-ERK")
                  :ARG0-of (s2 / signal-07))
            :manner (d3 / disrupt-01
                  :ARG0 s
                  :ARG1 (i / interact-01
                        :ARG0 (p2 / protein :name (n4 / name :op1 "PHB"))
                        :ARG1 (e / enzyme :name (n5 / name :op1 "CRAF")))
                  :location (c / cancer
                        :mod (p3 / pancreas))))
      :degree (f / further)
      :mod (c2 / collective))

# ::id pmid_2456_8222.82 ::date 2015-08-26T13:10:46 ::annotator SDL-AMR-09 ::preferred
# ::snt <sec-title level="2">RocA mimics the effect of PHB knockdown on epithelial-mesenchymal transition (EMT) markers and reverses the EMT phenotype in AsPC-1 cells</sec-title>
# ::save-date Mon Nov 23, 2015 ::file pmid_2456_8222_82.txt
(a / and
      :op1 (m / mimic-01
            :ARG0 (s / small-molecule :name (n / name :op1 "RocA"))
            :ARG1 (a2 / affect-01
                  :ARG0 (k / knock-down-02
                        :ARG1 (p / protein :name (n2 / name :op1 "PHB")))
                  :ARG1 (m2 / marker
                        :mod (t / transition-01
                              :ARG2 (c / cell
                                    :mod (m3 / mesenchyme))
                              :ARG3 (c3 / cell
                                    :mod (e / epithelium))))))
      :op1 (r / reverse-01
            :ARG0 s
            :ARG1 (p2 / phenotype
                  :mod t)
            :location (c2 / cell-line :name (n4 / name :op1 "AsPC-1"))))

# ::id pmid_2456_8222.83 ::date 2015-08-26T13:16:58 ::annotator SDL-AMR-09 ::preferred
# ::snt The oncogenic RAS-RAF-ERK pathway confers epithelial cells with critical motile and invasive capacities during carcinoma progression, often by promotion of EMT [<xref ref-type="bibr" rid="B25">25</xref>,<xref ref-type="bibr" rid="B26">26</xref>].
# ::save-date Mon Nov 23, 2015 ::file pmid_2456_8222_83.txt
(c / confer-02
      :ARG0 (p / pathway :name (n / name :op1 "PAS-RAF-ERK")
            :ARG0-of (c2 / cause-01
                  :ARG1 (c3 / cancer)))
      :ARG1 (a / and
            :op1 (c8 / capable-01
                  :ARG1 c4
                  :ARG2 (m / motile
                        :ARG1-of (c5 / critical-02)))
            :op1 (c10 / capable-01
                  :ARG1 c4
                  :ARG2 (i / invade-01
                        :ARG0 c4)))
      :ARG2 (c4 / cell
            :mod (e / epithelium))
      :time (p2 / progress-01
            :ARG1 (c7 / carcinoma))
      :manner (p3 / promote-01
            :ARG1 (t / transition-01
                  :ARG2 (c6 / cell
                        :mod (m2 / mesenchyme))
                  :ARG3 (c11 / cell
                        :mod (e2 / epithelium)))
            :frequency (o / often))
      :ARG1-of (d / describe-01
            :ARG0 (p4 / publication
                  :ARG1-of (c9 / cite-01
                        :ARG2 (a2 / and :op1 25 :op2 26)))))

# ::id pmid_2456_8222.84 ::date 2015-08-27T10:57:28 ::annotator SDL-AMR-09 ::preferred
# ::snt To further investigate the role of PHB in EMT, the effects of PHB siRNA and RocA on EMT markers were assayed in AsPC-1 cells.
# ::save-date Mon Dec 21, 2015 ::file pmid_2456_8222_84.txt
(a / assay-01
      :ARG1 (a3 / affect-01
            :ARG0 (a4 / and
                  :op1 (n4 / nucleic-acid :name (n / name :op1 "siRNA")
                        :ARG0-of (e / encode-01
                              :ARG1 (p / protein :name (n2 / name :op1 "PHB"))))
                  :op2 (s / small-molecule :name (n3 / name :op1 "RocA")))
            :ARG1 (m / marker
                  :mod (t / transition-01
                        :ARG2 (c / cell
                              :mod (m2 / mesenchyme))
                        :ARG3 (c2 / cell
                              :mod (e2 / epithelium)))))
      :location (c3 / cell-line :name (n5 / name :op1 "AsPC-1"))
      :purpose (i / investigate-01
            :ARG1 (r2 / role
                  :topic t
                  :poss p)
            :degree (f / further)))

# ::id pmid_2456_8222.85 ::date 2015-08-27T11:03:51 ::annotator SDL-AMR-09 ::preferred
# ::snt First, we detected EMT markers in AsPC-1 and Capan-2 cells (Figure <xref ref-type="fig" rid="F4">4</xref>A).
# ::save-date Mon Nov 23, 2015 ::file pmid_2456_8222_85.txt
(d / detect-01
      :ARG0 (w / we)
      :ARG1 (m / marker
            :mod (t / transition-01
                  :ARG2 (c / cell
                        :mod (m2 / mesenchyme))
                  :ARG3 (c2 / cell
                        :mod (e / epithelium))))
      :location (a / and
            :op1 (c3 / cell-line :name (n2 / name :op1 "AsPC-1"))
            :op2 (c4 / cell-line :name (n3 / name :op1 "Capan-2")))
      :time (f / first)
      :ARG1-of (d2 / describe-01
            :ARG0 (f2 / figure :mod "4A")))

# ::id pmid_2456_8222.86 ::date 2015-08-27T11:06:44 ::annotator SDL-AMR-09 ::preferred
# ::snt Knockdown of PHB in AsPC-1 cells by siRNA resulted in upregulation of E-cadherin and β-catenin and downregulation of vimentin (Figure <xref ref-type="fig" rid="F4">4</xref>B).
# ::save-date Mon Dec 21, 2015 ::file pmid_2456_8222_86.txt
(r / result-01
      :ARG1 (k / knock-down-02
            :ARG0 (n7 / nucleic-acid :name (n / name :op1 "siRNA"))
            :ARG1 (p / protein :name (n2 / name :op1 "PHB"))
            :location (c / cell-line :name (n3 / name :op1 "AsPC-1")))
      :ARG2 (a / and
            :op1 (u / upregulate-01
                  :ARG1 (a2 / and
                        :op1 (p2 / protein :name (n4 / name :op1 "E-cadherin"))
                        :op2 (p3 / protein :name (n5 / name :op1 "β-catenin"))))
            :op2 (d / downregulate-01
                  :ARG1 (p4 / protein :name (n6 / name :op1 "vimentin"))))
      :ARG1-of (d2 / describe-01
            :ARG0 (f / figure :mod "4B")))

# ::id pmid_2456_8222.87 ::date 2015-08-27T11:14:15 ::annotator SDL-AMR-09 ::preferred
# ::snt Similar to the effect of PHB knockdown, treatment of AsPC-1 cells with RocA showed the same results (Figure <xref ref-type="fig" rid="F4">4</xref>C).
# ::save-date Thu Aug 27, 2015 ::file pmid_2456_8222_87.txt
(s / show-01
      :ARG0 (t / treat-04
            :ARG1 (c / cell-line :name (n / name :op1 "AsPC-1"))
            :ARG2 (s2 / small-molecule :name (n2 / name :op1 "RocA")))
      :ARG1 (r2 / result-01
            :ARG1-of (s3 / same-01))
      :ARG1-of (r3 / resemble-01
            :ARG2 (a / affect-01
                  :ARG0 (k / knock-down-02
                        :ARG1 (p / protein :name (n3 / name :op1 "PHB")))))
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod "4C")))

# ::id pmid_2456_8222.88 ::date 2015-08-27T11:20:02 ::annotator SDL-AMR-09 ::preferred
# ::snt Activated ERK2 directly phosphorylates Snail, leading to nuclear accumulation, reduced ubiquitylation, and an increased protein half-life of Snail, and then promotion of breast cancer cell invasion and migration <i>in vitro</i> and metastasis <i>in vivo</i>[<xref ref-type="bibr" rid="B27">27</xref>].
# ::save-date Tue Sep 1, 2015 ::file pmid_2456_8222_88.txt
(p / phosphorylate-01
      :ARG1 (p2 / protein :name (n3 / name :op1 "Snail"))
      :ARG2 (e / enzyme :name (n2 / name :op1 "ERK2")
            :ARG1-of (a / activate-01))
      :ARG0-of (l / lead-03
            :ARG2 (a2 / and
                  :op1 (a3 / accumulate-01
                        :mod (n4 / nucleus))
                  :op2 (p3 / protein :name (n5 / name :op1 "Ubiquitin")
                        :ARG1-of (r / reduce-01))
                  :op3 (p4 / protein :name (n6 / name :op1 "Snail")
                        :ARG0-of (l2 / live-01
                              :degree (h / half))
                        :ARG1-of (i / increase-01))
                  :op4 (p5 / promote-01
                        :ARG1 (a4 / and
                              :op1 (a5 / and
                                    :op1 (i2 / invade-01
                                          :ARG0 (c / cell
                                                :mod (c2 / cancer
                                                      :mod (b / breast))))
                                    :op2 (m / migrate-01)
                                    :manner (i3 / in-vitro))
                              :op2 (m2 / metastasize-101
                                    :manner (i4 / in-vivo)))
                        :time (t / then))))
      :ARG1-of (d3 / describe-01
            :ARG0 (p6 / publication
                  :ARG1-of (c3 / cite-01
                        :ARG2 27)))
      :ARG1-of (d / direct-02))

# ::id pmid_2456_8222.89 ::date 2015-08-27T11:32:31 ::annotator SDL-AMR-09 ::preferred
# ::snt Another study has shown clear increases of ZEB1 and ZEB2 protein levels by ERK2 but not ERK1 [<xref ref-type="bibr" rid="B28">28</xref>].
# ::save-date Thu Aug 27, 2015 ::file pmid_2456_8222_89.txt
(s / show-01
      :ARG0 (s2 / study-01
            :mod (a / another))
      :ARG1 (c / contrast-01
            :ARG1 (i / increase-01
                  :ARG0 (e / enzyme :name (n3 / name :op1 "ERK2"))
                  :ARG1 (a2 / and
                        :op1 (l / level
                              :quant-of (p / protein :name (n / name :op1 "ZEB1")))
                        :op2 (l2 / level
                              :quant-of (p2 / protein :name (n2 / name :op1 "ZEB2"))))
                  :ARG1-of (c2 / clear-06))
            :ARG2 (i2 / increase-01 :polarity -
                  :ARG0 (e2 / enzyme :name (n4 / name :op1 "ERK1"))
                  :ARG1 a2))
      :ARG1-of (d / describe-01
            :ARG0 (p3 / publication
                  :ARG1-of (c3 / cite-01
                        :ARG2 28))))

# ::id pmid_2456_8222.90 ::date 2015-08-27T11:42:18 ::annotator SDL-AMR-09 ::preferred
# ::snt To further investigate the molecular basis of ERK-regulated EMT, we detected the levels of Snail1, ZEB1, and transcription factors known to regulate EMT which act downstream of ERK1/2.
# ::save-date Mon Nov 23, 2015 ::file pmid_2456_8222_90.txt
(d / detect-01
      :ARG0 (w / we)
      :ARG1 (a / and
            :op1 (l / level
                  :quant-of (p / protein :name (n / name :op1 "Snail")))
            :op2 (l2 / level
                  :quant-of (p2 / protein :name (n2 / name :op1 "ZEB1")))
            :op3 (l3 / level
                  :quant-of (f / factor
                        :ARG0-of (t / transcribe-01
                              :ARG2 (c / cell
                                    :mod (m2 / mesenchyme))
                              :ARG3 (c2 / cell
                                    :mod (e / epithelium)))
                        :ARG0-of (r / regulate-01
                              :ARG1 (t2 / transition-01)
                              :ARG1-of (k / know-01))
                        :ARG0-of (a2 / act-02
                              :location (r2 / relative-position
                                    :op1 (e2 / enzyme :name (n4 / name :op1 "ERK1/2"))
                                    :direction (d2 / downstream))))))
      :purpose (i / investigate-01
            :ARG0 w
            :ARG1 (b2 / base-02
                  :ARG1 (t3 / transition-01
                        :ARG2 c
                        :ARG3 c2
                        :ARG1-of (r3 / regulate-01
                              :ARG0 (p3 / protein-family :name (n6 / name :op1 "ERK"))))
                  :ARG2 (m / molecule))
            :degree (f2 / further)))

# ::id pmid_2456_8222.91 ::date 2015-08-27T11:54:19 ::annotator SDL-AMR-09 ::preferred
# ::snt Interestingly, we observed similar results in PHB-silenced and RocA-treated AsPC-1 cells (Figure <xref ref-type="fig" rid="F4">4</xref>B,C).
# ::save-date Tue Sep 1, 2015 ::file pmid_2456_8222_91.txt
(o / observe-01
      :ARG0 (w / we)
      :ARG1 (r / result-01
            :ARG2 (c / cell-line :name (n2 / name :op1 "ASPC-1")
                  :ARG1-of (t / treat-04
                        :ARG2 (s2 / small-molecule :name (n3 / name :op1 "RocA")))
                  :location-of (p / protein :name (n / name :op1 "PHB")
                        :ARG1-of (s / silence-01)))
            :ARG1-of (r3 / resemble-01))
      :ARG2-of (i / interest-01)
      :ARG1-of (d / describe-01
            :ARG0 (a2 / and
                  :op1 (f / figure :mod "4B")
                  :op2 (f2 / figure :mod "4C"))))

# ::id pmid_2456_8222.92 ::date 2015-08-27T11:59:31 ::annotator SDL-AMR-09 ::preferred
# ::snt AsPC-1 cells lacking PHB expression showed defective migration (Figure <xref ref-type="fig" rid="F4">4</xref>D), indicating that the formation of clusters is the consequence of reduced motility of cells that lack high levels of PHB.
# ::save-date Tue Sep 1, 2015 ::file pmid_2456_8222_92.txt
(s / show-01
      :ARG0 (c / cell-line :name (n / name :op1 "ASPC-1")
            :ARG0-of (l / lack-01
                  :ARG1 (e / express-03
                        :ARG2 (p / protein :name (n2 / name :op1 "PHB")))))
      :ARG1 (m / migrate-01
            :mod (d / defective))
      :ARG1-of (d2 / describe-01
            :ARG0 (f / figure :mod "4D"))
      :ARG0-of (i / indicate-01
            :ARG1 (c3 / cause-01
                  :ARG0 (m2 / motility
                        :ARG1-of (r / reduce-01)
                        :mod (c2 / cell)
                        :ARG0-of (l2 / lack-01
                              :ARG1 (l3 / level
                                    :ARG1-of (h / high-02)
                                    :quant-of p)))
                  :ARG1 (f2 / form-01
                        :ARG1 (c4 / cluster)))))

# ::id pmid_2456_8222.93 ::date 2015-08-27T12:06:24 ::annotator SDL-AMR-09 ::preferred
# ::snt Notably, AsPC-1 cells treated with RocA formed cell clusters similar to those formed by cells with reduced PHB expression (Figure <xref ref-type="fig" rid="F4">4</xref>D).
# ::save-date Tue Sep 1, 2015 ::file pmid_2456_8222_93.txt
(f / form-01
      :ARG0 (c / cell-line :wiki -
            :name (n / name :op1 "AsPC-1")
            :ARG1-of (t / treat-04
                  :ARG2 (s / small-molecule :wiki -
                        :name (n2 / name :op1 "RocA"))))
      :ARG1 (c2 / cluster
            :ARG1-of (r2 / resemble-01
                  :ARG2 (c5 / cluster
                        :ARG1-of (f2 / form-01
                              :ARG0 (c4 / cell
                                    :ARG3-of (e / express-03
                                          :ARG2 (p / protein :wiki "Prohibitin"
                                                :name (n3 / name :op1 "PHB"))
                                          :ARG1-of (r3 / reduce-01))))))
            :consist-of (c3 / cell))
      :ARG1-of (n4 / notable-04)
      :ARG1-of (d / describe-01
            :ARG0 (f3 / figure :mod "4D")))

# ::id pmid_2456_8222.94 ::date 2015-08-27T12:12:10 ::annotator SDL-AMR-09 ::preferred
# ::snt Taken together, RocA mimics the effect of PHB knockdown on EMT marker expression and reverses the EMT phenotype in AsPC-1 cells.
# ::save-date Mon Nov 23, 2015 ::file pmid_2456_8222_94.txt
(a2 / and
      :op1 (m / mimic-01
            :ARG0 (s / small-molecule :name (n / name :op1 "RocA"))
            :ARG1 (a / affect-01
                  :ARG0 (k / knock-down-02
                        :ARG1 (p / protein :name (n2 / name :op1 "PHB")))
                  :ARG1 (e2 / express-03
                        :ARG2 (m2 / marker
                              :mod (t / transition-01
                                    :ARG2 (c / cell
                                          :mod (m3 / mesenchyme))
                                    :ARG3 (c2 / cell
                                          :mod (e / epithelium)))))))
      :op2 (r / reverse-01
            :ARG0 s
            :ARG1 (p2 / phenotype
                  :mod t)
            :location (c3 / cell-line :name (n4 / name :op1 "AsPC-1")))
      :ARG1-of (t2 / take-01
            :manner (t3 / together)))

# ::id pmid_2456_8222.95 ::date 2015-08-27T12:19:04 ::annotator SDL-AMR-09 ::preferred
# ::snt <sec-title level="2">RocA selectively diminishes the viability of PHB-dependent pancreatic cancer cells <i>in vitro</i> and inhibits their migration <i>in vitro</i> and <i>in vivo</i></sec-title>
# ::save-date Tue Sep 15, 2015 ::file pmid_2456_8222_95.txt
(a / and
      :op1 (d2 / diminish-01
            :ARG0 (s / small-molecule :name (n2 / name :op1 "RocA"))
            :ARG1 (v / viable
                  :domain (c / cell
                        :mod (c2 / cancer
                              :mod (p / pancreas))
                        :ARG0-of (d3 / depend-01
                              :ARG1 (p2 / protein :name (n3 / name :op1 "PHB")))
                        :mod (i / in-vitro)))
            :manner (s2 / selective))
      :op2 (i2 / inhibit-01
            :ARG0 s
            :ARG1 (a2 / and
                  :op1 (m / migrate-01
                        :ARG0 c
                        :mod (i3 / in-vitro))
                  :op2 (m2 / migrate-01
                        :ARG0 c
                        :mod (i4 / in-vivo)))))

# ::id pmid_2456_8222.96 ::date 2015-08-27T12:26:12 ::annotator SDL-AMR-09 ::preferred
# ::snt To characterize the action of RocA on pancreatic cancer cell growth, AsPC-1 and Panc-1 cells were treated with RocA (100 nM) or DMSO for 16 h and then applied to CCK-8 assays.
# ::save-date Tue Sep 1, 2015 ::file pmid_2456_8222_96.txt
(a / and
      :op1 (t / treat-04
            :ARG1 (a2 / and
                  :op1 (c / cell-line :name (n2 / name :op1 "AsPC-1"))
                  :op2 (c2 / cell-line :name (n3 / name :op1 "Panc-1")))
            :ARG2 (o / or
                  :op1 (s / small-molecule :name (n4 / name :op1 "RocA")
                        :quant (c3 / concentration-quantity :quant 100
                              :unit (n6 / nanomolar)))
                  :op2 (s2 / small-molecule :name (n5 / name :op1 "DMSO")))
            :duration (t2 / temporal-quantity :quant 16
                  :unit (h / hour)))
      :op2 (a3 / apply-02
            :ARG1 a2
            :ARG2 (a4 / assay-01
                  :mod (t4 / thing :name (n7 / name :op1 "CCK-8")))
            :time (t3 / then))
      :purpose (c4 / characterize-01
            :ARG1 (a5 / act-02
                  :ARG0 (s3 / small-molecule :name (n8 / name :op1 "RocA"))
                  :ARG1 (g / grow-01
                        :ARG1 (c5 / cell
                              :mod (c6 / cancer
                                    :mod (p / pancreas)))))))

# ::id pmid_2456_8222.97 ::date 2015-08-27T12:41:23 ::annotator SDL-AMR-09 ::preferred
# ::snt RocA markedly impaired the growth of AsPC-1 and Panc-1 cells without affecting Hs 578Bst or L02 cells as controls (Figure <xref ref-type="fig" rid="F5">5</xref>A,B).
# ::save-date Tue Sep 1, 2015 ::file pmid_2456_8222_97.txt
(i / impair-01
      :ARG0 (s / small-molecule :name (n / name :op1 "RocA"))
      :ARG1 (g / grow-01
            :ARG1 (a / and
                  :op1 (c / cell-line :name (n2 / name :op1 "ASPC-1"))
                  :op2 (c2 / cell-line :name (n3 / name :op1 "Panc-1"))))
      :manner (m / marked)
      :ARG0-of (a2 / affect-01 :polarity -
            :ARG1 (o / or
                  :op1 (c3 / cell-line :name (n4 / name :op1 "Hs" :op2 "578Bst"))
                  :op2 (c4 / cell-line :name (n5 / name :op1 "L02")))
            :ARG0-of (c5 / control-01))
      :ARG1-of (d / describe-01
            :ARG0 (a3 / and
                  :op1 (f / figure :mod "5A")
                  :op2 (f2 / figure :mod "5B"))))

# ::id pmid_2456_8222.98 ::date 2015-08-27T12:49:25 ::annotator SDL-AMR-09 ::preferred
# ::snt Interestingly, Capan-2 cells did not show any detectable toxicity in the presence of RocA (Additional file <xref ref-type="supplementary-material" rid="S1">1</xref>: Figure S5), suggesting deficient expression of PHB in Capan-2 cells may rescue the effects of RocA.
# ::save-date Tue Sep 1, 2015 ::file pmid_2456_8222_98.txt
(s / show-01 :polarity -
      :ARG0 (c / cell-line :name (n / name :op1 "Capan-2"))
      :ARG1 (t / toxicity
            :ARG1-of (d2 / detect-01
                  :ARG1-of (p / possible-01))
            :mod (a3 / any))
      :condition (p2 / present-02
                  :ARG1 (s2 / small-molecule :name (n2 / name :op1 "RocA")))
      :ARG1-of (d3 / describe-01
            :ARG0 (f / figure :mod "S5"
                  :location (f2 / file :mod 1
                        :ARG1-of (a / add-02))))
      :ARG0-of (s3 / suggest-01
            :ARG1 (p3 / possible-01
                  :ARG1 (r / rescue-01
                        :ARG0 (e / express-03
                              :ARG2 (p4 / protein :name (n3 / name :op1 "PHB"))
                              :ARG3 c
                              :mod (d / deficient))
                        :ARG1 (a2 / affect-01
                              :ARG0 s2))))
      :ARG2-of (i / interest-01))

# ::id pmid_2456_8222.99 ::date 2015-08-27T12:56:19 ::annotator SDL-AMR-09 ::preferred
# ::snt Additionally, RocA impaired the migration of AsPC-1 and Panc-1 cells (Figure <xref ref-type="fig" rid="F5">5</xref>C).
# ::save-date Thu Aug 27, 2015 ::file pmid_2456_8222_99.txt
(i / impair-01
      :ARG0 (s / small-molecule :name (n / name :op1 "RocA"))
      :ARG1 (m / migrate-01
            :ARG0 (a / and
                  :op1 (c / cell-line :name (n2 / name :op1 "AsPC-1"))
                  :op2 (c2 / cell-line :name (n3 / name :op1 "Panc-1"))))
      :ARG1-of (a2 / add-02)
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod "5C")))

# ::id pmid_2456_8222.100 ::date 2015-08-27T12:58:16 ::annotator SDL-AMR-09 ::preferred
# ::snt To investigate the effect of RocA on metastasis, we established an orthotopic xenograft model in mice using AsPC-1 cells.
# ::save-date Fri Aug 28, 2015 ::file pmid_2456_8222_100.txt
(e / establish-01
      :ARG0 (w / we)
      :ARG1 (m / model
            :mod (x / xenograft)
            :mod (o / orthotopic)
            :location (m2 / mouse))
      :instrument (c / cell-line :name (n / name :op1 "AsPC-1"))
      :purpose (i / investigate-01
            :ARG0 w
            :ARG1 (a / affect-01
                  :ARG0 (s / small-molecule :name (n2 / name :op1 "RocA"))
                  :ARG1 (m3 / metastasize-101))))

# ::id pmid_2456_8222.101 ::date 2015-08-27T13:02:36 ::annotator SDL-AMR-09 ::preferred
# ::snt At 1 week after orthotopic implantation of AsPC-1 cells into severe combined immunodeficient (SCID) mice, RocA (5 mg/kg body weight) was administrated via intraperitoneal injection daily for 3 weeks.
# ::save-date Tue Sep 15, 2015 ::file pmid_2456_8222_101.txt
(a / administrate-01
      :ARG1 (s / small-molecule :name (n / name :op1 "RocA")
            :quant (c3 / concentration-quantity :quant 5
                  :unit (m2 / milligram-per-kilogram)))
      :frequency (t3 / temporal-quantity :quant 1
            :unit (d / day))
      :duration (t2 / temporal-quantity :quant 3
            :unit (w2 / week))
      :time (a2 / after
            :op1 (i3 / implant-01
                  :ARG1 (c / cell-line :name (n2 / name :op1 "AsPC-1"))
                  :ARG2 (m3 / mouse
                        :mod (i4 / immunodeficient)
                        :ARG1-of (c2 / combine-01
                              :degree (s2 / severe)))
                  :mod (o / orthotopic))
            :quant (t / temporal-quantity :quant 1
                  :unit (w / week)))
      :manner (i / inject-01
            :ARG1 s
            :ARG2 (b / body
                  :ARG1-of (w3 / weight-01))
            :mod (i2 / intraperitoneal)))

# ::id pmid_2456_8222.102 ::date 2015-08-27T13:19:34 ::annotator SDL-AMR-09 ::preferred
# ::snt As a result, treatment with RocA significantly suppressed cancer metastasis to the lung and liver in mice (Figure <xref ref-type="fig" rid="F5">5</xref>D).
# ::save-date Tue Sep 1, 2015 ::file pmid_2456_8222_102.txt
(s / suppress-01
      :ARG0 (t / treat-04
            :ARG2 (s2 / small-molecule :name (n2 / name :op1 "RocA")))
      :ARG1 (m / metastasize-101
            :ARG1 (c / cancer)
            :ARG2 (a / and
                  :op1 (l / lung)
                  :op2 (l2 / liver)))
      :ARG1-of (s3 / significant-02)
      :location (m2 / mouse)
      :ARG2-of (r / result-01)
      :ARG1-of (d2 / describe-01
            :ARG0 (f / figure :mod "5D")))

# ::id pmid_2456_8222.103 ::date 2015-08-27T13:22:46 ::annotator SDL-AMR-09 ::preferred
# ::snt Histological analysis of the lung and liver revealed that dissemination of cancer cells was absent in tissue sections from RocA-treated mice, but an abundance of cancer cells were observed in vehicle-treated mice (Figure <xref ref-type="fig" rid="F5">5</xref>D).
# ::save-date Tue Sep 1, 2015 ::file pmid_2456_8222_103.txt
(c3 / contrast-01
      :ARG1 (r / reveal-01
            :ARG0 (a / analyze-01
                  :ARG1 (a2 / and
                        :op1 (l / lung)
                        :op2 (l2 / liver))
                  :mod (h / histologic))
            :ARG1 (a3 / absent-01
                  :ARG1 (d2 / disseminate-01
                        :ARG1 (c / cell
                              :mod (c2 / cancer)))
                  :ARG2 (s / section-01
                        :ARG1 (t / tissue)
                        :ARG3 (m / mouse
                              :ARG1-of (t2 / treat-04
                                    :ARG2 (s2 / small-molecule :name (n2 / name :op1 "RocA")))))))
      :ARG2 (o / observe-01
            :ARG1 (a4 / abound-01
                  :ARG1 c)
            :location (m2 / mouse
                  :ARG1-of (t3 / treat-04
                        :ARG2 (v / vehicle))))
      :ARG1-of (d3 / describe-01
            :ARG0 (f / figure :mod "5D")))

# ::id pmid_2456_8222.104 ::date 2015-08-27T13:30:49 ::annotator SDL-AMR-09 ::preferred
# ::snt Comparison of the survival curve of RocA-treated mice with that of vehicle-treated mice showed that RocA treatment significantly prolonged the survival of tumor-bearing mice (Additional file <xref ref-type="supplementary-material" rid="S1">1</xref>: Figure S6A,B).
# ::save-date Tue Sep 1, 2015 ::file pmid_2456_8222_104.txt
(s / show-01
      :ARG0 (c / compare-01
            :ARG1 (c2 / curve
                  :mod (s2 / survive-01
                        :ARG0 (m / mouse
                              :ARG1-of (t / treat-04
                                    :ARG2 (s3 / small-molecule :name (n / name :op1 "RocA"))))))
            :ARG2 (c3 / curve
                  :mod (s6 / survive-01
                        :ARG0 (m2 / mouse
                              :ARG1-of (t3 / treat-04
                                    :ARG2 (v / vehicle))))))
      :ARG1 (p / prolong-01
            :ARG0 t
            :ARG1 (s5 / survive-01
                  :ARG0 (m3 / mouse
                        :ARG0-of (b / bear-01
                              :ARG1 (t4 / tumor))))
            :ARG1-of (s4 / significant-02))
      :ARG1-of (d / describe-01
            :ARG0 (a / and
                  :op1 (f / figure :mod "S6A")
                  :op2 (f2 / figure :mod "S6B")
                  :location (f3 / file :mod 1
                        :ARG1-of (a2 / add-02)))))

# ::id pmid_2456_8222.105 ::date 2015-08-27T13:37:57 ::annotator SDL-AMR-09 ::preferred
# ::snt Taken together, RocA impairs the migration of pancreatic cancer cells <i>in vitro</i> and <i>in vivo</i>.
# ::save-date Thu Aug 27, 2015 ::file pmid_2456_8222_105.txt
(i / impair-01
      :ARG0 (s / small-molecule :name (n2 / name :op1 "RocA"))
      :ARG1 (a / and
            :op1 (m / migrate-01
                  :ARG0 (c / cell
                        :mod (c2 / cancer
                              :mod (p / pancreas)))
                  :manner (i2 / in-vitro))
            :op2 (m2 / migrate-01
                  :ARG0 c
                  :manner (i3 / in-vivo)))
      :ARG1-of (t / take-01
            :manner (t2 / together)))

# ::id pmid_2456_8222.106 ::date 2015-08-27T13:41:15 ::annotator SDL-AMR-09 ::preferred
# ::snt <sec-title level="2">RocA suppresses <i>in vivo</i> growth of tumor xenografts</sec-title>
# ::save-date Thu Aug 27, 2015 ::file pmid_2456_8222_106.txt
(s / suppress-01
      :ARG0 (s2 / small-molecule :name (n / name :op1 "RocA"))
      :ARG1 (g / grow-01
            :ARG1 (x / xenograft
                  :mod (t / tumor)))
      :manner (i / in-vivo))

# ::id pmid_2456_8222.107 ::date 2015-08-27T13:43:12 ::annotator SDL-AMR-09 ::preferred
# ::snt To further evaluate the anti-tumor activity of RocA, we administered RocA to SCID mice bearing subcutaneous AsPC-1 tumor cell xenografts and monitored the tumor growth rate.
# ::save-date Tue Sep 1, 2015 ::file pmid_2456_8222_107.txt
(a2 / and
      :op1 (a / administer-01
            :ARG0 (w / we)
            :ARG1 (s / small-molecule :name (n / name :op1 "RocA"))
            :ARG2 (m / mouse
                  :mod (i / immunodeficient)
                  :ARG1-of (c / combine-01
                        :degree (s3 / severe))
                  :ARG0-of (b / bear-01
                        :ARG1 (x / xenograft
                              :mod (c2 / cell-line :name (n2 / name :op1 "AsPC-1")
                                    :mod (t / tumor))
                              :mod (s2 / subcutaneous)))))
      :op2 (m2 / monitor-01
            :ARG0 w
            :ARG1 (r / rate
                  :mod (g2 / grow-01
                        :ARG1 t)))
      :purpose (e / evaluate-01
            :ARG0 w
            :ARG1 (a3 / activity-06
                  :ARG0 s
                  :ARG0-of (c3 / counter-01
                        :ARG1 t))
            :degree (f / further)))

# ::id pmid_2456_8222.108 ::date 2015-08-27T13:55:01 ::annotator SDL-AMR-09 ::preferred
# ::snt RocA was administrated by intraperitoneal injection once per day.
# ::save-date Tue Sep 15, 2015 ::file pmid_2456_8222_108.txt
(a / administrate-01
      :ARG1 (s / small-molecule :name (n / name :op1 "RocA"))
      :frequency (r / rate-entity-91
            :ARG1 1
            :ARG2 (t / temporal-quantity :quant 1
                  :unit (d / day)))
      :manner (i / inject-01
            :ARG1 s
            :mod (i2 / intraperitoneal)))

# ::id pmid_2456_8222.109 ::date 2015-08-27T14:02:33 ::annotator SDL-AMR-09 ::preferred
# ::snt As a result, RocA significantly suppressed tumor growth compared with that in the control group.
# ::save-date Tue Sep 1, 2015 ::file pmid_2456_8222_109.txt
(s / suppress-01
      :ARG0 (s2 / small-molecule :name (n / name :op1 "RocA"))
      :ARG1 (g / grow-01
            :ARG1 (t / tumor))
      :ARG1-of (s3 / significant-02)
      :ARG2-of (r / result-01)
      :compared-to (g3 / grow-01
            :ARG1 t
            :location (g2 / group
                  :mod (c / control))))

# ::id pmid_2456_8222.110 ::date 2015-08-27T14:04:28 ::annotator SDL-AMR-09 ::preferred
# ::snt Tumor volumes in the RocA-treated group were 37 ± 8% of those in the control group (Figure <xref ref-type="fig" rid="F6">6</xref>A,B).
# ::save-date Tue Sep 15, 2015 ::file pmid_2456_8222_110.txt
(e / equal-01
      :ARG1 (v / volume
            :quant-of (t / tumor)
            :location (g / group
                  :ARG1-of (t2 / treat-04
                        :ARG2 (s / small-molecule :name (n / name :op1 "RocA")))))
      :ARG2 (v3 / value-interval
            :op1 (p4 / product-of
                  :op1 (p2 / percentage-entity :value 37
                        :ARG2-of (s2 / subtract-01
                              :ARG1 (p / percentage-entity :value 8)))
                  :op2 (v2 / volume
                        :location (g2 / group
                              :mod (c / control))
                        :quant-of t))
            :op2 (p5 / product-of
                  :op1 (p3 / percentage-entity :value 37
                        :ARG2-of (a / add-02
                              :ARG1 p))
                  :op2 v2))
      :ARG1-of (d / describe-01
            :ARG0 (a2 / and
                  :op1 (f / figure :mod "6A")
                  :op2 (f2 / figure :mod "6B"))))

# ::id pmid_2456_8222.111 ::date 2015-08-28T05:32:37 ::annotator SDL-AMR-09 ::preferred
# ::snt Intriguingly, RocA treatment neither caused any loss of body weight nor exhibited apparent signs of toxicity in mice during the treatments (Figure <xref ref-type="fig" rid="F6">6</xref>C), suggesting that RocA is generally well tolerated <i>in vivo</i>.
# ::save-date Tue Sep 1, 2015 ::file pmid_2456_8222_111.txt
(a / and
      :op1 (c / cause-01 :polarity -
            :ARG0 (t / treat-04
                  :ARG2 (s / small-molecule :name (n / name :op1 "RocA")))
            :ARG1 (l / lose-02
                  :ARG1 (w / weight-01
                        :ARG1 (b / body))
                  :mod (a2 / any)))
      :op2 (e / exhibit-01 :polarity -
            :ARG0 t
            :ARG1 (s2 / signal-07
                  :ARG1 (t2 / toxicity)
                  :ARG1-of (a3 / appear-02))
            :location (m / mouse))
      :time (t3 / treat-04)
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod "6C"))
      :ARG0-of (s3 / suggest-01
            :ARG1 (t4 / tolerate-01
                  :ARG1 s
                  :ARG1-of (w2 / well-09
                        :ARG1-of (g / general-02))
                  :manner (i / in-vivo)))
      :ARG0-of (i2 / intrigue-01))

# ::id pmid_2456_8222.112 ::date 2015-08-28T05:41:04 ::annotator SDL-AMR-09 ::preferred
# ::snt Moreover, although RocA-treated mice eventually died from the pancreatic tumors, treatment with RocA significantly extended their lifespan compared with that of vehicle treatment (Figure <xref ref-type="fig" rid="F6">6</xref>D,E).
# ::save-date Tue Sep 1, 2015 ::file pmid_2456_8222_112.txt
(a / and
      :op2 (h / have-concession-91
            :ARG1 (e2 / extend-01
                  :ARG0 t
                  :ARG1 (l / lifespan
                        :poss m)
                  :ARG1-of (s2 / significant-02)
                  :compared-to (l2 / lifespan
                        :poss (m2 / mouse
                              :ARG1-of (t4 / treat-04
                                    :ARG2 (v / vehicle)))))
            :ARG2 (d / die-01
                  :ARG1 (m / mouse
                        :ARG1-of (t / treat-04
                              :ARG2 (s / small-molecule :name (n / name :op1 "RocA"))))
                  :time (e / eventual)
                  :ARG1-of (c / cause-01
                        :ARG0 (t2 / tumor
                              :mod (p / pancreas)))))
      :ARG1-of (d2 / describe-01
            :ARG0 (a2 / and
                  :op1 (f / figure :mod "6D")
                  :op2 (f2 / figure :mod "6E"))))

# ::id pmid_2456_8222.113 ::date 2015-08-28T05:48:21 ::annotator SDL-AMR-09 ::preferred
# ::snt Next, we investigated the effect of RocA on cell proliferation <i>in vivo</i> by hematoxylin and eosin (H&E) staining and examining Ki-67 and cyclin D1 expression in tumor tissues harvested from vehicle- and RocA-treated mice.
# ::save-date Sat Feb 13, 2016 ::file pmid_2456_8222_113.txt
(i3 / investigate-01
      :ARG0 (w / we)
      :ARG1 (a / affect-01
            :ARG0 (s / small-molecule :name (n / name :op1 "RocA"))
            :ARG1 (p / proliferate-01
                  :ARG0 (c / cell)
                  :manner (i2 / in-vivo)))
      :manner (a6 / and
            :op1 (s2 / stain-01
                  :ARG0 w
                  :ARG2 (a2 / and
                        :op1 (s3 / small-molecule :name (n2 / name :op1 "hematoxylin"))
                        :op2 (s4 / small-molecule :name (n3 / name :op1 "eosin"))))
            :op2 (e2 / examine-01
                  :ARG0 w
                  :ARG1 (a4 / and
                        :op1 (e / express-03
                              :ARG2 (p2 / protein :name (n4 / name :op1 "Ki-67"))
                              :ARG3 (t / tissue
                                    :mod (t2 / tumor)
                                    :ARG1-of (h / harvest-01
                                          :source (a5 / and
                                                :op1 (m3 / mouse
                                                      :ARG1-of (t3 / treat-04
                                                            :ARG2 s))
                                                :op2 (m4 / mouse
                                                      :ARG1-of (t4 / treat-04
                                                            :ARG2 (v / vehicle)))))))
                        :op2 (e3 / express-03
                              :ARG2 (p3 / protein :name (n5 / name :op1 "cyclin" :op2 "D1"))
                              :ARG3 t))))
      :time (n6 / next))

# ::id pmid_2456_8222.114 ::date 2015-08-28T05:57:10 ::annotator SDL-AMR-09 ::preferred
# ::snt H&E staining showed a compact mass of epithelial cells in vehicle-treated mice, whereas RocA-treated tumors exhibited loose epithelial cell aggregates with a higher number of interspersed mesenchymal cells (Figure <xref ref-type="fig" rid="F6">6</xref>F, left).
# ::save-date Sat Feb 13, 2016 ::file pmid_2456_8222_114.txt
(c3 / contrast-01
      :ARG1 (s / show-01
            :ARG0 (s2 / stain-01
                  :ARG2 (a / and
                        :op1 (s4 / small-molecule :name (n / name :op1 "hematoxylin"))
                        :op2 (s5 / small-molecule :name (n2 / name :op1 "eosin"))))
            :ARG1 (m4 / mass-01
                  :ARG0 (c2 / cell
                        :mod (e / epithelium))
                  :location (m5 / mouse
                        :ARG1-of (t / treat-04
                              :ARG2 (v / vehicle)))
                  :ARG1-of (c / compact-01)))
      :ARG2 (e2 / exhibit-01
            :ARG0 (t2 / tumor
                  :ARG1-of (t3 / treat-04
                        :ARG2 (s3 / small-molecule :name (n3 / name :op1 "RocA"))))
            :ARG1 (a2 / aggregate-01
                  :ARG1 (c4 / cell)
                  :ARG1-of (l / loose-04)
                  :ARG0-of (h2 / have-03
                        :ARG1 (n4 / number
                              :ARG1-of (h / high-02
                                    :degree (m / more))
                              :quant-of (c5 / cell
                                    :mod (m6 / mesenchymal)
                                    :ARG1-of (i / intersperse-01))))
                  :mod e))
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod "6F"
                  :ARG1-of (l2 / left-20))))

# ::id pmid_2456_8222.115 ::date 2015-08-28T06:13:45 ::annotator SDL-AMR-09 ::preferred
# ::snt In addition, RocA treatment resulted in a 3.2-fold decrease of Ki-67-positive cells in tumor sections from RocA-treated mice compared with that in vehicle-treated mice (Figure <xref ref-type="fig" rid="F6">6</xref>F, middle and <xref ref-type="fig" rid="F6">6</xref>G, upper).
# ::save-date Tue Sep 1, 2015 ::file pmid_2456_8222_115.txt
(a2 / and
      :op2 (r / result-01
            :ARG1 (t / treat-04
                  :ARG2 (s / small-molecule :name (n / name :op1 "RocA")))
            :ARG2 (d / decrease-01
                  :ARG1 (c / cell
                        :mod (p2 / positive
                              :mod (p3 / protein :name (n2 / name :op1 "Ki-67"))))
                  :ARG2 (p / product-of :op1 3.2)
                  :location (s2 / section-01
                        :ARG1 (t2 / tumor)
                        :ARG3 (m / mouse
                              :ARG1-of t))
                  :compared-to (d3 / decrease-01
                        :location (m2 / mouse
                              :ARG1-of (t4 / treat-04
                                    :ARG2 (v / vehicle)))))
            :ARG1-of (d2 / describe-01
                  :ARG0 (a / and
                        :op1 (f / figure :mod "6F"
                              :direction (m3 / middle))
                        :op2 (f2 / figure :mod "6G"
                              :direction (u / upper))))))

# ::id pmid_2456_8222.116 ::date 2015-08-28T06:23:56 ::annotator SDL-AMR-09 ::preferred
# ::snt Furthermore, we found a 4.1-fold decrease of cyclin D1-positive cells in tumor sections from RocA-treated mice relative to that in vehicle-treated mice (Figure <xref ref-type="fig" rid="F6">6</xref>F, right and 6G, lower).
# ::save-date Sat Jan 30, 2016 ::file pmid_2456_8222_116.txt
(a / and
      :op2 (f / find-01
            :ARG0 (w / we)
            :ARG1 (d / decrease-01
                  :ARG1 (c / cell
                        :mod (p2 / positive
                              :mod (p3 / protein :name (n / name :op1 "cyclin" :op2 "D1"))))
                  :ARG2 (p / product-of :op1 4.1)
                  :location (s / section-01
                        :ARG1 (t / tumor)
                        :ARG3 (m2 / mouse
                              :ARG1-of (t2 / treat-04
                                    :ARG2 (s2 / small-molecule :name (n2 / name :op1 "RocA")))))
                  :ARG1-of (r / relative-05
                        :ARG3 (d3 / decrease-01
                              :location (m3 / mouse
                                    :ARG1-of (t4 / treat-04
                                          :ARG2 (v / vehicle)))))))
      :ARG1-of (d2 / describe-01
            :ARG0 (a2 / and
                  :op1 (f2 / figure :mod "6F"
                        :ARG1-of (r2 / right-04))
                  :op2 (f3 / figure :mod "6G"
                        :ARG1-of (l / low-04
                              :degree (m / more))))))

# ::id pmid_2456_8222.117 ::date 2015-08-28T06:28:45 ::annotator SDL-AMR-09 ::preferred
# ::snt Therefore, RocA is a potent small molecule that suppresses the growth of AsPC-1 cell-derived tumors <i>in vivo</i>.
# ::save-date Tue Sep 1, 2015 ::file pmid_2456_8222_117.txt
(c / cause-01
      :ARG1 (m / molecule
            :mod (s / small)
            :mod (p / potent)
            :domain (s2 / small-molecule :name (n / name :op1 "RocA"))
            :ARG0-of (s3 / suppress-01
                  :ARG1 (g / grow-01
                        :ARG1 (t / tumor
                              :mod (i / in-vivo)
                              :ARG1-of (d / derive-01
                                    :ARG2 (c2 / cell-line :name (n2 / name :op1 "AsPC-1"))))))))

# ::id pmid_2464_2271.1 ::date 2015-08-07T08:32:05 ::annotator SDL-AMR-09 ::preferred
# ::snt Prostate cancer ETS rearrangements switch a cell migration gene expression program from RAS/ERK to PI3K/AKT regulation (PMID:24642271)
# ::save-date Thu Dec 10, 2015 ::file pmid_2464_2271_1.txt
(s / switch-01
      :ARG0 (r / rearrange-01
            :ARG1 (p7 / protein-family :name (n2 / name :op1 "ETS"))
            :mod (d3 / disease :wiki "Prostate_cancer" :name (n5 / name :op1 "prostate" :op2 "cancer")))
      :ARG1 (p2 / program
            :mod (e / express-03
                  :ARG1 (g2 / gene)
                  :ARG3 (c / cell
                        :ARG0-of (m / migrate-01))))
      :ARG2 (r3 / regulate-01
            :ARG1 (p4 / pathway :name (n4 / name :op1 "PI3K/AKT")))
      :ARG3 (r2 / regulate-01
            :ARG1 (p3 / pathway :name (n3 / name :op1 "RAS/ERK")))
      :ARG1-of (d2 / describe-01
            :ARG0 (p5 / publication-91
                  :ARG8 "PMID24642271")))

# ::id pmid_2464_2271.8 ::date 2015-08-08T12:49:06 ::annotator SDL-AMR-09 ::preferred
# ::snt <sec-title level="1" sec-area="abstract">Results</sec-title>
# ::save-date Sat Aug 8, 2015 ::file pmid_2464_2271_8.txt
(t / thing
      :ARG2-of (r / result-01))

# ::id pmid_2464_2271.9 ::date 2015-08-08T13:41:18 ::annotator SDL-AMR-09 ::preferred
# ::snt We find that oncogenic ETS expression negatively correlates with <i>RAS</i> and <i>RAF</i> mutations in prostate tumors.
# ::save-date Fri Feb 5, 2016 ::file pmid_2464_2271_9.txt
(f / find-01
      :ARG0 (w / we)
      :ARG1 (c / correlate-01
            :ARG1 (e / express-03
                  :ARG2 (p2 / protein :name (n / name :op1 "ETS")
                        :ARG0-of (c2 / cause-01
                              :ARG1 (d / disease :wiki "Cancer" :name (n2 / name :op1 "cancer")))))
            :ARG2 (m / mutate-01
                  :ARG1 (a / and
                        :op1 (g / gene :name (n3 / name :op1 "RAS"))
                        :op2 (g2 / gene :name (n4 / name :op1 "RAF"))))
            :ARG2-of (n5 / negative-01)
            :location (t / tumor
                  :mod (p / prostate))))

# ::id pmid_2464_2271.10 ::date 2015-08-08T13:52:38 ::annotator SDL-AMR-09 ::preferred
# ::snt Furthermore, the oncogenic ETS transcription factors only increased cell migration in the absence of RAS/ERK activation.
# ::save-date Thu Sep 24, 2015 ::file pmid_2464_2271_10.txt
(a / and
      :op2 (i / increase-01
            :ARG0 (p / protein-family
                  :name (n / name :op1 "ETS" :op2 "transcription" :op3 "factor")
                  :ARG0-of (c2 / cause-01
                        :ARG1 (d / disease :wiki "Cancer"
                              :name (n3 / name :op1 "cancer"))))
            :ARG1 (m / migrate-01
                  :ARG0 (c / cell))
            :mod (o / only)
            :condition (a2 / absent-01
                  :ARG1 (a3 / activate-01
                        :ARG1 (p2 / pathway
                              :name (n2 / name :op1 "RAS/ERK"))))))

# ::id pmid_2464_2271.11 ::date 2015-08-08T23:49:25 ::annotator SDL-AMR-09 ::preferred
# ::snt In contrast to RAS/ERK, it has been reported that oncogenic ETS expression positively correlates with PI3K/AKT activation.
# ::save-date Sun Jan 17, 2016 ::file pmid_2464_2271_11.txt
(c / contrast-01
      :ARG1 (r / report-01
            :ARG1 (c2 / correlate-01
                  :ARG1 (e / express-03
                        :ARG2 (p4 / protein :name (n2 / name :op1 "ETS")
                              :ARG0-of (c3 / cause-01
                                    :ARG1 (d / disease :wiki "Cancer" :name (n4 / name :op1 "cancer")))))
                  :ARG2 (a / activate-01
                        :ARG1 (p / pathway :name (n / name :op1 "PI3K/AKT")))
                  :manner (p2 / positive)))
      :ARG2 (p3 / pathway :name (n3 / name :op1 "RAS/ERK")))

# ::id pmid_2464_2271.12 ::date 2015-08-08T23:52:16 ::annotator SDL-AMR-09 ::preferred
# ::snt We identified a mechanistic explanation for this finding by showing that oncogenic ETS proteins required AKT signaling to activate a cell migration gene expression program through ETS/AP-1 binding sequences.
# ::save-date Sun Jan 17, 2016 ::file pmid_2464_2271_12.txt
(i / identify-01
      :ARG0 (w / we)
      :ARG1 (e / explain-01
            :ARG1 (t / thing
                  :mod (t2 / this)
                  :ARG1-of (f / find-01))
            :mod (m2 / mechanistic))
      :manner (s / show-01
            :ARG0 w
            :ARG1 (r / require-01
                  :ARG0 (a / activate-01
                        :ARG0 (p / protein :name (n / name :op1 "ETS")
                              :ARG0-of (c / cause-01
                                    :ARG1 (d / disease :wiki "Cancer" :name (n2 / name :op1 "cancer"))))
                        :ARG1 (p2 / program
                              :mod (e2 / express-03
                                    :ARG1 (g / gene)
                                    :ARG3 (c2 / cell
                                          :ARG0-of (m / migrate-01))))
                        :instrument (p4 / protein-segment :name (n3 / name :op1 "ETS/AP-1")
                              :ARG2-of (b / bind-01)))
                  :ARG1 (s2 / signal-07
                        :ARG0 (p3 / pathway :name (n4 / name :op1 "AKT"))))))

# ::id pmid_2464_2271.13 ::date 2015-08-09T00:02:43 ::annotator SDL-AMR-09 ::preferred
# ::snt Levels of pAKT correlated with the ability of oncogenic ETS proteins to increase cell migration, but this process did not require mTORC1.
# ::save-date Sun Jan 17, 2016 ::file pmid_2464_2271_13.txt
(c / correlate-01
      :ARG1 (l / level
            :quant-of (e / enzyme :name (n / name :op1 "AKT")
                  :ARG3-of (p / phosphorylate-01)))
      :ARG2 (c2 / capable-01
            :ARG1 (p2 / protein :name (n2 / name :op1 "ETS")
                  :ARG0-of (c3 / cause-01
                        :ARG1 (d / disease :wiki "Cancer" :name (n3 / name :op1 "cancer"))))
            :ARG2 (i / increase-01
                  :ARG0 p2
                  :ARG1 (m / migrate-01
                        :ARG0 (c4 / cell))))
      :ARG1-of (c5 / contrast-01
            :ARG2 (r / require-01 :polarity -
                  :ARG0 (p3 / process
                        :mod (t / this))
                  :ARG1 (m2 / macro-molecular-complex :name (n4 / name :op1 "mTORC1")))))

# ::id pmid_2464_2271.48 ::date 2015-08-09T00:13:03 ::annotator SDL-AMR-09 ::preferred
# ::snt <sec-title level="1">Results</sec-title>
# ::save-date Sun Aug 9, 2015 ::file pmid_2464_2271_48.txt
(t / thing
      :ARG2-of (r / result-01))

# ::id pmid_2464_2271.49 ::date 2015-08-09T00:13:53 ::annotator SDL-AMR-09 ::preferred
# ::snt <sec-title level="2">Oncogenic ETS gene rearrangement occurs in tumors lacking RAS/ERK mutations</sec-title>
# ::save-date Sun Jan 17, 2016 ::file pmid_2464_2271_49.txt
(r / rearrange-01
      :ARG1 (g / gene
            :ARG0-of (c / cause-01
                  :ARG1 (d / disease :wiki "Cancer" :name (n2 / name :op1 "cancer")))
            :ARG0-of (e / encode-01
                  :ARG1 (p2 / protein-family :name (n / name :op1 "ETS"))))
      :location (t / tumor
            :ARG0-of (l / lack-01
                  :ARG1 (m / mutate-01
                        :ARG1 (p / pathway :name (n3 / name :op1 "RAS/ERK"))))))

# ::id pmid_2464_2271.50 ::date 2015-08-09T00:15:42 ::annotator SDL-AMR-09 ::preferred
# ::snt If oncogenic ETS gene rearrangements replace RAS/ERK activation, we predict that RAS/ERK mutations will occur only in ETS rearrangement negative tumors.
# ::save-date Sun Jan 17, 2016 ::file pmid_2464_2271_50.txt
(p / predict-01
      :ARG0 (w / we)
      :ARG1 (m / mutate-01
            :ARG1 (p2 / pathway :name (n / name :op1 "RAS/ERK"))
            :location (t / tumor
                  :mod (r / rearrange-01 :polarity -
                        :ARG1 (g / gene
                              :ARG0-of (e / encode-01
                                    :ARG1 (p3 / protein-family :name (n2 / name :op1 "ETS")))
                              :ARG0-of (c / cause-01
                                    :ARG1 (d / disease :wiki "Cancer" :name (n3 / name :op1 "cancer")))))
                  :mod (o / only)))
      :condition (r2 / replace-01
            :ARG1 (a / activate-01
                  :ARG1 p2)
            :ARG2 (r3 / rearrange-01
                  :ARG1 g)))

# ::id pmid_2464_2271.51 ::date 2015-08-09T00:22:36 ::annotator SDL-AMR-09 ::preferred
# ::snt To test this hypothesis, we examined the results of three recently published studies [<xref ref-type="bibr" rid="B6">6</xref>,<xref ref-type="bibr" rid="B22">22</xref>,<xref ref-type="bibr" rid="B23">23</xref>] that both sequence exons and identify chromosome rearrangements in prostate tumors (Table <xref ref-type="table" rid="T1">1</xref>).
# ::save-date Tue Jan 19, 2016 ::file pmid_2464_2271_51.txt
(e / examine-01
      :ARG0 (w / we)
      :ARG1 (a2 / and
            :op1 (s2 / sequence-01
                  :ARG0 (b / both)
                  :ARG1 (e2 / exon))
            :op2 (i / identify-01
                  :ARG0 b
                  :ARG1 (r3 / rearrange-01
                        :ARG1 (c2 / chromosome)
                        :location (t4 / tumor
                              :mod (p2 / prostate))))
            :ARG2-of (r / result-01
                  :ARG1 (s / study-01 :quant 3
                        :ARG1-of (p / publish-01
                              :time (r2 / recent))
                        :ARG1-of (c / cite-01
                              :ARG2 (a / and :op1 6 :op2 22 :op3 23)))))
      :purpose (t3 / test-01
            :ARG0 w
            :ARG1 (t / thing
                  :ARG1-of (h / hypothesize-01)
                  :mod (t6 / this)))
      :ARG1-of (d / describe-01
            :ARG0 (t5 / table :mod 1)))

# ::id pmid_2464_2271.52 ::date 2015-08-09T00:55:20 ::annotator SDL-AMR-09 ::preferred
# ::snt Together these studies examine 266 prostate tumors.
# ::save-date Sun Aug 9, 2015 ::file pmid_2464_2271_52.txt
(e / examine-01
      :ARG0 (s / study-01
            :mod (t / this)
            :mod (t3 / together))
      :ARG1 (t2 / tumor :quant 266
            :mod (p / prostate)))

# ::id pmid_2464_2271.53 ::date 2015-08-09T00:56:38 ::annotator SDL-AMR-09 ::preferred
# ::snt One-half (133) have ERG or ETV1 chromosome rearrangements.
# ::save-date Sun Aug 9, 2015 ::file pmid_2464_2271_53.txt
(h / have-03
      :ARG0 (t / thing :quant 133
            :ARG1-of (i / include-91
                  :ARG2 (t2 / thing)
                  :ARG3 "1/2"))
      :ARG1 (r / rearrange-01
            :ARG1 (o / or
                  :op1 (c / chromosome
                        :mod (g / gene :name (n / name :op1 "ERG")))
                  :op2 (c2 / chromosome
                        :mod (g2 / gene :name (n2 / name :op1 "ETV1"))))))

# ::id pmid_2464_2271.54 ::date 2015-08-09T01:07:18 ::annotator SDL-AMR-09 ::preferred
# ::snt We searched for either gene fusions, or point mutations in canonical RAS/ERK pathway genes (RAS, RAF, MEK, and ERK encoding genes).
# ::save-date Sat Jan 16, 2016 ::file pmid_2464_2271_54.txt
(s / search-01
      :ARG0 (w / we)
      :ARG2 (o / or
            :op1 (f / fuse-01
                  :ARG1 (g / gene
                        :mod (p2 / pathway :name (n5 / name :op1 "RAS/ERK")
                              :mod (c / canonical))
                        :ARG1-of (m2 / mean-01
                              :ARG2 (g2 / gene
                                    :ARG0-of (e5 / encode-01
                                          :ARG1 (a / and
                                                :op1 (e / enzyme :name (n / name :op1 "RAS"))
                                                :op2 (e2 / enzyme :name (n2 / name :op1 "RAF"))
                                                :op3 (e3 / enzyme :name (n3 / name :op1 "MEK"))
                                                :op4 (e4 / enzyme :name (n4 / name :op1 "ERK"))))))))
            :op2 (m / mutate-01
                  :ARG1 g
                  :mod (p / point))))

# ::id pmid_2464_2271.55 ::date 2015-08-09T01:14:37 ::annotator SDL-AMR-09 ::preferred
# ::snt Eight tumors had such aberrations, and all eight were negative for oncogenic ETS rearrangements.
# ::save-date Fri Feb 5, 2016 ::file pmid_2464_2271_55.txt
(a / and
      :op1 (h / have-03
            :ARG0 (t / tumor :quant 8)
            :ARG1 (a2 / aberration
                  :mod (s / such)))
      :op2 (n / negative-01
            :ARG1 (t2 / tumor
                  :ARG1-of (i / include-91
                        :ARG2 t
                        :ARG3 (a3 / all)))
            :ARG2 (r / rearrange-01
                  :ARG1 (g / gene :name (n2 / name :op1 "ETS")
                        :ARG0-of (c / cause-01
                              :ARG1 (d / disease :wiki "Cancer" :name (n3 / name :op1 "cancer")))))))

# ::id pmid_2464_2271.56 ::date 2015-08-09T01:19:56 ::annotator SDL-AMR-09 ::preferred
# ::snt This indicates that, while genomic alterations in RAS/ERK pathway components are rare in prostate cancer, there is a statistically significant (P = 0.007; Fisher’s exact test) mutual exclusivity of these alterations and ETS rearrangements.
# ::save-date Mon Dec 14, 2015 ::file pmid_2464_2271_56.txt
(i / indicate-01
      :ARG0 (t / this)
      :ARG1 (s / significant-02
            :ARG1 (e / exclusive-02
                  :ARG0 a3
                  :ARG2 (r / rearrange-01
                        :ARG1 (g / gene :name (n2 / name :op1 "ETS")))
                  :manner (m / mutual))
            :mod (s2 / statistics)
            :concession (r2 / rare-02
                  :ARG1 (a3 / alter-01
                        :ARG1 (c / component
                              :mod (p2 / pathway :name (n3 / name :op1 "RAS/ERK")))
                        :mod (g2 / genome))
                  :location (d2 / disease :wiki "Prostate_cancer" :name (n5 / name :op1 "prostate" :op2 "cancer")))
            :ARG1-of (s3 / statistical-test-91
                  :ARG2 0.007
                  :ARG4 (t2 / thing :name (n / name :op1 "Fisher’s" :op2 "exact" :op3 "test")))))

# ::id pmid_2464_2271.57 ::date 2015-08-09T01:40:18 ::annotator SDL-AMR-09 ::preferred
# ::snt It has been previously reported that PI3K/AKT activation via PTEN deletion positively correlates with ETS gene rearrangements [<xref ref-type="bibr" rid="B16">16</xref>,<xref ref-type="bibr" rid="B20">20</xref>].
# ::save-date Mon Sep 28, 2015 ::file pmid_2464_2271_57.txt
(r / report-01
      :ARG1 (c / correlate-01
            :ARG1 (a / activate-01
                  :ARG1 (p3 / pathway :name (n / name :op1 "PI3K/AKT"))
                  :manner (d / delete-01
                        :ARG1 (p4 / protein :name (n2 / name :op1 "PTEN"))))
            :ARG2 (r2 / rearrange-01
                  :ARG1 (g / gene
                        :ARG0-of (e / encode-01
                              :ARG1 (p6 / protein-family :name (n3 / name :op1 "ETS")))))
            :manner (p2 / positive))
      :time (p / previous)
      :ARG1-of (d2 / describe-01
            :ARG0 (p5 / publication
                  :ARG1-of (c2 / cite-01
                        :ARG2 (a2 / and :op1 16 :op2 20)))))

# ::id pmid_2464_2271.58 ::date 2015-08-09T01:48:03 ::annotator SDL-AMR-09 ::preferred
# ::snt A search for PTEN loss in these 266 tumors (Table <xref ref-type="table" rid="T1">1</xref>) confirms these findings and indicates that PTEN loss is more than twice as likely in tumors with ETS gene rearrangements than in those without (P = 0.0008; Fisher’s exact test).
# ::save-date Mon Dec 14, 2015 ::file pmid_2464_2271_58.txt
(a / and
      :op1 (c / confirm-01
            :ARG0 (s / search-01
                  :ARG1 (t / tumor :quant 266
                        :mod (t2 / this))
                  :ARG2 (l / lose-02
                        :ARG1 (p / protein :name (n / name :op1 "PTEN")))
                  :ARG1-of (d / describe-01
                        :ARG0 (t3 / table :mod 1)))
            :ARG1 (t4 / thing
                  :mod t2
                  :ARG1-of (f / find-01)))
      :op2 (i / indicate-01
            :ARG0 s
            :ARG1 (l2 / likely-01
                  :ARG1 (l3 / lose-02
                        :ARG1 p
                        :location (t5 / tumor
                              :mod (r / rearrange-01
                                    :ARG1 (g / gene
                                          :ARG0-of (e / encode-01
                                                :ARG1 (p4 / protein-family :name (n2 / name :op1 "ETS")))))))
                  :degree (m / more-than
                        :op1 (p2 / product-of :op1 2
                              :op2 (t6 / tumor
                                    :mod (r2 / rearrange-01 :polarity -
                                          :ARG1 g))))
                  :ARG1-of (s2 / statistical-test-91
                        :ARG2 0.0008
                        :ARG4 (t7 / thing :name (n3 / name :op1 "Fisher’s" :op2 "exact" :op3 "test"))))))

# ::id pmid_2464_2271.59 ::date 2015-08-09T02:08:28 ::annotator SDL-AMR-09 ::preferred
# ::snt In conclusion, <i>ERG</i> and <i>ETV1</i> gene rearrangements positively correlate with PTEN loss and negatively correlate with RAS/ERK mutations in tumors.
# ::save-date Fri Feb 5, 2016 ::file pmid_2464_2271_59.txt
(c / conclude-01
      :ARG1 (a / and
            :op1 (c2 / correlate-01
                  :ARG1 (r / rearrange-01
                        :ARG1 (a2 / and
                              :op1 (g / gene :name (n / name :op1 "ERG"))
                              :op2 (g2 / gene :name (n2 / name :op1 "ETV1"))))
                  :ARG2 (l / lose-02
                        :ARG1 (p2 / protein :name (n4 / name :op1 "PTEN")))
                  :manner (p / positive))
            :op2 (c3 / correlate-01
                  :ARG1 r
                  :ARG2 (m / mutate-01
                        :ARG1 (p3 / pathway :name (n5 / name :op1 "RAS/ERK")))
                  :ARG2-of (n3 / negative-01))
            :location (t / tumor)))

# ::id pmid_2464_2271.60 ::date 2015-08-09T02:13:31 ::annotator SDL-AMR-09 ::preferred
# ::snt <sec-title level="2">Prostate cancer cell lines as models of oncogenic ETS function</sec-title>
# ::save-date Sun Jan 17, 2016 ::file pmid_2464_2271_60.txt
(m / model-01
      :ARG1 (f / function-01
            :ARG0 (p / protein :name (n / name :op1 "ETS")
                  :ARG0-of (c / cause-01
                        :ARG1 (d / disease :wiki "Cancer" :name (n2 / name :op1 "cancer")))))
      :location (c2 / cell-line
            :mod (d2 / disease :wiki "Prostate_cancer" :name (n3 / name :op1 "prostate" :op2 "cancer"))))

# ::id pmid_2464_2271.61 ::date 2015-08-09T02:21:44 ::annotator SDL-AMR-09 ::preferred
# ::snt To test the effect of RAS/ERK signaling and PI3K/AKT signaling on oncogenic ETS function in prostate cell lines, we must first determine which cell lines have these characteristics.
# ::save-date Mon Sep 28, 2015 ::file pmid_2464_2271_61.txt
(o / obligate-01
      :ARG1 (w / we)
      :ARG2 (d / determine-01
            :ARG0 w
            :ARG1 (c4 / cell-line
                  :mod (a3 / amr-unknown)
                  :ARG0-of (h / have-03
                        :ARG1 (t2 / thing
                              :mod (t3 / this)
                              :ARG2-of (c3 / characteristic-02))))
            :ord (o2 / ordinal-entity :value 1))
      :purpose (t / test-01
            :ARG0 w
            :ARG1 (a / affect-01
                  :ARG0 (a2 / and
                        :op1 (s / signal-07
                              :ARG0 (p / pathway
                                    :name (n / name :op1 "RAS/ERK")))
                        :op2 (s2 / signal-07
                              :ARG0 (p2 / pathway
                                    :name (n2 / name :op1 "PI3K/AKT"))))
                  :ARG1 (f / function-01
                        :ARG0 (g / gene
                              :name (n3 / name :op1 "ETS")
                              :ARG0-of (c / cause-01
                                    :ARG1 (d2 / disease :wiki "Cancer"
                                          :name (n4 / name :op1 "cancer"))))
                        :location (c2 / cell-line
                              :source (p3 / prostate))))))

# ::id pmid_2464_2271.62 ::date 2015-08-09T02:33:40 ::annotator SDL-AMR-09 ::preferred
# ::snt Although some prostate cancer cell lines, such as VCaP (<i>ERG</i>) and LNCaP (<i>ETV1</i>) are reported to have oncogenic ETS gene rearrangements [<xref ref-type="bibr" rid="B11">11</xref>,<xref ref-type="bibr" rid="B14">14</xref>], the full extent of oncogenic ETS protein expression, including fusion-independent expression, in commonly used prostate cancer cell lines has not been determined.
# ::save-date Sun Jan 17, 2016 ::file pmid_2464_2271_62.txt
(d / determine-01 :polarity -
      :ARG1 (e / extent
            :degree-of (e2 / express-03
                  :ARG2 (p / protein :name (n / name :op1 "ETS")
                        :ARG0-of (c / cause-01
                              :ARG1 (d2 / disease :wiki "Cancer" :name (n2 / name :op1 "cancer"))))
                  :ARG3 (c2 / cell-line
                        :mod d2
                        :ARG1-of (u / use-01
                              :mod (c3 / common)))
                  :ARG2-of (i / include-91
                        :ARG1 (e3 / express-03
                              :ARG0-of (d3 / depend-01 :polarity -
                                    :ARG1 (f2 / fuse-01)))))
            :ARG1-of (f / full-09))
      :concession (r / report-01
            :ARG1 (h / have-03
                  :ARG0 (c4 / cell-line
                        :mod (s / some)
                        :example (a / and
                              :op1 (c5 / cell-line :name (n4 / name :op1 "VCaP")
                                    :mod (g / gene :name (n6 / name :op1 "ERG")))
                              :op2 (c6 / cell-line :name (n5 / name :op1 "LNCaP")
                                    :mod (g2 / gene :name (n7 / name :op1 "ETV1"))))
                        :mod (d4 / disease :wiki "Prostate_cancer" :name (n3 / name :op1 "prostate" :op2 "cancer")))
                  :ARG1 (r2 / rearrange-01
                        :ARG1 (g3 / gene
                              :ARG0-of c
                              :ARG0-of (e4 / encode-01
                                    :ARG1 (p4 / protein-family :name (n8 / name :op1 "ETS"))))))
            :ARG1-of (d5 / describe-01
                  :ARG0 (p3 / publication
                        :ARG1-of (c7 / cite-01
                              :ARG2 (a2 / and :op1 11 :op2 14))))))

# ::id pmid_2464_2271.63 ::date 2015-08-09T03:41:50 ::annotator SDL-AMR-09 ::preferred
# ::snt To identify the expression level of the four oncogenic ETS proteins, we first tested available antibodies using purified recombinant proteins (Figure <xref ref-type="fig" rid="F1">1</xref>A).
# ::save-date Mon Sep 28, 2015 ::file pmid_2464_2271_63.txt
(t / test-01
      :ARG0 (w / we)
      :ARG1 (a / antibody
            :ARG2-of (a2 / available-02))
      :ord (o / ordinal-entity :value 1)
      :manner (u / use-01
            :ARG0 w
            :ARG1 (p / protein
                  :ARG1-of (p2 / purify-01)
                  :ARG3-of (r / recombine-01)))
      :purpose (i / identify-01
            :ARG0 w
            :ARG1 (l / level
                  :degree-of (e / express-03
                        :ARG2 (p3 / protein :quant 4
                              :name (n / name :op1 "ETS")
                              :ARG0-of (c / cause-01
                                    :ARG1 (d / disease :wiki "Cancer"
                                          :name (n2 / name :op1 "cancer")))))))
      :ARG1-of (d2 / describe-01
            :ARG0 (f / figure :mod "1A")))

# ::id pmid_2464_2271.64 ::date 2015-08-09T03:49:20 ::annotator SDL-AMR-09 ::preferred
# ::snt We identified antibodies to ERG, ETV1, ETV4, and ETV5 that could detect each protein at femtomolar levels.
# ::save-date Sun Aug 9, 2015 ::file pmid_2464_2271_64.txt
(i / identify-01
      :ARG0 (w / we)
      :ARG1 (a / antibody
            :ARG0-of (c / counter-01
                  :ARG1 (a2 / and
                        :op1 (p / protein :name (n / name :op1 "ERG"))
                        :op2 (p2 / protein :name (n2 / name :op1 "ETV1"))
                        :op3 (p3 / protein :name (n3 / name :op1 "ETV4"))
                        :op4 (p4 / protein :name (n4 / name :op1 "ETV5"))))
            :ARG0-of (d / detect-01
                  :ARG1 (p6 / protein
                        :mod (e / each)
                        :quant (l / level
                              :mod (f / femtomolar)))
                  :ARG1-of (p5 / possible-01))))

# ::id pmid_2464_2271.65 ::date 2015-08-09T04:02:33 ::annotator SDL-AMR-09 ::preferred
# ::snt Because ETV1, ETV4, and ETV5 are homologous proteins, the sensitivity and specificity of these antibodies were compared.
# ::save-date Sun Aug 9, 2015 ::file pmid_2464_2271_65.txt
(c / compare-01
      :ARG1 (a / and
            :op1 (s / sensitive-03
                  :ARG0 (a2 / antibody
                        :mod (t / this)))
            :op2 (s2 / specific-02
                  :ARG1 a2))
      :ARG1-of (c2 / cause-01
            :ARG0 (p / protein
                  :mod (h / homologous)
                  :domain (a3 / and
                        :op1 (p2 / protein :name (n / name :op1 "ETV1"))
                        :op2 (p3 / protein :name (n2 / name :op1 "ETV4"))
                        :op3 (p4 / protein :name (n3 / name :op1 "ETV5"))))))

# ::id pmid_2464_2271.66 ::date 2015-08-09T04:05:16 ::annotator SDL-AMR-09 ::preferred
# ::snt ETV1 and ETV4 antibodies were specific, but the ETV5 antibody recognized ETV4 and ETV5 equally.
# ::save-date Sun Aug 9, 2015 ::file pmid_2464_2271_66.txt
(c / contrast-01
      :ARG1 (s / specific-02
            :ARG1 (a / and
                  :op1 (a2 / antibody
                        :ARG0-of (c2 / counter-01
                              :ARG1 (p / protein :name (n / name :op1 "ETV1"))))
                  :op2 (a3 / antibody
                        :ARG0-of (c3 / counter-01
                              :ARG1 (p2 / protein :name (n2 / name :op1 "ETV4"))))))
      :ARG2 (r / recognize-02
            :ARG0 (a4 / antibody
                  :ARG0-of (c4 / counter-01
                        :ARG1 (p3 / protein :name (n3 / name :op1 "ETV5"))))
            :ARG1 (a5 / and
                  :op1 p2
                  :op2 p3)
            :manner (e / equal-01)))

# ::id pmid_2464_2271.67 ::date 2015-08-09T05:16:30 ::annotator SDL-AMR-09 ::preferred
# ::snt We then examined oncogenic ETS protein levels, along with phosphorylated ERK (pERK: RAS/ERK pathway) and phosphorylated AKT (pAKT: PI3K/AKT pathway) levels in six prostate cancer cell lines (Figure <xref ref-type="fig" rid="F1">1</xref>B and Additional file <xref ref-type="supplementary-material" rid="S1">1</xref>: Figure S1A).
# ::save-date Sun Jan 17, 2016 ::file pmid_2464_2271_67.txt
(e2 / examine-01
      :ARG0 (w / we)
      :ARG1 (a / and
            :op1 (l / level
                  :quant-of (p / protein :name (n4 / name :op1 "ETS")
                        :ARG0-of (c2 / cause-01
                              :ARG1 (d3 / disease :wiki "Cancer" :name (n2 / name :op1 "cancer")))))
            :op2 (l2 / level
                  :quant-of (p3 / pathway :name (n5 / name :op1 "ERK")
                        :ARG3-of (p4 / phosphorylate-01)
                        :ARG1-of (m / mean-01
                              :ARG2 (p5 / pathway :name (n6 / name :op1 "RAS/ERK")))))
            :op3 (l3 / level
                  :quant-of (p6 / pathway :name (n7 / name :op1 "AKT")
                        :ARG3-of p4
                        :ARG1-of (m2 / mean-01
                              :ARG2 (p7 / pathway :name (n8 / name :op1 "PI3K/AKT")))))
            :location (c / cell-line :quant 6
                  :mod (d / disease :wiki "Prostate_cancer" :name (n / name :op1 "prostate" :op2 "cancer"))))
      :time (t / then)
      :ARG1-of (d2 / describe-01
            :ARG0 (a2 / and
                  :op1 (f / figure :mod "1B")
                  :op2 (f2 / figure :mod "S1A"
                        :location (f3 / file :mod 1
                              :ARG1-of (a3 / add-02))))))

# ::id pmid_2464_2271.68 ::date 2015-08-09T13:29:31 ::annotator SDL-AMR-09 ::preferred
# ::snt DU145 cells, which have a KRAS gene rearrangement [<xref ref-type="bibr" rid="B24">24</xref>], did not have high levels of any oncogenic ETS protein, or pAKT, but did have pERK, consistent with the small fraction of prostate cancers with RAS/ERK pathway mutations (Table <xref ref-type="table" rid="T1">1</xref>).
# ::save-date Sun Jan 17, 2016 ::file pmid_2464_2271_68.txt
(c / contrast-01
      :ARG1 (h / have-03 :polarity -
            :ARG0 (c2 / cell-line :name (n2 / name :op1 "DU145")
                  :ARG0-of (h3 / have-03
                        :ARG1 (r / rearrange-01
                              :ARG1 (g / gene :name (n5 / name :op1 "KRAS")))
                        :ARG1-of (d2 / describe-01
                              :ARG0 (p3 / publication
                                    :ARG1-of (c4 / cite-01
                                          :ARG2 24)))))
            :ARG1 (o / or
                  :op1 (l / level
                        :quant-of (p / protein :name (n / name :op1 "ETS")
                              :mod (a / any)
                              :ARG0-of (c3 / cause-01
                                    :ARG1 (d / disease :wiki "Cancer" :name (n3 / name :op1 "cancer")))))
                  :op2 (l2 / level
                        :quant-of (e / enzyme :name (n4 / name :op1 "AKT")
                              :ARG3-of (p2 / phosphorylate-01)))
                  :ARG1-of (h2 / high-02)))
      :ARG2 (h4 / have-03
            :ARG0 c2
            :ARG1 (e2 / enzyme :name (n6 / name :op1 "ERK")
                  :ARG3-of p2)
            :ARG1-of (c5 / consistent-01
                  :ARG2 (f / fraction
                        :mod (s / small)
                        :quant-of (d5 / disease :wiki "Prostate_cancer" :name (n9 / name :op1 "prostate" :op2 "cancer")
                              :ARG0-of (h5 / have-03
                                    :ARG1 (m / mutate-01
                                          :ARG1 (p5 / pathway :name (n8 / name :op1 "RAS/ERK"))))))))
      :ARG1-of (d4 / describe-01
            :ARG0 (t / table :mod 1)))

# ::id pmid_2464_2271.69 ::date 2015-08-09T13:40:22 ::annotator SDL-AMR-09 ::preferred
# ::snt Of the remaining five prostate cancer cell lines, four had high expression of a single oncogenic protein.
# ::save-date Thu Dec 10, 2015 ::file pmid_2464_2271_69.txt
(e / express-03
      :ARG2 (p2 / protein
            :ARG1-of (s / single-02)
            :ARG0-of (c3 / cause-01
                  :ARG1 (d2 / disease :wiki "Cancer" :name (n2 / name :op1 "cancer"))))
      :ARG3 (c / cell-line :quant 4
            :ARG1-of (i / include-91
                  :ARG2 (c2 / cell-line :quant 5
                        :ARG1-of (r / remain-01)
                        :mod (d3 / disease :wiki "Prostate_cancer" :name (n3 / name :op1 "prostate" :op2 "cancer")))))
      :ARG1-of (h / high-02))

# ::id pmid_2464_2271.70 ::date 2015-08-09T13:44:13 ::annotator SDL-AMR-09 ::preferred
# ::snt These included ERG in VCaP, consistent with a <i>TMRPSS2/ERG</i> rearrangement [<xref ref-type="bibr" rid="B11">11</xref>], ETV1 in MDA-PCa-2B, consistent with an <i>ETV1</i> gene rearrangement [<xref ref-type="bibr" rid="B14">14</xref>], and ETV4 in PC3, consistent with high <i>ETV4</i> mRNA [<xref ref-type="bibr" rid="B25">25</xref>].
# ::save-date Sun Jan 17, 2016 ::file pmid_2464_2271_70.txt
(i / include-91
      :ARG1 (a / and
            :op1 (p / protein :name (n / name :op1 "ERG")
                  :location (c / cell-line :name (n4 / name :op1 "VCaP"))
                  :ARG1-of (c4 / consistent-01
                        :ARG2 (r / rearrange-01
                              :ARG1 (g / gene :name (n7 / name :op1 "TMRPSS2/ERG")))
                        :ARG1-of (d / describe-01
                              :ARG0 (p4 / publication
                                    :ARG1-of (c5 / cite-01
                                          :ARG2 11)))))
            :op2 (p2 / protein :name (n2 / name :op1 "ETV1")
                  :location (c2 / cell-line :name (n5 / name :op1 "MDA-PCa-2B"))
                  :ARG1-of (c6 / consistent-01
                        :ARG2 (r2 / rearrange-01
                              :ARG1 (g2 / gene :name (n8 / name :op1 "ETV1")))
                        :ARG1-of (d2 / describe-01
                              :ARG0 (p5 / publication
                                    :ARG1-of (c7 / cite-01
                                          :ARG2 14)))))
            :op3 (p3 / protein :name (n3 / name :op1 "ETV4")
                  :location (c3 / cell-line :name (n6 / name :op1 "PC3"))
                  :ARG1-of (c8 / consistent-01
                        :ARG2 (n11 / nucleic-acid :name (n9 / name :op1 "mRNA")
                              :ARG0-of (e / encode-01
                                    :ARG1 (p7 / protein :name (n10 / name :op1 "ETV4")))
                              :ARG1-of (h / high-02))
                        :ARG1-of (d3 / describe-01
                              :ARG0 (p6 / publication
                                    :ARG1-of (c9 / cite-01
                                          :ARG2 25))))))
      :ARG2 (t / this))

# ::id pmid_2464_2271.71 ::date 2015-08-09T13:53:46 ::annotator SDL-AMR-09 ::preferred
# ::snt ETV4 protein was also present at high levels in CWR22Rv1.
# ::save-date Sun Aug 9, 2015 ::file pmid_2464_2271_71.txt
(p / present-02
      :ARG1 (p2 / protein :name (n / name :op1 "ETV4")
            :quant (l / level
                  :ARG1-of (h / high-02)))
      :ARG2 (c / cell-line :name (n2 / name :op1 "CWR22Rv1"))
      :mod (a / also))

# ::id pmid_2464_2271.72 ::date 2015-08-09T13:55:13 ::annotator SDL-AMR-09 ::preferred
# ::snt Of the four lines with high oncogenic ETS protein expression, all had high levels of pAKT, but only one (CWR22Rv1) had high levels of pERK, consistent with the analysis of prostate tumors in Table <xref ref-type="table" rid="T1">1</xref>.
# ::save-date Sun Jan 17, 2016 ::file pmid_2464_2271_72.txt
(c / contrast-01
      :ARG1 (h / have-03
            :ARG0 (c2 / cell-line
                  :ARG1-of (i / include-91
                        :ARG2 (c3 / cell-line :quant 4
                              :ARG3-of (e / express-03
                                    :ARG2 (p / protein :name (n / name :op1 "ETS")
                                          :ARG0-of (c4 / cause-01
                                                :ARG1 (d / disease :wiki "Cancer" :name (n2 / name :op1 "cancer"))))
                                    :ARG1-of (h2 / high-02)))
                        :ARG3 (a / all)))
            :ARG1 (l / level
                  :quant-of (e2 / enzyme :name (n3 / name :op1 "AKT")
                        :ARG3-of (p2 / phosphorylate-01))
                  :ARG1-of h2))
      :ARG2 (h3 / have-03
            :ARG0 (c5 / cell-line :quant 1
                  :mod (o / only)
                  :ARG1-of (m / mean-01
                        :ARG2 (c6 / cell-line :name (n4 / name :op1 "CWR22Rv1")))
                  :ARG1-of (i2 / include-91
                        :ARG2 c3))
            :ARG1 (l2 / level
                  :ARG1-of h2
                  :quant-of (e3 / enzyme :name (n5 / name :op1 "ERK")
                        :ARG3-of p2)))
      :ARG1-of (c7 / consistent-01
            :ARG2 (a2 / analyze-01
                  :ARG1 (t / tumor
                        :mod (p3 / prostate))
                  :location (t2 / table :mod 1))))

# ::id pmid_2464_2271.73 ::date 2015-08-09T14:01:34 ::annotator SDL-AMR-09 ::preferred
# ::snt Surprisingly, despite an ETV1 gene rearrangement [<xref ref-type="bibr" rid="B14">14</xref>], and high ETV1 mRNA levels [<xref ref-type="bibr" rid="B25">25</xref>], ETV1 protein was not observed in LNCaP cells.
# ::save-date Mon Sep 28, 2015 ::file pmid_2464_2271_73.txt
(o / observe-01 :polarity -
      :ARG1 (p / protein :name (n / name :op1 "ETV1"))
      :location (c / cell-line :name (n2 / name :op1 "LNCaP"))
      :concession (a / and
            :op1 (r / rearrange-01
                  :ARG1 (g / gene :name (n3 / name :op1 "ETV1"))
                  :ARG1-of (d / describe-01
                        :ARG0 (p2 / publication
                              :ARG1-of (c2 / cite-01
                                    :ARG2 14))))
            :op2 (l / level
                  :ARG1-of (h / high-02)
                  :quant-of (n5 / nucleic-acid :name (n4 / name :op1 "mRNA")
                        :ARG0-of (e / encode-01
                              :ARG1 g))
                  :ARG1-of (d2 / describe-01
                        :ARG0 (p3 / publication
                              :ARG1-of (c3 / cite-01
                                    :ARG2 25)))))
      :ARG0-of (s / surprise-01))

# ::id pmid_2464_2271.74 ::date 2015-08-09T14:05:59 ::annotator SDL-AMR-09 ::preferred
# ::snt However, this is consistent with results from Vitari <i>et al.</i> who showed low ETV1 protein levels in LNCaP cells due to proteasomal targeting by the COP1 E3 ubiquitin ligase [<xref ref-type="bibr" rid="B26">26</xref>].
# ::save-date Wed Nov 18, 2015 ::file pmid_2464_2271_74.txt
(c / contrast-01
      :ARG2 (c2 / consistent-01
            :ARG1 (t / this)
            :ARG2 (t2 / thing
                  :ARG2-of (r / result-01
                        :ARG1 (p / publication-91
                              :ARG0 (a / and
                                    :op1 (p2 / person :name (n / name :op1 "Vitari"))
                                    :op2 (p3 / person
                                          :mod (o / other))
                                    :ARG0-of (s / show-01
                                          :ARG1 (l / level
                                                :ARG1-of (l2 / low-04
                                                      :ARG1-of (c4 / cause-01
                                                            :ARG0 (t3 / target-01
                                                                  :ARG0 (e / enzyme :name (n4 / name :op1 "COP1" :op2 "E3" :op3 "ubiquitin" :op4 "ligase"))
                                                                  :ARG1 (m / macro-molecular-complex :name (n5 / name :op1 "proteasome")))))
                                                :quant-of (p4 / protein :name (n2 / name :op1 "ETV1"))
                                                :location (c3 / cell-line :name (n3 / name :op1 "LNCaP")))))))))
      :ARG1-of (d / describe-01
            :ARG0 (p6 / publication
                  :ARG1-of (c5 / cite-01
                        :ARG2 26))))

# ::id pmid_2464_2271.75 ::date 2015-08-09T14:17:15 ::annotator SDL-AMR-09 ::preferred
# ::snt Long exposures could identify pERK, pAKT, and some ETS proteins at low levels in immunoblots from most cell lines.
# ::save-date Sun Jan 17, 2016 ::file pmid_2464_2271_75.txt
(p / possible-01
      :ARG1 (i / identify-01
            :ARG0 (e3 / expose-01
                  :ARG1-of (l3 / long-03))
            :ARG1 (a / and
                  :op1 (e / enzyme :name (n / name :op1 "ERK")
                        :ARG3-of (p3 / phosphorylate-01))
                  :op2 (e2 / enzyme :name (n2 / name :op1 "AKT")
                        :ARG3-of p3)
                  :op3 (p2 / protein :name (n3 / name :op1 "ETS")
                        :mod (s / some))
                  :quant (l / level
                        :ARG1-of (l2 / low-04)))
            :location (i2 / immunoblot-01
                  :ARG2 (c / cell-line
                        :quant (m / most)))))

# ::id pmid_2464_2271.76 ::date 2015-08-10T16:25:15 ::annotator SDL-AMR-09 ::preferred
# ::snt To more quantitatively establish the “high-level” threshold shown in Figure <xref ref-type="fig" rid="F1">1</xref>B, ETS proteins in cell extracts were compared with purified standards (Additional file <xref ref-type="supplementary-material" rid="S1">1</xref>: Figure S1B).
# ::save-date Sun Jan 17, 2016 ::file pmid_2464_2271_76.txt
(c / compare-01
      :ARG1 (p / protein-family :name (n / name :op1 "ETS")
            :location (e / extract-01
                  :ARG1 (c2 / cell)))
      :ARG2 (s / standard-02
            :ARG1-of (p2 / purify-01))
      :purpose (e2 / establish-01
            :ARG1 (t / threshold
                  :mod (l / level
                        :ARG1-of (h / high-02))
                  :ARG1-of (s2 / show-01
                        :ARG0 (f / figure :mod "1B")))
            :manner (q / quantitative
                  :degree (m / more)))
      :ARG1-of (d / describe-01
            :ARG0 (f2 / file :mod 1
                  :ARG1-of (a / add-02)
                  :part (f3 / figure :mod "S1B"))))

# ::id pmid_2464_2271.77 ::date 2015-08-10T17:02:28 ::annotator SDL-AMR-09 ::preferred
# ::snt All “high-level” expression for ETS proteins exceeded 50,000 proteins per cell, and was highest at 330,000 proteins per cell for ERG in VCaP.
# ::save-date Sun Jan 17, 2016 ::file pmid_2464_2271_77.txt
(a / and
      :op1 (e / exceed-01
            :ARG0 (e2 / express-03
                  :ARG2 (p / protein-family :name (n / name :op1 "ETS"))
                  :mod (l / level
                        :ARG1-of (h / high-02))
                  :mod (a2 / all))
            :ARG1 (r / rate-entity-91
                  :ARG1 (p2 / protein :quant 50000)
                  :ARG2 (c / cell)))
      :op2 (h2 / high-02
            :ARG1 (e3 / express-03
                  :ARG1 (g / gene :name (n2 / name :op1 "ERG"))
                  :ARG2 p
                  :ARG3 (c2 / cell-line :name (n3 / name :op1 "VCaP")))
            :ARG2 (r2 / rate-entity-91
                  :ARG1 (p3 / protein :quant 330000)
                  :ARG2 c)
            :degree (m / most)))

# ::id pmid_2464_2271.78 ::date 2015-08-10T17:28:10 ::annotator SDL-AMR-09 ::preferred
# ::snt Low-level ETS expression was 10,000 proteins per cell (ETV4 in DU145) or less (Additional file <xref ref-type="supplementary-material" rid="S1">1</xref>: Figure S1B and data not shown).
# ::save-date Sun Jan 17, 2016 ::file pmid_2464_2271_78.txt
(e / express-03
      :ARG2 (p / protein-family :name (n / name :op1 "ETS"))
      :mod (l / level
            :ARG1-of (l2 / low-04))
      :quant (o / or
            :op1 (r / rate-entity-91
                  :ARG1 (p2 / protein :quant 10000)
                  :ARG2 (c / cell))
            :op2 (l3 / less-than
                  :op1 r))
      :ARG1-of (m / mean-01
            :ARG2 (e2 / express-03
                  :ARG1 (p3 / protein :name (n2 / name :op1 "ETV4"))
                  :ARG3 (c2 / cell-line :name (n3 / name :op1 "DU145"))))
      :ARG1-of (d / describe-01
            :ARG0 (a / and
                  :op1 (f / file :mod 1
                        :ARG1-of (a2 / add-02)
                        :part (f2 / figure :mod "S1B"))
                  :op1 (d2 / data
                        :ARG1-of (s / show-01 :polarity -)))))

# ::id pmid_2464_2271.79 ::date 2015-08-11T01:50:25 ::annotator SDL-AMR-09 ::preferred
# ::snt It is possible that oncogenic ETS expression and signaling pathway activation could influence each other.
# ::save-date Thu Aug 13, 2015 ::file pmid_2464_2271_79.txt
(p / possible-01
      :ARG1 (p2 / possible-01
            :ARG1 (a / and
                  :op1 (i / influence-01
                        :ARG0 (e / express-03
                              :ARG2 (p3 / protein
                                    :name (n / name :op1 "ETS")
                                    :ARG0-of (c / cause-01
                                          :ARG1 (d / disease :wiki "Cancer"
                                                :name (n2 / name :op1 "cancer")))))
                        :ARG1 (a2 / activate-01
                              :ARG1 (p4 / pathway
                                    :ARG0-of (s / signal-07))))
                  :op2 (i2 / influence-01
                        :ARG0 a2
                        :ARG1 e))))

# ::id pmid_2464_2271.80 ::date 2015-08-11T01:57:10 ::annotator SDL-AMR-09 ::preferred
# ::snt To test this, RWPE-1 (RWPE) cells derived from normal prostate [<xref ref-type="bibr" rid="B27">27</xref>] or variations of this line that express either Ki-RAS (RWPE-KRAS, also known as RWPE-2) or ERG (RWPE-ERG) were compared.
# ::save-date Sat Jan 16, 2016 ::file pmid_2464_2271_80.txt
(c / compare-01
      :ARG1 (c2 / cell-line :name (n / name :op1 "RWPE-1")
            :ARG1-of (d / derive-01
                  :ARG2 (p / prostate
                        :ARG1-of (n2 / normal-02)))
            :ARG1-of (d2 / describe-01
                  :ARG0 (p2 / publication
                        :ARG1-of (c3 / cite-01
                              :ARG2 27))))
      :ARG2 (o / or
            :op1 (v / vary-01
                  :ARG1 c2
                  :ARG3-of (e / express-03
                        :ARG2 (e4 / enzyme :name (n4 / name :op1 "Ki-RAS")))
                  :ARG1-of (k / know-02
                        :ARG2 (c4 / cell-line :name (n5 / name :op1 "RWPE-2"))
                        :mod (a / also)))
            :op2 (v2 / vary-01
                  :ARG1 c2
                  :ARG3-of (e2 / express-03
                        :ARG2 (p4 / protein :name (n3 / name :op1 "ERG"))))
            :mod (e3 / either))
      :purpose (t / test-01
            :ARG1 (t2 / this)))

# ::id pmid_2464_2271.81 ::date 2015-08-11T02:27:33 ::annotator SDL-AMR-09 ::preferred
# ::snt ERG levels in RWPE-ERG cells were similar to VCaP cells (Additional file <xref ref-type="supplementary-material" rid="S1">1</xref>: Figure S1C).
# ::save-date Sun Jan 17, 2016 ::file pmid_2464_2271_81.txt
(r / resemble-01
      :ARG1 (l / level
            :quant-of (p / protein :name (n / name :op1 "ERG"))
            :location (c / cell-line :name (n2 / name :op1 "RWPE-ERG")))
      :ARG2 (l2 / level
            :quant-of p
            :location (c2 / cell-line :name (n3 / name :op1 "VCaP")))
      :ARG1-of (d / describe-01
            :ARG0 (f / file :mod 1
                  :ARG1-of (a / add-02)
                  :part (f2 / figure :mod "S1C"))))

# ::id pmid_2464_2271.82 ::date 2015-08-11T02:35:58 ::annotator SDL-AMR-09 ::preferred
# ::snt None of the oncogenic ETS were expressed at high levels in RWPE or RWPE-KRAS cells, and only ERG was expressed in RWPE-ERG cells (Figure <xref ref-type="fig" rid="F1">1</xref>B).
# ::save-date Fri Aug 14, 2015 ::file pmid_2464_2271_82.txt
(a / and
      :op1 (e / express-03
            :ARG2 (i / include-91
                  :ARG1 (n / none)
                  :ARG2 (p / protein
                        :name (n2 / name :op1 "ETS")
                        :ARG0-of (c / cause-01
                              :ARG1 (d2 / disease :wiki "Cancer"
                                    :name (n3 / name :op1 "cancer")))))
            :ARG3 (o2 / or
                  :op1 (c2 / cell-line
                        :name (n4 / name :op1 "RWPE"))
                  :op2 (c3 / cell-line
                        :name (n6 / name :op1 "RWPE-KRAS")))
            :quant (l / level
                  :ARG1-of (h / high-02)))
      :op2 (e2 / express-03
            :ARG2 (p2 / protein
                  :name (n5 / name :op1 "ERG"))
            :ARG3 (c4 / cell-line
                  :name (n7 / name :op1 "RWPE-ERG"))
            :mod (o3 / only))
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod "1B")))

# ::id pmid_2464_2271.83 ::date 2015-08-11T02:51:39 ::annotator SDL-AMR-09 ::preferred
# ::snt As expected, KRAS increased both pERK and pAKT levels (Figure <xref ref-type="fig" rid="F1">1</xref>B).
# ::save-date Sun Jan 17, 2016 ::file pmid_2464_2271_83.txt
(i / increase-01
      :ARG0 (e / enzyme :name (n / name :op1 "KRAS"))
      :ARG1 (a / and
            :op1 (l / level
                  :quant-of (e2 / enzyme :name (n2 / name :op1 "ERK")
                        :ARG3-of (p / phosphorylate-01)))
            :op2 (l2 / level
                  :quant-of (e3 / enzyme :name (n3 / name :op1 "AKT")
                        :ARG3-of p)))
      :ARG1-of (e4 / expect-01)
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod "1B")))

# ::id pmid_2464_2271.84 ::date 2015-08-11T03:02:30 ::annotator SDL-AMR-09 ::preferred
# ::snt Interestingly, over-expression of ERG also resulted in activation of AKT and a small increase in pERK (Figure <xref ref-type="fig" rid="F1">1</xref>B).
# ::save-date Sun Jan 17, 2016 ::file pmid_2464_2271_84.txt
(r / result-01
      :ARG1 (o / overexpress-01
            :ARG1 (p / protein :name (n / name :op1 "ERG")))
      :ARG2 (a / and
            :op1 (a2 / activate-01
                  :ARG1 (e / enzyme :name (n2 / name :op1 "AKT")))
            :op2 (i / increase-01
                  :ARG1 (e2 / enzyme :name (n3 / name :op1 "ERK")
                        :ARG3-of (p2 / phosphorylate-01))
                  :degree (s / small)))
      :mod (a3 / also)
      :ARG2-of (i2 / interest-01)
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod "1B")))

# ::id pmid_2464_2271.85 ::date 2015-08-11T03:12:42 ::annotator SDL-AMR-09 ::preferred
# ::snt In other cell types, the RAS/ERK pathway activates ETV1, ETV4, and ETV5 expression [<xref ref-type="bibr" rid="B28">28</xref>].
# ::save-date Thu Aug 13, 2015 ::file pmid_2464_2271_85.txt
(a / activate-01
      :ARG0 (p / pathway :name (n / name :op1 "RAS/ERK"))
      :ARG1 (e / express-03
            :ARG2 (a2 / and
                  :op1 (p2 / protein :name (n2 / name :op1 "ETV1"))
                  :op2 (p3 / protein :name (n3 / name :op1 "ETV4"))
                  :op3 (p4 / protein :name (n4 / name :op1 "ETV5"))))
      :location (t / type
            :mod (c / cell)
            :mod (o / other))
      :ARG1-of (d / describe-01
            :ARG0 (p5 / publication
                  :ARG1-of (c2 / cite-01
                        :ARG2 28))))

# ::id pmid_2464_2271.86 ::date 2015-08-11T03:17:33 ::annotator SDL-AMR-09 ::preferred
# ::snt Therefore, high ETV4 expression in CWR22Rv1 cells could be the result of ERK activation.
# ::save-date Sun Jan 17, 2016 ::file pmid_2464_2271_86.txt
(c / cause-01
      :ARG1 (p / possible-01
            :ARG1 (r / result-01
                  :ARG1 (a / activate-01
                        :ARG1 (e / enzyme :name (n / name :op1 "ERK")))
                  :ARG2 (e2 / express-03
                        :ARG2 (p2 / protein :name (n2 / name :op1 "ETV4"))
                        :ARG3 (c2 / cell-line :name (n3 / name :op1 "CWR22Rv1"))
                        :ARG1-of (h / high-02)))))

# ::id pmid_2464_2271.87 ::date 2015-08-11T03:23:36 ::annotator SDL-AMR-09 ::preferred
# ::snt To test this, CWR22Rv1 and DU145 cells were treated with the MEK inhibitor U0126 for 24 hours.
# ::save-date Sat Jan 16, 2016 ::file pmid_2464_2271_87.txt
(t / treat-04
      :ARG1 (a / and
            :op1 (c / cell-line :name (n / name :op1 "CWR22Rv1"))
            :op2 (c2 / cell-line :name (n2 / name :op1 "DU145")))
      :ARG2 (s / small-molecule :name (n3 / name :op1 "U0126")
            :ARG0-of (i / inhibit-01
                  :ARG1 (p / protein-family :name (n4 / name :op1 "MEK"))))
      :duration (t2 / temporal-quantity :quant 24
            :unit (h / hour))
      :purpose (t3 / test-01
            :ARG1 (t4 / this)))

# ::id pmid_2464_2271.88 ::date 2015-08-11T03:29:53 ::annotator SDL-AMR-09 ::preferred
# ::snt In both cell lines, U0126 decreased pERK levels, but did not alter levels of ETV4 (Figure <xref ref-type="fig" rid="F1">1</xref>C).
# ::save-date Sun Jan 17, 2016 ::file pmid_2464_2271_88.txt
(c / contrast-01
      :ARG1 (d / decrease-01
            :ARG0 (s / small-molecule :name (n / name :op1 "U0126"))
            :ARG1 (l / level
                  :quant-of (e / enzyme :name (n2 / name :op1 "ERK")
                        :ARG3-of (p / phosphorylate-01))))
      :ARG2 (a / alter-01 :polarity -
            :ARG0 s
            :ARG1 (l2 / level
                  :quant-of (p2 / protein :name (n3 / name :op1 "ETV4"))))
      :location (c2 / cell-line
            :mod (b / both))
      :ARG1-of (d2 / describe-01
            :ARG0 (f / figure :mod "1C")))

# ::id pmid_2464_2271.89 ::date 2015-08-11T03:37:05 ::annotator SDL-AMR-09 ::preferred
# ::snt Therefore, RAS/ERK activation does not drive oncogenic ETS expression in prostate cancer cell lines, however in at least one context (ERG in RWPE) an oncogenic ETS could induce the phosphorylation of both AKT and, to a lesser degree, ERK.
# ::save-date Sun Jan 17, 2016 ::file pmid_2464_2271_89.txt
(c / cause-01
      :ARG1 (h / have-concession-91
            :ARG1 (d / drive-02 :polarity -
                  :ARG0 (a / activate-01
                        :ARG0 (p / pathway :name (n / name :op1 "RAS/ERK")))
                  :ARG1 (e / express-03
                        :ARG2 (p2 / protein :name (n2 / name :op1 "ETS")
                              :ARG0-of (c2 / cause-01
                                    :ARG1 (d2 / disease :wiki "Cancer" :name (n3 / name :op1 "cancer"))))
                        :ARG3 (c3 / cell-line
                              :mod (d3 / disease :wiki "Prostate_cancer" :name (n4 / name :op1 "prostate" :op2 "cancer")))))
            :ARG2 (p4 / possible-01
                  :ARG1 (i / induce-01
                        :ARG0 (p5 / protein :quant 1 :name (n5 / name :op1 "ETS")
                              :ARG0-of c2)
                        :ARG2 (a2 / and
                              :op1 (p6 / phosphorylate-01
                                    :ARG1 (e2 / enzyme :name (n6 / name :op1 "AKT")))
                              :op2 (p7 / phosphorylate-01
                                    :ARG1 (e3 / enzyme :name (n7 / name :op1 "ERK"))
                                    :degree (l / less
                                          :degree (m / more)))))
                  :location (c4 / context
                        :quant (a3 / at-least :op1 1)
                        :ARG1-of (m2 / mean-01
                              :ARG2 (e4 / express-03
                                    :ARG2 (p8 / protein :name (n8 / name :op1 "ERG"))
                                    :ARG3 (c5 / cell-line :name (n9 / name :op1 "RWPE"))))))))

# ::id pmid_2464_2271.90 ::date 2015-08-11T04:04:50 ::annotator SDL-AMR-09 ::preferred
# ::snt <sec-title level="2">Oncogenic ETS proteins and KRAS drive prostate cell migration, but not synergistically</sec-title>
# ::save-date Thu Aug 13, 2015 ::file pmid_2464_2271_90.txt
(c / contrast-01
      :ARG1 (d / drive-02
            :ARG0 (a / and
                  :op1 (p / protein
                        :name (n / name :op1 "ETS")
                        :ARG0-of (c2 / cause-01
                              :ARG1 (d2 / disease :wiki "Cancer"
                                    :name (n2 / name :op1 "cancer"))))
                  :op2 (e / enzyme
                        :name (n3 / name :op1 "KRAS")
                        :ARG0-of c2))
            :ARG1 (m / migrate-01
                  :ARG0 (c3 / cell
                        :mod (p2 / prostate))))
      :ARG2 (d3 / drive-02 :polarity -
            :ARG0 a
            :ARG1 m
            :manner (s / synergistical)))

# ::id pmid_2464_2271.91 ::date 2015-08-11T04:31:25 ::annotator SDL-AMR-09 ::preferred
# ::snt We next tested the role of signaling pathways in the ability of oncogenic ETS proteins to drive cell migration.
# ::save-date Thu Aug 13, 2015 ::file pmid_2464_2271_91.txt
(t / test-01
      :ARG0 (w / we)
      :ARG1 (r / role
            :poss (p / pathway
                  :ARG0-of (s / signal-07))
            :topic (c / capable-01
                  :ARG1 (p2 / protein
                        :name (n / name :op1 "ETS")
                        :ARG0-of (c2 / cause-01
                              :ARG1 (d / disease :wiki "Cancer"
                                    :name (n2 / name :op1 "cancer"))))
                  :ARG2 (d2 / drive-02
                        :ARG0 p2
                        :ARG1 (m / migrate-01
                              :ARG0 (c3 / cell)))))
      :time (n3 / next))

# ::id pmid_2464_2271.92 ::date 2015-08-11T04:36:13 ::annotator SDL-AMR-09 ::preferred
# ::snt Because cancer derived cell lines have many mutations and copy number alterations that affect cellular phenotypes, we used the RWPE-ERG and RWPE-KRAS cell lines to compare the ability of oncogenic ETS and RAS signaling to promote cell migration in the same cellular background.
# ::save-date Thu Aug 13, 2015 ::file pmid_2464_2271_92.txt
(c / cause-01
      :ARG0 (h / have-03
            :ARG0 (c2 / cell-line
                  :ARG1-of (d / derive-01
                        :ARG2 (d2 / disease :wiki "Cancer"
                              :name (n / name :op1 "cancer"))))
            :ARG1 (a / and
                  :op1 (m / mutate-01
                        :ARG2 c2
                        :quant (m2 / many))
                  :op2 (a2 / alter-01
                        :ARG1 (n2 / number-01
                              :ARG1 (c3 / copy-01
                                    :ARG1 c2)))
                  :ARG0-of (a3 / affect-01
                        :ARG1 (p / phenotype
                              :mod (c4 / cell)))))
      :ARG1 (u / use-01
            :ARG0 (w / we)
            :ARG1 (a4 / and
                  :op1 (c5 / cell-line
                        :name (n3 / name :op1 "RWPE-ERG"))
                  :op2 (c6 / cell-line
                        :name (n4 / name :op1 "RWPE-KRAS")))
            :ARG2 (c7 / compare-01
                  :ARG0 w
                  :ARG1 (c8 / capable-01
                        :ARG1 (s / signal-07
                              :ARG0 (a5 / and
                                    :op1 (p2 / protein
                                          :name (n5 / name :op1 "ETS")
                                          :ARG0-of (c9 / cause-01
                                                :ARG1 d2))
                                    :op2 (e / enzyme
                                          :name (n6 / name :op1 "RAS"))))
                        :ARG2 (p3 / promote-01
                              :ARG0 a5
                              :ARG1 (m3 / migrate-01
                                    :ARG0 (c10 / cell)))))
            :location (b / background
                  :mod (c11 / cell)
                  :ARG1-of (s2 / same-01))))

# ::id pmid_2464_2271.93 ::date 2015-08-11T04:58:36 ::annotator SDL-AMR-09 ::preferred
# ::snt RWPE-ERG and RWPE-KRAS cells migrated 5- and 10-fold more than RWPE cells (Figure <xref ref-type="fig" rid="F2">2</xref>A and Additional file <xref ref-type="supplementary-material" rid="S2">2</xref>: Figure S2), indicating that both ERG and KRAS induce cell migration.
# ::save-date Thu Aug 13, 2015 ::file pmid_2464_2271_93.txt
(m / migrate-01
      :ARG0 (a / and
            :op1 (c / cell-line :name (n / name :op1 "RWPE-ERG"))
            :op2 (c2 / cell-line :name (n2 / name :op1 "RWPE-KRAS")))
      :degree (m2 / more-than
            :op1 (a2 / and
                  :op1 (p / product-of :op1 5)
                  :op2 (p2 / product-of :op1 10)
                  :compared-to (c3 / cell-line :name (n3 / name :op1 "RWPE"))))
      :ARG1-of (d / describe-01
            :ARG0 (a3 / and
                  :op1 (f / figure :mod "2A")
                  :op2 (f2 / file :mod 2
                        :ARG1-of (a4 / add-02)
                        :part (f3 / figure :mod "S2"))))
      :ARG0-of (i / indicate-01
            :ARG1 (i2 / induce-01
                  :ARG0 (a5 / and
                        :op1 (p3 / protein :name (n4 / name :op1 "ERG"))
                        :op2 (e / enzyme :name (n5 / name :op1 "KRAS")))
                  :ARG2 (m3 / migrate-01
                        :ARG0 (c4 / cell)))))

# ::id pmid_2464_2271.94 ::date 2015-08-11T05:19:48 ::annotator SDL-AMR-09 ::preferred
# ::snt Similar to our previous findings [<xref ref-type="bibr" rid="B15">15</xref>], overexpression of oncogenic ETS proteins ETV1, ETV5, and ERG, but not other ETS proteins (FLI1 and SPDEF), promoted RWPE cell migration (Figure <xref ref-type="fig" rid="F2">2</xref>B and Additional file <xref ref-type="supplementary-material" rid="S2">2</xref>: Figure S2).
# ::save-date Thu Aug 13, 2015 ::file pmid_2464_2271_94.txt
(p / promote-01
      :ARG0 (o / overexpress-01
            :ARG1 (p2 / protein
                  :name (n / name :op1 "ETS")
                  :ARG0-of (c / cause-01
                        :ARG1 (d / disease :wiki "Cancer"
                              :name (n2 / name :op1 "cancer")))
                  :ARG1-of (m / mean-01
                        :ARG2 (a / and
                              :op1 (p3 / protein
                                    :name (n3 / name :op1 "ETV1"))
                              :op2 (p4 / protein
                                    :name (n4 / name :op1 "ETV5"))
                              :op3 (p5 / protein
                                    :name (n5 / name :op1 "ERG")))))
            :ARG1-of (c2 / contrast-01
                  :ARG2 (o2 / overexpress-01
                        :ARG1 (p6 / protein
                              :name (n6 / name :op1 "ETS")
                              :ARG1-of (m2 / mean-01
                                    :ARG2 (a2 / and
                                          :op1 (p7 / protein
                                                :name (n7 / name :op1 "FLI1"))
                                          :op2 (p8 / protein
                                                :name (n8 / name :op1 "SPDEF"))))
                              :mod (o3 / other)))))
      :ARG1 (m3 / migrate-01
            :ARG0 (c3 / cell-line
                  :name (n9 / name :op1 "RWPE")))
      :ARG1-of (r / resemble-01
            :ARG2 (t / thing
                  :ARG1-of (f / find-01
                        :ARG0 (w / we))
                  :time (p9 / previous)
                  :ARG1-of (d2 / describe-01
                        :ARG0 (p10 / publication
                              :ARG1-of (c4 / cite-01 :ARG2 15)))))
      :ARG1-of (d3 / describe-01
            :ARG0 (a3 / and
                  :op1 (f2 / figure :mod "2B")
                  :op2 (f3 / file :mod 2
                        :ARG1-of (a4 / add-02)
                        :part (f4 / figure :mod "S2")))))

# ::id pmid_2464_2271.95 ::date 2015-08-11T05:47:02 ::annotator SDL-AMR-09 ::preferred
# ::snt In contrast, when the same ETS proteins were over-expressed in RWPE-KRAS cells, none of the oncogenic ETS proteins induced additional cell migration (Figure <xref ref-type="fig" rid="F2">2</xref>C and Additional file <xref ref-type="supplementary-material" rid="S2">2</xref>: Figure S2), suggesting that these ETS proteins and KRAS were functioning to activate the same pathway.
# ::save-date Thu Aug 13, 2015 ::file pmid_2464_2271_95.txt
(c / contrast-01
      :ARG2 (i / induce-01
            :ARG0 (i2 / include-91
                  :ARG2 (p / protein
                        :name (n / name :op1 "ETS")
                        :ARG0-of (c2 / cause-01
                              :ARG1 (d / disease :wiki "Cancer"
                                    :name (n2 / name :op1 "cancer"))))
                  :ARG3 (n3 / none))
            :ARG2 (m / migrate-01
                  :ARG0 (c3 / cell)
                  :ARG1-of (a / add-02))
            :time (o / overexpress-01
                  :ARG1 (p2 / protein
                        :name (n4 / name :op1 "ETS")
                        :ARG1-of (s / same-01))
                  :location (c4 / cell-line
                        :name (n5 / name :op1 "RWPE-KRAS")))
            :ARG1-of (d2 / describe-01
                  :ARG0 (a2 / and
                        :op1 (f / figure :mod "2C")
                        :op2 (f2 / file :mod 2
                              :part (f3 / figure :mod "S2"))))
            :ARG0-of (s2 / suggest-01
                  :ARG1 (f4 / function-01
                        :ARG0 (a3 / and
                              :op1 p2
                              :op2 (e / enzyme
                                    :name (n6 / name :op1 "KRAS")))
                        :ARG1 (a4 / activate-01
                              :ARG0 a3
                              :ARG1 (p3 / pathway
                                    :ARG1-of s))))))

# ::id pmid_2464_2271.96 ::date 2015-08-11T06:04:53 ::annotator SDL-AMR-09 ::preferred
# ::snt These findings are consistent with our model that oncogenic ETS proteins can mimic RAS activation in cell lines lacking RAS activity, and are distinct from ETS proteins expressed in normal prostate.
# ::save-date Thu Aug 13, 2015 ::file pmid_2464_2271_96.txt
(c / consistent-01
      :ARG1 (t / thing
            :ARG1-of (f / find-01)
            :mod (t2 / this))
      :ARG2 (m / model-01
            :ARG0 (w / we)
            :ARG1 (a / and
                  :op1 (p / possible-01
                        :ARG1 (m2 / mimic-01
                              :ARG0 (p2 / protein
                                    :name (n / name :op1 "ETS")
                                    :ARG0-of (c2 / cause-01
                                          :ARG1 (d / disease :wiki "Cancer"
                                                :name (n2 / name :op1 "cancer"))))
                              :ARG1 (a2 / activate-01
                                    :ARG1 (e / enzyme
                                          :name (n3 / name :op1 "RAS"))))
                        :location (c3 / cell-line
                              :ARG0-of (l / lack-01
                                    :ARG1 (a3 / activity-06
                                          :ARG0 e))))
                  :op2 (d2 / distinct
                        :domain p2
                        :compared-to (p3 / protein
                              :name (n4 / name :op1 "ETS")
                              :ARG2-of (e2 / express-03
                                    :ARG3 (p4 / prostate
                                          :ARG1-of (n5 / normal-02))))))))

# ::id pmid_2464_2271.97 ::date 2015-08-11T06:16:41 ::annotator SDL-AMR-09 ::preferred
# ::snt <sec-title level="2">A role for the PI3K/AKT pathway in oncogenic ETS function</sec-title>
# ::save-date Thu Aug 13, 2015 ::file pmid_2464_2271_97.txt
(r / role
      :poss (p / pathway :wiki "Akt/PKB_signaling_pathway"
            :name (n / name :op1 "PI3K/AKT"))
      :topic (f / function-01
            :ARG0 (p2 / protein :wiki "ETS_transcription_factor_family"
                  :name (n2 / name :op1 "ETS")
                  :ARG0-of (c / cause-01
                        :ARG1 (d / disease :wiki "Cancer"
                              :name (n3 / name :op1 "cancer"))))))

# ::id pmid_2464_2271.98 ::date 2015-08-11T06:20:56 ::annotator SDL-AMR-09 ::preferred
# ::snt To identify signaling pathways required for the oncogenic function of ETS factors, a microarray analysis of <i>ETV4</i> knockdown in PC3 prostate cancer cells [<xref ref-type="bibr" rid="B25">25</xref>] was compared to the Connectivity Map database [<xref ref-type="bibr" rid="B29">29</xref>] that contains microarray data of PC3 cells treated with 1309 small molecules, including many signaling pathway inhibitors.
# ::save-date Thu Dec 10, 2015 ::file pmid_2464_2271_98.txt
(c / compare-01
      :ARG1 (a / analyze-01
            :ARG1 (k / knock-down-02
                  :ARG1 (g / gene :name (n / name :op1 "ETV4"))
                  :location (c2 / cell-line :name (n2 / name :op1 "PC3")
                        :mod (d / disease :wiki "Prostate_cancer" :name (n3 / name :op1 "prostate" :op2 "cancer"))))
            :mod (m / microarray)
            :ARG1-of (d2 / describe-01
                  :ARG0 (p2 / publication
                        :ARG1-of (c3 / cite-01
                              :ARG2 25))))
      :ARG2 (d3 / database :name (n4 / name :op1 "Connectivity" :op2 "Map")
            :ARG1-of (d4 / describe-01
                  :ARG0 (p3 / publication
                        :ARG1-of (c4 / cite-01
                              :ARG2 29)))
            :ARG0-of (c5 / contain-01
                  :ARG1 (d5 / data
                        :mod m
                        :topic (c6 / cell-line :name (n5 / name :op1 "PC3")
                              :ARG1-of (t / treat-04
                                    :ARG2 (s / small-molecule :quant 1309
                                          :ARG2-of (i / include-91
                                                :ARG1 (m2 / molecular-physical-entity
                                                      :ARG0-of (i2 / inhibit-01
                                                            :ARG1 (p4 / pathway
                                                                  :ARG0-of (s2 / signal-07)))
                                                      :quant (m3 / many)))))))))
      :purpose (i3 / identify-01
            :ARG1 (p5 / pathway
                  :ARG0-of s2
                  :ARG1-of (r / require-01
                        :ARG0 (f / function-01
                              :ARG0 (f2 / factor
                                    :mod (p6 / protein :name (n6 / name :op1 "ETS")))
                              :ARG0-of (c7 / cause-01
                                    :ARG1 (d6 / disease :wiki "Cancer" :name (n7 / name :op1 "cancer"))))))))

# ::id pmid_2464_2271.99 ::date 2015-08-11T06:48:24 ::annotator SDL-AMR-09 ::preferred
# ::snt Similarities between the gene expression profile of a signaling pathway inhibitor and <i>ETV4</i> knockdown would predict a role for that pathway in oncogenic ETS function.
# ::save-date Thu Aug 13, 2015 ::file pmid_2464_2271_99.txt
(p / predict-01
      :ARG0 (r / resemble-01
            :ARG1 (p2 / profile-01
                  :ARG0 (e / express-03
                        :ARG1 (g / gene))
                  :ARG1 (m / molecular-physical-entity
                        :ARG0-of (i / inhibit-01
                              :ARG1 (p3 / pathway
                                    :ARG0-of (s / signal-07)))))
            :ARG2 (k / knock-down-02
                  :ARG1 (g2 / gene
                        :name (n / name :op1 "ETV4"))))
      :ARG1 (r2 / role
            :poss p3
            :topic (f / function-01
                  :ARG0 (p4 / protein
                        :name (n2 / name :op1 "ETS")
                        :ARG0-of (c / cause-01
                              :ARG1 (d / disease :wiki "Cancer"
                                    :name (n3 / name :op1 "cancer")))))))

# ::id pmid_2464_2271.100 ::date 2015-08-11T07:09:12 ::annotator SDL-AMR-09 ::preferred
# ::snt The top two, and three of the top five small molecules that induced gene expression changes most similar to <i>ETV4</i> knockdown were inhibitors of either PI3K or mTOR, a downstream effector of PI3K (Table <xref ref-type="table" rid="T2">2</xref>).
# ::save-date Sun Jan 17, 2016 ::file pmid_2464_2271_100.txt
(m / molecular-physical-entity
      :domain (a / and
            :op1 (s / small-molecule :quant 2
                  :ARG0-of (t / top-02))
            :op2 (s2 / small-molecule :quant 3
                  :ARG1-of (i / include-91
                        :ARG2 (s3 / small-molecule :quant 5
                              :ARG0-of t)))
            :ARG0-of (i2 / induce-01
                  :ARG2 (c / change-01
                        :ARG1 (e / express-03
                              :ARG1 (g / gene))
                        :ARG1-of (r / resemble-01
                              :ARG2 (k / knock-down-02
                                    :ARG1 (g2 / gene :name (n / name :op1 "ETV4")))
                              :degree (m2 / most)))))
      :ARG0-of (i3 / inhibit-01
            :ARG1 (o / or
                  :op1 (p2 / protein-family :name (n2 / name :op1 "PI3K"))
                  :op2 (p / protein :name (n3 / name :op1 "mTOR")
                        :mod (e3 / effector
                              :poss p2
                              :location (d / downstream)))
                  :mod (e4 / either)))
      :ARG1-of (d2 / describe-01
            :ARG0 (t2 / table :mod 2)))

# ::id pmid_2464_2271.101 ::date 2015-08-11T07:37:29 ::annotator SDL-AMR-09 ::preferred
# ::snt These data suggest that in PC3 cells, PI3K and ETV4 activate a similar gene expression program.
# ::save-date Sun Jan 17, 2016 ::file pmid_2464_2271_101.txt
(s / suggest-01
      :ARG0 (d / data
            :mod (t / this))
      :ARG1 (a / activate-01
            :ARG0 (a2 / and
                  :op1 (e / enzyme :name (n / name :op1 "PI3K"))
                  :op2 (p / protein :name (n2 / name :op1 "ETV4")))
            :ARG1 (p2 / program-01
                  :ARG1 (e2 / express-03
                        :ARG1 (g / gene))
                  :ARG1-of (r / resemble-01))
            :location (c / cell-line :name (n3 / name :op1 "PC3"))))

# ::id pmid_2464_2271.102 ::date 2015-08-11T07:48:58 ::annotator SDL-AMR-09 ::preferred
# ::snt To test if the PI3K pathway is required for an oncogenic ETS protein to promote the cell migration phenotype, RWPE-ERG and RWPE-KRAS cells were treated with the PI3K inhibitor, LY294002.
# ::save-date Thu Aug 13, 2015 ::file pmid_2464_2271_102.txt
(t / treat-04
      :ARG1 (a / and
            :op1 (c / cell-line
                  :name (n / name :op1 "RWPE-ERG"))
            :op2 (c2 / cell-line
                  :name (n2 / name :op1 "RWPE-KRAS")))
      :ARG2 (s / small-molecule
            :name (n3 / name :op1 "LY294002")
            :ARG0-of (i / inhibit-01
                  :ARG1 (e / enzyme
                        :name (n4 / name :op1 "PI3K"))))
      :purpose (t2 / test-01
            :ARG1 (r / require-01 :mode interrogative
                  :ARG0 (p / promote-01
                        :ARG0 (p2 / protein
                              :name (n5 / name :op1 "ETS")
                              :ARG0-of (c3 / cause-01
                                    :ARG1 (d / disease :wiki "Cancer"
                                          :name (n6 / name :op1 "cancer"))))
                        :ARG1 (p3 / phenotype
                              :mod (m / migrate-01
                                    :ARG0 (c4 / cell))))
                  :ARG1 (p4 / pathway
                        :name (n7 / name :op1 "PI3K")))))

# ::id pmid_2464_2271.103 ::date 2015-08-11T08:02:28 ::annotator SDL-AMR-09 ::preferred
# ::snt LY294002 reduced AKT phosphorylation in both lines, consistent with PI3K inhibition (Figure <xref ref-type="fig" rid="F3">3</xref>A).
# ::save-date Tue Aug 11, 2015 ::file pmid_2464_2271_103.txt
(r / reduce-01
      :ARG0 (s / small-molecule :name (n / name :op1 "LY294002"))
      :ARG1 (p / phosphorylate-01
            :ARG2 (e / enzyme :name (n2 / name :op1 "AKT")))
      :location (c / cell-line
            :mod (b / both))
      :ARG1-of (c2 / consistent-01
            :ARG2 (i / inhibit-01
                  :ARG1 (e2 / enzyme :name (n3 / name :op1 "PI3K"))))
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod "3A")))

# ::id pmid_2464_2271.104 ::date 2015-08-11T08:10:13 ::annotator SDL-AMR-09 ::preferred
# ::snt Strikingly, PI3K inhibition completely abrogated cell migration induced by ERG, but not cell migration induced by KRAS (Figure <xref ref-type="fig" rid="F3">3</xref>B and Additional file <xref ref-type="supplementary-material" rid="S2">2</xref>: Figure S2).
# ::save-date Thu Aug 13, 2015 ::file pmid_2464_2271_104.txt
(c / contrast-01
      :ARG1 (a / abrogate-01
            :ARG0 (i / inhibit-01
                  :ARG1 (e / enzyme :name (n / name :op1 "PI3K")))
            :ARG1 (m / migrate-01
                  :ARG0 (c2 / cell)
                  :ARG2-of (i2 / induce-01
                        :ARG0 (p / protein :name (n2 / name :op1 "ERG"))))
            :ARG1-of (c3 / complete-01))
      :ARG2 (a2 / abrogate-01 :polarity -
            :ARG0 i
            :ARG1 (m2 / migrate-01
                  :ARG0 c2
                  :ARG2-of (i3 / induce-01
                        :ARG0 (e2 / enzyme :name (n3 / name :op1 "KRAS")))))
      :ARG1-of (s / strike-04)
      :ARG1-of (d / describe-01
            :ARG0 (a3 / and
                  :op1 (f / figure :mod "3B")
                  :op2 (f2 / file :mod 2
                        :ARG1-of (a4 / add-02)
                        :part (f3 / figure :mod "S2")))))

# ::id pmid_2464_2271.105 ::date 2015-08-11T08:21:52 ::annotator SDL-AMR-09 ::preferred
# ::snt In fact RWPE-KRAS cells actually migrated more when PI3K was inhibited.
# ::save-date Tue Aug 11, 2015 ::file pmid_2464_2271_105.txt
(m / migrate-01
      :ARG0 (c / cell-line :name (n / name :op1 "RWPE-KRAS"))
      :degree (m2 / more)
      :time (i / inhibit-01
            :ARG1 (e / enzyme :name (n2 / name :op1 "PI3K")))
      :ARG1-of (a / actual-02)
      :mod (i2 / in-fact))

# ::id pmid_2464_2271.106 ::date 2015-08-11T08:31:42 ::annotator SDL-AMR-09 ::preferred
# ::snt This increased migration may be due to relief of RAF inhibition by AKT [<xref ref-type="bibr" rid="B9">9</xref>], as RWPE-KRAS cells had higher pMEK levels after treatment by LY294002 (Figure <xref ref-type="fig" rid="F3">3</xref>A).
# ::save-date Tue Aug 11, 2015 ::file pmid_2464_2271_106.txt
(c / cause-01
      :ARG0 (h / have-03
            :ARG0 (c2 / cell-line :name (n / name :op1 "RWPE-KRAS"))
            :ARG1 (l / level
                  :quant-of (e / enzyme :name (n2 / name :op1 "MEK")
                        :ARG3-of (p / phosphorylate-01))
                  :ARG1-of (h2 / high-02
                        :degree (m / more)))
            :time (a / after
                  :op1 (t / treat-04
                        :ARG2 (s / small-molecule :name (n3 / name :op1 "LY294002")))))
      :ARG1 (p2 / possible-01
            :ARG1 (c3 / cause-01
                  :ARG0 (r / relieve-01
                        :ARG1 (i / inhibit-01
                              :ARG0 (e2 / enzyme :name (n4 / name :op1 "AKT"))
                              :ARG1 (e3 / enzyme :name (n5 / name :op1 "RAF"))))
                  :ARG1 (m2 / migrate-01
                        :ARG1-of (i2 / increase-01)
                        :mod (t2 / this)))
            :ARG1-of (d / describe-01
                  :ARG0 (p3 / publication
                        :ARG1-of (c4 / cite-01
                              :ARG2 9))))
      :ARG1-of (d2 / describe-01
            :ARG0 (f / figure :mod "3A")))

# ::id pmid_2464_2271.107 ::date 2015-08-10T06:30:53 ::annotator SDL-AMR-09 ::preferred
# ::snt To confirm the role of PI3K, a second PI3K inhibitor, ZSTK474, was also tested (Figures <xref ref-type="fig" rid="F3">3</xref>A and <xref ref-type="fig" rid="F3">3</xref>B).
# ::save-date Mon Aug 24, 2015 ::file pmid_2464_2271_107.txt
(t3 / test-01
      :ARG1 (s2 / small-molecule :name (n / name :op1 "ZSTK474")
            :ARG1-of (m / mean-01
                  :ARG2 (m2 / molecular-physical-entity
                        :ARG0-of (i2 / inhibit-01
                              :ARG1 p)
                        :ord (o / ordinal-entity :value 2))))
      :mod (a / also)
      :purpose (c / confirm-01
            :ARG1 (r / role
                  :poss (p / pathway :name (n2 / name :op1 "PI3K"))))
      :ARG1-of (d / describe-01
            :ARG0 (a2 / and
                  :op1 (f / figure :mod "3A")
                  :op2 (f2 / figure :mod "3B"))))

# ::id pmid_2464_2271.108 ::date 2015-08-10T09:08:31 ::annotator SDL-AMR-09 ::preferred
# ::snt Like LY294002, ZSTK474 significantly reduced migration of RWPE-ERG cells, but not RWPE-KRAS cells.
# ::save-date Mon Aug 24, 2015 ::file pmid_2464_2271_108.txt
(c / contrast-01
      :ARG1 (r / reduce-01
            :ARG0 (s / small-molecule :name (n2 / name :op1 "ZSTK474"))
            :ARG1 (m / migrate-01
                  :ARG0 (c2 / cell-line :name (n3 / name :op1 "RWPE-ERG")))
            :ARG1-of (r2 / resemble-01
                  :ARG2 (s2 / small-molecule :name (n / name :op1 "LY294002")))
            :ARG1-of (s3 / significant-02))
      :ARG2 (r3 / reduce-01 :polarity -
            :ARG0 s
            :ARG1 (m2 / migrate-01
                  :ARG0 (c3 / cell-line :name (n4 / name :op1 "RWPE-KRAS")))))

# ::id pmid_2464_2271.109 ::date 2015-08-10T09:13:11 ::annotator SDL-AMR-09 ::preferred
# ::snt Cell migration induced by other oncogenic ETS factors, ETV1, and ETV5, was also abrogated by PI3K inhibition (Figure <xref ref-type="fig" rid="F3">3</xref>C and Additional file <xref ref-type="supplementary-material" rid="S2">2</xref>: Figure S2).
# ::save-date Sun Jan 17, 2016 ::file pmid_2464_2271_109.txt
(a / abrogate-01
      :ARG1 (m / migrate-01
            :ARG0 (c2 / cell)
            :ARG2-of (i / induce-01
                  :ARG0 (f / factor
                        :mod (p4 / protein :name (n / name :op1 "ETS"))
                        :mod (o / other)
                        :ARG1-of (m2 / mean-01
                              :ARG2 (a2 / and
                                    :op1 (p2 / protein :name (n3 / name :op1 "ETV1"))
                                    :op2 (p / protein :name (n2 / name :op1 "ETV5"))))
                        :ARG0-of (c3 / cause-01
                              :ARG1 (d2 / disease :wiki "Cancer" :name (n5 / name :op1 "cancer"))))))
      :ARG2 (i2 / inhibit-01
            :ARG1 (e / enzyme :name (n4 / name :op1 "PI3K")))
      :mod (a3 / also)
      :ARG1-of (d / describe-01
            :ARG0 (a4 / and
                  :op1 (f2 / figure :mod "3C")
                  :op2 (f3 / file :mod 2
                        :mod (a5 / additional)
                        :location-of (f4 / figure :mod "S2")))))

# ::id pmid_2464_2271.110 ::date 2015-08-11T02:15:34 ::annotator SDL-AMR-09 ::preferred
# ::snt A second cell migration assay, the scratch assay, confirmed that PI3K inhibition reduced migration caused by ERG expression, but not migration caused by KRAS (Figure <xref ref-type="fig" rid="F3">3</xref>D and Additional file <xref ref-type="supplementary-material" rid="S3">3</xref>: Figure S3).
# ::save-date Sun Jan 17, 2016 ::file pmid_2464_2271_110.txt
(c / confirm-01
      :ARG0 (a3 / assay-01
            :ARG1 (m2 / migrate-01
                  :ARG0 (c2 / cell))
            :ARG1-of (m3 / mean-01
                  :ARG2 (a4 / assay-01
                        :mod (s / scratch-02)))
            :ord (o / ordinal-entity :value 2))
      :ARG1 (c3 / contrast-01
            :ARG1 (r2 / reduce-01
                  :ARG0 (i / inhibit-01
                        :ARG1 (e2 / enzyme :name (n / name :op1 "PI3K")))
                  :ARG1 (m4 / migrate-01
                        :ARG1-of (c4 / cause-01
                              :ARG0 (e / express-03
                                    :ARG2 (p / protein :name (n2 / name :op1 "ERG"))))))
            :ARG2 (r / reduce-01 :polarity -
                  :ARG0 i
                  :ARG1 (m5 / migrate-01
                        :ARG1-of (c6 / cause-01
                              :ARG0 (g / gene :name (n3 / name :op1 "KRAS"))))))
      :ARG1-of (d / describe-01
            :ARG0 (a / and
                  :op1 (f / figure :mod "3D")
                  :op2 (f2 / file :mod 3
                        :location-of (f3 / figure :mod "S3")))))

# ::id pmid_2464_2271.111 ::date 2015-08-10T15:51:18 ::annotator SDL-AMR-09 ::preferred
# ::snt An AKT inhibitor had a similar effect (Figure <xref ref-type="fig" rid="F3">3</xref>D and Additional file <xref ref-type="supplementary-material" rid="S3">3</xref>: Figure S3), indicating that PI3K is functioning via AKT activation.
# ::save-date Thu Aug 13, 2015 ::file pmid_2464_2271_111.txt
(a / affect-02
      :ARG0 (m / molecular-physical-entity
            :ARG0-of (i / inhibit-01
                  :ARG1 e))
      :ARG0-of (i2 / indicate-01
            :ARG1 (f / function-01
                  :ARG0 (p / pathway :name (n2 / name :op1 "PI3K"))
                  :instrument (a2 / activate-01
                        :ARG1 (e / enzyme :name (n / name :op1 "AKT")))))
      :ARG1-of (r / resemble-01)
      :ARG1-of (d / describe-01
            :ARG0 (a3 / and
                  :op1 (f2 / figure :mod "3D")
                  :op2 (f3 / file :mod 3
                        :mod (a4 / additional)
                        :part-of (f4 / figure :mod "S3")))))

# ::id pmid_2464_2271.112 ::date 2015-08-10T16:04:45 ::annotator SDL-AMR-09 ::preferred
# ::snt These results indicate that overexpression of an oncogenic ETS gene can switch the control of prostate cell migration from the RAS/ERK pathway to the PI3K/AKT pathway.
# ::save-date Thu Dec 10, 2015 ::file pmid_2464_2271_112.txt
(i / indicate-01
      :ARG0 (t / thing
            :ARG2-of (r / result-01)
            :mod (t2 / this))
      :ARG1 (p2 / possible-01
            :ARG1 (s / switch-01
                  :ARG0 (o / overexpress-01
                        :ARG1 (g / gene :name (n2 / name :op1 "ETS")
                              :ARG0-of (c4 / cause-01
                                    :ARG1 (d / disease :wiki "Cancer" :name (n / name :op1 "cancer")))))
                  :ARG1 (c / control-01
                        :ARG1 (m / migrate-01
                              :ARG1 (c3 / cell
                                    :source (p3 / prostate))))
                  :ARG2 (p5 / pathway :name (n4 / name :op1 "PI3K/AKT"))
                  :ARG3 (p4 / pathway :name (n3 / name :op1 "RAS/ERK")))))

# ::id pmid_2464_2271.113 ::date 2015-08-10T16:13:59 ::annotator SDL-AMR-09 ::preferred
# ::snt We next tested if the PI3K pathway was regulating the ability of ERG to activate the transcription of RAS- and ERG-responsive target genes near enhancers that are co-occupied by ETS and AP-1 proteins.
# ::save-date Mon Aug 24, 2015 ::file pmid_2464_2271_113.txt
(t / test-01
      :ARG0 (w / we)
      :ARG1 (r / regulate-01 :mode interrogative
            :ARG0 (p / pathway :name (n3 / name :op1 "PI3K"))
            :ARG1 (c / capable-01
                  :ARG1 (p2 / protein :name (n4 / name :op1 "ERG"))
                  :ARG2 (a / activate-01
                        :ARG0 p2
                        :ARG1 (t2 / transcribe-01
                              :ARG1 (a2 / and
                                    :op1 (g / gene
                                          :ARG0-of (r2 / responsive-02
                                                :ARG1 (e / enzyme :name (n / name :op1 "Ras"))))
                                    :op2 (g2 / gene
                                          :ARG0-of (r3 / responsive-02
                                                :ARG1 p2))
                                    :ARG1-of (t3 / target-01)))
                        :ARG1-of (n6 / near-01
                              :ARG2 (m / molecular-physical-entity
                                    :ARG0-of (e3 / enhance-01)
                                    :ARG1-of (o / occupy-01
                                          :ARG0 (a3 / and
                                                :op1 (p3 / protein :name (n7 / name :op1 "ETS"))
                                                :op2 (p4 / protein :name (n8 / name :op1 "AP-1")))))))))
      :time (n2 / next))

# ::id pmid_2464_2271.114 ::date 2015-08-10T16:27:15 ::annotator SDL-AMR-09 ::preferred
# ::snt The expression levels of two such genes, <i>ARHGAP29</i>, and <i>SMAD3,</i> were measured by quantitative reverse transcription PCR (qRT-PCR) (Figure <xref ref-type="fig" rid="F4">4</xref>A and B).
# ::save-date Sun Jan 17, 2016 ::file pmid_2464_2271_114.txt
(m / measure-01
      :ARG1 (l / level
            :degree-of (e / express-03
                  :ARG1 (a2 / and :quant 2
                        :op1 (g / gene :name (n2 / name :op1 "ARHGAP29"))
                        :op2 (g2 / gene :name (n3 / name :op1 "SMAD3"))
                        :mod (s / such))))
      :ARG2 (r / react-01
            :ARG0 (p / polymerase)
            :ARG1-of (c / chain-01))
      :ARG1-of (d / describe-01
            :ARG0 (a / and
                  :op1 (f / figure :mod "4A")
                  :op2 (f2 / figure :mod "4B"))))

# ::id pmid_2464_2271.115 ::date 2015-08-11T03:08:33 ::annotator SDL-AMR-09 ::preferred
# ::snt Both <i>ARHGAP29</i> and <i>SMAD3</i> have roles in cell migration and/or cell morphology [<xref ref-type="bibr" rid="B30">30</xref>,<xref ref-type="bibr" rid="B31">31</xref>], are direct targets of oncogenic ETS proteins and AP-1 by ChIP-seq [<xref ref-type="bibr" rid="B15">15</xref>], and are activated by KRAS and oncogenic ETS expression (Figure <xref ref-type="fig" rid="F4">4</xref>A and B).
# ::save-date Thu Dec 10, 2015 ::file pmid_2464_2271_115.txt
(a / and
      :op1 (h / have-03
            :ARG0 (a4 / and
                  :op1 (g2 / gene :name (n2 / name :op1 "ARHGAP29"))
                  :op2 (g / gene :name (n / name :op1 "SMAD3")))
            :ARG1 (r / role
                  :topic (o / or
                        :op1 (m / migrate-01
                              :ARG0 (c / cell))
                        :op2 (m2 / morphology
                              :mod c)))
            :ARG1-of (d2 / describe-01
                  :ARG0 (p / publication
                        :ARG1-of (c2 / cite-01
                              :ARG2 (a6 / and :op1 30 :op2 31)))))
      :op2 (t / target-01
            :ARG0 (a7 / and
                  :op1 (p2 / protein :name (n3 / name :op1 "ETS"))
                  :op2 (p3 / protein :name (n4 / name :op1 "AP-1"))
                  :ARG0-of (c4 / cause-01
                        :ARG1 (d5 / disease :wiki "Cancer" :name (n8 / name :op1 "cancer"))))
            :ARG1 a4
            :ARG2 (t2 / thing :name (n5 / name :op1 "ChIP-seq"))
            :ARG1-of (d4 / describe-01
                  :ARG0 (p4 / publication
                        :ARG1-of (c3 / cite-01
                              :ARG2 15)))
            :ARG1-of (d3 / direct-02))
      :op3 (a3 / activate-01
            :ARG0 (a8 / and
                  :op1 (e / express-03
                        :ARG1 (g3 / gene :name (n7 / name :op1 "KRAS")))
                  :op2 (e2 / express-03
                        :ARG1 (g4 / gene :name (n6 / name :op1 "ETS")
                              :ARG0-of c4)))
            :ARG1 a4)
      :ARG1-of (d / describe-01
            :ARG0 (a2 / and
                  :op1 (f / figure :mod "4A")
                  :op2 (f2 / figure :mod "4b"))))

# ::id pmid_2464_2271.116 ::date 2015-08-11T02:28:11 ::annotator SDL-AMR-09 ::preferred
# ::snt Similar to the cell migration phenotype, the activation of both genes was significantly attenuated by PI3K inhibition in RWPE-ERG cells, but not in RWPE-KRAS cells (Figure <xref ref-type="fig" rid="F4">4</xref>A and B).
# ::save-date Sun Jan 17, 2016 ::file pmid_2464_2271_116.txt
(c5 / contrast-01
      :ARG1 (a4 / attenuate-01
            :ARG0 (i / inhibit-01
                  :ARG1 (e / enzyme :name (n / name :op1 "PI3K")))
            :ARG1 (a2 / activate-01
                  :ARG1 (g / gene
                        :mod (b / both)))
            :ARG1-of (s / significant-02)
            :location (c2 / cell-line :name (n2 / name :op1 "RWPE-ERG")))
      :ARG2 (a5 / attenuate-01 :polarity -
            :ARG0 i
            :ARG1 a2
            :location (c / cell-line :name (n3 / name :op1 "RWPE-KRAS")))
      :ARG1-of (d / describe-01
            :ARG0 (a3 / and
                  :op1 (f / figure :mod "4A")
                  :op2 (f2 / figure :mod "4B")))
      :ARG1-of (r / resemble-01
            :ARG2 (p2 / phenotype
                  :mod (m / migrate-01
                        :ARG0 (c4 / cell)))))

# ::id pmid_2464_2271.117 ::date 2015-08-10T13:36:55 ::annotator SDL-AMR-09 ::preferred
# ::snt Therefore cell migration changes are consistent with changes in the expression of these two oncogenic ETS target genes.
# ::save-date Thu Dec 10, 2015 ::file pmid_2464_2271_117.txt
(c6 / cause-01
      :ARG1 (c / consistent-01
            :ARG1 (c2 / change-01
                  :ARG1 (m / migrate-01
                        :ARG0 (c3 / cell)))
            :ARG2 (c4 / change-01
                  :ARG1 (e / express-03
                        :ARG1 (g / gene :quant 2
                              :mod (t / this)
                              :ARG1-of (t2 / target-01
                                    :ARG0 (p / protein :name (n / name :op1 "ETS")
                                          :ARG0-of (c7 / cause-01
                                                :ARG1 (d / disease :wiki "Cancer" :name (n2 / name :op1 "cancer"))))))))))

# ::id pmid_2464_2271.118 ::date 2015-08-10T14:10:50 ::annotator SDL-AMR-09 ::preferred
# ::snt These results indicate that the PI3K/AKT pathway functions through ERG to regulate expression of cell migration genes.
# ::save-date Thu Aug 13, 2015 ::file pmid_2464_2271_118.txt
(i / indicate-01
      :ARG0 (t / thing
            :ARG2-of (r / result-01)
            :mod (t2 / this))
      :ARG1 (f / function-01
            :ARG0 (p / pathway :name (n / name :op1 "PI3K/AKT"))
            :ARG1 (r2 / regulate-01
                  :ARG0 p
                  :ARG1 (e / express-03
                        :ARG1 (g / gene
                              :mod (m / migrate-01
                                    :ARG0 (c2 / cell)))))
            :instrument (p2 / protein :name (n2 / name :op1 "ERG"))))

# ::id pmid_2464_2271.119 ::date 2015-08-10T14:26:21 ::annotator SDL-AMR-09 ::preferred
# ::snt We next used a reporter assay to test if these gene expression changes were mediated by the ETS/AP-1 binding sequences we found in the enhancers of oncogenic ETS target genes.
# ::save-date Thu Dec 10, 2015 ::file pmid_2464_2271_119.txt
(u / use-01
      :ARG0 (w / we)
      :ARG1 (a / assay-01
            :ARG1 (g / gene
                  :ARG0-of (r / report-01)))
      :ARG2 (t / test-01
            :ARG0 w
            :ARG1 (m / mediate-01 :mode interrogative
                  :ARG0 (p / protein-segment :name (n2 / name :op1 "ETS/AP-1")
                        :ARG2-of (b2 / bind-01)
                        :ARG1-of (f / find-01
                              :ARG0 w
                              :location (m2 / molecular-physical-entity
                                    :ARG0-of (e2 / enhance-01
                                          :ARG1 (g2 / gene
                                                :ARG1-of (t4 / target-01
                                                      :ARG0 (p4 / protein :name (n3 / name :op1 "ETS")
                                                            :ARG0-of (c3 / cause-01
                                                                  :ARG1 (d / disease :wiki "Cancer" :name (n4 / name :op1 "cancer"))))))))))
                  :ARG1 (c / change-01
                        :ARG1 (e / express-03
                              :ARG1 g2))))
      :time (n / next))

# ::id pmid_2464_2271.120 ::date 2015-08-10T14:32:21 ::annotator SDL-AMR-09 ::preferred
# ::snt Three copies of an ETS/AP-1 consensus sequence were cloned upstream of a minimal promoter driving firefly luciferase.
# ::save-date Mon Aug 24, 2015 ::file pmid_2464_2271_120.txt
(c / clone-01
      :ARG1 (c2 / copy-01 :quant 3
            :ARG1 (p2 / protein-segment :name (n / name :op1 "ETS/AP-1")
                  :mod (c3 / consensus)))
      :direction (u / upstream
            :op1 (m2 / molecular-physical-entity
                  :ARG1-of (m / minimal-02)
                  :ARG0-of (p / promote-01)
                  :ARG0-of (d / drive-02
                        :ARG1 (e / enzyme :name (n2 / name :op1 "firefly" :op2 "luciferase"))))))

# ::id pmid_2464_2271.121 ::date 2015-08-10T06:43:55 ::annotator SDL-AMR-09 ::preferred
# ::snt Luciferase expression from this vector was higher when the ERK pathway was active, indicating that this pathway regulates the reporter construct (Figure <xref ref-type="fig" rid="F4">4</xref>C).
# ::save-date Thu Aug 13, 2015 ::file pmid_2464_2271_121.txt
(h2 / high-02
      :ARG1 (e2 / express-03
            :ARG2 (l / luciferase)
            :ARG3 (v / vector
                  :mod (t / this)))
      :degree (m / more)
      :time (a / activity-06
            :ARG0 (p / pathway :name (n / name :op1 "ERK")))
      :ARG0-of (i / indicate-01
            :ARG1 (r / regulate-01
                  :ARG0 p
                  :ARG1 (c / construct-01
                        :ARG0 (g / gene
                              :ARG0-of (r2 / report-01)))))
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod "4C")))

# ::id pmid_2464_2271.122 ::date 2015-08-10T06:52:01 ::annotator SDL-AMR-09 ::preferred
# ::snt Point mutations in either the ETS or AP-1 binding sequences completely eliminated luciferase expression indicating that both binding sites are required for activity (Figure <xref ref-type="fig" rid="F4">4</xref>C).
# ::save-date Mon Aug 24, 2015 ::file pmid_2464_2271_122.txt
(e / eliminate-01
      :ARG0 (m / mutate-01
            :ARG1 (o / or
                  :op1 (d2 / dna-sequence
                        :ARG2-of (b2 / bind-01
                              :ARG1 (p2 / protein :name (n / name :op1 "ETS"))))
                  :op2 (p4 / protein-segment
                        :ARG2-of (b / bind-01
                              :ARG1 (p3 / protein :name (n2 / name :op1 "AP-1")))))
            :mod (p / point))
      :ARG1 (e2 / express-03
            :ARG2 (l / luciferase))
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod "4C"))
      :ARG1-of (c / complete-02)
      :ARG0-of (i / indicate-01
            :ARG1 (r / require-01
                  :ARG0 (a / activity-06
                        :ARG0 o)
                  :ARG1 o)))

# ::id pmid_2464_2271.123 ::date 2015-08-11T02:02:21 ::annotator SDL-AMR-09 ::preferred
# ::snt The PI3K inhibitor, LY294002, caused a significant decrease in the activity of this reporter in RWPE-ERG cells (Figure <xref ref-type="fig" rid="F4">4</xref>D), but significantly increased activity in RWPE-KRAS cells (Figure <xref ref-type="fig" rid="F4">4</xref>E), consistent with the cell migration findings.
# ::save-date Sun Jan 17, 2016 ::file pmid_2464_2271_123.txt
(c / contrast-01
      :ARG1 (c2 / cause-01
            :ARG0 (s3 / small-molecule :name (n2 / name :op1 "LY294002")
                  :ARG0-of (i2 / inhibit-01
                        :ARG1 (p / protein-family :name (n / name :op1 "PI3K"))))
            :ARG1 (d / decrease-01
                  :ARG1 (a / activity-06
                        :ARG0 (g / gene
                              :ARG0-of (r / report-01)
                              :mod (t / this))
                        :location (c5 / cell-line :name (n3 / name :op1 "RWPE-ERG")))
                  :ARG1-of (s / significant-02))
            :ARG1-of (d2 / describe-01
                  :ARG0 (f2 / figure :mod "4D")))
      :ARG2 (i / increase-01
            :ARG0 s3
            :ARG1 (a2 / activity-06
                  :ARG0 g
                  :location (c6 / cell-line :name (n4 / name :op1 "RWPE-KRAS")))
            :ARG1-of (c3 / consistent-01
                  :ARG2 (f / find-01
                        :ARG1 (m / migrate-01
                              :ARG0 (c4 / cell))))
            :ARG1-of (d3 / describe-01
                  :ARG0 (f3 / figure :mod "4E"))
            :ARG1-of s))

# ::id pmid_2464_2271.124 ::date 2015-08-10T14:54:42 ::annotator SDL-AMR-09 ::preferred
# ::snt Therefore, the PI3K pathway can alter the expression of cell migration genes via ETS/AP-1 sites.
# ::save-date Thu Aug 13, 2015 ::file pmid_2464_2271_124.txt
(c / cause-01
      :ARG1 (p / possible-01
            :ARG1 (a / alter-01
                  :ARG0 (p2 / pathway :name (n / name :op1 "PI3K"))
                  :ARG1 (e / express-03
                        :ARG1 (g / gene
                              :mod (m / migrate-01
                                    :ARG0 (c2 / cell))))
                  :instrument (p3 / protein-segment :name (n2 / name :op1 "ETS/AP-1")))))

# ::id pmid_2464_2271.125 ::date 2015-08-10T14:28:13 ::annotator SDL-AMR-09 ::preferred
# ::snt <sec-title level="2">The role of AKT in oncogenic ETS function is not via mTORC1</sec-title>
# ::save-date Thu Dec 10, 2015 ::file pmid_2464_2271_125.txt
(r / role
      :poss (e / enzyme :name (n / name :op1 "AKT"))
      :topic (f / function-01
            :ARG0 (g / gene :name (n2 / name :op1 "ETS")
                  :ARG0-of (c2 / cause-01
                        :ARG1 (d / disease :wiki "Cancer" :name (n4 / name :op1 "cancer")))))
      :instrument (m2 / macro-molecular-complex :polarity - :name (n3 / name :op1 "mTORC1")))

# ::id pmid_2464_2271.126 ::date 2015-08-10T14:31:32 ::annotator SDL-AMR-09 ::preferred
# ::snt PI3K/AKT signaling has a number of cellular functions including the activation of the mTOR-containing complexes mTORC1 and mTORC2 [<xref ref-type="bibr" rid="B8">8</xref>].
# ::save-date Mon Aug 24, 2015 ::file pmid_2464_2271_126.txt
(f2 / function-01
      :ARG0 (s / signal-07
            :ARG0 (p2 / pathway :name (n2 / name :op1 "PI3K/AKT")))
      :ARG1 (c / cell)
      :ARG1-of (d / describe-01
            :ARG0 (p3 / publication
                  :ARG1-of (c3 / cite-01
                        :ARG2 8)))
      :ARG1-of (i / include-91
            :ARG2 (a / activate-01
                  :ARG0 p2
                  :ARG1 (a2 / and
                        :op1 (m2 / macro-molecular-complex :name (n3 / name :op1 "mTORC1"))
                        :op2 (m3 / macro-molecular-complex :name (n4 / name :op1 "mTORC2"))
                        :ARG0-of (c2 / contain-01
                              :ARG1 (p / protein :name (n / name :op1 "mTOR"))))))
      :quant (n5 / number))

# ::id pmid_2464_2271.127 ::date 2015-08-10T08:01:38 ::annotator SDL-AMR-09 ::preferred
# ::snt mTORC1 includes the Raptor protein and regulates gene expression via translational control.
# ::save-date Thu Aug 13, 2015 ::file pmid_2464_2271_127.txt
(a / and
      :op1 (i2 / include-91
            :ARG1 (m2 / macro-molecular-complex :name (n2 / name :op1 "mTORC1"))
            :ARG2 (p2 / protein :name (n / name :op1 "Raptor")))
      :op2 (r / regulate-01
            :ARG0 m2
            :ARG1 (e / express-03
                  :ARG1 (g / gene))
            :instrument (c / control-01
                  :ARG1 (t / translate-02))))

# ::id pmid_2464_2271.128 ::date 2015-08-10T08:35:16 ::annotator SDL-AMR-09 ::preferred
# ::snt mTORC2 includes the Rictor protein and provides positive feedback by phosphorylating and activating AKT.
# ::save-date Thu Aug 13, 2015 ::file pmid_2464_2271_128.txt
(a / and
      :op1 (i / include-91
            :ARG1 (m2 / macro-molecular-complex :name (n / name :op1 "mTORC2"))
            :ARG2 (p5 / protein :name (n2 / name :op1 "Rictor")))
      :op2 (p / provide-01
            :ARG0 m2
            :ARG1 (f / feedback
                  :mod (p2 / positive))
            :manner (a2 / and
                  :op1 (p3 / phosphorylate-01
                        :ARG1 p4
                        :ARG2 m2)
                  :op2 (a3 / activate-01
                        :ARG0 m2
                        :ARG1 (p4 / pathway :name (n3 / name :op1 "AKT"))))))

# ::id pmid_2464_2271.129 ::date 2015-08-10T08:58:28 ::annotator SDL-AMR-09 ::preferred
# ::snt To test the role of mTOR-containing complexes in oncogenic ETS function, shRNAs were used to knockdown mTOR, Raptor, and Rictor, in RWPE-ERG cells (Figure <xref ref-type="fig" rid="F5">5</xref>A).
# ::save-date Thu Dec 10, 2015 ::file pmid_2464_2271_129.txt
(u / use-01
      :ARG1 (n8 / nucleic-acid :name (n3 / name :op1 "shRNA"))
      :ARG2 (k / knock-down-02
            :ARG1 (a / and
                  :op1 m
                  :op2 (p2 / protein :name (n6 / name :op1 "Raptor"))
                  :op3 (p3 / protein :name (n7 / name :op1 "Rictor"))
                  :location (c3 / cell-line :name (n4 / name :op1 "RWPE-ERG"))))
      :purpose (t / test-01
            :ARG1 (r / role
                  :poss (m / macro-molecular-complex
                        :ARG0-of (c / contain-01
                              :ARG1 (p / protein :name (n / name :op1 "mTOR"))))
                  :topic (f / function-01
                        :ARG0 (g / gene :name (n2 / name :op1 "ETS")
                              :ARG0-of (c4 / cause-01
                                    :ARG1 (d2 / disease :wiki "Cancer" :name (n5 / name :op1 "cancer")))))))
      :ARG1-of (d / describe-01
            :ARG0 (f2 / figure :mod "5A")))

# ::id pmid_2464_2271.130 ::date 2015-08-10T16:40:03 ::annotator SDL-AMR-09 ::preferred
# ::snt Loss of Raptor resulted in an increase in cell migration, indicating that mTORC1 is not required for the ability of PI3K/AKT to promote cell migration (Figure <xref ref-type="fig" rid="F5">5</xref>B and Additional file <xref ref-type="supplementary-material" rid="S2">2</xref>: Figure S2).
# ::save-date Mon Aug 24, 2015 ::file pmid_2464_2271_130.txt
(r / result-01
      :ARG1 (l / lose-02
            :ARG1 (p2 / protein :name (n2 / name :op1 "Raptor")))
      :ARG2 (i / increase-01
            :ARG1 (m / migrate-01
                  :ARG0 (c / cell)))
      :ARG1-of (d / describe-01
            :ARG0 (a / and
                  :op1 (f / figure :mod "5B")
                  :op2 (f2 / file :mod 2
                        :part (f3 / figure :mod "S2"))))
      :ARG0-of (i2 / indicate-01
            :ARG1 (r2 / require-01 :polarity -
                  :ARG0 (c3 / capable-01
                        :ARG1 (p5 / pathway :name (n4 / name :op1 "PI3K/AKT"))
                        :ARG2 (p4 / promote-01
                              :ARG0 p5
                              :ARG1 m))
                  :ARG1 (m2 / macro-molecular-complex :name (n3 / name :op1 "mTORC1")))))

# ::id pmid_2464_2271.131 ::date 2015-08-10T14:44:02 ::annotator SDL-AMR-09 ::preferred
# ::snt Loss of mTOR had little effect on RWPE-ERG migration, while loss of Rictor decreased migration (Figure <xref ref-type="fig" rid="F5">5</xref>B and Additional file <xref ref-type="supplementary-material" rid="S2">2</xref>: Figure S2).
# ::save-date Thu Aug 13, 2015 ::file pmid_2464_2271_131.txt
(c / contrast-01
      :ARG1 (a2 / affect-01
            :ARG0 (l2 / lose-02
                  :ARG1 (p / protein :name (n2 / name :op1 "mTOR")))
            :ARG1 (m2 / migrate-01
                  :ARG0 (c2 / cell-line :name (n / name :op1 "RWPE-ERG")))
            :degree (l / little))
      :ARG2 (d2 / decrease-01
            :ARG0 (l3 / lose-02
                  :ARG1 (p2 / protein :name (n3 / name :op1 "Rictor")))
            :ARG1 m2)
      :ARG1-of (d / describe-01
            :ARG0 (a / and
                  :op1 (f / figure :mod "5B")
                  :op2 (f2 / file :mod 2
                        :location-of (f3 / figure :mod "S2")))))

# ::id pmid_2464_2271.132 ::date 2015-08-10T14:53:58 ::annotator SDL-AMR-09 ::preferred
# ::snt Because the major role of the Rictor-containing mTORC2 complex is thought to be the phosphorylation of AKT, we hypothesized that these results were due to changes in AKT phosphorylation.
# ::save-date Wed Nov 18, 2015 ::file pmid_2464_2271_132.txt
(c / cause-01
      :ARG0 (t / think-01
            :ARG1 (r / role
                  :mod (m / major)
                  :poss (m2 / macro-molecular-complex :name (n2 / name :op1 "mTORC2")
                        :ARG0-of (c2 / contain-01
                              :ARG1 (p2 / protein :name (n3 / name :op1 "Rictor"))))
                  :domain (p / phosphorylate-01
                        :ARG1 (e / enzyme :name (n / name :op1 "AKT")))))
      :ARG1 (h / hypothesize-01
            :ARG0 (w / we)
            :ARG1 (c3 / cause-01
                  :ARG0 (c4 / change-01
                        :ARG1 p)
                  :ARG1 (t2 / thing
                        :ARG2-of (r2 / result-01)
                        :mod (t3 / this)))))

# ::id pmid_2464_2271.133 ::date 2015-08-10T13:23:58 ::annotator SDL-AMR-09 ::preferred
# ::snt Consistent with previous findings [<xref ref-type="bibr" rid="B32">32</xref>-<xref ref-type="bibr" rid="B34">34</xref>], Raptor knockdown increased AKT phosphorylation, and Rictor knockdown decreased AKT phosphorylation (Figure <xref ref-type="fig" rid="F5">5</xref>C).
# ::save-date Mon Aug 24, 2015 ::file pmid_2464_2271_133.txt
(a / and
      :op1 (i / increase-01
            :ARG0 (k / knock-down-02
                  :ARG1 (p3 / protein :name (n2 / name :op1 "Raptor")))
            :ARG1 (p / phosphorylate-01
                  :ARG1 (e / enzyme :name (n / name :op1 "AKT"))))
      :op2 (d2 / decrease-01
            :ARG0 (k2 / knock-down-02
                  :ARG1 (p4 / protein :name (n3 / name :op1 "Rictor")))
            :ARG1 p)
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod "5C"))
      :ARG1-of (c / consistent-01
            :ARG2 (t / thing
                  :ARG1-of (f2 / find-01
                        :time (p2 / previous))
                  :ARG1-of (d3 / describe-01
                        :ARG0 (p5 / publication
                              :ARG1-of (c2 / cite-01
                                    :ARG2 (v / value-interval :op1 32 :op2 34)))))))

# ::id pmid_2464_2271.134 ::date 2015-08-10T15:06:02 ::annotator SDL-AMR-09 ::preferred
# ::snt Therefore, the effect of mTOR containing complexes on RWPE-ERG cell migration can be explained indirectly by changes to pAKT levels, rather than by a direct role.
# ::save-date Mon Aug 24, 2015 ::file pmid_2464_2271_134.txt
(c / cause-01
      :ARG1 (p / possible-01
            :ARG1 (e / explain-01
                  :ARG0 (c6 / change-01
                        :ARG1 (l / level
                              :quant-of (e3 / enzyme :name (n3 / name :op1 "AKT")
                                    :ARG3-of (p5 / phosphorylate-01)))
                        :ARG1-of (i / instead-of-91
                              :ARG2 (r / role
                                    :ARG1-of (d2 / direct-02))))
                  :ARG1 (a / affect-01
                        :ARG0 (m3 / macro-molecular-complex
                              :ARG0-of (c4 / contain-01
                                    :ARG1 (p3 / protein :name (n / name :op1 "mTOR"))))
                        :ARG1 (m2 / migrate-01
                              :ARG0 (c3 / cell-line :name (n2 / name :op1 "RWPE-ERG"))))
                  :ARG1-of (d / direct-02 :polarity -))))

# ::id pmid_2465_1010.1 ::date 2015-02-09T09:42:41 ::annotator SDL-AMR-09 ::preferred
# ::snt Dragging Ras Back in the Ring (PMID:24651010)
# ::save-date Thu Dec 31, 2015 ::file pmid_2465_1010_1.txt
(p / publication-91
      :ARG1 (d / drag-01
            :ARG1 (e / enzyme :name (n / name :op1 "Ras"))
            :ARG2 (r / ring)
            :direction (b / back))
      :ARG8 "PMID24651010")

# ::id pmid_2465_1010.2 ::date 2015-02-10T04:25:26 ::annotator SDL-AMR-09 ::preferred
# ::snt Ras proteins play a major role in human cancers but have not yielded to therapeutic attack.
# ::save-date Sat Jan 16, 2016 ::file pmid_2465_1010_2.txt
(c / contrast-01
      :ARG1 (p / play-08
            :ARG0 (p2 / protein-family :name (n / name :op1 "Ras"))
            :ARG1 (d / disease :wiki "Cancer" :name (n2 / name :op1 "cancer")
                  :mod (h / human))
            :ARG1-of (m / major-02))
      :ARG2 (y / yield-02 :polarity -
            :ARG0 p2
            :ARG2 (a / attack-01
                  :ARG0 (t / therapy)
                  :ARG1 p2)))

# ::id pmid_2465_1010.3 ::date 2015-02-10T13:22:39 ::annotator SDL-AMR-09 ::preferred
# ::snt Ras-driven cancers are among the most difficult to treat and often excluded from therapies.
# ::save-date Fri Feb 13, 2015 ::file pmid_2465_1010_3.txt
(a / and
      :op1 (i / include-91
            :ARG1 (d / disease :wiki "Cancer"
                  :name (n / name :op1 "cancer")
                  :ARG1-of (d2 / drive-02
                        :ARG0 (e / enzyme
                              :name (n2 / name :op1 "Ras"))))
            :ARG2 (d3 / disease :wiki "Cancer"
                  :name (n3 / name :op1 "cancer")
                  :ARG2-of (t / treat-03
                        :manner (d4 / difficult
                              :degree (m / most)))))
      :op2 (e2 / exclude-01
            :ARG1 d
            :ARG2 (t2 / therapy)
            :frequency (o / often)))

# ::id pmid_2465_1010.4 ::date 2015-02-10T14:22:33 ::annotator SDL-AMR-09 ::preferred
# ::snt The Ras proteins have been termed “undruggable,” based on failures from an era in which understanding of signaling transduction, feedback loops, redundancy, tumor heterogeneity, and Ras’ oncogenic role was poor.
# ::save-date Tue Jan 19, 2016 ::file pmid_2465_1010_4.txt
(t / term-01
      :ARG1 (e / enzyme :name (n / name :op1 "Ras"))
      :ARG3 (p / possible-01 :polarity -
            :ARG1 (d / drug-01
                  :ARG1 e))
      :ARG1-of (b / base-02
            :ARG2 (f / fail-01
                  :time (e2 / era
                        :time-of (p2 / poor
                              :domain (u / understand-01
                                    :ARG1 (a / and
                                          :op1 (t2 / transduce-01
                                                :ARG1 (s / signal-07))
                                          :op2 (l / loop
                                                :mod (f2 / feedback))
                                          :op3 (r / redundancy)
                                          :op4 (h / heterogeneous
                                                :domain (t3 / tumor))
                                          :op5 (c / cause-01
                                                :ARG0 e
                                                :ARG1 (d2 / disease :wiki "Cancer" :name (n2 / name :op1 "cancer"))))))))))

# ::id pmid_2465_1010.5 ::date 2015-02-10T15:36:53 ::annotator SDL-AMR-09 ::preferred
# ::snt Structures of Ras oncoproteins bound to their effectors or regulators are unsolved, and it is unknown precisely how Ras proteins activate their downstream targets.
# ::save-date Sat Jan 16, 2016 ::file pmid_2465_1010_5.txt
(a / and
      :op1 (s / solve-01 :polarity -
            :ARG1 (s2 / structure
                  :consist-of (e / enzyme :name (n / name :op1 "Ras")
                        :ARG0-of (c / cause-01
                              :ARG1 (d2 / disease :wiki "Cancer" :name (n3 / name :op1 "cancer")))
                        :ARG1-of (b / bind-01
                              :ARG2 (o2 / or
                                    :op1 (e2 / effector
                                          :poss e)
                                    :op2 (m / molecular-physical-entity
                                          :ARG0-of (r / regulate-01
                                                :ARG1 e)))))))
      :op2 (k / know-01 :polarity -
            :ARG1 (t / thing
                  :manner-of (a2 / activate-01
                        :ARG0 (p2 / protein-family :name (n2 / name :op1 "Ras"))
                        :ARG1 (m2 / molecular-physical-entity
                              :ARG1-of (t2 / target-01
                                    :ARG0 p2)
                              :location (d / downstream))))
            :manner (p / precise)))

# ::id pmid_2465_1010.6 ::date 2015-02-10T22:50:20 ::annotator SDL-AMR-09 ::preferred
# ::snt These knowledge gaps have impaired development of therapeutic strategies.
# ::save-date Tue Mar 17, 2015 ::file pmid_2465_1010_6.txt
(i / impair-01
      :ARG0 (g / gap
            :mod (t2 / this)
            :topic (k / know-03))
      :ARG1 (d / develop-02
            :ARG1 (s / strategy
                  :mod (t / therapy))))

# ::id pmid_2465_1010.7 ::date 2015-02-10T22:58:33 ::annotator SDL-AMR-09 ::preferred
# ::snt A better understanding of Ras biology and biochemistry, coupled with new ways of targeting undruggable proteins, is likely to lead to new ways of defeating Ras-driven cancers.
# ::save-date Fri Feb 5, 2016 ::file pmid_2465_1010_7.txt
(l / likely-01
      :ARG1 (l2 / lead-03
            :ARG0 (u / understand-01
                  :ARG1 (a / and
                        :op1 (b / biology
                              :mod (p3 / protein-family :name (n / name :op1 "Ras")))
                        :op2 (b2 / biochemistry
                              :mod p3))
                  :ARG1-of (c / couple-01
                        :ARG2 (w2 / way
                              :ARG1-of (n4 / new-01)
                              :manner-of (t / target-01
                                    :ARG1 (p / protein
                                          :ARG1-of (d4 / drug-01
                                                :ARG1-of (p2 / possible-01 :polarity -))))))
                  :ARG1-of (g / good-02
                        :degree (m / more)))
            :ARG2 (w / way
                  :ARG1-of (n2 / new-01)
                  :manner-of (d / defeat-01
                        :ARG1 (d2 / disease :wiki "Cancer" :name (n3 / name :op1 "cancer")
                              :ARG1-of (d3 / drive-02
                                    :ARG0 p3))))))

# ::id pmid_2465_1010.8 ::date 2015-02-10T23:12:32 ::annotator SDL-AMR-09 ::preferred
# ::snt Main Text
# ::save-date Tue Feb 10, 2015 ::file pmid_2465_1010_8.txt
(t / text
      :mod (m / main))

# ::id pmid_2465_1010.9 ::date 2015-02-10T23:14:13 ::annotator SDL-AMR-09 ::preferred
# ::snt Fifty years have passed since the transforming power of Ras genes was first recognized.
# ::save-date Thu Dec 31, 2015 ::file pmid_2465_1010_9.txt
(p / pass-03
      :ARG1 (t / temporal-quantity :quant 50
            :unit (y / year))
      :time (s / since
            :op1 (r / recognize-02
                  :ARG1 (p2 / possible-01
                        :ARG1 (t2 / transform-01
                              :ARG0 (g / gene :wiki -
                                    :name (n / name :op1 "Ras"))))
                  :ord (o / ordinal-entity :value 1))))

# ::id pmid_2465_1010.10 ::date 2015-02-11T03:01:29 ::annotator SDL-AMR-09 ::preferred
# ::snt Harvey sarcoma virus, Kirsten sarcoma virus, and Rasheed sarcoma virus contain Ras genes (so named for their role in forming <i>ra</i>t <i>s</i>arcomas; reviewed in <ce:cross-refs id="crosrefs0010" refid="bib3 bib31">Barbacid, 1987; Karnoub and Weinberg, 2008</ce:cross-refs>).
# ::save-date Mon Jan 4, 2016 ::file pmid_2465_1010_10.txt
(c / contain-01
      :ARG0 (a / and
            :op1 (v / virus :name (n2 / name :op1 "Harvey" :op2 "sarcoma" :op3 "virus"))
            :op2 (v2 / virus :name (n3 / name :op1 "Kirsten" :op2 "sarcoma" :op3 "virus"))
            :op3 (v3 / virus :name (n4 / name :op1 "Rasheed" :op2 "sarcoma" :op3 "virus")))
      :ARG1 (g / gene :name (n / name :op1 "Ras")
            :ARG1-of (n5 / name-01
                  :ARG1-of (c2 / cause-01
                        :ARG0 (p6 / play-08
                              :ARG0 g
                              :ARG1 (f / form-01
                                    :ARG1 (s / sarcoma
                                          :mod (r / rat)))))))
      :ARG1-of (r2 / review-02
            :ARG2 (a2 / and
                  :op1 (p / publication-91
                        :ARG0 (p3 / person :name (n6 / name :op1 "Barbacid"))
                        :time (d / date-entity :year 1987))
                  :op2 (p2 / publication-91
                        :ARG0 (a3 / and
                              :op1 (p4 / person :name (n7 / name :op1 "Karnoub"))
                              :op2 (p5 / person :name (n8 / name :op1 "Weinberg")))
                        :time (d2 / date-entity :year 2008)))))

# ::id pmid_2465_1010.11 ::date 2015-02-11T03:47:55 ::annotator SDL-AMR-09 ::preferred
# ::snt These retroviruses initiated tumors efficiently and, using temperature-sensitive mutants, were shown to be necessary for tumor maintenance (<ce:cross-ref id="crosref0040" refid="bib62">Shih et al., 1979</ce:cross-ref>).
# ::save-date Fri Feb 13, 2015 ::file pmid_2465_1010_11.txt
(a / and
      :op1 (i / initiate-01
            :ARG0 (r / retrovirus
                  :mod (t / this))
            :ARG1 (t2 / tumor)
            :ARG2-of (e / efficient-01
                  :ARG1 r))
      :op2 (s / show-01
            :ARG1 (n / need-01
                  :ARG0 (m / maintain-01
                        :ARG1 t2)
                  :ARG1 r)
            :manner (u / use-01
                  :ARG1 (v / virus
                        :ARG2-of (m2 / mutate-01)
                        :ARG0-of (s2 / sensitive-03
                              :ARG1 (t3 / temperature)))))
      :ARG1-of (d / describe-01
            :ARG0 (p / publication-91
                  :ARG0 (a2 / and
                        :op1 (p2 / person :name (n2 / name :op1 "Shih"))
                        :op2 (p3 / person
                              :mod (o / other)))
                  :time (d2 / date-entity :year 1979))))

# ::id pmid_2465_1010.12 ::date 2015-02-11T04:14:45 ::annotator SDL-AMR-09 ::preferred
# ::snt They formed part of a fascinating collection of retroviruses that was assembled in the 1970s, each able to transform cells in culture and in avian and rodent models.
# ::save-date Fri Feb 13, 2015 ::file pmid_2465_1010_12.txt
(i / include-91
      :ARG1 (t / they)
      :ARG2 (c / collection
            :ARG0-of (f2 / fascinate-01)
            :consist-of (r / retrovirus
                  :ARG0-of (t2 / transform-01
                        :ARG1 (c2 / cell
                              :source (a2 / and
                                    :op1 (c3 / culture)
                                    :op2 (m / model
                                          :mod (b / bird))
                                    :op3 (m2 / model
                                          :mod (r2 / rodent))))
                        :ARG1-of (p2 / possible-01))
                  :mod (e / each))
            :ARG1-of (a / assemble-02
                  :time (d / date-entity :decade 1970))))

# ::id pmid_2465_1010.13 ::date 2015-02-11T04:48:49 ::annotator SDL-AMR-09 ::preferred
# ::snt These experiments were, essentially, unbiased screens for genes that cause cancer; the nature of the proteins that the genes encoded was completely unknown.
# ::save-date Fri Jan 1, 2016 ::file pmid_2465_1010_13.txt
(m / multi-sentence
      :snt1 (s / screen-01
            :ARG0 (e / experiment-01
                  :mod (t / this))
            :ARG2 (g / gene
                  :ARG0-of (c / cause-01
                        :ARG1 (d / disease :wiki "Cancer" :name (n / name :op1 "cancer"))))
            :ARG1-of (b / bias-01 :polarity -)
            :mod (e2 / essential))
      :snt2 (k / know-01 :polarity -
            :ARG1 (n2 / nature
                  :mod (p / protein
                        :ARG1-of (e3 / encode-01
                              :ARG0 (g2 / gene))))
            :ARG1-of (c2 / complete-02)))

# ::id pmid_2465_1010.14 ::date 2015-02-11T05:08:05 ::annotator SDL-AMR-09 ::preferred
# ::snt Remarkably, the majority of these viruses encoded proteins that were later identified as components of the tyrosine kinase-Ras signaling pathway (<ce:cross-ref id="crosref0045" refid="bib75">Vogt, 2012</ce:cross-ref>), even though the biochemical nature of these proteins was unknown, and tyrosine kinase activity had not been discovered (<ce:cross-ref id="crosref0050" refid="bib17">Eckhart et al., 1979</ce:cross-ref>).
# ::save-date Fri Jan 1, 2016 ::file pmid_2465_1010_14.txt
(e / encode-01
      :ARG0 (v / virus
            :ARG1-of (i / include-91
                  :ARG2 (v2 / virus
                        :mod (t / this))
                  :ARG3 (m / majority)))
      :ARG1 (p / protein
            :ARG1-of (i2 / identify-01
                  :ARG2 (c / component
                        :part-of (p2 / pathway :name (n / name :op1 "tyrosine" :op2 "kinase-Ras")
                              :ARG0-of (s / signal-07)))
                  :time (l / late
                        :degree (m2 / more))
                  :ARG1-of (h / have-concession-91
                        :ARG2 (a / and
                              :op1 (k / know-01 :polarity -
                                    :ARG1 (n2 / nature
                                          :mod (b / biochemical)
                                          :poss p))
                              :op2 (d / discover-01 :polarity -
                                    :ARG1 (a2 / activity-06
                                          :ARG0 (e2 / enzyme :name (n3 / name :op1 "tyrosine" :op2 "kinase")))))
                        :ARG1-of (d3 / describe-01
                              :ARG0 (p4 / publication-91
                                    :ARG0 (a3 / and
                                          :op1 (p5 / person :name (n4 / name :op1 "Eckhart"))
                                          :op2 (p6 / person
                                                :mod (o / other)))
                                    :time (d4 / date-entity :year 1979))))))
      :ARG1-of (r / remarkable-02)
      :ARG1-of (d2 / describe-01
            :ARG0 (p7 / publication-91
                  :ARG0 (a4 / and
                        :op1 (p8 / person :name (n5 / name :op1 "Vogt")))
                  :time (d5 / date-entity :year 2012))))

# ::id pmid_2465_1010.15 ::date 2015-02-11T06:42:30 ::annotator SDL-AMR-09 ::preferred
# ::snt Of the hundreds of mutant proteins now known to contribute to cancer that could have been identified in these assays, including those involved in DNA repair, cellular metabolism, RNA splicing, and the other hallmarks of cancer (<ce:cross-ref id="crosref0055" refid="bib25">Hanahan and Weinberg, 2011</ce:cross-ref>), those in the tyrosine kinase-Ras pathway stand out as the major drivers and have been the richest source of targets of successful cancer therapies (Abl, epidermal growth factor receptor [EGFR], Her2/neu, B-Raf, Kit, ALK, etc.).
# ::save-date Wed Jan 13, 2016 ::file pmid_2465_1010_15.txt
(a / and
      :op1 (s / stand-out-06
            :ARG1 (p / protein
                  :location (p2 / pathway :name (n / name :op1 "tyrosine" :op2 "kinase-Ras"))
                  :ARG1-of (i / include-91
                        :ARG2 (p4 / protein
                              :ARG2-of (m2 / mutate-01)
                              :quant (m3 / multiple :op1 100)
                              :ARG0-of (c2 / contribute-01
                                    :ARG2 d2
                                    :ARG1-of (k / know-01
                                          :time (n9 / now)))
                              :ARG1-of (i2 / identify-01
                                    :ARG0 (a3 / assay-01
                                          :mod (t4 / this))
                                    :ARG1-of (p5 / possible-01))
                              :ARG2-of (i3 / include-91
                                    :ARG1 (a4 / and
                                          :op1 (p6 / protein
                                                :ARG1-of (i4 / involve-01
                                                      :ARG2 (a5 / and
                                                            :op1 (r / repair-01
                                                                  :ARG1 (n12 / nucleic-acid :wiki "DNA" :name (n13 / name :op1 "DNA")))
                                                            :op2 (m4 / metabolism
                                                                  :mod (c3 / cell))
                                                            :op3 (s5 / splice-01
                                                                  :ARG1 (n14 / nucleic-acid :name (n15 / name :op1 "RNA")))
                                                            :op4 (h / hallmark
                                                                  :mod (o / other)
                                                                  :mod d2)))))))
                        :ARG1-of (d4 / describe-01
                              :ARG0 (p7 / publication-91
                                    :ARG0 (a6 / and
                                          :op1 (p8 / person :name (n10 / name :op1 "Hanahan"))
                                          :op2 (p9 / person :name (n11 / name :op1 "Weinberg")))
                                    :time (d5 / date-entity :year 2011)))))
            :ARG1-of (c / cause-01
                  :ARG0 (d / drive-02
                        :ARG0 p
                        :ARG1-of (m / major-02))))
      :op2 (s2 / source-02
            :ARG0 p
            :ARG1 (t / thing
                  :ARG1-of (t2 / target-01
                        :ARG0 (t3 / therapy
                              :mod (d2 / disease :wiki "Cancer" :name (n2 / name :op1 "cancer"))
                              :ARG0-of (s3 / succeed-01))
                        :example (a2 / and
                              :op1 (p10 / protein :name (n3 / name :op1 "Abl"))
                              :op2 (e / enzyme :name (n4 / name :op1 "epidermal" :op2 "growth" :op3 "factor" :op4 "receptor"))
                              :op3 (p3 / protein :name (n5 / name :op1 "Her2/neu"))
                              :op4 (e2 / enzyme :name (n6 / name :op1 "B-Raf"))
                              :op5 (e5 / enzyme :name (n7 / name :op1 "Kit"))
                              :op6 (e6 / enzyme :name (n8 / name :op1 "ALK"))
                              :op7 (e3 / et-cetera))))
            :mod (r3 / rich
                  :degree (m5 / most))))

# ::id pmid_2465_1010.16 ::date 2015-02-11T11:09:35 ::annotator SDL-AMR-09 ::preferred
# ::snt These successes can therefore be attributed to the central, dominant role of this pathway in cancer, as well as the fortuitous abundance of druggable targets.
# ::save-date Fri Feb 13, 2015 ::file pmid_2465_1010_16.txt
(i / infer-01
      :ARG1 (p / possible-01
            :ARG1 (a / attribute-01
                  :ARG1 (s / succeed-01
                        :mod (t / this))
                  :ARG2 (a2 / and
                        :op1 (p2 / play-08
                              :ARG0 (p3 / pathway
                                    :mod t)
                              :ARG1 (d / disease :wiki "Cancer"
                                    :name (n / name :op1 "cancer"))
                              :ARG0-of (d2 / dominate-01)
                              :mod (c / central))
                        :op2 (t2 / thing
                              :ARG1-of (t3 / target-01)
                              :mod (a3 / abundance
                                    :mod (f / fortuity))
                              :ARG1-of (d3 / drug-01
                                    :ARG1-of (p4 / possible-01)))))))

# ::id pmid_2465_1010.17 ::date 2015-02-11T11:55:47 ::annotator SDL-AMR-09 ::preferred
# ::snt However, specific therapies have not been developed for mutant Ras proteins themselves or for the cancers that they drive.
# ::save-date Fri Jul 24, 2015 ::file pmid_2465_1010_17.txt
(h / have-concession-91
      :ARG1 (d / develop-02 :polarity -
            :ARG1 (t / therapy
                  :ARG1-of (s / specific-02))
            :ARG3 (o / or
                  :op1 (e / enzyme
                        :name (n / name :op1 "Ras")
                        :ARG2-of (m / mutate-01))
                  :op2 (d2 / disease :wiki "Cancer"
                        :name (n2 / name :op1 "cancer")
                        :ARG1-of (d3 / drive-02
                              :ARG0 e)))))

# ::id pmid_2465_1010.18 ::date 2015-02-11T12:06:32 ::annotator SDL-AMR-09 ::preferred
# ::snt Worse yet, tumors driven by Ras genes are excluded from treatment with other targeted therapies.
# ::save-date Mon Dec 21, 2015 ::file pmid_2465_1010_18.txt
(b / bad-05
      :ARG1 (e / exclude-01
            :ARG1 (t / tumor
                  :ARG1-of (d / drive-02
                        :ARG0 (g / gene :name (n / name :op1 "Ras"))))
            :ARG2 (t2 / treat-03
                  :ARG2 t
                  :ARG3 (t3 / therapy
                        :mod (o / other)
                        :ARG2-of (t4 / target-01))))
      :degree (m / more)
      :mod (y / yet))

# ::id pmid_2465_1010.19 ::date 2015-02-11T12:14:27 ::annotator SDL-AMR-09 ::preferred
# ::snt Early efforts to block Ras cancers by preventing Ras farnesylation, once thought to be an essential posttranslational modification for Ras activity, were thwarted by the unexpected presence of a backup system (geranylgeranyltransferase) that restored activity of K-Ras and N-Ras after farnesyltransferase treatment.
# ::save-date Thu Jan 21, 2016 ::file pmid_2465_1010_19.txt
(t / thwart-01
      :ARG0 (p / present-02
            :ARG1 (e2 / enzyme :name (n / name :op1 "geranylgeranyltransferase")
                  :ARG0-of (b / back-up-04)
                  :ARG0-of (r / restore-01
                        :ARG1 (a / activity-06
                              :ARG0 (a2 / and
                                    :op1 (e3 / enzyme :name (n2 / name :op1 "K-Ras"))
                                    :op2 (e4 / enzyme :name (n3 / name :op1 "N-Ras"))))
                        :time (a3 / after
                              :op1 (t2 / treat-04
                                    :ARG1 (e5 / enzyme :name (n4 / name :op1 "farnesyltransferase"))))))
            :ARG1-of (e / expect-01 :polarity -))
      :ARG1 (e6 / effort-01
            :ARG1 (b2 / block-01
                  :ARG1 (d / disease :wiki "Cancer" :name (n5 / name :op1 "cancer")
                        :ARG1-of (c / cause-01
                              :ARG0 (e8 / enzyme :name (n6 / name :op1 "Ras"))))
                  :ARG3 (p2 / prevent-01
                        :ARG1 (f / farnesylate-01
                              :ARG1 e8
                              :ARG1-of (t3 / think-01
                                    :ARG2 (m / modify-01
                                          :ARG1 (a5 / activity-06
                                                :ARG0 e8)
                                          :time (a4 / after
                                                :op1 (t4 / translate-02))
                                          :mod (e9 / essential))
                                    :time (o / once)))))
            :mod (e7 / early)))

# ::id pmid_2465_1010.20 ::date 2015-02-11T12:38:20 ::annotator SDL-AMR-09 ::preferred
# ::snt Likewise, efforts to kill Ras cancers by blocking one of Ras’ major downstream effectors, Raf kinase (<ce:cross-ref id="crosref0060" refid="fig1">Figure 1</ce:cross-ref><ce:float-anchor refid="fig1" />), ran into the unexpected discovery that, in Ras-transformed cells, Raf inhibitors activate the pathway rather than inhibit it (see below and discussion in <ce:cross-ref id="crosref0065" refid="bib27">Holderfield et al., 2013</ce:cross-ref> and <ce:cross-ref id="crosref0070" refid="bib39">Lito et al., 2013</ce:cross-ref>).
# ::save-date Thu Jan 21, 2016 ::file pmid_2465_1010_20.txt
(r / run-07
      :ARG0 (e / effort-01
            :ARG1 (k / kill-01
                  :ARG1 (d6 / disease :wiki "Cancer" :name (n3 / name :op1 "cancer")
                        :ARG1-of (c2 / cause-01
                              :ARG0 (e2 / enzyme :name (n / name :op1 "Ras"))))
                  :ARG2 (b / block-01
                        :ARG1 (k2 / kinase :name (n2 / name :op1 "Raf")
                              :ARG1-of (i / include-91
                                    :ARG2 (e4 / effector
                                          :location (d2 / downstream)
                                          :ARG1-of (m / major-02)
                                          :poss e2))
                              :ARG1-of (d3 / describe-01
                                    :ARG0 (f / figure :mod 1))))))
      :ARG1 (d / discover-01
            :ARG1 (a / activate-01
                  :ARG0 (m2 / molecular-physical-entity
                        :ARG0-of (i2 / inhibit-01
                              :ARG1 k2))
                  :ARG1 (p / pathway)
                  :ARG1-of (i3 / instead-of-91
                        :ARG2 (i4 / inhibit-01
                              :ARG1 p))
                  :location (c3 / cell
                        :ARG2-of (t / transform-01
                              :ARG0 e2)))
            :ARG1-of (e3 / expect-01 :polarity -))
      :manner (l / likewise)
      :ARG1-of (s / see-01
            :location (b2 / below))
      :ARG1-of (d4 / discuss-01
            :ARG0 (a2 / and
                  :op1 (p2 / publication-91
                        :ARG0 (a3 / and
                              :op1 (p4 / person :name (n4 / name :op1 "Holderfield"))
                              :op2 (p5 / person
                                    :mod (o / other)))
                        :time (d5 / date-entity :year 2013))
                  :op2 (p3 / publication-91
                        :ARG0 (p6 / person :name (n5 / name :op1 "Lito"))
                        :time d5))))

# ::id pmid_2465_1010.21 ::date 2015-02-11T13:01:03 ::annotator SDL-AMR-09 ::preferred
# ::snt MAP kinase kinase (MEK) inhibitors and phosphatidylinositol 3-kinase (PI3K) inhibitors have not yet shown significant clinical activity in Ras cancers, for reasons relating to feedback loops and poor therapeutic windows, among other issues discussed below.
# ::save-date Sun Jan 17, 2016 ::file pmid_2465_1010_21.txt
(s / show-01 :polarity -
      :ARG1 (a2 / activity-06
            :ARG0 (a / and
                  :op1 (m / molecular-physical-entity
                        :ARG0-of (i / inhibit-01
                              :ARG1 (p3 / protein-family :name (n / name :op1 "MAP" :op2 "kinase" :op3 "kinase"))))
                  :op2 (m2 / molecular-physical-entity
                        :ARG0-of (i2 / inhibit-01
                              :ARG1 (p / protein-family :name (n2 / name :op1 "phosphatidylinositol" :op2 "3-kinase")))))
            :ARG1 (d2 / disease :wiki "Cancer" :name (n4 / name :op1 "cancer")
                  :ARG1-of (c3 / cause-01
                        :ARG0 (e2 / enzyme :name (n3 / name :op1 "Ras"))))
            :mod (c / clinic)
            :ARG1-of (s2 / significant-02))
      :time (y / yet)
      :ARG1-of (c4 / cause-01
            :ARG0 (r / reason
                  :ARG1-of (r2 / relate-01
                        :ARG2 (a3 / and
                              :op1 (l / loop
                                    :mod (f / feedback))
                              :op2 (w / window
                                    :mod (t / therapy)
                                    :mod (p2 / poor))
                              :ARG1-of (i3 / include-91
                                    :ARG2 (i4 / issue-02
                                          :mod (o / other))
                                    :ARG1-of (d / discuss-01
                                          :location (b / below))))))))

# ::id pmid_2465_1010.22 ::date 2015-02-11T13:23:40 ::annotator SDL-AMR-09 ::preferred
# ::snt A convergence of urgent unmet clinical needs and advances in drug discovery has energized new efforts to target Ras cancers within academic centers and in the biopharmaceutical industry.
# ::save-date Fri Feb 5, 2016 ::file pmid_2465_1010_22.txt
(e / energize-01
      :ARG0 (c / converge-01
            :ARG0 (n / need-01
                  :ARG1-of (m / meet-01 :polarity -)
                  :mod (u / urgent)
                  :mod (c2 / clinical))
            :ARG1 (a / advance-01
                  :ARG1 (d / discover-01
                        :ARG1 (d2 / drug))))
      :ARG1 (e2 / effort-01
            :ARG1 (t / target-01
                  :ARG1 (d3 / disease :wiki "Cancer" :name (n4 / name :op1 "cancer")
                        :ARG1-of (c4 / cause-01
                              :ARG0 (e3 / enzyme :name (n3 / name :op1 "Ras"))))
                  :location (a2 / and
                        :op1 (c5 / center
                              :mod (a3 / academia))
                        :op2 (i / industry
                              :mod (b / biopharmaceutical))))
            :ARG1-of (n2 / new-01)))

# ::id pmid_2465_1010.23 ::date 2015-02-11T13:35:19 ::annotator SDL-AMR-09 ::preferred
# ::snt To catalyze these renewed efforts, the National Cancer Institute recently launched a national Ras program at Frederick National Laboratory for Cancer (see <ce:inter-ref>http://webdefence.global.blackspider.com/urlwrap/?q=AXicY2Rn8FrCwHB9AQNDUU6liXmKXnFRmV5uYmZOcn5eSVF-jl5yfi5DiaGJuaeHSY6Bgam5mRFDUlJiSmJRYqlDcQpEPqOkpMBKXz8osdg5FagrMUcvvyidAQIA65QdsA&Z</ce:inter-ref>), whose goal is to fill critical knowledge gaps that are essential to target Ras cancers effectively and to engage the research community toward solving the Ras problem.
# ::save-date Mon Jan 25, 2016 ::file pmid_2465_1010_23.txt
(l / launch-01
      :ARG0 (r / research-institute :name (n / name :op1 "National" :op2 "Cancer" :op3 "Institute"))
      :ARG1 (p / program
            :mod (n2 / nation)
            :topic (e2 / enzyme :name (n3 / name :op1 "Ras"))
            :purpose (a / and
                  :op1 (f2 / fill-01
                        :ARG1 (g / gap
                              :topic (k / know-03
                                    :mod (e3 / essential)
                                    :purpose (t2 / target-01
                                          :ARG1 (d / disease :wiki "Cancer" :name (n5 / name :op1 "cancer")
                                                :ARG1-of (c4 / cause-01
                                                      :ARG0 e2))
                                          :ARG1-of (e4 / effective-04)))
                              :ARG1-of (c2 / critical-02)))
                  :op2 (e5 / engage-01
                        :ARG1 (c5 / community
                              :ARG0-of (r4 / research-01))
                        :ARG2 (s / solve-01
                              :ARG0 c5
                              :ARG1 (p2 / problem
                                    :topic e2)))))
      :time (r2 / recent)
      :purpose (c / catalyze-01
            :ARG0 r
            :ARG1 (e / effort-01
                  :ARG1-of (r3 / renew-01)
                  :mod (t / this)))
      :location (f / facility :name (n4 / name :op1 "Frederick" :op2 "National" :op3 "Laboratory" :op4 "for" :op5 "Cancer"))
      :ARG1-of (s2 / see-01
            :ARG0 (y / you)
            :medium (u / url-entity :value "http://webdefence.global.blackspider.com/urlwrap/?q=AXicY2Rn8FrCwHB9AQNDUU6liXmKXnFRmV5uYmZOcn5eSVF-jl5yfi5DiaGJuaeHSY6Bgam5mRFDUlJiSmJRYqlDcQpEPqOkpMBKXz8osdg5FagrMUcvvyidAQIA65QdsA&Z")))

# ::id pmid_2465_1010.24 ::date 2015-02-11T13:53:05 ::annotator SDL-AMR-09 ::preferred
# ::snt Here, we will discuss some of these knowledge gaps, as well as recent advances and the challenges that lie ahead.
# ::save-date Thu Dec 31, 2015 ::file pmid_2465_1010_24.txt
(d / discuss-01
      :ARG0 (w / we)
      :ARG1 (a / and
            :op1 (g / gap
                  :ARG1-of (i / include-91
                        :ARG2 (g2 / gap
                              :topic (k / know-03)
                              :mod (t / this)))
                  :mod (s / some))
            :op2 (a2 / advance-01
                  :time (r / recent))
            :op3 (c / challenge-01
                  :ARG1-of (l / lie-07
                        :ARG2 (a3 / ahead))))
      :medium (h / here))

# ::id pmid_2465_1010.25 ::date 2015-02-11T13:57:41 ::annotator SDL-AMR-09 ::preferred
# ::snt Ras Mutations in Cancer
# ::save-date Thu Dec 10, 2015 ::file pmid_2465_1010_25.txt
(m / mutate-01
      :ARG2 (e / enzyme :name (n / name :op1 "Ras"))
      :location (d / disease :wiki "Cancer" :name (n2 / name :op1 "cancer")))

# ::id pmid_2465_1010.26 ::date 2015-02-11T14:03:22 ::annotator SDL-AMR-09 ::preferred
# ::snt Ras genes were the first oncogenes identified in human cancer cells.
# ::save-date Thu Dec 10, 2015 ::file pmid_2465_1010_26.txt
(o / oncogene
      :ARG1-of (i / identify-01
            :location (c / cell
                  :mod (d / disease :wiki "Cancer" :name (n2 / name :op1 "cancer")
                        :mod (h / human))))
      :ord (o2 / ordinal-entity :value 1)
      :domain (g / gene :name (n / name :op1 "Ras")))

# ::id pmid_2465_1010.27 ::date 2015-02-11T14:10:56 ::annotator SDL-AMR-09 ::preferred
# ::snt In a series of classic experiments, the groups of Weinberg, Cooper, Barbacid, and Wigler independently identified the transforming genes from T24/EJ bladder carcinoma cells as H-Ras (<ce:cross-refs id="crosrefs0015" refid="bib15 bib50 bib58 bib69">Der et al., 1982; Parada et al., 1982; Santos et al., 1982; Taparowsky et al., 1982</ce:cross-refs>).
# ::save-date Fri Feb 13, 2015 ::file pmid_2465_1010_27.txt
(i / identify-01
      :ARG0 (a / and
            :op1 (g / group
                  :ARG1-of (l / lead-02
                        :ARG0 (p / person :name (n / name :op1 "Weinberg"))))
            :op2 (g2 / group
                  :ARG1-of (l2 / lead-02
                        :ARG0 (p2 / person :name (n2 / name :op1 "Cooper"))))
            :op3 (g3 / group
                  :ARG1-of (l3 / lead-02
                        :ARG0 (p3 / person :name (n3 / name :op1 "Barbacid"))))
            :op4 (g4 / group
                  :ARG1-of (l4 / lead-02
                        :ARG0 (p4 / person :name (n4 / name :op1 "Wigler")))))
      :ARG1 (g5 / gene
            :ARG0-of (t / transform-01)
            :part-of (c2 / cell-line :name (n5 / name :op1 "T24/EJ")
                  :mod (c3 / carcinoma
                        :mod (b / bladder))))
      :ARG2 (e2 / enzyme :name (n6 / name :op1 "H-Ras"))
      :manner (s / series
            :consist-of (e / experiment-01
                  :mod (c / classic)))
      :ARG0-of (d3 / depend-01 :polarity -)
      :ARG1-of (d / describe-01
            :ARG0 (a2 / and
                  :op1 (p5 / publication-91
                        :ARG0 (a3 / and
                              :op1 (p9 / person :name (n7 / name :op1 "Der"))
                              :op2 (p10 / person
                                    :mod (o / other)))
                        :time (d2 / date-entity :year 1982))
                  :op2 (p6 / publication-91
                        :ARG0 (a4 / and
                              :op1 (p11 / person :name (n8 / name :op1 "Parada"))
                              :op2 p10)
                        :time d2)
                  :op3 (p7 / publication-91
                        :ARG0 (a5 / and
                              :op1 (p12 / person :name (n9 / name :op1 "Santos"))
                              :op2 p10)
                        :time d2)
                  :op4 (p8 / publication-91
                        :ARG0 (a6 / and
                              :op1 (p13 / person :name (n10 / name :op1 "Taparowsky"))
                              :op2 p10)
                        :time d2))))

# ::id pmid_2465_1010.28 ::date 2015-02-11T14:34:09 ::annotator SDL-AMR-09 ::preferred
# ::snt More than 30 years later, Ras genes are well established as the most frequently mutated oncogenes in human cancer (<ce:cross-ref id="crosref0075" refid="tbl1">Table 1</ce:cross-ref><ce:float-anchor refid="tbl1" />), though H-Ras itself is rarely one of them.
# ::save-date Thu Dec 10, 2015 ::file pmid_2465_1010_28.txt
(e3 / establish-01
      :ARG1 (g / gene :name (n / name :op1 "Ras"))
      :ARG2 (o / oncogene
            :ARG1-of (m2 / mutate-01
                  :ARG1-of (f / frequent-02
                        :degree (m3 / most)))
            :location (d2 / disease :wiki "Cancer" :name (n3 / name :op1 "cancer")
                  :mod (h / human)))
      :mod (w / well)
      :time (l / late
            :op1 (m / more-than
                  :op1 (t / temporal-quantity :quant 30
                        :unit (y / year))))
      :concession (i / include-91
                  :ARG1 (g2 / gene :name (n2 / name :op1 "H-Ras"))
                  :ARG2 g
                  :ARG1-of (r / rare-02))
      :ARG1-of (d / describe-01
            :ARG0 (t2 / table :mod 1)))

# ::id pmid_2465_1010.29 ::date 2015-02-10T00:38:54 ::annotator SDL-AMR-09 ::preferred
# ::snt Although these numbers are, by now, painfully familiar, they underscore major gaps in our knowledge of Ras biology.
# ::save-date Wed Mar 9, 2016 ::file pmid_2465_1010_29.txt
(u / underscore-01
      :ARG0 (n2 / number
            :mod (t / this))
      :ARG1 (g / gap
            :ARG1-of (m / major-02)
            :topic (k / know-03
                  :ARG0 (w / we)
                  :ARG1 (b / biology
                        :mod (e2 / enzyme :name (n3 / name :op1 "Ras")))))
      :concession (f / familiarize-01
            :ARG1 n2
            :degree (p / pain-01)
            :time (b2 / by
                  :op1 (n / now))))

# ::id pmid_2465_1010.30 ::date 2015-02-10T00:40:36 ::annotator SDL-AMR-09 ::preferred
# ::snt Most obviously, we do not understand why K-Ras mutation is much more frequent in human cancer than N-Ras or H-Ras, even though each of these is a powerful transforming gene in model systems, and all forms are expressed widely in adult tissues and in tumors.
# ::save-date Mon Dec 21, 2015 ::file pmid_2465_1010_30.txt
(u2 / understand-01 :polarity -
      :ARG0 (w / we)
      :ARG1 (t / thing
            :ARG0-of (c / cause-01
                  :ARG1 (f / frequent-02
                        :ARG1 (m3 / mutate-01
                              :ARG1 (e3 / enzyme :name (n4 / name :op1 "K-Ras")))
                        :degree (m / more
                              :quant (m2 / much))
                        :location (d / disease :wiki "Cancer" :name (n2 / name :op1 "cancer")
                              :mod (h / human))
                        :compared-to (o3 / or
                              :op1 (m5 / mutate-01
                                    :ARG1 (e4 / enzyme :name (n5 / name :op1 "N-Ras")))
                              :op2 (m7 / mutate-01
                                    :ARG1 (e5 / enzyme :name (n6 / name :op1 "H-Ras")))))))
      :ARG1-of (o / obvious-01
            :degree (m4 / most))
      :concession (a2 / and
            :op1 (g / gene
                  :domain (a / and
                        :op1 e3
                        :op2 e4
                        :op3 e5)
                  :ARG0-of (t2 / transform-01)
                  :location (s / system
                        :mod (m6 / model))
                  :ARG1-of (p / powerful-02))
            :op2 (e / express-03
                  :ARG1 (f2 / form
                        :mod (a3 / all))
                  :ARG3 (a4 / and
                        :op1 (t3 / tissue
                              :mod (a5 / adult))
                        :op2 (t4 / tumor))
                  :ARG1-of (w2 / wide-02))))

# ::id pmid_2465_1010.31 ::date 2015-02-10T00:43:28 ::annotator SDL-AMR-09 ::preferred
# ::snt A simple explanation for the high frequency of K-Ras mutations, relative to H-Ras and N-Ras, is that the K-Ras protein has unique properties that favor oncogenesis.
# ::save-date Mon Jan 4, 2016 ::file pmid_2465_1010_31.txt
(e3 / explain-01
      :ARG0 (p / property
            :mod (u / unique)
            :poss (e / enzyme :name (n / name :op1 "K-Ras"))
            :ARG0-of (f / favor-01
                  :ARG1 (c / create-01
                        :ARG1 (d / disease :wiki "Cancer" :name (n4 / name :op1 "cancer")))))
      :ARG1 (f2 / frequent-02
            :ARG1 (m / mutate-01
                  :ARG1 e)
            :ARG1-of (h / high-02)
            :compared-to (a2 / and
                  :op1 (m2 / mutate-01
                        :ARG1 (e2 / enzyme :name (n2 / name :op1 "H-Ras")))
                  :op2 (m3 / mutate-01
                        :ARG1 (e4 / enzyme :name (n3 / name :op1 "N-Ras")))))
      :ARG1-of (s / simple-02))

# ::id pmid_2465_1010.32 ::date 2015-02-10T00:44:03 ::annotator SDL-AMR-09 ::preferred
# ::snt At first sight, this seems unlikely because the Ras proteins are highly conserved, especially in their effector-binding regions where they are actually identical.
# ::save-date Sat Jan 16, 2016 ::file pmid_2465_1010_32.txt
(s / seem-01
      :ARG1 (l / likely-01 :polarity -
            :ARG1 (t / thing
                  :mod (t2 / this)))
      :ARG1-of (c / cause-01
            :ARG0 (c2 / conserve-01
                  :ARG1 (p2 / protein-family :name (n2 / name :op1 "Ras"))
                  :ARG1-of (h / high-02)
                  :location (p / protein-segment
                        :ARG1-of (b / bind-01
                              :ARG2 (e / effector))
                        :part-of p2
                        :ARG1-of (i / identical-01
                              :ARG1-of (a / actual-02))
                        :degree (e4 / especially))))
      :time (s2 / see-01
            :ord (o / ordinal-entity :value 1)))

# ::id pmid_2465_1010.33 ::date 2015-02-10T00:46:36 ::annotator SDL-AMR-09 ::preferred
# ::snt However, K-Ras, but not N-Ras or H-Ras, confers stem-like properties on certain cell types (<ce:cross-ref id="crosref0080" refid="bib54">Quinlan and Settleman, 2009</ce:cross-ref>).
# ::save-date Mon Dec 21, 2015 ::file pmid_2465_1010_33.txt
(c4 / contrast-01
      :ARG2 (c / confer-02
            :ARG0 (e / enzyme :name (n / name :op1 "K-Ras"))
            :ARG1 (p / property
                  :ARG1-of (r / resemble-01
                        :ARG2 (p5 / property
                              :poss (c5 / cell
                                    :mod (s / stem)))))
            :ARG2 (t / type-03
                  :ARG1 (c2 / cell)
                  :mod (c3 / certain))
            :ARG1-of (c6 / contrast-01
                  :ARG0 (c7 / confer-02 :polarity -
                        :ARG0 (o / or
                              :op1 (e3 / enzyme :name (n3 / name :op1 "N-Ras"))
                              :op2 (e2 / enzyme :name (n2 / name :op1 "H-Ras")))
                        :ARG1 p
                        :ARG2 t))
            :ARG1-of (d2 / describe-01
                  :ARG0 (p2 / publication-91
                        :ARG0 (a / and
                              :op1 (p3 / person :name (n4 / name :op1 "Quinlan"))
                              :op2 (p4 / person :name (n5 / name :op1 "Settleman")))
                        :time (d / date-entity :year 2009)))))

# ::id pmid_2465_1010.34 ::date 2015-02-10T00:47:09 ::annotator SDL-AMR-09 ::preferred
# ::snt K-Ras-4B, the most highly expressed splice variant of K-Ras, binds calmodulin; H-Ras and N- Ras do not (<ce:cross-ref id="crosref0085" refid="bib74">Villalonga et al., 2001</ce:cross-ref>).
# ::save-date Mon Dec 21, 2015 ::file pmid_2465_1010_34.txt
(m / multi-sentence
      :snt1 (b / bind-01
            :ARG1 (e / enzyme :name (n / name :op1 "K-Ras-4B")
                  :mod (v2 / variant
                        :ARG1-of (e5 / express-03
                              :ARG1-of (h / high-02
                                    :degree (m2 / most))
                              :compared-to r)
                        :ARG2-of (r / result-01
                              :ARG1 (s / splice-01
                                    :ARG1 (e4 / enzyme :name (n4 / name :op1 "K-Ras"))))))
            :ARG2 (p / protein :name (n5 / name :op1 "calmodulin")))
      :snt2 (b2 / bind-01 :polarity -
            :ARG1 (a / and
                  :op1 (e2 / enzyme :name (n2 / name :op1 "H-Ras"))
                  :op2 (e3 / enzyme :name (n3 / name :op1 "N-Ras")))
            :ARG2 (p5 / protein :name (n7 / name :op1 "calmodulin")))
      :ARG1-of (d2 / describe-01
            :ARG0 (p2 / publication-91
                  :ARG0 (a2 / and
                        :op1 (p3 / person :name (n6 / name :op1 "Villalonga"))
                        :op2 (p4 / person
                              :mod (o / other)))
                  :time (d / date-entity :year 2001))))

# ::id pmid_2465_1010.35 ::date 2015-02-10T00:47:51 ::annotator SDL-AMR-09 ::preferred
# ::snt We believe that this unique property of K-Ras-4B confers stem-like properties to cells expressing oncogenic K-Ras-4B proteins (M. Wang and F.M., unpublished data).
# ::save-date Thu Dec 10, 2015 ::file pmid_2465_1010_35.txt
(b / believe-01
      :ARG0 (w / we)
      :ARG1 (c / confer-02
            :ARG0 (p / property
                  :mod (t / this)
                  :mod (u / unique)
                  :poss (e / enzyme :name (n / name :op1 "K-Ras-4B")))
            :ARG1 (p2 / property
                  :ARG1-of (r / resemble-01
                        :ARG2 (p6 / property
                              :poss (c5 / cell
                                    :mod (s / stem)))))
            :ARG2 (c2 / cell
                  :ARG3-of (e2 / express-03
                        :ARG2 (e3 / enzyme :name (n2 / name :op1 "K-Ras-4B")
                              :ARG0-of (c3 / cause-01
                                    :ARG1 (d3 / disease :wiki "Cancer" :name (n5 / name :op1 "cancer")))))))
      :ARG1-of (d / describe-01
            :ARG0 (d2 / data
                  :ARG1-of (p3 / publish-01 :polarity -
                        :ARG0 (a / and
                              :op1 (p4 / person :name (n3 / name :op1 "M." :op2 "Wang"))
                              :op2 (p5 / person :name (n4 / name :op1 "F.M.")))))))

# ::id pmid_2465_1010.36 ::date 2015-02-10T00:48:23 ::annotator SDL-AMR-09 ::preferred
# ::snt Analysis of human syndromes caused by germline mutations in H-Ras or K-Ras supports the idea that K-Ras is a stronger oncogene.
# ::save-date Mon Jul 13, 2015 ::file pmid_2465_1010_36.txt
(s / support-01
      :ARG0 (a / analyze-01
            :ARG1 (s2 / syndrome
                  :mod (h / human)
                  :ARG1-of (c / cause-01
                        :ARG0 (m / mutate-01
                              :ARG1 (g / germline)
                              :location (o / or
                                    :op1 (e / enzyme :name (n / name :op1 "H-Ras"))
                                    :op2 (e2 / enzyme :name (n2 / name :op1 "K-Ras")))))))
      :ARG1 (i / idea
            :mod (o2 / oncogene
                  :domain e2
                  :compared-to e
                  :ARG1-of (s3 / strong-02
                        :degree (m2 / more)))))

# ::id pmid_2465_1010.37 ::date 2015-02-10T00:48:49 ::annotator SDL-AMR-09 ::preferred
# ::snt Unexpectedly, humans can tolerate germline-activating mutations in H-Ras—the same activating mutations that drive somatic mutations.
# ::save-date Fri Mar 13, 2015 ::file pmid_2465_1010_37.txt
(p / possible-01
      :ARG1 (t / tolerate-01
            :ARG0 (h / human)
            :ARG1 (m / mutate-01
                  :ARG0-of (a / activate-01
                        :ARG1 (g / germline))
                  :location (e / enzyme :name (n / name :op1 "H-Ras"))
                  :ARG1-of (s2 / same-01
                        :ARG2 (m2 / mutate-01
                              :ARG0 (d / drive-02
                                    :ARG1 (m3 / mutate-01
                                          :mod (s / somatic)))
                              :ARG0-of (a2 / activate-01)))))
      :ARG1-of (e2 / expect-01 :polarity -))

# ::id pmid_2465_1010.38 ::date 2015-02-10T00:49:16 ::annotator SDL-AMR-09 ::preferred
# ::snt Costello syndrome, which is characterized by germline H-Ras mutations, is associated with a broad spectrum of developmental abnormalities and a high risk for rhabdomyosarcomas and neuroblastomas (reviewed in <ce:cross-ref id="crosref0090" refid="bib55">Rauen, 2013</ce:cross-ref>).
# ::save-date Fri Jan 1, 2016 ::file pmid_2465_1010_38.txt
(a / associate-01
      :ARG1 (d2 / disease :name (n2 / name :op1 "Costello" :op2 "syndrome")
            :ARG1-of (c / characterize-01
                  :ARG2 (m / mutate-01
                        :ARG1 (e / enzyme :name (n / name :op1 "H-Ras"))
                        :location (g2 / germline))))
      :ARG2 (a3 / and
            :op1 (a2 / abnormality
                  :quant (s / spectrum
                        :ARG1-of (b / broad-02))
                  :mod (g / growth))
            :op2 (r / risk-01
                  :ARG2 (a4 / and
                        :op1 (m2 / medical-condition :name (n3 / name :op1 "rhabdomyosarcoma"))
                        :op2 (m3 / medical-condition :name (n4 / name :op1 "neuroblastoma")))
                  :ARG1-of (h / high-02)))
      :ARG1-of (r2 / review-02
            :ARG2 (p2 / publication-91
                  :ARG0 (p3 / person :name (n5 / name :op1 "Rauen"))
                  :time (d / date-entity :year 2013))))

# ::id pmid_2465_1010.39 ::date 2015-02-10T00:52:57 ::annotator SDL-AMR-09 ::preferred
# ::snt It is puzzling that these individuals do not succumb to malignancies associated with sporadic H-Ras mutations (<ce:cross-ref id="crosref0095" refid="tbl1">Table 1</ce:cross-ref>).
# ::save-date Wed Feb 18, 2015 ::file pmid_2465_1010_39.txt
(p / puzzle-01
      :ARG0 (s / succumb-01 :polarity -
            :ARG0 (i / individual
                  :mod (t / this))
            :ARG1 (m / malignancy
                  :ARG1-of (a / associate-01
                        :ARG2 (m2 / mutate-01
                              :ARG1 (e / enzyme :name (n / name :op1 "H-Ras"))
                              :time (s2 / sporadic)))))
      :ARG1-of (d / describe-01
            :ARG0 (t2 / table :mod 1)))

# ::id pmid_2465_1010.40 ::date 2015-02-10T00:53:50 ::annotator SDL-AMR-09 ::preferred
# ::snt Although fully activating alleles of H-Ras can be tolerated, fully activated alleles of K-Ras may not.
# ::save-date Mon Dec 21, 2015 ::file pmid_2465_1010_40.txt
(p / possible-01 :polarity -
      :ARG1 (t / tolerate-01
            :ARG1 (a / allele
                  :ARG1-of (a2 / activate-01
                        :degree (f / full))
                  :mod (e2 / enzyme :name (n2 / name :op1 "K-Ras"))))
      :concession (p2 / possible-01
            :ARG1 (t2 / tolerate-01
                  :ARG1 (a3 / allele
                        :ARG0-of (a4 / activate-01
                              :manner f)
                        :mod (e / enzyme :name (n / name :op1 "H-Ras"))))))

# ::id pmid_2465_1010.41 ::date 2015-02-10T00:54:21 ::annotator SDL-AMR-09 ::preferred
# ::snt Variant alleles of K-Ras that account for a small fraction of Noonan’s syndrome and cardiofaciocutaneous syndrome are weakly activated relative to their sporadic oncogenic counterparts (<ce:cross-ref id="crosref0100" refid="bib61">Schubbert et al., 2007</ce:cross-ref>).
# ::save-date Thu Dec 10, 2015 ::file pmid_2465_1010_41.txt
(a / activate-01
      :ARG1 (a2 / allele
            :mod (v2 / variant)
            :mod (e / enzyme :name (n / name :op1 "K-Ras"))
            :ARG0-of (a3 / account-01
                  :ARG1 (a4 / and
                        :op1 (d2 / disease :name (n2 / name :op1 "Noonan’s" :op2 "syndrome"))
                        :op2 (d3 / disease :name (n3 / name :op1 "cardiofaciocutaneous" :op2 "syndrome"))
                        :quant (f / fraction
                              :mod (s / small)))))
      :ARG1-of (w / weak-02)
      :compared-to (c / counterpart
            :mod (s2 / sporadic)
            :poss v2
            :ARG0-of (c2 / cause-01
                  :ARG1 (d5 / disease :wiki "Cancer" :name (n5 / name :op1 "cancer"))))
      :ARG1-of (d4 / describe-01
            :ARG0 (p / publication-91
                  :ARG0 (a5 / and
                        :op1 (p2 / person :name (n4 / name :op1 "Schubbert"))
                        :op2 (p3 / person
                              :mod (o / other)))
                  :time (d / date-entity :year 2007))))

# ::id pmid_2465_1010.42 ::date 2015-02-10T00:54:57 ::annotator SDL-AMR-09 ::preferred
# ::snt Further support for the idea that K-Ras has functions distinct from H-Ras and N-Ras comes from analyses of the roles of Ras genes in development.
# ::save-date Tue Feb 17, 2015 ::file pmid_2465_1010_42.txt
(s / support-01
      :ARG0 (a / analyze-01
            :ARG1 (r / role
                  :mod (g / gene :name (n3 / name :op1 "Ras")))
            :ARG1-of (d / develop-02))
      :ARG1 (i / idea
            :mod (f2 / function-01
                  :ARG0 (e / enzyme :name (n / name :op1 "K-Ras"))
                  :mod (d2 / distinct
                        :compared-to (a2 / and
                              :op1 (f3 / function-01
                                    :ARG0 (e2 / enzyme :name (n2 / name :op1 "H-Ras")))
                              :op2 (f4 / function-01
                                    :ARG0 (e4 / enzyme :name (n4 / name :op1 "N-Ras")))))))
      :degree (f / further))

# ::id pmid_2465_1010.43 ::date 2015-02-10T00:55:23 ::annotator SDL-AMR-09 ::preferred
# ::snt Mice that lack K-Ras die during embryogenesis, whereas mice lacking H-Ras and/or N-Ras are viable (<ce:cross-ref id="crosref0105" refid="bib30">Johnson et al., 1997</ce:cross-ref>).
# ::save-date Mon Jan 4, 2016 ::file pmid_2465_1010_43.txt
(c2 / contrast-01
      :ARG1 (d2 / die-01
            :ARG1 (m / mouse
                  :ARG0-of (l / lack-01
                        :ARG1 (e / enzyme :name (n / name :op1 "K-Ras"))))
            :time (c / create-01
                  :ARG1 (e3 / embryo)))
      :ARG2 (v / viable
            :domain (m2 / mouse
                  :ARG0-of (l2 / lack-01
                        :ARG1 (a / and-or
                              :op1 (e2 / enzyme :name (n2 / name :op1 "H-Ras"))
                              :op2 (e4 / enzyme :name (n3 / name :op1 "N-Ras"))))))
      :ARG1-of (d3 / describe-01
            :ARG0 (p / publication-91
                  :ARG0 (a2 / and
                        :op1 (p2 / person :name (n4 / name :op1 "Johnson"))
                        :op2 (p3 / person
                              :mod (o / other)))
                  :time (d / date-entity :year 1997))))

# ::id pmid_2465_1010.44 ::date 2015-02-10T00:55:46 ::annotator SDL-AMR-09 ::preferred
# ::snt However, replacing K-Ras with H-Ras at the K-Ras genomic locus allows mice to develop, suggesting that differential regulation of K-Ras and H-Ras gene expression determines their relative importance in development rather than the properties of the proteins themselves (<ce:cross-ref id="crosref0110" refid="bib51">Potenza et al., 2005</ce:cross-ref>).
# ::save-date Fri Jan 1, 2016 ::file pmid_2465_1010_44.txt
(h / have-concession-91
      :ARG1 (a / allow-01
            :ARG0 (r / replace-01
                  :ARG1 (g2 / gene :name (n / name :op1 "K-Ras"))
                  :ARG2 (g3 / gene :name (n2 / name :op1 "H-Ras"))
                  :location (l / locus
                        :mod (g / genomic)
                        :ARG0-of (c2 / contain-01
                              :ARG1 g2)))
            :ARG1 (d2 / develop-01
                  :ARG1 (m / mouse))
            :ARG0-of (s / suggest-01
                  :ARG1 (d3 / determine-01
                        :ARG0 (r2 / regulate-01
                              :ARG1 (e3 / express-03
                                    :ARG1 (a2 / and
                                          :op1 g2
                                          :op2 g3))
                              :mod (d4 / differential))
                        :ARG1 (i / important
                              :ARG1-of (r3 / relative-05)
                              :poss a2
                              :purpose (d5 / develop-01))
                        :ARG1-of (i2 / instead-of-91
                              :ARG2 (p2 / property
                                    :poss a2)))))
      :ARG1-of (d6 / describe-01
            :ARG0 (p3 / publication-91
                  :ARG0 (a3 / and
                        :op1 (p4 / person :name (n3 / name :op1 "Potenza"))
                        :op2 (p / person
                              :mod (o / other)))
                  :time (d / date-entity :year 2005))))

# ::id pmid_2465_1010.45 ::date 2015-02-10T00:56:22 ::annotator SDL-AMR-09 ::preferred
# ::snt Furthermore, Balmain and colleagues discovered that these H-Ras knock-in mice develop tumors in response to carcinogens at normal frequencies, except that they are now driven by H-Ras instead of K-Ras (<ce:cross-ref id="crosref0115" refid="bib70">To et al., 2008</ce:cross-ref>).
# ::save-date Fri Jul 24, 2015 ::file pmid_2465_1010_45.txt
(a / and
      :op2 (d2 / discover-01
            :ARG0 (a2 / and
                  :op1 (p / person :name (n3 / name :op1 "Balmain"))
                  :op2 (c / colleague
                        :poss p))
            :ARG1 (d3 / develop-01
                  :ARG1 (m / mouse
                        :ARG3-of (e4 / express-03
                              :ARG2 (e / enzyme :name (n / name :op1 "H-Ras")))
                        :mod (t2 / this))
                  :ARG2 (t / tumor)
                  :ARG2-of (r / respond-01
                        :ARG1 (c3 / carcinogen))
                  :frequency (n4 / normal-02)
                  :ARG1-of (e3 / except-01
                        :ARG2 (d4 / drive-02
                              :ARG0 e
                              :ARG1 c3
                              :time (n5 / now)
                              :ARG1-of (i / instead-of-91
                                    :ARG2 (d5 / drive-02
                                          :ARG0 (e2 / enzyme :name (n2 / name :op1 "K-Ras"))
                                          :ARG1 c3))))))
      :ARG1-of (d6 / describe-01
            :ARG0 (p2 / publication-91
                  :ARG0 (a3 / and
                        :op1 (p3 / person :name (n6 / name :op1 "To"))
                        :op2 (p4 / person
                              :mod (o / other)))
                  :time (d / date-entity :year 2008))))

# ::id pmid_2465_1010.46 ::date 2015-02-10T00:57:10 ::annotator SDL-AMR-09 ::preferred
# ::snt These data argue strongly that the locus is critical and that the specific Ras paralog encoded at that locus does not affect the frequency at which tumors arise.
# ::save-date Fri Jul 24, 2015 ::file pmid_2465_1010_46.txt
(a / argue-01
      :ARG0 (d / data
            :mod (t / this))
      :ARG1 (a2 / and
            :op1 (c / critical-02
                  :ARG1 (l / locus))
            :op2 (a3 / affect-01 :polarity -
                  :ARG0 (p / paralog
                        :mod (e / enzyme :name (n / name :op1 "Ras"))
                        :ARG1-of (s2 / specific-02)
                        :ARG1-of (e2 / encode-01
                              :location l))
                  :ARG1 (h / have-frequency-91
                        :ARG1 (a4 / arise-02
                              :ARG1 (t3 / tumor)))))
      :ARG1-of (s / strong-02))

# ::id pmid_2465_1010.47 ::date 2015-02-10T00:57:37 ::annotator SDL-AMR-09 ::preferred
# ::snt Equally important, they find that K-Ras-4A, not K-Ras-4B, is necessary for lung tumor initiation, although K-Ras-4B is much more highly expressed during progression.
# ::save-date Sun Jul 26, 2015 ::file pmid_2465_1010_47.txt
(f / find-01
      :ARG0 (t / they)
      :ARG1 (n2 / need-01
            :ARG1 (e / enzyme :name (n3 / name :op1 "K-Ras-4A"))
            :purpose (i2 / initiate-01
                  :ARG1 (t2 / tumor
                        :mod (l / lung)))
            :concession (e4 / express-03
                  :ARG2 e2
                  :ARG1-of (h / high-02
                        :degree (m / more
                              :quant (m2 / much)))
                  :time (p / progress-01
                        :ARG1 t2))
            :ARG1-of (c / contrast-01
                  :ARG2 (n / need-01 :polarity -
                        :ARG1 (e2 / enzyme :name (n4 / name :op1 "K-Ras-4B"))
                        :purpose i2)))
      :mod (i3 / important
            :degree (e3 / equal)))

# ::id pmid_2465_1010.48 ::date 2015-02-10T00:58:05 ::annotator SDL-AMR-09 ::preferred
# ::snt This supports the idea that K-Ras-4B is the more important target in established tumors but raises the concern that K-Ras-4A may have an important role in minor stem-like populations of established tumors.
# ::save-date Wed Jan 20, 2016 ::file pmid_2465_1010_48.txt
(c / contrast-01
      :ARG1 (s / support-01
            :ARG0 (t / thing
                  :mod (t2 / this))
            :ARG1 (i / idea
                  :mod (t3 / target-01
                        :ARG1 (e / enzyme :name (n / name :op1 "K-Ras-4B"))
                        :mod (i2 / important
                              :degree (m / more)
                              :location (t4 / tumor
                                    :ARG1-of (e2 / establish-01))))))
      :ARG2 (r3 / raise-01
            :ARG0 t
            :ARG1 (c2 / concern-01
                  :ARG0 (p / possible-01
                        :ARG1 (r2 / role
                              :poss (e3 / enzyme :name (n2 / name :op1 "K-Ras-4A"))
                              :mod (i3 / important)
                              :topic (p2 / population
                                    :ARG1-of (m2 / minor-01)
                                    :ARG1-of (c3 / consist-01
                                          :ARG2 (c4 / cell
                                                :ARG1-of (r / resemble-01
                                                      :ARG2 (c5 / cell
                                                            :mod (s2 / stem)))))
                                    :part-of t4))))))

# ::id pmid_2465_1010.49 ::date 2015-02-10T00:59:25 ::annotator SDL-AMR-09 ::preferred
# ::snt These findings point toward an urgent need to validate K-Ras-4A and K-Ras-4B as drug targets, a major issue that has not yet been addressed.
# ::save-date Fri Jul 31, 2015 ::file pmid_2465_1010_49.txt
(p / point-01
      :ARG0 (t / thing
            :ARG1-of (f / find-01)
            :mod (t2 / this))
      :ARG2 (n / need-01
            :ARG1 (v / validate-01
                  :ARG1 (a / and
                        :op1 (e / enzyme :name (n2 / name :op1 "K-Ras-4A"))
                        :op2 (e2 / enzyme :name (n3 / name :op1 "K-Ras-4B"))
                        :ARG1-of (t3 / target-01
                              :ARG0 (d / drug))))
            :mod (u / urgent)
            :ARG0-of (i / issue-02
                  :ARG1-of (m / major-02)
                  :ARG1-of (a2 / address-02 :polarity -
                        :time (y / yet)))))

# ::id pmid_2465_1010.50 ::date 2015-02-10T00:59:44 ::annotator SDL-AMR-09 ::preferred
# ::snt Different frequencies of K-Ras, N-Ras, and H-Ras mutations in human tumors may also reflect differences in gene expression resulting from differential codon usage; rare codons limit K-Ras expression and thus allow more efficient oncogenesis by preventing oncogene-induced senescence (<ce:cross-ref id="crosref0120" refid="bib35">Lampson et al., 2013</ce:cross-ref>).
# ::save-date Thu Dec 10, 2015 ::file pmid_2465_1010_50.txt
(m / multi-sentence
      :snt1 (p / possible-01
            :ARG1 (r / reflect-01
                  :ARG1 (h / have-frequency-91
                        :ARG1 (m2 / mutate-01
                              :ARG1 (a / and
                                    :op1 (e / enzyme :name (n / name :op1 "K-Ras"))
                                    :op2 (e2 / enzyme :name (n2 / name :op1 "N-Ras"))
                                    :op3 (e3 / enzyme :name (n3 / name :op1 "H-Ras"))))
                        :ARG1-of (d3 / differ-02)
                        :location (t / tumor
                              :mod (h2 / human)))
                  :ARG2 (d4 / differ-02
                        :ARG1 (e4 / express-03
                              :ARG1 (g / gene))
                        :ARG2-of (r3 / result-01
                              :ARG1 (u / use-01
                                    :ARG1 (c / codon)
                                    :mod (d5 / differential)))))
            :mod (a3 / also))
      :snt2 (a2 / and
            :op1 (l / limit-01
                  :ARG0 (d7 / dna-sequence :name (n7 / name :op1 "codon")
                        :ARG1-of (r2 / rare-02))
                  :ARG1 (e5 / express-03
                        :ARG1 (e7 / enzyme :name (n8 / name :op1 "K-Ras"))))
            :op2 (a4 / allow-01
                  :ARG0 d7
                  :ARG1 (e6 / efficient-01
                        :ARG2 (o / originate-01
                              :ARG1 (d / disease :wiki "Cancer" :name (n5 / name :op1 "cancer")))
                        :degree (m3 / more))
                  :mod (t2 / thus)
                  :manner (p2 / prevent-01
                        :ARG0 d7
                        :ARG1 (s / senescence
                              :ARG2-of (i / induce-01
                                    :ARG0 (o2 / oncogene))))))
      :ARG1-of (d6 / describe-01
            :ARG0 (p3 / publication-91
                  :ARG0 (a5 / and
                        :op1 (p4 / person :name (n4 / name :op1 "Lampson"))
                        :op2 (p5 / person
                              :mod (o3 / other)))
                  :time (d2 / date-entity :year 2013))))

# ::id pmid_2465_1010.51 ::date 2015-02-10T01:01:43 ::annotator SDL-AMR-09 ::preferred
# ::snt In addition, different rates of DNA repair have been reported for the K-Ras gene relative to N-Ras and H-Ras (<ce:cross-ref id="crosref0125" refid="bib18">Feng et al., 2002</ce:cross-ref>).
# ::save-date Sat Jan 16, 2016 ::file pmid_2465_1010_51.txt
(a / and
      :op2 (r / report-01
            :ARG1 (d2 / differ-02
                  :ARG1 (g / gene :name (n / name :op1 "K-Ras"))
                  :ARG2 (a2 / and
                        :op1 (g2 / gene :name (n2 / name :op1 "H-Ras"))
                        :op2 (g3 / gene :name (n3 / name :op1 "N-Ras")))
                  :ARG3 (r2 / rate
                        :mod (r3 / repair-01
                              :ARG1 (n5 / nucleic-acid :wiki "DNA" :name (n6 / name :op1 "DNA"))))))
      :ARG1-of (d3 / describe-01
            :ARG0 (p / publication-91
                  :ARG0 (a3 / and
                        :op1 (p2 / person :name (n4 / name :op1 "Feng"))
                        :op2 (p3 / person
                              :mod (o / other)))
                  :time (d / date-entity :year 2002))))

# ::id pmid_2465_1010.52 ::date 2015-02-09T08:42:31 ::annotator SDL-AMR-09 ::preferred
# ::snt The underlying reasons for different frequencies of specific activating mutations are not well understood either.
# ::save-date Thu Dec 17, 2015 ::file pmid_2465_1010_52.txt
(u / understand-01 :polarity -
      :ARG1 (r / reason
            :ARG0-of (u2 / underlie-01
                  :ARG1 (h2 / have-frequency-91
                        :ARG1 (m2 / mutate-01
                              :ARG1-of (s / specific-02)
                              :ARG0-of (a2 / activate-01))
                        :ARG1-of (d2 / differ-02))))
      :mod (e / either)
      :ARG1-of (w / well-09))

# ::id pmid_2465_1010.53 ::date 2015-02-11T22:40:35 ::annotator SDL-AMR-09 ::preferred
# ::snt Some of these differences reflect different mutagenic insults to the genome; the G12C mutation, for example, is a hallmark of exposure to tobacco smoke and, accordingly, is the most common mutation in K-Ras in lung cancer (reviewed in <ce:cross-ref id="crosref0130" refid="bib52">Prior et al., 2012</ce:cross-ref>; <ce:cross-ref id="crosref0135" refid="tbl2">Table 2</ce:cross-ref><ce:float-anchor refid="tbl2" />).
# ::save-date Sun Dec 20, 2015 ::file pmid_2465_1010_53.txt
(e / exemplify-01
      :ARG0 (a / and
            :op1 (c / characteristic-02
                  :ARG1 (e2 / expose-01
                        :ARG2 (s2 / smoke-02
                              :ARG1 (t4 / tobacco)))
                  :ARG2 (m4 / mutate-01 :value "G12C"
                        :ARG2 (e3 / enzyme :name (n / name :op1 "K-Ras"))))
            :op2 (m3 / mutate-01
                  :ARG2 e3
                  :mod (c2 / common
                        :degree (m5 / most))
                  :manner (a2 / accordingly)
                  :location (d3 / disease :wiki "Lung_cancer" :name (n5 / name :op1 "lung" :op2 "cancer"))))
      :ARG1 (r / reflect-01
            :ARG1 (t / thing
                  :quant (s / some)
                  :ARG1-of (i / include-91
                        :ARG2 (t2 / thing
                              :ARG1-of (d / differ-02
                                    :mod (t3 / this)))))
            :ARG2 (i2 / insult-01
                  :ARG1 (g / genome)
                  :ARG1-of (d2 / differ-02)
                  :ARG0-of (g2 / generate-01
                        :ARG1 (m2 / mutate-01
                              :ARG1 (n3 / nucleic-acid :wiki "DNA" :name (n4 / name :op1 "DNA"))))))
      :ARG1-of (r2 / review-02
            :ARG2 (p / publication-91
                  :ARG0 (a3 / and
                        :op1 (p2 / person :name (n2 / name :op1 "Prior"))
                        :op2 (p3 / person
                              :mod (o / other)))
                  :time (d5 / date-entity :year 2012)
                  :part (t5 / table :mod 2))))

# ::id pmid_2465_1010.54 ::date 2015-02-09T12:26:15 ::annotator SDL-AMR-09 ::preferred
# ::snt Other differences in frequency may reflect different biological properties of mutant proteins.
# ::save-date Tue May 12, 2015 ::file pmid_2465_1010_54.txt
(p / possible-01
      :ARG1 (r / reflect-01
            :ARG1 (d2 / differ-02
                  :ARG3 (f / frequency)
                  :mod (o / other))
            :ARG2 (p2 / property
                  :ARG1-of (h / have-03
                        :ARG0 (p3 / protein
                              :ARG2-of (m / mutate-01)))
                  :ARG1-of (d / differ-02)
                  :mod (b / biology))))

# ::id pmid_2465_1010.55 ::date 2015-02-12T08:34:10 ::annotator SDL-AMR-09 ::preferred
# ::snt For example, G12C and G12V K-Ras mutations in lung adenocarcinoma preferentially activate the RalGDS pathway, whereas G12D prefers the Raf/mitogen-activated protein kinase (MAPK) and PI3K pathways (<ce:cross-ref id="crosref0140" refid="bib29">Ihle et al., 2012</ce:cross-ref>).
# ::save-date Sun Dec 13, 2015 ::file pmid_2465_1010_55.txt
(a / activate-01
      :ARG0 (a2 / and
            :op1 (m / mutate-01 :value "G12C"
                  :ARG2 (e2 / enzyme :name (n2 / name :op1 "K-Ras")))
            :op2 (m2 / mutate-01 :value "G12V"
                  :ARG2 e2)
            :location (a4 / adenocarcinoma
                  :mod (l2 / lung)))
      :ARG1 (p3 / pathway :name (n / name :op1 "RalGDS"))
      :ARG1-of (p2 / prefer-01)
      :ARG1-of (c / contrast-01
            :ARG2 (p / prefer-01
                  :ARG0 (m3 / mutate-01 :value "G12D"
                        :ARG2 e2)
                  :ARG1 (a3 / and
                        :op1 (p4 / pathway :name (n3 / name :op1 "Raf/MAPK"))
                        :op2 (p7 / pathway :name (n6 / name :op1 "PI3K"))))
            :ARG0-of (e3 / exemplify-01))
      :ARG1-of (d / describe-01
            :ARG0 (p6 / publication-91
                  :ARG0 (a7 / and
                        :op1 (p8 / person :name (n7 / name :op1 "Ihle"))
                        :op2 (p9 / person
                              :mod (o / other)))
                  :time (d2 / date-entity :year 2012))))

# ::id pmid_2465_1010.56 ::date 2015-02-10T00:12:53 ::annotator SDL-AMR-09 ::preferred
# ::snt In addition, mutations at codon 61 have a more profound effect on intrinsic GTPase when these Ras proteins are bound to Raf kinase.
# ::save-date Fri Mar 13, 2015 ::file pmid_2465_1010_56.txt
(a / and
      :op2 (a2 / affect-01
            :ARG0 (m / mutate-01
                  :ARG1 (c2 / codon :mod 61
                        :part-of (e3 / enzyme :name (n3 / name :op1 "Ras"))))
            :ARG1 (e2 / enzyme :name (n2 / name :op1 "GTPase")
                  :mod (i / intrinsic))
            :mod (p / profound
                  :degree (m2 / more))
            :condition (b / bind-01
                  :ARG1 e3
                  :ARG2 (k / kinase :name (n6 / name :op1 "Raf")))))

# ::id pmid_2465_1010.57 ::date 2015-02-10T00:34:41 ::annotator SDL-AMR-09 ::preferred
# ::snt This may drive a stronger signal through this effector pathway and account for higher frequency of N-Ras position 61 mutations in melanoma, a disease frequently driven by hyperactivation of Raf kinase through B-Raf mutations (<ce:cross-ref id="crosref0145" refid="bib8">Buhrman et al., 2010</ce:cross-ref>).
# ::save-date Thu Jan 14, 2016 ::file pmid_2465_1010_57.txt
(p / possible-01
      :ARG1 (a / and
            :op1 (d3 / drive-02
                  :ARG0 (t / this)
                  :ARG1 (s / signal-07
                        :ARG0 (p4 / pathway
                              :mod (e / effector))
                        :ARG1-of (s2 / strong-02
                              :degree (m / more))))
            :op2 (a3 / account-01
                  :ARG0 t
                  :ARG1 (h / have-frequency-91
                        :ARG1 (m2 / mutate-01 :value 61
                              :ARG2 (e2 / enzyme :name (n / name :op1 "N-Ras"))
                              :location (m3 / medical-condition :name (n5 / name :op1 "melanoma")
                                    :ARG1-of (d5 / drive-02
                                          :ARG0 (h4 / hyperactivate-00
                                                :ARG0 (m6 / mutate-01
                                                      :ARG2 (e3 / enzyme :name (n6 / name :op1 "B-Raf")))
                                                :ARG1 (k4 / kinase :name (n7 / name :op1 "Raf")))
                                          :ARG1-of (f / frequent-02))))
                        :ARG1-of (h2 / high-02
                              :degree (m5 / more)))))
      :ARG1-of (d / describe-01
            :ARG0 (p2 / publication-91
                  :ARG0 (a2 / and
                        :op1 (p3 / person :name (n2 / name :op1 "Buhrman"))
                        :op2 (p5 / person
                              :mod (o / other)))
                  :time (d2 / date-entity :year 2010))))

# ::id pmid_2465_1010.58 ::date 2015-02-13T14:33:15 ::annotator SDL-AMR-09 ::preferred
# ::snt From a clinical viewpoint, lung adenocarcinomas driven by K-Ras mutations at G12C and G12V have a worse outcome than G12D, possibly because these mutations engage different downstream effectors as described above (<ce:cross-ref id="crosref0150" refid="fig1">Figure 1</ce:cross-ref>; <ce:cross-ref id="crosref0155" refid="bib29">Ihle et al., 2012</ce:cross-ref>).
# ::save-date Wed Apr 29, 2015 ::file pmid_2465_1010_58.txt
(h / have-03
      :ARG0 (a / adenocarcinoma
            :mod (l / lung)
            :ARG1-of (d4 / drive-02
                  :ARG0 (a2 / and
                        :op1 (m2 / mutate-01 :value "G12C"
                              :ARG2 (e / enzyme :name (n / name :op1 "K-Ras")))
                        :op2 (m3 / mutate-01 :value "G12V"
                              :ARG2 e))))
      :ARG1 (o / outcome
            :ARG1-of (b / bad-07
                  :degree (m / more)
                  :compared-to (m4 / mutate-01 :value "G12D"
                        :ARG2 e)))
      :ARG1-of (c3 / cause-01
            :ARG0 (e2 / engage-01
                  :ARG0 a2
                  :ARG1 (e3 / effector
                        :location (d / downstream)
                        :ARG1-of (d2 / differ-02)))
            :ARG1-of (p / possible-01))
      :ARG1-of (d3 / describe-01
            :ARG0 (p2 / publication-91
                  :ARG0 (a4 / and
                        :op1 (p3 / person :name (n2 / name :op1 "Ihle"))
                        :op2 (p4 / person
                              :mod (o2 / other)))
                  :time (d5 / date-entity :year 2012)
                  :part (f / figure :mod 1))
            :medium (a3 / above))
      :ARG1-of (v2 / view-02
            :mod (c2 / clinic)))

# ::id pmid_2465_1010.59 ::date 2015-02-10T11:18:06 ::annotator SDL-AMR-09 ::preferred
# ::snt As MEK and PI3K inhibitors are tested in the clinic, it will be important to ask whether Ras alleles respond differently to these treatments.
# ::save-date Sat Jan 16, 2016 ::file pmid_2465_1010_59.txt
(i / important
      :domain (a / ask-01
            :ARG1 (r / respond-01 :mode interrogative
                  :ARG0 (e3 / enzyme :name (n / name :op1 "Ras")
                        :ARG2-of (m3 / mutate-01))
                  :ARG1 (t / treat-03
                        :ARG1 e3
                        :mod (t2 / this))
                  :ARG1-of (d / differ-02)))
      :ARG1-of (c / cause-01
            :ARG0 (t3 / test-01
                  :ARG1 (a3 / and
                        :op1 (m / molecular-physical-entity
                              :ARG0-of (i2 / inhibit-01
                                    :ARG1 (p2 / protein-family :name (n2 / name :op1 "MEK"))))
                        :op2 (m2 / molecular-physical-entity
                              :ARG0-of (i3 / inhibit-01
                                    :ARG1 (p / protein-family :name (n3 / name :op1 "PI3K")))))
                  :location (c2 / clinic))))

# ::id pmid_2465_1010.60 ::date 2015-02-10T22:37:25 ::annotator SDL-AMR-09 ::preferred
# ::snt Patients suffering from cancers driven by any of these Ras mutations are excluded from treatment with cetuximab (colorectal cancer) or erlotinib (lung adenocarcinoma) because these treatments are ineffective for cancers with these Ras mutations and may even increase rates of progression.
# ::save-date Thu Dec 10, 2015 ::file pmid_2465_1010_60.txt
(e / exclude-01
      :ARG1 (p / patient
            :ARG0-of (s / suffer-01
                  :ARG1 (d5 / disease :wiki "Cancer" :name (n8 / name :op1 "cancer")
                        :ARG1-of (d / drive-02
                              :ARG0 (m / mutate-01
                                    :ARG1 (e5 / enzyme :name (n3 / name :op1 "Ras"))
                                    :mod (a6 / any
                                          :ARG1-of (i3 / include-91))
                                    :mod (t2 / this))))))
      :ARG2 (o / or
            :op1 (t / treat-03
                  :ARG1 p
                  :ARG3 (s2 / small-molecule :name (n / name :op1 "cetuximab")
                        :condition (d2 / disease :wiki "Colorectal_cancer" :name (n4 / name :op1 "colorectal" :op2 "cancer"))))
            :op2 (t5 / treat-03
                  :ARG1 p
                  :ARG3 (s3 / small-molecule :name (n2 / name :op1 "erlotinib")
                        :condition (m2 / medical-condition :name (n7 / name :op1 "adenocarcinoma")
                              :mod (l / lung)))))
      :ARG1-of (c5 / cause-01
            :ARG0 (a3 / and
                  :op1 (e2 / effective-04 :polarity -
                        :ARG0 o
                        :condition (d3 / disease :wiki "Cancer" :name (n5 / name :op1 "cancer")
                              :ARG1-of (c6 / cause-01
                                    :ARG0 (m3 / mutate-01))))
                  :op2 (p2 / possible-01
                        :ARG1 (i2 / increase-01
                              :ARG0 o
                              :ARG1 (r2 / rate
                                    :degree-of (p4 / progress-01
                                          :ARG1 (d4 / disease :wiki "Cancer" :name (n6 / name :op1 "cancer"))))
                              :mod (e4 / even))))))

# ::id pmid_2465_1010.61 ::date 2015-02-10T22:46:40 ::annotator SDL-AMR-09 ::preferred
# ::snt Likewise, malignant melanomas with mutant N-Ras are excluded from treatment with vemurafenib.
# ::save-date Thu Jan 14, 2016 ::file pmid_2465_1010_61.txt
(e / exclude-01
      :ARG1 (m4 / medical-condition :name (n3 / name :op1 "melanoma")
            :ARG2-of (m2 / malignant-02)
            :ARG0-of (h / have-03
                  :ARG1 (e2 / enzyme :name (n2 / name :op1 "N-Ras")
                        :ARG2-of (m3 / mutate-01))))
      :ARG2 (t / treat-03
            :ARG1 m4
            :ARG3 (s / small-molecule :name (n / name :op1 "vemurafenib")))
      :manner (l / likewise))

# ::id pmid_2465_1010.62 ::date 2015-02-10T23:30:04 ::annotator SDL-AMR-09 ::preferred
# ::snt However, surprisingly, K-Ras-G13D-bearing colorectal cancers may show clinical benefit when treated with cetuximab.
# ::save-date Thu Dec 10, 2015 ::file pmid_2465_1010_62.txt
(c4 / contrast-01
      :ARG2 (p / possible-01
            :ARG1 (s2 / show-01
                  :ARG0 (d / disease :wiki "Colorectal_cancer" :name (n3 / name :op1 "colorectal" :op2 "cancer")
                        :ARG0-of (b2 / bear-01
                              :ARG1 (e / enzyme :name (n2 / name :op1 "K-Ras"))
                              :ARG2-of (m2 / mutate-01 :value "G13D")))
                  :ARG1 (b / benefit-01
                        :ARG0 (t / treat-03
                              :ARG1 d
                              :ARG3 (s / small-molecule :name (n / name :op1 "cetuximab")))
                        :mod (c2 / clinic)))
            :ARG0-of (s3 / surprise-01)))

# ::id pmid_2465_1010.63 ::date 2015-02-11T02:01:28 ::annotator SDL-AMR-09 ::preferred
# ::snt This result challenges our understanding of how these Ras mutations actually function in clinical situations (<ce:cross-ref id="crosref0160" refid="bib16">De Roock et al., 2010</ce:cross-ref>).
# ::save-date Mon Dec 21, 2015 ::file pmid_2465_1010_63.txt
(c / challenge-01
      :ARG0 (t4 / thing
            :ARG2-of (r2 / result-01)
            :mod (t6 / this))
      :ARG1 (u / understand-01
            :ARG0 (w / we)
            :ARG1 (t / thing
                  :manner-of (f / function-01
                        :ARG0 (m2 / mutate-01
                              :ARG1 (e2 / enzyme :name (n3 / name :op1 "Ras"))
                              :mod (t3 / this))
                        :ARG1-of (a / actual-02)
                        :condition (s / situation
                              :mod (c2 / clinic)))))
      :ARG1-of (d / describe-01
            :ARG0 (p / publication-91
                  :ARG0 (a2 / and
                        :op1 (p2 / person :name (n2 / name :op1 "De" :op2 "Roock"))
                        :op2 (p3 / person
                              :mod (o / other)
                              :time (d2 / date-entity :year 2010))))))

# ::id pmid_2465_1010.64 ::date 2015-02-11T07:43:35 ::annotator SDL-AMR-09 ::preferred
# ::snt Even the prototypic oncogenes of Harvey and Kirsten sarcoma viruses are not fully understood; each has a codon 12 mutation, but each also carries a mutation of alanine 59 to threonine, which becomes phosphorylated by guanosine triphosphate (GTP).
# ::save-date Wed Mar 2, 2016 ::file pmid_2465_1010_64.txt
(m / multi-sentence
      :snt1 (u / understand-01 :polarity -
            :ARG1 (a / and
                  :op1 (g3 / gene
                        :part-of (v / virus :name (n / name :op1 "Harvey" :op2 "Sarcoma" :op3 "Virus")))
                  :op2 (g4 / gene
                        :part-of (v2 / virus :name (n2 / name :op1 "Kirsten" :op2 "Sarcoma" :op3 "Virus")))
                  :mod (p / prototypic)
                  :ARG0-of (c / cause-01
                        :ARG1 (d / disease :wiki "Cancer" :name (n3 / name :op1 "cancer")))
                  :mod (e / even))
            :degree (f / full))
      :snt2 (c3 / contrast-01
            :ARG1 (m2 / mutate-01
                  :ARG1 (c5 / codon :mod 12
                        :part-of (o / oncogene
                              :mod (e2 / each))))
            :ARG2 (c4 / carry-01
                  :ARG0 e2
                  :ARG1 (m3 / mutate-01
                        :ARG2 (a4 / amino-acid :name (n8 / name :op1 "threonine")
                              :ARG1-of (p2 / phosphorylate-01
                                    :ARG2 (s4 / small-molecule :name (n4 / name :op1 "guanosine" :op2 "triphosphate"))))
                        :ARG3 (a3 / amino-acid :mod 59 :name (n7 / name :op1 "alanine")))
                  :mod (a5 / also))))

# ::id pmid_2465_1010.65 ::date 2015-02-12T11:09:01 ::annotator SDL-AMR-09 ::preferred
# ::snt This must have helped Scolnick and colleagues (<ce:cross-ref id="crosref0165" refid="bib62">Shih et al., 1979</ce:cross-ref>) identify Ras’ crucial guanosine diphosphate (GDP)/GTP properties; without covalent phosphorylation, association with these nucleotides would have been very hard to detect.
# ::save-date Fri Jan 1, 2016 ::file pmid_2465_1010_65.txt
(a3 / and
      :op1 (i / infer-01
            :ARG1 (h / help-01
                  :ARG0 (t / this)
                  :ARG1 (i2 / identify-01
                        :ARG0 a
                        :ARG1 (c3 / characteristic-02
                              :ARG1 (e / enzyme :name (n2 / name :op1 "Ras"))
                              :ARG2 (s / slash
                                    :op1 (n5 / nucleotide :name (n3 / name :op1 "guanosine" :op2 "diphosphate"))
                                    :op2 (s2 / small-molecule :name (n4 / name :op1 "GTP")))
                              :mod (c4 / crucial)))
                  :ARG2 (a / and
                        :op1 (p2 / person :name (n / name :op1 "Scolnick"))
                        :op2 (c / colleague)))
            :ARG1-of (d / describe-01
                  :ARG0 (p / publication-91
                        :ARG0 (a4 / and
                              :op1 (p4 / person :name (n7 / name :op1 "Shih"))
                              :op2 (p5 / person
                                    :mod (o / other)))
                        :time (d3 / date-entity :year 1979))))
      :op2 (h2 / hard-02
            :ARG1 (d2 / detect-01
                  :ARG1 (a2 / associate-01
                        :ARG0 e
                        :ARG2 s))
            :degree (v / very)
            :condition (p3 / phosphorylate-01 :polarity -
                  :ARG1 e
                  :mod (c5 / covalent))))

# ::id pmid_2465_1010.66 ::date 2015-02-11T07:44:04 ::annotator SDL-AMR-09 ::preferred
# ::snt However, how phosphorylation at threonine 59 contributes to Ras’ potent oncogenicity is unclear.
# ::save-date Thu Dec 10, 2015 ::file pmid_2465_1010_66.txt
(h / have-concession-91
      :ARG1 (c / clear-06 :polarity -
            :ARG1 (t / thing
                  :ARG1-of (c2 / contribute-01
                        :ARG0 (p2 / phosphorylate-01
                              :ARG1 (a / amino-acid :mod 59 :name (n2 / name :op1 "threonine")
                                    :part-of e))
                        :ARG2 (c3 / cause-01
                              :ARG0 (e / enzyme :name (n / name :op1 "Ras"))
                              :ARG1 (d / disease :wiki "Cancer" :name (n3 / name :op1 "cancer"))
                              :mod (p3 / potent))))))

# ::id pmid_2465_1010.67 ::date 2015-02-11T09:13:24 ::annotator SDL-AMR-09 ::preferred
# ::snt This A59T mutation inhibits Ras-Raf interaction (<ce:cross-ref id="crosref0170" refid="bib63">Shirouzu et al., 1994</ce:cross-ref>) and is extremely rare in human cancer.
# ::save-date Sun Dec 20, 2015 ::file pmid_2465_1010_67.txt
(a / and
      :op1 (i / inhibit-01
            :ARG0 (m / mutate-01 :value "A59T"
                  :mod (t / this))
            :ARG1 (i2 / interact-01
                  :ARG0 (e3 / enzyme :name (n2 / name :op1 "Raf"))
                  :ARG1 (e2 / enzyme :name (n / name :op1 "Ras")))
            :ARG1-of (d / describe-01
                  :ARG0 (p / publication-91
                        :ARG0 (a2 / and
                              :op1 (p2 / person :name (n3 / name :op1 "Shirouzu"))
                              :op2 (p3 / person
                                    :mod (o / other)))
                        :time (d2 / date-entity :year 1994))))
      :op2 (r / rare-02
            :ARG1 m
            :degree (e / extreme)
            :location (d3 / disease :wiki "Cancer" :name (n4 / name :op1 "cancer")
                  :mod (h / human))))

# ::id pmid_2465_1010.68 ::date 2015-02-11T11:04:46 ::annotator SDL-AMR-09 ::preferred
# ::snt These anecdotes simply remind us that after 50 years, we still have a lot to learn about the biological and biochemical functions of Ras proteins.
# ::save-date Sat Jan 16, 2016 ::file pmid_2465_1010_68.txt
(r / remind-01
      :ARG0 (a / anecdote
            :mod (t / this))
      :ARG1 (n / need-01
            :ARG0 (w3 / we)
            :ARG1 (l / learn-01
                  :ARG0 w3
                  :ARG1 (a2 / and
                        :op1 (f2 / function-01
                              :ARG0 (p / protein-family :name (n3 / name :op1 "Ras"))
                              :mod (b / biology))
                        :op2 (f / function-01
                              :ARG0 p
                              :mod (b2 / biochemical)))
                  :quant (l2 / lot))
            :mod (s2 / still)
            :time (a3 / after
                  :op1 (t2 / temporal-quantity :quant 50
                        :unit (y / year))))
      :ARG2 (w / we)
      :ARG1-of (s / simple-02))

# ::id pmid_2465_1010.69 ::date 2015-02-13T07:47:56 ::annotator SDL-AMR-09 ::preferred
# ::snt Although K-Ras has emerged as by far the major Ras gene mutated in human cancer, it is surprising that other activating mutations in other members of the Ras superfamily, such as R-Ras or Rap proteins, occur very rarely.
# ::save-date Mon Jan 4, 2016 ::file pmid_2465_1010_69.txt
(s / surprise-01
      :ARG0 (m / mutate-01
            :ARG0-of (a / activate-01)
            :ARG1-of (r / rare-02
                  :degree (v / very))
            :location (m2 / member
                  :mod (o3 / other)
                  :ARG1-of (i / include-91
                        :ARG2 (p / protein-family :name (n / name :op1 "Ras")))
                  :example (o2 / or
                        :op1 (e3 / enzyme :name (n6 / name :op1 "R-Ras"))
                        :op2 (e4 / enzyme :name (n7 / name :op1 "Rap"))))
            :mod (o / other))
      :concession (e / emerge-02
            :ARG0 (g2 / gene :name (n2 / name :op1 "K-Ras"))
            :ARG1 (g / gene :name (n3 / name :op1 "Ras")
                  :ARG1-of (m3 / major-02)
                  :ARG1-of (m4 / mutate-01)
                  :location (d / disease :wiki "Cancer" :name (n4 / name :op1 "cancer")
                        :mod (h / human)))
            :degree (b / by-far)))

# ::id pmid_2465_1010.70 ::date 2015-02-09T08:46:03 ::annotator SDL-AMR-09 ::preferred
# ::snt This is surprising because these proteins share identical or near-identical effector-binding regions.
# ::save-date Mon Dec 21, 2015 ::file pmid_2465_1010_70.txt
(s / surprise-01
      :ARG0 (t / this)
      :ARG1-of (c / cause-01
            :ARG0 (s2 / share-01
                  :ARG0 (p / protein
                        :mod (t2 / this))
                  :ARG1 (o / or
                        :op1 (r / region
                              :ARG0-of (b / bind-01
                                    :ARG1 (e / effector))
                              :ARG1-of (i / identical-01))
                        :op1 (r2 / region
                              :ARG0-of b
                              :ARG1-of (i2 / identical-01
                                    :degree (n / near)))))))

# ::id pmid_2465_1010.71 ::date 2015-02-09T08:52:20 ::annotator SDL-AMR-09 ::preferred
# ::snt However, only H-Ras, N-Ras, and K-Ras are capable of binding and activating Raf kinases, and this unique property may well account for their predominance as human oncogenes.
# ::save-date Sun Jun 21, 2015 ::file pmid_2465_1010_71.txt
(a / and
      :op1 (h2 / have-concession-91
            :ARG2 (p / possible-01
                  :ARG1 (c2 / capable-01
                        :ARG1 (a2 / and
                              :op1 (e / enzyme :name (n / name :op1 "H-Ras"))
                              :op2 (e2 / enzyme :name (n2 / name :op1 "N-Ras"))
                              :op3 (e3 / enzyme :name (n3 / name :op1 "K-Ras"))
                              :mod (o / only))
                        :ARG2 (a3 / and
                              :op1 (b / bind-01
                                    :ARG0 a2
                                    :ARG1 (k / kinase :name (n4 / name :op1 "RAF")))
                              :op2 (a4 / activate-01
                                    :ARG0 a2
                                    :ARG1 k)))))
      :op2 (p3 / possible-01
            :ARG1 (a5 / account-01
                  :ARG0 (p5 / property
                        :mod (u / unique)
                        :mod (t / this))
                  :ARG1 (p4 / predominate-01
                        :ARG1 a2
                        :manner (o2 / oncogene
                              :mod (h / human)))
                  :mod (w / well))))

# ::id pmid_2465_1010.72 ::date 2015-02-09T23:50:07 ::annotator SDL-AMR-09 ::preferred
# ::snt In contrast, the closely related R-Ras proteins bind and activate PI3Ks but are rarely mutated in human cancer (<ce:cross-ref id="crosref0175" refid="bib56">Rodriguez-Viciana et al., 2004</ce:cross-ref>).
# ::save-date Sun Jan 17, 2016 ::file pmid_2465_1010_72.txt
(c / contrast-01
      :ARG2 (c3 / contrast-01
            :ARG1 (a / and
                  :op1 (b / bind-01
                        :ARG0 (e / enzyme :name (n2 / name :op1 "R-Ras")
                              :ARG1-of (r / relate-01
                                    :ARG1-of (c2 / close-10)))
                        :ARG1 (p4 / protein-family :name (n4 / name :op1 "PI3K")))
                  :op2 (a2 / activate-01
                        :ARG0 e
                        :ARG1 p4))
            :ARG2 (m / mutate-01
                  :ARG1 e
                  :location (d3 / disease :wiki "Cancer" :name (n3 / name :op1 "cancer")
                        :mod (h / human))
                  :ARG1-of (r2 / rare-02)))
      :ARG1-of (d2 / describe-01
            :ARG0 (p / publication-91
                  :ARG0 (a3 / and
                        :op1 (p3 / person :name (n5 / name :op1 "Rodriguez-Viciana"))
                        :op2 (p2 / person
                              :mod (o / other)))
                  :time (d / date-entity :year 2004))))

# ::id pmid_2465_1010.73 ::date 2015-02-10T00:32:30 ::annotator SDL-AMR-09 ::preferred
# ::snt Activating mutations in Ras genes, coupled with a long history of Ras biology, implicate these mutant Ras proteins as major drivers in many cancers.
# ::save-date Sat Jan 16, 2016 ::file pmid_2465_1010_73.txt
(i / implicate-01
      :ARG0 (a / activate-01
            :ARG0 (e3 / enzyme)
            :ARG1 (m2 / mutate-01
                  :ARG1 (g / gene
                        :mod p))
            :ARG1-of (c / couple-01
                  :ARG2 (h / history
                        :topic (b / biology
                              :mod (p / protein-family :name (n / name :op1 "Ras")))
                        :ARG1-of (l / long-03))))
      :ARG2 (d2 / drive-02
            :ARG0 m2
            :ARG1-of (m3 / major-02)
            :location (d3 / disease :wiki "Cancer" :name (n4 / name :op1 "cancer")
                  :quant (m4 / many))))

# ::id pmid_2465_1010.74 ::date 2015-02-10T00:39:05 ::annotator SDL-AMR-09 ::preferred
# ::snt Loss of the Ras GTPase-activating protein (GAP) neurofibromin inculpates hyperactive wild-type Ras proteins as drivers in many more cancers.
# ::save-date Fri Jun 5, 2015 ::file pmid_2465_1010_74.txt
(i / inculpate-00
      :ARG0 (l / lose-02
            :ARG1 (a / activate-01
                  :ARG0 (p2 / protein
                        :name (n2 / name :op1 "neurofibromin"))
                  :ARG1 (p / protein
                        :name (n / name :op1 "Ras" :op2 "GTPase"))))
      :ARG1 (e / enzyme
            :name (n3 / name :op1 "Ras")
            :mod (w / wild-type
                  :mod (h / hyperactive))
            :ARG0-of (d3 / drive-02
                  :ARG1 (d2 / disease :wiki "Cancer"
                        :name (n4 / name :op1 "cancer")
                        :mod (m / more
                              :mod (m2 / many))))))

# ::id pmid_2465_1010.75 ::date 2015-02-10T07:24:40 ::annotator SDL-AMR-09 ::preferred
# ::snt Somatic loss of neurofibromin expression by mutation, deletion, or by other means occurs in about 14% glioblastoma, 13%–14% melanoma, 8%–10% lung adenocarcinoma, and at single-digit frequency in most other cancers (E.A. Collisson, personal communication).
# ::save-date Wed Mar 2, 2016 ::file pmid_2465_1010_75.txt
(l / lose-02
      :ARG1 (e / express-03
            :ARG2 (p3 / protein :name (n / name :op1 "neurofibromin"))
            :manner (o2 / or
                  :op1 (m / mutate-01)
                  :op2 (d / delete-01)
                  :op3 (m2 / means
                        :mod (o / other)))
            :location (a2 / and
                  :op1 (m4 / medical-condition :name (n4 / name :op1 "glioblastoma")
                        :mod (p2 / percentage-entity :value 14))
                  :op2 (m6 / medical-condition :name (n2 / name :op1 "melanoma")
                        :mod (p5 / percentage-entity
                              :value (b / between :op1 13 :op2 14)))
                  :op3 (m5 / medical-condition :name (n3 / name :op1 "adenocarcinoma")
                        :mod (p6 / percentage-entity
                              :value (b2 / between :op1 8 :op2 10))
                        :mod (l2 / lung))
                  :op4 (d6 / disease :wiki "Cancer" :name (n6 / name :op1 "cancer")
                        :mod (o3 / other
                              :degree (m3 / most))
                        :frequency (d2 / digit
                              :ARG1-of (s2 / single-02)))))
      :mod (s / somatic)
      :ARG1-of (d5 / describe-01
            :ARG0 (c2 / communicate-01
                  :ARG0 (p / person :name (n5 / name :op1 "E.A." :op2 "Collisson"))
                  :ARG1-of (p4 / personal-02))))

# ::id pmid_2465_1010.76 ::date 2015-02-10T07:54:08 ::annotator SDL-AMR-09 ::preferred
# ::snt Neurofibromin must now be considered as a major tumor suppressor, along with p53 and phosphatase and tensin homolog, in human cancers.
# ::save-date Sun Jan 17, 2016 ::file pmid_2465_1010_76.txt
(o2 / obligate-01
      :ARG2 (c / consider-01
            :ARG1 (a / and
                  :op1 (p2 / protein :name (n / name :op1 "Neurofibromin"))
                  :op2 (p3 / protein :name (n2 / name :op1 "p53"))
                  :op3 (e / enzyme :name (n3 / name :op1 "phosphatase"))
                  :op4 (p / protein :name (n5 / name :op1 "tensin" :op2 "homolog"))
                  :ARG0-of (s / suppress-01
                        :ARG1 (t / tumor)
                        :ARG1-of (m / major-02)
                        :location (d / disease :wiki "Cancer" :name (n6 / name :op1 "cancer")
                              :mod (h / human))))
            :time (n4 / now)))

# ::id pmid_2465_1010.77 ::date 2015-02-10T08:01:09 ::annotator SDL-AMR-09 ::preferred
# ::snt Loss of neurofibromin is usually mutually exclusive with Ras mutation and receptor tyrosine kinase (RTK) activation, suggesting that these genetic events represent different ways of activating similar pathways.
# ::save-date Fri Jan 1, 2016 ::file pmid_2465_1010_77.txt
(s2 / suggest-01
      :ARG0 (e2 / exclusive-02
            :ARG0 (l / lose-02
                  :ARG1 (p / protein :name (n2 / name :op1 "neurofibromin")))
            :ARG2 (a2 / and
                  :op1 (m2 / mutate-01
                        :ARG1 (e / enzyme :name (n / name :op1 "Ras")))
                  :op2 (a3 / activate-01
                        :ARG1 (e3 / enzyme :name (n3 / name :op1 "receptor" :op2 "tyrosine" :op3 "kinase"))))
            :manner (m / mutual)
            :mod (u / usual))
      :ARG1 (r / represent-01
            :ARG0 (e4 / event
                  :mod (g / gene)
                  :mod (t / this))
            :ARG1 (w / way
                  :manner-of (a / activate-01
                        :ARG0 e4
                        :ARG1 (p3 / pathway
                              :ARG1-of (r2 / resemble-01)))
                  :ARG1-of (d / differ-02))))

# ::id pmid_2465_1010.78 ::date 2015-02-11T13:50:37 ::annotator SDL-AMR-09 ::preferred
# ::snt However, the precise consequences of losing neurofibromin are not entirely clear.
# ::save-date Sun Dec 20, 2015 ::file pmid_2465_1010_78.txt
(h / have-concession-91
      :ARG2 (c3 / clear-06 :polarity -
            :ARG1 (c / consequence
                  :mod (p2 / precise)
                  :ARG1-of (c2 / cause-01
                        :ARG0 (l / lose-02
                              :ARG1 (p / protein :name (n / name :op1 "neurofibromin")))))
            :degree (e / entire)))

# ::id pmid_2465_1010.79 ::date 2015-02-11T13:57:11 ::annotator SDL-AMR-09 ::preferred
# ::snt Levels of Ras-GTP are high in cells lacking neurofibromin, but which forms of hyperactive wild-type Ras proteins are most important to the malignant phenotype is a more difficult question.
# ::save-date Tue Jul 28, 2015 ::file pmid_2465_1010_79.txt
(c / contrast-01
      :ARG1 (h / high-02
            :ARG1 (l / level
                  :mod (m3 / macro-molecular-complex
                        :part (s / small-molecule :name (n4 / name :op1 "GTP"))
                        :part e))
            :location (c2 / cell
                  :ARG0-of (l2 / lack-01
                        :ARG1 (p / protein :polarity - :name (n2 / name :op1 "neurofibromin")))))
      :ARG2 (i2 / important :mode interrogative
            :domain (f / form
                  :mod (e / enzyme :name (n / name :op1 "Ras")
                        :mod (w / wild-type)
                        :mod (h2 / hyperactive)))
            :beneficiary (p4 / phenotype
                  :ARG1-of (m2 / malignant-02))
            :degree (m5 / most)
            :ARG1-of (q / question-01
                  :mod (d / difficult
                        :degree (m / more)))
            :degree (m4 / most)))

# ::id pmid_2465_1010.80 ::date 2015-02-11T20:29:37 ::annotator SDL-AMR-09 ::preferred
# ::snt Perhaps elevated H-Ras, N-Ras, K-Ras-4A, and K-Ras-4B all contribute to some extent.
# ::save-date Mon Mar 2, 2015 ::file pmid_2465_1010_80.txt
(p / possible-01
      :ARG1 (c / contribute-01
            :ARG1 (a / and
                  :op1 (e / enzyme :name (n / name :op1 "H-Ras"))
                  :op2 (e2 / enzyme :name (n2 / name :op1 "N-Ras"))
                  :op3 (e3 / enzyme :name (n3 / name :op1 "K-Ras-4A"))
                  :op4 (e4 / enzyme :name (n4 / name :op1 "K-Ras-4B"))
                  :ARG1-of (e5 / elevate-01)
                  :mod (a2 / all))
            :degree (e6 / extent
                  :mod (s2 / some))))

# ::id pmid_2465_1010.81 ::date 2015-02-11T20:36:08 ::annotator SDL-AMR-09 ::preferred
# ::snt However, neurofibromin is also a GAP for R-Ras proteins, and hyperactivation of these proteins can also contribute to the malignant phenotype because R-Ras proteins activate p110α, p110γ, and p110δ isoforms of PI3Ks (<ce:cross-refs id="crosrefs0020" refid="bib42 bib28">Marte et al., 1997; Huang et al., 2004</ce:cross-refs>).
# ::save-date Sun Jan 17, 2016 ::file pmid_2465_1010_81.txt
(h2 / have-concession-91
      :ARG2 (a / and
            :op1 (p2 / protein :name (n / name :op1 "GAP")
                  :domain (p / protein :name (n2 / name :op1 "neurofibromin")
                        :mod (a2 / also))
                  :beneficiary (e2 / enzyme :name (n3 / name :op1 "R-Ras"))
                  :mod (a8 / also))
            :op2 (p3 / possible-01
                  :ARG1 (c2 / contribute-01
                        :ARG0 (a3 / activate-01
                              :ARG1 a5
                              :degree (h3 / hyper))
                        :ARG2 (p4 / phenotype
                              :ARG1-of (m2 / malignant-02))
                        :mod a8)
                  :ARG1-of (c3 / cause-01
                        :ARG0 (a4 / activate-01
                              :ARG0 e2
                              :ARG1 (i / include-91
                                    :ARG1 (a5 / and
                                          :op1 (i2 / isoform :name (n4 / name :op1 "p110α"))
                                          :op2 (i3 / isoform :name (n5 / name :op1 "p110γ"))
                                          :op3 (i4 / isoform :name (n6 / name :op1 "p110δ"))
                                          :mod (e / enzyme :name (n7 / name :op1 "PI3K"))))))))
      :ARG1-of (d3 / describe-01
            :ARG0 (a6 / and
                  :op1 (p6 / publication-91
                        :ARG0 (a9 / and
                              :op1 (p5 / person :name (n9 / name :op1 "Marte"))
                              :op2 (p8 / person
                                    :mod (o / other)))
                        :time (d / date-entity :year 1997))
                  :op2 (p7 / publication-91
                        :ARG0 (a7 / and
                              :op1 (p9 / person :name (n10 / name :op1 "Huang"))
                              :op2 (p10 / person
                                    :mod (o2 / other)))
                        :time (d2 / date-entity :year 2004)))))

# ::id pmid_2465_1010.82 ::date 2015-02-10T14:32:38 ::annotator SDL-AMR-09 ::preferred
# ::snt Recently, Legius and colleagues (<ce:cross-ref id="crosref0180" refid="bib7">Brems et al., 2007</ce:cross-ref>) discovered mutations in the Sprouty-related protein, SPRED1, in a form of neurofibromatosis type I (NF1) in which the neurofibromin gene is wild-type.
# ::save-date Sun Jan 17, 2016 ::file pmid_2465_1010_82.txt
(d2 / discover-01
      :ARG0 (a / and
            :op1 (p / person :name (n / name :op1 "Legius"))
            :op2 (c / colleague)
            :ARG1-of (d3 / describe-01
                  :ARG0 (p5 / publication-91
                        :ARG0 (a2 / and
                              :op1 (p6 / person :name (n6 / name :op1 "Brems"))
                              :op2 (p7 / person
                                    :mod (o2 / other)))
                        :time (d / date-entity :year 2007))))
      :ARG1 (m / mutate-01
            :ARG1 (p2 / protein :name (n2 / name :op1 "SPRED1")
                  :ARG1-of (r2 / relate-01
                        :ARG2 (p3 / protein :name (n3 / name :op1 "Sprouty"))))
            :location (f / form
                  :mod (d4 / disease :name (n4 / name :op1 "neurofibromatosis" :op2 "type" :op3 "I")
                        :location-of (g / gene
                              :ARG0-of (e / encode-01
                                    :ARG1 (p4 / protein :name (n5 / name :op1 "neurofibromin")))
                              :mod (w / wild-type)))))
      :time (r / recent))

# ::id pmid_2465_1010.83 ::date 2015-02-10T14:33:54 ::annotator SDL-AMR-09 ::preferred
# ::snt This disease is now called Legius syndrome (<ce:cross-ref id="crosref0185" refid="bib7">Brems et al., 2007</ce:cross-ref>).
# ::save-date Sat Feb 14, 2015 ::file pmid_2465_1010_83.txt
(c / call-01
      :ARG1 (d2 / disease
            :mod (t / this))
      :ARG2 (n / name :op1 "Legius" :op2 "syndrome")
      :time (n2 / now)
      :ARG1-of (d4 / describe-01
            :ARG0 (p / publication-91
                  :ARG0 (a / and
                        :op1 (p2 / person :name (n3 / name :op1 "Brems"))
                        :op2 (p3 / person
                              :mod (o / other)))
                  :time (d / date-entity :year 2007))))

# ::id pmid_2465_1010.84 ::date 2015-02-10T14:41:06 ::annotator SDL-AMR-09 ::preferred
# ::snt SPRED1 has a well-established pedigree as a negative regulator of the Raf/MAPK pathway, though the mechanism has been unclear.
# ::save-date Thu Nov 5, 2015 ::file pmid_2465_1010_84.txt
(h / have-03
      :ARG0 (p / protein :name (n / name :op1 "SPRED1")
            :ARG2-of (d / downregulate-01
                  :ARG1 (p3 / pathway :name (n2 / name :op1 "Raf/MAPK"))))
      :ARG1 (p2 / pedigree
            :ARG1-of (e / establish-01
                  :ARG1-of (w / well-09)))
      :concession (c / clear-06 :polarity -
                  :ARG1 (m2 / mechanism)))

# ::id pmid_2465_1010.85 ::date 2015-02-10T14:46:29 ::annotator SDL-AMR-09 ::preferred
# ::snt However, the fact that loss of neurofibromin is, to a significant extent, phenocopied by loss of SPRED1, supports the idea that NF1 is a disease of hyperactive Ras and that the major function of neurofibromin is to turn Ras off.
# ::save-date Fri Jan 1, 2016 ::file pmid_2465_1010_85.txt
(h2 / have-concession-91
      :ARG1 (s / support-01
            :ARG0 (p / phenocopy-00
                  :ARG0 (l / lose-01
                        :ARG1 (p2 / protein :name (n2 / name :op1 "SPRED1")))
                  :ARG1 (l2 / lose-02
                        :ARG1 (p3 / protein :name (n3 / name :op1 "neurofibromin")))
                  :ARG1-of (s2 / significant-02))
            :ARG1 (i / idea
                  :topic (a / and
                        :op1 (d / disease
                              :ARG1-of (c2 / cause-01
                                    :ARG0 (e / enzyme :name (n / name :op1 "Ras")
                                          :ARG0-of (a2 / activity-06
                                                :degree (h / hyper))))
                              :domain (d2 / disease :name (n4 / name :op1 "NF1")))
                        :op1 (f / function-01
                              :ARG0 p3
                              :ARG1 (t / turn-off-07
                                    :ARG0 p3
                                    :ARG1 (e2 / enzyme :name (n5 / name :op1 "Ras")))
                              :ARG1-of (m / major-02))))))

# ::id pmid_2465_1010.86 ::date 2015-02-10T14:46:48 ::annotator SDL-AMR-09 ::preferred
# ::snt The neurofibromin protein itself is over 2,800 amino acids in length, and the GAP domain only accounts for about 300 amino acids, raising the possibility that neurofibromin has other functions that are not directly related to negative regulation of Ras.
# ::save-date Fri Jul 24, 2015 ::file pmid_2465_1010_86.txt
(a2 / and
      :op1 (l / long-03
            :ARG1 (p / protein :name (n2 / name :op1 "neurofibromin"))
            :ARG2 (a3 / amino-acid
                  :quant (o / over :op1 2800)))
      :op2 (a4 / account-01
            :ARG0 (p2 / protein-segment :name (n3 / name :op1 "GAP" :op2 "domain"))
            :ARG1 (a5 / amino-acid
                  :quant (a / about :op1 300))
            :mod (o3 / only))
      :ARG0-of (r / raise-01
            :ARG1 (p3 / possible-01
                  :ARG1 (f / function-01
                        :ARG0 p
                        :ARG1 (o2 / other
                              :ARG1-of (r2 / relate-01 :polarity -
                                    :ARG2 (d4 / downregulate-01
                                          :ARG1 (e / enzyme :name (n / name :op1 "Ras")))
                                    :ARG1-of (d / direct-02)))))))

# ::id pmid_2465_1010.87 ::date 2015-02-10T14:47:04 ::annotator SDL-AMR-09 ::preferred
# ::snt Most attempts to identify additional functions have failed, however, and it seems most likely that neurofibromin senses an unidentified cellular metabolite and downregulates Ras accordingly, just as p120 Ras-GAP senses phosphotyrosine residues, and downregulates Ras when it binds to these residues on activated receptors in the plasma membrane (reviewed in <ce:cross-ref id="crosref0190" refid="bib6">Bos et al., 2007</ce:cross-ref>).
# ::save-date Sun Dec 20, 2015 ::file pmid_2465_1010_87.txt
(a / and
      :op1 (h / have-concession-91
            :ARG1 (f / fail-01
                  :ARG1 (a2 / attempt-01
                        :ARG1 (i2 / identify-01
                              :ARG1 (f2 / function-01
                                    :mod (a3 / additional)))
                        :quant (m2 / most))))
      :op2 (l / likely-01
            :ARG1 (s / seem-01
                  :ARG1 (a4 / and
                        :op1 (s2 / sense-01
                              :ARG0 (p / protein :name (n2 / name :op1 "neurofibromin"))
                              :ARG1 (m4 / metabolite
                                    :mod (c2 / cell)
                                    :ARG1-of (i / identify-01 :polarity -)))
                        :op2 (d2 / downregulate-01
                              :ARG1 (e / enzyme :name (n / name :op1 "Ras"))
                              :ARG2 p
                              :manner (a5 / accordingly))
                        :ARG1-of (r / resemble-01
                              :ARG2 (a7 / and
                                    :op1 (s3 / sense-01
                                          :ARG0 (p2 / protein :name (n3 / name :op1 "p120" :op2 "Ras-GAP"))
                                          :ARG1 (r2 / residue
                                                :mod (a6 / amino-acid :name (n4 / name :op1 "threonine")
                                                      :ARG3-of (p3 / phosphorylate-01))))
                                    :op2 (d3 / downregulate-01
                                          :ARG1 e
                                          :ARG2 p2
                                          :time (b / bind-01
                                                :ARG1 p2
                                                :ARG2 r2
                                                :ARG3 (r3 / receptor
                                                      :ARG1-of (a8 / activate-01))
                                                :location (m3 / membrane
                                                      :part-of (p4 / plasma)))))
                              :mod (j / just))))
            :degree (m / most))
      :ARG1-of (r4 / review-02
            :ARG2 (p5 / publication-91
                  :ARG0 (a9 / and
                        :op1 (p6 / person :name (n5 / name :op1 "Bos"))
                        :op2 (p7 / person
                              :mod (o / other)))
                  :time (d / date-entity :year 2007))))

# ::id pmid_2465_1010.88 ::date 2015-02-11T10:42:28 ::annotator SDL-AMR-09 ::preferred
# ::snt Whatever neurofibromin senses (if this model is correct) is likely to be conserved between <i>S. cerevisiae</i> and humans because the <i>S. cerevisiae</i> IRA1 and IRA2 proteins look very much like neurofibromin.
# ::save-date Sun Jul 26, 2015 ::file pmid_2465_1010_88.txt
(l / likely-01
      :ARG1 (c / conserve-01
            :ARG1 (t / thing
                  :ARG1-of (s / sense-01
                        :ARG0 (p / protein :name (n / name :op1 "neurofibromin"))))
            :location (b / between
                  :op1 (o / organism :name (n2 / name :op1 "S." :op2 "cerevisiae"))
                  :op2 (h / human)))
      :condition (c2 / correct-02
            :ARG1 (m2 / model
                  :mod (t2 / this)))
      :ARG1-of (c3 / cause-01
            :ARG0 (r / resemble-01
                  :ARG1 (a / and
                        :op1 (p2 / protein :name (n3 / name :op1 "IRA1")
                              :mod o)
                        :op2 (p3 / protein :name (n4 / name :op1 "IRA2")
                              :mod o))
                  :ARG2 p
                  :degree (m / much
                        :degree (v / very)))))

# ::id pmid_2465_1010.89 ::date 2015-02-11T11:20:33 ::annotator SDL-AMR-09 ::preferred
# ::snt Unfortunately, the complete lack of any recognizable domains or motifs outside the GAP domain and a SEC14 domain has not helped in identifying what these proteins recognize.
# ::save-date Fri Jan 1, 2016 ::file pmid_2465_1010_89.txt
(h / help-01 :polarity -
      :ARG0 (l / lack-01
            :ARG1 (o / or
                  :op1 (d / domain
                        :mod (a / any))
                  :op2 (m / motif
                        :mod a)
                  :ARG1-of (r / recognize-02
                        :ARG1-of (p / possible-01)))
            :ARG1-of (c / complete-02)
            :location (o2 / outside
                  :op1 (a2 / and
                        :op1 (p2 / protein-segment :name (n / name :op1 "GAP" :op2 "domain"))
                        :op2 (p4 / protein-segment :name (n2 / name :op1 "SEC14" :op2 "domain")))))
      :ARG1 (i / identify-01
            :ARG1 (t / thing
                  :ARG1-of (r2 / recognize-02
                        :ARG0 (p3 / protein
                              :mod (t2 / this)))))
      :ARG2-of (f / fortunate-01 :polarity -))

# ::id pmid_2465_1010.90 ::date 2015-02-11T11:28:02 ::annotator SDL-AMR-09 ::preferred
# ::snt By comparing proteins that bind to wild-type SPRED1 versus mutants from Legius syndrome, we found that neurofibromin binds directly to SPRED proteins, via their EVH1 domains, and that SPRED proteins bring neurofibromin to the plasma membrane (<ce:cross-ref id="crosref0195" refid="bib67">Stowe et al., 2012</ce:cross-ref>).
# ::save-date Fri Jul 24, 2015 ::file pmid_2465_1010_90.txt
(f / find-01
      :ARG0 (w / we)
      :ARG1 (a2 / and
            :op1 (b / bind-01
                  :ARG1 (p / protein :name (n / name :op1 "neurofibromin"))
                  :ARG2 (p2 / protein :name (n2 / name :op1 "SPRED"))
                  :ARG3 (a / and
                        :op1 (p10 / protein-segment :name (n3 / name :op1 "EVH1" :op2 "domain")
                              :part-of p)
                        :op1 (p3 / protein-segment :name (n7 / name :op1 "EVH1" :op2 "domain")
                              :part-of p2))
                  :ARG1-of (d2 / direct-02))
            :op2 (b2 / bring-01
                  :ARG0 p2
                  :ARG1 p
                  :ARG2 (m / membrane
                        :part-of (p4 / plasma))))
      :manner (c / compare-01
            :ARG1 (p5 / protein
                  :ARG1-of (b3 / bind-01
                        :ARG2 (p6 / protein :name (n4 / name :op1 "SPRED1")
                              :mod (w2 / wild-type))))
            :ARG2 (p11 / protein
                  :ARG2-of (m2 / mutate-01)
                  :source (d5 / disease :name (n5 / name :op1 "Legius" :op2 "syndrome"))))
      :ARG1-of (d6 / describe-01
            :ARG0 (p7 / publication-91
                  :ARG0 (a3 / and
                        :op1 (p8 / person :name (n6 / name :op1 "Stowe"))
                        :op2 (p9 / person
                              :mod (o / other)))
                  :time (d / date-entity :year 2012))))

# ::id pmid_2465_1010.91 ::date 2015-02-11T12:22:22 ::annotator SDL-AMR-09 ::preferred
# ::snt SPRED proteins also bind to c-Kit, and perhaps to other RTKs, suggesting that neurofibromin regulates Ras locally in response to specific receptor signaling, rather than simply suppressing Ras throughout the plasma membrane.
# ::save-date Fri Jan 1, 2016 ::file pmid_2465_1010_91.txt
(b / bind-01
      :ARG1 (p2 / protein :name (n2 / name :op1 "SPRED"))
      :ARG2 (a / and
            :op1 (e2 / enzyme :name (n3 / name :op1 "c-Kit"))
            :op2 (e3 / enzyme :name (n4 / name :op1 "RTK")
                  :mod (o / other)
                  :ARG1-of (p / possible-01)))
      :mod (a2 / also)
      :ARG0-of (s / suggest-01
            :ARG1 (r / regulate-01
                  :ARG0 (p4 / protein :name (n5 / name :op1 "neurofibromin"))
                  :ARG1 (e / enzyme :name (n / name :op1 "Ras"))
                  :ARG1-of (l / local-02)
                  :ARG2-of (r2 / respond-01
                        :ARG1 (s2 / signal-07
                              :ARG0 (r3 / receptor
                                    :ARG1-of (s3 / specific-02))))
                  :ARG1-of (i / instead-of-91
                        :ARG2 (s4 / suppress-01
                              :ARG0 p4
                              :ARG1 e
                              :location (m / membrane
                                    :part-of (p5 / plasma))
                              :ARG1-of (s5 / simple-02))))))

# ::id pmid_2465_1010.92 ::date 2015-02-11T12:35:28 ::annotator SDL-AMR-09 ::preferred
# ::snt In this case, loss of neurofibromin may lead to local activation of Ras that is coupled to specific receptors, suggesting that inhibitors of these receptors might reverse the effects of neurofibromin loss.
# ::save-date Sat Jan 30, 2016 ::file pmid_2465_1010_92.txt
(p / possible-01
      :ARG1 (l / lead-03
            :ARG0 (l2 / lose-02
                  :ARG1 (p2 / protein :name (n2 / name :op1 "neurofibromin")))
            :ARG2 (a / activate-01
                  :ARG1 (e / enzyme :name (n / name :op1 "Ras"))
                  :ARG1-of (l3 / local-02)
                  :ARG1-of (c / couple-01
                        :ARG2 (r / receptor
                              :ARG1-of (s / specific-02))))
            :ARG0-of (s2 / suggest-01
                  :ARG1 (p3 / possible-01
                        :ARG1 (r2 / reverse-01
                              :ARG0 (m / molecular-physical-entity
                                    :ARG0-of (i / inhibit-01
                                          :ARG1 r))
                              :ARG1 (a2 / affect-01
                                    :ARG0 l2)))))
      :prep-in (c2 / case-04
            :ARG1 (t / this)))

# ::id pmid_2465_1010.93 ::date 2015-02-11T12:47:31 ::annotator SDL-AMR-09 ::preferred
# ::snt The recent Cancer Genome Atlas analysis of mutations in lung cancer revealed an intriguing overlap between neurofibromin loss and Met amplification, suggesting a functional connection that merits further investigation (E.A. Collisson, personal communication).
# ::save-date Sun Dec 20, 2015 ::file pmid_2465_1010_93.txt
(r / reveal-01
      :ARG0 (a / analyze-01
            :ARG0 (t / thing :name (n3 / name :op1 "Cancer" :op2 "Genome" :op3 "Atlas"))
            :ARG1 (m / mutate-01
                  :ARG0 (d2 / disease :wiki "Lung_cancer" :name (n2 / name :op1 "lung" :op2 "cancer")))
            :time (r2 / recent))
      :ARG1 (o / overlap-01
            :ARG0 (l / lose-02
                  :ARG1 (p2 / protein :name (n4 / name :op1 "neurofibromin")))
            :ARG1 (a2 / amplify-01
                  :ARG1 (p3 / protein :name (n5 / name :op1 "Met")))
            :ARG0-of (i2 / intrigue-01))
      :ARG0-of (s / suggest-01
            :ARG1 (c / connect-01
                  :ARG0-of (f / function-01)
                  :ARG0-of (m2 / merit-01
                        :ARG1 (i / investigate-01
                              :ARG1 c
                              :degree (f2 / further)))))
      :ARG1-of (c2 / communicate-01
            :ARG0 (p4 / person :name (n / name :op1 "E.A" :op2 "Collisson"))
            :ARG1-of (p / personal-02)))

# ::id pmid_2465_1010.94 ::date 2015-02-10T14:47:37 ::annotator SDL-AMR-09 ::preferred
# ::snt Validation of Ras as a Target
# ::save-date Sat Feb 14, 2015 ::file pmid_2465_1010_94.txt
(v / validate-01
      :ARG1 (t / target-01
            :ARG1 (e / enzyme :name (n / name :op1 "Ras"))))

# ::id pmid_2465_1010.95 ::date 2015-02-10T14:50:45 ::annotator SDL-AMR-09 ::preferred
# ::snt Ras oncogenes can certainly initiate cancer in model organisms and probably do so in humans.
# ::save-date Sat Jan 16, 2016 ::file pmid_2465_1010_95.txt
(a / and
      :op1 (p / possible-01
            :ARG1 (i / initiate-01
                  :ARG0 (e / enzyme :name (n / name :op1 "Ras")
                        :ARG0-of (c2 / cause-01
                              :ARG1 d))
                  :ARG1 (d / disease :wiki "Cancer" :name (n2 / name :op1 "cancer"))
                  :location (o2 / organism
                        :mod (m / model)))
            :mod (c / certain))
      :op2 (p2 / probable
            :domain (i2 / initiate-01
                  :ARG0 e
                  :ARG1 d
                  :location (h / human))))

# ::id pmid_2465_1010.96 ::date 2015-02-10T14:58:06 ::annotator SDL-AMR-09 ::preferred
# ::snt However, their role in maintaining tumors is less clear.
# ::save-date Fri May 29, 2015 ::file pmid_2465_1010_96.txt
(h / have-concession-91
      :ARG1 (c / clear-06
            :ARG1 (r / role
                  :poss (t / they)
                  :topic (m / maintain-01
                        :ARG1 (t2 / tumor)))
            :degree (l / less)))

# ::id pmid_2465_1010.97 ::date 2015-02-10T15:05:31 ::annotator SDL-AMR-09 ::preferred
# ::snt There is significant evidence that supports K-Ras as a continued candidate for direct therapeutic targeting, dating back to the classic studies of temperature-sensitive mutants of Ras, by Scolnick, Lowy, and colleagues and including microinjection studies with antibodies that block Ras activity (<ce:cross-ref id="crosref0200" refid="bib34">Kung et al., 1986</ce:cross-ref>) or block specific mutant alleles of Ras (<ce:cross-ref id="crosref0205" refid="bib19">Feramisco et al., 1985</ce:cross-ref>).
# ::save-date Fri Jul 24, 2015 ::file pmid_2465_1010_97.txt
(e3 / evidence-01
      :ARG1-of (s / significant-02)
      :ARG0-of (s2 / support-01
            :ARG1 (c / candidate
                  :purpose (t / target-01
                        :ARG0 (t2 / therapy)
                        :ARG1-of (d3 / direct-02))
                  :ARG1-of (c2 / continue-01)
                  :domain (e / enzyme :name (n / name :op1 "K-Ras"))))
      :ARG1-of (d4 / date-01
            :ARG2 (s3 / study-01
                  :ARG0 (a / and
                        :op1 (p / person :name (n3 / name :op1 "Scolnick"))
                        :op2 (p2 / person :name (n4 / name :op1 "Lowy"))
                        :op3 (c3 / colleague))
                  :ARG1 (e2 / enzyme :name (n2 / name :op1 "Ras")
                        :ARG2-of (m / mutate-01)
                        :ARG0-of (s4 / sensitive-03
                              :ARG1 (t3 / temperature)))
                  :mod (c4 / classic))
            :direction (b / back))
      :ARG2-of (i / include-01
            :ARG1 (s5 / study-01
                  :ARG1 (i2 / inject-01
                        :mod (m3 / micro))
                  :instrument (o / or
                        :op1 (a2 / antibody
                              :ARG0-of (b2 / block-01
                                    :ARG1 (a3 / activity-06
                                          :ARG0 (e4 / enzyme :name (n5 / name :op1 "Ras")))
                                    :ARG1-of (d5 / describe-01
                                          :ARG0 (p3 / publication-91
                                                :ARG0 (a4 / and
                                                      :op1 (p4 / person :name (n6 / name :op1 "Kung"))
                                                      :op2 (p5 / person
                                                            :mod (o2 / other)))
                                                :time (d / date-entity :year 1986)))))
                        :op2 (a5 / antibody
                              :ARG0-of (b3 / block-01
                                    :ARG1 (a6 / allele
                                          :mod e4
                                          :ARG2-of (m2 / mutate-01)
                                          :ARG1-of (s6 / specific-02))
                                    :ARG1-of (d6 / describe-01
                                          :ARG0 (p6 / publication-91
                                                :ARG0 (a7 / and
                                                      :op1 (p7 / person :name (n7 / name :op1 "Feramisco"))
                                                      :op2 (p8 / person
                                                            :mod o2))
                                                :time (d2 / date-entity :year 1985)))))))))

# ::id pmid_2465_1010.98 ::date 2015-02-10T15:05:59 ::annotator SDL-AMR-09 ::preferred
# ::snt Ablation of K-Ras in mouse models of lung adenocarcinoma (<ce:cross-ref id="crosref0210" refid="bib20">Fisher et al., 2001</ce:cross-ref>) or pancreas cancer (<ce:cross-ref id="crosref0215" refid="bib83">Ying et al., 2012</ce:cross-ref>) led to dramatic tumor regression, just as ablation of H-Ras leads to tumor regression in mouse models of melanoma (<ce:cross-ref id="crosref0220" refid="bib10">Chin et al., 1999</ce:cross-ref>).
# ::save-date Thu Dec 10, 2015 ::file pmid_2465_1010_98.txt
(l / lead-03
      :ARG0 (a / ablate-01
            :ARG1 (e / enzyme :name (n / name :op1 "K-Ras"))
            :location (o / or
                  :op1 (m / model
                        :mod (m2 / mouse)
                        :ARG1-of (d4 / describe-01
                              :ARG0 (p2 / publication-91
                                    :ARG0 (a3 / and
                                          :op1 (p3 / person :name (n2 / name :op1 "Fisher"))
                                          :op2 (p4 / person
                                                :mod (o2 / other)))
                                    :time (d / date-entity :year 2001)))
                        :topic (m6 / medical-condition :name (n6 / name :op1 "lung" :op2 "adenocarcinoma")))
                  :op2 (m3 / model
                        :mod m2
                        :ARG1-of (d5 / describe-01
                              :ARG0 (p5 / publication-91
                                    :ARG0 (a4 / and
                                          :op1 (p6 / person :name (n4 / name :op1 "Ying"))
                                          :op2 (p7 / person
                                                :mod o2))
                                    :time (d2 / date-entity :year 2012)))
                        :topic (d9 / disease :name (n7 / name :op1 "pancreas" :op2 "cancer")))))
      :ARG2 (r / regress-01
            :ARG1 (t / tumor)
            :degree (d6 / dramatic))
      :ARG1-of (r2 / resemble-01
            :ARG2 (l3 / lead-03
                  :ARG0 (a5 / ablate-01
                        :ARG1 (e2 / enzyme :name (n3 / name :op1 "H-Ras")))
                  :ARG2 (r3 / regress-01
                        :ARG1 (t2 / tumor)
                        :location (m4 / model
                              :mod (m5 / mouse)
                              :topic (m7 / medical-condition :name (n8 / name :op1 "melanoma"))))
                  :ARG1-of (d7 / describe-01
                        :ARG0 (p8 / publication-91
                              :ARG0 (a6 / and
                                    :op1 (p9 / person :name (n5 / name :op1 "Chin"))
                                    :op2 (p10 / person
                                          :mod o2))
                              :time (d3 / date-entity :year 1999))))))

# ::id pmid_2465_1010.99 ::date 2015-02-10T15:06:14 ::annotator SDL-AMR-09 ::preferred
# ::snt On the other hand, K-Ras knockdown in human cell lines resulted in a spectrum of responses, revealing a range of K-Ras dependencies (<ce:cross-ref id="crosref0225" refid="bib64">Singh et al., 2009</ce:cross-ref>).
# ::save-date Mon Dec 21, 2015 ::file pmid_2465_1010_99.txt
(c / contrast-01
      :ARG2 (r / result-01
            :ARG1 (k / knock-down-02
                  :ARG1 (e / enzyme :name (n / name :op1 "K-Ras"))
                  :location (c2 / cell-line
                        :mod (h / human)))
            :ARG2 (t / thing
                  :ARG2-of (r2 / respond-01)
                  :quant (s / spectrum)
                  :ARG0-of (r3 / reveal-01
                        :ARG1 (r4 / range-01
                              :ARG1 (d2 / depend-01
                                    :ARG1 e)))))
      :ARG1-of (d3 / describe-01
            :ARG0 (p / publication-91
                  :ARG0 (a / and
                        :op1 (p2 / person :name (n2 / name :op1 "Singh"))
                        :op2 (p3 / person
                              :mod (o / other)))
                  :time (d / date-entity :year 2009))))

# ::id pmid_2465_1010.100 ::date 2015-02-10T15:17:50 ::annotator SDL-AMR-09 ::preferred
# ::snt Assessment of Ras dependency in 3D culture systems suggests that this assay system is a more stringent measure of Ras dependency.
# ::save-date Sun Dec 20, 2015 ::file pmid_2465_1010_100.txt
(s / suggest-01
      :ARG0 (a / assess-01
            :ARG1 (d / depend-01
                  :ARG1 (e / enzyme :name (n / name :op1 "Ras")))
            :location (s2 / system
                  :mod (c / culture
                        :mod (d2 / dimension :quant 3))))
      :ARG1 (m / measure-01
            :ARG0 (s3 / system
                  :mod (t / this)
                  :instrument-of (a2 / assay-01))
            :ARG1 d
            :mod (s4 / stringent
                  :degree (m2 / more))))

# ::id pmid_2465_1010.101 ::date 2015-02-10T15:25:13 ::annotator SDL-AMR-09 ::preferred
# ::snt These studies raise the question of what is the most relevant system to measure this essential parameter and, in general, responses to candidate therapeutics targeting K-Ras.
# ::save-date Fri Dec 18, 2015 ::file pmid_2465_1010_101.txt
(r / raise-01
      :ARG0 (t / thing
            :ARG1-of (s / study-01)
            :mod (t2 / this))
      :ARG1 (q / question-01
            :ARG1 (s2 / system
                  :ARG1-of (r2 / relevant-01
                        :ARG2 (m2 / measure-01
                              :ARG1 (a / and
                                    :op1 (p / parameter
                                          :mod (e2 / essential)
                                          :mod t2)
                                    :op2 (t3 / thing
                                          :ARG2-of (r3 / respond-01
                                                :ARG1 (t4 / therapeutics
                                                      :mod (c / candidate)
                                                      :ARG0-of (t5 / target-01
                                                            :ARG1 (e / enzyme :name (n / name :op1 "K-Ras"))))
                                                :ARG1-of (g / general-02)))))
                        :degree (m / most)))))

# ::id pmid_2465_1010.102 ::date 2015-02-10T15:25:42 ::annotator SDL-AMR-09 ::preferred
# ::snt Furthermore, the degree to which Ras genes are knocked down may be critical.
# ::save-date Fri Jun 26, 2015 ::file pmid_2465_1010_102.txt
(a / and
      :op2 (p / possible-01
            :ARG1 (c / critical-02
                  :ARG1 (d2 / degree
                        :degree-of (k / knock-down-02
                              :ARG1 (g / gene
                                    :ARG0-of (e2 / encode-01
                                          :ARG1 (e / enzyme :name (n / name :op1 "Ras")))))))))

# ::id pmid_2465_1010.103 ::date 2015-02-10T15:31:03 ::annotator SDL-AMR-09 ::preferred
# ::snt Genetic ablation is obviously different than small interfering RNA- or small hairpin RNA (shRNA)-mediated knockdown.
# ::save-date Tue May 12, 2015 ::file pmid_2465_1010_103.txt
(d / differ-02
      :ARG1 (a / ablate-01
            :ARG1 (g / gene))
      :ARG2 (k / knock-down-02
            :ARG1-of (m / mediate-01
                  :ARG0 (o / or
                        :op1 (n3 / nucleic-acid :name (n2 / name :op1 "small" :op2 "interfering" :op3 "RNA"))
                        :op2 (n4 / nucleic-acid :name (n / name :op1 "small" :op2 "hairpin" :op3 "RNA")))))
      :ARG1-of (o2 / obvious-01))

# ::id pmid_2465_1010.104 ::date 2015-02-10T15:31:29 ::annotator SDL-AMR-09 ::preferred
# ::snt It is also clear that knocking down activated Ras can lead to hyperactivation of upstream pathways, such as EGFR signaling (<ce:cross-ref id="crosref0230" refid="bib84">Young et al., 2013</ce:cross-ref>).
# ::save-date Thu Feb 4, 2016 ::file pmid_2465_1010_104.txt
(c / clear-06
      :ARG1 (p / possible-01
            :ARG1 (l / lead-03
                  :ARG0 (k / knock-down-02
                        :ARG1 (e / enzyme :name (n / name :op1 "Ras")
                              :ARG1-of (a2 / activate-01)))
                  :ARG2 (a3 / activate-01
                        :ARG0 k
                        :ARG1 (p2 / pathway
                              :location (u / upstream)
                              :example (s / signal-07
                                    :ARG0 (e2 / enzyme :name (n2 / name :op1 "EGFR"))))
                        :degree (h / hyper))
                  :ARG1-of (d2 / describe-01
                        :ARG0 (p3 / publication-91
                              :ARG0 (a4 / and
                                    :op1 (p4 / person :name (n3 / name :op1 "Young"))
                                    :op2 (p5 / person
                                          :mod (o / other)))
                              :time (d / date-entity :year 2013)))))
      :mod (a / also))

# ::id pmid_2465_1010.105 ::date 2015-02-10T15:31:50 ::annotator SDL-AMR-09 ::preferred
# ::snt Presumably, these pathways are suppressed in cells with activated Ras and rebound when the suppressor is removed.
# ::save-date Sat Feb 14, 2015 ::file pmid_2465_1010_105.txt
(a / and
      :op1 (s / suppress-01
            :ARG1 (p / pathway
                  :mod (t / this))
            :location (c / cell
                  :ARG0-of (c2 / contain-01
                        :ARG1 (e / enzyme :name (n / name :op1 "Ras")
                              :ARG1-of (a2 / activate-01)))))
      :op2 (r / rebound-01
            :ARG1 p
            :time (r2 / remove-01
                  :ARG1 (m / molecular-physical-entity
                        :ARG0-of s)))
      :ARG1-of (p2 / presume-01))

# ::id pmid_2465_1010.106 ::date 2015-02-10T15:36:31 ::annotator SDL-AMR-09 ::preferred
# ::snt Although this rebound effect may not be sufficient to sustain a malignant phenotype, it may offset proapoptotic effects associated with oncogene inactivation.
# ::save-date Tue Jul 28, 2015 ::file pmid_2465_1010_106.txt
(h / have-concession-91
      :ARG1 (p3 / possible-01
            :ARG1 (o / offset-01
                  :ARG0 a
                  :ARG1 (a2 / affect-01
                        :ARG2 (f / favor-01
                              :ARG1 (a5 / apoptosis))
                        :ARG1-of (a3 / associate-01
                              :ARG2 (a4 / activate-01 :polarity -
                                    :ARG1 (o2 / oncogene))))))
      :ARG2 (p / possible-01
            :ARG1 (s / suffice-01 :polarity -
                  :ARG0 (a / affect-01
                        :ARG2 (r / rebound-01)
                        :mod (t / this))
                  :purpose (s2 / sustain-01
                        :ARG0 a
                        :ARG1 (p2 / phenotype
                              :ARG2-of (m / malignant-02))))))

# ::id pmid_2465_1010.107 ::date 2015-02-14T09:30:14 ::annotator SDL-AMR-09 ::preferred
# ::snt Do K-Ras Therapies Have to Be Allele Specific?
# ::save-date Fri Jul 24, 2015 ::file pmid_2465_1010_107.txt
(o / obligate-01 :mode interrogative
      :ARG2 (s / specific-02
            :ARG1 (t / therapy
                  :mod (e / enzyme :name (n / name :op1 "K-Ras")))
            :ARG2 (a / allele)))

# ::id pmid_2465_1010.108 ::date 2015-02-14T10:05:25 ::annotator SDL-AMR-09 ::preferred
# ::snt The most specific way to block oncogenic Ras would be to target the activating substitution itself.
# ::save-date Thu Dec 10, 2015 ::file pmid_2465_1010_108.txt
(w / way
      :ARG1-of (s2 / specific-02
            :degree (m / most))
      :manner-of (b / block-01
            :ARG1 (e / enzyme :name (n / name :op1 "Ras")
                  :ARG0-of (c / cause-01
                        :ARG1 (d / disease :wiki "Cancer" :name (n2 / name :op1 "cancer")))))
      :domain (t / target-01
            :ARG1 (s / substitute-01
                  :ARG0-of (a / activate-01))))

# ::id pmid_2465_1010.109 ::date 2015-02-14T10:20:14 ::annotator SDL-AMR-09 ::preferred
# ::snt The first example was recently published by Shokat and colleagues, who identified electrophilic compounds that react covalently with cysteine-12 in G12C mutant K-Ras (<ce:cross-ref id="crosref0235" refid="bib49">Ostrem et al., 2013</ce:cross-ref>).
# ::save-date Mon Feb 16, 2015 ::file pmid_2465_1010_109.txt
(p / publish-01
      :ARG0 (a / and
            :op1 (p2 / person :name (n / name :op1 "Shokat"))
            :op2 (c / colleague)
            :ARG0-of (i / identify-01
                  :ARG1 (c2 / compound
                        :mod (e2 / electrophile)
                        :ARG0-of (r2 / react-01
                              :ARG1 (a2 / amino-acid :mod 12 :name (n2 / name :op1 "cysteine"))
                              :manner (c3 / covalent)
                              :location (e3 / enzyme :name (n3 / name :op1 "K-Ras")
                                    :ARG2-of (m / mutate-01 :value "G12C"))))))
      :ARG1 (e / exemplify-01
            :ord (o / ordinal-entity :value 1))
      :time (r / recent)
      :ARG1-of (d / describe-01
            :ARG0 (p3 / publication-91
                  :ARG0 (a3 / and
                        :op1 (p4 / person :name (n4 / name :op1 "Ostrem"))
                        :op2 (p5 / person
                              :mod (o2 / other)))
                  :time (d2 / date-entity :year 2013))))

# ::id pmid_2465_1010.110 ::date 2015-02-14T10:55:47 ::annotator SDL-AMR-09 ::preferred
# ::snt These compounds interact selectively with the GDP form of K-Ras-G12C protein (<ce:cross-ref id="crosref0240" refid="fig2">Figure 2</ce:cross-ref><ce:float-anchor refid="fig2" />) and bind at a pocket near switch 2 that had not been apparent from analysis of crystal structures.
# ::save-date Sun Jul 26, 2015 ::file pmid_2465_1010_110.txt
(a / and
      :op1 (i / interact-01
            :ARG0 (c / compound
                  :mod (t / this))
            :ARG1 (m2 / macro-molecular-complex
                  :part (e / enzyme :name (n / name :op1 "K-Ras")
                        :ARG2-of (m / mutate-01 :value "G12C"))
                  :part (s2 / small-molecule :name (n2 / name :op1 "GDP")))
            :manner (s / selective)
            :ARG1-of (d / describe-01
                  :ARG0 (f / figure :mod 2)))
      :op2 (b / bind-01
            :ARG1 c
            :location (p / pocket
                  :ARG1-of (n3 / near-02
                        :ARG2 (s3 / switch :mod 2))
                  :ARG1-of (a2 / appear-01 :polarity -
                        :manner (a3 / analyze-01
                              :ARG1 (s4 / structure
                                    :poss (c2 / crystal)))))))

# ::id pmid_2465_1010.111 ::date 2015-02-14T13:41:13 ::annotator SDL-AMR-09 ::preferred
# ::snt A similar approach led to the identification of a GDP analog that covalently and specifically binds G12C and renders this oncogenic protein inactive (<ce:cross-ref id="crosref0245" refid="bib38">Lim et al., 2014</ce:cross-ref>).
# ::save-date Mon Dec 21, 2015 ::file pmid_2465_1010_111.txt
(l / lead-03
      :ARG0 (a / approach-02
            :ARG1-of (r / resemble-01))
      :ARG1 (i / identify-01
            :ARG1 (s / small-molecule :name (n / name :op1 "GDP")
                  :mod (a2 / analog)
                  :ARG1-of (b / bind-01
                        :ARG2 (e / enzyme :name (n2 / name :op1 "Ras")
                              :ARG2-of (m / mutate-01 :value "G12C")
                              :ARG0-of (c2 / cause-01
                                    :ARG1 (d4 / disease :wiki "Cancer" :name (n4 / name :op1 "cancer"))))
                        :manner (c / covalent)
                        :ARG1-of (s2 / specific-02))
                  :ARG0-of (d3 / deactivate-01
                        :ARG1 e)))
      :ARG1-of (d / describe-01
            :ARG0 (p3 / publication-91
                  :ARG0 (a4 / and
                        :op1 (p / person :name (n3 / name :op1 "Lim"))
                        :op2 (p2 / person
                              :mod (o / other)))
                  :time (d2 / date-entity :year 2014))))

# ::id pmid_2465_1010.112 ::date 2015-02-14T14:00:23 ::annotator SDL-AMR-09 ::preferred
# ::snt Perhaps other compounds could be identified that interact specifically with the G12D and G13D mutant forms using similar strategies.
# ::save-date Mon Dec 21, 2015 ::file pmid_2465_1010_112.txt
(p / possible-01
      :ARG1 (i / identify-01
            :ARG1 (c / compound
                  :mod (o / other)
                  :ARG0-of (i2 / interact-01
                        :ARG1 (a / and
                              :op1 (e / enzyme :name (n / name :op1 "Ras")
                                    :ARG1-of (m / mutate-01 :value "G12D"))
                              :op2 (e2 / enzyme :name (n2 / name :op1 "Ras")
                                    :ARG1-of (m2 / mutate-01 :value "G13D")))
                        :ARG1-of (s / specific-02)))
            :ARG2-of (u / use-01
                  :ARG1 (s2 / strategy
                        :ARG1-of (r / resemble-01)))))

# ::id pmid_2465_1010.113 ::date 2015-02-14T14:14:28 ::annotator SDL-AMR-09 ::preferred
# ::snt These brilliant experiments remind us that these proteins are in dynamic and flexible states that might present more opportunities for small molecule attack than was previously realized.
# ::save-date Mon Dec 21, 2015 ::file pmid_2465_1010_113.txt
(r / remind-01
      :ARG0 (e / experiment-01
            :mod (t / this)
            :ARG1-of (b / brilliant-01))
      :ARG1 (p / possible-01
            :ARG1 (p2 / present-01
                  :ARG0 (s / state
                        :mod (d / dynamic)
                        :ARG1-of (f / flexible-03)
                        :poss (p3 / protein
                              :mod (t2 / this)))
                  :ARG1 (o / opportunity
                        :mod (a / attack-01
                              :ARG0 (m / molecule
                                    :mod (s2 / small)))
                        :quant (m2 / more-than
                              :op1 (r2 / realize-01
                                    :time (p4 / previous))))))
      :ARG2 (w / we))

# ::id pmid_2465_1010.114 ::date 2015-02-14T15:08:58 ::annotator SDL-AMR-09 ::preferred
# ::snt Indeed, it is well established that Ras-GTP exists in two states, only one of which is active and each with distinct binding properties for effectors, GAPs, and nucleotide (<ce:cross-refs id="crosrefs0025" refid="bib21 bib36">Geyer et al., 1996; Liao et al., 2008</ce:cross-refs>).
# ::save-date Fri Jan 1, 2016 ::file pmid_2465_1010_114.txt
(e / establish-01
      :ARG1 (e2 / exist-01
            :ARG1 (m / macro-molecular-complex
                  :part (e4 / enzyme :name (n3 / name :op1 "Ras"))
                  :part (s3 / small-molecule :name (n4 / name :op1 "GTP")))
            :ARG2 (s / state :quant 2
                  :ARG2-of (i / include-91
                        :ARG1 (s2 / state :quant 1
                              :mod (o / only)
                              :ARG0-of (a / activity-06)))
                  :poss-of (p / property
                        :mod (b / bind-01
                              :ARG1 (a2 / and
                                    :op1 (e3 / effector)
                                    :op2 (p2 / protein :name (n / name :op1 "GAP"))
                                    :op3 (n2 / nucleotide)))
                        :mod (d / distinct))))
      :mod (i2 / indeed)
      :ARG1-of (d2 / describe-01
            :ARG0 (a3 / and
                  :op1 (p3 / publication-91
                        :ARG0 (a4 / and
                              :op1 (p4 / person :name (n5 / name :op1 "Geyer"))
                              :op2 (p5 / person
                                    :mod (o2 / other)))
                        :time (d3 / date-entity :year 1996))
                  :op2 (p6 / publication-91
                        :ARG0 (a5 / and
                              :op1 (p7 / person :name (n6 / name :op1 "Liao"))
                              :op2 (p8 / person
                                    :mod (o3 / other)))
                        :time (d4 / date-entity :year 2008))))
      :degree (w / well))

# ::id pmid_2465_1010.115 ::date 2015-02-15T03:20:28 ::annotator SDL-AMR-09 ::preferred
# ::snt The idea of targeting the GDP-bound form of an oncogenic mutant seems counterintuitive because we often think of oncogenic mutants as being locked in their GTP-bound states, signaling persistently downstream.
# ::save-date Thu Dec 10, 2015 ::file pmid_2465_1010_115.txt
(s / seem-01
      :ARG1 (i3 / intuitive :polarity -
            :domain (i2 / idea
                  :mod (t / target-01
                        :ARG1 (m2 / macro-molecular-complex
                              :part (e / enzyme
                                    :ARG1-of (m / mutate-01)
                                    :ARG0-of (c3 / cause-01
                                          :ARG1 (d2 / disease :wiki "Cancer" :name (n3 / name :op1 "cancer"))))
                              :part (s2 / small-molecule :name (n / name :op1 "GDP"))))))
      :ARG1-of (c2 / cause-01
            :ARG0 (t2 / think-01
                  :ARG0 (w / we)
                  :ARG1 e
                  :ARG2 (a / and
                        :op1 (l / lock-01
                              :ARG1 e
                              :ARG3 (m3 / macro-molecular-complex
                                    :part e
                                    :part (s4 / small-molecule :name (n2 / name :op1 "GTP")
                                          :ARG2-of (b2 / bind-01))))
                        :op2 (s5 / signal-07
                              :ARG0 e
                              :location (d / downstream)
                              :ARG1-of (p / persist-01)))
                  :frequency (o / often))))

# ::id pmid_2465_1010.116 ::date 2015-02-15T05:57:59 ::annotator SDL-AMR-09 ::preferred
# ::snt However, codon 12 mutants retain measurable intrinsic GTPase activity, even though they are all refractory to GAP-mediated GTPase stimulation.
# ::save-date Sun Jan 17, 2016 ::file pmid_2465_1010_116.txt
(h / have-concession-91
      :ARG1 (r / retain-01
            :ARG0 (e2 / enzyme
                  :part (c / codon :mod 12
                        :ARG2-of (m / mutate-01)))
            :ARG1 (a / activity-06
                  :ARG0 (e / enzyme :wiki "GTPase" :name (n / name :op1 "GTPase"))
                  :mod (i / intrinsic)
                  :ARG1-of (m2 / measure-01
                        :ARG1-of (p / possible-01))))
      :ARG2 (r2 / refractory
            :prep-to (s / stimulate-01
                  :ARG1 e
                  :ARG1-of (m3 / mediate-01
                        :ARG0 (p2 / protein :wiki "GTPase-activating_protein" :name (n2 / name :op1 "GAP"))))
            :domain (e3 / enzyme
                  :mod (a2 / all)
                  :part c)))

# ::id pmid_2465_1010.117 ::date 2015-02-15T11:21:58 ::annotator SDL-AMR-09 ::preferred
# ::snt Although GTP hydrolysis rates are slow, the GDP off rates are also slow, and indeed, oncogenic mutants often exist with similar levels of GTP and GDP: if intrinsic GTPase and GDP off rates were identical, Ras proteins would be 50% GTP bound and 50% GDP bound.
# ::save-date Sun Jan 17, 2016 ::file pmid_2465_1010_117.txt
(m / multi-sentence
      :snt1 (a / and
            :op1 (h / have-concession-91
                  :ARG1 (s / slow-05
                        :ARG1 (r / rate
                              :degree-of (s2 / small-molecule :wiki "Guanosine_diphosphate" :name (n / name :op1 "GDP")
                                    :ARG1-of (d / deactivate-01)))
                        :mod (a2 / also))
                  :ARG2 (s3 / slow-05
                        :ARG1 (r2 / rate
                              :degree-of (h2 / hydrolyze-01
                                    :ARG1 (s4 / small-molecule :wiki "Guanosine_triphosphate" :name (n2 / name :op1 "GTP"))))))
            :op2 (r3 / resemble-01
                  :ARG1 (l / level
                        :degree-of (s9 / small-molecule :wiki "Guanosine_triphosphate" :name (n11 / name :op1 "GTP")
                              :part-of (e2 / enzyme
                                    :ARG2-of (m2 / mutate-01)
                                    :ARG0-of (c / cause-01
                                          :ARG1 (d3 / disease :wiki "Cancer" :name (n12 / name :op1 "cancer"))))))
                  :ARG2 (l2 / level
                        :degree-of (s5 / small-molecule :wiki "Guanosine_diphosphate" :name (n3 / name :op1 "GDP")
                              :part-of e2))
                  :frequency (o / often)
                  :mod (i4 / indeed)))
      :snt2 (h3 / have-condition-91
            :ARG1 (i2 / include-91
                  :ARG1 (a3 / and
                        :op1 (e5 / enzyme
                              :ARG1-of (b2 / bind-01
                                    :ARG2 (s7 / small-molecule :wiki "Guanosine_triphosphate" :name (n9 / name :op1 "GTP")))
                              :quant (p / percentage-entity :value 50)
                              :mod (p3 / protein-family :wiki "Ras_subfamily" :name (n7 / name :op1 "Ras")))
                        :op2 (e6 / enzyme
                              :ARG1-of (b / bind-01
                                    :ARG2 (s8 / small-molecule :wiki "Guanosine_diphosphate" :name (n10 / name :op1 "GDP")))
                              :quant p
                              :mod p3))
                  :ARG2 (e4 / enzyme
                        :mod p3))
            :ARG2 (i / identical-01
                  :ARG1 (r4 / rate
                        :degree-of (e / enzyme :wiki "GTPase" :name (n4 / name :op1 "GTPase"))
                        :mod (i5 / intrinsic))
                  :ARG2 (r5 / rate
                        :degree-of (s6 / small-molecule :wiki "Guanosine_diphosphate" :name (n5 / name :op1 "GDP")
                              :ARG1-of (d2 / deactivate-01))
                        :mod i5))))

# ::id pmid_2465_1010.118 ::date 2015-02-15T12:27:12 ::annotator SDL-AMR-09 ::preferred
# ::snt This presents an opportunity for targeting the GDP-bound state and trapping it in the off state and so preventing recharging with GTP.
# ::save-date Mon Feb 16, 2015 ::file pmid_2465_1010_118.txt
(p / present-01
      :ARG0 (t3 / this)
      :ARG1 (o / opportunity
            :mod (t / target-01
                  :ARG1 (m / macro-molecular-complex
                        :part (s / small-molecule :name (n / name :op1 "GDP")
                              :ARG1-of (b2 / bind-01))))
            :mod (t2 / trap-01
                  :ARG1 m
                  :ARG2 (d / deactivate-01
                        :ARG1 m)
                  :purpose (p2 / prevent-01
                        :ARG1 (r / recharge-01
                              :ARG2 (s2 / small-molecule :name (n2 / name :op1 "GTP")))))))

# ::id pmid_2465_1010.119 ::date 2015-02-15T12:58:24 ::annotator SDL-AMR-09 ::preferred
# ::snt As an alternative to targeting specific Ras mutants, such as G12C, compounds could be developed that target individual Ras isoforms but do not discriminate between wild-type and mutant Ras proteins.
# ::save-date Thu Feb 4, 2016 ::file pmid_2465_1010_119.txt
(p / possible-01
      :ARG1 (d / develop-02
            :ARG1 (c / compound
                  :ARG0-of (t / target-01
                        :ARG1 (i / isoform
                              :mod (e / enzyme :name (n / name :op1 "Ras"))
                              :mod (i2 / individual))
                        :ARG1-of (c2 / contrast-01
                              :ARG2 (d2 / discriminate-01 :polarity -
                                    :ARG0 c
                                    :ARG1 (b / between
                                          :op1 (e3 / enzyme :name (n3 / name :op1 "Ras")
                                                :mod (w / wild-type))
                                          :op2 e2)))))
            :ARG4 (a / alternative
                  :prep-to (t2 / target-01
                        :ARG1 (e2 / enzyme :name (n2 / name :op1 "Ras")
                              :ARG2-of (m / mutate-01)
                              :ARG1-of (s / specific-02)
                              :example (e6 / enzyme :name (n5 / name :op1 "Ras")
                                    :ARG2-of (m2 / mutate-01 :value "G12C")))))))

# ::id pmid_2465_1010.120 ::date 2015-02-15T13:29:14 ::annotator SDL-AMR-09 ::preferred
# ::snt This could be achieved by targeting specific hypervariable regions at the C terminus where the Ras proteins differ most widely (<ce:cross-ref id="crosref0250" refid="fig3">Figure 3</ce:cross-ref><ce:float-anchor refid="fig3" />).
# ::save-date Sat Jan 16, 2016 ::file pmid_2465_1010_120.txt
(p / possible-01
      :ARG1 (a / achieve-01
            :ARG1 (t / this)
            :manner (t2 / target-01
                  :ARG1 (r / region
                        :ARG1-of (s / specific-02)
                        :ARG1-of (v / vary-01
                              :degree (h / hyper))
                        :location-of (d / differ-02
                              :ARG1 (p3 / protein-family :name (n2 / name :op1 "Ras"))
                              :degree (w / wide
                                    :degree (m / most)))
                        :part-of (p2 / protein-segment :name (n / name :op1 "C" :op2 "terminus")))))
      :ARG1-of (d2 / describe-01
            :ARG0 (f / figure :mod 3)))

# ::id pmid_2465_1010.121 ::date 2015-02-15T13:47:52 ::annotator SDL-AMR-09 ::preferred
# ::snt The C-terminal hypervariable region of K-Ras-4B is very different from the hypervariable regions of other Ras proteins and is involved in the specific interaction of K-Ras-4B with calmodulin (<ce:cross-ref id="crosref0255" refid="bib40">Lopez-Alcalá et al., 2008</ce:cross-ref>).
# ::save-date Wed Jan 13, 2016 ::file pmid_2465_1010_121.txt
(a / and
      :op1 (d / differ-02
            :ARG1 (r2 / region
                  :mod (h / hypervariable)
                  :part-of (p / protein-segment :name (n / name :op1 "C-terminus")
                        :part-of (e / enzyme :name (n2 / name :op1 "K-Ras-4B"))))
            :ARG2 (r / region
                  :mod h
                  :part-of (e2 / enzyme :name (n3 / name :op1 "Ras")
                        :mod (o / other)))
            :degree (v / very))
      :op2 (i / involve-01
            :ARG1 r2
            :ARG2 (i2 / interact-01
                  :ARG0 e
                  :ARG1 (p5 / protein :name (n5 / name :op1 "calmodulin"))
                  :ARG1-of (s / specific-02)))
      :ARG1-of (d2 / describe-01
            :ARG0 (p2 / publication-91
                  :ARG0 (a3 / and
                        :op1 (p3 / person :name (n4 / name :op1 "Lopez-Alcalá"))
                        :op2 (p4 / person
                              :mod (o2 / other)))
                  :time (d3 / date-entity :year 2008))))

# ::id pmid_2465_1010.122 ::date 2015-02-15T14:04:48 ::annotator SDL-AMR-09 ::preferred
# ::snt Because K-Ras-4B seems to be the major form of K-Ras in established tumors, these specific biochemical properties may afford unique opportunities for therapeutic attack.
# ::save-date Thu Jul 30, 2015 ::file pmid_2465_1010_122.txt
(c / cause-01
      :ARG0 (s / seem-01
            :ARG1 (f / form
                  :mod (e / enzyme :name (n / name :op1 "K-Ras"))
                  :ARG1-of (m / major-02)
                  :domain (e2 / enzyme :name (n2 / name :op1 "K-Ras-4B"))
                  :location (t / tumor
                        :ARG1-of (e3 / establish-01))))
      :ARG1 (p / possible-01
            :ARG1 (a / afford-02
                  :ARG0 (p2 / property
                        :mod (t2 / this)
                        :ARG1-of (s2 / specific-02)
                        :mod (b / biochemical))
                  :ARG1 (o / opportunity
                        :mod (u / unique)
                        :mod (a2 / attack-01
                              :ARG0 (t3 / therapy))))))

# ::id pmid_2465_1010.123 ::date 2015-02-15T14:18:44 ::annotator SDL-AMR-09 ::preferred
# ::snt Mouse models suggest that such compounds would be well tolerated because animals lacking any single isoform of Ras are viable (A. Balmain, personal communication).
# ::save-date Thu Nov 5, 2015 ::file pmid_2465_1010_123.txt
(s / suggest-01
      :ARG0 (m / model
            :mod (m2 / mouse))
      :ARG1 (t / tolerate-01
            :ARG1 (c / compound
                  :mod (s2 / such))
            :manner (w / well-09))
      :ARG1-of (c2 / cause-01
            :ARG0 (v / viable
                  :domain (a / animal
                        :ARG0-of (l / lack-01
                              :ARG1 (i / isoform
                                    :ARG1-of (s3 / single-02)
                                    :mod (a2 / any)
                                    :mod (e / enzyme :name (n / name :op1 "Ras")))))))
      :ARG1-of (c3 / communicate-01
            :ARG0 (p / person :name (n2 / name :op1 "A." :op2 "Balmain"))
            :ARG1-of (p2 / personal-02)))

# ::id pmid_2465_1010.124 ::date 2015-02-15T14:30:27 ::annotator SDL-AMR-09 ::preferred
# ::snt Targeting GDP/GTP Binding and Exchange
# ::save-date Tue Feb 17, 2015 ::file pmid_2465_1010_124.txt
(t / target-01
      :ARG1 (a / and
            :op1 (b / bind-01
                  :ARG2 (s3 / slash
                        :op1 (s / small-molecule :wiki "Guanosine_diphosphate"
                              :name (n / name :op1 "GDP"))
                        :op2 (s2 / small-molecule :wiki "Guanosine_triphosphate"
                              :name (n2 / name :op1 "GTP"))))
            :op2 (e / exchange-01
                  :ARG1 s
                  :ARG3 s2)))

# ::id pmid_2465_1010.125 ::date 2015-02-15T14:36:54 ::annotator SDL-AMR-09 ::preferred
# ::snt Ras proteins bind GDP and GTP with picomolar affinity.
# ::save-date Fri Jan 1, 2016 ::file pmid_2465_1010_125.txt
(b / bind-01
      :ARG1 (p2 / protein-family :name (n / name :op1 "Ras"))
      :ARG2 (a2 / and
            :op1 (s / small-molecule :name (n2 / name :op1 "GDP")
                  :mod (a / affinity
                        :mod (p / picomolar)))
            :op2 (s2 / small-molecule :name (n3 / name :op1 "GTP")
                  :mod a)))

# ::id pmid_2465_1010.126 ::date 2015-02-15T14:46:57 ::annotator SDL-AMR-09 ::preferred
# ::snt It is generally accepted that oncogenic Ras proteins cannot be attacked with nucleotide analogs because high GTP concentrations make competition impossible.
# ::save-date Sat Jan 16, 2016 ::file pmid_2465_1010_126.txt
(a / accept-01
      :ARG1 (p / possible-01 :polarity -
            :ARG1 (a2 / attack-01
                  :ARG0 (a3 / analog
                        :mod (n2 / nucleotide))
                  :ARG1 (e / enzyme :name (n / name :op1 "Ras")
                        :ARG0-of (c / cause-01
                              :ARG1 (d / disease :wiki "Cancer" :name (n4 / name :op1 "cancer")))))
            :ARG1-of (c3 / cause-01
                  :ARG0 (m / make-02
                        :ARG0 (c4 / concentrate-02
                              :ARG1 (s / small-molecule :name (n3 / name :op1 "GTP"))
                              :ARG1-of (h / high-02))
                        :ARG1 (p2 / possible-01 :polarity -
                              :ARG1 (c5 / compete-01)))))
      :ARG1-of (g / general-02))

# ::id pmid_2465_1010.127 ::date 2015-02-15T15:04:14 ::annotator SDL-AMR-09 ::preferred
# ::snt The high affinity for GTP is also considered a barrier, though it is easy to imagine that analogs could be developed with equally high affinity.
# ::save-date Sun Jul 26, 2015 ::file pmid_2465_1010_127.txt
(h / have-concession-91
      :ARG1 (c / consider-01
            :ARG1 (b / barrier
                  :domain (a / affinity
                        :ARG1-of (h2 / high-02)
                        :topic (s / small-molecule :name (n / name :op1 "GTP"))))
            :mod (a4 / also))
      :ARG2 (e / easy-05
            :ARG1 (i / imagine-01
                  :ARG1 (p / possible-01
                        :ARG1 (d / develop-02
                              :ARG1 (a2 / analog
                                    :poss-of (a3 / affinity
                                          :ARG1-of (h3 / high-02
                                                :degree (e2 / equal)))))))))

# ::id pmid_2465_1010.128 ::date 2015-02-15T15:15:28 ::annotator SDL-AMR-09 ::preferred
# ::snt This approach to targeting Ras has therefore been abandoned.
# ::save-date Sun Feb 15, 2015 ::file pmid_2465_1010_128.txt
(c / cause-01
      :ARG1 (a / abandon-01
            :ARG1 (a2 / approach-02
                  :ARG1 (t2 / target-01
                        :ARG1 (e / enzyme :name (n / name :op1 "Ras")))
                  :mod (t / this))))

# ::id pmid_2465_1010.129 ::date 2015-02-15T15:19:36 ::annotator SDL-AMR-09 ::preferred
# ::snt However, Ras proteins in their GTP state exist in complexes with effectors (Raf kinases, RalGDS, PI3K, other Ras-binding proteins), as well as regulators (GAPs and guanine nucleotide exchange factors [GEFs]).
# ::save-date Thu Feb 4, 2016 ::file pmid_2465_1010_129.txt
(h / have-concession-91
      :ARG1 (a3 / and
            :op1 (e / exist-01
                  :ARG1 (p7 / protein-family :name (n / name :op1 "Ras")
                        :ARG1-of (b / bind-01
                              :ARG2 (s / small-molecule :name (n2 / name :op1 "GTP"))))
                  :location (m / macro-molecular-complex
                        :part (e3 / effector
                              :example (a / and
                                    :op1 (p6 / protein-family :name (n3 / name :op1 "Raf"))
                                    :op2 (p4 / protein :name (n5 / name :op1 "RalGDS"))
                                    :op3 (e5 / enzyme :name (n4 / name :op1 "PI3K"))
                                    :op4 (p / protein
                                          :mod (o / other)
                                          :ARG1-of (b2 / bind-01
                                                :ARG2 (p5 / protein-family :name (n6 / name :op1 "Ras"))))))))
            :op2 (e2 / exist-01
                  :ARG1 p7
                  :location (m3 / macro-molecular-complex
                        :part (m2 / molecular-physical-entity
                              :ARG0-of (r / regulate-01)
                              :example (a2 / and
                                    :op1 (p2 / protein :name (n7 / name :op1 "GAP"))
                                    :op2 (p3 / protein :name (n8 / name :op1 "guanine" :op2 "nucleotide" :op3 "exchange" :op4 "factor"))))))))

# ::id pmid_2465_1010.130 ::date 2015-02-15T15:40:43 ::annotator SDL-AMR-09 ::preferred
# ::snt The effects of most of these proteins on nucleotide binding have not been measured.
# ::save-date Mon Feb 16, 2015 ::file pmid_2465_1010_130.txt
(m / measure-01 :polarity -
      :ARG1 (e / effect-03
            :ARG0 (p / protein
                  :ARG1-of (i / include-91
                        :ARG2 (p2 / protein
                              :mod (t / this))
                        :ARG3 (m2 / most)))
            :ARG1 (b / bind-01
                  :ARG1 (n / nucleotide))))

# ::id pmid_2465_1010.131 ::date 2015-02-15T15:51:08 ::annotator SDL-AMR-09 ::preferred
# ::snt GEFs, of course, greatly reduce the affinity for nucleotides, allowing GDP to be released rapidly and replaced by GTP.
# ::save-date Tue Feb 17, 2015 ::file pmid_2465_1010_131.txt
(r / reduce-01
      :ARG0 (p / protein :name (n / name :op1 "GEF"))
      :ARG1 (a / affinity
            :topic (n2 / nucleotide))
      :mod (o / of-course)
      :degree (g / great)
      :ARG0-of (a2 / allow-01
            :ARG1 (a3 / and
                  :op1 (r2 / release-01
                        :ARG1 (s / small-molecule :name (n3 / name :op1 "GDP"))
                        :manner (r3 / rapid))
                  :op2 (r4 / replace-01
                        :ARG1 s
                        :ARG2 (s2 / small-molecule :name (n4 / name :op1 "GTP"))))))

# ::id pmid_2465_1010.132 ::date 2015-02-15T15:57:55 ::annotator SDL-AMR-09 ::preferred
# ::snt Although oncogenic mutants do not need GEFs to put them in the active state, they are still sensitive to GEF-mediated exchange and cycle through a complex state in which nucleotide-free Ras protein is bound to the GEF; this may provide a potential opportunity for a mutant-specific nucleotide analog to bind.
# ::save-date Thu Dec 10, 2015 ::file pmid_2465_1010_132.txt
(h / have-concession-91
      :ARG1 (a2 / and
            :op1 (s / sensitive-03
                  :ARG0 e
                  :ARG1 (e2 / exchange-01
                        :ARG1-of (m2 / mediate-01
                              :ARG0 p))
                  :mod (s2 / still))
            :op2 (c3 / cycle-02
                  :ARG1 e
                  :path (m4 / macro-molecular-complex
                        :part (e3 / enzyme :name (n3 / name :op1 "Ras")
                              :ARG1-of (f / free-04
                                    :ARG2 (n4 / nucleotide))
                              :ARG1-of (b / bind-01
                                    :ARG2 p))))
            :ARG0-of (p2 / provide-01
                  :ARG1 (o / opportunity
                        :mod (b2 / bind-01
                              :ARG1 (a3 / analog
                                    :mod (n5 / nucleotide)
                                    :ARG1-of (s3 / specific-02
                                          :ARG2 (m3 / mutate-01))))
                        :mod (p4 / potential))
                  :ARG1-of (p3 / possible-01)))
      :ARG2 (n / need-01 :polarity -
            :ARG0 (e / enzyme
                  :ARG0-of (c / cause-01
                        :ARG1 (d / disease :wiki "Cancer" :name (n6 / name :op1 "cancer")))
                  :ARG2-of (m / mutate-01))
            :ARG1 (a / activate-01
                  :ARG0 (p / protein :name (n2 / name :op1 "GEF"))
                  :ARG1 e)))

# ::id pmid_2465_1010.133 ::date 2015-02-15T15:58:26 ::annotator SDL-AMR-09 ::preferred
# ::snt In support of this, we noted many years ago that antibodies directed against specific codon 12 mutants were effective at reversing transformation in cells, as cited above, yet these antibodies do not bind to nucleotide-loaded Ras (<ce:cross-ref id="crosref0260" refid="bib11">Clark et al., 1985</ce:cross-ref>).
# ::save-date Fri Jul 24, 2015 ::file pmid_2465_1010_133.txt
(n / note-01
      :ARG0 (w / we)
      :ARG1 (h / have-concession-91
            :ARG1 (b2 / bind-01 :polarity -
                  :ARG1 a
                  :ARG2 (e2 / enzyme :name (n3 / name :op1 "Ras")
                        :ARG1-of (l / load-01
                              :ARG2 (n4 / nucleotide))))
            :ARG2 (e / effective-04
                  :ARG0 (a / antibody
                        :ARG1-of (d / direct-01
                              :ARG2 (a2 / against
                                    :op1 (e3 / enzyme
                                          :part (c / codon :mod 12
                                                :ARG2-of (m2 / mutate-01))
                                          :ARG1-of (s / specific-02)))))
                  :ARG1 (r / reverse-01
                        :ARG0 a
                        :ARG1 (t2 / transform-01
                              :ARG1 (c2 / cell)))))
      :time (b / before
            :op1 (n2 / now)
            :quant (m / many
                  :op1 (t / temporal-quantity :quant 1
                        :unit (y / year))))
      :ARG0-of (s2 / support-01
            :ARG1 (t3 / this))
      :ARG1-of (c3 / cite-01
            :medium (a3 / above))
      :ARG1-of (d2 / describe-01
            :ARG0 (p / publication-91
                  :ARG0 (a4 / and
                        :op1 (p2 / person :name (n5 / name :op1 "Clark"))
                        :op2 (p3 / person
                              :mod (o / other)))
                  :time (d3 / date-entity :year 1985))))

# ::id pmid_2465_1010.134 ::date 2015-02-18T04:08:59 ::annotator SDL-AMR-09 ::preferred
# ::snt We therefore speculate that oncogenic Ras exists in a nucleotide-free state frequently enough to make it vulnerable to attack.
# ::save-date Thu Dec 10, 2015 ::file pmid_2465_1010_134.txt
(s / speculate-01
      :ARG0 (w / we)
      :ARG1 (e2 / exist-01
            :ARG1 (e / enzyme :name (n / name :op1 "Ras")
                  :ARG0-of (c / cause-01
                        :ARG1 (d / disease :wiki "Cancer" :name (n3 / name :op1 "cancer")))
                  :mod (v / vulnerable))
            :ARG2 (s2 / state
                  :ARG1-of (f / free-04
                        :ARG2 (n2 / nucleotide)))
            :ARG1-of (f2 / frequent-02
                  :degree (e3 / enough))
            :ARG0-of (m / make-02
                  :ARG1 (v2 / vulnerable
                        :domain e
                        :prep-to (a / attack-01))))
      :ARG1-of (i / infer-01))

# ::id pmid_2465_1010.135 ::date 2015-02-18T04:36:13 ::annotator SDL-AMR-09 ::preferred
# ::snt Whether oncogenic Ras proteins are regulated at all by Sos and other GEFs has been surprisingly difficult to determine definitively, partly because there are many types of GEFs in mammalian cells.
# ::save-date Mon Dec 21, 2015 ::file pmid_2465_1010_135.txt
(d / difficult
      :domain (d2 / determine-01
            :ARG1 (r / regulate-01 :mode interrogative
                  :ARG0 (a3 / and
                        :op1 (p / protein :name (n2 / name :op1 "Sos"))
                        :op2 (p2 / protein :name (n3 / name :op1 "GEF")
                              :mod (o / other)))
                  :ARG1 (e / enzyme :name (n / name :op1 "Ras")
                        :ARG0-of (c / cause-01
                              :ARG1 (d4 / disease :wiki "Cancer" :name (n4 / name :op1 "cancer"))))
                  :degree (a2 / at-all))
            :manner (d3 / definitive))
      :ARG0-of (s / surprise-01)
      :ARG1-of (c3 / cause-01
            :ARG0 (t / type-03
                  :ARG1 p2
                  :quant (m / many)
                  :location (c4 / cell
                        :mod (m2 / mammal)))
            :degree (p3 / part)))

# ::id pmid_2465_1010.136 ::date 2015-02-18T06:13:33 ::annotator SDL-AMR-09 ::preferred
# ::snt Furthermore, GEFs such as Sos have allosteric sites for Ras binding as well as sites for GDP/GTP exchange, and it is hard to measure GTP loading on individual Ras isoforms in cells.
# ::save-date Sat Jul 25, 2015 ::file pmid_2465_1010_136.txt
(a / and
      :op2 (a2 / and
            :op1 (h / have-03
                  :ARG0 (p / protein :name (n3 / name :op1 "GEF")
                        :example (p2 / protein :name (n4 / name :op1 "Sos")))
                  :ARG1 (a4 / and
                        :op1 (s2 / site
                              :mod (a3 / allosteric)
                              :purpose (b / bind-01
                                    :ARG1 (e / enzyme :name (n / name :op1 "Ras"))))
                        :op2 (s3 / site
                              :purpose (e2 / exchange-01
                                    :ARG1 (s / small-molecule :name (n2 / name :op1 "GTP"))
                                    :ARG2 (s4 / small-molecule :name (n5 / name :op1 "GDP"))))))
            :op2 (h2 / hard-02
                  :ARG1 (m / measure-01
                        :ARG1 (l / load-01
                              :ARG1 (i / isoform
                                    :mod e
                                    :mod (i2 / individual))
                              :ARG2 s)
                        :location (c / cell)))))

# ::id pmid_2465_1010.137 ::date 2015-02-18T06:30:21 ::annotator SDL-AMR-09 ::preferred
# ::snt However, it is clear that mutant Ras proteins are not 100% GTP bound, and GEFs could increase the fraction of Ras-GTP to some extent.
# ::save-date Fri May 29, 2015 ::file pmid_2465_1010_137.txt
(h / have-concession-91
      :ARG1 (a / and
            :op1 (c / clear-06
                  :ARG1 (b / bind-01 :polarity -
                        :ARG1 (e / enzyme :name (n / name :op1 "Ras")
                              :ARG1-of (m / mutate-01))
                        :ARG2 (s / small-molecule :name (n2 / name :op1 "GTP"))
                        :extent (p3 / percentage-entity :value 100)))
            :op2 (p4 / possible-01
                  :ARG1 (i / increase-01
                        :ARG0 (p5 / protein :name (n3 / name :op1 "GEF"))
                        :ARG1 (f / fraction
                              :mod (m2 / macro-molecular-complex
                                    :part e
                                    :part s))
                        :ARG2 (s3 / some)))))

# ::id pmid_2465_1010.138 ::date 2015-02-18T06:42:54 ::annotator SDL-AMR-09 ::preferred
# ::snt However, targeting Sos or other GEFs for treating mutant Ras cancers does not appear an attractive proposition.
# ::save-date Thu Dec 10, 2015 ::file pmid_2465_1010_138.txt
(h / have-concession-91
      :ARG1 (a / appear-02 :polarity -
            :ARG1 (t / target-01
                  :ARG1 (o / or
                        :op1 (p / protein :name (n2 / name :op1 "Sos"))
                        :op2 (p2 / protein :name (n3 / name :op1 "GEF")
                              :mod (o2 / other)))
                  :purpose (t2 / treat-03
                        :ARG2 (d / disease :wiki "Cancer" :name (n4 / name :op1 "cancer")
                              :location-of (m / mutate-01
                                    :ARG1 (e / enzyme :name (n / name :op1 "Ras")))))
                  :ARG1-of (p3 / propose-01
                        :ARG0-of (a2 / attract-01)))))

# ::id pmid_2465_1010.139 ::date 2015-02-18T06:54:25 ::annotator SDL-AMR-09 ::preferred
# ::snt Oncogenic mutants may or may not depend on GEFs, to some degree, but wild-type Ras proteins most certainly do.
# ::save-date Thu Dec 10, 2015 ::file pmid_2465_1010_139.txt
(c / contrast-01
      :ARG1 (o / or
            :op1 (p / possible-01
                  :ARG1 (d / depend-01
                        :ARG0 (p2 / protein
                              :ARG2-of (m / mutate-01
                                    :ARG0-of (c2 / cause-01
                                          :ARG1 (d3 / disease :wiki "Cancer" :name (n3 / name :op1 "cancer")))))
                        :ARG1 (p3 / protein :name (n2 / name :op1 "GEF"))))
            :op2 (p4 / possible-01 :polarity -
                  :ARG1 d)
            :degree (s / some))
      :ARG2 (d2 / depend-01
            :ARG0 (e / enzyme :name (n / name :op1 "Ras")
                  :mod (w / wild-type))
            :ARG1 p3
            :mod (c4 / certain
                  :degree (m2 / most))))

# ::id pmid_2465_1010.140 ::date 2015-02-18T07:05:45 ::annotator SDL-AMR-09 ::preferred
# ::snt For these reasons, recent efforts to target mutant Ras that led to compounds that bind at the Sos-binding site may seem disappointing (<ce:cross-refs id="crosrefs0030" refid="bib44 bib68">Maurer et al., 2012; Sun et al., 2012</ce:cross-refs>).
# ::save-date Thu Jan 21, 2016 ::file pmid_2465_1010_140.txt
(p / possible-01
      :ARG1 (s / seem-01
            :ARG1 (d3 / disappoint-01
                  :ARG0 (e2 / effort-01
                        :ARG1 (t / target-01
                              :ARG1 (e / enzyme :name (n / name :op1 "Ras")
                                    :ARG1-of (m / mutate-01)
                                    :ARG0-of (l / lead-03
                                          :ARG2 (c / compound
                                                :ARG0-of (b / bind-01
                                                      :location (s2 / site
                                                            :location-of (b2 / bind-01
                                                                  :ARG2 (p2 / protein :name (n2 / name :op1 "Sos")))))))))
                        :time (r / recent))))
      :ARG1-of (c2 / cause-01
            :ARG0 (r2 / reason
                  :mod (t2 / this)))
      :ARG1-of (d4 / describe-01
            :ARG0 (a / and
                  :op1 (p3 / publication-91
                        :ARG0 (a2 / and
                              :op1 (p4 / person :name (n3 / name :op1 "Maurer"))
                              :op2 (p5 / person
                                    :mod (o2 / other)))
                        :time (d2 / date-entity :year 2012))
                  :op2 (p6 / publication-91
                        :ARG0 (a3 / and
                              :op1 (p7 / person :name (n5 / name :op1 "Sun"))
                              :op2 (p8 / person
                                    :mod (o / other)))
                        :time (d / date-entity :year 2012)))))

# ::id pmid_2465_1010.141 ::date 2015-02-18T07:20:58 ::annotator SDL-AMR-09 ::preferred
# ::snt However, the compounds that these groups discovered could be excellent starting points toward the discovery of compounds that have selectivity for mutant forms of K-Ras or block effector interactions.
# ::save-date Sun Jul 26, 2015 ::file pmid_2465_1010_141.txt
(h / have-concession-91
      :ARG1 (p2 / possible-01
            :ARG1 (p3 / point
                  :source-of (s / start-01)
                  :ARG1-of (e2 / excellent-02)
                  :domain (c / compound
                        :ARG1-of (d / discover-01
                              :ARG0 (g / group
                                    :mod (t / this))))
                  :direction (o / or
                        :op1 (d2 / discover-01
                              :ARG1 (c2 / compound
                                    :ARG0-of (s2 / select-01
                                          :ARG1 (f / form
                                                :mod (e / enzyme :name (n / name :op1 "K-Ras"))
                                                :ARG2-of (m / mutate-01)))))
                        :op2 (d3 / discover-01
                              :ARG1 (c3 / compound
                                    :ARG0-of (b / block-01
                                          :ARG1 (i / interact-01
                                                :ARG0 (e3 / effector)))))))))

# ::id pmid_2465_1010.142 ::date 2015-02-18T07:42:56 ::annotator SDL-AMR-09 ::preferred
# ::snt Restoring GTP Hydrolysis
# ::save-date Wed Feb 18, 2015 ::file pmid_2465_1010_142.txt
(r / restore-01
      :ARG1 (h / hydrolyze-01
            :ARG1 (s / small-molecule :name (n / name :op1 "GTP"))))

# ::id pmid_2465_1010.143 ::date 2015-02-18T07:47:36 ::annotator SDL-AMR-09 ::preferred
# ::snt Mutations at codons 12, 13, and 61 inhibit GAP-mediated GTP hydrolysis.
# ::save-date Fri Mar 13, 2015 ::file pmid_2465_1010_143.txt
(i / inhibit-01
      :ARG0 (m / mutate-01
            :location (a / and
                  :op1 (c / codon :mod 12)
                  :op2 (c2 / codon :mod 13)
                  :op3 (c3 / codon :mod 61)))
      :ARG1 (h / hydrolyze-01
            :ARG1 (s / small-molecule :name (n / name :op1 "GTP"))
            :ARG1-of (m2 / mediate-01
                  :ARG0 (p / protein :name (n5 / name :op1 "GAP")))))

# ::id pmid_2465_1010.144 ::date 2015-02-18T07:51:37 ::annotator SDL-AMR-09 ::preferred
# ::snt As a result, mutant Ras proteins accumulate with elevated GTP-bound proportion.
# ::save-date Fri Jan 1, 2016 ::file pmid_2465_1010_144.txt
(a / accumulate-01
      :ARG1 (a2 / and
            :op1 (e / enzyme :name (n / name :op1 "Ras")
                  :ARG1-of (m / mutate-01))
            :op2 (p / proportion
                  :ARG1-of (e2 / elevate-01)
                  :quant-of (e3 / enzyme :name (n3 / name :op1 "Ras")
                        :ARG1-of (b / bind-01
                              :ARG2 (s / small-molecule :name (n2 / name :op1 "GTP"))))))
      :ARG2-of (r / result-01))

# ::id pmid_2465_1010.145 ::date 2015-02-18T07:56:55 ::annotator SDL-AMR-09 ::preferred
# ::snt Trahey and McCormick discovered GAP while seeking to explain how relatively small changes in intrinsic GTPase between wild-type and mutant Ras proteins accounted for profound differences in transforming activity (<ce:cross-ref id="crosref0265" refid="bib71">Trahey and McCormick, 1987</ce:cross-ref>).
# ::save-date Wed Nov 4, 2015 ::file pmid_2465_1010_145.txt
(d2 / discover-01
      :ARG0 (a / and
            :op1 (p / person :name (n3 / name :op1 "Trahey"))
            :op2 (p2 / person :name (n4 / name :op1 "McCormick")))
      :ARG1 (p3 / protein :name (n5 / name :op1 "GAP"))
      :ARG1-of (d4 / describe-01
            :ARG0 (p5 / publication-91
                  :ARG0 a
                  :time (d / date-entity :year 1987)))
      :time (s / seek-01
            :ARG0 a
            :ARG1 (e3 / explain-01
                  :ARG0 a
                  :ARG1 (a2 / account-01
                        :ARG0 (c / change-01
                              :ARG1 (e / enzyme :name (n / name :op1 "GTPase")
                                    :mod (i / intrinsic))
                              :mod (s2 / small
                                    :ARG2-of (r / relative-05))
                              :location (e2 / enzyme :name (n2 / name :op1 "Ras")
                                    :mod (w / wild-type)
                                    :compared-to (e4 / enzyme :name (n6 / name :op1 "Ras")
                                          :ARG1-of (m / mutate-01))))
                        :ARG1 (d3 / differ-02
                              :ARG1 e2
                              :ARG2 e4
                              :ARG3 (a3 / activity-06
                                    :ARG1 (t / transform-01)
                                    :mod (p4 / profound)))))))

# ::id pmid_2465_1010.146 ::date 2015-02-18T08:10:30 ::annotator SDL-AMR-09 ::preferred
# ::snt Intrinsic rates of GTP hydrolysis are five orders of magnitude slower than rates catalyzed by GAPs and therefore do not contribute significantly to steady-state levels of Ras-GTP.
# ::save-date Wed Mar 2, 2016 ::file pmid_2465_1010_146.txt
(s3 / slow-05
      :ARG1 (r / rate
            :mod (i / intrinsic)
            :degree-of (h / hydrolyze-01
                  :ARG1 (s / small-molecule :name (n / name :op1 "GTP"))))
      :degree (m / more
            :degree (o / order :quant 5
                  :mod (m2 / magnitude)))
      :compared-to (r2 / rate
            :degree-of (c / catalyze-01
                  :ARG0 (p / protein :name (n2 / name :op1 "GAP"))))
      :ARG0-of (c2 / cause-01
            :ARG1 (c3 / contribute-01 :polarity -
                  :ARG0 r
                  :ARG2 (l / level
                        :mod (s2 / state
                              :ARG1-of (s5 / steady-01))
                        :quant-of (m3 / macro-molecular-complex
                              :part (e / enzyme :name (n3 / name :op1 "Ras"))
                              :part s))
                  :ARG1-of (s4 / significant-02))))

# ::id pmid_2465_1010.147 ::date 2015-02-18T08:27:42 ::annotator SDL-AMR-09 ::preferred
# ::snt However, once Ras proteins bind effectors, GAPs can no longer interact, and intrinsic GTPase may become important in determining how long Ras and its effectors remain engaged.
# ::save-date Wed Mar 2, 2016 ::file pmid_2465_1010_147.txt
(h / have-concession-91
      :ARG1 (a / and
            :op1 (p / possible-01
                  :ARG1 (i / interact-01 :polarity -
                        :ARG0 (p2 / protein :name (n4 / name :op1 "GAP")))
                  :time (n5 / no-longer))
            :op2 (p3 / possible-01
                  :ARG1 (b / become-01
                        :ARG1 (e2 / enzyme :name (n3 / name :op1 "GTPase")
                              :mod (i2 / intrinsic))
                        :ARG2 (i3 / important
                              :purpose (d2 / determine-01
                                    :ARG1 (t / temporal-quantity
                                          :time-of (r / remain-01
                                                :ARG1 (a2 / and
                                                      :op1 (e / enzyme :name (n / name :op1 "Ras"))
                                                      :op2 (e5 / effector
                                                            :poss e))
                                                :ARG3 (e4 / engage-01
                                                      :ARG1 e5)))))))
            :time (b2 / bind-01
                  :ARG1 (p4 / protein-family :name (n2 / name :op1 "ras"))
                  :ARG2 (e3 / effector))))

# ::id pmid_2465_1010.148 ::date 2015-02-18T08:52:15 ::annotator SDL-AMR-09 ::preferred
# ::snt Indeed, effector binding may well affect intrinsic GTPase activity of Ras as it does for heterotrimeric G proteins.
# ::save-date Mon Dec 21, 2015 ::file pmid_2465_1010_148.txt
(p / possible-01
      :ARG1 (a / affect-01
            :ARG0 (b / bind-01
                  :ARG1 (e3 / effector))
            :ARG1 (a2 / activity-06
                  :ARG0 (e2 / enzyme :name (n2 / name :op1 "Ras"))
                  :ARG1 (e / enzyme :name (n / name :op1 "GTPase"))
                  :mod (i / intrinsic))
            :ARG1-of (s / same-01
                  :ARG2 (a3 / affect-01
                        :ARG0 b
                        :ARG1 (p2 / protein :name (n3 / name :op1 "G")
                              :mod (h / heterotrimeric))))
            :degree (w / well))
      :mod (i2 / indeed))

# ::id pmid_2465_1010.149 ::date 2015-02-18T09:01:21 ::annotator SDL-AMR-09 ::preferred
# ::snt If indeed intrinsic GTPase limits signal output, perhaps assays for compounds that stimulate intrinsic GTPase of Ras effector complexes may merit consideration.
# ::save-date Sat Jan 16, 2016 ::file pmid_2465_1010_149.txt
(p2 / possible-01
      :ARG1 (m / merit-01
            :ARG0 (a / assay-01
                  :ARG1 (c2 / compound
                        :ARG0-of (s / stimulate-01
                              :ARG1 (a2 / act-01
                                    :ARG0 (c3 / complex
                                          :part (e4 / effector
                                                :mod (p / protein-family :name (n2 / name :op1 "Ras"))))
                                    :ARG1 (e / enzyme :name (n / name :op1 "GTPase")
                                          :mod (i / intrinsic))))))
            :ARG1 (c / consider-01))
      :mod (p3 / perhaps)
      :condition (l / limit-01
            :ARG0 e
            :ARG1 (o2 / output
                  :mod (s2 / signal))
            :mod (i2 / indeed)))

# ::id pmid_2465_1010.150 ::date 2015-02-18T09:18:52 ::annotator SDL-AMR-09 ::preferred
# ::snt Mattos and colleagues recently showed that the Ras-binding domain of Raf (the RBD) has a profound effect on suppressing intrinsic hydrolysis rates of Ras Q61 mutants, but not wild-type Ras or G12V mutants (<ce:cross-ref id="crosref0270" refid="bib8">Buhrman et al., 2010</ce:cross-ref>).
# ::save-date Fri Mar 13, 2015 ::file pmid_2465_1010_150.txt
(s / show-01
      :ARG0 (a / and
            :op1 (p / person :name (n3 / name :op1 "Mattos"))
            :op2 (c / colleague
                  :poss p))
      :ARG1 (a2 / affect-01
            :ARG0 (p7 / protein-segment :name (n9 / name :op1 "RBD")
                  :part-of (e / enzyme :name (n / name :op1 "Raf"))
                  :ARG0-of (b / bind-01
                        :ARG1 (e2 / enzyme :name (n2 / name :op1 "Ras"))))
            :ARG1 (s2 / suppress-01
                  :ARG1 (r2 / rate
                        :degree-of (h / hydrolyze-01
                              :ARG1 (e3 / enzyme :name (n4 / name :op1 "Ras")
                                    :ARG2-of (m / mutate-01 :value "Q61")))
                        :mod (i / intrinsic)))
            :degree (p2 / profound)
            :ARG1-of (c3 / contrast-01
                  :ARG2 (a4 / affect-01 :polarity -
                        :ARG0 p7
                        :ARG1 (s3 / suppress-01 :polarity -
                              :ARG1 (o / or
                                    :op1 (e4 / enzyme :name (n5 / name :op1 "Ras")
                                          :mod (w / wild-type))
                                    :op2 (e5 / enzyme :name (n6 / name :op1 "Ras")
                                          :ARG2-of (m2 / mutate-01 :value "G12V"))))
                        :mod p2)))
      :time (r / recent)
      :ARG1-of (d3 / describe-01
            :ARG0 (p3 / publication-91
                  :ARG0 (a3 / and
                        :op1 (p5 / person :name (n8 / name :op1 "Buhrman"))
                        :op2 (p4 / person
                              :mod (o2 / other)))
                  :time (d / date-entity :year 2010))))

# ::id pmid_2465_1010.151 ::date 2015-02-18T09:33:47 ::annotator SDL-AMR-09 ::preferred
# ::snt They propose that suppression of intrinsic GTPase stabilizes Ras-Raf complexes and increases signal output to the MAPK pathway selectively; this accounts for the preference of Q61 mutants over G12 mutants in melanoma, a disease that is clearly Raf-MAPK driven (<ce:cross-ref id="crosref0275" refid="bib8">Buhrman et al., 2010</ce:cross-ref>).
# ::save-date Thu Dec 10, 2015 ::file pmid_2465_1010_151.txt
(m / multi-sentence
      :snt1 (p2 / propose-01
            :ARG0 (t / they)
            :ARG1 (a / and
                  :op1 (s / stabilize-01
                        :ARG0 (s2 / suppress-01
                              :ARG1 (e / enzyme :name (n / name :op1 "GTPase")
                                    :mod (i / intrinsic)))
                        :ARG1 (m2 / macro-molecular-complex
                              :part (e2 / enzyme :name (n3 / name :op1 "Ras"))
                              :part (e3 / enzyme :name (n4 / name :op1 "Raf"))))
                  :op2 (i2 / increase-01
                        :ARG0 s2
                        :ARG1 (o2 / output
                              :mod (s3 / signal)
                              :direction (p / pathway :name (n2 / name :op1 "MAPK"))))
                  :manner (s4 / select-01)))
      :snt2 (a2 / account-01
            :ARG0 (t2 / this)
            :ARG1 (p3 / prefer-01
                  :ARG1 (e4 / enzyme
                        :ARG2-of (m3 / mutate-01 :value "Q61"))
                  :ARG2 (e5 / enzyme
                        :ARG2-of (m4 / mutate-01 :value "G12"))
                  :location (m5 / medical-condition :name (n5 / name :op1 "melanoma")
                        :ARG1-of (d3 / drive-02
                              :ARG0 (p4 / pathway :name (n6 / name :op1 "Raf-MAPK"))
                              :ARG1-of (c / clear-06)))))
      :ARG1-of (d4 / describe-01
            :ARG0 (p5 / publication-91
                  :ARG0 (a3 / and
                        :op1 (p6 / person :name (n7 / name :op1 "Buhrman"))
                        :op2 (p7 / person
                              :mod (o / other)))
                  :time (d / date-entity :year 2010))))

# ::id pmid_2465_1010.152 ::date 2015-02-20T00:22:10 ::annotator SDL-AMR-09 ::preferred
# ::snt In the 1980s, several groups, including those at Cetus and Hoffmann La Roche, screened for compounds that restore GTP hydrolysis to mutant Ras, in the presence or absence of GAP.
# ::save-date Tue Jul 14, 2015 ::file pmid_2465_1010_152.txt
(s2 / screen-01
      :ARG0 (g / group
            :quant (s3 / several)
            :ARG2-of (i / include-01
                  :ARG1 (a2 / and
                        :op1 (g2 / group
                              :location (c / company :name (n3 / name :op1 "Cetus")))
                        :op2 (g3 / group
                              :location (c2 / company :name (n4 / name :op1 "Hoffmann" :op2 "La" :op3 "Roche")))
                        :mod (t / that))))
      :ARG2 (c3 / compound
            :ARG0-of (r / restore-01
                  :ARG1 (h / hydrolyze-01
                        :ARG1 (s / small-molecule :name (n / name :op1 "GTP"))
                        :ARG2 (e / enzyme :name (n2 / name :op1 "Ras")
                              :ARG1-of (m / mutate-01)))
                  :condition (o / or
                        :op1 (p2 / present-02
                              :ARG1 (p / protein :name (n5 / name :op1 "GAP")))
                        :op2 (a / absent-01
                              :ARG1 p))))
      :time (d / date-entity :decade 1980))

# ::id pmid_2465_1010.153 ::date 2015-02-20T00:35:36 ::annotator SDL-AMR-09 ::preferred
# ::snt These screens failed to find compounds that increased GTPase rates.
# ::save-date Mon Feb 23, 2015 ::file pmid_2465_1010_153.txt
(f / fail-01
      :ARG1 (s / screen-01
            :mod (t / this))
      :ARG2 (f2 / find-01
            :ARG0 s
            :ARG1 (c / compound
                  :ARG0-of (i / increase-01
                        :ARG1 (r / rate
                              :degree-of (e / enzyme :name (n / name :op1 "GTPase")))))))

# ::id pmid_2465_1010.154 ::date 2015-02-20T00:37:54 ::annotator SDL-AMR-09 ::preferred
# ::snt Furthermore, as structures of Ras proteins emerged, mostly from Wittinghofer’s group, it became clear that codon 12 substitutions presented a steric block to GAP-mediated GTP hydrolysis that could not be overcome by a small molecule.
# ::save-date Sat Jan 16, 2016 ::file pmid_2465_1010_154.txt
(a / and
      :op2 (b / become-01
            :ARG2 (c / clear-06
                  :ARG1 (p2 / present-01
                        :ARG0 (s2 / substitute-01
                              :ARG2 (c2 / codon :mod 12))
                        :ARG1 (b2 / block-01
                              :ARG1 (h / hydrolyze-01
                                    :ARG1 (s / small-molecule :name (n2 / name :op1 "GTP"))
                                    :ARG1-of (m / mediate-01
                                          :ARG0 (p3 / protein :name (n3 / name :op1 "GAP"))))
                              :manner (s3 / steric)
                              :ARG1-of (o / overcome-01
                                    :ARG0 (s4 / small-molecule)
                                    :ARG1-of (p / possible-01 :polarity -)))))
            :ARG1-of (c3 / cause-01
                  :ARG0 (e2 / emerge-02
                        :ARG0 (s5 / structure
                              :poss (p5 / protein-family :name (n / name :op1 "Ras")))
                        :source (g / group
                              :poss (p4 / person :name (n4 / name :op1 "Wittinghofer"))
                              :degree (m2 / most))))))

# ::id pmid_2465_1010.155 ::date 2015-02-20T00:52:34 ::annotator SDL-AMR-09 ::preferred
# ::snt These studies were mostly based on G12V mutations because these were the most widely used at that time.
# ::save-date Mon Dec 21, 2015 ::file pmid_2465_1010_155.txt
(b / base-02
      :ARG1 (s / study-01
            :mod (t / this))
      :ARG2 (m2 / mutate-01 :value "G12V")
      :degree (m / most)
      :ARG1-of (c / cause-01
            :ARG0 (u / use-01
                  :ARG1 m2
                  :ARG1-of (w / wide-02
                        :degree (m3 / most))
                  :time (t2 / that))))

# ::id pmid_2465_1010.156 ::date 2015-02-20T00:59:12 ::annotator SDL-AMR-09 ::preferred
# ::snt Whether the same conclusion can be applied to other mutations such as G12D or G13D remains to be seen because structures of these proteins bound to GAP have not been solved.
# ::save-date Mon Feb 23, 2015 ::file pmid_2465_1010_156.txt
(r / remain-01
      :ARG1 (s2 / see-01
            :ARG1 (p / possible-01 :mode interrogative
                  :ARG1 (a / apply-02
                        :ARG1 (c / conclude-01
                              :ARG1-of (s / same-01))
                        :ARG2 (m / mutate-01
                              :mod (o / other)
                              :example (o2 / or
                                    :op1 (m2 / mutate-01 :value "G12D")
                                    :op2 (m3 / mutate-01 :value "G13D"))))))
      :ARG1-of (c2 / cause-01
            :ARG0 (s3 / solve-01 :polarity -
                  :ARG1 (s4 / structure
                        :poss (p2 / protein
                              :mod (t / this))
                        :ARG1-of (b / bind-01
                              :ARG2 (p3 / protein :name (n / name :op1 "GAP")))))))

# ::id pmid_2465_1010.157 ::date 2015-02-20T01:09:37 ::annotator SDL-AMR-09 ::preferred
# ::snt The approach of restoring GTP hydrolysis to mutant proteins received a brief infusion of hope when Scheffzek and colleagues showed that G12V H-Ras could indeed hydrolyze a GTP analog diaminobenzophenone-phosphoroamidate-GTP in which the aromatic amino group mimics the catalytic effects of GAP’s arginine finger (<ce:cross-ref id="crosref0280" refid="bib2">Ahmadian et al., 1999</ce:cross-ref>).
# ::save-date Fri Jan 1, 2016 ::file pmid_2465_1010_157.txt
(r / receive-01
      :ARG0 (a / approach-02
            :ARG1 (r2 / restore-01
                  :ARG1 (h / hydrolyze-01
                        :ARG1 (s / small-molecule :name (n / name :op1 "GTP")))
                  :ARG2 (p2 / protein
                        :ARG1-of (m / mutate-01))))
      :ARG1 (i / infuse-01
            :ARG1 (h2 / hopeful-03)
            :duration (b / brief))
      :time (s2 / show-01
            :ARG0 (a2 / and
                  :op1 (p3 / person :name (n3 / name :op1 "Scheffzek"))
                  :op2 (c / colleague))
            :ARG1 (p / possible-01
                  :ARG1 (h3 / hydrolyze-01
                        :ARG1 (s3 / small-molecule :name (n4 / name :op1 "diaminobenzophenone-phosphoroamidate-GTP")
                              :mod (a3 / analog
                                    :domain s)
                              :location-of (m3 / mimic-01
                                    :ARG0 (g / group
                                          :mod (a4 / aromatic)
                                          :mod (a5 / amine))
                                    :ARG1 (e2 / effect-03
                                          :ARG0 (f / finger
                                                :part-of (p4 / protein :name (n5 / name :op1 "GAP"))
                                                :mod (a6 / amino-acid :name (n6 / name :op1 "arginine")))
                                          :ARG1 (c2 / catalyze-01))))
                        :ARG2 (e / enzyme :name (n2 / name :op1 "H-Ras")
                              :ARG2-of (m2 / mutate-01 :value "G12V")))
                  :mod (i2 / indeed)))
      :ARG1-of (d2 / describe-01
            :ARG0 (p5 / publication-91
                  :ARG0 (a7 / and
                        :op1 (p6 / person :name (n7 / name :op1 "Ahmadian"))
                        :op2 (p7 / person
                              :mod (o / other)))
                  :time (d / date-entity :year 1999))))

# ::id pmid_2465_1010.158 ::date 2015-02-20T01:32:08 ::annotator SDL-AMR-09 ::preferred
# ::snt A small molecule that provided this local charge might therefore trick mutant Ras into GTP hydrolysis.
# ::save-date Mon Dec 21, 2015 ::file pmid_2465_1010_158.txt
(p2 / possible-01
      :ARG1 (t / trick-01
            :ARG0 (s2 / small-molecule
                  :ARG0-of (p3 / provide-01
                        :ARG1 (c / charge-03
                              :ARG1-of (l / local-02)
                              :mod (t2 / this))))
            :ARG1 (e / enzyme :name (n / name :op1 "Ras")
                  :ARG1-of (m / mutate-01))
            :ARG2 (h / hydrolyze-01
                  :ARG1 (s / small-molecule :name (n2 / name :op1 "GTP"))))
      :ARG1-of (i / infer-01))

# ::id pmid_2465_1010.159 ::date 2015-02-19T22:59:47 ::annotator SDL-AMR-09 ::preferred
# ::snt At first sight, the GTD-/GTP-binding site of Ras does not offer any room for such a molecule to bind.
# ::save-date Fri Mar 13, 2015 ::file pmid_2465_1010_159.txt
(s / seem-01
      :ARG1 (o2 / offer-01 :polarity -
            :ARG0 (b / bind-01
                  :ARG1 (e / enzyme :name (n / name :op1 "Ras"))
                  :ARG2 (s2 / slash
                        :op1 (s3 / small-molecule :name (n2 / name :op1 "GTD"))
                        :op2 (s4 / small-molecule :name (n3 / name :op1 "GTP"))))
            :ARG1 (r / room
                  :mod (a / any))
            :purpose b)
      :time (s5 / see-01
            :ord (o / ordinal-entity :value 1)))

# ::id pmid_2465_1010.160 ::date 2015-02-21T23:04:58 ::annotator SDL-AMR-09 ::preferred
# ::snt However, these issues deserve rethinking—perhaps G12D offers more possibilities for this kind of attack than G12V, for example.
# ::save-date Fri Jan 1, 2016 ::file pmid_2465_1010_160.txt
(c / contrast-01
      :ARG2 (a / and
            :op1 (d / deserve-01
                  :ARG0 (i / issue-02
                        :mod (t2 / this))
                  :ARG1 (r / rethink-01
                        :ARG1 i))
            :op2 (p / possible-01
                  :ARG1 (o / offer-01
                        :ARG0 (m / mutate-01 :value "G12D")
                        :ARG1 (p2 / possibility
                              :mod (m2 / more)
                              :mod (a2 / attack-01
                                    :mod (k / kind
                                          :mod (t / this)))
                              :compared-to (m3 / mutate-01 :value "G12V")))
                  :example-of i)))

# ::id pmid_2465_1010.161 ::date 2015-02-22T02:28:33 ::annotator SDL-AMR-09 ::preferred
# ::snt Targeting Ras Posttranslational Modification Pathways
# ::save-date Tue Jun 16, 2015 ::file pmid_2465_1010_161.txt
(t / target-01
      :ARG1 (p / pathway :name (n / name :op1 "Ras")
            :ARG1-of (m / modify-01
                  :time (a / after
                        :op1 (t2 / translate-02)))))

# ::id pmid_2465_1010.162 ::date 2015-02-22T02:40:57 ::annotator SDL-AMR-09 ::preferred
# ::snt Ras proteins are processed in several steps (reviewed in <ce:cross-ref id="crosref0285" refid="bib24">Gysin et al., 2011</ce:cross-ref>), including farnesylation, proteolytic cleavage at the C terminus by RCE1, and carboxymethylation by isoprenylcysteine carboxyl methyltransferase (ICMT).
# ::save-date Sat Jan 16, 2016 ::file pmid_2465_1010_162.txt
(p / process-01
      :ARG1 (p7 / protein-family :name (n / name :op1 "Ras"))
      :manner (s / step-01
            :ARG4 a2
            :quant (s2 / several)
            :ARG2-of (i / include-91
                  :ARG1 (a2 / and
                        :op1 (f / farnesylate-01
                              :ARG1 p7)
                        :op2 (c / cleave-01
                              :ARG0 (e2 / enzyme :name (n3 / name :op1 "RCE1"))
                              :ARG1 (p6 / protein-segment :name (n4 / name :op1 "C-terminus")
                                    :part-of p7)
                              :mod (p5 / proteolytic))
                        :op3 (c2 / carboxymethylate-00
                              :ARG1 p7
                              :ARG2 (e3 / enzyme :name (n5 / name :op1 "isoprenylcysteine" :op2 "carboxyl" :op3 "methyltransferase"))))))
      :ARG1-of (r / review-02
            :ARG2 (p2 / publication-91
                  :ARG0 (a / and
                        :op1 (p3 / person :name (n2 / name :op1 "Gysin"))
                        :op2 (p4 / person
                              :mod (o / other)))
                  :time (d / date-entity :year 2011))))

# ::id pmid_2465_1010.163 ::date 2015-02-22T03:47:03 ::annotator SDL-AMR-09 ::preferred
# ::snt K-Ras-4A, H-Ras, and N-Ras are further processed by palmitoylation (<ce:cross-ref id="crosref0290" refid="fig3">Figure 3</ce:cross-ref>).
# ::save-date Sun Dec 20, 2015 ::file pmid_2465_1010_163.txt
(p / process-01
      :ARG1 (a / and
            :op1 (e / enzyme :name (n / name :op1 "K-Ras-4A"))
            :op2 (e2 / enzyme :name (n2 / name :op1 "H-Ras"))
            :op3 (e3 / enzyme :name (n3 / name :op1 "N-Ras")))
      :manner (p2 / palmitoylate-01
            :ARG1 a)
      :degree (f / further)
      :ARG1-of (d / describe-01
            :ARG0 (f2 / figure :mod 3)))

# ::id pmid_2465_1010.164 ::date 2015-02-22T04:05:38 ::annotator SDL-AMR-09 ::preferred
# ::snt These reactions are not only essential for plasma membrane localization but also for Raf kinase activation.
# ::save-date Fri Feb 27, 2015 ::file pmid_2465_1010_164.txt
(e / essential
      :purpose (a / and
            :op1 (b / be-located-at-91
                  :ARG2 (m / membrane
                        :mod (p / plasma)))
            :op2 (a2 / activate-01
                  :ARG1 (k / kinase :name (n / name :op1 "Raf"))))
      :domain (r / react-01
            :mod (t / this)))

# ::id pmid_2465_1010.165 ::date 2015-02-22T07:03:47 ::annotator SDL-AMR-09 ::preferred
# ::snt The failure of farnesyltransferase inhibitors has been well documented.
# ::save-date Thu Dec 17, 2015 ::file pmid_2465_1010_165.txt
(d / document-01
      :ARG1 (f / fail-01
            :ARG1 (m / molecular-physical-entity
                  :ARG0-of (i / inhibit-01
                        :ARG1 (e / enzyme :name (n / name :op1 "farnesyltransferase")))))
      :ARG1-of (w / well-09))

# ::id pmid_2465_1010.166 ::date 2015-02-22T07:30:17 ::annotator SDL-AMR-09 ::preferred
# ::snt By sheer bad luck, the forms of Ras that play the major roles in human cancer, K-Ras and N-Ras, can be geranylgeranylated when farnesyltransferase is inhibited, allowing newly synthesized Ras proteins to be inserted correctly in the membrane and to function normally.
# ::save-date Mon Dec 21, 2015 ::file pmid_2465_1010_166.txt
(p / possible-01
      :ARG1 (g / geranylgeranylate-01
            :ARG1 (a / and
                  :op1 (e / enzyme :name (n / name :op1 "K-Ras"))
                  :op2 (e2 / enzyme :name (n2 / name :op1 "N-Ras"))
                  :ARG0-of (p2 / play-08
                        :ARG1 (d / disease :wiki "Cancer" :name (n7 / name :op1 "cancer")
                              :mod (h / human))
                        :ARG1-of (m / major-02)))
            :ARG1-of (c2 / cause-01
                  :ARG0 (l / luck
                        :ARG1-of (b / bad-07)
                        :mod (s / sheer)))
            :ARG0-of (a4 / allow-01
                  :ARG1 (a3 / and
                        :op1 (i2 / insert-01
                              :ARG1 (e4 / enzyme :name (n5 / name :op1 "Ras")
                                    :ARG1-of (s2 / synthesize-01
                                          :ARG1-of (n6 / new-01)))
                              :ARG2 (m2 / membrane)
                              :ARG1-of (c3 / correct-02))
                        :op2 (f / function-01
                              :ARG0 e4
                              :ARG1-of (n4 / normal-02)))))
      :condition (i / inhibit-01
            :ARG1 (e3 / enzyme :name (n3 / name :op1 "farnesyltransferase"))))

# ::id pmid_2465_1010.167 ::date 2015-02-22T08:59:39 ::annotator SDL-AMR-09 ::preferred
# ::snt H-Ras, on the other hand, is not geranylgeranylated, suggesting that tumors driven by mutant H-Ras, such as bladder cancer or thyroid cancer, might be susceptible to farnesyltransferase inhibition.
# ::save-date Thu Dec 10, 2015 ::file pmid_2465_1010_167.txt
(c3 / contrast-01
      :ARG2 (g / geranylgeranylate-01 :polarity -
            :ARG1 (e3 / enzyme :name (n3 / name :op1 "H-Ras"))
            :ARG0-of (s2 / suggest-01
                  :ARG1 (p / possible-01
                        :ARG1 (s / susceptible
                              :domain (t / tumor
                                    :ARG1-of (d / drive-02
                                          :ARG0 (e2 / enzyme :name (n2 / name :op1 "H-Ras")
                                                :ARG2-of (m / mutate-01)))
                                    :example (o / or
                                          :op1 (d2 / disease :wiki "Cancer" :name (n4 / name :op1 "cancer")
                                                :mod (b / bladder))
                                          :op2 (d3 / disease :wiki "Thyroid_cancer" :name (n5 / name :op1 "thyroid" :op2 "cancer"))))
                              :prep-to (i2 / inhibit-01
                                    :ARG1 (e / enzyme :name (n / name :op1 "farnesyltransferase"))))))))

# ::id pmid_2465_1010.168 ::date 2015-02-22T09:56:43 ::annotator SDL-AMR-09 ::preferred
# ::snt Targeting RCE1 or ICMT has also been evaluated, though the consequences of blocking these enzymes are difficult to predict or understand.
# ::save-date Sun Feb 22, 2015 ::file pmid_2465_1010_168.txt
(c / contrast-01
      :ARG1 (e / evaluate-01
            :ARG1 (t / target-01
                  :ARG1 (o / or
                        :op1 (e2 / enzyme :name (n / name :op1 "RCE1"))
                        :op2 (e3 / enzyme :name (n2 / name :op1 "ICMT"))))
            :mod (a / also))
      :ARG2 (d / difficult
            :domain (o3 / or
                  :op1 (p / predict-01
                        :ARG1 (c2 / consequence
                              :ARG1-of (c3 / cause-01
                                    :ARG0 (b / block-01
                                          :ARG1 o))))
                  :op2 (u / understand-01
                        :ARG1 c2))))

# ::id pmid_2465_1010.169 ::date 2015-02-22T22:27:43 ::annotator SDL-AMR-09 ::preferred
# ::snt For example, inhibition of either enzyme can actually lead to increased Ras-mediated tumorigenesis (<ce:cross-refs id="crosrefs0035" refid="bib13 bib76">Court et al., 2013; Wahlstrom et al., 2007</ce:cross-refs>).
# ::save-date Mon Dec 21, 2015 ::file pmid_2465_1010_169.txt
(p / possible-01
      :ARG1 (l / lead-03
            :ARG0 (i2 / inhibit-01
                  :ARG1 (e2 / enzyme
                        :mod (e3 / either)))
            :ARG2 (c / create-01
                  :ARG1 (t / tumor)
                  :ARG1-of (i / increase-01)
                  :ARG1-of (m / mediate-01
                        :ARG0 (e / enzyme :name (n / name :op1 "Ras"))))
            :ARG1-of (a / actual-02))
      :ARG0-of (e4 / exemplify-01)
      :ARG1-of (d / describe-01
            :ARG0 (a2 / and
                  :op1 (p4 / publication-91
                        :ARG0 (a4 / and
                              :op1 (p2 / person :name (n2 / name :op1 "Court"))
                              :op2 (p3 / person
                                    :mod (o2 / other)))
                        :time (d2 / date-entity :year 2013))
                  :op2 (p5 / publication-91
                        :ARG0 (a3 / and
                              :op1 (p6 / person :name (n3 / name :op1 "Wahlstrom"))
                              :op2 (p7 / person
                                    :mod (o / other)))
                        :time (d3 / date-entity :year 2007)))))

# ::id pmid_2465_1010.170 ::date 2015-02-23T00:04:29 ::annotator SDL-AMR-09 ::preferred
# ::snt Palmitoylation and depalmitoylation of H-Ras, K-Ras-4A, and N-Ras proteins provide dynamic aspects to membrane localization and may present therapeutic opportunities for these proteins.
# ::save-date Fri Feb 27, 2015 ::file pmid_2465_1010_170.txt
(a / and
      :op1 (p / provide-01
            :ARG0 (a2 / and
                  :op1 (p3 / palmitoylate-01
                        :ARG1 (a3 / and
                              :op1 (e / enzyme :name (n / name :op1 "H-Ras"))
                              :op2 (e2 / enzyme :name (n2 / name :op1 "K-Ras-4A"))
                              :op3 (e3 / enzyme :name (n3 / name :op1 "N-Ras"))))
                  :op2 (d / depalmitoylate-01
                        :ARG1 a3))
            :ARG1 (a4 / aspect
                  :mod (d2 / dynamic))
            :ARG2 (b / be-located-at-91
                  :ARG1 a3
                  :ARG2 (m / membrane)))
      :op2 (p2 / possible-01
            :ARG1 (p4 / present-01
                  :ARG0 a2
                  :ARG1 (o / opportunity
                        :mod (t / therapy))
                  :ARG2 a3)))

# ::id pmid_2465_1010.171 ::date 2015-02-23T01:10:24 ::annotator SDL-AMR-09 ::preferred
# ::snt Recent work demonstrated that acyl protein thioesterase 1 (APT1), which is responsible for Ras depalmitoylation, could be targeted by palmostatin B to selectively inhibit the growth of N-Ras mutant leukemia cells (<ce:cross-ref id="crosref0295" refid="bib80">Xu et al., 2012</ce:cross-ref>).
# ::save-date Wed Mar 2, 2016 ::file pmid_2465_1010_171.txt
(p / possible-01
      :ARG1 (t / target-01
            :ARG0 (s / small-molecule :name (n3 / name :op1 "palmostatin" :op2 "B"))
            :ARG1 (e4 / enzyme :name (n6 / name :op1 "acyl" :op2 "protein" :op3 "thioesterase" :op4 "1")
                  :ARG0-of (r2 / responsible-01
                        :ARG1 (d / depalmitoylate-01
                              :ARG1 (e / enzyme :name (n2 / name :op1 "Ras"))
                              :ARG2 e4)))
            :purpose (i / inhibit-01
                  :ARG0 e4
                  :ARG1 (g / grow-01
                        :ARG1 (c2 / cell
                              :source (l / leukemia)
                              :ARG1-of (e2 / encode-01
                                    :ARG0 (n / nucleic-acid :wiki "DNA" :name (n7 / name :op1 "DNA")
                                          :part (g2 / gene :name (n4 / name :op1 "N-Ras")
                                                :ARG0-of (m / mutate-01))))))
                  :manner (s2 / selective)))
      :ARG1-of (d2 / demonstrate-01
            :ARG0 (w / work-01
                  :time (r / recent)))
      :ARG1-of (d3 / describe-01
            :ARG0 (p3 / publication-91
                  :ARG0 (a / and
                        :op1 (p4 / person :name (n5 / name :op1 "Xu"))
                        :op2 (p5 / person
                              :mod (o / other)))
                  :time (d4 / date-entity :year 2012))))

# ::id pmid_2465_1010.172 ::date 2015-02-23T02:50:23 ::annotator SDL-AMR-09 ::preferred
# ::snt In contrast, K-Ras-4B localization seemed relatively static and stable: specific localization of K-Ras-4B to plasma membranes is based on electrostatic interactions between lysine residues in the hypervariable region and phospholipids in the membrane.
# ::save-date Sun Dec 20, 2015 ::file pmid_2465_1010_172.txt
(c2 / cause-01
      :ARG0 (b / base-02
            :ARG1 (b3 / be-located-at-91
                  :ARG1 (e2 / enzyme :name (n / name :op1 "K-Ras-4B"))
                  :ARG2 (m / membrane
                        :mod (p / plasma))
                  :ARG1-of (s4 / specific-02))
            :ARG2 (i / interact-01
                  :ARG0 (r2 / residue
                        :mod (a2 / amino-acid :name (n2 / name :op1 "lysine"))
                        :location (r3 / region
                              :mod (h / hypervariable)))
                  :ARG1 (p2 / phospholipid
                        :location (m3 / membrane))
                  :mod (e3 / electrostatic)))
      :ARG1 (s / seem-01
            :ARG1 (a / and
                  :op1 (s2 / static
                        :ARG2-of (r / relative-05)
                        :domain b3)
                  :op2 (s3 / stable-03
                        :ARG1 b3))
            :ARG2-of (c3 / contrast-01)))

# ::id pmid_2465_1010.173 ::date 2015-02-23T09:26:17 ::annotator SDL-AMR-09 ::preferred
# ::snt However, another therapeutic opportunity has been presented by the discovery that PDE6δ acts as a solubilizing factor that modulates Ras proteins by sustaining their dynamic distribution in cellular membranes.
# ::save-date Sat Jan 16, 2016 ::file pmid_2465_1010_173.txt
(c / contrast-01
      :ARG2 (p / present-01
            :ARG0 (d / discover-01
                  :ARG1 (a2 / act-01
                        :ARG0 (p2 / protein :name (n / name :op1 "PDE6δ"))
                        :ARG1 (f / factor
                              :ARG0-of (s / solubilize-00
                                    :ARG1 p3)
                              :ARG0-of (m / modulate-01
                                    :ARG1 (p3 / protein-family :name (n2 / name :op1 "Ras"))
                                    :manner (s2 / sustain-01
                                          :ARG0 f
                                          :ARG1 (d2 / distribute-01
                                                :ARG1 p3
                                                :ARG2 (m2 / membrane
                                                      :location (c2 / cell))
                                                :manner (d3 / dynamic)))))))
            :ARG1 (o / opportunity
                  :mod (t / therapy)
                  :mod (a / another))))

# ::id pmid_2465_1010.174 ::date 2015-02-23T10:20:29 ::annotator SDL-AMR-09 ::preferred
# ::snt A small molecule was identified that prevents association of K-Ras-4B, and other proteins, with PDEδ and so delocalizes these proteins and inhibits downstream signaling (<ce:cross-ref id="crosref0300" refid="bib86">Zimmermann et al., 2013</ce:cross-ref>).
# ::save-date Wed Mar 4, 2015 ::file pmid_2465_1010_174.txt
(i / identify-01
      :ARG1 (s / small-molecule
            :ARG0-of (p / prevent-01
                  :ARG1 (a / associate-01
                        :ARG1 (a2 / and
                              :op1 (e / enzyme :name (n / name :op1 "K-Ras-4B"))
                              :op2 (p3 / protein
                                    :mod (o / other)))
                        :ARG2 (p4 / protein :name (n2 / name :op1 "PDEδ")))
                  :ARG0-of (c2 / cause-01
                        :ARG1 (a4 / and
                              :op1 (d2 / delocalize-01
                                    :ARG0 s
                                    :ARG1 a2)
                              :op2 (i2 / inhibit-01
                                    :ARG0 s
                                    :ARG1 (s2 / signal-07
                                          :source (d / downstream)))))))
      :ARG1-of (d3 / describe-01
            :ARG0 (p5 / publication-91
                  :ARG0 (a5 / and
                        :op1 (p6 / person :name (n3 / name :op1 "Zimmermann"))
                        :op2 (p7 / person
                              :mod (o2 / other)))
                  :time (d4 / date-entity :year 2013))))

# ::id pmid_2465_1010.175 ::date 2015-02-23T22:29:39 ::annotator SDL-AMR-09 ::preferred
# ::snt Little is still known about the trafficking of Ras to and from the membrane, and there are likely to be additional factors or chaperones involved in the movement of the proteins that could serve as targets for small molecules.
# ::save-date Fri Mar 13, 2015 ::file pmid_2465_1010_175.txt
(a / and
      :op1 (k / know-01
            :ARG1 (l2 / little
                  :topic (a2 / and
                        :op1 (t2 / traffic-01
                              :ARG1 (e / enzyme :name (n / name :op1 "Ras"))
                              :destination (m / membrane))
                        :op2 (t3 / traffic-01
                              :ARG1 e
                              :source (m2 / membrane))))
            :mod (s / still))
      :op2 (l / likely-01
            :ARG1 (i / involve-01
                  :ARG1 (o / or
                        :op1 (f / factor
                              :mod (a3 / additional))
                        :op2 (c / chaperone))
                  :ARG2 (m3 / move-01
                        :ARG1 (p / protein
                              :ARG0-of (s2 / serve-01
                                    :ARG1 (t / target-01
                                          :ARG0 (s3 / small-molecule)
                                          :ARG1 p)
                                    :ARG1-of (p2 / possible-01)))))))

# ::id pmid_2465_1010.176 ::date 2015-02-24T00:03:46 ::annotator SDL-AMR-09 ::preferred
# ::snt In a related study, K-Ras-4B was shown to undergo retrograde trafficking from the plasma membrane to endomembranes.
# ::save-date Sun Dec 20, 2015 ::file pmid_2465_1010_176.txt
(s / show-01
      :ARG1 (u / undergo-28
            :ARG1 (e2 / enzyme :name (n / name :op1 "K-Ras-4B"))
            :ARG2 (t / traffic-01
                  :ARG1-of (r2 / retrograde-01)
                  :source (m / membrane
                        :mod (p2 / plasma))
                  :direction (e / endomembrane)))
      :medium (s2 / study-01
            :ARG1-of (r / relate-01)))

# ::id pmid_2465_1010.177 ::date 2015-02-24T00:42:28 ::annotator SDL-AMR-09 ::preferred
# ::snt This may serve as an additional pathway to specifically disrupt for therapeutic benefit (<ce:cross-ref id="crosref0305" refid="bib4">Bivona et al., 2006</ce:cross-ref>).
# ::save-date Mon Dec 21, 2015 ::file pmid_2465_1010_177.txt
(p / possible-01
      :ARG1 (s / serve-01
            :ARG0 (t / this)
            :ARG1 (p2 / pathway
                  :mod (a / additional))
            :purpose (d / disrupt-01
                  :ARG0 p2
                  :ARG1-of (s2 / specific-02)
                  :purpose (b / benefit-01
                        :ARG0 p2
                        :mod (t2 / therapy))))
      :ARG1-of (d2 / describe-01
            :ARG0 (p3 / publication-91
                  :ARG0 (a2 / and
                        :op1 (p4 / person :name (n / name :op1 "Bivona"))
                        :op2 (p5 / person
                              :mod (o / other)))
                  :time (d3 / date-entity :year 2006))))

# ::id pmid_2465_1010.178 ::date 2015-02-24T02:00:05 ::annotator SDL-AMR-09 ::preferred
# ::snt In addition to these processing events, several recent papers have highlighted other posttranslational modifications of K-Ras that could serve as therapeutic targets.
# ::save-date Wed Mar 2, 2016 ::file pmid_2465_1010_178.txt
(h / highlight-01
      :ARG0 (p / paper
            :quant (s / several)
            :time (r / recent))
      :ARG1 (a / and
            :op1 (e / event
                  :mod (t / this)
                  :topic (p2 / process-01))
            :op2 (m / modify-01
                  :ARG1 (e2 / enzyme :name (n / name :op1 "K-Ras"))
                  :mod (o / other)
                  :time (a2 / after
                        :op1 (t2 / translate-02))
                  :ARG0-of (s2 / serve-01
                        :ARG1 (t3 / target-01
                              :ARG0 (t4 / therapy)
                              :ARG1 m)
                        :ARG1-of (p3 / possible-01)))))

# ::id pmid_2465_1010.179 ::date 2015-02-24T07:15:46 ::annotator SDL-AMR-09 ::preferred
# ::snt Mono-ubiquitination at Lys147 has been shown to enhance GTP loading and effector-binding affinity of K-Ras (<ce:cross-ref id="crosref0310" refid="bib59">Sasaki et al., 2011</ce:cross-ref>), suggesting that targeting of ubiquitin pathway enzymes might have an effect on K-Ras activity.
# ::save-date Mon Jul 6, 2015 ::file pmid_2465_1010_179.txt
(s / show-01
      :ARG1 (e / enhance-01
            :ARG0 (u / ubiquitinate-01 :quant 1
                  :ARG1 (a / amino-acid :mod 147 :name (n / name :op1 "lysine")))
            :ARG1 (a2 / and
                  :op1 (l / load-01
                        :ARG2 (s2 / small-molecule :name (n2 / name :op1 "GTP")))
                  :op2 (a3 / affinity
                        :poss (e2 / enzyme :name (n3 / name :op1 "K-Ras"))
                        :topic (b / bind-01
                              :ARG2 (e3 / effector)))))
      :ARG1-of (d / describe-01
            :ARG0 (p / publication-91
                  :ARG0 (a4 / and
                        :op1 (p2 / person :name (n4 / name :op1 "Sasaki"))
                        :op2 (p3 / person
                              :mod (o / other)))
                  :time (d2 / date-entity :year 2011)))
      :ARG0-of (s3 / suggest-01
            :ARG1 (a5 / affect-01
                  :ARG0 (t / target-01
                        :ARG1 (e4 / enzyme
                              :part-of (p5 / pathway :name (n5 / name :op1 "ubiquitin"))))
                  :ARG1 (a6 / activity-06
                        :ARG0 e2)
                  :ARG1-of (p4 / possible-01))))

# ::id pmid_2465_1010.180 ::date 2015-02-24T09:47:03 ::annotator SDL-AMR-09 ::preferred
# ::snt Acetylation of Lys104 was shown to decrease GEF-induced nucleotide exchange, leading to reduced transformation efficiency in cells, and the deacetylases SIRT2 and HDAC6 were shown to regulate the level of acetylation of K-Ras (<ce:cross-ref id="crosref0315" refid="bib81">Yang et al., 2013</ce:cross-ref>), suggesting that inhibitors of these enzymes might have an effect on the oncogenic potential of mutant K-Ras tumors.
# ::save-date Fri Jan 1, 2016 ::file pmid_2465_1010_180.txt
(a / and
      :op1 (s / show-01
            :ARG1 (d / decrease-01
                  :ARG0 (a2 / acetylate-01
                        :ARG1 (a3 / amino-acid :mod 104 :name (n / name :op1 "lysine"))
                        :ARG0-of (l / lead-03
                              :ARG2 (r / reduce-01
                                    :ARG1 (e2 / efficient-01
                                          :ARG2 (t / transform-01
                                                :ARG1 (c / cell))))))
                  :ARG1 (e / exchange-01
                        :ARG1 (n2 / nucleotide)
                        :ARG2-of (i / induce-01
                              :ARG0 (p / protein :name (n3 / name :op1 "GEF"))))))
      :op2 (s2 / show-01
            :ARG1 (r2 / regulate-01
                  :ARG0 (a4 / and
                        :op1 (e4 / enzyme :name (n4 / name :op1 "SIRT2"))
                        :op2 (e5 / enzyme :name (n5 / name :op1 "HDAC6"))
                        :ARG2-of (d2 / deacetylate-01 :polarity -))
                  :ARG1 (l2 / level
                        :degree-of (a5 / acetylate-01
                              :ARG1 (e3 / enzyme :name (n8 / name :op1 "K-Ras")))))
            :ARG0-of (s3 / suggest-01
                  :ARG1 (a7 / affect-01
                        :ARG0 (i2 / inhibit-01
                              :ARG1 a4)
                        :ARG1 (p6 / possible-01
                              :ARG1 (c2 / cause-01
                                    :ARG0 (t2 / tumor
                                          :ARG2-of (m / mutate-01)
                                          :mod e3)
                                    :ARG1 (d3 / disease :wiki "Cancer" :name (n6 / name :op1 "cancer"))))
                        :ARG1-of (p5 / possible-01))))
      :ARG1-of (d4 / describe-01
            :ARG0 (p2 / publication-91
                  :ARG0 (a6 / and
                        :op1 (p3 / person :name (n7 / name :op1 "Yang"))
                        :op2 (p4 / person
                              :mod (o / other)))
                  :time (d5 / date-entity :year 2013))))

# ::id pmid_2465_1010.181 ::date 2015-02-19T06:25:35 ::annotator SDL-AMR-09 ::preferred
# ::snt Finally, nitrosylation of Cys118 in H-Ras has been shown to activate Ras by enhancing nucleotide dissociation, leading to higher levels of GTP-bound protein.
# ::save-date Tue Feb 2, 2016 ::file pmid_2465_1010_181.txt
(s / show-01 :li "-1"
      :ARG1 (a / activate-01
            :ARG0 (n3 / nitrosylate-01
                  :ARG1 (a2 / amino-acid :mod 118 :name (n6 / name :op1 "cysteine"))
                  :location (e / enzyme :name (n / name :op1 "H-Ras")))
            :ARG1 (e2 / enzyme :name (n2 / name :op1 "Ras"))
            :manner (e3 / enhance-01
                  :ARG0 n3
                  :ARG1 (d / dissociate-01
                        :ARG1 (n4 / nucleotide))
                  :ARG0-of (l / lead-03
                        :ARG2 (l2 / level
                              :ARG1-of (h / high-02
                                    :degree (m / more))
                              :degree-of (p / protein
                                    :ARG1-of (b / bind-01
                                          :ARG0 (s2 / small-molecule :name (n5 / name :op1 "GTP")))))))))

# ::id pmid_2465_1010.182 ::date 2015-02-20T03:11:21 ::annotator SDL-AMR-09 ::preferred
# ::snt The eNos protein was identified as a strong enhancer of nitrosylation and therefore could also be a therapeutic target to attack mutant Ras (<ce:cross-ref id="crosref0320" refid="bib37">Lim et al., 2008</ce:cross-ref>).
# ::save-date Tue Feb 2, 2016 ::file pmid_2465_1010_182.txt
(c / cause-01
      :ARG0 (i / identify-01
            :ARG1 (p2 / protein :name (n2 / name :op1 "eNos"))
            :ARG2 (e2 / enhance-01
                  :ARG1 (n3 / nitrosylate-01)
                  :ARG2 p2
                  :ARG1-of (s / strong-02)))
      :ARG1 (p / possible-01
            :ARG1 (t2 / target-01
                  :ARG0 (t / therapy)
                  :ARG1 p2
                  :mod (a3 / also)
                  :purpose (a / attack-01
                        :ARG0 p2
                        :ARG1 (e / enzyme :name (n / name :op1 "Ras")
                              :ARG1-of (m / mutate-01)))))
      :ARG0-of (d2 / describe-01
            :ARG1 (p3 / publication-91
                  :ARG0 (a2 / and
                        :op1 (p4 / person :name (n4 / name :op1 "Lim"))
                        :op2 (p5 / person
                              :mod (o / other)))
                  :time (d / date-entity :year 2008))))

# ::id pmid_2465_1010.183 ::date 2015-02-23T08:32:01 ::annotator SDL-AMR-09 ::preferred
# ::snt Downstream Pathways and Drug Targets
# ::save-date Wed Feb 25, 2015 ::file pmid_2465_1010_183.txt
(a / and
  :op1 (p / pathway
         :mod (d / downstream))
  :op2 (t / target-01
         :ARG0 (d2 / drug)))

# ::id pmid_2465_1010.184 ::date 2015-02-23T08:34:45 ::annotator SDL-AMR-09 ::preferred
# ::snt When it became clear that targeting mutant Ras proteins directly was technically impossible with the tools available at that time, the search for drugs that block Ras activity moved downstream.
# ::save-date Sat Jul 25, 2015 ::file pmid_2465_1010_184.txt
(s / search-01
      :ARG2 (d / drug
            :ARG0-of (b / block-01
                  :ARG1 (a / activity-06
                        :ARG0 e)))
      :ARG0-of (m / move-01
            :ARG2 (d2 / downstream))
      :time (c / clear-06
            :ARG1 (p / possible-01 :polarity -
                  :ARG1 (t / target-01
                        :ARG1 (e / enzyme :name (n / name :op1 "Ras")
                              :ARG1-of (m2 / mutate-01))
                        :ARG1-of (d3 / direct-02)
                        :instrument (t3 / tool
                              :ARG2-of (a2 / available-02
                                    :time (t4 / time
                                          :mod (t5 / that)))))
                  :mod (t2 / technical))))

# ::id pmid_2465_1010.185 ::date 2015-02-23T16:17:29 ::annotator SDL-AMR-09 ::preferred
# ::snt In the early 1990s, the MAPK pathway and the PI3K pathway were known to be downstream of Ras (<ce:cross-ref id="crosref0325" refid="fig1">Figure 1</ce:cross-ref>).
# ::save-date Fri Mar 13, 2015 ::file pmid_2465_1010_185.txt
(k / know-01
      :ARG1 (b / be-located-at-91
            :ARG1 (a / and
                  :op1 (p / pathway :name (n / name :op1 "MAPK"))
                  :op2 (p2 / pathway :name (n3 / name :op1 "PI3K")))
            :ARG2 (r / relative-position
                  :op1 (e2 / enzyme :name (n2 / name :op1 "Ras"))
                  :direction (d3 / downstream)))
      :time (e / early
            :op1 (d / date-entity :decade 1990))
      :ARG1-of (d2 / describe-01
            :ARG0 (f / figure :mod 1)))

# ::id pmid_2465_1010.186 ::date 2015-02-23T16:43:14 ::annotator SDL-AMR-09 ::preferred
# ::snt In 1993, four groups showed that Ras binds directly to Raf kinase (<ce:cross-refs id="crosrefs0040" refid="bib47 bib73 bib77 bib85">Moodie et al., 1993; Van Aelst et al., 1993; Warne et al., 1993; Zhang et al., 1993</ce:cross-refs>), and later, activation of Raf kinase by Ras was achieved in vitro (<ce:cross-ref id="crosref0330" refid="bib66">Stokoe and McCormick, 1997</ce:cross-ref>).
# ::save-date Fri Jul 24, 2015 ::file pmid_2465_1010_186.txt
(a / and
      :op1 (s / show-01
            :ARG0 (g / group :quant 4)
            :ARG1 (b / bind-01
                  :ARG0 (e / enzyme :name (n / name :op1 "Ras"))
                  :ARG1 (k / kinase :name (n2 / name :op1 "Raf"))
                  :ARG1-of (d2 / direct-02))
            :time (d / date-entity :year 1993)
            :ARG1-of (d3 / describe-01
                  :ARG0 (a5 / and
                        :op1 (p / publication-91
                              :ARG0 (a4 / and
                                    :op1 (p2 / person :name (n3 / name :op1 "Moodie"))
                                    :op2 (p3 / person
                                          :mod (o / other)))
                              :time (d4 / date-entity :year 1993))
                        :op2 (p4 / publication-91
                              :ARG0 (a6 / and
                                    :op1 (p5 / person :name (n4 / name :op1 "Van" :op2 "Aelst"))
                                    :op2 (p6 / person
                                          :mod (o2 / other)))
                              :time d4)
                        :op3 (p7 / publication-91
                              :ARG0 (a7 / and
                                    :op1 (p8 / person :name (n5 / name :op1 "Warne"))
                                    :op2 (p9 / person
                                          :mod (o3 / other)))
                              :time d4)
                        :op4 (p10 / publication-91
                              :ARG0 (a8 / and
                                    :op1 (p11 / person :name (n6 / name :op1 "Zhang"))
                                    :op2 (p12 / person
                                          :mod (o4 / other)))
                              :time d4))))
      :op2 (a2 / activate-01
            :ARG0 e
            :ARG1 k
            :ARG1-of (a3 / achieve-01
                  :manner (i / in-vitro))
            :time (l / late
                  :degree (m / more))
            :ARG1-of (d5 / describe-01
                  :ARG0 (p13 / publication-91
                        :ARG0 (a9 / and
                              :op1 (p14 / person :name (n7 / name :op1 "Stokoe"))
                              :op2 (p15 / person :name (n8 / name :op1 "McCormick")))
                        :time (d6 / date-entity :year 1997)))))

# ::id pmid_2465_1010.187 ::date 2015-02-23T16:55:30 ::annotator SDL-AMR-09 ::preferred
# ::snt This was unexpectedly difficult; for one thing, Raf activation by Ras required fully processed Ras in a lipid environment, and direct binding of unprocessed Ras failed to activate the kinase.
# ::save-date Mon Dec 21, 2015 ::file pmid_2465_1010_187.txt
(m / multi-sentence
      :snt1 (d / difficult
            :domain (t / this)
            :ARG1-of (e3 / expect-01 :polarity -))
      :snt2 (a3 / and :li 1
            :op1 (r / require-01
                  :ARG0 (a / activate-01
                        :ARG0 e2
                        :ARG1 (k / kinase :name (n / name :op1 "Raf")))
                  :ARG1 (p / process-01
                        :ARG1 e2
                        :degree (f / full))
                  :location (e4 / environment
                        :mod (l / lipid)))
            :op2 (f2 / fail-01
                  :ARG1 (b / bind-01
                        :ARG1 (e2 / enzyme :name (n2 / name :op1 "Ras")
                              :ARG1-of (p2 / process-01 :polarity -))
                        :ARG1-of (d2 / direct-02))
                  :ARG2 (a2 / activate-01
                        :ARG0 b
                        :ARG1 k))))

# ::id pmid_2465_1010.188 ::date 2015-02-23T17:15:35 ::annotator SDL-AMR-09 ::preferred
# ::snt Furthermore, autophosphorylation rapidly shut down Raf kinase in vitro; we had to preincubate processed Ras with Raf in the absence of ATP before measuring Raf kinase activity.
# ::save-date Tue Feb 2, 2016 ::file pmid_2465_1010_188.txt
(a4 / and
      :op2 (c / cause-01
            :ARG0 (s2 / shut-down-05
                  :ARG1 (k / kinase :name (n3 / name :op1 "Raf"))
                  :ARG2 (p / phosphorylate-01
                        :ARG1 k
                        :ARG2 k)
                  :manner (r / rapid)
                  :manner (i / in-vitro))
            :ARG1 (o / obligate-01
                  :ARG1 (w / we)
                  :ARG2 (p2 / preincubate-01
                        :ARG0 w
                        :ARG1 (a / and
                              :op1 (e2 / enzyme :name (n2 / name :op1 "Ras")
                                    :ARG1-of (p3 / process-01))
                              :op2 k)
                        :condition (a3 / absent-01
                              :ARG1 (s / small-molecule :name (n4 / name :op1 "ATP")))
                        :time (b / before
                              :op1 (m2 / measure-01
                                    :ARG0 w
                                    :ARG1 (a2 / activity-06
                                          :ARG0 k)))))))

# ::id pmid_2465_1010.189 ::date 2015-02-23T17:19:03 ::annotator SDL-AMR-09 ::preferred
# ::snt This autophosphorylation accounts, at least in part, for paradoxical activation of Raf kinase by Raf inhibitors, a phenomenon that was discovered 16 years later (reviewed in <ce:cross-ref id="crosref0335" refid="bib27">Holderfield et al., 2013</ce:cross-ref>).
# ::save-date Fri Feb 26, 2016 ::file pmid_2465_1010_189.txt
(a4 / account-01
      :ARG0 (p / phosphorylate-01
            :mod (s / self)
            :mod (t3 / this))
      :ARG1 (a2 / activate-01
            :ARG0 (m2 / molecular-physical-entity
                  :ARG0-of (i2 / inhibit-01
                        :ARG1 k))
            :ARG1 (k / kinase :name (n2 / name :op1 "Raf"))
            :manner (p3 / paradox))
      :extent (p7 / part
            :mod (a / at-least))
      :ARG1-of (d2 / discover-01
            :mod (l / late
                  :degree (m / more
                        :quant (t / temporal-quantity :quant 16
                              :unit (y / year)))))
      :ARG1-of (r / review-02
            :ARG2 (p4 / publication-91
                  :ARG0 (a3 / and
                        :op1 (p5 / person :name (n3 / name :op1 "Holderfield"))
                        :op1 (p6 / person
                              :mod (o / other)))
                  :time (d / date-entity :year 2013))))

# ::id pmid_2465_1010.190 ::date 2015-02-23T19:26:24 ::annotator SDL-AMR-09 ::preferred
# ::snt These issues complicate the development of in vitro assays for compounds that prevent Ras-dependent activation of Raf kinase, an obvious system for therapeutic intervention.
# ::save-date Fri Nov 13, 2015 ::file pmid_2465_1010_190.txt
(c / complicate-01
      :ARG0 (i / issue-02
            :mod (t / this))
      :ARG1 (d / develop-02
            :ARG1 (a / assay-01
                  :ARG1 (c2 / compound
                        :ARG0-of (p / prevent-01
                              :ARG1 (a2 / activate-01
                                    :ARG1 (k / kinase :name (n / name :op1 "Raf"))
                                    :ARG0-of (d2 / depend-01
                                          :ARG1 (e2 / enzyme :name (n2 / name :op1 "Ras"))))))
                  :manner (i2 / in-vitro))
            :mod (s / system
                  :ARG1-of (o / obvious-01)
                  :ARG0-of (i3 / intervene-01
                        :ARG1 (t2 / therapy)))))

# ::id pmid_2465_1010.191 ::date 2015-02-23T19:37:43 ::annotator SDL-AMR-09 ::preferred
# ::snt Direct blocking of Ras-Raf binding with small molecules does not appear to be a promising approach because the binding surface (two antiparallel β strands) offers no foothold in which a compound could bind.
# ::save-date Fri Jul 24, 2015 ::file pmid_2465_1010_191.txt
(a / appear-02 :polarity -
      :ARG1 (p2 / promise-01
            :ARG2 (a2 / approach
                  :domain (b / block-01
                        :ARG0 (s / small-molecule)
                        :ARG1 (b2 / bind-01
                              :ARG1 (e / enzyme :name (n / name :op1 "Ras"))
                              :ARG2 (e2 / enzyme :name (n2 / name :op1 "Raf")))
                        :ARG1-of (d / direct-02))))
      :ARG1-of (c / cause-01
            :ARG0 (o / offer-01 :polarity -
                  :ARG0 (b4 / bind-01
                        :ARG3 (s2 / surface))
                  :ARG1 (f / foothold
                        :location-of (p3 / possible-01
                              :ARG1 (b3 / bind-01
                                    :ARG1 (c3 / compound)
                                    :ARG1-of (m / mean-01
                                          :ARG2 (s3 / strand :quant 2 :name (n3 / name :op1 "β")
                                                :mod (a3 / antiparallel)))))))))

# ::id pmid_2465_1010.192 ::date 2015-02-23T19:52:41 ::annotator SDL-AMR-09 ::preferred
# ::snt However, for example, preventing binding using peptides or by indirect allosteric approaches has been considered (see <ce:cross-ref id="crosref0340" refid="bib79">Wu et al., 2013</ce:cross-ref>).
# ::save-date Fri Mar 13, 2015 ::file pmid_2465_1010_192.txt
(h2 / have-concession-91
      :ARG1 (e2 / exemplify-01
            :ARG0 (c2 / consider-01
                  :ARG1 (p / prevent-01
                        :ARG1 (b / bind-01)
                        :manner (o3 / or
                              :op1 (u / use-01
                                    :ARG1 (p5 / peptide))
                              :op2 (a / approach-02
                                    :ARG0 (m2 / molecular-physical-entity
                                          :mod (i / indirect)
                                          :mod (a3 / allosteric)))))))
      :ARG1-of (s / see-01
            :location (p2 / publication-91
                  :ARG0 (a2 / and
                        :op1 (p3 / person :name (n3 / name :op1 "Wu"))
                        :op2 (p4 / person
                              :mod (o2 / other)))
                  :time (d / date-entity :year 2013))))

# ::id pmid_2465_1010.193 ::date 2015-02-23T20:01:55 ::annotator SDL-AMR-09 ::preferred
# ::snt The drug discovery group at Onyx Pharmaceuticals began screening for Raf kinase inhibitors in 1992 after it was able produce active c-Raf kinase in baculovirus (by coinfection with v-Src) and to reconstitute the MAPK pathway in vitro (<ce:cross-ref id="crosref0345" refid="bib41">Macdonald et al., 1993</ce:cross-ref>).
# ::save-date Sun Jan 17, 2016 ::file pmid_2465_1010_193.txt
(b / begin-01
      :ARG1 (s / screen-01
            :ARG0 (g / group
                  :part-of (c / company :name (n5 / name :op1 "Onyx" :op2 "Pharmaceuticals"))
                  :ARG0-of (d3 / discover-01
                        :ARG1 (d4 / drug)))
            :ARG1 (m / molecular-physical-entity
                  :ARG0-of (i / inhibit-01
                        :ARG1 (k / kinase :name (n4 / name :op1 "Raf"))))
            :time (d / date-entity :year 1992)
            :time (a / after
                  :op1 (c2 / capable-01
                        :ARG1 g
                        :ARG2 (a4 / and
                              :op1 (p / produce-01
                                    :ARG0 g
                                    :ARG1 (e2 / enzyme :name (n2 / name :op1 "c-Raf")
                                          :ARG0-of (a2 / activity-06))
                                    :manner (c3 / coinfect-00
                                          :ARG0 (e3 / enzyme :name (n7 / name :op1 "v-Src")))
                                    :location (o / organism :name (n3 / name :op1 "baculovirus")))
                              :op2 (r / reconstitute-01
                                    :ARG0 g
                                    :ARG1 (p2 / pathway :name (n / name :op1 "MAPK"))
                                    :manner (i3 / in-vitro))))))
      :ARG1-of (d2 / describe-01
            :ARG0 (p3 / publication-91
                  :ARG0 (a3 / and
                        :op1 (p4 / person :name (n6 / name :op1 "Macdonald"))
                        :op2 (p5 / person
                              :mod (o2 / other))))
            :time (d5 / date-entity :year 1993)))

# ::id pmid_2465_1010.194 ::date 2015-02-24T05:16:39 ::annotator SDL-AMR-09 ::preferred
# ::snt It was then assumed that in cancer cells with mutant Ras, the Raf/MAPK pathway would be hyperactive and that drugs that inhibit Raf would be effective ways of treating Ras mutant cancers.
# ::save-date Fri Jan 1, 2016 ::file pmid_2465_1010_194.txt
(a / assume-02
      :ARG1 (a2 / and
            :op1 (h / hyperactive
                  :domain (p / pathway :name (n4 / name :op1 "Raf" :op2 "MAPK")))
            :op2 (t / treat-04
                  :ARG0 (d2 / drug
                        :ARG0-of (i / inhibit-01
                              :ARG1 (e2 / enzyme :name (n3 / name :op1 "Raf"))))
                  :ARG1 (d / disease :wiki "Cancer" :name (n / name :op1 "cancer")
                        :mod (m / mutate-01
                              :ARG1 (e / enzyme :name (n2 / name :op1 "Ras")))
                        :ARG0-of (h3 / have-03
                              :ARG1 m2))
                  :ARG1-of (e3 / effective-04)))
      :location (c / cell
            :mod (d3 / disease :wiki "Cancer" :name (n5 / name :op1 "cancer"))
            :ARG0-of (h2 / have-03
                  :ARG1 (m2 / mutate-01
                        :ARG1 e)))
      :time (t2 / then))

# ::id pmid_2465_1010.195 ::date 2015-02-24T05:31:21 ::annotator SDL-AMR-09 ::preferred
# ::snt It was also assumed that MEK and extracellular signal-regulated kinase (ERK) inhibitors would have the same effect.
# ::save-date Sat Jan 16, 2016 ::file pmid_2465_1010_195.txt
(a / assume-02
      :ARG1 (p / possible-01
            :ARG1 (a2 / affect-01
                  :ARG0 (a3 / and
                        :op1 (m / molecular-physical-entity
                              :ARG0-of (i2 / inhibit-01
                                    :ARG1 (p3 / protein-family :name (n / name :op1 "MEK"))))
                        :op2 (m2 / molecular-physical-entity
                              :ARG0-of (i / inhibit-01
                                    :ARG1 (p2 / protein-family :name (n2 / name :op1 "extracellular" :op2 "signal-regulated" :op3 "kinase")))))
                  :ARG1-of (s / same-01)))
      :mod (a4 / also))

# ::id pmid_2465_1010.196 ::date 2015-02-24T05:50:42 ::annotator SDL-AMR-09 ::preferred
# ::snt In hindsight, most of the assumptions were incorrect: the Raf/MAPK pathway is not often hyperactive in human cancer cells with mutant Ras, as measured by steady-state levels of phospho-MEK or phospho-ERK.
# ::save-date Thu Feb 4, 2016 ::file pmid_2465_1010_196.txt
(c2 / correct-02 :polarity -
      :ARG1 (a / assume-02
            :quant (m / most)
            :example (h / hyperactive
                  :frequency (o / often :polarity -)
                  :domain (p / pathway :name (n3 / name :op1 "Raf" :op2 "MAPK"))
                  :location (c / cell
                        :mod (d / disease :wiki "Cancer" :name (n / name :op1 "cancer")
                              :mod (h2 / human))
                        :prep-with (e / enzyme :name (n2 / name :op1 "Ras")
                              :ARG1-of (m3 / mutate-01)))
                  :ARG1-of (m2 / measure-01
                        :ARG2 (l / level
                              :degree-of (o2 / or
                                    :op1 (p2 / phosphorylate-01
                                          :ARG2 (e4 / enzyme :name (n4 / name :op1 "MEK")))
                                    :op2 (p3 / phosphorylate-01
                                          :ARG2 (e3 / enzyme :name (n5 / name :op1 "ERK"))))
                              :ARG1-of (s / steady-01
                                    :mod (s2 / state))))))
      :prep-in (h3 / hindsight))

# ::id pmid_2465_1010.197 ::date 2015-02-24T05:58:51 ::annotator SDL-AMR-09 ::preferred
# ::snt Raf inhibitors lead to paradoxical activation of Raf kinase following exposure to Raf inhibitors, especially in Ras mutant cancers (reviewed in <ce:cross-ref id="crosref0350" refid="bib39">Lito et al., 2013</ce:cross-ref>).
# ::save-date Sun Dec 20, 2015 ::file pmid_2465_1010_197.txt
(l / lead-03
      :ARG0 (m2 / molecular-physical-entity
            :ARG0-of (i2 / inhibit-01
                  :ARG1 (k2 / kinase :name (n6 / name :op1 "Raf"))))
      :ARG2 (a / activate-01
            :ARG1 k2
            :manner (p / paradox))
      :location (d2 / disease :wiki "Cancer" :name (n4 / name :op1 "cancer")
            :mod (m / mutate-01
                  :ARG1 (e / enzyme :name (n2 / name :op1 "Ras")))
            :mod (e2 / especially))
      :ARG1-of (r / review-02
            :ARG2 (p3 / publication-91
                  :ARG0 (a2 / and
                        :op1 (p4 / person :name (n5 / name :op1 "Lito"))
                        :op2 (p5 / person
                              :mod (o / other)))
                  :time (d / date-entity :year 2013)))
      :time (f / follow-01
            :ARG2 (e3 / expose-01
                  :ARG2 m2)))

# ::id pmid_2465_1010.198 ::date 2015-02-21T08:40:45 ::annotator SDL-AMR-09 ::preferred
# ::snt MEK and ERK inhibitors do not show paradoxical activation but are generally ineffective on their own because they relieve feedback inhibition on upstream kinases, leading to activation of PI3K, among other effects (<ce:cross-refs id="crosrefs0045" refid="bib45 bib12 bib72 bib46">Mirzoeva et al., 2009; Corcoran et al., 2012; Turke et al., 2012; Montero-Conde et al., 2013</ce:cross-refs>), and because they lack a clear therapeutic window.
# ::save-date Sat Jan 16, 2016 ::file pmid_2465_1010_198.txt
(c / contrast-01
      :ARG1 (s / show-01 :polarity -
            :ARG0 (m / molecular-physical-entity
                  :ARG0-of (i / inhibit-01
                        :ARG1 (a2 / and
                              :op1 (p11 / protein-family :name (n / name :op1 "MEK"))
                              :op2 (p12 / protein-family :name (n2 / name :op1 "ERK")))))
            :ARG1 (a / activate-01
                  :mod (p / paradox)))
      :ARG2 (e / effective-04 :polarity -
            :ARG0 m
            :mod (b / by-oneself)
            :ARG1-of (g / general-02)
            :ARG1-of (c2 / cause-01
                  :ARG0 (a5 / and
                        :op1 (r / relieve-01
                              :ARG0 m
                              :ARG1 (i2 / inhibit-01
                                    :subevent-of (f / feedback))
                              :ARG2 (k / kinase
                                    :location (u / upstream))
                              :ARG0-of (l / lead-03
                                    :ARG2 (a3 / activate-01
                                          :ARG1 (e4 / enzyme :name (n3 / name :op1 "PI3K"))
                                          :ARG1-of (i3 / include-91
                                                :ARG2 (a4 / affect-01
                                                      :mod (o / other)))))
                              :ARG1-of (d2 / describe-01
                                    :ARG0 (a6 / and
                                          :op1 (p2 / publication-91
                                                :ARG0 (a7 / and
                                                      :op1 (p6 / person :name (n4 / name :op1 "Mirzoeva"))
                                                      :op2 (p7 / person
                                                            :mod (o2 / other)))
                                                :time (d3 / date-entity :year 2009))
                                          :op2 (p3 / publication-91
                                                :ARG0 (a8 / and
                                                      :op1 (p8 / person :name (n5 / name :op1 "Corcoran"))
                                                      :op2 p7)
                                                :time (d4 / date-entity :year 2012))
                                          :op3 (p4 / publication-91
                                                :ARG0 (a9 / and
                                                      :op1 (p9 / person :name (n6 / name :op1 "Turke"))
                                                      :op2 p7)
                                                :time d4)
                                          :op4 (p5 / publication-91
                                                :ARG0 (a10 / and
                                                      :op1 (p10 / person :name (n7 / name :op1 "Montero-Conde"))
                                                      :op2 p7)
                                                :time (d5 / date-entity :year 2013)))))
                        :op2 (l2 / lack-01
                              :ARG0 m
                              :ARG1 (w / window
                                    :ARG1-of (c3 / clear-06)
                                    :mod (t / therapy)))))))

# ::id pmid_2465_1010.199 ::date 2015-02-21T10:06:31 ::annotator SDL-AMR-09 ::preferred
# ::snt MEK1/MEK2 isoforms have a high degree of amino acid identity, suggesting redundant roles in signaling.
# ::save-date Sun Jul 26, 2015 ::file pmid_2465_1010_199.txt
(i4 / identical-01
      :ARG1 (s / slash
            :op1 (i / isoform
                  :mod (e / enzyme :name (n / name :op1 "MEK1")))
            :op2 (i3 / isoform
                  :mod (e2 / enzyme :name (n2 / name :op1 "MEK2"))))
      :ARG2 (a / amino-acid)
      :ARG1-of (h / high-02)
      :ARG0-of (s2 / suggest-01
            :ARG1 (p / play-08
                  :ARG0 s
                  :ARG1 (s3 / signal-07)
                  :mod (r / redundant))))

# ::id pmid_2465_1010.200 ::date 2015-02-21T11:28:34 ::annotator SDL-AMR-09 ::preferred
# ::snt The same is true for ERK1/ERK2.
# ::save-date Wed Nov 4, 2015 ::file pmid_2465_1010_200.txt
(t / true-01
      :ARG1 (t2 / thing
            :ARG1-of (s / same-01))
      :ARG2 (s2 / slash
            :op1 (e / enzyme :name (n / name :op1 "ERK1"))
            :op2 (e2 / enzyme :name (n2 / name :op1 "ERK2"))))

# ::id pmid_2465_1010.201 ::date 2015-02-21T12:00:31 ::annotator SDL-AMR-09 ::preferred
# ::snt However, knocking out the gene encoding MEK1, <i>Map2k1</i> (<ce:cross-ref id="crosref0355" refid="bib22">Giroux et al., 1999</ce:cross-ref>), or the gene encoding ERK2, <i>Mapk1</i> (<ce:cross-refs id="crosrefs0050" refid="bib26 bib57 bib82">Hatano et al., 2003; Saba-El-Leil et al., 2003; Yao et al., 2003</ce:cross-refs>), is embryonic lethal, indicating a requirement for signaling from a particular isoform, at least in the context of embryogenesis.
# ::save-date Thu Feb 26, 2015 ::file pmid_2465_1010_201.txt
(c2 / contrast-01
      :ARG2 (c / cause-01
            :ARG0 (k / knock-out-03
                  :ARG1 (o / or
                        :op1 (g / gene :name (n / name :op1 "Map2k1")
                              :ARG0-of (e / encode-01
                                    :ARG1 (e2 / enzyme :name (n2 / name :op1 "MEK1")))
                              :ARG1-of (d2 / describe-01
                                    :ARG0 (p2 / publication-91
                                          :ARG0 (a2 / and
                                                :op1 (p4 / person :name (n5 / name :op1 "Giroux"))
                                                :op2 (p3 / person
                                                      :mod (o2 / other)))
                                          :time (d3 / date-entity :year 1999))))
                        :op2 (g2 / gene :name (n3 / name :op1 "Mapk1")
                              :ARG0-of (e3 / encode-01
                                    :ARG1 (e4 / enzyme :name (n4 / name :op1 "ERK2")))
                              :ARG1-of (d4 / describe-01
                                    :ARG0 (a3 / and
                                          :op1 (p5 / publication-91
                                                :ARG0 (a4 / and
                                                      :op1 (p8 / person :name (n6 / name :op1 "Hatano"))
                                                      :op2 p3)
                                                :time (d5 / date-entity :year 2003))
                                          :op2 (p6 / publication-91
                                                :ARG0 (a5 / and
                                                      :op1 (p9 / person :name (n7 / name :op1 "Saba-El-Leil"))
                                                      :op2 p3)
                                                :time d5)
                                          :op3 (p7 / publication-91
                                                :ARG0 (a6 / and
                                                      :op1 (p10 / person :name (n8 / name :op1 "Yao"))
                                                      :op2 p3)
                                                :time d5))))))
            :ARG1 (d / die-01
                  :ARG1 (e5 / embryo))
            :ARG0-of (i / indicate-01
                  :ARG1 (r / require-01
                        :ARG1 (s / signal-07
                              :ARG0 i2)
                        :ARG2 (i2 / isoform
                              :mod (p / particular))
                        :condition (e6 / embryogenesis
                              :mod (a / at-least))))))

# ::id pmid_2465_1010.202 ::date 2015-02-21T12:41:19 ::annotator SDL-AMR-09 ::preferred
# ::snt Although <i>Map2k2</i><sup loc="post"><i>−/−</i></sup> (MEK2 null) and <i>Mapk3</i><sup loc="post"><i>−/−</i></sup> (ERK1 null) mice are viable, in vivo ablation of MEK1 in a <i>Map2k2</i><sup loc="post"><i>−/−</i></sup> background (<ce:cross-refs id="crosrefs0055" refid="bib60 bib5">Scholl et al., 2007; Blasco et al., 2011</ce:cross-refs>) or ERK2 in a <i>Mapk3</i><sup loc="post"><i>−/−</i></sup> background (<ce:cross-ref id="crosref0360" refid="bib9">Chan et al., 2013</ce:cross-ref>) results in apoptosis and lethality in adult mice.
# ::save-date Thu Feb 26, 2015 ::file pmid_2465_1010_202.txt
(h / have-concession-91
      :ARG1 (r / result-01
            :ARG1 (o / or
                  :op1 (a2 / ablate-01
                        :ARG1 (e3 / enzyme :name (n7 / name :op1 "MEK1"))
                        :manner (i / in-vivo)
                        :location (b / background
                              :mod g)
                        :ARG1-of (d / describe-01
                              :ARG0 (a6 / and
                                    :op1 (p / publication-91
                                          :ARG0 (a7 / and
                                                :op1 (p3 / person :name (n9 / name :op1 "Scholl"))
                                                :op2 (p4 / person
                                                      :mod (o2 / other)))
                                          :time (d2 / date-entity :year 2007))
                                    :op2 (p2 / publication-91
                                          :ARG0 (a8 / and
                                                :op1 (p5 / person :name (n10 / name :op1 "Blasco"))
                                                :op2 p4)
                                          :time (d3 / date-entity :year 2011)))))
                  :op2 (a3 / ablate-01
                        :ARG1 (e4 / enzyme :name (n8 / name :op1 "ERK2"))
                        :manner i
                        :location (b2 / background
                              :mod g2)
                        :ARG1-of (d4 / describe-01
                              :ARG0 (p7 / publication-91
                                    :ARG0 (a9 / and
                                          :op1 (p8 / person :name (n11 / name :op1 "Chan"))
                                          :op2 p4)
                                    :time (d5 / date-entity :year 2013)))))
            :ARG2 (a4 / and
                  :op1 (a5 / apoptosis
                        :mod m5)
                  :op2 (d6 / die-01
                        :ARG1 (m5 / mouse
                              :mod (a10 / adult)))))
      :ARG2 (v / viable
            :domain (a / and
                  :op1 (m / mouse
                        :mod (g / gene :name (n / name :op1 "Map2k2−/−")
                              :ARG1-of (e5 / express-03 :polarity -
                                    :ARG2 (e / enzyme :name (n3 / name :op1 "MEK2")))))
                  :op2 (m2 / mouse
                        :mod (g2 / gene :name (n2 / name :op1 "Mapk3−/−")
                              :ARG1-of (e6 / express-03 :polarity -
                                    :ARG2 (e2 / enzyme :name (n5 / name :op1 "ERK1"))))))))

# ::id pmid_2465_1010.203 ::date 2015-02-21T13:21:26 ::annotator SDL-AMR-09 ::preferred
# ::snt This may suggest a limited therapeutic window for any pan inhibitor of these kinases, and the clinical toxicity of potential drugs in this target class bears this out.
# ::save-date Mon Mar 16, 2015 ::file pmid_2465_1010_203.txt
(a / and
      :op1 (p / possible-01
            :ARG1 (s / suggest-01
                  :ARG0 (t / this)
                  :ARG1 (w / window
                        :mod (t2 / therapy)
                        :ARG1-of (l / limit-01)
                        :poss (m / molecular-physical-entity
                              :mod (p2 / pan)
                              :ARG0-of (i / inhibit-01
                                    :ARG1 (k / kinase
                                          :mod (t3 / this)))))))
      :op2 (b / bear-out-05
            :ARG0 (t4 / toxic
                  :mod (c / clinic)
                  :domain (d / drug
                        :mod (p3 / potential)
                        :ARG1-of (i2 / include-91
                              :ARG2 (c2 / class
                                    :ARG1-of (t5 / target-01)))))
            :ARG1 p))

# ::id pmid_2465_1010.204 ::date 2015-02-21T22:09:03 ::annotator SDL-AMR-09 ::preferred
# ::snt The Onyx/Bayer screen for c-Raf inhibitors led to the discovery and development of sorafenib.
# ::save-date Sat Feb 21, 2015 ::file pmid_2465_1010_204.txt
(l / lead-03
      :ARG0 (s / screen-01
            :ARG0 (s2 / slash
                  :op1 (c / company :name (n / name :op1 "Onyx"))
                  :op2 (c2 / company :name (n2 / name :op1 "Bayer")))
            :ARG2 (m / molecular-physical-entity
                  :ARG0-of (i / inhibit-01
                        :ARG1 (e / enzyme :name (n3 / name :op1 "C-Raf")))))
      :ARG2 (a / and
            :op1 (d / discover-01
                  :ARG1 (s3 / small-molecule :name (n4 / name :op1 "sorafenib")))
            :op2 (d2 / develop-02
                  :ARG1 s3)))

# ::id pmid_2465_1010.205 ::date 2015-02-21T22:38:00 ::annotator SDL-AMR-09 ::preferred
# ::snt However, it was disappointing when sorafenib failed to show clinical benefit in early clinical trials against Ras mutant cancers, and this lack of response was difficult to understand because sorafenib does indeed inhibit Raf kinase.
# ::save-date Fri Dec 18, 2015 ::file pmid_2465_1010_205.txt
(h / have-concession-91
      :ARG1 (a / and
            :op1 (d / disappoint-01
                  :ARG0 (s2 / show-01 :polarity -
                        :ARG0 (s3 / small-molecule :wiki "Sorafenib"
                              :name (n / name :op1 "sorafenib"))
                        :ARG1 (b / benefit-01
                              :ARG0 s3
                              :mod (c / clinic))
                        :time (t / trial-06
                              :mod c
                              :time (e / early)
                              :purpose (c2 / counter-01
                                    :ARG1 (d3 / disease :wiki "Cancer"
                                          :name (n4 / name :op1 "cancer")
                                          :mod (e2 / enzyme :wiki "Ras_subfamily"
                                                :name (n2 / name :op1 "Ras")
                                                :ARG2-of (m / mutate-01)))))))
            :op2 (d2 / difficult
                  :domain (u / understand-01
                        :ARG1 (l / lack-01
                              :ARG1 (r / respond-01)
                              :mod (t2 / this)))
                  :ARG1-of (c3 / cause-01
                        :ARG0 (i / inhibit-01
                              :ARG0 s3
                              :ARG1 (k / kinase :wiki "RAF_kinase"
                                    :name (n3 / name :op1 "Raf"))
                              :mod (i2 / indeed))))))

# ::id pmid_2465_1010.206 ::date 2015-02-22T01:00:29 ::annotator SDL-AMR-09 ::preferred
# ::snt Despite this, sorafenib and fluoro-sorafenib (regorafenib) have since been approved for the treatment of renal cell carcinoma, hepatocellular carcinoma, thyroid cancer, colorectal cancer, and gastrointestinal stromal cancer.
# ::save-date Thu Dec 10, 2015 ::file pmid_2465_1010_206.txt
(h / have-concession-91
      :ARG1 (a / approve-01
            :ARG1 (a2 / and
                  :op1 (s2 / small-molecule :name (n / name :op1 "sorafenib"))
                  :op2 (s3 / small-molecule :name (n2 / name :op1 "fluoro-sorafenib")
                        :ARG1-of (m / mean-01
                              :ARG2 (s4 / small-molecule :name (n3 / name :op1 "regorafenib")))))
            :ARG2 (t2 / treat-03
                  :ARG2 (a3 / and
                        :op1 (c / carcinoma
                              :mod (c2 / cell
                                    :mod (k / kidney)))
                        :op2 (c3 / carcinoma
                              :mod (h2 / hepatocellular))
                        :op3 (d / disease :wiki "Thyroid_cancer" :name (n4 / name :op1 "thyroid" :op2 "cancer"))
                        :op4 (d2 / disease :wiki "Colorectal_cancer" :name (n5 / name :op1 "colorectal" :op2 "cancer"))
                        :op5 (d3 / disease :wiki "Cancer" :name (n6 / name :op1 "cancer")
                              :mod (s5 / stroma
                                    :mod (g / gastrointestinal)))))
            :time (s / since))
      :ARG2 (t / this))

# ::id pmid_2465_1010.207 ::date 2015-02-22T01:27:11 ::annotator SDL-AMR-09 ::preferred
# ::snt In hepatocellular carcinoma, biomarker analysis in Phase II clinical trials showed a clear correlation between levels of phospho-ERK and clinical response, suggesting that inhibition of Raf kinase is responsible for part of the clinical benefit (<ce:cross-ref id="crosref0365" refid="bib1">Abou-Alfa et al., 2006</ce:cross-ref>), but in the other indications, it appears likely that inhibition of vascular endothelial growth factor receptor 2 or other kinases is responsible.
# ::save-date Sun Jan 17, 2016 ::file pmid_2465_1010_207.txt
(c / contrast-01
      :ARG1 (s / show-01
            :ARG0 (a / analyze-01
                  :ARG1 (b / biomarker))
            :ARG1 (c3 / correlate-01
                  :ARG1 (l / level
                        :degree-of (e / enzyme :name (n / name :op1 "ERK")
                              :ARG3-of (p2 / phosphorylate-01)))
                  :ARG2 (r / respond-01
                        :mod c2)
                  :ARG1-of (c4 / clear-06))
            :subevent-of (t / trial-06
                  :mod (c2 / clinic)
                  :mod (p / phase
                        :ord (o / ordinal-entity :value 2)))
            :ARG0-of (s2 / suggest-01
                  :ARG1 (r2 / responsible-01
                        :ARG0 (i / inhibit-01
                              :ARG1 (k / kinase :name (n2 / name :op1 "Raf")))
                        :ARG1 (b2 / benefit-01
                              :mod (c5 / clinic)
                              :degree (p3 / part))))
            :ARG1-of (d / describe-01
                  :ARG0 (p4 / publication-91
                        :ARG0 (a2 / and
                              :op1 (p5 / person :name (n3 / name :op1 "Abou-Alfa"))
                              :op2 (p6 / person
                                    :mod (o2 / other)))
                        :time (d2 / date-entity :year 2006)))
            :condition (c6 / carcinoma
                  :mod (h2 / hepatocellular)))
      :ARG2 (a3 / appear-02
            :ARG1 (l2 / likely-01
                  :ARG1 (r3 / responsible-01
                        :ARG0 (i3 / inhibit-01
                              :ARG1 (o4 / or
                                    :op1 (e3 / enzyme :name (n4 / name :op1 "vascular" :op2 "endothelial" :op3 "growth" :op4 "factor" :op5 "receptor" :op6 "2"))
                                    :op2 (k3 / kinase
                                          :mod (o5 / other))))
                        :ARG1 b2))
            :condition (i2 / indicate-101
                  :mod (o3 / other))))

# ::id pmid_2465_1010.208 ::date 2015-02-22T08:58:46 ::annotator SDL-AMR-09 ::preferred
# ::snt Hopefully, a clearer picture will emerge through analysis of exceptional responders or through deciphering mechanisms of drug resistance.
# ::save-date Fri Jan 1, 2016 ::file pmid_2465_1010_208.txt
(e / emerge-01
      :ARG0 (p / picture
            :ARG1-of (c / clear-06
                  :degree (m / more)))
      :ARG1 (o / or
            :op1 (a / analyze-01
                  :ARG1 (t / thing
                        :ARG0-of (r / respond-01)
                        :mod (e2 / exceptional)))
            :op2 (d / decipher-01
                  :ARG1 (m2 / mechanism
                        :mod (r2 / resist-01
                              :ARG1 (d2 / drug)))))
      :ARG1-of (h / hopeful-03))

# ::id pmid_2465_1010.209 ::date 2015-02-22T09:17:41 ::annotator SDL-AMR-09 ::preferred
# ::snt Inhibitors of PI3K pathway have not yet fared much better in the clinic, also because of feedback mechanisms that activate upstream signaling, as well as poor therapeutic index.
# ::save-date Fri Dec 18, 2015 ::file pmid_2465_1010_209.txt
(c / cause-01
      :ARG0 (a / and
            :op1 (m4 / mechanism
                  :mod (f2 / feedback)
                  :ARG0-of (a2 / activate-01
                        :ARG1 (s / signal-07
                              :source (u / upstream)))
                  :mod (a3 / also))
            :op2 (i2 / index
                  :mod (t / therapy)
                  :mod (p2 / poor)))
      :ARG1 (f / fare-01 :polarity -
            :ARG0 (m3 / molecular-physical-entity
                  :ARG0-of (i / inhibit-01
                        :ARG1 (p / pathway :name (n / name :op1 "PI3K"))))
            :ARG1-of (g / good-02
                  :degree (m / more
                        :quant (m2 / much)))
            :location (c2 / clinic)
            :time (y / yet)))

# ::id pmid_2465_1010.210 ::date 2015-02-22T09:42:33 ::annotator SDL-AMR-09 ::preferred
# ::snt However, the relative failure of these downstream approaches does not mean that they are not critical to Ras oncogenesis.
# ::save-date Thu Dec 10, 2015 ::file pmid_2465_1010_210.txt
(c2 / contrast-01
      :ARG2 (m / mean-01 :polarity -
            :ARG1 (f / fail-01
                  :ARG1 (a / approach-02
                        :mod (t / this)
                        :mod (d / downstream))
                  :ARG2-of (r / relative-05))
            :ARG2 (c / critical-02 :polarity -
                  :ARG1 a
                  :ARG2 (c3 / cause-01
                        :ARG0 (e / enzyme :name (n / name :op1 "Ras"))
                        :ARG1 (d2 / disease :wiki "Cancer" :name (n2 / name :op1 "cancer"))))))

# ::id pmid_2465_1010.211 ::date 2015-02-22T10:03:43 ::annotator SDL-AMR-09 ::preferred
# ::snt Indeed, ablation of c-Raf (but not B-Raf) in mice inhibits development and delays progression of Ras-driven tumors in a lung adenocarcinoma model (<ce:cross-ref id="crosref0370" refid="bib5">Blasco et al., 2011</ce:cross-ref>).
# ::save-date Fri Mar 13, 2015 ::file pmid_2465_1010_211.txt
(a / and
      :op1 (i / inhibit-01
            :ARG0 (a2 / ablate-01
                  :ARG1 (e / enzyme :name (n / name :op1 "C-Raf"))
                  :location (m / mouse)
                  :ARG1-of (c / contrast-01
                        :ARG2 (a5 / ablate-01 :polarity -
                              :ARG1 (e2 / enzyme :name (n2 / name :op1 "B-Raf")))))
            :ARG1 (d2 / develop-01
                  :ARG1 m2
                  :ARG2 t))
      :op2 (d / delay-01
            :ARG0 a2
            :ARG1 (p / progress-01
                  :ARG1 (t / tumor
                        :ARG1-of (d3 / drive-02
                              :ARG0 (e3 / enzyme :name (n3 / name :op1 "Ras"))))
                  :location (m2 / model
                        :topic (a3 / adenocarcinoma
                              :mod (l / lung)))))
      :mod (i2 / indeed)
      :ARG1-of (d4 / describe-01
            :ARG0 (p2 / publication-91
                  :ARG0 (a4 / and
                        :op1 (p3 / person :name (n4 / name :op1 "Blasco"))
                        :op2 (p4 / person
                              :mod (o / other)))
                  :time (d5 / date-entity :year 2011))))

# ::id pmid_2465_1010.212 ::date 2015-02-22T10:22:39 ::annotator SDL-AMR-09 ::preferred
# ::snt However, in an in vivo pancreatic cancer mouse model, B-Raf was shown to be required for tumor progression (<ce:cross-ref id="crosref0375" refid="bib65">Sobczak et al., 2008</ce:cross-ref>).
# ::save-date Fri Jan 1, 2016 ::file pmid_2465_1010_212.txt
(c2 / contrast-01
      :ARG2 (s / show-01
            :ARG1 (r / require-01
                  :ARG0 (p / progress-01
                        :ARG1 (t / tumor))
                  :ARG1 (e / enzyme :name (n / name :op1 "B-Raf")))
            :condition (m / model
                  :mod (m2 / mouse)
                  :mod (i / in-vivo)
                  :topic (d3 / disease :wiki "Pancreatic_cancer" :name (n4 / name :op1 "pancreatic" :op2 "cancer")))
            :ARG1-of (d / describe-01
                  :ARG0 (p3 / publication-91
                        :ARG0 (a / and
                              :op1 (p4 / person :name (n2 / name :op1 "Sobczak"))
                              :op2 (p5 / person
                                    :mod (o / other)))
                        :time (d2 / date-entity :year 2008)))))

# ::id pmid_2465_1010.213 ::date 2015-02-22T11:21:14 ::annotator SDL-AMR-09 ::preferred
# ::snt This suggests tissue-specific signaling cascades and will require more investigation.
# ::save-date Mon Dec 21, 2015 ::file pmid_2465_1010_213.txt
(a / and
      :op1 (s / suggest-01
            :ARG0 (t / this)
            :ARG1 (c / cascade
                  :subevent (s2 / signal-07)
                  :ARG1-of (s3 / specific-02
                        :ARG2 (t2 / tissue))))
      :op2 (r / require-01
            :ARG0 t
            :ARG1 (i / investigate-01
                  :degree (m / more))))

# ::id pmid_2465_1010.214 ::date 2015-02-22T11:29:00 ::annotator SDL-AMR-09 ::preferred
# ::snt Genetic disruption of Ras binding to PI3K-α has a similar effect.
# ::save-date Sun Feb 22, 2015 ::file pmid_2465_1010_214.txt
(a / affect-01
      :ARG0 (d / disrupt-01
            :ARG1 (b / bind-01
                  :ARG1 (e / enzyme :name (n / name :op1 "Ras"))
                  :ARG2 (e2 / enzyme :name (n2 / name :op1 "PI3K-α")))
            :mod (g / genetic))
      :ARG1-of (r / resemble-01))

# ::id pmid_2465_1010.215 ::date 2015-02-22T11:38:20 ::annotator SDL-AMR-09 ::preferred
# ::snt We can therefore assume that small molecules that can block downstream signaling without triggering feedback and with the correct specificity and biochemical properties may still be effective, but more work needs to be done to develop such compounds effectively.
# ::save-date Fri Jan 1, 2016 ::file pmid_2465_1010_215.txt
(h / have-concession-91
      :ARG1 (n / need-01
            :ARG1 (w2 / work-01
                  :degree (m2 / more)
                  :purpose (d2 / develop-02
                        :ARG0 w
                        :ARG1 (c2 / compound
                              :mod (s5 / such))
                        :ARG1-of (e2 / effective-04))))
      :ARG2 (i / infer-01
            :ARG1 (p / possible-01
                  :ARG1 (a / assume-02
                        :ARG0 (w / we)
                        :ARG1 (p2 / possible-01
                              :ARG1 (e / effective-04
                                    :ARG0 (m / molecule
                                          :mod (s / small)
                                          :ARG0-of (b / block-01
                                                :ARG1 (s2 / signal-07
                                                      :source (d / downstream))
                                                :manner (t / trigger-01 :polarity -
                                                      :ARG0 m
                                                      :ARG1 (f / feedback))
                                                :ARG1-of (p4 / possible-01))
                                          :ARG0-of (h2 / have-03
                                                :ARG1 (a2 / and
                                                      :op1 (s3 / specificity
                                                            :ARG1-of (c / correct-02))
                                                      :op2 (p3 / property
                                                            :mod (b2 / biochemical)
                                                            :ARG1-of c))))
                                    :mod (s4 / still)))))))

# ::id pmid_2465_1010.216 ::date 2015-02-22T11:58:37 ::annotator SDL-AMR-09 ::preferred
# ::snt The third direct effector arm of Ras signaling that plays a major role in human cancer is the RalGDS (Ral guanine nucleotide dissociation stimulator) pathway (<ce:cross-ref id="crosref0380" refid="fig1">Figure 1</ce:cross-ref>).
# ::save-date Wed Jan 13, 2016 ::file pmid_2465_1010_216.txt
(a / arm
      :mod (e / effector
            :ARG1-of (d3 / direct-02))
      :poss (s / signal-07
            :ARG0 (e2 / enzyme :name (n2 / name :op1 "Ras")))
      :ord (o / ordinal-entity :value 3)
      :ARG0-of (p2 / play-08
            :ARG1 (d / disease :wiki "Cancer" :name (n3 / name :op1 "cancer")
                  :mod (h / human))
            :ARG1-of (m / major-02))
      :domain (p / protein :name (n / name :op1 "RalGDS"))
      :ARG1-of (d2 / describe-01
            :ARG0 (f / figure :mod 1)))

# ::id pmid_2465_1010.217 ::date 2015-02-22T12:07:02 ::annotator SDL-AMR-09 ::preferred
# ::snt Perhaps the best evidence of the importance of this effector pathway comes from demonstration that mice null for RalGDS have reduced skin carcinogen-induced tumor incidence, size, and progression to malignancy compared to wild-type mice (<ce:cross-ref id="crosref0385" refid="bib23">González-García et al., 2005</ce:cross-ref>).
# ::save-date Wed Jan 13, 2016 ::file pmid_2465_1010_217.txt
(p / possible-01
      :ARG1 (e / evidence-01
            :ARG0 (d / demonstrate-01
                  :ARG1 (h / have-03
                        :ARG0 (m3 / mouse
                              :mod (n3 / null
                                    :mod (p7 / protein :name (n / name :op1 "RalGDS"))))
                        :ARG1 (a / and
                              :op1 (i2 / incidence
                                    :frequency-of (t / tumor
                                          :ARG2-of (i3 / induce-01
                                                :ARG0 (c2 / carcinogen))
                                          :mod (s / skin)))
                              :op2 (s2 / size
                                    :mod t)
                              :op3 (p3 / progress-01
                                    :ARG1 t
                                    :ARG4 (m2 / malignancy))
                              :ARG1-of (r / reduce-01
                                    :ARG1-of (c3 / compare-01
                                          :ARG2 (m4 / mouse
                                                :mod (w / wild-type)))))))
            :ARG1 (i / important
                  :domain (p2 / pathway
                        :mod (e2 / effector)
                        :mod (t2 / this)))
            :ARG1-of (g / good-02
                  :degree (m / most)))
      :ARG1-of (d2 / describe-01
            :ARG0 (p4 / publication-91
                  :ARG0 (a2 / and
                        :op1 (p5 / person :name (n2 / name :op1 "González-García"))
                        :op2 (p6 / person
                              :mod (o / other)))
                  :time (d3 / date-entity :year 2005))))

# ::id pmid_2465_1010.218 ::date 2015-02-22T12:30:02 ::annotator SDL-AMR-09 ::preferred
# ::snt These data, and many others (<ce:cross-refs id="crosrefs0060" refid="bib43 bib32">Martin et al., 2011; Kashatus, 2013</ce:cross-refs>), support a role for RalGDS both in vitro and in vivo as an important effector pathway utilized by oncogenic Ras to drive tumorigenesis that could potentially be exploited for therapeutic intervention, although the absence of somatic mutations in this effector pathway makes its precise role less clear than the Raf/MAPK and PI3K pathways.
# ::save-date Wed Jan 13, 2016 ::file pmid_2465_1010_218.txt
(s / support-01
      :ARG0 (a / and
            :op2 (d / data
                  :mod (t / this))
            :op2 (o / other
                  :quant (m / many))
            :ARG1-of (d2 / describe-01
                  :ARG0 (a2 / and
                        :op1 (p / publication-91
                              :ARG0 (a3 / and
                                    :op1 (p2 / person :name (n / name :op1 "Martin"))
                                    :op2 (p3 / person
                                          :mod (o2 / other)))
                              :time (d3 / date-entity :year 2011))
                        :op2 (p4 / publication-91
                              :ARG0 (p5 / person :name (n2 / name :op1 "Kashatus"))
                              :time (d4 / date-entity :year 2013)))))
      :ARG1 (a6 / and
            :op1 (p6 / play-02
                  :ARG0 (p15 / pathway :name (n3 / name :op1 "RalGDS"))
                  :ARG1 (p7 / pathway
                        :mod (e / effector)
                        :mod (i / important)
                        :ARG1-of (u / utilize-01
                              :ARG0 (e2 / enzyme :name (n4 / name :op1 "Ras")
                                    :ARG0-of (c / cause-01
                                          :ARG1 (d6 / disease :wiki "Cancer" :name (n7 / name :op1 "cancer"))))
                              :purpose (d5 / drive-02
                                    :ARG0 e2
                                    :ARG1 (c3 / create-01
                                          :ARG1 (t2 / tumor)
                                          :ARG1-of (e3 / exploit-01
                                                :ARG2 (i4 / intervene-01
                                                      :mod (t3 / therapy))
                                                :ARG1-of (p8 / possible-01)
                                                :mod (p9 / potential))))))
                  :manner (i2 / in-vitro))
            :op2 (p14 / play-02
                  :ARG0 p15
                  :ARG1 p7
                  :manner (i3 / in-vivo)))
      :concession (m2 / make-02
                  :ARG0 (a4 / absent-01
                        :ARG1 (m3 / mutate-01
                              :mod (s2 / somatic))
                        :ARG2 p7)
                  :ARG1 (p10 / play-02
                        :ARG0 p15
                        :mod (p11 / precise)
                        :ARG1-of (c4 / clear-06
                              :degree (l / less)
                              :ARG1-of (c5 / compare-01
                                    :ARG2 (a5 / and
                                          :op1 (p12 / pathway :name (n5 / name :op1 "Raf/MAPK"))
                                          :op2 (p13 / pathway :name (n6 / name :op1 "PI3K"))))))))

# ::id pmid_2465_1010.219 ::date 2015-02-22T12:54:40 ::annotator SDL-AMR-09 ::preferred
# ::snt On the other hand, Ral signaling is upstream of NF-κB and TBK1, both of which have been implicated as essential genes downstream of K-Ras (<ce:cross-refs id="crosrefs0065" refid="bib48 bib32">Neel et al., 2011; Kashatus, 2013</ce:cross-refs>).
# ::save-date Sun Jan 17, 2016 ::file pmid_2465_1010_219.txt
(c / contrast-01
      :ARG2 (b / be-located-at-91
            :ARG1 (s / signal-07
                  :ARG0 (p6 / protein :name (n / name :op1 "Ral")))
            :ARG2 (r / relative-position
                  :op1 (a / and
                        :op1 (p7 / protein :name (n2 / name :op1 "NF-κB"))
                        :op2 (e / enzyme :name (n3 / name :op1 "TBK1"))
                        :ARG1-of (i / implicate-01
                              :location (r2 / relative-position
                                    :op1 (e2 / enzyme :name (n4 / name :op1 "K-Ras"))
                                    :direction (d / downstream))
                              :prep-as (g3 / gene
                                    :mod (e3 / essential))))
                  :direction (u / upstream)))
      :ARG1-of (d2 / describe-01
            :ARG0 (a2 / and
                  :op1 (p / publication-91
                        :ARG0 (a3 / and
                              :op1 (p3 / person :name (n5 / name :op1 "Neel"))
                              :op2 (p4 / person
                                    :mod (o / other)))
                        :time (d3 / date-entity :year 2011))
                  :op2 (p2 / publication-91
                        :ARG0 (p5 / person :name (n6 / name :op1 "Kashatus"))
                        :time (d4 / date-entity :year 2013)))))

# ::id pmid_2465_1010.220 ::date 2015-02-22T13:26:44 ::annotator SDL-AMR-09 ::preferred
# ::snt Other potential Ras effectors that could be important in cancer and therefore a source of potential therapeutic targets include phospholipase CE and Tiam1, a GEF that stimulates the activation of Rac (<ce:cross-ref id="crosref0390" refid="fig1">Figure 1</ce:cross-ref>).
# ::save-date Sat Jan 16, 2016 ::file pmid_2465_1010_220.txt
(i / include-01
      :ARG1 (a / and
            :op1 (p4 / phospholipase :name (n3 / name :op1 "CE"))
            :op2 (p7 / protein :name (n4 / name :op1 "Tiam1")
                  :ARG1-of (m / mean-01
                        :ARG2 (p5 / protein :name (n5 / name :op1 "GEF")
                              :ARG0-of (s2 / stimulate-01
                                    :ARG1 (a2 / activate-01
                                          :ARG1 (p6 / protein :name (n6 / name :op1 "Rac"))))))))
      :ARG2 (e / effector
            :mod (p / potential)
            :mod (p8 / protein-family :name (n / name :op1 "Ras"))
            :mod (o / other)
            :mod (i2 / important
                  :ARG1-of (p2 / possible-01)
                  :topic (d / disease :wiki "Cancer" :name (n2 / name :op1 "cancer"))
                  :ARG0-of (c / cause-01
                        :ARG1 (s / source-02
                              :ARG0 e
                              :ARG1 (t / target-01
                                    :ARG0 (t2 / therapy)
                                    :ARG1 e
                                    :mod (p3 / potential))))))
      :ARG1-of (d2 / describe-01
            :ARG0 (f / figure :mod 1)))

# ::id pmid_2465_1010.221 ::date 2015-02-22T13:44:55 ::annotator SDL-AMR-09 ::preferred
# ::snt Rac1 is necessary for K-Ras tumor initiation, further implicating the importance of this pathway in K-Ras tumorigenesis, though not yet providing obvious therapeutic targets (<ce:cross-ref id="crosref0395" refid="bib24">Gysin et al., 2011</ce:cross-ref>).
# ::save-date Fri Nov 13, 2015 ::file pmid_2465_1010_221.txt
(n / need-01
      :ARG0 (i / initiate-01
            :ARG0 (e / enzyme :name (n3 / name :op1 "K-Ras"))
            :ARG1 (t / tumor))
      :ARG1 (p / pathway :name (n2 / name :op1 "Rac1"))
      :ARG0-of (i2 / implicate-01
            :ARG1 (i3 / important
                  :domain p
                  :topic (c / create-01
                        :ARG0 e
                        :ARG1 (t2 / tumor)))
            :concession (p2 / provide-01 :polarity -
                        :ARG0 p
                        :ARG1 (t3 / target-01
                              :ARG0 (t4 / therapy)
                              :ARG1-of (o / obvious-01))
                        :time (y / yet))
            :mod (f / further))
      :ARG1-of (d / describe-01
            :ARG0 (p3 / publication-91
                  :ARG0 (a / and
                        :op1 (p4 / person :name (n4 / name :op1 "Gysin"))
                        :op2 (p5 / person
                              :mod (o2 / other)))
                  :time (d2 / date-entity :year 2011))))

# ::id pmid_2465_1010.222 ::date 2015-02-23T09:53:14 ::annotator SDL-AMR-09 ::preferred
# ::snt Likewise, cyclin D1, NF-κB, and Myc are necessary for Ras tumorigenesis; further analysis of the role of these pathways may lead to new therapeutic insights.
# ::save-date Fri Feb 5, 2016 ::file pmid_2465_1010_222.txt
(m / multi-sentence
      :snt1 (r / require-01
            :ARG0 (c / create-01
                  :ARG0 (e / enzyme :name (n2 / name :op1 "Ras"))
                  :ARG1 (t / tumor))
            :ARG1 (a / and
                  :op1 (p / protein :name (n / name :op1 "cyclin" :op2 "D1"))
                  :op2 (p2 / protein :name (n3 / name :op1 "NF-κB"))
                  :op3 (p3 / protein :name (n4 / name :op1 "Myc")))
            :mod (l2 / likewise))
      :snt2 (p4 / possible-01
            :ARG1 (l / lead-03
                  :ARG0 (a2 / analyze-01
                        :ARG1 (r2 / role
                              :topic (p5 / pathway
                                    :mod (t2 / this)))
                        :degree (f / further))
                  :ARG2 (i / insight
                        :mod (t3 / therapy)
                        :ARG1-of (n5 / new-01)))))

# ::id pmid_2465_1010.223 ::date 2015-02-23T10:13:56 ::annotator SDL-AMR-09 ::preferred
# ::snt For example, <ce:cross-ref id="crosref0400" refid="bib53">Puyol et al. (2010)</ce:cross-ref> recently demonstrated that germline or conditional deletion of <i>Cdk4</i> led to senescence in lung cells expressing activated K-Ras.
# ::save-date Sun Jan 17, 2016 ::file pmid_2465_1010_223.txt
(d2 / demonstrate-01
      :ARG0 (p / publication-91
            :ARG0 (a / and
                  :op1 (p2 / person :name (n2 / name :op1 "Puyol"))
                  :op2 (p3 / person
                        :mod (o / other)))
            :time (d / date-entity :year 2010))
      :ARG1 (l / lead-03
            :ARG0 (o2 / or
                  :op1 (d3 / delete-01
                        :ARG0 (g / germline)
                        :ARG1 (g2 / gene :name (n4 / name :op1 "Cdk4")))
                  :op2 (d4 / delete-01
                        :ARG1 g2
                        :mod (c2 / conditional)))
            :ARG2 (s / senescence)
            :location (c3 / cell
                  :ARG3-of (e4 / express-03
                        :ARG2 (e2 / enzyme :name (n / name :op1 "K-Ras")
                              :ARG1-of (a2 / activate-01)))
                  :mod (l2 / lung)))
      :ARG0-of (e / exemplify-01)
      :time (r / recent))

# ::id pmid_2465_1010.224 ::date 2015-02-23T10:22:39 ::annotator SDL-AMR-09 ::preferred
# ::snt Furthermore, treatment with a Cdk4 inhibitor reduced the growth of K-Ras-driven tumors.
# ::save-date Sun Jan 17, 2016 ::file pmid_2465_1010_224.txt
(a / and
      :op2 (r / reduce-01
            :ARG0 (t2 / treat-04
                  :ARG2 (m / molecular-physical-entity
                        :ARG0-of (i / inhibit-01
                              :ARG1 (e2 / enzyme :name (n / name :op1 "Cdk4")))))
            :ARG1 (g / grow-01
                  :ARG1 (t3 / tumor
                        :ARG1-of (d / drive-02
                              :ARG0 (e / enzyme :name (n2 / name :op1 "K-Ras")))))))

# ::id pmid_2465_1010.225 ::date 2015-02-23T10:25:51 ::annotator SDL-AMR-09 ::preferred
# ::snt Finally, unbiased shRNA screens have revealed potential targets for K-Ras cancers.
# ::save-date Fri Oct 23, 2015 ::file pmid_2465_1010_225.txt
(r / reveal-01 :li -1
      :ARG0 (s / screen-01
            :ARG1 (n4 / nucleic-acid
                  :name (n2 / name :op1 "shRNA"))
            :ARG1-of (b / bias-01 :polarity -))
      :ARG1 (t / target-01
            :ARG1 (d / disease :wiki "Cancer"
                  :name (n3 / name :op1 "cancer")
                  :mod (e / enzyme
                        :name (n / name :op1 "K-Ras")))
            :mod (p / potential)))

# ::id pmid_2465_1010.226 ::date 2015-02-23T10:30:21 ::annotator SDL-AMR-09 ::preferred
# ::snt These include STK33, TBK1, and GATA-2.
# ::save-date Sun Jan 17, 2016 ::file pmid_2465_1010_226.txt
(i / include-01
      :ARG1 (a / and
            :op1 (e2 / enzyme :name (n / name :op1 "STK33"))
            :op2 (e / enzyme :name (n2 / name :op1 "TBK1"))
            :op3 (p3 / protein :name (n3 / name :op1 "GATA-2")))
      :ARG2 (t / this))

# ::id pmid_2465_1010.227 ::date 2015-02-23T10:32:57 ::annotator SDL-AMR-09 ::preferred
# ::snt So far, STK33 inhibition does not appear to be a useful approach to K-Ras cancers (<ce:cross-ref id="crosref0405" refid="bib78">Weiwer et al., 2012</ce:cross-ref>).
# ::save-date Mon Jul 6, 2015 ::file pmid_2465_1010_227.txt
(a / appear-02 :polarity -
      :ARG1 (a2 / approach-02
            :ARG0 (i / inhibit-01
                  :ARG1 (p / protein
                        :name (n3 / name :op1 "STK33")))
            :ARG1 (d2 / disease :wiki "Cancer"
                  :name (n2 / name :op1 "cancer")
                  :mod (e / enzyme
                        :name (n / name :op1 "K-Ras")))
            :ARG1-of (u / useful-05))
      :time (s / so-far)
      :ARG1-of (d3 / describe-01
            :ARG0 (p2 / publication-91
                  :ARG0 (a3 / and
                        :op1 (p3 / person
                              :name (n4 / name :op1 "Weiwer"))
                        :op2 (p4 / person
                              :mod (o / other)))
                  :time (d / date-entity :year 2012))))

# ::id pmid_2465_1010.228 ::date 2015-02-23T10:37:30 ::annotator SDL-AMR-09 ::preferred
# ::snt TBK1 inhibitors are still being investigated: this target is of particular interest because it is part of the well-validated RalGDS pathway.
# ::save-date Sun Jan 17, 2016 ::file pmid_2465_1010_228.txt
(m / multi-sentence
      :snt1 (i2 / investigate-01
            :ARG1 (m2 / molecular-physical-entity
                  :ARG0-of (i / inhibit-01
                        :ARG1 (e / enzyme :name (n / name :op1 "TBK1"))))
            :mod (s / still))
      :snt2 (i3 / interest-01
            :ARG2 (t / thing
                  :ARG1-of (t2 / target-01)
                  :mod (t3 / this))
            :mod (p2 / particular)
            :ARG1-of (c / cause-01
                  :ARG0 (i4 / include-91
                        :ARG1 t
                        :ARG2 (p3 / pathway :name (n2 / name :op1 "RalGDS")
                              :ARG1-of (v / validate-01
                                    :manner (w / well)))))))

# ::id pmid_2465_1010.229 ::date 2015-02-23T10:44:03 ::annotator SDL-AMR-09 ::preferred
# ::snt GATA2 is also of considerable interest; genetic ablation leads to tumor regression in mouse models of adenocarcinoma of the lung, and whereas this transcription factor may appear to be the least druggable of targets, its role in regulating the proteasome suggested therapeutic approaches that appear very promising (<ce:cross-ref id="crosref0410" refid="bib33">Kumar et al., 2012</ce:cross-ref>).
# ::save-date Thu Dec 10, 2015 ::file pmid_2465_1010_229.txt
(m / multi-sentence
      :snt1 (i / interest-01
            :ARG2 (p / protein :name (n / name :op1 "GATA2"))
            :mod (a / also)
            :degree (c / considerable))
      :snt2 (a2 / and
            :op1 (l / lead-03
                  :ARG0 (a3 / ablate-01
                        :mod (g / genetic))
                  :ARG2 (r / regress-01
                        :ARG1 (t / tumor)
                        :location (m2 / model
                              :mod (m5 / medical-condition :name (n2 / name :op1 "adenocarcinoma")
                                    :mod (l2 / lung))
                              :mod (m3 / mouse))))
            :op2 (h / have-concession-91
                  :ARG1 (s / suggest-01
                        :ARG0 (r2 / role
                              :poss f
                              :topic (r3 / regulate-01
                                    :ARG0 f
                                    :ARG1 (m4 / macro-molecular-complex :name (n3 / name :op1 "proteasome"))))
                        :ARG1 (a5 / approach-02
                              :ARG2 (t6 / therapy)
                              :ARG0-of (p4 / promise-01
                                    :degree (v / very)
                                    :ARG1-of (a6 / appear-02))))
                  :ARG2 (p2 / possible-01
                        :ARG1 (a4 / appear-02
                              :ARG1 (p3 / possible-01
                                    :ARG1 (d4 / drug-01
                                          :ARG2 (f / factor
                                                :ARG0-of (t2 / transcribe-01)
                                                :mod (t3 / this))
                                          :degree (l3 / least)
                                          :compared-to (t4 / thing
                                                :ARG0-of (t5 / target-01))))))
                  :ARG1-of (d5 / describe-01
                        :ARG0 (p5 / publication-91
                              :ARG0 (a7 / and
                                    :op1 (p6 / person :name (n4 / name :op1 "Kumar"))
                                    :op2 (p7 / person
                                          :mod (o / other)))
                              :time (d / date-entity :year 2012))))))

# ::id pmid_2465_1010.230 ::date 2015-02-23T12:05:35 ::annotator SDL-AMR-09 ::preferred
# ::snt Future Prospects
# ::save-date Sun Jul 26, 2015 ::file pmid_2465_1010_230.txt
(p / prospect-02
      :time (f / future))

# ::id pmid_2465_1010.231 ::date 2015-02-23T12:06:38 ::annotator SDL-AMR-09 ::preferred
# ::snt In this Review, we have summarized some of the challenges of targeting Ras cancers.
# ::save-date Sun Dec 20, 2015 ::file pmid_2465_1010_231.txt
(s / summarize-01
      :ARG0 (w / we)
      :ARG1 (t / thing
            :ARG1-of (i / include-91
                  :ARG2 (t2 / thing
                        :ARG0-of (c / challenge-01
                              :ARG1 (t3 / target-01
                                    :ARG1 (d / disease :wiki "Cancer" :name (n2 / name :op1 "cancer")
                                          :mod (e / enzyme :name (n / name :op1 "Ras"))))))
                  :ARG3 (s2 / some)))
      :medium (r / review
            :mod (t4 / this)))

# ::id pmid_2465_1010.232 ::date 2015-02-23T12:11:47 ::annotator SDL-AMR-09 ::preferred
# ::snt Despite the tremendous progress that has been made, we still have to learn a great deal about these cancers before we can be confident that we can treat them effectively.
# ::save-date Thu Dec 10, 2015 ::file pmid_2465_1010_232.txt
(h / have-concession-91
      :ARG1 (o / obligate-01
            :ARG2 (l / learn-01
                  :ARG0 (w / we)
                  :ARG1 (d2 / disease :wiki "Cancer" :name (n / name :op1 "cancer")
                        :mod (t / this))
                  :quant (d / deal
                        :mod (g / great))
                  :time (b / before
                        :op1 (p / possible-01
                              :ARG1 (c2 / confident-01
                                    :ARG1 w
                                    :ARG2 (p2 / possible-01
                                          :ARG1 (t2 / treat-04
                                                :ARG0 w
                                                :ARG1 d2
                                                :ARG1-of (e / effective-04))))))
                  :mod (s / still)))
      :ARG2 (p3 / progress-01
            :degree (t3 / tremendous)))

# ::id pmid_2465_1010.233 ::date 2015-02-23T12:17:12 ::annotator SDL-AMR-09 ::preferred
# ::snt Recent experience in targeting Raf and MEK has underscored how a pathway that appeared simple and linear is extremely complex and poorly understood at the level of detail required to shut it down effectively.
# ::save-date Fri Jan 1, 2016 ::file pmid_2465_1010_233.txt
(u / underscore-01
      :ARG0 (e3 / experience-01
            :ARG1 (t / target-01
                  :ARG1 (a / and
                        :op1 (e / enzyme :name (n / name :op1 "Raf"))
                        :op2 (e2 / enzyme :name (n2 / name :op1 "MEK"))))
            :time (r / recent))
      :ARG1 (t2 / thing
            :manner-of (a2 / and
                  :op1 (c / complex
                        :degree (e4 / extreme)
                        :domain (p / pathway
                              :ARG1-of (s / simple-02)
                              :mod (l / linear)
                              :ARG1-of (a3 / appear-02)))
                  :op2 (u2 / understand-01
                        :ARG1 p
                        :ARG2 (l2 / level
                              :mod (d / detail-01
                                    :ARG1-of (r2 / require-01
                                          :ARG0 (s2 / shut-down-05
                                                :ARG1 p
                                                :ARG1-of (e5 / effective-04)))))
                        :degree (p2 / poor)))))

# ::id pmid_2465_1010.234 ::date 2015-02-23T13:53:46 ::annotator SDL-AMR-09 ::preferred
# ::snt Nobody expected that Raf inhibitors would activate Raf kinase in Ras-transformed cells, for example, or that inhibition of downstream kinases like MEK would lead to activation of upstream signaling.
# ::save-date Thu Feb 4, 2016 ::file pmid_2465_1010_234.txt
(e4 / expect-01 :polarity -
      :ARG0 (a / anybody)
      :ARG1 (o / or
            :op1 (a2 / activate-01
                  :ARG0 (m / molecular-physical-entity
                        :ARG0-of (i / inhibit-01
                              :ARG1 (k / kinase :name (n / name :op1 "Raf")))
                        :ARG0-of (a3 / activate-01
                              :ARG1 k
                              :location (c / cell
                                    :ARG1-of (t2 / transform-01
                                          :ARG0 (e6 / enzyme :name (n4 / name :op1 "Ras"))))))
                  :ARG0-of (e2 / exemplify-01))
            :op2 (l / lead-03
                  :ARG0 (i2 / inhibit-01
                        :ARG1 (k2 / kinase
                              :mod (d / downstream)
                              :example (e3 / enzyme :name (n2 / name :op1 "MEK"))))
                  :ARG2 (a4 / activate-01
                        :ARG1 (s / signal-07
                              :direction (u / upstream))))))

# ::id pmid_2465_1010.235 ::date 2015-02-23T13:59:53 ::annotator SDL-AMR-09 ::preferred
# ::snt We need a much deeper analysis of the molecular mechanisms underlying Ras regulation and effector engagement before we can expect to interfere with these mechanisms effectively.
# ::save-date Sun Jul 26, 2015 ::file pmid_2465_1010_235.txt
(n3 / need-01
      :ARG0 (w / we)
      :ARG1 (a / analyze-01
            :ARG1 (m / mechanism
                  :mod (m2 / molecule)
                  :ARG0-of (u / underlie-01
                        :ARG1 (a2 / and
                              :op1 (r / regulate-01
                                    :ARG1 (e / enzyme :name (n2 / name :op1 "Ras")))
                              :op2 (e2 / engage-01
                                    :ARG1 (e3 / effector)))))
            :ARG1-of (d / deep-02
                  :degree (m3 / more
                        :mod (m4 / much)))
            :time (b / before
                  :op1 (p / possible-01
                        :ARG1 (e4 / expect-01
                              :ARG0 w
                              :ARG1 (i / interfere-01
                                    :ARG0 w
                                    :ARG1 m
                                    :ARG1-of (e5 / effective-04)))))))

# ::id pmid_2465_1010.236 ::date 2015-02-23T14:05:46 ::annotator SDL-AMR-09 ::preferred
# ::snt It seems to us more likely that these deeper insights will lead to productive approaches for intervention than to the conclusion that Ras is indeed undruggable.
# ::save-date Sun Jul 26, 2015 ::file pmid_2465_1010_236.txt
(s / seem-01
      :ARG1 (l / lead-03
            :ARG0 (i / insight
                  :ARG1-of (d / deep-03
                        :degree (m / more))
                  :mod (t / this))
            :ARG1 (a / approach-02
                  :ARG1-of (p / productive-03)
                  :purpose (i2 / intervene-01)
                  :ARG1-of (i3 / instead-of-91
                        :ARG2 (c2 / conclude-01
                              :ARG1 (p2 / possible-01 :polarity -
                                    :ARG1 (d2 / drug-01
                                          :ARG1 (e / enzyme :name (n2 / name :op1 "Ras")))
                                    :mod (i4 / indeed))))))
      :ARG2 (w / we)
      :ARG1-of (l2 / likely-01
            :degree (m2 / more)))

# ::id pmid_2465_1010.237 ::date 2015-02-23T13:42:16 ::annotator SDL-AMR-09 ::preferred
# ::snt New technologies and insights and fresh eyes are likely to solve this problem.
# ::save-date Fri Feb 5, 2016 ::file pmid_2465_1010_237.txt
(s / solve-01
      :ARG0 (a / and
            :op1 (t2 / technology
                  :ARG1-of (n / new-01))
            :op2 (i / insight
                  :ARG1-of n)
            :op3 (e / eye
                  :ARG1-of (f / fresh-04)))
      :ARG1 (p / problem
            :mod (t / this))
      :ARG1-of (l / likely-01))

# ::id pmid_2465_1010.238 ::date 2015-02-23T14:12:44 ::annotator SDL-AMR-09 ::preferred
# ::snt We are also optimistic that completely different approaches to treating cancer will contribute to eliminating Ras cancers, including new ways of knocking down/out genes using RNAi and CRISPR technologies and delivering these payloads to tumors (<ce:cross-ref id="crosref0415" refid="bib14">Davis et al., 2010</ce:cross-ref>), as well as new ways of deploying the immune system.
# ::save-date Sat Feb 13, 2016 ::file pmid_2465_1010_238.txt
(o / optimistic
      :domain (w / we)
      :mod (a / also)
      :topic (c / contribute-01
            :ARG0 (a2 / approach-02
                  :ARG1 (t / treat-04
                        :ARG1 (d2 / disease :wiki "Cancer" :name (n / name :op1 "cancer")))
                  :ARG1-of (d3 / differ-02
                        :ARG1-of (c2 / complete-02))
                  :ARG2-of (i / include-01
                        :ARG1 (a3 / and
                              :op1 (w2 / way
                                    :ARG1-of (n4 / new-01)
                                    :manner-of (a5 / and
                                          :op1 (s / slash
                                                :op1 (k / knock-down-02
                                                      :ARG1 (g / gene)
                                                      :ARG5 (u / use-01
                                                            :ARG1 (a4 / and
                                                                  :op1 (t2 / technology
                                                                        :mod (i3 / interfere-01
                                                                              :ARG0 (n5 / nucleic-acid :name (n8 / name :op1 "RNA"))))
                                                                  :op2 (t3 / technology
                                                                        :mod (d8 / dna-sequence :name (n6 / name :op1 "CRISPR"))))))
                                                :op2 (k2 / knock-out-03
                                                      :ARG1 g
                                                      :ARG2 u))
                                          :op2 (d5 / deliver-01
                                                :ARG1 (p / payload
                                                      :mod (t4 / this))
                                                :ARG2 (t5 / tumor)))
                                    :ARG1-of (d6 / describe-01
                                          :ARG0 (p2 / publication-91
                                                :ARG0 (a6 / and
                                                      :op1 (p3 / person :name (n7 / name :op1 "Davis"))
                                                      :op2 (p4 / person
                                                            :mod (o2 / other)))
                                                :time (d / date-entity :year 2010))))
                              :op2 (w3 / way
                                    :ARG1-of n4
                                    :manner-of (d7 / deploy-01
                                          :ARG1 (s2 / system
                                                :ARG1-of (i2 / immune-02)))))))
            :ARG2 (e2 / eliminate-01
                  :ARG1 (d4 / disease :wiki "Cancer" :name (n3 / name :op1 "cancer")
                        :mod (e / enzyme :name (n2 / name :op1 "Ras"))))))

# ::id pmid_2465_1010.239 ::date 2015-02-24T13:50:16 ::annotator SDL-AMR-09 ::preferred
# ::snt In this respect, it is noteworthy that anti-CTLA-4 therapy appears to be equally effective in treating melanoma driven by N-Ras or B-Raf; therefore, Ras cancers may not be excluded from these approaches as they have been from others.
# ::save-date Wed Mar 9, 2016 ::file pmid_2465_1010_239.txt
(m / multi-sentence
      :snt1 (r / recommend-01
            :ARG1 (n4 / note-01
                  :ARG1 (a / appear-02
                        :ARG1 (e / effective-04
                              :ARG0 (t / therapy
                                    :mod (a2 / antibody
                                          :ARG0-of (c / counter-01
                                                :ARG1 (p2 / protein :name (n / name :op1 "CTLA-4")))))
                              :ARG1 (t2 / treat-04
                                    :ARG1 (m2 / medical-condition :name (n6 / name :op1 "melanoma")
                                          :ARG1-of (d / drive-02
                                                :ARG0 (o / or
                                                      :op1 (e6 / enzyme :name (n7 / name :op1 "N-Ras"))
                                                      :op2 (e2 / enzyme :name (n2 / name :op1 "B-Raf"))))))
                              :degree (e5 / equal))))
            :mod (i3 / in-respect
                  :mod (t4 / this)))
      :snt2 (i2 / infer-01
            :ARG1 (p / possible-01 :polarity -
                  :ARG1 (e7 / exclude-01
                        :ARG1 (d4 / disease :wiki "Cancer" :name (n8 / name :op1 "cancer")
                              :mod (e3 / enzyme :name (n3 / name :op1 "Ras")))
                        :ARG2 (a3 / approach-02
                              :mod (t3 / this))
                        :ARG1-of (r2 / resemble-01
                              :ARG2 (e8 / exclude-01
                                    :ARG1 d4
                                    :ARG2 (a4 / approach-02
                                          :mod (o2 / other))))))))

# ::id pmid_2465_1010.240 ::date 2015-02-24T14:09:30 ::annotator SDL-AMR-09 ::preferred
# ::snt All of these considerations lead us to be optimistic about future prospects of finally delivering the knockout punch.
# ::save-date Sun Jul 26, 2015 ::file pmid_2465_1010_240.txt
(l / lead-03
      :ARG0 (c2 / consider-01
            :mod (t / this)
            :mod (a / all))
      :ARG1 (w / we)
      :ARG2 (o / optimistic
            :domain w
            :topic (p / prospect-02
                  :ARG1 (d / deliver-01
                        :ARG1 (p2 / punch-01
                              :mod (k / knock-out-03))
                        :time (f2 / final))
                  :time (f / future))))

# ::id pmid_2465_1010.241 ::date 2015-02-23T12:18:36 ::annotator SDL-AMR-09 ::preferred
# ::snt Figure 1
# ::save-date Mon Feb 23, 2015 ::file pmid_2465_1010_241.txt
(f / figure :mod 1)

# ::id pmid_2465_1010.242 ::date 2015-02-23T12:18:58 ::annotator SDL-AMR-09 ::preferred
# ::snt Simplified View of the Ras Pathway
# ::save-date Mon Feb 23, 2015 ::file pmid_2465_1010_242.txt
(v / view-02
      :ARG1 (p / pathway :name (n2 / name :op1 "Ras"))
      :ARG1-of (s / simplify-01))

# ::id pmid_2465_1010.243 ::date 2015-02-24T14:16:38 ::annotator SDL-AMR-09 ::preferred
# ::snt Ras proteins are converted from their GDP state to their GTP state by GEFs, in response to upstream signals (<ce:cross-ref id="crosref0425" refid="bib6">Bos et al., 2007</ce:cross-ref>).
# ::save-date Sat Jan 16, 2016 ::file pmid_2465_1010_243.txt
(c / convert-01
      :ARG0 (p2 / protein :name (n4 / name :op1 "GEF"))
      :ARG1 (p5 / protein-family :name (n / name :op1 "Ras"))
      :ARG2 (s4 / state
            :mod (s2 / small-molecule :name (n3 / name :op1 "GTP"))
            :mod p5)
      :ARG3 (s3 / state
            :mod (s / small-molecule :name (n2 / name :op1 "GDP"))
            :poss p5)
      :ARG2-of (r / respond-01
            :ARG1 (s5 / signal-07
                  :direction (u / upstream)))
      :ARG1-of (d2 / describe-01
            :ARG0 (p / publication-91
                  :ARG0 (a / and
                        :op1 (p3 / person :name (n5 / name :op1 "Bos"))
                        :op2 (p4 / person
                              :mod (o / other)))
                  :time (d / date-entity :year 2007))))

# ::id pmid_2465_1010.244 ::date 2015-02-23T12:25:19 ::annotator SDL-AMR-09 ::preferred
# ::snt GAPs convert Ras-GTP back to Ras-GDP.
# ::save-date Mon Feb 23, 2015 ::file pmid_2465_1010_244.txt
(c / convert-01
      :ARG0 (p / protein :name (n / name :op1 "GAP"))
      :ARG1 (m / macro-molecular-complex
            :part (e / enzyme :name (n2 / name :op1 "Ras"))
            :part (s / small-molecule :name (n3 / name :op1 "GTP")))
      :ARG3 (m2 / macro-molecular-complex
            :part e
            :part (s2 / small-molecule :name (n4 / name :op1 "GDP")))
      :direction (b / back))

# ::id pmid_2465_1010.245 ::date 2015-02-24T14:22:49 ::annotator SDL-AMR-09 ::preferred
# ::snt p120 GAP does this when recruited to activated RTKs.
# ::save-date Fri Jan 1, 2016 ::file pmid_2465_1010_245.txt
(d / do-02
      :ARG0 (p / protein :name (n / name :op1 "p120" :op2 "GAP"))
      :ARG1 (t / this)
      :time (r / recruit-01
            :ARG1 p
            :ARG2 (e / enzyme :name (n2 / name :op1 "RTK")
                  :ARG1-of (a / activate-01))))

# ::id pmid_2465_1010.246 ::date 2015-02-24T14:26:16 ::annotator SDL-AMR-09 ::preferred
# ::snt The signal that directs NF1 (neurofibromin)/SPRED to inactivate Ras is not known.
# ::save-date Tue Feb 24, 2015 ::file pmid_2465_1010_246.txt
(k / know-01 :polarity -
      :ARG1 (s / signal-07
            :ARG0-of (d / direct-01
                  :ARG1 (s2 / slash
                        :op1 (p / protein :name (n2 / name :op1 "neurofibromin"))
                        :op2 (p2 / protein :name (n3 / name :op1 "SPRED")))
                  :ARG2 (a / activate-01 :polarity -
                        :ARG0 s2
                        :ARG1 (e / enzyme :name (n / name :op1 "Ras"))))))

# ::id pmid_2465_1010.247 ::date 2015-02-24T14:28:52 ::annotator SDL-AMR-09 ::preferred
# ::snt Several other GAPs are capable of downregulating Ras (<ce:cross-ref id="crosref0430" refid="bib6">Bos et al., 2007</ce:cross-ref>).
# ::save-date Tue Feb 24, 2015 ::file pmid_2465_1010_247.txt
(c / capable-01
      :ARG1 (p / protein :name (n2 / name :op1 "GAP")
            :quant (s / several)
            :mod (o / other))
      :ARG2 (d2 / downregulate-01
            :ARG1 (e / enzyme :name (n / name :op1 "Ras"))
            :ARG2 p)
      :ARG1-of (d3 / describe-01
            :ARG0 (p2 / publication-91
                  :ARG0 (a / and
                        :op1 (p3 / person :name (n3 / name :op1 "Bos"))
                        :op2 (p4 / person
                              :mod o))
                  :time (d / date-entity :year 2007))))

# ::id pmid_2465_1010.248 ::date 2015-02-24T14:29:43 ::annotator SDL-AMR-09 ::preferred
# ::snt Ras-GTP binds and activates multiple downstream effectors.
# ::save-date Wed Feb 25, 2015 ::file pmid_2465_1010_248.txt
(a / and
      :op1 (b / bind-01
            :ARG0 (m / macro-molecular-complex
                  :part (e / enzyme :name (n / name :op1 "Ras"))
                  :part (s / small-molecule :name (n2 / name :op1 "GTP")))
            :ARG1 (e2 / effector
                  :mod (d / downstream)
                  :quant (m2 / multiple)))
      :op2 (a2 / activate-01
            :ARG0 m
            :ARG1 e))

# ::id pmid_2465_1010.249 ::date 2015-02-25T12:38:37 ::annotator SDL-AMR-09 ::preferred
# ::snt The group of proteins shown on the left includes potential effectors whose significance is less well understood relative to RalGDS, Raf kinases, and PI3Ks (<ce:cross-ref id="crosref0435" refid="bib24">Gysin et al., 2011</ce:cross-ref>).
# ::save-date Sat Jan 30, 2016 ::file pmid_2465_1010_249.txt
(i / include-01
      :ARG2 (g / group
            :consist-of (p / protein)
            :ARG1-of (s / show-01
                  :location (l / left-20))
            :ARG2-of (i2 / include-01
                  :ARG1 (e2 / effector
                        :mod (p2 / potential)
                        :ARG0-of (s2 / signify-01
                              :ARG1-of (u / understand-01
                                    :mod (w / well
                                          :degree (l2 / less)
                                          :compared-to (a / and
                                                :op1 (p3 / protein :name (n2 / name :op1 "RalGDS"))
                                                :op2 (p8 / protein-family :name (n3 / name :op1 "Raf"))
                                                :op3 (p7 / protein-family :name (n / name :op1 "PI3K")))))))))
      :ARG1-of (d2 / describe-01
            :ARG0 (p4 / publication-91
                  :ARG0 (a2 / and
                        :op1 (p5 / person :name (n4 / name :op1 "Gysin"))
                        :op2 (p6 / person
                              :mod (o / other)))
                  :time (d / date-entity :year 2011))))

# ::id pmid_2465_1010.250 ::date 2015-02-26T13:01:57 ::annotator SDL-AMR-09 ::preferred
# ::snt Protein families are represented as single proteins to simplify the schematic; in addition, feedback loops are not included.
# ::save-date Fri Jan 1, 2016 ::file pmid_2465_1010_250.txt
(m / multi-sentence
      :snt1 (r / represent-01
            :ARG0 (p / protein
                  :ARG1-of (s / single-02))
            :ARG1 (p3 / protein-family)
            :purpose (s2 / simplify-01
                        :ARG0 r
                        :ARG1 (s3 / schematic)))
      :snt2 (a / and
            :op2 (i / include-01 :polarity -
                  :ARG1 (l / loop-01
                        :mod (f2 / feedback)))))

# ::id pmid_2465_1010.251 ::date 2015-02-23T12:31:30 ::annotator SDL-AMR-09 ::preferred
# ::snt Figure 2
# ::save-date Mon Feb 23, 2015 ::file pmid_2465_1010_251.txt
(f / figure :mod 2)

# ::id pmid_2465_1010.252 ::date 2015-02-23T12:31:52 ::annotator SDL-AMR-09 ::preferred
# ::snt Structure Showing Small Molecule-Directed Electrophilic Attack of K-Ras-G12C
# ::save-date Thu Feb 26, 2015 ::file pmid_2465_1010_252.txt
(s / show-01
      :ARG0 (s2 / structure-01)
      :ARG1 (a / attack-01
            :ARG1 (e2 / enzyme :name (n / name :op1 "K-Ras")
                  :ARG1-of (m / mutate-01 :value "G12C"))
            :mod (e / electrophile)
            :ARG1-of (d / direct-01
                  :ARG0 (s3 / small-molecule))))

# ::id pmid_2465_1010.253 ::date 2015-02-26T11:13:12 ::annotator SDL-AMR-09 ::preferred
# ::snt K-Ras-G12C (Protein Data Bank <ce:inter-ref>4LUC_A</ce:inter-ref>) is displayed in surface representation.
# ::save-date Fri Dec 18, 2015 ::file pmid_2465_1010_253.txt
(d / display-01
      :ARG1 (e / enzyme :name (n / name :op1 "K-Ras")
            :ARG1-of (m / mutate-01 :value "G12C")
            :part-of (d2 / data-bank :name (n2 / name :op1 "4LUC_A")
                  :mod (p / protein)))
      :ARG2 (r / represent-01
            :ARG2 (s / surface)))

# ::id pmid_2465_1010.254 ::date 2015-02-25T12:57:00 ::annotator SDL-AMR-09 ::preferred
# ::snt The cocrystallized ligands, GDP and N-(1-[(2,4-dichlorophenoxy)acetyl]piperidin- 4-yl)-4-sulfanylbutanamide, are shown in stick mode.
# ::save-date Mon Dec 21, 2015 ::file pmid_2465_1010_254.txt
(s2 / show-01
      :ARG1 (l / ligand
            :ARG1-of (c / cocrystallize-00)
            :ARG1-of (m / mean-01
                  :ARG2 (a / and
                        :op1 (l2 / ligand :name (n2 / name :op1 "GDP"))
                        :op1 (l3 / ligand :name (n3 / name :op1 "N-(1-[(2,4-dichlorophenoxy)acetyl]piperidin-4-yl)-4-sulfanylbutanamide")))))
      :manner (m2 / mode
            :mod (s / stick)))

# ::id pmid_2465_1010.255 ::date 2015-02-25T13:22:45 ::annotator SDL-AMR-09 ::preferred
# ::snt The location of calcium ion is shown as a green ball.
# ::save-date Mon Oct 26, 2015 ::file pmid_2465_1010_255.txt
(s / show-01
      :ARG1 (l / location
            :location-of (c / calcium
                  :ARG1-of (i2 / ionize-01)))
      :manner (b / ball
            :ARG1-of (g / green-02)))

# ::id pmid_2465_1010.256 ::date 2015-02-25T13:25:59 ::annotator SDL-AMR-09 ::preferred
# ::snt Switch 1 (28–38) and switch 2 (57–63) are highlighted by orange and red colors, respectively.
# ::save-date Thu Jun 18, 2015 ::file pmid_2465_1010_256.txt
(a2 / and
      :op1 (h / highlight-01
            :ARG1 (s / switch
                  :ord (o / ordinal-entity :value 1)
                  :mod (v / value-interval :op1 28 :op2 38))
            :manner (o2 / orange))
      :op2 (h2 / highlight-01
            :ARG1 (s2 / switch
                  :ord (o3 / ordinal-entity :value 2)
                  :mod (v2 / value-interval :op1 57 :op2 63))
            :manner (r / red-02)))

# ::id pmid_2465_1010.257 ::date 2015-02-25T13:52:56 ::annotator SDL-AMR-09 ::preferred
# ::snt Key ligand-interacting residue (C12, V9, V7, F78, I100, M72, Q99, and R68) positions are colored green.
# ::save-date Sun Dec 20, 2015 ::file pmid_2465_1010_257.txt
(c / color-01
      :ARG1 (a / and
            :op1 (p / position
                  :location-of (r / residue
                              :mod (a2 / amino-acid :mod 12 :name (n / name :op1 "cysteine"))))
            :op2 (p2 / position
                  :location-of (r2 / residue
                              :mod (a3 / amino-acid :mod 9 :name (n2 / name :op1 "valine"))))
            :op3 (p3 / position
                  :location-of (r3 / residue
                              :mod (a4 / amino-acid :mod 7 :name (n3 / name :op1 "valine"))))
            :op4 (p4 / position
                  :location-of (r4 / residue :mod 78
                              :mod (a5 / amino-acid :name (n4 / name :op1 "phenylalanine"))))
            :op5 (p5 / position
                  :location-of (r5 / residue :mod 100
                              :mod (a6 / amino-acid :name (n5 / name :op1 "isoleucine"))))
            :op6 (p6 / position
                  :location-of (r6 / residue :mod 72
                              :mod (a7 / amino-acid :name (n6 / name :op1 "methionine"))))
            :op7 (p7 / position
                  :location-of (r7 / residue :mod 99
                              :mod (a8 / amino-acid :name (n7 / name :op1 "glutamine"))))
            :op8 (p8 / position
                  :location-of (r8 / residue :mod 68
                              :mod (a9 / amino-acid :name (n8 / name :op1 "arginine"))))
            :ARG0-of (i / interact-01
                  :ARG1 (l / ligand))
            :ARG1-of (k / key-02))
      :ARG2 (g / green-02
            :ARG1 a))

# ::id pmid_2465_1010.258 ::date 2015-02-25T13:59:12 ::annotator SDL-AMR-09 ::preferred
# ::snt Position of C12 residue is shown in ball and stick (green).
# ::save-date Sun Dec 20, 2015 ::file pmid_2465_1010_258.txt
(s / show-01
      :ARG1 (p / position-01
            :ARG1 (r / residue
                  :mod (a / amino-acid :mod 12 :wiki "Cysteine"
                        :name (n / name :op1 "cysteine"))))
      :manner (a2 / and
            :op1 (b / ball)
            :op2 (s2 / stick)
            :ARG1-of (g / green-02)))

# ::id pmid_2465_1010.259 ::date 2015-02-25T14:05:02 ::annotator SDL-AMR-09 ::preferred
# ::snt Note that residues 58 and 60 are part of both switch 2 and the key ligand-interacting group (shown in blue).
# ::save-date Sun Dec 20, 2015 ::file pmid_2465_1010_259.txt
(n / note-01
      :ARG1 (a / and
            :op1 (r / residue
                  :mod (a2 / amino-acid :mod 58))
            :op2 (r2 / residue
                  :mod (a3 / amino-acid :mod 60))
            :part-of (a4 / and
                  :op1 (s / switch :mod 2)
                  :op2 (g / group
                        :ARG0-of (i / interact-01
                              :ARG1 (l / ligand))
                        :ARG1-of (k / key-02))))
      :ARG1-of (s2 / show-01
            :manner (b / blue)))

# ::id pmid_2465_1010.260 ::date 2015-02-23T14:16:26 ::annotator SDL-AMR-09 ::preferred
# ::snt Figure 3
# ::save-date Mon Feb 23, 2015 ::file pmid_2465_1010_260.txt
(f / figure :mod 3)

# ::id pmid_2465_1010.261 ::date 2015-02-23T14:16:48 ::annotator SDL-AMR-09 ::preferred
# ::snt Schematic Representation of the Ras Isoforms
# ::save-date Tue May 19, 2015 ::file pmid_2465_1010_261.txt
(r / representation-02
      :ARG1 (i / isoform :name (n2 / name :op1 "Ras"))
      :ARG2 (s / schematic))

# ::id pmid_2465_1010.262 ::date 2015-02-23T14:19:16 ::annotator SDL-AMR-09 ::preferred
# ::snt The structures of the G domain of H-Ras, N-Ras, and K-Ras have been solved and are virtually identical, but the structure of processed hypervariable regions has not been solved and is therefore depicted as a linear sequence.
# ::save-date Thu Feb 26, 2015 ::file pmid_2465_1010_262.txt
(a / and
      :op1 (s / solve-01
            :ARG1 (a2 / and
                  :op1 (s2 / structure-01
                        :ARG1 (p / protein-segment :name (n3 / name :op1 "G" :op2 "domain")
                              :part-of (e / enzyme :name (n / name :op1 "H-Ras"))))
                  :op2 (s3 / structure-01
                        :ARG1 (p2 / protein-segment :name (n4 / name :op1 "G" :op2 "domain")
                              :part-of (e3 / enzyme :name (n5 / name :op1 "N-Ras"))))
                  :op3 (s4 / structure-01
                        :ARG1 (p3 / protein-segment :name (n6 / name :op1 "G" :op2 "domain")
                              :part-of (e2 / enzyme :name (n2 / name :op1 "K-Ras"))))))
      :op2 (i / identical-01
            :ARG1 a2
            :mod (v / virtual))
      :ARG1-of (c / contrast-01
            :ARG2 (a3 / and
                  :op1 (s5 / solve-01 :polarity -
                        :ARG1 (s6 / structure-01
                              :ARG1 (r / region
                                    :ARG1-of (v2 / vary-01
                                          :degree (h / hyper))
                                    :ARG1-of (p4 / process-01))))
                  :op2 (d / depict-01
                        :ARG1 s6
                        :ARG2 (s7 / sequence
                              :mod (l / linear))))))

# ::id pmid_2465_1010.263 ::date 2015-02-25T13:15:55 ::annotator SDL-AMR-09 ::preferred
# ::snt Lipid modifications with farnesyl (purple) and palmitoyl (orange) chains are shown.
# ::save-date Fri Jan 1, 2016 ::file pmid_2465_1010_263.txt
(s / show-01
      :ARG1 (m / modify-01
            :ARG1 (l / lipid)
            :instrument (a / and
                  :op1 (c / chain
                        :mod (f / farnesyl)
                        :ARG1-of (p / purple-02))
                  :op2 (c2 / chain
                        :mod (p2 / palmitoyl
                              :ARG1-of (r4 / represent-01
                                    :ARG0 (o / orange)))))))

# ::id pmid_2470_8867.1 ::date 2015-08-26T08:04:52 ::annotator SDL-AMR-09 ::preferred
# ::snt Met receptor-induced Grb2 or Shc signals both promote transformation of intestinal epithelial cells, albeit they are required for distinct oncogenic functions (PMID:24708867)
# ::save-date Tue Nov 24, 2015 ::file pmid_2470_8867_1.txt
(p / promote-02
      :ARG0 (s / signal-07
            :ARG0 (a / and
                  :op1 (p2 / protein :name (n / name :op1 "Grb2"))
                  :op2 (p3 / protein :name (n2 / name :op1 "Shc")))
            :ARG2-of (i / induce-01
                  :ARG0 (r / receptor :name (n3 / name :op1 "Met"))))
      :ARG1 (t / transform-01
            :ARG1 (c / cell
                  :source (e / epithelium
                        :part-of (i2 / intestine))))
      :concession (r2 / require-01
                  :ARG0 (f / function-01
                        :ARG0-of (c2 / cause-01
                              :ARG1 (c3 / cancer))
                        :mod (d / distinct))
                  :ARG1 a)
      :ARG1-of (d2 / describe-01
            :ARG0 (p4 / publication-91
                  :ARG8 "PMID24708867")))

# ::id pmid_2470_8867.9 ::date 2015-08-26T09:09:27 ::annotator SDL-AMR-09 ::preferred
# ::snt <sec-title level="1" sec-area="abstract">Results</sec-title>
# ::save-date Wed Aug 26, 2015 ::file pmid_2470_8867_9.txt
(t / thing
      :ARG2-of (r / result-01))

# ::id pmid_2470_8867.10 ::date 2015-08-26T09:39:11 ::annotator SDL-AMR-09 ::preferred
# ::snt We show, for the first time, that constitutive activation of either Grb2 or Shc signals in IEC-6 cells, promotes morphological transformation associated with down-regulation of E-cadherin, as well as increased cell growth, loss of growth contact inhibition, anchorage-independent growth, and resistance to serum deprivation and anoikis.
# ::save-date Sun Jan 17, 2016 ::file pmid_2470_8867_10.txt
(s / show-01
      :ARG0 (w / we)
      :ARG1 (p / promote-02
            :ARG0 (a / activate-01
                  :ARG1 (s2 / signal-07
                        :ARG0 (o2 / or
                              :op1 (p2 / protein :name (n / name :op1 "Grb2"))
                              :op2 (p3 / protein :name (n2 / name :op1 "Shc"))))
                  :mod (c / constitutive)
                  :location (c2 / cell-line :name (n3 / name :op1 "IEC-6")))
            :ARG1 (a2 / and
                  :op1 (t / transform-01
                        :mod (m / morphological)
                        :ARG1-of (a3 / associate-01
                              :ARG2 (d / downregulate-01
                                    :ARG1 (p4 / protein :name (n4 / name :op1 "E-cadherin")))))
                  :op2 (g / grow-01
                        :ARG1 (c3 / cell)
                        :ARG1-of (i / increase-01))
                  :op3 (l / lose-01
                        :ARG1 (i2 / inhibit-01
                              :ARG0 (c4 / contact-01)
                              :ARG1 (g2 / grow-01)))
                  :op4 (g3 / grow-01
                        :ARG0-of (d2 / depend-01 :polarity -
                              :ARG1 (a4 / anchorage)))
                  :op5 (r / resist-01
                        :ARG1 (a5 / and
                              :op1 (d3 / deprive-01
                                    :ARG1 (s3 / serum))
                              :op2 (a6 / anoikis)))))
      :ord (o / ordinal-entity :value 1))

# ::id pmid_2470_8867.11 ::date 2015-08-26T10:20:39 ::annotator SDL-AMR-09 ::preferred
# ::snt Oncogenic activation of Met was revealed to induce morphological transformation, E-cadherin down-regulation, and protection against anoikis by mechanisms dependent on Grb2, while Shc was shown to be partly required for enhanced cell growth.
# ::save-date Sun Sep 6, 2015 ::file pmid_2470_8867_11.txt
(c / contrast-01
      :ARG1 (r / reveal-01
            :ARG1 (i / induce-01
                  :ARG0 (a / activate-01
                        :ARG1 (p5 / protein :name (n / name :op1 "Met"))
                        :ARG0-of (c2 / cause-01
                              :ARG1 (c3 / cancer)))
                  :ARG1 (a2 / and
                        :op1 (t / transform-01
                              :mod (m / morphological))
                        :op2 (d / downregulate-01
                              :ARG1 (p / protein :name (n2 / name :op1 "E-cadherin")))
                        :op3 (p2 / protect-01
                              :ARG2 (a3 / anoikis)
                              :ARG3 (m2 / mechanism
                                    :ARG0-of (d2 / depend-01
                                          :ARG1 (p3 / protein :name (n3 / name :op1 "Grb2"))))))))
      :ARG2 (s / show-01
            :ARG1 (r3 / require-01
                  :ARG0 (g / grow-01
                        :ARG1 (c4 / cell)
                        :ARG1-of (e / enhance-01))
                  :ARG1 (p4 / protein :name (n4 / name :op1 "Shc"))
                  :degree (p6 / part))))

# ::id pmid_2470_8867.12 ::date 2015-08-26T10:48:31 ::annotator SDL-AMR-09 ::preferred
# ::snt The coupling of activated Met to the Ras/MEK/Erk and PI3K/Akt pathways, and the sustained engagement of Grb2 or Shc in IECs, was shown to trigger negative feedback, limiting the extent of activation of these pathways.
# ::save-date Fri Feb 5, 2016 ::file pmid_2470_8867_12.txt
(s / show-01
      :ARG1 (t / trigger-01
            :ARG0 (a / and
                  :op1 (c / couple-01
                        :ARG1 (p / protein :name (n / name :op1 "Met")
                              :ARG1-of (a3 / activate-01))
                        :ARG2 (a2 / and
                              :op1 (p2 / pathway :name (n2 / name :op1 "Ras/MEK/Erk"))
                              :op2 (p3 / pathway :name (n3 / name :op1 "PI3K/Akt"))))
                  :op2 (e / engage-01
                        :ARG1 (o / or
                              :op1 (p4 / protein :name (n4 / name :op1 "Grb2"))
                              :op2 (p5 / protein :name (n5 / name :op1 "Shc")))
                        :ARG2 (c2 / cell :name (n6 / name :op1 "IEC"))
                        :ARG1-of (s2 / sustain-01)))
            :ARG1 (f / feedback
                  :ARG0-of (n7 / negative-03))
            :ARG0-of (l / limit-01
                  :ARG1 (e2 / extent
                        :extent-of (a5 / activate-01
                              :ARG1 (a6 / and
                                    :op1 p2
                                    :op2 p3
                                    :mod (t2 / this)))))))

# ::id pmid_2470_8867.13 ::date 2015-08-26T11:07:52 ::annotator SDL-AMR-09 ::preferred
# ::snt Nonetheless, morphological alterations and E-cadherin down-regulation induced by the oncogenic Tpr-Met, and by Grb2 or Shc signals, were blocked by MEK, but not PI3K, inhibitors while the enhanced growth and resistance to anoikis induced by Tpr-Met were nearly abolished by co-treatment with both inhibitors.
# ::save-date Sun Jan 17, 2016 ::file pmid_2470_8867_13.txt
(h / have-concession-91
      :ARG1 (c / contrast-01
            :ARG1 (c2 / contrast-01
                  :ARG1 (b / block-01
                        :ARG0 (m2 / molecular-physical-entity
                              :ARG0-of (i2 / inhibit-01
                                    :ARG1 (p6 / protein-family :name (n5 / name :op1 "MEK"))))
                        :ARG1 (a / and
                              :op1 (a2 / alter-01
                                    :mod (m / morphological))
                              :op2 (d / downregulate-01
                                    :ARG1 (p / protein :name (n / name :op1 "E-cadherin"))
                                    :ARG2-of (i / induce-01
                                          :ARG0 (a3 / and
                                                :op1 (p2 / protein :name (n2 / name :op1 "Tpr-Met")
                                                      :ARG0-of (c3 / cause-01
                                                            :ARG1 (c4 / cancer)))
                                                :op1 (s / signal-07
                                                      :ARG0 (o / or
                                                            :op1 (p3 / protein :name (n3 / name :op1 "Grb2"))
                                                            :op2 (p4 / protein :name (n4 / name :op1 "Shc")))))))))
                  :ARG2 (b2 / block-01 :polarity -
                        :ARG0 (m3 / molecular-physical-entity
                              :ARG0-of (i3 / inhibit-01
                                    :ARG1 (p5 / protein-family :name (n6 / name :op1 "PI3K"))))
                        :ARG1 a))
            :ARG2 (a4 / abolish-01
                  :ARG1 (a5 / and
                        :op1 (g / grow-01
                              :ARG1-of (e3 / enhance-01))
                        :op2 (r / resist-01
                              :ARG1 (a6 / anoikis
                                    :ARG2-of (i4 / induce-01
                                          :ARG0 p2))))
                  :mod (n7 / near)
                  :instrument (t / treat-04
                        :ARG2 (a7 / and
                              :op1 m2
                              :op2 m3)))))

# ::id pmid_2470_8867.95 ::date 2015-08-26T12:14:10 ::annotator SDL-AMR-09 ::preferred
# ::snt <sec-title level="1">Results</sec-title>
# ::save-date Wed Aug 26, 2015 ::file pmid_2470_8867_95.txt
(t / thing
      :ARG2-of (r / result-01))

# ::id pmid_2470_8867.96 ::date 2015-08-26T12:14:48 ::annotator SDL-AMR-09 ::preferred
# ::snt <sec-title level="2">Oncogenic engagement of Grb2 or Shc signaling promotes morphological transformation in normal IECs and reduces E-cadherin expression</sec-title>
# ::save-date Sun Sep 13, 2015 ::file pmid_2470_8867_96.txt
(a / and
      :op1 (p / promote-02
            :ARG0 (e / engage-01
                  :ARG1 (s / signal-07
                        :ARG0 (o / or
                              :op1 (p2 / protein :name (n / name :op1 "Grb2"))
                              :op2 (p3 / protein :name (n2 / name :op1 "Shc"))))
                  :ARG0-of (c / cause-01
                        :ARG1 (c2 / cancer)))
            :ARG1 (t / transform-01
                  :ARG1 (c3 / cell :name (n3 / name :op1 "IEC")
                        :ARG1-of (n4 / normal-02))
                  :mod (m / morphological)))
      :op2 (r / reduce-01
            :ARG0 e
            :ARG1 (e2 / express-03
                  :ARG2 (p4 / protein :name (n5 / name :op1 "E-cadherin")))))

# ::id pmid_2470_8867.97 ::date 2015-08-26T12:23:55 ::annotator SDL-AMR-09 ::preferred
# ::snt In contrast with many other RTKs, the ability of the Met receptor to recruit signaling proteins, and thus its biological activities, is dependent on two phospho-Tyr residues located within its C-terminus (Y1349/Y1356 in Met; Y482/Y489 in Tpr-Met [<xref ref-type="bibr" rid="B28">28</xref>-<xref ref-type="bibr" rid="B30">30</xref>]).
# ::save-date Fri Feb 5, 2016 ::file pmid_2470_8867_97.txt
(c / contrast-01
      :ARG1 (d / depend-01
            :ARG0 (c2 / capable-01
                  :ARG1 (r / receptor :name (n / name :op1 "Met"))
                  :ARG2 (r2 / recruit-01
                        :ARG0 r
                        :ARG1 (p / protein
                              :ARG0-of (s / signal-07)))
                  :ARG0-of (c3 / cause-01
                        :ARG1 (a4 / activity-06
                              :ARG0 r
                              :mod (b2 / biology))))
            :ARG1 (a2 / and
                  :op1 (r3 / residue
                        :ARG1-of (p2 / phosphorylate-01)
                        :location (p3 / protein-segment :name (n3 / name :op1 "C-terminus")
                              :part-of r)
                        :mod (s2 / slash
                              :op1 (a / amino-acid :mod 1349 :name (n5 / name :op1 "tyrosine"))
                              :op2 (a3 / amino-acid :mod 1356 :name (n6 / name :op1 "tyrosine"))
                              :part-of (p7 / protein :name (n10 / name :op1 "Met"))))
                  :op2 (r4 / residue
                        :ARG1-of p2
                        :mod (s3 / slash
                              :op1 (a5 / amino-acid :mod 482 :name (n4 / name :op1 "tyrosine"))
                              :op2 (a6 / amino-acid :mod 489 :name (n9 / name :op1 "tyrosine"))
                              :part-of (p4 / protein :name (n2 / name :op1 "Tpr-Met"))))
                  :ARG1-of (d2 / describe-01
                        :ARG0 (p6 / publication
                              :ARG1-of (c4 / cite-01
                                    :ARG2 (v / value-interval :op1 28 :op2 30))))))
      :ARG2 (e / enzyme :name (n7 / name :op1 "RTK")
            :quant (m / many)
            :mod (o / other)))

# ::id pmid_2470_8867.98 ::date 2015-08-26T13:29:45 ::annotator SDL-AMR-09 ::preferred
# ::snt This unique characteristic has been exploited to generate Met receptor variants capable of binding exclusively to a single RTK-proximal signaling protein [<xref ref-type="bibr" rid="B8">8</xref>].
# ::save-date Sun Sep 13, 2015 ::file pmid_2470_8867_98.txt
(e / exploit-01
      :ARG1 (t2 / thing
            :mod (u / unique)
            :mod (t / this)
            :ARG2-of (c / characteristic-02))
      :ARG2 (g / generate-01
            :ARG1 (v / variant
                  :mod (r / receptor :wiki "C-Met"
                        :name (n / name :op1 "Met"))
                  :ARG1-of (c2 / capable-01
                        :ARG2 (b / bind-01
                              :ARG1 v
                              :ARG2 (p / protein
                                    :ARG0-of (s / signal-07
                                          :ARG1 (e3 / enzyme :wiki "Receptor_tyrosine_kinase"
                                                :name (n2 / name :op1 "RTK"))
                                          :mod (p2 / proximal))
                                    :ARG1-of (s2 / single-02))
                              :manner (e2 / exclusive-02)))))
      :ARG1-of (d / describe-01
            :ARG0 (p3 / publication
                  :ARG0-of (c3 / cite-01 :ARG2 8))))

# ::id pmid_2470_8867.99 ::date 2015-08-26T13:44:55 ::annotator SDL-AMR-09 ::preferred
# ::snt These well-characterized docking-specific Met variants consist of the cytosolic oncogenic form of the Met receptor, Tpr-Met, in which the multi-substrate binding region has been replaced with a motif selective for the recruitment of a single signaling protein, found in other RTKs (Additional file <xref ref-type="supplementary-material" rid="S1">1</xref> and [<xref ref-type="bibr" rid="B8">8</xref>]).
# ::save-date Sun Sep 13, 2015 ::file pmid_2470_8867_99.txt
(c / consist-01
      :ARG1 (v / variant
            :mod (r / receptor :name (n / name :op1 "Met")
                  :mod (o / other))
            :ARG1-of (s / specific-02
                  :ARG2 (d / dock-01))
            :ARG1-of (c2 / characterize-01
                  :ARG1-of (w / well-09))
            :mod (t / this))
      :ARG2 (f / form
            :ARG0-of (c3 / cause-01
                  :ARG1 (c4 / cancer))
            :mod (c5 / cytosol)
            :mod (r2 / receptor :name (n2 / name :op1 "Met"))
            :ARG1-of (m / mean-01
                  :ARG2 (r3 / receptor :name (n3 / name :op1 "Tpr-Met")))
            :location-of (r4 / region
                        :ARG1-of (b2 / bind-01)
                        :mod (s5 / substrate
                              :quant (m2 / multiple))
                        :ARG1-of (r5 / replace-01
                              :ARG2 (m3 / motif
                                    :ARG0-of (s2 / select-01
                                          :ARG1 (r6 / recruit-01
                                                :ARG1 (p / protein
                                                      :ARG0-of (s3 / signal-07)
                                                      :ARG1-of (s4 / single-02)
                                                      :ARG1-of (f3 / find-01
                                                            :location (e / enzyme :name (n4 / name :op1 "RTK")
                                                                  :mod (o2 / other))))))))))
      :ARG1-of (d2 / describe-01
            :ARG0 (a / and
                  :op1 (f2 / file :mod 1
                        :mod (a2 / additional))
                  :op2 (p2 / publication
                        :ARG0-of (c6 / cite-01
                              :ARG2 8)))))

# ::id pmid_2470_8867.100 ::date 2015-08-26T14:38:58 ::annotator SDL-AMR-09 ::preferred
# ::snt To determine whether the selective oncogenic engagement of either the Grb2 or the Shc adaptor protein was sufficient to induce transformation of IECs, we generated populations of IEC-6 cells [<xref ref-type="bibr" rid="B25">25</xref>] expressing Tpr-Met variants that specifically bind to either the Grb2 (TM-Grb2-IEC-6 cells) or Shc (TM-Shc1-IEC-6 and TM-Shc2-IEC-6 cells, respectively) adaptor proteins, through retroviral infection.
# ::save-date Wed Sep 16, 2015 ::file pmid_2470_8867_100.txt
(g / generate-01
      :ARG0 (w / we)
      :ARG1 (p / population
            :consist-of (c / cell-line :name (n / name :op1 "IEC-6")
                  :ARG1-of (d / describe-01
                        :ARG0-of (c2 / cite-01
                              :ARG2 25))
                  :ARG3-of (e / express-03
                        :ARG2 (v / variant
                              :mod (p2 / protein :name (n2 / name :op1 "Tpr-Met"))
                              :ARG1-of (b / bind-01
                                    :ARG2 (o / or
                                          :op1 (p3 / protein :name (n3 / name :op1 "Grb2")
                                                :mod (a / adaptor)
                                                :location (c3 / cell-line :name (n4 / name :op1 "TM-Grb2-IEC-6")))
                                          :op2 (p4 / protein :name (n5 / name :op1 "Shc")
                                                :mod a
                                                :location (a3 / and
                                                      :op1 (c4 / cell-line :name (n6 / name :op1 "TM-Shc1-IEC-6"))
                                                      :op2 (c5 / cell-line :name (n7 / name :op1 "TM-Shc2-IEC-6")))))
                                    :instrument (i / infect-01
                                          :mod (r / retrovirus))
                                    :manner (s / specific-02))))))
      :purpose (d2 / determine-01
            :ARG0 w
            :ARG1 (s2 / suffice-01 :mode interrogative
                  :ARG0 (e2 / engage-01
                        :ARG1 (o2 / or
                              :op1 (p5 / protein :name (n8 / name :op1 "Grb2")
                                    :mod a)
                              :op2 (p6 / protein :name (n9 / name :op1 "Shc")
                                    :mod a))
                        :ARG0-of (c6 / cause-01
                              :ARG1 (c7 / cancer))
                        :mod (s3 / selective))
                  :ARG1 (i2 / induce-01
                        :ARG0 e2
                        :ARG2 (t / transform-01
                              :ARG2 (c8 / cell :name (n10 / name :op1 "IEC")))))))

# ::id pmid_2470_8867.101 ::date 2015-08-26T15:35:43 ::annotator SDL-AMR-09 ::preferred
# ::snt For each experiment, these cells were compared with the previously characterized untransformed sham-infected IEC-6 (Control-IEC-6) cells or those transformed by unmodified Tpr-Met (Tpr-Met-IEC-6) [<xref ref-type="bibr" rid="B5">5</xref>].
# ::save-date Sun Sep 13, 2015 ::file pmid_2470_8867_101.txt
(c / compare-01
      :ARG1 (c2 / cell
            :mod (t / this))
      :ARG2 (o / or
            :op1 (c5 / cell-line :name (n / name :op1 "IEC-6")
                  :ARG1-of (c4 / characterize-01
                        :time (p / previous))
                  :ARG1-of (t2 / transform-01 :polarity -)
                  :ARG1-of (i / infect-01
                        :mod (s / sham))
                  :ARG1-of (m / mean-01
                        :ARG2 (c3 / cell-line :name (n2 / name :op1 "Control-IEC-6"))))
            :op2 (c6 / cell
                  :ARG1-of c4
                  :ARG1-of (t3 / transform-01
                        :ARG0 (p3 / protein :name (n3 / name :op1 "Tpr-Met")
                              :ARG1-of (m3 / modify-01 :polarity -)))
                  :ARG1-of (m2 / mean-01
                        :ARG2 (c7 / cell-line :name (n4 / name :op1 "Tpr-Met-IEC-6")))))
      :ARG1-of (d / describe-01
            :ARG0 (p2 / publication
                  :ARG0-of (c9 / cite-01
                        :ARG2 5)))
      :beneficiary (e / experiment-01
            :mod (e2 / each)))

# ::id pmid_2470_8867.102 ::date 2015-08-26T16:01:38 ::annotator SDL-AMR-09 ::preferred
# ::snt TM-Grb2-IEC-6, TM-Shc1-IEC-6, and TM-Shc2-IEC-6 cells were morphologically transformed to a similar extent relative to Control-IEC-6 cells, which grew in colonies and displayed typical normal epithelioid morphology (Figure <xref ref-type="fig" rid="F1">1</xref>A).
# ::save-date Sun Sep 13, 2015 ::file pmid_2470_8867_102.txt
(t / transform-01
      :ARG1 (a / and
            :op1 (c / cell-line :name (n / name :op1 "TM-Grb2-IEC-6"))
            :op2 (c2 / cell-line :name (n2 / name :op1 "TM-Shc1-IEC-6"))
            :op3 (c3 / cell-line :name (n3 / name :op1 "TM-Shc2-IEC-6")))
      :ARG2 (e / extent
            :ARG1-of (r / resemble-01)
            :ARG1-of (r2 / relative-05
                  :ARG3 (c4 / cell-line :name (n4 / name :op1 "Control-IEC-6")
                        :ARG1-of (g / grow-01
                              :location (c5 / colony))
                        :ARG0-of (d / display-01
                              :ARG1 (m2 / morphology
                                    :ARG1-of (t2 / typical-02)
                                    :ARG1-of (n5 / normal-02)
                                    :ARG1-of (r3 / resemble-01
                                          :ARG2 (e2 / epithelium)))))))
      :manner (m / morphological)
      :ARG1-of (d2 / describe-01
            :ARG2 (f / figure :mod "1A")))

# ::id pmid_2470_8867.103 ::date 2015-08-26T16:28:03 ::annotator SDL-AMR-09 ::preferred
# ::snt Morphological changes induced in the TM-Grb2-IEC-6, TM-Shc1-IEC-6, and TM-Shc2-IEC-6 cells include an apparent breakdown of cell-cell contacts, cell dispersal, the acquisition of a fibroblast-like spindle-shaped morphology, and a more refractile appearance than the Control-IEC-6 cells.
# ::save-date Sun Sep 13, 2015 ::file pmid_2470_8867_103.txt
(i / include-01
      :ARG1 (a2 / and
            :op1 (b / break-down-12
                  :ARG1 (c5 / contact-01
                        :ARG0 (c6 / cell)
                        :ARG1 (c7 / cell))
                  :ARG1-of (a3 / appear-01))
            :op2 (d / disperse-01
                  :ARG1 c6)
            :op3 (a4 / acquire-01
                  :ARG1 (m2 / morphology
                        :ARG1-of (r / resemble-01
                              :ARG2 (f / fibroblast))
                        :ARG1-of (s / shape-01
                              :ARG2 (s2 / spindle))))
            :op4 (a5 / appear-01
                  :mod (r2 / refractile
                        :degree (m3 / more))
                  :compared-to (c8 / cell-line :name (n4 / name :op1 "Control-IEC-6"))))
      :ARG2 (c / change-01
            :mod (m / morphology)
            :ARG2-of (i2 / induce-01
                  :location (a / and
                        :op1 (c2 / cell-line :name (n / name :op1 "TM-Grb2-IEC-6"))
                        :op2 (c3 / cell-line :name (n2 / name :op1 "TM-Shc1-IEC-6"))
                        :op3 (c4 / cell-line :name (n3 / name :op1 "TM-Shc2-IEC-6"))))))

# ::id pmid_2470_8867.104 ::date 2015-08-26T17:03:03 ::annotator SDL-AMR-09 ::preferred
# ::snt Cells expressing the Grb2 and Shc docking-specific oncoproteins also displayed many cell membrane protrusions typical of lamellipodia and invadopodia-like structures.
# ::save-date Sun Sep 13, 2015 ::file pmid_2470_8867_104.txt
(d / display-01
      :ARG0 (c / cell
            :ARG3-of (e / express-03
                  :ARG2 (a / and
                        :op1 (p2 / protein :name (n / name :op1 "Grb2")
                              :ARG0-of (c2 / cause-01
                                    :ARG1 (c3 / cancer)))
                        :op2 (p / protein :name (n2 / name :op1 "Shc")
                              :ARG0-of c2)
                        :ARG1-of (s / specific-02
                              :ARG2 (d2 / dock-01)))))
      :ARG1 (p3 / protrude-01
            :ARG2 (m / membrane
                  :part-of (c4 / cell))
            :ARG1-of (t / typical-02
                  :ARG2 (a3 / and
                        :op1 (s2 / structure
                              :mod (l / lamellipodium))
                        :op2 (s3 / structure
                              :ARG1-of (r / resemble-01
                                    :ARG2 (i / invadopodium)))))
            :quant (m2 / many))
      :mod (a2 / also))

# ::id pmid_2470_8867.105 ::date 2015-08-26T22:13:53 ::annotator SDL-AMR-09 ::preferred
# ::snt The Tpr-Met variants exhibited comparable levels of Tyr phosphorylation in IEC-6 cells, relative to their expression levels (Figure <xref ref-type="fig" rid="F1">1</xref>A).
# ::save-date Wed Sep 16, 2015 ::file pmid_2470_8867_105.txt
(e / exhibit-01
      :ARG0 (v / variant
            :mod (p / protein :name (n / name :op1 "Tpr-Met")))
      :ARG1 (l / level
            :ARG1-of (c / comparable-03)
            :degree-of (p2 / phosphorylate-01
                  :ARG1 (a / amino-acid :name (n3 / name :op1 "tyrosine"))
                  :location (c2 / cell-line :name (n2 / name :op1 "IEC-6")))
            :ARG1-of (r / relative-05
                  :ARG3 (l2 / level
                        :degree-of (e2 / express-03
                              :ARG2 v))))
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod "1A")))

# ::id pmid_2470_8867.106 ::date 2015-08-26T22:51:34 ::annotator SDL-AMR-09 ::preferred
# ::snt They also demonstrated the predicted binding selectivity [<xref ref-type="bibr" rid="B8">8</xref>,<xref ref-type="bibr" rid="B9">9</xref>,<xref ref-type="bibr" rid="B15">15</xref>,<xref ref-type="bibr" rid="B16">16</xref>,<xref ref-type="bibr" rid="B20">20</xref>] (Additional file <xref ref-type="supplementary-material" rid="S1">1</xref>).
# ::save-date Sun Sep 13, 2015 ::file pmid_2470_8867_106.txt
(d / demonstrate-01
      :ARG0 (t / they)
      :ARG1 (s / select-01
            :ARG1-of (p / predict-01)
            :mod (b / bind-01))
      :mod (a / also)
      :ARG1-of (d2 / describe-01
            :ARG0 (a2 / and
                  :op1 (p2 / publication
                        :ARG1-of (c / cite-01
                              :ARG2 (a3 / and :op1 8 :op2 9 :op3 15 :op4 16 :op5 20)))
                  :op2 (f / file :mod 1
                        :mod (a4 / additional)))))

# ::id pmid_2470_8867.107 ::date 2015-08-27T04:13:27 ::annotator SDL-AMR-09 ::preferred
# ::snt Since such morphological changes in epithelial cells are typically associated with down-regulation of E-cadherin, immunoblot (IB) analysis of the E-cadherin protein levels were performed [<xref ref-type="bibr" rid="B31">31</xref>].
# ::save-date Sun Sep 13, 2015 ::file pmid_2470_8867_107.txt
(c / cause-01
      :ARG0 (a / associate-01
            :ARG1 (c2 / change-01
                  :ARG1 (c3 / cell
                        :source (e / epithelium))
                  :mod (m / morphological)
                  :mod (s / such))
            :ARG2 (d / downregulate-01
                  :ARG1 (p / protein :name (n / name :op1 "E-cadherin")))
            :ARG1-of (t / typical-02))
      :ARG1 (p2 / perform-02
            :ARG2 (a2 / analyze-01
                  :ARG1 (l / level
                        :quant-of p)
                  :mod (i2 / immunoblot-01)))
      :ARG1-of (d2 / describe-01
            :ARG0 (p4 / publication
                  :ARG1-of (c4 / cite-01
                        :ARG2 31))))

# ::id pmid_2470_8867.108 ::date 2015-08-27T10:32:19 ::annotator SDL-AMR-09 ::preferred
# ::snt Consistent with the previous characterization of Tpr-Met-IEC-6 cells [<xref ref-type="bibr" rid="B5">5</xref>], also presented herein, oncogenic activation of Grb2- and especially Shc-specific signals led to a dramatic decrease in E-cadherin protein levels relative to the Control-IEC-6 cells (Figure <xref ref-type="fig" rid="F1">1</xref>B).
# ::save-date Sun Sep 13, 2015 ::file pmid_2470_8867_108.txt
(l / lead-03
      :ARG0 (a / activate-01
            :ARG1 (s / signal-07
                  :ARG1-of (s2 / specific-02
                        :ARG2 (a2 / and
                              :op1 (p / protein :name (n / name :op1 "Grb2"))
                              :op2 (p2 / protein :name (n2 / name :op1 "Shc")
                                    :ARG1-of (s3 / special-02)))))
            :ARG0-of (c / cause-01
                  :ARG1 (c2 / cancer)))
      :ARG2 (d / decrease-01
            :ARG1 (l2 / level
                  :quant-of (p3 / protein :name (n3 / name :op1 "E-cadherin"))
                  :ARG1-of (r / relative-05
                        :ARG2 (c3 / cell-line :name (n4 / name :op1 "Control-IEC-6"))))
            :manner (d2 / dramatic))
      :ARG1-of (c4 / consistent-01
            :ARG2 (c5 / characterize-01
                  :ARG1 (c6 / cell-line :name (n5 / name :op1 "Tpr-Met-IEC-6"))
                  :time (p4 / previous)
                  :ARG1-of (p6 / present-01
                        :mod (a3 / also)
                        :medium (h / herein)))
            :ARG1-of (d3 / describe-01
                  :ARG0 (p5 / publication
                        :ARG0-of (c7 / cite-01
                              :ARG2 5))))
      :ARG1-of (d4 / describe-01
            :ARG2 (f / figure :mod "1B")))

# ::id pmid_2470_8867.109 ::date 2015-08-27T11:05:01 ::annotator SDL-AMR-09 ::preferred
# ::snt Likewise, a marked reduction in E-cadherin (<i>Cdh1</i>) mRNA levels was observed in these cells, as determined by semi-quantitative and quantitative real-time RT–PCR analyses (Figure <xref ref-type="fig" rid="F1">1</xref>C and D).
# ::save-date Mon Dec 21, 2015 ::file pmid_2470_8867_109.txt
(o / observe-01
      :ARG1 (r / reduce-01
            :ARG1 (l / level
                  :quant-of (n5 / nucleic-acid :name (n / name :op1 "mRNA")
                        :ARG0-of (e / encode-01
                              :ARG1 (p / protein :name (n2 / name :op1 "E-cadherin")
                                    :ARG1-of (m2 / mean-01
                                          :ARG2 (p2 / protein :name (n3 / name :op1 "Cdh1")))))))
            :ARG1-of (m / mark-01))
      :location (c / cell
            :mod (t / this))
      :ARG1-of (d / determine-01
            :ARG0 (a / and
                  :op1 (a2 / analyze-01
                        :mod (t2 / thing :name (n4 / name :op1 "RT-PCR"))
                        :mod (q / quantitative
                              :degree (s / semi))
                        :mod (r3 / real-time))
                  :op2 (a3 / analyze-01
                        :mod (q2 / quantitative)
                        :mod r3
                        :mod t2)))
      :manner (l2 / likewise)
      :ARG1-of (d2 / describe-01
            :ARG2 (a4 / and
                  :op1 (f / figure :mod "1C")
                  :op2 (f2 / figure :mod "1D"))))

# ::id pmid_2470_8867.110 ::date 2015-08-27T12:19:27 ::annotator SDL-AMR-09 ::preferred
# ::snt Analysis of the expression profiles of E-cadherin transcriptional repressors in these IECs suggests that a combined up-regulation of <i>Snail2</i>, <i>Twist1,</i> or <i>Twist2</i>, but not of <i>Snail1</i> or <i>Zeb1</i>, may partly account for the E-cadherin repression induced by oncogenic Met-dependent signaling, including that one driven by Grb2 and Shc signals (Additional file <xref ref-type="supplementary-material" rid="S2">2</xref>).
# ::save-date Sun Jan 17, 2016 ::file pmid_2470_8867_110.txt
(s / suggest-01
      :ARG0 (a / analyze-01
            :ARG1 (p / profile-01
                  :ARG1 (e / express-03
                        :ARG2 (m / molecular-physical-entity
                              :ARG0-of (r / repress-01
                                    :ARG1 (t / transcribe-01
                                          :ARG1 (p2 / protein :name (n / name :op1 "E-cadherin")))))))
            :location (c / cell :name (n2 / name :op1 "IEC")
                  :mod (t2 / this)))
      :ARG1 (c2 / contrast-01
            :ARG1 (p3 / possible-01
                  :ARG1 (a2 / account-01
                        :ARG0 (u / upregulate-01
                              :ARG1 (o / or
                                    :op1 (g / gene :name (n3 / name :op1 "Snail2"))
                                    :op2 (g2 / gene :name (n4 / name :op1 "Twist1"))
                                    :op3 (g3 / gene :name (n5 / name :op1 "Twist2")))
                              :ARG1-of (c3 / combine-01))
                        :ARG1 (r2 / repress-01
                              :ARG1 p2
                              :ARG2-of (i / induce-01
                                    :ARG0 (s2 / signal-07
                                          :ARG0-of (d / depend-01
                                                :ARG1 (p6 / protein :name (n7 / name :op1 "Met")))
                                          :ARG0-of (c4 / cause-01
                                                :ARG1 (c5 / cancer))))
                              :ARG2-of (i2 / include-01
                                    :ARG1 (r3 / repress-01
                                          :ARG1-of (d2 / drive-02
                                                :ARG0 (s3 / signal-07
                                                      :ARG0 (a3 / and
                                                            :op1 (p7 / protein :name (n8 / name :op1 "Grb2"))
                                                            :op2 (p8 / protein :name (n9 / name :op1 "Shc"))))))))
                        :degree (p4 / part)))
            :ARG2 (a5 / account-01 :polarity -
                  :ARG0 (u2 / upregulate-01
                        :ARG1 (o2 / or
                              :op1 (g4 / gene :name (n10 / name :op1 "Snail1"))
                              :op2 (g5 / gene :name (n11 / name :op1 "Zeb1")))
                        :ARG1-of c3)
                  :ARG1 r2))
      :ARG1-of (d3 / describe-01
            :ARG0 (f / figure :mod 2
                  :mod (a4 / additional))))

# ::id pmid_2470_8867.111 ::date 2015-08-27T13:11:30 ::annotator SDL-AMR-09 ::preferred
# ::snt Overall, these results demonstrate that oncogenic activation of Grb2- and Shc-dependent signaling pathways, such as those activated by Tpr-Met, is sufficient to induce an epithelial-mesenchymal morphological-like transformation in normal IECs.
# ::save-date Wed Sep 16, 2015 ::file pmid_2470_8867_111.txt
(d / demonstrate-01
      :ARG0 (t / thing
            :ARG2-of (r / result-01)
            :mod (t2 / this))
      :ARG1 (s / suffice-01
            :ARG0 (a / activate-01
                  :ARG1 (p / pathway
                        :ARG0-of (s2 / signal-07
                              :ARG0-of (d2 / depend-01
                                    :ARG1 (a2 / and
                                          :op1 (p2 / protein :name (n / name :op1 "Grb2"))
                                          :op2 (p3 / protein :name (n2 / name :op1 "Shc")))))
                        :example (p4 / pathway
                                    :ARG1-of (a3 / activate-01
                                          :ARG0 (p5 / protein :name (n3 / name :op1 "Tpr-Met")))))
                  :ARG0-of (c / cause-01
                        :ARG1 (c2 / cancer)))
            :ARG1 (i / induce-01
                  :ARG0 a
                  :ARG2 (t3 / transform-01
                        :ARG1 (c3 / cell :name (n4 / name :op1 "IEC")
                              :ARG1-of (n5 / normal-02))
                        :ARG1-of (r2 / resemble-01
                              :ARG2 (m / morphology))
                        :mod (e2 / epithelium
                              :mod (m2 / mesenchyme)))))
      :mod (o / overall))

# ::id pmid_2470_8867.112 ::date 2015-08-27T13:38:25 ::annotator SDL-AMR-09 ::preferred
# ::snt <sec-title level="2">Oncogenic engagement of Grb2 or Shc signaling enhances cell growth and loss of contact inhibition in IECs</sec-title>
# ::save-date Sun Jan 17, 2016 ::file pmid_2470_8867_112.txt
(e / enhance-01
      :ARG0 (e2 / engage-01
            :ARG1 (s / signal-07
                  :ARG0 (o / or
                        :op1 (p / protein :name (n / name :op1 "Grb2"))
                        :op2 (p2 / protein :name (n2 / name :op1 "Shc"))))
            :ARG0-of (c / cause-01
                  :ARG1 (c2 / cancer)))
      :ARG1 (a2 / and
            :op1 (g / grow-01
                  :ARG1 (c3 / cell))
            :op2 (l / lose-01
                  :ARG1 (i / inhibit-01
                        :ARG0 (c4 / contact-01))
                  :location (c5 / cell :name (n3 / name :op1 "IEC")))))

# ::id pmid_2470_8867.113 ::date 2015-08-27T13:45:40 ::annotator SDL-AMR-09 ::preferred
# ::snt We next tested the oncogenic growth characteristics of IEC-6 cells transformed by the Tpr-Met variants.
# ::save-date Wed Sep 16, 2015 ::file pmid_2470_8867_113.txt
(t / test-01
      :ARG0 (w / we)
      :ARG1 (c / characteristic-02
            :ARG1 (c4 / cell-line :name (n / name :op1 "IEC-6")
                  :ARG1-of (t2 / transform-01
                        :ARG0 (v / variant
                              :mod (p / protein :name (n3 / name :op1 "Tpr-Met")))))
            :ARG2 (g / grow-01
                  :ARG1 c4)
            :ARG0-of (c2 / cause-01
                  :ARG1 (c3 / cancer)))
      :time (n2 / next))

# ::id pmid_2470_8867.114 ::date 2015-08-27T13:58:25 ::annotator SDL-AMR-09 ::preferred
# ::snt First, cell-counting assays were performed to determine the growth rate of each cell population.
# ::save-date Thu Aug 27, 2015 ::file pmid_2470_8867_114.txt
(p / perform-02
      :ARG1 (a / assay-01
            :ARG1 (c / count-01
                  :ARG1 (c2 / cell)))
      :purpose (d / determine-01
            :ARG1 (r / rate-01
                  :mod (g / grow-01
                        :ARG1 (p2 / population
                              :consist-of (c3 / cell)
                              :mod (e / each)))))
      :ord (o / ordinal-entity :value 1))

# ::id pmid_2470_8867.115 ::date 2015-08-27T14:11:23 ::annotator SDL-AMR-09 ::preferred
# ::snt The TM-Grb2-IEC-6, TM-Shc1-IEC-6, and TM-Shc2-IEC-6 cells displayed more rapid growth than Control-IEC-6 cells, albeit to a lesser extent than Tpr-Met-IEC-6 cells (Figure <xref ref-type="fig" rid="F2">2</xref>A).
# ::save-date Sun Sep 13, 2015 ::file pmid_2470_8867_115.txt
(d / display-01
      :ARG0 (a / and
            :op1 (c / cell-line :name (n / name :op1 "TM-Grb2-IEC-6"))
            :op2 (c2 / cell-line :name (n2 / name :op1 "TM-Shc1-IEC-6"))
            :op3 (c3 / cell-line :name (n3 / name :op1 "TM-Shc2-IEC-6")))
      :ARG1 (g / grow-01
            :mod (r / rapid
                  :degree (m / more)
                  :compared-to (c4 / cell-line :name (n4 / name :op1 "Control-IEC-6"))))
      :concession (d2 / display-01
                  :ARG0 a
                  :ARG1 (g2 / grow-01
                        :mod (r2 / rapid
                              :degree (l / less)
                              :compared-to (c5 / cell-line :name (n5 / name :op1 "Tpr-Met-IEC-6")))))
      :ARG1-of (d3 / describe-01
            :ARG0 (f / figure :mod "2A")))

# ::id pmid_2470_8867.116 ::date 2015-08-27T14:27:53 ::annotator SDL-AMR-09 ::preferred
# ::snt Notably, TM-Shc1-IEC-6 cells exhibited accelerated growth relative to TM-Grb2-IEC-6 and TM-Shc2-IEC-6 cells, between which the doubling time did not differ significantly.
# ::save-date Sun Sep 13, 2015 ::file pmid_2470_8867_116.txt
(e / exhibit-01
      :ARG0 (c / cell-line :name (n / name :op1 "TM-Shc1-IEC-6"))
      :ARG1 (g / grow-01
            :ARG1-of (a / accelerate-01)
            :ARG1-of (r / relative-05
                  :ARG3 (a2 / and
                        :op1 (c3 / cell-line :name (n3 / name :op1 "TM-Grb2-IEC-6")
                              :ARG1-of (d / differ-02 :polarity -
                                    :ARG2 c2
                                    :ARG3 (t / time
                                          :duration-of (d2 / double-01))
                                    :ARG1-of (s / significant-02)))
                        :op2 (c2 / cell-line :name (n2 / name :op1 "TM-Shc2-IEC-6")))))
      :ARG1-of (n4 / notable-04))

# ::id pmid_2470_8867.117 ::date 2015-08-27T14:44:54 ::annotator SDL-AMR-09 ::preferred
# ::snt The enhanced growth promoting activity of the TM-Shc1 relative to the TM-Shc2 correlates with the affinity of their respective Shc binding sites [<xref ref-type="bibr" rid="B8">8</xref>].
# ::save-date Wed Sep 16, 2015 ::file pmid_2470_8867_117.txt
(c / correlate-01
      :ARG1 (a / activity-06
            :ARG0 (p3 / protein :name (n / name :op1 "TM-Shc1"))
            :ARG1-of (e / enhance-01)
            :ARG0-of (p / promote-02
                  :ARG1 (g / grow-01))
            :ARG1-of (r / relative-05
                  :ARG2 (p2 / protein :name (n2 / name :op1 "TM-Shc2"))))
      :ARG2 (a2 / affinity
            :poss (a3 / and
                  :op1 (p6 / protein-segment
                        :part-of p3)
                  :op2 (p7 / protein-segment
                        :part-of p2)
                  :ARG2-of (b / bind-01
                        :ARG1 (p4 / protein :name (n3 / name :op1 "Shc")))))
      :ARG1-of (d / describe-01
            :ARG0 (p5 / publication
                  :ARG1-of (c2 / cite-01
                        :ARG2 8))))

# ::id pmid_2470_8867.118 ::date 2015-08-27T15:09:18 ::annotator SDL-AMR-09 ::preferred
# ::snt Typical of untransformed cells, IEC-6 cells ceased proliferation upon the establishment of cell-cell contacts [<xref ref-type="bibr" rid="B5">5</xref>,<xref ref-type="bibr" rid="B25">25</xref>].
# ::save-date Sun Sep 13, 2015 ::file pmid_2470_8867_118.txt
(c / cease-01
      :ARG1 (p / proliferate-01
            :ARG0 (c2 / cell-line :name (n / name :op1 "IEC-6")))
      :time (e / establish-01
            :ARG1 (c3 / contact-01
                  :ARG0 (c4 / cell)
                  :ARG1 (c5 / cell)))
      :ARG1-of (t / typical-02
            :ARG2 (c6 / cell
                  :ARG1-of (t2 / transform-01 :polarity -)))
      :ARG1-of (d / describe-01
            :ARG0 (p2 / publication
                  :ARG1-of (c7 / cite-01
                        :ARG2 (a / and :op1 5 :op2 25)))))

# ::id pmid_2470_8867.119 ::date 2015-08-27T15:20:08 ::annotator SDL-AMR-09 ::preferred
# ::snt As such, Control-IEC-6 cells formed a monolayer of well-organized epithelial cells upon reaching confluence (Figure <xref ref-type="fig" rid="F2">2</xref>B).
# ::save-date Sun Sep 13, 2015 ::file pmid_2470_8867_119.txt
(f / form-01
      :ARG0 (c / cell-line :name (n / name :op1 "Control-IEC-6"))
      :ARG1 (l / layer :quant 1
            :consist-of (c2 / cell
                  :source (e / epithelium)
                  :ARG1-of (o / organize-01
                        :ARG1-of (w / well-09))))
      :prep-as (s / such)
      :time (r / reach-01
            :ARG1 (c3 / confluence))
      :ARG1-of (d / describe-01
            :ARG2 (f2 / figure :mod "2B")))

# ::id pmid_2470_8867.120 ::date 2015-08-27T15:28:37 ::annotator SDL-AMR-09 ::preferred
# ::snt In sharp contrast, each of the oncogenic transformed IEC-6 cell populations appeared highly disorganized and grew in multiple layers at confluence (Figure <xref ref-type="fig" rid="F2">2</xref>B).
# ::save-date Sun Sep 13, 2015 ::file pmid_2470_8867_120.txt
(c / contrast-01
      :ARG2 (a / and
            :op1 (a2 / appear-02
                  :ARG1 (o2 / organize-01 :polarity -
                        :ARG1 (p / population
                              :consist-of (c2 / cell-line :name (n / name :op1 "IEC-6"))
                              :ARG0-of (c3 / cause-01
                                    :ARG1 (c4 / cancer))
                              :ARG1-of (t / transform-01)
                              :mod (e / each))
                        :ARG1-of (h / high-02)))
            :op2 (g / grow-01
                  :ARG1 p
                  :manner (l / layer
                        :quant (m / multiple))
                  :time (c5 / confluence)))
      :ARG1-of (s / sharp-02)
      :ARG1-of (d / describe-01
            :ARG2 (f / figure :mod "2B")))

# ::id pmid_2470_8867.121 ::date 2015-08-27T15:42:31 ::annotator SDL-AMR-09 ::preferred
# ::snt Thus, oncogenic specific activation of Grb2- or Shc-dependent signals permits IECs to bypass contact inhibition of growth.
# ::save-date Thu Aug 27, 2015 ::file pmid_2470_8867_121.txt
(i / infer-01
      :ARG1 (p / permit-01
            :ARG0 (a / activate-01
                  :ARG1 (s / signal-07
                        :ARG0-of (d / depend-01
                              :ARG1 (a2 / and
                                    :op1 (p2 / protein :name (n / name :op1 "Grb2"))
                                    :op2 (p3 / protein :name (n2 / name :op1 "Shc")))))
                  :ARG0-of (c / cause-01
                        :ARG1 (c2 / cancer))
                  :ARG1-of (s2 / specific-02))
            :ARG1 (b / bypass-01
                  :ARG0 c3
                  :ARG1 (i2 / inhibit-01
                        :ARG0 (c4 / contact-01)
                        :ARG1 (g / grow-01)))
            :ARG2 (c3 / cell :name (n3 / name :op1 "IEC"))))

# ::id pmid_2470_8867.122 ::date 2015-08-27T15:53:01 ::annotator SDL-AMR-09 ::preferred
# ::snt To validate this in a quantitative manner, focus formation assays were performed.
# ::save-date Thu Aug 27, 2015 ::file pmid_2470_8867_122.txt
(p / perform-02
      :ARG1 (a / assay-01
            :ARG1 (f / form-01
                  :ARG1 (f2 / focus)))
      :purpose (v / validate-01
            :ARG1 (t / this)
            :manner (q / quantitative)))

# ::id pmid_2470_8867.123 ::date 2015-08-27T15:57:54 ::annotator SDL-AMR-09 ::preferred
# ::snt As expected [<xref ref-type="bibr" rid="B5">5</xref>], Control-IEC-6 cells failed to form foci, whereas TM-Grb2-IEC-6, TM-Shc1-IEC-6, and TM-Shc2-IEC-6 cells displayed strong focus-forming capacities, though less than that of Tpr-Met-IEC-6 cells (Figure <xref ref-type="fig" rid="F2">2</xref>C and D).
# ::save-date Sun Sep 13, 2015 ::file pmid_2470_8867_123.txt
(c / contrast-01
      :ARG1 (f / fail-01
            :ARG1 (c2 / cell-line :name (n / name :op1 "Control-IEC-6"))
            :ARG2 (f2 / form-01
                  :ARG0 c2
                  :ARG1 (f3 / focus)))
      :ARG2 (d / display-01
            :ARG0 (a / and
                  :op1 (c3 / cell-line :name (n2 / name :op1 "TM-Grb2-IEC-6"))
                  :op2 (c4 / cell-line :name (n3 / name :op1 "TM-Shc1-IEC-6"))
                  :op3 (c5 / cell-line :name (n4 / name :op1 "TM-Shc2-IEC-6")))
            :ARG1 (c6 / capable-01
                  :ARG1 a
                  :ARG2 (f4 / form-01
                        :ARG0 a
                        :ARG1 (f5 / focus))
                  :ARG1-of (s / strong-02))
            :concession (d2 / display-01
                        :ARG0 a
                        :ARG1 (c7 / capable-01
                              :ARG1 a
                              :ARG2 f4
                              :degree (l / less)
                              :compared-to (c8 / cell-line :name (n5 / name :op1 "Tpr-Met-IEC-6")))))
      :ARG1-of (d3 / describe-01
            :ARG0 (a2 / and
                  :op1 (f6 / figure :mod "2C")
                  :op2 (f7 / figure :mod "2D")))
      :ARG1-of (e / expect-01
            :ARG1-of (d4 / describe-01
                  :ARG0 (p / publication
                        :ARG0-of (c9 / cite-01
                              :ARG2 5)))))

# ::id pmid_2470_8867.124 ::date 2015-08-28T06:33:59 ::annotator SDL-AMR-09 ::preferred
# ::snt The number and size of foci formed by the TM-Shc1-IEC-6 cells were markedly greater than those of the TM-Grb2-IEC-6 or TM-Shc2-IEC-6 cells (Figure <xref ref-type="fig" rid="F2">2</xref>C and D), likely reflecting their accelerated growth rate (Figure <xref ref-type="fig" rid="F2">2</xref>A).
# ::save-date Fri Sep 11, 2015 ::file pmid_2470_8867_124.txt
(g2 / great
      :domain (a3 / and
            :op1 (n / number
                  :quant-of (f / focus
                        :ARG1-of (f2 / form-01
                              :ARG0 (c4 / cell-line :name (n8 / name :op1 "TM-Shc1-IEC-6")))))
            :op2 (s / size
                  :poss f)
            :manner (m3 / marked))
      :compared-to (a2 / and
            :op1 (n4 / number
                  :quant-of (f3 / focus
                        :ARG1-of (f4 / form-01
                              :ARG0 (o / or
                                    :op1 (c2 / cell-line :name (n2 / name :op1 "TM-Grb2-IEC-6"))
                                    :op2 (c5 / cell-line :name (n3 / name :op1 "TM-Shc2-IEC-6"))))))
            :op2 (s2 / size
                  :poss f3))
      :ARG1-of (d / describe-01
            :ARG0 (a4 / and
                  :op1 (f5 / figure :mod "2C")
                  :op2 (f6 / figure :mod "2D")))
      :ARG1-of (r2 / reflect-01
            :ARG2 (a5 / accelerate-01
                  :ARG1 (r3 / rate
                        :mod (g / grow-01
                              :ARG1 f)))
            :ARG1-of (l / likely-01)
            :ARG1-of (d2 / describe-01
                  :ARG0 (f7 / figure :mod "2A")))
      :degree (m / more))

# ::id pmid_2470_8867.125 ::date 2015-08-28T09:02:27 ::annotator SDL-AMR-09 ::preferred
# ::snt These results indicate that the oncogenic engagement of Grb2- and Shc-dependent signals is sufficient to relieve contact inhibition of growth in IECs.
# ::save-date Tue Sep 8, 2015 ::file pmid_2470_8867_125.txt
(i / indicate-01
      :ARG0 (t / thing
            :ARG2-of (r / result-01)
            :mod (t2 / this))
      :ARG1 (s / suffice-01
            :ARG0 (e / engage-01
                  :ARG1 (s2 / signal-07
                        :ARG0-of (d / depend-01
                              :ARG1 (a / and
                                    :op1 (p / protein :name (n / name :op1 "Grb2"))
                                    :op2 (p2 / protein :name (n2 / name :op1 "Shc")))))
                  :ARG2 (c / cancer))
            :ARG1 (r2 / relieve-01
                  :ARG0 e
                  :ARG1 (i2 / inhibit-01
                        :ARG0 (c3 / contact-01)
                        :ARG1 (g / grow-01
                              :location (c2 / cell :name (n3 / name :op1 "IEC")))))))

# ::id pmid_2470_8867.126 ::date 2015-08-28T09:16:27 ::annotator SDL-AMR-09 ::preferred
# ::snt <sec-title level="2">Oncogenic engagement of Grb2 and Shc signaling induces anchorage-independent growth and anoikis resistance in IECs</sec-title>
# ::save-date Tue Sep 8, 2015 ::file pmid_2470_8867_126.txt
(i / induce-01
      :ARG0 (e / engage-01
            :ARG1 (s / signal-07
                  :ARG1 (a / and
                        :op1 (p / protein :name (n / name :op1 "Grb2"))
                        :op2 (p2 / protein :name (n2 / name :op1 "Shc"))))
            :ARG2 (c / cancer))
      :ARG2 (a2 / and
            :op1 (g / grow-01
                  :ARG0-of (d / depend-01 :polarity -
                        :ARG1 (a3 / anchorage)))
            :op2 (r / resist-01
                  :ARG1 (a4 / anoikis))
            :location (c2 / cell :name (n3 / name :op1 "IEC"))))

# ::id pmid_2470_8867.127 ::date 2015-08-29T02:24:53 ::annotator SDL-AMR-09 ::preferred
# ::snt We next verified whether the oncogenic activation of Grb2- or Shc-dependent signals is sufficient to confer to non-transformed IEC-6 cells the capacity to grow in the absence of anchorage to the extra-cellular matrix (ECM), by performing soft agar growth assays.
# ::save-date Sat Feb 13, 2016 ::file pmid_2470_8867_127.txt
(v / verify-01
      :ARG0 (w / we)
      :ARG1 (s / suffice-01 :mode interrogative
            :ARG0 (a / activate-01
                  :ARG1 (s2 / signal-07
                        :ARG0-of (d / depend-01
                              :ARG1 (o / or
                                    :op1 (p / protein :name (n2 / name :op1 "Grb2"))
                                    :op2 (p2 / protein :name (n3 / name :op1 "Shc")))))
                  :ARG0-of (c5 / cause-01
                        :ARG1 (c6 / cancer)))
            :ARG1 (c2 / confer-02
                  :ARG0 a
                  :ARG1 (c / capable-01
                        :ARG1 (c3 / cell-line :name (n4 / name :op1 "IEC-6")
                              :ARG1-of (t / transform-01 :polarity -))
                        :ARG2 (g / grow-01
                              :ARG1 c3
                              :condition (a2 / absent-01
                                    :ARG1 (a3 / anchor-01
                                          :location (m / matrix
                                                :mod (e / extracellular))))))
                  :ARG2 c3))
      :time (n / next)
      :manner (p3 / perform-01
            :ARG0 w
            :ARG1 (a4 / assay-01
                  :ARG1 (g2 / grow-01
                        :condition (a5 / agar
                              :ARG1-of (s3 / soft-02))))))

# ::id pmid_2470_8867.128 ::date 2015-08-29T02:47:46 ::annotator SDL-AMR-09 ::preferred
# ::snt Consistent with previous findings [<xref ref-type="bibr" rid="B5">5</xref>], Control-IEC-6 cells failed to grow in soft agar whereas Tpr-Met-IEC-6 cells grew efficiently, forming numerous large colonies (Figure <xref ref-type="fig" rid="F3">3</xref>A–C).
# ::save-date Mon Jan 4, 2016 ::file pmid_2470_8867_128.txt
(c / contrast-01
      :ARG1 (f2 / fail-01
            :ARG1 (c8 / cell-line :name (n5 / name :op1 "IEC-6")
                  :ARG0-of (c5 / control-01))
            :ARG2 (g / grow-01
                  :ARG1 c8
                  :location (a / agar
                        :ARG1-of (s / soft-02))))
      :ARG2 (g2 / grow-01
            :ARG1 (c4 / cell-line :name (n / name :op1 "Tpr-Met-IEC-6")
                  :ARG2-of (f3 / form-01
                        :ARG1 (c6 / colony
                              :mod (l / large)
                              :quant (n4 / numerous))))
            :ARG2-of (e2 / efficient-01))
      :ARG1-of (c2 / consistent-01
            :ARG2 (t / thing
                  :ARG1-of (f / find-01)
                  :time (p / previous))
            :ARG1-of (d / describe-01
                  :ARG0 (p3 / publication
                        :ARG1-of (c7 / cite-01
                              :ARG2 5))))
      :ARG1-of (d2 / describe-01
            :ARG0 (a2 / and
                  :op1 (f4 / figure :mod "3A")
                  :op2 (f5 / figure :mod "3B")
                  :op3 (f6 / figure :mod "3C"))))

# ::id pmid_2470_8867.129 ::date 2015-08-30T00:33:57 ::annotator SDL-AMR-09 ::preferred
# ::snt TM-Grb2-IEC-6, TM-Shc1-IEC-6, and TM-Shc2-IEC-6 cells also formed colonies in soft agar, but with lower efficiencies.
# ::save-date Wed Sep 16, 2015 ::file pmid_2470_8867_129.txt
(f / form-01
      :ARG0 (a / and
            :op1 (c6 / cell-line :name (n7 / name :op1 "TM-Grb2-IEC-6"))
            :op2 (c7 / cell-line :name (n8 / name :op1 "TM-Shc1-IEC-6"))
            :op3 (c8 / cell-line :name (n9 / name :op1 "TM-Shc2-IEC-6")))
      :ARG1 (c4 / colony)
      :location (a2 / agar
            :ARG1-of (s / soft-02))
      :ARG1-of (c5 / contrast-01
            :ARG2 (e4 / efficient-01
                  :ARG2 f
                  :ARG1-of (l / low-04
                        :degree (m2 / more))))
      :mod (a3 / also))

# ::id pmid_2470_8867.130 ::date 2015-08-30T00:51:32 ::annotator SDL-AMR-09 ::preferred
# ::snt While the three IEC-6 cell populations expressing docking-specific Tpr-Met variants formed similar numbers of colonies (Figure <xref ref-type="fig" rid="F3">3</xref>A), those produced by the TM-Shc1-IEC-6 cells were larger and displayed a different morphology from those produced by the TM-Shc2-IEC-6 and TM-Grb2-IEC-6 cells (Figure <xref ref-type="fig" rid="F3">3</xref>B and C).
# ::save-date Thu Sep 10, 2015 ::file pmid_2470_8867_130.txt
(c / contrast-01
      :ARG1 (f / form-01
            :ARG0 (p / population :quant 3
                  :mod (c2 / cell-line :name (n / name :op1 "IEC-6"))
                  :ARG3-of (e / express-03
                        :ARG2 (v / variant
                              :mod (p2 / protein :name (n2 / name :op1 "Tpr-Met")
                                    :ARG1-of (s2 / specific-02
                                          :ARG2 (d / dock-01))))))
            :ARG1 (n3 / number-01
                  :ARG1 (c3 / colony)
                  :ARG1-of (r / resemble-01))
            :ARG1-of (d2 / describe-01
                  :ARG0 (f2 / figure :mod "3A")))
      :ARG2 (p3 / produce-01
            :ARG0 (c4 / cell-line :name (n4 / name :op1 "TM-Shc1-IEC-6"))
            :ARG1 (c6 / colony
                  :mod (l / large
                        :degree (m / more))
                  :ARG0-of (d3 / display-01
                        :ARG1 (m2 / morphology
                              :ARG1-of (d4 / differ-02
                                    :ARG2 (c7 / colony
                                          :ARG1-of (p5 / produce-01
                                                :ARG0 (a / and
                                                      :op1 (c5 / cell-line :name (n6 / name :op1 "TM-Shc2-IEC-6"))
                                                      :op2 (c8 / cell-line :name (n7 / name :op1 "TM-Grb2-IEC-6")))))))))
            :ARG1-of (d5 / describe-01
                  :ARG0 (a2 / and
                        :op1 (f3 / figure :mod "3B")
                        :op2 (f4 / figure :mod "3C")))))

# ::id pmid_2470_8867.131 ::date 2015-08-30T01:11:28 ::annotator SDL-AMR-09 ::preferred
# ::snt Colonies formed by the TM-Shc1-IEC-6 cells were composed mainly of loosely associated cells with apparently limited cell-cell contacts, similar to Tpr-Met-IEC-6 colonies (Figure <xref ref-type="fig" rid="F3">3</xref>B).
# ::save-date Thu Sep 10, 2015 ::file pmid_2470_8867_131.txt
(c / compose-01
      :ARG1 (c3 / colony
            :ARG1-of (f / form-01
                  :ARG0 (c2 / cell-line :name (n / name :op1 "TM-Shc1-IEC-6"))))
      :ARG2 (c4 / cell
            :ARG1-of (a / associate-01
                  :ARG1-of (l / loose-04))
            :ARG0-of (h / have-03
                  :ARG1 (c5 / contact-01
                        :ARG0 (c6 / cell)
                        :ARG1 (c7 / cell)
                        :ARG1-of (l2 / limit-01))
                  :ARG1-of (a2 / appear-02)))
      :mod (m / main)
      :ARG1-of (r / resemble-01
            :ARG2 (c9 / colony
                  :mod (c10 / cell-line :name (n3 / name :op1 "Tpr-Met-IEC-6"))))
      :ARG1-of (d / describe-01
            :ARG0 (f2 / figure :mod "3B")))

# ::id pmid_2470_8867.132 ::date 2015-08-30T01:20:15 ::annotator SDL-AMR-09 ::preferred
# ::snt By contrast, colonies produced by the TM-Grb2-IEC-6 or TM-Shc2-IEC-6 cells were compact and composed of tightly associated cells (Figure <xref ref-type="fig" rid="F3">3</xref>B).
# ::save-date Wed Sep 16, 2015 ::file pmid_2470_8867_132.txt
(c / contrast-01
      :ARG2 (p / produce-01
            :ARG0 (o / or
                  :op1 (c3 / cell-line :name (n / name :op1 "TM-Grb2-IEC-6"))
                  :op2 (c4 / cell-line :name (n2 / name :op1 "TM-Shc2-IEC-6")))
            :ARG2 (c2 / colony
                  :ARG1-of (c5 / compact-01)
                  :ARG1-of (c6 / compose-01
                        :ARG2 (c7 / cell
                              :ARG1-of (a / associate-01
                                    :ARG1-of (t / tight-05))))))
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod "3B")))

# ::id pmid_2470_8867.133 ::date 2015-08-30T01:24:53 ::annotator SDL-AMR-09 ::preferred
# ::snt Growth in soft agar reflects not only the capacity of cells to proliferate in the absence of ECM attachment, but also to avoid anoikis, a form of apoptosis induced upon loss of matrix attachment [<xref ref-type="bibr" rid="B32">32</xref>].
# ::save-date Sat Feb 13, 2016 ::file pmid_2470_8867_133.txt
(r / reflect-01
      :ARG1 (g / grow-01
            :location (a / agar
                  :ARG1-of (s / soft-02)))
      :ARG2 (c / capable-01
            :ARG1 (c2 / cell)
            :ARG2 (a2 / and
                  :op1 (p / proliferate-01
                        :condition (a3 / absent-01
                              :ARG1 (a4 / attach-01
                                    :ARG1 c2
                                    :ARG2 (m3 / matrix
                                          :mod (e / extracellular)))))
                  :op2 (a5 / avoid-01
                        :ARG1 (a6 / anoikis)
                        :ARG1-of (m / mean-01
                              :ARG2 (f / form
                                    :mod (a7 / apoptosis
                                          :ARG2-of (i / induce-01
                                                :condition (l / lose-02
                                                      :ARG1 (a8 / attach-01
                                                            :ARG2 (m2 / matrix))))))))))
      :ARG1-of (d / describe-01
            :ARG0 (p2 / publication
                  :ARG1-of (c3 / cite-01
                        :ARG2 32))))

# ::id pmid_2470_8867.134 ::date 2015-08-30T01:43:03 ::annotator SDL-AMR-09 ::preferred
# ::snt Anoikis assays were performed by monitoring the viability of cells seeded in the absence of serum under adherent and suspension conditions.
# ::save-date Thu Sep 10, 2015 ::file pmid_2470_8867_134.txt
(p / perform-01
      :ARG1 (a / assay-01
            :ARG1 (a2 / anoikis))
      :ARG2 (m / monitor-01
            :ARG1 (v / viable
                  :domain (c / cell
                        :ARG2-of (s / seed-02
                              :condition (a3 / absent-01
                                    :ARG1 (s2 / serum)
                                    :condition (a4 / and
                                          :op1 (a5 / adhere-01)
                                          :op2 (s3 / suspend-02))))))))

# ::id pmid_2470_8867.135 ::date 2015-08-30T02:07:23 ::annotator SDL-AMR-09 ::preferred
# ::snt As expected for normal IECs [<xref ref-type="bibr" rid="B33">33</xref>,<xref ref-type="bibr" rid="B34">34</xref>], Control-IEC-6 cells displayed anoikis sensitivity under suspension culture conditions (Figure <xref ref-type="fig" rid="F3">3</xref>D).
# ::save-date Thu Sep 10, 2015 ::file pmid_2470_8867_135.txt
(d / display-01
      :ARG0 (c / cell-line :name (n / name :op1 "IEC-6")
            :ARG0-of (c2 / control-01))
      :ARG1 (s / sensitive-03
            :ARG0 c
            :ARG1 (a / anoikis))
      :condition (c3 / culture
            :ARG1-of (s2 / suspend-02))
      :ARG1-of (e / expect-01
            :topic (c4 / cell :name (n2 / name :op1 "IEC")
                  :ARG1-of (n3 / normal-02))
            :ARG1-of (d2 / describe-01
                  :ARG0 (p / publication
                        :ARG1-of (c5 / cite-01
                              :ARG2 (a2 / and :op1 33 :op2 34)))))
      :ARG1-of (d3 / describe-01
            :ARG0 (f / figure :mod "3D")))

# ::id pmid_2470_8867.136 ::date 2015-08-30T02:13:33 ::annotator SDL-AMR-09 ::preferred
# ::snt In contrast, IEC-6 cells transformed by either Tpr-Met, or the Grb2 or Shc docking-specific oncoproteins, displayed potent resistance to anoikis, with more than half surviving under non-adherent conditions.
# ::save-date Tue Jan 12, 2016 ::file pmid_2470_8867_136.txt
(c / contrast-01
      :ARG2 (d / display-01
            :ARG0 (c2 / cell-line :wiki -
                  :name (n / name :op1 "IEC-6")
                  :ARG1-of (t / transform-01
                        :ARG0 (o / or
                              :op1 (p / protein :wiki "Tpr-met_fusion_protein"
                                    :name (n2 / name :op1 "Tpr-Met"))
                              :op2 (o4 / or
                                    :op1 (p2 / protein :wiki "GRB2"
                                          :name (n5 / name :op1 "Grb2"))
                                    :op2 (p3 / protein :wiki "SHC1"
                                          :name (n6 / name :op1 "Shc"))
                                    :ARG0-of (c5 / cause-01
                                          :ARG1 (d3 / disease :wiki "Cancer"
                                                :name (n3 / name :op1 "cancer"))))
                              :mod (e / either)
                              :ARG1-of (s / specific-02
                                    :ARG2 (d2 / dock-01)))))
            :ARG1 (r / resist-01
                  :ARG0 c2
                  :ARG1 (a / anoikis)
                  :mod (p4 / potent)
                  :mod (s2 / survive-01
                        :ARG0 (c4 / cell
                              :ARG1-of (i / include-91
                                    :ARG2 c2
                                    :ARG3 (m2 / more-than :op1 "1/2")))
                        :ARG1 (c3 / condition
                              :ARG1-of (a2 / adhere-01 :polarity -))))))

# ::id pmid_2470_8867.137 ::date 2015-08-30T02:25:28 ::annotator SDL-AMR-09 ::preferred
# ::snt Likewise, the viability of these transformed cells was significantly higher than that of Control-IEC-6 cells when seeded in the absence of serum and under adherent conditions (Figure <xref ref-type="fig" rid="F3">3</xref>E).
# ::save-date Fri Sep 11, 2015 ::file pmid_2470_8867_137.txt
(h / high-02
      :ARG1 (v / viable
            :domain (c2 / cell
                  :ARG1-of (t / transform-01)
                  :mod (t2 / this)
                  :ARG0-of (s / seed-01
                        :condition (a / and
                              :op1 (a2 / absent-01
                                    :ARG1 (s2 / serum))
                              :op2 (c5 / condition
                                    :mod (a3 / adhere-01)))))
            :ARG1-of (s3 / significant-02))
      :compared-to (c3 / cell-line :name (n / name :op1 "IEC-6")
            :ARG0-of (c4 / control-01))
      :manner (l / likewise)
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod "3E"))
      :degree (m / more))

# ::id pmid_2470_8867.138 ::date 2015-08-30T02:32:52 ::annotator SDL-AMR-09 ::preferred
# ::snt Overall, these results indicate that the oncogenic engagement of signals downstream of Grb2 or Shc is sufficient to alleviate the anchorage-dependence of growth, and to reduce sensitivity to growth factor deprivation and to anoikis in IECs.
# ::save-date Wed Feb 24, 2016 ::file pmid_2470_8867_138.txt
(i / indicate-01
      :ARG0 (t / thing
            :ARG2-of (r / result-01)
            :mod (t2 / this))
      :ARG1 (s / suffice-01
            :ARG0 (e / engage-01
                  :ARG1 (s2 / signal-07
                        :ARG1 (o2 / or
                              :op1 (p / protein :name (n / name :op1 "Grb2"))
                              :op2 (p2 / protein :name (n2 / name :op1 "Shc")))
                        :mod (d / downstream))
                  :ARG2 (c / cancer))
            :ARG1 (a2 / and
                  :op1 (a3 / alleviate-01
                        :ARG0 e
                        :ARG1 (d2 / depend-01
                              :ARG0 (g / grow-01)
                              :ARG1 (a4 / anchorage)))
                  :op2 (r2 / reduce-01
                        :ARG0 e
                        :ARG1 (s3 / sensitive-03
                              :ARG1 (a5 / and
                                    :op1 (d3 / deprive-01
                                          :ARG1 (g2 / growth-factor))
                                    :op2 (a6 / anoikis)
                                    :location (c2 / cell :name (n3 / name :op1 "IEC")))))))
      :mod (o / overall))

# ::id pmid_2470_8867.139 ::date 2015-08-30T02:42:15 ::annotator SDL-AMR-09 ::preferred
# ::snt <sec-title level="2">Silencing of Grb2 impairs Tpr-Met-induced morphological transformation and anoikis resistance in IECs, but reduced expression of Shc decreases cell growth</sec-title>
# ::save-date Sun Jan 17, 2016 ::file pmid_2470_8867_139.txt
(c / contrast-01
      :ARG1 (i2 / impair-01
            :ARG0 (s / silence-01
                  :ARG1 (p / protein :name (n / name :op1 "Grb2")))
            :ARG1 (a / and
                  :op1 (t / transform-01
                        :ARG2-of (i / induce-01
                              :ARG0 (p2 / protein :name (n2 / name :op1 "Tpr-Met")))
                        :mod (m / morphologic))
                  :op2 (r / resist-01
                        :ARG1 (a2 / anoikis))
                  :location (c2 / cell :name (n3 / name :op1 "IEC"))))
      :ARG2 (d / decrease-01
            :ARG0 (e / express-03
                  :ARG2 (p3 / protein :name (n4 / name :op1 "Shc"))
                  :ARG1-of (r2 / reduce-01))
            :ARG1 (g / grow-01
                  :ARG1 (c3 / cell))))

# ::id pmid_2470_8867.140 ::date 2015-08-30T03:03:22 ::annotator SDL-AMR-09 ::preferred
# ::snt The above results with the docking-specific Tpr-Met-derived variants established that the oncogenic activation of either Grb2 or Shc signaling pathways was each sufficient to promote transformation of IECs, conferring upon them aberrant growth characteristics and resistance to anoikis.
# ::save-date Fri Sep 11, 2015 ::file pmid_2470_8867_140.txt
(e / establish-01
      :ARG0 (t / thing
            :ARG2-of (r / result-01)
            :location (a / above)
            :accompanier (v / variant
                  :ARG1-of (d / derive-01
                        :ARG2 (p / protein :name (n / name :op1 "Tpr-Met")))
                  :ARG1-of (s / specific-02
                        :ARG2 (d2 / dock-01))))
      :ARG1 (s2 / suffice-01
            :ARG0 (a2 / activate-01
                  :ARG1 (o / or
                        :op1 (p6 / pathway :name (n5 / name :op1 "Grb2"))
                        :op2 (p7 / pathway :name (n6 / name :op1 "Shc"))
                        :ARG0-of (s4 / signal-07))
                  :ARG0-of (c4 / cause-01
                        :ARG1 (c5 / cancer)))
            :ARG1 (p5 / promote-01
                  :ARG0 a2
                  :ARG1 (t2 / transform-01
                        :ARG1 (c / cell :name (n4 / name :op1 "IEC")
                              :ARG2-of (c2 / confer-02
                                    :ARG1 (a3 / and
                                          :op1 (c3 / characteristic-02
                                                :ARG1 c
                                                :ARG2 (g / grow-01
                                                      :mod (a4 / aberrant)))
                                          :op2 (r2 / resist-01
                                                :ARG0 c
                                                :ARG1 (a5 / anoikis)))))))
            :mod (e3 / each)))

# ::id pmid_2470_8867.141 ::date 2015-08-30T03:46:12 ::annotator SDL-AMR-09 ::preferred
# ::snt We next sought to determine whether signaling pathways downstream of these adaptor proteins were required for the oncogenic potential of Met in IECs.
# ::save-date Fri Sep 11, 2015 ::file pmid_2470_8867_141.txt
(s / seek-01
      :ARG0 (w / we)
      :ARG1 (d / determine-01
            :ARG0 w
            :ARG1 (r / require-01 :mode interrogative
                  :ARG0 (p3 / potential
                        :poss (p4 / protein :name (n2 / name :op1 "Met"))
                        :location (c2 / cell :name (n3 / name :op1 "IEC"))
                        :ARG0-of (c3 / cause-01
                              :ARG1 (c4 / cancer)))
                  :ARG1 (p / pathway
                        :ARG0-of (s2 / signal-07)
                        :mod (d2 / downstream)
                        :poss (p2 / protein
                              :mod (t / this)
                              :ARG0-of (a / adapt-01)))))
      :time (n / next))

# ::id pmid_2470_8867.142 ::date 2015-08-30T04:35:55 ::annotator SDL-AMR-09 ::preferred
# ::snt The impact of silencing the expression of Grb2 or Shc on the features of the Tpr-Met-IEC-6 cells was evaluated.
# ::save-date Sun Jan 17, 2016 ::file pmid_2470_8867_142.txt
(e / evaluate-01
      :ARG1 (i / impact-01
            :ARG0 (s / silence-01
                  :ARG1 (e2 / express-03
                        :ARG2 (o / or
                              :op1 (p / protein :name (n / name :op1 "Grb2"))
                              :op2 (p2 / protein :name (n2 / name :op1 "Shc")))))
            :ARG1 (f / feature-01
                  :ARG1 (c / cell-line :name (n3 / name :op1 "IEC-6")
                        :ARG3-of (e3 / express-03
                              :ARG2 (p3 / protein :name (n4 / name :op1 "Tpr-Met")))))))

# ::id pmid_2470_8867.143 ::date 2015-08-30T04:39:21 ::annotator SDL-AMR-09 ::preferred
# ::snt Stable populations of Tpr-Met-IEC-6 cells displaying marked and selective knockdown of Grb2 (TM-shGrb2) or Shc (TM-shShc) were generated using shRNAs.
# ::save-date Sun Jan 17, 2016 ::file pmid_2470_8867_143.txt
(g / generate-01
      :ARG1 (p / population
            :mod (c / cell-line :name (n2 / name :op1 "Tpr-Met-IEC-6")
                  :ARG1-of (m4 / mean-01
                        :ARG2 (a / and
                              :op1 (c2 / cell-line :name (n5 / name :op1 "TM-shGrb2")
                                    :ARG0-of (d / display-01
                                          :ARG1 (k / knock-down-02
                                                :ARG1 (p3 / protein :name (n4 / name :op1 "Grb2"))
                                                :ARG2-of (m3 / mark-02)
                                                :mod (s2 / selective))))
                              :op2 (c3 / cell-line :name (n7 / name :op1 "TM-shShc")
                                    :ARG0-of (d2 / display-01
                                          :ARG1 (k2 / knock-down-02
                                                :ARG1 (p5 / protein :name (n6 / name :op1 "Shc"))
                                                :ARG2-of m3
                                                :mod s2))))))
            :ARG1-of (s / stable-02))
      :ARG2-of (u / use-01
            :ARG1 (n3 / nucleic-acid :name (n / name :op1 "shRNA"))))

# ::id pmid_2470_8867.144 ::date 2015-08-30T04:57:14 ::annotator SDL-AMR-09 ::preferred
# ::snt As demonstrated by IB analyses (Figure <xref ref-type="fig" rid="F4">4</xref>A), Grb2 and Shc (all ShcA isoforms) protein levels were selectively reduced by more than 60% in TM-shGrb2 and TM-shShc cell populations, respectively, compared to Tpr-Met-IEC-6 cells expressing a non-targeting shRNA (TM-shCTRL).
# ::save-date Mon Dec 21, 2015 ::file pmid_2470_8867_144.txt
(r / reduce-01
      :ARG1 (l / level
            :quant-of (a / and
                  :op1 (p2 / protein :name (n / name :op1 "Grb2"))
                  :op2 (p3 / protein :name (n2 / name :op1 "Shc"))
                  :ARG1-of (m / mean-01
                        :ARG2 (i / isoform
                              :mod (p4 / protein :name (n3 / name :op1 "ShcA"))
                              :mod (a2 / all)))))
      :ARG2 (m2 / more-than
            :op2 (p5 / percentage-entity :value 60))
      :mod (s / selective)
      :location (p / population
            :mod (r2 / respective)
            :mod (c3 / cell-line :name (n11 / name :op1 "TM-shGrb2"))
            :mod (c4 / cell-line :name (n12 / name :op1 "TM-shShc")))
      :compared-to (c / cell-line :name (n6 / name :op1 "Tpr-Met-IEC-6")
            :ARG3-of (e3 / express-03
                  :ARG2 (n4 / nucleic-acid :name (n9 / name :op1 "shRNA")
                        :ARG0-of (t / target-01 :polarity -)))
            :ARG1-of (m3 / mean-01
                  :ARG2 (c2 / cell-line :name (n8 / name :op1 "TM-shCTRL"))))
      :ARG1-of (d / demonstrate-01
            :ARG0 (a3 / analyze-01
                  :mod (i2 / immunoblot-01))
            :ARG1-of (d2 / describe-01
                  :ARG0 (f / figure :mod "4A"))))

# ::id pmid_2470_8867.145 ::date 2015-08-30T04:58:42 ::annotator SDL-AMR-09 ::preferred
# ::snt Protein levels of Tpr-Met and actin remained equivalent amongst all these cell populations.
# ::save-date Wed Sep 16, 2015 ::file pmid_2470_8867_145.txt
(r / remain-01
      :ARG1 (a / and
            :op1 (l / level
                  :quant-of (p5 / protein :name (n3 / name :op1 "Tpr-Met")))
            :op2 (l2 / level
                  :quant-of (p6 / protein :name (n4 / name :op1 "actin"))))
      :ARG3 (e / equal-01)
      :location (p4 / population
            :mod (c / cell)
            :mod (t / this)
            :mod (a2 / all)))

# ::id pmid_2470_8867.146 ::date 2015-08-30T05:06:31 ::annotator SDL-AMR-09 ::preferred
# ::snt Phase contrast microscopy revealed that the TM-shGrb2 cells exhibited a partial reversal of the transformed morphology, relative to TM-shCTRL cells, characterized by a decrease in cell refractility and an increase in cell spreading (Figure <xref ref-type="fig" rid="F4">4</xref>B).
# ::save-date Sat Jan 30, 2016 ::file pmid_2470_8867_146.txt
(r / reveal-01
      :ARG0 (m2 / microscopy
            :mod (c2 / contrast-01
                  :ARG1 (p / phase)))
      :ARG1 (e / exhibit-01
            :ARG0 (c6 / cell-line :name (n4 / name :op1 "TM-shGrb2")
                  :ARG1-of (r3 / relative-05
                        :ARG3 (c / cell-line :name (n / name :op1 "TM-shCTRL"))))
            :ARG1 (r2 / reverse-01
                  :ARG1 (t / transform-01
                        :ARG1 (m / morphology))
                  :degree (p2 / part)
                  :ARG1-of (c3 / characterize-01
                        :ARG2 (a / and
                              :op1 (d / decrease-01
                                    :ARG1 (r4 / refractility
                                          :mod (c4 / cell)))
                              :op2 (i / increase-01
                                    :ARG1 (s / spread-02
                                          :ARG1 c4))))))
      :ARG1-of (d2 / describe-01
            :ARG0 (f / figure :mod "4B")))

# ::id pmid_2470_8867.147 ::date 2015-08-30T05:10:33 ::annotator SDL-AMR-09 ::preferred
# ::snt In contrast, the TM-shShc cells maintained the transformed morphology, and even adopted a slightly more elongated and spindle-shaped appearance than the control TM-shCTRL cells.
# ::save-date Sun Jan 17, 2016 ::file pmid_2470_8867_147.txt
(c / contrast-01
      :ARG2 (a / and
            :op1 (m / maintain-01
                  :ARG0 (c3 / cell-line :name (n2 / name :op1 "TM-shShc"))
                  :ARG1 (t / transform-01
                        :ARG1 (m2 / morphology)))
            :op2 (a2 / adopt-01
                  :ARG0 (c2 / cell)
                  :ARG1 (a3 / appear-02
                        :ARG1-of (e3 / elongate-01)
                        :ARG1-of (s / shape-01
                              :mod (s2 / spindle))
                        :mod (s3 / slight)
                        :degree (m3 / more)
                        :compared-to (c5 / cell-line :name (n3 / name :op1 "TM-shCTRL")
                              :ARG0-of (c6 / control-01)))
                  :mod (e2 / even))))

# ::id pmid_2470_8867.148 ::date 2015-08-30T05:34:54 ::annotator SDL-AMR-09 ::preferred
# ::snt Concordant with these morphological changes, E-cadherin protein levels were enhanced in TM-shGrb2 cells and reduced in TM-shShc cells, when compared to TM-shCTRL cells (Figure <xref ref-type="fig" rid="F4">4</xref>C and D).
# ::save-date Fri Sep 11, 2015 ::file pmid_2470_8867_148.txt
(a / and
      :op1 (e / enhance-01
            :ARG1 (l / level
                  :quant-of (p / protein :name (n / name :op1 "E-cadherin")))
            :location (c5 / cell-line :name (n5 / name :op1 "TM-shGrb2")))
      :op2 (r / reduce-01
            :ARG1 l
            :location (c / cell-line :name (n2 / name :op1 "TM-shShc")))
      :ARG1-of (a2 / accord-02
            :ARG2 (c4 / change-01
                  :ARG1 (m / morphology)
                  :mod (t / this)))
      :ARG1-of (d / describe-01
            :ARG0 (a3 / and
                  :op1 (f / figure :mod "4C")
                  :op2 (f2 / figure :mod "4D")))
      :compared-to (c2 / cell-line :name (n3 / name :op1 "TM-shCTRL")))

# ::id pmid_2470_8867.149 ::date 2015-08-30T05:43:36 ::annotator SDL-AMR-09 ::preferred
# ::snt Growth and survival characteristics of these cells were then evaluated in cell-count and anoikis assays, respectively.
# ::save-date Wed Sep 16, 2015 ::file pmid_2470_8867_149.txt
(e / evaluate-01
      :ARG1 (c / characteristic-02
            :ARG1 (c2 / cell
                  :mod (t / this))
            :ARG2 (a / and
                  :op1 (g / grow-01
                        :ARG1 c2)
                  :op2 (s / survive-01
                        :ARG0 c2)))
      :time (t2 / then)
      :manner (a2 / and
            :op1 (a5 / assay-01
                  :ARG1 (c3 / count-02
                        :ARG1 (c4 / cell)))
            :op2 (a3 / assay-01
                  :ARG1 (a4 / anoikis))
            :mod (r / respective)))

# ::id pmid_2470_8867.150 ::date 2015-08-30T05:48:40 ::annotator SDL-AMR-09 ::preferred
# ::snt While the TM-shGrb2 cells displayed similar growth capacity to TM-shCTRL cells, growth of the TM-shShc cells was observed to decrease in a time-dependent manner, reaching significant inhibition (37.67 ± 5.32%) 3 days after seeding (Figure <xref ref-type="fig" rid="F4">4</xref>E).
# ::save-date Wed Sep 16, 2015 ::file pmid_2470_8867_150.txt
(h / have-concession-91
      :ARG1 (d2 / display-01
            :ARG0 (c6 / cell-line :name (n4 / name :op1 "TM-shGrb2"))
            :ARG1 (c2 / capacity
                  :domain (g / grow-01)
                  :ARG1-of (c3 / comparable-03
                        :ARG2 (c / cell-line :name (n / name :op1 "TM-shCTRL")))))
      :ARG2 (o / observe-01
            :ARG1 (g2 / grow-01
                  :ARG1 (c4 / cell-line :name (n2 / name :op1 "TM-shShc"))
                  :ARG1-of (d3 / decrease-01
                        :manner (d4 / depend-01
                              :ARG1 (t2 / time)))
                  :ARG0-of (r2 / reach-01
                        :ARG1 (i / inhibit-01
                              :ARG1-of (s / significant-02)
                              :mod (p5 / percentage-entity
                                    :value (v / value-interval :op1 37.67 :op2 5.32))
                              :time (a2 / after
                                    :op1 (t3 / temporal-quantity :quant 3
                                          :unit (d5 / day)
                                          :time (a / after
                                                :op1 (s2 / seed-01))))))))
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod "4E")))

# ::id pmid_2470_8867.151 ::date 2015-08-30T06:13:53 ::annotator SDL-AMR-09 ::preferred
# ::snt The TM-shGrb2 cells displayed enhanced anoikis sensitivity when compared to the TM-shCTRL and TM-shShc cells, between which no difference in survival in suspension was observed (Figure <xref ref-type="fig" rid="F4">4</xref>F).
# ::save-date Wed Sep 16, 2015 ::file pmid_2470_8867_151.txt
(d / display-01
      :ARG0 (c4 / cell-line :name (n4 / name :op1 "TM-shGrb2"))
      :ARG1 (s / sensitive-03
            :ARG0 c4
            :ARG1 (a / anoikis)
            :ARG1-of (e2 / enhance-01))
      :ARG1-of (d3 / describe-01
            :ARG0 (f / figure :mod "4F"))
      :time (c3 / compare-01
            :ARG1 c4
            :ARG2 (a3 / and
                  :op1 (c / cell-line :name (n / name :op1 "TM-shCTRL"))
                  :op2 (c5 / cell-line :name (n5 / name :op1 "TM-shShc"))
                  :location-of (o / observe-01
                        :ARG1 (d2 / differ-02 :polarity -
                              :ARG3 (s2 / survive-01
                                    :ARG1 (s3 / suspend-02)))))))

# ::id pmid_2470_8867.152 ::date 2015-08-30T06:41:00 ::annotator SDL-AMR-09 ::preferred
# ::snt As shown in Figure <xref ref-type="fig" rid="F4">4</xref>G, no significant difference in cell viability was observed between the TM-shGrb2, TM-shShc, and TM-shCTRL cells 18 hours following seeding in the absence of serum under adherent conditions (Figure <xref ref-type="fig" rid="F4">4</xref>G).
# ::save-date Fri Sep 11, 2015 ::file pmid_2470_8867_152.txt
(o / observe-01
      :ARG1 (d / differ-02 :polarity -
            :ARG1 (a3 / and
                  :op1 (c5 / cell-line :name (n3 / name :op1 "TM-shGrb2"))
                  :op2 (c6 / cell-line :name (n5 / name :op1 "TM-shCTRL"))
                  :op3 (c7 / cell-line :name (n6 / name :op1 "TM-shShc")))
            :ARG3 (v / viable
                  :domain (c / cell))
            :ARG1-of (s / significant-02))
      :duration (t2 / temporal-quantity :quant 18
            :unit (h2 / hour)
            :ARG1-of (f / follow-01
                  :ARG2 (s2 / seed-02
                        :condition (a / absent-01
                              :ARG1 (s3 / serum)
                              :condition (a2 / adhere-01)))))
      :ARG1-of (s4 / show-01
            :location (f2 / figure :mod "4G"))
      :ARG1-of (d2 / describe-01
            :ARG0 (f3 / figure :mod "4G")))

# ::id pmid_2470_8867.153 ::date 2015-08-30T06:51:58 ::annotator SDL-AMR-09 ::preferred
# ::snt Together, these results suggest that signals downstream of Grb2 and Shc proteins are required for non-overlapping functions promoted by the oncogenic Met receptor in IECs.
# ::save-date Wed Sep 16, 2015 ::file pmid_2470_8867_153.txt
(s / suggest-01
      :ARG0 (t / thing
            :ARG2-of (r / result-01)
            :mod (t2 / this)
            :mod (t3 / together))
      :ARG1 (r2 / require-01
            :ARG0 (f / function-01
                  :ARG1-of (p3 / promote-01
                        :ARG0 (r5 / receptor :name (n5 / name :op1 "Met"))
                        :location (c2 / cell :name (n4 / name :op1 "IEC")))
                  :ARG0-of (o / overlap-01 :polarity -))
            :ARG1 (s2 / signal-07
                  :location (r4 / relative-position
                        :op1 (a / and
                              :op1 (p / protein :name (n / name :op1 "Grb2"))
                              :op2 (p2 / protein :name (n2 / name :op1 "Shc")))
                        :direction (d / downstream)))))

# ::id pmid_2470_8867.154 ::date 2015-08-30T06:59:26 ::annotator SDL-AMR-09 ::preferred
# ::snt <sec-title level="2">MEK, but not PI3K inhibitors reduce IEC transformation promoted by the oncogenic engagement of Met, Grb2, or Shc signals</sec-title>
# ::save-date Sun Jan 17, 2016 ::file pmid_2470_8867_154.txt
(r / reduce-01
      :ARG0 (m / molecular-physical-entity
            :ARG0-of (i / inhibit-01
                  :ARG1 (p / protein-family :name (n / name :op1 "MEK")))
            :ARG1-of (c / contrast-01
                  :ARG2 (m2 / molecular-physical-entity
                        :ARG0-of (i2 / inhibit-01
                              :ARG1 (p6 / protein-family :name (n2 / name :op1 "PI3K"))))))
      :ARG1 (t2 / transform-01
            :ARG1 (c2 / cell :name (n3 / name :op1 "IEC"))
            :ARG1-of (p2 / promote-01
                  :ARG0 (e2 / engage-01
                        :ARG1 (s / signal-07
                              :ARG0 (o / or
                                    :op1 (p3 / protein :name (n4 / name :op1 "Met"))
                                    :op2 (p4 / protein :name (n5 / name :op1 "Grb2"))
                                    :op3 (p5 / protein :name (n6 / name :op1 "Shc"))))
                        :ARG2 (c3 / cancer)))))

# ::id pmid_2470_8867.155 ::date 2015-08-30T07:12:25 ::annotator SDL-AMR-09 ::preferred
# ::snt The Grb2 and Shc adaptor proteins are known to couple RTKs, such as the Met receptor, to the Ras/MAPK and PI3K/Akt signaling pathways [<xref ref-type="bibr" rid="B28">28</xref>-<xref ref-type="bibr" rid="B30">30</xref>].
# ::save-date Wed Sep 16, 2015 ::file pmid_2470_8867_155.txt
(k / know-02
      :ARG1 (a5 / and
            :op1 (p3 / protein :name (n2 / name :op1 "Grb2"))
            :op2 (p4 / protein :name (n3 / name :op1 "Shc"))
            :ARG0-of (a6 / adapt-01))
      :ARG3 (c / couple-01
            :ARG0 a5
            :ARG1 (e / enzyme :name (n4 / name :op1 "RTK")
                  :example (r2 / receptor :name (n6 / name :op1 "Met")))
            :ARG2 (a2 / and
                  :op1 (p6 / pathway :name (n5 / name :op1 "Ras/MAPK"))
                  :op2 (p7 / pathway :name (n7 / name :op1 "PI3K/Akt"))
                  :ARG0-of (s2 / signal-07)))
      :ARG1-of (d / describe-01
            :ARG0 (p8 / publication
                  :ARG1-of (c2 / cite-01
                        :ARG2 (a4 / and :op1 28 :op2 30)))))

# ::id pmid_2470_8867.156 ::date 2015-08-30T07:27:05 ::annotator SDL-AMR-09 ::preferred
# ::snt The Ras/MAPK and PI3K/Akt pathways are important regulators of RTK-mediated epithelial cell transformation, but their actions are cell type-specific [<xref ref-type="bibr" rid="B31">31</xref>].
# ::save-date Fri Sep 11, 2015 ::file pmid_2470_8867_156.txt
(c / contrast-01
      :ARG1 (r2 / regulate-01
            :ARG0 (a / and
                  :op1 (p2 / pathway :name (n2 / name :op1 "Ras/MAPK"))
                  :op2 (p3 / pathway :name (n3 / name :op1 "PI3K/Akt")))
            :ARG1 (t / transform-01
                  :ARG1 (c2 / cell
                        :part-of (e / epithelium))
                  :ARG1-of (m / mediate-01
                        :ARG0 (e2 / enzyme :name (n4 / name :op1 "RTK"))))
            :mod (i / important))
      :ARG2 (a2 / act-02
            :ARG0 a
            :ARG1-of (s / specific-02
                  :ARG2 (t3 / type
                        :mod (c3 / cell))))
      :ARG1-of (d / describe-01
            :ARG0 (p4 / publication
                  :ARG1-of (c4 / cite-01
                        :ARG2 31))))

# ::id pmid_2470_8867.157 ::date 2015-08-30T07:34:06 ::annotator SDL-AMR-09 ::preferred
# ::snt To define the role of these signaling pathways in IEC transformation, we first compared their activation status in IEC-6 cells transformed by the Tpr-Met, TM-Grb2, TM-Shc1, and TM-Shc2 oncoproteins, to that one in non-transformed Control-IEC-6 cells.
# ::save-date Sun Jan 17, 2016 ::file pmid_2470_8867_157.txt
(c / compare-01
      :ARG0 (w / we)
      :ARG1 (s3 / status
            :mod (a3 / activate-01)
            :location (c3 / cell-line :name (n2 / name :op1 "IEC-6")
                  :ARG1-of (t4 / transform-01
                        :ARG0 (a2 / and
                              :op1 (p2 / protein :name (n3 / name :op1 "Tpr-Met"))
                              :op2 (p3 / protein :name (n4 / name :op1 "TM-Grb2"))
                              :op3 (p4 / protein :name (n5 / name :op1 "TM-Shc1"))
                              :op4 (p5 / protein :name (n6 / name :op1 "TM-Shc2"))
                              :ARG0-of (c5 / cause-01
                                    :ARG1 (d2 / disease :wiki "Cancer" :name (n8 / name :op1 "cancer"))))))
            :poss p)
      :ARG2 (s4 / status
            :mod (t3 / that)
            :location (c4 / cell-line :name (n7 / name :op1 "Control-IEC-6")
                  :ARG1-of (t6 / transform-01 :polarity -))
            :mod a3
            :poss p)
      :time (f / first)
      :purpose (d / define-01
            :ARG0 w
            :ARG1 (r / role
                  :poss (p / pathway
                        :ARG1-of (s / signal-07)
                        :mod (t / this))
                  :purpose (t2 / transform-01
                        :ARG1 (c2 / cell :name (n / name :op1 "IEC"))))))

# ::id pmid_2470_8867.158 ::date 2015-08-30T07:55:41 ::annotator SDL-AMR-09 ::preferred
# ::snt The phosphorylation/activation levels of the downstream effectors of MEK and PI3K, Erk1/2 and Akt, respectively, were assessed by IB analyses of lysates prepared from serum-starved IEC-6 cells.
# ::save-date Fri Sep 11, 2015 ::file pmid_2470_8867_158.txt
(a / assess-01
      :ARG1 (l / level
            :degree-of (s / slash
                  :op1 (p2 / phosphorylate-01
                        :ARG1 (a3 / and
                              :op1 (e / enzyme :name (n2 / name :op1 "MEK"))
                              :op2 (e3 / enzyme :name (n3 / name :op1 "PI3K"))
                              :op3 (e4 / enzyme :name (n4 / name :op1 "Erk1/2"))
                              :op4 (e5 / enzyme :name (n5 / name :op1 "Akt"))
                              :mod (e2 / effector
                                    :mod (d2 / downstream))
                              :mod (r / respective)))
                  :op2 (a2 / activate-01
                        :ARG1 a3)))
      :manner (a4 / analyze-01
            :ARG1 (l2 / lysate
                  :ARG1-of (p / prepare-01
                        :ARG2 (c / cell-line :name (n6 / name :op1 "IEC-6")
                              :ARG1-of (s2 / starve-01
                                    :ARG2 (s3 / serum)))))
            :mod (i / immunoblot-01)))

# ::id pmid_2470_8867.159 ::date 2015-08-30T08:05:47 ::annotator SDL-AMR-09 ::preferred
# ::snt Phosphorylation levels of neither Erk1/2 nor Akt were elevated in Tpr-Met-IEC-6, TM-Grb2-IEC-6, TM-Shc1-IEC-6, or TM-Shc2-IEC-6 cells, relative to Control-IEC-6 cells (Figure <xref ref-type="fig" rid="F5">5</xref>A).
# ::save-date Fri Sep 11, 2015 ::file pmid_2470_8867_159.txt
(e / elevate-01 :polarity -
      :ARG1 (l / level
            :degree-of (p2 / phosphorylate-01
                  :ARG1 (a / and
                        :op1 (e2 / enzyme :name (n / name :op1 "Erk1/2"))
                        :op2 (e3 / enzyme :name (n2 / name :op1 "Akt"))))
            :location (o / or
                  :op1 (c3 / cell-line :name (n9 / name :op1 "Tpr-Met-IEC-6"))
                  :op2 (c4 / cell-line :name (n10 / name :op1 "Tpr-Grb2-IEC-6"))
                  :op3 (c5 / cell-line :name (n11 / name :op1 "Tpr-Shc1-IEC-6"))
                  :op4 (c6 / cell-line :name (n12 / name :op1 "Tpr-Shc2-IEC-6"))))
      :ARG1-of (r / relative-05
            :ARG3 (c / cell-line :name (n8 / name :op1 "Control-IEC-6")))
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod "5A")))

# ::id pmid_2470_8867.160 ::date 2015-08-30T08:27:59 ::annotator SDL-AMR-09 ::preferred
# ::snt Both Erk2 and Akt protein levels were comparable in all IEC-6 cell populations.
# ::save-date Fri Sep 11, 2015 ::file pmid_2470_8867_160.txt
(c / comparable-03
      :ARG1 (l / level
            :quant-of (p2 / protein :name (n / name :op1 "Erk2")))
      :ARG2 (l2 / level
            :quant-of (p / protein :name (n2 / name :op1 "Akt")))
      :mod (b / both)
      :location (p3 / population
            :mod (c2 / cell-line :name (n3 / name :op1 "IEC-6"))
            :mod (a / all)))

# ::id pmid_2470_8867.161 ::date 2015-08-30T08:30:54 ::annotator SDL-AMR-09 ::preferred
# ::snt A similar trend of Erk1/2 and Akt phosphorylation was observed in cells maintained in the presence of serum (data not shown).
# ::save-date Wed Sep 16, 2015 ::file pmid_2470_8867_161.txt
(o / observe-01
      :ARG1 (t / trend-01
            :ARG1 (p3 / phosphorylate-01
                  :ARG1 (a2 / and
                        :op1 (e / enzyme :name (n / name :op1 "Erk1/2"))
                        :op2 (e2 / enzyme :name (n2 / name :op1 "Akt"))))
            :ARG1-of (r2 / resemble-01))
      :location (c / cell
            :ARG1-of (m / maintain-01
                  :condition (p2 / present-02
                        :ARG1 (s / serum))))
      :ARG1-of (d2 / describe-01
            :ARG0 (d3 / data
                  :ARG1-of (s3 / show-01 :polarity -))))

# ::id pmid_2470_8867.162 ::date 2015-08-30T08:36:15 ::annotator SDL-AMR-09 ::preferred
# ::snt The lack of evidence for Erk1/2 and Akt activation in IEC-6 cells stably expressing the constitutively activated form of the Met receptor, or the Grb2 and Shc docking-specific oncoproteins, is consistent with both the Ras/MAPK and PI3K/Akt pathways being subject to negative feedback mechanisms [<xref ref-type="bibr" rid="B35">35</xref>].
# ::save-date Fri Feb 5, 2016 ::file pmid_2470_8867_162.txt
(c / consistent-01
      :ARG1 (l / lack-01
            :ARG1 (e / evidence-01
                  :ARG1 (a / activate-01
                        :ARG1 (a2 / and
                              :op1 (e2 / enzyme :name (n2 / name :op1 "Erk1/2"))
                              :op2 (e3 / enzyme :name (n3 / name :op1 "Akt")))
                        :location (c2 / cell-line :name (n4 / name :op1 "IEC-6")
                              :ARG3-of (e4 / express-03
                                    :ARG2 (o2 / or
                                          :op1 (r / receptor :name (n6 / name :op1 "Met")
                                                :ARG1-of (a6 / activate-01
                                                      :mod (c5 / constitutive)))
                                          :op2 (a4 / and
                                                :op1 (p4 / protein :name (n / name :op1 "Grb2"))
                                                :op2 (p5 / protein :name (n5 / name :op1 "Shc"))
                                                :ARG1-of (s2 / specific-02
                                                      :ARG2 (d / dock-01))
                                                :ARG0-of (c3 / cause-01
                                                      :ARG1 (d3 / disease :wiki "Cancer" :name (n10 / name :op1 "cancer")))))
                                    :ARG1-of (s / stable-02))))))
      :ARG2 (a5 / and
            :op1 (p / pathway :name (n7 / name :op1 "Ras/MAPK"))
            :op2 (p2 / pathway :name (n8 / name :op1 "PI3K/Akt"))
            :ARG1-of (s3 / subject-01
                  :ARG2 (m / mechanism
                        :mod (f2 / feedback
                              :ARG0-of (n9 / negative-03))))
            :mod (b / both))
      :ARG1-of (d2 / describe-01
            :ARG0 (p3 / publication
                  :ARG1-of (c4 / cite-01
                        :ARG2 35))))

# ::id pmid_2470_8867.163 ::date 2015-08-31T23:38:53 ::annotator SDL-AMR-09 ::preferred
# ::snt It cannot be explained as merely a cell type–specific event, since similarly stable expression of these oncoproteins in fibroblasts failed to promote Erk1/2 or Akt activation [<xref ref-type="bibr" rid="B36">36</xref>] and unpublished observation].
# ::save-date Sun Jan 17, 2016 ::file pmid_2470_8867_163.txt
(p2 / possible-01 :polarity -
      :ARG1 (e / explain-01
            :ARG1 (i / it)
            :manner (e2 / event
                  :ARG1-of (s / specific-02
                        :ARG2 (t / type
                              :mod (c / cell))
                        :degree (m / mere))))
      :ARG1-of (c2 / cause-01
            :ARG0 (f / fail-01
                  :ARG1 (e3 / express-03
                        :ARG2 (p / protein
                              :ARG0-of (c3 / cause-01
                                    :ARG1 (c4 / cancer))
                              :mod (t2 / this))
                        :ARG3 (f2 / fibroblast)
                        :ARG1-of (s2 / stable-03
                              :ARG1-of (r / resemble-01)))
                  :ARG2 (p3 / promote-01
                        :ARG0 e3
                        :ARG1 (a / activate-01
                              :ARG1 (o / or
                                    :op1 (s3 / slash
                                          :op1 (e6 / enzyme :name (n / name :op1 "Erk1"))
                                          :op2 (e5 / enzyme :name (n2 / name :op1 "Erk2")))
                                    :op2 (e4 / enzyme :name (n3 / name :op1 "Akt")))))))
      :ARG1-of (d / describe-01
            :ARG0 (a2 / and
                  :op1 (p4 / publication
                        :ARG1-of (c5 / cite-01
                              :ARG2 36))
                  :op2 (t3 / thing
                        :ARG1-of (o2 / observe-01)
                        :ARG1-of (p5 / publish-01 :polarity -)))))

# ::id pmid_2470_8867.164 ::date 2015-08-31T23:48:44 ::annotator SDL-AMR-09 ::preferred
# ::snt We next investigated whether, even at the low levels observed, MEK or PI3K activities were implicated in the induction of transformation features in IEC-6 cells by the Tpr-Met, TM-Grb2, TM-Shc1, or TM-Shc2 oncoproteins.
# ::save-date Sun Jan 17, 2016 ::file pmid_2470_8867_164.txt
(i / investigate-01
      :ARG0 (w / we)
      :ARG1 (i2 / implicate-01 :mode interrogative
            :ARG1 (a / activity-06
                  :ARG0 (o / or
                        :op1 (e / enzyme :name (n / name :op1 "MEK"))
                        :op2 (e2 / enzyme :name (n3 / name :op1 "PI3K"))))
            :ARG2 (i3 / induce-01
                  :ARG2 (f / feature
                        :mod (t / transform-01
                              :ARG0 (o2 / or
                                    :op1 (p / protein :name (n5 / name :op1 "Tpr-Met"))
                                    :op2 (p2 / protein :name (n6 / name :op1 "TM-Grb2"))
                                    :op3 (p3 / protein :name (n7 / name :op1 "TM-Shc1"))
                                    :op4 (p4 / protein :name (n8 / name :op1 "TM-Shc2"))
                                    :ARG0-of (c2 / cause-01
                                          :ARG1 (c3 / cancer)))
                              :ARG1 (c / cell-line :name (n4 / name :op1 "IEC-6")))))
            :condition (l / level
                  :ARG1-of (l2 / low-04)
                  :ARG1-of (o3 / observe-01)
                  :mod (e3 / even)))
      :time (n2 / next))

# ::id pmid_2470_8867.165 ::date 2015-08-31T23:57:07 ::annotator SDL-AMR-09 ::preferred
# ::snt Cells were treated with vehicle (DMSO), 10 μM U0126 (a MEK1/2 inhibitor), 10 μM LY294002 (a PI3K inhibitor), or a combination of both inhibitors, and their morphology was examined by phase contrast microscopy, following 24 (Additional file <xref ref-type="supplementary-material" rid="S3">3</xref>) and 48 hours of treatment (Figure <xref ref-type="fig" rid="F5">5</xref>B).
# ::save-date Sun Jan 17, 2016 ::file pmid_2470_8867_165.txt
(a / and
      :op1 (t3 / treat-04
            :ARG1 (c / cell)
            :ARG2 (o / or
                  :op1 (v / vehicle
                        :mod (s2 / small-molecule :name (n2 / name :op1 "DMSO")))
                  :op2 (s / small-molecule :name (n / name :op1 "U0126")
                        :quant (c2 / concentration-quantity :quant 10
                              :unit (m / micromolar))
                        :ARG0-of (i2 / inhibit-01
                              :ARG1 (s3 / slash
                                    :op1 (e / enzyme :name (n3 / name :op1 "MEK1"))
                                    :op2 (e2 / enzyme :name (n4 / name :op1 "MEK2")))))
                  :op3 (s4 / small-molecule :name (n5 / name :op1 "LY294002")
                        :quant c2
                        :ARG0-of (i3 / inhibit-01
                              :ARG1 (p2 / protein-family :name (n6 / name :op1 "PI3K"))))
                  :op4 (c3 / combine-01
                        :ARG1 s
                        :ARG2 s4
                        :mod (b / both))))
      :op2 (e4 / examine-01
            :ARG1 (m2 / morphology
                  :poss c)
            :manner (m3 / microscopy
                  :mod (c4 / contrast-01
                        :ARG1 (p / phase)))
            :time (a2 / and
                  :op1 (a3 / after
                        :op1 t3
                        :quant (t5 / temporal-quantity :quant 24
                              :unit (h / hour))
                        :ARG1-of (d / describe-01
                              :ARG0 (f / file :mod 3
                                    :mod (a5 / additional))))
                  :op2 (a4 / after
                        :op1 t3
                        :quant (t / temporal-quantity :quant 48
                              :unit h)
                        :ARG1-of (d2 / describe-01
                              :ARG0 (f2 / figure :mod "5B"))))))

# ::id pmid_2470_8867.166 ::date 2015-09-01T00:09:13 ::annotator SDL-AMR-09 ::preferred
# ::snt Neither individual inhibitor treatment, nor the combination, had an obvious effect on the morphology of the Control-IEC-6 cells.
# ::save-date Sun Jan 17, 2016 ::file pmid_2470_8867_166.txt
(a / affect-01 :polarity -
      :ARG0 (a2 / and
            :op1 (t2 / treat-04
                  :ARG2 (m2 / molecular-physical-entity
                        :ARG0-of (i / inhibit-01)
                        :mod (i2 / individual)))
            :op2 (c / combine-01))
      :ARG1 (m / morphology
            :poss (c2 / cell-line :name (n / name :op1 "IEC-6")
                  :mod (c3 / control)))
      :ARG1-of (o / obvious-01))

# ::id pmid_2470_8867.167 ::date 2015-09-01T00:14:23 ::annotator SDL-AMR-09 ::preferred
# ::snt Interestingly, the MEK1/2 inhibitor, but not the PI3K inhibitor, induced a potent reversion of the transformed morphological features of the Tpr-Met-IEC-6, TM-Grb2-IEC-6, TM-Shc1-IEC-6, and TM-Shc2-IEC-6 cells, observed within 24 hours of treatment (Additional file <xref ref-type="supplementary-material" rid="S3">3</xref>) and more striking in appearance after 48 hours (Figure <xref ref-type="fig" rid="F5">5</xref>B).
# ::save-date Sun Jan 17, 2016 ::file pmid_2470_8867_167.txt
(c8 / contrast-01
      :ARG1 (i2 / induce-01
            :ARG0 (m3 / molecular-physical-entity
                  :ARG0-of (i / inhibit-01
                        :ARG1 (s2 / slash
                              :op1 (e / enzyme :name (n / name :op1 "MEK1"))
                              :op2 (e2 / enzyme :name (n2 / name :op1 "MEK2")))))
            :ARG2 (r / reverse-01
                  :ARG1 (f / feature
                        :mod (m / morphology)
                        :ARG1-of (t4 / transform-01)
                        :poss (a / and
                              :op1 (c / cell-line :name (n3 / name :op1 "IEC-6")
                                    :ARG1-of (t3 / transform-01
                                          :ARG0 (p2 / protein :name (n7 / name :op1 "Tpr-Met"))))
                              :op2 (c2 / cell-line :name (n4 / name :op1 "IEC-6")
                                    :ARG3-of (e4 / express-03
                                          :ARG2 (p3 / protein :name (n8 / name :op1 "TM-Grb2"))))
                              :op3 (c3 / cell-line :name (n5 / name :op1 "IEC-6")
                                    :ARG3-of (e5 / express-03
                                          :ARG2 (p4 / protein :name (n9 / name :op1 "TM-Shc1"))))
                              :op4 (c4 / cell-line :name (n6 / name :op1 "IEC-6")
                                    :ARG3-of (e6 / express-03
                                          :ARG2 (p5 / protein :name (n10 / name :op1 "TM-Shc2"))))))
                  :mod (p / potent)
                  :ARG1-of (o / observe-01
                        :time (a2 / after
                              :op1 (t5 / treat-04)
                              :quant (u / up-to
                                    :op1 (t / temporal-quantity :quant 24
                                          :unit (h / hour))))
                        :ARG1-of (d / describe-01
                              :ARG0 (f2 / file :mod 3
                                    :mod (a3 / additional))))
                  :ARG1-of (s3 / strike-04
                        :ARG2 (a4 / appear-01)
                        :degree (m2 / more)
                        :time (a5 / after
                              :op1 t5
                              :quant (t2 / temporal-quantity :quant 48
                                    :unit (h2 / hour)))
                        :ARG1-of (d2 / describe-01
                              :ARG0 (f3 / figure :mod "5B")))))
      :ARG2 (i4 / induce-01 :polarity -
            :ARG0 (m4 / molecular-physical-entity
                  :ARG0-of (i5 / inhibit-01
                        :ARG1 (p6 / protein-family :name (n11 / name :op1 "PI3K"))))
            :ARG1 r)
      :ARG2-of (i3 / interest-01))

# ::id pmid_2470_8867.168 ::date 2015-09-01T00:33:10 ::annotator SDL-AMR-09 ::preferred
# ::snt In the presence of U0126, the MEK1/2 inhibitor, either alone or in combination with the PI3K inhibitor, the formerly transformed Tpr-IEC-6 cells progressively lost their fibroblast-like spindle-shaped morphology, adopted a flatter cobblestone-like appearance, reformed apparent cell-cell contacts and grew again in colonies; much like the non-transformed Control-IEC-6 cells.
# ::save-date Sun Jan 17, 2016 ::file pmid_2470_8867_168.txt
(a / and
      :op1 (l / lose-02
            :ARG0 (c / cell-line :name (n2 / name :op1 "IEC-6")
                  :ARG1-of (t2 / transform-01
                        :ARG0 (p / protein :name (n3 / name :op1 "Tpr"))
                        :time (f / former)))
            :ARG1 (m / morphology
                  :ARG1-of (r / resemble-01
                        :ARG2 (f2 / fibroblast))
                  :ARG1-of (s2 / shape-01
                        :ARG2 (s3 / spindle)))
            :manner (p2 / progress-01))
      :op2 (a2 / adopt-01
            :ARG0 c
            :ARG1 (a3 / appear-01
                  :ARG1 c
                  :ARG1-of (f3 / flat-06
                        :degree (m2 / more))
                  :ARG1-of (r2 / resemble-01
                        :ARG2 (c4 / cobblestone))))
      :op3 (r3 / reform-01
            :ARG0 c
            :ARG1 (c5 / contact-01
                  :ARG0 (c6 / cell)
                  :ARG1 (c7 / cell)
                  :ARG1-of (a4 / appear-01)))
      :op4 (g / grow-02
            :ARG1 c
            :ARG2 (c8 / colony)
            :mod (a5 / again))
      :condition (p3 / present-02
            :ARG1 (s / small-molecule :name (n / name :op1 "U0126")
                  :ARG0-of (i / inhibit-01
                        :ARG1 (s4 / slash
                              :op1 (e / enzyme :name (n4 / name :op1 "MEK1"))
                              :op2 (e2 / enzyme :name (n5 / name :op1 "MEK2")))))
            :manner (o / or
                  :op1 (a6 / alone)
                  :op2 (c9 / combine-01
                        :ARG1 s
                        :ARG2 (m4 / molecular-physical-entity
                              :ARG0-of (i2 / inhibit-01
                                    :ARG1 (p4 / protein-family :name (n6 / name :op1 "PI3K")))))))
      :ARG1-of (r4 / resemble-01
            :ARG2 (c10 / cell :name (n7 / name :op1 "IEC-6")
                  :ARG1-of (t / transform-01 :polarity -)
                  :mod (c11 / control))
            :degree (m3 / much)))

# ::id pmid_2470_8867.169 ::date 2015-09-01T00:52:54 ::annotator SDL-AMR-09 ::preferred
# ::snt Concordant with this restoration of epithelioid-like morphological features in IEC-6 cells transformed by the oncogenic Tpr-Met and its derived variants, treatment with U0126 also induced an increase in E-cadherin protein levels (Figure <xref ref-type="fig" rid="F5">5</xref>C and D, and Additional file <xref ref-type="supplementary-material" rid="S3">3</xref>).
# ::save-date Sun Jan 17, 2016 ::file pmid_2470_8867_169.txt
(i / induce-01
      :ARG0 (t / treat-04
            :ARG2 (s / small-molecule :name (n / name :op1 "U0126")))
      :ARG2 (i2 / increase-01
            :ARG1 (l / level
                  :quant-of (p / protein :name (n2 / name :op1 "E-cadherin"))))
      :mod (a / also)
      :ARG0-of (a2 / agree-01
            :ARG2 (r / restore-02
                  :ARG1 (f / feature
                        :mod (m / morphology)
                        :ARG1-of (r2 / resemble-01
                              :ARG2 (e / epithelioid))
                        :poss (c / cell-line :name (n3 / name :op1 "IEC-6")
                              :ARG1-of (t2 / transform-01
                                    :ARG0 (a3 / and
                                          :op1 (p2 / protein :name (n4 / name :op1 "Tpr-Met")
                                                :ARG0-of (c2 / cause-01
                                                      :ARG1 (c3 / cancer)))
                                          :op2 (v / variant
                                                :ARG1-of (d / derive-01
                                                      :ARG0 p2))))))))
      :ARG1-of (d2 / describe-01
            :ARG0 (a4 / and
                  :op1 (f2 / figure :mod "5C")
                  :op2 (f3 / figure :mod "5D")
                  :op3 (f4 / file :mod 3
                        :mod (a5 / additional)))))

# ::id pmid_2470_8867.170 ::date 2015-09-01T01:01:49 ::annotator SDL-AMR-09 ::preferred
# ::snt By contrast, none of the inhibitor treatments affected E-cadherin protein levels in the Control-IEC-6 cells (Figure <xref ref-type="fig" rid="F5">5</xref>C and D).
# ::save-date Sun Jan 17, 2016 ::file pmid_2470_8867_170.txt
(c / contrast-01
      :ARG2 (a / affect-01 :polarity -
            :ARG0 (t2 / treat-04
                  :ARG2 (m / molecular-physical-entity
                        :ARG0-of (i / inhibit-01)))
            :ARG1 (l / level
                  :quant-of (p / protein :name (n / name :op1 "E-cadherin")))
            :location (c2 / cell-line :name (n2 / name :op1 "IEC-6")
                  :mod (c3 / control)))
      :ARG1-of (d / describe-01
            :ARG0 (a2 / and
                  :op1 (f / figure :mod "5C")
                  :op2 (f2 / figure :mod "5D"))))

# ::id pmid_2470_8867.171 ::date 2015-09-01T01:04:58 ::annotator SDL-AMR-09 ::preferred
# ::snt Notably, reversion of the transformed phenotype and E-cadherin up-regulation were also promoted in transformed IEC-6 cell populations by treatment with 10 μM AZD6244 or PD184352, two additional pharmacological inhibitors of MEK1/2 (Figure <xref ref-type="fig" rid="F5">5</xref>B and C, and Additional file <xref ref-type="supplementary-material" rid="S3">3</xref>).
# ::save-date Sun Jan 17, 2016 ::file pmid_2470_8867_171.txt
(p / promote-01
      :ARG0 (t3 / treat-04
            :ARG2 (o / or
                  :op1 (s2 / small-molecule :name (n4 / name :op1 "AZD6244"))
                  :op2 (s3 / small-molecule :name (n5 / name :op1 "PD184352"))
                  :quant (c2 / concentration-quantity :quant 10
                        :unit (m / micromolar))
                  :mod (s / small-molecule :quant 2
                        :mod (a3 / additional)
                        :ARG0-of (i / inhibit-01
                              :ARG1 (s4 / slash
                                    :op1 (e / enzyme :name (n / name :op1 "MEK1"))
                                    :op2 (e2 / enzyme :name (n6 / name :op1 "MEK2"))))
                        :mod (p5 / pharmacology))))
      :ARG1 (a / and
            :op1 (r / reverse-01
                  :ARG1 (p2 / phenotype
                        :ARG1-of (t2 / transform-01)))
            :op2 (u / upregulate-01
                  :ARG1 (p3 / protein :name (n2 / name :op1 "E-cadherin"))))
      :mod (a2 / also)
      :location (p4 / population
            :consist-of (c / cell-line :name (n3 / name :op1 "IEC-6")
                  :ARG1-of t2))
      :ARG1-of (d / describe-01
            :ARG0 (a4 / and
                  :op1 (f / figure :mod "5B")
                  :op2 (f2 / figure :mod "5C")
                  :op3 (f3 / file :mod 3
                        :mod a3)))
      :ARG1-of (n7 / notable-04))

# ::id pmid_2470_8867.172 ::date 2015-09-01T01:13:06 ::annotator SDL-AMR-09 ::preferred
# ::snt Furthermore, these observations could not be attributed to the cytosolic localization of the Tpr-Met oncoprotein, since both the morphological transformation and the E-cadherin down-regulation induced by a cell surface-localized active chimeric colony stimulating factor 1 (CSF)-Met receptor [<xref ref-type="bibr" rid="B37">37</xref>], were reverted in a similar manner upon the inhibition of MEK1/2 activity, but not of PI3K activity (Additional file <xref ref-type="supplementary-material" rid="S3">3</xref>).
# ::save-date Mon Sep 7, 2015 ::file pmid_2470_8867_172.txt
(a7 / and
      :op2 (p2 / possible-01 :polarity -
            :ARG1 (a / attribute-01
                  :ARG1 (t / thing
                        :ARG1-of (o / observe-01)
                        :mod (t2 / this))
                  :ARG2 (b2 / be-located-at-91
                        :ARG1 (p / protein :name (n / name :op1 "Tpr-Met")
                              :ARG0-of (c2 / cause-01
                                    :ARG1 (c3 / cancer)))
                        :ARG2 (c / cytosol)))
            :ARG1-of (c4 / cause-01
                  :ARG0 (c8 / contrast-01
                        :ARG1 (r2 / revert-01
                              :ARG0 (i2 / inhibit-01
                                    :ARG1 (a4 / activity-06
                                          :ARG0 (s2 / slash
                                                :op1 (e / enzyme :name (n4 / name :op1 "MEK1"))
                                                :op2 (e2 / enzyme :name (n5 / name :op1 "MEK2")))))
                              :ARG1 (a2 / and
                                    :op1 (t3 / transform-01
                                          :ARG1 (m2 / morphology))
                                    :op2 (d / downregulate-01
                                          :ARG1 (p3 / protein :name (n2 / name :op1 "E-cadherin")))
                                    :ARG2-of (i / induce-01
                                          :ARG0 (p4 / protein :name (n3 / name :op1 "colony" :op2 "stimulating" :op3 "factor" :op4 "1" :op5 "Met" :op6 "receptor")
                                                :location (s / surface
                                                            :part-of (c5 / cell))
                                                :ARG1-of (a3 / activate-01)
                                                :mod (c6 / chimera)))
                                    :ARG1-of (d2 / describe-01
                                          :ARG0 (p5 / publication
                                                :ARG1-of (c7 / cite-01
                                                      :ARG2 37))))
                              :manner (m / manner
                                    :ARG1-of (r / resemble-01)))
                        :ARG2 (r3 / revert-01 :polarity -
                              :ARG0 (i3 / inhibit-01
                                    :ARG1 (a5 / activity-06
                                          :ARG0 (e3 / enzyme :name (n6 / name :op1 "PI3K"))))
                              :ARG1 a2
                              :manner m
                              :ARG1-of (d3 / describe-01
                                    :ARG0 (f / file :mod 3
                                          :mod (a6 / additional))))))))

# ::id pmid_2470_8867.173 ::date 2015-09-01T01:38:47 ::annotator SDL-AMR-09 ::preferred
# ::snt Since Erk1/2 and Akt activities remained at basal levels in transformed IEC-6 cell populations, the efficacy of these pharmacological inhibitors was evaluated by testing their ability to suppress serum-induced Erk1/2 and Akt phosphorylation.
# ::save-date Sun Jan 17, 2016 ::file pmid_2470_8867_173.txt
(e / evaluate-01
      :ARG1 (e2 / efficient-01
            :ARG1 (m / molecular-physical-entity
                  :ARG0-of (i / inhibit-01)
                  :mod (t2 / this)
                  :mod (p2 / pharmacology)))
      :manner (t3 / test-01
            :ARG1 (c / capable-01
                  :ARG1 m
                  :ARG2 (s2 / suppress-01
                        :ARG0 m
                        :ARG1 (p / phosphorylate-01
                              :ARG1 (a / and
                                    :op1 (s4 / slash
                                          :op1 (e3 / enzyme :name (n / name :op1 "Erk1"))
                                          :op2 (e4 / enzyme :name (n2 / name :op1 "Erk2")))
                                    :op2 (e5 / enzyme :name (n3 / name :op1 "Akt")))
                              :ARG2-of (i2 / induce-01
                                    :ARG0 (s3 / serum))))))
      :ARG1-of (c2 / cause-01
            :ARG0 (r / remain-01
                  :ARG1 (a2 / activity-06
                        :ARG0 a)
                  :ARG3 (l / level
                        :mod (b / base))
                  :location (p3 / population
                        :consist-of (c3 / cell-line :name (n4 / name :op1 "IEC-6")
                              :ARG1-of (t / transform-01))))))

# ::id pmid_2470_8867.174 ::date 2015-09-01T01:52:42 ::annotator SDL-AMR-09 ::preferred
# ::snt Serum-starved Tpr-Met and control IEC-6 cell populations were treated for 1 hour with DMSO or inhibitors, followed by 5 minutes of stimulation with 10% serum.
# ::save-date Sun Jan 17, 2016 ::file pmid_2470_8867_174.txt
(t4 / treat-04
      :ARG1 (a / and
            :op1 (p4 / population
                  :consist-of (c / cell-line :name (n4 / name :op1 "IEC-6")
                        :ARG1-of (t3 / transform-01
                              :ARG0 (p2 / protein :name (n / name :op1 "Tpr-Met")))))
            :op2 (p3 / population
                  :consist-of (c2 / cell-line :name (n2 / name :op1 "IEC-6"))
                  :mod (c4 / control))
            :ARG1-of (s / starve-01
                  :ARG2 (s2 / serum)))
      :ARG2 (o / or
            :op1 (s3 / small-molecule :name (n3 / name :op1 "DMSO"))
            :op2 (m2 / molecular-physical-entity
                  :ARG0-of (i / inhibit-01)))
      :duration (t / temporal-quantity :quant 1
            :unit (h / hour))
      :ARG2-of (f / follow-01
            :ARG1 (s5 / stimulate-01
                  :ARG1 a
                  :ARG2 (s6 / serum
                        :quant (p / percentage-entity :value 10))
                  :duration (t2 / temporal-quantity :quant 5
                        :unit (m / minute)))))

# ::id pmid_2470_8867.175 ::date 2015-09-01T02:10:22 ::annotator SDL-AMR-09 ::preferred
# ::snt A robust phosphorylation of Erk1/2 and Akt proteins was seen upon serum stimulation of Control-IEC-6 cells (Figure <xref ref-type="fig" rid="F5">5</xref>E).
# ::save-date Sun Jan 17, 2016 ::file pmid_2470_8867_175.txt
(s / see-01
      :ARG1 (p / phosphorylate-01
            :ARG1 (a / and
                  :op1 (s2 / slash
                        :op1 (e / enzyme :name (n / name :op1 "Erk1"))
                        :op2 (e2 / enzyme :name (n2 / name :op1 "Erk2")))
                  :op2 (p4 / protein-family :name (n3 / name :op1 "Akt")))
            :mod (r / robust))
      :time (s3 / stimulate-01
            :ARG1 (c / cell-line :name (n4 / name :op1 "IEC-6")
                  :mod (c2 / control))
            :ARG2 (s4 / serum))
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod "5E")))

# ::id pmid_2470_8867.176 ::date 2015-09-01T02:15:14 ::annotator SDL-AMR-09 ::preferred
# ::snt In sharp contrast, although the levels of Erk2 and Akt proteins were equivalent for each cell population, serum-induced Erk1/2 and Akt activation were severely attenuated in the Tpr-Met-IEC-6 cells (Figure <xref ref-type="fig" rid="F5">5</xref>E).
# ::save-date Sun Jan 17, 2016 ::file pmid_2470_8867_176.txt
(c / contrast-01
      :ARG2 (a / attenuate-01
            :ARG1 (a4 / and
                  :op1 (a2 / activate-01
                        :ARG1 (s2 / slash
                              :op1 (e2 / enzyme :name (n / name :op1 "Erk1"))
                              :op2 (e3 / enzyme :name (n2 / name :op1 "Erk2"))))
                  :op2 (a5 / activate-01
                        :ARG1 (p2 / protein-family :name (n3 / name :op1 "Akt")))
                  :ARG2-of (i / induce-01
                        :ARG0 (s3 / serum)))
            :degree (s4 / severe)
            :location (c2 / cell-line :name (n4 / name :op1 "IEC-6")
                  :ARG1-of (t / transform-01
                        :ARG0 (p / protein :name (n5 / name :op1 "Tpr-Met"))))
            :concession (e5 / equal-01
                  :ARG1 (l / level
                        :quant-of e3)
                  :ARG2 (l2 / level
                        :quant-of p2)
                  :ARG3 (p5 / population
                        :mod (c5 / cell)
                        :mod (e / each))))
      :ARG1-of (s / sharp-02)
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod "5E")))

# ::id pmid_2470_8867.177 ::date 2015-09-01T02:26:41 ::annotator SDL-AMR-09 ::preferred
# ::snt This further substantiates the conclusion that sustained activation of Met signaling pathways, such as those downstream of Grb2 and Shc, can activate negative feedback control of both the Erk1/2 and Akt pathways in IECs.
# ::save-date Fri Feb 5, 2016 ::file pmid_2470_8867_177.txt
(s / substantiate-01
      :ARG0 (t / this)
      :ARG1 (c / conclude-01
            :ARG1 (p / possible-01
                  :ARG1 (a / activate-01
                        :ARG0 (a2 / activate-01
                              :ARG1 (p2 / pathway :name (n / name :op1 "Met")
                                    :ARG0-of (s3 / signal-07)
                                    :example (p3 / pathway
                                          :location (r / relative-position
                                                :op1 (a3 / and
                                                      :op1 (p4 / protein :name (n2 / name :op1 "Grb2"))
                                                      :op2 (p5 / protein :name (n3 / name :op1 "Shc")))
                                                :direction (d / downstream))
                                          :mod (t2 / that)))
                              :ARG1-of (s2 / sustain-01))
                        :ARG1 (c2 / control-01
                              :ARG1 (a4 / and
                                    :op1 (p6 / pathway :name (n5 / name :op1 "Erk1/2"))
                                    :op2 (p7 / pathway :name (n6 / name :op1 "Akt")))
                              :ARG2-of (n4 / negative-01)
                              :mod (f2 / feedback))
                        :location (c3 / cell :name (n7 / name :op1 "IEC")))))
      :degree (f / further))

# ::id pmid_2470_8867.178 ::date 2015-09-01T02:34:56 ::annotator SDL-AMR-09 ::preferred
# ::snt Importantly, the MEK1/2 and PI3K inhibitors were confirmed to efficiently suppress serum-induced Erk1/2 and Akt phosphorylation, respectively (Figure <xref ref-type="fig" rid="F5">5</xref>E).
# ::save-date Sun Jan 17, 2016 ::file pmid_2470_8867_178.txt
(c / confirm-01
      :ARG1 (a / and
            :op1 (s / suppress-01
                  :ARG0 (m / molecular-physical-entity
                        :ARG0-of (i / inhibit-01
                              :ARG1 (s5 / slash
                                    :op1 (e2 / enzyme :name (n3 / name :op1 "MEK1"))
                                    :op2 (e3 / enzyme :name (n4 / name :op1 "MEK2")))))
                  :ARG1 (p / phosphorylate-01
                        :ARG1 (s3 / slash
                              :op1 (e5 / enzyme :name (n / name :op1 "Erk1"))
                              :op2 (e6 / enzyme :name (n2 / name :op1 "Erk2")))
                        :ARG2-of (i2 / induce-01
                              :ARG0 (s2 / serum)))
                  :ARG2-of (e / efficient-01))
            :op2 (s6 / suppress-01
                  :ARG0 (m2 / molecular-physical-entity
                        :ARG0-of (i3 / inhibit-01
                              :ARG1 (p6 / protein-family :name (n5 / name :op1 "PI3K"))))
                  :ARG1 (p4 / phosphorylate-01
                        :ARG1 (e4 / enzyme :name (n6 / name :op1 "Akt"))
                        :ARG2-of i2)
                  :ARG2-of e)
            :manner (r / respective))
      :mod (i4 / important)
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod "5E")))

# ::id pmid_2470_8867.179 ::date 2015-09-01T02:42:49 ::annotator SDL-AMR-09 ::preferred
# ::snt Although the potential off-target effects of these inhibitors cannot be excluded in these experiments, our results suggest that the morphological transformation induced by the oncogenic Met receptor, and driven by the constitutive activation of Grb2 and Shc signals in IECs, relies, at least in part, on the activation of the Ras/MAPK pathway, but not on PI3K signaling.
# ::save-date Sun Jan 17, 2016 ::file pmid_2470_8867_179.txt
(s / suggest-01
      :ARG0 (t2 / thing
            :ARG2-of (r / result-01)
            :poss (w / we))
      :ARG1 (c5 / contrast-01
            :ARG1 (r2 / rely-01
                  :ARG0 (t3 / transform-01
                        :ARG1 (m / morphology)
                        :ARG2-of (i2 / induce-01
                              :ARG0 (r4 / receptor :name (n / name :op1 "Met")
                                    :ARG0-of (c / cause-01
                                          :ARG1 (c2 / cancer))))
                        :ARG1-of (d / drive-02
                              :ARG0 (a2 / activate-01
                                    :ARG1 (a3 / and
                                          :op1 (s2 / signal-07
                                                :ARG0 (p3 / protein :name (n2 / name :op1 "Grb2")))
                                          :op2 (s3 / signal-07
                                                :ARG0 (p4 / protein :name (n3 / name :op1 "Shc"))))
                                    :mod (c3 / constitutive)
                                    :location (c4 / cell :name (n4 / name :op1 "IEC")))))
                  :ARG1 (a5 / activate-01
                        :ARG1 (p6 / pathway :name (n5 / name :op1 "Ras/MAPK")))
                  :degree (p5 / part
                        :mod (a4 / at-least)))
            :ARG2 (r3 / rely-01 :polarity -
                  :ARG0 t3
                  :ARG1 (s4 / signal-07
                        :ARG0 (p8 / pathway :name (n6 / name :op1 "PI3K")))))
      :concession (p / possible-01 :polarity -
            :ARG1 (e2 / exclude-01
                  :ARG1 (a6 / affect-01
                        :ARG0 (m2 / molecular-physical-entity
                              :ARG0-of (i / inhibit-01)
                              :mod (t / this))
                        :mod (p7 / potential)
                        :mod (t4 / target
                              :mod (o / off)))
                  :ARG2 (e3 / experiment-01
                        :mod t))))

# ::id pmid_2470_8867.180 ::date 2015-09-01T02:55:14 ::annotator SDL-AMR-09 ::preferred
# ::snt <sec-title level="2">The growth promoting effect of oncogenic Met in IECs is blocked by MEK inhibition, but anoikis sensitivity is restored by concomitant treatment with MEK and PI3K inhibitors</sec-title>
# ::save-date Sun Jan 17, 2016 ::file pmid_2470_8867_180.txt
(c / contrast-01
      :ARG1 (b / block-01
            :ARG0 (i / inhibit-01
                  :ARG1 (p / protein-family :name (n / name :op1 "MEK")))
            :ARG1 (a / affect-01
                  :ARG0 (p3 / protein :name (n2 / name :op1 "Met")
                        :ARG0-of (c2 / cause-01
                              :ARG1 (c3 / cancer)))
                  :ARG1 (c4 / cell :name (n3 / name :op1 "IEC"))
                  :ARG0-of (p2 / promote-01
                        :ARG1 (g / grow-01))))
      :ARG2 (r / restore-02
            :ARG0 (t / treat-04
                  :ARG2 (a3 / and
                        :op1 (m / molecular-physical-entity
                              :ARG0-of i)
                        :op2 (m2 / molecular-physical-entity
                              :ARG0-of (i2 / inhibit-01
                                    :ARG1 (p4 / protein-family :name (n4 / name :op1 "PI3K")))))
                  :time (c5 / concomitant))
            :ARG1 (s / sensitive-03
                  :ARG1 (a2 / anoikis))))

# ::id pmid_2470_8867.181 ::date 2015-09-01T03:02:03 ::annotator SDL-AMR-09 ::preferred
# ::snt We next investigated whether the growth capacity promoted by the oncogenic Met in IECs required MEK or PI3K activity.
# ::save-date Tue Sep 1, 2015 ::file pmid_2470_8867_181.txt
(i / investigate-01
      :ARG0 (w / we)
      :ARG1 (r / require-01 :mode interrogative
            :ARG0 (c / capable-01
                  :ARG1 (c4 / cell :name (n4 / name :op1 "IEC"))
                  :ARG2 (g / grow-01)
                  :ARG1-of (p2 / promote-01
                        :ARG0 (p3 / protein :name (n3 / name :op1 "Met")
                              :ARG0-of (c2 / cause-01
                                    :ARG1 (c3 / cancer)))))
            :ARG1 (o / or
                  :op1 (a / activity-06
                        :ARG0 (e / enzyme :name (n / name :op1 "MEK")))
                  :op2 (a2 / activity-06
                        :ARG0 (e2 / enzyme :name (n5 / name :op1 "PI3K")))))
      :time (n2 / next))

# ::id pmid_2470_8867.182 ::date 2015-09-01T03:06:13 ::annotator SDL-AMR-09 ::preferred
# ::snt Cell-count assays were performed with Tpr-Met and Control-IEC-6 cells that were treated for 24 or 48 hours with vehicle, U0126 or LY294002 inhibitor, or a combination of both inhibitors.
# ::save-date Tue Jan 12, 2016 ::file pmid_2470_8867_182.txt
(p / perform-01
      :ARG1 (a / assay-01
            :mod (c / count-01
                  :ARG1 (c2 / cell)))
      :ARG2 (a2 / and
            :op1 (c3 / cell-line :wiki -
                  :name (n5 / name :op1 "IEC-6")
                  :ARG1-of (t2 / transform-01
                        :ARG0 (p2 / protein :wiki "Tpr-met_fusion_protein"
                              :name (n2 / name :op1 "Tpr-Met"))))
            :op2 (c4 / cell-line :wiki -
                  :name (n3 / name :op1 "IEC-6")
                  :mod (c6 / control))
            :ARG1-of (t3 / treat-04
                  :ARG2 (o2 / or
                        :op1 (v / vehicle)
                        :op2 (s / small-molecule :wiki "U0126"
                              :name (n / name :op1 "U0126")
                              :ARG0-of (i / inhibit-01))
                        :op3 (s2 / small-molecule :wiki "LY294002"
                              :name (n4 / name :op1 "LY294002")
                              :ARG0-of i)
                        :op4 (c7 / combine-01
                              :ARG1 s
                              :ARG2 s2
                              :mod (b / both)))
                  :duration (o / or
                        :op1 (t4 / temporal-quantity :quant 24
                              :unit h)
                        :op2 (t / temporal-quantity :quant 48
                              :unit (h / hour))))))

# ::id pmid_2470_8867.183 ::date 2015-09-01T03:14:55 ::annotator SDL-AMR-09 ::preferred
# ::snt As anticipated, treatment with DMSO did not significantly impact cell growth, even after 48 hours.
# ::save-date Tue Sep 1, 2015 ::file pmid_2470_8867_183.txt
(i / impact-01 :polarity -
      :ARG0 (t2 / treat-04
            :ARG2 (s2 / small-molecule :name (n / name :op1 "DMSO")))
      :ARG1 (g / grow-01
            :ARG1 (c / cell))
      :ARG1-of (s / significant-02)
      :time (a / after
            :quant (t / temporal-quantity :quant 48
                  :unit (h / hour))
            :mod (e / even))
      :ARG1-of (a2 / anticipate-01))

# ::id pmid_2470_8867.184 ::date 2015-09-01T03:17:17 ::annotator SDL-AMR-09 ::preferred
# ::snt Treatment with LY294002 exerted similar inhibitory effects upon the growth of both the Tpr-Met-transformed and control IEC-6 cells, reducing the number of cells by 44% and 36%, respectively relative to DMSO-treated cells, after 48 hours (Figure <xref ref-type="fig" rid="F6">6</xref>A).
# ::save-date Sun Jan 17, 2016 ::file pmid_2470_8867_184.txt
(e / exert-01
      :ARG0 (t2 / treat-04
            :ARG2 (s / small-molecule :name (n / name :op1 "LY294002")))
      :ARG1 (a / affect-01
            :ARG1-of (r / resemble-01)
            :ARG0-of (i / inhibit-01))
      :ARG2 (a2 / and
            :op1 (g / grow-01
                  :ARG1 (c / cell-line :name (n7 / name :op1 "IEC-6")
                        :ARG1-of (t3 / transform-01
                              :ARG0 (p3 / protein :name (n2 / name :op1 "Tpr-Met")))))
            :op2 (g2 / grow-01
                  :ARG1 (c2 / cell-line :name (n3 / name :op1 "IEC-6")
                        :mod (c5 / control)))
            :mod (b / both))
      :ARG0-of (r2 / reduce-01
            :ARG1 (n4 / number
                  :quant-of c)
            :ARG2 (p / percentage-entity :value 44
                  :ARG1-of (r4 / relative-05
                        :ARG3 (c6 / cell
                              :ARG1-of (t4 / treat-04
                                    :ARG2 (s2 / small-molecule :name (n6 / name :op1 "DMSO"))))))
            :time (a3 / after
                  :quant (t / temporal-quantity :quant 48
                        :unit (h / hour))))
      :ARG0-of (r3 / reduce-01
            :ARG1 (n5 / number
                  :quant-of c2)
            :ARG2 (p2 / percentage-entity :value 36
                  :ARG1-of r4)
            :time a3)
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod "6A")))

# ::id pmid_2470_8867.185 ::date 2015-09-01T03:26:40 ::annotator SDL-AMR-09 ::preferred
# ::snt In contrast, in the presence of U0126, the growth of Tpr-Met-IEC-6 cells was significantly attenuated but not that of Control-IEC-6 cells (Figure <xref ref-type="fig" rid="F6">6</xref>A).
# ::save-date Sun Jan 17, 2016 ::file pmid_2470_8867_185.txt
(c / contrast-01
      :ARG2 (c2 / contrast-01
            :ARG1 (a / attenuate-01
                  :ARG1 (g / grow-01
                        :ARG1 (c3 / cell-line :name (n2 / name :op1 "IEC-6")
                              :ARG1-of (t / transform-01
                                    :ARG0 (p / protein :name (n3 / name :op1 "Tpr-Met")))))
                  :ARG1-of (s2 / significant-02))
            :ARG2 (a2 / attenuate-01 :polarity -
                  :ARG1 (g2 / grow-01
                        :ARG1 (c4 / cell-line :name (n4 / name :op1 "IEC-6")
                              :mod (c7 / control)))
                  :ARG1-of s2)
            :condition (p2 / present-02
                  :ARG1 (s / small-molecule :name (n / name :op1 "U0126"))))
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod "6A")))

# ::id pmid_2470_8867.186 ::date 2015-09-01T04:11:44 ::annotator SDL-AMR-09 ::preferred
# ::snt Furthermore, while co-treatment with U0126 failed to potentiate the growth inhibiting effect of LY294002 in Control-IEC-6 cells, the growth of Tpr-Met-IEC-6 cells was further reduced in a time-dependent manner upon exposure to both inhibitors (Figure <xref ref-type="fig" rid="F6">6</xref>A).
# ::save-date Sun Jan 17, 2016 ::file pmid_2470_8867_186.txt
(a / and
      :op2 (c / contrast-01
            :ARG1 (r / reduce-01
                  :ARG0 (e2 / expose-01
                        :ARG1 c3
                        :ARG2 (a3 / and
                              :op1 s
                              :op2 s2
                              :ARG0-of (i2 / inhibit-01)))
                  :ARG1 (g2 / grow-01
                        :ARG1 (c3 / cell-line :name (n4 / name :op1 "IEC-6")
                              :ARG1-of (t2 / transform-01
                                    :ARG0 (p2 / protein :name (n5 / name :op1 "Tpr-Met")))))
                  :degree (f2 / further)
                  :manner (d / depend-01
                        :ARG0 r
                        :ARG1 (t / time)))
            :ARG2 (f / fail-01
                  :ARG1 (t3 / treat-04
                        :ARG2 (a4 / and
                              :op1 s2
                              :op2 (s / small-molecule :name (n / name :op1 "U0126"))))
                  :ARG2 (p / potentiate-01
                        :ARG1 (a2 / affect-01
                              :ARG0 (s2 / small-molecule :name (n2 / name :op1 "LY294002"))
                              :ARG1 (c2 / cell-line :name (n3 / name :op1 "IEC-6")
                                    :mod (c4 / control))
                              :ARG0-of (i / inhibit-01
                                    :ARG1 (g / grow-01))))))
      :ARG1-of (d2 / describe-01
            :ARG0 (f3 / figure :mod "6A")))

# ::id pmid_2470_8867.187 ::date 2015-09-01T04:22:57 ::annotator SDL-AMR-09 ::preferred
# ::snt The impact of inhibiting MEK1/2 or PI3K activity on the viability of Tpr-Met-IEC-6 cells in suspension was also evaluated.
# ::save-date Sun Jan 17, 2016 ::file pmid_2470_8867_187.txt
(e / evaluate-01
      :ARG1 (i / impact-01
            :ARG0 (i2 / inhibit-01
                  :ARG1 (o / or
                        :op1 (a2 / activity-06
                              :ARG0 (s / slash
                                    :op1 (e2 / enzyme :name (n / name :op1 "MEK1"))
                                    :op2 (e3 / enzyme :name (n2 / name :op1 "MEK2"))))
                        :op2 (a3 / activity-06
                              :ARG0 (e4 / enzyme :name (n3 / name :op1 "PI3K")))))
            :ARG1 (v / viability
                  :poss (c / cell-line :name (n4 / name :op1 "IEC-6")
                        :ARG1-of (s2 / suspend-02)
                        :ARG1-of (t / transform-01
                              :ARG0 (p / protein :name (n5 / name :op1 "Tpr-Met"))))))
      :mod (a / also))

# ::id pmid_2470_8867.188 ::date 2015-09-01T04:28:30 ::annotator SDL-AMR-09 ::preferred
# ::snt In these anoikis assays, vehicle or the indicated inhibitors were added when cells were seeded and cell viability was measured 24 and 48 hours later.
# ::save-date Tue Sep 1, 2015 ::file pmid_2470_8867_188.txt
(a / and
      :op1 (a2 / add-02
            :ARG1 (o / or
                  :op1 (v / vehicle)
                  :op2 (m3 / molecular-physical-entity
                        :ARG0-of (i / inhibit-01)
                        :ARG1-of (i2 / indicate-01)))
            :time (s / seed-02
                  :ARG2 (c / cell)))
      :op2 (m4 / measure-01
            :ARG1 (v2 / viability
                  :mod c)
            :time (a3 / and
                  :op1 (l2 / late
                        :degree (m2 / more
                              :quant (t2 / temporal-quantity :quant 24
                                    :unit h)))
                  :op2 (l / late
                        :degree (m / more
                              :quant (t / temporal-quantity :quant 48
                                    :unit (h / hour))))))
      :condition (a4 / assay-01
            :mod (a5 / anoikis)
            :mod (t3 / this)))

# ::id pmid_2470_8867.189 ::date 2015-09-01T04:34:49 ::annotator SDL-AMR-09 ::preferred
# ::snt Treatment with the PI3K inhibitor restored anoikis sensitivity to the Tpr-Met-IEC-6 cells in a time-dependent manner, reducing their viability by close to 45% relative to DMSO-treated cells after 48 hours (Figure <xref ref-type="fig" rid="F6">6</xref>B).
# ::save-date Sun Jan 17, 2016 ::file pmid_2470_8867_189.txt
(r / restore-02
      :ARG0 (t3 / treat-04
            :ARG2 (m / molecular-physical-entity
                  :ARG0-of (i / inhibit-01
                        :ARG1 (p3 / protein-family :name (n / name :op1 "PI3K")))))
      :ARG1 (s / sensitive-03
            :ARG0 (c / cell-line :name (n2 / name :op1 "IEC-6")
                  :ARG1-of (t5 / transform-01
                        :ARG0 (p2 / protein :name (n3 / name :op1 "Tpr-Met"))))
            :ARG1 (a / anoikis))
      :manner (d / depend-01
            :ARG0 r
            :ARG1 (t2 / time))
      :ARG0-of (r2 / reduce-01
            :ARG1 (v / viability
                  :poss c)
            :ARG2 (c4 / close-11
                  :ARG2 (p / percentage-entity :value 45)
                  :ARG1-of (r3 / relative-05
                        :ARG3 (c5 / cell
                              :ARG1-of (t4 / treat-04
                                    :ARG2 (s2 / small-molecule :name (n4 / name :op1 "DMSO"))))))
            :time (a2 / after
                  :quant (t / temporal-quantity :quant 48
                        :unit (h / hour))))
      :ARG1-of (d2 / describe-01
            :ARG0 (f / figure :mod "6B")))

# ::id pmid_2470_8867.190 ::date 2015-09-01T04:42:15 ::annotator SDL-AMR-09 ::preferred
# ::snt The MEK1/2 inhibitor, on the other hand, did not substantially impact the viability of the Tpr-Met-IEC-6 cells grown in suspension.
# ::save-date Sun Jan 17, 2016 ::file pmid_2470_8867_190.txt
(c / contrast-01
      :ARG2 (i2 / impact-01 :polarity -
            :ARG0 (m / molecular-physical-entity
                  :ARG0-of (i / inhibit-01
                        :ARG1 (s / slash
                              :op1 (e / enzyme :name (n / name :op1 "MEK1"))
                              :op2 (e2 / enzyme :name (n2 / name :op1 "MEK2")))))
            :ARG1 (v / viability
                  :poss (c2 / cell-line :name (n3 / name :op1 "IEC-6")
                        :ARG1-of (g / grow-01
                              :manner (s3 / suspend-02))
                        :ARG1-of (t / transform-01
                              :ARG0 (p / protein :name (n4 / name :op1 "Tpr-Met")))))
            :manner (s2 / substantial)))

# ::id pmid_2470_8867.191 ::date 2015-09-01T04:48:43 ::annotator SDL-AMR-09 ::preferred
# ::snt Nonetheless, U0126 treatment did elicit a marked synergistic effect on LY294002-induced anoikis, reducing Tpr-Met-IEC-6 cell viability to levels well below those seen upon treatment with the PI3K inhibitor alone (Figure <xref ref-type="fig" rid="F6">6</xref>B).
# ::save-date Tue Feb 2, 2016 ::file pmid_2470_8867_191.txt
(h / have-concession-91
      :ARG1 (e / elicit-01
            :ARG0 (t2 / treat-04
                  :ARG2 (s / small-molecule :name (n / name :op1 "U0126")))
            :ARG1 (a / affect-01
                  :ARG1 (a2 / anoikis
                        :ARG2-of (i2 / induce-01
                              :ARG0 (s4 / small-molecule :name (n2 / name :op1 "LY294002"))))
                  :ARG2 (s2 / synergize-01)
                  :mod (m / marked))
            :ARG0-of (r / reduce-01
                  :ARG1 (v / viability
                        :poss (c / cell-line :name (n3 / name :op1 "IEC-6")
                              :ARG1-of (t / transform-01
                                    :ARG0 (p / protein :name (n4 / name :op1 "Tpr-Met")))))
                  :ARG4 (l / level
                        :mod (b / below
                              :degree (w / well)
                              :compared-to (l2 / level
                                    :mod (t3 / that)
                                    :ARG1-of (s3 / see-01
                                          :time (t4 / treat-04
                                                :ARG2 (m3 / molecular-physical-entity
                                                      :ARG0-of (i / inhibit-01
                                                            :ARG1 (p2 / protein-family :name (n5 / name :op1 "PI3K")))
                                                      :mod (a3 / alone)))))))))
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod "6B")))

# ::id pmid_2470_8867.192 ::date 2015-09-01T04:56:10 ::annotator SDL-AMR-09 ::preferred
# ::snt These results suggest that Tpr-Met-mediated growth promoting effects observed in IECs implicate MEK-dependent mechanisms, but that the anoikis resistance involves the integration of both MEK- and PI3K-dependent signaling pathways.
# ::save-date Mon Sep 7, 2015 ::file pmid_2470_8867_192.txt
(s2 / suggest-01
      :ARG0 (t / thing
            :ARG2-of (r / result-01)
            :mod (t2 / this))
      :ARG1 (c / contrast-01
            :ARG1 (i / implicate-01
                  :ARG0 (a / affect-01
                        :ARG0-of (p2 / promote-01
                              :ARG1 (g / grow-01))
                        :ARG1-of (m / mediate-01
                              :ARG0 (p3 / protein :name (n2 / name :op1 "Tpr-Met")))
                        :ARG1-of (o / observe-01
                              :location (c4 / cell :name (n3 / name :op1 "IEC"))))
                  :ARG1 (m2 / mechanism
                        :ARG0-of (d / depend-01
                              :ARG1 (e / enzyme :name (n / name :op1 "MEK")))))
            :ARG2 (i2 / involve-01
                  :ARG1 (i3 / integrate-01
                        :ARG1 (a3 / and
                              :op1 (p / pathway
                                    :ARG0-of (d2 / depend-01
                                          :ARG1 e))
                              :op2 (p4 / pathway
                                    :ARG0-of (d3 / depend-01
                                          :ARG1 (e2 / enzyme :name (n4 / name :op1 "PI3K"))))
                              :ARG0-of (s / signal-07)))
                  :ARG2 (r2 / resist-01
                        :ARG1 (a2 / anoikis)))))

# ::id pmid_2493_9055.1 ::date 2015-08-29T03:25:23 ::annotator SDL-AMR-09 ::preferred
# ::snt Antitumor activity of selective MEK1/2 inhibitor AZD6244 in combination with PI3K/mTOR inhibitor BEZ235 in gefitinib-resistant NSCLC xenograft models (PMID:24939055)
# ::save-date Mon Nov 23, 2015 ::file pmid_2493_9055_1.txt
(a / activity-06
      :ARG0 (s / small-molecule :name (n2 / name :op1 "AZD6244")
            :ARG0-of (i / inhibit-01
                  :ARG1 (e / enzyme :name (n / name :op1 "MEK1/2")))
            :ARG1-of (c2 / combine-01
                  :ARG2 (s2 / small-molecule :name (n4 / name :op1 "BEZ235")
                        :ARG0-of (i2 / inhibit-01
                              :ARG1 (p / pathway :name (n3 / name :op1 "PI3K/mTOR")))))
            :ARG0-of (s3 / select-01))
      :ARG0-of (c / counter-01
            :ARG1 (t / tumor))
      :location (m / model
            :mod (x / xenograft
                  :mod (d / disease :name (n5 / name :op1 "NSCLC"))
                  :ARG0-of (r / resist-01
                        :ARG1 (s4 / small-molecule :name (n6 / name :op1 "gefitinib")))))
      :ARG1-of (d2 / describe-01
            :ARG0 (p2 / publication-91
                  :ARG8 "PMID24939055")))

# ::id pmid_2493_9055.9 ::date 2015-08-28T02:13:52 ::annotator SDL-AMR-09 ::preferred
# ::snt <sec-title level="1" sec-area="abstract">Results</sec-title>
# ::save-date Fri Aug 28, 2015 ::file pmid_2493_9055_9.txt
(t / thing
      :ARG2-of (r / result-01))

# ::id pmid_2493_9055.10 ::date 2015-08-28T08:48:58 ::annotator SDL-AMR-09 ::preferred
# ::snt AZD6244 could inhibit the tumor growth of NCI-H1993, but slightly inhibit the tumor growth of NCI-1975 and NCI-H460.
# ::save-date Sun Aug 30, 2015 ::file pmid_2493_9055_10.txt
(c / contrast-01
      :ARG1 (p2 / possible-01
            :ARG1 (i2 / inhibit-01
                  :ARG0 (s / small-molecule :name (n / name :op1 "AZD6244"))
                  :ARG1 (g / grow-01
                        :ARG0 (c3 / cell-line :name (n3 / name :op1 "NCI-H1993"))
                        :ARG1 (t / tumor))))
      :ARG2 (i / inhibit-01
            :ARG1 (g2 / grow-01
                  :ARG0 (a / and
                        :op1 (c2 / cell-line :name (n2 / name :op1 "NCI-1975"))
                        :op2 (c4 / cell-line :name (n4 / name :op1 "NCI-H460")))
                  :ARG1 t)
            :manner (s2 / slight)))

# ::id pmid_2493_9055.11 ::date 2015-08-28T09:31:31 ::annotator SDL-AMR-09 ::preferred
# ::snt Combining AZD6244 with BEZ235 markedly enhanced their antitumor effects and without any marked adverse events.
# ::save-date Tue Sep 15, 2015 ::file pmid_2493_9055_11.txt
(a2 / and
      :op1 (e / enhance-01
            :ARG0 (c / combine-01
                  :ARG1 (s / small-molecule :name (n / name :op1 "AZD6244"))
                  :ARG2 (s2 / small-molecule :name (n2 / name :op1 "BEZ235")))
            :ARG1 (a / affect-01
                  :ARG0 (a4 / and
                        :op1 s
                        :op2 s2)
                  :ARG0-of (c2 / counter-01
                        :ARG1 (t / tumor)))
            :manner (m / marked))
      :op2 (e2 / enhance-01
            :ARG0 c
            :ARG0-of (c3 / cause-01 :polarity -
                  :ARG1 (e3 / event
                        :mod (a3 / adverse)
                        :mod m))))

# ::id pmid_2493_9055.12 ::date 2015-08-29T01:45:10 ::annotator SDL-AMR-09 ::preferred
# ::snt Western blot analysis and immunohistochemical staining revealed that AZD6244 alone reduced ERK1/2 phosphorylation, angiogenesis, and tumor cell proliferation.
# ::save-date Sun Jan 3, 2016 ::file pmid_2493_9055_12.txt
(r / reveal-01
      :ARG0 (a / and
            :op1 (a2 / analyze-01
                  :mod (i2 / immunoblot-01))
            :op2 (s2 / stain-01
                  :mod (i / immunohistochemical)))
      :ARG1 (r2 / reduce-01
            :ARG0 (s / small-molecule :name (n2 / name :op1 "AZD6244")
                  :mod (a5 / alone))
            :ARG1 (a3 / and
                  :op1 (p / phosphorylate-01
                        :ARG1 (e / enzyme :name (n / name :op1 "ERK1/2")))
                  :op2 (a4 / angiogenesis)
                  :op3 (p2 / proliferate-01
                        :ARG0 (c / cell
                              :mod (t / tumor))))))

# ::id pmid_2493_9055.13 ::date 2015-08-28T08:56:36 ::annotator SDL-AMR-09 ::preferred
# ::snt Moreover, MEK1/2 inhibition resulted in decreased AKT phosphorylation in NCI-H1993 tumor model.
# ::save-date Fri Aug 28, 2015 ::file pmid_2493_9055_13.txt
(a / and
      :op2 (r / result-01
            :ARG1 (i / inhibit-01
                  :ARG1 (e / enzyme :name (n / name :op1 "MEK1/2")))
            :ARG2 (p / phosphorylate-01
                  :ARG1 (e2 / enzyme :name (n2 / name :op1 "AKT"))
                  :location (m / model
                        :mod (t / tumor)
                        :mod (c / cell-line :name (n3 / name :op1 "NCI-H1993")))
                  :ARG1-of (d / decrease-01))))

# ::id pmid_2493_9055.14 ::date 2015-08-28T09:17:42 ::annotator SDL-AMR-09 ::preferred
# ::snt BEZ235 also inhibited AKT phosphorylation as well as their downstream molecules in all three tumor models.
# ::save-date Tue Sep 15, 2015 ::file pmid_2493_9055_14.txt
(i / inhibit-01
      :ARG0 (s / small-molecule :name (n / name :op1 "BEZ235"))
      :ARG1 (a / and
            :op1 (p / phosphorylate-01
                  :ARG1 (e / enzyme :name (n2 / name :op1 "AKT")))
            :op2 (m / molecule
                  :direction (d / downstream)
                  :location (m2 / model :quant 3
                        :mod (t / tumor)
                        :mod (a2 / all))
                  :poss s))
      :mod (a3 / also))

# ::id pmid_2493_9055.15 ::date 2015-08-29T01:56:00 ::annotator SDL-AMR-09 ::preferred
# ::snt The antiangiogenic effects were substantially enhanced when the agents were combined, which may due to the reduced expression of matrix metallopeptidase-9 in tumor tissues (MMP-9).
# ::save-date Mon Nov 23, 2015 ::file pmid_2493_9055_15.txt
(e / enhance-01
      :ARG0 (a2 / affect-01
            :ARG0-of (c4 / counter-01
                  :ARG1 (a3 / angiogenesis)))
      :degree (s / substantial)
      :condition (c3 / combine-01
            :ARG1 (a / agent))
      :ARG1-of (c2 / cause-01
            :ARG0 (e2 / express-03
                  :ARG2 (e3 / enzyme :name (n / name :op1 "matrix" :op2 "metallopeptidase-9"))
                  :ARG3 (t / tissue
                        :source (t2 / tumor))
                  :ARG1-of (r / reduce-01))
            :ARG1-of (p / possible-01)))

# ::id pmid_2493_9055.94 ::date 2015-08-28T08:54:36 ::annotator SDL-AMR-09 ::preferred
# ::snt <sec-title level="1">Results</sec-title>
# ::save-date Fri Aug 28, 2015 ::file pmid_2493_9055_94.txt
(t / thing
      :ARG2-of (r / result-01))

# ::id pmid_2493_9055.95 ::date 2015-08-29T02:00:50 ::annotator SDL-AMR-09 ::preferred
# ::snt <sec-title level="2">Effect of AZD6244 and BEZ235 on viability of gefitinib-resistant NSCLC <i>in vitro</i></sec-title>
# ::save-date Tue Sep 15, 2015 ::file pmid_2493_9055_95.txt
(a / affect-01
      :ARG0 (a2 / and
            :op1 (s / small-molecule :name (n / name :op1 "AZD6244"))
            :op2 (s2 / small-molecule :name (n2 / name :op1 "BEZ235")))
      :ARG1 (v / viability
            :poss (d / disease :name (n3 / name :op1 "NSCLC")
                  :ARG0-of (r / resist-01
                        :ARG1 (s3 / small-molecule :name (n4 / name :op1 "gefitinib"))))
            :manner (i / in-vitro)))

# ::id pmid_2493_9055.96 ::date 2015-08-29T02:05:45 ::annotator SDL-AMR-09 ::preferred
# ::snt Before evaluating the effect of AZD6244, BEZ235 and AZD6244 plus BEZ235 treatment on gefitinib-resistant NSCLC xenograft models in nude mice, the sensitivity of cell lines to compounds was evaluated <i>in vitro.</i>
# ::save-date Tue Sep 15, 2015 ::file pmid_2493_9055_96.txt
(e / evaluate-01
      :ARG1 (s2 / sensitive-03
            :ARG0 (c2 / cell-line)
            :ARG1 (c / compound))
      :manner (i / in-vitro)
      :time (b / before
            :op1 (e2 / evaluate-01
                  :ARG1 (a / affect-01
                        :ARG0 (t / treat-04
                              :ARG1 (m / model
                                    :mod (x / xenograft
                                          :mod (d / disease :name (n3 / name :op1 "NSCLC")))
                                    :ARG0-of (r / resist-01
                                          :ARG1 (s4 / small-molecule :name (n4 / name :op1 "gefitinib")))
                                    :location (m2 / mouse
                                          :mod (n5 / nude)))
                              :ARG2 (a2 / and
                                    :op1 (s / small-molecule :name (n / name :op1 "AZD6244"))
                                    :op2 (s3 / small-molecule :name (n2 / name :op1 "BEZ235"))
                                    :op3 (a3 / and
                                          :op1 s
                                          :op2 s3)))))))

# ::id pmid_2493_9055.97 ::date 2015-08-29T12:25:56 ::annotator SDL-AMR-09 ::preferred
# ::snt Cell proliferation was analyzed by MTT assay in cells treated with 0, 0.01, 0.1, 1, 10 and 100 μM of AZD6244 or BEZ235 for 72 h.
# ::save-date Sat Feb 13, 2016 ::file pmid_2493_9055_97.txt
(a / analyze-01
      :ARG1 (p / proliferate-01
            :ARG0 (c / cell))
      :instrument (a2 / assay-01
            :instrument (s3 / small-molecule :name (n / name :op1 "MTT")))
      :location (c2 / cell
            :ARG1-of (t / treat-04
                  :ARG2 (a3 / and
                        :op1 (c3 / concentration-quantity :quant 0
                              :unit m3)
                        :op2 (c4 / concentration-quantity :quant 0.01
                              :unit m3)
                        :op3 (c5 / concentration-quantity :quant 0.1
                              :unit m3)
                        :op4 (c6 / concentration-quantity :quant 1
                              :unit m3)
                        :op5 (c7 / concentration-quantity :quant 10
                              :unit (m3 / micromolar))
                        :op6 (c8 / concentration-quantity :quant 100
                              :unit m3)
                        :quant-of (o / or
                              :op1 (s / small-molecule :name (n2 / name :op1 "AZD6244"))
                              :op2 (s2 / small-molecule :name (n3 / name :op1 "BEZ235"))))
                  :duration (t2 / temporal-quantity :quant 72
                        :unit (h / hour)))))

# ::id pmid_2493_9055.98 ::date 2015-08-30T05:44:04 ::annotator SDL-AMR-09 ::preferred
# ::snt The results showed that AZD6244 significantly suppressed the growth of NCI-H1993 with a low micromolar IC50 value of 5.6 μM (Figure <xref ref-type="fig" rid="F1">1</xref>A).
# ::save-date Tue Sep 15, 2015 ::file pmid_2493_9055_98.txt
(s / show-01
      :ARG0 (t / thing
            :ARG2-of (r / result-01))
      :ARG1 (s2 / suppress-01
            :ARG0 (s3 / small-molecule :name (n / name :op1 "AZD6244"))
            :ARG1 (g / grow-01
                  :ARG1 (c / cell-line :name (n3 / name :op1 "NCI-H1993"))
                  :ARG2 (v / value-01
                        :ARG1 (t2 / thing :name (n2 / name :op1 "IC50"))
                        :ARG2 (c2 / concentration-quantity :quant 5.6
                              :unit (m / micromolar))
                        :ARG1-of (l / low-04)))
            :ARG1-of (s4 / significant-02))
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod "1A")))

# ::id pmid_2493_9055.99 ::date 2015-08-30T05:48:56 ::annotator SDL-AMR-09 ::preferred
# ::snt Moreover, AZD6244 alone mildly inhibited cell growth with IC50 values of 37.5 μM and 26.8 μM in NCI-H1975 and NCI-H460 cells, respectively (Figure <xref ref-type="fig" rid="F1">1</xref>A).
# ::save-date Tue Sep 15, 2015 ::file pmid_2493_9055_99.txt
(a / and
      :op2 (i / inhibit-01
            :ARG0 (a3 / and
                  :op1 (s / small-molecule :name (n / name :op1 "AZD6244")
                        :mod (v / value-01
                              :ARG1 (t / thing :name (n2 / name :op1 "IC50"))
                              :ARG2 (c3 / concentration-quantity :quant 37.5
                                    :unit (m2 / micromolar))
                              :location (c4 / cell-line :name (n3 / name :op1 "NCI-H1975"))))
                  :op2 (s2 / small-molecule :name (n5 / name :op1 "AZD6244")
                        :mod (v2 / value-01
                              :ARG1 t
                              :ARG2 (c2 / concentration-quantity :quant 26.8
                                    :unit (m3 / micromolar))
                              :location (c5 / cell-line :name (n4 / name :op1 "NCI-H460"))))
                  :mod (a2 / alone))
            :ARG1 (g / grow-01
                  :ARG1 (c / cell))
            :manner (m / mild))
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod "1A")))

# ::id pmid_2493_9055.100 ::date 2015-08-30T05:55:39 ::annotator SDL-AMR-09 ::preferred
# ::snt BEZ235 alone also suppressed the growth of three cell lines with slightly high IC50 values of 23.5, 67.8 and 16.8 μM in NCI-H1993, NCI-H1975 and NCI-H460 cells, respectively (Figure <xref ref-type="fig" rid="F1">1</xref>B).
# ::save-date Tue Sep 15, 2015 ::file pmid_2493_9055_100.txt
(s / suppress-01
      :ARG0 (s2 / small-molecule :name (n / name :op1 "BEZ235"))
      :ARG1 (g / grow-01
            :ARG1 (a4 / and
                  :op1 (c / cell-line
                        :location (c3 / cell-line :name (n3 / name :op1 "NCI-H1993"))
                        :mod (v / value-01
                              :ARG1 (t / thing :name (n2 / name :op1 "IC50"))
                              :ARG2 (c2 / concentration-quantity :quant 23.5
                                    :unit (m / micromolar))
                              :ARG1-of (h / high-04
                                    :degree (s3 / slight))))
                  :op2 (c8 / cell-line
                        :location (c7 / cell-line :name (n4 / name :op1 "NCI-H1975"))
                        :mod (v2 / value-01
                              :ARG1 t
                              :ARG2 (c4 / concentration-quantity :quant 67.8
                                    :unit m)))
                  :op3 (c9 / cell-line
                        :location (c6 / cell-line :name (n5 / name :op1 "NCI-H460"))
                        :mod (v3 / value-01
                              :ARG1 t
                              :ARG2 (c5 / concentration-quantity :quant 16.8
                                    :unit m)))
                  :mod (a3 / alone)))
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod "1B"))
      :mod (a / also))

# ::id pmid_2493_9055.101 ::date 2015-08-29T03:41:13 ::annotator SDL-AMR-09 ::preferred
# ::snt <sec-title level="2">Concurrent inhibition of MEK and PI3K/mTOR has a synergistic effect on gefitinib-resistant NSCLC cell lines growth <i>in vitro</i></sec-title>
# ::save-date Tue Feb 2, 2016 ::file pmid_2493_9055_101.txt
(a / affect-01
      :ARG0 (i / inhibit-01
            :ARG1 (e / enzyme :name (n / name :op1 "MEK"))
            :ARG1-of (c2 / concur-01
                  :ARG0 (i2 / inhibit-01
                        :ARG1 (p / pathway :name (n2 / name :op1 "PI3K/mTOR")))))
      :ARG1 (g / grow-01
            :ARG1 (c / cell-line
                  :mod (d / disease :name (n3 / name :op1 "NSCLC"))
                  :ARG0-of (r / resist-01
                        :ARG1 (s2 / small-molecule :name (n4 / name :op1 "gefitinib"))))
            :manner (i3 / in-vitro))
      :ARG2 (s / synergize-01))

# ::id pmid_2493_9055.102 ::date 2015-08-29T03:45:29 ::annotator SDL-AMR-09 ::preferred
# ::snt The anti-proliferative effect of combining a MEK and PI3K/mTOR inhibitor was measured in NCI-H1993, NCI-H1975 and NCI-H460 cells by calculating the combination index (CI) according to the Chou-Talalay method [<xref ref-type="bibr" rid="B21">21</xref>] using a fixed dose ratio.
# ::save-date Sat Jan 16, 2016 ::file pmid_2493_9055_102.txt
(m / measure-01
      :ARG1 (a / affect-01
            :ARG0 (c2 / combine-01
                  :ARG1 (m2 / molecular-physical-entity
                        :ARG0-of (i / inhibit-01
                              :ARG1 (p4 / protein-family :name (n2 / name :op1 "MEK"))))
                  :ARG2 (m3 / molecular-physical-entity
                        :ARG0-of (i2 / inhibit-01
                              :ARG1 (p2 / pathway :name (n / name :op1 "PI3K/mTOR")))))
            :ARG0-of (c / counter-01
                  :ARG1 (p / proliferate-01)))
      :ARG2 (c6 / calculate-01
            :ARG1 (i3 / index
                  :mod (c7 / combine-01)))
      :ARG3 (u / use-01
            :ARG1 (r / ratio
                  :mod (d / dose
                        :ARG1-of (f / fix-03)))
            :ARG1-of (s / say-01
                  :ARG0 (m4 / method :name (n6 / name :op1 "Chou-Talalay")))
            :ARG1-of (d2 / describe-01
                  :ARG0 (p3 / publication
                        :ARG0-of (c8 / cite-01
                              :ARG1 21))))
      :location (a2 / and
            :op1 (c3 / cell-line :name (n3 / name :op1 "NCI-H1993"))
            :op2 (c4 / cell-line :name (n4 / name :op1 "NCI-H1975"))
            :op3 (c5 / cell-line :name (n5 / name :op1 "NCI-H460"))))

# ::id pmid_2493_9055.103 ::date 2015-08-30T08:08:19 ::annotator SDL-AMR-09 ::preferred
# ::snt Both AZD6244 and BEZ235 were introduced to cell cultures at 0.25×, 0.5×, 1×, 2× and 4× their respective IC50s in NCI-H1993, NCI-H1975 and NCI-H460 cell lines for 72 h.
# ::save-date Wed Sep 16, 2015 ::file pmid_2493_9055_103.txt
(i / introduce-01
      :ARG1 (a / and
            :op1 (s / small-molecule :name (n / name :op1 "AZD6244"))
            :op2 (s2 / small-molecule :name (n2 / name :op1 "BEZ235"))
            :mod (t / thing :name (n3 / name :op1 "IC50"))
            :quant (a3 / and
                  :op1 (p / product-of :op1 0.25
                        :op2 t)
                  :op2 (p2 / product-of :op1 0.5
                        :op2 t)
                  :op3 (p3 / product-of :op1 1
                        :op2 t)
                  :op4 (p4 / product-of :op2 2
                        :op2 t)
                  :op5 (p5 / product-of :op2 4
                        :op2 t)
                  :mod (r / respective)))
      :ARG2 (c / culture-01
            :ARG1 (c2 / cell))
      :location (a2 / and
            :op1 (c3 / cell-line :name (n4 / name :op1 "NCI-H1993"))
            :op2 (c4 / cell-line :name (n5 / name :op1 "NCI-H1975"))
            :op3 (c5 / cell-line :name (n6 / name :op1 "NCI-H460")))
      :duration (t2 / temporal-quantity :quant 72
            :unit (h / hour)))

# ::id pmid_2493_9055.104 ::date 2015-08-29T02:06:48 ::annotator SDL-AMR-09 ::preferred
# ::snt Cell growth in all cell lines was markedly decreased following combination treatment at multiple paired concentrations when compared with either single agent alone.
# ::save-date Tue Sep 15, 2015 ::file pmid_2493_9055_104.txt
(d / decrease-01
      :ARG1 (g / grow-01
            :ARG1 (c / cell)
            :location (c2 / cell-line
                  :mod (a / all)))
      :ARG2 (m / marked)
      :ARG1-of (f / follow-01
            :ARG2 (t / treat-04
                  :ARG2 (c4 / concentrate-01
                        :ARG1-of (p / pair-01)
                        :quant (m2 / multiple))
                  :mod (c3 / combine-01)))
      :ARG1-of (c5 / compare-01
            :ARG2 (a2 / agent
                  :ARG1-of (s / single-02)
                  :mod (e / either)
                  :mod (a3 / alone))))

# ::id pmid_2493_9055.105 ::date 2015-08-29T02:09:58 ::annotator SDL-AMR-09 ::preferred
# ::snt The cells viability data were processed to get the CI under the corresponding effective dose (ED) in NCI-H1993, NCI-H1975 and NCI-H460 cell lines (Figure <xref ref-type="fig" rid="F2">2</xref>) by CalcuSyn software.
# ::save-date Fri Feb 12, 2016 ::file pmid_2493_9055_105.txt
(p / process-01
      :ARG1 (d / data
            :topic (v / viability
                  :poss (c / cell)))
      :purpose (g / get-03
            :ARG1 (i / interval
                  :mod (c7 / confidence))
            :ARG2 (u / under
                  :op1 (c6 / concentration-quantity
                        :ARG4-of (h2 / have-percentage-maximal-effective-dose-01
                              :ARG5 (a2 / and
                                    :op1 (c3 / cell-line :name (n4 / name :op1 "NCI-H1993"))
                                    :op2 (c4 / cell-line :name (n3 / name :op1 "NCI-H1975"))
                                    :op3 (c5 / cell-line :name (n2 / name :op1 "NCI-H460"))))
                        :ARG1-of (c2 / correspond-01))))
      :ARG1-of (d4 / describe-01
            :ARG0 (f / figure :mod 2))
      :instrument (s / software :name (n5 / name :op1 "CalcuSyn")))

# ::id pmid_2493_9055.106 ::date 2015-08-30T06:03:45 ::annotator SDL-AMR-09 ::preferred
# ::snt For the NCI-H1993 cell line the following CI value was obtained: 0.4101 (ED50).
# ::save-date Fri Feb 12, 2016 ::file pmid_2493_9055_106.txt
(o / obtain-01
      :ARG1 (v / value-01
            :ARG1 (i / interval
                  :mod (c / confidence))
            :ARG2 0.4101
            :ARG2-of (f / follow-01)
            :ARG1-of (m / mean-01
                  :ARG2 (h / have-percentage-maximal-effective-dose-01
                        :ARG2 50)))
      :purpose (c2 / cell-line :name (n2 / name :op1 "NCI-H1993")))

# ::id pmid_2493_9055.107 ::date 2015-08-30T06:07:33 ::annotator SDL-AMR-09 ::preferred
# ::snt For NCI-H1975 and NCI-H460 cell line the CI values were 0.02052 (ED50), and 0.0440 (ED50) respectively.
# ::save-date Fri Feb 12, 2016 ::file pmid_2493_9055_107.txt
(a / and
      :op1 (v / value-01
            :ARG1 (i / interval
                  :mod (c3 / confidence))
            :ARG2 0.02052
            :purpose (c / cell-line :name (n / name :op1 "NCI-H1975"))
            :ARG1-of (m / mean-01
                  :ARG2 (h / have-percentage-maximal-effective-dose-01
                        :ARG2 50)))
      :op2 (v2 / value-01
            :ARG1 i
            :ARG2 0.0440
            :purpose (c2 / cell-line :name (n2 / name :op1 "NCI-H460"))
            :ARG1-of (d2 / describe-01
                  :ARG0 (p / publication-91))
            :ARG1-of m))

# ::id pmid_2493_9055.108 ::date 2015-08-30T06:11:05 ::annotator SDL-AMR-09 ::preferred
# ::snt The CI results suggested that AZD6244 and BEZ235 worked synergistically to produce an anti-proliferative effect in NCI-H1993, NCI-H1975 and NCI-H460 cell lines (Figures <xref ref-type="fig" rid="F2">2</xref>A-C).
# ::save-date Sun Jan 17, 2016 ::file pmid_2493_9055_108.txt
(s / suggest-01
      :ARG0 (t / thing
            :ARG2-of (r / result-01
                  :ARG1 (i / index
                        :mod (c5 / combine-01))))
      :ARG1 (w / work-01
            :ARG0 (a / and
                  :op1 (s3 / small-molecule :name (n2 / name :op1 "AZD6244"))
                  :op2 (s4 / small-molecule :name (n3 / name :op1 "BEZ235")))
            :ARG1 (p / produce-01
                  :ARG0 a
                  :ARG1 (a2 / affect-01
                        :ARG0-of (c / counter-01
                              :ARG1 (p2 / proliferate-01
                                    :location (a3 / and
                                          :op1 (c2 / cell-line :name (n4 / name :op1 "NCI-H1993"))
                                          :op2 (c3 / cell-line :name (n5 / name :op1 "NCI-H1975"))
                                          :op3 (c4 / cell-line :name (n6 / name :op1 "NCI-H460")))))))
            :manner (s2 / synergistical))
      :ARG1-of (d / describe-01
            :ARG0 (a4 / and
                  :op1 (f / figure :mod "2A")
                  :op2 (f2 / figure :mod "2B")
                  :op3 (f3 / figure :mod "2C"))))

# ::id pmid_2493_9055.109 ::date 2015-08-29T03:00:20 ::annotator SDL-AMR-09 ::preferred
# ::snt <sec-title level="2">Tumor growth inhibition effect of MEK and PI3K/mTOR inhibitors in gefitinib-resistant NSCLC tumor models</sec-title>
# ::save-date Sun Jan 17, 2016 ::file pmid_2493_9055_109.txt
(a / affect-01
      :ARG0 (a2 / and
            :op1 (m2 / molecular-physical-entity
                  :ARG0-of (i2 / inhibit-01
                        :ARG1 (p2 / protein-family :name (n2 / name :op1 "MEK"))))
            :op2 (m3 / molecular-physical-entity
                  :ARG0-of (i3 / inhibit-01
                        :ARG1 (p / pathway :name (n3 / name :op1 "PI3K/mTOR")))))
      :ARG1 (i / inhibit-01
            :ARG1 (g / grow-01
                  :ARG0 (t / tumor)))
      :location (m / model
            :mod (t2 / tumor
                  :mod (d / disease :name (n / name :op1 "NSCLC")))
            :ARG0-of (r / resist-01
                  :ARG1 (s / small-molecule :name (n4 / name :op1 "gefitinib")))))

# ::id pmid_2493_9055.110 ::date 2015-08-29T03:05:30 ::annotator SDL-AMR-09 ::preferred
# ::snt In order to investigate tumor growth inhibition effect of AZD6244 and/or BEZ235 <i>in vivo</i>, we used AZD6244, BEZ235, and AZD6244 plus BEZ235 to treat NCI-H1993, NCI-H1975 and NCI-H460 subcutaneous tumor models respectively for 3 weeks.
# ::save-date Tue Sep 15, 2015 ::file pmid_2493_9055_110.txt
(u / use-01
      :ARG0 (w / we)
      :ARG1 (a / and
            :op1 (s / small-molecule :name (n / name :op1 "AZD6244"))
            :op2 (s2 / small-molecule :name (n2 / name :op1 "BEZ235"))
            :op3 (a5 / and
                  :op1 s
                  :op2 s2))
      :ARG2 (t / treat-04
            :ARG0 w
            :ARG1 (a2 / and
                  :op1 (m / model
                        :mod (t3 / tumor)
                        :mod (c / cell-line :name (n3 / name :op1 "NCI-H1993")))
                  :op2 (m2 / model
                        :mod t3
                        :mod (c2 / cell-line :name (n4 / name :op1 "NCI-H1975")))
                  :op3 (m3 / model
                        :mod t3
                        :mod (c3 / cell-line :name (n5 / name :op1 "NCI-H460")))
                  :mod (s3 / subcutaneous))
            :duration (t2 / temporal-quantity :quant 3
                  :unit (w2 / week))
            :manner (r / respective))
      :purpose (i2 / investigate-01
            :ARG0 w
            :ARG1 (a3 / affect-01
                  :ARG0 (a4 / and-or
                        :op1 s
                        :op2 s2)
                  :ARG1 (i / inhibit-01
                        :ARG1 (g / grow-01
                              :ARG1 t3))
                  :manner (i3 / in-vivo))))

# ::id pmid_2493_9055.111 ::date 2015-08-29T03:11:54 ::annotator SDL-AMR-09 ::preferred
# ::snt As shown in Figure <xref ref-type="fig" rid="F3">3</xref>A-C, treatment with AZD6244 for 3 weeks was able to inhibit tumor growth of NCI-H1993 (T/C value 40%), but slightly inhibit tumor growth in both NCI-H1975 and NCI-H460 subcutaneous tumor models (T/C values 60% and 65%), whereas BEZ235 treatment caused an approximately 50% reduction in tumor growth in all three subcutaneous tumor models.
# ::save-date Fri Feb 5, 2016 ::file pmid_2493_9055_111.txt
(c7 / contrast-01
      :ARG1 (c3 / contrast-01
            :ARG1 (p6 / possible-01
                  :ARG1 (i / inhibit-01
                        :ARG0 (t2 / treat-04
                              :ARG2 (s / small-molecule :name (n / name :op1 "AZD6244")))
                        :ARG1 (g / grow-01
                              :ARG1 (t3 / tumor)
                              :location (c2 / cell-line :name (n2 / name :op1 "NCI-H1993")))
                        :ARG1-of (m / mean-01
                              :ARG2 (v / value-01
                                    :ARG2 (p / percentage-entity :value 40)))))
            :ARG2 (i2 / inhibit-01
                  :ARG1 (g2 / grow-01
                        :ARG1 t3)
                  :degree (s3 / slight)
                  :location (a / and
                        :op1 (m2 / model
                              :mod t3
                              :location (c4 / cell-line :name (n3 / name :op1 "NCI-H1975")))
                        :op2 (m3 / model
                              :mod t3
                              :location (c5 / cell-line :name (n4 / name :op1 "NCI-H460")))
                        :mod (s2 / subcutaneous))
                  :ARG1-of (m4 / mean-01
                        :ARG2 (a2 / and
                              :op1 (v2 / value-01
                                    :ARG2 (p2 / percentage-entity :value 60))
                              :op2 (v3 / value-01
                                    :ARG2 (p3 / percentage-entity :value 65))))))
      :ARG2 (c6 / cause-01
            :ARG0 (t4 / treat-04
                  :ARG2 (s5 / small-molecule :name (n5 / name :op1 "BEZ235")))
            :ARG1 (r / reduce-01
                  :ARG1 (g3 / grow-01
                        :ARG1 t3)
                  :ARG2 (a3 / approximately
                        :op1 (p4 / percentage-entity :value 50))
                  :location (m5 / model :quant 3
                        :mod s2
                        :mod t3
                        :mod (a4 / all))))
      :ARG1-of (s6 / show-01
            :ARG0 (a5 / and
                  :op1 (f / figure :mod "3A")
                  :op2 (f2 / figure :mod "3B")
                  :op3 (f3 / figure :mod "3C"))))

# ::id pmid_2493_9055.112 ::date 2015-08-29T12:26:42 ::annotator SDL-AMR-09 ::preferred
# ::snt In contrast, the combined treatments with the two drugs almost completely inhibited NCI-H1993, NCI-H1975 and NCI-H460 tumor growth at the end of the 3 weeks of therapy (Figure <xref ref-type="fig" rid="F3">3</xref>A-D).
# ::save-date Sun Jan 3, 2016 ::file pmid_2493_9055_112.txt
(c / contrast-01
      :ARG2 (i / inhibit-01
            :ARG0 (t4 / treat-04
                  :ARG1-of (c6 / combine-01
                        :ARG2 (d2 / drug :quant 2)))
            :ARG1 (a2 / and
                  :op1 (g / grow-01
                        :ARG0 (c3 / cell-line :name (n / name :op1 "NCI-H1993"))
                        :ARG1 (t3 / tumor))
                  :op2 (g2 / grow-01
                        :ARG0 (c4 / cell-line :name (n2 / name :op1 "NCI-H1975"))
                        :ARG1 t3)
                  :op3 (g3 / grow-01
                        :ARG0 (c5 / cell-line :name (n3 / name :op1 "NCI-H460"))
                        :ARG1 t3))
            :ARG1-of (c2 / complete-02
                  :degree (a / almost))
            :time (e / end-01
                  :ARG1 (t2 / therapy
                        :duration (t / temporal-quantity :quant 3
                              :unit (w / week)))))
      :ARG1-of (d / describe-01
            :ARG0 (a3 / and
                  :op1 (f / figure :mod "3A")
                  :op2 (f2 / figure :mod "3B")
                  :op3 (f3 / figure :mod "3C")
                  :op4 (f4 / figure :mod "3D"))))

# ::id pmid_2493_9055.113 ::date 2015-08-29T02:14:32 ::annotator SDL-AMR-09 ::preferred
# ::snt Single agent and combination treatment protocols were well tolerated by mice, with no weight loss or other signs of acute or delayed toxicity (Figure <xref ref-type="fig" rid="F4">4</xref>A-C).
# ::save-date Sun Jan 3, 2016 ::file pmid_2493_9055_113.txt
(t / tolerate-01
      :ARG0 (m / mouse
            :ARG0-of (l / lose-02 :polarity -
                  :ARG1 (w / weight))
            :ARG0-of (s / signal-07
                  :ARG1 (o3 / or
                        :op1 (t2 / toxicity
                              :mod (a2 / acute))
                        :op2 (t3 / toxicity
                              :ARG1-of (d / delay-01)))
                  :mod (o2 / other)))
      :ARG1 (a / and
            :op1 (p / protocol
                  :topic (t4 / treat-04
                        :ARG2 (a3 / agent
                              :ARG1-of (s2 / single-02))))
            :op2 (p2 / protocol
                  :topic (t5 / treat-04
                        :ARG1-of (c / combine-01))))
      :manner (w2 / well)
      :ARG1-of (d2 / describe-01
            :ARG0 (a4 / and
                  :op1 (f / figure :mod "4A")
                  :op2 (f2 / figure :mod "4B")
                  :op3 (f3 / figure :mod "4C"))))

# ::id pmid_2493_9055.114 ::date 2015-08-29T02:17:57 ::annotator SDL-AMR-09 ::preferred
# ::snt <sec-title level="2">Effect of MEK and PIK3/mTOR inhibitors on signaling transduction pathways in gefitinib-resistant NSCLC tumor models</sec-title>
# ::save-date Fri Feb 5, 2016 ::file pmid_2493_9055_114.txt
(a / affect-01
      :ARG0 (a2 / and
            :op1 (m2 / molecular-physical-entity
                  :ARG0-of (i2 / inhibit-01
                        :ARG1 (p2 / protein-family :name (n / name :op1 "MEK"))))
            :op2 (m / molecular-physical-entity
                  :ARG0-of (i / inhibit-01
                        :ARG1 (p / pathway :name (n2 / name :op1 "PIK3/mTOR")))))
      :ARG1 (p3 / pathway
            :ARG2-of (t / transduce-01)
            :location (m4 / model
                  :mod (t2 / tumor
                        :mod (d / disease :name (n4 / name :op1 "NSCLC")))
                  :ARG0-of (r / resist-01
                        :ARG1 (s2 / small-molecule :name (n3 / name :op1 "gefitinib"))))
            :ARG0-of (s / signal-07)))

# ::id pmid_2493_9055.115 ::date 2015-08-29T02:56:07 ::annotator SDL-AMR-09 ::preferred
# ::snt To assess the impact of both compounds on downstream molecules of the MEK and PI3K pathways, we used Western blot analysis to observe phosphorylation status and total protein expression in tumor tissues.
# ::save-date Sun Jan 3, 2016 ::file pmid_2493_9055_115.txt
(u / use-01
      :ARG0 (w / we)
      :ARG1 (a / analyze-01
            :mod (i2 / immunoblot-01))
      :ARG2 (o / observe-01
            :ARG0 w
            :ARG1 (a2 / and
                  :op1 (s / status
                        :mod (p / phosphorylate-01))
                  :op2 (e / express-03
                        :ARG2 (p2 / protein)
                        :ARG3 (t / tissue
                              :source (t2 / tumor))
                        :ARG1-of (t3 / total-01))))
      :purpose (a3 / assess-01
            :ARG0 w
            :ARG1 (i / impact-01
                  :ARG0 (c / compound
                        :mod (b / both))
                  :ARG1 (m / molecule
                        :direction (d / downstream)
                        :source (a4 / and
                              :op1 (p3 / pathway :name (n2 / name :op1 "MEK"))
                              :op2 (p4 / pathway :name (n3 / name :op1 "PI3K")))))))

# ::id pmid_2493_9055.116 ::date 2015-08-29T14:02:27 ::annotator SDL-AMR-09 ::preferred
# ::snt The results showed that p-MEK1/2, p-ERK1/2, p-AKT, p-S6 and p-4E-BP1 appeared to be inhibited by AZD6244 and BEZ235 combination treatment, whereas the total protein levels of MEK1/2, ERK1/2, AKT, S6 and 4E-BP1 remained unchanged in each tumor model (Figure <xref ref-type="fig" rid="F5">5</xref>).
# ::save-date Wed Sep 16, 2015 ::file pmid_2493_9055_116.txt
(s2 / show-01
      :ARG0 (t / thing
            :ARG2-of (r / result-01))
      :ARG1 (c2 / contrast-01
            :ARG1 (a / appear-01
                  :ARG1 (i / inhibit-01
                        :ARG0 (t2 / treat-04
                              :ARG0-of (c / combine-01
                                    :ARG1 (s4 / small-molecule :name (n8 / name :op1 "AZD6244"))
                                    :ARG2 (s3 / small-molecule :name (n7 / name :op1 "BEZ235"))))
                        :ARG1 (a2 / and
                              :op1 (e / enzyme :name (n2 / name :op1 "MEK1/2")
                                    :ARG3-of (p / phosphorylate-01))
                              :op2 (e2 / enzyme :name (n3 / name :op1 "ERK1/2")
                                    :ARG1-of p)
                              :op3 (e3 / enzyme :name (n4 / name :op1 "AKT")
                                    :ARG1-of p)
                              :op4 (p3 / protein :name (n5 / name :op1 "S6")
                                    :ARG1-of p)
                              :op5 (p4 / protein :name (n6 / name :op1 "4E-BP1")
                                    :ARG1-of p))))
            :ARG2 (r2 / remain-01
                  :ARG1 (a3 / and
                        :op1 (l / level
                              :degree-of e)
                        :op2 (l2 / level
                              :degree-of e2)
                        :op3 (l3 / level
                              :degree-of e3)
                        :op4 (l4 / level
                              :degree-of p3)
                        :op5 (l5 / level
                              :degree-of p4))
                  :ARG2 (m / model
                        :mod (t3 / tumor))
                  :ARG3 (c3 / change-01 :polarity -)))
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod 5)))

# ::id pmid_2493_9055.117 ::date 2015-08-30T07:07:39 ::annotator SDL-AMR-09 ::preferred
# ::snt Western blot analysis of downstream signals also showed treatment with AZD6244 or BEZ235 inhibited the phosphorylation of ERK1/2 or AKT in all three tumor models respectively.
# ::save-date Sun Jan 3, 2016 ::file pmid_2493_9055_117.txt
(s / show-01
      :ARG0 (a / analyze-01
            :ARG1 (s2 / signal-07
                  :direction (d / downstream))
            :mod (i2 / immunoblot-01))
      :ARG1 (i / inhibit-01
            :ARG0 (t / treat-04
                  :ARG2 (o / or
                        :op1 (s3 / small-molecule :name (n2 / name :op1 "AZD6244"))
                        :op2 (s4 / small-molecule :name (n3 / name :op1 "BEZ235"))))
            :ARG1 (p / phosphorylate-01
                  :ARG1 (o2 / or
                        :op1 (e / enzyme :name (n4 / name :op1 "ERK1/2"))
                        :op2 (e2 / enzyme :name (n5 / name :op1 "AKT")))
                  :location (m / model :quant 3
                        :mod (t2 / tumor)
                        :mod (a2 / all)))
            :manner (r / respective))
      :mod (a3 / also))

# ::id pmid_2493_9055.118 ::date 2015-08-29T12:41:12 ::annotator SDL-AMR-09 ::preferred
# ::snt In addition, combined treatment with AZD6244 and BEZ235 showed greater inhibition of p-ERK1/2 and p-AKT than observed in control group or mice treated with each compound alone <i>in vivo</i> (Figure <xref ref-type="fig" rid="F5">5</xref>).
# ::save-date Tue Sep 15, 2015 ::file pmid_2493_9055_118.txt
(a / and
      :op2 (s2 / show-01
            :ARG0 (t / treat-04
                  :ARG1-of (c / combine-01
                        :ARG2 (a2 / and
                              :op1 (s / small-molecule :name (n / name :op1 "AZD6244"))
                              :op2 (s3 / small-molecule :name (n2 / name :op1 "BEZ235")))))
            :ARG1 (i / inhibit-01
                  :ARG1 (a3 / and
                        :op1 (e / enzyme :name (n3 / name :op1 "ERK1/2")
                              :ARG3-of (p / phosphorylate-01))
                        :op2 (e2 / enzyme :name (n4 / name :op1 "AKT")
                              :ARG1-of p))
                  :mod (g / great
                        :degree (m / more)
                        :compared-to (i2 / inhibit-01
                              :ARG1-of (o / observe-01
                                    :location (o2 / or
                                          :op1 (g2 / group
                                                :ARG1-of (c3 / control-01))
                                          :op2 (m2 / mouse
                                                :ARG1-of (t2 / treat-04
                                                      :ARG2 (c4 / compound
                                                            :mod (e3 / each)
                                                            :mod (a4 / alone))
                                                      :manner (i3 / in-vivo)))))))))
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod 5)))

# ::id pmid_2493_9055.119 ::date 2015-08-29T12:53:21 ::annotator SDL-AMR-09 ::preferred
# ::snt Interestingly, the impact from both inhibitors on p-S6 and p-4E-BP1 levels was, alternatively, tumor model specific.
# ::save-date Wed Sep 16, 2015 ::file pmid_2493_9055_119.txt
(s2 / specific-02
      :ARG1 (i3 / impact-01
            :ARG0 (m / molecular-physical-entity
                  :mod (b / both)
                  :ARG0-of (i2 / inhibit-01))
            :ARG1 (a / and
                  :op1 (l / level
                        :quant-of (p2 / protein :name (n / name :op1 "S6")
                              :ARG3-of (p / phosphorylate-01)))
                  :op2 (l2 / level
                        :quant-of (p3 / protein :name (n2 / name :op1 "4E-BP1")
                              :ARG3-of p))))
      :ARG2 (m2 / model
            :mod (t / tumor))
      :ARG2-of (i / interest-01)
      :mod (a2 / alternative))

# ::id pmid_2493_9055.120 ::date 2015-08-29T13:03:15 ::annotator SDL-AMR-09 ::preferred
# ::snt For example, AZD6244 and BEZ235 alone and in combination markedly inhibited p-S6 and p-4E-BP1 expression levels in NCI-H1993 tumor models, compared with the minimal suppression observed in NCI-H460 tumor model (Figure <xref ref-type="fig" rid="F5">5</xref>).
# ::save-date Sun Jan 17, 2016 ::file pmid_2493_9055_120.txt
(i / inhibit-01
      :ARG0 (a / and
            :op1 (a2 / and
                  :op1 (s / small-molecule :name (n / name :op1 "AZD6244"))
                  :op2 (s2 / small-molecule :name (n2 / name :op1 "BEZ235")))
            :op2 (c / combine-01
                  :ARG1 s
                  :ARG2 s2)
            :mod (a4 / alone))
      :ARG1 (a3 / and
            :op1 (l / level
                  :degree-of (e2 / express-03
                        :ARG2 (p2 / protein :name (n3 / name :op1 "S6")
                              :ARG3-of (p / phosphorylate-01))
                        :ARG3 m2))
            :op2 (l2 / level
                  :degree-of (e3 / express-03
                        :ARG2 (p3 / protein :name (n4 / name :op1 "4E-BP1")
                              :ARG1-of p
                              :ARG3-of p)
                        :ARG3 (m2 / model
                              :mod (t / tumor
                                    :mod (c3 / cell-line :name (n5 / name :op1 "NCI-H1993")))))))
      :ARG0-of (e / exemplify-01)
      :manner (m / marked)
      :compared-to (s3 / suppress-01
            :ARG1-of (o / observe-01
                  :location (m4 / model
                        :mod t
                        :mod (c2 / cell-line :name (n6 / name :op1 "NCI-H460"))))
            :degree (m3 / minimal))
      :ARG1-of (d2 / describe-01
            :ARG0 (f / figure :mod 5)))

# ::id pmid_2493_9055.121 ::date 2015-08-30T07:35:33 ::annotator SDL-AMR-09 ::preferred
# ::snt Neither AZD6244 nor BEZ235 alone suppressed p-S6 and p-4E-BP1 in NCI-H1975 tumor model.
# ::save-date Tue Sep 15, 2015 ::file pmid_2493_9055_121.txt
(s / suppress-01 :polarity -
      :ARG0 (a / and
            :op1 (s2 / small-molecule :name (n2 / name :op1 "AZD6244"))
            :op2 (s3 / small-molecule :name (n / name :op1 "BEZ235"))
            :mod (a3 / alone))
      :ARG1 (a2 / and
            :op1 (p2 / protein :name (n4 / name :op1 "S6")
                  :ARG3-of (p / phosphorylate-01))
            :op2 (p3 / protein :name (n5 / name :op1 "4E-BP1")
                  :ARG1-of p))
      :location (m2 / model
            :mod (t / tumor)
            :mod (c / cell-line :name (n3 / name :op1 "NCI-H1975"))))

# ::id pmid_2493_9055.122 ::date 2015-08-30T06:58:30 ::annotator SDL-AMR-09 ::preferred
# ::snt We also found that the expression of MMP-9 was significantly inhibited by AZD6244 and BEZ235 combination treatment, whereas the expression of MMP-2 was not affected by the treatment.
# ::save-date Tue Sep 15, 2015 ::file pmid_2493_9055_122.txt
(f / find-01
      :ARG0 (w / we)
      :ARG1 (c / contrast-01
            :ARG1 (i / inhibit-01
                  :ARG0 (t2 / treat-04
                        :ARG2 (c2 / combine-01
                              :ARG1 (s2 / small-molecule :name (n3 / name :op1 "AZD6244"))
                              :ARG2 (s3 / small-molecule :name (n4 / name :op1 "BEZ235"))))
                  :ARG1 (e3 / express-03
                        :ARG2 (e4 / enzyme :name (n2 / name :op1 "MMP-9")))
                  :ARG1-of (s / significant-02))
            :ARG2 (a2 / affect-01 :polarity -
                  :ARG0 t2
                  :ARG1 (e / express-03
                        :ARG2 (e2 / enzyme :name (n / name :op1 "MMP-2")))))
      :mod (a / also))

# ::id pmid_2493_9055.123 ::date 2015-08-30T06:28:03 ::annotator SDL-AMR-09 ::preferred
# ::snt <sec-title level="2">Effect of MEK and PIK3/mTOR inhibitors on the expressions of Ki-67 and CD31 in gefitinib-resistant NSCLC tumor models</sec-title>
# ::save-date Sat Jan 16, 2016 ::file pmid_2493_9055_123.txt
(a / affect-01
      :ARG0 (a2 / and
            :op1 (m3 / molecular-physical-entity
                  :ARG0-of (i / inhibit-01
                        :ARG1 (p4 / protein-family :name (n2 / name :op1 "MEK"))))
            :op2 (m2 / molecular-physical-entity
                  :ARG0-of (i2 / inhibit-01
                        :ARG1 (p / pathway :name (n3 / name :op1 "PIK3/mTOR")))))
      :ARG1 (a3 / and
            :op1 (e / express-03
                  :ARG2 (p2 / protein :name (n4 / name :op1 "Ki-67"))
                  :ARG3 (m / model
                        :mod (t / tumor
                              :mod (d / disease :name (n / name :op1 "NSCLC")))
                        :ARG0-of (r / resist-01
                              :ARG1 (s / small-molecule :name (n6 / name :op1 "gefitinib")))))
            :op3 (e2 / express-03
                  :ARG1 (p3 / protein :name (n5 / name :op1 "CD31"))
                  :ARG3 m)))

# ::id pmid_2493_9055.124 ::date 2015-08-30T06:47:18 ::annotator SDL-AMR-09 ::preferred
# ::snt To characterize the mechanism of tumor growth inhibition observed in our gefitinib-resistant NSCLC tumor models by AZD6244 and BEZ235, lung tumor tissues were assessed by evaluating Ki-67 expression using immunohistochemical analyses.
# ::save-date Wed Sep 16, 2015 ::file pmid_2493_9055_124.txt
(a / assess-01
      :ARG1 (t / tissue
            :source (t2 / tumor
                  :part-of (l / lung)))
      :manner (e / evaluate-01
            :ARG1 (e2 / express-03
                  :ARG2 (p / protein :name (n / name :op1 "Ki-67"))))
      :manner (u / use-01
            :ARG1 (a2 / analyze-01
                  :mod (i / immunohistochemical)))
      :purpose (c / characterize-01
            :ARG1 (m / mechanism
                  :ARG1-of (o / observe-01
                        :ARG0 (a3 / and
                              :op1 (s / small-molecule :name (n3 / name :op1 "AZD6244"))
                              :op2 (s2 / small-molecule :name (n4 / name :op1 "BEZ235")))
                        :location (m2 / model
                              :ARG0-of (r / resist-01
                                    :ARG1 (s3 / small-molecule :name (n2 / name :op1 "gefitinib")))
                              :mod (t4 / tumor
                                    :mod (d / disease :name (n5 / name :op1 "NSCLC")))
                              :poss (w / we)))
                  :instrument-of (i2 / inhibit-01
                        :ARG1 (g / grow-01
                              :ARG1 (t3 / tumor))))))

# ::id pmid_2493_9055.125 ::date 2015-08-30T06:54:17 ::annotator SDL-AMR-09 ::preferred
# ::snt We observed active cell proliferation in NCI-H1993 tumor model, with a 56% proliferation index (Figure <xref ref-type="fig" rid="F6">6</xref>A).
# ::save-date Sun Aug 30, 2015 ::file pmid_2493_9055_125.txt
(o / observe-01
      :ARG0 (w / we)
      :ARG1 (p2 / proliferate-01
            :ARG0 (c / cell)
            :ARG0-of (a / activity-06)
            :location (m / model
                  :mod (t / tumor)
                  :mod (c2 / cell-line :name (n / name :op1 "NCI-H199")))
            :ARG1-of (i / index-01
                  :ARG2 (p / percentage-entity :value 56)))
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod "6A")))

# ::id pmid_2493_9055.126 ::date 2015-08-30T06:17:34 ::annotator SDL-AMR-09 ::preferred
# ::snt Monotherapy with AZD6244 or BEZ235 slightly decreased the percentage of Ki-67-positive proliferating tumor tissues, with proliferation indices of 42% and 39%, respectively (Figure <xref ref-type="fig" rid="F6">6</xref>A).
# ::save-date Wed Sep 16, 2015 ::file pmid_2493_9055_126.txt
(d / decrease-01
      :ARG0 (m / monotherapy
            :instrument (a / and
                  :op1 (s / small-molecule :name (n / name :op1 "AZD6244"))
                  :op2 (s3 / small-molecule :name (n2 / name :op1 "BEZ235"))))
      :ARG1 (p3 / percentage
            :quant-of (t / tissue
                  :source (t2 / tumor)
                  :ARG0-of (p5 / proliferate-01)
                  :mod (p4 / protein :name (n3 / name :op1 "Ki-67")
                        :mod (p6 / positive))
                  :ARG0-of (h / have-03
                        :ARG1 (a2 / and
                              :op1 (i / index
                                    :mod p5
                                    :mod (p / percentage-entity :value 42))
                              :op2 (i2 / index
                                    :mod p5
                                    :mod (p2 / percentage-entity :value 39))))))
      :degree (s2 / slight)
      :ARG1-of (d2 / describe-01
            :ARG0 (f / figure :mod "6A")))

# ::id pmid_2493_9055.127 ::date 2015-08-30T06:22:05 ::annotator SDL-AMR-09 ::preferred
# ::snt Combined treatment with AZD6244 and BEZ235 markedly decreased the percentage of Ki-67-positive proliferating tumor tissues to 10%, consistent with the marked inhibition of ERK1/2 and AKT phosphorylation.
# ::save-date Tue Sep 15, 2015 ::file pmid_2493_9055_127.txt
(d / decrease-01
      :ARG0 (t / treat-04
            :ARG1-of (c2 / combine-01
                  :ARG2 (a2 / and
                        :op1 (s / small-molecule :name (n3 / name :op1 "AZD6244"))
                        :op2 (s2 / small-molecule :name (n4 / name :op1 "BEZ235")))))
      :ARG1 (p3 / percentage
            :quant-of (t2 / tissue
                  :source (t3 / tumor)
                  :ARG0-of (p4 / proliferate-01)
                  :mod (p5 / protein :name (n5 / name :op1 "Ki-67")
                        :mod (p7 / positive))))
      :ARG2 (m / marked)
      :ARG4 (p6 / percentage-entity :value 10)
      :ARG1-of (c / consistent-01
            :ARG2 (i / inhibit-01
                  :ARG1 (a / and
                        :op1 (p / phosphorylate-01
                              :ARG1 (e / enzyme :name (n / name :op1 "ERK1/2")))
                        :op2 (p2 / phosphorylate-01
                              :ARG1 (e2 / enzyme :name (n2 / name :op1 "AKT"))))
                  :degree m)))

# ::id pmid_2493_9055.128 ::date 2015-08-30T07:14:35 ::annotator SDL-AMR-09 ::preferred
# ::snt We also found the similar results in NCI-H1975 and NCI-H460 tumor models (Figure <xref ref-type="fig" rid="F6">6</xref>A).To evaluate the potential antiangiogenic mechanism of AZD6244 and BEZ235, gefitinib-resistant NSCLC tumor tissues were analyzed by immunostaining for CD31 (platelet endothelial cell adhesion molecule 1).
# ::save-date Tue Jan 19, 2016 ::file pmid_2493_9055_128.txt
(m / multi-sentence
      :snt1 (f / find-01
            :ARG0 (w / we)
            :ARG1 (t / thing
                  :ARG2-of (r / result-01)
                  :ARG1-of (r2 / resemble-01))
            :ARG1-of (d / describe-01
                  :ARG0 (f2 / figure :mod "6A"))
            :mod (a / also)
            :location (a2 / and
                  :op1 (m2 / model
                        :mod (t2 / tumor)
                        :mod (c / cell-line :name (n2 / name :op1 "NCI-H1975")))
                  :op2 (m3 / model
                        :mod t2
                        :mod (c2 / cell-line :name (n / name :op1 "NCI-H460")))))
      :snt2 (a3 / analyze-01
            :ARG0 (i / immunostain-01
                  :ARG3 (p / protein :name (n3 / name :op1 "CD31")))
            :ARG1 (t3 / tissue
                  :source (t4 / tumor)
                  :mod (d2 / disease :name (n4 / name :op1 "NSCLC"))
                  :ARG0-of (r3 / resist-01
                        :ARG1 (s3 / small-molecule :name (n7 / name :op1 "gefitinib"))))
            :purpose (e / evaluate-01
                  :ARG1 (m4 / mechanism
                        :poss (a4 / and
                              :op1 (s / small-molecule :name (n5 / name :op1 "AZD6244"))
                              :op2 (s2 / small-molecule :name (n6 / name :op1 "BEZ235")))
                        :ARG0-of (c3 / counter-01
                              :ARG1 (a5 / angiogenesis
                                    :mod (p2 / potential)))))))

# ::id pmid_2493_9055.129 ::date 2015-08-29T04:34:16 ::annotator SDL-AMR-09 ::preferred
# ::snt The results showed BEZ235 significantly decreased the vascular density of all three gefitinib-resistant NSCLC tumors, whereas AZD6244 monotherapy had only a mildly effect upon lung tumor angiogenesis.
# ::save-date Tue Sep 15, 2015 ::file pmid_2493_9055_129.txt
(c / contrast-01
      :ARG1 (s2 / show-01
            :ARG0 (t2 / thing
                  :ARG2-of (r / result-01))
            :ARG1 (d / decrease-01
                  :ARG0 (s5 / small-molecule :name (n3 / name :op1 "BEZ235"))
                  :ARG1 (d2 / density)
                  :mod (v / vessel)
                  :location (t3 / tumor :quant 3
                        :mod (d3 / disease :name (n / name :op1 "NSCLC"))
                        :ARG0-of (r2 / resist-01
                              :ARG1 (s / small-molecule :name (n4 / name :op1 "gefitinib"))))
                  :ARG1-of (s4 / significant-02)))
      :ARG2 (a / affect-01
            :ARG0 (m2 / monotherapy
                  :mod (s3 / small-molecule :name (n2 / name :op1 "AZD6244")))
            :ARG1 (a2 / angiogenesis
                  :mod (t / tumor
                        :source (l / lung)))
            :manner (m / mild)
            :mod (o / only)))

# ::id pmid_2493_9055.130 ::date 2015-08-28T09:38:25 ::annotator SDL-AMR-09 ::preferred
# ::snt The antiangiogenic effects AZD6244 and BEZ235 were markedly increased when they were combined (Figure <xref ref-type="fig" rid="F6">6</xref>B).
# ::save-date Wed Sep 16, 2015 ::file pmid_2493_9055_130.txt
(i / increase-01
      :ARG1 (a / affect-01
            :ARG0 (a2 / and
                  :op1 (s / small-molecule :name (n / name :op1 "AZD6244"))
                  :op2 (s2 / small-molecule :name (n2 / name :op1 "BEZ235")))
            :ARG0-of (c4 / counter-01
                  :ARG1 (a3 / angiogenesis)))
      :ARG2 (m / marked)
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod "6B"))
      :condition (c2 / combine-01
            :ARG1 a2))

# ::id pmid_2493_9055.131 ::date 2015-08-29T03:46:05 ::annotator SDL-AMR-09 ::preferred
# ::snt <sec-title level="2">MEK and PIK3/mTOR inhibitors had no effect on caspase-3, 8 and 9 activities in gefitinib-resistant NSCLC tumor models</sec-title>
# ::save-date Sat Jan 16, 2016 ::file pmid_2493_9055_131.txt
(a / affect-01 :polarity -
      :ARG0 (a2 / and
            :op1 (m / molecular-physical-entity
                  :ARG0-of (i / inhibit-01
                        :ARG1 (p5 / protein-family :name (n / name :op1 "MEK"))))
            :op2 (m2 / molecular-physical-entity
                  :ARG0-of (i2 / inhibit-01
                        :ARG1 (p / pathway :name (n2 / name :op1 "PIK3/mTOR")))))
      :ARG1 (a3 / and
            :op1 (a4 / activity-06
                  :ARG0 (p2 / protein :name (n4 / name :op1 "Caspase" :op2 "3")))
            :op2 (a5 / activity-06
                  :ARG0 (p3 / protein :name (n5 / name :op1 "Caspase" :op2 "8")))
            :op3 (a6 / activity-06
                  :ARG0 (p4 / protein :name (n6 / name :op1 "Caspase" :op2 "9")))
            :location (m3 / model
                  :mod (t / tumor
                        :mod (d / disease :name (n3 / name :op1 "NSCLC")))
                  :ARG0-of (r / resist-01
                        :ARG1 (s / small-molecule :name (n7 / name :op1 "gefitinib"))))))

# ::id pmid_2493_9055.132 ::date 2015-08-29T01:44:31 ::annotator SDL-AMR-09 ::preferred
# ::snt In order to investigate whether AZD6244 and/or BEZ235 would induce apoptosis in gefitinib-resistant NSCLC tumor models, activity of caspase-3, 8 and 9 were measured by the colorimetric assay.
# ::save-date Wed Sep 16, 2015 ::file pmid_2493_9055_132.txt
(m / measure-01
      :ARG0 (a / assay-01
            :mod (c / colorimetric))
      :ARG1 (a2 / and
            :op1 (p / protein :name (n2 / name :op1 "Caspase" :op2 "3"))
            :op2 (p2 / protein :name (n3 / name :op1 "Caspase" :op2 "8"))
            :op3 (p3 / protein :name (n4 / name :op1 "Caspase" :op2 "9")))
      :purpose (i / investigate-01
            :ARG1 (i2 / induce-01 :mode interrogative
                  :ARG0 (a3 / and-or
                        :op1 (s / small-molecule :name (n / name :op1 "AZD6244"))
                        :op2 (s2 / small-molecule :name (n5 / name :op1 "BEZ235")))
                  :ARG2 (a4 / apoptosis)
                  :location (m5 / model
                        :mod (t / tumor
                              :mod (d / disease :name (n6 / name :op1 "NSCLC")))
                        :ARG0-of (r / resist-01
                              :ARG1 (s3 / small-molecule :name (n7 / name :op1 "gefitinib")))))))

# ::id pmid_2493_9055.133 ::date 2015-08-29T03:15:43 ::annotator SDL-AMR-09 ::preferred
# ::snt The results showed that AZD6244 and/or BEZ235 had no effect on caspase-3, 8 and 9 activities in all three gefitinib-resistant NSCLC tumor models (Figure <xref ref-type="fig" rid="F7">7</xref>).
# ::save-date Tue Sep 15, 2015 ::file pmid_2493_9055_133.txt
(s2 / show-01
      :ARG0 (t / thing
            :ARG2-of (r / result-01))
      :ARG1 (a / affect-01 :polarity -
            :ARG0 (a2 / and-or
                  :op1 (s / small-molecule :name (n / name :op1 "AZD6244"))
                  :op2 (s3 / small-molecule :name (n3 / name :op1 "BEZ235")))
            :ARG1 (a3 / and
                  :op1 (a4 / activity-06
                        :ARG0 (p / protein :name (n5 / name :op1 "Caspase" :op2 "3")))
                  :op2 (a5 / activity-06
                        :ARG0 (p3 / protein :name (n4 / name :op1 "Caspase" :op2 "8")))
                  :op3 (a6 / activity-06
                        :ARG0 (p2 / protein :name (n6 / name :op1 "Caspase" :op2 "9")))
                  :location (m / model :quant 3
                        :mod (t2 / tumor
                              :mod (d2 / disease :name (n2 / name :op1 "NSCLC")))
                        :ARG0-of (r2 / resist-01
                              :ARG1 (s4 / small-molecule :name (n7 / name :op1 "gefitinib")))
                        :mod (a7 / all))))
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod 7)))

# ::id pmid_2540_9876.1 ::date 2015-09-01T04:01:25 ::annotator SDL-AMR-09 ::preferred
# ::snt Selective inhibition of RET mediated cell proliferation in vitro by the kinase inhibitor SPP86 (PMID:25409876)
# ::save-date Wed Nov 25, 2015 ::file pmid_2540_9876_1.txt
(i2 / inhibit-01
      :ARG0 (s2 / small-molecule :name (n2 / name :op1 "SPP86")
            :ARG0-of (i / inhibit-01
                  :ARG1 (k / kinase)))
      :ARG1 (p / proliferate-01
            :ARG0 (c / cell)
            :ARG1-of (m / mediate-01
                  :ARG0 (p2 / protein :name (n / name :op1 "RET")))
            :mod (i3 / in-vitro))
      :ARG0-of (s / select-01)
      :ARG1-of (d / describe-01
            :ARG0 (p3 / publication-91
                  :ARG8 "PMID25409876")))

# ::id pmid_2540_9876.10 ::date 2015-09-01T04:12:07 ::annotator SDL-AMR-09 ::preferred
# ::snt <sec-title level="1" sec-area="abstract">Results</sec-title>
# ::save-date Tue Sep 1, 2015 ::file pmid_2540_9876_10.txt
(t / thing
      :ARG2-of (r / result-01))

# ::id pmid_2540_9876.11 ::date 2015-09-01T04:12:39 ::annotator SDL-AMR-09 ::preferred
# ::snt SPP86 inhibited MAPK signaling and proliferation in RET/PTC1 expressing TPC1 but not 8505C or C643 cells.
# ::save-date Sun Jan 17, 2016 ::file pmid_2540_9876_11.txt
(c2 / contrast-01
      :ARG1 (i / inhibit-01
            :ARG0 (s / small-molecule :name (n2 / name :op1 "SPP86"))
            :ARG1 (a / and
                  :op1 (s2 / signal-07
                        :ARG0 (p / pathway :name (n / name :op1 "MAPK")))
                  :op2 (p2 / proliferate-01
                        :ARG0 p))
            :location (c / cell-line :name (n3 / name :op1 "TPC1")
                  :mod (d / disease :wiki "Cancer" :name (n4 / name :op1 "cancer"))
                  :ARG3-of (e / express-03
                        :ARG2 (p4 / protein :name (n5 / name :op1 "RET/PTC1")))))
      :ARG2 (i2 / inhibit-01 :polarity -
            :ARG0 s
            :ARG1 a
            :location (o / or
                  :op1 (c3 / cell-line :name (n6 / name :op1 "8505C"))
                  :op2 (c4 / cell-line :name (n7 / name :op1 "C643")))))

# ::id pmid_2540_9876.12 ::date 2015-09-01T04:57:51 ::annotator SDL-AMR-09 ::preferred
# ::snt In TPC1 cells, the inhibition of RET phosphorylation required co-exposure to SPP86 and the focal adhesion kinase (FAK) inhibitor PF573228.
# ::save-date Thu Sep 17, 2015 ::file pmid_2540_9876_12.txt
(r / require-01
      :ARG0 (i / inhibit-01
            :ARG1 (p / phosphorylate-01
                  :ARG1 (p2 / protein :name (n / name :op1 "RET"))))
      :ARG1 (e / expose-01
            :ARG2 (a / and
                  :op1 (s / small-molecule :name (n2 / name :op1 "SPP86"))
                  :op2 (s2 / small-molecule :name (n4 / name :op1 "PF573228")
                        :ARG0-of (i2 / inhibit-01
                              :ARG1 (e2 / enzyme :name (n3 / name :op1 "focal-adhesion-kinase"))))))
      :location (c / cell-line :name (n5 / name :op1 "TPC1")))

# ::id pmid_2540_9876.13 ::date 2015-09-01T05:21:39 ::annotator SDL-AMR-09 ::preferred
# ::snt In MCF7 cells, SPP86 inhibited RET- induced phosphatidylinositide 3-kinases (PI3K)/Akt and MAPK signaling and estrogen receptorα (ERα) phosphorylation, and inhibited proliferation to a similar degree as tamoxifen.
# ::save-date Sun Jan 17, 2016 ::file pmid_2540_9876_13.txt
(a3 / and
      :op1 (i / inhibit-01
            :ARG0 (s / small-molecule :name (n2 / name :op1 "SPP86"))
            :ARG1 (a2 / and
                  :op1 (s2 / signal-07
                        :ARG0 (a / and
                              :op1 (s3 / slash
                                    :op1 (e3 / enzyme :name (n9 / name :op1 "phosphatidylinositide" :op2 "3-kinase"))
                                    :op2 (e / enzyme :name (n4 / name :op1 "Akt")))
                              :op2 (p / pathway :name (n / name :op1 "MAPK")))
                        :ARG2-of (i3 / induce-01
                              :ARG0 (p6 / protein :name (n8 / name :op1 "RET"))))
                  :op2 (p2 / phosphorylate-01
                        :ARG1 (p3 / protein :name (n5 / name :op1 "estrogen-receptor-α")))))
      :op2 (i2 / inhibit-01
            :ARG0 s
            :ARG1 (p5 / proliferate-01)
            :degree (d / degree
                  :ARG1-of (r / resemble-01
                        :ARG2 (s5 / small-molecule :name (n6 / name :op1 "tamoxifen")))))
      :location (c / cell-line :name (n7 / name :op1 "MCF7")))

# ::id pmid_2540_9876.14 ::date 2015-09-01T05:36:03 ::annotator SDL-AMR-09 ::preferred
# ::snt Interestingly, SPP86 and PF573228 inhibited RET/PTC1 and GDNF- RET induced activation of Akt and MAPK signaling to a similar degree.
# ::save-date Sun Jan 17, 2016 ::file pmid_2540_9876_14.txt
(a / and
      :op1 (i / inhibit-01
            :ARG0 (a2 / and
                  :op1 (s / small-molecule :name (n2 / name :op1 "SPP86"))
                  :op2 (s2 / small-molecule :name (n3 / name :op1 "PF573228")))
            :ARG1 (p2 / protein :name (n4 / name :op1 "RET/PTC1")))
      :op2 (i2 / induce-01
            :ARG0 (p3 / protein :name (n6 / name :op1 "GDNF-RET"))
            :ARG2 (a3 / activate-01
                  :ARG1 (s3 / signal-07
                        :ARG0 (a4 / and
                              :op1 (p4 / pathway :name (n7 / name :op1 "Akt"))
                              :op2 (p / pathway :name (n8 / name :op1 "MAPK"))))
                  :degree (d2 / degree
                        :ARG1-of (r2 / resemble-01))))
      :ARG2-of (i3 / interest-01))

# ::id pmid_2540_9876.107 ::date 2015-09-01T05:41:00 ::annotator SDL-AMR-09 ::preferred
# ::snt <sec-title level="1">Results</sec-title>
# ::save-date Tue Sep 1, 2015 ::file pmid_2540_9876_107.txt
(t / thing
      :ARG2-of (r / result-01))

# ::id pmid_2540_9876.108 ::date 2015-09-01T05:41:29 ::annotator SDL-AMR-09 ::preferred
# ::snt We investigated the effect of SPP86 on ERK1/2 phosphorylation in thyroid cancer derived cell lines expressing the RET/PTC1 rearrangement (TPC1), BRAF<sup>V600E</sup> (8505C) or RAS<sup>G13R</sup> (C643) mutations [<xref ref-type="bibr" rid="CR47">47</xref>, <xref ref-type="bibr" rid="CR48">48</xref>].
# ::save-date Fri Jan 15, 2016 ::file pmid_2540_9876_108.txt
(i / investigate-01
      :ARG0 (w / we)
      :ARG1 (a / affect-01
            :ARG0 (s / small-molecule :name (n3 / name :op1 "SPP86"))
            :ARG1 (p / phosphorylate-01
                  :ARG1 (s2 / slash
                        :op1 (e / enzyme :name (n4 / name :op1 "ERK1"))
                        :op2 (e2 / enzyme :name (n5 / name :op1 "ERK2"))))
            :location (o2 / or
                  :op1 (c5 / cell-line :name (n12 / name :op1 "TPC1")
                        :ARG3-of (e3 / express-03
                              :ARG2 (r / rearrange-01
                                    :ARG1 (p2 / protein :name (n6 / name :op1 "RET/PTC1")))))
                  :op2 (c4 / cell-line :name (n2 / name :op1 "8505C")
                        :ARG3-of (e6 / express-03
                              :ARG2 (e4 / enzyme :name (n9 / name :op1 "BRAF")
                                    :ARG2-of (m2 / mutate-01 :value "V600E"))))
                  :op3 (c2 / cell-line :name (n11 / name :op1 "C643")
                        :ARG3-of (e7 / express-03
                              :ARG2 (e5 / enzyme :name (n10 / name :op1 "RAS")
                                    :ARG2-of (m4 / mutate-01 :value "G13R"))))
                  :ARG1-of (d2 / derive-01
                        :ARG2 (d / disease :wiki "Cancer" :name (n / name :op1 "cancer")
                              :mod (t / thyroid)))))
      :ARG1-of (d3 / describe-01
            :ARG0 (p6 / publication
                  :ARG1-of (c3 / cite-01
                        :ARG2 (a4 / and :op1 47 :op2 48)))))

# ::id pmid_2540_9876.109 ::date 2015-09-01T05:58:33 ::annotator SDL-AMR-09 ::preferred
# ::snt These mutations have previously been shown to induce constitutive activation of the MAPK signaling pathway in these cell lines [<xref ref-type="bibr" rid="CR47">47</xref>–<xref ref-type="bibr" rid="CR49">49</xref>].
# ::save-date Thu Sep 17, 2015 ::file pmid_2540_9876_109.txt
(s / show-01
      :ARG1 (i / induce-01
            :ARG0 (m / mutate-01
                  :mod (t / this))
            :ARG2 (a / activate-01
                  :ARG1 (p2 / pathway :name (n2 / name :op1 "MAPK")
                        :ARG0-of (s2 / signal-07))
                  :mod (c / constitutive))
            :location (c2 / cell-line
                  :mod (t2 / this)))
      :ARG1-of (d / describe-01
            :ARG0 (p3 / publication
                  :ARG1-of (c3 / cite-01
                        :ARG2 (v / value-interval :op1 47 :op2 49))))
      :time (p4 / previous))

# ::id pmid_2540_9876.110 ::date 2015-09-01T06:04:04 ::annotator SDL-AMR-09 ::preferred
# ::snt Since TPC1 but not 8505C and C643 cells depend predominantly on RET/PTC1 signaling for proliferation, we hypothesized that SPP86 should only inhibit the proliferation of the former.
# ::save-date Thu Sep 17, 2015 ::file pmid_2540_9876_110.txt
(h / hypothesize-01
      :ARG0 (w / we)
      :ARG1 (r / recommend-01
            :ARG1 (i / inhibit-01
                  :ARG0 (s2 / small-molecule :name (n / name :op1 "SPP86"))
                  :ARG1 (p2 / proliferate-01
                        :ARG0 c3)
                  :mod (o / only)))
      :ARG1-of (c / cause-01
            :ARG0 (c2 / contrast-01
                  :ARG1 (d / depend-01
                        :ARG0 (c3 / cell-line :name (n2 / name :op1 "TPC1"))
                        :ARG1 (s / signal-07
                              :ARG0 (p3 / protein :name (n3 / name :op1 "RET/PTC1")))
                        :purpose (p4 / proliferate-01
                              :ARG0 c3)
                        :ARG1-of (p5 / predominate-01))
                  :ARG2 (d2 / depend-01 :polarity -
                        :ARG0 (a / and
                              :op1 (c4 / cell-line :name (n4 / name :op1 "8505C"))
                              :op2 (c5 / cell-line :name (n5 / name :op1 "C643")))
                        :ARG1 s
                        :purpose (p6 / proliferate-01
                              :ARG0 (a2 / and
                                    :op1 c4
                                    :op2 c5))))))

# ::id pmid_2540_9876.111 ::date 2015-09-02T22:45:56 ::annotator SDL-AMR-09 ::preferred
# ::snt Sorafenib, which inhibits both RET and RAF family kinases, was used as an internal control in these experiments.
# ::save-date Thu Sep 17, 2015 ::file pmid_2540_9876_111.txt
(u / use-01
      :ARG1 (s / small-molecule :name (n2 / name :op1 "sorafenib")
            :ARG0-of (i2 / inhibit-01
                  :ARG1 (a / and
                        :op1 (p / protein-family :name (n3 / name :op1 "RET"))
                        :op2 (p2 / protein-family :name (n4 / name :op1 "RAF")))))
      :ARG2 (c / control-01
            :ARG0 s
            :ARG1-of (i / internal-02)
            :location (e3 / experiment-01
                  :mod (t / this))))

# ::id pmid_2540_9876.112 ::date 2015-09-02T22:53:12 ::annotator SDL-AMR-09 ::preferred
# ::snt <sec-title level="2">SPP86 inhibits MAPK pathway activation in RET/PTC1 expressing cell lines</sec-title>
# ::save-date Wed Sep 2, 2015 ::file pmid_2540_9876_112.txt
(i / inhibit-01
      :ARG0 (s / small-molecule :name (n2 / name :op1 "SPP86"))
      :ARG1 (a / activate-01
            :ARG1 (p2 / pathway :name (n3 / name :op1 "MAPK")))
      :location (c / cell-line
            :ARG3-of (e / express-03
                  :ARG2 (p3 / protein :name (n4 / name :op1 "RET/PTC1")))))

# ::id pmid_2540_9876.113 ::date 2015-09-02T22:56:23 ::annotator SDL-AMR-09 ::preferred
# ::snt As previously reported [<xref ref-type="bibr" rid="CR45">45</xref>], SPP86 effectively inhibits ERK1/2 phosphorylation in TPC1 cells expressing the RET/PTC1 rearrangement at a concentration of 1 μM (Figure <xref ref-type="fig" rid="Fig1">1</xref>A).
# ::save-date Thu Sep 17, 2015 ::file pmid_2540_9876_113.txt
(i / inhibit-01
      :ARG0 (s / small-molecule :name (n / name :op1 "SPP86"))
      :ARG1 (p / phosphorylate-01
            :ARG1 (s2 / slash
                  :op1 (e2 / enzyme :name (n2 / name :op1 "ERK1"))
                  :op2 (e3 / enzyme :name (n3 / name :op1 "ERK2")))
            :location (c / cell-line :name (n4 / name :op1 "TPC1")
                  :ARG3-of (e4 / express-03
                        :ARG2 (r2 / rearrange-01
                              :ARG1 (p2 / protein :name (n5 / name :op1 "RET/PTC1"))
                              :quant (c2 / concentration-quantity :quant 1
                                    :unit (m / micromolar))))))
      :ARG1-of (e / effective-04)
      :ARG1-of (r / report-01
            :time (p3 / previous)
            :ARG1-of (d / describe-01
                  :ARG0 (p4 / publication
                        :ARG1-of (c3 / cite-01
                              :ARG2 45))))
      :ARG1-of (d2 / describe-01
            :ARG0 (f / figure :mod "1A")))

# ::id pmid_2540_9876.114 ::date 2015-09-02T23:05:26 ::annotator SDL-AMR-09 ::preferred
# ::snt In contrast, SPP86 had no effect on ERK1/2 phosphorylation in 8505C or C643 cells (Figure <xref ref-type="fig" rid="Fig1">1</xref>B and C).
# ::save-date Thu Sep 17, 2015 ::file pmid_2540_9876_114.txt
(c / contrast-01
      :ARG2 (a / affect-01 :polarity -
            :ARG0 (s / small-molecule :name (n / name :op1 "SPP86"))
            :ARG1 (p / phosphorylate-01
                  :ARG1 (s2 / slash
                        :op1 (e / enzyme :name (n2 / name :op1 "ERK1"))
                        :op2 (e2 / enzyme :name (n3 / name :op1 "ERK2"))))
            :location (o / or
                  :op1 (c2 / cell-line :name (n4 / name :op1 "8505C"))
                  :op2 (c3 / cell-line :name (n5 / name :op1 "C643"))))
      :ARG1-of (d2 / describe-01
            :ARG0 (a2 / and
                  :op1 (f / figure :mod "1B")
                  :op2 (f2 / figure :mod "1C"))))

# ::id pmid_2540_9876.115 ::date 2015-09-02T23:14:23 ::annotator SDL-AMR-09 ::preferred
# ::snt Sorafenib, which targets both RET and RAF kinases, effectively inhibited ERK1/2 phosphorylation in TPC1 cells at a concentration of 0.1 μM (Figure <xref ref-type="fig" rid="Fig1">1</xref>A).
# ::save-date Sun Jan 17, 2016 ::file pmid_2540_9876_115.txt
(i / inhibit-01
      :ARG0 (s / small-molecule :name (n2 / name :op1 "sorafenib")
            :quant (c2 / concentration-quantity :quant 0.1
                  :unit (m / micromolar))
            :ARG0-of (t / target-01
                  :ARG1 (a / and
                        :op1 (p3 / protein-family :name (n3 / name :op1 "RET"))
                        :op2 (p / protein-family :name (n4 / name :op1 "RAF")))))
      :ARG1 (p2 / phosphorylate-01
            :ARG1 (s2 / slash
                  :op1 (e2 / enzyme :name (n6 / name :op1 "ERK1"))
                  :op2 (e3 / enzyme :name (n7 / name :op1 "ERK2"))))
      :ARG1-of (e / effective-04)
      :location (c / cell-line :name (n5 / name :op1 "TPC1"))
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod "1A")))

# ::id pmid_2540_9876.116 ::date 2015-09-02T23:22:12 ::annotator SDL-AMR-09 ::preferred
# ::snt Sorafenib (10 μM) also inhibited ERK1/2 phosphorylation in 8505C cells, and to a lesser extent in C643 cells consistent with previous reports [<xref ref-type="bibr" rid="CR49">49</xref>] (Figure <xref ref-type="fig" rid="Fig1">1</xref>B and C).
# ::save-date Wed Nov 25, 2015 ::file pmid_2540_9876_116.txt
(a2 / and
      :op1 (i / inhibit-01
            :ARG0 (s / small-molecule :name (n / name :op1 "sorafenib")
                  :quant (c / concentration-quantity :quant 10
                        :unit (m / micromolar)))
            :ARG1 (p / phosphorylate-01
                  :ARG1 (s2 / slash
                        :op1 (e / enzyme :name (n2 / name :op1 "ERK1"))
                        :op2 (e2 / enzyme :name (n3 / name :op1 "ERK2"))))
            :location (c2 / cell-line :name (n4 / name :op1 "8505C"))
            :mod (a3 / also))
      :op2 (i2 / inhibit-01
            :ARG0 s
            :ARG1 p
            :location (c3 / cell-line :name (n5 / name :op1 "C643"))
            :ARG1-of (c4 / consistent-01
                  :ARG2 (t / thing
                        :ARG1-of (r / report-01)
                        :time (p2 / previous)))
            :ARG1-of (d2 / describe-01
                  :ARG0 (p3 / publication
                        :ARG1-of (c5 / cite-01
                              :ARG2 49)))
            :degree (l / less
                  :degree (m2 / more))
            :compared-to c2)
      :ARG1-of (d3 / describe-01
            :ARG0 (a / and
                  :op1 (f / figure :mod "1B")
                  :op2 (f2 / figure :mod "1C"))))

# ::id pmid_2540_9876.117 ::date 2015-09-02T23:55:19 ::annotator SDL-AMR-09 ::preferred
# ::snt The differential sensitivity of 8505C and C643 cells to SPP86 and sorafenib likely results from the latter’s effect on RAF signaling [<xref ref-type="bibr" rid="CR49">49</xref>].
# ::save-date Thu Sep 17, 2015 ::file pmid_2540_9876_117.txt
(l / likely-01
      :ARG1 (r / result-01
            :ARG1 (a3 / affect-01
                  :ARG0 s3
                  :ARG1 (s4 / signal-07
                        :ARG0 (e / enzyme :name (n6 / name :op1 "RAF"))))
            :ARG2 (s / sensitive-03
                  :ARG0 (a / and
                        :op1 (c / cell-line :name (n2 / name :op1 "8505C"))
                        :op2 (c2 / cell-line :name (n3 / name :op1 "C643")))
                  :ARG1 (a2 / and
                        :op1 (s2 / small-molecule :name (n4 / name :op1 "SPP86"))
                        :op2 (s3 / small-molecule :name (n5 / name :op1 "sorafenib")))
                  :ARG1-of (d / differ-02)))
      :ARG1-of (d2 / describe-01
            :ARG0 (p2 / publication
                  :ARG1-of (c3 / cite-01
                        :ARG2 49))))

# ::id pmid_2540_9876.118 ::date 2015-09-03T00:01:38 ::annotator SDL-AMR-09 ::preferred
# ::snt Interestingly, SPP86 induced only modest inhibition of RET/PTC1 phosphorylation Tyr1062 at a concentration of 1 μM (Figure <xref ref-type="fig" rid="Fig1">1</xref>D).
# ::save-date Thu Sep 17, 2015 ::file pmid_2540_9876_118.txt
(i / induce-01
      :ARG0 (s / small-molecule :name (n / name :op1 "SPP86")
            :quant (c / concentration-quantity :quant 1
                  :unit (m2 / micromolar)))
      :ARG2 (i3 / inhibit-01
            :ARG1 (p / phosphorylate-01
                  :ARG1 (a / amino-acid :mod 1062 :name (n3 / name :op1 "tyrosine")
                        :part-of (p2 / protein :name (n2 / name :op1 "RET/PTC1"))))
            :mod (m / modest)
            :mod (o / only))
      :ARG2-of (i2 / interest-01)
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod "1D")))

# ::id pmid_2540_9876.119 ::date 2015-09-03T00:05:54 ::annotator SDL-AMR-09 ::preferred
# ::snt Complete inhibition required 10 μM of SPP86 (Figure <xref ref-type="fig" rid="Fig1">1</xref>D).
# ::save-date Thu Sep 17, 2015 ::file pmid_2540_9876_119.txt
(r / require-01
      :ARG0 (i / inhibit-01
            :ARG1-of (c / complete-02))
      :ARG1 (c2 / concentration-quantity :quant 10
            :unit (m / micromolar)
            :quant-of (s / small-molecule :name (n / name :op1 "SPP86")))
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod "1D")))

# ::id pmid_2540_9876.120 ::date 2015-09-03T00:08:41 ::annotator SDL-AMR-09 ::preferred
# ::snt Thus, the ability of SPP86 to abolish ERK1/2 phosphorylation at 1 μM does not strictly correlate with its inhibition of RET phosphorylation.
# ::save-date Sun Jan 17, 2016 ::file pmid_2540_9876_120.txt
(c / cause-01
      :ARG1 (c2 / correlate-01 :polarity -
            :ARG1 (c3 / capable-01
                  :ARG1 (s / small-molecule :name (n / name :op1 "SPP86")
                        :quant (c4 / concentration-quantity :quant 1
                              :unit (m / micromolar)))
                  :ARG2 (a / abolish-01
                        :ARG0 s
                        :ARG1 (p / phosphorylate-01
                              :ARG1 (s2 / slash
                                    :op1 (e / enzyme :name (n2 / name :op1 "ERK1"))
                                    :op2 (e2 / enzyme :name (n3 / name :op1 "ERK2"))))))
            :ARG2 (i / inhibit-01
                  :ARG0 s
                  :ARG1 (p2 / phosphorylate-01
                        :ARG1 (p3 / protein :name (n4 / name :op1 "RET"))))
            :mod (s3 / strict)))

# ::id pmid_2540_9876.121 ::date 2015-09-03T00:13:39 ::annotator SDL-AMR-09 ::preferred
# ::snt Similar observations have previously been reported with the RET inhibitor RPI-1 [<xref ref-type="bibr" rid="CR28">28</xref>].
# ::save-date Sun Jan 17, 2016 ::file pmid_2540_9876_121.txt
(r2 / report-01
      :ARG1 (o / observe-01
            :ARG1-of (r3 / resemble-01))
      :time (p / previous)
      :condition (i2 / inhibit-01
            :ARG0 (p2 / protein :name (n / name :op1 "RPI-1"))
            :ARG1 (p4 / protein :name (n2 / name :op1 "RET")))
      :ARG1-of (d / describe-01
            :ARG0 (p3 / publication
                  :ARG1-of (c / cite-01
                        :ARG2 28))))

# ::id pmid_2540_9876.122 ::date 2015-09-03T00:18:15 ::annotator SDL-AMR-09 ::preferred
# ::snt SPP86 also inhibited Akt phosphorylation on Ser473 at a concentration of 1.0 μM (Figure <xref ref-type="fig" rid="Fig1">1</xref>E and F).
# ::save-date Thu Sep 17, 2015 ::file pmid_2540_9876_122.txt
(i / inhibit-01
      :ARG0 (s / small-molecule :name (n / name :op1 "SPP86")
            :quant (c / concentration-quantity :quant 1.0
                  :unit (m / micromolar)))
      :ARG1 (p / phosphorylate-01
            :ARG1 (a / amino-acid :mod 473 :name (n3 / name :op1 "serine")
                  :part-of (e / enzyme :name (n2 / name :op1 "Akt"))))
      :mod (a2 / also)
      :ARG1-of (d / describe-01
            :ARG0 (a3 / and
                  :op1 (f / figure :mod "1E")
                  :op2 (f2 / figure :mod "1F"))))

# ::id pmid_2540_9876.123 ::date 2015-09-03T00:21:27 ::annotator SDL-AMR-09 ::preferred
# ::snt Prolonged exposure (20 h) to 0.5- 1 μM SPP86 was also associated with a decline in cyclin D1 levels in this cell line (Figure <xref ref-type="fig" rid="Fig1">1</xref>E).
# ::save-date Wed Nov 25, 2015 ::file pmid_2540_9876_123.txt
(a / associate-01
      :ARG1 (e / expose-01
            :ARG2 (c / concentration-quantity
                  :quant (v / value-interval :op1 0.5 :op2 1)
                  :unit (m2 / micromolar)
                  :quant-of (s / small-molecule :name (n / name :op1 "SPP86")))
            :ARG1-of (p / prolong-01)
            :ARG1-of (m / mean-01
                  :ARG2 (t / temporal-quantity :quant 20
                        :unit (h / hour))))
      :ARG2 (d / decline-01
            :ARG1 (l / level
                  :quant-of (p3 / protein :name (n3 / name :op1 "cyclin" :op2 "D1")))
            :location (c2 / cell-line
                  :mod (t2 / this)))
      :ARG1-of (d2 / describe-01
            :ARG0 (f / figure :mod "1E"))
      :mod (a2 / also))

# ::id pmid_2540_9876.124 ::date 2015-09-03T00:28:11 ::annotator SDL-AMR-09 ::preferred
# ::snt In contrast, prolonged exposure to SPP86 did not affect ERK1/2 phosphorylation or cyclin D1 expression in 8505C and C643 cells (Figure <xref ref-type="fig" rid="Fig1">1</xref>G).
# ::save-date Wed Nov 25, 2015 ::file pmid_2540_9876_124.txt
(c / contrast-01
      :ARG2 (a / affect-01 :polarity -
            :ARG0 (e / expose-01
                  :ARG2 (s / small-molecule :name (n / name :op1 "SPP86"))
                  :ARG1-of (p2 / prolong-01))
            :ARG1 (o / or
                  :op1 (p / phosphorylate-01
                        :ARG1 (s2 / slash
                              :op1 (e2 / enzyme :name (n2 / name :op1 "ERK1"))
                              :op2 (e3 / enzyme :name (n3 / name :op1 "ERK2"))))
                  :op2 (e4 / express-03
                        :ARG2 (p4 / protein :name (n7 / name :op1 "cyclin" :op2 "D1"))
                        :ARG3 (a2 / and
                              :op1 (c2 / cell-line :name (n5 / name :op1 "8505C"))
                              :op2 (c3 / cell-line :name (n6 / name :op1 "C643"))))))
      :ARG1-of (d2 / describe-01
            :ARG0 (f / figure :mod "1G")))

# ::id pmid_2540_9876.125 ::date 2015-09-03T00:32:37 ::annotator SDL-AMR-09 ::preferred
# ::snt We noted however, that prolonged exposure to SPP86 (0.5- 1.0 μM) was associated with a decrease in Akt Ser473 phosphorylation in C643 in cells (Figure <xref ref-type="fig" rid="Fig1">1</xref>G).
# ::save-date Thu Sep 17, 2015 ::file pmid_2540_9876_125.txt
(c3 / contrast-01
      :ARG2 (n / note-01
            :ARG0 (w / we)
            :ARG1 (a / associate-01
                  :ARG1 (e / expose-01
                        :ARG2 (s / small-molecule :name (n2 / name :op1 "SPP86")
                              :quant (c / concentration-quantity
                                    :unit (m / micromolar)
                                    :quant (v / value-interval :op1 0.5 :op2 1.0)))
                        :ARG1-of (p2 / prolong-01))
                  :ARG2 (d / decrease-01
                        :ARG1 (p / phosphorylate-01
                              :ARG1 (a2 / amino-acid :mod 473 :name (n3 / name :op1 "serine")
                                    :part-of (e2 / enzyme :name (n4 / name :op1 "Akt")))
                              :location (c2 / cell-line :name (n5 / name :op1 "C643"))))))
      :ARG1-of (d2 / describe-01
            :ARG0 (f / figure :mod "1G")))

# ::id pmid_2540_9876.126 ::date 2015-09-03T00:39:03 ::annotator SDL-AMR-09 ::preferred
# ::snt C643 cells express wild type RET [<xref ref-type="bibr" rid="CR47">47</xref>].
# ::save-date Sun Jan 17, 2016 ::file pmid_2540_9876_126.txt
(e / express-03
      :ARG2 (p2 / protein :name (n2 / name :op1 "RET")
            :mod (w / wild-type))
      :ARG3 (c / cell-line :name (n / name :op1 "C643"))
      :ARG1-of (d / describe-01
            :ARG0 (p / publication
                  :ARG1-of (c2 / cite-01
                        :ARG2 47))))

# ::id pmid_2540_9876.127 ::date 2015-09-03T00:41:05 ::annotator SDL-AMR-09 ::preferred
# ::snt SPP86 may thus inhibit RET- mediated Akt activation in this cell line.
# ::save-date Sun Jan 17, 2016 ::file pmid_2540_9876_127.txt
(c / cause-01
      :ARG1 (p / possible-01
            :ARG1 (i / inhibit-01
                  :ARG0 (s / small-molecule :name (n / name :op1 "SPP86"))
                  :ARG1 (a / activate-01
                        :ARG1 (e / enzyme :name (n2 / name :op1 "Akt"))
                        :ARG1-of (m / mediate-01
                              :ARG0 (p2 / protein :name (n3 / name :op1 "RET"))))
                  :location (c2 / cell-line
                        :mod (t / this)))))

# ::id pmid_2540_9876.128 ::date 2015-09-03T00:44:20 ::annotator SDL-AMR-09 ::preferred
# ::snt These results demonstrate that unlike sorafenib, SPP86 appears to selectively inhibit RET/PTC1- activated MAPK signaling in these cell lines.
# ::save-date Sun Jan 17, 2016 ::file pmid_2540_9876_128.txt
(d / demonstrate-01
      :ARG0 (t / thing
            :ARG2-of (r2 / result-01))
      :ARG1 (a / appear-01
            :ARG1 (i / inhibit-01
                  :ARG0 (s / small-molecule :name (n2 / name :op1 "SPP86"))
                  :ARG1 (s3 / signal-07
                        :ARG0 (p / pathway :name (n3 / name :op1 "MAPK"))
                        :ARG1-of (a2 / activate-01
                              :ARG0 (p3 / protein :name (n4 / name :op1 "RET/PTC1"))))
                  :manner (s2 / selective)
                  :location (c / cell-line
                        :mod (t2 / this))
                  :ARG1-of (r / resemble-01 :polarity -
                        :ARG2 (s4 / small-molecule :name (n5 / name :op1 "sorafenib"))))))

# ::id pmid_2540_9876.129 ::date 2015-09-03T00:49:38 ::annotator SDL-AMR-09 ::preferred
# ::snt We next investigated if FAK could maintain RET phosphorylation on Tyr1062 despite the inhibition of RET autophosphorylation by SPP86 [<xref ref-type="bibr" rid="CR24">24</xref>].
# ::save-date Sun Jan 17, 2016 ::file pmid_2540_9876_129.txt
(i / investigate-01
      :ARG0 (w / we)
      :ARG1 (p3 / possible-01 :mode interrogative
            :ARG1 (m / maintain-01
                  :ARG0 (e / enzyme :name (n2 / name :op1 "FAK"))
                  :ARG1 (p2 / phosphorylate-01
                        :ARG1 (a2 / amino-acid :mod 1062 :name (n4 / name :op1 "tyrosine")
                              :part-of (p / protein :name (n3 / name :op1 "RET"))))
                  :concession (i2 / inhibit-01
                        :ARG0 (s / small-molecule :name (n5 / name :op1 "SPP86"))
                        :ARG1 (p4 / phosphorylate-01
                              :ARG1 p
                              :ARG2 p))))
      :time (n / next)
      :ARG1-of (d / describe-01
            :ARG0 (p5 / publication
                  :ARG1-of (c / cite-01
                        :ARG2 24))))

# ::id pmid_2540_9876.130 ::date 2015-09-03T00:55:30 ::annotator SDL-AMR-09 ::preferred
# ::snt Exposure to 2.5 μM of the FAK inhibitor PF573228 [<xref ref-type="bibr" rid="CR50">50</xref>] alone, did not inhibit RET phosphorylation in TPC1 cells (Figure <xref ref-type="fig" rid="Fig2">2</xref>A).
# ::save-date Sun Jan 17, 2016 ::file pmid_2540_9876_130.txt
(i2 / inhibit-01 :polarity -
      :ARG0 (e / expose-01
            :ARG2 (c / concentration-quantity :quant 2.5
                  :unit (m / micromolar)
                  :quant-of (s / small-molecule :name (n / name :op1 "PF573228")
                        :ARG0-of (i3 / inhibit-01
                              :ARG1 (e2 / enzyme :name (n2 / name :op1 "FAK")))
                        :mod (a / alone)))
            :ARG1-of (d / describe-01
                  :ARG0 (p2 / publication
                        :ARG1-of (c2 / cite-01
                              :ARG2 50))))
      :ARG1 (p / phosphorylate-01
            :ARG1 (p3 / protein :name (n3 / name :op1 "RET"))
            :location (c3 / cell-line :name (n4 / name :op1 "TPC1")))
      :ARG1-of (d2 / describe-01
            :ARG0 (f / figure :mod "2A")))

# ::id pmid_2540_9876.131 ::date 2015-09-03T01:00:07 ::annotator SDL-AMR-09 ::preferred
# ::snt In contrast, exposure to 2.5 μM of the FAK inhibitor PF573228 in combination with 1 μM SPP86 was sufficient to inhibit RET phosphorylation on Tyr1062 (Figure <xref ref-type="fig" rid="Fig2">2</xref>A).
# ::save-date Sun Jan 17, 2016 ::file pmid_2540_9876_131.txt
(c / contrast-01
      :ARG2 (s2 / suffice-01
            :ARG0 (e / expose-01
                  :ARG2 (c2 / concentration-quantity :quant 2.5
                        :unit (m / micromolar)
                        :quant-of (s3 / small-molecule :name (n2 / name :op1 "PF573228")
                              :ARG0-of (i / inhibit-01
                                    :ARG1 (e2 / enzyme :name (n / name :op1 "FAK")))
                              :ARG1-of (c3 / combine-01
                                    :ARG2 (c4 / concentration-quantity :quant 1
                                          :quant-of (s / small-molecule :name (n3 / name :op1 "SPP86"))
                                          :unit m)))))
            :ARG1 (i2 / inhibit-01
                  :ARG0 e
                  :ARG1 (p / phosphorylate-01
                        :ARG1 (a2 / amino-acid :mod 1062 :name (n5 / name :op1 "tyrosine")
                              :part-of (p2 / protein :name (n4 / name :op1 "RET")))))
            :ARG1-of (d / describe-01
                  :ARG0 (f / figure :mod "2A"))))

# ::id pmid_2540_9876.132 ::date 2015-09-03T01:25:07 ::annotator SDL-AMR-09 ::preferred
# ::snt Interestingly, PF273228 and SPP86 inhibited Akt and ERK1/2 phosphorylation to a similar degree (Figure <xref ref-type="fig" rid="Fig2">2</xref>B and C).
# ::save-date Thu Sep 3, 2015 ::file pmid_2540_9876_132.txt
(i / inhibit-01
      :ARG0 (a / and
            :op1 (s / small-molecule :name (n / name :op1 "PF273228"))
            :op2 (s2 / small-molecule :name (n2 / name :op1 "SPP86")))
      :ARG1 (p / phosphorylate-01
            :ARG1 (a2 / and
                  :op1 (e / enzyme :name (n3 / name :op1 "Akt"))
                  :op2 (s3 / slash
                        :op1 (e2 / enzyme :name (n4 / name :op1 "ERK1"))
                        :op2 (e3 / enzyme :name (n5 / name :op1 "ERK2")))))
      :ARG2-of (i2 / interest-01)
      :degree (d / degree
            :ARG1-of (r / resemble-01))
      :ARG1-of (d2 / describe-01
            :ARG0 (a3 / and
                  :op1 (f / figure :mod "2B")
                  :op2 (f2 / figure :mod "2C"))))

# ::id pmid_2540_9876.133 ::date 2015-09-03T01:29:32 ::annotator SDL-AMR-09 ::preferred
# ::snt Exposure to PF573288 but not SPP86 was associated with a reduction of FAK Tyr576 phosphorylation (Figure <xref ref-type="fig" rid="Fig2">2</xref>B).
# ::save-date Thu Sep 3, 2015 ::file pmid_2540_9876_133.txt
(c / contrast-01
      :ARG1 (a / associate-01
            :ARG1 (e / expose-01
                  :ARG2 (s / small-molecule :name (n / name :op1 "PF573288")))
            :ARG2 (r / reduce-01
                  :ARG1 (p / phosphorylate-01
                        :ARG1 (a2 / amino-acid :mod 576 :name (n2 / name :op1 "tyrosine")
                              :part-of (e2 / enzyme :name (n3 / name :op1 "FAK"))))))
      :ARG2 (a3 / associate-01 :polarity -
            :ARG1 (e3 / expose-01
                  :ARG2 (s2 / small-molecule :name (n4 / name :op1 "SPP86")))
            :ARG2 r)
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod "2B")))

# ::id pmid_2540_9876.134 ::date 2015-09-03T01:33:52 ::annotator SDL-AMR-09 ::preferred
# ::snt Neither PF273228 nor SPP86 suppressed Src phosphorylation (Figure <xref ref-type="fig" rid="Fig2">2</xref>D).
# ::save-date Thu Sep 17, 2015 ::file pmid_2540_9876_134.txt
(s / suppress-01 :polarity -
      :ARG0 (a / and
            :op1 (s2 / small-molecule :name (n / name :op1 "PF273228"))
            :op2 (s3 / small-molecule :name (n2 / name :op1 "SPP86")))
      :ARG1 (p / phosphorylate-01
            :ARG1 (p2 / protein :name (n3 / name :op1 "Src")))
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod "2D")))

# ::id pmid_2540_9876.135 ::date 2015-09-03T01:37:03 ::annotator SDL-AMR-09 ::preferred
# ::snt SPP86 inhibited TPC1 cell proliferation more effectively than PF573228 (49% proliferation <i>vs.</i> 77%) but no additive effect was observed following co-exposure to both drugs (Figure <xref ref-type="fig" rid="Fig2">2</xref>E).
# ::save-date Wed Nov 25, 2015 ::file pmid_2540_9876_135.txt
(c2 / contrast-01
      :ARG1 (i / inhibit-01
            :ARG0 (s / small-molecule :name (n / name :op1 "SPP86"))
            :ARG1 (p3 / proliferate-01
                  :ARG0 (c / cell-line :name (n2 / name :op1 "TPC1"))
                  :degree (p / percentage-entity :value 49))
            :ARG1-of (e / effective-04
                  :ARG0 s
                  :degree (m / more)
                  :compared-to (i2 / inhibit-01
                        :ARG0 (s3 / small-molecule :name (n4 / name :op1 "PF573228"))
                        :ARG1 (p4 / proliferate-01
                              :ARG0 c
                              :degree (p2 / percentage-entity :value 77)))))
      :ARG2 (o / observe-01 :polarity -
            :ARG1 (a / affect-01
                  :ARG2 (a2 / add-02))
            :ARG1-of (f2 / follow-01
                  :ARG2 (e2 / expose-01
                        :ARG2 (a3 / and
                              :op1 s
                              :op2 s3))))
      :ARG1-of (d2 / describe-01
            :ARG0 (f / figure :mod "2E")))

# ::id pmid_2540_9876.136 ::date 2015-09-03T01:45:25 ::annotator SDL-AMR-09 ::preferred
# ::snt Our observations strongly suggested that SPP86 would selectively inhibit RET- induced proliferation.
# ::save-date Sun Jan 17, 2016 ::file pmid_2540_9876_136.txt
(s / suggest-01
      :ARG0 (o / observe-01
            :ARG0 (w / we))
      :ARG1 (i / inhibit-01
            :ARG0 (s3 / small-molecule :name (n / name :op1 "SPP86"))
            :ARG1 (p / proliferate-01
                  :ARG2-of (i2 / induce-01
                        :ARG0 (p2 / protein :name (n2 / name :op1 "RET"))))
            :manner (s4 / select-01))
      :ARG1-of (s2 / strong-02))

# ::id pmid_2540_9876.137 ::date 2015-09-03T01:49:44 ::annotator SDL-AMR-09 ::preferred
# ::snt We thus compared the effect of sorafenib and SPP86 on the proliferation of TPC1, 8505C and C643 cells in media containing 0.1% serum (i.e. low culture conditions).
# ::save-date Thu Sep 17, 2015 ::file pmid_2540_9876_137.txt
(c / cause-01
      :ARG1 (c2 / compare-01
            :ARG0 (w / we)
            :ARG1 (a / affect-01
                  :ARG0 (a2 / and
                        :op1 (s / small-molecule :name (n / name :op1 "sorafenib"))
                        :op2 (s2 / small-molecule :name (n2 / name :op1 "SPP86")))
                  :ARG1 (p2 / proliferate-01
                        :ARG0 (a3 / and
                              :op1 (c3 / cell-line :name (n3 / name :op1 "TPC1"))
                              :op2 (c4 / cell-line :name (n4 / name :op1 "8505C"))
                              :op3 (c5 / cell-line :name (n5 / name :op1 "C643"))))
                  :location (m / medium
                        :ARG0-of (c6 / contain-01
                              :ARG1 (p / percentage-entity :value 0.1
                                    :quant-of (s3 / serum))
                              :example (c7 / condition
                                          :mod (c8 / culture
                                                :ARG1-of (l / low-04))))))))

# ::id pmid_2540_9876.138 ::date 2015-09-03T01:54:59 ::annotator SDL-AMR-09 ::preferred
# ::snt Under these conditions, signaling pathway activation is predominantly under the control of the respective oncogenes expressed by these cell lines.
# ::save-date Thu Sep 17, 2015 ::file pmid_2540_9876_138.txt
(a / activate-01
      :ARG1 (p / pathway
            :ARG0-of (s / signal-07))
      :ARG1-of (c / control-01
            :ARG0 (o / oncogene
                  :mod (r / respective)
                  :ARG1-of (e / express-03
                        :ARG3 (c2 / cell-line
                              :mod (t / this))))
            :ARG1-of (p2 / predominate-01))
      :condition (t2 / this))

# ::id pmid_2540_9876.139 ::date 2015-09-03T02:03:13 ::annotator SDL-AMR-09 ::preferred
# ::snt C643 and TPC1 cells showed marked differential sensitivity to SPP86 (IC<sub>50</sub>, 61.5 vs 1.5 μM for C643 and TPC1 cells respectively) (Figure <xref ref-type="fig" rid="Fig3">3</xref>A).
# ::save-date Mon Dec 21, 2015 ::file pmid_2540_9876_139.txt
(s / show-01
      :ARG0 (a / and
            :op1 (c / cell-line :name (n / name :op1 "C643"))
            :op2 (c2 / cell-line :name (n2 / name :op1 "TPC1")))
      :ARG1 (s2 / sensitive-03
            :ARG0 a
            :ARG1 (s3 / small-molecule :name (n3 / name :op1 "SPP86"))
            :ARG1-of (d / differ-02)
            :ARG1-of (m / mean-01
                  :ARG2 (a2 / and
                        :op1 (h3 / have-percentage-maximal-inhibitory-concentration-01
                              :ARG1 s3
                              :ARG2 50
                              :ARG4 (c3 / concentration-quantity :quant 61.5
                                    :unit (m2 / micromolar))
                              :location c)
                        :op2 (h / have-percentage-maximal-inhibitory-concentration-01
                              :ARG1 s3
                              :ARG2 50
                              :ARG4 (c4 / concentration-quantity :quant 1.5
                                    :unit m2)
                              :location c2)))
            :ARG1-of (m4 / mark-01))
      :ARG1-of (d2 / describe-01
            :ARG0 (f / figure :mod "3A")))

# ::id pmid_2540_9876.140 ::date 2015-09-03T02:10:59 ::annotator SDL-AMR-09 ::preferred
# ::snt In contrast, 8505C cells grew poorly under low serum conditions (data not shown), but their proliferation was enhanced when exposed to doses of SPP86 from 1–10 μM (Figure <xref ref-type="fig" rid="Fig3">3</xref>A).
# ::save-date Thu Sep 17, 2015 ::file pmid_2540_9876_140.txt
(c / contrast-01
      :ARG2 (c3 / contrast-01
            :ARG1 (g / grow-01
                  :ARG1 (c2 / cell-line :name (n / name :op1 "8505C"))
                  :mod (p / poor)
                  :condition (s / serum
                        :ARG1-of (l / low-04))
                  :ARG1-of (d / describe-01
                        :ARG0 (d2 / data
                              :ARG1-of (s2 / show-01 :polarity -))))
            :ARG2 (e / enhance-01
                  :ARG1 (p2 / proliferate-01
                        :ARG0 c2)
                  :condition (e2 / expose-01
                        :ARG1 c2
                        :ARG2 (d3 / dose-01
                              :ARG1 (s3 / small-molecule :name (n2 / name :op1 "SPP86")
                                    :quant (c4 / concentration-quantity
                                          :quant (v / value-interval :op1 1 :op2 10)
                                          :unit (m / micromolar)))))))
      :ARG1-of (d4 / describe-01
            :ARG0 (f / figure :mod "3A")))

# ::id pmid_2540_9876.141 ::date 2015-09-03T02:18:02 ::annotator SDL-AMR-09 ::preferred
# ::snt Under similar conditions, the IC<sub>50</sub> values for sorafenib were 3.1 μM, 0.28 μM, and 33.3 μM for C643, TPC1 and 8505C cells respectively (Figure <xref ref-type="fig" rid="Fig3">3</xref>B).
# ::save-date Mon Dec 21, 2015 ::file pmid_2540_9876_141.txt
(a / and
      :op1 (h4 / have-percentage-maximal-inhibitory-concentration-01
            :ARG1 (s / small-molecule :name (n4 / name :op1 "sorafenib"))
            :ARG2 50
            :ARG4 (c2 / concentration-quantity :quant 3.1
                  :unit (m / micromolar))
            :location (c / cell-line :name (n / name :op1 "C643")))
      :op2 (h / have-percentage-maximal-inhibitory-concentration-01
            :ARG1 s
            :ARG2 50
            :ARG4 (c4 / concentration-quantity :quant 0.28
                  :unit m)
            :location (c3 / cell-line :name (n2 / name :op1 "TPC1")))
      :op3 (h2 / have-percentage-maximal-inhibitory-concentration-01
            :ARG1 s
            :ARG2 50
            :ARG4 (c6 / concentration-quantity :quant 33.3
                  :unit m)
            :location (c5 / cell-line :name (n3 / name :op1 "8505C")))
      :condition (c7 / condition
            :ARG1-of (r / resemble-01))
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod "3B")))

# ::id pmid_2540_9876.142 ::date 2015-08-31T13:34:35 ::annotator SDL-AMR-09 ::preferred
# ::snt In general, low doses of SPP86 do not inhibit the activity of signaling proteins downstream of RET or other kinases that directly interact with it [<xref ref-type="bibr" rid="CR45">45</xref>].
# ::save-date Wed Sep 16, 2015 ::file pmid_2540_9876_142.txt
(i / inhibit-01 :polarity -
      :ARG0 (d / dose-01
            :ARG2 (s / small-molecule :name (n / name :op1 "SPP86"))
            :ARG1-of (l / low-04))
      :ARG1 (a / activity-06
            :ARG0 (o2 / or
                  :op1 (p / protein
                        :ARG0-of (s2 / signal-07)
                        :location (r / relative-position
                              :op1 (p2 / protein :name (n2 / name :op1 "RET"))
                              :direction (d2 / downstream)))
                  :op2 (k / kinase
                        :mod (o / other)
                        :ARG0-of (i2 / interact-01
                              :ARG1 s
                              :ARG1-of (d3 / direct-02)))))
      :ARG1-of (g / general-02)
      :ARG1-of (d4 / describe-01
            :ARG0 (p3 / publication
                  :ARG1-of (c / cite-01
                        :ARG2 45))))

# ::id pmid_2540_9876.143 ::date 2015-08-31T13:34:46 ::annotator SDL-AMR-09 ::preferred
# ::snt SPP86 thus selectively inhibited the proliferation of TPC1 cells dependent on oncogenic RET but not 8505C and C643 cells respectively dependent on oncogenic BRAF and RAS.
# ::save-date Sun Jan 17, 2016 ::file pmid_2540_9876_143.txt
(c / cause-01
      :ARG1 (c5 / contrast-01
            :ARG1 (i / inhibit-01
                  :ARG0 (s / small-molecule :name (n / name :op1 "SPP86"))
                  :ARG1 (p / proliferate-01
                        :ARG0 (c2 / cell-line :name (n2 / name :op1 "TPC1")
                              :ARG0-of (d / depend-01
                                    :ARG1 (p2 / protein :name (n3 / name :op1 "RET")
                                          :ARG0-of (c3 / cause-01
                                                :ARG1 (c4 / cancer))))))
                  :manner (s3 / selective))
            :ARG2 (i2 / inhibit-01 :polarity -
                  :ARG0 s
                  :ARG1 (a / and
                        :op1 (c6 / cell-line :name (n4 / name :op1 "8505C"))
                        :op2 (c7 / cell-line :name (n5 / name :op1 "C643"))
                        :ARG0-of (d2 / depend-01
                              :ARG1 (a2 / and
                                    :op1 (e / enzyme :name (n6 / name :op1 "BRAF"))
                                    :op2 (e2 / enzyme :name (n7 / name :op1 "RAS"))
                                    :ARG0-of c3))
                        :mod (r / respective)))))

# ::id pmid_2540_9876.144 ::date 2015-08-31T14:01:59 ::annotator SDL-AMR-09 ::preferred
# ::snt <sec-title level="2">SPP86 inhibits RET signaling in ERα positive breast cancer cells</sec-title>
# ::save-date Wed Sep 16, 2015 ::file pmid_2540_9876_144.txt
(i / inhibit-01
      :ARG0 (s / small-molecule :name (n / name :op1 "SPP86"))
      :ARG1 (s2 / signal-07
            :ARG0 (p / protein :name (n2 / name :op1 "RET")))
      :location (c / cell
            :mod (c2 / cancer
                  :mod (b / breast))
            :mod (p3 / protein :name (n3 / name :op1 "ERα")
                  :mod (p2 / positive))))

# ::id pmid_2540_9876.145 ::date 2015-08-31T14:03:46 ::annotator SDL-AMR-09 ::preferred
# ::snt In addition to its role in thyroid cancers, RET has been shown to functionally interact with ERα in human breast cancer cell lines [<xref ref-type="bibr" rid="CR5">5</xref>, <xref ref-type="bibr" rid="CR6">6</xref>, <xref ref-type="bibr" rid="CR51">51</xref>, <xref ref-type="bibr" rid="CR52">52</xref>].
# ::save-date Tue Sep 1, 2015 ::file pmid_2540_9876_145.txt
(s / show-01
      :ARG1 (i / interact-01
            :ARG0 (p / protein :name (n / name :op1 "RET"))
            :ARG1 (p2 / protein :name (n2 / name :op1 "ERα"))
            :ARG1-of (f / function-01)
            :location (c / cell-line
                  :mod (h / human)
                  :mod (c2 / cancer
                        :mod (b / breast))))
      :ARG1-of (a / add-02
            :ARG2 (r / role
                  :topic (c3 / cancer
                        :mod (t / thyroid))
                  :poss p))
      :ARG1-of (d / describe-01
            :ARG0 (p3 / publication
                  :ARG1-of (c4 / cite-01
                        :ARG2 (a2 / and :op1 5 :op2 6 :op3 51 :op4 52)))))

# ::id pmid_2540_9876.146 ::date 2015-08-31T14:20:53 ::annotator SDL-AMR-09 ::preferred
# ::snt We thus evaluated the utility of using SPP86 to interrogate RET signaling in MCF7 breast cancer cells.
# ::save-date Wed Sep 16, 2015 ::file pmid_2540_9876_146.txt
(c / cause-01
      :ARG1 (e / evaluate-01
            :ARG0 (w / we)
            :ARG1 (u / utility
                  :poss (u2 / use-01
                        :ARG0 w
                        :ARG1 (s / small-molecule :name (n / name :op1 "SPP86"))
                        :ARG2 (i / interrogate-01
                              :ARG0 w
                              :ARG1 (s2 / signal-07
                                    :ARG0 (p / protein :name (n2 / name :op1 "RET")))
                              :location (c2 / cell-line :name (n3 / name :op1 "MCF7")
                                    :mod (c3 / cancer
                                          :mod (b / breast))))))))

# ::id pmid_2540_9876.147 ::date 2015-08-31T14:25:18 ::annotator SDL-AMR-09 ::preferred
# ::snt Firstly, we studied the effect of SPP86 on RET- mediated ERα phosphorylation on serine residue 167 (Ser167).
# ::save-date Wed Sep 16, 2015 ::file pmid_2540_9876_147.txt
(s / study-01
      :ARG0 (w / we)
      :ARG1 (a / affect-01
            :ARG0 (s2 / small-molecule :name (n / name :op1 "SPP86"))
            :ARG1 (p / phosphorylate-01
                  :ARG1 (r / residue
                        :mod (a2 / amino-acid :mod 167 :name (n4 / name :op1 "serine"))
                        :part-of (p2 / protein :name (n2 / name :op1 "ERα")))
                  :ARG1-of (m / mediate-01
                        :ARG0 (p3 / protein :name (n3 / name :op1 "RET")))))
      :time (f / first))

# ::id pmid_2540_9876.148 ::date 2015-08-31T14:30:28 ::annotator SDL-AMR-09 ::preferred
# ::snt Estrogen deprived and serum starved MCF7 cells were exposed to 10 ng/ml GDNF in the absence or presence of increasing does of SPP86.
# ::save-date Wed Sep 16, 2015 ::file pmid_2540_9876_148.txt
(e / expose-01
      :ARG1 (c / cell-line :name (n / name :op1 "MCF7")
            :ARG2-of (d / deprive-01
                  :ARG1 (s / small-molecule :name (n2 / name :op1 "estrogen")))
            :ARG1-of (s2 / starve-01
                  :ARG2 (s3 / serum)))
      :ARG2 (p / protein :name (n3 / name :op1 "GDNF")
            :quant (c2 / concentration-quantity :quant 10
                  :unit (n4 / nanogram-per-milliliter)))
      :condition (o / or
            :op1 (a / absent-01
                  :ARG1 (d2 / dose-01
                        :ARG2 (s4 / small-molecule :name (n5 / name :op1 "SPP86"))
                        :ARG1-of (i / increase-01)))
            :op2 (p2 / present-02
                  :ARG1 d2)))

# ::id pmid_2540_9876.149 ::date 2015-08-31T14:45:52 ::annotator SDL-AMR-09 ::preferred
# ::snt In these experiments, SPP86 effectively inhibited GDNF/RET- induced ERα phosphorylation at a concentration of 0.1 μM (Figure <xref ref-type="fig" rid="Fig4">4</xref>A).
# ::save-date Wed Sep 16, 2015 ::file pmid_2540_9876_149.txt
(i / inhibit-01
      :ARG0 (s / small-molecule :name (n / name :op1 "SPP86")
            :quant (c / concentration-quantity :quant 0.1
                  :unit (m / micromolar)))
      :ARG1 (p / phosphorylate-01
            :ARG1 (p2 / protein :name (n2 / name :op1 "ERα"))
            :ARG2-of (i2 / induce-01
                  :ARG0 (p3 / pathway :name (n3 / name :op1 "GDNF/RET"))))
      :location (e / experiment-01
            :mod (t / this))
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod "4A"))
      :ARG1-of (e2 / effective-04))

# ::id pmid_2540_9876.150 ::date 2015-08-31T14:53:18 ::annotator SDL-AMR-09 ::preferred
# ::snt Higher concentrations of SPP86, 1–10 μM, reduced ERα phosphorylation even below baseline levels.
# ::save-date Tue Sep 1, 2015 ::file pmid_2540_9876_150.txt
(r / reduce-01
      :ARG0 (c / concentrate-02
            :ARG1 (s / small-molecule :name (n / name :op1 "SPP86")
                  :quant (c2 / concentration-quantity
                        :quant (v / value-interval :op1 1 :op2 10)
                        :unit (m2 / micromolar)))
            :ARG1-of (h / high-02
                  :degree (m / more)))
      :ARG1 (p / phosphorylate-01
            :ARG1 (p2 / protein :name (n3 / name :op1 "ERα")))
      :ARG2 (b / below
            :op1 (l / level
                  :mod (b2 / baseline))
            :mod (e / even)))

# ::id pmid_2540_9876.151 ::date 2015-08-31T14:57:44 ::annotator SDL-AMR-09 ::preferred
# ::snt In addition, exposure of MCF7 cells to SPP86 was associated with a moderate decrease in ERα levels in these experiments (Figure <xref ref-type="fig" rid="Fig4">4</xref>A) We next investigated the effect of SPP86 on RET- mediated activation of these pathways in MCF7 cells.
# ::save-date Wed Sep 16, 2015 ::file pmid_2540_9876_151.txt
(m / multi-sentence
      :snt1 (a / associate-01
            :ARG1 (e / expose-01
                  :ARG1 (c / cell-line :name (n / name :op1 "MCF7"))
                  :ARG2 (s / small-molecule :name (n2 / name :op1 "SPP86")))
            :ARG2 (d / decrease-01
                  :ARG1 (l / level
                        :quant-of (p / protein :name (n3 / name :op1 "ERα")))
                  :ARG2 (m2 / moderate-03))
            :location (e2 / experiment-01
                  :mod (t / this))
            :ARG1-of (d2 / describe-01
                  :ARG0 (f / figure :mod "4A"))
            :ARG1-of (a4 / add-02))
      :snt2 (i / investigate-01
            :ARG0 (w / we)
            :ARG1 (a2 / affect-01
                  :ARG0 (s2 / small-molecule :name (n4 / name :op1 "SPP86"))
                  :ARG1 (a3 / activate-01
                        :ARG1 (p3 / pathway
                              :mod t)
                        :ARG1-of (m3 / mediate-01
                              :ARG0 (p2 / protein :name (n5 / name :op1 "RET")))
                        :location (c2 / cell-line :name (n6 / name :op1 "MCF7"))))
            :time (n7 / next)))

# ::id pmid_2540_9876.152 ::date 2015-08-31T15:03:30 ::annotator SDL-AMR-09 ::preferred
# ::snt SPP86 inhibited GDNF/ RET- induced phosphorylation of Akt and its downstream signaling at concentrations as low as 0.1 μM (Figure <xref ref-type="fig" rid="Fig4">4</xref>B).
# ::save-date Wed Sep 16, 2015 ::file pmid_2540_9876_152.txt
(i / inhibit-01
      :ARG0 (s / small-molecule :name (n / name :op1 "SPP86"))
      :ARG1 (a / and
            :op1 (p / phosphorylate-01
                  :ARG1 (e / enzyme :name (n2 / name :op1 "Akt"))
                  :ARG2-of (i2 / induce-01
                        :ARG0 (p2 / pathway :name (n3 / name :op1 "GDNF/RET"))))
            :op2 (s3 / signal-07
                  :ARG0 e
                  :location (d / downstream)))
      :ARG1-of (d2 / describe-01
            :ARG0 (f / figure :mod "4B"))
      :condition (c2 / concentration-quantity :quant 0.1
            :unit (m / micromolar)
            :ARG1-of (l / low-04)))

# ::id pmid_2540_9876.153 ::date 2015-08-31T15:17:08 ::annotator SDL-AMR-09 ::preferred
# ::snt We noted that SPP86 inhibited phosphorylation of Akt more effectively than that of its downstream target p70S6K at this concentration.
# ::save-date Wed Sep 16, 2015 ::file pmid_2540_9876_153.txt
(n / note-01
      :ARG0 (w / we)
      :ARG1 (i / inhibit-01
            :ARG0 (s / small-molecule :name (n2 / name :op1 "SPP86"))
            :ARG1 (p / phosphorylate-01
                  :ARG1 (e / enzyme :name (n3 / name :op1 "Akt")))
            :ARG1-of (e2 / effective-04
                  :degree (m / more)
                  :compared-to (t / target-01
                        :ARG0 s
                        :ARG1 (e3 / enzyme :name (n4 / name :op1 "p70S6K"))
                        :location (d / downstream)))
            :condition (c / concentration-quantity
                  :mod (t2 / this))))

# ::id pmid_2540_9876.154 ::date 2015-08-31T15:24:08 ::annotator SDL-AMR-09 ::preferred
# ::snt Similarly, SPP86 inhibited Akt phosphorylation at markedly lower concentrations than those required to inhibit MAPK phosphorylation (0.1 vs. 1.0 μM) (Figure <xref ref-type="fig" rid="Fig4">4</xref>B).
# ::save-date Sun Jan 17, 2016 ::file pmid_2540_9876_154.txt
(i / inhibit-01
      :ARG0 (s / small-molecule :name (n / name :op1 "SPP86"))
      :ARG1 (p / phosphorylate-01
            :ARG1 (e / enzyme :name (n2 / name :op1 "Akt")))
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod "4B"))
      :ARG1-of (r2 / resemble-01)
      :condition (c3 / concentration-quantity :quant 0.1
            :unit (m3 / micromolar)
            :ARG1-of (l / low-04
                  :degree (m / more
                        :degree (m4 / marked))
                  :compared-to (c4 / concentration-quantity :quant 1.0
                        :unit m3
                        :ARG1-of (r / require-01
                              :ARG2 (i2 / inhibit-01
                                    :ARG1 (p2 / phosphorylate-01
                                          :ARG1 (e2 / enzyme :name (n3 / name :op1 "MAPK")))))))))

# ::id pmid_2540_9876.155 ::date 2015-08-31T15:24:58 ::annotator SDL-AMR-09 ::preferred
# ::snt SPP86 effectively inhibited GDNF- induced RET phosphorylation Tyr1062 at a concentration of 1.0 μM.
# ::save-date Wed Sep 16, 2015 ::file pmid_2540_9876_155.txt
(i / inhibit-01
      :ARG0 (s / small-molecule :name (n / name :op1 "SPP86")
            :quant (c / concentration-quantity :quant 1.0
                  :unit (m / micromolar)))
      :ARG1 (p / phosphorylate-01
            :ARG1 (a / amino-acid :mod 1062 :name (n4 / name :op1 "tyrosine")
                  :part-of (p2 / protein :name (n2 / name :op1 "RET")))
            :ARG2-of (i2 / induce-01
                  :ARG0 (p3 / protein :name (n3 / name :op1 "GDNF"))))
      :ARG1-of (e / effective-04))

# ::id pmid_2540_9876.156 ::date 2015-09-01T12:41:21 ::annotator SDL-AMR-09 ::preferred
# ::snt In contrast, FAK inhibition with PF573228 only moderately inhibited RET phosphorylation.
# ::save-date Sun Jan 17, 2016 ::file pmid_2540_9876_156.txt
(c / contrast-01
      :ARG2 (i / inhibit-01
            :ARG0 (i2 / inhibit-01
                  :ARG0 (s / small-molecule :name (n / name :op1 "PF573228"))
                  :ARG1 (e / enzyme :name (n2 / name :op1 "FAK")))
            :ARG1 (p2 / phosphorylate-01
                  :ARG1 (p3 / protein :name (n3 / name :op1 "RET")))
            :ARG1-of (m / moderate-03
                  :mod (o / only))))

# ::id pmid_2540_9876.157 ::date 2015-09-01T12:46:41 ::annotator SDL-AMR-09 ::preferred
# ::snt Co- exposure to PF573228 and SPP86 however, exerted an additive inhibitory effect on RET phosphorylation (Figure <xref ref-type="fig" rid="Fig4">4</xref>C).
# ::save-date Mon Dec 21, 2015 ::file pmid_2540_9876_157.txt
(h / have-concession-91
      :ARG1 (e / exert-01
            :ARG0 (c / coexpose-00
                  :ARG2 (a / and
                        :op1 (s / small-molecule :name (n / name :op1 "PF573228"))
                        :op2 (s2 / small-molecule :name (n2 / name :op1 "SPP86"))))
            :ARG1 (a2 / affect-01
                  :ARG0 c
                  :ARG1 (p / phosphorylate-01
                        :ARG1 (p2 / protein :name (n3 / name :op1 "RET")))
                  :ARG2 (i / inhibit-01)
                  :ARG1-of (a3 / add-02)))
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod "4C")))

# ::id pmid_2540_9876.158 ::date 2015-09-01T13:02:40 ::annotator SDL-AMR-09 ::preferred
# ::snt Both PF573228 and SPP86 inhibited GDNF- induced ERK1/2 and Akt phosphorylation (Figure <xref ref-type="fig" rid="Fig4">4</xref>C and Additional file <xref ref-type="media" rid="MOESM1">1</xref>A).
# ::save-date Wed Sep 16, 2015 ::file pmid_2540_9876_158.txt
(i / inhibit-01
      :ARG0 (a / and
            :op1 (s / small-molecule :name (n / name :op1 "PF573228"))
            :op2 (s2 / small-molecule :name (n2 / name :op1 "SPP86")))
      :ARG1 (p / phosphorylate-01
            :ARG1 (a2 / and
                  :op1 (e / enzyme :name (n3 / name :op1 "ERK1/2"))
                  :op2 (e2 / enzyme :name (n4 / name :op1 "Akt")))
            :ARG2-of (i2 / induce-01
                  :ARG0 (p2 / protein :name (n5 / name :op1 "GDNF"))))
      :ARG1-of (d / describe-01
            :ARG0 (a3 / and
                  :op1 (f / figure :mod "4C")
                  :op2 (f2 / file :mod "1A"
                        :ARG1-of (a4 / add-02)))))

# ::id pmid_2540_9876.159 ::date 2015-09-01T13:07:39 ::annotator SDL-AMR-09 ::preferred
# ::snt Prolonged exposure of MCF7 cells to SPP86 also lead to the suppression of cyclin D1 expression (Figure <xref ref-type="fig" rid="Fig4">4</xref>D).
# ::save-date Sun Jan 17, 2016 ::file pmid_2540_9876_159.txt
(l / lead-03
      :ARG0 (e / expose-01
            :ARG1 (c / cell-line :name (n / name :op1 "MCF7"))
            :ARG2 (s / small-molecule :name (n2 / name :op1 "SPP86"))
            :ARG1-of (p / prolong-01))
      :ARG2 (s2 / suppress-01
            :ARG0 e
            :ARG1 (e2 / express-03
                  :ARG1 (p2 / protein :name (n3 / name :op1 "cyclin" :op2 "D1"))))
      :mod (a / also)
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod "4D")))

# ::id pmid_2540_9876.160 ::date 2015-09-01T13:12:05 ::annotator SDL-AMR-09 ::preferred
# ::snt We next compared the effects of sorafenib and SPP86 on PI3K/Akt and MAPK pathway signaling, with a view to discriminate the direct effects of RET inhibition from those of a combined inhibition of RET and RAF.
# ::save-date Wed Nov 25, 2015 ::file pmid_2540_9876_160.txt
(c / compare-01
      :ARG0 (w / we)
      :ARG1 (a / affect-01
            :ARG0 (a2 / and
                  :op1 (s / small-molecule :name (n / name :op1 "sorafenib"))
                  :op2 (s2 / small-molecule :name (n2 / name :op1 "SPP86")))
            :ARG1 (s3 / signal-07
                  :ARG0 (a3 / and
                        :op1 (p / pathway :name (n3 / name :op1 "PI3K/Akt"))
                        :op2 (p2 / pathway :name (n4 / name :op1 "MAPK")))))
      :purpose (d / discriminate-01
                  :ARG0 w
                  :ARG1 (a5 / and
                        :op1 (a4 / affect-01
                              :ARG0 (i / inhibit-01
                                    :ARG1 (p3 / protein :name (n5 / name :op1 "RET")))
                              :ARG1-of (d2 / direct-02))
                        :op2 (a6 / affect-01
                              :ARG0 (i2 / inhibit-01
                                    :ARG1 (a7 / and
                                          :op1 p3
                                          :op2 (p5 / protein-family :name (n7 / name :op1 "RAF")))
                                    :ARG1-of (c2 / combine-01)))))
      :time (n8 / next))

# ::id pmid_2540_9876.161 ::date 2015-09-01T13:23:36 ::annotator SDL-AMR-09 ::preferred
# ::snt In these experiments, estrogen deprived and serum starved MCF7 cells were exposed to 10 ng/ml GDNF alone or in the presence of either sorafenib or SPP86.
# ::save-date Sun Jan 17, 2016 ::file pmid_2540_9876_161.txt
(e / expose-01
      :ARG1 (c / cell-line :name (n / name :op1 "MCF7")
            :ARG2-of (d / deprive-01
                  :ARG1 (s / small-molecule :name (n2 / name :op1 "estrogen")))
            :ARG1-of (s2 / starve-01
                  :ARG2 (s3 / serum)))
      :ARG2 (p / protein :name (n3 / name :op1 "GDNF")
            :quant (c2 / concentration-quantity :quant 10
                  :unit (n4 / nanogram-per-milliliter)))
      :manner (o / or
            :op1 (a / alone)
            :op2 (p2 / present-02
                  :ARG1 (o2 / or
                        :op1 (s4 / small-molecule :name (n5 / name :op1 "sorafenib"))
                        :op2 (s5 / small-molecule :name (n6 / name :op1 "SPP86")))))
      :location (e2 / experiment-01
            :mod (t / this)))

# ::id pmid_2540_9876.162 ::date 2015-09-01T13:33:49 ::annotator SDL-AMR-09 ::preferred
# ::snt Analyses of the relative levels of phosphorylated Akt and ERK1/2 demonstrated that both compounds effectively block GDNF- induced RET signaling at concentrations as low as 1 μM (Figure <xref ref-type="fig" rid="Fig4">4</xref>E).
# ::save-date Wed Sep 16, 2015 ::file pmid_2540_9876_162.txt
(d / demonstrate-01
      :ARG0 (a / analyze-01
            :ARG1 (a2 / and
                  :op1 (l / level
                        :quant-of (e / enzyme :name (n / name :op1 "Akt")
                              :ARG3-of (p / phosphorylate-01))
                        :ARG1-of (r / relative-05))
                  :op2 (l2 / level
                        :quant-of (e2 / enzyme :name (n2 / name :op1 "ERK1/2")
                              :ARG3-of p)
                        :ARG1-of r)))
      :ARG1 (b / block-01
            :ARG0 (c / compound
                  :mod (b2 / both)
                  :quant (c2 / concentration-quantity :quant 1
                        :unit (m / micromolar)
                        :ARG1-of (l3 / low-04)))
            :ARG1 (s / signal-07
                  :ARG0 (p2 / protein :name (n3 / name :op1 "RET"))
                  :ARG2-of (i / induce-01
                        :ARG0 (p3 / protein :name (n4 / name :op1 "GDNF"))))
            :ARG1-of (e3 / effective-04))
      :ARG1-of (d2 / describe-01
            :ARG0 (f / figure :mod "4E")))

# ::id pmid_2540_9876.163 ::date 2015-09-01T13:45:51 ::annotator SDL-AMR-09 ::preferred
# ::snt We noted however, that sorafenib inhibited Akt and ERK1/2 slightly more effectively than SPP86 under these conditions (Figure <xref ref-type="fig" rid="Fig4">4</xref>E).
# ::save-date Wed Sep 16, 2015 ::file pmid_2540_9876_163.txt
(h / have-concession-91
      :ARG1 (n / note-01
            :ARG0 (w / we)
            :ARG1 (i / inhibit-01
                  :ARG0 (s / small-molecule :name (n2 / name :op1 "sorafenib"))
                  :ARG1 (a / and
                        :op1 (e / enzyme :name (n3 / name :op1 "Akt"))
                        :op2 (e3 / enzyme :name (n5 / name :op1 "ERK1/2")))
                  :ARG1-of (e2 / effective-04
                        :degree (m / more
                              :degree (s2 / slight))
                        :compared-to (s3 / small-molecule :name (n4 / name :op1 "SPP86")))
                  :condition (c / condition
                        :mod (t / this))))
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod "4E")))

# ::id pmid_2540_9876.164 ::date 2015-09-01T13:52:38 ::annotator SDL-AMR-09 ::preferred
# ::snt These differential effects on PI3K/Akt and MAPK signaling may result may stem from the fact that sorafenib and SPP86 target different kinases at low concentrations.
# ::save-date Mon Jan 4, 2016 ::file pmid_2540_9876_164.txt
(p / possible-01
      :ARG1 (s / stem-01
            :ARG1 (a / affect-01
                  :ARG1 (s2 / signal-07
                        :ARG0 (a2 / and
                              :op1 (p2 / pathway :name (n / name :op1 "PI3K/Akt"))
                              :op2 (p3 / pathway :name (n2 / name :op1 "MAPK"))))
                  :mod (d / differential)
                  :mod (t / this))
            :ARG2 (t2 / target-01
                  :ARG0 (a3 / and
                        :op1 (s3 / small-molecule :name (n3 / name :op1 "sorafenib"))
                        :op2 (s4 / small-molecule :name (n4 / name :op1 "SPP86")))
                  :ARG1 (k / kinase
                        :ARG1-of (d2 / differ-02))
                  :condition (c / concentration-quantity
                        :ARG1-of (l / low-04)))))

# ::id pmid_2540_9876.165 ::date 2015-09-01T14:03:25 ::annotator SDL-AMR-09 ::preferred
# ::snt The enhanced inhibition of MAPK signaling observed with sorafenib may also result from the fact that it targets both RET and RAF family kinases [<xref ref-type="bibr" rid="CR37">37</xref>, <xref ref-type="bibr" rid="CR45">45</xref>].
# ::save-date Mon Jan 4, 2016 ::file pmid_2540_9876_165.txt
(p / possible-01
      :ARG1 (r / result-01
            :ARG1 (t / target-01
                  :ARG0 s2
                  :ARG1 (a / and
                        :op1 (p3 / protein-family :name (n3 / name :op1 "RET"))
                        :op2 (p4 / protein-family :name (n4 / name :op1 "RAF"))))
            :ARG2 (i / inhibit-01
                  :ARG0 (s2 / small-molecule :name (n2 / name :op1 "sorafenib"))
                  :ARG1 (s / signal-07
                        :ARG0 (p2 / pathway :name (n / name :op1 "MAPK")))
                  :ARG1-of (e / enhance-01)
                  :ARG1-of (o / observe-01)))
      :ARG1-of (d / describe-01
            :ARG0 (p5 / publication
                  :ARG1-of (c / cite-01
                        :ARG2 (a2 / and :op2 37 :op2 45))))
      :mod (a3 / also))

# ::id pmid_2540_9876.166 ::date 2015-09-01T14:15:02 ::annotator SDL-AMR-09 ::preferred
# ::snt Since these observations suggested that SPP86 disrupts ERα- RET crosstalk, we investigated the effect of SPP86 on the proliferation of MCF7 cells.
# ::save-date Sun Jan 17, 2016 ::file pmid_2540_9876_166.txt
(i / investigate-01
      :ARG0 (w / we)
      :ARG1 (a / affect-01
            :ARG0 (s / small-molecule :name (n / name :op1 "SPP86"))
            :ARG1 (p / proliferate-01
                  :ARG0 (c / cell-line :name (n2 / name :op1 "MCF7"))))
      :ARG1-of (c2 / cause-01
            :ARG0 (s2 / suggest-01
                  :ARG0 (o / observe-01
                        :mod (t / this))
                  :ARG1 (d / disrupt-01
                        :ARG0 s
                        :ARG1 (c3 / crosstalk-00
                              :ARG1 (p2 / protein :name (n3 / name :op1 "ERα"))
                              :ARG2 (p3 / protein :name (n4 / name :op1 "RET")))))))

# ::id pmid_2540_9876.167 ::date 2015-09-01T14:22:15 ::annotator SDL-AMR-09 ::preferred
# ::snt Estrogen deprived and serum starved cells were cultured in the presence of 1 ng/ml β- estradiol (E2) or 10 ng/ml GDNF alone and in combination in the presence of 1 μM SPP86 for 7 days.
# ::save-date Wed Sep 16, 2015 ::file pmid_2540_9876_167.txt
(c / culture-01
      :ARG1 (c2 / cell
            :ARG2-of (d / deprive-01
                  :ARG1 (s / small-molecule :name (n / name :op1 "estrogen")))
            :ARG1-of (s2 / starve-01
                  :ARG2 (s3 / serum)))
      :manner (a2 / and
            :op1 (p2 / present-02
                  :ARG1 (o / or
                        :op1 (s4 / small-molecule :name (n2 / name :op1 "β-estradiol")
                              :quant (c3 / concentration-quantity :quant 1
                                    :unit (n3 / nanogram-per-milliliter)))
                        :op2 (p / protein :name (n4 / name :op1 "GDNF")
                              :quant (c4 / concentration-quantity :quant 10
                                    :unit n3)))
                  :mod (a / alone))
            :op2 (p3 / present-02
                  :ARG1 (s5 / small-molecule :name (n5 / name :op1 "SPP86")
                        :quant (c5 / concentration-quantity :quant 1
                              :unit (m / micromolar)))
                  :mod (c6 / combine-01)))
      :duration (t / temporal-quantity :quant 7
            :unit (d2 / day)))

# ::id pmid_2540_9876.168 ::date 2015-09-01T14:39:04 ::annotator SDL-AMR-09 ::preferred
# ::snt SPP86 effectively inhibited E2 and/or GDNF- induced proliferation (<i>p</i> <0.05) (Figure <xref ref-type="fig" rid="Fig5">5</xref>A).
# ::save-date Mon Dec 21, 2015 ::file pmid_2540_9876_168.txt
(i / inhibit-01
      :ARG0 (s / small-molecule :name (n / name :op1 "SPP86"))
      :ARG1 (p2 / proliferate-01
            :ARG2-of (i2 / induce-01
                  :ARG0 (a / and-or
                        :op1 (s2 / small-molecule :name (n2 / name :op1 "E2"))
                        :op2 (p / protein :name (n3 / name :op1 "GDNF")))))
      :ARG1-of (e / effective-04)
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod "5A"))
      :ARG1-of (s3 / statistical-test-91
            :ARG2 (l / less-than :op1 0.05)))

# ::id pmid_2540_9876.169 ::date 2015-09-01T14:47:26 ::annotator SDL-AMR-09 ::preferred
# ::snt In contrast, SPP86 did not inhibit proliferation when MCF7 cells were co-exposed to 1 ng/ml E2 and 5 ng/insulin under similar conditions (Figure <xref ref-type="fig" rid="Fig5">5</xref>B).
# ::save-date Sun Jan 17, 2016 ::file pmid_2540_9876_169.txt
(c / contrast-01
      :ARG2 (i / inhibit-01 :polarity -
            :ARG0 (s / small-molecule :name (n / name :op1 "SPP86"))
            :ARG1 (p / proliferate-01)
            :condition (c2 / coexpose-00
                  :ARG1 (c3 / cell-line :name (n2 / name :op1 "MCF7"))
                  :ARG2 (a / and
                        :op1 (s2 / small-molecule :name (n3 / name :op1 "E2")
                              :quant (c4 / concentration-quantity :quant 1
                                    :unit (n4 / nanogram-per-milliliter)))
                        :op2 (p2 / protein :name (n5 / name :op1 "insulin")
                              :quant (c5 / concentration-quantity :quant 5
                                    :unit n4)))
                  :condition (c6 / condition
                        :ARG1-of (r / resemble-01))))
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod "5B")))

# ::id pmid_2540_9876.170 ::date 2015-09-01T14:53:57 ::annotator SDL-AMR-09 ::preferred
# ::snt We next compared the effect of SPP86 and tamoxifen on the proliferation of MCF7 cells.
# ::save-date Sun Jan 17, 2016 ::file pmid_2540_9876_170.txt
(c / compare-01
      :ARG0 (w / we)
      :ARG1 (a / affect-01
            :ARG0 (a2 / and
                  :op1 (s / small-molecule :name (n / name :op1 "SPP86"))
                  :op2 (s2 / small-molecule :name (n2 / name :op1 "tamoxifen")))
            :ARG1 (p / proliferate-01
                  :ARG0 (c2 / cell-line :name (n3 / name :op1 "MCF7"))))
      :time (n4 / next))

# ::id pmid_2540_9876.171 ::date 2015-09-01T14:56:00 ::annotator SDL-AMR-09 ::preferred
# ::snt Estrogen deprived and serum starved cells were cultured in the presence of 1 ng/ml β- estradiol (E2) and 10 ng/ml GDNF with increasing doses of either SPP86 or tamoxifen, in medium containing 1 ng/ml β- estradiol (E2) and 10 ng/ml GDNF and incubated for 7 days.
# ::save-date Wed Sep 16, 2015 ::file pmid_2540_9876_171.txt
(a3 / and
      :op1 (c / culture-01
            :ARG1 (c2 / cell
                  :ARG2-of (d / deprive-01
                        :ARG1 (s / small-molecule :name (n / name :op1 "estrogen")))
                  :ARG1-of (s2 / starve-01
                        :ARG2 (s3 / serum)))
            :manner (a2 / and
                  :op1 (p2 / present-02
                        :ARG1 (a / and
                              :op1 (s4 / small-molecule :name (n2 / name :op1 "β-estradiol")
                                    :quant (c3 / concentration-quantity :quant 1
                                          :unit (n3 / nanogram-per-milliliter)))
                              :op2 (p / protein :name (n4 / name :op1 "GDNF")
                                    :quant (c4 / concentration-quantity :quant 10
                                          :unit n3))))
                  :op2 (d2 / dose-01
                        :ARG2 (o / or
                              :op1 (s5 / small-molecule :name (n5 / name :op1 "SPP86"))
                              :op2 (s6 / small-molecule :name (n6 / name :op1 "tamoxifen")))
                        :ARG1-of (i / increase-01)))
            :location (m / medium
                  :ARG0-of (c5 / contain-01
                        :ARG1 a)))
      :op2 (i2 / incubate-01
            :ARG1 c2
            :duration (t / temporal-quantity :quant 7
                  :unit (d3 / day))))

# ::id pmid_2540_9876.172 ::date 2015-09-01T15:08:49 ::annotator SDL-AMR-09 ::preferred
# ::snt In these experiments, SPP86 and tamoxifen inhibited proliferation to a similar degree with IC<sub>50</sub> values of 1.0 and 1.4 μM respectively (Figure <xref ref-type="fig" rid="Fig5">5</xref>C).
# ::save-date Wed Nov 25, 2015 ::file pmid_2540_9876_172.txt
(i / inhibit-01
      :ARG0 (a / and
            :op1 (s / small-molecule :name (n / name :op1 "SPP86"))
            :op2 (s2 / small-molecule :name (n2 / name :op1 "tamoxifen")))
      :ARG1 (p / proliferate-01)
      :degree (r / resemble-01
            :ARG2 (a3 / and
                  :op1 (v / value
                        :mod (c3 / concentrate-02
                              :ARG1-of (e / equal-01
                                    :ARG2 (c / concentration-quantity :quant 1.0
                                          :unit (m / micromolar)))
                              :mod (i2 / inhibit-01
                                    :degree (p2 / percentage-entity :value 50))))
                  :op2 (v2 / value
                        :mod (c4 / concentrate-02
                              :ARG1-of (e3 / equal-01
                                    :ARG2 (c2 / concentration-quantity :quant 1.4
                                          :unit m))
                              :mod i2))
                  :mod (r2 / respective)))
      :location (e2 / experiment-01
            :mod (t2 / this))
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod "5C")))

# ::id pmid_2541_3220.1 ::date 2015-07-01T13:00:16 ::annotator SDL-AMR-09 ::preferred
# ::snt Constitutive activation of the ERK pathway in melanoma and skin melanocytes in Grey horses (PMID:25413220)
# ::save-date Thu Dec 10, 2015 ::file pmid_2541_3220_1.txt
(a / activate-01
      :ARG1 (p / pathway :name (n / name :op1 "ERK"))
      :mod (c / constitutive)
      :location (a2 / and
            :op1 (m / medical-condition :name (n3 / name :op1 "melanoma"))
            :op2 (m2 / melanocyte
                  :mod (s / skin))
            :location (h / horse
                  :ARG1-of (g / gray-02)))
      :ARG1-of (d2 / describe-01
            :ARG0 (p2 / publication-91
                  :ARG8 (p3 / pmid :mod 25413220))))

# ::id pmid_2541_3220.12 ::date 2015-07-01T13:10:39 ::annotator SDL-AMR-09 ::preferred
# ::snt <sec-title level="1" sec-area="abstract">Results</sec-title>
# ::save-date Wed Jul 1, 2015 ::file pmid_2541_3220_12.txt
(t / thing
      :ARG2-of (r / result-01))

# ::id pmid_2541_3220.13 ::date 2015-07-01T13:12:15 ::annotator SDL-AMR-09 ::preferred
# ::snt We found that the ERK pathway is constitutively activated in Grey horse melanoma tumours and cell lines in the absence of somatic activating mutations in <i>BRAF</i>, <i>RAS</i>, <i>GNAQ</i>, <i>GNA11</i> and <i>KIT</i> genes or alterations in the expression of the main components of the pathway.
# ::save-date Thu Dec 10, 2015 ::file pmid_2541_3220_13.txt
(f / find-01
      :ARG0 (w / we)
      :ARG1 (a / activate-01
            :ARG1 (p / pathway :name (n / name :op1 "ERK"))
            :manner (c / constitutive)
            :location (a2 / and
                  :op1 (t / tumor
                        :mod (m / medical-condition :name (n8 / name :op1 "melanoma")))
                  :op2 (c2 / cell-line)
                  :mod (h / horse
                        :ARG1-of (g6 / gray-02)))
            :condition (o / or
                  :op1 (a6 / absent-01
                        :ARG1 (m2 / mutate-01
                              :ARG1 (a4 / and
                                    :op1 (g / gene :name (n3 / name :op1 "BRAF"))
                                    :op2 (g2 / gene :name (n4 / name :op1 "RAS"))
                                    :op3 (g3 / gene :name (n5 / name :op1 "GNAQ"))
                                    :op4 (g4 / gene :name (n6 / name :op1 "GNA11"))
                                    :op5 (g5 / gene :name (n7 / name :op1 "KIT")))
                              :ARG0-of (a3 / activate-01)
                              :mod (s / somatic)))
                  :op2 (a5 / alter-01
                        :ARG1 (e / express-03
                              :ARG2 (c3 / component
                                    :mod (m3 / main)
                                    :part-of p))))))

# ::id pmid_2541_3220.14 ::date 2015-07-01T13:33:03 ::annotator SDL-AMR-09 ::preferred
# ::snt The pathway is mitogenic and is mediated by BRAF, CRAF and KRAS kinases.
# ::save-date Tue Jan 12, 2016 ::file pmid_2541_3220_14.txt
(a / and
      :op1 (m / mitogenic
            :domain (p / pathway))
      :op2 (m2 / mediate-01
            :ARG0 (a2 / and
                  :op1 (k / kinase :wiki -
                        :name (n / name :op1 "BRAF"))
                  :op2 (k2 / kinase :wiki "C-Raf"
                        :name (n2 / name :op1 "CRAF"))
                  :op3 (k3 / kinase :wiki "KRAS"
                        :name (n3 / name :op1 "KRAS")))
            :ARG1 p))

# ::id pmid_2541_3220.15 ::date 2015-07-01T13:37:00 ::annotator SDL-AMR-09 ::preferred
# ::snt Importantly, we found high activation of the ERK pathway also in epidermal melanocytes, suggesting a general predisposition to melanomagenesis in these horses.
# ::save-date Mon Dec 21, 2015 ::file pmid_2541_3220_15.txt
(f / find-01
      :ARG0 (w / we)
      :ARG1 (a / activate-01
            :ARG1 (p / pathway :name (n / name :op1 "ERK"))
            :ARG1-of (h / high-02)
            :location (m / melanocyte
                  :mod (e / epidermis))
            :mod (a2 / also))
      :mod (i / important)
      :ARG0-of (s / suggest-01
            :ARG1 (p2 / predispose-01
                  :ARG1 (h2 / horse
                        :mod (t / this))
                  :ARG2 (m2 / melanomagenesis)
                  :ARG1-of (g / general-02))))

# ::id pmid_2541_3220.98 ::date 2015-07-01T13:45:00 ::annotator SDL-AMR-09 ::preferred
# ::snt <sec-title level="1">Results</sec-title>
# ::save-date Wed Jul 1, 2015 ::file pmid_2541_3220_98.txt
(t / thing
      :ARG2-of (r / result-01))

# ::id pmid_2541_3220.99 ::date 2015-07-01T13:45:37 ::annotator SDL-AMR-09 ::preferred
# ::snt <sec-title level="2">ERK1/2 activation in Grey horse melanomas</sec-title>
# ::save-date Sun Jan 17, 2016 ::file pmid_2541_3220_99.txt
(a / activate-01
      :ARG1 (e / enzyme :name (n / name :op1 "ERK1/2"))
      :location (m / medical-condition :name (n3 / name :op1 "melanoma")
            :mod (h / horse
                  :ARG1-of (g / gray-02))))

# ::id pmid_2541_3220.100 ::date 2015-07-01T13:48:35 ::annotator SDL-AMR-09 ::preferred
# ::snt Given the importance of the MAPK/ERK pathway activation in melanoma development, we examined the levels of the activated (phosphorylated) ERK1/2 (P-ERK1/2) in primary cutaneous melanoma tumours from Grey (n = 19) and non-Grey (n = 12) horses of different breeds from three geographic locations across Europe by indirect immunofluorescence, using an anti-MITF antibody to mark melanocytic lineage [<xref ref-type="bibr" rid="CR23">23</xref>].
# ::save-date Tue Feb 2, 2016 ::file pmid_2541_3220_100.txt
(e / examine-01
      :ARG0 (w / we)
      :ARG1 (l / level
            :mod (e2 / enzyme :name (n / name :op1 "ERK1/2")
                  :ARG3-of (p2 / phosphorylate-01)
                  :ARG1-of (a / activate-01))
            :location (t / tumor
                  :mod (p4 / primary)
                  :mod (c / cutis)
                  :location (a5 / and
                        :op1 (h / horse :quant 19
                              :ARG1-of (g / gray-02))
                        :op2 (h2 / horse :quant 12
                              :ARG1-of (g3 / gray-02 :polarity -))
                        :ARG1-of (b / breed-01
                              :ARG1-of (d2 / differ-02))
                        :source (l2 / location :quant 3
                              :mod (g2 / geography)
                              :location (a2 / across
                                    :op1 (c2 / continent :wiki "Europe" :name (n5 / name :op1 "Europe")))))
                  :mod (m / medical-condition :name (n2 / name :op1 "melanoma"))))
      :manner (i / immunofluoresce-01
            :mod (i2 / indirect))
      :manner (u / use-01
            :ARG0 w
            :ARG1 (a3 / antibody
                  :ARG0-of (c3 / counter-01
                        :ARG1 (p5 / protein :name (n6 / name :op1 "MITF"))))
            :ARG2 (m2 / mark-02
                  :ARG0 w
                  :ARG1 (l3 / lineage
                        :mod (m3 / melanocyte)))
            :ARG1-of (d3 / describe-01
                  :ARG0 (p6 / publication-91
                        :ARG1-of (c4 / cite-01
                              :ARG2 23))))
      :ARG1-of (c5 / cause-01
            :ARG0 (i3 / importance
                  :domain (a4 / activate-01
                        :ARG1 (p7 / pathway :name (n7 / name :op1 "MAPK/ERK"))
                        :purpose (d4 / develop-01
                              :ARG2 m)))))

# ::id pmid_2541_3220.101 ::date 2015-07-01T14:25:57 ::annotator SDL-AMR-09 ::preferred
# ::snt All the tumours expressed nuclear and occasionally cytoplasmic P-ERK1/2, however, both signals were by far more abundant in the GHM samples (80.2% ±8.5 <i>vs</i>. 7.6% ±21.3 in Grey and non-grey MITF<sup>+</sup> cells, respectively; Figure <xref ref-type="fig" rid="Fig1">1</xref>A, B).
# ::save-date Sun Dec 20, 2015 ::file pmid_2541_3220_101.txt
(h / have-concession-91
      :ARG1 (a3 / abundant
            :domain (s / signal-07
                  :mod (b / both)
                  :quant (b5 / between
                        :op1 (p / percentage-entity :value 80.2
                              :ARG2-of (a6 / add-02
                                    :ARG1 (p4 / percentage-entity :value 8.5)))
                        :op2 (p5 / percentage-entity :value 80.2
                              :ARG2-of (s3 / subtract-01
                                    :ARG1 p4))
                        :compared-to (s4 / signal-07
                              :quant (b4 / between
                                    :op1 (p2 / percentage-entity :value 7.6
                                          :ARG2-of (a7 / add-02
                                                :ARG1 (p6 / percentage-entity :value 21.3)))
                                    :op2 (p7 / percentage-entity :value 7.6
                                          :ARG2-of (s5 / subtract-01
                                                :ARG1 p6))
                                    :location (c3 / cell
                                          :mod p3
                                          :mod (o / organism
                                                :ARG1-of (g2 / gray-02 :polarity -)))))
                        :location (c2 / cell
                              :mod (p3 / protein :name (n4 / name :op1 "MITF"))
                              :mod (o3 / organism
                                    :ARG1-of (g / gray-02)))))
            :degree (m / more
                  :degree (b2 / by-far))
            :location (s2 / sample-01
                  :ARG1 (d / disease :name (n3 / name :op1 "GHM")))
            :ARG1-of (d2 / describe-01
                  :ARG0 (a5 / and
                        :op1 (f / figure :mod "A")
                        :op2 (f2 / figure :mod "B")
                        :part-of (f3 / figure :mod 1))))
      :ARG2 (e / express-03
            :ARG2 (e2 / enzyme :name (n / name :op1 "ERK1/1")
                  :ARG3-of (p9 / phosphorylate-01)
                  :mod (n9 / nucleus)
                  :mod (c4 / cytoplasma
                        :frequency (o2 / occasional)))
            :ARG3 (t / tumor
                  :mod (a / all))))

# ::id pmid_2541_3220.102 ::date 2015-07-01T15:00:10 ::annotator SDL-AMR-09 ::preferred
# ::snt Although non-grey melanomas were much more heterogeneous for the P-ERK1/2 staining than the Grey counterparts, the quantitative difference between the signals reached statistical significance (<i>P</i> <0.001).
# ::save-date Mon Dec 21, 2015 ::file pmid_2541_3220_102.txt
(h / have-concession-91
      :ARG1 (r / reach-01
            :ARG0 (d3 / differ-02
                  :ARG1 (s2 / signal-07)
                  :mod (q / quantity))
            :ARG1 (s3 / significance
                  :mod (s4 / statistics)
                  :value (l / less-than :op1 0.001)))
      :ARG2 (h2 / heterogeneity
            :degree (m / more
                  :mod (m2 / much))
            :prep-for (s / stain-01
                  :ARG1 (e / enzyme :name (n3 / name :op1 "ERK1/2")
                        :ARG3-of (p / phosphorylate-01)))
            :compared-to (h3 / heterogeneity
                  :domain (m3 / medical-condition :name (n / name :op1 "melanoma")
                        :mod (o / organism
                              :ARG1-of (g / gray-02))))
            :domain (m4 / medical-condition :name (n5 / name :op1 "melanoma")
                  :mod (o2 / organism
                        :ARG1-of (g2 / gray-02 :polarity -)))))

# ::id pmid_2541_3220.103 ::date 2015-07-01T15:15:46 ::annotator SDL-AMR-09 ::preferred
# ::snt The total ERK1/2 signal was similarly heterogeneous in both Grey and non-grey samples (71.2 ± 17.4 <i>vs</i>. 50.5% ±13.0 in MITF<sup>+</sup> cells of the respective melanoma type; Figure <xref ref-type="fig" rid="Fig1">1</xref>A, B).
# ::save-date Mon Dec 21, 2015 ::file pmid_2541_3220_103.txt
(h / heterogeneity
      :domain (s / signal-07
            :ARG0 (e / enzyme :name (n / name :op1 "ERK1/2"))
            :mod (t / total)
            :location (a2 / and
                  :op1 (t3 / thing
                        :ARG1-of (s2 / sample-01
                              :ARG2 (o / organism
                                    :ARG1-of (g / gray-02))))
                  :op2 (t4 / thing
                        :ARG1-of (s3 / sample-01
                              :ARG2 (o2 / organism
                                    :ARG1-of (g2 / gray-02 :polarity -))))))
      :ARG1-of (r / resemble-01)
      :quant (b / between
            :op1 (p3 / percentage-entity :value 71.2
                  :ARG2-of (a3 / add-02
                        :ARG1 (p4 / percentage-entity :value 17.4)))
            :op2 (p5 / percentage-entity
                  :ARG2-of (s4 / subtract-01
                        :ARG1 p4))
            :compared-to (s5 / signal-07
                  :quant (b2 / between
                        :op1 (p / percentage-entity :value 50.5
                              :ARG2-of (a4 / add-02
                                    :ARG1 (p6 / percentage-entity :value 13.0)))
                        :op2 (p7 / percentage-entity
                              :ARG2-of (s6 / subtract-01
                                    :ARG1 p6))))
            :location (c / cell
                  :mod (p2 / protein :name (n3 / name :op1 "MITF"))
                  :source (m / medical-condition :name (n5 / name :op1 "melanoma")
                        :ARG1-of (t2 / type-03
                              :mod (r2 / respective))))
            :ARG1-of (d2 / describe-01
                  :ARG0 (a / and
                        :op1 (f / figure :mod "A")
                        :op2 (f2 / figure :mod "B")
                        :part-of (f3 / figure :mod 1)))))

# ::id pmid_2541_3220.104 ::date 2015-07-01T15:28:09 ::annotator SDL-AMR-09 ::preferred
# ::snt In line with the elevated P-ERK1/2 levels in the GHM tissues, high P-ERK1/2 levels were detected in two GHM cell lines, HoMel-L1 and HoMel-A1, established from a primary and metastatic melanoma tumour of a Grey Lipizzaner and Arabian horse, respectively [<xref ref-type="bibr" rid="CR24">24</xref>].
# ::save-date Thu Dec 10, 2015 ::file pmid_2541_3220_104.txt
(d / detect-01
      :ARG1 (l / level
            :quant-of (e / enzyme :name (n / name :op1 "ERK1/2")
                  :ARG3-of (p3 / phosphorylate-01))
            :ARG1-of (h / high-02)
            :ARG2-of (a4 / align-01
                  :ARG1 (l2 / level
                        :ARG1-of (e3 / elevate-01)
                        :location (t2 / tissue
                              :mod (d5 / disease :name (n7 / name :op1 "GHM")))
                        :quant-of e)))
      :location (c / cell-line :quant 2
            :ARG2-of (i / include-91
                  :ARG1 (a / and
                        :op1 (c2 / cell-line :name (n3 / name :op1 "HoMel-L1"))
                        :op2 (c3 / cell-line :name (n4 / name :op1 "HoMel-A1"))
                        :ARG1-of (e2 / establish-01
                              :source (a3 / and
                                    :op1 (t / tumor
                                          :mod (p / primary)
                                          :mod (m2 / medical-condition :name (n2 / name :op1 "melanoma"))
                                          :part-of (o3 / organism :name (n5 / name :op1 "Grey" :op2 "Lipizzaner" :op3 "horse")))
                                    :op2 (t3 / tumor
                                          :mod (m / metastasis)
                                          :mod m2
                                          :part-of (o4 / organism :name (n6 / name :op1 "Arabian" :op2 "horse")))))))
            :mod d5)
      :ARG1-of (d4 / describe-01
            :ARG0 (p2 / publication-91
                  :ARG1-of (c4 / cite-01
                        :ARG2 24))))

# ::id pmid_2541_3220.105 ::date 2015-07-01T15:48:38 ::annotator SDL-AMR-09 ::preferred
# ::snt The P-ERK1/2 levels were comparable to those seen in human melanoma cell lines with oncogenic BRAF or NRAS mutations, in contrast to a cell line with wild-type BRAF and NRAS (Figure <xref ref-type="fig" rid="Fig1">1</xref>C, D; Table <xref ref-type="table" rid="Tab1">1</xref>).
# ::save-date Sat Jan 16, 2016 ::file pmid_2541_3220_105.txt
(c4 / comparable-03
      :ARG1 (l / level
            :quant-of (e / enzyme :name (n / name :op1 "ERK1/2")
                  :ARG3-of (p / phosphorylate-01)))
      :ARG2 (l2 / level
            :ARG1-of (s / see-01
                  :location (c / cell-line
                        :mod (h / human)
                        :mod (o / or
                              :op1 (m2 / mutate-01
                                    :ARG1 (e5 / enzyme :name (n3 / name :op1 "BRAF")
                                          :ARG0-of (c5 / cause-01
                                                :ARG1 (d / disease :wiki "Cancer" :name (n2 / name :op1 "cancer")))))
                              :op2 (m3 / mutate-01
                                    :ARG1 (e4 / enzyme :name (n4 / name :op1 "NRAS")
                                          :ARG0-of c5)))
                        :ARG1-of (c2 / contrast-01
                              :ARG2 (c3 / cell-line
                                    :mod (e3 / enzyme :name (n5 / name :op1 "BRAF")
                                          :mod (w / wild-type))
                                    :mod (e2 / enzyme :name (n6 / name :op1 "NRAS")
                                          :mod w)))
                        :mod (m / medical-condition :name (n7 / name :op1 "melanoma")))))
      :ARG1-of (d2 / describe-01
            :ARG0 (a2 / and
                  :op1 (a3 / and
                        :op1 (f / figure :mod "C")
                        :op2 (f2 / figure :mod "D")
                        :part-of (f3 / figure :mod 1))
                  :op2 (t / table :mod 1))))

# ::id pmid_2541_3220.106 ::date 2015-07-01T16:03:07 ::annotator SDL-AMR-09 ::preferred
# ::snt ERK1/2 was activated even in the absence of serum and serum addition had a minimal stimulatory effect on the P-ERK1/2 levels (Additional file <xref ref-type="media" rid="MOESM2">2</xref>: Figure S1A, B).
# ::save-date Sun Dec 20, 2015 ::file pmid_2541_3220_106.txt
(a / and
      :op1 (a2 / activate-01
            :ARG1 (e / enzyme :name (n / name :op1 "ERK1/2"))
            :concession (a7 / absent-01
                  :ARG1 (s / serum)))
      :op2 (a3 / affect-01
            :ARG0 (a4 / add-02
                  :ARG1 s)
            :ARG1 (l2 / level
                  :quant-of (e2 / enzyme :name (n2 / name :op1 "ERK1/2")
                        :ARG3-of (p / phosphorylate-01)))
            :ARG2 (s2 / stimulate-01
                  :ARG1-of (m / minimal-02)))
      :ARG1-of (d / describe-01
            :ARG0 (a5 / and
                  :op1 (f / figure :mod "A")
                  :op2 (f2 / figure :mod "B")
                  :part-of (f3 / figure :mod "S1"
                        :part-of (f4 / file :mod 2
                              :mod (a6 / additional))))))

# ::id pmid_2541_3220.107 ::date 2015-07-01T17:00:17 ::annotator SDL-AMR-09 ::preferred
# ::snt <sec-title level="2">MEK/ERK module is required for growth of Grey horse melanoma cells</sec-title>
# ::save-date Thu Dec 10, 2015 ::file pmid_2541_3220_107.txt
(r / require-01
      :ARG0 (g / grow-01
            :ARG1 (c / cell
                  :mod (m2 / medical-condition :name (n3 / name :op1 "melanoma")
                        :mod (h / horse
                              :ARG1-of (g2 / gray-02)))))
      :ARG1 (m / module
            :mod (p / pathway :name (n / name :op1 "MEK/ERK"))))

# ::id pmid_2541_3220.108 ::date 2015-07-01T23:50:56 ::annotator SDL-AMR-09 ::preferred
# ::snt To assess the involvement of the ERK pathway in proliferation of the GHM cells, we treated the HoMel-L1 and HoMel-A1 cell lines with U0126, a specific inhibitor of MEK1/2 and therefore ERK phosphorylation.
# ::save-date Mon Dec 21, 2015 ::file pmid_2541_3220_108.txt
(t / treat-04
      :ARG0 (w / we)
      :ARG1 (a / and
            :op1 (c / cell-line :name (n / name :op1 "HoMel-L1"))
            :op2 (c2 / cell-line :name (n2 / name :op1 "HoMel-A1")))
      :ARG2 (s / small-molecule :name (n3 / name :op1 "U0126")
            :ARG1-of (m2 / mean-01
                  :ARG2 (m / molecular-physical-entity
                        :ARG0-of (i / inhibit-01
                              :ARG1 (e / enzyme :name (n4 / name :op1 "MEK1/2"))
                              :ARG0-of (c4 / cause-01
                                    :ARG1 (i3 / inhibit-01
                                          :ARG1 (p / phosphorylate-01
                                                :ARG1 p2))))
                        :ARG1-of (s2 / specific-02))))
      :purpose (a3 / assess-01
            :ARG0 w
            :ARG1 (i2 / involve-01
                  :ARG1 (p2 / pathway :name (n6 / name :op1 "ERK"))
                  :ARG2 (p3 / proliferate-01
                        :ARG0 (c3 / cell
                              :mod (d / disease :name (n7 / name :op1 "GHM")))))))

# ::id pmid_2541_3220.109 ::date 2015-07-02T00:05:03 ::annotator SDL-AMR-09 ::preferred
# ::snt Western blot analysis showed an expected decrease in P-ERK1/2 in both cell lines upon the treatment (Figure <xref ref-type="fig" rid="Fig2">2</xref>A).
# ::save-date Sun Dec 13, 2015 ::file pmid_2541_3220_109.txt
(s / show-01
      :ARG0 (a / analyze-01
            :manner (i / immunoblot-01))
      :ARG1 (d / decrease-01
            :ARG1 (e2 / enzyme :name (n / name :op1 "ERK1/2")
                  :ARG3-of (p / phosphorylate-01))
            :location (c / cell-line
                  :mod (b2 / both))
            :condition (t / treat-04
                  :ARG1 c)
            :ARG1-of (e / expect-01))
      :ARG1-of (d2 / describe-01
            :ARG0 (f / figure :mod "2A")))

# ::id pmid_2541_3220.110 ::date 2015-07-02T00:11:39 ::annotator SDL-AMR-09 ::preferred
# ::snt The treatment also largely reduced cell viability in both cell lines (Figure <xref ref-type="fig" rid="Fig2">2</xref>B).
# ::save-date Mon Jul 20, 2015 ::file pmid_2541_3220_110.txt
(r / reduce-01
      :ARG0 (t / treat-04)
      :ARG1 (v / viability
            :mod (c / cell)
            :location (c2 / cell-line
                  :mod (b / both)))
      :ARG2 (l / large)
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod "2B"))
      :mod (a / also))

# ::id pmid_2541_3220.111 ::date 2015-07-02T00:14:52 ::annotator SDL-AMR-09 ::preferred
# ::snt As judged from the calculated IC<sub>50</sub> values, HoMel-L1 appeared more sensitive to the MEK1/2 inhibition than HoMel-A1 (P <0.05) and at least as sensitive as the human <sup>Q61R</sup>NRAS line BL (Figure <xref ref-type="fig" rid="Fig2">2</xref>C).
# ::save-date Sun Jan 17, 2016 ::file pmid_2541_3220_111.txt
(a / appear-02
      :ARG1 (a2 / and
            :op1 (s / sensitive-03
                  :ARG0 (c / cell-line :name (n / name :op1 "HoMel-L1"))
                  :ARG1 (i / inhibit-01
                        :ARG1 (e / enzyme :name (n2 / name :op1 "MEK1/2")))
                  :degree (m / more)
                  :compared-to (c3 / cell-line :name (n3 / name :op1 "HoMel-A1")))
            :op2 (s2 / sensitive-03
                  :ARG0 c
                  :mod (a3 / at-least)
                  :ARG1-of (e2 / equal-01)
                  :compared-to (c5 / cell-line :name (n4 / name :op1 "BL")
                        :mod (e3 / enzyme :name (n5 / name :op1 "NRAS")
                              :ARG2-of (m2 / mutate-01 :value "Q61R")))))
      :ARG2-of (j / judge-01
            :ARG3 (c4 / concentration-quantity
                  :ARG4-of (h / have-percentage-maximal-inhibitory-concentration-01
                        :ARG2 50)
                  :ARG1-of (c2 / calculate-01)))
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod "2C"))
      :ARG1-of (s3 / statistical-test-91
            :ARG2 (l / less-than :op1 0.05)))

# ::id pmid_2541_3220.112 ::date 2015-07-02T00:43:13 ::annotator SDL-AMR-09 ::preferred
# ::snt Both GHM cell lines were less sensitive to the U0126 treatment than the human <sup>V600E</sup>BRAF line Mel-Ho, although, this did not reach statistical significance for HoMel-L1.
# ::save-date Sat Jan 16, 2016 ::file pmid_2541_3220_112.txt
(h / have-concession-91
      :ARG1 (s / sensitive-03
            :ARG0 (c / cell-line
                  :mod (d / disease :name (n / name :op1 "GHM"))
                  :mod (b / both))
            :ARG1 (t / treat-04
                  :ARG2 (s2 / small-molecule :name (n2 / name :op1 "U0126")))
            :degree (l / less)
            :compared-to (c2 / cell-line :name (n3 / name :op1 "Mel-Ho")
                  :mod (e / enzyme :name (n4 / name :op1 "BRAF")
                        :mod (h2 / human)
                        :ARG2-of (m / mutate-01 :value "V600E"))))
      :ARG2 (r / reach-01 :polarity -
            :ARG0 s
            :ARG1 (s3 / signify-01
                  :mod (s4 / statistics))
            :prep-for (c3 / cell-line :name (n5 / name :op1 "HoMel-L1"))))

# ::id pmid_2541_3220.113 ::date 2015-07-02T00:55:45 ::annotator SDL-AMR-09 ::preferred
# ::snt In contrast, cell viability of the human <sup>WT</sup>BRAF <sup>WT</sup>RAS line M5 was only weakly inhibited by the treatment (Figure <xref ref-type="fig" rid="Fig2">2</xref>B).
# ::save-date Sat Jan 30, 2016 ::file pmid_2541_3220_113.txt
(c / contrast-01
      :ARG2 (i / inhibit-01
            :ARG0 (t / treat-04)
            :ARG1 (v / viability
                  :mod (c2 / cell)
                  :poss (c3 / cell-line :name (n / name :op1 "M5")
                        :mod (e / enzyme :name (n2 / name :op1 "BRAF")
                              :mod (w2 / wild-type))
                        :mod (e2 / enzyme :name (n3 / name :op1 "RAS")
                              :mod (w3 / wild-type))))
            :degree (w / weak-02
                  :mod (o / only)))
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod "2B")))

# ::id pmid_2541_3220.114 ::date 2015-07-02T01:02:29 ::annotator SDL-AMR-09 ::preferred
# ::snt These results demonstrate that ERK signaling is an important component for GHM cell growth; however the incomplete inhibition by U0126 suggests that additional ERK-independent mechanisms are involved.
# ::save-date Sun Jan 17, 2016 ::file pmid_2541_3220_114.txt
(c4 / contrast-01
      :ARG1 (d / demonstrate-01
            :ARG0 (t2 / thing
                  :mod (t / this)
                  :ARG2-of (r / result-01))
            :ARG1 (c / component
                  :mod (i / important)
                  :domain (s / signal-07
                        :ARG0 (e / enzyme :name (n / name :op1 "ERK")))
                  :purpose (g / grow-01
                        :ARG1 (c2 / cell
                              :mod (d2 / disease :name (n2 / name :op1 "GHM"))))))
      :ARG2 (s2 / suggest-01
            :ARG0 (i2 / inhibit-01
                  :ARG0 (s3 / small-molecule :name (n3 / name :op1 "U0126"))
                  :ARG1-of (c3 / complete-01 :polarity -))
            :ARG1 (i4 / involve-01
                  :ARG1 (m / mechanism
                        :ARG0-of (d3 / depend-01 :polarity -
                              :ARG1 e)
                        :mod (a / additional)))))

# ::id pmid_2541_3220.115 ::date 2015-07-02T01:15:07 ::annotator SDL-AMR-09 ::preferred
# ::snt <sec-title level="2">Activation of ERK pathway in Grey horse melanoma cells is not linked to common oncogenic alterations</sec-title>
# ::save-date Thu Dec 10, 2015 ::file pmid_2541_3220_115.txt
(l / link-01 :polarity -
      :ARG1 (a / activate-01
            :ARG1 (p / pathway :name (n / name :op1 "ERK"))
            :location (c / cell
                  :mod (m / medical-condition :name (n3 / name :op1 "melanoma")
                        :mod (h / horse
                              :ARG1-of (g / gray-02)))))
      :ARG2 (a2 / alter-01
            :mod (c2 / common)
            :ARG0-of (c3 / cause-01
                  :ARG1 (d / disease :wiki "Cancer" :name (n2 / name :op1 "cancer")))))

# ::id pmid_2541_3220.116 ::date 2015-07-02T01:18:01 ::annotator SDL-AMR-09 ::preferred
# ::snt To test whether the constitutive ERK1/2 activation was due to the presence of oncogenic mutations commonly associated with ERK1/2 activation in melanocytic neoplasms, we screened the horse cell lines and seven additional GHM tumours for mutations in exons 11 and 15 of <i>BRAF</i>, the full coding regions of <i>N</i>-, <i>K</i>- and <i>HRAS</i>, exon 4 and 5 of <i>GNAQ</i> and <i>GNA11</i>, and exons 9–21 of <i>KIT</i>.
# ::save-date Mon Dec 21, 2015 ::file pmid_2541_3220_116.txt
(s / screen-01
      :ARG0 (w / we)
      :ARG1 (a / and
            :op1 (c / cell-line
                  :mod (h / horse))
            :op2 (t / tumor :quant 7
                  :mod (d / disease
                        :name (n / name :op1 "GHM"))
                  :mod (a2 / additional)))
      :ARG2 (m / mutate-01
            :ARG1 (a3 / and
                  :op1 (a4 / and
                        :op1 (p7 / protein-segment
                              :name (n15 / name :op1 "exon" :op2 11))
                        :op2 (p2 / protein-segment
                              :name (n2 / name :op1 "exon" :op2 15))
                        :part-of (g / gene
                              :name (n4 / name :op1 "BRAF")))
                  :op2 (r / region
                        :ARG1-of (f / full-09)
                        :ARG0-of (c2 / code-01)
                        :part-of (a5 / and
                              :op1 (g2 / gene
                                    :name (n5 / name :op1 "NRAS"))
                              :op2 (g3 / gene
                                    :name (n6 / name :op1 "KRAS"))
                              :op3 (g4 / gene
                                    :name (n7 / name :op1 "HRAS"))))
                  :op3 (a6 / and
                        :op1 (p3 / protein-segment
                              :name (n3 / name :op1 "exon" :op2 4))
                        :op2 (p8 / protein-segment
                              :name (n17 / name :op1 "exon" :op2 5))
                        :part-of (a7 / and
                              :op1 (g5 / gene
                                    :name (n10 / name :op1 "GNAQ"))
                              :op2 (g6 / gene
                                    :name (n11 / name :op1 "GNA11"))))
                  :op4 (p4 / protein-segment
                        :name (n8 / name :op1 "exon")
                        :value (b / between :op1 9 :op2 21)
                        :part-of (g7 / gene
                              :name (n13 / name :op1 "KIT")))))
      :purpose (t2 / test-01
            :ARG0 w
            :ARG1 (c3 / cause-01 :mode interrogative
                  :ARG0 (p / present-02
                        :ARG1 (m2 / mutate-01
                              :ARG1-of (a9 / associate-01
                                    :ARG2 (a10 / activate-01
                                          :ARG1 e6
                                          :location (n16 / neoplasm
                                                :mod (m3 / melanocyte)))
                                    :mod (c7 / common))
                              :ARG0-of (c5 / cause-01
                                    :ARG1 (d2 / disease :wiki "Cancer"
                                          :name (n9 / name :op1 "cancer")))))
                  :ARG1 (a8 / activate-01
                        :ARG1 (e6 / enzyme
                              :name (n14 / name :op1 "ERK1/2"))
                        :mod (c4 / constitutive)))))

# ::id pmid_2541_3220.117 ::date 2015-07-02T01:44:00 ::annotator SDL-AMR-09 ::preferred
# ::snt In all the genes except <i>KIT</i>, no mutations were found, indicating the wild-type status of the genes in this melanoma type.
# ::save-date Mon Dec 21, 2015 ::file pmid_2541_3220_117.txt
(i / indicate-01
      :ARG0 (f / find-01 :polarity -
            :ARG1 (m / mutate-01
                  :ARG1 (g / gene
                        :mod (a / all)
                        :ARG2-of (e / except-01
                              :ARG1 (g2 / gene :name (n / name :op1 "KIT"))))))
      :ARG1 (s / status
            :mod (w / wild-type)
            :poss g
            :location (m2 / medical-condition :name (n3 / name :op1 "melanoma")
                  :ARG1-of (t3 / type-03))))

# ::id pmid_2541_3220.118 ::date 2015-07-02T01:51:43 ::annotator SDL-AMR-09 ::preferred
# ::snt In <i>KIT</i>, four single nucleotide polymorphisms (SNPs) were found in exon 14, 15, 19 and 20 (11% each) in each of 4 different tumours (Table <xref ref-type="table" rid="Tab2">2</xref>).
# ::save-date Fri Nov 6, 2015 ::file pmid_2541_3220_118.txt
(f / find-01
      :ARG1 (t4 / thing :quant 4 :name (n / name :op1 "single" :op2 "nucleotide" :op3 "polymorphism"))
      :location (a / and
            :op1 (p6 / protein-segment :name (n2 / name :op1 "exon" :op2 "14"))
            :op2 (p / protein-segment :name (n3 / name :op1 "exon" :op2 "15"))
            :op3 (p3 / protein-segment :name (n4 / name :op1 "exon" :op2 "19"))
            :op4 (p4 / protein-segment :name (n5 / name :op1 "exon" :op2 "20"))
            :value (p2 / percentage-entity :value 11
                  :mod (e5 / each))
            :location (e6 / each
                  :ARG1-of (i / include-91
                        :ARG2 (t / tumor :quant 4
                              :ARG1-of (d5 / differ-02))))
            :part-of (g2 / gene :name (n8 / name :op1 "KIT")))
      :ARG1-of (d6 / describe-01
            :ARG0 (t2 / table :mod 2)))

# ::id pmid_2541_3220.119 ::date 2015-06-30T07:13:18 ::annotator SDL-AMR-09 ::preferred
# ::snt However, these SNPs were silent on the protein level and present in the constitutional DNA from both Grey and non-Grey horses of different breeds (Table <xref ref-type="table" rid="Tab2">2</xref>), and therefore were considered as common germline polymorphisms with no link to the Grey phenotype.
# ::save-date Mon Jan 4, 2016 ::file pmid_2541_3220_119.txt
(c / contrast-01
      :ARG2 (a / and
            :op1 (s / silent
                  :domain (d / dna-sequence :name (n / name :op1 "SNP")
                        :mod (t2 / this))
                  :location (l / level
                        :mod (p2 / protein)))
            :op2 (p / present-02
                  :ARG1 d
                  :ARG2 (n3 / nucleic-acid :name (n4 / name :op1 "DNA")
                        :ARG1-of (c2 / constitute-01)
                        :source (a2 / and
                              :op1 (h / horse
                                    :ARG1-of (g / gray-02))
                              :op2 (h2 / horse
                                    :ARG1-of (g2 / gray-02 :polarity -))
                              :part-of (b / breed
                                    :ARG1-of (d3 / differ-02)))))
            :ARG1-of (d4 / describe-01
                  :ARG0 (t / table :mod 2))
            :ARG0-of (c3 / cause-01
                  :ARG1 (c4 / consider-01
                        :ARG1 (p3 / polymorphism
                              :mod (c5 / common)
                              :part-of (c6 / cell-line :name (n2 / name :op1 "germline"))
                              :ARG1-of (l2 / link-01 :polarity -
                                    :ARG2 (p4 / phenotype
                                          :mod h))
                              :domain d)))))

# ::id pmid_2541_3220.120 ::date 2015-06-30T07:13:40 ::annotator SDL-AMR-09 ::preferred
# ::snt Another possible mechanism for a constitutive activation of the ERK pathway may involve overexpression of a component of the pathway or underexpression of its negative regulator.
# ::save-date Fri Feb 5, 2016 ::file pmid_2541_3220_120.txt
(p / possible-01
      :ARG1 (i / involve-01
            :ARG0 (m / mechanism
                  :ARG1-of (p2 / possible-01)
                  :instrument-of (a2 / activate-01
                        :ARG1 (p3 / pathway :name (n / name :op1 "ERK"))
                        :mod (c / constitutive))
                  :mod (a / another))
            :ARG1 (o / or
                  :op1 (o2 / overexpress-01
                        :ARG1 (c2 / component
                              :part-of p3))
                  :op2 (u / underexpress-00
                        :ARG1 (m2 / molecular-physical-entity
                              :part-of p3
                              :ARG2-of (d / downregulate-01))))))

# ::id pmid_2541_3220.121 ::date 2015-06-30T07:13:54 ::annotator SDL-AMR-09 ::preferred
# ::snt To address this possibility we compared expression levels of the key kinases and two major negative regulators of the pathway, SPROUTY2 and RKIP, in the GHM <i>vs</i>. human melanoma cell lines with activated ERK1/2 due to oncogenic BRAF or NRAS mutations.
# ::save-date Sun Jan 17, 2016 ::file pmid_2541_3220_121.txt
(c / compare-01
      :ARG0 (w / we)
      :ARG1 (l / level
            :degree-of (e / express-03
                  :ARG1 (a / and
                        :op1 (k / kinase
                              :ARG1-of (k2 / key-02))
                        :op2 (m4 / molecular-physical-entity :quant 2
                              :ARG2-of (d / downregulate-01
                                    :ARG1 (p / pathway))
                              :ARG1-of (m / major-02)
                              :ARG1-of (m2 / mean-01
                                    :ARG2 (a2 / and
                                          :op1 (e2 / enzyme :name (n / name :op1 "SPROUTY2"))
                                          :op2 (p3 / protein :name (n2 / name :op1 "RKIP")))))))
            :compared-to (l2 / level
                  :degree-of e
                  :location (c3 / cell
                        :mod (m5 / medical-condition :name (n4 / name :op1 "melanoma"))))
            :location (c2 / cell
                  :mod (d2 / disease :name (n3 / name :op1 "GHM"))))
      :ARG2 (e4 / enzyme :name (n5 / name :op1 "ERK1/2")
            :ARG1-of (a3 / activate-01
                  :ARG1-of (c5 / cause-01
                        :ARG0 (m3 / mutate-01
                              :ARG1 (o / or
                                    :op1 (e5 / enzyme :name (n6 / name :op1 "BRAF")
                                          :ARG0-of (c6 / cause-01
                                                :ARG1 (d4 / disease :wiki "Cancer" :name (n8 / name :op1 "cancer"))))
                                    :op2 (e6 / enzyme :name (n7 / name :op1 "NRAS")
                                          :ARG0-of c6))))))
      :purpose (a4 / address-02
            :ARG0 w
            :ARG1 (p2 / possible-01
                  :mod (t / this))))

# ::id pmid_2541_3220.122 ::date 2015-06-30T07:27:57 ::annotator SDL-AMR-09 ::preferred
# ::snt We found no substantial differences in the levels of ERK1/2 (Figure <xref ref-type="fig" rid="Fig1">1</xref>C), MEK1/2, BRAF, NRAS (Figure <xref ref-type="fig" rid="Fig3">3</xref>A and Additional file <xref ref-type="media" rid="MOESM3">3</xref>: Figure S2A) between the horse and human melanoma cells.
# ::save-date Thu Jan 14, 2016 ::file pmid_2541_3220_122.txt
(f / find-01 :polarity -
      :ARG0 (w / we)
      :ARG1 (d / differ-02
            :ARG1 (a4 / and
                  :op1 (l / level
                        :quant-of (e / enzyme :name (n / name :op1 "ERK1/2")
                              :ARG1-of (d2 / describe-01
                                    :ARG0 (f2 / figure :mod "1C"))))
                  :op2 (l2 / level
                        :quant-of (e2 / enzyme :name (n2 / name :op1 "MEK1/2")))
                  :op3 (l3 / level
                        :quant-of (e3 / enzyme :name (n3 / name :op1 "BRAF")))
                  :op4 (l4 / level
                        :quant-of (e4 / enzyme :name (n4 / name :op1 "NRAS")
                              :ARG1-of (d3 / describe-01
                                    :ARG0 (a2 / and
                                          :op1 (f3 / figure :mod "3A")
                                          :op2 (f4 / file
                                                :ARG1-of (m / mean-01
                                                      :ARG2 (f5 / figure :mod "S2A"))
                                                :ARG1-of (a3 / add-02))))))
                  :location (c / cell
                        :source (m4 / medical-condition :name (n5 / name :op1 "melanoma")
                              :mod (h / horse))))
            :ARG2 (a / and
                  :op1 l
                  :op2 l2
                  :op3 l3
                  :op4 l4
                  :location (c2 / cell
                        :source (m2 / medical-condition :name (n6 / name :op1 "melanoma")
                              :mod (h2 / human))))
            :degree (s / substantial)))

# ::id pmid_2541_3220.123 ::date 2015-06-30T07:28:13 ::annotator SDL-AMR-09 ::preferred
# ::snt The levels of SPROUTY2 and RKIP in the horse lines were not lower than those in the human lines (Figure <xref ref-type="fig" rid="Fig3">3</xref>A and Additional file <xref ref-type="media" rid="MOESM3">3</xref>: Figure S2A).
# ::save-date Sun Jan 17, 2016 ::file pmid_2541_3220_123.txt
(l / low-04 :polarity -
      :ARG1 (a / and
            :op1 (l2 / level
                  :quant-of (e / enzyme :name (n / name :op1 "SPROUTY2")))
            :op2 (l3 / level
                  :quant-of (p / protein :name (n2 / name :op1 "RKIP")))
            :location (l4 / line
                  :mod (h / horse)))
      :degree (m / more)
      :compared-to (a4 / and
            :op1 l2
            :op2 l3
            :location (l6 / line
                  :mod (h2 / human)))
      :ARG1-of (d / describe-01
            :ARG0 (a2 / and
                  :op1 (f / figure :mod "3A")
                  :op2 (f2 / file
                        :ARG1-of (m2 / mean-01
                              :ARG0 (f3 / figure :mod "S2A"))
                        :ARG1-of (a3 / add-02)))))

# ::id pmid_2541_3220.124 ::date 2015-06-30T07:28:31 ::annotator SDL-AMR-09 ::preferred
# ::snt Together, these results suggest that neither oncogenic mutations in the components of the ERK pathway nor alteration in their expression or of that of the pathway’s major negative regulators is likely to be responsible for the constitutive activation of ERK1/2 in GHM cells.
# ::save-date Sun Dec 20, 2015 ::file pmid_2541_3220_124.txt
(s / suggest-01
      :ARG0 (t / thing
            :ARG1-of (r / result-01)
            :mod (t2 / this))
      :ARG1 (l / likely-01 :polarity -
            :ARG1 (r2 / responsible-01
                  :ARG0 (o / or
                        :op1 (m / mutate-01
                              :ARG1 (c3 / component
                                    :part-of (p / pathway :name (n / name :op1 "ERK")))
                              :ARG0-of (c / cause-01
                                    :ARG1 (d3 / disease :wiki "Cancer" :name (n4 / name :op1 "cancer"))))
                        :op2 (a / alter-01
                              :ARG1 (e / express-03
                                    :ARG2 (o2 / or
                                          :op1 c3
                                          :op2 (m3 / molecular-physical-entity
                                                :ARG1-of (m2 / major-02)
                                                :ARG0-of (d / deregulate-01
                                                      :ARG1 p))))))
                  :ARG1 (a2 / activate-01
                        :ARG1 (e2 / enzyme :name (n2 / name :op1 "ERK1/2"))
                        :location (c4 / cell
                              :mod (d2 / disease :name (n3 / name :op1 "GHM")))
                        :mod (c5 / constitutive))))
      :mod (t3 / together))

# ::id pmid_2541_3220.125 ::date 2015-06-30T07:28:44 ::annotator SDL-AMR-09 ::preferred
# ::snt <sec-title level="2">ERK1/2 activation is BRAF, CRAF and KRAS-dependent in Grey horse melanoma cells</sec-title>
# ::save-date Thu Dec 10, 2015 ::file pmid_2541_3220_125.txt
(d / depend-01
      :ARG0 (a / activate-01
            :ARG1 (e / enzyme :name (n / name :op1 "ERK1/2")))
      :ARG1 (a2 / and
            :op1 (e2 / enzyme :name (n2 / name :op1 "BRAF"))
            :op2 (e3 / enzyme :name (n3 / name :op1 "CRAF"))
            :op3 (e4 / enzyme :name (n4 / name :op1 "KRAS")))
      :location (c / cell
            :source (m / medical-condition :name (n5 / name :op1 "melanoma")
                  :mod (h / horse
                        :ARG1-of (g / gray-02)))))

# ::id pmid_2541_3220.126 ::date 2015-06-30T07:40:11 ::annotator SDL-AMR-09 ::preferred
# ::snt In order to identify upstream signaling components involved in the constitutive ERK1/2 activation in GHM cells we used specific inhibitors against RAF (L779450), RAS (farnesyl thiosalicylic acid, FTS) and PI3K/AKT (LY294002) proteins.
# ::save-date Sun Jan 17, 2016 ::file pmid_2541_3220_126.txt
(u / use-01
      :ARG0 (w / we)
      :ARG1 (a4 / and
            :op1 (m / molecular-physical-entity
                  :ARG0-of (i4 / inhibit-01
                        :ARG1 (p / protein-family :name (n4 / name :op1 "RAF")))
                  :ARG1-of (m2 / mean-01
                        :ARG2 (s2 / small-molecule :name (n / name :op1 "L779450"))))
            :op2 (m3 / molecular-physical-entity
                  :ARG0-of (i5 / inhibit-01
                        :ARG1 (p3 / protein-family :name (n5 / name :op1 "RAS")))
                  :ARG1-of (m4 / mean-01
                        :ARG2 (s3 / small-molecule :name (n2 / name :op1 "farnesyl" :op2 "thiosalicylic" :op3 "acid"))))
            :op3 (m5 / molecular-physical-entity
                  :ARG0-of (i6 / inhibit-01
                        :ARG1 (p2 / pathway :name (n6 / name :op1 "PI3K/AKT")))
                  :ARG1-of (m6 / mean-01
                        :ARG2 (s4 / small-molecule :name (n3 / name :op1 "LY294002"))))
            :ARG1-of (s / specific-02))
      :ARG2 (i2 / identify-01
            :ARG0 w
            :ARG1 (c / component
                  :ARG0-of (s5 / signal-07
                        :direction (u2 / upstream))
                  :ARG1-of (i3 / involve-01
                        :ARG2 (a3 / activate-01
                              :ARG1 (e4 / enzyme :name (n7 / name :op1 "ERK1/2"))
                              :location (c2 / cell
                                    :mod (d / disease :name (n8 / name :op1 "GHM")))
                              :mod (c3 / constitutive))))))

# ::id pmid_2541_3220.127 ::date 2015-07-01T05:46:10 ::annotator SDL-AMR-09 ::preferred
# ::snt Only the L779450 treatment was able to reduce P-ERK1/2 levels, suggesting involvement of RAF kinases in the control of ERK activation (Figure <xref ref-type="fig" rid="Fig3">3</xref>B and Additional file <xref ref-type="media" rid="MOESM3">3</xref>: Figure S2B; FTS treatment not shown).
# ::save-date Sun Jan 17, 2016 ::file pmid_2541_3220_127.txt
(p2 / possible-01
      :ARG1 (r / reduce-01
            :ARG0 (t / treat-04
                  :ARG2 (s / small-molecule :name (n3 / name :op1 "L779450"))
                  :mod (o / only))
            :ARG1 (l / level
                  :quant-of (e / enzyme :name (n / name :op1 "ERK1/2")
                        :ARG3-of (p / phosphorylate-01)))
            :ARG0-of (s2 / suggest-01
                  :ARG1 (i / involve-01
                        :ARG1 (p4 / protein-family :name (n2 / name :op1 "RAF"))
                        :ARG2 (c / control-01
                              :ARG1 (a / activate-01
                                    :ARG1 (p3 / protein-family :name (n4 / name :op1 "ERK")))))))
      :ARG1-of (d / describe-01
            :ARG0 (a2 / and
                  :op1 (f / figure :mod "3B")
                  :op2 (f2 / file :mod 3
                        :ARG1-of (a4 / add-02)
                        :ARG1-of (m / mean-01
                              :ARG2 (f3 / figure :mod "S2B")))
                  :op3 (t2 / treat-04
                        :ARG2 (s3 / small-molecule :name (n5 / name :op1 "FTS"))
                        :ARG1-of (s4 / show-01 :polarity -)))))

# ::id pmid_2541_3220.128 ::date 2015-07-01T06:05:39 ::annotator SDL-AMR-09 ::preferred
# ::snt The treatment attenuated cell growth in both cell lines (Figure <xref ref-type="fig" rid="Fig3">3</xref>C, D) to the levels comparable to those attained by the U0126 treatment, supporting a role of RAF kinases in GHM cell growth through ERK1/2 activation.
# ::save-date Sun Jan 17, 2016 ::file pmid_2541_3220_128.txt
(a / attenuate-01
      :ARG0 (t / treat-04
            :ARG1-of (d / describe-01
                  :ARG0 (a2 / and
                        :op1 (f / figure :mod "3C")
                        :op2 (f2 / figure :mod "3D")))
            :ARG0-of (s2 / support-01
                  :ARG1 (r / role
                        :poss (p / protein-family :name (n2 / name :op1 "RAF"))
                        :beneficiary (g2 / grow-01
                              :ARG1 (c4 / cell
                                    :mod (d2 / disease :name (n3 / name :op1 "GHM")))))
                  :manner (a4 / activate-01
                        :ARG1 (e / enzyme :name (n4 / name :op1 "ERK1/2")))))
      :ARG1 (g / grow-01
            :ARG1 (c / cell))
      :location (c2 / cell-line
            :mod (b / both))
      :destination (l / level
            :ARG1-of (c3 / comparable-03
                  :ARG2 (l2 / level
                        :ARG1-of (a3 / attain-01
                              :ARG0 (t2 / treat-04
                                    :ARG2 (s / small-molecule :name (n / name :op1 "U0126"))))))))

# ::id pmid_2541_3220.129 ::date 2015-07-01T07:31:32 ::annotator SDL-AMR-09 ::preferred
# ::snt We also examined the contribution of individual RAF isoforms on ERK1/2 activation by RNA silencing (siRNA).
# ::save-date Fri Nov 6, 2015 ::file pmid_2541_3220_129.txt
(e2 / examine-01
      :ARG0 (w / we)
      :ARG1 (c / contribute-01
            :ARG0 (i / isoform
                  :mod (e / enzyme :name (n / name :op1 "RAF"))
                  :mod (i2 / individual))
            :ARG2 (a / activate-01
                  :ARG1 (e3 / enzyme :name (n2 / name :op1 "ERK1/2")))
            :manner (s / silence-01
                  :ARG1 (n4 / nucleic-acid :name (n3 / name :op1 "siRNA"))))
      :mod (a2 / also))

# ::id pmid_2541_3220.130 ::date 2015-07-01T07:46:12 ::annotator SDL-AMR-09 ::preferred
# ::snt While no considerable reduction in ERK1/2 activation was achieved by ARAF depletion, BRAF and CRAF silencing each reduced the level of ERK1/2 phosphorylation (Figure <xref ref-type="fig" rid="Fig4">4</xref>A-E).
# ::save-date Mon Jan 4, 2016 ::file pmid_2541_3220_130.txt
(c / contrast-01
      :ARG1 (a / achieve-01 :polarity -
            :ARG1 (r / reduce-01
                  :ARG1 (a2 / activate-01
                        :ARG1 (e / enzyme :name (n / name :op1 "ERK1/2")))
                  :mod (c2 / considerable))
            :manner (d / deplete-01
                  :ARG1 (e2 / enzyme :name (n2 / name :op1 "ARAF"))))
      :ARG2 (r2 / reduce-01
            :ARG0 (a3 / and
                  :op1 (s / silence-01
                        :ARG1 (e3 / enzyme :name (n3 / name :op1 "BRAF")))
                  :op2 (s2 / silence-01
                        :ARG1 (e4 / enzyme :name (n4 / name :op1 "CRAF"))))
            :ARG1 (l / level
                  :quant-of (p / phosphorylate-01
                        :ARG1 e)))
      :ARG1-of (d2 / describe-01
            :ARG0 (a4 / and
                  :op1 (f / figure :mod "4A")
                  :op2 (f2 / figure :mod "4B")
                  :op3 (f3 / figure :mod "4C")
                  :op4 (f4 / figure :mod "4D")
                  :op5 (f5 / figure :mod "4E"))))

# ::id pmid_2541_3220.131 ::date 2015-07-01T09:23:26 ::annotator SDL-AMR-09 ::preferred
# ::snt Since RAS kinases are known upstream activators of wild-type RAF kinases, the failure of the FTS treatment to affect the P-ERK1/2 levels was somewhat unexpected.
# ::save-date Sat Jan 16, 2016 ::file pmid_2541_3220_131.txt
(c / cause-01
      :ARG0 (m / molecular-physical-entity
            :ARG0-of (a2 / activate-01
                  :ARG1 (p2 / protein-family :name (n4 / name :op1 "RAF")
                        :mod (w / wild-type))
                  :direction (u / upstream))
            :domain (k2 / kinase :name (n3 / name :op1 "RAS"))
            :ARG1-of (k / know-01))
      :ARG1 (e3 / expect-01 :polarity -
            :ARG1 (f / fail-01
                  :ARG1 (t3 / treat-04
                        :ARG2 (s2 / small-molecule :name (n5 / name :op1 "FTS")))
                  :ARG2 (a3 / affect-01
                        :ARG0 t3
                        :ARG1 (l / level
                              :quant-of (e4 / enzyme :name (n6 / name :op1 "ERK1/2")
                                    :ARG3-of (p / phosphorylate-01)))))
            :degree (s / somewhat)))

# ::id pmid_2541_3220.132 ::date 2015-07-01T09:41:37 ::annotator SDL-AMR-09 ::preferred
# ::snt We therefore decided to directly manipulate the levels of RAS kinases by siRNA-based approach to address their potential contribution to the ERK1/2 pathway in GHM cells.
# ::save-date Sat Jan 16, 2016 ::file pmid_2541_3220_132.txt
(c / cause-01
      :ARG1 (d / decide-01
            :ARG0 (w / we)
            :ARG1 (m / manipulate-01
                  :ARG0 w
                  :ARG1 (l / level
                        :quant-of (p3 / protein-family :name (n2 / name :op1 "RAS")))
                  :manner (a / approach-02
                        :ARG1-of (b / base-02
                              :ARG2 (n5 / nucleic-acid :name (n / name :op1 "siRNA"))))
                  :purpose (a2 / address-02
                        :ARG0 w
                        :ARG1 (c2 / contribute-01
                              :ARG0 l
                              :ARG2 (p2 / pathway :name (n3 / name :op1 "ERK1/2")
                                    :location (c3 / cell
                                          :mod (d3 / disease :name (n4 / name :op1 "GHM"))))
                              :mod (p / potential)))
                  :ARG1-of (d2 / direct-02))))

# ::id pmid_2541_3220.133 ::date 2015-07-01T09:55:17 ::annotator SDL-AMR-09 ::preferred
# ::snt The initial experiment with combined depletion of NRAS, HRAS and KRAS indicated their involvement in the signaling (Figure <xref ref-type="fig" rid="Fig5">5</xref>B, C left panels).
# ::save-date Sat Jan 30, 2016 ::file pmid_2541_3220_133.txt
(i / indicate-01
      :ARG0 (e / experiment-01
            :ARG1 (d / deplete-01
                  :ARG1 (a / and
                        :op1 (e2 / enzyme :name (n / name :op1 "NRAS"))
                        :op2 (e3 / enzyme :name (n2 / name :op1 "HRAS"))
                        :op3 (e4 / enzyme :name (n3 / name :op1 "KRAS")))
                  :ARG3-of (c / combine-01))
            :mod (i2 / initial))
      :ARG1 (i3 / involve-01
            :ARG1 a
            :ARG2 (s / signal-07))
      :ARG1-of (d2 / describe-01
            :ARG0 (a2 / and
                  :op1 (f / figure :mod "5B")
                  :op2 (f2 / figure :mod "5C")
                  :location (p / panel
                        :ARG1-of (l / left-20)))))

# ::id pmid_2541_3220.134 ::date 2015-07-01T10:07:58 ::annotator SDL-AMR-09 ::preferred
# ::snt Further investigation of individual contribution of the RAS isoforms indicated KRAS as major RAS activator of the ERK signaling in these cells (Figure <xref ref-type="fig" rid="Fig5">5</xref>B-E).
# ::save-date Mon Jan 4, 2016 ::file pmid_2541_3220_134.txt
(i / indicate-01
      :ARG0 (i2 / investigate-01
            :ARG2 (c / contribute-01
                  :ARG0 (i4 / isoform
                        :mod (e3 / enzyme :name (n3 / name :op1 "RAS")))
                  :mod (i3 / individual))
            :degree (f / further))
      :ARG1 (e4 / enzyme :name (n4 / name :op1 "KRAS")
            :ARG0-of (a2 / activate-01
                  :ARG1 (s / signal-07
                        :ARG0 (p / protein-family :name (n / name :op1 "ERK"))
                        :location (c2 / cell
                              :mod (t / this)))
                  :topic e3
                  :ARG1-of (m / major-02)))
      :ARG1-of (d / describe-01
            :ARG0 (a / and
                  :op1 (f2 / figure :mod "5B")
                  :op2 (f3 / figure :mod "5C")
                  :op3 (f4 / figure :mod "5D")
                  :op4 (f5 / figure :mod "5E"))))

# ::id pmid_2541_3220.135 ::date 2015-07-01T10:38:20 ::annotator SDL-AMR-09 ::preferred
# ::snt <sec-title level="2">ERK pathway is activated already in skin melanocytes of Grey horses</sec-title>
# ::save-date Fri Nov 6, 2015 ::file pmid_2541_3220_135.txt
(a / activate-01
      :ARG1 (p / pathway :name (n2 / name :op1 "ERK"))
      :time (a2 / already)
      :location (m / melanocyte
            :part-of (s / skin)
            :poss (h / horse
                  :ARG1-of (g / gray-02))))

# ::id pmid_2541_3220.136 ::date 2015-07-01T10:41:47 ::annotator SDL-AMR-09 ::preferred
# ::snt The absence of the oncogenic mutations commonly linked to the activation of the ERK pathway in melanomas, the strong association of the <i>Grey</i> mutation with the melanoma predisposition [<xref ref-type="bibr" rid="CR17">17</xref>] and the notion that the <i>Grey</i> mutation has an effect throughout melanocyte development [<xref ref-type="bibr" rid="CR18">18</xref>], prompted us to test if the ERK pathway was already activated at the level of normal skin melanocytes in Grey horses.
# ::save-date Mon Dec 21, 2015 ::file pmid_2541_3220_136.txt
(p / prompt-02
      :ARG0 (a / and
            :op1 (a2 / absent-01
                  :ARG1 (m / mutate-01
                        :ARG0-of (c2 / cause-01
                              :ARG1 (d5 / disease :wiki "Cancer"
                                    :name (n2 / name :op1 "cancer")))
                        :ARG1-of (l / link-01
                              :ARG2 (a3 / activate-01
                                    :ARG1 (p2 / pathway :wiki "MAPK/ERK_pathway"
                                          :name (n3 / name :op1 "ERK"))
                                    :location (m5 / medical-condition :wiki "Melanoma"
                                          :name (n7 / name :op1 "melanoma")))
                              :degree (c6 / common))))
            :op2 (a4 / associate-01
                  :ARG1 (m3 / mutate-01
                        :mod (o / organism
                              :ARG1-of (g / gray-02)))
                  :ARG2 (p3 / predispose-01
                        :ARG2 m5)
                  :ARG1-of (s / strong-02)
                  :ARG1-of (d / describe-01
                        :ARG0 (p4 / publication-91
                              :ARG1-of (c / cite-01 :ARG2 17))))
            :op3 (n / notion
                  :topic (a5 / affect-01
                        :ARG0 m3
                        :time (d2 / develop-02
                              :ARG1 (m2 / melanocyte))
                        :ARG1-of (d4 / describe-01
                              :ARG0 (p6 / publication-91
                                    :ARG1-of (c7 / cite-01 :ARG2 18))))))
      :ARG1 (w / we)
      :ARG2 (t / test-01
            :ARG0 w
            :ARG2 (a6 / activate-01 :mode interrogative
                  :ARG1 p2
                  :time (a7 / already)
                  :location (m4 / melanocyte
                        :part-of (s2 / skin
                              :ARG1-of (n6 / normal-02))
                        :location (h / horse
                              :ARG1-of g)))))

# ::id pmid_2541_3220.137 ::date 2015-07-01T11:17:21 ::annotator SDL-AMR-09 ::preferred
# ::snt We analyzed expression of both phosphorylated and total ERK1/2 in skin samples from Grey (<i>n</i> =9) <i>vs</i>. non-grey horses (<i>n</i> =12) of different breeds from the same and different geographic locations, as was done for the melanoma samples.
# ::save-date Sun Dec 20, 2015 ::file pmid_2541_3220_137.txt
(a / analyze-01
      :ARG0 (w / we)
      :ARG1 (e / express-03
            :ARG1 (a2 / and
                  :op1 (e2 / enzyme :name (n / name :op1 "ERK1/2")
                        :ARG3-of (p / phosphorylate-01))
                  :op2 (e3 / enzyme :name (n2 / name :op1 "ERK1/2")
                        :mod (t / total)))
            :location (s / sample-01
                  :ARG1 (s2 / skin)
                  :ARG2 (a3 / and
                        :op1 (h / horse :quant 9
                              :ARG1-of (g / gray-02))
                        :op2 (h2 / horse :quant 12
                              :ARG1-of (g2 / gray-02 :polarity -))
                        :mod (b / breed
                              :ARG1-of (d / differ-02)
                              :source (a4 / and
                                    :op1 (l / location
                                          :mod (g3 / geographic
                                                :ARG1-of (s3 / same-01)))
                                    :op2 (l2 / location
                                          :mod (g4 / geographic
                                                :ARG1-of d)))))))
      :ARG2-of (r / resemble-01
            :ARG1 (d3 / do-02
                  :ARG2 (s4 / sample-01
                        :ARG1 (m / medical-condition :name (n3 / name :op1 "melanoma"))))))

# ::id pmid_2541_3220.138 ::date 2015-07-01T12:15:52 ::annotator SDL-AMR-09 ::preferred
# ::snt A high percentage of MITF<sup>+</sup> epidermal melanocytes positive for the P-ERK1/2 was detected in all Grey horse skins (75.8% ±10.0) in sharp contrast to non-grey horse skins, where the phosphorylated ERK was absent (Figure <xref ref-type="fig" rid="Fig6">6</xref>A, B).
# ::save-date Sun Jan 17, 2016 ::file pmid_2541_3220_138.txt
(d / detect-01
      :ARG1 (p / percentage
            :ARG1-of (h / high-02)
            :quant-of (m2 / melanocyte
                  :part-of (e / epidermis)
                  :mod (p2 / protein :name (n2 / name :op1 "MITF+"))
                  :mod (p3 / positive
                        :mod (e2 / enzyme :name (n3 / name :op1 "ERK1/2")
                              :ARG3-of (p4 / phosphorylate-01))))
            :ARG1-of (m / mean-01
                  :quant (p5 / percentage-entity :value 75.8
                        :ARG2-of (a2 / add-02
                              :ARG1 (p6 / percentage-entity :value 10.0))
                        :ARG2-of (s2 / subtract-01
                              :ARG1 (p7 / percentage-entity :value 10.0)))))
      :location (s / skin
            :part-of (h2 / horse
                  :ARG1-of (g / gray-02))
            :mod (a / all))
      :ARG1-of (c2 / contrast-01
            :ARG2 (s4 / skin
                  :part-of (h3 / horse
                        :ARG1-of (g2 / gray-02 :polarity -))
                  :location-of (e3 / enzyme :name (n4 / name :op1 "ERK")
                        :ARG1-of (a3 / absent-01)
                        :ARG3-of p4))
            :ARG1-of (s3 / sharp-02))
      :ARG1-of (d2 / describe-01
            :ARG0 (a4 / and
                  :op1 (f / figure :mod "6A")
                  :op2 (f2 / figure :mod "6B"))))

# ::id pmid_2541_3220.139 ::date 2015-07-01T13:32:37 ::annotator SDL-AMR-09 ::preferred
# ::snt The activated ERK1/2 was detected both in the cytoplasm and the nucleus in Grey melanocytes.
# ::save-date Fri Nov 6, 2015 ::file pmid_2541_3220_139.txt
(d / detect-01
      :ARG1 (e / enzyme :name (n / name :op1 "ERK1/2")
            :ARG1-of (a / activate-01))
      :location (a2 / and
            :op1 (c / cytoplasm)
            :op2 (n2 / nucleus)
            :part-of (m / melanocyte
                  :mod (o / organism
                        :ARG1-of (g / gray-02)))))

# ::id pmid_2541_3220.140 ::date 2015-07-01T13:35:33 ::annotator SDL-AMR-09 ::preferred
# ::snt Percentage of the total ERK1/2 positive cells was 99.5% ±0.5 in Grey and 77.1% ±11.3 in non-grey skins (Figure <xref ref-type="fig" rid="Fig6">6</xref>A, B).
# ::save-date Fri Nov 6, 2015 ::file pmid_2541_3220_140.txt
(a / and
      :op1 (p3 / percentage-entity :value 99.5
            :ARG2-of (a2 / add-02
                  :ARG1 (p4 / percentage-entity :value 0.5))
            :ARG2-of (s / subtract-01
                  :ARG1 (p5 / percentage-entity :value 0.5))
            :location (s2 / skin
                  :ARG1-of (g / gray-02)))
      :op2 (p6 / percentage-entity :value 77.1
            :ARG2-of (a3 / add-02
                  :ARG1 (p7 / percentage-entity :value 11.3))
            :ARG2-of (s3 / subtract-01
                  :ARG1 (p8 / percentage-entity :value 11.3))
            :location (s4 / skin
                  :ARG1-of (g2 / gray-02 :polarity -)))
      :domain (p9 / percentage
            :quant-of (c / cell
                  :mod (p10 / positive
                        :mod (e / enzyme :name (n / name :op1 "ERK1/2")
                              :mod (t / total)))))
      :ARG1-of (d / describe-01
            :ARG0 (a4 / and
                  :op1 (f / figure :mod "6A")
                  :op2 (f2 / figure :mod "6B"))))

# ::id pmid_2541_3220.141 ::date 2015-07-01T14:01:03 ::annotator SDL-AMR-09 ::preferred
# ::snt Interestingly, keratinocytes from Grey but not non-grey horses were also positive for P-ERK1/2 (Figure <xref ref-type="fig" rid="Fig6">6</xref>A).
# ::save-date Fri Nov 6, 2015 ::file pmid_2541_3220_141.txt
(c / contrast-01
      :ARG1 (p / positive
            :mod (e / enzyme :name (n / name :op1 "ERK1/2")
                  :ARG3-of (p2 / phosphorylate-01))
            :domain (k2 / keratinocyte
                  :source (h / horse
                        :ARG1-of (g / gray-02)))
            :mod (a / also))
      :ARG2 (p3 / positive :polarity -
            :mod e
            :domain (k / keratinocyte
                  :source (h2 / horse
                        :ARG1-of (g2 / gray-02 :polarity -))))
      :ARG1-of (d / describe-01
            :ARG0 (f / figure :mod "6A"))
      :ARG0-of (i / interest-01))

# ::id pmid_2541_3220.142 ::date 2015-07-01T23:34:49 ::annotator SDL-AMR-09 ::preferred
# ::snt The staining pattern of both P-ERK1/2 and ERK1/2 was highly reproducible in samples coming from different studs and prepared in different laboratories.
# ::save-date Sun Dec 20, 2015 ::file pmid_2541_3220_142.txt
(r / reproduce-01
      :ARG1 (p2 / pattern
            :topic (s / stain-01
                  :ARG1 (a / and
                        :op1 (e / enzyme :name (n / name :op1 "ERK1/2")
                              :ARG3-of (p3 / phosphorylate-01))
                        :op2 (e2 / enzyme :name (n2 / name :op1 "ERK1/2")))))
      :ARG1-of (p / possible-01)
      :ARG1-of (h / high-02)
      :location (t / thing
            :ARG1-of (p4 / prepare-01
                  :location (l / laboratory
                        :ARG1-of d))
            :ARG1-of (s2 / sample-01
                  :ARG2 (s3 / stud
                        :ARG1-of (d / differ-02)))))