# AMR (Abstract Meaning Representation) release v3.0 # Bio AMR corpus (6952 sentences) # generated on Thu Jan 25, 2018 at 16:17:06 # ::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 KRAS and BRAF. # ::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 serpinE2 mRNA levels, indicating that expression of serpinE2 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 11, 2018 ::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 / adenoma :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) :ARG1-of (c2 / compare-01 :ARG2 (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 Wed Jan 3, 2018 ::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 :ARG2-of (h2 / have-degree-91 :ARG1 n5 :ARG3 (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 [3]. # ::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 Serpin clade E member 2 (serpinE2 or PN-1) 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, serpinE2 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 Mon Oct 23, 2017 ::file a_pmid_2094_2929_44.txt (i / induce-01 :ARG2 (e / express-03 :ARG1 (g / gene :name (n / name :op1 "serpinE2"))) :ARG3 (t / times :quant (m2 / more-than :op1 28)) :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)))) :ARG1-of (d / describe-01 :ARG0 (d2 / data :ARG1-of (s2 / show-01 :polarity -))) :ARG1-of (s3 / statistical-test-91 :ARG2 (l / less-than :op1 0.05)) :ARG1-of (c3 / compare-01 :ARG2 (c2 / cell :ARG3-of (e3 / express-03 :ARG2 (e4 / enzyme :name (n3 / name :op1 "MEK") :mod (w / wild-type)))))) # ::id a_pmid_2094_2929.45 ::date 2015-05-20T13:46:38 ::annotator SDL-AMR-09 ::preferred # ::snt Overexpression of serpinE2 in caMEK-expressing IECs was furthermore confirmed following RT-PCR analysis as shown in Figure 1A. # ::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 1B and 1C). # ::save-date Mon Dec 25, 2017 ::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 (t5 / times :quant 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 (t4 / times :quant 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 1C). # ::save-date Thu Oct 12, 2017 ::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") :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"))) :ARG3-of (f3 / fuse-01)))))) :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 1A) and BRAF (Figure 1C), 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 [22,33], 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 1D). # ::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 1D). # ::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 1E, 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 1E, lane 4), while it was not detectable in the surrounding monolayer (Figure 1E, 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 Tue Oct 17, 2017 ::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 (h / have-degree-91 :ARG2 (s / strong-02 :ARG1 e) :ARG3 (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 [14] 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-serpinE2 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 2A, 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 2B). # ::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 [14]. # ::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, serpinE2 silencing markedly reduced the size of foci (Figure 2C) 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 2D). # ::save-date Tue Oct 17, 2017 ::file a_pmid_2094_2929_68.txt (r / reveal-01 :ARG0 (t / thing :name (n / name :op1 "phase-contrast" :op2 "microscopy")) :ARG1 (h / have-degree-91 :ARG1 (c / colony) :ARG2 (s / small :time (d / downregulate-01 :ARG1 (p / protein :name (n2 / name :op1 "serpinE2")))) :ARG3 (m / more)) :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 2E). # ::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)) :ARG1-of (i / important-01) :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 [14]. # ::save-date Tue Oct 17, 2017 ::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) :ARG1-of (c7 / compare-01 :ARG2 (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 in vitro 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 2F), two extracellular matrix proteins which can interact with serpinE2 [34,35]. # ::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 KRAS (HCT-116, DLD-1, LoVo, SW480, T84) or BRAF (Colo-205, HT-29) [36]. # ::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 3A, serpinE2 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 / barely) :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 KRAS gene resulting in elevated MEK/ERK activities [37], 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) [14]. # ::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 3B, treatment of these CRC cell lines with U0126 markedly and significantly reduced serpinE2 mRNA levels, indicating that expression of serpinE2 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 serpinE2 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 4A, serpinE2 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 serpinE2 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 4B). # ::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 serpinE2 expression alters the ability of colon cancer cells to form colonies in soft agarose. # ::save-date Fri Sep 15, 2017 ::file a_pmid_2094_2929_86.txt (v / verify-01 :ARG0 (w / we) :ARG1 (t2 / truth-value :polarity-of (a / alter-01 :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 4C, 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 serpinE2 gene expression (Figure 4A) was also less efficient to reduce colony formation. # ::save-date Tue Oct 17, 2017 ::file a_pmid_2094_2929_88.txt (e / efficient-01 :ARG1 (p / protein :name (n / name :op1 "shSerpinE2") :ARG1-of (l2 / label-01 :ARG2 15) :ARG1-of (n4 / note-02) :ARG1-of (h / have-degree-91 :ARG2 (e2 / efficient-01 :ARG2 (r4 / reduce-01 :ARG0 p :ARG1 (e3 / express-03 :ARG1 (g / gene :name (n3 / name :op1 "serpinE2")))) :ARG1-of (d / describe-01 :ARG0 (f2 / figure :mod "4A"))) :ARG3 (l / less) :ARG4 (n6 / nucleic-acid :name (n2 / name :op1 "shRNA") :ARG1-of (l3 / label-01 :ARG2 16)))) :ARG2 (r / reduce-01 :ARG0 p :ARG1 (f / form-01 :ARG1 (c / colony))) :mod (a / also) :ARG2-of (h2 / have-degree-91 :ARG1 p :ARG3 (l4 / less))) # ::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 4D). # ::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 5A and 5B, HCT116 and LoVo cell lines induced palpable tumors with a short latency period of respectively 15 and 10 days after their injection. # ::save-date Fri Dec 8, 2017 ::file a_pmid_2094_2929_92.txt (a5 / and :op1 (i4 / induce-01 :ARG0 (c / cell-line :name (n / name :op1 "HCT116")) :ARG2 (t / tumor :mod (p3 / palpable) :mod (p4 / period :mod (l2 / latency) :ARG1-of (s3 / short-07) :time (a / after :op1 (i5 / inject-01 :ARG1 c) :quant (t3 / temporal-quantity :quant 15 :unit (d2 / day)))))) :op2 (i3 / induce-01 :ARG0 (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 c2) :quant (t4 / temporal-quantity :quant 10 :unit (d / day)))))) :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 Thu Oct 19, 2017 ::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) :ARG1-of (h / have-degree-91 :ARG2 (i2 / important-01 :ARG1 i) :ARG3 (m2 / more))) # ::id a_pmid_2094_2929.94 ::date 2015-05-21T01:10:20 ::annotator SDL-AMR-09 ::preferred # ::snt Finally, in vitro 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-01 :ARG1 (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 6A, 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 6B, 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 6C), suggesting that serpinE2 expression decreases adhesion of colorectal carcinoma cells to the substrate. # ::save-date Mon Oct 2, 2017 ::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-01)) :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 SerpinE2 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 serpinE2 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 7, mRNA levels of serpinE2 were markedly increased in human adenomas in comparison to healthy adjacent tissues. # ::save-date Tue Oct 17, 2017 ::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)) :location (m2 / medical-condition :name (n3 / name :op1 "adenoma") :mod (h / human)) :ARG1-of (c / compare-01 :ARG2 (l2 / level :location (t / tissue :mod (h2 / healthy) :mod (a2 / adjacent)) :quant-of n4))) # ::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 Tue Oct 17, 2017 ::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")))) :ARG1-of (s / significant-02) :ARG2-of (h2 / have-degree-91 :ARG1 l :ARG3 (m / more) :ARG4 (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 K-RASwt 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 K-RASmt 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 K-RASwt cells following the overexpression of mutated K-RAS, 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 K-RAS 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 K-RASmt cells K-RAS 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 1A and 1B). # ::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 1C, the ratio of P-YB-1/YB-1 is significantly higher in tumor cells than in fibroblasts. # ::save-date Tue Oct 17, 2017 ::file a_pmid_2139_2397_117.txt (h3 / have-degree-91 :ARG1 (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 (c / cell :mod (t / tumor))) :ARG2 (h2 / high-02 :ARG1 r) :ARG3 (m / more) :ARG4 (f2 / fibroblast) :ARG1-of (s / show-01 :ARG0 (f / figure :mod "1C")) :ARG1-of (s2 / significant-02)) # ::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 1B and 1C). # ::save-date Tue Oct 17, 2017 ::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 :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 (h / have-degree-91 :ARG2 (s / strong-02 :ARG1 d :mod (e2 / even)) :ARG3 (m2 / more))) :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 [12,35]. # ::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 [30,36]. # ::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 Fri Sep 15, 2017 ::file a_pmid_2139_2397_121.txt (c / cause-01 :ARG1 (a / ask-01 :ARG0 (w / we) :ARG1 (t / truth-value :polarity-of (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 1D, 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 1D). # ::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 K-RASwt 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 Fri Dec 15, 2017 ::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 (t / truth-value :polarity-of (c / cause-01 :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 1F, 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 K-RASmt MDA-MB-231 cells (Figure 1F). # ::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 K-RAS gene [37]. # ::save-date Mon Nov 20, 2017 ::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 [30]. # ::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 1D and 1E). # ::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 K-RAS [37]. # ::save-date Fri Sep 15, 2017 ::file a_pmid_2139_2397_134.txt (c / cause-01 :ARG1 (i / investigate-01 :ARG0 (w / we) :ARG1 (t / truth-value :polarity-of (c2 / cause-01 :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 2A, K-RAS siRNA led to a strong reduction in P-ERK1/2 and P-YB-1 (Figure 2A). # ::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 2B, 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 1D, 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 Thu Nov 2, 2017 ::file a_pmid_2139_2397_143.txt (i / indicate-01 :ARG0 (t / thing :ARG2-of (r / result-01) :mod (t2 / this)) :ARG1 (c / consequence-03 :ARG1 (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)))) :ARG2 (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"))))) # ::id a_pmid_2139_2397.144 ::date 2015-05-27T13:33:31 ::annotator SDL-AMR-09 ::preferred # ::snt Overexpression of mutated K-RASV12 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 K-RAS 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 K-RAS gene revealed that none of these cell lines presents a K-RAS point mutation in codon 12, codon 13 or 61. # ::save-date Mon Nov 20, 2017 ::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 K-RASV12 could upregulate YB-1 phosphorylation, we introduced mutated K-RAS into K-RASwt, SKBr3 and MCF-7 cells. # ::save-date Fri Sep 15, 2017 ::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 (t / truth-value :polarity-of (p3 / possible-01 :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 K-RAS, pEGFP-C1/K-RASV12 (indicated as K-RASV12). # ::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 K-RASV12 revealed that GFP in K-RASV12 vector-transfected cells was localized to the plasma membrane, but that in con.-vector-transfected cells it was not (Figure 3A). # ::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 3A). # ::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 3B). # ::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 K-RASV12 vector, the expression of K-Ras (21 kDa) resulted in a shift of GFP from 27 kDa to 48 kDa (Figure 3B). # ::save-date Wed Sep 21, 2016 ::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 (k3 / kilodalton)) :ARG3 (m3 / mass-quantity :quant 27 :unit (k2 / kilodalton))) :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 K-RASV12 in K-RASwt, SKBr3 and MCF-7 cells resulted in markedly enhanced basal phosphorylation of YB-1 at S102 (Figure 3B), which prevents further enhancement of phosphorylation by IR (Figure 3C). # ::save-date Wed Aug 9, 2017 ::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 (i2 / in-line-04 :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 K-RAS, 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 [11]. # ::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 [11], Stratford et al. 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 [11]. # ::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 [24,25], we tested whether the IR-induced YB-1 phosphorylation shown in Figure 1D could be blocked by erbB1 tyrosine kinase inhibitors. # ::save-date Wed Jan 24, 2018 ::file a_pmid_2139_2397_161.txt (t2 / test-01 :ARG0 (w / we) :ARG1 (t / truth-value :polarity-of (p2 / possible-01 :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 w :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 4A) as well as in cytoplasmic and nuclear fractions (Figure 4B). # ::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 4A). # ::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 [38] 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 4B, 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 Oct 22, 2017 ::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) :ARG2-of (h / have-degree-91 :ARG1 c :ARG3 (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 Fri Sep 15, 2017 ::file a_pmid_2139_2397_169.txt (i2 / investigate-01 :ARG0 (w / we) :ARG1 (t2 / truth-value :polarity-of (a / affect-01 :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 4C and 4D 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 K-RAS 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 K-RASmt-dependent constitutive phosphorylation of YB-1 might be sensitive to the inhibition of erbB1, PI3K and MEK. # ::save-date Fri Sep 15, 2017 ::file a_pmid_2139_2397_173.txt (i / investigate-01 :ARG0 (w / we) :ARG1 (t / truth-value :polarity-of (p3 / possible-01 :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, K-RASwt MCF-7 cells were transiently transfected with con.-vector or K-RASV12 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 Wed Sep 21, 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 (h2 / hour))) :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 3, overexpression of K-RASV12 resulted in an about 2.5-fold stimulation of YB-1 phosphorylation. # ::save-date Tue Jan 16, 2018 ::file a_pmid_2139_2397_175.txt (i2 / increase-01 :ARG0 (o / overexpress-01 :ARG1 (g / gene :name (n2 / name :op1 "K-RAS") :ARG2-of (m / mutate-01 :value "V12"))) :ARG1 (s / stimulate-01 :ARG1 (p / phosphorylate-01 :ARG1 (p2 / protein :name (n / name :op1 "YB-1")))) :ARG2 (t2 / times :quant (a / about :op1 2.5)) :ARG1-of (r / resemble-01 :ARG2 (t / thing :ARG2-of (r2 / 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 K-RAS V12-induced YB-1 phosphorylation by about 50%, while the PI3K inhibitor and the MEK inhibitor reduced K-RASV12-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 K-RAS V12-induced YB-1 phosphorylation completely (Figure 5A). # ::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 K-RAS 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 Sun Oct 22, 2017 ::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)) :ARG2-of (h / have-degree-91 :ARG1 m2 :ARG3 (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 3 and 5A), we next analyzed whether phosphorylation of YB-1 in K-RASwt cells after irradiation or stimulation with EGF depends on K-Ras expression. # ::save-date Fri Sep 15, 2017 ::file a_pmid_2139_2397_180.txt (a / analyze-01 :ARG0 (w / we) :ARG1 (t / truth-value :polarity-of (d / depend-01 :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 5B, 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 K-RAS-siRNA on P-ERK1/2 was observed as well (Figure 5B). # ::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 [39]. # ::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 [40]. # ::save-date Wed Aug 9, 2017 ::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 (i2 / in-line-04 :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 K-RAS on repair of DNA-DSB have been demonstrated previously [15,34,41,42]. # ::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 Wed Sep 20, 2017 ::file a_pmid_2139_2397_189.txt (c2 / cause-01 :ARG1 (a / ask-01 :ARG0 (w / we) :ARG1 (t / truth-value :polarity-of (e / exert-01 :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) :mod (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, D37, 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 Wed Sep 21, 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 :location (c2 / cell-line :name (n2 / name :op1 "MDA-MB-23")) :unit (g2 / gray)) :op3 (r3 / radiation-quantity :quant 1.35 :location (c3 / cell-line :name (n3 / name :op1 "MCF-7")) :unit (g3 / gray)) :op4 (r4 / radiation-quantity :quant 1.10 :location (c4 / cell-line :name (n4 / name :op1 "HBL100")) :unit (g4 / gray)))) # ::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 Fri Sep 15, 2017 ::file a_pmid_2139_2397_192.txt (i / investigate-01 :ARG0 (w / we) :ARG1 (t / truth-value :polarity-of (i2 / involve-01 :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 6, downregulation of YB-1 by siRNA, either in K-RASmt MDA-MB-231 or in K-RASwt 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 Oct 23, 2017 ::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") :ARG1-of (h / have-quant-91 :ARG3 (t3 / times :quant 3.5) :ARG4 (l2 / littermate :mod (n2 / naive))))) :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 (p6 / protein :name (n6 / name :op1 "IGF-1") :ARG1-of (h2 / have-quant-91 :ARG3 (m9 / more) :ARG4 (m6 / medium :ARG1-of (c4 / condition-01 :ARG0 (m7 / macrophage :mod (n3 / naive)))))))) :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 [6,7,13]. # ::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 Kras mutations [18]. # ::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 1A-C), and colonization on new ultra-low adherence, neutrally-charged plastic (Figure 1D-F), macrophage-conditioned media potently stimulated the proliferation of two Kras 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 in vitro, which may shed light on the role of macrophage recruitment to lung cancer in vivo. # ::save-date Mon Aug 21, 2017 ::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 (p2 / possible-01))) :ARG0-of (s4 / shed-light-10 :ARG1 (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 / possible-01)))) # ::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 Thu Jan 4, 2018 ::file a_pmid_2169_9731_66.txt (s / stimulate-01 :ARG0 (a / and :op1 (c / coculture-01 :ARG1 (m / macrophage) :mod (n / naive) :mod (p / primary)) :op2 (c2 / coculture-01 :ARG1 (m2 / macrophage :ARG1-of (e / educate-01 :ARG0 (t / tumor))) :mod p)) :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 Oct 18, 2017 ::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)) :ARG1-of (r2 / relative-05 :ARG3 (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 2A). # ::save-date Thu Jan 4, 2018 ::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 / coculture-01))) :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 per se, 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 2A). # ::save-date Thu Jan 4, 2018 ::file a_pmid_2169_9731_70.txt (a / and :op1 (i / increase-01 :ARG0 (c / coculture-01 :ARG1 (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 (t / times :quant 2.3) :ARG4 (t4 / times :quant 4.1) :time (a2 / after :quant (t2 / temporal-quantity :quant 48 :unit (h / hour)))) :op2 (i2 / increase-01 :ARG0 c :ARG1 n2 :ARG2 s :ARG3 (t5 / times :quant 3.5) :ARG4 (t6 / times :quant 7.5) :time (a3 / after :quant (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 Wed Jan 10, 2018 ::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 / coculture-01 :ARG1 (m / macrophage) :duration (t2 / temporal-quantity :quant 72 :unit (h / hour))) :ARG2 (c3 / cell :mod (t3 / tumor) :mod (m2 / more :quant (b / between :op1 (t6 / times :quant 2) :op2 (t5 / times :quant (m3 / more-than :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 2B) and JF32 (Figure 2C) cells. # ::save-date Sat Nov 18, 2017 ::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 (t2 / truth-value :polarity-of (s / stimulate-01 :ARG0 (m4 / macrophage :ARG1-of (e / educate-01 :ARG0 t)) :ARG1 (g / grow-01 :ARG1 t) :ARG1-of (h / have-degree-91 :ARG2 (e2 / effective-04 :ARG0 s) :ARG3 (m5 / more) :ARG4 (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 2C). # ::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 Sun Nov 19, 2017 ::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 (t2 / truth-value :polarity-of (s / stimulate-01 :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 2D) when maintained in serum-free conditions; only tumor-educated macrophages stimulated E10 proliferation when cultured in the presence of serum (Figure 2E). # ::save-date Mon Oct 23, 2017 ::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 (t3 / times :quant 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 Thu Jan 4, 2018 ::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 / coculture-01 :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 in vitro 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 2B-E). # ::save-date Thu Jan 4, 2018 ::file a_pmid_2169_9731_78.txt (i / increase-01 :ARG0 (c / coculture-01 :ARG1 (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 in vitro. # ::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 in vivo 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 [22,23], and the tumorigenic lines examined herein contain Kras 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 [32,33]. # ::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 3A-C). # ::save-date Wed Oct 18, 2017 ::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 (h2 / have-degree-91 :ARG1 (l / level :quant-of (e2 / enzyme :name (n4 / name :op1 "C-Raf") :ARG3-of (p2 / phosphorylate-01))) :ARG2 (h / high-02) :ARG3 (m2 / more :ARG1-of (s2 / significant-02))) :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 3A). # ::save-date Wed Oct 18, 2017 ::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)))) :ARG1-of (h3 / have-degree-91 :ARG2 (s / small) :ARG3 (m3 / more))) :ARG1-of (h4 / have-degree-91 :ARG2 (h / high-02 :ARG1 a2) :ARG3 (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 :ARG1-of (e3 / equal-01 :ARG2 (a5 / approximately :op1 (m6 / mass-quantity :quant 100 :unit (k2 / kilodalton)))) :ARG1-of (h5 / have-degree-91 :ARG2 (l / large) :ARG3 (m5 / more))) :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 Wed Oct 18, 2017 ::file a_pmid_2169_9731_87.txt (h / have-degree-91 :ARG1 (i2 / immunoblot-01 :ARG1 (e / enzyme :name (n2 / name :op1 "C-Raf")) :ARG2 (c / cell-line :quant 3 :mod (a2 / all)) :mod (t / total)) :ARG2 (a / abundant :domain (i / isoform :quant (m2 / mass-quantity :quant 74 :unit (k / kilodalton)))) :ARG3 (m / most)) # ::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 3A, D and 3E), which correlates with the observed increases in proliferation (Figure 2). # ::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 [21]. # ::save-date Wed Oct 18, 2017 ::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 (h / have-degree-91 :ARG2 (l / low-04) :ARG3 (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 3A, D and 3E). # ::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 3A and 3F). # ::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 3F). # ::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 3A). # ::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 3A and 3G). # ::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 [32]. # ::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 3A and 3H); 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 3A-C). # ::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 [34]. # ::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 [21,35], and were activated with macrophage co-culture. # ::save-date Wed Oct 18, 2017 ::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 (h / have-degree-91 :ARG1 a4 :ARG2 (a2 / activity-06 :ARG0 a4 :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))) :ARG3 (m / more) :ARG4 (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 Kras-driven lung tumor growth in vivo [25], we determined whether selective inhibition of MEK and PI3K affected macrophage-stimulated proliferation in these Kras mutant lung tumor cell lines. # ::save-date Fri Sep 15, 2017 ::file a_pmid_2169_9731_102.txt (d / determine-01 :ARG0 (w / we) :ARG1 (t3 / truth-value :polarity-of (a / affect-01 :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 4A and 4B, respectively). # ::save-date Fri Dec 8, 2017 ::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 (a4 / and :op1 (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 (c2 / cell-line :name (n5 / name :op1 "LM2")) :ARG1-of (d3 / describe-01 :ARG0 (f / figure :mod "4A"))) :op2 (b3 / block-01 :ARG0 o2 :ARG1 g :location (c3 / cell-line :name (n6 / name :op1 "JF32")) :ARG1-of (d4 / describe-01 :ARG0 (f2 / figure :mod "4B"))))) # ::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 4). # ::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 [34,36,37], 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 [4,18], 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 5 "Total" vs. Figure 2B). # ::save-date Wed Oct 18, 2017 ::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 :ARG1-of (d2 / describe-01 :ARG0 (f2 / figure :mod "2B")) :ARG2-of (h / have-degree-91 :ARG1 p2 :ARG3 (l / less) :ARG4 (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 5). # ::save-date Tue Jan 9, 2018 ::file a_pmid_2169_9731_110.txt (s / stimulate-01 :ARG0 (m2 / molecule :mod (b2 / between :op1 (m3 / mass-quantity :quant 3 :unit (k / kilodalton)) :op2 (m6 / mass-quantity :quant 10 :unit (k2 / kilodalton)))) :ARG1 (g2 / grow-01 :ARG1 (c / cell-line :name (n / name :op1 "LM2"))) :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)) :ARG1-of (h / have-degree-91 :ARG2 (g / great) :ARG3 (m / most))) # ::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 [11,18]. # ::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 in silico 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 y = y0 + a(1-e-bx) as described, with regression r2 = 0.997, 0.842 and 0.918 for the > 3, > 10 and > 30 kDa fractions, respectively. # ::save-date Mon Nov 20, 2017 ::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 Tue Jan 9, 2018 ::file a_pmid_2169_9731_115.txt (a / appear-02 :ARG1 (w / weigh-01 :ARG1 (f / factor :ARG0-of (r / responsible-01)) :ARG3 (s / size :mod (b2 / between :op1 (m / mass-quantity :quant 7.23 :unit (k / kilodalton)) :op2 (m5 / mass-quantity :quant 10.8 :unit (k3 / kilodalton)))) :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 in vivo, as well as stimulating growth in vitro [27], and alveolar macrophages produce high levels of IGF-1 in response to quartz dust-induced lung injury [30]. # ::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 :ARG1-of (i3 / important-01) :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 6A). # ::save-date Mon Oct 23, 2017 ::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") :ARG1-of (h / have-quant-91 :ARG3 (t2 / times :quant 3.5) :ARG4 (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, P < 0.01, mean ± SD), suggesting that more IGF-1 is produced in the lungs of tumor-bearing mice. # ::save-date Tue Dec 19, 2017 ::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)))))) :ARG2 (d2 / distribution-range-91 :ARG1 (m4 / mass-quantity :quant 1.81 :unit (p5 / picogram)) :ARG4 (m / mass-quantity :quant 0.33 :unit (p7 / picogram)) :ARG6 (s4 / standard-error-of-the-mean)) :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)))) :ARG1-of (s / significant-02) :concession (n4 / normalize-01 :ARG1 p :prep-to (l / level :quant-of (p2 / protein :mod f) :mod (t2 / total))) :ARG2-of (h3 / have-degree-91 :ARG1 l3 :ARG3 (m5 / more) :ARG4 (l4 / level :quant-of (p4 / protein :name (n5 / name :op1 "IGF-1") :source (c / control :mod (n3 / naive))) :ARG1-of (h2 / high-02 :ARG2 (d / distribution-range-91 :ARG1 (m7 / mass-quantity :quant 0.95 :unit (p6 / picogram)) :ARG4 (m6 / mass-quantity :quant 0.36 :unit (p8 / picogram)) :ARG6 (s3 / standard-error-of-the-mean)))))) # ::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 6B, grey bars). # ::save-date Mon Dec 25, 2017 ::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 :ARG1-of (h / have-quant-91 :ARG3 (m6 / more :ARG1-of (s2 / significant-02)) :ARG4 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 [38]. # ::save-date Wed Oct 18, 2017 ::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 (h / have-degree-91 :ARG1 p2 :ARG2 (a4 / abundant :location (l / lung :ARG0-of (b / bear-01 :ARG1 (t / tumor)))) :ARG3 (m2 / more) :ARG4 (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 [6] and increased macrophage IGF-1 production [39]. # ::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 6B, green bars). # ::save-date Sun Dec 24, 2017 ::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 (h / have-quant-91 :ARG1 (p2 / protein :name (n2 / name :op1 "IGF-1")) :ARG3 (m4 / more) :ARG1-of (s / significant-02)) :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-of (c / compare-01 :ARG2 (t4 / thing :mod (n5 / naive) :ARG1-of (s2 / sample-01)))) :ARG1 (o / output :mod (p4 / protein :name (n4 / name :op1 "IGF-1"))) :mod (m7 / more-than)) :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 6E). # ::save-date Mon Oct 23, 2017 ::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") :ARG1-of (h / have-quant-91 :ARG3 (t4 / times :quant 20) :ARG4 (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 6B correlated with their IGF-1 content, MØCM was added to neoplastic LM2 cells. # ::save-date Fri Sep 15, 2017 ::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 (t3 / truth-value :polarity-of (c2 / correlate-01 :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 6C, green bars), with IL-4 treated tumor-educated MØCM being the most potent. # ::save-date Wed Oct 18, 2017 ::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 (h / have-degree-91 :ARG1 m2 :ARG2 (p3 / potent) :ARG3 (m3 / most))) # ::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 6C, grey bars), corresponding to previous co-culture results (Figure 2B). # ::save-date Wed Oct 18, 2017 ::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"))) :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"))))) :ARG2-of (h / have-degree-91 :ARG1 m :ARG3 (m3 / more :quant (s2 / significant)) :ARG4 (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 6D). # ::save-date Mon Nov 27, 2017 ::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)))) :quant (t / times)) :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 7A-D). # ::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 7A-D). # ::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 [27]. # ::save-date Mon Oct 23, 2017 ::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 :ARG2-of (h2 / have-degree-91 :ARG1 i :ARG3 (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 EC50 for growth stimulation and 20-times higher than levels found in the BALF from tumor-bearing animals (Figure 6A). # ::save-date Tue Jan 2, 2018 ::file a_pmid_2169_9731_138.txt (a / and :op1 (h4 / have-quant-91 :ARG1 (t / this) :ARG3 (t4 / times :quant (r4 / roughly :op1 500)) :ARG4 (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 (h5 / have-quant-91 :ARG1 t :ARG3 (t2 / times :quant 20) :ARG4 (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 7E, F). # ::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 KRAS mutations [40]. # ::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 Sep 15, 2017 ::file a_pmid_2169_9731_141.txt (d / determine-01 :ARG0 (w / we) :ARG1 (t / truth-value :polarity-of (a / add-02 :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 7A-D); 2 ng/mL IGF is the reported EC50 for IGF-1 stimulated proliferation in vitro as well as the concentration detected in the BALF of tumor-bearing mice in vivo (Figure 6A). # ::save-date Wed Sep 21, 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 (n3 / nanogram-per-milliliter)) :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 Thu Sep 14, 2017 ::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 :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))))) :polarity (a3 / amr-unknown)))) # ::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 7G, H). # ::save-date Wed Sep 21, 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 (h2 / hour))))) :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 (r2 = 0.7912 and 0.8201 for LM2 and JF32, respectively, p < 0.0001, data not shown). # ::save-date Tue Jan 2, 2018 ::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 :op1 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+ LM2 cells 12-24 hrs after treatment, corresponding with significantly increased cell numbers (data not shown). # ::save-date Wed Jan 10, 2018 ::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 (b / between :op1 (t2 / temporal-quantity :quant 12 :unit (h / hour)) :op2 (t3 / temporal-quantity :quant 24 :unit (h2 / 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 in vitro, consistent with the elevated IGF-1 levels observed in lung-tumor bearing animals in vivo. # ::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 Wed Jan 24, 2018 ::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 w :ARG1 (t / truth-value :polarity-of (r2 / responsible-01 :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 [39]. # ::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 8A). # ::save-date Sat Jan 6, 2018 ::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 (b / between :op1 (p4 / percentage-entity :value 40) :op2 (p / percentage-entity :value 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 8B). # ::save-date Wed Oct 18, 2017 ::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")))) :ARG1-of (d3 / describe-01 :ARG0 (f / figure :mod "8B")) :ARG1-of (c5 / compare-01 :ARG2 (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))))) # ::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 8C). # ::save-date Wed Oct 18, 2017 ::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")))) :ARG2-of (h / have-degree-91 :ARG1 c :ARG3 (m / more) :ARG4 (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 8C). # ::save-date Thu Oct 12, 2017 ::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"))) :ARG1-of (h / have-quant-91 :ARG3 (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 8D). # ::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 8D-F). # ::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 9A, B). # ::save-date Thu Jan 4, 2018 ::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"))) :mod (a2 / analogous :topic (t / thing :ARG2-of (r2 / result-01 :ARG1 (c3 / coculture-01 :ARG1 (m2 / macrophage)) :mod (p4 / previous)))) :ARG1-of (h / have-degree-91 :ARG2 (g / great) :ARG3 (m / more) :ARG4 (b2 / block-01 :ARG1 (g3 / grow-01 :ARG1-of (s2 / stimulate-01 :ARG0 (o2 / or :op1 p :op2 m3)))))) # ::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 [41]) was reduced by these inhibitors (Figure 9C-E). # ::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 9C, D). # ::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 9H and 9I). # ::save-date Wed Oct 18, 2017 ::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)))) :ARG2-of (h / have-degree-91 :ARG1 s :ARG3 (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 9F, H and 9I). # ::save-date Wed Sep 21, 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 (h5 / hour)))) :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 Mon Dec 25, 2017 ::file a_pmid_2169_9731_169.txt (o / observe-01 :ARG0 (w / we) :ARG1 (a3 / and :op1 (c / change-01 :ARG1 (p / pathway :name (n2 / name :op1 "Erk")) :mod (r / reciprocal) :ARG2-of (r2 / respond-01 :ARG1 (t / thing :ARG0-of (i / inhibit-01 :ARG1 (p3 / protein-family :name (n4 / name :op1 "Erk")))))) :op2 (c2 / change-01 :ARG1 (p2 / pathway :name (n3 / name :op1 "Akt")) :mod r :ARG2-of (r3 / respond-01 :ARG1 (t2 / thing :ARG0-of (i2 / inhibit-01 :ARG1 (p4 / protein-family :name (n5 / name :op1 "Akt")))))))) # ::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 9C). # ::save-date Wed Jan 3, 2018 ::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 (h / hour))) :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 Wed Sep 21, 2016 ::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 (h3 / hour)))))) # ::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 9D). # ::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 9G, H). # ::save-date Wed Sep 21, 2016 ::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 (h / hour)))) :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 9A, B), 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 9C-I). # ::save-date Wed Oct 18, 2017 ::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 (h2 / have-degree-91 :ARG1 (l / level) :ARG2 (h / high-02 :ARG1 l) :ARG3 (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 9F-I). # ::save-date Wed Jan 10, 2018 ::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))) :ARG1-of (s / significant-02) :time (a4 / after :op1 (t3 / treat-04) :quant (b / between :op1 (t2 / temporal-quantity :quant 4 :unit (h3 / hour)) :op2 (t6 / temporal-quantity :quant 24 :unit (h5 / 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)))) :ARG2-of (h2 / have-degree-91 :ARG1 a :ARG3 (m2 / more))) :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 9E). # ::save-date Wed Oct 18, 2017 ::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)))))) :mod (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 (h2 / have-degree-91 :ARG1 (l / level :quant-of p3) :ARG2 (l2 / low-04 :ARG1 l) :ARG3 (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 Mon Nov 27, 2017 ::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 (t4 / times :quant (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 10A-E). # ::save-date Wed Oct 18, 2017 ::file a_pmid_2169_9731_180.txt (a / and :op1 (h3 / have-degree-91 :ARG1 (a2 / activate-01 :ARG1 (k / kinase)) :ARG2 (g2 / great) :ARG3 (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 10C, D). # ::save-date Mon Oct 23, 2017 ::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 (h5 / have-quant-91 :ARG3 (t3 / times :quant 1000) :ARG4 (a5 / amount :quant-of p :location (m3 / media :ARG1-of (c3 / condition-01 :ARG2 (c4 / cell))))) :ARG1-of (h / have-quant-91 :ARG3 (t4 / times :quant 40) :ARG4 (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 BRAFV600E significantly induces cell migration and invasion properties in vitro 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 BRAFV600E 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, KRASG12V enhances the ability of colon adenocarcinoma cells Caco-2 to migrate and invade through filopodia formation and PI3K-dependent Cdc42 activation. # ::save-date Tue Jan 16, 2018 ::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 / filopodium)) :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 HRASG12V 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 BRAFV600E induces distinct morphological changes in colon adenocarcinoma cells as compared to KRASG12V and loss of their epithelial architecture in 3D culture # ::save-date Wed Oct 18, 2017 ::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") :ARG1-of (c5 / compare-01 :ARG2 (e3 / enzyme :name (n2 / name :op1 "KRAS") :ARG1-of (m3 / mutate-01 :value "G12V")))) :ARG2 (a4 / and :op1 (c / change-01 :ARG0 e2 :ARG1 (c2 / cell :source (a / adenocarcinoma :mod (c3 / colon))) :mod (m2 / morphology) :mod (d / distinct)) :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 [21]. # ::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 1A, Additional Figure 1). # ::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 KRASG12V, 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 BRAFV600E and KRASG13D respectively, have also been analyzed in the present study. # ::save-date Fri Dec 8, 2017 ::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)) :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 (KRASG13D), especially since both of these cell types share high levels of p-BRAF (later analyzed). # ::save-date Fri Oct 20, 2017 ::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 (a3 / after))))) :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 [21]. # ::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))) :ARG1-of (i / important-01)) :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 1A). # ::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 1A-ii, arrow). # ::save-date Wed Oct 18, 2017 ::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 (h / have-degree-91 :ARG2 (s / specific-02 :ARG1 c) :ARG3 (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 Wed Jan 3, 2018 ::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)) :manner (i2 / in-depth))) # ::id a_pmid_2194_3101.142 ::date 2015-05-22T12:03:37 ::annotator SDL-AMR-09 ::preferred # ::snt As also previously shown [22], 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 1B). # ::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 1B, 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 [23,24]. # ::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 1B, lower panel). # ::save-date Wed Oct 18, 2017 ::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 (h / have-degree-91 :ARG2 (l2 / low-04 :ARG1 p) :ARG3 (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 Thu Oct 19, 2017 ::file a_pmid_2194_3101_147.txt (f / form-01 :ARG0 (c2 / cell-line :name (n / name :op1 "Caco-BR13") :ARG1-of (c4 / compare-01 :ARG2 (c3 / cell-line :name (n2 / name :op1 "Caco-2")))) :ARG1 (s / spheroid :ARG1-of (e / enlarge-01 :ARG2 (s2 / significant-02)) :ARG0-of (h / have-03 :polarity - :ARG1 (l2 / lumen)) :ARG1-of (h2 / have-degree-91 :ARG2 (c / compact-01 :ARG1 s) :ARG3 (m / more)))) # ::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 BRAFV600E overexpression managed to alter the morphology of colon adenocarcinoma cells, rendering them a more mesenchymal-like phenotype, while KRASG12V conserved the epithelial architecture of Caco-2 cells in general. # ::save-date Wed Oct 18, 2017 ::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 (h / have-degree-91 :ARG2 (r2 / resemble-01 :ARG1 p :ARG2 (p2 / phenotype :mod (m5 / mesenchyme))) :ARG3 (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 BRAFV600E 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 HRASG12V converts Caco-2 epithelial into mesenchymal cells by inducing loss of E-cadherin and overexpression of vimentin [25]. # ::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 BRAFV600E had a similar effect on Caco-2 cells, the expression and localization of E-cadherin was analyzed (Figure 2A, B). # ::save-date Fri Oct 27, 2017 ::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 (t / truth-value :polarity-of (p2 / possible-01 :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 BRAFV600E led to a significant decrease in the mRNA levels of E-cadherin but had no significant effect on the actual protein expression (Figure 2A). # ::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 2A-lower panel, high exposure), whereas the decrease in the actual precursors at 135 kDa (Figure 2A-lower panel, low exposure), is considerably less. # ::save-date Thu Jan 11, 2018 ::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 (h2 / have-degree-91 :ARG2 (l4 / low-04 :ARG1 p3 :ARG2 (w / weight-01 :ARG1 (m4 / molecule))) :ARG3 (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 (k2 / kilodalton))))) :mod (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 (h3 / have-degree-91 :ARG2 (l5 / low-04 :ARG1 p6) :ARG3 (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 (h4 / have-degree-91 :ARG2 (l / low-04 :ARG1 p2) :ARG3 (m2 / more))) :op3 (e / expose-01 :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 BRAFV600E but not upstream KRASG12V activation is able to suppress the mature E-cadherin, while the precursor remained mostly unaffected. # ::save-date Tue Oct 31, 2017 ::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 - :ARG2-of (h / have-degree-91 :ARG1 p2 :ARG3 (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 2B, upper panel magnification). # ::save-date Thu Oct 12, 2017 ::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 "adherens" :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 2B, lower panel). # ::save-date Wed Oct 18, 2017 ::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 (h / have-degree-91 :ARG2 (l / low-04 :ARG1 p) :ARG3 (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 2B, 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 2C). # ::save-date Fri Sep 15, 2017 ::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 (t2 / truth-value :polarity-of (a2 / acquire-01 :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 2D), since it is known that some cancer epithelial cells abnormally express N-cadherin which has been shown to promote motility and invasion [26,27], N-cadherin expression was examined (Figure 2E). # ::save-date Tue Dec 26, 2017 ::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)) :ARG2 (t / times :quant (a4 / about :op1 3)))) :ARG2 (s / show-01 :polarity - :ARG0 (i3 / image :mod (c8 / confocal)) :ARG1 (d4 / differ-02 :ARG1-of (s4 / significant-02) :ARG1-of (c3 / compare-01 :ARG2 (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 Mon Oct 23, 2017 ::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 (t / times :quant (a2 / about :op1 12)) :prep-at (a / and :op1 (l2 / level :mod (n5 / nucleic-acid :name (n4 / name :op1 "mRNA"))) :op2 (l / level :mod (p3 / protein))) :ARG1-of (c3 / compare-01 :ARG2 (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 2F. # ::save-date Fri Jan 12, 2018 ::file a_pmid_2194_3101_162.txt (c / confirm-01 :ARG0 (i3 / image :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 BRAFV600E overexpression failed to induce an integrated EMT phenotype, which is the case with HRASG12V overexpression [25], 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 :ARG1-of (i3 / important-01) :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 BRAFV600E, KRASG12V and HRASG12V effect on the migration and invasion ability of Caco-2 cells in vitro # ::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 KRASG12V (Caco-K cells), BRAFV600E (Caco-BR cells) and HRASG12V (Caco-H cells) managed to increase the ability of Caco-2 cells to migrate and invade in vitro, independently of their proliferating ability, which has been previously analyzed in [21]. # ::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, BRAFV600E and HRASG12V provided Caco-2 cells with highly migrating and invasive properties, some similar to those in DLD-1 cells (Figure 3A, B), which is compatible with their more elongated morphology described earlier (Figure 1). # ::save-date Fri Oct 20, 2017 ::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 :ARG1-of 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 (d2 / describe-01 :ARG0 (f3 / figure :mod 1) :time (b / before)) :ARG1-of (h2 / have-degree-91 :ARG2 (e3 / elongate-01 :ARG1 m4) :ARG3 (m5 / more)))) :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 Tue Dec 26, 2017 ::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 :mod (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 BRAFV600E or KRASG12V oncogene affected the ability of Caco-2 cells to migrate and invade in vitro, 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 BRAF and KRAS oncogenes in altering cytoskeletal properties was further emphasized following depletion of BRAFV600E by shRNA in HT29 cells, where migration ability of HT-ShBR3 cells, with downregulated expression of mtBRAF 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 KRASG13D in DLD-1 cells (DKO-4) [28] significantly reverted the migration ability of DLD-1 cells (Figure 3C). # ::save-date Tue Oct 3, 2017 ::file a_pmid_2194_3101_171.txt (r / revert-01 :ARG0 (k / knock-out-12 :ARG1 c :ARG2 (e / enzyme :name (n2 / name :op1 "KRAS") :ARG2-of (m2 / mutate-01 :value "G13D")) :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 BRAFV600E enhances the ability of Caco-2 cells to migrate and invade in vitro 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 BRAFV600E in Caco-2 cells had a profound effect on the RAS effector protein RhoA (Figure 4). # ::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 4A) as well as phosphorylation of its downstream target Cofilin, a protein that is related to stress fibre formation (Figure 4B). # ::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 1). # ::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 4A). # ::save-date Wed Oct 18, 2017 ::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 (h / have-degree-91 :ARG2 (l / low-04 :ARG1 w) :ARG3 (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 [7]. # ::save-date Wed Oct 18, 2017 ::file a_pmid_2194_3101_177.txt (r / report-01 :ARG1 (v / variant :ARG1-of (w / weight-01 :mod (m / molecule) :ARG1-of (h / have-degree-91 :ARG2 (l / low-04 :ARG1 w) :ARG3 (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 Tue Dec 26, 2017 ::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 :manner (f / fast-02 :ARG2-of (h2 / have-degree-91 :ARG1 m :ARG3 (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 BRAFV600E in the activation of the RhoA pathway, transient transfection of the oncogene in Caco-2 cells was performed (Additional Figure 2). # ::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 2A, B). # ::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 2C), suggesting that a stable expression of BRAFV600E 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 5A). # ::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-01 :ARG1 (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 BRAFV600E oncogene-induced transformation of colon adenocarcinoma cells (Figure 5B). # ::save-date Wed Oct 18, 2017 ::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 :location (c / cell-line :name (n2 / name :op1 "Caco-BR13")) :ARG1-of (h / have-degree-91 :ARG2 (p3 / profound) :ARG3 (m / more))) :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 Wed Oct 18, 2017 ::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) :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 (c3 / compare-01 :ARG2 (c / cell-line :name (n2 / name :op1 "Caco-BR") :location-of (o / observe-01 :ARG1 (a3 / alter-01 :polarity - :mod (s3 / such)))))) :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 KRASG13D and BRAFV600E respectively, RhoA depletion was also performed in selected clones where KRASG13D (DKO4) or BRAFV600E (HTshBR3) was knocked out or down regulated via shRNA respectively. # ::save-date Mon Dec 25, 2017 ::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 :ARG1-of (s / select-01) :location-of (k / knock-out-12 :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")))) :ARG3 (n7 / nucleic-acid :name (n6 / name :op1 "shRNA")))) :op2 (c3 / clone :ARG1-of s :location-of (d4 / downregulate-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")))) :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)))) # ::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 KRASG13D is knocked out, (Figure 5C). # ::save-date Tue Oct 3, 2017 ::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") :ARG1-of (k / knock-out-12 :ARG2 (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 BRAFV600E) cells with suppressed BRAFV600E 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 5D). # ::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 BRAF and KRAS 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 [21]. # ::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 3), resulted in the decreased activation of RhoA illustrating that mutant BRAFV600E utilises the MAPK pathway to activate RhoA (Figure 5E, upper panel). # ::save-date Wed Oct 18, 2017 ::file a_pmid_2194_3101_193.txt (r / result-01 :ARG1 (t / treat-04 :ARG2 (s / small-molecule :name (n / name :op1 "UO126")) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod 3 :ARG1-of (a / add-02))) :condition (h / have-degree-91 :ARG1 (c / condition) :ARG2 (o / optimal) :ARG3 (m / most))) :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 5E, lower panel). # ::save-date Tue Dec 26, 2017 ::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 (h / have-degree-91 :ARG2 (l / low-04 :ARG1 p6) :ARG3 (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 6A-B). # ::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 6C). # ::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 Mon Dec 25, 2017 ::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-of (h / have-degree-91 :ARG2 (p4 / promise-01) :ARG3 (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 Wed Oct 18, 2017 ::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 :ARG1-of (h / have-degree-91 :ARG2 (a2 / adverse) :ARG3 (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 BRAFV600E transformed cells (Figure 6D). # ::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 KRASG12V 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 [29,30]. # ::save-date Wed Jan 17, 2018 ::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 "Cancer" :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 KRASG12V (Caco-K), selective activation for Cdc42 was detected (Figure 7A). # ::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 7B, upper panel). # ::save-date Fri Oct 20, 2017 ::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")) :time (b / before))) # ::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 7B, upper panel). # ::save-date Thu Oct 19, 2017 ::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 :mod (a / 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 :mod (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 (h2 / have-degree-91 :ARG1 s :ARG2 (l / long-03 :ARG1 s) :ARG3 (m / more) :ARG4 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 7B, lower panel). # ::save-date Wed Oct 18, 2017 ::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 :part-of (f / figure :mod "7B") :ARG1-of (h2 / have-degree-91 :ARG2 (l / low-04 :ARG1 p2) :ARG3 (m2 / more))))) # ::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 Jan 22, 2018 ::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 (s2 / species :wiki "Chinese_hamster" :name (n2 / name :op1 "Chinese" :op2 "hamster"))) :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 [31]. # ::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 KRASG12V 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 7C-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 7C-lower panel). # ::save-date Tue Dec 26, 2017 ::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)) :mod (l / less)) :op2 (a4 / and :op1 (m4 / migrate-01 :ARG0 (c4 / cell-line :name (n3 / name :op1 "Caco-2"))) :op2 (p6 / possible-01 :ARG1 (i2 / invade-01 :ARG0 c4)) :mod l)) :ARG2 (s2 / significant-02) :ARG1-of (d4 / describe-01 :ARG0 (f2 / figure :mod "7C" :part-of (p4 / panel :ARG1-of (h2 / have-degree-91 :ARG2 (l3 / low-04 :ARG1 p4) :ARG3 (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 7D). # ::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 KRASG12V 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 [16,21]. # ::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 4), resulted in reduced Cdc42 activity. # ::save-date Sun Jan 14, 2018 ::file a_pmid_2194_3101_218.txt (r / result-01 :ARG1 (f3 / follow-01 :ARG2 (t / treat-04 :ARG2 (w / wortmannin)) :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 :ARG1-of (h2 / have-degree-91 :ARG2 (o2 / optimal) :ARG3 (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 KRASG12V-PI3K signalling pathway can be potentially essential for Cdc42-dependent cell migration and invasion properties (Figure 7E). # ::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 HRASG12V 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 [15,25] (Figure 8A). # ::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 [32]. # ::save-date Mon Dec 25, 2017 ::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 (e3 / event :name (n3 / name :op1 "epithelial−mesenchymal" :op2 "transition") :location (c3 / cell :mod (e / epithelium) :mod (m / mammary)))) :ARG0-of (c7 / correlate-01 :ARG1 p :ARG2 (i / inhibit-01 :ARG1 (p2 / protein :name (n4 / name :op1 "E-cadherin")) :location (c4 / cell :mod (p3 / pancreas) :mod (c5 / carcinoma)))) :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 8A) and could be explained by the known antagonistic effect that exists between RhoA and Rac1 [33]. # ::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, HRASG12V-transfected Caco-2 cells (Caco-H2) have undergone EMT, followed by the dramatic reduction of E-cadherin expression [16]. # ::save-date Fri Oct 20, 2017 ::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 (b / before)) :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 4), Rac1 activity was successfully inhibited only in Caco-2 cells, leaving Caco-H2 cells unaffected (Figure 8B, upper panel). # ::save-date Wed Oct 18, 2017 ::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 :ARG1-of (h / have-degree-91 :ARG2 (o2 / optimum) :ARG3 (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 8B, lower panel). # ::save-date Wed Oct 18, 2017 ::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 (h / have-degree-91 :ARG2 (l / low-04 :ARG1 p2) :ARG3 (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, HRASG12V 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 HRASG12V in Caco-2 cells, pharmacological inhibition of Rac1 was established using the selective inhibitor NSC23766 (Figure 8C) [34]. # ::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 8D), 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 BRAFV600E and KRASG12V 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 BRAFV600E and KRASG12V oncogenes did not manage to fully transform Caco-2 cells nor induced an EMT phenotype, as HRASG12V did, it was further investigated whether co-operation of oncogene-growth factor can produce synergistic effect. # ::save-date Fri Sep 15, 2017 ::file a_pmid_2194_3101_231.txt (i / investigate-01 :ARG1 (t2 / truth-value :polarity-of (p2 / possible-01 :ARG1 (p / produce-01 :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 BRAFV600E and KRASG12V 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 9A). # ::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 9B, upper panel). # ::save-date Wed Oct 18, 2017 ::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 :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 (h / have-degree-91 :ARG2 (g / great) :ARG3 (m3 / more))) :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 9B, lower panel-arrows). # ::save-date Wed Oct 18, 2017 ::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 (h / have-degree-91 :ARG2 (l2 / low-04 :ARG1 p3) :ARG3 (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 [35]. # ::save-date Mon Jun 1, 2015 ::file a_pmid_2194_3101_236.txt (m / mechanism :ARG1-of (i / important-01) :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 in vitro, while no effect in the migrating ability of these cells was recorded (Figure 9C). # ::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 5). # ::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 KRASG12V-transfected cells acquired a more elongated morphology and slightly downregulated E-cadherin. # ::save-date Wed Oct 18, 2017 ::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 (h / have-degree-91 :ARG2 (e / elongate-01 :ARG1 m3) :ARG3 (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 KRASG12V and BRAFV600E oncogenes to provide Caco-2 cells with a more transforming phenotype. # ::save-date Wed Oct 18, 2017 ::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 (h / have-degree-91 :ARG2 (t3 / transform-01 :ARG1 p2) :ARG3 (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 [36]. # ::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 [37-39]. # ::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 9D). # ::save-date Thu Jan 4, 2018 ::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 :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_2234_3622.60 ::date 2015-05-28T07:09:27 ::annotator SDL-AMR-09 ::preferred # ::snt Combined treatment of selumetinib and standard of care agents results in enhanced anti-tumour efficacy # ::save-date Thu Jan 12, 2017 ::file a_pmid_2234_3622_60.txt (r / result-01 :ARG1 (t / treat-04 :ARG2 (a3 / and :op1 (s2 / small-molecule :name (n / name :op1 "selumetinib")) :op2 (s / standard :mod (a2 / agent :mod (c / care-03)))) :ARG3-of (c2 / combine-01)) :ARG2 (e / efficacy :ARG1-of (e2 / enhance-01) :mod (c3 / counter-01 :ARG1 (t2 / tumor)))) # ::id a_pmid_2234_3622.61 ::date 2015-05-28T15:47:00 ::annotator SDL-AMR-09 ::preferred # ::snt Mechanistic biomarker studies of the effects of selumetinib in human tumour xenograft models have shown that, in addition to pERK1/2 downregulation, a sustained exposure to the agent results in an increase in downstream apoptotic signalling and a decrease in cell cycle progression (Davies et al, 2007). # ::save-date Mon Dec 21, 2015 ::file a_pmid_2234_3622_61.txt (s / show-01 :ARG0 (s2 / study-01 :ARG1 (a / affect-01 :ARG0 (s3 / small-molecule :name (n3 / name :op1 "selumetinib")) :ARG1 (m2 / model :mod (x / xenograft :mod (t / tumor)) :mod (h / human))) :mod (b / biomarker :mod (m / mechanistic))) :ARG1 (r / result-01 :ARG1 (e / expose-01 :ARG2 s3 :ARG1-of (s4 / sustain-01)) :ARG2 (a7 / and :op1 (d2 / downregulate-01 :ARG1 (e2 / enzyme :name (n / name :op1 "ERK1/2") :ARG3-of (p / phosphorylate-01))) :op2 (i / increase-01 :ARG1 (s5 / signal-07 :mod (a5 / apoptosis) :location (d4 / downstream))) :op3 (d3 / decrease-01 :ARG1 (p2 / progress-01 :ARG1 (c / cycle-02 :ARG1 (c2 / cell)))))) :ARG1-of (d5 / describe-01 :ARG0 (p5 / publication-91 :ARG0 (a3 / and :op1 (p3 / person :name (n2 / name :op1 "Davies")) :op2 (p4 / person :mod (o / other))) :time (d / date-entity :year 2007)))) # ::id a_pmid_2234_3622.62 ::date 2015-05-29T11:36:12 ::annotator SDL-AMR-09 ::preferred # ::snt Furthermore, a chronic dosing schedule of selumetinib (25 mg kg–1 per bid for 14 doses) in HCT-116 xenografts increased the levels of the pro-apoptotic BH3 protein Bim-EL (∼4-fold increase) compared with no change with the level of this protein following a shorter dosing period (three doses) (Figure 1). # ::save-date Mon Oct 23, 2017 ::file a_pmid_2234_3622_62.txt (a / and :op2 (i / increase-01 :ARG0 (s / schedule-01 :ARG1 (d2 / dose-01 :quant 14 :ARG2 (s2 / small-molecule :name (n4 / name :op1 "selumetinib") :quant (c4 / concentration-quantity :quant 25 :unit (m / milligram-per-kilogram))) :mod (c / chronic) :frequency (r / rate-entity-91 :ARG1 2 :ARG2 (t / temporal-quantity :quant 1 :unit (d5 / day))) :location (x / xenograft :mod (c3 / cell-line :name (n / name :op1 "HCT-116"))))) :ARG1 (l / level :quant-of (p / protein :name (n2 / name :op1 "Bim-EL") :ARG0-of (f / favor-01 :ARG1 (a2 / apoptosis)) :ARG1-of (i2 / include-91 :ARG2 (p4 / protein-family :name (n3 / name :op1 "BH3"))))) :ARG2 (t2 / times :quant 4) :ARG1-of (c5 / compare-01 :ARG2 (c2 / change-01 :polarity - :ARG1 (l2 / level :quant-of p) :ARG1-of (f3 / follow-01 :ARG2 (p3 / period :time-of (d3 / dose-01) :ARG1-of (m3 / mean-01 :ARG3 (d4 / dose-01 :quant 3)) :ARG1-of (h / have-degree-91 :ARG2 (s3 / short-07 :ARG1 p3) :ARG3 (m2 / more))))))) :ARG1-of (d / describe-01 :ARG0 (f2 / figure :mod 1))) # ::id a_pmid_2234_3622.63 ::date 2015-05-28T15:50:33 ::annotator SDL-AMR-09 ::preferred # ::snt In order to exploit the apoptotic threshold of selumetinib, we wanted to study the effects of combining it with agents known to induce the apoptotic cascade to drive tumour growth inhibition and/or cell death. # ::save-date Tue Dec 22, 2015 ::file a_pmid_2234_3622_63.txt (w / want-01 :ARG0 (w2 / we) :ARG1 (s / study-01 :ARG0 w2 :ARG1 (a / affect-01 :ARG0 (c / combine-01 :ARG1 s2 :ARG2 (a2 / agent :ARG0-of (i / induce-01 :ARG2 (c2 / cascade :mod a3) :purpose (d / drive-02 :ARG0 a2 :ARG1 (a4 / and-or :op1 (i2 / inhibit-01 :ARG1 (g / grow-01 :ARG1 (t2 / tumor))) :op2 (d2 / die-01 :ARG1 (c3 / cell)))) :ARG1-of (k / know-01)))))) :purpose (e / exploit-01 :ARG0 w2 :ARG1 (t / threshold :poss (s2 / small-molecule :name (n / name :op1 "selumetinib")) :mod (a3 / apoptosis)))) # ::id a_pmid_2234_3622.64 ::date 2015-05-28T15:56:00 ::annotator SDL-AMR-09 ::preferred # ::snt The effects of selumetinib in combination with a number of key standard of care agents were tested pre-clinically in human tumour xenograft models and resulted in enhanced anti-tumour activity. # ::save-date Mon Dec 21, 2015 ::file a_pmid_2234_3622_64.txt (a / and :op1 (t / test-01 :ARG1 (a2 / affect-01 :ARG0 (s / small-molecule :name (n2 / name :op1 "selumetinib")) :ARG1-of (c / combine-01 :ARG2 (s2 / standard :ARG1-of (k / key-02) :mod (a4 / agent :mod (c3 / care-03) :quant (n / number))))) :time (b / before :op1 (c2 / clinic)) :location (m / model :mod (x / xenograft :mod (t2 / tumor)) :mod (h / human))) :op2 (r / result-01 :ARG1 a2 :ARG2 (a3 / activity-06 :ARG1-of (e / enhance-01) :ARG0-of (c4 / counter-01 :ARG1 t2)))) # ::id a_pmid_2234_3622.65 ::date 2015-05-28T15:59:44 ::annotator SDL-AMR-09 ::preferred # ::snt A number of compounds including the DNA-alkylating agent TMZ and the anti-mitotic drug docetaxel resulted in a greatly enhanced tumour growth inhibition compared with monotherapies (Table 1 and supplementary Table 1). # ::save-date Thu Oct 19, 2017 ::file a_pmid_2234_3622_65.txt (r / result-01 :ARG1 (c2 / compound :ARG2-of (i3 / include-91 :ARG1 (a3 / and :op1 (a4 / agent :ARG0-of (a / alkylate-01 :ARG1 (n / nucleic-acid :wiki "DNA" :name (n5 / name :op1 "DNA"))) :ARG1-of (m3 / mean-01 :ARG2 (s3 / small-molecule :name (n3 / name :op1 "TMZ")))) :op2 (s2 / small-molecule :name (n4 / name :op1 "docetaxel") :ARG0-of (c3 / counter-01 :ARG1 (m2 / mitosis))))) :quant (n2 / number) :ARG1-of (c / compare-01 :ARG2 (m / monotherapy))) :ARG2 (i / inhibit-01 :ARG1 (g / grow-01 :ARG1 (t / tumor)) :ARG1-of (e / enhance-01 :ARG3 (g2 / great))) :ARG1-of (d / describe-01 :ARG0 (a2 / and :op1 (t2 / table :mod 1) :op2 (t3 / table :mod 1 :ARG2-of (s / supplement-01))))) # ::id a_pmid_2234_3622.66 ::date 2015-05-28T15:47:43 ::annotator SDL-AMR-09 ::preferred # ::snt However, combining selumetinib with gemcitabine did not enhance the anti-tumour activity of the individual agents (supplementary Table 1). # ::save-date Mon Dec 21, 2015 ::file a_pmid_2234_3622_66.txt (c / contrast-01 :ARG2 (e / enhance-01 :polarity - :ARG0 (c2 / combine-01 :ARG1 (s2 / small-molecule :name (n / name :op1 "selumetinib")) :ARG2 (s3 / small-molecule :name (n2 / name :op1 "gemcitabine"))) :ARG1 (a / activity-06 :ARG0 (a2 / agent :mod (i / individual)) :ARG0-of (c3 / counter-01 :ARG1 (t2 / tumor)))) :ARG1-of (d / describe-01 :ARG0 (t / table :mod 1 :ARG2-of (s / supplement-01)))) # ::id a_pmid_2234_3622.67 ::date 2015-05-28T15:50:05 ::annotator SDL-AMR-09 ::preferred # ::snt The data presented here suggests that when selumetinib is combined, with either TMZ or docetaxel, the resulting anti-tumour phenotypes maybe due to mechanistic interactions between the two compounds. # ::save-date Sun Dec 20, 2015 ::file a_pmid_2234_3622_67.txt (s / suggest-01 :ARG0 (d / data :ARG1-of (p2 / present-01 :medium (h / here))) :ARG1 (p3 / possible-01 :ARG1 (c2 / cause-01 :ARG0 (i / interact-01 :ARG0 s2 :ARG1 o :ARG2 (m / mechanistic)) :ARG1 (p / phenotype :ARG2-of (r / result-01) :ARG0-of (c3 / counter-01 :ARG1 (t2 / tumor)))) :time (c / combine-01 :ARG1 (s2 / small-molecule :name (n2 / name :op1 "selumetinib")) :ARG2 (o / or :op1 (s4 / small-molecule :name (n3 / name :op1 "TMZ")) :op2 (s3 / small-molecule :name (n / name :op1 "docetaxel")))))) # ::id a_pmid_2234_3622.68 ::date 2015-05-28T16:03:06 ::annotator SDL-AMR-09 ::preferred # ::snt Selumetinib in combination with TMZ enhances DNA damage # ::save-date Tue Jun 9, 2015 ::file a_pmid_2234_3622_68.txt (e / enhance-01 :ARG0 (c / combine-01 :ARG1 (s / small-molecule :name (n / name :op1 "selumetinib")) :ARG2 (s2 / small-molecule :name (n2 / name :op1 "TMZ"))) :ARG1 (d / damage-01 :ARG0 c :ARG1 (n3 / nucleic-acid :wiki "DNA" :name (n4 / name :op1 "DNA")))) # ::id a_pmid_2234_3622.69 ::date 2015-05-28T16:04:17 ::annotator SDL-AMR-09 ::preferred # ::snt The combination of selumetinib and TMZ in the SW-620 human tumour xenograft model resulted in a significantly enhanced anti-tumour efficacy (103.5% inhibition; P<0.0005), compared with selumetinib (52% inhibition; P<0.0005) and TMZ (88% inhibition; P<0.0005) alone (Figure 2A). # ::save-date Thu Oct 19, 2017 ::file a_pmid_2234_3622_69.txt (r / result-01 :ARG1 (c2 / combine-01 :ARG1 s2 :ARG2 s3 :location (c3 / cell-line :name (n / name :op1 "SW-620") :mod (x / xenograft :mod (t3 / tumor :mod (h / human)))) :ARG1-of (c4 / compare-01 :ARG2 (a / and :op1 (s2 / small-molecule :name (n2 / name :op1 "selumetinib") :ARG0-of (i / inhibit-01 :degree (p2 / percentage-entity :value 52)) :mod s4) :op2 (s3 / small-molecule :name (n3 / name :op1 "TMZ") :ARG0-of (i2 / inhibit-01 :degree (p3 / percentage-entity :value 88)) :mod s4) :mod (a2 / alone)))) :ARG2 (e / efficacy :ARG0-of (c / counter-01 :ARG1 t3) :ARG1-of (e2 / enhance-01 :ARG1-of (s / significant-02)) :ARG1-of (m5 / mean-01 :ARG2 (a3 / and :op1 (i3 / inhibit-01 :degree (p / percentage-entity :value 103.5)) :op2 (s4 / statistical-test-91 :ARG2 (l / less-than :op1 0.0005))))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "2A"))) # ::id a_pmid_2234_3622.70 ::date 2015-05-29T11:05:55 ::annotator SDL-AMR-09 ::preferred # ::snt At the end of the dosing period, the monotherapy and combination treatment groups were left to observe the growth rate following the cessation of dosing (animals in the control group had to be killed due to tumour size). # ::save-date Mon Jul 27, 2015 ::file a_pmid_2234_3622_70.txt (l / leave-17 :ARG1 (a / and :op1 (g / group :ARG1-of (t / treat-04 :ARG2 (m / monotherapy))) :op2 (g2 / group :mod (t2 / treat-04 :ARG1-of (c / combine-01)))) :time (e / end-01 :ARG1 (p / period :time-of (d / dose-01))) :purpose (o / observe-01 :ARG1 (r / rate :mod (g3 / grow-01) :ARG1-of (f / follow-01 :ARG2 (c2 / cease-01 :ARG1 d :ARG1-of (m2 / mean-01 :ARG2 (o2 / obligate-01 :ARG1 (k / kill-01 :ARG1 (a2 / animal :part-of (g4 / group :mod (c4 / control)))) :ARG1-of (c3 / cause-01 :ARG0 (s / size :poss (t3 / tumor)))))))))) # ::id a_pmid_2234_3622.71 ::date 2015-05-28T22:00:08 ::annotator SDL-AMR-09 ::preferred # ::snt In the selumetinib and TMZ monotherapy-treated groups, tumour growth progressed rapidly once compound treatment had been removed. # ::save-date Tue Jun 9, 2015 ::file a_pmid_2234_3622_71.txt (p / progress-01 :ARG1 (g / grow-01 :ARG1 (t / tumor)) :manner (r / rapid) :ARG1-of (c / cause-01 :ARG0 (r2 / remove-01 :ARG1 (t2 / treat-04 :ARG2 (c2 / compound)))) :location (a / and :op1 (g2 / group :ARG1-of (t3 / treat-04 :ARG2 (s / small-molecule :name (n / name :op1 "selumetinib") :mod (m2 / monotherapy)))) :op2 (g3 / group :ARG1-of (t4 / treat-04 :ARG2 (s2 / small-molecule :name (n2 / name :op1 "TMZ") :mod m2))))) # ::id a_pmid_2234_3622.72 ::date 2015-05-28T22:03:28 ::annotator SDL-AMR-09 ::preferred # ::snt In contrast, the start of tumour growth in the combination group was delayed for approximately 24 days from the start of the experiment compared with 15 days in the TMZ alone group. # ::save-date Thu Oct 19, 2017 ::file a_pmid_2234_3622_72.txt (c / contrast-01 :ARG2 (d3 / delay-01 :ARG1 (s / start-01 :ARG1 (g / grow-01 :ARG1 (t3 / tumor) :location (g2 / group :mod (c2 / combine-01)))) :ARG2 (a / approximately :op1 (t / temporal-quantity :quant 24 :unit (d / day))) :time (s4 / start-01 :ARG1 (e / experiment-01)) :ARG1-of (c3 / compare-01 :ARG2 (d4 / delay-01 :ARG2 (t2 / temporal-quantity :quant 15 :unit (d2 / day)) :location (g4 / group :mod (s5 / small-molecule :name (n / name :op1 "TMZ") :mod (a2 / alone))))))) # ::id a_pmid_2234_3622.73 ::date 2015-05-29T11:48:06 ::annotator SDL-AMR-09 ::preferred # ::snt In order to investigate potential mechanisms, to explain the enhanced combination effect with TMZ, we used the growth inhibition data generated from our anti-tumour studies to guide our pharmacodynamic sampling times (Figure 2A). # ::save-date Tue Jun 9, 2015 ::file a_pmid_2234_3622_73.txt (u / use-01 :ARG0 (w / we) :ARG1 (d / data :topic (i / inhibit-01 :ARG1 (g / grow-01)) :ARG1-of (g2 / generate-01 :ARG2 (s / study-01 :ARG0 w :ARG0-of (c2 / counter-01 :ARG1 (t3 / tumor))))) :ARG2 (g3 / guide-01 :ARG0 d :ARG1 (t / time :time-of (s2 / sample-01 :ARG0 w :mod (p / pharmacodynamic)))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure :mod "2A")) :purpose (a / and :op1 (i2 / investigate-01 :ARG0 w :ARG1 (m / mechanism :mod (p2 / potential))) :op2 (e / explain-01 :ARG0 w :ARG1 (a2 / affect-01 :ARG0 (c / combine-01 :ARG2 (s3 / small-molecule :name (n / name :op1 "TMZ"))) :ARG1-of (e2 / enhance-01))))) # ::id a_pmid_2234_3622.74 ::date 2015-05-29T11:56:18 ::annotator SDL-AMR-09 ::preferred # ::snt Samples were collected at the end of the TMZ dosing (PD1), when the TMZ and combination groups growth rate started to diverge (PD2), at the end of selumetinib dosing (PD3) and at the end of the re-growth period (PD4) (Figure 2A; white arrows on graph). # ::save-date Sun Dec 20, 2015 ::file a_pmid_2234_3622_74.txt (c / collect-01 :ARG1 (t5 / thing :ARG1-of (s / sample-01)) :ARG1-of (d2 / describe-01 :ARG0 (a / and :op1 (f / figure :mod "2A") :op2 (a2 / arrow :ARG1-of (w / white-03) :location (g2 / graph)))) :time (a6 / and :op1 (e / end-01 :ARG1 (d / dose-01 :ARG2 (s4 / small-molecule :name (n6 / name :op1 "TMZ"))) :ARG1-of (l / label-01 :ARG2 (t2 / thing :name (n / name :op1 "PD1")))) :op2 (s2 / start-01 :ARG1 (d4 / diverge-01 :ARG0 (r / rate :mod (g6 / grow-01 :ARG1 (g / group :mod s4))) :ARG1 (r2 / rate :mod (g7 / grow-01 :ARG1 (g8 / group :mod (c2 / combine-01))))) :ARG1-of (l2 / label-01 :ARG2 (t3 / thing :name (n4 / name :op1 "PD2")))) :op3 (e2 / end-01 :ARG1 (d3 / dose-01 :ARG2 (s3 / small-molecule :name (n5 / name :op1 "selumetinib"))) :ARG1-of (l3 / label-01 :ARG2 (t4 / thing :name (n3 / name :op1 "PD3")))) :op4 (e3 / end-01 :ARG1 (g3 / grow-01 :mod (a4 / again)) :ARG1-of (l4 / label-01 :ARG2 (t / thing :name (n2 / name :op1 "PD4")))))) # ::id a_pmid_2234_3622.75 ::date 2015-05-29T12:07:22 ::annotator SDL-AMR-09 ::preferred # ::snt IHC analysis and histological scoring was performed on all the tissues collected to examine, selumetinib effects (pERK1/2), DNA damage (γH2A.X), apoptosis (cleaved caspase 3) and the cell cycle (pHH3) (scoring data not shown). # ::save-date Sun Jan 17, 2016 ::file a_pmid_2234_3622_75.txt (p / perform-02 :ARG1 (a5 / and :op1 (a6 / analyze-01 :mod (i / immunohistochemistry)) :op2 (s2 / score-01 :ARG3 (h / histology))) :location (t / tissue :mod (a7 / all) :ARG1-of (c3 / collect-01 :purpose (a4 / and :op1 (e / examine-01 :ARG1 (a3 / affect-01 :ARG0 (s / small-molecule :name (n5 / name :op1 "selumetinib")) :ARG2 (e2 / enzyme :name (n / name :op1 "ERK1/2") :ARG3-of (p2 / phosphorylate-01)))) :op2 (e3 / examine-01 :ARG1 (d / damage-01 :ARG1 (n7 / nucleic-acid :wiki "DNA" :name (n8 / name :op1 "DNA"))) :instrument (p5 / protein :name (n2 / name :op1 "γH2A.X"))) :op3 (e4 / examine-01 :ARG1 (a2 / apoptosis) :instrument (p6 / protein :name (n3 / name :op1 "Cleaved" :op2 "Caspase" :op3 3))) :op4 (e5 / examine-01 :ARG1 (c / cycle-02 :ARG1 (c2 / cell)) :instrument (p4 / protein :name (n4 / name :op1 "HH3") :ARG3-of (p3 / phosphorylate-01)))))) :ARG1-of (s3 / show-01 :polarity - :ARG0 (d3 / data :mod (s4 / score-01)))) # ::id a_pmid_2234_3622.76 ::date 2015-05-29T13:21:18 ::annotator SDL-AMR-09 ::preferred # ::snt The sampling timepoint, which gave us the greatest insight into the mechanistic effects of these agents was that taken when we started to see the TMZ and combination groups diverge (PD2). # ::save-date Thu Oct 19, 2017 ::file a_pmid_2234_3622_76.txt (t3 / timepoint :mod (t5 / thing :name (n / name :op1 "PD2")) :ARG1-of (t4 / take-01 :ARG0 w :time (s3 / start-01 :ARG0 w :ARG1 (s2 / see-01 :ARG0 w :ARG1 (d / diverge-01 :ARG0 (g4 / group :mod (s4 / small-molecule :name (n2 / name :op1 "TMZ"))) :ARG1 (g3 / group :mod (c / combine-01) :ARG1-of (m3 / mean-01)))))) :domain (t / timepoint :time-of (s / sample-01) :ARG0-of (g2 / give-01 :ARG1 (i / insight :topic (a / affect-01 :ARG0 (a2 / agent :mod (t2 / this)) :mod (m2 / mechanistic)) :ARG1-of (h / have-degree-91 :ARG2 (g / great) :ARG3 (m / most))) :ARG2 (w / we)))) # ::id a_pmid_2234_3622.77 ::date 2015-05-29T13:30:43 ::annotator SDL-AMR-09 ::preferred # ::snt As expected, in response to selumetinib or TMZ alone we saw changes in the mechanistic biomarkers pERK1/2 (decrease) and γH2A.X (increase), respectively, and a reduction in mitotic cells as shown by pHH3 in the selumetinib group compared with an increase in the TMZ tissues (Figure 2B). # ::save-date Thu Oct 19, 2017 ::file a_pmid_2234_3622_77.txt (r2 / respond-01 :ARG1 (o / or :op1 (s2 / small-molecule :name (n4 / name :op1 "selumetinib")) :op2 (s4 / small-molecule :name (n5 / name :op1 "TMZ")) :mod (a / alone)) :ARG2 (s3 / see-01 :ARG0 w :ARG1 (a3 / and :op1 (c / change-01 :ARG1 (b2 / biomarker :mod (m3 / mechanistic) :ARG1-of (m5 / mean-01 :ARG2 (a4 / and :op1 (e2 / enzyme :name (n / name :op1 "ERK1/2") :ARG1-of (d / decrease-01) :ARG3-of p2) :op2 (p3 / protein :name (n2 / name :op1 "γH2A.X") :mod m3 :ARG1-of (i / increase-01)))))) :op2 (r / reduce-01 :ARG1 (c2 / cell :mod (m4 / mitosis)) :ARG1-of (s / show-01 :ARG0 (p / protein :name (n3 / name :op1 "HH3") :ARG3-of (p2 / phosphorylate-01)) :location (g / group :mod s2)) :ARG1-of (c3 / compare-01 :ARG2 (i2 / increase-01 :ARG1 (t2 / tissue :mod s4))))) :ARG1-of (e / expect-01 :ARG0 (w / we)))) # ::id a_pmid_2234_3622.78 ::date 2015-05-28T22:04:00 ::annotator SDL-AMR-09 ::preferred # ::snt Level of the apoptotic marker, cleaved caspase 3, was comparable in the combination group compared with the TMZ monotherapy (Figure 2B). # ::save-date Tue Jun 9, 2015 ::file a_pmid_2234_3622_78.txt (p / possible-01 :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "2B")) :ARG1 (c / compare-01 :ARG1 (l / level :degree-of (m / marker :name (n / name :op1 "cleaved" :op2 "caspase" :op3 "3") :mod (a / apoptosis)) :location (g / group :mod (c2 / combine-01))) :ARG2 (m2 / monotherapy :mod (s / small-molecule :name (n2 / name :op1 "TMZ"))))) # ::id a_pmid_2234_3622.79 ::date 2015-05-28T22:07:33 ::annotator SDL-AMR-09 ::preferred # ::snt However, in the combination group we observed a greatly enhanced upregulation of γH2A.X compared with the TMZ group alone, suggesting that when selumetinib and TMZ are combined DNA damage is enhanced (Figure 2B). # ::save-date Thu Oct 19, 2017 ::file a_pmid_2234_3622_79.txt (c / contrast-01 :ARG2 (o / observe-01 :ARG0 (w / we) :ARG1 (u / upregulate-01 :ARG1 (p / protein :name (n / name :op1 "γH2A.X")) :location (g / group :mod (c2 / combine-01) :ARG1-of (c4 / compare-01 :ARG2 (g3 / group :mod (s3 / small-molecule :name (n3 / name :op1 "TMZ") :mod (a2 / alone))))) :ARG1-of (e / enhance-01 :ARG3 (g2 / great)) :ARG0-of (s / suggest-01 :ARG1 (e2 / enhance-01 :ARG1 (d / damage-01 :ARG1 (n4 / nucleic-acid :wiki "DNA" :name (n5 / name :op1 "DNA"))) :time (c3 / combine-01 :ARG1 (s2 / small-molecule :name (n2 / name :op1 "selumetinib")) :ARG2 s3))))) :ARG1-of (d3 / describe-01 :ARG0 (f / figure :mod "2B"))) # ::id a_pmid_2234_3622.80 ::date 2015-05-29T08:39:59 ::annotator SDL-AMR-09 ::preferred # ::snt Selumetinib is efficacious in combination with docetaxel when dosed concurrently or following docetaxel # ::save-date Mon Jul 27, 2015 ::file a_pmid_2234_3622_80.txt (e / efficacious :time (o / or :op1 (d / dose-01 :ARG1 (a / and :op1 s3 :op2 s2) :ARG1-of (c2 / concurrent-02)) :op2 (f / follow-01 :ARG1 s3 :ARG2 s2)) :domain (s3 / small-molecule :name (n2 / name :op1 "selumetinib") :ARG1-of (c / combine-01 :ARG2 (s2 / small-molecule :name (n / name :op1 "docetaxel"))))) # ::id a_pmid_2234_3622.81 ::date 2015-05-29T08:46:53 ::annotator SDL-AMR-09 ::preferred # ::snt Continuous, concurrent combinations of selumetinib and docetaxel resulted in significant anti-tumour effects in several models (Table 1 and Figure 3A). # ::save-date Mon Jul 27, 2015 ::file a_pmid_2234_3622_81.txt (r / result-01 :ARG1 (c / combine-01 :ARG1 (s / small-molecule :name (n / name :op1 "selumetinib")) :ARG2 (s4 / small-molecule :name (n2 / name :op1 "docetaxel")) :ARG1-of (c2 / concurrent-02) :ARG1-of (c3 / continue-01)) :ARG2 (a / affect-01 :ARG2 (c4 / counter-01 :ARG0 (t / tumor)) :location (m / model :quant (s2 / several)) :ARG1-of (s3 / significant-02)) :ARG1-of (d2 / describe-01 :ARG0 (a2 / and :op1 (t2 / table :mod 1) :op2 (f / figure :mod "3A")))) # ::id a_pmid_2234_3622.82 ::date 2015-05-29T08:54:24 ::annotator SDL-AMR-09 ::preferred # ::snt However, we were interested to explore the effect of dose sequencing on the anti-tumour efficacy of these two agents as administration of selumetinib and docetaxel as monotherapies results in distinct cell cycle phenotypes; a G1 or mitotic arrest, respectively. # ::save-date Tue Jan 19, 2016 ::file a_pmid_2234_3622_82.txt (c / contrast-01 :ARG2 (c2 / cause-01 :ARG0 (r / result-01 :ARG1 (a3 / administer-01 :ARG1 (a4 / and :op1 (s2 / small-molecule :name (n2 / name :op1 "selumetinib")) :op2 (s3 / small-molecule :name (n3 / name :op1 "docetaxel"))) :manner (m / monotherapy)) :ARG2 (p / phenotype :mod (c4 / cycle-02 :ARG1 (c5 / cell) :mod (d2 / distinct)) :ARG1-of (m5 / mean-01 :ARG2 (a5 / and :op2 (a6 / arrest-02 :time (e3 / event :name (n / name :op1 "G1"))) :op3 (a7 / arrest-02 :time (m2 / mitosis)))))) :ARG1 (i / interest-01 :ARG1 (w / we) :ARG2 (e / explore-01 :ARG0 w :ARG1 (a / affect-01 :ARG0 (s / sequence-01 :ARG1 (d / dose-01)) :ARG1 (e2 / efficacy :poss (a2 / agent :quant 2 :mod (t2 / this) :ARG1-of (m4 / mean-01 :ARG2 a4) :ARG0-of (c3 / counter-01 :ARG1 (t / tumor))))))))) # ::id a_pmid_2234_3622.83 ::date 2015-05-29T11:05:20 ::annotator SDL-AMR-09 ::preferred # ::snt Two schedules were designed in which mice bearing HCT-116 CRC tumours were treated with either a single dose of docetaxel (15 mg kg–1) followed 24 h later by selumetinib (25 mg kg–1 per bid) for 7 days (schedule 1) or selumetinib was administered as above for 7 days followed 24 h later with docetaxel (schedule 2) (Figure 3B). # ::save-date Tue Dec 19, 2017 ::file a_pmid_2234_3622_83.txt (d2 / design-01 :ARG1 (s / schedule :quant 2) :ARG3 (o / or :op1 (t2 / treat-04 :ARG1 (m2 / mouse :ARG0-of (b / bear-01 :ARG1 (t3 / tumor :mod (c / cell-line :name (n / name :op1 "HCT-116") :mod (d4 / disease :name (n4 / name :op1 "CRC")))))) :ARG2 (s5 / small-molecule :name (n3 / name :op1 "docetaxel") :ARG2-of (d5 / dose-01 :ARG1-of (s2 / single-02)) :ARG2-of (f2 / follow-01 :ARG1 (d6 / dose-01 :ARG2 (s3 / small-molecule :name (n2 / name :op1 "selumetinib") :quant (c3 / concentration-quantity :quant 25 :unit (m4 / milligram-per-kilogram))) :duration (t / temporal-quantity :quant 7 :unit (d / day)) :frequency (r / rate-entity-91 :ARG1 2 :ARG2 (t5 / temporal-quantity :quant 1 :unit (d7 / day)))) :time (a2 / after :quant (t4 / temporal-quantity :quant 24 :unit (h / hour)))) :quant (c2 / concentration-quantity :quant 15 :unit (m3 / milligram-per-kilogram)))) :op2 (a / administer-01 :ARG1 s3 :duration t :ARG2-of (f3 / follow-01 :ARG1 (a3 / administer-01 :ARG1 s5) :time (a4 / after)) :mod t2)) :ARG1-of (d3 / describe-01 :ARG0 (f / figure :mod "3B"))) # ::id a_pmid_2234_3622.84 ::date 2015-05-29T12:36:05 ::annotator SDL-AMR-09 ::preferred # ::snt As monotherapies, docetaxel and selumetinib resulted in 77% (P<0.0005) and 50% (P<0.005) tumour growth inhibition, respectively (Figure 3C). # ::save-date Mon Dec 21, 2015 ::file a_pmid_2234_3622_84.txt (r / result-01 :ARG1 (a / and :op1 (s2 / small-molecule :name (n2 / name :op1 "docetaxel")) :op2 (s / small-molecule :name (n / name :op1 "selumetinib")) :mod (m / monotherapy)) :ARG2 (a2 / and :op1 (i / inhibit-01 :ARG1 (g / grow-01 :ARG1 (t / tumor) :mod (p / percentage-entity :value 77)) :ARG1-of (s3 / statistical-test-91 :ARG2 (l / less-than :op1 0.0005))) :op2 (i2 / inhibit-01 :ARG1 (g2 / grow-01 :ARG1 t :mod (p2 / percentage-entity :value 50)) :ARG1-of (s4 / statistical-test-91 :ARG2 (l2 / less-than :op1 0.005)))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "3C"))) # ::id a_pmid_2234_3622.85 ::date 2015-05-29T12:40:17 ::annotator SDL-AMR-09 ::preferred # ::snt Interestingly, in the two combination schedules docetaxel administered before selumetinib (schedule 1) resulted in a 110% (P<0.0005) compared with 61% (P<0.005) tumour growth inhibition when docetaxel was administered after selumetinib (schedule 2). # ::save-date Thu Oct 19, 2017 ::file a_pmid_2234_3622_85.txt (r / result-01 :ARG1 (a / administer-01 :ARG1 (s5 / small-molecule :name (n / name :op1 "docetaxel")) :time (b / before :op1 (a2 / administer-01 :ARG1 (s / small-molecule :name (n2 / name :op1 "selumetinib"))) :ARG1-of (m / mean-01 :ARG2 (s3 / schedule :mod 1)))) :ARG2 (i3 / inhibit-01 :quant (p / percentage-entity :value 110) :ARG1-of (s6 / statistical-test-91 :ARG2 (l2 / less-than :op1 0.0005)) :ARG1-of (c2 / compare-01 :ARG2 (i / inhibit-01 :ARG1 (g / grow-01 :ARG1 (t / tumor)) :degree (p2 / percentage-entity :value 61) :time (a3 / administer-01 :ARG1 s5 :time (a4 / after :op1 s) :ARG1-of (m4 / mean-01 :ARG2 (s4 / schedule :mod 2)))))) :ARG0-of (i2 / interest-01) :condition (s2 / schedule :quant 2 :mod (c / combine-01))) # ::id a_pmid_2234_3622.86 ::date 2015-05-28T22:12:42 ::annotator SDL-AMR-09 ::preferred # ::snt These results suggest that selumetinib could enhance the efficacy of docetaxel when administered in the sequence of docetaxel followed by selumetinib. # ::save-date Tue Jun 9, 2015 ::file a_pmid_2234_3622_86.txt (s / suggest-01 :ARG0 (t / thing :ARG2-of (r / result-01) :mod (t2 / this)) :ARG1 (p / possible-01 :ARG1 (e / enhance-01 :ARG0 (s3 / small-molecule :name (n2 / name :op1 "selumetinib")) :ARG1 (e2 / efficacy :poss (s4 / small-molecule :name (n / name :op1 "docetaxel"))) :condition (a / administrate-01 :manner (s2 / sequence :poss s4 :mod (f / follow-01 :ARG1 s3 :ARG2 s4)))))) # ::id a_pmid_2234_3622.87 ::date 2015-05-28T22:16:07 ::annotator SDL-AMR-09 ::preferred # ::snt The sequence dependency of selumetinib when combined with docetaxel enhances apoptotic cell death # ::save-date Tue Jun 9, 2015 ::file a_pmid_2234_3622_87.txt (e / enhance-01 :ARG0 (d / depend-01 :ARG0 (s2 / small-molecule :name (n / name :op1 "selumetinib") :ARG1-of (c / combine-01 :ARG2 (s3 / small-molecule :name (n2 / name :op1 "docetaxel")))) :ARG1 (s / sequence)) :ARG1 (d2 / die-01 :ARG1 (c2 / cell) :mod (a / apoptosis))) # ::id a_pmid_2234_3622.88 ::date 2015-05-29T08:38:19 ::annotator SDL-AMR-09 ::preferred # ::snt In order to determine the mechanism of action in the scheduling studies with docetaxel, a series of tumour tissue samples were taken at different time points following exposure to the two dosing regimens (Figure 4Ai and Bi). # ::save-date Mon Nov 20, 2017 ::file a_pmid_2234_3622_88.txt (s / sample-01 :ARG1 (t2 / tissue :mod (t3 / tumor)) :time (p / point :mod (t / time) :ARG1-of (d4 / differ-02)) :ARG1-of (f / follow-01 :ARG2 (e / expose-01 :ARG2 (r2 / regimen :quant 2 :ARG0-of (d / dose-01)))) :ARG1-of (d2 / describe-01 :ARG0 (a / and :op1 (f2 / figure :mod "4Ai") :op2 (f3 / figure :mod "4Bi"))) :quant (s2 / series) :purpose (d3 / determine-01 :ARG1 (m / mechanism :mod (a2 / act-02) :purpose (s3 / study-01 :ARG1 (s5 / small-molecule :name (n / name :op1 "docetaxel")) :ARG1-of (s4 / schedule-01))))) # ::id a_pmid_2234_3622.89 ::date 2015-05-29T09:40:00 ::annotator SDL-AMR-09 ::preferred # ::snt To assess the cell cycle mechanistic effects the mitotic marker pHH3 was quantitated. # ::save-date Tue Jan 19, 2016 ::file a_pmid_2234_3622_89.txt (q / quantitate-01 :ARG1 (m / marker :mod (m2 / mitosis) :ARG1-of (m4 / mean-01 :ARG2 (p / protein :name (n / name :op1 "HH3") :ARG1-of (p2 / phosphorylate-01)))) :purpose (a / assess-01 :ARG1 (a2 / affect-01 :ARG1 (c / cycle-02 :ARG1 (c2 / cell)) :mod (m3 / mechanistic)))) # ::id a_pmid_2234_3622.90 ::date 2015-05-29T09:44:56 ::annotator SDL-AMR-09 ::preferred # ::snt In the sequence when docetaxel was administered before selumetinib, increased levels of pHH3 were observed at the early timepoints (PD1 & PD2) (2.7- and 2.3-fold change, respectively; P<0.0005). # ::save-date Tue Dec 26, 2017 ::file a_pmid_2234_3622_90.txt (o / observe-01 :ARG1 (l / level :ARG1-of (i / increase-01 :ARG1-of (s4 / statistical-test-91 :ARG2 (l2 / less-than :op1 0.0005))) :quant-of (p4 / protein :name (n / name :op1 "HH3") :ARG3-of (p5 / phosphorylate-01))) :time (t / timepoint :mod (e / early)) :location (s / sequence :mod (a / administer-01 :ARG1 (s3 / small-molecule :name (n5 / name :op1 "docetaxel")) :time (b2 / before :op1 (a2 / administer-01 :ARG1 (s2 / small-molecule :name (n4 / name :op1 "selumetinib")))))) :ARG1-of (m2 / mean-01 :ARG2 (a3 / and :op1 (t2 / thing :name (n2 / name :op1 "PD1")) :op2 (t3 / thing :name (n3 / name :op1 "PD2")))) :ARG1-of (m3 / mean-01 :ARG2 (a5 / and :op1 (c / change-01 :ARG2 (t4 / times :quant 2.7)) :op2 (c2 / change-01 :ARG2 (t5 / times :quant 2.3))))) # ::id a_pmid_2234_3622.91 ::date 2015-05-29T12:26:53 ::annotator SDL-AMR-09 ::preferred # ::snt In schedule 2, pHH3 levels were seen to increase following docetaxel (PD7) (3.4-fold; P<0.0005) (Figure 4Aii and 4Bii). # ::save-date Mon Oct 23, 2017 ::file a_pmid_2234_3622_91.txt (s / see-01 :ARG1 (i / increase-01 :ARG1 (l / level :quant-of (p3 / protein :name (n2 / name :op1 "HH3") :ARG3-of (p4 / phosphorylate-01))) :ARG2 (t2 / times :quant 3.4) :ARG1-of (f / follow-01 :ARG2 (s2 / small-molecule :name (n3 / name :op1 "docetaxel"))) :ARG1-of (s4 / statistical-test-91 :ARG2 (l2 / less-than :op1 0.0005))) :ARG1-of (d2 / describe-01 :ARG0 (a / and :op1 (f2 / figure :mod "4Aii") :op2 (f3 / figure :mod "4Bii"))) :condition (s3 / schedule :mod 2) :ARG1-of (m3 / mean-01 :ARG2 (t / thing :name (n / name :op1 "PD7")))) # ::id a_pmid_2234_3622.92 ::date 2015-05-29T12:35:08 ::annotator SDL-AMR-09 ::preferred # ::snt When selumetinib was administered alone levels of pHH3 decreased at several measurement points compared with controls (PD2 P<0.0005; PD4 P<0.005; PD5 P<0.0005; PD6 P<0.0005) consistent with the inhibition of the MEK/ERK pathway resulting in a G1/S arrest. # ::save-date Mon Nov 20, 2017 ::file a_pmid_2234_3622_92.txt (d / decrease-01 :ARG1 (l / level :quant-of (p7 / protein :name (n3 / name :op1 "HH3") :ARG3-of (p8 / phosphorylate-01))) :time (a / administer-01 :ARG1 (s / small-molecule :name (n8 / name :op1 "selumetinib") :mod (a3 / alone) :ARG1-of (c3 / compare-01 :ARG2 (c / control)))) :time (p2 / point :quant (s2 / several) :mod (m3 / measure-01) :ARG1-of (m4 / mean-01 :ARG2 (a4 / and :op1 (t / thing :name (n4 / name :op1 "PD2")) :op2 (t2 / thing :name (n5 / name :op1 "PD4")) :op3 (t4 / thing :name (n6 / name :op1 "PD5")) :op4 (t5 / thing :name (n7 / name :op1 "PD6"))))) :ARG1-of (c2 / consistent-01 :ARG2 (i / inhibit-01 :ARG1 (p / pathway :name (n / name :op1 "MEK/ERK")) :ARG1-of (r / result-01 :ARG2 (a2 / arrest-02 :time (e / event :name (n2 / name :op1 "G1/S")))))) :ARG1-of (s3 / statistical-test-91 :ARG2 (l2 / less-than :op1 0.0005))) # ::id a_pmid_2234_3622.93 ::date 2015-05-29T13:41:36 ::annotator SDL-AMR-09 ::preferred # ::snt Interestingly, in both sequences in the combination there is a reduction in pHH3 compared with the docetaxel alone group at that timepoint (PD2 and PD7) (3.8- and 2.5-fold change, respectively; P<0.0005). # ::save-date Tue Dec 26, 2017 ::file a_pmid_2234_3622_93.txt (r / reduce-01 :ARG1 (p4 / protein :name (n / name :op1 "HH3") :ARG3-of (p5 / phosphorylate-01)) :ARG0-of (i / interest-01) :location (s / sequence :mod (b / both) :mod (c / combine-01) :ARG1-of (c4 / compare-01 :ARG2 (g / group :mod (s2 / small-molecule :name (n4 / name :op1 "docetaxel") :mod (a / alone))))) :time (t / timepoint :mod (t2 / that) :ARG1-of (m2 / mean-01 :ARG2 (a2 / and :op1 (t3 / thing :name (n2 / name :op1 "PD2")) :op2 (t4 / thing :name (n3 / name :op1 "PD7"))))) :ARG1-of (m5 / mean-01 :ARG2 (a3 / and :op1 (c2 / change-01 :ARG2 (t5 / times :quant 3.8)) :op2 (c3 / change-01 :ARG2 (t6 / times :quant 2.5)))) :ARG1-of (s3 / statistical-test-91 :ARG2 (l / less-than :op1 0.0005))) # ::id a_pmid_2234_3622.94 ::date 2015-05-29T14:26:40 ::annotator SDL-AMR-09 ::preferred # ::snt Levels of the apoptotic marker cleaved caspase 3, in tumour tissue taken from the docetaxel followed by selumetinib group, increased in this combination group (16.8-fold change from the control; P<0.0005) compared with the single agents alone (3.5- and 2.4-fold change for docetaxel and selumetinib, respectively) (Figure 4Aiii PD2). # ::save-date Tue Dec 26, 2017 ::file a_pmid_2234_3622_94.txt (i / increase-01 :ARG1 (l / level :quant-of (m / marker :name (n / name :op1 "cleaved" :op2 "caspase" :op3 "3") :mod (a3 / apoptosis) :location (t / tissue :source (t2 / tumor) :ARG1-of (t3 / take-01 :ARG2 (g / group :mod (s3 / small-molecule :name (n2 / name :op1 "docetaxel")) :ARG2-of (f2 / follow-01 :ARG1 (g2 / group :mod (s2 / small-molecule :name (n3 / name :op1 "selumetinib")))))) :ARG1-of (c5 / compare-01 :ARG2 (a / agent :ARG1-of (s / single-02) :mod (a2 / alone) :ARG1-of (m2 / mean-01 :ARG2 (a5 / and :op1 (c3 / change-01 :ARG0 s3 :ARG2 (t4 / times :quant 3.5)) :op2 (c4 / change-01 :ARG0 s2 :ARG2 (t5 / times :quant 2.4))))))))) :ARG4 (a4 / and :op1 (c / change-01 :ARG1 (c2 / control) :ARG2 (t6 / times :quant 16.8))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "4AiiiPD2")) :location g :ARG1-of (s4 / statistical-test-91 :ARG2 (l2 / less-than :op1 0.0005))) # ::id a_pmid_2234_3622.95 ::date 2015-05-29T12:08:32 ::annotator SDL-AMR-09 ::preferred # ::snt In comparison, tumour tissue analysed in the same study after the chronic dosing schedule of selumetinib did not demonstrate an increase in cleaved caspase 3 levels in the combination group when compared with the single agents alone. # ::save-date Sun Jan 17, 2016 ::file a_pmid_2234_3622_95.txt (c / compare-01 :ARG1 (d / demonstrate-01 :polarity - :ARG0 (t / tissue :source (t2 / tumor) :ARG1-of (a3 / analyze-01 :ARG0 (s2 / study-01 :ARG1-of (s3 / same-01) :time (a4 / after :op1 (s4 / schedule-01 :ARG1 (d2 / dose-01 :ARG2 (s5 / small-molecule :name (n2 / name :op1 "selumetinib")) :mod (c4 / chronic))))))) :ARG1 (i / increase-01 :ARG1 (l / level :location (g / group :mod (c2 / combine-01)) :quant-of (p / protein :name (n / name :op1 "cleaved" :op2 "caspase" :op3 "3")))) :time (c3 / compare-01 :ARG2 (a / agent :ARG1-of (s / single-02)) :mod (a2 / alone)))) # ::id a_pmid_2234_3622.96 ::date 2015-05-29T09:45:32 ::annotator SDL-AMR-09 ::preferred # ::snt When selumetinib was dosed before docetaxel an increase in cleaved caspase 3 was not observed in the combination group at any of the sampling timepoints compared with at least one of the monotherapies (Figure 4Biii). # ::save-date Thu Oct 19, 2017 ::file a_pmid_2234_3622_96.txt (o / observe-01 :polarity - :ARG1 (i / increase-01 :ARG1 (p / protein :name (n / name :op1 "cleaved" :op2 "caspase" :op3 "3") :ARG1-of (c2 / compare-01 :ARG2 (m2 / monotherapy :quant (a / at-least :op1 1) :ARG1-of (i2 / include-91 :ARG2 (m3 / monotherapy)))))) :time (d / dose-01 :ARG2 (s / small-molecule :name (n3 / name :op1 "selumetinib")) :time (b / before :op1 (d2 / dose-01 :ARG2 (s3 / small-molecule :name (n2 / name :op1 "docetaxel"))))) :location (g / group :mod (c / combine-01)) :time (t / timepoint :time-of (s2 / sample-01)) :ARG1-of (d4 / describe-01 :ARG0 (f / figure :mod "4Biii"))) # ::id a_pmid_2234_3622.97 ::date 2015-06-02T09:01:36 ::annotator SDL-AMR-09 ::preferred # ::snt Representative IHC images from PD2 highlights the increase in pHH3 following docetaxel exposure and the increase in cleaved caspase 3 in the docetaxel followed by selumetinib group (Figure 4C). # ::save-date Sun Jan 17, 2016 ::file a_pmid_2234_3622_97.txt (h / highlight-01 :ARG0 (i / image :ARG0-of (r / represent-01) :source (t2 / thing :name (n7 / name :op1 "PD2")) :mod (i4 / immunohistochemistry)) :ARG1 (a / and :op1 (i2 / increase-01 :ARG1 (p / protein :name (n2 / name :op1 "HH3") :ARG3-of (p3 / phosphorylate-01)) :ARG1-of (f / follow-01 :ARG2 (e / expose-01 :ARG1 p :ARG2 (s / small-molecule :name (n3 / name :op1 "docetaxel"))))) :op2 (i3 / increase-01 :ARG1 (p2 / protein :name (n4 / name :op1 "caspase" :op2 "3") :ARG1-of (c / cleave-01)) :location (g / group :mod (s2 / small-molecule :name (n5 / name :op1 "docetaxel") :ARG2-of (f3 / follow-01 :ARG1 (s3 / small-molecule :name (n6 / name :op1 "selumetinib"))))))) :ARG1-of (d / describe-01 :ARG0 (f2 / figure :mod "4C"))) # ::id a_pmid_2234_3622.98 ::date 2015-06-02T09:44:05 ::annotator SDL-AMR-09 ::preferred # ::snt The data presented here suggests that the combination efficacy effect seen when docetaxel was dosed before selumetinib was due to an increase in apoptosis. # ::save-date Thu Jun 11, 2015 ::file a_pmid_2234_3622_98.txt (s / suggest-01 :ARG0 (d / data :ARG1-of (p / present-01 :location (h / here))) :ARG1 (c / cause-01 :ARG0 (i / increase-01 :ARG1 (a / apoptosis)) :ARG1 (a2 / affect-01 :ARG0 (e / efficient-01 :ARG1 (c2 / combine-01)) :ARG1-of (s2 / see-01 :time (d2 / dose-01 :ARG2 (s3 / small-molecule :name (n / name :op1 "docetaxel")) :time (b / before :op1 (d3 / dose-01 :ARG2 (s4 / small-molecule :name (n2 / name :op1 "selumetinib"))))))))) # ::id a_pmid_2234_3622.99 ::date 2015-06-02T10:16:19 ::annotator SDL-AMR-09 ::preferred # ::snt Sequence scheduling of selumetinib and the Aurora B kinase inhibitor, barasertib (AZD1152), results in tumour regression and increased cell death # ::save-date Sun Jun 14, 2015 ::file a_pmid_2234_3622_99.txt (r / result-01 :ARG1 (s / schedule-01 :ARG1 (a2 / and :op1 (s2 / small-molecule :name (n / name :op1 "selumetinib")) :op2 (s3 / small-molecule :name (n2 / name :op1 "barasertib") :ARG0-of (i2 / inhibit-01 :ARG1 (k / kinase :name (n3 / name :op1 "Aurora" :op2 "B"))))) :manner (s4 / sequence)) :ARG2 (a / and :op1 (r2 / regress-01 :ARG1 (t / tumor)) :op2 (d / die-01 :ARG1 (c / cell) :ARG1-of (i / increase-01)))) # ::id a_pmid_2234_3622.100 ::date 2015-06-02T10:32:21 ::annotator SDL-AMR-09 ::preferred # ::snt The dose-scheduling effects of combining selumetinib and docetaxel lead us to investigate the sequence dependency of selumetinib combined with another mitotic targeting agent, the Aurora B kinase inhibitor, barasertib (AZD1152) (16). # ::save-date Mon Jun 15, 2015 ::file a_pmid_2234_3622_100.txt (l / lead-03 :ARG0 (a / affect-01 :ARG0 (c / combine-01 :ARG1 (s / small-molecule :name (n / name :op1 "selumetinib")) :ARG2 (s2 / small-molecule :name (n2 / name :op1 "docetaxel"))) :ARG1 (s6 / schedule-01 :ARG1 (d2 / dose-01))) :ARG1 (w / we) :ARG2 (i / investigate-01 :ARG0 w :ARG1 (d / depend-01 :ARG0 (s3 / small-molecule :name (n3 / name :op1 "selumetinib") :ARG1-of (c2 / combine-01 :ARG2 (a2 / agent :ARG0-of (t / target-01 :ARG1 (m / mitosis)) :ARG1-of (m2 / mean-01 :ARG2 (s5 / small-molecule :name (n5 / name :op1 "barasertib") :ARG0-of (i3 / inhibit-01 :ARG1 (k / kinase :name (n4 / name :op1 "Aurora" :op2 "B"))))) :mod (a3 / another)))) :ARG1 (s4 / sequence))) :ARG1-of (d3 / describe-01 :ARG0 (p / publication :ARG1-of (c3 / cite-01 :ARG2 16)))) # ::id a_pmid_2234_3622.101 ::date 2015-06-02T10:49:07 ::annotator SDL-AMR-09 ::preferred # ::snt We designed two regimes in which barasertib was dosed at 150 mg kg–1 per qd for 2 consecutive days through a mini-pump (MP) with a 24 h gap followed by selumetinib 25 mg kg–1 per bid for 14 consecutive days (schedule 1) or the reverse of this schedule where barasertib was dosed following selumetinib treatment (schedule 2) (Figure 5A). # ::save-date Wed Sep 21, 2016 ::file a_pmid_2234_3622_101.txt (d7 / design-01 :ARG0 (w / we) :ARG1 (r4 / regime :quant 2 :consist-of (o / or :op1 (d / dose-01 :ARG2 (a / and :op1 (s / small-molecule :quant 150 :name (n / name :op1 "barasertib") :quant (c2 / concentration-quantity :quant 150 :ARG1-of (r / rate-entity-91 :ARG2 (t / temporal-quantity :quant 24 :unit (h / hour))) :unit (m2 / milligram-per-kilogram)))) :duration (t2 / temporal-quantity :quant 2 :unit (d3 / day :mod (c / consecutive))) :instrument (p / pump :mod (m3 / mini)) :manner (g / gap :duration (t3 / temporal-quantity :quant 24 :unit (h2 / hour))) :ARG2-of (f / follow-01 :ARG1 (d5 / dose-01 :ARG1 (s2 / small-molecule :name (n2 / name :op1 "selumetinib") :quant (c3 / concentration-quantity :quant 25 :ARG1-of (r2 / rate-entity-91 :ARG2 (t4 / temporal-quantity :quant 12 :unit (h3 / hour))) :unit (m / milligram-per-kilogram))) :duration (t5 / temporal-quantity :quant 14 :unit (d2 / day :mod (c4 / consecutive))))) :ARG1-of (m9 / mean-01 :ARG2 (s5 / schedule :mod 1))) :op2 (d6 / dose-01 :ARG1 (s3 / small-molecule :name (n3 / name :op1 "barasertib")) :ARG2-of (f2 / follow-01 :ARG1 (t6 / treat-03 :ARG3 (s4 / small-molecule :name (n4 / name :op1 "selumetinib")))) :ARG1-of (d8 / describe-01 :ARG0 (f3 / figure :mod "5A")) :ARG1-of (m10 / mean-01 :ARG2 (s6 / schedule :mod 2)) :ARG1-of (r3 / reverse-01 :ARG2 d))))) # ::id a_pmid_2234_3622.102 ::date 2015-06-02T14:53:51 ::annotator SDL-AMR-09 ::preferred # ::snt The CaLu-6 NSCLC human tumour xenograft model was used in this study as previous experience with both agents allowed us to select appropriate dose levels in order to investigate these schedules (Davies et al, 2007; Wilkinson et al, 2007). # ::save-date Mon Dec 21, 2015 ::file a_pmid_2234_3622_102.txt (u / use-01 :ARG1 (m / model :mod (x2 / xenograft :name (n / name :op1 "CaLu-6") :mod (t / tumor :mod (h / human) :mod (d / disease :name (n2 / name :op1 "NSCLC"))))) :ARG2 (t2 / thing :ARG1-of (s / study-01) :mod (t3 / this)) :ARG1-of (c2 / cause-01 :ARG0 (a / allow-01 :ARG0 (e / experience-01 :ARG0 w :ARG1 (a2 / agent :mod (b / both)) :time (p7 / previous)) :ARG1 (s2 / select-01 :ARG0 (w / we) :ARG1 (l / level :quant-of (d2 / dose-01 :ARG1-of (a3 / appropriate-02))) :ARG3 (i / investigate-01 :ARG0 w :ARG1 (s3 / schedule :mod t3))))) :ARG1-of (d3 / describe-01 :ARG0 (a4 / and :op1 (p / publication-91 :ARG0 (a5 / and :op1 (p2 / person :name (n3 / name :op1 "Davies")) :op2 (p3 / person :mod (o / other))) :time (d4 / date-entity :year 2007)) :op2 (p4 / publication-91 :ARG0 (a6 / and :op1 (p5 / person :name (n4 / name :op1 "Wilkinson")) :op2 p3) :time d4)))) # ::id a_pmid_2234_3622.103 ::date 2015-06-02T15:30:10 ::annotator SDL-AMR-09 ::preferred # ::snt Selumetinib and barasertib alone resulted in 57% (P<0.005) and 95% (P<0.0005) tumour growth inhibition compared with the vehicle-treated controls at day 21 after the start of dosing. # ::save-date Tue Dec 15, 2015 ::file a_pmid_2234_3622_103.txt (a3 / and :op1 (r / result-01 :ARG1 (s / small-molecule :name (n / name :op1 "selumetinib") :mod (a / alone) :ARG1-of (c / compare-01 :ARG2 (c3 / control :ARG1-of (t2 / treat-04 :ARG2 (v / vehicle))))) :ARG2 (i / inhibit-01 :ARG1 (g / grow-01 :ARG1 (t / tumor)) :quant (p / percentage-entity :value 57) :time (a2 / after :op1 (s2 / start-01 :ARG1 (d / dose-01)) :quant (t3 / temporal-quantity :quant 21 :unit (d2 / day))) :ARG1-of (s4 / statistical-test-91 :ARG2 (l / less-than :op1 0.005)))) :op2 (r2 / result-01 :ARG1 (s3 / small-molecule :name (n2 / name :op1 "barasertib") :mod a :ARG1-of c) :ARG2 (i2 / inhibit-01 :ARG1 g :quant (p2 / percentage-entity :value 95) :time a2 :ARG1-of (s5 / statistical-test-91 :ARG2 (l2 / less-than :op1 0.0005))))) # ::id a_pmid_2234_3622.104 ::date 2015-06-02T15:31:49 ::annotator SDL-AMR-09 ::preferred # ::snt In comparison when selumetinib was dosed before barasertib the anti-tumour efficacy was 74% (P<0.0005) in contrast to 106% (P<0.0005) observed when selumetinib was dosed following barasertib. # ::save-date Sun Jan 3, 2016 ::file a_pmid_2234_3622_104.txt (e3 / efficient-01 :ARG1 (d / dose-01 :ARG1 (s / small-molecule :name (n / name :op1 "selumetinib")) :time (b / before :op1 (d2 / dose-01 :ARG1 (s2 / small-molecule :name (n2 / name :op1 "barasertib"))))) :ARG2 (o / oppose-01 :ARG1 (t / tumor)) :ARG1-of (c / contrast-01 :ARG2 (e2 / efficient-01 :quant (p3 / percentage-entity :value 106) :ARG1-of (o2 / observe-01 :time (d3 / dose-01 :ARG1 s :ARG1-of (f / follow-01 :ARG2 s2))) :ARG1-of (s4 / statistical-test-91 :ARG2 l))) :ARG1-of (c2 / compare-01) :quant (p / percentage-entity :value 74) :ARG1-of (s3 / statistical-test-91 :ARG2 (l / less-than :op1 0.0005))) # ::id a_pmid_2234_3622.105 ::date 2015-06-02T15:34:02 ::annotator SDL-AMR-09 ::preferred # ::snt At 21 days after the start of dosing the control, animals had to be culled due to tumour size; however, the monotherapy and combination-treated groups were kept on study for a further 14 days. # ::save-date Wed Sep 21, 2016 ::file a_pmid_2234_3622_105.txt (m / multi-sentence :snt1 (o / obligate-01 :ARG2 (c / cull-01 :ARG1 (a / animal) :ARG1-of (c2 / cause-01 :ARG0 (s / size-01 :ARG1 (t / tumor))) :time (a2 / after :op1 (s2 / start-01 :ARG1 (d / dose-01 :ARG1 (c3 / control))) :quant (t2 / temporal-quantity :quant 21 :unit (d2 / day))))) :snt2 (h / have-concession-91 :ARG2 (k / keep-01 :ARG1 (a3 / and :op1 (g / group :mod (m2 / monotherapy)) :op2 (g2 / group :ARG1-of (t3 / treat-04 :ARG2 (c5 / combine-01))) :ARG1-of (s3 / study-01)) :duration (t5 / temporal-quantity :quant 14 :mod (f / further) :unit (d3 / day))))) # ::id a_pmid_2234_3622.106 ::date 2015-06-02T16:10:24 ::annotator SDL-AMR-09 ::preferred # ::snt During this time, the tumours in the monotherapy and schedule 2 groups started to re-grow. # ::save-date Thu Jun 11, 2015 ::file a_pmid_2234_3622_106.txt (s / start-01 :ARG0 (t / tumor :source (a / and :op1 (g / group :mod (m / monotherapy)) :op2 (g2 / group :mod (s2 / schedule :mod 2)))) :ARG1 (g3 / grow-01 :ARG1 t :mod (a2 / again)) :time (t3 / time :mod (t4 / this))) # ::id a_pmid_2234_3622.107 ::date 2015-06-03T13:18:28 ::annotator SDL-AMR-09 ::preferred # ::snt Interestingly, the tumours in the group where barasertib was administered before selumetinib (schedule 1) tumour re-growth was delayed (Figure 5B). # ::save-date Thu Jun 11, 2015 ::file a_pmid_2234_3622_107.txt (d / delay-01 :ARG1 (g / grow-01 :ARG1 (t / tumor :source (g2 / group :ARG2-of (a / administer-01 :ARG1 (s / small-molecule :name (n / name :op1 "barasertib")) :time (b / before :op1 (a2 / administer-01 :ARG1 (s2 / small-molecule :name (n2 / name :op1 "selumetinib")))) :ARG2-of (m / mean-01 :ARG1 (s3 / schedule :mod 1)))))) :mod (i / interesting) :ARG1-of (d2 / describe-01 :ARG0 (f / figure :mod "5B"))) # ::id a_pmid_2234_3622.108 ::date 2015-06-03T13:52:34 ::annotator SDL-AMR-09 ::preferred # ::snt In order to investigate this further, we performed pharmacodynamic analysis on tumour tissue. # ::save-date Tue Jul 28, 2015 ::file a_pmid_2234_3622_108.txt (p / perform-02 :ARG0 (w / we) :ARG1 (a / analyze-01 :ARG0 w :ARG1 (t / tissue :mod (t2 / tumor)) :mod (p2 / pharmacodynamic)) :purpose (i / investigate-01 :ARG0 w :ARG1 (t3 / this) :degree (f / further))) # ::id a_pmid_2234_3622.109 ::date 2015-06-03T14:03:40 ::annotator SDL-AMR-09 ::preferred # ::snt In schedule 1 we analysed tumour tissue at 24 h after the end of the barasertib infusion (PD1) and at the end of the selumetinib-dosing period (PD2) (Figure 5A). # ::save-date Sun Jan 3, 2016 ::file a_pmid_2234_3622_109.txt (a / analyze-01 :ARG0 (w / we) :ARG1 (t / tissue :mod (t2 / tumor)) :time (a2 / after :op1 (e / end-01 :ARG1 (i / infuse-01 :ARG1 (s / small-molecule :name (n / name :op1 "barasertib")))) :quant (t3 / temporal-quantity :quant 24 :unit (h / hour))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure :mod "5A")) :location (s3 / schedule :mod 1) :time (a5 / and :op1 (a3 / after :op1 (e3 / end-01 :ARG1 (p2 / period :duration-of (i2 / infuse-01 :ARG2 (s4 / small-molecule :name (n3 / name :op1 "barasertib")) :ARG1-of (d3 / describe-01 :ARG2 (s5 / string-entity :value "PD1")))))) :op2 (a4 / after :op1 (e2 / end-01 :ARG1 (p / period :duration-of (d / dose-01 :ARG2 (s2 / small-molecule :name (n2 / name :op1 "selumetinib"))) :ARG1-of (d4 / describe-01 :ARG2 (s6 / string-entity :value "PD2"))))))) # ::id a_pmid_2234_3622.110 ::date 2015-06-03T14:17:55 ::annotator SDL-AMR-09 ::preferred # ::snt In schedule 2, tumours were harvested 24 h after the end of the barasertib infusion at the end of the study (PD3) (Figure 5A). # ::save-date Sun Jan 3, 2016 ::file a_pmid_2234_3622_110.txt (h / harvest-01 :ARG1 (t / tumor) :time (a / and :op1 (a2 / after :op1 (e / end-01 :ARG1 (i / infuse-01 :ARG1 (s / small-molecule :name (n / name :op1 "barasertib"))))) :op2 (a3 / after :op1 (e2 / end-01 :ARG1 (t2 / thing :ARG1-of (s2 / study-01)))) :quant (t3 / temporal-quantity :quant 24 :unit (h2 / hour))) :location (s3 / schedule :mod 2) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "5A")) :ARG1-of (d2 / describe-01 :ARG2 (s4 / string-entity :value "PD3"))) # ::id a_pmid_2234_3622.111 ::date 2015-06-03T14:23:05 ::annotator SDL-AMR-09 ::preferred # ::snt Using flow cytometry we assessed tissues for polyploidy and demonstrated that compared with the vehicle-treated control group, barasertib-treated tumours resulted in increased polyploidy (1.7-fold change; P<0.05) in the PD1 samples consistent with the mechanism of this agent (Figure 5C) (Wilkinson et al, 2007). # ::save-date Mon Oct 23, 2017 ::file a_pmid_2234_3622_111.txt (a / and :op1 (a2 / assess-01 :ARG0 (w / we) :ARG1 (t / tissue) :ARG2 (p / polyploidy)) :op2 (d / demonstrate-01 :ARG0 w :ARG1 (r / result-01 :ARG1 (t2 / tumor :ARG1-of (t3 / treat-04 :ARG2 (s / small-molecule :name (n / name :op1 "barasertib"))) :ARG1-of (c3 / compare-01 :ARG2 (g / group :ARG0-of (c4 / control-01) :ARG1-of (t6 / treat-03 :ARG2 (v / vehicle))))) :ARG2 (p2 / polyploidy :ARG1-of (i / increase-01 :ARG2 (t7 / times :quant 1.7) :ARG2-of (m / mean-01 :ARG1 (c / change-01 :ARG1 p2)) :source (s2 / sample-01 :ARG2 (t4 / thing :name (n2 / name :op1 "PD1"))) :ARG1-of (c2 / consistent-01 :ARG2 (m2 / mechanism :poss (a3 / agent :mod (t5 / this)))) :ARG1-of (s3 / statistical-test-91 :ARG2 (l / less-than :op1 0.05)))))) :ARG2-of (u / use-01 :ARG0 w :ARG1 (c5 / cytometry :mod (f / flow))) :ARG1-of (d2 / describe-01 :ARG0 (f2 / figure :mod "5C")) :ARG1-of (d3 / describe-01 :ARG0 (p4 / publication-91 :ARG0 (a4 / and :op1 (p5 / person :name (n3 / name :op1 "Wilkinson")) :op2 (p6 / person :mod (o / other))) :time (d4 / date-entity :year 2007)))) # ::id a_pmid_2234_3622.112 ::date 2015-06-03T15:03:40 ::annotator SDL-AMR-09 ::preferred # ::snt In the same experiment, we monitored the population of sub G1 cells in these groups. # ::save-date Mon Jun 15, 2015 ::file a_pmid_2234_3622_112.txt (m / monitor-01 :ARG0 (w / we) :ARG1 (p / population :consist-of (c / cell-line :name (n / name :op1 "sub" :op2 "G1"))) :location (g / group :mod (t / this)) :medium (e / experiment-01 :ARG1-of (s / same-01))) # ::id a_pmid_2234_3622.113 ::date 2015-06-03T15:23:12 ::annotator SDL-AMR-09 ::preferred # ::snt At the end of the dosing period in schedule 1 (PD2), there was a significant increase (3.5-fold change; P<0.0005) in the sub G1 population in the combination compared with the vehicle-treated controls and selumetinib monotherapy (Figure 5Cii). # ::save-date Mon Oct 23, 2017 ::file a_pmid_2234_3622_113.txt (i / increase-01 :ARG1 (p / population :consist-of (c / cell-line :name (n / name :op1 "sub" :op2 "G1")) :ARG1-of (c3 / combine-01)) :ARG2 (t2 / times :quant 3.5) :ARG1-of (s / significant-02) :ARG2-of (m / mean-01) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "5Cii")) :ARG1-of (c4 / compare-01 :ARG2 (a / and :op1 (c5 / control :ARG1-of (t / treat-04 :ARG2 (v / vehicle))) :op2 (m2 / monotherapy :mod (s2 / small-molecule :name (n2 / name :op1 "selumetinib"))))) :time (a2 / after :op1 (e / end-01 :ARG1 (p4 / period :duration-of (d2 / dose-01) :ARG1-of (d3 / describe-01 :ARG2 (s5 / string-entity :value "PD2")) :time (s3 / schedule :mod 1)))) :ARG1-of (s4 / statistical-test-91 :ARG2 (l / less-than :op1 0.0005))) # ::id a_pmid_2234_3622.114 ::date 2015-06-03T15:48:09 ::annotator SDL-AMR-09 ::preferred # ::snt In comparison, the sub G1 populations in schedule 2 (PD3) were increased ∼2-fold in both the monotherapy and combination groups (Figure 5Dii). # ::save-date Mon Oct 23, 2017 ::file a_pmid_2234_3622_114.txt (i / increase-01 :ARG1 (p / population :consist-of (c2 / cell-line :name (n / name :op1 "sub" :op2 "G1"))) :ARG2 (t / times :quant (a2 / approximately :op1 2)) :time (s / schedule :mod 2 :ARG1-of (d2 / describe-01 :ARG2 (s2 / string-entity :value "PD3"))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "5Dii")) :ARG1-of (c / compare-01) :location (a / and :op1 (g / group :mod (m / monotherapy)) :op2 (g2 / group :ARG3-of (c3 / combine-01)))) # ::id a_pmid_2234_3622.115 ::date 2015-06-03T16:00:12 ::annotator SDL-AMR-09 ::preferred # ::snt These results suggest that the sustained anti-tumour effect and regression observed when barasertib is scheduled before selumetinib is likely to be due to an avoidance of cell cycle-mediated antagonism which allowed an increase in cell death. # ::save-date Thu Dec 7, 2017 ::file a_pmid_2234_3622_115.txt (s / suggest-01 :ARG0 (t / thing :ARG2-of (r / result-01) :mod (t2 / this)) :ARG1 (l / likely-01 :ARG1 (c / cause-01 :ARG0 (a / avoid-01 :ARG1 (a2 / antagonize-02 :ARG1-of (m / mediate-01 :ARG0 (c2 / cycle-02 :ARG1 (c3 / cell))) :ARG0-of (a3 / allow-01 :ARG1 (i / increase-01 :ARG1 (d / die-01 :ARG1 (c4 / cell)))))) :ARG1 (a4 / and :op1 (a5 / affect-01 :ARG2 (o / oppose-01 :ARG1 (t3 / tumor)) :ARG1-of (s6 / sustain-01)) :op2 (r2 / regress-01) :ARG1-of (o2 / observe-01 :time (s2 / schedule-01 :ARG1 (s3 / small-molecule :name (n / name :op1 "barasertib")) :ARG3 (b / before :op1 (d2 / due-03 :ARG1 (s5 / small-molecule :name (n2 / name :op1 "selumetinib")))))))))) # ::id a_pmid_2251_5704.8 ::date 2015-09-01T21:44:10 ::annotator SDL-AMR-09 ::preferred # ::snt Fourteen cutaneous melanoma cell lines with different driver mutations were sensitive to the antiproliferative effects of TAK733, with a higher proportion of BRAFV600E mutant cell lines being highly sensitive with IC50s below 1 nM. # ::save-date Thu Oct 19, 2017 ::file a_pmid_2251_5704_8.txt (s / sensitive-03 :ARG0 (c / cell-line :quant 14 :mod (m2 / medical-condition :name (n / name :op1 "melanoma") :mod (s2 / skin)) :ARG0-of (h3 / have-03 :ARG1 (s3 / sensitive-03 :ARG0 (p2 / proportion :quant-of (c2 / cell-line :part (g / gene :name (n3 / name :op1 "BRAF") :ARG2-of (m3 / mutate-01 :value "V600E"))) :ARG1-of (h5 / have-degree-91 :ARG2 (h / high-02 :ARG1 p2) :ARG3 (m4 / more))) :ARG1-of (h2 / high-02) :condition (t / thing :name (n4 / name :op1 "IC50") :ARG1-of (e / equal-01 :ARG2 (b / below :op1 (c3 / concentration-quantity :quant 1 :unit (n5 / nanomolar))))))) :ARG0-of (h4 / have-03 :ARG1 (m / mutate-01 :ARG0-of (d2 / drive-02) :ARG1-of (d3 / differ-02)))) :ARG1 (a / affect-01 :ARG0 (s4 / small-molecule :name (n2 / name :op1 "TAK733")) :ARG0-of (o / oppose-01 :ARG1 (p / proliferate-01)))) # ::id a_pmid_2251_5704.9 ::date 2015-06-03T07:51:32 ::annotator SDL-AMR-09 ::preferred # ::snt The five uveal melanoma cell lines had GNAQ or GNA11 mutations and were either moderately or highly sensitive to TAK733. # ::save-date Sun Dec 20, 2015 ::file a_pmid_2251_5704_9.txt (a / and :op1 (h / have-03 :ARG0 (c / cell-line :quant 5 :mod (m4 / medical-condition :name (n / name :op1 "melanoma") :mod (u / uvea))) :ARG1 (m2 / mutate-01 :ARG1 (o / or :op1 (g / gene :name (n2 / name :op1 "GNAQ") :ARG2-of (m / mutate-01)) :op2 (g2 / gene :name (n3 / name :op1 "GNA11"))))) :op2 (s / sensitive-03 :ARG0 c :ARG1 (s2 / small-molecule :name (n4 / name :op1 "TAK733")) :degree (o2 / or :op1 (h2 / high-02) :op2 (m3 / moderate-03)))) # ::id a_pmid_2251_5704.10 ::date 2015-06-03T07:58:09 ::annotator SDL-AMR-09 ::preferred # ::snt The tested cell lines wild type for NRAS, BRAF, GNAQ and GNA11 driver mutations were moderately to highly resistant to TAK733. # ::save-date Sun Dec 20, 2015 ::file a_pmid_2251_5704_10.txt (r / resist-01 :ARG0 (c / cell-line :ARG1-of (t / test-01 :ARG2 (m / mutate-01 :ARG2 (a / and :op1 (g2 / gene :name (n / name :op1 "NRAS")) :op2 (g / gene :name (n2 / name :op1 "BRAF")) :op3 (g3 / gene :name (n3 / name :op1 "GNAQ")) :op4 (g4 / gene :name (n4 / name :op1 "GNA11"))) :ARG0-of (d / drive-02))) :mod (w / wild-type)) :ARG1 (s / small-molecule :name (n5 / name :op1 "TAK733")) :degree (b / between :op1 (m2 / moderate-03) :op2 (h / high-02))) # ::id a_pmid_2251_5704.11 ::date 2015-06-03T08:12:27 ::annotator SDL-AMR-09 ::preferred # ::snt TAK733 led to a decrease in pERK and G1 arrest in most of these melanoma cell lines regardless of their origin, driver oncogenic mutations and in vitro sensitivity to TAK733. # ::save-date Sat Jan 16, 2016 ::file a_pmid_2251_5704_11.txt (l / lead-03 :ARG0 (s2 / small-molecule :name (n / name :op1 "TAK733")) :ARG2 (d / decrease-01 :ARG1 (a / and :op1 (e / enzyme :name (n2 / name :op1 "ERK") :ARG3-of (p / phosphorylate-01)) :op2 (a2 / arrest-02 :time (e2 / event :name (n5 / name :op1 "G1"))))) :location (c / cell-line :ARG1-of (i2 / include-91 :ARG2 (c2 / cell-line :mod (m / medical-condition :name (n3 / name :op1 "melanoma")) :mod (t / this))) :mod (m2 / most)) :ARG1-of (r / regardless-91 :ARG2 (a3 / and :op1 (o / originate-01 :ARG1 c) :op2 (m3 / mutate-01 :ARG1 c :ARG0-of (d3 / drive-02) :ARG0-of (c3 / cause-01 :ARG1 (d4 / disease :wiki "Cancer" :name (n4 / name :op1 "cancer")))) :op3 (s / sensitive-03 :ARG0 c :ARG1 s2 :mod (i3 / in-vitro))))) # ::id a_pmid_2251_5704.12 ::date 2015-06-03T08:29:47 ::annotator SDL-AMR-09 ::preferred # ::snt MEK inhibition resulted in increase in pMEK more prominently in NRASQ61L mutant and GNAQ mutant cell lines than in BRAFV600E mutant cell lines. # ::save-date Thu Oct 19, 2017 ::file a_pmid_2251_5704_12.txt (r / result-01 :ARG1 (i / inhibit-01 :ARG1 (e / enzyme :name (n / name :op1 "MEK"))) :ARG2 (i2 / increase-01 :ARG1 (e2 / enzyme :name (n2 / name :op1 "MEK") :ARG3-of (p / phosphorylate-01)) :location (a / and :op1 (c3 / cell-line :mod (g / gene :name (n3 / name :op1 "NRAS") :ARG2-of (m / mutate-01 :value "Q61L"))) :op2 (c / cell-line :mod (g2 / gene :name (n4 / name :op1 "GNAQ") :ARG2-of (m5 / mutate-01)))) :ARG1-of (h / have-degree-91 :ARG2 (p2 / prominent) :ARG3 (m4 / more) :ARG4 (i3 / increase-01 :ARG1 e2 :location (c2 / cell-line :mod (g3 / gene :name (n6 / name :op1 "BRAF") :ARG2-of (m3 / mutate-01 :value "V600E"))))))) # ::id a_pmid_2251_5704.13 ::date 2015-06-03T08:36:52 ::annotator SDL-AMR-09 ::preferred # ::snt Uptake of the metabolic tracers FDG and FLT was inhibited by TAK733 in a manner that closely paralleled the in vitro sensitivity assays. # ::save-date Fri Feb 12, 2016 ::file a_pmid_2251_5704_13.txt (i / inhibit-01 :ARG0 (s2 / small-molecule :name (n3 / name :op1 "TAK733")) :ARG1 (t2 / take-up-13 :ARG1 (a / and :op1 (s3 / small-molecule :name (n / name :op1 "FDG")) :op2 (s4 / small-molecule :name (n2 / name :op1 "FLT")) :ARG0-of (t / trace-02 :ARG1 (m3 / metabolism)))) :manner (p / parallel-01 :ARG1 (a2 / assay-01 :ARG1 (s / sensitive-03) :manner (i3 / in-vitro)) :ARG1-of (c / close-10))) # ::id a_pmid_2251_5704.37 ::date 2015-06-04T00:54:05 ::annotator SDL-AMR-09 ::preferred # ::snt Sensitivity of cutaneous and uveal melanoma cell lines to TAK733 # ::save-date Thu Dec 10, 2015 ::file a_pmid_2251_5704_37.txt (s / sensitive-03 :ARG0 (a / and :op1 (c / cell-line :mod (m / medical-condition :name (n3 / name :op1 "melanoma") :mod (s2 / skin))) :op2 (c2 / cell-line :mod (m2 / medical-condition :name (n / name :op1 "melanoma") :mod (u / uvea)))) :ARG1 (s3 / small-molecule :name (n2 / name :op1 "TAK733"))) # ::id a_pmid_2251_5704.38 ::date 2015-06-04T01:03:43 ::annotator SDL-AMR-09 ::preferred # ::snt Cutaneous and uveal melanoma cell lines were cultured in vitro in the presence of increasing concentrations of TAK-733 for 72 hours to determine the half maximal inhibitory concentration (IC50) in cell proliferation assays. # ::save-date Mon Dec 21, 2015 ::file a_pmid_2251_5704_38.txt (c / culture-01 :ARG1 (a / and :op1 (c2 / cell-line :mod (m / medical-condition :name (n3 / name :op1 "melanoma") :mod (s / skin))) :op2 (c3 / cell-line :mod (m2 / medical-condition :name (n / name :op1 "melanoma") :mod (u / uvea)))) :manner (i / in-vitro) :condition (p / present-02 :ARG1 (c4 / concentrate-02 :ARG1 (s2 / small-molecule :name (n2 / name :op1 "TAK-733")) :ARG1-of (i2 / increase-01))) :duration (t2 / temporal-quantity :quant 72 :unit (h2 / hour)) :purpose (d2 / determine-01 :ARG1 (c5 / concentrate-02 :mod (i3 / inhibit-01 :degree (p3 / percentage-entity :value 50)) :time (a2 / assay-01 :ARG1 (p2 / proliferate-01 :ARG0 (c6 / cell)))))) # ::id a_pmid_2251_5704.39 ::date 2015-06-04T01:12:44 ::annotator SDL-AMR-09 ::preferred # ::snt Cell lines with an IC50 less than 10 nM were considered sensitive, and cell lines with IC50 less than 1 nM were considered highly sensitive. # ::save-date Mon Dec 21, 2015 ::file a_pmid_2251_5704_39.txt (a / and :op1 (c / consider-01 :ARG1 (s / sensitive-03 :ARG0 (c2 / cell-line :ARG1-of (h4 / have-percentage-maximal-inhibitory-concentration-01 :ARG2 50 :ARG4 (l / less-than :op1 (c3 / concentration-quantity :quant 10 :unit (n2 / nanomolar))))))) :op2 (c4 / consider-01 :ARG1 (s2 / sensitive-03 :ARG0 (c5 / cell-line :ARG1-of (h / have-percentage-maximal-inhibitory-concentration-01 :ARG2 50 :ARG4 (l4 / less-than :op1 (c6 / concentration-quantity :quant 1 :unit (n4 / nanomolar))))) :ARG1-of (h3 / high-02)))) # ::id a_pmid_2251_5704.40 ::date 2015-06-04T01:21:26 ::annotator SDL-AMR-09 ::preferred # ::snt Among 12 BRAFV600E mutated cutaneous cell lines tested, seven were highly sensitive to TAK-733 with IC50s less than 1 nM (Figure 1 and Additional file 1: Figure S1). # ::save-date Mon Dec 21, 2015 ::file a_pmid_2251_5704_40.txt (s / sensitive-03 :ARG0 (c / cell-line :quant 7 :mod (s2 / skin) :mod (g / gene :name (n / name :op1 "BRAF") :ARG2-of (m / mutate-01 :value "V600E")) :ARG1-of (i / include-91 :ARG2 (c2 / cell-line :quant 12 :ARG1-of (t2 / test-01) :mod s2 :mod g))) :ARG1 (s3 / small-molecule :name (n3 / name :op1 "TAK-733") :ARG1-of (h3 / have-percentage-maximal-inhibitory-concentration-01 :ARG2 50 :ARG4 (l2 / less-than :op1 (c3 / concentration-quantity :quant 1 :unit (n2 / nanomolar))))) :ARG1-of (h / high-02) :ARG1-of (d2 / describe-01 :ARG0 (a / and :op1 (f / figure :mod 1) :op2 (f2 / file :ARG1-of (a2 / add-02) :ARG1-of (m4 / mean-01 :ARG2 (f3 / figure :mod "S1")))))) # ::id a_pmid_2251_5704.41 ::date 2015-06-04T01:31:44 ::annotator SDL-AMR-09 ::preferred # ::snt Five BRAFV600E mutant cutaneous cell lines had an IC50 higher than 100 nM and were considered highly resistant to this agent.. # ::save-date Fri Dec 15, 2017 ::file a_pmid_2251_5704_41.txt (a / and :op1 (h2 / have-03 :ARG0 (c2 / cell-line :quant 5 :mod (s / skin) :mod (g / gene :name (n / name :op1 "BRAF") :ARG2-of (m2 / mutate-01 :value "V600E"))) :ARG1 (t / thing :name (n2 / name :op1 "IC50") :ARG1-of (h3 / have-degree-91 :ARG2 (h / high-02 :ARG1 t) :ARG3 (m3 / more) :ARG4 (c3 / concentration-quantity :quant 100 :unit (n3 / nanomolar))))) :op2 (c / consider-01 :ARG1 (r / resist-01 :ARG0 c2 :ARG1 (a2 / agent :mod (t2 / this)) :degree (h4 / high-02)))) # ::id a_pmid_2251_5704.42 ::date 2015-06-04T01:37:55 ::annotator SDL-AMR-09 ::preferred # ::snt Among ten NRASQ61 mutant cutaneous melanoma cell lines, four were sensitive with IC50s below 10 nM, but none was highly sensitive. # ::save-date Mon Dec 21, 2015 ::file a_pmid_2251_5704_42.txt (c / contrast-01 :ARG1 (s / sensitive-03 :ARG0 (c2 / cell-line :quant 4 :mod (m2 / medical-condition :name (n / name :op1 "melanoma") :mod (s2 / skin)) :mod (g / gene :name (n2 / name :op1 "NRAS") :ARG2-of (m / mutate-01 :value "Q61")) :ARG1-of (i / include-91 :ARG2 (c3 / cell-line :quant 10 :mod g :mod m2)) :mod (h3 / have-percentage-maximal-inhibitory-concentration-01 :ARG2 50 :ARG4 (b / below :op1 (c4 / concentration-quantity :quant 10 :unit (n3 / nanomolar)))))) :ARG2 (s4 / sensitive-03 :ARG0 (n6 / none) :ARG1-of (h / high-02))) # ::id a_pmid_2251_5704.43 ::date 2015-06-04T03:46:22 ::annotator SDL-AMR-09 ::preferred # ::snt Our panel also included five cutaneous melanoma cell lines wild type for mutations in NRAS, BRAF, GNAQ and GNA11 and only one was highly sensitive to TAK733 with IC50s below 1 nM, while two were considered sensitive with IC50 less than 10 nM. # ::save-date Mon Dec 21, 2015 ::file a_pmid_2251_5704_43.txt (a2 / and :op1 (i / include-01 :ARG1 (c / cell-line :quant 5 :mod (m2 / medical-condition :name (n / name :op1 "melanoma") :mod (s / skin)) :mod (w2 / wild-type)) :ARG2 (p / panel :poss (w / we)) :purpose (m / mutate-01 :ARG1 (a / and :op1 (g / gene :name (n2 / name :op1 "NRAS")) :op2 (g2 / gene :name (n3 / name :op1 "BRAF")) :op3 (g3 / gene :name (n4 / name :op1 "GNAQ")) :op4 (g4 / gene :name (n5 / name :op1 "GNA11")))) :mod (a3 / also)) :op2 (c4 / contrast-01 :ARG1 (s2 / sensitive-03 :ARG0 (c2 / cell-line :quant 1 :ARG1-of (h4 / have-percentage-maximal-inhibitory-concentration-01 :ARG2 50 :ARG4 (b / below :op1 (c3 / concentration-quantity :quant 1 :unit (n8 / nanomolar))))) :ARG1 (s4 / small-molecule :name (n6 / name :op1 "TAK733")) :ARG1-of (h / high-02)) :ARG2 (c5 / consider-01 :ARG1 (s3 / sensitive-03 :ARG0 (c6 / cell-line :quant 2 :ARG1-of (h2 / have-percentage-maximal-inhibitory-concentration-01 :ARG2 50 :ARG4 (l2 / less-than :op1 (c7 / concentration-quantity :quant 10 :unit (n10 / nanomolar))))))))) # ::id a_pmid_2251_5704.44 ::date 2015-06-04T03:57:34 ::annotator SDL-AMR-09 ::preferred # ::snt All five uveal melanoma cell lines were sensitive to TAK733 with IC50 values below 10 nM, with three of them being highly sensitive. # ::save-date Mon Dec 21, 2015 ::file a_pmid_2251_5704_44.txt (a2 / and :op1 (s / sensitive-03 :ARG0 (c / cell-line :quant 5 :mod (m / medical-condition :name (n / name :op1 "melanoma") :mod (u / uvea)) :mod (a / all)) :ARG1 (s3 / small-molecule :name (n2 / name :op1 "TAK733") :ARG1-of (h / have-percentage-maximal-inhibitory-concentration-01 :ARG2 50 :ARG4 (b / below :op1 (c2 / concentration-quantity :quant 10 :unit (n4 / nanomolar)))))) :op2 (s2 / sensitive-03 :ARG0 (c3 / cell-line :quant 3 :ARG1-of (i2 / include-91 :ARG2 c)) :ARG1-of (h2 / high-02))) # ::id a_pmid_2251_5704.45 ::date 2015-06-04T04:04:03 ::annotator SDL-AMR-09 ::preferred # ::snt All these cell lines carried GNAQ or GNA11 driver mutations (Figure 1 and Table 1). # ::save-date Tue Aug 4, 2015 ::file a_pmid_2251_5704_45.txt (c / carry-01 :ARG0 (c2 / cell-line :mod (t / this) :mod (a / all)) :ARG1 (m / mutate-01 :ARG1 (o / or :op1 (g / gene :name (n / name :op1 "GNAQ")) :op2 (g2 / gene :name (n2 / name :op1 "GNA11"))) :ARG0-of (d / drive-02)) :ARG1-of (d3 / describe-01 :ARG0 (a2 / and :op1 (f / figure :mod 1) :op2 (t2 / table :mod 1)))) # ::id a_pmid_2251_5704.46 ::date 2015-06-04T04:07:47 ::annotator SDL-AMR-09 ::preferred # ::snt Overall, there was a clear trend of higher sensitivity in BRAF mutant cell lines, but all subgroups included cell lines with variable sensitivity and also high resistance to exposure to the MEK inhibitor. # ::save-date Thu Oct 19, 2017 ::file a_pmid_2251_5704_46.txt (c3 / contrast-01 :ARG1 (e2 / exist-01 :ARG1 (t2 / trend :ARG1-of (c / clear-06) :topic (s / sensitive-03 :ARG0 (c2 / cell-line :mod (g / gene :name (n2 / name :op1 "BRAF") :ARG2-of (m3 / mutate-01))) :ARG1-of (h4 / have-degree-91 :ARG2 (h / high-02 :ARG1 s) :ARG3 (m2 / more)))) :mod (o / overall)) :ARG2 (i2 / include-01 :ARG1 (c4 / cell-line :ARG0-of (h3 / have-03 :ARG1 (a2 / and :op1 (s3 / sensitive-03 :ARG0 c4 :ARG1-of (v / vary-01)) :op2 (r / resist-01 :ARG0 c4 :ARG1 (e3 / expose-01 :ARG1 c4 :ARG2 (m4 / molecular-physical-entity :ARG0-of (i3 / inhibit-01 :ARG1 (p / protein-family :name (n3 / name :op1 "MEK"))))) :ARG1-of (h2 / high-02) :mod (a3 / also))))) :ARG2 (s2 / subgroup :mod (a / all)))) # ::id a_pmid_2251_5704.47 ::date 2015-06-04T04:30:41 ::annotator SDL-AMR-09 ::preferred # ::snt Characterization of oncogenic alterations in melanoma cell lines tested for sensitivity to TAK733 # ::save-date Thu Dec 10, 2015 ::file a_pmid_2251_5704_47.txt (c3 / characterize-01 :ARG1 (a / alter-01 :ARG1 (c2 / cell-line :mod (m / medical-condition :name (n / name :op1 "melanoma")) :ARG1-of (t2 / test-01 :ARG2 (s / sensitive-03 :ARG1 (s2 / small-molecule :name (n2 / name :op1 "TAK733"))))) :ARG0-of (c4 / cause-01 :ARG1 (d2 / disease :wiki "Cancer" :name (n3 / name :op1 "cancer"))))) # ::id a_pmid_2251_5704.48 ::date 2015-06-04T04:34:48 ::annotator SDL-AMR-09 ::preferred # ::snt Legend: 1Tandem mutation where the codon changed from GTG to GAA. # ::save-date Sun Jun 14, 2015 ::file a_pmid_2251_5704_48.txt (m2 / mutate-01 :ARG1 (c2 / codon) :ARG2 (p2 / protein :name (n2 / name :op1 "GAA")) :ARG3 (p / protein :name (n / name :op1 "GTG")) :ARG1-of (d / describe-01 :ARG2 (l2 / legend)) :mod (t / tandem)) # ::id a_pmid_2251_5704.49 ::date 2015-06-04T04:39:24 ::annotator SDL-AMR-09 ::preferred # ::snt TAK733 has similar inhibitory effects on cell cycle in sensitive and resistant cutaneous melanoma cell lines # ::save-date Sun Dec 20, 2015 ::file a_pmid_2251_5704_49.txt (a2 / affect-01 :ARG0 (s3 / small-molecule :name (n / name :op1 "TAK733")) :ARG1 (c / cycle :mod (c2 / cell)) :ARG2 (i2 / inhibit-01) :ARG1-of (r2 / resemble-01) :location (c3 / cell-line :mod (m / medical-condition :name (n2 / name :op1 "melanoma") :mod (s / skin)) :ARG0-of (r3 / resist-01) :ARG0-of (s2 / sensitive-03))) # ::id a_pmid_2251_5704.50 ::date 2015-06-04T04:45:23 ::annotator SDL-AMR-09 ::preferred # ::snt To study the effects of TAK733 on cell cycle progression downstream of MEK signaling we used DAPI flow cytometric staining (representative examples of flow histograms in Figure 2a and b). # ::save-date Wed Jan 24, 2018 ::file a_pmid_2251_5704_50.txt (u / use-01 :ARG0 (w / we) :ARG1 (s4 / stain-01 :ARG2 (s5 / small-molecule :name (n3 / name :op1 "DAPI") :mod (c3 / cytometry :mod (f4 / flow)))) :purpose (s / study-01 :ARG0 w :ARG1 (a / affect-01 :ARG0 (s3 / small-molecule :name (n2 / name :op1 "TAK733")) :ARG1 (p2 / progress-01 :ARG1 (c / cycle-02 :ARG1 (c2 / cell)) :location (r / relative-position :op1 (s2 / signal-07 :ARG1 (e / enzyme :name (n / name :op1 "MEK"))) :direction (d / downstream))))) :ARG0-of (e3 / exemplify-01 :ARG1 (h2 / histogram :mod (f5 / flow)) :ARG1-of (r2 / represent-01) :ARG1-of (d2 / describe-01 :ARG0 (a2 / and :op1 (f / figure :mod "2a") :op2 (f2 / figure :mod "2b"))))) # ::id a_pmid_2251_5704.51 ::date 2015-06-05T00:21:23 ::annotator SDL-AMR-09 ::preferred # ::snt For these studies we chose two NRAS mutants and four BRAF mutants that represented the spectrum of sensitivities of these cell lines. # ::save-date Sun Jun 14, 2015 ::file a_pmid_2251_5704_51.txt (c / choose-01 :ARG0 (w / we) :ARG1 (a / and :op1 (g / gene :quant 2 :name (n / name :op1 "NRAS") :ARG2-of (m / mutate-01)) :op2 (g2 / gene :quant 4 :name (n2 / name :op1 "BRAF") :ARG2-of m) :ARG0-of (r / represent-01 :ARG1 (s / spectrum :quant-of (s2 / sensitive-03 :ARG0 (c2 / cell-line :mod (t / this)))))) :purpose (s3 / study-01 :mod (t2 / this))) # ::id a_pmid_2251_5704.52 ::date 2015-06-05T00:28:39 ::annotator SDL-AMR-09 ::preferred # ::snt The NRAS mutants M207 (sensitive) and M244 (highly resistant) both had a dose-dependent G1 arrest with increasing concentrations of TAK733 (Figure 2c). # ::save-date Sun Jan 3, 2016 ::file a_pmid_2251_5704_52.txt (h / have-03 :ARG0 (a / and :op1 (c2 / cell-line :name (n2 / name :op1 "M207") :mod (g / gene :name (n / name :op1 "NRAS") :ARG2-of (m / mutate-01)) :ARG0-of (s / sensitive-03)) :op2 (c3 / cell-line :name (n4 / name :op1 "M244") :mod g :ARG0-of (r / resist-01 :ARG1-of (h2 / high-02)))) :ARG1 (a2 / arrest-02 :ARG0-of (d / depend-01 :ARG1 (d2 / dose)) :accompanier (c / concentrate-02 :ARG1 (s2 / small-molecule :name (n5 / name :op1 "TAK733")) :ARG1-of (i2 / increase-01)) :time (e / event :name (n3 / name :op1 "G1"))) :ARG1-of (d3 / describe-01 :ARG0 (f / figure :mod "2c"))) # ::id a_pmid_2251_5704.53 ::date 2015-06-05T00:47:26 ::annotator SDL-AMR-09 ::preferred # ::snt The same was evident with the four BRAF mutants, including the two with high sensitivity (M229 and M249) and the highly resistant (M233 and M263). # ::save-date Fri Dec 15, 2017 ::file a_pmid_2251_5704_53.txt (e / evident :topic (g / gene :quant 4 :name (n / name :op1 "BRAF") :ARG2-of (i / include-01 :ARG1 (a / and :op1 (g2 / gene :quant 2 :name (n2 / name :op1 "BRAF") :ARG0-of (s2 / sensitive-03 :ARG1-of (h / high-02)) :ARG2-of (m / mutate-01) :ARG1-of (m2 / mean-01 :ARG2 (a2 / and :op1 (c / cell-line :name (n8 / name :op1 "M229") :mod (g4 / gene :name (n4 / name :op1 "BRAF") :ARG2-of m)) :op2 (c2 / cell-line :name (n9 / name :op1 "M249") :mod g4)))) :op2 (g3 / gene :name (n3 / name :op1 "BRAF") :ARG0-of (r / resist-01 :degree (h2 / high-02)) :ARG2-of m :ARG1-of (m6 / mean-01 :ARG2 (a3 / and :op1 (c3 / cell-line :name (n10 / name :op1 "M233") :mod (g6 / gene :name (n6 / name :op1 "BRAF") :ARG2-of m)) :op2 (c4 / cell-line :name (n11 / name :op1 "M263") :mod g6)))))) :ARG2-of m) :domain (t / thing :ARG1-of (s / same-01))) # ::id a_pmid_2251_5704.54 ::date 2015-06-05T00:57:46 ::annotator SDL-AMR-09 ::preferred # ::snt The sub-G1 peak also did not predict the cell proliferation assay results, even though the sharpest increase was in M249, one of the most sensitive cell lines (Figure 2 a and c). # ::save-date Thu Oct 19, 2017 ::file a_pmid_2251_5704_54.txt (h / have-concession-91 :ARG1 (p / predict-01 :polarity - :ARG0 (p2 / peak-01 :time (e / event :name (n2 / name :op1 "sub-G1"))) :ARG1 (r / result-01 :ARG1 (a / assay-01 :ARG1 (p3 / proliferate-01 :ARG0 (c / cell)))) :mod (a3 / also)) :ARG2 (i / increase-01 :ARG1 (c2 / cell-line :quant 1 :name (n / name :op1 "M249") :ARG1-of (i2 / include-91 :ARG2 (c3 / cell-line :ARG1-of (h2 / have-degree-91 :ARG2 (s2 / sensitive-03 :ARG1 c3) :ARG3 (m / most))))) :mod (s / sharp)) :ARG1-of (d / describe-01 :ARG0 (a2 / and :op1 (f / figure :mod "2a") :op2 (f2 / figure :mod "2c")))) # ::id a_pmid_2251_5704.55 ::date 2015-06-05T01:04:31 ::annotator SDL-AMR-09 ::preferred # ::snt Overall, TAK733 exposure for up to 48 hours led to a similar G1 arrest in melanoma cell lines regardless of their origin, driver oncogenic mutations and in vitro sensitivity to TAK733). # ::save-date Tue Dec 26, 2017 ::file a_pmid_2251_5704_55.txt (l / lead-03 :ARG0 (e / expose-01 :ARG2 (s2 / small-molecule :name (n / name :op1 "TAK733")) :duration (u / up-to :op1 (t / temporal-quantity :quant 48 :unit (h2 / hour)))) :ARG1 (a / arrest-02 :ARG1-of (r2 / resemble-01) :time (e2 / event :name (n5 / name :op1 "G1"))) :location (c / cell-line :mod (m / medical-condition :name (n2 / name :op1 "melanoma"))) :mod (o3 / overall) :ARG1-of (r / regardless-91 :ARG2 (a2 / and :op1 (o / originate-01 :ARG1 c) :op2 (m2 / mutate-01 :ARG2 c :ARG0-of (c2 / cause-01 :ARG1 (d / disease :wiki "Cancer" :name (n4 / name :op1 "cancer"))) :ARG0-of (d3 / drive-02)) :op3 (s / sensitive-03 :ARG0 c :ARG1 s2 :manner (i2 / in-vitro))))) # ::id a_pmid_2251_5704.56 ::date 2015-06-05T01:12:56 ::annotator SDL-AMR-09 ::preferred # ::snt Modulation of MAPK and PI3k/akt signaling pathways upon exposure to TAK733 # ::save-date Sun Jun 14, 2015 ::file a_pmid_2251_5704_56.txt (m / modulate-01 :ARG1 (a / and :op1 (p3 / pathway :name (n3 / name :op1 "MAPK")) :op2 (p4 / pathway :name (n4 / name :op1 "PI3k/akt")) :ARG0-of (s / signal-07)) :time (e / expose-01 :ARG2 (s3 / small-molecule :name (n5 / name :op1 "TAK733")))) # ::id a_pmid_2251_5704.57 ::date 2015-06-04T13:03:06 ::annotator SDL-AMR-09 ::preferred # ::snt To explore how cell lines with different mutations respond differently to TAK733 we analyzed signaling pathways in representative cell lines with similar growth kinetics but with markedly different sensitivities to TAK733. # ::save-date Sun Nov 19, 2017 ::file a_pmid_2251_5704_57.txt (a / analyze-01 :ARG0 w :ARG1 (p / pathway :ARG0-of (s / signal-07) :location (c / cell-line :ARG0-of (r3 / represent-01) :prep-with (k / kinetics :mod (g / grow-01) :ARG1-of (r4 / resemble-01) :ARG1-of (c2 / contrast-01 :ARG2 (s2 / sensitive-03 :ARG0 p :ARG1 s3 :ARG1-of d :manner (m4 / marked)))))) :purpose (e / explore-01 :ARG0 (w / we) :ARG1 (t / thing :manner-of (r / respond-01 :ARG0 (m2 / mutate-01 :ARG1-of (d / differ-02)) :ARG2 (s3 / small-molecule :name (n / name :op1 "TAK733")))))) # ::id a_pmid_2251_5704.58 ::date 2015-06-04T14:09:01 ::annotator SDL-AMR-09 ::preferred # ::snt Among the NRASQ61L mutant cutaneous group we chose the resistant M244 and the sensitive M207. # ::save-date Tue Jun 23, 2015 ::file a_pmid_2251_5704_58.txt (c / choose-01 :ARG0 (w / we) :ARG1 (a / and :op1 (c2 / cell-line :name (n2 / name :op1 "M244") :ARG1-of (r / resist-01)) :op2 (c3 / cell-line :name (n3 / name :op1 "M207") :ARG0-of (s / sensitive-03)) :ARG1-of (i / include-91 :ARG2 (g3 / group :mod (g2 / gene :name (n / name :op1 "NRAS") :ARG2-of (m / mutate-01 :value "Q61L")) :mod (s2 / skin))))) # ::id a_pmid_2251_5704.59 ::date 2015-06-04T14:33:48 ::annotator SDL-AMR-09 ::preferred # ::snt Among the BRAFV600E mutant cutaneous group we chose M229 and M249 as representatives of highly sensitive cutaneous cell lines, and M233 and M263 as resistant cutaneous cell lines. # ::save-date Mon Dec 21, 2015 ::file a_pmid_2251_5704_59.txt (c / choose-01 :ARG0 (w / we) :ARG1 (a / and :op1 (a2 / and :op1 (c5 / cell-line :name (n / name :op1 "M229")) :op2 (c4 / cell-line :name (n2 / name :op1 "M249")) :ARG0-of (r / represent-01 :ARG1 (c3 / cell-line :ARG0-of (s2 / sensitive-03 :ARG1-of (h / high-02)) :mod s))) :op2 (a3 / and :op1 (c6 / cell-line :name (n3 / name :op1 "M233")) :op2 (c7 / cell-line :name (n4 / name :op1 "M263")) :ARG0-of (r2 / represent-01 :ARG1 (c2 / cell-line :mod s :ARG0-of (r3 / resist-01)))) :ARG1-of (i / include-91 :ARG2 (g5 / group :mod (s / skin) :mod (g / gene :name (n5 / name :op1 "BRAF") :ARG2-of (m / mutate-01 :value "V600E")))))) # ::id a_pmid_2251_5704.60 ::date 2015-06-04T15:31:38 ::annotator SDL-AMR-09 ::preferred # ::snt In our panel, all the uveal melanoma cell lines were sensitive to TAK733 and we picked three as representative samples with GNAQ mutations. # ::save-date Thu Jan 14, 2016 ::file a_pmid_2251_5704_60.txt (a2 / and :op1 (s / sensitive-03 :ARG0 (c2 / cell-line :mod (a / all) :source (m3 / medical-condition :name (n3 / name :op1 "melanoma") :mod (u / uvea))) :ARG1 (s3 / small-molecule :name (n / name :op1 "TAK733")) :location (p / panel :poss (w / we))) :op2 (p2 / pick-01 :ARG0 w :ARG1 (c3 / cell-line :quant 3) :purpose (s2 / sample-01 :ARG0-of (r / represent-01) :mod (g2 / gene :name (n2 / name :op1 "GNAQ") :ARG2-of (m2 / mutate-01))))) # ::id a_pmid_2251_5704.61 ::date 2015-06-05T03:31:34 ::annotator SDL-AMR-09 ::preferred # ::snt As expected based on prior data [21], MEK inhibition resulted in increase of pMEK in non-BRAFV600E mutant cell lines (Figure 3). # ::save-date Tue Jun 23, 2015 ::file a_pmid_2251_5704_61.txt (r / result-01 :ARG1 (i / inhibit-01 :ARG1 (e2 / enzyme :name (n / name :op1 "MEK"))) :ARG2 (i2 / increase-01 :ARG1 (e3 / enzyme :name (n2 / name :op1 "MEK") :ARG3-of (p3 / phosphorylate-01)) :location (c2 / cell-line :mod (g / gene :name (n3 / name :op1 "BRAF") :ARG1-of (m / mutate-01 :polarity - :value "V600E")))) :ARG1-of (e / expect-01 :ARG1-of (b / base-02 :ARG2 (d / data :time (p / prior)))) :ARG1-of (d3 / describe-01 :ARG0 (f / figure :mod 3)) :ARG1-of (d2 / describe-01 :ARG0 (p2 / publication :ARG1-of (c / cite-01 :ARG2 21)))) # ::id a_pmid_2251_5704.62 ::date 2015-06-05T03:38:21 ::annotator SDL-AMR-09 ::preferred # ::snt This was more prominent in NRASQ61L mutant and uveal melanoma cell lines than in BRAFV600E mutant cell lines, which had a higher baseline level of pMEK. # ::save-date Sun Oct 22, 2017 ::file a_pmid_2251_5704_62.txt (h3 / have-degree-91 :ARG1 (t / this) :ARG2 (p3 / prominent) :ARG3 (m / more) :location (a / and :op1 (c / cell-line :mod (g / gene :name (n2 / name :op1 "NRAS") :ARG2-of (m3 / mutate-01 :value "Q61L"))) :op2 (c3 / cell-line :mod (m6 / medical-condition :name (n4 / name :op1 "melanoma") :mod (u / uvea))) :ARG1-of (c2 / compare-01 :ARG2 (c4 / cell-line :mod (g2 / gene :name (n3 / name :op1 "BRAF") :ARG2-of (m4 / mutate-01 :value "V600E")) :ARG0-of (h / have-03 :ARG1 (l / level :mod (b / baseline) :quant-of (e / enzyme :name (n / name :op1 "MEK") :ARG3-of (p2 / phosphorylate-01)) :ARG1-of (h4 / have-degree-91 :ARG2 (h2 / high-02 :ARG1 l) :ARG3 (m5 / more)))))))) # ::id a_pmid_2251_5704.63 ::date 2015-06-05T03:45:12 ::annotator SDL-AMR-09 ::preferred # ::snt In all cases, TAK733 induced a marked dose-dependent decrease of pERK, regardless of the driver oncogenic mutation or the sensitivity or resistance to this agent in cell viability assays. # ::save-date Sat Jan 30, 2016 ::file a_pmid_2251_5704_63.txt (i / induce-01 :ARG0 (s2 / small-molecule :name (n / name :op1 "TAK733")) :ARG2 (d / decrease-01 :ARG1 (e / enzyme :name (n2 / name :op1 "ERK") :ARG3-of (p / phosphorylate-01)) :ARG0-of (d2 / depend-01 :ARG1 (d3 / dose)) :mod (m2 / marked)) :prep-in (c / case-04 :mod (a2 / all)) :ARG1-of (r2 / regardless-91 :ARG2 (o / or :op1 (m3 / mutate-01 :ARG0-of (d4 / drive-02) :ARG0-of (c4 / cause-01 :ARG1 (d5 / disease :wiki "Cancer" :name (n3 / name :op1 "cancer")))) :op2 (o2 / or :op1 (s / sensitive-03 :ARG1 s2) :op2 (r / resist-01 :ARG1 s2) :location (a / assay-01 :ARG1 (v / viable :domain (c2 / cell))))))) # ::id a_pmid_2251_5704.64 ::date 2015-06-05T03:58:28 ::annotator SDL-AMR-09 ::preferred # ::snt On the contrary, effects on pAKT and pS6K varied according to the cell origin, oncogenic events and sensitivity to TAK733. # ::save-date Wed Dec 9, 2015 ::file a_pmid_2251_5704_64.txt (c / contrast-01 :ARG2 (v / vary-01 :ARG1 (a / affect-01 :ARG1 (a2 / and :op1 (e2 / enzyme :name (n / name :op1 "AKT") :ARG3-of (p / phosphorylate-01)) :op2 (e3 / enzyme :name (n2 / name :op1 "S6K") :ARG3-of p))) :ARG1-of (c5 / conform-01 :ARG2 (a3 / and :op1 (o2 / originate-01 :ARG1 (c2 / cell)) :op2 (e / event :ARG0-of (c3 / cause-01 :ARG1 (d / disease :wiki "Cancer" :name (n4 / name :op1 "cancer")))) :op3 (s2 / sensitive-03 :ARG1 (s3 / small-molecule :name (n3 / name :op1 "TAK733"))))))) # ::id a_pmid_2251_5704.65 ::date 2015-06-05T04:03:39 ::annotator SDL-AMR-09 ::preferred # ::snt BRAFV600E mutant cell lines resistant to TAK733 showed no inhibition of pAKT or pS6K, while there was a general trend towards inhibition of these two phosphorylated molecules in sensitive cell lines. # ::save-date Fri Dec 18, 2015 ::file a_pmid_2251_5704_65.txt (c / contrast-01 :ARG1 (s / show-01 :ARG0 (c2 / cell-line :ARG0-of (r / resist-01 :ARG1 (s3 / small-molecule :name (n / name :op1 "TAK733"))) :mod (g / gene :name (n2 / name :op1 "BRAF") :ARG2-of (m2 / mutate-01 :value "V600E"))) :ARG1 (i / inhibit-01 :polarity - :ARG1 (o / or :op1 (e / enzyme :name (n3 / name :op1 "AKT") :ARG3-of (p / phosphorylate-01)) :op2 (e2 / enzyme :name (n4 / name :op1 "S6K") :ARG3-of p)))) :ARG2 (t / trend-01 :ARG2 (i2 / inhibit-01 :ARG1 o :location (c3 / cell-line :ARG0-of (s2 / sensitive-03))) :ARG1-of (g2 / general-02))) # ::id a_pmid_2251_5704.66 ::date 2015-06-05T04:11:27 ::annotator SDL-AMR-09 ::preferred # ::snt Of note, in the uveal melanoma cell lines and in the cutaneous melanoma cell line M229, the baseline level of pAKT was undetectable by Western blot, so no inhibition could be recorded in them. # ::save-date Thu Jan 4, 2018 ::file a_pmid_2251_5704_66.txt (c / cause-01 :ARG0 (p2 / possible-01 :polarity - :ARG1 (d / detect-01 :ARG0 (i2 / immunoblot-01) :ARG1 (l / level :mod (b / baseline) :quant-of (e / enzyme :name (n3 / name :op1 "AKT") :ARG3-of (p3 / phosphorylate-01)))) :location (a / and :op1 (c2 / cell-line :source (m3 / medical-condition :name (n4 / name :op1 "melanoma") :mod (u / uvea))) :op2 (c3 / cell-line :name (n2 / name :op1 "M229") :mod (m / medical-condition :name (n5 / name :op1 "melanoma") :mod (s / skin))))) :ARG1 (p / possible-01 :ARG1 (r / record-01 :ARG1 (i / inhibit-01 :polarity -) :location a)) :ARG1-of (n / note-02)) # ::id a_pmid_2251_5704.67 ::date 2015-06-05T04:26:14 ::annotator SDL-AMR-09 ::preferred # ::snt Changes in pS6 tended to follow changes in pS6K in the cutaneous melanoma cell lines but not in the uveal melanoma cell lines. # ::save-date Sun Jan 17, 2016 ::file a_pmid_2251_5704_67.txt (t / tend-02 :ARG1 c :ARG2 (f / follow-01 :ARG1 (c / change-01 :ARG1 (p2 / protein :name (n / name :op1 "S6") :ARG3-of (p / phosphorylate-01))) :ARG2 (c2 / change-01 :ARG1 (e2 / enzyme :name (n2 / name :op1 "S6K") :ARG3-of p)) :ARG1-of (c4 / contrast-01 :ARG2 (f2 / follow-01 :polarity - :ARG1 c :ARG2 c2 :location (c5 / cell-line :mod (m3 / medical-condition :name (n3 / name :op1 "melanoma") :mod (u / uvea))))) :location (c3 / cell-line :mod (m2 / medical-condition :name (n4 / name :op1 "melanoma") :mod (s / skin))))) # ::id a_pmid_2251_5704.68 ::date 2015-06-05T04:34:27 ::annotator SDL-AMR-09 ::preferred # ::snt In a time-course analysis of signaling events upon exposure to TAK733, both the sensitive M229 and the resistant M233 cell lines with BRAFV600E mutations showed initial inhibition of pERK, but the resistant cell line recovered pERK signaling with time (Additional file 2: Figure S2). # ::save-date Wed Mar 2, 2016 ::file a_pmid_2251_5704_68.txt (c / contrast-01 :ARG1 (s / show-01 :ARG0 (a2 / and :op1 (c2 / cell-line :name (n2 / name :op1 "M229") :ARG0-of (s3 / sensitive-03)) :op2 (c3 / cell-line :name (n3 / name :op1 "M233") :ARG0-of (r2 / resist-01)) :mod (g / gene :name (n4 / name :op1 "BRAF") :ARG2-of (m2 / mutate-01 :value "V600E"))) :ARG1 (i / inhibit-01 :ARG0 (e3 / enzyme :name (n5 / name :op1 "ERK") :ARG3-of (p / phosphorylate-01)) :ARG1 a2 :mod (i2 / initial))) :ARG2 (r / recover-02 :ARG0 c3 :ARG1 (s4 / signal-07 :ARG0 e3) :time (t2 / time)) :ARG1-of (d / describe-01 :ARG0 (a3 / and :op1 (f2 / file :mod 2 :mod (a4 / additional)) :op2 (f / figure :mod "S2"))) :time (a / analyze-01 :ARG1 (e / event :ARG0-of (s2 / signal-07) :time (e2 / expose-01 :ARG2 (s5 / small-molecule :name (n / name :op1 "TAK733")))) :mod (t / timecourse))) # ::id a_pmid_2251_5704.69 ::date 2015-06-05T05:01:18 ::annotator SDL-AMR-09 ::preferred # ::snt This different time-course effect was not evident for the inhibition of pAKT or pS6K in the resistant cell line, while they were permanently inhibited over the 48 hour study period in the sensitive cell line. # ::save-date Wed Mar 2, 2016 ::file a_pmid_2251_5704_69.txt (c / contrast-01 :ARG1 (e / evident :polarity - :domain (a / affect-01 :ARG1-of (d / differ-02) :mod (t2 / timecourse) :mod (t3 / this)) :topic (i / inhibit-01 :ARG1 (a2 / and :op1 (e2 / enzyme :name (n / name :op1 "AKT") :ARG3-of (p / phosphorylate-01)) :op2 (e3 / enzyme :name (n2 / name :op1 "S6K") :ARG3-of p) :location (c2 / cell-line :ARG0-of (r2 / resist-01))))) :ARG2 (i2 / inhibit-01 :ARG1 a2 :mod (p3 / permanent) :time (p4 / period) :location (c3 / cell-line :ARG0-of (s2 / sensitive-03)) :duration (t / temporal-quantity :quant 48 :unit (h / hour) :duration-of (s / study-01)))) # ::id a_pmid_2251_5704.70 ::date 2015-06-05T04:56:58 ::annotator SDL-AMR-09 ::preferred # ::snt Differential metabolic tracer uptake between cell lines sensitive and resistant to TAK733 # ::save-date Fri Dec 18, 2015 ::file a_pmid_2251_5704_70.txt (d2 / differ-02 :ARG1 (t / take-up-13 :ARG1 (c / cell-line :ARG0-of (s / sensitive-03 :ARG1 s2)) :ARG2 (t2 / tracer :mod (m2 / metabolism))) :ARG2 (t3 / take-up-30 :ARG1 (c2 / cell-line :ARG0-of (r / resist-01 :ARG1 (s2 / small-molecule :name (n / name :op1 "TAK733")))) :ARG2 t2)) # ::id a_pmid_2251_5704.71 ::date 2015-06-05T05:00:34 ::annotator SDL-AMR-09 ::preferred # ::snt We explored the use of metabolic tracers to differentiate response or resistance to TAK733 in six cutaneous melanoma cell lines with the goal of a future use of these tracers in PET scanning studies in the clinic. # ::save-date Thu Jan 14, 2016 ::file a_pmid_2251_5704_71.txt (e / explore-01 :ARG0 (w / we) :ARG1 (u / use-01 :ARG1 (t / tracer :mod (m / metabolism)) :ARG2 (d / differentiate-101 :ARG0 w :ARG1 (o / or :op1 (r / respond-01 :ARG0 (c3 / cell-line :quant 6 :source (m2 / medical-condition :name (n3 / name :op1 "melanoma") :mod (s3 / skin))) :ARG1 (s4 / small-molecule :name (n / name :op1 "TAK733"))) :op2 (r2 / resist-01 :ARG0 c3 :ARG1 s4)))) :ARG2 (u2 / use-01 :ARG1 t :ARG2 (s / study-01 :manner (s2 / scan-01 :mod (t2 / thing :name (n2 / name :op1 "PET"))) :medium (c2 / clinic)) :time (f / future))) # ::id a_pmid_2251_5704.72 ::date 2015-06-05T05:22:45 ::annotator SDL-AMR-09 ::preferred # ::snt Thymidine is taken up by proliferating cells and the PET tracer [18 F]FLT can be used in patients. # ::save-date Fri Feb 12, 2016 ::file a_pmid_2251_5704_72.txt (a / and :op1 (t2 / take-up-13 :ARG1 (s / small-molecule :name (n / name :op1 "Thymidine")) :ARG2 (c / cell :ARG0-of (p / proliferate-01))) :op2 (p2 / possible-01 :ARG1 (u / use-01 :ARG1 (s2 / small-molecule :name (n3 / name :op1 "FLT") :ARG0-of (t / trace-02) :mod (t3 / thing :name (n2 / name :op1 "PET"))) :ARG2 (p3 / patient)))) # ::id a_pmid_2251_5704.73 ::date 2015-06-05T05:48:19 ::annotator SDL-AMR-09 ::preferred # ::snt Consistent with the cell cycle analysis data, all the tested cell lines had some degree of inhibition of tritium-labeled thymidine (3H-thymidine) uptake upon exposure to TAK733 regardless of their sensitivity in vitro. # ::save-date Fri Feb 12, 2016 ::file a_pmid_2251_5704_73.txt (h / have-03 :ARG0 (c4 / cell-line :mod (a2 / all) :ARG1-of (t / test-01)) :ARG1 (d2 / degree :quant (s / some) :degree-of (i / inhibit-01 :ARG1 (t2 / take-up-13 :ARG2 (s4 / small-molecule :name (n / name :op1 "tritium-labeled" :op2 "thymidine"))) :ARG1-of (c5 / cause-01 :ARG0 (e / expose-01 :ARG1 c4 :ARG2 (s3 / small-molecule :name (n2 / name :op1 "TAK733")))))) :ARG1-of (c / consistent-01 :ARG2 (d / data :mod (a / analyze-01 :ARG1 (c2 / cycle-02 :ARG1 (c3 / cell))))) :ARG1-of (r / regardless-91 :ARG2 (s2 / sensitive-03 :ARG0 c4 :manner (i2 / in-vitro)))) # ::id a_pmid_2251_5704.74 ::date 2015-06-05T04:35:26 ::annotator SDL-AMR-09 ::preferred # ::snt The highest levels of inhibition were in the highly sensitive BRAFV600E mutant cell lines M229 and M249 and the relatively resistant M263 cell line (Figure 4a). # ::save-date Thu Oct 19, 2017 ::file a_pmid_2251_5704_74.txt (i2 / inhibit-01 :location (a / and :op1 (a2 / and :op1 (c / cell-line :name (n / name :op1 "M229")) :op2 (c2 / cell-line :name (n2 / name :op1 "M249")) :mod (g / gene :name (n3 / name :op1 "BRAF") :ARG2-of (m2 / mutate-01 :value "V600E")) :ARG0-of (s / sensitive-03 :ARG1-of (h2 / high-02))) :op2 (c3 / cell-line :name (n4 / name :op1 "M263") :ARG0-of (r / resist-01 :ARG2-of (r2 / relative-05)))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "4a")) :ARG1-of (h3 / have-degree-91 :ARG2 (h / high-02) :ARG3 (m / most))) # ::id a_pmid_2251_5704.75 ::date 2015-06-05T04:56:25 ::annotator SDL-AMR-09 ::preferred # ::snt Changes in uptake of tritium-labeled 2'-deoxy-D-glucose (3H-2DDG) were analyzed to study effects of TAK733 on PET scans with the commonly used PET tracer [18F]FDG. # ::save-date Fri Feb 12, 2016 ::file a_pmid_2251_5704_75.txt (a / analyze-01 :ARG1 (c / change-01 :ARG1 (t2 / take-up-13 :ARG2 (s4 / small-molecule :name (n3 / name :op1 "tritium-labeled" :op2 "2'-deoxy-D-glucose")))) :purpose (s / study-01 :ARG1 (a2 / affect-01 :ARG0 (s3 / small-molecule :name (n / name :op1 "TAK733")) :ARG1 (s2 / scan-01 :instrument (s5 / small-molecule :name (n5 / name :op1 "FDG") :ARG1-of (u / use-01 :manner (c2 / common)) :ARG0-of (t / trace-02)) :mod (t3 / thing :name (n2 / name :op1 "PET")))))) # ::id a_pmid_2251_5704.76 ::date 2015-06-04T13:29:49 ::annotator SDL-AMR-09 ::preferred # ::snt The lowest degree of inhibition was in the two most resistant cell lines, the BRAFV600E mutant M233 and the NRASQ61K mutant M244 (Figure 4b). # ::save-date Thu Oct 19, 2017 ::file a_pmid_2251_5704_76.txt (i / inhibit-01 :location (a2 / and :op1 (c / cell-line :name (n / name :op1 "M233") :mod (g / gene :name (n3 / name :op1 "BRAF") :ARG2-of (m3 / mutate-01 :value "V600E"))) :op2 (c2 / cell-line :name (n4 / name :op1 "M244") :mod (g2 / gene :name (n2 / name :op1 "NRAS") :ARG2-of (m4 / mutate-01 :value "Q61K"))) :ARG1-of (h2 / have-degree-91 :ARG2 (r / resist-01 :ARG1 a2) :ARG3 (m / most))) :degree (d / degree) :ARG1-of (d2 / describe-01 :ARG0 (f / figure :mod "4b")) :ARG1-of (h / have-degree-91 :ARG2 (l / low-04 :ARG1 i) :ARG3 (m2 / most))) # ::id a_pmid_2251_5704.77 ::date 2015-06-04T13:45:52 ::annotator SDL-AMR-09 ::preferred # ::snt Therefore, changes in the uptake of the 3H-2DDG metabolic tracer most closely followed the results of the cell viability assays. # ::save-date Thu Oct 19, 2017 ::file a_pmid_2251_5704_77.txt (i / infer-01 :ARG1 (f / follow-01 :ARG1 (c4 / change-01 :ARG1 (t2 / take-up-13 :ARG1 (s / small-molecule :name (n / name :op1 "3H-2DDG") :ARG0-of (t4 / trace-02)))) :ARG2 (t / thing :ARG2-of (r / result-01 :ARG1 (a / assay-01 :ARG1 (v / viable :domain (c2 / cell))))) :manner (c / close-10 :ARG2-of (h / have-degree-91 :ARG1 f :ARG3 (m / most))))) # ::id a_pmid_2256_9000.96 ::date 2015-06-06T02:10:03 ::annotator SDL-AMR-09 ::preferred # ::snt In-vitro 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 μℳ for 48, 72, and 96 h. # ::save-date Wed Sep 21, 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 (m / micromolar))))) :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 Figure 1, there was a wide range of sensitivity, with IC50 values varying between 0.01 and >10 μℳ. # ::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 IC50 at 96 h ⩽1 or >1 μℳ, respectively. # ::save-date Tue Dec 19, 2017 ::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 :ARG2 50 :ARG1 (s2 / small-molecule :name (n3 / name :op1 "selumetinib")) :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 :quant (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 :ARG2 50 :ARG1 s2 :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 μℳ was within the average plasma concentrations of selumetinib achieved in patients at the maximum tolerated dose for this agent (Adjei et al, 2008). # ::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 IC50 of ⩽1 μℳ. # ::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 IC50 of ⩽0.01 μℳ (Figure 1A and B). # ::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 :op2 0.01 :op1 (l / less-than :op1 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 IC50 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 (Figure 2A). # ::save-date Thu Oct 19, 2017 ::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"))) :ARG1-of (c6 / compare-01 :ARG2 (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 Thu Oct 19, 2017 ::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 (h3 / have-degree-91 :ARG2 (l / long-03 :ARG1 t :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))))) :ARG3 (m / more))) :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 (Figure 2A). # ::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 (Figure 2A). # ::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 Garon et al (2010), 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 (Huynh et al, 2007a; Huynh et al, 2007b; Meng et al, 2009; Meng et al, 2010). # ::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 (Figure 2B). # ::save-date Wed Sep 21, 2016 ::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 (h2 / hour)))) :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 (Figure 2B). # ::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 μℳ. # ::save-date Mon Nov 20, 2017 ::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 (Figure 3A–D). # ::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 (Figure 3A and B). # ::save-date Fri Dec 22, 2017 ::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) :ARG1-of (c2 / complete-02) :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 (m2 / minute)))) :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 (Figure 3C and D). # ::save-date Thu Oct 19, 2017 ::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"))))) :ARG2-of (h / have-degree-91 :ARG1 i :ARG3 (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 Fri Dec 22, 2017 ::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"))) :ARG1-of (c / complete-02) :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 (Figure 3C and D). # ::save-date Tue Jan 23, 2018 ::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 :polarity - :ARG1 p :ARG1-of (c3 / complete-02) :time (e2 / ever)) :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 (Balmanno et al, 2009). # ::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 Figure 3E–H, 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 Figure 4A and B, 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−1 were 40% and 15%, respectively, as compared with control untreated mice. # ::save-date Fri Dec 8, 2017 ::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 :ARG1-of (c5 / compare-01 :ARG2 (m5 / mouse :ARG1-of (t6 / treat-04 :polarity -) :mod (c6 / control)))) :location (m2 / mouse :ARG0-of (b / bear-01 :ARG1 (x2 / xenograft :source (t3 / tumor :mod (c / cell-line :name (n / name :op1 "HCT116"))))) :ARG1-of (t2 / treat-04 :ARG2 (s / small-molecule :name (n3 / name :op1 "selumetinib") :quant (c3 / concentration-quantity :quant 25 :unit (m / milligram-per-kilogram)))))) :op2 (a5 / average-01 :ARG1 v :ARG2 (p2 / percentage-entity :value 15 :ARG1-of c5) :location (m4 / mouse :ARG1-of (t4 / treat-04 :ARG2 (s2 / small-molecule :name (n4 / name :op1 "selumetinib") :quant (c2 / concentration-quantity :quant 50 :unit (m3 / milligram-per-kilogram)))) :ARG0-of b)) :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))) :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−1 were 22% and 8%, respectively, as compared with control untreated mice. # ::save-date Fri Dec 8, 2017 ::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 :ARG1-of (c / compare-01 :ARG2 (m5 / mouse :ARG1-of (t2 / treat-04 :polarity -) :mod (c4 / control)))) :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"))))) :ARG1-of (t4 / treat-04 :ARG2 (s2 / small-molecule :name (n4 / name :op1 "selumetinib") :quant (c2 / concentration-quantity :quant 25 :unit (m3 / milligram-per-kilogram)))))) :op2 (a3 / average-01 :ARG1 v :ARG2 (p2 / percentage-entity :value 8 :ARG1-of c) :location (m2 / mouse :ARG1-of (t3 / treat-04 :ARG2 (s / small-molecule :name (n3 / name :op1 "selumetinib") :quant (c3 / concentration-quantity :quant 50 :unit (m4 / milligram-per-kilogram)))) :ARG0-of b)) :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 (Figure 4C and D). # ::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 (Balmanno et al, 2009; Dry et al, 2010; Garon et al, 2010; Tendler et al, 2010). # ::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 Supplementary Figure 1A, 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 Supplementary Figure 1B, 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 Fri Jan 19, 2018 ::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 "lung" :op2 "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 KRAS, NRAS, BRAF, PIK3CA, p53, PTEN, MEK1/2, AKT, EGFR (Table 1; Supplementary Table 1A–F). # ::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 KRAS 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 PI3KCA 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 KRAS and PI3KCA 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 NRAS mutation (Table 1; Supplementary Table 1A–F). # ::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 KRAS 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 PI3KCA mutation in exon 9 or 20 and a KRAS 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 NRAS 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 BRAF 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 Supplementary Table 1E and F, 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 (Supplementary Figure 2A and B). # ::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 t-test with Benjamini–Hochberg multiple test correction, 21 and 18 genes were identified as upregulated or downregulated, respectively, in selumetinib-resistant cancer cell lines (t-test, P<0.05) (Supplementary Figure 3). # ::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 Table 2 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, ADCY7 and AKAP13, which are involved in the cAMP-dependent protein kinase (PKA) pathway (Table 2A; Supplementary Figure 3). # ::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 ADCY7 gene encodes a membrane-bound adenylatecyclase that convert ATP into 3', 5'-adenosine monophosphate (cAMP) and pyrophosphate (Supplementary Figure 4). # ::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 (Tasken et al, 1997). # ::save-date Sat Jan 20, 2018 ::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 (m2 / mammal)) :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 AKAP13 gene encodes the A-kinase anchor protein 13 that has the function of binding to the regulatory subunits of PKA (Supplementary Figure 4). # ::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 (NCOA3, TAF3, NR1H2, and RXRA), which are upregulated in selumetinib-resistant cancer cell lines, belong to the retinoic acid pathway, which is also activated by PKA (Altucci et al, 2007). # ::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 (Tortora and Ciardiello, 2000; Naviglio et al, 2009). # ::save-date Sun Nov 19, 2017 ::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 (t4 / truth-value :polarity-of (p3 / possible-01 :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 Figure 5A. # ::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 μℳ) and 8-Cl-cAMP (range, 0.01–5 μℳ) each day, for a total of 3 days at a fixed drug ratio selumetinib to 8-Cl-cAMP of 1 : 1. # ::save-date Tue Jan 9, 2018 ::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 (b / between :op1 (c4 / concentration-quantity :quant 0.01 :unit (m / micromolar)) :op2 (c3 / concentration-quantity :quant 10 :unit (m3 / micromolar)) :ARG1-of (d3 / differ-02))) :op2 (s2 / small-molecule :name (n4 / name :op1 "8-Cl-cAMP") :mod (b2 / between :op1 (c5 / concentration-quantity :quant 0.01 :unit (m2 / micromolar)) :op2 (c6 / concentration-quantity :quant 5 :unit (m4 / micromolar)) :ARG1-of (d4 / differ-02)))) :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 (Figure 5B). # ::save-date Wed Jan 10, 2018 ::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 (b / between :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 Figure 3C, 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 RIα. # ::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 in vitro and in vivo (Yokozaki et al, 1993; Nesterova and Cho-Chung, 1995; Tortora et al, 1997a). # ::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 RIα 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 (Figure 6A). # ::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 (IC50 between 0.25 and 1 μℳ), while the IC50 values were >5 μℳ in the selumetinib-sensitive cancer cells. # ::save-date Tue Jan 9, 2018 ::file a_pmid_2256_9000_182.txt (c / contrast-01 :ARG1 (p / pronounced-02 :ARG1 (i / inhibit-01 :ARG1 (g / grow-01)) :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 (b / between :op1 (c4 / concentration-quantity :quant 0.25 :unit (m3 / micromolar)) :op2 (c3 / concentration-quantity :quant 1 :unit (m4 / micromolar)))))) :mod (d / disease :wiki "Cancer" :name (n / name :op1 "cancer"))) :ARG2-of (h / have-degree-91 :ARG1 i :ARG3 (m / more))) :ARG2 (h3 / have-percentage-maximal-inhibitory-concentration-01 :ARG2 50 :ARG4 (m5 / more-than :op1 (c7 / concentration-quantity :quant 5 :unit (m2 / micromolar))) :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 μℳ, showed only 5–15% growth inhibition among all of the cell lines tested (Figure 6A). # ::save-date Sat Jan 6, 2018 ::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 (b / between :op1 (p / percentage-entity :value 5) :op2 (p2 / perentage-entity :value 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 Thu Oct 19, 2017 ::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 (t2 / truth-value :polarity-of (p2 / possible-01 :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))) :ARG1-of (c5 / compare-01 :ARG2 (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 Figure 6B, 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 RIα 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 Fri Sep 15, 2017 ::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 (t3 / truth-value :polarity-of (c / correlate-01 :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, RIα levels were substantially unchanged, even in cells treated with a higher dose of the control oligonucleotide HYB 239 (1 μℳ) and selumetinib (5 μℳ). # ::save-date Tue Dec 26, 2017 ::file a_pmid_2256_9000_187.txt (c / change-01 :polarity - :ARG1 (l / level :quant-of (p / protein-segment :name (n / name :op1 "RIα")) :ARG1-of (c7 / compare-01 :ARG2 (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 :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))) :ARG1-of (h2 / have-degree-91 :ARG2 (h / high-02 :ARG1 d) :ARG3 (m / more))) :op2 (d2 / dose :ARG1-of h :quant-of (s2 / small-molecule :name (n4 / name :op1 "selumetinib")) :ARG1-of (m5 / mean-01 :ARG2 (c6 / concentration-quantity :quant 5 :unit (m4 / micromolar))))))) # ::id a_pmid_2256_9000.188 ::date 2015-06-02T13:30:31 ::annotator SDL-AMR-09 ::preferred # ::snt However, reduction of RIα expression was seen when H460 cells were treated with oligonucleotide HYB 190 (Figure 6C). # ::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 RIα expression was seen in the combination treatment (Figure 6C). # ::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"))) :ARG1-of (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 in vivo in selumetinib-resistant HCT15 and H460 xenografts (Figure 7). # ::save-date Fri Sep 15, 2017 ::file a_pmid_2256_9000_190.txt (e2 / evaluate-01 :li "-1" :ARG0 (w2 / we) :ARG1 (t2 / truth-value :polarity-of (a / activity-06 :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−1, and 8-Cl-cAMP, 0.5 mg kg−1, were 20% and 16%, respectively, as compared with control untreated mice. # ::save-date Thu Oct 19, 2017 ::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)))) :ARG1-of (c7 / compare-01 :ARG2 (m6 / mouse :ARG0-of (c5 / control-01) :ARG1-of (t7 / treat-04 :polarity -))))) :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)))) # ::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 Oct 19, 2017 ::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 (h6 / have-degree-91 :ARG2 (b / bad-07 :ARG1 p2) :ARG3 (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 Tue Dec 19, 2017 ::file a_pmid_2458_8908_11.txt (l / likely-01 :ARG1 (h / have-03 :ARG0 (p / person :mod (t / this) :ARG0-of (h2 / have-rel-role-91 :ARG2 (p3 / patient)) :ARG1-of (c2 / compare-01 :ARG2 (c / counterpart :mod (e / enzyme :name (n / name :op1 "N-RAS") :mod (w / wild-type))))) :ARG1 (m / metastasize-101 :ARG2 (b / brain)) :time (p2 / present-102 :ARG0 p :ARG1 (d / disease :ARG1-of (m2 / metastasize-101)))) :ARG2-of (h3 / have-degree-91 :ARG1 l :ARG3 (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 1. # ::save-date Tue Jan 2, 2018 ::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 4))) :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-RAFV600E) or to lysine (19% were B-RAFV600K). # ::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 Thu Oct 19, 2017 ::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 (h / have-degree-91 :ARG2 (f / frequent-02 :ARG1 i) :ARG3 (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 Tue Dec 26, 2017 ::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 :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)) :ARG1-of (h2 / have-degree-91 :ARG2 (h / high-02 :ARG1 p2) :ARG3 (m2 / more :quant (s / slight)) :ARG4 (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 Oct 19, 2017 ::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 :ARG1-of (h / have-degree-91 :ARG2 (y / young) :ARG3 (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 Fri Dec 8, 2017 ::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))))) :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 Thu Oct 19, 2017 ::file a_pmid_2458_8908_68.txt (n3 / note-02 :ARG1 (r / rate :mod (p4 / percentage-entity :value 75) :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 (h4 / have-degree-91 :ARG2 (h2 / high-02 :ARG1 r) :ARG3 (m3 / more) :ARG4 (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 Jan 10, 2018 ::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 (h2 / have-degree-91 :ARG2 (s2 / short-07 :ARG1 s) :ARG3 (m2 / more) :ARG4 (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 :mod (u / univariate) :mod (p3 / person :wiki "David_Cox_(statistician)" :name (n2 / name :op1 "Cox")))) # ::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 Fri Dec 8, 2017 ::file a_pmid_2458_8908_71.txt (a2 / and :op1 (s / survive-01 :mod (m2 / median) :duration (t / temporal-quantity :quant 13 :unit (m / month))) :op2 (s2 / survive-01 :mod m2 :duration (t4 / temporal-quantity :quant 19.6 :unit (m3 / month)))) # ::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 1a for the three groups of patients (BRAF or NRAS mutant or WT for both) and Figure 1b 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 Jan 2, 2018 ::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 4)) :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 (h4 / have-degree-91 :ARG2 (h2 / high-02 :ARG1 r4) :ARG3 (m2 / more) :ARG4 (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 Wed Dec 13, 2017 ::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 (h / have-degree-91 :ARG2 (l3 / long-03 :ARG1 l2) :ARG3 (m2 / more))) :op2 (d3 / develop-01 :ARG2 m :mod (o / over-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 In vitro 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 IC50 for RAF265 and MEK162 are shown in Table 2. # ::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 IC50 for trametinib (Additional file 1: 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 Thu Oct 19, 2017 ::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 (n2 / nanomolar)))) :mod (e / each)) :manner (i / individual)) :op2 (a2 / analyze-01 :ARG1 c :time (a3 / after :op1 t :quant (t3 / temporal-quantity :quant 3 :unit (d3 / day))))) # ::id a_pmid_2458_8908.81 ::date 2015-06-14T04:50:12 ::annotator SDL-AMR-09 ::preferred # ::snt As shown in Table 2, the IC50 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 Fri Dec 8, 2017 ::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 (n4 / nanomolar))) :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 (n6 / nanomolar)) :ARG4 (c7 / concentration-quantity :quant 2004 :unit (n7 / nanomolar)) :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 (n8 / nanomolar)) :ARG4 (c9 / concentration-quantity :quant 2082 :unit (n9 / nanomolar)) :location (c3 / culture-01 :mod (m3 / mutate-01 :ARG2 (e2 / enzyme :name (n3 / name :op1 "N-RAS"))))))) # ::id a_pmid_2458_8908.82 ::date 2015-06-15T10:43:18 ::annotator SDL-AMR-09 ::preferred # ::snt The IC50 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 Fri Dec 8, 2017 ::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 (n7 / nanomolar)))) :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 (n4 / nanomolar))) :ARG4 (c7 / concentration-quantity :quant 150 :unit (n / nanomolar))) :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 (n8 / nanomolar)) :ARG4 (c9 / concentration-quantity :quant 13 :unit (n10 / nanomolar)))) # ::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 Thu Oct 19, 2017 ::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"))) :ARG2-of (h / have-degree-91 :ARG1 a :ARG3 (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 Oct 19, 2017 ::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 (h / have-degree-91 :ARG2 (g / good-02) :ARG3 (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 Sep 21, 2016 ::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 (n11 / nanomolar))) :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 (h2 / hour)))) # ::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 2A.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 Oct 19, 2017 ::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)))) :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"))))) :ARG2-of (h / have-degree-91 :ARG1 a5 :ARG3 (m3 / more) :ARG4 (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")))))))) # ::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 2A). # ::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_2488_5690.10 ::date 2015-06-08T05:01:37 ::annotator SDL-AMR-09 ::preferred # ::snt Genetic targeting of mutant BRAF resulted in restoration of sensitivity to serum starvation-induced apoptosis and efficiently inhibited cell proliferation in the absence of growth factors. # ::save-date Wed Feb 24, 2016 ::file a_pmid_2488_5690_10.txt (a / and :op1 (r2 / result-01 :ARG1 (t / target-01 :ARG1 (g2 / gene :wiki "BRAF_(gene)" :name (n / name :op1 "BRAF") :ARG1-of (m / mutate-01)) :mod (g / gene)) :ARG2 (r / restore-01 :ARG1 (s / sensitive-03 :ARG1 (a2 / apoptosis :ARG2-of (i / induce-01 :ARG0 (s2 / starve-01 :ARG2 (s3 / serum))))))) :op2 (i2 / inhibit-01 :ARG0 t :ARG1 (p / proliferate-01 :ARG0 (c / cell) :condition (a3 / absent-01 :ARG1 (g3 / growth-factor))) :ARG2-of (e / efficient-01) :condition a3)) # ::id a_pmid_2488_5690.11 ::date 2015-06-08T23:25:37 ::annotator SDL-AMR-09 ::preferred # ::snt Among tested agents, the B-Raf inhibitor dabrafenib was found to induce a strong V600E-dependent shift in cell viability. # ::save-date Sun Dec 20, 2015 ::file a_pmid_2488_5690_11.txt (f / find-01 :ARG1 (i2 / induce-01 :ARG0 (s / small-molecule :name (n3 / name :op1 "dabrafenib") :ARG0-of (i3 / inhibit-01 :ARG1 (e2 / enzyme :name (n2 / name :op1 "B-Raf"))) :ARG1-of (i4 / include-01 :ARG2 (a / agent :ARG1-of (t2 / test-01)))) :ARG2 (s2 / shift-01 :ARG1 (v / viability :mod (c / cell)) :ARG0-of (d / depend-01 :ARG1 (m / mutate-01 :value "V600E")) :mod (s3 / strong)))) # ::id a_pmid_2488_5690.12 ::date 2015-06-08T23:42:39 ::annotator SDL-AMR-09 ::preferred # ::snt In contrast, no differential sensitizing effect was observed for conventional chemotherapeutic agents (mitomycin C, oxaliplatin, paclitaxel, etoposide, 5-fluorouracil), nor for the targeted agents cetuximab, sorafenib, vemurafenib, RAF265, or for inhibition of PI3 kinase. # ::save-date Sun Jun 14, 2015 ::file a_pmid_2488_5690_12.txt (c / contrast-01 :ARG2 (o / observe-01 :ARG1 (a / affect-01 :polarity - :ARG0 (a2 / and :op1 (a3 / agent :mod (c2 / conventional) :mod (c3 / chemotherapy) :ARG1-of (m / mean-01 :ARG2 (a5 / and :op1 (s2 / small-molecule :name (n / name :op1 "mitomycin" :op2 "C")) :op2 (s3 / small-molecule :name (n2 / name :op1 "oxaliplatin")) :op3 (s4 / small-molecule :name (n3 / name :op1 "paclitaxel")) :op4 (s5 / small-molecule :name (n4 / name :op1 "etoposide")) :op5 (s6 / small-molecule :name (n5 / name :op1 "5-fluorouracil"))))) :op2 (a4 / agent :ARG1-of (t / target-01) :ARG1-of (m2 / mean-01 :ARG2 (a6 / and :op1 (s7 / small-molecule :name (n6 / name :op1 "cetuximab")) :op2 (s8 / small-molecule :name (n7 / name :op1 "sorafenib")) :op3 (s9 / small-molecule :name (n8 / name :op1 "vemurafenib")) :op4 (s10 / small-molecule :name (n9 / name :op1 "RAF265"))))) :op3 (i / inhibit-01 :ARG1 (k / kinase :name (n10 / name :op1 "PI3")))) :ARG2 (s / sensitize-01) :ARG1-of (d / differ-02)))) # ::id a_pmid_2488_5690.13 ::date 2015-06-08T23:54:05 ::annotator SDL-AMR-09 ::preferred # ::snt Treatment with dabrafenib efficiently inhibited phosphorylation of the B-Raf downstream targets Mek 1/2 and Erk 1/2. # ::save-date Sun Jan 3, 2016 ::file a_pmid_2488_5690_13.txt (i / inhibit-01 :ARG0 (t / treat-04 :ARG2 (s / small-molecule :name (n5 / name :op1 "dabrafenib"))) :ARG1 (p2 / phosphorylate-01 :ARG1 (a / and :op1 (e3 / enzyme :name (n3 / name :op1 "Mek1/2")) :op2 (e4 / enzyme :name (n4 / name :op1 "Erk1/2")) :ARG1-of (t2 / target-01 :ARG0 (e2 / enzyme :name (n2 / name :op1 "B-Raf"))) :direction (d / downstream))) :ARG2-of (e / efficient-01 :ARG1 t)) # ::id a_pmid_2488_5690.33 ::date 2015-06-09T00:01:34 ::annotator SDL-AMR-09 ::preferred # ::snt BRAF targeting in RKO # ::save-date Tue Jun 9, 2015 ::file a_pmid_2488_5690_33.txt (t / target-01 :ARG1 (g / gene :name (n / name :op1 "BRAF")) :location (c / cell-line :name (n2 / name :op1 "RKO"))) # ::id a_pmid_2488_5690.34 ::date 2015-06-09T00:10:23 ::annotator SDL-AMR-09 ::preferred # ::snt It has been shown that B-RafV600E is sufficient to promote proliferation via Erk 1/2 signaling independently of exogenous growth factors and confers mechanisms to evade apoptosis [14-16]. # ::save-date Wed Feb 24, 2016 ::file a_pmid_2488_5690_34.txt (s / show-01 :ARG0 (p3 / publication :ARG1-of (c2 / cite-01 :ARG2 (v / value-interval :op1 14 :op2 16))) :ARG1 (a / and :op1 (s2 / suffice-01 :ARG0 (e2 / enzyme :name (n2 / name :op1 "B-Raf") :ARG1-of (m / mutate-01 :value "V600E")) :ARG1 (p / promote-01 :ARG0 e2 :ARG1 (p2 / proliferate-01 :instrument (s3 / signal-07 :ARG0 (e3 / enzyme :name (n3 / name :op1 "Erk1/2"))) :ARG0-of (d / depend-01 :polarity - :ARG1 (g / growth-factor :mod (e4 / exogenous)))))) :op2 (c / confer-02 :ARG0 e2 :ARG1 (m2 / mechanism :purpose (e5 / evade-01 :ARG1 (a2 / apoptosis)))))) # ::id a_pmid_2488_5690.35 ::date 2015-06-09T00:20:02 ::annotator SDL-AMR-09 ::preferred # ::snt However, these results are primarily based on non-quantitative RNA interference (RNAi) methods which are prone to artifacts in mammalian cells due to nonspecific defense mechanisms [17]. # ::save-date Sat Jan 20, 2018 ::file a_pmid_2488_5690_35.txt (c / contrast-01 :ARG2 (b / base-02 :ARG1 (t2 / thing :ARG2-of (r / result-01) :mod (t / this)) :ARG2 (m / method :ARG1-of (p / prone-01 :ARG2 (a / artifact) :location (c2 / cell :part-of (m3 / mammal)) :ARG1-of (c3 / cause-01 :ARG0 (m2 / mechanism :purpose (d / defend-01) :ARG1-of (s / specific-02 :polarity -)))) :mod (q / quantitative :polarity -) :manner-of (i / interfere-01 :ARG1 (n / nucleic-acid :name (n3 / name :op1 "RNA")))) :manner (p3 / primary)) :ARG1-of (d2 / describe-01 :ARG0 (p2 / publication :ARG1-of (c4 / cite-01 :ARG2 17)))) # ::id a_pmid_2488_5690.36 ::date 2015-06-09T00:25:38 ::annotator SDL-AMR-09 ::preferred # ::snt In contrast, somatic cell gene targeting enables quantitative knockouts of single alleles (Figure 1A) and the generation of endogenous models featuring well-defined genetic backgrounds [18]. # ::save-date Tue Oct 3, 2017 ::file a_pmid_2488_5690_36.txt (c / contrast-01 :ARG2 (e / enable-01 :ARG0 (t / target-01 :ARG1 (g / gene :part-of (c2 / cell :mod (s / somatic)))) :ARG1 (a / and :op1 (k / knock-out-12 :ARG1 (a2 / allele :ARG1-of (s2 / single-02)) :mod (q / quantity) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "1A"))) :op2 (g2 / generate-01 :ARG1 (m / model :mod (e2 / endogenous) :ARG0-of (f2 / feature-01 :ARG1 (b / background :mod (g3 / gene) :ARG1-of (d2 / define-01 :manner (w / well)))))))) :ARG1-of (d3 / describe-01 :ARG0 (p / publication :ARG1-of (c3 / cite-01 :ARG2 18)))) # ::id a_pmid_2488_5690.37 ::date 2015-06-09T00:31:02 ::annotator SDL-AMR-09 ::preferred # ::snt Utilizing this method, we have disrupted BRAF alleles in the colorectal cancer cell line RKO and established syngeneic clones which harbor a single BRAF allele of either wild-type or mutant genotype. # ::save-date Sun Jan 3, 2016 ::file a_pmid_2488_5690_37.txt (a / and :op1 (d2 / disrupt-01 :ARG0 (w2 / we) :ARG1 (a2 / allele :name (n2 / name :op1 "BRAF")) :location (c / cell-line :name (n3 / name :op1 "RKO") :mod (d3 / disease :wiki "Colorectal_cancer" :name (n6 / name :op1 "colorectal" :op2 "cancer")))) :op2 (e / establish-01 :ARG0 w2 :ARG1 (c2 / clone :mod (s / syngeneic) :ARG0-of (h2 / harbor-01 :ARG1 (o / or :op1 (a3 / allele :name (n4 / name :op1 "BRAF") :mod (w3 / wild-type) :ARG1-of (s2 / single-02)) :op2 (a4 / allele :name (n5 / name :op1 "BRAF") :ARG1-of (m / mutate-01) :ARG1-of s2))))) :manner (u / utilize-01 :ARG0 w2 :ARG1 (m2 / method :mod (t / this)))) # ::id a_pmid_2488_5690.38 ::date 2015-06-09T00:36:59 ::annotator SDL-AMR-09 ::preferred # ::snt Despite its near-diploid karyotype and MSI phenotype, the colorectal cancer cell line RKO carries a stable triplication of the BRAF gene locus (dup (7) (q21q36)) with one wild-type and two mutant alleles present in parental cells [13]. # ::save-date Sun Jan 3, 2016 ::file a_pmid_2488_5690_38.txt (c / carry-01 :ARG0 (c2 / cell-line :name (n2 / name :op1 "RKO") :mod (d / disease :wiki "Colorectal_cancer" :name (n / name :op1 "colorectal" :op2 "cancer"))) :ARG1 (t / triplicate-00 :ARG1 (l / locus :mod (g / gene :name (n3 / name :op1 "BRAF")) :ARG1-of (l2 / label-01 :ARG2 (s2 / string-entity :value "dup(7)(q21q36)"))) :ARG1-of (s / stable-03) :ARG1-of (m / mean-01 :ARG2 (b / be-located-at-91 :ARG1 (a / and :op1 (a2 / allele :quant 1 :mod (w / wild-type)) :op2 (a3 / allele :quant 2 :ARG1-of (m2 / mutate-01))) :ARG2 (c3 / cell :mod (p / parent))))) :concession (h2 / have-03 :ARG0 c2 :ARG1 (a4 / and :op1 (k / karyotype :ARG1-of (n4 / near-01 :ARG2 (d3 / diploid))) :op2 (p2 / phenotype :name (n5 / name :op1 "microsattelite" :op2 "instability")))) :ARG1-of (d2 / describe-01 :ARG0 (p3 / publication :ARG1-of (c4 / cite-01 :ARG2 13)))) # ::id a_pmid_2488_5690.39 ::date 2015-06-09T00:45:57 ::annotator SDL-AMR-09 ::preferred # ::snt This genotype was verified by DNA sequencing in RKO-E1, a subclone obtained from RKO that was found to be comparable to the parental cell line in terms of morphology and proliferation (Figure 1B and data not shown). # ::save-date Tue Feb 2, 2016 ::file a_pmid_2488_5690_39.txt (v / verify-01 :ARG1 (g / genotype :mod (t / this)) :location (c / cell-line :name (n2 / name :op1 "RKO-E1") :ARG3-of (s2 / subclone-01 :ARG1-of (o / obtain-01 :ARG2 (c2 / cell-line :name (n3 / name :op1 "RKO"))) :ARG1-of (c3 / compare-01 :ARG2 (c4 / cell-line :mod (p2 / parent)) :ARG1-of (p / possible-01) :topic (a / and :op1 (m / morphology) :op2 (p3 / proliferate-01)) :ARG1-of (f / find-01)))) :ARG1-of (d / describe-01 :ARG0 (a2 / and :op1 (f2 / figure :mod "1B") :op2 (d2 / data :ARG1-of (s / show-01 :polarity -)))) :manner (s3 / sequence-01 :ARG1 (n / nucleic-acid :wiki "DNA" :name (n4 / name :op1 "DNA")))) # ::id a_pmid_2488_5690.40 ::date 2015-06-09T04:41:16 ::annotator SDL-AMR-09 ::preferred # ::snt In the first targeting round, an oncogenic allele of BRAF exon 15 was recombined and deleted by somatic cell gene targeting to generate the cell clone RBOW (RKO-derived BRAFonc/wt/-). # ::save-date Mon Jan 4, 2016 ::file a_pmid_2488_5690_40.txt (a / and :op1 (r / recombine-01 :ARG1 (a2 / allele :mod (o2 / oncogenic) :mod (e / exon :mod 15 :part-of (g / gene :name (n / name :op1 "BRAF"))))) :op2 (d / delete-01 :ARG1 a2) :time (r2 / round-05 :ARG1 (t / target-01) :ord (o / ordinal-entity :value 1)) :instrument (t2 / target-01 :ARG1 (g4 / gene :part-of (c / cell :mod (s / somatic)))) :purpose (g2 / generate-01 :ARG1 (c2 / cell :name (n2 / name :op1 "RBOW") :ARG1-of (m / mean-01 :ARG2 (c4 / cell-line :location-of (g3 / gene :name (n3 / name :op1 "BRAF") :ARG1-of (d2 / derive-01 :ARG2 (c3 / cell-line :name (n4 / name :op1 "RKO"))) :ARG1-of (l / label-01 :ARG2 (s2 / string-entity :value "onc/wt/-"))))) :ARG1-of (c5 / clone-01)))) # ::id a_pmid_2488_5690.41 ::date 2015-06-09T04:51:08 ::annotator SDL-AMR-09 ::preferred # ::snt Subsequently, either wild-type or V600E-mutant B-Raf was disrupted by targeting a second allele in RBOW, yielding six BRAF-mutant and one wild-type clone from approximately 104 screened colonies. # ::save-date Tue Oct 17, 2017 ::file a_pmid_2488_5690_41.txt (d / disrupt-01 :ARG1 (o2 / or :op1 (e2 / enzyme :name (n2 / name :op1 "B-Raf") :mod (w / wild-type)) :op2 (e / enzyme :name (n / name :op1 "B-Raf") :ARG2-of (m / mutate-01 :value "V600E"))) :manner (t2 / target-01 :ARG1 (a2 / allele :part-of (c / cell :name (n3 / name :op1 "RBOW")) :ord (o / ordinal-entity :value 2))) :ARG0-of (y / yield-01 :ARG1 (a3 / and :op1 (c2 / clone :quant 6 :mod (m2 / mutate-01 :ARG1 (g / gene :name (n4 / name :op1 "BRAF")))) :op2 (c3 / clone :quant 1 :mod w)) :source (c4 / colony :ARG1-of (s2 / screen-01) :quant (a / approximately :op1 10000))) :time (s3 / subsequent)) # ::id a_pmid_2488_5690.42 ::date 2015-06-09T05:02:53 ::annotator SDL-AMR-09 ::preferred # ::snt Out of these double positive clones, BRAF knockout cell lines RBO-1 and RBO-2 (RKO-derived BRAFonc/-/- 1 and 2) as well as RBW-1 (RKO-derived BRAFwt/-/-) were established (Figure 1B). # ::save-date Tue Oct 3, 2017 ::file a_pmid_2488_5690_42.txt (e / establish-01 :ARG1 (a / and :op1 (c / cell-line :name (n / name :op1 "RBO-1") :ARG1-of (m / mean-01 :ARG2 (c3 / cell-line :mod 1 :location-of (g2 / gene :name (n4 / name :op1 "BRAF") :ARG1-of (d / derive-01 :ARG2 (c4 / cell-line :name (n5 / name :op1 "RKO"))) :ARG2-of (m2 / mutate-01 :mod "−/−") :ARG0-of (c9 / cause-01 :ARG1 (d4 / disease :wiki "Cancer" :name (n8 / name :op1 "cancer")))))) :ARG1-of (k / knock-out-12 :ARG2 (g / gene :name (n3 / name :op1 "BRAF")))) :op2 (c2 / cell-line :name (n2 / name :op1 "RBO-2") :ARG1-of (m3 / mean-01 :ARG2 (c5 / cell-line :mod 2 :location-of g2)) :location-of k) :op3 (c6 / cell-line :name (n6 / name :op1 "RBW-1") :ARG1-of (m4 / mean-01 :ARG2 (c7 / cell-line :location-of (g3 / gene :name (n7 / name :op1 "BRAF") :ARG2-of (m5 / mutate-01 :mod "−/−") :ARG1-of d :mod (w / wild-type))))) :source (c8 / clone :mod (p / positive :mod (d2 / double)) :mod (t / this))) :ARG1-of (d3 / describe-01 :ARG0 (f / figure :mod "1B"))) # ::id a_pmid_2488_5690.43 ::date 2015-06-09T05:16:43 ::annotator SDL-AMR-09 ::preferred # ::snt The apparent counterselection against inactivation of B RafV600E might indicate the presence of an oncogene addiction for B-RafV600E as a cancer cell trait in RKO [19]. # ::save-date Wed Dec 9, 2015 ::file a_pmid_2488_5690_43.txt (p2 / possible-01 :ARG1 (i / indicate-01 :ARG0 (c / counterselect-00 :mod (a / apparent) :ARG0-of (c6 / counter-01 :ARG1 (a3 / activate-01 :polarity - :ARG1 (e3 / enzyme :name (n3 / name :op1 "B-Raf") :ARG2-of (m / mutate-01 :value "V600E"))))) :ARG1 (t / trait :domain (a2 / addict-01 :ARG1 e3 :ARG2 (o / oncogene)) :mod (c2 / cell :mod (d / disease :wiki "Cancer" :name (n / name :op1 "cancer"))) :location (c4 / cell-line :name (n5 / name :op1 "RKO")))) :ARG1-of (d2 / describe-01 :ARG0 (p3 / publication :ARG1-of (c5 / cite-01 :ARG2 19)))) # ::id a_pmid_2488_5690.44 ::date 2015-06-09T05:24:19 ::annotator SDL-AMR-09 ::preferred # ::snt For structural confirmation of the deleted alleles, DNA sequencing was performed and all genotypes were verified (Figure 1B). # ::save-date Tue Jan 19, 2016 ::file a_pmid_2488_5690_44.txt (a / and :op1 (p / perform-01 :ARG1 (s / sequence-01 :ARG1 (n / nucleic-acid :wiki "DNA" :name (n2 / name :op1 "DNA")))) :op2 (v / verify-01 :ARG1 (g / genotype :mod (a2 / all))) :purpose (c / confirm-01 :ARG1 (a3 / allele :ARG1-of (d / delete-01)) :mod (s2 / structure)) :ARG1-of (d3 / describe-01 :ARG0 (f / figure :mod "1B"))) # ::id a_pmid_2488_5690.45 ::date 2015-06-09T05:27:35 ::annotator SDL-AMR-09 ::preferred # ::snt Furthermore, all cells expressed BRAF protein at comparable levels (Figure 1C). # ::save-date Tue Jan 12, 2016 ::file a_pmid_2488_5690_45.txt (a / and :op2 (p2 / possible-01 :ARG1 (c2 / compare-01 :ARG1 (l / level :quant-of (e / express-03 :ARG2 (e2 / enzyme :wiki - :name (n / name :op1 "BRAF")) :ARG3 (c / cell :mod (a2 / all)))))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "1C"))) # ::id a_pmid_2488_5690.46 ::date 2015-06-09T05:31:04 ::annotator SDL-AMR-09 ::preferred # ::snt While the expression of Mek 1/2 and Erk 1/2 was independent of serum concentration and BRAF status, the phosphorylation of these effector kinases was constantly active in the BRAF-mutant clones but low in BRAF-wild-type cells (Figure 1C). # ::save-date Sun Jan 3, 2016 ::file a_pmid_2488_5690_46.txt (c / contrast-01 :ARG1 (c3 / contrast-01 :ARG1 (a3 / active :domain (p / phosphorylate-01 :ARG1 a) :manner (c4 / constant) :location (c5 / clone :location-of (g2 / gene :name (n4 / name :op1 "BRAF") :ARG2-of (m / mutate-01)))) :ARG2 (l / low-04 :ARG1 (c6 / cell :location-of (g3 / gene :name (n5 / name :op1 "BRAF") :mod (w / wild-type))) :ARG2 p)) :ARG2 (d / depend-01 :polarity - :ARG0 (e3 / express-03 :ARG2 (a / and :op1 (k / kinase :name (n / name :op1 "Mek1/2")) :op2 (k2 / kinase :name (n2 / name :op1 "Erk1/2")) :ARG0-of (e / effect-03))) :ARG1 (a2 / and :op1 (c2 / concentrate-02 :ARG1 (s / serum)) :op2 (s2 / status :mod (g / gene :name (n3 / name :op1 "BRAF"))))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure :mod "1C"))) # ::id a_pmid_2488_5690.47 ::date 2015-06-09T05:39:53 ::annotator SDL-AMR-09 ::preferred # ::snt This was found to be independent of the serum concentration, indicating that the phosphorylation status of Mek and Erk is dependent on mutant BRAF in RKO. # ::save-date Sat Jan 16, 2016 ::file a_pmid_2488_5690_47.txt (f / find-01 :ARG1 (d / depend-01 :polarity - :ARG0 (t / this) :ARG1 (c / concentrate-02 :ARG1 (s / serum)) :ARG0-of (i / indicate-01 :ARG1 (d2 / depend-01 :ARG0 (s2 / status :mod (p / phosphorylate-01 :ARG1 (a / and :op1 (e / enzyme :name (n / name :op1 "Mek")) :op2 (e2 / enzyme :name (n2 / name :op1 "Erk"))))) :ARG1 (g / gene :name (n3 / name :op1 "BRAF") :ARG2-of (m / mutate-01)) :location (c2 / cell-line :name (n4 / name :op1 "RKO")))))) # ::id a_pmid_2488_5690.48 ::date 2015-06-09T09:55:59 ::annotator SDL-AMR-09 ::preferred # ::snt Cell-biological phenotypes related to mutant BRAF # ::save-date Sun Jun 14, 2015 ::file a_pmid_2488_5690_48.txt (p / phenotype :mod (b / biology :mod (c / cell)) :ARG1-of (r / relate-01 :ARG2 (g / gene :name (n / name :op1 "BRAF") :ARG2-of (m / mutate-01)))) # ::id a_pmid_2488_5690.49 ::date 2015-06-09T09:59:07 ::annotator SDL-AMR-09 ::preferred # ::snt Under standard long-term cell culture conditions no differences in morphology or growth were observed between the cell clones (Figures 1B and 2A). # ::save-date Mon Dec 21, 2015 ::file a_pmid_2488_5690_49.txt (o / observe-01 :ARG1 (d / differ-02 :polarity - :ARG1 (c2 / cell :ARG1-of (c / clone-01)) :ARG3 (o2 / or :op1 (m / morphology) :op2 (g / grow-01))) :condition (c3 / condition :ARG1-of (s / standard-02) :mod (c4 / culture-01 :ARG1 (c5 / cell) :ARG1-of (l2 / long-03))) :ARG1-of (d2 / describe-01 :ARG0 (a / and :op1 (f / figure :mod "1B") :op2 (f2 / figure :mod "2A")))) # ::id a_pmid_2488_5690.50 ::date 2015-06-09T10:02:11 ::annotator SDL-AMR-09 ::preferred # ::snt Expectedly, decreased serum concentrations led to lower proliferation rates in these cells, but exponential growth was sustained under all applied conditions. # ::save-date Thu Oct 19, 2017 ::file a_pmid_2488_5690_50.txt (c3 / contrast-01 :ARG1 (l2 / lead-03 :ARG0 (c / concentrate-02 :ARG1 (s / serum) :ARG1-of (d / decrease-01)) :ARG2 (p / proliferate-01 :ARG1-of (h / have-degree-91 :ARG2 (l / low-04 :ARG1 p :location (c2 / cell :mod (t / this))) :ARG3 (m / more))) :ARG1-of (e2 / expect-01)) :ARG2 (s2 / sustain-01 :ARG1 (g / grow-01 :ARG2 (e / exponential)) :condition (c4 / condition :ARG1-of (a / apply-02) :mod (a2 / all)))) # ::id a_pmid_2488_5690.51 ::date 2015-06-09T10:05:20 ::annotator SDL-AMR-09 ::preferred # ::snt However, the withdrawal of serum resulted in the inhibition of cell growth of the wild-type cells RBW-1 (Figure 2B and C). # ::save-date Wed Jun 10, 2015 ::file a_pmid_2488_5690_51.txt (c / contrast-01 :ARG2 (r / result-01 :ARG1 (w / withdraw-01 :ARG1 (s / serum)) :ARG2 (i / inhibit-01 :ARG1 (g / grow-01 :ARG0 (c2 / cell-line :name (n / name :op1 "RBW-1") :mod (w2 / wild-type))))) :ARG1-of (d / describe-01 :ARG0 (a / and :op1 (f / figure :mod "2B") :op2 (f2 / figure :mod "2C")))) # ::id a_pmid_2488_5690.52 ::date 2015-06-09T10:07:28 ::annotator SDL-AMR-09 ::preferred # ::snt It has been shown previously that BRAF wild-type cells require glucose supply for survival whereas BRAF-mutant cell clones maintain proliferation in low-glucose environments [20]. # ::save-date Sun Jan 17, 2016 ::file a_pmid_2488_5690_52.txt (c / contrast-01 :ARG1 (r / require-01 :ARG0 (c2 / cell :location-of (g / gene :name (n / name :op1 "BRAF") :mod (w / wild-type))) :ARG1 (s2 / supply-01 :ARG1 (s3 / small-molecule :name (n2 / name :op1 "glucose"))) :purpose (s4 / survive-01 :ARG0 c2)) :ARG2 (m / maintain-01 :ARG0 (c4 / cell :ARG1-of (c3 / clone-01 :location-of (g2 / gene :name (n3 / name :op1 "BRAF") :ARG1-of (m2 / mutate-01)))) :ARG1 (p2 / proliferate-01) :location (e / environment :ARG1-of (l / low-04 :ARG2 s3))) :ARG1-of (s / show-01 :ARG0 (p3 / publication :ARG1-of (c5 / cite-01 :ARG2 20)) :time (p / previous))) # ::id a_pmid_2488_5690.53 ::date 2015-06-09T10:21:30 ::annotator SDL-AMR-09 ::preferred # ::snt Here we show that the V600E mutation of B-Raf also provides independency of serum-derived growth signals in RKO and that targeting of oncogenically mutant BRAF is sufficient to deprive this vital feature of malignancy from the cells, thereby corroborating previous reports [6]. # ::save-date Wed Dec 9, 2015 ::file a_pmid_2488_5690_53.txt (a / and :op1 (p / provide-01 :ARG0 (e2 / enzyme :name (n2 / name :op1 "B-Raf") :ARG2-of (m / mutate-01 :value "V600E")) :ARG1 (d / depend-01 :polarity - :ARG1 (s / signal-07 :ARG1 (g / grow-01) :ARG1-of (d2 / derive-01 :ARG2 (s2 / serum)))) :mod (a2 / also) :location (c / cell-line :name (n3 / name :op1 "RKO"))) :op2 (s3 / suffice-01 :ARG0 (t / target-01 :ARG1 (g2 / gene :name (n4 / name :op1 "BRAF") :ARG1-of (m2 / mutate-01 :ARG0-of (c6 / cause-01 :ARG1 (d5 / disease :wiki "Cancer" :name (n / name :op1 "cancer")))))) :ARG1 (d3 / deprive-01 :ARG0 t :ARG1 (f / feature-01 :ARG0 c2 :ARG1 (m3 / malignancy) :mod (t2 / this) :mod (v / vital)) :ARG2 (c2 / cell))) :ARG1-of (s4 / show-01 :ARG0 (w / we) :location (h / here) :ARG0-of (c3 / cause-01 :ARG1 (c4 / corroborate-01 :ARG1 (r / report :time (p2 / previous) :ARG1-of (d4 / describe-01 :ARG0 (p3 / publication :ARG1-of (c5 / cite-01 :ARG2 6)))))))) # ::id a_pmid_2488_5690.54 ::date 2015-06-09T10:31:52 ::annotator SDL-AMR-09 ::preferred # ::snt Sustained proliferative signaling is considered one of the major traits of cancer cells and is therefore used as a target mechanism of individualized therapy approaches including anti EGFR therapy strategies in colorectal cancer [21,22]. # ::save-date Thu Jan 28, 2016 ::file a_pmid_2488_5690_54.txt (c / consider-01 :ARG1 (i / include-01 :ARG1 (s / signal-07 :ARG0-of (p / proliferate-01) :ARG1-of (s2 / sustain-01)) :ARG2 (t / trait :poss (c2 / cell :mod (d2 / disease :wiki "Cancer" :name (n3 / name :op1 "cancer"))) :ARG1-of (m / major-02))) :ARG0-of (c4 / cause-01 :ARG1 (u / use-01 :ARG1 s :ARG2 (m2 / mechanism :ARG1-of (t2 / target-01) :poss (a / approach-02 :mod (t3 / therapy :ARG1-of (i2 / individualize-02)) :ARG2-of (i3 / include-91 :ARG1 (s3 / strategy :mod (t4 / therapy :ARG0-of (c7 / counter-01 :ARG1 (e / enzyme :name (n2 / name :op1 "EGFR")))) :prep-in (d / disease :wiki "Colorectal_cancer" :name (n / name :op1 "colorectal" :op2 "cancer"))) :ARG1-of (d4 / describe-01 :ARG0 (p3 / publication :ARG1-of (c6 / cite-01 :ARG2 22)))))))) :ARG1-of (d3 / describe-01 :ARG0 (p2 / publication :ARG1-of (c5 / cite-01 :ARG2 21)))) # ::id a_pmid_2488_5690.55 ::date 2015-06-09T23:18:51 ::annotator SDL-AMR-09 ::preferred # ::snt In another context, mutant B-Raf induced cellular senescence rather than proliferation [23,24]. # ::save-date Sun Dec 20, 2015 ::file a_pmid_2488_5690_55.txt (i / induce-01 :ARG0 (e2 / enzyme :name (n2 / name :op1 "B-Raf") :ARG2-of (m / mutate-01)) :ARG2 (s / senescence :mod (c / cell) :ARG1-of (i2 / instead-of-91 :ARG2 (p / proliferate-01 :ARG0 c))) :condition (c2 / context :mod (a / another)) :ARG1-of (d / describe-01 :ARG0 (p2 / publication :ARG1-of (c3 / cite-01 :ARG2 (a2 / and :op1 23 :op2 24))))) # ::id a_pmid_2488_5690.56 ::date 2015-06-09T23:22:38 ::annotator SDL-AMR-09 ::preferred # ::snt However, senescence can be overcome by phosphoinositide 3-kinase (PI3K)/AKT signaling [24] which is hyperactivated in RKO due to a PIK3CA mutation. # ::save-date Sun Jun 14, 2015 ::file a_pmid_2488_5690_56.txt (c / contrast-01 :ARG2 (p / possible-01 :ARG1 (o / overcome-01 :ARG0 (s2 / signal-07 :ARG0 (p2 / pathway :name (n2 / name :op1 "phosphoinositide" :op2 "3-kinase" :op3 "AKT")) :ARG1-of (a / activate-01 :degree (h / hyper) :location (c3 / cell-line :name (n3 / name :op1 "RKO")) :ARG1-of (c4 / cause-01 :ARG0 (m / mutate-01 :ARG1 (g / gene :name (n / name :op1 "PIK3CA")))))) :ARG1 (s / senescence)) :ARG1-of (d / describe-01 :ARG0 (p3 / publication :ARG1-of (c2 / cite-01 :ARG2 24))))) # ::id a_pmid_2488_5690.57 ::date 2015-06-09T23:29:10 ::annotator SDL-AMR-09 ::preferred # ::snt By staining of senescence-associated β-galactosidase activity [25] we examined whether the differential proliferation rates observed upon serum deprivation were attributable to cellular senescence. # ::save-date Fri Sep 15, 2017 ::file a_pmid_2488_5690_57.txt (e / examine-01 :ARG0 (w / we) :ARG1 (t / truth-value :polarity-of (p / possible-01 :ARG1 (a / attribute-01 :ARG1 (r / rate :mod (p2 / proliferate-01) :ARG1-of (d / differ-02) :ARG1-of (o / observe-01 :condition (d3 / deprive-01 :ARG1 (s3 / serum)))) :ARG2 (s / senescence :mod (c / cell))))) :manner (s2 / stain-01 :ARG1 (a2 / activity-06 :ARG0 (e2 / enzyme :name (n / name :op1 "senescence-associated" :op2 "β-galactosidase"))) :ARG1-of (d2 / describe-01 :ARG0 (p3 / publication :ARG1-of (c2 / cite-01 :ARG2 25))))) # ::id a_pmid_2488_5690.58 ::date 2015-06-09T23:32:53 ::annotator SDL-AMR-09 ::preferred # ::snt Cellular senescence was detected at very low levels in less than 5% of cells (Figure 2D-E), indicating that senescence alone cannot explain the strong reduction in cell growth observed upon withdrawal of serum. # ::save-date Thu Jun 18, 2015 ::file a_pmid_2488_5690_58.txt (d / detect-01 :ARG1 (l2 / level :quant-of (s / senescence :mod (c / cell)) :ARG1-of (l3 / low-04 :degree (v / very))) :location (c2 / cell :quant (l / less-than :op1 (p / percentage-entity :value 5))) :ARG1-of (d2 / describe-01 :ARG0 (a / and :op1 (f / figure :name (n / name :op1 "2D")) :op2 (f2 / figure :name (n2 / name :op1 "2E")))) :ARG0-of (i / indicate-01 :ARG1 (p2 / possible-01 :polarity - :ARG1 (e / explain-01 :ARG0 (s2 / senescence :mod (a2 / alone)) :ARG1 (r / reduce-01 :ARG1 (g / grow-01 :ARG1 (c3 / cell)) :ARG2 (s4 / strong) :ARG1-of (o / observe-01 :condition (w / withdraw-01 :ARG1 (s3 / serum)))))))) # ::id a_pmid_2488_5690.59 ::date 2015-06-09T23:38:16 ::annotator SDL-AMR-09 ::preferred # ::snt Flow cytometry revealed a significant increase of apoptotic cells in wild-type compared to mutant clones upon withdrawal of serum (Figure 2F and G). # ::save-date Thu Oct 19, 2017 ::file a_pmid_2488_5690_59.txt (r / reveal-01 :ARG0 (t / thing :name (n / name :op1 "flow" :op2 "cytometry")) :ARG1 (i / increase-01 :ARG1 (c / cell :mod (a / apoptosis)) :ARG2 (s / significant-02) :location (c2 / cell :mod (w / wild-type) :ARG1-of (c4 / compare-01 :ARG2 (c3 / clone :ARG2-of (m / mutate-01)))) :condition (w2 / withdraw-01 :ARG1 (s2 / serum))) :ARG1-of (d / describe-01 :ARG0 (a2 / and :op1 (f / figure :mod "2F") :op2 (f2 / figure :mod "2G")))) # ::id a_pmid_2488_5690.60 ::date 2015-06-09T23:42:19 ::annotator SDL-AMR-09 ::preferred # ::snt Apoptosis was confirmed by the detection of cleaved caspase 3 at considerable levels in serum-starved RBW-1, while all other samples showed full-length protein only (Figure 2H). # ::save-date Sun Jan 17, 2016 ::file a_pmid_2488_5690_60.txt (c5 / contrast-01 :ARG1 (c / confirm-01 :ARG0 (d / detect-01 :ARG1 (l / level :quant-of (p2 / protein :name (n / name :op1 "caspase" :op2 "3") :ARG1-of (c2 / cleave-01)) :quant (c3 / considerable)) :location (c4 / cell-line :name (n2 / name :op1 "RBW-1") :ARG1-of (s / starve-01 :ARG2 (s2 / serum)))) :ARG1 (a / apoptosis)) :ARG2 (s3 / show-01 :ARG0 (t / thing :mod (a2 / all) :mod (o / other) :ARG1-of (s4 / sample-01)) :ARG1 (p / protein :ARG1-of (l2 / long-03 :degree (f / full))) :mod (o2 / only)) :ARG1-of (d2 / describe-01 :ARG0 (f2 / figure :mod "2H"))) # ::id a_pmid_2488_5690.61 ::date 2015-06-09T23:49:47 ::annotator SDL-AMR-09 ::preferred # ::snt Consistent with RKO modeling a distinct subpopulation of patients characterized by the presence of certain molecular features and the absence of others [7], no implication of p53 in apoptosis was observed (Figure 2H). # ::save-date Wed Oct 14, 2015 ::file a_pmid_2488_5690_61.txt (o / observe-01 :ARG1 (i / implicate-01 :polarity - :ARG1 (p / protein :name (n / name :op1 "p53")) :ARG2 (a / apoptosis)) :ARG1-of (c / consistent-01 :ARG2 (m / model-01 :ARG0 (c2 / cell-line :name (n2 / name :op1 "RKO")) :ARG1 (s / subpopulation :mod (p2 / patient) :mod (d / distinct) :ARG1-of (c3 / characterize-01 :ARG2 (a2 / and :op1 (h / have-03 :ARG0 s :ARG1 (f / feature :mod (m2 / molecule) :mod (c4 / certain))) :op2 (l / lack-01 :ARG0 s :ARG1 (f2 / feature :mod m2 :mod (o2 / other)))))) :ARG1-of (d2 / describe-01 :ARG0 (p3 / publication :ARG1-of (c5 / cite-01 :ARG2 7))))) :ARG1-of (d3 / describe-01 :ARG0 (f3 / figure :mod "2H"))) # ::id a_pmid_2488_5690.62 ::date 2015-06-09T23:56:19 ::annotator SDL-AMR-09 ::preferred # ::snt Since serum starvation is often used to model apoptosis mediated via the PUMA pathway [26], we also analyzed PUMA protein levels. # ::save-date Fri Feb 5, 2016 ::file a_pmid_2488_5690_62.txt (a / analyze-01 :ARG0 (w / we) :ARG1 (l / level :quant-of (p / protein :name (n / name :op1 "PUMA"))) :ARG1-of (c / cause-01 :ARG0 (u / use-01 :ARG1 (s / starve-01 :ARG2 (s2 / serum)) :frequency (o / often) :purpose (m / model-01 :ARG0 s :ARG1 (a2 / apoptosis :ARG1-of (m2 / mediate-01 :instrument (p2 / pathway :name (n2 / name :op1 "PUMA"))))) :ARG1-of (d / describe-01 :ARG0 (p3 / publication :ARG1-of (c2 / cite-01 :ARG2 26))))) :mod (a3 / also)) # ::id a_pmid_2488_5690.63 ::date 2015-06-10T00:00:07 ::annotator SDL-AMR-09 ::preferred # ::snt PUMA was found to be highly abundant specifically in serum starved RBW-1 (Figure 2H). # ::save-date Sun Jan 3, 2016 ::file a_pmid_2488_5690_63.txt (a / abundant :op1 (c / cell-line :name (n2 / name :op1 "RBW-1") :ARG1-of (s / starve-01 :ARG2 (s2 / serum))) :ARG1-of (h / high-02) :domain (p / protein :name (n / name :op1 "PUMA")) :ARG1-of (f / find-01) :ARG1-of (d / describe-01 :ARG0 (f2 / figure :mod "2H")) :ARG1-of (s3 / specific-02)) # ::id a_pmid_2488_5690.64 ::date 2015-06-10T00:05:29 ::annotator SDL-AMR-09 ::preferred # ::snt Consistent with data previously shown by others, starvation-induced apoptosis is mediated by PUMA in a p53-independent fashion in our experiments [27]. # ::save-date Sun Dec 20, 2015 ::file a_pmid_2488_5690_64.txt (m / mediate-01 :ARG0 (p / protein :name (n / name :op1 "PUMA")) :ARG1 (a / apoptosis :ARG2-of (i / induce-01 :ARG0 (s / starve-01))) :manner (d / depend-01 :polarity - :ARG1 (p2 / protein :name (n2 / name :op1 "p53"))) :time (e / experiment-01 :ARG0 (w / we)) :ARG1-of (c / consistent-01 :ARG2 (d2 / data :ARG1-of (s2 / show-01 :ARG0 (p5 / person :mod (o / other)) :time (p3 / previous)) :ARG1-of (d3 / describe-01 :ARG0 (p4 / publication :ARG1-of (c2 / cite-01 :ARG2 27)))))) # ::id a_pmid_2488_5690.65 ::date 2015-06-10T00:10:01 ::annotator SDL-AMR-09 ::preferred # ::snt Programmed cell death is a key feature of proliferation control in homeostasis and overcoming apoptosis is considered another hallmark of cancer cells [28]. # ::save-date Sun Dec 20, 2015 ::file a_pmid_2488_5690_65.txt (a / and :op1 (f / feature :ARG1-of (k / key-02 :ARG2 (d2 / die-01 :ARG1 (c / cell) :ARG1-of (p / program-01))) :part-of (c2 / control-01 :ARG1 (p2 / proliferate-01)) :prep-in (h / homeostasis)) :op2 (c3 / consider-01 :ARG1 (h2 / hallmark :mod (c4 / cell :mod (d / disease :wiki "Cancer" :name (n / name :op1 "cancer"))) :domain (o / overcome-01 :ARG1 (a2 / apoptosis)) :mod (a3 / another)) :ARG1-of (d3 / describe-01 :ARG0 (p3 / publication :ARG1-of (c6 / cite-01 :ARG2 28))))) # ::id a_pmid_2488_5690.66 ::date 2015-06-10T00:16:49 ::annotator SDL-AMR-09 ::preferred # ::snt Since virtually all malignant cancer cells show apoptosis resistance, the induction of apoptotic pathways is considered a particularly promising approach for therapeutic strategies [29]. # ::save-date Mon Feb 15, 2016 ::file a_pmid_2488_5690_66.txt (c / consider-01 :ARG1 (a / approach-02 :ARG0 (i / induce-01 :ARG2 (p3 / pathway :mod a4)) :ARG1 (s / strategy :mod (t / therapy)) :ARG2-of (p / promise-01 :degree (p2 / particular))) :ARG1-of (c2 / cause-01 :ARG0 (s2 / show-01 :ARG0 (c3 / cell :mod (a3 / all :degree (v / virtual)) :mod (d / disease :wiki "Cancer" :name (n / name :op1 "cancer") :ARG2-of (m / malignant-02))) :ARG1 (r / resist-01 :ARG0 c3 :ARG1 (a4 / apoptosis)))) :ARG1-of (d2 / describe-01 :ARG0 (p4 / publication :ARG1-of (c5 / cite-01 :ARG2 29)))) # ::id a_pmid_2488_5690.67 ::date 2015-06-10T00:22:21 ::annotator SDL-AMR-09 ::preferred # ::snt Our results show that in RKO this particular cancer cell trait is modulated by and dependent on B-RafV600E and that targeting mutant BRAF is sufficient to restore sensitivity to caspase-dependent apoptosis after serum withdrawal via p53-independent PUMA induction [27]. # ::save-date Wed Dec 9, 2015 ::file a_pmid_2488_5690_67.txt (s / show-01 :ARG0 (t4 / thing :ARG1-of (r / result-01) :poss (w / we)) :ARG1 (a / and :op1 (a2 / and :op1 (m / modulate-01 :ARG0 (e2 / enzyme :name (n3 / name :op1 "B-Raf") :ARG2-of (m2 / mutate-01 :value "V600E")) :ARG1 (t / trait :mod (c / cell :mod (d5 / disease :wiki "Cancer" :name (n / name :op1 "cancer"))) :mod (p / particular) :mod (t3 / this))) :op2 (d2 / depend-01 :ARG0 t :ARG1 e2) :location (c3 / cell-line :name (n4 / name :op1 "RKO"))) :op2 (s2 / suffice-01 :ARG0 (t2 / target-01 :ARG1 (g / gene :name (n5 / name :op1 "BRAF") :ARG2-of (m3 / mutate-01))) :ARG1 (r2 / restore-01 :ARG0 t2 :ARG1 (s3 / sensitive-03 :ARG1 (a3 / apoptosis :ARG0-of (d3 / depend-01 :ARG1 (p2 / protein :name (n6 / name :op1 "caspase"))) :time (a4 / after :op1 (w2 / withdraw-01 :ARG1 (s4 / serum))) :instrument (i / induce-01 :ARG2 (p3 / protein :name (n7 / name :op1 "PUMA")) :ARG0-of (d4 / depend-01 :polarity - :ARG1 (p4 / protein :name (n8 / name :op1 "p53"))) :ARG1-of (d / describe-01 :ARG0 (p5 / publication :ARG1-of (c4 / cite-01 :ARG2 27)))))))))) # ::id a_pmid_2488_5690.68 ::date 2015-06-10T00:40:15 ::annotator SDL-AMR-09 ::preferred # ::snt Complementing and extending previous studies, we thus provide evidence from an endogenous and quantitative genetic model of BRAF-mutant colorectal cancer cells, thereby ruling out the occurrence of artifacts caused by unspecific cellular response or incomplete knockdown in RNAi setups and, likewise, avoiding inter-species bias potentially experienced in mouse models of colorectal cancer [30]. # ::save-date Mon Dec 21, 2015 ::file a_pmid_2488_5690_68.txt (i / infer-01 :ARG1 (p / provide-01 :ARG0 (w / we) :ARG1 (e / evidence :source (m2 / model :mod (c / cell :location-of (g / gene :name (n3 / name :op1 "BRAF") :ARG2-of (m / mutate-01)) :mod (d / disease :wiki "Colorectal_cancer" :name (n / name :op1 "colorectal" :op2 "cancer"))) :mod (q / quantity) :mod (e2 / endogenous) :mod (g2 / gene))) :ARG0-of (c2 / cause-01 :ARG1 (a / and :op1 (r / rule-out-02 :ARG1 (a2 / artifact :ARG1-of (c3 / cause-01 :ARG0 (o2 / or :op1 (r2 / respond-01 :ARG0 (c4 / cell) :ARG1-of (s / specific-02 :polarity -)) :op2 (k / knock-down-02 :ARG1-of (c5 / complete-01 :polarity -) :location (s2 / setup :mod (i3 / interfere-01 :ARG1 (n2 / nucleic-acid :name (n4 / name :op1 "RNA"))))))))) :op2 (a3 / avoid-01 :ARG1 (b / bias-01 :mod (i2 / inter-species) :ARG1-of (e3 / experience-01 :ARG1-of (p2 / possible-01) :location (m3 / model :mod (d2 / disease) :mod (m4 / mouse) :ARG1-of (d3 / describe-01 :ARG0 (p3 / publication :ARG1-of (c6 / cite-01 :ARG2 30)))))))))) :ARG1-of (c7 / complement-01 :ARG2 (s3 / study-01 :time (p4 / previous))) :ARG0-of (e4 / extend-01 :ARG1 s3)) # ::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 (IC50) < 1 μM; intermediately sensitive, IC50 1-2 μM; and resistant, >2 μM. Fifteen of 21 (71%) BRAF mutants, including 4 with innate vemurafenib resistance, were sensitive to SCH772984. # ::save-date Tue Jan 9, 2018 ::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 (b2 / between :op1 (c3 / concentration-quantity :quant 1 :unit (m8 / micromolar)) :op2 (c4 / concentration-quantity :quant 2 :unit (m11 / micromolar)))))) :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 (m10 / micromolar)))))))))) :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%) BRAF/NRAS double mutants, 11 of 14 (78%) NRAS mutants and 5 of 7 (71%) wild-type melanomas were sensitive. # ::save-date Tue Dec 26, 2017 ::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))) :op3 (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 BRAFV600 mutants with in vitro 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 BRAF 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 BRAFV600E was the most frequently observed BRAF mutation, present in 17 of 21 cell lines. # ::save-date Thu Oct 19, 2017 ::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 (h / have-degree-91 :ARG2 (f / frequent-02 :ARG1 o) :ARG3 (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 BRAFV600R substitution, M414 contains BRAFV600K, M417 contains BRAFG466E and M420 contains BRAFL597S 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, IC50 < 1 μM), intermediate sensitivity (IC50 1–2 μM) and resistant (IC50 > 2 μM). # ::save-date Tue Jan 9, 2018 ::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 (b2 / between :op1 (c3 / concentration-quantity :quant 1 :unit (m7 / micromolar)) :op2 (c5 / concentration-quantity :quant 2 :unit (m9 / micromolar)))))) :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 (m8 / micromolar)))))))))) # ::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 IC50 less than or equal to 1 μM. Of the 12 cell lines highly sensitive to vemurafenib, all contain BRAFV600E and were also sensitive to SCH-772984. # ::save-date Wed Jan 3, 2018 ::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 (a4 / at-most :op1 (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 1A). # ::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 (IC50 < 2nM), intermediately sensitive (IC50 2-30nM) and resistant (IC50 > 30 nM) (Additional file 1: Figure S1). # ::save-date Tue Jan 9, 2018 ::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 (b2 / between :op1 (c4 / concentration-quantity :quant 2 :unit (n4 / nanomolar)) :op2 (c6 / concentration-quantity :quant 30 :unit (n6 / nanomolar)))))) :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 (n5 / nanomolar))))))))) :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.

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. # ::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 IC50 (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 Tue Jan 9, 2018 ::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") :ARG1-of (d / describe-01 :ARG0 (b2 / bar :ARG1-of (b3 / black-04))) :quant (b7 / between :op1 (c2 / concentration-quantity :quant 0 :unit (m / micromolar)) :op2 (c3 / concentration-quantity :quant 10 :unit (m4 / micromolar)))) :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 Thu Jan 11, 2018 ::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-01)))) :ARG2-of (i2 / infer-01 :ARG1 (e2 / equal-01 :ARG1 (v / variable :wiki - :name (n / name :op1 "n")) :ARG2 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 Sep 12, 2016 ::file a_pmid_2514_2146_69.txt (d / describe-01 :ARG0 (b / bar :mod (e / error)) :ARG1 (s / standard-deviation)) # ::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, BRAFL597S; M381, BRAFV600R , M417, BRAFG466E, M414, BRAFV600K). # ::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 IC50 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 B. # ::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 (C). # ::save-date Wed Sep 21, 2016 ::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 (h2 / hour)) :op3 (t4 / temporal-quantity :quant 6 :unit (h3 / hour)) :op4 (t5 / temporal-quantity :quant 12 :unit (h4 / hour)) :op5 (t6 / temporal-quantity :quant 24 :unit (h5 / hour)) :op6 (t7 / temporal-quantity :quant 48 :unit (h6 / hour)))) :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 C. # ::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 (+).

 # ::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 BRAFV600E-mutant melanoma cell line and M233, a SCH772984-resistant BRAFV600E-mutant melanoma cell line (Figure 1B). # ::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 Wed Sep 21, 2016 ::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 (h4 / hour))))) # ::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 Tue Dec 19, 2017 ::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 :ARG3 (m / mild)) :time (a2 / after :quant (t3 / temporal-quantity :quant 48 :unit (h2 / hour))))) # ::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 Tue Dec 19, 2017 ::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 :quant (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 Tue Dec 19, 2017 ::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 :quant (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 Tue Dec 19, 2017 ::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 :quant (t2 / temporal-quantity :quant 48 :unit (h2 / hour))) :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 Tue Dec 19, 2017 ::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 :quant (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 :quant (t3 / temporal-quantity :quant 48 :unit (h2 / hour))) :mod (e4 / even) :ARG1-of (c / complete-02)) :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 Tue Dec 19, 2017 ::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 :quant (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 (m4 / more-than :op1 t))) :time a3))))) :ARG1-of (h2 / have-degree-91 :ARG2 (g / good-02 :ARG1 b) :ARG3 (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 1C, three BRAF 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, BRAFV600E), an intermediately sensitive cell line (M409, BRAFV600E), and a resistant cell line (M381, BRAFV600R). # ::save-date Tue Dec 19, 2017 ::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 :quant (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 Tue Dec 19, 2017 ::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) :ARG3 (s2 / slight)) :time (a2 / after :quant (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 Tue Dec 19, 2017 ::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 :quant (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 2: 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 1B). # ::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 BRAFV600E melanoma cell lines, which appeared to have increased pAKT at baseline compared to other BRAF mutant cell lines. # ::save-date Tue Dec 19, 2017 ::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 :ARG1-of (c / compare-01 :ARG2 (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 AKT1 amplification [31]. # ::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 1B), 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 AKT1 amplified cell line [31] 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 1C). # ::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 AKT1 or AKT2 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 1A). # ::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 2: 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 3: Figures S3A and 3B). # ::save-date Thu Oct 19, 2017 ::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)) :ARG1-of (h / have-degree-91 :ARG2 (p2 / potent) :ARG3 (m / more) :ARG4 (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 Thu Oct 19, 2017 ::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)) :ARG1-of (h / have-degree-91 :ARG2 (c2 / complete) :ARG3 (m / more) :ARG4 (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 3: 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 BRAF-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 BRAF 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 NRAS mutant melanoma and seven cells lines with wild-type BRAF and NRAS 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 2A, while all NRAS-mutant cell lines were resistant to vemurafenib, 11 of 14 were highly sensitive to SCH772984 (IC50 < 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 4: Figures S4A and 4B for NRAS-mutant and wild-type melanoma cell lines, respectively. # ::save-date Thu Dec 21, 2017 ::file a_pmid_2514_2146_118.txt (a / and :op1 (s / show-01 :ARG0 (f2 / figure :mod "S4A" :part-of (f / file :mod 4 :ARG1-of (a4 / add-02))) :ARG1 (s2 / sensitive-03 :ARG0 (c2 / cell-line :mod (e / enzyme :name (n2 / name :op1 "NRAS") :ARG2-of (m3 / mutate-01))) :ARG1 (s3 / small-molecule :name (n / name :op1 "trametinib")))) :op2 (s4 / show-01 :ARG0 (f3 / figure :mod "S4B" :part-of f) :ARG1 (s5 / sensitive-03 :ARG0 (c / cell-line :mod (m4 / medical-condition :name (n3 / name :op1 "melanoma") :mod (w / wild-type))) :ARG1 s3))) # ::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 Mon Oct 23, 2017 ::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)) :ARG3 (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 2B). # ::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 3: 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 3: Figure S3A-C).

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. # ::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 IC50 (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 NRAS were exposed to 0–10 μM SCH-722984 (black bars) or vemurafenib (grey bars), and the cell viability determined. # ::save-date Tue Jan 9, 2018 ::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 (b4 / between :op1 (c3 / concentration-quantity :quant 0 :unit (m / micromolar)) :op2 (c4 / concentration-quantity :quant 10 :unit (m4 / 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 Oct 23, 2017 ::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 2) :ARG1-of (m2 / mean-01 :ARG2 (e2 / equal-01 :ARG1 (s / sample-size :poss 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 Sep 12, 2016 ::file a_pmid_2514_2146_127.txt (d / describe-01 :ARG0 (b / bar :mod (e / error)) :ARG1 (s / standard-deviation)) # ::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 IC50 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 B. # ::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.

 # ::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 BRAF and NRAS wild-type melanoma cell lines, all seven were sensitive to ERK inhibition, with six of seven highly sensitive to SCH772984 (Figure 3A), including M418, which is a KRASG12A 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)) :ARG1-of (c3 / complete-02)) :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 Tue Dec 19, 2017 ::file a_pmid_2514_2146_136.txt (d / disappear-01 :ARG1 (e / enzyme :name (n / name :op1 "RSK") :ARG3-of (p / phosphorylate-01)) :ARG1-of (c / complete-02 :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) :ARG3 (s2 / slight) :time (a / after :quant (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 3B). # ::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 BRAF wild-type cell lines including NRAS mutants and BRAF/NRAS wild-type melanoma cell lines which remain dependent on the MAPK pathway for continued growth.

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 IC50 (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 Tue Jan 9, 2018 ::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 (b6 / between :op1 (c2 / concentration-quantity :quant 0 :unit (m / micromolar)) :op2 (c3 / concentration-quantity :quant 10 :unit (m2 / 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 Tue Dec 26, 2017 ::file a_pmid_2514_2146_143.txt (m / mean :domain (t / thing :ARG2-of (r / result-01)) :mod (e / experiment-01 :frequency 2 :ARG1-of (p / perform-01 :frequency 3) :ARG1-of (m2 / mean-01 :ARG2 (e2 / equal-01 :ARG1 (s / sample-size :poss 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 Sep 12, 2016 ::file a_pmid_2514_2146_144.txt (d / describe-01 :ARG0 (b / bar :mod (e / error)) :ARG1 (s / standard-deviation)) # ::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 IC50 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.

 # ::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 BRAF-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 IC50 of SCH722984 or vemurafenib was next determined in eight BRAF-mutant vemurafenib-resistant melanoma cell lines (Figure 4A). # ::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 BRAF/NRAS 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 BRAFV600E mutant melanoma cell lines with in vitro-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) [7, 24], or via secondary NRAS mutation (M249AR4) [6]. # ::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 [6]. # ::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.

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 IC50 (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 BRAF mutant melanoma cell lines and their paired in vitro 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 Tue Jan 9, 2018 ::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") :quant (b4 / between :op1 (c6 / concentration-quantity :quant 0 :unit (m2 / micromolar)) :op2 (c7 / concentration-quantity :quant 10 :unit (m5 / 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 b4) :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 Oct 23, 2017 ::file a_pmid_2514_2146_163.txt (m / mean :domain (v / value) :mod (e / experiment-01 :quant 3 :ARG1-of (p / perform-01 :frequency 2) :ARG1-of (m2 / mean-01 :ARG2 (e2 / equal-01 :ARG1 (s / sample-size :poss 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 Sep 12, 2016 ::file a_pmid_2514_2146_164.txt (d / describe-01 :ARG0 (b / bar :mod (e / error)) :ARG1 (s / standard-deviation)) # ::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 IC50 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.

 # ::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 BRAF/NRAS double mutants (M376, M398, M249AR4) displayed decreased pRSK and pERK1/2 at 24 hours with no detectable change in pMEK. # ::save-date Tue Dec 19, 2017 ::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 :quant (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 Thu Oct 19, 2017 ::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) :ARG1-of (h / have-degree-91 :ARG2 (p3 / potent) :ARG3 (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 4B). # ::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) :mod (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 Fri Sep 15, 2017 ::file a_pmid_2514_2146_178.txt (d / determine-01 :ARG0 (w / we) :ARG1 (t / truth-value :polarity-of (p3 / possible-01 :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 BRAFV600E-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 IC50 of 10nM (Figure 5A, 5B). # ::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 Thu Oct 19, 2017 ::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))) :ARG1-of (h2 / have-degree-91 :ARG2 (p / profound) :ARG3 (m / more) :ARG4 (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 5C). # ::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)